HPV types and variants among cervical cancer tumors in three regions of Tunisia

Cervical cancer is the second most common cancer among Tunisian women, and the incidence rates vary by region. Three Tunisian registries report age-standardized rates of 6.3/10 5 in the central region, 5.4/10 5 in the north, and 2.7/10 5 in the south. High-risk human papillomavirus (HPV) types and their variants differ in carcinogenic potential and geographic distribution. The HPV type and variant distribution could be a factor in the differing rates between regions of Tunisia. Tumor tissue was collected from 142 Tunisian cervical cancer patients. Demographic and reproductive characteristics of the patients were abstracted from cancer registry and hospital records. HPV type and variant analyses were performed using PCR-based Luminex and dot-blot hybridization assays. Eighty-three percent of tumors were infected with at least one HPV type. European variants of HPV16/18 were the most prevalent in tumors from all three regions, with all HPV18 infections and 64% of HPV16 infections being of European lineage. A higher frequency of HPV16 was present in Northern Tunisia (80%) than in Central (68%) or Southern Tunisia (50%) ( P  = 0.02). HPV18/45 was significantly more common in adenocarcinomas (50%) than in squamous cell carcinomas (11%) ( P  = 0.004). Frequent infection with European HPV variants most likely reflects the history of European migration to Tunisia. In addition to the importance of understanding the variants of HPV in Tunisia, behavioral and cultural attitudes towards screening and age-specific infection rates should be investigated to aid the development of future vaccination and HPV screening programs and policies. J. Med. Virol. 83:651–657, 2011. © 2011 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/83181/1/22011_ftp.pd

Assessment of diagnosis of inflammatory breast cancer cases at two cancer centers in E gypt and T unisia

The diagnosis of inflammatory breast cancer ( IBC ) is largely clinical and therefore inherently somewhat subjective. The objective of this study was to evaluate the diagnosis of IBC at two centers in N orth A frica where a higher proportion of breast cancer is diagnosed as IBC than in the U nited S tates ( U . S .). Physicians prospectively enrolled suspected IBC cases at the National Cancer Institute ( NCI ) –  C airo, E gypt, and the I nstitut S alah A zaiz ( ISA ), T unisia, recorded extent and duration of signs/symptoms of IBC on standardized forms, and took digital photographs of the breast. After second‐level review at study hospitals, photographs and clinical information for confirmed IBC cases were reviewed by two U . S . oncologists. We calculated percent agreement between study hospital and U . S . oncologist diagnoses. Among cases confirmed by at least one U . S . oncologist, we calculated median extent and duration of signs and S pearman correlations. At least one U . S . oncologist confirmed the IBC diagnosis for 69% (39/50) of cases with photographs at the NCI ‐ C airo and 88% (21/24) of cases at the ISA . All confirmed cases had at least one sign of IBC (erythema, edema, peau d'orange) that covered at least one‐third of the breast. The median duration of signs ranged from 1 to 3 months; extent and duration of signs were not statistically significantly correlated. From the above‐mentioned outcomes, it can be concluded that the diagnosis of a substantial proportion of IBC cases is unambiguous, but a subset is difficult to distinguish from other types of locally advanced breast cancer. Among confirmed cases, the extent of signs was not related to delay in diagnosis. The diagnosis of inflammatory breast cancer ( IBC ) is largely clinical and therefore inherently somewhat subjective. The objective of this pilot study was to evaluate the diagnosis of IBC at two centers in N orth A frica, where a higher proportion of breast cancer is diagnosed as IBC than in the U nited S tates ( U.S. ). The diagnosis of a substantial proportion of IBC cases at the study centers was unambiguous, but a subset was difficult to distinguish from other types of locally advanced breast cancer.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/97479/1/cam448.pd

Genome profiling of ERBB2-amplified breast cancers

<p>Abstract</p> <p>Background</p> <p>Around 20% of breast cancers (BC) show <it>ERBB2 </it>gene amplification and overexpression of the ERBB2 tyrosine kinase receptor. They are associated with a poor prognosis but can benefit from targeted therapy. A better knowledge of these BCs, genomically and biologically heterogeneous, may help understand their behavior and design new therapeutic strategies.</p> <p>Methods</p> <p>We defined the high resolution genome and gene expression profiles of 54 <it>ERBB2</it>-amplified BCs using 244K oligonucleotide array-comparative genomic hybridization and whole-genome DNA microarrays. Expression of ERBB2, phosphorylated ERBB2, EGFR, IGF1R and FOXA1 proteins was assessed by immunohistochemistry to evaluate the functional ERBB2 status and identify co-expressions.</p> <p>Results</p> <p>First, we identified the <it>ERBB2</it>-<it>C17orf37</it>-<it>GRB7 </it>genomic segment as the minimal common 17q12-q21 amplicon, and <it>CRKRS </it>and <it>IKZF3 </it>as the most frequent centromeric and telomeric amplicon borders, respectively. Second, GISTIC analysis identified 17 other genome regions affected by copy number aberration (CNA) (amplifications, gains, losses). The expression of 37 genes of these regions was deregulated. Third, two types of heterogeneity were observed in <it>ERBB2</it>-amplified BCs. The genomic profiles of estrogen receptor-postive (ER+) and negative (ER-) <it>ERBB2</it>-amplified BCs were different. The WNT/β-catenin signaling pathway was involved in ER- <it>ERBB2</it>-amplified BCs, and <it>PVT1 </it>and <it>TRPS1 </it>were candidate oncogenes associated with ER+ <it>ERBB2</it>-amplified BCs. The size of the <it>ERBB2 </it>amplicon was different in inflammatory (IBC) and non-inflammatory BCs. <it>ERBB2</it>-amplified IBCs were characterized by the downregulated and upregulated mRNA expression of ten and two genes in proportion to CNA, respectively. IHC results showed (i) a linear relationship between <it>ERBB2 </it>gene amplification and its gene and protein expressions with a good correlation between ERBB2 expression and phosphorylation status; (ii) a potential signaling cross-talk between EGFR or IGF1R and ERBB2, which could influence response of <it>ERBB2</it>-positive BCs to inhibitors. FOXA1 was frequently coexpressed with ERBB2 but its expression did not impact on the outcome of patients with <it>ERBB2</it>-amplified tumors.</p> <p>Conclusion</p> <p>We have shown that ER+ and ER- <it>ERBB2</it>-amplified BCs are different, distinguished <it>ERBB2 </it>amplicons in IBC and non-IBC, and identified genomic features that may be useful in the design of alternative therapeutical strategies.</p

Targeting Tumor Metabolism: A New Challenge to Improve Immunotherapy

Currently, a marked number of clinical trials on cancer treatment have revealed the success of immunomodulatory therapies based on immune checkpoint inhibitors that activate tumor-specific T cells. However, the therapeutic efficacy of cancer immunotherapies is only restricted to a small fraction of patients. A deeper understanding of key mechanisms generating an immunosuppressive tumor microenvironment (TME) remains a major challenge for more effective antitumor immunity. There is a growing evidence that the TME supports inappropriate metabolic reprogramming that dampens T cell function, and therefore impacts the antitumor immune response and tumor progression. Notably, the immunosuppressive TME is characterized by a lack of crucial carbon sources critical for T cell function and increased inhibitory signals. Here, we summarize the basics of intrinsic and extrinsic metabolic remodeling and metabolic checkpoints underlying the competition between cancer and infiltrating immune cells for nutrients and metabolites. Intriguingly, the upregulation of tumor programmed death-L1 and cytotoxic T lymphocyte-associated antigen 4 alters the metabolic programme of T cells and drives their exhaustion. In this context, targeting both tumor and T cell metabolism can beneficially enhance or temper immunity in an inhospitable microenvironment and markedly improve the success of immunotherapies

Assessment of diagnosis of inflammatory breast cancer cases at two cancer centers in Egypt and Tunisia

The diagnosis of inflammatory breast cancer (IBC) is largely clinical and therefore inherently somewhat subjective. The objective of this study was to evaluate the diagnosis of IBC at two centers in North Africa where a higher proportion of breast cancer is diagnosed as IBC than in the United States (U.S.). Physicians prospectively enrolled suspected IBC cases at the National Cancer Institute (NCI) – Cairo, Egypt, and the Institut Salah Azaiz (ISA), Tunisia, recorded extent and duration of signs/symptoms of IBC on standardized forms, and took digital photographs of the breast. After second-level review at study hospitals, photographs and clinical information for confirmed IBC cases were reviewed by two U.S. oncologists. We calculated percent agreement between study hospital and U.S. oncologist diagnoses. Among cases confirmed by at least one U.S. oncologist, we calculated median extent and duration of signs and Spearman correlations. At least one U.S. oncologist confirmed the IBC diagnosis for 69% (39/50) of cases with photographs at the NCI-Cairo and 88% (21/24) of cases at the ISA. All confirmed cases had at least one sign of IBC (erythema, edema, peau d’orange) that covered at least one-third of the breast. The median duration of signs ranged from 1 to 3 months; extent and duration of signs were not statistically significantly correlated. From the above-mentioned outcomes, it can be concluded that the diagnosis of a substantial proportion of IBC cases is unambiguous, but a subset is difficult to distinguish from other types of locally advanced breast cancer. Among confirmed cases, the extent of signs was not related to delay in diagnosis

High Throughput Analysis Reveals Changes in Gut Microbiota and Specific Fecal Metabolomic Signature in Hematopoietic Stem Cell Transplant Patients

There is mounting evidence for the emerging role of gut microbiota (GM) and its metabolites in profoundly impacting allogenic hematopoietic stem cell transplantation (allo-HSCT) and its subsequent complications, mainly infections and graft versus host-disease (GvHD). The present study was performed in order to investigate changes in GM composition and fecal metabolic signature between transplant patients (n = 15) and healthy controls (n = 18). The intestinal microbiota was characterized by NGS and gas chromatography–mass spectrometry was employed to perform untargeted analysis of fecal metabolites. We found lower relative abundances of Actinobacteria, Firmicutes, and Bacteroidetes and a higher abundance of Proteobacteria phylum after allo-HSCT. Particularly, the GvHD microbiota was characterized by a lower relative abundance of the short-chain fatty acid-producing bacteria, namely, the Feacalibacterium, Akkermansia, and Veillonella genera and the Lachnospiraceae family, and an enrichment in multidrug-resistant bacteria belonging to Escherichia, Shigella, and Bacteroides. Moreover, network analysis showed that GvHD was linked to a higher number of positive interactions of Blautia and a significant mutual-exclusion rate of Citrobacter. The fecal metabolome was dominated by lipids in the transplant group when compared with the healthy individuals (p &lt; 0.05). Overall, 76 metabolites were significantly altered within transplant recipients, of which 24 were selected as potential biomarkers. Furthermore, the most notable altered metabolic pathways included the TCA cycle; butanoate, propanoate, and pyruvate metabolisms; steroid biosynthesis; and glycolysis/gluconeogenesis. Specific biomarkers and altered metabolic pathways were correlated to GvHD onset. Our results showed significant shifts in gut microbiota structure and fecal metabolites characterizing allo-HSCT

Inflammatory breast cancers in Tunisia and France show similar immunophenotypes

International audiencePurpose: Inflammatory breast cancers (IBC) have specific immunophenotypic profiles as compared to non-inflammatory (non-IBC): combined differential expression of estrogen receptor, Ki67, E-cadherin, MUC1, and ERBB2 can be used as an IBC signature. It is thought that IBC occurs with a high frequency in Tunisia. The aim of this study is to evaluate this signature on a Tunisian series. Methods: The expression of five proteins (E-cadherin, ERBB2, estrogen receptor, Ki67, MUC1) was studied by immunohistochemistry on a consecutive series of 91 cases of IBC (T4D) treated at Tunisian Salah Azaiz Institute (ISA) and deposited in a tissue microarray (TMA). Results were compared to the same study on a series of 85 cases treated in France. Results: The ISA cases were characterized by a significantly younger age of patients (median: 42 years old in ISA for 53.5 in IPC, p = 0.00042) and a higher frequency of invasive micropapillary pattern. None of the five parameters was expressed differentially in the two series. In non-metastatic patients, high level of proliferation (Ki67) and overexpression of ERBB2 were associated with poor outcome. Conclusion: The IBC from Tunisia were not different from those observed in France on the basis of IHC profiles. However, the younger age of the patients suggest a specific epidemiological context that should be investigated. (C) 2007 Elsevier Ltd. All rights reserved

Fecal Metabolic Profiling of Breast Cancer Patients during Neoadjuvant Chemotherapy Reveals Potential Biomarkers

International audienceBreast cancer (BC) is the most common form of cancer among women worldwide. Despite the huge advancements in its treatment, the exact etiology of breast cancer still remains unresolved. There is an increasing interest in the role of the gut microbiome in modulating the anti-cancer therapeutic response. It seems that alteration of the microbiome-derived metabolome potentially promotes carcinogenesis. Taken together, metabolomics has arisen as a fascinating new omics field to screen promising metabolic biomarkers. In this study, fecal metabolite profiling was performed using NMR spectroscopy, to identify potential biomarker candidates that can predict response to neoadjuvant chemotherapy (NAC) for breast cancer. Metabolic profiles of feces from patients (n = 8) following chemotherapy treatment cycles were studied. Interestingly, amino acids were found to be upregulated, while lactate and fumaric acid were downregulated in patients under the second and third cycles compared with patients before treatment. Furthermore, short-chain fatty acids (SCFAs) were significantly differentiated between the studied groups. These results strongly suggest that chemotherapy treatment plays a key role in modulating the fecal metabolomic profile of BC patients. In conclusion, we demonstrate the feasibility of identifying specific fecal metabolic profiles reflecting biochemical changes that occur during the chemotherapy treatment. These data give an interesting insight that may complement and improve clinical tools for BC monitoring

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

Abstract 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