Gut microbiota, an emergent target to shape the efficiency of cancer therapy.

It is now well-acknowledged that microbiota has a profound influence on both human health and illness. The gut microbiota has recently come to light as a crucial element that influences cancer through a variety of mechanisms. The connections between the microbiome and cancer therapy are further highlighted by a number of preclinical and clinical evidence, suggesting that these complicated interactions may vary by cancer type, treatment, or even by tumor stage. The paradoxical relationship between gut microbiota and cancer therapies is that in some cancers, the gut microbiota may be necessary to maintain therapeutic efficacy, whereas, in other cancers, gut microbiota depletion significantly increases efficacy. Actually, mounting research has shown that the gut microbiota plays a crucial role in regulating the host immune response and boosting the efficacy of anticancer medications like chemotherapy and immunotherapy. Therefore, gut microbiota modulation, which aims to restore gut microbial balance, is a viable technique for cancer prevention and therapy given the expanding understanding of how the gut microbiome regulates treatment response and contributes to carcinogenesis. This review will provide an outline of the gut microbiota's role in health and disease, along with a summary of the most recent research on how it may influence the effectiveness of various anticancer medicines and affect the growth of cancer. This study will next cover the newly developed microbiota-targeting strategies including prebiotics, probiotics, and fecal microbiota transplantation (FMT) to enhance anticancer therapy effectiveness, given its significance.

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 < 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.

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

Breast 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.

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.

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.

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.

Genome profiling of ERBB2-amplified breast cancers.

BACKGROUND: Around 20% of breast cancers (BC) show ERBB2 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. METHODS: We defined the high resolution genome and gene expression profiles of 54 ERBB2-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. RESULTS: First, we identified the ERBB2-C17orf37-GRB7 genomic segment as the minimal common 17q12-q21 amplicon, and CRKRS and IKZF3 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 ERBB2-amplified BCs. The genomic profiles of estrogen receptor-positive (ER+) and negative (ER-) ERBB2-amplified BCs were different. The WNT/ß-catenin signaling pathway was involved in ER- ERBB2-amplified BCs, and PVT1 and TRPS1 were candidate oncogenes associated with ER+ ERBB2-amplified BCs. The size of the ERBB2 amplicon was different in inflammatory (IBC) and non-inflammatory BCs. ERBB2-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 ERBB2 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 ERBB2-positive BCs to inhibitors. FOXA1 was frequently coexpressed with ERBB2 but its expression did not impact on the outcome of patients with ERBB2-amplified tumors. CONCLUSION: We have shown that ER+ and ER- ERBB2-amplified BCs are different, distinguished ERBB2 amplicons in IBC and non-IBC, and identified genomic features that may be useful in the design of alternative therapeutical strategies.

Phase 2 study of single-agent IV vinflunine as third-line treatment of metastatic breast cancer after failure of anthracycline-/taxane-based chemotherapy.

OBJECTIVE: A multicenter, open-label, phase 2 study evaluated the efficacy and safety of intravenous vinflunine as third-line treatment in patients with progressing metastatic breast cancer (MBC) after failure of anthracycline- and taxane-based chemotherapy. PATIENTS AND METHODS: Fifty-six patients with MBC, relapsing after receiving 2 previous treatments for advanced disease, including both anthracyclines and taxanes, received 320 mg/m(2) of vinflunine once every 3 weeks (median number of 2.5 cycles, range: 1-13). RESULTS: According to an independent radiologist, the response rate was 12.5% (95% CI: 5.2-24.1) and 14% (95% CI: 5.3-27.9) (6 partial responses) in the treated and evaluable populations, respectively. Disease control was achieved in 42.9% and 51.2% of the patients, respectively. Median progression-free survival was 2.6 months (95% CI: 1.6-4.0 months) with a median overall survival of 11.4 months (95% CI: 7.4-14.2 months). Duration of response was 6.8 months (95% CI: 5.6 months, upper limit not reached). Leukopenia was the most frequent hematologic toxicity, with grade 3/4 severity in 49.1% of the patients. Grade 3 neutropenia in 30.9%, grade 4 in 40.0% of patients, febrile neutropenia (5.4%), and 1 case of neutropenia infection (1.8%) were reported. Other grade 3 toxicities included anemia (5.5%), fatigue (14.3%), and constipation (7.1%), which were noncumulative. The adverse events associated with vinflunine were predictable and manageable. CONCLUSIONS: Vinflunine is an active and well-tolerated agent as third-line treatment of patients with MBC after failure of anthracycline- and taxane-based therapy. These results warrant further investigation of vinflunine monotherapy or in combination for the treatment of MBC.

[Penetrance of BRCA1 gene mutation and DNA mitochondrial in Tunisian breast cancer occurrence]. / Pénétrance des mutations du gène BRCA1 et de l'ADN mitochondrial dans l'occurrence du cancer du sein en Tunisie.

AIM: The aim of this study is to evaluate the implication of BRCA1 gene and the mitochondrial micro satellite (situated between 303 and 315 positions) mutations in the occurrence of breast cancer in Tunisia. METHODS: Nine Tunisian patients with hereditary breast cancer have been analyzed. For each patient, total genomic DNA was extracted and used as a template for the amplification of 24 exons of the BRCA1 gene and an hyper variable mitochondrial region. The obtained products were purified and automatically sequenced. RESULTS: The results revealed five types of mutations for the micro satellite situated between the 303 and 315 positions and two deleterious BRCA1 mutations for two unrelated patients which present the same mitochondrial mutation (315.insC) suggesting his implication in the modulation of the BRCA1 deleterious mutations penetrance.

First genetic analysis in Tunisian familial adenomatous polyposis probands.

Familial adenomatous polyposis (FAP) is an autosomal dominant inherited disease characterized by the development of hundreds to thousands of adenomatous polyps in colon and rectum. The APC gene (adenomatous polyposis coli) is considered as the major mutated gene in FAP. It has been shown that biallelic germline mutations in the base-excision-repair gene MYH can be responsible for a recessive inheritance of adenomatous polyposis (AP). This study is the first Tunisian genetic analysis on AP patients. Multiplex ligation-dependent probe amplification (MLPA) was used to screen the APC gene for large genomic rearrangements. The total APC and MYH exon sequences and exon-intron edges were sequenced in an effort to detect germline mutations, four were explored. Mutations were detected in four patients that fulfil the clinical criteria of AP. Three mutations were found in the APC gene, of which two were novel (c.1636_1639delAGTG and c.2514 G>T) and all gave rise to a truncated APC protein. The missense G382D mutation, already described in north and south European populations was found in the MYH gene at the homozygous state in the fourth patient with moderate AP. Our preliminary study provides a basis for implementation of genetic counselling for AP.

Dietary risk factors for nasopharyngeal carcinoma in Maghrebian countries.

North Africa is one of the major Nasopharyngeal Carcinoma (NPC) endemic regions. Specific food items unique to this area were implicated to be associated with NPC risk, but results were inconsistent. Here we have performed a large-scale case-control study in the Maghrebian population from Tunisia, Algeria and Morocco. From 2002 to 2005, interviews were conducted on 636 cases and 615 controls. Controls were hospitalized individuals from 15 non-cancer hospital departments, or friends and family members of non-NPC cancer subjects, matched by center, childhood household type (rural or urban), age and sex. Conditional logistic regression is used to evaluate the risk of factors. In results, consumption of rancid butter, rancid sheep fat and preserved meat not spicy (mainly quaddid) were associated with significantly increased risk of NPC, while consumption of cooked vegetables and industrial preserved fish was associated with reduced risk. Other foods such as fresh citrus fruits and spicy preserved meat (mainly osban) in childhood, industrial made olive condiments in adulthood, were marginally associated. In multivariate analyses, only rancid butter, rancid sheep fat and cooked vegetables were significantly associated with NPC. In regard to possible causative substances, our results implicate the involvement of butyric acid, a potential Epstein-Barr virus (EBV) activator.

Inflammatory breast cancers in Tunisia and France show similar immunophenotypes.

PURPOSE: 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.

HLA class II polymorphism: protective or risk factors to breast cancer in Tunisia?

HLA system plays a key role in the tumor cells' escape from immune surveillance. Herein is the first report on the correlation of the susceptibility to breast cancer with HLA class II markers in Tunisia. Molecular typing of HLA-DRB1 and -DQB1 loci was undertaken for 70 Tunisian female patients. Comparison of allele and haplotype distribution between patients and 70 female control subjects reveals a negative association between HLADRB1* 07-DQB1*02 and the incidence of breast cancer in the Tunisian population.

Islands inside an island: reproductive isolates on Jerba island.

Jerba Island, located in South Eastern Tunisia, is inhabited by four ethnic groups: Berbers, Arabs, sub-Saharans, and Jews. All live in distinct areas, although the Arabs are also distributed all over the island. The first Arab settlement was founded in the 7th century A.D., so co-existence with Berbers has lasted for more than a millennium. Religious and cultural differences have represented an obstacle to the intermixing of these groups, and among both Arabs and Berbers marriages usually occur between members from the same extended family. Using new mtDNA data and previously described Y-chromosome STR-defined haplotypes, we tested whether this reported inbreeding would be reflected in the differentiation between Berber and Arab communities. Concerning mtDNA, the Berber group presented a greater Eurasian contribution (87%), and, surprisingly, no U6 haplotypes were found; in contrast, the Arabs showed a larger contribution of sub-Saharan lineages (24%) and the U6 haplogroup amounted to 10%. Another source of evidence for the reproductive isolation of the two groups was revealed through the analysis of haplotype matching (both mtDNA and Y-chromosome), showing that matching probabilities between them is of the same order of magnitude of that observed when contrasting samples from different European countries.

Knowledge gained after a brief CME module on breast cancer diagnosis.

BACKGROUND: In developing countries, continuing medical education (CME) is lacking and physicians' knowledge of cancer control may also be lacking. METHOD: We evaluated knowledge of 144 primary care physicians in Egypt and 50 in Tunisia regarding breast cancer (BC) and inflammatory BC (IBC) in particular. We invited the physicians to pretesting, presentation of an educational module, and post-testing. RESULTS: We found significant improvement in knowledge about risk factors for IBC and BC, importance of early detection and clinical examination, and referral of IBC cases. The variables that were independently associated with improved BC knowledge, were rural practice location, being a female physician, and greater numbers of BC patients seen in the last year. CONCLUSION. We developed and evaluated a CME module to improve BC diagnostic knowledge of primary care physicians in developing countries. The evaluation showed that physicians most lacking in this knowledge had the greatest gains. With the anticipated adoption of this module in Egypt and Tunisia, we expect to see more appropriate referrals to cancer centers. These results could guide future oncology CME for physicians in developing countries.

Esthesioneuroblastoma metastatic to the breast in a young woman.

BACKGROUND: Metastases to the breast are rare and can be missed without knowledge of the clinical history. We report an unusual breast metastasis originating in an olfactory neuroblastoma. CASE: A breast metastasis from esthesioneuroblastoma occurred in a 20-year-old woman 2 years after the onset of the disease. The aspirates were hypercellular and composed of cellular aggregates and single cells with a monomorphic appearance. The cytoplasm was scanty and inconspicuous. The nucleus was large, with granular, hyperchromatic chromatin. Mitoses and apoptotic bodies were numerous. Because we were unaware of the past history at the time of the cytologic analysis, a definitive diagnosis was made only after pathologic study. CONCLUSION: Esthesioneuroblastoma metastatic to the breast must be considered in the differential diagnosis of breast metastases. Fine needle aspiration, in conjunction with clinical information, can be effective in the diagnosis of esthesioneuroblastoma metastatic to the breast.

[Preoperative concurrent chemotherapy and radiation therapy in cervix cancer: preliminary results]. / La radiochimiothérapie concomitante préopératoire dans le cancer du col utérin: résultats préliminaires.

This is a retrospective study of patients treated for cervix cancer staged IB2, IIA or IIB with bulky tumor (> 4cm). Treatment was concurrent radiotherapy (45Gy with 1,8Gy daily fraction) and chemotherapy (5 cycles of Platinum 40mg/m2/week). All patients underwent Brachytherapy (15Gy on the reference isodose according to Paris system) followed by surgery (radical abdominal hysterectomy and bilateral pelvic lymphadenectomy: Piver 3) Between October 1999 and December 2002, forty five patients were treated in this protocol. Median age was 46 years (21- 68). Histology was squamous cell carcinoma in 93% and glandular carcinoma in 7%. Average external radiation dose was 44Gy (20-50). Ninety three percent of patients had at least 3 cycles of chemotherapy and 46,5% received the planned 5 cycles. On the operative specimens, there was 62,5% complete response and only 7 pelvic node involvement (17,5%). Four postoperative complications were noted (one vascular injury, one urinary fistula, one phlebitis and one lymph collection). Preoperative combined radiotherapy and chemotherapy in the early bulky stages of uterine cervix cancer is well tolerated and "gives" a high rate of sterilisation. There was no increase in surgical morbidity.

Cervical cancer in Tunisia: an epidemiological, clinical and pathological study.

BACKGROUND: This study was undertaken to determine epidemiological and pathological profile of cervical cancer in Tunisia. DESIGN STUDY: Registration and analysis of all cervical cancer newly diagnosed during the year 1994 (year of general census) based on review of all pathology laboratory files in the country with exclusion of previously diagnosed cases according to clinical data. RESULTS: During the year 1994, 216 new cases were registered among which 195 cases (89.81%) were invasive carcinoma. The standardized incidence (invasive cancer) is 5.91 per 100000 women per year. The average age was 53.7 year. Sixty-three percent cases are diagnosed at an advanced stage (IIB, III, IV FIGO stages). Invasive carcinoma has distributed as follows: 177 cases (91.23%) were squamous invasive carcinoma, 17 cases (8.77%) were invasive adenocarcinoma. In the same year, 21 cases of in situ squamous carcinoma were registered with an average age equal to 44.21 year. Only one case of cervical cancer was a sarcoma (0.52%). CONCLUSION: The incidence of cervical cancer in Tunisia is relatively low in spite of the absence of a screening program. This may be related to monogamy and observance of legal age of marriage. Squamous invasive carcinoma is the most frequent pathological type. CONDENSATION: The incidence of cervical cancer in Tunisia is relatively low in spite of the absence of a screening program.

[Bioclinical correlations in bony metastases. Results of a prospective study. 60 cases]. / Corrélations biocliniques dans les métastases osseuses. Résultats d'une étude prospective. A propos de 60 cas.

UNLABELLED: Our objective is to compare clinical and biological presentation of patients with bone metastatic disease. PATIENTS AND METHODS: We collected prospectively 60 patients (adults and children) with proven bone metastasis. Tumors are mainly breast cancer (25/60) or nasopharyngeal carcinoma (8/60). All 8 children presented all with abdominal neuroblastoma. Bone lesions are lytic in 85% of cases. ALP and LDH seem to be sensitive markers for bone mestatasis with 75% and 80% pathologic rates. The highest rates have been observed in patients with multiple bones lesions (> 8) and painful metastases (more than 7 in the VAS). The median survival was 8 months (3 to 54). CONCLUSION: Even conventional, some biochemical markers as ALP and LDH remain useful in the diagnosis and prognosis in patients with proven bone metastasis.