[Phenotypical plasticity and targeted therapies in non-small cell lung carcinomas]. / Plasticité phénotypique et thérapies ciblées dans les cancers bronchiques non à petites cellules.

Lung cancer is the most diagnosed and deathly type of cancer worldwide. It has a poor prognosis because of a late diagnosis, high metastatic potential and resistance to conventional therapies. Since the 2000s, the emergence of targeted therapies has improved patients' outcomes. However, these therapies concern only a small proportion of patients, selected by the presence of molecular biomarkers that indicate the targeting relevance. Here, we discuss the possibility that new phenotypical biomarkers could be predictive factors for targeted therapies in lung cancer.

The E-cadherin-repressed hNanos1 gene induces tumor cell invasion by upregulating MT1-MMP expression.

In this study, we examined the role of the E-cadherin-repressed gene human Nanos1 (hNanos1) in tumor invasion process. First, our in vivo study revealed that hNanos1 mRNAs were overexpressed in invasive lung carcinomas. Moreover, hNanos1 was co-localized with MT1-MMP (membrane type 1-matrix metalloproteinase) in E-cadherin-negative invasive lung tumor clusters. Using an inducible Tet-on system, we showed that induction of hNanos1 expression in DLD1 cells increased their migratory and invasive abilities in a three-dimensional migration and in a modified Boyden chamber assay. Accordingly, we demonstrated that hNanos1 upregulated MT1-MMP expression at the mRNA and protein levels. Inversely, using an RNA interference strategy to inhibit hNanos1 expression in invasive Hs578T, BT549 and BZR cancer cells, we observed a downregulation of MT1-MMP mRNA and protein and concomitantly a decrease of the invasive capacities of tumor cells in a modified Boyden chamber assay. Taken together, our results demonstrate that hNanos1, by regulating MT1-MMP expression, plays an important role in the acquisition of invasive properties by epithelial tumor cells.

Dynamics of HPV16 DNA load reflect the natural history of cervical HPV-associated lesions.

BACKGROUND: High burden of high risk human papillomavirus (HR HPV) has been shown to be predictive for the development of high grade cervical lesions and invasive cancers. However, low viral load cannot inevitably exclude progression towards cervical diseases. Moreover, few studies addressed whether viral load could predict infection clearance. OBJECTIVES: We carried out a retrospective study to analyze the variations of HPV16 load over time as a predictive marker of clinical outcome. STUDY DESIGN: The population consisted of 38 women who were found HR HPV positive by HCII test at study entry. Among them, 13 had developed a CIN2/3 (cases) and 25 had a negative HCII test and a normal cytology (controls) at study exit. The HPV16 DNA loads were quantified in 132 longitudinal cervical samples using quantitative real-time PCR. RESULTS: At study entry, the median of HPV16 load was not statistically different between controls and cases. However, when using a cut-off value of 200 copies/10(3) cells, the rate of cumulative incidence of CIN2/3 at 18 months increased from 14% in women with a load200 copies/10(3) cells. The longitudinal analysis performed on follow-up samples showed that in cases the progression to CIN2/3 was linked to HPV16 burden increasing over time, whereas in controls a decrease of at least 1 log HPV16 DNA load was observed over>or=2 time points. CONCLUSIONS: These results show that kinetics of HPV load, rather than a single HPV detection, might be more reliable to estimate whether a HPV infection will progress or be cleared.

Detection of cervical precancer and cancer in a hospital population; benefits of testing for human papillomavirus.

The aim was to determine the relevance of human papillomavirus (HPV) testing in identifying high-grade cervical intraepithelial neoplasia or worse (CIN2/3+) in a hospital population (n=3574) characterised by a high rate of cytological abnormalities and high-risk HPV infections. According to the results of the initial Papanicolaou and HPV test, women were directly referred for colposcopy/biopsy or recalled for a control visit. Sensitivity and specificity were corrected for verification bias. HPV-testing sensitivity was 94.3%, higher than that of cytological testing at any cut-off point (65.1%-86.8%), while specificity was greater for cytology than for HPV testing (99.3% or 91.8% versus 83.4%). The combination of both tests allowed 100% sensitivity and negative predictive value. We conclude that HPV testing is a relevant tool for the detection of cervical disease. The best way of combining cytology and HPV detection in screening programmes should be evaluated in large-scale studies.

[Merkel cell carcinoma: descriptive study of 24 cases (1993-2001)]. / Carcinome à cellules de Merkel: étude descriptive de 24 cas (1993-2001).

INTRODUCTION: Merkel cell carcinoma (MCC) is a rare skin tumor with a highly malignant nature whose appropriate treatment is still debated. Wide surgery is the treatment of choice, but the question concerning protocols for adjuvant radiotherapy or chemotherapy remains open. PATIENTS AND METHODS: A retrospective analysis of 24 cases of MCC collected over a period of 9 years was performed, focusing on clinical and histologic features, and response to treatment. RESULTS: There were 17 women and 7 men with a mean age of 74.3 years. The median follow up was 34 months. The annual incidence per 100,000 habitants was 0.378. The head and neck localization was predominant (54%). Fifteen (68%) of patients presented with local disease (stage I), and 32% of patients presented with regional node (stage II) or distant metastases (stage III). Patients with stage I had a 5-years overall survival rate of 73,85%. Among them, five patients (33%) developed a local or nodal recurrence, although two patients were initially treated with surgery and local post-operative radiotherapy. Patients with stage II and III demonstrated a 5-year overall survival rate of 51,43%. DISCUSSION: Our series illustrates the clinical characteristics of this tumor of the elderly, which is mainly located on head and neck and associated with a poor prognosis. Treatments are discussed.

[Epidemiology of cervical papillomavirus infections. Recent knowledge]. / Epidémiologie des infections cervicales à papillomavirus. Acquisitions récentes.

GENERAL DATA: There is now considerable evidence that high risk human papillomaviruses (HPV), such as HPV 16, are closely associated with cancer of the cervix. HPVs that are primarily transmitted through sexual contact, are found in over 99% of the cases of invasive cervical cancer. Although most women can be infected during their sexual life, a small minority is at risk for developing cancer. The long latency period between primary infection and cancer emergence suggests that additional factors are involved in the process of tumor development: sexual behavior, immune status, genetic predispositions, nutritional status, tobacco use, socio-economical level. NATURAL HISTORY: HPVs infect epithelial cells of the transformation zone of the cervix. As with other sexually transmitted diseases, the incidence of HPV infection is highest among young women. However, this viral infection is more often than not transient, because most individuals develop an effective type-specific immune response. Approximately 1% of the population has genital warts and 4% of women have cervical precancerous lesions: low grade squamous intraepithelial lesion (LGSIL) or high grade SIL. These last lesions preferentially observed in women aged 35-40 yrs are at high risk of progression towards an invasive cancer. ONCOGENIC POTENTIAL OF HPV: Pre-malignant and malignant cells arise as a result of HPV DNA integration in the host cellular genome, and overexpression of the viral E6 and E7 oncogenes. Cells acquire a proliferative advantage by escaping growth control exerted by p53 and p 105Rb. Both cellular proteins are indeed inactivated respectively by E6 and E7 proteins. Aneuploidy and karyotypic abnormalities are also key events in the tumor progression. A PREVENTABLE DISEASE: Cervical cancer is more than ever a preventable disease. While waiting for clinically applicable vaccination programs, strategies to prevent cervical cancer include 1) improved screening covering the widest possible population and using HPV testing, 2) close management and follow-up of women with precancerous lesions.