Patient navigation for colorectal cancer screening in deprived areas: the COLONAV cluster randomized controlled trial.

BACKGROUND: The objective of this study was to assess the effectiveness of a Patient Navigation Intervention targeting deprived patients for Colo-Rectal Cancer (CRC) screening participation. METHODS: A cluster randomized controlled trial was conducted in 5 districts. Peer Lay Patient Navigators were recruited to operate in deprived areas. Eligible participants had to be between 50 and 74 years old, live in these deprived areas and receive an invitation to the nationally organized Colo-Rectal Cancer (CRC) screening during the study period. The theory-driven navigation intervention was deployed for 18 months. A population Health Intervention Research assessment method was used to assess effectiveness and context interaction. The primary criterion was screening participation at 12 months. RESULTS: Twenty-four thousand two hundred eighty-one individuals were included inside 40 clusters. The increase in participation in the intervention group was estimated at 23%, (ORa = 1.23, CI95% [1.07-1.41], p = 0.003). For the subgroup of individuals who participated, the time delay to participating was reduced by 26% (ORa = 0.74, CI95% [0.57-0.96], p = 0.021). Main factors modulating the effect of the intervention were: closeness of navigator profiles to the targeted population, navigators' abilities to adapt their modus operandi, and facilitating attachment structure. CONCLUSION: The ColoNav Intervention succeeded in demonstrating its effectiveness, for CRC screening. Patient Navigation should be disseminate with broader health promotion goals in order to achieve equity in health care. TRIAL REGISTRATION: clinicaltrials.gov NCT02369757 24/02/2015.

ColoNav: patient navigation for colorectal cancer screening in deprived areas - Study protocol.

BACKGROUND: The mass colorectal cancer screening program was implemented in 2008 in France, targeting 16 million French people aged between 50 and 74. The current adhesion is insufficient and the participation rate is even lower among the underserved population, increasing health inequalities within our health care system. Patient Navigation programs have proved their efficiency to promote the access to cancer screening and diagnosis. METHODS/DESIGN: The purpose of the study is to assess the implementation of a patient navigation intervention that has been described in another cultural environment and another health care system. The main objective of the program is to increase the colorectal cancer screening participation rate among the deprived population through the intervention of a navigator to promote the Fecal Occult Blood Test (FOBT) and complementary exams. We performed a multisite cluster randomized controlled trial, with three groups (one experimental group and two control groups) for 18 months. DISCUSSION: The study attempts to give a better understanding of the adhesion barriers to colorectal cancer screening among underserved populations. If this project is cost-effective, it could create a dynamic based on peer approaches that could be developed for other cancer screening programs and other chronic diseases. TRIAL REGISTRATION: NCT02369757.

[Gynaecologists' attitudes and practices towards HPV vaccination: a quantitative-qualitative study in Rhône-Alpes]. / Perception et pratique de la vaccination HPV par les gynécologues : une étude quantitative et qualitative en Rhône-Alpes.

OBJECTIVES: Acceptance of the human papilloma virus (HPV) vaccine by targeted population will mainly depend on its acceptability among gynaecologists. We examined the perceptions, attitudes and practices of gynaecologists in relation to HPV vaccination 1 year after licensing. POPULATION AND METHODS: From November 2007 to April 2008, a cross-sectional survey was carried among a representative 10% sample of gynaecologists in the French Rhône-Alpes region. Both quantitative (self-administered questionnaire) and qualitative (interview) approaches were used. RESULTS: Among the 52 respondents, 90.4% of gynaecologists reported a favourable opinion about HPV vaccination, 5.8% were uncertain and 1.9% was opposed (one did not answer). The main justification for a favourable opinion related to the public health effects of the HPV vaccination (cited by 31.9% of those favouring vaccination). The main justification for an uncertain or opposed opinion was the too recent introduction of the vaccine (cited by 100%). During the month preceding the survey, 40.4% had provided HPV vaccination, mainly in 15-23 years old girls (38.5%). The major difficulties in providing HPV vaccination were questions asked by patients (cited by 44.2% of the respondents) and the targeted age of 14 years (13.5%). A total of 87.5% of respondents reported to have discussed with 14-year-old vaccinated girls of Pap-smear and 12.5% of STI prevention. CONCLUSION: One year after HPV vaccine licensing, gynaecologists of Rhône-Alpes region had a favourable opinion about it, despite some difficulties. Little information about STI prevention to vaccinated girls was reported opposite to information about Pap-smear.

Human papillomavirus (HPV) vaccination: perception and practice among French general practitioners in the year since licensing.

Acceptance of the Human Papillomavirus (HPV) vaccine by targeted populations will depend to a large extent on its acceptability among physicians. We examined the perceptions, attitudes and practices of general practitioners (GPs) in relation to HPV vaccination. From November 2007 to April 2008, a cross-sectional survey was carried out among a representative 5% sample of GPs in the large Rhône-Alpes region of France. Both quantitative (self-administered questionnaire) and qualitative (interview) approaches were used. During the month preceding the survey, 75.6% of the 279 GPs who responded had given at least one HPV vaccination and 47.6% had given a vaccination at the routine target age of 14 years. Overall, 80.8% of GPs reported a favourable opinion about HPV vaccination, 17.4% were uncertain and 1.8% were opposed. The main justification for a favourable opinion related to the public health benefits of the HPV vaccination (cited by 60% of those favouring vaccination). The main justification for an "opposed or uncertain" opinion was the too recent introduction of the vaccine (cited by 43.4%). The major difficulties in providing HPV vaccination were patients' concerns about potential side effects (cited by 37% of the respondents) and the target age of 14 years (28.9%). Interviews suggested that the concern about age may relate to the need, as perceived by GPs, to discuss sexually transmitted infections with adolescent patients. A favourable opinion about HPV vaccination was associated with seeing more female patients per week, younger age, and GPs' intention to recommend hepatitis B vaccination. This representative survey of GPs in a major region of France finds a favourable opinion about the HPV vaccine and widespread use of it, despite some concerns that the recent introduction of the vaccine means that we do not yet fully understand the potential for side effects and about the recommended target age of recipients.

[Influence of social and cultural patterns on decision-making in oncology]. / Influence des facteurs socioculturels dans la prise de décision médicale en cancérologie.

Shared decision-making is based on the idea of an enlightened participation of the patient to the therapeutic decision process, especially when the ratio between risks and benefits of treatment options is uncertain. The physician owes to ponder the advantages and the inconveniences of chemotherapy, which can be enlightened by a discussion with the patient. Thus, neither shared decision-making nor decision tools are currently used in France. Our aim is to evaluate the variables that step in the therapeutic choice of French physicians concerning the adjuvant chemotherapy prescription in breast cancer. We focus on the impact of different medical cultures on decision processes and shared decision-making conceptions. A socio-anthropological study is carried out with the participation of six French medical centre. First results show the influence of local specificities, professional groups and individual sociocultural background of physicians.

Creation and characterization of temperature-sensitive CENP-C mutants in vertebrate cells.

CENP-C is an evolutionarily conserved centromere protein that is thought to be an important component in kinetochore assembly in vertebrate cells. However, the functional role of CENP-C in cell cycle progression remains unclear. To further understand CENP-C function, we developed a method incorporating the hyper-recombinogenic chicken B lymphocyte cell line DT40 to create several temperature-sensitive CENP-C mutants in DT40 cells. We found that, under restrictive conditions, one temperature-sensitive mutant, ts4-11, displayed metaphase delay and chromosome missegregation but proceeded through the cell cycle until arrest at G(1) phase. Furthermore, ts4-11 cells were transfected with a human HeLa cell cDNA library maintained in a retroviral vector, and genes that suppressed the temperature-sensitive phenotype were identified. One of these suppressor genes encodes SUMO-1, which is a ubiquitin-like protein. This finding suggests that SUMO-1 may be involved in centromere function in vertebrate cells. The novel strategy reported here will be useful and applicable to a wide range of proteins that have general cell-autonomous function in vertebrate cells.

CENP-H, a constitutive centromere component, is required for centromere targeting of CENP-C in vertebrate cells.

CENP-H has recently been discovered as a constitutive component of the centromere that co-localizes with CENP-A and CENP-C throughout the cell cycle. The precise function, however, remains poorly understood. We examined the role of CENP-H in centromere function and assembly by generating a conditional loss-of-function mutant in the chicken DT40 cell line. In the absence of CENP-H, cell cycle arrest at metaphase, consistent with loss of centromere function, was observed. Immunocytochemical analysis of the CENP-H-deficient cells demonstrated that CENP-H is necessary for CENP-C, but not CENP-A, localization to the centromere. These findings indicate that centromere assembly in vertebrate cells proceeds in a hierarchical manner in which localization of the centromere-specific histone CENP-A is an early event that occurs independently of CENP-C and CENP-H.

Electroporation-mediated delivery of 3'-protected phosphodiester oligodeoxynucleotides to the skin.

The feasibility of topical delivery in the skin of 3' end modified phosphodiester oligonucleotides using electroporation was investigated. Experiments were performed in vitro, using hairless rat skin. Five pulses of (200 V, 450 ms) were applied. The 3' end modifications of the 15 mer oligonucleotide were: (1) 3'-aminohexyl, (2) biotin, with a triethyleneglycol arm, (3) methylphosphonate links between nucleotides 13, 14 and 15, and (4) 2-O-methyl nucleotides at 13, 14 and 15 positions. All the modifications were efficient to protect the oligonucleotides against degradation in the skin. Electroporation increased the topical delivery of the 3' end-modified phosphodiesters by two orders of magnitude compared to passive diffusion, without significant differences between the derivatives. Oligonucleotide concentrations in the range of 1 microm could be achieved in the viable skin. The delivery of a phosphorothioate congener was lower than phosphodiester delivery due to the interaction of phosphorothioate with the stratum corneum. Consequently, 3' end-protected phosphodiesters could be an interesting alternative to phosphorothioate oligonucleotides for topical treatment of cutaneous diseases.

Mechanisms of a phosphorothioate oligonucleotide delivery by skin electroporation.

Skin electroporation has great potential for topical delivery of oligonucleotides. Controled therapeutic levels of an intact phosphorothioate oligonucleotide (PS) can be reached in the viable tissue of the skin. The aim of this work was to investigate the transport mechanisms of a PS in hairless rat skin by electroporation, and hence to allow optimization of oligonucleotides (ONs) topical delivery. The pulsing condition used was five exponentially-decaying pulses of 100 V and 500 ms pulse time. The main mechanism of PS transport in the skin viable tissues during pulsing was electrophoresis. The electroosmosis contribution was negligible. Electrophoresis created within minutes a reservoir of PS in the skin viable tissues, which persisted within a therapeutic range of hours. A strong PS/stratum corneum interaction occurred.

Localization of a FITC-labeled phosphorothioate oligodeoxynucleotide in the skin after topical delivery by iontophoresis and electroporation.

PURPOSE: The aim of this study was to verify the hypothesis that the application of high voltage to the skin enhances both stratum corneum and keratinocyte permeability. Therefore, the transport of FITC labelled phosphorothioate oligonucleotides (FITC-PS) administered by passive diffusion, iontophoresis or electroporation was localized. METHODS: Fluorescent microscopy and laser scanning confocal microscopy were used to visualize the FITC-PS transport at the tissue and cell level respectively in hairless rat skin after electroporation (5 x (200 V approximately 500 ms) or iontophoresis (same amount of charges transferred). RESULTS: FITC-PS did not penetrate the viable skin by passive diffusion. Molecular transport in the skin upon electroporation or iontophoresis was localized and implied mainly hair follicles for iontophoresis. In the stratum corneum, the pathways for FITC-PS transport were more transcellular during electroporation and paracellular during iontophoresis. FITC-PS were detected in the nucleus of the keratinocytes a few minutes after pulsing. In contrast, iontophoresis did not lead to an uptake of the oligomer. CONCLUSIONS: The internalization of FITC-PS in the keratinocytes after electroporation confirms the hypothesis and suggests that electroporation, which allows both efficient topical delivery and rapid cellular uptake of the oligonucleotides, might be useful for antisense therapy of epidermal diseases.

Parameters controlling topical delivery of oligonucleotides by electroporation.

Electroporation, using high voltage electrical pulses has been recognized as a powerful method for delivering macromolecules such as DNA and proteins in cells, or smaller molecules through the skin. Transdermal electroporation could combine targeted delivery of drugs to the skin and permeabilization of skin cells, suggesting that electroporation could be an interesting alternative for topical delivery of oligonucleotides. This work is devoted to the determination of the electroporation parameters that allow optimal delivery of oligonucleotides to the viable tissues of hairless rat skin in vitro. Phosphorothioate derivatives were preferred to the phosphodiester congeners as the former were found to be much less degraded when extracted from the tissues. Long duration (100-500 ms)--medium voltage (100-200 V)--exponentially decaying pulses appeared to be the best conditions for delivering oligonucleotides to the skin. The oligonucleotide quantity permeating the viable tissues of the skin was controlled by the selection of the electrical parameters of the pulses (voltage, pulse time and number of pulses) or by the ON concentration in the donor compartment. After delivery by electroporation, therapeutic levels of oligonucleotides were reached in the viable tissues of the skin (above 1 microM or 10 microM in intact or stripped skin respectively). Taken together, our results show that electroporation could be an interesting method for the delivery of oligonucleotides to the skin.

Emergence and scattering of multiple neurofibromatosis (NF1)-related sequences during hominoid evolution suggest a process of pericentromeric interchromosomal transposition.

Type 1 neurofibromatosis (NF1) gene encodes for a member of the GTPase activating protein family and is considered to be a tumor suppressor gene. Its very high rate of de novo mutation in humans led us to study a specific feature of this gene: the presence of numerous NF1-related sequences. According to our results, the human genome contains at least 11 NF1-related sequences, nine of which are scattered near centromeric sequences of seven different chromosomes. These NF1-related sequences, whose extent is quite varied according to loci, are unprocessed copies of the NF1 gene, and bear numerous mutations. A phylogenetic analysis of the six largest sequences indicates that they are all derived from a common ancestor, which would have appeared 22-33 million years ago, and was subsequently duplicated several times during hominoid evolution. The most recent duplication and interchromosomal transposition occurred in the last million years suggesting that the process could still be ongoing. Intriguing similarities between the evolution of alpha-satellite DNA and NF1-related sequences suggest the involvement of a common genetic mechanism for the generation and pericentric spreading of these NF1 partial copies.

A Tsp509I variant in exon 13 of the neurofibromatosis type 1 (NF1) gene allows the identification of both alleles at the mRNA level.

We describe here a new sequence variant occurring in the coding region of the neurofibromatosis (NF1) gene (exon 13). This exonic polymorphism can be directly investigated by simple restriction enzyme digestion of RT-PCR (reverse transcription-polymerase chain reaction) products, making it a powerful tool for examining allele-specific mRNA expression levels.

Neurofibromatosis 1 (NF1) mRNAs expressed in the central nervous system are differentially spliced in the 5' part of the gene.

The neurofibromatosis 1 gene seems to play essential roles at several different stages of life. During embryogenesis, it is involved in cardiac development while in the adult, neurofibromin (the corresponding protein) is mainly expressed in the nervous system, and therein, essentially in neurons, non-myelinating Schwann cells and oligodendrocytes. In addition, the NF1 gene is considered a tumor suppressor gene, since mutations have been associated with the occurrence of benign and malignant tumors in neuralcrest-derived tissues. Using reverse transcription-polymerase chain reaction (RT-PCR) analyses with primers located in exons 7 and 13, we have identified evidence of alternative splicing in this region of the NF1 gene. Cloning and sequencing of cDNA allowed the characterization of an isoform bearing an extra 30 bp sequence between exons 9 and 10a, leading to the insertion of 10 amino acids between residues 420 and 421 of neurofibromin. The insertion is conserved in the mouse. Examination of the pattern of expression of this isoform demonstrated a high level of expression in the central nervous system and an absence of expression in all the other normal tissues tested including peripheral nervous tissues derived from the neural crest. Analysis of brain tumors indicated a reduced expression of the alternative exon in medulloblastomas and oligodendrogliomas. The results presented here are consistent with tissue-specific expression of this alternative exon which we propose to call exon 9br.