Using Simulation to Model and Validate Invasive Breast Cancer Progression in Women in the Study and Control Groups of the Canadian National Breast Screening Studies I and II.

BACKGROUND: Modeling breast cancer progression and the effect of various risk is helpful in deciding when a woman should start and end screening, and how often the screening should be undertaken. METHODS: We modeled the natural progression of breast cancer using a hidden Markov process, and incorporated the effects of covariates. Patients are women aged 50-59 (older) and 40-49 (younger) years from the Canadian National Breast Screening Studies. We included prevalent cancers, estimated the screening sensitivities and rates of over-diagnosis, and validated the models using simulation. RESULTS: We found that older women have a higher rate of transition from a healthy to preclinical state and other causes of death but a lower rate of transition from preclinical to clinical state. Reciprocally, younger women have a lower rate of transition from a healthy to preclinical state and other causes of death but a higher rate of transition from a preclinical to clinical state. Different risk factors were significant for the age groups. The mean sojourn times for older and younger women were 2.53 and 2.96 years, respectively. In the study group, the sensitivities of the initial physical examination and mammography for older and younger women were 0.87 and 0.81, respectively, and the sensitivity of the subsequent screens were 0.78 and 0.53, respectively. In the control groups, the sensitivities of the initial physical examination for older and younger women were 0.769 and 0.671, respectively, and the sensitivity of the subsequent physical examinations for the control group aged 50-59 years was 0.37. The upper-bounds for over-diagnosis in older and younger women were 25% and 27%, respectively. CONCLUSIONS: The present work offers a basis for the better modeling of cancer incidence for a population with the inclusion of prevalent cancers.

Postoperative pelvic pain: An imaging approach.

Postoperative pelvic pain after gynecological surgery is a readily detected but unspecific sign of complication. Imaging as a complement to physical examination helps establish the etiological diagnosis. In the context of emergency surgery, vascular, urinary and digestive injuries constitute the most frequent intraoperative complications. During the follow-up of patients who had undergone pelvic surgery, imaging should be performed to detect recurrent disease, postoperative fibrosis, adhesions and more specific complications related to prosthetic material. Current guidelines recommend using pelvic ultrasonography as the first line imaging modality whereas the use of pelvic computed tomography and/or magnetic resonance imaging should be restricted to specific situations, depending on local availability of equipment and suspected disease.

Overview of digital breast tomosynthesis: Clinical cases, benefits and disadvantages.

In France, the national breast cancer-screening program is based on mammography combined with clinical breast examination, and sometimes breast ultrasound for patients with high breast density. Digital breast tomosynthesis is a currently assessed 3D imaging technique in which angular projections of the stationary compressed breast are acquired automatically. When combined with mammography, clinicians can review both conventional (2D) as well as three-dimensional (3D) data. The purpose of this article is to review recent reports on this new breast imaging technique and complements this information with our personal experience. The main advantages of tomosynthesis are that it facilitates the detection and characterization of breast lesions, as well as the diagnosis of occult lesions in dense breasts. However, to do this, patients are exposed to higher levels of radiation than with 2D mammography. In France, the indications for tomosynthesis and its use in breast cancer-screening (individual and organized) are yet to be defined, as is its role in the diagnosis and staging of breast cancer (multiple lesions). Further studies assessing in particular the combined reconstruction of the 2D view using 3D tomosynthesis data acquired during a single breast compression event, and therefore reducing patient exposure to radiation, are expected to provide valuable insight.

Evaluation of tubal microinserts position using 3D ultrasound and pelvic X-ray.

PURPOSE: To retrospectively compare three-dimensional ultrasonography (3D-US) and pelvic X-rays to assess the position of tubal sterilization microinserts. MATERIAL AND METHODS: Forty-four patients who underwent tubal sterilization with Essure(®) microinserts in our institution were included. The microinserts'position was evaluated three months after the procedure using 3D-US and pelvic X-rays. Placement on 3D-US was binary categorized as correct or incorrect and the distance between the two devices was reported. The orientation and symmetric deployment of the microinserts and the distance between the proximal parts of the two devices was assessed on pelvic X-rays. Performance of 3D-US and pelvic X-ray were compared using Mac Nemar test. Comparison of the distance between the two devices measured on pelvic X-rays and 3D-US was made with the paired Student t test. RESULTS: 3D-US images showed microinserts in 93% (41/44). Eighty-six percent (38/44) were correctly positioned on 3D-US and 82% (36/44) on pelvic X-rays. No significant differences between the performances of the two imaging techniques were found. No significant differences for the distance between the two devices measured on pelvic X-ray and 3D-US was found. CONCLUSION: 3D-US is a simple, non-ionizing technique, which appears as a promising alternate technique to pelvic X-rays to assess the correct position of Essure(®) microinserts.

[Hedrocele, an unknown pelvic organ prolapse]. / Mise au point sur l'hédrocèle, un trouble de la statique pelvienne méconnu.

Pelvic floor disorders are frequent and source of symptoms which can be invalidating for patients. Between them, hedrocele is a pathology often unknown and clinically difficult to diagnose. It is a herniation of fat pad, small bowel or sigmoid colon in the recto-uterine pouch (cul-de-sac of Douglas) exercising a mass effect on the anterior wall of the rectum. Pelvic magnetic resonance imaging with morphological sequences and dynamic sequences in thrust can be very useful, allowing a comprehensive study of pelvic floor dysfunction and confirming the complete diagnosis, especially before surgery. We suggest you some examples to illustrate this pathology in order to emphasize the importance of its diagnosis, especially preoperative. A better understanding of this pelvic floor dysfunction would improve the care of patients.

Effects of the self-myocardial retroperfusion with aortic-coronary sinus shunt on cardiac output and ischemic events in high-risk patients undergoing OPCAB surgery.

AIM: Despite controversies, off-pump coronary artery bypass (OPCAB) surgery has become a routine procedure. Obvious advantages have been demonstrated in high-risk patients. However, OPCAB surgery has limitations in specific high-risk situations with hazards of operative deleterious events. We describe an innovative procedure of self-myocardial retroperfusion (SMR) with an aortic-coronary sinus shunt (ACSS). We prospectively evaluated the protective effects and benefits of SMR in high-risk coronary patients with impaired LVEF. METHODS: Eighteen consecutive high-risk (ES>10) coronary patients (mean age: 65.94 years; range: 34-85; mean ES: 26.97%) with LVEF≤35% who were not eligible for IABP were assigned for OPCAB surgery. Following sternotomy, the cardiac indexes (CI) were measured before, during SMR and after completion of coronary artery bypasses. Operative events with and without SMR were accurately collected, and postoperative cardiac Troponin T release was measured. RESULTS: OPCAB procedures were performed in all patients. Intraoperative use of SMR significantly increased CI (P=3.1041810.10-8) and reversed deleterious operative events (ECG changes/low cardiac output). Hospital mortality was 0%. Incidence of transient atrial fibrillation was 33.33%. Neither stroke nor renal insufficiency was observed. The mean graft number/patient was 2.05. Mean postoperative cardiac Troponin T value was 0.79 µg/L. Beating heart preservation optimized by SMR contributed to reduce ischemia-reperfusion injury, as validated by an immediate increase of CI after completion of coronary bypasses (P=3.35009.10-9). CONCLUSION: The concept of SMR with an ACSS during OPCAB procedures definitely improved CI and reversed ischemic features in high-risk patients and should be considered as an operative temporary myocardial assistance.

Structural proteins of Kaposi's sarcoma-associated herpesvirus antagonize p53-mediated apoptosis.

The tumor suppressor p53 is a central regulatory molecule of apoptosis and is commonly mutated in tumors. Kaposi's sarcoma-associated herpesvirus (KSHV)-related malignancies express wild-type p53. Accordingly, KSHV encodes proteins that counteract the cell death-inducing effects of p53. Here, the effects of all KSHV genes on the p53 signaling pathway were systematically analyzed using the reversely transfected cell microarray technology. With this approach we detected eight KSHV-encoded genes with potent p53 inhibiting activity in addition to the previously described inhibitory effects of KSHV genes ORF50, K10 and K10.5. Interestingly, the three most potent newly identified inhibitors were KSHV structural proteins, namely ORF22 (glycoprotein H), ORF25 (major capsid protein) and ORF64 (tegument protein). Validation of these results with a classical transfection approach showed that these proteins inhibited p53 signaling in a dose-dependent manner and that this effect could be reversed by small interfering RNA-mediated knockdown of the respective viral gene. All three genes inhibited p53-mediated apoptosis in response to Nutlin-3 treatment in non-infected and KSHV-infected cells. Addressing putative mechanisms, we could show that these proteins could also inhibit the transactivation of the promoters of apoptotic mediators of p53 such as BAX and PIG3. Altogether, we demonstrate for the first time that structural proteins of KSHV can counteract p53-induced apoptosis. These proteins are expressed in the late lytic phase of the viral life cycle and are incorporated into the KSHV virion. Accordingly, these genes may inhibit cell death in the productive and in the early entrance phase of KSHV infection.

Efficacy of TachoSil® as a sutureless hemostatic patch to repair a perforation of the interventricular groove during endocardial radiofrequency ablation.

Catheter ablation is a well-established therapeutic option for management of recurrent ventricular tachycardia in patients with ischemic/non-ischemic heart disease and procedural complications include a mortality rate of up to 3% and a risk of major complications up to 10%. Cardiac perforation following a catheter ablation is rare but serious complication and occurs in 1% of ventricular ablation procedures. The appropriate surgical repair may be challenging and need cardiopulmonary bypass support according to the location of the lesion and the hemodynamic status of the patient. We report the case of a free wall right ventricular perforation of the interventricular groove with cardiac tamponade following catheter ablation for recurrent ventricular tachycardia. Due to the proximity of the left anterior descending artery and the extreme fragility of tissues, the patient was treated successfully by a sutureless patch technique using a fibrin tissue-adhesive collagen fleece (TachoSil®). This technique is a safe and effective surgical option to repair a ventricular perforation especially when the ventricular tissues are fragile. It is simple and enable to realize surgical repair also if the localization of tear is difficult to access and without the need for cardiopulmonary bypass support if hemodynamic conditions are stable.

Dual-energy contrast-enhanced digital mammography in routine clinical practice in 2013.

To date, analysis of the vascularisation of breast lesions mainly relies on MR imaging. However, the accessibility of MRI is sometimes limited and has led to the development of new means of imaging, such as dual-energy contrast-enhanced mammography, which provides data on the vascularisation of the breast along with the usual morphological information. The purpose of this paper is to present this new imaging technique as well as the recent references, illustrated by clinical reports derived from our everyday practice to focus on the advantages and disadvantages of this new breast exploration. Dual-energy contrast-enhanced mammography is a recent, seemingly promising technique, in the management of breast cancer. The main advantages consist of its easy installation, the good tolerance and the comfort in the interpretation of difficult to read mammograms. However, the indications and the role of dual-energy contrast-enhanced mammography still have to be determined within the diagnostic strategy of breast tumours. New studies are expected, especially to compare dual-energy contrast-enhanced mammography with breast MRI.

An update on adenomyosis.

Adenomyosis is a common benign uterine pathology that is defined by the presence of islands of ectopic endometrial tissue within the myometrium. It is asymptomatic in one third of cases, but when there are clinical signs they remain non-specific. It can often be misdiagnosed on sonography as it may be taken to be multiple uterine leiomyomata or endometrial thickening, both of which have a different prognosis and treatment. Adenomyosis is often associated with hormone-dependent pelvic lesions (myoma, endometriosis, or endometrial hyperplasia). It is less commonly connected to infertility or obstetrical complications and indeed any direct relationship remains controversial. The purpose of imaging is to make the diagnosis, to determine the extent of spread (focal or diffuse, superficial or deep adenomyosis, adenomyoma), and to check whether there is any associated disease, in particular endometriosis. The aim of this article is to provide assistance in recognising adenomyosis on imaging and to identify the pathologies that are commonly associated with it in order to guide the therapeutic management of symptomatic patients. Pelvic ultrasonography is the first line investigation. Sonohysterography can assist with diagnosis in some cases (pseudothickening of the endometrium seen on sonography). MRI may be used in addition to sonography to back up the diagnosis and to look for any associated disease.

Spectrophotometric characterization of human impacted surface waters in the Moselle watershed.

In order to characterize the pollution discharged into the Moselle River and some of its tributaries, spectroscopic techniques, namely UV-vis spectroscopy and synchronous fluorescence spectroscopy, have been combined. UV-visible spectra were analysed using the maximum of the second derivative at 225 nm (related to nitrates), the SUVA254 and E2/E3 indices (related to the nature of organic matter). Synchronous fluorescence spectra (delta lambda = 50 nm) presented different shapes depending upon the type of pollution. The pollution results from anthropogenic activities: untreated domestic sewage due to misconnections in a periurban river, effluent from urban WWTPS, agricultural runoff (nitrates) in several streams, discharge from a paper mill (humic-like substances due to wood processing) and from steel mills (PAHs).

Assessment of deoxynivalenol (DON) adsorbents and characterisation of their efficacy using complementary in vitro tests.

Deoxynivalenol (DON) is a prevalent and resistant mycotoxin found in cereals and related products. Adsorbents appear to provide an opportunity to decrease DON absorption in animals but, due to their specificity, it is very difficult to evaluate their actual efficacy. It is pointless to extrapolate results obtained with one mycotoxin to another and even to extrapolate results obtained in vitro in buffer to an in vivo situation. We carried out experiments to characterize the properties of potential DON adsorbents. Initial tests in buffer pH 7 allowed us to focus on six adsorbents: activated charcoal, cholestyramin, Saccharomyces cerevisiae mannans, algal beta-glycan, fungal beta-glycan and leguminous plant. The use of equilibrium sorption models suggested a non-saturated phenomenon and involved variable mechanisms according to the specific material. Subsequent tests with a Caco-2 cell model showed a high reduction in DON cytotoxicity on proliferative intestinal cells and DON absorption by differentiated intestinal cells when adsorbent was added (except for cholestyramin). Otherwise, values were not always in accordance with those obtained in buffer. Our work allowed us to identify five potential DON adsorbents and to propose a complementary in vitro test allowing improved determination of adsorbent properties.

Genotype-phenotype correlations in fetuses and neonates with autosomal recessive polycystic kidney disease.

The prognosis of autosomal recessive polycystic kidney disease is known to correlate with genotype. The presence of two truncating mutations in the PKHD1 gene encoding the fibrocystin protein is associated with neonatal death while patients who survive have at least one missense mutation. To determine relationships between genotype and renal and hepatic abnormalities we correlated the severity of renal and hepatic histological lesions to the type of PKHD1 mutations in 54 fetuses (medical pregnancy termination) and 20 neonates who died shortly after birth. Within this cohort, 55.5% of the mutations truncated fibrocystin. The severity of cortical collecting duct dilatations, cortical tubule and glomerular lesions, and renal cortical and hepatic portal fibrosis increased with gestational age. Severe genotypes, defined by two truncating mutations, were more frequent in patients of less than 30 weeks gestation compared to older fetuses and neonates. When adjusted to gestational age, the extension of collecting duct dilatation into the cortex and cortical tubule lesions, but not portal fibrosis, was more prevalent in patients with severe than in those with a non-severe genotype. Our results show the presence of two truncating mutations of the PKHD1 gene is associated with the most severe renal forms of prenatally detected autosomal recessive polycystic kidney disease. Their absence, however, does not guarantee survival to the neonatal period.

Tumour growth and resistance to gemcitabine of pancreatic cancer cells are decreased by AP-2alpha overexpression.

BACKGROUND: Activator protein-2alpha (AP-2alpha) is a transcription factor that belongs to the family of AP-2 proteins that have essential roles in tumorigenesis. Indeed, AP-2alpha is considered as a tumour-suppressor gene in different tissues such as colonic, prostatic or breast epithelial cells. Moreover, AP-2alpha also participates in the control of colon and breast cancer cells sensitivity towards chemotherapeutic drugs. Despite its potential interest, very few data are available regarding the roles of AP-2alpha in pancreatic cancer. METHODS: We have developed a stable pancreatic CAPAN-1 cell line overexpressing AP-2alpha. Consequences of overexpression were studied in terms of in vivo cell growth, gene expression, migration capacity and chemosensitivity. RESULTS: In vivo tumour growth of CAPAN-1 cells overexpressing AP-2alpha was significantly decreased by comparison to control cells. An altered expression pattern of cell cycle-controlling factors (CDK-4, CDK-6, cyclin-G1, p27(kip1) and p57(kip2)) was observed in AP-2alpha-overexpressing clones by microarrays and western blot analysis. Promoter activity and ChIP analysis indicated that AP-2alpha induces p27(kip1) protein levels by direct binding to and transactivation of its promoter. Moreover, AP-2alpha overexpression increased the chemosensitivity of CAPAN-1 cells to low doses of gemcitabine and reduced their in vitro migration capacity. CONCLUSION: Our data suggested that AP-2alpha overexpression could be exploited to decrease in vivo tumour growth of pancreatic cancer cells and to increase their sensitivity to gemcitabine.

Molecular heterogeneity in fetal forms of type II lissencephaly.

Type II lissencephaly (type II LIS) is a group of autosomal recessive congenital muscular dystrophies (CMD) associated with defects in alpha-DG O-glycosylation, which comprises Walker-Warburg syndrome, Fukuyama cerebral and muscular dystrophy, or muscle-eye-brain disease. The most severe forms of these diseases often have a fetal presentation and lead to a pregnancy termination. We report here the first molecular study on fetal type II LIS in a series of 47 fetuses from 41 unrelated families. Sequencing of the different genes known to be involved in alpha-DG O-glycosylation allowed the molecular diagnosis in 22 families: involvement of POMT1 was demonstrated in 32% of cases, whereas POMGNT1 and POMT2 were incriminated in 15% and in 7% of cases, respectively. We found 30 different mutations in these three genes, 25 were described herein for the first time, 15 in POMT1, and five in POMT2 and POMGNT1. Despite sequencing of FKRP, FCMD, and LARGE, no definitive molecular diagnosis could be made for the other half of our cases. Preliminary results concerning genotype-phenotype correlations show that the choice of the first gene sequenced should depend on the clinical severity of the type II LIS; POMT1 and POMT2 for severest clinical picture and POMGNT1 for milder disease. The other genes, FKRP, FCMD, and LARGE, seem not to be implicated in the fetal form of CMD.

RB1 and TP53 pathways in radiation-induced sarcomas.

The tumour suppressor genes, TP53 and RB1, and four genes involved in their regulation, INK4a, ARF, MDM2 and MDMX, were analysed in a series of 36 post-radiotherapy radiation-induced sarcomas. One-third of the tumours developed in patients carrying a germline mutation of RB1 that predisposed them to retinoblastoma and radiation-induced sarcomas. The genetic inactivation of RB1 and/or TP53 genes was frequently observed in these sarcomas. These inactivations were owing to an interplay between point mutations and losses of large chromosome segments. Radiation-induced somatic mutations were observed in TP53, but not in RB1 or in the four other genes, indicating an early role of TP53 in the radio-sarcomagenesis. RB1 and TP53 genes were biallelically coinactivated in all sarcomas developing in the context of the predisposition, indicating that both genes played a major role in the formation of these sarcomas. In the absence of predisposition, TP53 was biallelically inactivated in one-third of the sarcomas, whereas at least one allele of RB1 was wild type. In both genetic contexts, the TP53 pathway was inactivated by genetic lesions and not by the activation of the ARF/MDM2/MDMX pathway, as recently shown in retinoblastomas. Together, these findings highlight the intricate tissue- and aetiology-specific relationships between TP53 and RB1 pathways in tumorigenesis.

Syndromic encephalocele in a fetal case with a 1p35-pter deletion and a 14q32-qter duplication inherited from a maternal balanced translocation.

Occipital encephalocele belongs to the family of neural tube defects, which occur in one among 2000 to 5000 live births. Syndromic encephaloceles include Meckel-Gruber syndrome and various chromosomal abnormalities. We report on a fetal case (13 WG) with bilateral cleft lip and palate, choanal atresia, occipital encephalocele, bilateral club feet, bilateral multicystic kidneys, enlarged bladder and urethral atresia. The fetal chromosome analysis showed a maternally inherited unbalanced translocation between the short arm of chromosome 1 and the long arm of chromosome 14, resulting in 1p35-pter deletion and 14q32-qter duplication (46,XY,der(1),t(1;14)(p35;q32)). Since the chromosomal breakpoints have not previously been implicated in syndromic encephalocele, this observation is of interest for the identification of other genes responsible for occipital encephalocele.