Jean Christophe Noël

Phase II Double-Blind, Placebo-Controlled Study of the Safety and Efficacy of Cidofovir Topical Gel for the Treatment of Patients with Human Papillomavirus Infection

Genital condylomata acuminata are nonmalignant human papillomavirus (HPV)-induced tumors in which HPV types 6 and 11 are most commonly found. Usual treatments for condylomata acuminata are nonspecific and are based on the destruction or removal of infected tissue. These procedures are often painful and are characterized by a high relapse rate. We report here what is to our knowledge the first double-blind, placebo-controlled study of the use of cidofovir, a nucleotide analogue, for the treatment of genital papillomavirus infections. Thirty patients were enrolled in the study; 19 received cidofovir, and 11 received placebo. The median number of warts and the median baseline wart area were comparable for both groups. Nine (47%) of 19 patients in the cidofovir group had a complete response (total healing), compared with 0 of the patients in the placebo group (P=.006). None of the patients in the cidofovir group experienced progression of the disease, compared with 5 (45%) of 11 patients in the placebo group. The side effects recorded for both groups were comparable.

Gene expression profile for ectopic versus eutopic endometrium provides new insights into endometriosis oncogenic potential.

Endometriosis is a common gynecological disorder characterized by pain and infertility, where the lesions disseminate everywhere in the body with a preference for the pelvis. In that, it could be regarded as a benign metastatic disease, because its issue is not fatal. However, the molecular bases of this intriguing clinical condition are not well known. The objective of this study is to characterize the transcriptome differences between eutopic vs. ectopic endometrium with a special interest in pathways involved in cancerogenesis. We performed two hybridizations in technical replicate on highly specific long oligonucleotides microarrays (NimbleGen), with cDNA prepared from six-patients pools, where the same patient provided both eutopic and ectopic endometrium (endometriomas). To confirm the expression microarrays data, quantitative RT-PCR validation was performed on 12 individuals for 20 genes. Over 8000 transcripts were significantly modified (more than twice) in the lesions corresponding to 5600 down- or up-regulated genes. These were clustered through DAVID Bioinformatics Resources into 55 functional groups. The data are presented in a detailed and visual way on 24 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways implemented with induction ratios for each differentially expressed gene. An outstanding control of the cell cycle and a very specific modulation of the HOX genes were observed and provide some new evidence on why endometriosis only very rarely degenerates into cancer. The study constitutes a noteworthy update of gene profiling in endometriosis, by delivering the most complete and reliable list of dysregulated genes to date.

Possible Mechanisms of Action of Transurethral Needle Ablation of the Prostate on Benign Prostatic Hyperplasia Symptoms: A Neurohistochemical Study

PURPOSE Transurethral needle ablation of benign prostatic hypertrophy (BPH) is a rapid, anesthesia-free outpatient procedure using low level radiofrequency energy that produces coagulative necrosis lesions at temperatures of approximately 100C. Clinically, significant improvement in objective and subjective parameters has been observed in BPH patients. Transurethral needle ablation has also been shown to be effective in relieving urinary retention. However, the precise mechanism of action of this procedure remains to be clarified. Ablation could produce its action on the dynamic component of the infravesical outlet obstruction. We analyzed the possible effects of transurethral needle ablation on the intraprostatic innervation. MATERIALS AND METHODS Histological sections from 10 open prostatectomy specimens (BPH) recovered 1 to 46 days after transurethral needle ablation were stained with hematoxylin and eosin and an immunohistochemical technique, using antibodies against S100 proteins and nonspecific enolase as specific nerve markers, and against anti-prostate specific antigen and anti-desmin for glandular and muscle cells, respectively. We used 5 BPH specimens as controls. RESULTS Microscopic examination of the treated areas showed necrotic lesions affecting epithelial and smooth muscle cells in the transition zone at a depth of 0.3 to 1.0 cm, from the preserved urethra. Nerve fibers in the control specimens and untreated prostatic areas were predominant in the urethral submucosal layer and in the stroma surrounding the epithelial nodules. No staining of any axon or isolated nerve cell was observed in any specimen treated by transurethral needle ablation, and there was a sharp and clear delineation between treated and untreated areas. CONCLUSIONS Our study demonstrated severe thermal damage to intraprostatic nerve fibers caused by transurethral needle ablation. A long-term denervation of alpha-receptors and/or sensory nerves could explain the clinical effects of transurethral needle ablation of the prostate. Theoretically, the best location to produce necrotic lesions should include submucosal and subcapsular nerve endings. Differences in the distribution of the adrenoreceptors and morphometry of the prostate transition zone could partly explain differences in clinical outcome observed after transurethral needle ablation of the prostate.

Cidofovir, a new approach for the treatment of cervix intraepithelial neoplasia grade III (CIN III)

Cervix intraepithelial neoplasia grade III (CIN III) is an intraepithelial proliferative process with different levels of severity depending on both the extension of the proliferation in the epithelium and the presence of cellular atypia. Human papillomavirus (HPV) has been clearly associated with such lesions. The results of a preliminary study are described on the local application of cidofovir, an acyclic nucleoside phosphonate derivative with broad‐spectrum anti‐DNA virus activity for the treatment of CIN III. Cidofovir 1% in gel was applied three times, every other day, on the cervix of each of 15 women with biopsy proven CIN III. Within 1 month after the start of treatment, the cervix was removed surgically. Histology and human papillomavirus polymerase chain reaction (HPV‐PCR) were carried out. In 7 of the 15 patients the histology showed a complete response, whereas 5 patients had a partial response characterized by the persistence of CIN II‐III lesions, 1 patient had a dysplasia of lower grade (CIN I), and 2 patients did not show differences in the histology. Complete response was confirmed by PCR in 4 of the 7 patients, with complete response histologically. Cidofovir was not toxic to the normal epithelium. Cidofovir 1% gel was able to inhibit partially or completely cervical dysplasia lesions after only three applications (every other day). This effect was specific and tissue other than the dysplastic epithelium was not affected by the treatment. J. Med. Virol. 60:205–209, 2000.

Methotrexate induces apoptotic cell death in human keratinocytes

Abstract The mechanism by which low doses of methotrexate act in psoriasis to restore a clinically normal skin is poorly understood. Apoptosis is a programmed cell death activated when cell removal is needed. The purpose of the present work was to examine using an organotypical model of keratinocyte culture, the possibility that low doses of methotrexate can induce apoptosis of keratinocytes. Epidermal explants were cultivated on dead deepidermized dermis under air-exposed conditions. After 10 days, methotrexate (10 –7 M ) was added. After a further 5 days, one part of each culture was fixed and submitted to routine histology, DNA nick end labelling (TUNEL) to detect DNA fragmentation (a molecular marker of apoptotic cell death) and immunohistochemical detection of p53 (a protein involved in apoptosis induced by DNA-damaging agents). The other part of each culture was processed for electron microscopy. A significant proportion of keratinocytes (1%) were damaged and exhibited the morphological features of apoptotic cell death. Immunohistochemical overexpression of p53 was detected in the basal layer of the cultures treated with methotrexate. Low doses of methotrexate induce apoptosis. This mode of action could explain the reduction in epidermal hyperplasia during treatment of psoriasis with methotrexate.

Herpesvirus‐like DNA sequences and Kaposi's sarcoma: Relationship with epidemiology, clinical spectrum, and histologic features

The evidence of an infectious agent other than human immunodeficiency virus (HIV) acting as a possible etiologic cause of Kaposis sarcoma (KS) has received considerable attention in the last years. Recently, DNA sequences from a new herpesvirus (HHV‐8) have been observed in several cases of KS. The discovery suggests that this virus may play a role in the pathogenesis of KS. To evaluate these results, we determined the frequency of HHV‐8 DNA sequences in 78 specimens of KS according to different epidemiologic origins (sporadic KS: 6, immunosuppressive drug‐associated: 11, and AIDS‐associated: 61), clinical forms (cutaneous: 69, mucocutaneous: 4 and visceral: 5) and histologic variants (early‐patch: 40, late‐plaque or nodular: 38).

Endometriosis: Contribution of 3.0-T Pelvic MR Imaging in Preoperative Assessment—Initial Results

PURPOSE To determine the accuracy of 3.0-T pelvic magnetic resonance (MR) imaging in the preoperative assessment of endometriosis and to evaluate colon wall involvement after intrarectal gel administration. MATERIALS AND METHODS Institutional review board approval for this study was obtained, and each patient gave written informed consent. Forty-one consecutive patients with clinical suspicion of endometriosis underwent pelvic MR imaging at 3.0 T before surgery. Single-shot and high-spatial-resolution axial T2-weighted, sagittal fat-suppressed T2-weighted, and axial fat-suppressed T1-weighted sequences were performed. T2-weighted sequences were repeated after the rectum was filled with ultrasonographic (US) gel. Two blinded readers interpreted images independently. Image quality was scored by using a four-point scale. Detailed mapping of deep endometriosis was performed. Colon wall infiltration was graded (none, serosa, muscularis, submucosa, mucosa). MR imaging results were compared with surgical and pathologic findings. Interobserver agreement was assessed by using kappa statistics. Nonparametric tests were performed to compare colon wall infiltration scores without and those with US gel and between observers. RESULTS Twenty-seven of 41 patients had deep endometriosis at surgery and histopathologic examination. Sensitivity, specificity, positive and negative predictive values, and accuracy for the diagnosis of deep endometriosis at MR imaging were 96.3% (26 of 27), 100% (14 of 14), 100% (26 of 26), 93.3% (14 of 15), and 97.6% (40 of 41), respectively. kappa Values ranged from 0.65 to 1.0, depending on the location of deep endometriosis. Colon wall infiltration assessment by both readers correlated well with pathologic findings (Spearman coefficient, >0.93), although median wall involvement scores were lower at pathologic examination than for both readers both before (P = .042 and P = .011) and after (P = .079 and P = .011) intrarectal gel filling. CONCLUSION MR imaging of the pelvis at 3.0 T is accurate in the diagnosis and staging of deep endometriosis for the preoperative assessment of patients clinically suspected of having endometriosis.

Ovarian endometrioma: severe pelvic pain is associated with deeply infiltrating endometriosis

BACKGROUND The objective of this study was to evaluate the significance of severe preoperative pain for patients presenting with ovarian endometrioma (OMA). METHODS Three hundred consecutive patients with histologically proven OMA were enrolled at a single university tertiary referral centre between January 2004 and May 2010. Complete surgical excision of all recognizable endometriotic lesions was performed for each patient. Pain intensity was assessed with a 10-cm visual analogue scale (VAS). Pain was considered as severe when VAS was ≥ 7. Prospective preoperative assessment of type and severity of pain symptoms (VAS) was compared with the peroperative findings (surgical removal and histological analysis) of endometriomas and associated deeply infiltrating endometriosis. Correlations were sought with univariate analysis and a multiple regression logistic model. RESULTS After multiple logistic regression analysis, uterosacral ligaments involvement was related with a high severity of chronic pelvic pain [odds ratios (OR) = 2.1; 95% confidence interval (CI): 1.1-4.3] and deep dyspareunia (OR = 2.0; 95% CI: 1.1-3.5); vaginal involvement was related with a higher intensity of lower urinary symptoms (OR = 13.4; 95% CI: 3.2-55.8); intestinal involvement was related with an increased severity of dysmenorrhoea (OR = 5.2; 95% CI: 2.7-10.3) and gastro-intestinal symptoms (OR = 7.1; 95% CI: 3.3-15.3). CONCLUSIONS In case of OMA, severe pelvic pain is significantly associated with deeply infiltrating lesions. In this situation, the practitioner should perform an appropriate preoperative imaging work-up in order to evaluate the existence of associated deep nodules and inform the patient in order to plan the surgical intervention strategy.

Impact of Surgical Resection of Rectovaginal Pouch of Douglas Endometriotic Nodules on Pelvic Pain and Some Elements of Patients' Sex Life

STUDY OBJECTIVE To assess the impact of laparoscopic resection of endometriotic nodules in the rectovaginal pouch of Douglas on womens pain symptoms, analgesic intake, work absenteeism, work difficulties, and some elements of sex life. DESIGN Observational study (Canadian Task Force classification II-2). SETTING Gynecology department at a university hospital. PATIENTS Twenty-six women with rectovaginal pouch of Douglas endometriotic nodules and no evidence of other potential cause of pain at physical examination, laparoscopy, and transvaginal ultrasonography. INTERVENTION Laparoscopic resection of endometriotic nodules with the CO2 laser until no residual induration was felt in surrounding tissues. MEASUREMENTS AND MAIN RESULTS Significant statistical differences were found between preoperative and postoperative pain scores, percentages of women absent from work, percentages taking analgesics or nonsteroidal antiinflammatory drugs, and percentages having work difficulties due to pain. A significant difference also was found in frequencies of sexual desire and coitus. CONCLUSION Endometriotic nodules in the rectovaginal pouch of Douglas may be responsible for major pelvic pain and also for sexual dysfunction (lack of sexual desire, dyspareunia). Laparoscopic resection of the nodules significantly improves these conditions. (J Am Assoc Gynecol Laparosc 8(1):55-60, 2001)

Mapping labels in the human developing visual system and the evolution of binocular vision.

Topographic representation of visual fields from the retina to the brain is a central feature of vision. The development of retinotopic maps has been studied extensively in model organisms and is thought to be controlled in part by molecular labels, including ephrin/Eph axon guidance molecules, displayed in complementary gradients across the retina and its targeting areas. The visual system in these organisms is primarily monocular, with each retina mapping topographically to its contralateral target. In contrast, mechanisms of retinal mapping in binocular species such as primates, characterized by the congruent, aligned mapping of both retinas onto the same brain target, remain completely unknown. Here, we show that the distribution of ephrin/Eph genes in the human developing visual system is fundamentally different from what is known in model organisms. In the human embryonic retina, EphA receptors are displayed along two gradients, sloping down from the center of the retina to its periphery. The EphB1 receptor, which controls the ipsilateral routing of retinal axons in the mouse, is expressed throughout the human temporal retina in coordination with the changes in EphA gene expression. In the dorsal lateral geniculate nucleus, ephrin-A/EphAs are displayed along complementary retinotopic gradients. Our data point to an evolutionary model in which the coordinated divergence of the distribution of the receptors controlling retinal guidance and retinal mapping enabled the emergence of a fully binocular system. They also indicate that ephrin/Eph signaling plays a potentially major role in the development of neuronal connectivity in humans.