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Video 3 shows the toxicity of SQ-CDDP NP (8 microM) on HT-29 cells.

Video 2 shows that HT-29 cells treated with 8 microM CDDP still proliferated and generated large cell clusters.

Video 1 shows untreated HT-29 cells. Images were captured at 1 h intervals for 14h.

Supplementary Materials and Methods, Supplementary Tables I and II, and Supplementary Figure Legends

Nanotechnology offers many possibilities to improve drug treatments, including with regard to drug pharmacology. The current study reports a simple approach to improve cisplatin efficacy in the treatment of colon cancer through the creation of orally administered squalenoylated nanoparticles loaded with cisplatin (SQ-CDDP NP). Cytotoxic effects of SQ-CDDP NP were assessed in human colonic cells and in mouse models of intestinal cancer. In cell culture, SQ-CDDP NP exhibited at least 10-fold greater cytotoxic potency compared with uncomplexed cisplatin, reflecting an enhancement in intracellular accumulation and DNA platination. Mechanistic investigations showed that SQ-CDDP NP stimulated ROS production, expression of heavy metal–inducible and stress-inducible genes, stress kinase cascades, and apoptosis. In ApcMin/+ mice, a model of intestinal tumorigenesis, oral administration of SQ-CDDP NP curtailed spontaneous tumor formation and azoxymethane-induced colon carcinogenesis with no apparent evidence of tissue toxicity. Our results offer preclinical validation of a nanocarrier formulation that can safely improve chemotherapeutic efficacy, address risks of drug resistance, and improve patient compliance by enabling oral administration. Cancer Res; 77(11); 2964–75. ©2017 AACR.

Supplementary Table III presents the selection of Genes of HT29 colonic cells treated by drugs with Expression Altered at least 2-Fold by SQ-CDDP NP

Resistance to apoptosis is a recurrent theme in colon cancer. We have shown previously that the 7-transmembrane spanning receptor OX1R for orexins promotes robust apoptosis in the human colon cancer cell line HT29 through an entirely novel mechanism involving phosphorylation of tyrosine-based motifs in OX1R. Here, we investigated the status of OX1R in a large series of human colorectal tumors and hepatic metastases. All primary colorectal tumors regardless of their localization and Duke's stages and all hepatic metastases tested expressed OX1R mRNA and/or protein. In sharp contrast, adjacent normal colonocytes or hepatocytes as well as control normal tissues were negative. Next, we showed that nine human colon cancer cell lines established from primary tumors or metastases expressed OX1R mRNA and underwent important apoptosis on orexin-A challenge. Most interestingly, orexin-A also promoted robust apoptosis in cells that are resistant to the most commonly used drug in colon cancer chemotherapy, 5-fluorouracil. When human colon cancer cells were xenografted in nude mice, orexin-A administered at day 0 strongly slowed the tumor growth and even reversed the development of established tumors when administered 7 days after cell inoculation. Orexin-A also acts by promoting tumor apoptosis in vivo because caspase-3 is activated in tumors on orexin treatment of nude mice. These findings support that OX1R is an Achilles heel of colon cancers, even after metastasis or chemoresistance. They suggest that OX1R agonists might be novel candidates for colon cancer therapy. Cancer Res; 71(9); 3341–51. ©2011 AACR.

Supplementary Figure 3 from Aberrant Expression of OX1 Receptors for Orexins in Colon Cancers and Liver Metastases: an Openable Gate to Apoptosis

Supplementary Figure 1 from Aberrant Expression of OX1 Receptors for Orexins in Colon Cancers and Liver Metastases: an Openable Gate to Apoptosis

Supplementary Figure 4 from Aberrant Expression of OX1 Receptors for Orexins in Colon Cancers and Liver Metastases: an Openable Gate to Apoptosis

Supplementary Figure 2 from Aberrant Expression of OX1 Receptors for Orexins in Colon Cancers and Liver Metastases: an Openable Gate to Apoptosis

Introduction Studies have shown that the PD-1/PD-L1 immunomodulatory pathway slows down anti-tumor immunity in a number of cancers. The description of the expression of these molecules has never been performed in anal low-grade/high grade squamous intra-epithelial lesions (LSIL/HSIL respectively). Materials and methods Patients followed in the AIN3 cohort were routinely sampled. For each selected sample, an immunohistochemical study was performed with anti-CD8, PD-1, PD-L1 antibodies. The presence and distribution of CD8+ lymphocytes, and the presence of PD-1+ lymphocytes and PD-L1+ epithelial cells were assessed. The comparison of these characteristics was performed between the HSIL and LSIL groups. Results 33 patients were included and 78 samples selected (60 HSIL and 18 LSIL). CD8+ lymphocytes were observed more frequently in HSIL versus LSIL in the lamina propria or intra epithelial (respectively 90% vs. 60%, p = 0.01; and 62% vs. 33%, p = 0.04). PD-1+ lymphocytes were observed more frequently in HSIL versus LSIL (41% vs 11%, p = 0.03). There was no difference between HSIL and LSIL for PD-L1+ epithelial cells. Conclusions Anal dysplastic lesions are accompanied by an inflammatory lymphocytic infiltrate expressing CD8 and PD-1, more frequent in high-grade lesions. These results highlight the involvement of the PD-1/PD-L1 pathway in the natural history of anal dysplasia.

Aim Anal dysplasia is caused by chronic infection with the human papillomavirus and exposes to the risk of anal cancer. Usually during a surgery for anal condylomas only one or two biopsies on visible lesions are performed to classify the level of dysplasia. The aim of this study was to evaluate the distribution of dysplasia anal grade among patients operated on for multiple anal condylomas with no macroscopic differences. Method Cross-sectional study of patients operated on for multiple anal condylomas including a mapping of dysplasia by performing systematically for each patient one biopsy on visible lesion from each of the 4 quadrants on anal margin and in anal canal. All biopsies were read independently by 2 different pathologists. Results Among 72 patients, 60 were men, 48 were HIV-infected with a median age of 37.5 years. The proportion of high-grade squamous intraepithelial lesion (HSIL) was higher in the anal canal (41.7%) compared to the margin (20.8%) (p= 0.004). HSIL frequency did not differ according to the quadrant (anterior, posterior, right or left) of the two areas. HSIL on anal canal was not associated with HSIL on anal margin and vice versa (p=0.39). Neither age nor sex was associated to HSIL but HIV positivity increased the risk of HSIL on the anal margin (p=0.01). Conclusion Anal dysplasia is heterogeneously distributed in the anal canal as well as between anal canal and anal margin. The diagnostic of the grade of dysplasia for a person should require multiple biopsies on the canal and anal margin.

We previously have identified the ectopic expression of Rac1b, an activated and novel splice variant of Rac1, in a subset of human colorectal adenocarcinomas, as well as in inflammatory bowel diseases and in colitis mouse model. Rac1b overexpression has been further evidenced in breast, pancreatic, thyroid, ovarian, and lung cancers. In this context, the aim of our study was to investigate the physiopathological implications of Rac1b in intestinal inflammation and carcinogenesis in vivo. The ectopic expression of Rac1b was induced in mouse intestinal epithelial cells after crossing Rosa26-LSL-Rac1b and villin-Cre mice. These animals were let to age or were challenged with dextran sulfate sodium (DSS) to induce experimental colitis, or either received azoxymethane (AOM)/DSS treatment, or were bred with ApcMin/+ or Il10-/- mice to trigger intestinal tumors. Rac1b ectopic expression increased the intestinal epithelial cell proliferation and migration, enhanced the production of reactive oxygen species, and promoted the Paneth cell lineage. Although Rac1b overexpression alone was not sufficient to drive intestinal neoplasia, it enhanced Apc-dependent intestinal tumorigenesis. In the context of Il10 knockout, the Rac1b transgene strengthened colonic inflammation due to induced intestinal mucosa permeability and promoted cecum and proximal colon carcinogenesis. In contrast, Rac1b alleviated carcinogen/acute inflammation-associated colon carcinogenesis (AOM/DSS). This resulted at least partly from the early mucosal repair after resolution of inflammation. Our data highlight the critical role of Rac1b in driving wound-healing after resolution of intestinal inflammation, and in cooperating with Wnt pathway dysregulation and chronic inflammation to promote intestinal carcinogenesis. info:eu-repo/semantics/publishedVersion

ObjectivesEndometrial carcinoma mortality is mainly caused by recurrent disease, and various immunohistochemical markers to predict recurrences have been studied. Loss of the estrogen receptor (ER) and progesterone receptor (PR) and the presence of the L1 cell adhesion molecule (L1CAM) are promising markers, but their combined value has not been studied.Materials and MethodsExpression of ER, PR, and L1CAM was immunohistochemically determined in 293 endometrial carcinomas from 11 collaborating European Network for Individualized Treatment of Endometrial Cancer centers. Estrogen receptor, PR, or L1CAM staining was considered positive or negative when expressed by greater than or equal to 10% or less than 10% of the tumor cells, respectively. The association between these markers and clinicopathological markers, and their combined value in predicting survival were calculated, both in the entire cohort and in a selected groups of stage I endometrioid and low-risk stage I endometrioid carcinomas.ResultsEstrogen receptor and PR were negative in 19% and 28% of the cases, respectively, and L1CAM was positive in 18%. All 3 were associated with advanced stage, high-grade, nonendometrioid histology, lymphovascular space invasion (LVSI), and reduced disease-free survival. Only advanced stage, loss of PR, and LVSI were associated with reduced disease-free survival in multivariate analysis. A prognostic model including these 3 markers was superior to 1 including only the 3 immunohistochemical markers, which was superior to the traditional model. In both the stage I endometrioid and the low-risk stage I endometrioid groups, only loss of PR was associated with reduced disease-free survival.ConclusionsLoss of ER and PR, and the presence of L1CAM are associated with high risk characteristics, and loss of PR is the strongest predictor of recurrent disease. Although a combination of these 3 markers is slightly superior to the traditional histological markers, a prognostic model including stage, PR expression, and LVSI is the most promising model in the identification of high risk carcinomas. In the stage I endometrioid carcinomas, PR immunohistochemistry appears to be of additional value in predicting recurrences.

Reactive oxygen species (ROS) produced by the phagocyte NADPH oxidase (NOX2) are required for microbial clearance; however, when produced in excess they exacerbate inflammatory response and injure surrounding tissues. NOX2 is a multicomponent enzyme composed of membrane-associated cytochrome b588 and cytosolic components p47phox, p67phox, p40phox, and rac1/2. We investigated whether vasoactive intestinal peptide (VIP), an endogenous immune-modulatory peptide, could affect ROS production by NOX2 in primary human phagocytes. VIP did not modulate basal ROS production by phagocytes, but it inhibited monocyte and not neutrophil ROS production in response to the bacterial peptide N-formyl-methionyl-leucyl-phenylalanine (fMLF). The action of VIP was essentially mediated by high-affinity G-protein coupled receptors VPAC1 as its specific agonist, [ALA11,22,28]VIP, mimicked VIP-inhibitory effect, whereas the specific VPAC1 antagonist, PG97-269, blunted VIP action. Further, we showed that VIP inhibited fMLF-induced phosphorylation of ERK1/2 (extracellular signal-regulated kinase 1/2), p38MAPK (p38 mitogen-activated protein kinase) pathways, and phosphorylation of p47phox on Ser345 residue. Also, VIP exerted an anti-inflammatory effect in a model of carrageenan-induced inflammation in rats. We thus found that VIP exerts anti-inflammatory effects by inhibiting the "MAPK-p47phox phosphorylation-NOX2 activation" axis. These data suggest that VIP acts as a natural anti-inflammatory agent of the mucosal system and its analogs could be novel anti-inflammatory molecules.

Aim Anal screening is recommended in HIV-positive patients, especially men who have sex with men (MSM), due to an increased incidence of anal cancer. The optimal screening methods are not generally agreed. Method Screening for anal lesions by anorectal examination, including anoscopy, was offered to HIV-positive outpatients in a tertiary care university hospital regardless of gender or sexual orientation. Results Among the 1206 screened patients (701 MSM, 247 heterosexual men, 258 women), 311 (26%) had histologically proven lesions related to human papilloma virus (HPV) (34% MSM, 14% heterosexual men, 14% women); 123 (10%) had low-grade dysplasia and 70 (6%) high-grade dysplasia. Seven anal cancers were also diagnosed. Determinants of any lesion were age < 45 years [OR = 1.56 (95% CI, 1.16–2.11)], a CD4 count of < 200/mm3 [OR = 2.54 (1.71–3.78)], receptive anal intercourse [OR =3.03 (2.06–4.47)], sub-Saharan African origin [OR = 0.53 (0.33–0.85)], and history of HPV-related lesion [OR = 1.84 (1.35–2.51)]. These determinants were similar for all different grades of dysplasia. In patient subgroup analysis, receptive anal intercourse, the CD4 cell count and a history of HPV lesions were determinants of HPV-positivity in all patients, whereas age was only a determinant in men. Conclusion Anoscopy is an alternative method for anal screening in an HIV-positive population. This screening has to be compared with other tools in populations at high risk of anal cancer.

Background: Cooking may impair meat protein digestibility. When undigested proteins are fermented by the colon microbiota, they can generate compounds that potentially are harmful to the mucosa. Objectives: This study addressed the effects of typical cooking processes and the amount of bovine meat intake on the quantity of undigested proteins entering the colon, as well as their effects on the intestinal mucosa. Methods: Male Wistar rats (n = 88) aged 8 wk were fed 11 different diets containing protein as 20% of energy. In 10 diets, bovine meat proteins represented 5% [low-meat diet (LMD)] or 15% [high-meat diet (HMD)] of energy, with the rest as total milk proteins. Meat was raw or cooked according to 4 processes (boiled, barbecued, grilled, or roasted). A meat-free diet contained only milk proteins. After 3 wk, rats ingested a 15N-labeled meat meal and were killed 6 h later after receiving a 13C-valine injection. Meat protein digestibility was determined from 15N enrichments in intestinal contents. Cecal shortand branched-chain fatty acids and hydrogen sulfide were measured. Intestinal tissues were used for the assessment of protein synthesis rates, inflammation, and histopathology. Results:Meat protein digestibility was lower in rats fed boiled meat (94.5%6 0.281%) than in the other 4 groups (97.5%6 0.0581%, P < 0.001). Cecal and colonic bacterial metabolites, inflammation indicators, and protein synthesis rates were not affected by cooking processes. The meat protein amount had a significant effect on cecal protein synthesis rates (LMD > HMD) and on myeloperoxidase activity in the proximal colon (HMD > LMD), but not on other outcomes. The ingestion of bovine meat, whatever the cooking process and the intake amount, resulted in discrete histologic modifications of the colon (epithelium abrasion, excessive mucus secretion, and inflammation). Conclusions: Boiling bovine meat at a high temperature (100C) for a long time (3 h) moderately lowered protein digestibility compared with raw meat and other cooking processes, but did not affect cecal bacterial metabolites related to protein fermentation. The daily ingestion of raw or cooked bovine meat had no marked effect on intestinal tissues, despite some slight histologic modifications on distal colon.

We recently reported that human melanoma cells, but not benign melanocytes, aberrantly express kallikrein-related peptidase 7 (KLK7). Here, we show a KLK7 overexpression-mediated decrease of cell adhesion to extracellular matrix binding proteins, associated with downregulation of α5/β1/αv/β3 integrin expression. We also report an up-regulation of MCAM/CD146 and an increase in spheroid formation of these cells. Our results demonstrate that aberrant KLK7 expression leads to a switch to a more malignant phenotype suggesting a potential role of KLK7 in melanoma invasion. Thus, KLK7 may represent a biomarker for melanoma progression and may be a potential therapeutic target for melanoma.

Study Objective To compare the accuracies of magnetic resonance imaging (MRI) and rectal endoscopic sonography (RES) in the prediction of the infiltration depth of colorectal endometriosis. Design A retrospective cohort study (Canadian Task Force classification II-2). Setting A university teaching hospital. Patients Forty patients with symptomatic deep infiltrating endometriosis (DIE) of the rectum who underwent colorectal resection were included. Interventions All patients underwent abdominopelvic MRI and RES preoperatively to assess the infiltration depth of colorectal endometriosis, and segmental resection of the rectosigmoid by laparoscopy was performed if RES showed bowel invasion. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive and negative likelihood ratios (LRs), and intermethod agreement were calculated for DIE muscularis and submucosal/mucosal infiltration confirmed by histopathological analysis. Measurements and Main Results For MRI detection of DIE muscularis infiltration, the sensitivity, specificity, PPV, NPV, and negative LR were 68%, 100%, 100%, 20%, and 0.32, respectively. For the MRI detection of DIE submucosal/mucosal involvement, the sensitivity, specificity, PPV, NPV, and positive and negative LRs were 47%, 81%, 69%, 63%, 2.49, and 0.65, respectively. The PPV of RES detection of DIE muscularis infiltration was 93%. For the RES detection of DIE submucosal/mucosal layers, the sensitivity, specificity, PPV, NPV, and positive and negative LRs were 79%, 48%, 58%, 71%, 1.51, and 0.44, respectively. Conclusion In the current study, MRI is valuable for detecting endometriosis of the rectum but is less accurate in detecting submucosal/mucosal involvement than RES. Magnetic resonance imaging was not successful for preoperative determination of segmental resection versus a more conservative approach. When bowel involvement is detected by MRI, RES is not essential. When symptoms suggest DIE in patients without intestinal lesions detected by MRI, RES is necessary to exclude bowel invasion.

Emerging evidence indicates that serine proteases of the tissue kallikrein-related peptidases family (KLK) are implicated in tumorigenesis. We recently reported the ectopic expression of KLK4 and KLK14 in colonic cancers and their signaling to control cell proliferation. Human tissue kallikrein-related peptidase 7 (KLK7) is often dysregulated in many cancers; however, its role in colon tumorigenesis has not yet been established. In the present study, we analyzed expression of KLK7 in 15 colon cancer cell lines and in 38 human colonic tumors. In many human colon cancer cells, KLK7 mRNA was observed, which leads to KLK7 protein expression and secretion. Furthermore, KLK7 was detected in human colon adenocarcinomas, but it was absent in normal epithelia. KLK7 overexpression in HT29 colon cancer cells upon stable transfection with a KLK7 expression plasmid resulted in increased cell proliferation. Moreover, subcutaneous inoculation of transfected cells into nude mice led to increased tumor growth that was associated with increased tumor cell proliferation as reflected by a positive Ki-67 staining. Our results demonstrate the aberrant expression of KLK7 in colon cancer cells and tissues and its involvement in cell proliferation in vitro and in vivo. Thus, KLK7 may represent a potential therapeutic target for human colon tumorigenesis.

Objectives To evaluate the diagnostic accuracy of rectal endoscopic sonography (RES) in the prediction of the infiltration depth of rectal endometriosis and to ascertain whether RES could be used to choose between segmental bowel resection and a more conservative approach, such as shaving or discoid resection. Methods In this retrospective study, 38 consecutive patients with symptomatic deep infiltrating endometriosis of the rectum who underwent laparoscopic colorectal resection were included. RES results for infiltration depth of rectal endometriosis were compared with results of pathological examination. The sensitivity, specificity, positive and negative predictive values (PPV and NPV, respectively), positive and negative likelihood ratios (LRs) and test accuracy were calculated for the presence of infiltration of the muscularis layers and submucosal/mucosal layers, as demonstrated by RES and confirmed by histopathological analysis. Results For the detection of muscularis layer infiltration by endometriosis, the PPV of RES was 100%, whereas for the detection of submucosal/mucosal layer involvement, the sensitivity was 89%, specificity was 26%, PPV was 55%, NPV was 71%, test accuracy was 58% and positive and negative LRs were 1.21 and 0.40, respectively. Conclusions RES is a valuable tool for detecting rectal endometriosis as endometriotic infiltration of the muscularis layer can be predicted accurately. However, RES is less accurate in detecting submucosal/mucosal layer involvement and cannot, therefore, be used to choose between bowel resection and a more conservative approach. Copyright © 2013 ISUOG. Published by John Wiley & Sons Ltd

Optimal identification of endometrial carcinoma (EC) patients at high risk of recurrence is currently lacking. Hypoxia is an important feature of aggressive EC leading to activation of hypoxic and angiogenetic target genes. The present study investigates the prognostic role of hypoxia and angiogenesis in EC. Data and tissues were used from 11 collaborating European Network for Individualized Treatment of Endometrial Cancer (ENITEC) centers. Tumor slides were stained for CAIX as a hypoxic marker and CD-34 for assessment of microvessel density (MVD) as a marker for angiogenesis. Complete slides were digitalized and analyzed using ImageJ software after exclusion of areas without tumor. A cutoff of 1% for the fraction of CAIX positive tumor cells was used. The MVD was assessed according to the Weidner method with the median as cutoff. Correlations with disease-specific survival (DSS), disease-free survival (DFS) and distant disease-free survival (DDFS) were calculated using Cox regression analysis. Sixty-three (16.4%) of 385 ECs showed positive CAIX-expression with high vascular density. Multivariable analysis showed that ECs with combined positive CAIX-expression and high vascular density had a reduced DSS (hazard ratio [HR] 3.71, p = 0.002) and DDFS (HR 2.68, p = 0.009) and a trend for reduced DFS (HR 1.87, p = 0.054). Multivariable analyses with CAIX-expression and vascular density as separate markers, showed that both were independent prognostic markers as well. This study found an impaired DSS and DDFS in ECs with positive CAIX-expression and high vascular density. Differential adjuvant treatment might be indicated for these ECs. Citation Format: Casper Reijnen, Willem Jan van Weelden, Martijn SJP Arts, Johan P. Peters, Paul F. Rijken, Koen van de Vijver, Maria Santacana, Peter Bronsert, Johan Bulten, Marc Hirschfeld, Eva Colas, Antonio Gil-Moreno, Amando Reques, Gemma Mancebo, Fransesc Alameda, Camilla Krakstad, Jone Trovik, Ingfrid S. Haldorsen, Jutta Huvila, Stefanie Schrouwen, Martin Koskas, Francine Walker, Vit Weinberger, Lubos Minar, Eva Jandakova, Marc PLM Snijders, Saskia van den Berg-van Erp, Heidi VN Küsters-Vandevelde, Xavier Matias-Guiu, Frederic Amant, ENITEC-consortium, Leon FAG Massuger, Johan Bussink, Johanna MA Pijnenborg. Poor outcome in hypoxic endometrial carcinoma is related to vascular density [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4879.

Nanotechnology offers many possibilities to improve drug treatments, including with regard to drug pharmacology. The current study reports a simple approach to improve cisplatin efficacy in the treatment of colon cancer through the creation of orally administered squalenoylated nanoparticles loaded with cisplatin (SQ-CDDP NP). Cytotoxic effects of SQ-CDDP NP were assessed in human colonic cells and in mouse models of intestinal cancer. In cell culture, SQ-CDDP NP exhibited at least 10-fold greater cytotoxic potency compared with uncomplexed cisplatin, reflecting an enhancement in intracellular accumulation and DNA platination. Mechanistic investigations showed that SQ-CDDP NP stimulated ROS production, expression of heavy metal–inducible and stress-inducible genes, stress kinase cascades, and apoptosis. In ApcMin/+ mice, a model of intestinal tumorigenesis, oral administration of SQ-CDDP NP curtailed spontaneous tumor formation and azoxymethane-induced colon carcinogenesis with no apparent evidence of tissue toxicity. Our results offer preclinical validation of a nanocarrier formulation that can safely improve chemotherapeutic efficacy, address risks of drug resistance, and improve patient compliance by enabling oral administration. Cancer Res; 77(11); 2964–75. ©2017 AACR.

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide and has significant morbidity and mortality as 20–40% of patients progress to end-stage renal disease (ESRD) within 20 years after disease onset. We aimed to gain insight into the molecular mechanisms involved in IgAN progression. A systematic evaluation of renal biopsy specimens from IgAN patients revealed that the MAPK/ERK signaling pathway was activated in mesangial areas of patients presenting with >1 g/day proteinuria and elevated blood pressure, but was absent in biopsy specimens from IgAN patients with modest proteinuria (

In endometrial carcinoma (EC) and atypical hyperplasia (AH) diagnosed in childbearing years, the principle of uterine sparing consists in prescription of antigonadotropic treatment to obtain the remission of the endometrial lesion and allow pregnancy, always with a close follow-up looking for progression or persistence of the tumour. Studies evaluating this strategy have suggested the safety of such an approach, but numerous questions remain unanswered, like those concerning the type and the duration of treatment, and the systematic use of Assisted Reproductive Technologies… We performed a critical literature review in order to analyse patients and tumoral characteristics, treatment management and the results of fertility sparing strategy. This review shows that fertility sparing management of AH and intramucous EC permits to obtain pregnancy in one third of candidates. Few disease-related deaths have been reported after this management. One-third of patients experienced progression lesion beyond the endometrium, but generally limited to the myometrium. Progestins have been widely evaluated in this indication and provide an overall remission rate of 80% with a recurrence risk of 25%.

Study Objective This study was undertaken to ascertain whether the incidence of spontaneous pregnancy is increased in infertile women with deep and intraperitoneal endometriosis undergoing extensive surgery compared with those undergoing only intraperitoneal surgery. Design Retrospective case control study (Canadian Task Force classification II-1). Setting University teaching hospital. Patients Infertile women under the age of 40 years with deep and intraperitoneal endometriosis and no other associated major infertility factors. Only patients with at least 1 year of postoperative follow-up were included. Interventions Intraperitoneal surgery only (group 1) or extensive surgery (group 2) according to a shared decision-making approach. Measurements and Main Results Among the 34 women in group 1, 6 became pregnant, compared with 8 of the 41 women who had extensive surgery (12-month cumulative probabilities, 24.8% and 11.4%, respectively, and 24-month cumulative probabilities, 24.8% and 23.2%, respectively; p = .82). Perioperative surgical complication rate was higher in group 2 (6/41 versus 0/34; p = .02). Conclusion Extensive surgery for intraperitoneal and deep endometriosis in infertile women does not modify global fertility outcome but is associated with a higher complication rate.

Among the numerous renal diseases observed in human immunodeficiency virus (HIV) patients, HIV-associated nephropathy (HIVAN) is a major cause of end-stage renal disease (ESRD). The purpose of our study was to describe the presentation and outcome of HIVAN in the era of highly active antiretroviral therapy (HAART).We analysed clinical features and outcome of 57 patients with histologically proven HIVAN diagnosed between 2000 and 2009 in four teaching hospitals in Paris, France.This series was characterized by median age of 41 years (18-58), frequent African origin (87%), severe renal dysfunction [estimated glomerular filtration rate (eGFR) 20 mL/min/1.73m(2) (1-68)], high-grade proteinuria [4.1 g/day (0.6-16.8)], high proportion of sclerotic glomeruli [31.5% (0-95)], high HIV load [4.5 log copies/mL (0-6.7)] and low CD4+ count [127/mm(3) (3-713)]. Nevertheless, a non-negligible proportion of patients did not present with these typical features. Follow-up data were available for 51 patients. ESRD occurred in 30 patients (58.8%). Median renal survival was 40 months. Baseline characteristics significantly associated with ESRD were as follows: severity of renal dysfunction, percentage of sclerotic glomeruli, time from HIV infection to HIVAN diagnosis longer than 1 year and prior exposure to antiretroviral drugs. There was an insignificant trend towards better renal outcome being associated with viral suppression during follow-up. Use of renin-angiotensin system (RAS) blockers was associated with higher renal survival (P0.05).Despite HAART, HIVAN led to ESRD in more than half of the cases. Early recognition of the disease is crucial to start HAART and RAS blockers before irreversible renal injury.

Resistance to apoptosis is a recurrent theme in colon cancer. We have shown previously that the 7-transmembrane spanning receptor OX1R for orexins promotes robust apoptosis in the human colon cancer cell line HT29 through an entirely novel mechanism involving phosphorylation of tyrosine-based motifs in OX1R. Here, we investigated the status of OX1R in a large series of human colorectal tumors and hepatic metastases. All primary colorectal tumors regardless of their localization and Duke's stages and all hepatic metastases tested expressed OX1R mRNA and/or protein. In sharp contrast, adjacent normal colonocytes or hepatocytes as well as control normal tissues were negative. Next, we showed that nine human colon cancer cell lines established from primary tumors or metastases expressed OX1R mRNA and underwent important apoptosis on orexin-A challenge. Most interestingly, orexin-A also promoted robust apoptosis in cells that are resistant to the most commonly used drug in colon cancer chemotherapy, 5-fluorouracil. When human colon cancer cells were xenografted in nude mice, orexin-A administered at day 0 strongly slowed the tumor growth and even reversed the development of established tumors when administered 7 days after cell inoculation. Orexin-A also acts by promoting tumor apoptosis in vivo because caspase-3 is activated in tumors on orexin treatment of nude mice. These findings support that OX1R is an Achilles heel of colon cancers, even after metastasis or chemoresistance. They suggest that OX1R agonists might be novel candidates for colon cancer therapy. Cancer Res; 71(9); 3341–51. ©2011 AACR.

Nasal inverted papilloma is a rare benign tumor of epithelial origin with aggressive evolution, bone destruction, recurrence, and malignant transformation. Msx2 is a homeobox gene implicated in organ development, bone metabolism, and tumorigenesis. Using reverse transcriptase-polymerase chain reaction and immunohistochemistry, Msx2 expression was examined in nasal inverted papilloma and in nontumorigenic tissue counterparts. For the first time, Msx2 was detected in all inverted papillomas but not in the nasal polyps or in the normal mucosa. The protein expression level was directly and significantly associated with tumor recurrence. Furthermore, Msx2 was associated with bone resorption markers receptor activator of nuclear factor-kappa B ligand and tartrate-resistant acid phosphatase, suggesting a role in osteolysis. In conclusion, Msx2 expression may represent a useful prognostic marker in inverted papilloma.

Background: Several models (preoperative and postoperative) have been developed to predict lymph node metastasis (LNM) in patients with endometrial cancer. The purpose of our investigation was to compare available models in a multicentre study. Methods: In a cohort of 519 patients with endometrial cancer who had undergone primary hysterectomy and at least a pelvic lymphadenectomy, we compared the areas under the receiver-operating characteristic curves (AUCs), calibrations, rates of false negatives (FN), and the number of patients at low-risk for LNM using ten different models (three preoperative and seven postoperative). Results: In all, 17.5% of patients among the study population (91 in 519) had LNM. Only one of the three preoperative models and three of the seven postoperative models had an AUC > 0.75. Six models were well calibrated. Eight models yielded an FN rate of 0.75, to yield an FN rate of

Contains fulltext : 165692.pdf (Publisher’s version ) (Open Access) BACKGROUND: Identification of aggressive endometrioid endometrial carcinomas (EECs) and non-endometrioid carcinomas (NEECs) is essential to improve outcome. L1 cell adhesion molecule (L1CAM) expression is a strong prognostic marker in stage I EECs, but less is known about L1CAM expression in advanced-stage EECs and NEECs. This study analyses L1CAM expression in a clinically representative cohort of endometrial carcinomas. METHODS: The expression of L1CAM was immunohistochemically determined in 1199 endometrial carcinomas, treated at one of the European Network for Individualized Treatment of Endometrial Cancer (ENITEC) centres. Staining was considered positive when >10% of the tumour cells expressed L1CAM. The association between L1CAM expression and several clincopathological characteristics and disease outcome was calculated. RESULTS: In all, L1CAM was expressed in 10% of the 935 stage I EECs, 18% of the 160 advanced stage EECs, and 75% of the 104 NEECs. The expression of L1CAM was associated with advanced stage, nodal involvement, high tumour grade, non-endometrioid histology, lymphovascular space invasion, and distant recurrences in all cases, and with reduced survival in the EECs, but not in the NEECs. CONCLUSIONS: The expression of L1CAM is a strong predictor of poor outcome in EECs, but not NEECs. It is strongly associated with non-endometrioid histology and distant spread, and could improve the postoperative selection of high-risk endometrial carcinomas. The value of L1CAM expression in the preoperative selection of high-risk endometrial carcinomas should be studied.

The effect of colitis induced with dextran sodium sulfate (DSS) in rats on the bioavailability of drugs transported by the oligopeptide transporter PepT-1 was analyzed by studying the pharmacokinetics of PepT-1 substrates: cephalexin and valacyclovir, the prodrug of antiviral acyclovir. Western blot, immunohistochemistry, and real-time PCR were used to determine the PepT-1 protein and gene expression. We observed (1) no significant modification of PepT-1 expression in the duodenum and jejunum; (2) a slight decrease in both PepT-1 mRNA (50%) and protein expression (25%) in the ileum following DSS challenge; and (3) ectopic PepT-1 immunostaining in regenerative hyperplasia segments in the distal colon from DSS-treated rats where focal inflammation is localized. However, no modification of pharmacokinetic parameters (C (max), T (max), AUC) of cephalexin or acyclovir was detected. In conclusion, DSS-induced rat colitis did not alter PepT-1 substrate bioavailability despite certain modifications in PepT-1 expression profile.

The specificity of an immunohistochemical reaction is guaranteed by two sets of controls. Positive controls verify the specificity of the primary antibody and demonstrate that it binds only to the protein which was used as an immunogen. Negative controls ensure that the labelling technique is specific and that the primary antibody is responsible for generation of the immunostaining. In fact, the production of a labelling may also be related to cross reactivity or to non-specific physical or chemical interactions. This paper reviews the characteristics of various epitopes and antibodies, describes different strategies which prove the specificity of the immunohistochemical reaction in research or diagnostic pathology and point towards the essential information which should be reported in a paper.

To compare the risk of developing endometrial carcinoma (EC) in young women with atypical endometrial hyperplasia (AEH) undergoing fertility-sparing management compared to women treated by primary hysterectomy.In this multicentric retrospective study, 111 patients with a diagnosis of AEH by endometrial biopsy were included. EC incidence was compared in two groups: 32 patients treated with fertility-sparing management and 79 older patients treated with primary hysterectomy.The rates of EC diagnosed by pathology of hysterectomy specimens were comparable between the groups. The probability of developing EC at 12, 24 and 36 months were 14%, 21% and 26%, respectively, in patients managed conservatively, and 29%, 37% and 37%, respectively, in patients treated with primary hysterectomy.Fertility-sparing management of AEH does not increase the risk of diagnosing EC from the hysterectomy specimen.

An outbreak of rectal lymphogranuloma venereum (LGV) has been reported since 2003 in men who have sex with men, most of them being infected with human immunodeficiency virus. In these patients, unusual clinical presentations such as rectal tumor or intense lymphoproliferation on rectal biopsies may lead to an erroneous diagnosis of aggressive non-Hodgkin lymphoma. Three patients were referred to our center for the management of rectal B-cell non-Hodgkin lymphoma on the basis of a rectal pathologic specimen showing intense lymphoproliferation, the very suspect of lymphoma. Because of anamnesis of anal intercourses and venereal diseases, additional study revealed that all 3 had a positive Chlamydia trachomatis polymerase chain reaction on the rectal biopsy specimen. Rectal LGV was therefore considered and successfully treated with antibiotics. We propose that all patients presenting with a suspected rectal lymphoma should have a careful anamnesis of sexual behavior and a specific detection of C. trachomatis using polymerase chain reaction analysis on biopsy specimen to rule out the possibility of rectal LGV.

Background and Objectives To compare uterine leiomyosarcomas (LMS) and leiomyomas (LM) with normal myometrium in terms of microvessel density (MVD), and to correlate this parameter with vascular endothelial growth factor (VEGF) expression and clinical/pathological parameters. Methods An immunohistochemical technique, using antibodies against von Willebrand factor (FvW), CD34, CD31, and VEGF, was applied to formalin-fixed paraffin-embedded samples of 32 normal myometria, 32 uterine LM, and 12 LMS. MVD was calculated by a digital image analyzer. Results Using anti-FvW, mean ± SD MVD in myometrium, LM, and LMS was 107.0 ± 53.6, 66.2 ± 55.4, and 64.4 ± 44.2, respectively (P = 0.001). MVD was lower in LMS (P = 0.021) and in LM (P = 0.0004) than in normal myometrium. Using anti-CD34, mean ± SD MVD in myometrium, LM, and LMS was 187.6 ± 91.2, 106.1 ± 55.5, and 114.2 ± 98.8, respectively (P = 0.001). MVD was lower in LMS (P = 0.012) and LM (P = 0.0004) than in normal myometrium. No such differences were found using anti-CD31 and anti-VEGF. No correlation was found between MVD and VEGF expression. In women with uterine LMS, low MVD (assessed with anti-FvW) correlated with recurrence (P = 0.04) and poor overall survival (P = 0.03). Conclusions Uterine smooth muscle tumors exhibit a lower MVD than normal myometrium, as assessed using anti-FvW or anti-CD34 antibodies. A reduced MVD, as assessed by FvW staining, has prognostic value in uterine LMS. J. Surg. Oncol. 2004;86:84–90. © 2004 Wiley-Liss, Inc.

Resume Les lesions de splenose sont des auto-transplants de tissu splenique le plus souvent decrits dans les suites de traumatismes abdominaux. Rares en sont les localisations pelviennes. Nous rapportons le cas d’une patiente de 36 ans, suivie pour une infertilite secondaire, dont le bilan echographique a revele des images nodulaires para-cervicales vascularisees. Les antecedents de splenectomie ont fait evoquer le diagnostic de tissu splenique ectopique. La localisation de la lesion, l’evaluation du risque lie a la ponction ovarienne pour fecondation in vitro (FIV) et l’impossibilite d’evaluation du risque hemorragique a l’accouchement nous ont fait decider de l’exerese des lesions. La conduite a tenir generalement recommandee est conservatrice en raison d’une possible fonction immunologique residuelle.

We have previously shown that high-protein (HP) diet ingestion causes marked changes in the luminal environment of the colonic epithelium. This study aimed to evaluate the impact of such modifications on small intestinal and colonic mucosa, two segments with different transit time and physiological functions. Rats were fed with either normal protein (NP; 14% protein) or HP (53% protein) isocaloric diet for 2 weeks, and parameters related to intestinal mucous-secreting cells and to several innate/adaptive immune characteristics (myeloperoxidase activity, cytokine and epithelial TLR expression, proportion of immune cells in gut-associated lymphoid tissues) were measured in the ileum and colon. In ileum from HP animals, we observed hyperplasia of mucus-producing cells concomitant with an increased expression of Muc2 at both gene and protein levels, reduction of mucosal myeloperoxidase activity, down-regulation of TIr4 gene expression in enterocytes and down-regulation of mucosal Th cytokines associated with CD4+ lymphocyte reduction in mesenteric lymph nodes. These changes coincided with an increased amount of acetate in the ileal luminal content. In colon, HP diet ingestion resulted in a lower number of goblet cells at the epithelial surface but increased goblet cell number in colonic crypts together with an increased Muc3 and a slight reduction of 11-6 gene expression. Our data suggest that HP diet modifies the goblet cell distribution in colon and, in ileum, increases goblet cell activity and decreases parameters related to basal gut inflammatory status. The impact of HP diet on intestinal mucosa in terms of beneficial or deleterious effects is discussed.

Acta Obstet Gynecol Scand 2002; 81: 195-203. © Acta Obstet Gynecol Scand 2002 Background. To evaluate (a) cadherins and CD44 expression in normal endometrium and in peritoneal endometriosis, and (b) to correlate, their expressions with clinicopathological parameters. Methods. E- and N-cadherin, CD44 isoforms, CD44v3 and CD44v6 expressions were evaluated: (a) by immunoblotting in endometrium ( n = 6) and in peritoneal endometriotic samples ( n = 7) and, (b) by immunohistochemistry in endometrium ( n = 15) and in peritoneal endometriotic samples ( n = 23). Results. By immunoblotting, endometrium expressed E- and N-cadherin, CD44 isoforms, CD44v3 and CD44v6. Similar results were observed in peritoneal endometriosis. By immunohistochemistry, in endometrium, E-cadherin was restricted to epithelial cells. Its expression remained constant throughout the menstrual cycle. N-cadherin was detected in both epithelial and stromal cells in the proliferative phase but was restricted to epithelial cells in the secretory ...

Anti-N-methyl-D-aspartate receptor encephalitis is an emerging disease that affects young women. Its diagnosis can be delayed because of the neuropsychiatric symptoms in the foreground, but early removal of the associated teratoma improves the prognosis. We report the treatment of a patient with anti-N-methyl-D-aspartate receptor encephalitis that was related to an ovarian teratoma.

Introduction et but de l’etude Dans un contexte d’augmentation de l’incidence du surpoids et de l’obesite, les regimes hyperproteiques (HP) a finalite amaigrissante sont couramment utilises bien que les consequences d’une telle consommation sur la physiologie intestinale aient ete peu etudiees. Nous avons precedemment montre que l’ingestion d’un regime HP entraine des modifications de l’environnement luminal de l’epithelium colique, qui sont susceptibles de perturber l’homeostasie intestinale. Partant de ce constat, notre etude avait pour but d’evaluer les effets de tels changements suite a la consommation d’un regime HP au niveau des muqueuses ileale et colique, deux segments intestinaux qui presentent des temps de transit et des fonctions physiologiques differentes. Materiel et methodes Des rats ont ete nourris avec un regime HP (53 % de proteines) ou un regime normoproteique (NP, 14 % de proteines) isocalorique pendant deux semaines. Des parametres associes a la fonction barriere (nombre et taille des cellules mucosecretantes ; expression de mucines, de peptides anti-microbiens et de proteines de jonctions serrees) et aux reponses immunitaires innees et adaptatives (activite myeloperoxydase, production d’IgA secretoires, expression de cytokines et « Toll-Like Receptors », proportions des populations lymphocytaires dans les tissus lymphoides associes a l’intestin) ont ete mesures dans l’ileon et le colon. Resultats et Analyse statistique Au niveau de l’ileon, les animaux ayant recu un regime HP presentent une hyperplasie des cellules muco-secretantes (18,5 ± 1,9 % vs 13,6 ± 0,9 % de la surface totale de la muqueuse ileale, p =0,037) associee a une augmentation de l’expression de la mucine MUC2 (p Tlr4 dans les enterocytes (p =0,043) et une reduction de moitie de l’activite myeloperoxydase (2,68 ± 0,31 vs 4,85 ± 0,82 UA MPO/mg proteines, p =0,038) et de l’expression transcriptionnelle des cytokines pro-inflammatoires IL1- β et Tnf α (p (IFNγ, Il-4, Il-10, Il-17f , 3 a 5 moins exprimees, p Tgf β (p vs 5,65 ± 0,54 μmol/contenu intestinal total, p =0,031). Au niveau colique on observe chez les animaux HP une diminution significative du nombre de cellules muco-secretantes de l’epithelium de surface (8,7 ± 0,6 % vs 20,7 ± 4,4 % des cellules de l’epithelium de plateau, p =0,026) et une augmentation de leur nombre dans les cryptes coliques (155,3 ± 4,8 vs 135,3 ± 5,9 cellules muco-secretantes/mm de crypte, p =0,018) associee a une surexpression du gene Muc3 (p =0,033) et une diminution modeste de l’expression d’ Il-6 (p =0,050). Conclusion Ces resultats indiquent que l’ingestion du regime HP modifie differemment les caracteristiques des cellules muco-secretantes dans l’ileon et le colon. Au niveau de l’ileon, une diminution de parametres associes au statut inflammatoire basal est observee apres consommation du regime HP. Cet effet pourrait etre associe a la modification de l’activite des cellules muco-secretantes susceptible de reduire la stimulation par des facteurs luminaux. Les consequences de l’ingestion d’un regime HP, en termes d’effets benefiques ou deleteres, sur la muqueuse intestinale seront discutees.

Molecular and genetic investigations in endometrial carcinogenesis may have prognostic and therapeutic implications. We studied the expression of EGFR, c-Met, PTEN and the mTOR signalling pathway (phospho-AKT/phospho-mTOR/phospho-RPS6) in 69 consecutive tumours and 16 tissue microarrays. We also analysed PIK3CA, K-Ras mutations and microsatellite instability (MSI). We distinguished two groups: group 1 (grade 1 and 2 endometrioid cancers) and group 2 (grade 3 endometrioid and type II clear and serous cell cancers). We hypothesised that these histological groups might have different features. We found that a) survival was higher in group 1 with less aggressive tumours (P⟨0.03); b) EGFR (P=0.01), PTEN and the AKT/mTOR/RPS6 signalling pathway were increased in group 1 versus group 2 (P=0.05 for phospho-mTOR); c) conversely, c-Met was higher (P⟨0.03) in group 2 than in group 1; d) In group 1, EGFR was correlated with c-Met, phospho-mTOR, phospho-RPS6 and the global activity of the phospho-AKT/phospho-mTOR/phospho-RPS6 pathway. In group 2, EGFR was correlated only with the phospho-AKT/phospho-mTOR/phospho-RPS6 pathway, whereas c-Met was correlated with PTEN; e) survival was higher for tumours with more than 50% PTEN-positive cells; f) K-RAS and PIK3CA mutations occurred in 10-12% of the available tumours and MSI in 40.4%, with a loss of MLH1 and PMS2 expression. Our results for endometrial cancers provide the first evidence for a difference in status between groups 1 and 2. The patients may benefit from different targeted treatments, anti-EGFR agents and rapamycin derivatives (anti-mTOR) for group 1 and an anti c-MET/ligand complex for group 2.

Alterations of CD44 proteins, a family of cell adhesion molecule, have been linked with tumorigenesis, carcinogenesis, and prognosis in various neoplasms. Our aims were to evaluate and compare CD44 isoforms expression patterns in normal myometrium, uterine leiomyomas, and leiomyosarcomas and to correlate CD44 expression with clinicopathologic parameters. Fresh (n = 15) and formalin-fixed, paraffin-embedded (n = 76) tissues samples of myometrium, leiomyomas, and leiomyosarcomas were used for immunoblotting and immunohistochemistry, respectively. Semiquantitative evaluation was made after immunostaining. Monoclonal antibodies were used. By immunoblotting in myometrium and leiomyomas samples, we observed a band at 85 kd, corresponding to the apparent molecular weight of CD44s, and bands at 140 kd with the monoclonal antibodies against CD44v3 and CD44v6. In leiomyosarcomas, CD44s and CD44v6 were detected, but not CD44v3. By immunohistochemistry, decreased CD44s expression was found in leiomyomas and leiomyosarcomas (73.9% +/- 16.6% and 82.1% +/- 20.7%, respectively) compared with myometrium (97.3% +/- 6.2%; P.0001). No CD44v6 staining was detected in myometrium, leiomyomas, and leiomyosarcomas. No CD44v3 expression was detected in leiomyosarcomas, whereas myometrium and leiomyomas expressed CD44v3. For the diagnosis of leiomyosarcoma, the absence of CD44v3 staining had a sensitivity, specificity, and positive and negative predictive values of 100%. In patients with recurrence of leiomyosarcomas, CD44s expression was decreased (P = .03). We conclude that CD44s immunostaining in leiomyosarcomas may have prognostic significance. The loss of CD44v3 expression could be used as a putative diagnostic tool for uterine leiomyosarcomas.

Leptin, the product of the ob gene, plays a key role in the regulation of food intake via a cross-talk between hypothalamic leptin receptors and neuropeptides that affect feeding behaviour. Recent studies have shown a synergistic interaction between leptin and cholecystokinin (CCK) leading to suppression of food intake, which involves CCK-1 receptors and capsaicin-sensitive vagal fibres. In this study, we have investigated the presence of leptin receptors in afferent and efferent neurons of the vagus nerve. By using reverse transcription-polymerase chain reaction, mRNAs encoding long (Ob-Rb) and short (Ob-Ra) leptin receptor isoforms were detected in the rat nodose ganglion, which contains the cell bodies of the vagal afferent neurons. Western blot analysis confirmed the presence of leptin receptor-immunoreactive proteins in extracts from the vagal trunk. Immunohistochemistry showed the presence of leptin receptors and the leptin-induced transcription factor STAT3 in the cytoplasm of nodose ganglion cells. In cervical vagal segments, levels of leptin receptor protein displayed physiological regulation, with decreased amounts after feeding and increased levels after food restriction. In addition, leptin receptor and STAT3 immunoreactivities were detected in neurons of the nucleus of tractus solitarius (NTS) and the dorsal motor nucleus of the vagus nerve (DMNX) by immunofluorescence histochemistry. Furthermore, direct double-labelling demonstrated colocalization of Ob-Rb and STAT3 immunoreactivities in cholinergic vagal efferent cell bodies of the DMNX. It is speculated that vagal leptin receptors, apart from being activated by adipocyte-derived leptin, may also be influenced by leptin produced by the stomach. This may explain the synergistic action of leptin and CCK on neuronal activity in the NTS and on food intake.

The incidence of anal cancer is higher in patients with anal canal condyloma, a sexually transmitted disease, than in the general population. We determined the prevalence of anal dysplasia and cancer in patients with anal canal condyloma with respect to human immunodeficiency virus (HIV) status, immunity status, and human papillomavirus types.In 174 consecutive patients (114 HIV positive, 60 HIV negative) with anal canal condyloma, lesions were cured, and the patients were then followed up prospectively. Langerhans cells (LCs) in normal anal mucosa were quantified, and viruses (Epstein-Barr virus, cytomegalovirus, human simplex virus 1, and various human papillomavirus [HPV] types) were characterized on inclusion. During follow-up (median 26 months), relapsed condylomas were resected and examined histologically. HIV load and CD4 T-lymphocyte counts in serum were determined at each visit.Several factors differed significantly between HIV-positive and HIV-negative patients: LCs/mm anal tissue (15 vs. 30), oncogenic HPV (27% vs. 13%), other current anal infections (44% vs. 0%), and sex ratio (93% vs. 73% male). During follow-up, condylomas relapsed in 75% of the HIV-positive patients, with 19 high-grade dysplasias (HGDs) and 1 invasive carcinoma, but in only 6% of HIV-negative patients, with 1 HGD. Male sex, HIV positivity, and15 LCs/mm tissue were independent risk factors for condyloma relapse. HIV positivity, HGD before inclusion, and condyloma relapse were independent risk factors for HGD and cancer. Serum HIV load was associated with relapse, whereas CD4 T-lymphocyte counts were not.The prevalence of HGD and carcinoma is higher in HIV-positive than in HIV-negative patients, probably because of HPV activity. HIV-positive patients with high serum HIV load and/or a history of anal dysplasia should be examined by anoscopy, and condylomas should be analyzed histologically.