Incidence of Recurrent High-Grade Anal Dysplasia in HIV-1-Infected Men and Women Following Infrared Coagulation Ablation: A Retrospective Cohort Study.

This single-center, retrospective cohort study sought to estimate the cumulative incidence in HIV-1-infected patients of biopsy-proven high-grade anal intraepithelial neoplasia (HGAIN) recurrence after infrared coagulation (IRC) treatment. The study was based on data from a prospectively compiled database of 665 HIV-1-infected outpatients who attended a hospital Clinical Proctology/HIV Unit between January 2012 and December 2015. Patient records were checked to see which ones had received IRC treatment but later experienced a recurrence of HGAIN. Cytology samples were also checked for the presence of human papilloma virus (HPV). A total of 81 of the 665 patients (12%, 95%CI: 10-15%), of whom 65 were men and 16 women, were diagnosed with HGAIN and again treated with IRC. Of these 81, 20 (25%) experienced recurrent HGAIN, this incidence being true of both men (16/65, 95%CI: 19-57%) and women (4/16, 95%CI: 10-50%). The median time to recurrence was 6 (2-19) months overall, 6 (2-19) months in men, and 4 (2-6) months in women. HPV infection was detected in all patients except two, with HPV-16 being the most common genotype. This rate of incidence of recurrent HGAIN following IRC treatment is consistent with other reports and highlights the importance of continued post-treatment surveillance, particularly in the first year.

Resident memory T cells are a cellular reservoir for HIV in the cervical mucosa.

HIV viral reservoirs are established very early during infection. Resident memory T cells (TRM) are present in tissues such as the lower female genital tract, but the contribution of this subset of cells to the pathogenesis and persistence of HIV remains unclear. Here, we show that cervical CD4+TRM display a unique repertoire of clusters of differentiation, with enrichment of several molecules associated with HIV infection susceptibility, longevity and self-renewing capacities. These protein profiles are enriched in a fraction of CD4+TRM expressing CD32. Cervical explant models show that CD4+TRM preferentially support HIV infection and harbor more viral DNA and protein than non-TRM. Importantly, cervical tissue from ART-suppressed HIV+ women contain high levels of viral DNA and RNA, being the TRM fraction the principal contributor. These results recognize the lower female genital tract as an HIV sanctuary and identify CD4+TRM as primary targets of HIV infection and viral persistence. Thus, strategies towards an HIV cure will need to consider TRM phenotypes, which are widely distributed in tissues.

Dendritic Cells From the Cervical Mucosa Capture and Transfer HIV-1 via Siglec-1.

Antigen presenting cells from the cervical mucosa are thought to amplify incoming HIV-1 and spread infection systemically without being productively infected. Yet, the molecular mechanism at the cervical mucosa underlying this viral transmission pathway remains unknown. Here we identified a subset of HLA-DR+ CD14+ CD11c+ cervical DCs at the lamina propria of the ectocervix and the endocervix that expressed the type-I interferon inducible lectin Siglec-1 (CD169), which promoted viral uptake. In the cervical biopsy of a viremic HIV-1+ patient, Siglec-1+ cells harbored HIV-1-containing compartments, demonstrating that in vivo, these cells trap viruses. Ex vivo, a type-I interferon antiviral environment enhanced viral capture and trans-infection via Siglec-1. Nonetheless, HIV-1 transfer via cervical DCs was effectively prevented with antibodies against Siglec-1. Our findings contribute to decipher how cervical DCs may boost HIV-1 replication and promote systemic viral spread from the cervical mucosa, and highlight the importance of including inhibitors against Siglec-1 in microbicidal strategies.

Incidence of cervical high-grade squamous intraepithelial lesions in HIV-1-infected women with no history of cervical pathology: up to 17 years of follow-up.

Currently, Papanicolaou smears are proposed at three-year intervals for cervical screening to all women living with HIV. The aim of this retrospective cohort study was to provide data on the incidence of cervical high-grade squamous intraepithelial lesions (HSIL) in cervical smear confirmed by histology in HIV-1-infected women (two consecutive normal Papanicolaou smears at baseline) after a long-term follow-up. Sixty-seven women (recruited between March 1999 and January 2003) were analyzed. The median period of follow-up was 13.2 years (range: 7.4-17.1 years) with a total of 583 Papanicolaou smears. Twenty-seven percent of these HIV-1-infected women had poorly-controlled HIV. Cumulative incidence of HSIL was 18% (12/67; 95%CI: 11-29%) of which one was an invasive squamous cell carcinoma and two were carcinoma in situ. These women had not been well-engaged with the annual Papanicolaou smear screening program and had poor adherence to antiretroviral therapy. Development of HSIL was associated with high-risk-HPV infection (OR: 14.9; 95%CI: 3.0, 75.1). At last Papanicolaou smear, prevalence of high-risk-HPV infection was 30% (20/66, 95%CI: 21-42%). In conclusion, the incidence of cervical HSIL in HIV-1-infected women with poor antiretroviral therapy adherence or poor immunological status reinforces the need to identify those HIV-1-infected women at risk of developing cervical cancer.

Expression of CD11c Is Associated with Unconventional Activated T Cell Subsets with High Migratory Potential.

CD11c is an α integrin classically employed to define myeloid dendritic cells. Although there is little information about CD11c expression on human T cells, mouse models have shown an association of CD11c expression with functionally relevant T cell subsets. In the context of genital tract infection, we have previously observed increased expression of CD11c in circulating T cells from mice and women. Microarray analyses of activated effector T cells expressing CD11c derived from naïve mice demonstrated enrichment for natural killer (NK) associated genes. Here we find that murine CD11c+ T cells analyzed by flow cytometry display markers associated with non-conventional T cell subsets, including γδ T cells and invariant natural killer T (iNKT) cells. However, in women, only γδ T cells and CD8+ T cells were enriched within the CD11c fraction of blood and cervical tissue. These CD11c+ cells were highly activated and had greater interferon (IFN)-γ secretory capacity than CD11c- T cells. Furthermore, circulating CD11c+ T cells were associated with the expression of multiple adhesion molecules in women, suggesting that these cells have high tissue homing potential. These data suggest that CD11c expression distinguishes a population of circulating T cells during bacterial infection with innate capacity and mucosal homing potential.

Appendiceal mixed adenoneuroendocrine carcinomas, a rare entity that can present as a Krukenberg tumor: case report and review of the literature.

BACKGROUND: Mixed adenoneuroendocrine carcinoma is a rare tumor recently recognized as a new category in the last World Health Organization (WHO) classification of appendiceal tumors (2010). This term has been proposed to designate carcinomas of the appendix that arise by progression from a pre-existing goblet cell carcinoid. Mixed adenoneuroendocrine carcinomas are more aggressive tumors than typical goblet cell carcinoids and usually present with peritoneal spreading and ovarian masses. Staging, some histological features, and completeness of surgery are factors that determine its evolution. CASE PRESENTATION: We report the case of a mixed adenoneuroendocrine carcinoma--signet ring cell subtype--that presented as a Krukenberg tumor of unknown primary. CONCLUSION: The review of literature is focused on the most recent WHO pathologic classification of appendiceal tumors containing goblet cell clusters, which seems to correlate with prognosis. A management proposal for mixed adenoneuroendocrine carcinomas reported in previous literature is also discussed. This ranges from right hemicolectomy to cytoreduction plus hyperthermic intraperitoneal chemotherapy, in both cases usually followed by intravenous chemotherapy.

Human papillomavirus infection in HIV-1 infected women in Catalonia (Spain): implications for prevention of cervical cancer.

BACKGROUND: High-risk human Papillomavirus infection is a necessary factor for cervical squamous intraepithelial lesions and invasive cervical cancer. In HIV-1-infected women, HPV infection is more prevalent and a higher risk of cervical cancer has been identified. We aimed to calculate the prevalence of infection by HR-HPV, determine the factors associated with this infection and abnormal cytology findings and to describe the history of cervical cancer screening in HIV-1-infected women. METHODS: We enrolled 479 HIV-1-infected women from the PISCIS cohort. Each patient underwent a gynecological check-up, PAP smear, HPV AND Hybrid capture, HPV genotyping, and colposcopy and biopsy, if necessary. We applied questionnaires to obtain information on sociodemographic, behavioral, clinical, and cervical screening variables. We present a cross-sectional analysis. RESULTS: Median age was 42 years. The prevalence of HR-HPV infection was 33.2% and that of high-grade squamous intraepithelial lesions (HSIL) was 3.8%. The most common genotypes were 16(23%), 53(20.3%), and 52(16.2%). The factor associated with HR-HPV infection was age <30 years (odds ratio[OR],2.5; 95%confidence interval[CI],1.1-5.6). The factors associated with the presence of HSIL or low-grade squamous intraepithelial lesions (LSIL) were CD4T-lymphocyte count <200 cells/mm(3) versus >500 cells/mm(3) (OR,8.4; 95%CI,3.7-19.2), HIV-1 viral load >10,000 copies/mL versus <400 copies/mL (OR,2.1; 95%CI,1.0-4.4), and use of oral contraceptives (OR,2.0; 95%CI,1.0-3.9). Sixty percent of HIV-1-infected women had had one Pap smear within the last 2 years. CONCLUSIONS: The high prevalence of HPV infection and cervical lesions in the HIV-1-infected population in Catalonia, as well as the low coverage and frequency of screening in this group, means that better preventive efforts are necessary and should include vaccination against HPV, better accessibility to screening programs, training of health care professionals, and specific health education for HIV-1-infected women.

Comparison between two human papillomavirus genotyping assays targeting the L1 or E6/E7 region in cervical cancer biopsies

Introduction: Human papillomavirus (HPV) testing is increasingly used in cervical cancer prevention strategies, and a variety of HPV genotyping assays have been developed. We aimed to compare the performance of two HPV genotyping techniques in formalin-fixed paraffin-embedded (FFPE) tissue specimens from a series of invasive squamous cell carcinoma (SCC) cases. Methods Archival FFPE tissue blocks from 78 SCC cases were initially considered. DNA was extracted from dewaxed tissue sections and tested with the INNO-LiPA HPV Genotyping Extra assay (Innogenetics), and the F-HPV typing kit (Genomed) targeting the L1 and E6/E7 regions, respectively. Results The INNO-LiPA assay showed a higher sensitivity (98.6%) than the F-HPV assay (78.6%). A total of 12 (17.1%) biopsies showed multiple-type infections evidenced by at least one assay. Among the SCC cases tested, HPV16 and/or 18 were detected in 70% of the cases, and 18.4% of them had multiple infections with other high-risk types. Conclusions Our results suggest that the INNO-LiPA assay has a better performance than the F-HPV in FFPE specimens, probably due to its smaller amplicon size and the wider range of detectable HPV types. The prevalence of multiple infections could be higher than previously reported, as evidenced by the combination of the two assays (AU)

Introducción: La detección del virus del papiloma humano (VPH) es cada vez más utilizada en los algoritmos de prevención del cáncer cervical, y se ha desarrollado una gran variedad de ensayos para su detección y genotipado. Nuestro objetivo fue comparar dos técnicas de genotipado del VPH en muestras de tejido (..) (AU)

Comparison between two human papillomavirus genotyping assays targeting the L1 or E6/E7 region in cervical cancer biopsies.

INTRODUCTION: Human papillomavirus (HPV) testing is increasingly used in cervical cancer prevention strategies, and a variety of HPV genotyping assays have been developed. We aimed to compare the performance of two HPV genotyping techniques in formalin-fixed paraffin-embedded (FFPE) tissue specimens from a series of invasive squamous cell carcinoma (SCC) cases. METHODS: Archival FFPE tissue blocks from 78 SCC cases were initially considered. DNA was extracted from dewaxed tissue sections and tested with the INNO-LiPA HPV Genotyping Extra assay (Innogenetics), and the F-HPV typing kit (Genomed) targeting the L1 and E6/E7 regions, respectively. RESULTS: The INNO-LiPA assay showed a higher sensitivity (98.6%) than the F-HPV assay (78.6%). A total of 12 (17.1%) biopsies showed multiple-type infections evidenced by at least one assay. Among the SCC cases tested, HPV16 and/or 18 were detected in 70% of the cases, and 18.4% of them had multiple infections with other high-risk types. CONCLUSIONS: Our results suggest that the INNO-LiPA assay has a better performance than the F-HPV in FFPE specimens, probably due to its smaller amplicon size and the wider range of detectable HPV types. The prevalence of multiple infections could be higher than previously reported, as evidenced by the combination of the two assays.

Low levels of adherence to antiretroviral therapy in HIV-1-infected women with menstrual disorders.

We evaluated the prevalence of menstrual disorders in HIV-1-infected women and explored the association between such disorders and adherence to antiretroviral therapy, sexual functioning, and depressive symptoms in a group of HIV-1-infected women aged younger than 46 years and on antiretroviral therapy. Participants were included in a cross-sectional survey between June 2005 and December 2006. Women provided information about their menstrual cycle and adherence in a single visit and responded to the Greene Climacteric Scale, the Massachusetts General Hospital Sexual Functioning Questionnaire and the Beck Depression Inventory. Women with and without menstrual disorders were compared using parametric and nonparametric tests. A multivariate stepwise logistic regression model was developed. The participants were 107 Caucasian women with a median (interquartile range [IQR]) age of 39 years (IQR, 36-42 years) and a median CD4 cell count of 483 cells/mm(3) (IQR, 332-679 cells/mm(3)). The viral load was below 50 copies per milliliter in 76.6% of the women. Sixty-four percent of the women had acquired HIV-1 infection through sexual intercourse. Menstrual disorders, observed in 32% of participants, were more frequent in women with detectable viral loads (p = 0.018). Women with menstrual disorders reported worse adherence (p = 0.005) and more sexual dysfunction (p < 0.05). Sixty-nine percent of the women who attributed their menstrual disorders to the use of antiretrovirals had inadequate adherence. Depressive symptoms were not observed. Vasomotor symptoms (p = 0.004), having a detectable viral load (p = 0.03) and adherence less than 95% (p = 0.02) were predictors of menstrual disorder. A third of the HIV-1-infected women assessed had menstrual disorders that impacted negatively on adherence to therapy and sexual function. The subjective attribution of these irregularities to antiretrovirals seems to affect medication intake, possibly favoring negative clinical consequences.

Evaluation of an array-based method for human papillomavirus detection and genotyping in comparison with conventional methods used in cervical cancer screening.

Cervical cancer is the second-most prevalent cancer in young women around the world. Infection with human papillomavirus (HPV), especially high-risk HPV types (HR-HPV), is necessary for the development of this cancer. HPV-DNA detection is increasingly being used in cervical cancer screening programs, together with the Papanicolau smear test. We evaluated the usefulness of introducing this new array-based HPV genotyping method (i.e., Clinical Arrays Papillomavirus Humano) in the cervical cancer screening algorithm in our center. The results obtained using this method were compared to those obtained by the hybrid capture II high-risk HPV DNA test (HC-II) and Papanicolau in a selected group of 408 women. The array-based assay was performed in women that were HC-II positive or presented cytological alterations. Among 246 array-positive patients, 123 (50%) presented infection with >or=2 types, and HR-HPV types were detected in 206 (83.7%), mainly HPV-16 (24.0%). Up to 132 (33.2%) specimens were classified as ASCUS (for atypical squamous cells of undetermined significance), and only 48 (36.4%) of them were HPV-DNA positive by either assay; however, 78.7% of these cases were caused by HR-HPV types. The agreement between both HPV-DNA detection techniques was fairly good (n = 367). Screening with Papanicolau smear and HC-II tests, followed by HPV detection and genotyping, provided an optimal identification of women at risk for the development of cervical cancer. Furthermore, with the identification of specific genotypes, either in single or multiple infections, a better prediction of disease progression was achieved. The array method also made allowed us to determine the possible contribution of the available vaccines in our setting.

Epidemiological data of different human papillomavirus genotypes in cervical specimens of HIV-1-infected women without history of cervical pathology.

AIM: To study the epidemiology of different human papillomavirus (HPV) genotypes in cervical samples of HIV-1-infected women with normal Papanicolau smears. DESIGN: : Retrospective analysis of a prospective cohort. PATIENTS AND METHODS: We selected HIV-1-infected women with 2 consecutive normal Papanicolau smears at baseline and at least 1 baseline and 1 follow-up cervical sample. HPV infection was assessed by second-generation hybrid capture (HC-2) and multiplex polymerase chain reaction (mPCR). HPV genotypes were determined by mPCR. RESULTS: From a cohort of 139 women followed up to 4 years, 93 women meeting the inclusion criteria were analyzed. The mean period between samples was 20 months (range, 6-44 months). HPV baseline prevalence was 63% [59/93; 95% confidence interval (CI), 53% to 73%] using polymerase chain reaction and 41% (38/93; 95% CI, 31% to 51%) using HC-2, P = 0.007 (kappa, 0.45; P = 0.001). The most prevalent high oncogenic risk genotypes (HR-HPV) were HPV-16 (28%), HPV-33 (18%), HPV-52 (12%), HPV-58 (11%), and HPV-39 (11%). Infection with multiple HPV genotypes was detected in >40% of women. HPV infection persisted at follow-up in 86% (51/59; 95% CI, 77% to 95%) by polymerase chain reaction and 76% (29/38; 95% CI, 62% to 90%) by HC-2. HPV infection persisted in 55% of women with samples available beyond 3 years. The actuarial probabilities of clearance and incidence of HPV infection at 36 months were 16% and 45%, respectively. CONCLUSIONS: HPV infection is highly prevalent and persistent among HIV-1-infected women with normal Papanicolau smears. HR-HPV genotypes other than HPV-16 (HPV-33, HPV-52) are frequently detected in HIV-infected women. mPCR provides better surveillance of HPV infection than HC-2 methods.

Highly active antiretroviral therapy and incidence of cervical squamous intraepithelial lesions among HIV-infected women with normal cytology and CD4 counts above 350 cells/mm3.

OBJECTIVES: To provide evidence for the long-term effect of highly active antiretroviral therapy (HAART) on the incidence of cervical squamous intraepithelial lesions (SILs) among HIV-positive women with normal cytology test and CD4 count above 350 cells/mm(3). PATIENTS AND METHODS: A retrospective cohort study was carried out in HIV-positive women with two consecutive normal cervical cytological tests (Papanicolaou test) and at least one subsequent test, without previous cervical history of SIL or cancer diagnosis, and with an immunological status >350 CD4 cells/mm(3). The patients were divided into two groups: treated with HAART (HAART group) or not treated with HAART (NO-HAART group), during the period of time between cytology tests included in the survival analysis and time until SIL. RESULTS: Between January 1997 and December 2006, 127 women were included: 90 in the HAART group and 37 in the NO-HAART group. Both groups of patients were similar with respect to demographic data, except for HIV viral load and previous HAART inclusion (P < 0.001). SIL was diagnosed in 27 of 90 (30%) patients in the HAART group and in 7 of 37 (19%) patients in the NO-HAART group (OR = 1.84, 95% CI: 0.72-4.69, P = 0.202). The actuarial probability of remaining free of SIL at 3 years was 70% in the HAART group and 78% in the NO-HAART group. No variable was associated with an increased risk of developing SILs. CONCLUSIONS: These results suggest that when the patients' immunological status is above 350 CD4 cells/mm(3), the HIV-infected women treated with HAART present a similar cervical SIL incidence to women not on HAART.

Evolution of cervical cytologic changes among HIV-infected women with normal cytology in the HAART era.

The influence of HAART on the evolution to cervical squamous intraepithelial lesions (SIL) among HIV(+) women with a normal cytological test in the HAART era was studied. A retrospective cohort study (1997-2005) of HIV-infected women treated with HAART was conducted. Those with a normal cervical cytology (Papanicolaou test) and at least one subsequent test were included. Survival (time until diagnosis of SIL), univariate, and multivariate analyses were performed. A total of 133 HIV-infected patients treated with HAART were included. The incidence of SIL was 35% (47 patients). SIL was diagnosed in 36 of 110 (33%) patients with a baseline and final immunological status of >200 CD4 cells/microl and in 6 of 9 (67%) patients with a baseline and final immunological status of < or =200 CD4 (OR: 0.24, 95% CI: 0.06-1.03, p = 0.041). SIL was diagnosed in 10 of 60 (17%) patients with an undetectable baseline and final HIV viral load and in 36 of 70 (51%) patients with a detectable HIV viral load (OR: 0.19, 95% CI: 0.07-0.46, p < 0.001). A high incidence of SIL (cancer precursor lesions) was observed among HIV(+) women without a background of cervical pathology. The effect of HAART on the control of HIV replication and of immunological status (>200 CD4) through the follow-up was associated with a reduction of SIL.