Routine Screening of Anal Cytology in Persons With Human Immunodeficiency Virus and the Impact on Invasive Anal Cancer: A Prospective Cohort Study.

BACKGROUND: The efficacy of screening programs to prevent anal cancer in persons with human immunodeficiency virus 1 (HIV-1) is unclear. METHODS: To examine the impact of a screening program to detect anal cancer precursors on the incidence of cases of invasive anal squamous-cell carcinoma (IASCC) in persons with HIV-1, we performed a single-center, retrospective analysis of a prospective cohort of outpatients with HIV-1 attending a reference HIV unit from January 2005 onward. All participants were invited to participate in a continued structured screening program for anal cancer prevention. We estimated the incidence of IASCC and performed a comparative analysis between subjects enrolled in the screening program (screening group) and those who declined to participate (nonscreening group). To reduce any selection bias, a propensity score analysis was applied. RESULTS: We included 3111 persons with HIV-1 (1596 men-who-have-sex-with-men [MSM], 888 men-who-have-sex-with-women [MSW], 627 women; mean age, 41 years), with a median follow-up of 4.7 years (14 595 patient-years of follow-up); 1691 (54%) participated in the screening program. Ten patients were diagnosed with IASCC: 2 (MSM) in the screening group and 8 (4 MSM, 2 MSW, and 2 women) in the nonscreening group. The incidence rates of IASCC were 21.9 (95% confidence interval [CI], 2.7-70.3) and 107.0 (95% CI, 46.2-202.0) per 100 000 person-years, respectively. After a propensity score adjustment, the difference was significant in favor of the screening group (hazard ratio, 0.17; 95% CI, .03-.86). CONCLUSIONS: The number of cases of IASCC was significantly lower in persons with HIV engaged in an anal cytology screening program. These results should be validated in a randomized clinical trial.

Advancement Flap Technique for Anal Fistula in Patients With Crohn's Disease: A Systematic Review of the Literature. / Resultados del tratamiento quirúrgico de la fístula anal en pacientes con enfermedad de Crohn mediante técnica de colgajo de avance endorrectal: revisión sistemática de la literatura.

INTRODUCTION: Treatment for anal fistulas in patients with Crohn's disease is still challenging, even for the expert surgeon. The advancement flap technique is characterized by the preservation of the anal sphincter complex. METHODS: A systematic review of the literature, selecting series of patients affected by Crohn's disease and anal fistulas and treated using advancement flap technique was performed. Patients followed during at least 6 months have been included. RESULTS: From 128 initial studies, 11 studies were selected, including overall 135 patients. Those studies show low- level evidence. Results in a series with follow-up from 8,4 to 82 months, stated a clinical success of 66% and recurrence rate around 30%. However there was an evident heterogeneity of results. CONCLUSION: The review concludes that the advancement flap technique to treat anal fistulas in patients with Crohn's disease is an adequate alternative. New studies are necessary to provide higher-level evidence.

Natural history of human papillomavirus infections involving anal, penile, and oral sites among HIV-positive men.

AIM: The aim of this study was to characterize the natural history of human papillomavirus (HPV) infection at anal canal, penile, and oral sites in HIV-positive men based on their sexual behavior. METHODS: This is a single-center, prospective cohort study. The prevalence, clearance, and incidence of HPV infection at anal, penile, and oral sites were studied in HIV-positive men who have sex with men (MSM) and heterosexual individuals using multiplex polymerase chain reaction. Risk factors associated with HPV infection were analyzed. RESULTS: In total, 733 patients (538 MSM, 195 heterosexual) were included in the study between 2005 and 2009. The prevalence, clearance, and incidence of HPV infection were 73%, 30%, and 36% at anal site; 26%, 56%, and 17% at penile site; and 16%, 44%, and 11% at oral site, respectively. At anal site, MSM had a higher HPV prevalence (84% vs. 42%; odds ratio,7.3; 95% confidence interval [CI], 5.2-10.6) mainly for multiple (≥3) HPV types, higher incidence rate (324 vs. 92 new HPV-infected person per 1000 person-years [hazard ratio, 8.1; 95% CI, 3.8-17.3]), and a lower clearance rate (125 vs. 184 cleared HPV-infected person per 1000 person-years [hazard ratio, 0.5; 95% CI, 0.3-0.9]) than did heterosexuals. Similar prevalence, clearance, and incidence rates of penile and oral HPV infection were found between groups. The most common high-risk HPV type for the 3 body sites studied was the HPV-16. Finally, a similar proportion of heterosexuals (7%) and MSM (6%) presented concurrent HPV infections (anal-penile-oral sites). History of anal warts was associated with higher HPV prevalence in the 3 body parts. CONCLUSIONS: Although MSM presented the highest risk of anal HPV infection, heterosexual men also showed a remarkable prevalence of anal HPV infection and a comparable risk to MSM for penile and oral HPV infection. Taking into account all these results, the careful inspection of the anal canal, penile, and oral sites should at least be routine in each clinic visit of HIV-infected men independently of their sexual behavior.

Distribution of human papillomavirus genotypes in anal cytological and histological specimens from HIV-infected men who have sex with men and men who have sex with women.

BACKGROUND: Anal cancer is caused by human papillomavirus (HPV). Moreover, human immunodeficiency virus (HIV) is an additional risk factor for anal cancer. Therefore, when designing preventive protocols for HIV-infected men, it is important to detect high-risk (HR) oncogenic HPV genotypes present in their anal canals. However, most studies have focused only on men who have sex with men (MSM). OBJECTIVE: To estimate the prevalence of HPV and describe its genotype distribution using anal cytology and histology specimens from HIV-infected populations of MSM and men who have sex with women (MSW). DESIGN: Crosssectional study of the CARH·MEN cohort. SETTING: Single-center prospective cohort of HIV-infected men attending the Outpatient HIV Clinic of Hospital Germans Trias i Pujol (Spain), where they undergo annual screening for HPV infection of the anus, penis and mouth. PATIENTS: Four hundred eighty-three HIV-infected men (341 MSM, 142 MSW) with no current or previous history of anal condylomata. MAIN OUTCOME MEASURES: HPV genotypes detected (multiplex-PCR), cytology results (Papanicolaou test) and histology results (biopsy-based). RESULTS: Cytological abnormalities were detected in 40% of MSM (129/321; 95%CI, 35-46) and 20% of MSW (26/131; 95%CI, 13-28) (OR=2.7; 95%CI, 1.7-4.4). All high-grade squamous intraepithelial lesions (HSIL) were positive for HR-HPV in both groups. High-resolution anoscopy was performed in 146 patients (120 MSM, 26 MSW) with abnormal cytological diagnoses. Lesions were visualized in 80 MSM (67%) and 14 MSW (54%) (OR=1.7 [95%CI, 0.7-4.0]). Histological diagnosis was anal intraepithelial neoplasia (AIN)-1 in 51 MSM (64%) and 6 MSW (43%), AIN-2 in 9 MSM (11%) and 3 MSW (21%), AIN-3 in 7 MSM (9%) and 1 MSW (7%), and normal in 13 MSM (16%) and 4 MSW (29%). HPV16 was the most prevalent HR genotype. LIMITATIONS: Study limitations include its crosssectional design. CONCLUSIONS: Anal cancer screening should be offered to all HIV-infected men, regardless of their sexual orientation.

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.

Human papillomavirus 16 integration and risk factors associated in anal samples of HIV-1 infected men.

BACKGROUND: The integration of HPV-16 DNA into the host genome is considered an important event in the progression of premalignant cervical lesions to cervical cancer. The aim of our study was to assess the prevalence of HPV-16 integration in anal cytologic specimens of HIV-1 infected men and its association with risk factors. PATIENTS METHODS: This cross-sectional study included 269 HIV-infected males. Detection and typing of HPV-infection was done by multiplex PCR, and integration of HPV-16 by real-time PCR. RESULTS: The overall anal HPV-infection prevalence was 78% (209/269), 29% (77/269) for HPV-16 infection, and 9% (25/269) for HPV-16 integration. In HPV-16 infected group, the integration prevalence represented 32% (25/77). The only risk factor associated with HPV-16 integration was the time since HIV diagnosis (OR = 1.2, 95% CI: 1.0-1.3; P = 0.010). The risk factors associated with abnormal cytology results were: HPV infection (OR = 17.8, 95% CI: 6.8-46.6), HPV-16 infection (OR = 4.6, 95% CI: 2.5-8.4), and presence of HPV-16 integrated forms (OR = 11.7, 95% CI: 1.5-93.5). Moreover, in the multivariate analysis, the HPV-16 integration continued representing the most important risk factor (OR = 20, 95% CI: 1.6-226) for anal cytologic abnormalities. CONCLUSION: HPV-16 infection and its integration in anal cells were highly prevalent in HIV-infected men. The assessment of HPV-16 integration rather than HPV-infection could be a good biomarker for predicting anal precancerous lesions in HIV-positive men.

ADAR1 function affects HPV replication and is associated to recurrent human papillomavirus-induced dysplasia in HIV coinfected individuals.

Infection by human papillomavirus (HPV) alters the microenvironment of keratinocytes as a mechanism to evade the immune system. A-to-I editing by ADAR1 has been reported to regulate innate immunity in response to viral infections. Here, we evaluated the role of ADAR1 in HPV infection in vitro and in vivo. Innate immune activation was characterized in human keratinocyte cell lines constitutively infected or not with HPV. ADAR1 knockdown induced an innate immune response through enhanced expression of RIG-I-like receptors (RLR) signaling cascade, over-production of type-I IFNs and pro-inflammatory cytokines. ADAR1 knockdown enhanced expression of HPV proteins, a process dependent on innate immune function as no A-to-I editing could be identified in HPV transcripts. A genetic association study was performed in a cohort of HPV/HIV infected individuals followed for a median of 6 years (range 0.1-24). We identified the low frequency haplotype AACCAT significantly associated with recurrent HPV dysplasia, suggesting a role of ADAR1 in the outcome of HPV infection in HIV+ individuals. In summary, our results suggest that ADAR1-mediated innate immune activation may influence HPV disease outcome, therefore indicating that modification of innate immune effectors regulated by ADAR1 could be a therapeutic strategy against HPV infection.

Impact of azathioprine on the prevention of postoperative Crohn's disease recurrence: results of a prospective, observational, long-term follow-up study.

BACKGROUND: Postoperative recurrence (PR) occurs early after intestinal resection in >75% of Crohn's disease (CD) patients. No well-established strategy for long-term PR prevention is available. The aim was to prospectively evaluate the long-term endoscopic and clinical outcomes of postoperative CD on maintenance treatment with azathioprine (AZA), especially in patients who developed endoscopic lesions confined to the ileocolic anastomosis. METHODS: Long-term AZA therapy (2-2.5 mg/kg/day) was initiated immediately after surgery in 56 consecutive patients who underwent a curative intestinal resection. Clinical and biological assessments every 3 months, as well as yearly endoscopic evaluation, were performed until the end of the study or clinical PR (CPR). RESULTS: Thirty-seven patients (70%) showed mucosal lesions at endoscopy after a median of 12 months (range 12-60); however, in 15 of these patients lesions were confined to the anastomosis and only 6 showed endoscopic progression, but none of them developed CPR. Among the remaining 22 patients with endoscopic PR (EPR), 23% suffered a CPR during follow-up. Thirty percent of patients remained free of EPR after a median follow-up of 33 months (range 12-84). The cumulative probability of EPR was 44%, 53%, 69%, and 82%, at 1, 2, 3, and 5 years, respectively. No predictive factors of EPR were found. CONCLUSIONS: Early postoperative use of AZA seems to delay EPR development in comparison to historical series or placebo groups in randomized controlled trials. Although usually considered as endoscopic recurrence, those lesions confined to the ileocolonic anastomosis are not likely to progress or to become symptomatic in the short term.

Effectiveness of physically ablative and pharmacological treatments for anal condyloma in HIV-infected men.

BACKGROUND: There is limited information on the effectiveness of available treatments for anal condyloma acuminata in HIV-1-infected men. AIM: To provide data on the effectiveness of electrosurgical excision, infrared coagulation and pharmacological (imiquimod) treatments for anal condyloma acuminata (peri-anal and/or intra-anal) in HIV-1-infected men based on authors' practice. METHODS: Single-center, retrospective descriptive analysis of HIV-1-infected men, 18 years or older treated for anal condyloma acuminata. Standard treatments were offered: electrosurgery excision, infrared coagulation and topical imiquimod. Effectiveness was evaluated by the recurrence rate at 1 year after treatment. Recurrence was defined as any anal condyloma acuminata diagnosed after 3 months of condyloma-free survival post-treatment. Anal cytology and human-papillomavirus-infection (HPV) was assessed. RESULTS: Between January 2005 and May 2009, 101 men were treated for anal condyloma acuminata: 65 (64%) with electrosurgery, 27 (27%) with infrared coagulation and 9 (9%) with imiquimod. At 1 year after treatment, the cumulative recurrence rate was 8% (4/65, 95%CI: 2-15%) with electrosurgery excision, 11% (3/27, 95%CI: 4-28%) with infrared coagulation and 11% (1/9, 95%CI: 2-44%) with imiquimod treatment. No predictive factors were associated with recurrence. Anal HPV-6 or HPV-11 was detectable in 98 (97%) patients and all had high-risk HPV genotypes, and 89 (88%) patients had abnormal anal canal cytology. Limitations: this was a retrospective descriptive analysis; limited to a single center; it cannot know if the recurrence is related to new infection. CONCLUSION: Recurrence of anal condyloma after any treatment was common. Abnormal anal cytology and high-risk HPV-infection were highly prevalent in this population, therefore at high-risk of anal cancer, and warrants careful follow-up.

High prevalence of human papillomavirus infection in the anus, penis and mouth in HIV-positive men.

Human papillomavirus (HPV) types are associated with squamous cell cancers. HIV infection is linked with a higher prevalence of anal HPV infection. It is important to assess whether HPV is present in other body parts involved in sexual practices to establish a cancer prevention program. A high prevalence of high-risk HPV types was present in the anus, penis and mouth (78, 36 and 30%, respectively) in a cohort of HIV-infected males (men who have sex with men and heterosexual), without evidence of pathology in these areas.

Long-term effectiveness of infrared coagulation for the treatment of anal intraepithelial neoplasia grades 2 and 3 in HIV-infected men and women.

AIMS: To assess the effectiveness and safety of infrared coagulation (IRC) for the ablation of anal intraepithelial neoplasia (AIN) and to provide data on the prevalence of AIN in HIV-infected patients. PATIENTS AND METHODS: We performed a single-center, retrospective cohort study based on data collected from a prospectively compiled database of outpatients attended in the Clinical-Proctology-HIV-Unit (first visit). The effectiveness (normal anal cytology after 12 months of IRC) and safety of IRC were estimated. RESULTS: Between January 2005 and December 2011, a total of 69 (5%) patients with biopsy-proven AIN-2 or AIN-3 from among 1518 patients (1310 men; 208 women) were treated with IRC. The prevalence of cytological abnormalities was 49.5% [751/1518; (atypical squamous cells of unknown significance, 14%; low-grade squamous intraepithelial lesions, 27.5%; high-grade squamous intraepithelial lesions, 8%)]. High-resolution anoscopy revealed intra-anal condylomata in 31% of patients (236/751), nonvisualized lesions in 30% (227/751), and visualized lesions (from which biopsy specimens were taken) in 38% (288/751). The histological diagnosis was: AIN-1, 52% (151/288); AIN-2, 15% (44/288); AIN-3, 9% (25/288); normal, 19% (56/288); and nonevaluable, 4% (12/288). IRC was applied in-office in 66 patients (three refused to undergo treatment). At 12 months, all patients (n = 56) had a normal anal cytology result. Seven (13%) patients had biopsy-proven recurrence [mean (range) time-to-recurrence, 30 (18-43) months]. High-risk-human papilloma virus (HPV) infection was detected in all anal lesions (HPV-16 was the most common genotype). Agreement between cytological and histological results was poor. CONCLUSION: A high prevalence of AIN was found in both HIV-infected men and HIV-infected women. Although randomized clinical trials are lacking, IRC ablation of AIN-2 and AIN-3 lesions without concomitant condylomata could help prevent anal squamous cell carcinoma.

Addition of metronidazole to azathioprine for the prevention of postoperative recurrence of Crohn's disease: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Endoscopic recurrence occurs in up to 80% of patients with Crohn's disease 1 year after intestinal resection. Imidazole antibiotics, thiopurines, and particularly their combination have proven efficacy in preventing endoscopic recurrence. The aim of the study was to compare the efficacy of the addition of metronidazole (for 3 months after the surgical treatment) to azathioprine for the prevention of postsurgical endoscopic recurrence. METHODS: A pilot study was made of 50 patients with Crohn's disease undergoing intestinal resection with ileocolic anastomosis and treated with 2 to 2.5 mg/kg of azathioprine per day for 1 year. The patients were randomized to receive additional 15 to 20 mg/kg of metronidazole per day or placebo for the first 3 months (n = 25 per arm). Endoscopic assessment was performed 6 and 12 months after the surgical resection. The primary end point was the prevention of endoscopic recurrence as defined by a Rutgeerts score of <2 at 6 months. The initial sample size had an 80% statistical power in detecting an absolute risk reduction of ≥30%. RESULTS: Endoscopic recurrence occurred in 28% and 44% of the patients at 6 months (P = 0.19) and in 36% and 56% (P = 0.15) at 12 months in the metronidazole and placebo groups, respectively. No statistically significant differences were found between the treatment groups regarding severe endoscopic recurrence (Rutgeerts score ≥ 3) at 6 and 12 months. Likewise, there were no differences in the rate of adverse events between the treatment groups. CONCLUSIONS: The addition of metronidazole to azathioprine did not significantly reduce the risk of endoscopic recurrence beyond azathioprine alone in this study but does not worsen its safety profile.

Resultados del tratamiento quirúrgico de la fístula anal en pacientes con enfermedad de Crohn mediante técnica de colgajo de avance endorrectal: revisión sistemática de la literatura / Advancement Flap Technique for Anal Fistula in Patients With Crohn's Disease: A Systematic Review of the Literature

Introducción: La técnica de colgajo de avance endorrectal es una de las alternativas en el tratamiento de la fístula anal en pacientes con enfermedad de Crohn. Métodos: Diseñamos una revisión sistemática de la literatura, seleccionando estudios que incluyeron a pacientes afectos de enfermedad de Crohn y fístula anal tratados mediante esta técnica. De esos estudios solo se seleccionaron los pacientes seguidos durante al menos 6 meses. Resultados: Se seleccionaron 11 estudios con un total de 135 pacientes. Los resultados, con seguimientos de 8,4 a 82 meses, indicaron una curación del 66% y una tasa de recurrencia de alrededor del 30%. Sin embargo, se observó importante heterogeneidad en los resultados de las series revisadas. Conclusiones: El colgajo de avance endorrectal es una alternativa adecuada en los pacientes con fístula anal y enfermedad de Crohn. Sin embargo, es necesario desarrollar nuevos estudios que aporten un mayor nivel de evidencia científica (AU)

Introduction: Treatment for anal fistulas in patients with Crohn's disease is still challenging, even for the expert surgeon. The advancement flap technique is characterized by the preservation of the anal sphincter complex. Methods: A systematic review of the literature, selecting series of patients affected by Crohn's disease and anal fistulas and treated using advancement flap technique was performed. Patients followed during at least 6 months have been included. Results: From 128 initial studies, 11 studies were selected, including overall 135 patients. Those studies show low- level evidence. Results in a series with follow-up from 8,4 to 82 months, stated a clinical success of 66% and recurrence rate around 30%. However there was an evident heterogeneity of results. Conclusion: The review concludes that the advancement flap technique to treat anal fistulas in patients with Crohn's disease is an adequate alternative. New studies are necessary to provide higher-level evidence (AU)

Idiopathic myointimal hyperplasia of mesenteric veins and pneumatosis intestinalis: a previously unreported association.

Idiopathic myointimal hyperplasia of mesenteric veins is a very rare disease occurring in young male patients, with no more than eight cases reported in the world literature. It causes venous ischemia in the sigmoid colon and rectum that clinically resembles inflammatory bowel disease. Pneumatosis intestinalis is also a rare condition usually associated to a wide range of diseases including bowel ischemia. We herein report on a case of pneumatosis intestinalis associated to idiopathic myointimal hyperplasia of mesenteric veins. To our knowledge, this is the first report of such an association, and the first one of idiopathic myointimal hyperplasia of mesenteric veins occurring in a female patient as well.