Safety and immunogenicity of the quadrivalent human papillomavirus (qHPV) vaccine in HIV-positive Spanish men who have sex with men (MSM).

BACKGROUND: Safety and immunogenicity of the quadrivalent human papillomavirus (qHPV) vaccine were evaluated in HIV-positive Spanish MSM. The prevalence of High Squamous Intraepithelial Lesions (HSIL) and genotypes of high-risk human papillomavirus (HR-HPV) were also determined, as well as risk factors associated with the presence of HR-HPV in anal mucosa. METHODS: This is a randomised, double blind, placebo-controlled trial of the quadrivalent HPV (qHPV) vaccine. The study enrolled from May 2012 to May 2014. Vaccine and placebo were administered at 0, 2 and 6 months (V1, V2, V3 clinical visits). Vaccine antibody titres were evaluated at 7 months. Cytology (Thin Prep® Pap Test), HPV PCR genotyping (Linear Array HPV Genotyping Test), and high-resolution anoscopy (Zeiss 150 fc© colposcope) were performed at V1. RESULTS: Patients (n = 162; mean age 37.9 years) were screened for inclusion; 14.2% had HSIL, 73.1% HR-HPV and 4.5% simultaneous infection with HPV16 and 18. Study participants (n = 129) were randomized to qHPV vaccine or placebo. The most common adverse event was injection-site pain predominating in the placebo group [the first dose (83.6% vs. 56.1%; p = 0.0001]; the second dose (87.8% vs. 98.4%; p = 0.0001); the third dose (67.7% vs. 91.9%; p = 0.0001). The vaccine did not influence either the viral load of HIV or the levels of CD4. Of those vaccinated, 76% had antibodies to HPV vs. 30.2% of those receiving placebo (p = 0.0001). In the multivariate analysis, Older age was associated with lower HR-HPV infection (RR 0.97; 95% CI 0.96-0.99), and risk factor were viral load of HIV >200 copies/µL (RR 1.42 95% CI 1.17-1.73) and early commencement of sexual activity (RR 1.35; 95% CI 1.001-1.811). CONCLUSIONS: This trial showed significantly higher anti-HR-HPV antibody titres in vaccinated individuals than in unvaccinated controls. There were no serious adverse events attributable to the vaccine. In our cohort, 1 of every 7 patients had HSIL and the prevalence of combined infection by genotypes 16 and 18 was low. This suggests that patients could benefit from receiving qHPV vaccine. Older age was the main protective factor against HR-HPV infection, and non-suppressed HIV viremia was a risk factor. CLINICAL TRIAL REGISTRATION: ISRCTN14732216 ( http://www.isrctn.com/ISRCTN14732216 ).

Alveolar overdistension as a cause of lung injury: differences among three animal species.

This study analyses characteristics of lung injuries produced by alveolar overdistension in three animal species. Mechanical ventilation at normal tidal volume (10 mL/Kg) and high tidal volume (50 mL/Kg) was applied for 30 min in each species. Data were gathered on wet/dry weight ratio, histological score, and area of alveolar collapse. Five out of six rabbits with high tidal volume developed tension pneumothorax, and the rabbit results were therefore not included in the histological analysis. Lungs from the pigs and rats showed minimal histological lesions. Pigs ventilated with high tidal volume had significantly greater oedema, higher neutrophil infiltration, and higher percentage area of alveolar collapse than rats ventilated with high tidal volume. We conclude that rabbits are not an appropriate species for in vivo studies of alveolar overdistension due to their fragility. Although some histological lesions are observed in pigs and rats, the lesions do not appear to be relevant.

High prevalence and incidence of HPV-related anal cancer precursor lesions in HIV-positive women in the late HAART era. / Alta prevalencia e incidencia de lesiones precursoras de cáncer anal asociada a la infección por VPH en mujeres VIH positivas en la era tardía del TAR.

INTRODUCTION: Anal cancer is one of the most common non-AIDS defining malignancies, especially in men who have sex with men and women living with HIV (WLHIV). OBJECTIVES: To evaluate the prevalence and incidence of precursor lesions (high-grade squamous intraepithelial lesions [HSIL]) and anal cancer in our cohort of women and to compare them to cervical lesions; to calculate the percentage of patients that acquire and clear oncogenic genotypes (HR-HPV) in the anal canal; and to determine predictive factors for anal HPV infection. PATIENTS AND METHODS: Prospective-longitudinal study (May 2012-December 2016). At baseline (V1) and follow up visits, anal mucosa samples were taken in liquid medium for cytology and HPV PCR. In cases of abnormal anal cytology and/or positive HR-HPV PCR results, a high resolution anoscopy was performed. Patients were also referred to the gynaecologist. RESULTS: Ninety five women with an average age of 43.7years were included. At baseline, 11.6% had cervical abnormalities (4.1% CIN1, 2.2% CIN2/3, 1.1% cervical cancer), 64.3% anal abnormalities (50% LSIL/AIN1, 9.5% HSIL/AIN2/3 and 2.4% anal cancer) and 49.4% had HR-HPV genotypes. During 36months of follow up, the incidence of anal HSIL was 16×1,000 person-years; 14.8% acquired HR-HPV genotypes and 51.2% cleared them, P=.007. No patients presented CIN1/2/3/ or cervical cancer. In the multivariate analysis we found the following predictive factors for HR-HPV infection: smoking (RR: 1.55, 95%CI: 0.99-2.42), number of sexual partners >3 (RR: 1.69; 95%CI: 1.09-2.62), cervical and anal dysplasia (RR: 1.83; 95%CI: 1.26-2.67) and (RR: 1.55; 95%CI: 1.021-2.35), respectively. CONCLUSIONS: Despite clearance rates of anal oncogenic genotypes being higher than acquisition rates, prevalence and incidence of HSIL were still high and greater than cervical HSIL. Therefore, screening for these lesions should perhaps be offered to all WLHIV.

Risk factors for infection by oncogenic human papillomaviruses in HIV-positive MSM patients in the ART era (2010-2016).

Squamous cell carcinoma of anus (SCCA) is one of the most frequent non-AIDS-defining diseases in HIV patients, mainly in men who have sex with men (MSM), and it is associated with human papillomavirus (HPV) infection.To determine the prevalence of high-risk HPV (HR-HPV) genotypes, premalignant lesions (HSIL) and SCCA in a cohort of HIV-positive MSM; to study the distribution of HPV genotypes according to anal histology results; and to analyze risk factors for this infection.This prospective single-center study was conducted between May 2010 and September 2016. At the study visit, cotton swabs were used to collect anal samples for cytology study in ThinPrep Pap Test liquid medium (Thin Prep Processor 2000, Hologic Corp, USA), and for HPV PCR (Linear Array HPV Genotyping Test). After, high-resolution anoscopy (HRA) (Zeiss 150 fc) was carried out. Logistic regression analysis was performed to identify risk factors for HR-HPV infection.The study included 319 patients, with mean age of 36.7 years; HR-HPV was detected in 81.3%. The prevalence of HSIL was 13.5% and SCCA was 0.3%. With regard to the distribution of HPV genotypes according to histology results, HPV 16 was the most frequent genotype in normal anal mucosa (26.7%), in LSILs (36.9%), and in HSILs (38%). In multivariate analysis, CD4 nadir < 200 cells/µL was the factor associated with infection by HR-HPV (OR 3.66, 95% CI 1.05%-12.75%).HIV-positive MSM showed a high prevalence of HSIL+ lesions and of infection by oncogenic HPV, which appears to be favored by a deficient immune system. HPV 16 was the most frequently isolated genotype in anal mucosa, regardless of lesion type.

Tumor-promoting activity of p-hydroxybenzenediazonium is accelerated in Mg-deficient rats.

Tumor-promoting activity caused by the short-term administration of p-hydroxybenzenediazonium (PDQ) has been assayed in rats fed on a Mg-deficient diet as a reference model versus rats fed on a standard diet as controls. For 5 weeks groups of 20 rats, fed either on the Mg-deficient or standard diet, were treated simultaneously with PDQ. A group of 10 Mg-deficient rats remained untreated. Topical application of PDQ was followed by the appearance of macroscopic alterations in the skin, which were more evident in the Mg-deficient rats. No deaths occurred during the treatment. After 5 weeks' PDQ treatment the rats were killed and histological analyses were made. Tissues from the skin, liver, heart, kidney, lung and thymus were screened by conventional staining methods. Both the PDQ-treated Mg-deficient and PDQ-treated control rats presented tissue lesions, although to a different extent. The untreated Mg-deficient rats showed no such lesions. Mg-deficient rats treated with PDQ developed significant incipient fibrosarcomas (p<0.05) and extended hyperplasia (p<0.001), particularly in the skin, accompanied by a significant increase in the thickness of collagen (mean value: 445.4+/-47.2microm, p<0.05) compared to the control PDQ-treated group (mean values: 258.7+/-36.4microm). The overall results provide objective proof of tumor-promoting activity after 5 weeks' treatment with PDQ. Such a fast response is interpreted as being linked to the increased vulnerability of the membrane caused by Mg deficiency, which would more readily facilitate the toxic activity of p-hydroxybenzenediazonium ions.

Age determination in subadults using histological analysis of bones / Determinación de la edad en subadultos usando análisis histológico de los huesos

Abstract Introduction: According to the literature, the amount of osteons has been suggested as a good proxy to determine the age of death in adults. However in subadults research has not been carried out yet. Objective: To determine the accuracy of the histomorphometric technique predicting the age at death in subadults using bone remains. Methodology: The information of static histomorphometric parameters from about 120 iliac bones retrieved from the exhumed remains of subadults whose age at death was known was taken from the Granada collection. In order to predict the age at death we performed a step by step linear regression to estimate the fittest model. Results: The most closely and significantly associated biopsy findings with age were: the osteon count, the internal cortical width, and the trabecular bone volume. Pearson's correlation index indicated a weak linear association among these variables. To assess the accuracy of the model we used a coefficient of determination with a 0.32 value. 32% of the age variation in the subadults was explained by the three variables. Conclusion: This regression model explains a percentage of the total age variation in the subadult population. However this model is not enough to determine the age at death.

Resumen Introducción: La capacidad de predicción de las osteonas para determinar la edad de muerte de los individuos ha sido descrito en la literatura científica. No obstante, no se ha determinado dicha capacidad en individuos subadultos. Objetivo: Determinar la eficacia de lo parámetros histomorfometricos en población subadulta. Metodología: Se realizaron biopsias de hueso ilíaco en los restos de 120 subadultos, de la Colección Osteológica de Granada, con edad conocida en el momento de la muerte. Para establecer la capacidad de predicción se utilizó el R2 obtenido a partir de regresión lineal múltiple. Resultados: Las variables con mayor nivel predictivo y significativo para la estimación de la edad fueron: recuento de osteonas tipo 2 de la cortical interna y externa, y el volumen óseo trabecular; En la evaluación del modelo, se obtuvo un coeficiente de determinación de 0.32, es decir, el 32% de la variación en la edad de los subadultos se explica por el modelo. Sin embargo, se evidenció diferencias en la capacidad de predicción por sexo. Conclusión: Este modelo de regresión explica un porcentaje sustancial de la varianza de la edad de los individuos en la muestra. No obstante, no es suficiente para garantizar una adecuada predicción de la edad al momento de muerte de los individuos subdultos.

Endoscopic ultrasonography-fine needle aspiration versus PET-CT in undiagnosed mediastinal and upper abdominal lymphadenopathy: a comparative clinical study.

BACKGROUND AND STUDY AIMS: The wide use of PET-CT for the staging of neoplasms has extended to enlarged lymph nodes of unknown origin. Nevertheless, upper abdominal and mediastinal nodes are accessible to endoscopic ultrasonography-fine needle aspiration (EUS-FNA), providing a cytological diagnosis, with a high diagnostic yield in previous reports. In this paper, we have compared the accuracy of both procedures in this particular setting. PATIENTS AND METHODS: After the finding of a lymphadenopathy in a conventional CT, both PET-CT and EUS-FNA were performed. The endoscopist had no information about PET-CT results. FNA was performed after a systematic EUS exam, with a 25 G needle and no suction. We considered the pathologic results as the gold standard or, if not available, the patients' outcome as a surrogate marker. RESULTS: A total of 54 patients were included. Common locations of nodes included subcarinal space (33.3%), porta hepatis (31.5%), upper mediastinum (15%), peripancreatic (7.4%), and other locations (12.8%). Adequate specimens were obtained in 48/54 patients (89%). The most common diagnoses based on cytology were benign/reactive (42%), epidermoid carcinoma (8.4%), lymphoma (8.4%), and ductal adenocarcinoma of pancreatic origin (6.3%). PET was positive in 67% of patients. The sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy of EUS-FNA were 91.3, 100, 100, 92.5, and 95.8%, respectively. The same values for PET-CT were 75, 25, 50, 50, and 50%, respectively. CONCLUSION: In our series, EUS-FNA has proven to be the best diagnostic procedure to accurately establish the etiology of isolated adenopathies, showing a much better diagnostic yield than PET-CT, the role of which should be re-evaluated in this setting.

The role of polymerase chain reaction of high-risk human papilloma virus in the screening of high-grade squamous intraepithelial lesions in the anal mucosa of human immunodeficiency virus-positive males having sex with males.

OBJECTIVES: To evaluate the advantages of cytology and PCR of high-risk human papilloma virus (PCR HR-HPV) infection in biopsy-derived diagnosis of high-grade squamous intraepithelial lesions (HSIL = AIN2/AIN3) in HIV-positive men having sex with men (MSM). METHODS: This is a single-centered study conducted between May 2010 and May 2014 in patients (n = 201, mean age 37 years) recruited from our outpatient clinic. Samples of anal canal mucosa were taken into liquid medium for PCR HPV analysis and for cytology. Anoscopy was performed for histology evaluation. RESULTS: Anoscopy showed 33.8% were normal, 47.8% low-grade squamous intraepithelial lesions (LSIL), and 18.4% HSIL; 80.2% had HR-HPV. PCR of HR-HPV had greater sensitivity than did cytology (88.8% vs. 75.7%) in HSIL screening, with similar positive (PPV) and negative predictive value (NPV) of 20.3 vs. 22.9 and 89.7 vs. 88.1, respectively. Combining both tests increased the sensitivity and NPV of HSIL diagnosis to 100%. Correlation of cytology vs. histology was, generally, very low and PCR of HR-HPV vs. histology was non-existent (<0.2) or low (<0.4). Area under the receiver operating characteristics (AUROC) curve analysis of cytology and PCR HR-HPV for the diagnosis of HSIL was poor (<0.6). Multivariate regression analysis showed protective factors against HSIL were: viral suppression (OR: 0.312; 95%CI: 0.099-0.984), and/or syphilis infection (OR: 0.193; 95%CI: 0.045-0.827). HSIL risk was associated with HPV-68 genotype (OR: 20.1; 95%CI: 2.04-197.82). CONCLUSIONS: When cytology and PCR HR-HPV findings are normal, the diagnosis of pre-malignant HSIL can be reliably ruled-out in HIV suppression with treatment protects against the appearance of HSIL [corrected].

Antiretroviral therapy as a factor protective against anal dysplasia in HIV-infected males who have sex with males.

OBJECTIVES: Chronic infection with oncogenic HPV genotype is associated with the development of anal dysplasia. Antiretroviral therapy (ART) has been shown to decrease the incidence of cervical carcinoma in women with HIV. We sought to: 1) describe the prevalence and grade of anal dysplasia and HPV infection in our study subjects; 2) analyze the grade of correlation between anal cytology, PCR of high-risk HPV, and histology; 3) identify the factors associated with the appearance of ≥ AIN2 lesions. DESIGN: Cross-sectional, prospective study. METHODS: A cohort of HIV-positive males (n = 140, mean age  = 37 years) who have sex with males (MSM) had epidemiological, clinical and analytical data collected. Anal mucosa samples were taken for cytology, HPV PCR genotyping, and anoscopy for histological analysis. RESULTS: Within the cohort, 77.1% were being treated with ART, 8.5% anoscopy findings were AIN2, and 11.4% carcinoma in situ; 74.2% had high-risk (HR), 59.7% low-risk (LR) HPV genotypes and 46.8% had both. The combination of cytology with PCR identifying HR-HPV better predicts the histology findings than either of these factors alone. Logistic regression highlighted ART as a protective factor against ≥ AIN2 lesions (OR: 0.214; 95%CI: 0.054-0.84). Anal/genital condylomas (OR: 4.26; 95%CI: 1.27-14.3), and HPV68 genotype (OR: 10.6; 95%CI: 1.23-91.47) were identified as risk factors. CONCLUSIONS: In our cohort, ART has a protective effect against dysplastic anal lesions. Anal/genital warts and HPV68 genotype are predictors of ≥ AIN2 lesions. Introducing PCR HPV genotype evaluation improves screening success over that of cytology alone.

HPV Direct Flow CHIP: a new human papillomavirus genotyping method based on direct PCR from crude-cell extracts.

HPV Direct Flow CHIP is a newly developed test for identifying 18 high-risk and 18 low-risk human papillomavirus (HPV) genotypes. It is based on direct PCR from crude-cell extracts, automatic flow-through hybridization, and colorimetric detection. The aim of this study was to evaluate the performance of HPV Direct Flow CHIP in the analysis of 947 samples from routine cervical screening or the follow-up of abnormal Pap smears. The specimens were dry swab samples, liquid-based cytology samples, or formalin-fixed paraffin-embedded tissues. The genotype distribution was in agreement with known epidemiological data for the Spanish population. Three different subgroups of the samples were also tested by Linear Array (LA) HPV Genotyping Test (n=108), CLART HPV2 (n=82), or Digene Hybrid Capture 2 (HC2) HPV DNA Test (n=101). HPV positivity was 73.6% by HPV Direct Flow CHIP versus 67% by LA, 65.9% by HPV Direct Flow CHIP versus 59.8% by CLART, and 62.4% by HPV Direct Flow CHIP versus 42.6% by HC2. HPV Direct Flow CHIP showed a positive agreement of 88.6% with LA (k=0.798), 87.3% with CLART (k=0.818), and 68.2% with HC2 (k=0.618). In conclusion, HPV Direct Flow CHIP results were comparable with those of the other methods tested. Although further investigation is needed to compare the performance of this new test with a gold-standard reference method, these preliminary findings evidence the potential value of HPV Direct Flow CHIP in HPV vaccinology and epidemiology studies.