Alberto Agarossi

p16INK4A expression is related to grade of CIN and high-risk human papillomavirus but does not predict virus clearance after conization or disease outcome

The role of p16INK4a as a marker of HR-HPV and in the diagnosis of CIN has been well established, but its predictive value in the clearance of the virus after CIN treatment and its use as a prognostic marker of cervical cancer has not been studied. A series of 302 archival samples, including 150 squamous cell carcinomas (SCCs) and 152 CIN lesions, were subjected to immunohistochemical staining for p16INK4a and HPV testing using PCR with three primer sets (MY09/11, GP5+/GP6+, SPF). Follow-up data were available of 88 SCC patients, and 67 of the CIN lesions had been followed-up with serial PCR after conization. HR-HPV types were closely associated with CIN (OR 19.12; 95%CI 2.31–157.81) and SCC (OR 27.25; 95%CI 3.28–226.09). There was a significant linear relationship between the lesion grade and intensity of p16INK4a staining (p = 0.0001). The expression of p16INK4a was also closely related to HR-HPV (p = 0.0001). p16INK4a staining was a 100% specific indicator of CIN, with 100% PPV, and showed 83.5% sensitivity and 80.1% PPV in detecting HR-HPV. However, p16INK4a staining did not predict clearance/persistence of HR-HPV after treatment of CIN. Similarly, despite a slightly more favorable survival in women with strong/intense p16INK4a staining in univariate analysis, p16INK4a expression was not an independent prognostic predictor in multivariate survival (Cox) analysis. After adjustment for p16INK4a staining, HR-HPV, histological grade, International Federation of Gynecology and Obstetrics (FIGO) stage, and age, only the last two were significant prognostic predictors (p = 0.0001 and p = 0.003, respectively). The present data confirm the role of p16INK4a as a highly specific marker of CIN and HR-HPV type, but expression of this protein does not seem to be of any prognostic value in cervical cancer or in predicting the clearance of HR-HPV after treatment of CIN. We speculate that different subgroups of cervical cancer are characterized by aberrant p16INK4a/cyclin D/Rb pathways that are due to different mechanisms that can be mutually exclusive.

Factors predicting the persistence of genital human papillomavirus infections and PAP smear abnormality in HIV-positive and HIV-negative women during prospective follow-up:

As part of an extensive multi-institutional DIANAIDS study focused on assessing the risk factors, natural history, diagnosis and follow-up of genital human papillomavirus (HPV) infections in HIV-infected women, the present communication reports a sub-cohort of 142 women (89 HIV+ and 48 HIV-), followed-up for a mean of 14.07 (±10.84) months to analyse the factors predicting the persistence and clearance of HPV infections (polymerase chain reaction [PCR] and sequencing) and cervical Papanicolaou (PAP) smear abnormalities, using both univariate (Kaplan-Meier) and multivariate (Cox) survival analysis. The appearance of new HPV infections during the follow-up was significantly more frequent in HIV-positive than in HIV-negative women, odds ratio (OR) 8.800 (95% confidence interval [CI]: 1.199-64.611), and also the clearance rate was significantly less frequent in HIV-positive than in HIV-negative women, 69.2% vs 22.8%, respectively (OR 0.330; 95% CI: 0.163-0.670). These two groups were also markedly different with respect to the clinical course of the cervical lesions, in the frequency of progressive disease (determined by PAP smear) was higher in HIV-positive group (12/89) than in HIV-negative women (2/52) (OR 3.506; 95% CI 0.816-15.055) (P = 0.055), in whom the disease regressed more frequently than in HIV-positive women (13.5% vs 7.9%) (OR 0.584; 95% CI 0.217-1.573). Using (1) HPV-positivity, (2) oncogenic HPV-type and (3) significant PAP smear abnormality at the end of follow-up as outcome measures, (1) was significantly (P < 0.001) predicted by the following variables in univariate analysis: age, mode of contraception, CD4 count, and HIV-positivity. The significant predictors of (2) were age and mode of contraception. The outcome measure (3) was significantly predicted by CD4 count, PAP smear abnormality and PCR status at entry. In the multivariate analysis, the significant independent predictive factors for HPV-positivity proved to be only the HIV status (P < 0.001), and PCR status at entry, p53 polymorphism at aa-72, oncogenic HPV type and significant PAP smear at entry remained independent predictors, with the significance level of P < 0.05. None of the significant predictors of oncogenic HPV type in univariate analysis retained their independent value in multivariate analysis. Oncogenic HPV type at entry proved to be an independent predictor of significant PAP smear (P < 0.05). The present results indicate that HIV-infected women, even on highly active antiretroviral therapy, demonstrate a more aggressive clinical course of cervical HPV infections, and fail to eradicate the disease more frequently than HIV-negative women. This persistence of HPV-positivity, oncogenic HPV type and significant PAP smear abnormality can be predicted by the results of PAP test and HPV typing in univariate analyses, and partly retain their independent predictive value also in multivariate analysis. Clearly, in addition to regular monitoring by PAP smear, HPV testing for the oncogenic HPV types seems to provide additional prognostic information in the management of cervical lesions in HIV-infected women.

Prevalence and type distribution of high-risk human papillomavirus infection in women undergoing voluntary cervical cancer screening in Italy

The aim of this survey was to assess the prevalence and distribution of oncogenic human papillomavirus (HPV) genotypes in women who underwent screening for cervical cancer in Italy. The correlation of genotypes with the cytological results was also evaluated. Cervical samples were collected from 9,947 self‐referring women for cervical cancer screening. Participants were screened by liquid‐based cytology and high‐risk HPV testing using the Hybrid Capture 2 test. Positive samples were genotyped by PCR. Samples (1,474; 14.8%) were positive for high‐risk HPV. The prevalence was 29.4% in the 15–19 years‐group, decreasing progressively to 6.1% at 50–54 years of age and increasing to 12.2% in those aged over 65 years. HPV 16 was the genotype detected most frequently followed by HPV 31, HPV 18, HPV 56, and HPV 51. HPV 16 or 18 were present in 4% of women with normal cytology and both were detected contemporarily in only 14 women. Twenty‐two percent of atypical squamous cells, 26% of low‐grade and 56% of high‐grade squamous intraepithelial lesions at cytology were positive for HPV 16 and/or 18. The prevalence of HPV infection in Italy is in agreement with that reported worldwide. HPV 16 was the prevalent genotype. The concomitant infection with HPV 16 and HPV 18 (vaccine targets) was found rarely. Apart from HPV 16 and 18, there was a substantial presence of HPV genotypes against which the vaccines available currently have shown cross‐protection efficacy. The findings of this study may contribute to reliable predictions on the potential efficacy of an HPV vaccine in clinical practice. J. Med. Virol. 81:529–535, 2009.

Activation of the ERK/MAP kinase pathway in cervical intraepithelial neoplasia is related to grade of the lesion but not to high-risk human papillomavirus, virus clearance, or prognosis in cervical cancer.

We subjected 302 archival samples (150 squamous cell carcinomas [SCCs] and 152 cervical intraepithelial neoplasia [CIN] lesions) to immunohistochemical staining with extracellular signal-regulated kinase-1 (ERK1) antibody and human papillomavirus (HPV) testing with 3 primer sets. Follow-up data were available for all SCC cases and 67 CIN cases. High-risk (HR) HPV types were associated with CIN (odds ratio [OR], 19.12; 95% confidence interval [CI], 2.31-157.81) and SCC (OR, 27.25; 95% CI, 3.28226.09). There was a significant linear relationship between lesion grade and ERK1 staining intensity (P = .0001). ERK1 staining was a 100% specific indicator of CIN, with a 100% positive predictive value, but a poor predictor of HR HPV. ERK1 expression did not predict clearance or persistence of HR HPV after CIN treatment. ERK1 staining did not significantly predict survival in cervical cancer in univariate (P = .915) or multivariate analysis. After adjustment for HR HPV, stage, age, and tumor grade in the Cox regression model, only stage (P = .0001) and age (P = .002) remained independent prognostic factors. ERK1 expression seems to be an early marker of cervical carcinogenesis. ERK1 overexpression is not a specific marker of HR-HPV in CIN and cervical cancer, nor does it predict virus clearance after CIN treatment or disease outcome in cervical cancer.

Colposcopy is not necessary to assess the risk to the cervix in HIV‐positive women: An international cohort study of cervical pathology in HIV‐1 positive women

The objectives of this prospective multicentre international cohort study are to describe the characteristics of a cohort of HIV‐1 positive women and determine the best management system by comparing cervical pathology according to results of cytology, colposcopy and human papillomavirus (HPV) testing at baseline and throughout follow‐up. A. Cohorts of known HIV‐positive women were recruited from 6 hospital‐based European centres and a community‐based South African centre. Following registration, women were reviewed every 6 months to undergo cervical surveillance including cytology, colposcopy, histopathology and HPV testing, using the HPV hybrid capture assay. Independent risk factors for the incidence of cytological abnormality and acquisition/clearance of HPV infection during follow up were identified. A total of 1,534 women were recruited, 400 of which were from South Africa. At baseline, among European women, 66% had normal cytology and half were HPV negative and among South African women, 45% had normal cytology and one third (32%) were HPV negative. The sensitivity of cytology (≥ASCUS) matched with that of colposcopy to detect CIN2+. Rate of detection of high grade CIN at 2 years was similar in European and South African women (11 and 9.3%, respectively). Cytology and HPV testing alone were each sufficiently sensitive as a screening test at 2 yearly intervals. Our data confirm the high prevalence of low‐grade cytological abnormalities and high‐risk HPV infection. Cytology appears to be sufficient for cervical surveillance, with HPV testing being less specific with poor positive predictive value. There appears to be no additional benefit from routine colposcopy.

Cesarean section using the Misgav Ladach method

Objective: To stress the advantages of the Misgav Ladach method for cesarean section. Study design: In this study operative details and the postoperative course of 139 patients who underwent cesarean section according to the Misgav Ladach method in 1995–1996 are presented. Results: The Misgav Ladach method reduces operation time, time of child delivery, and time of recovery. The rates of febrile morbidity, wound infection and wound dehiscence are not affected by the new technique. Conclusion: Our study highlights the efficiency and safety of the Misgav Ladach method, and points out the speeded recovery, with early ambulation and resumption of drinking and eating, that makes the cesarean section delivery closer and closer to natural childbirth.

Knowledge of HPV infection and vaccination among vaccinated and unvaccinated teenaged girls.

To assess the knowledge of teenaged girls on human papillomavirus (HPV) infection and vaccination 12 months after the start of a vaccine administration and information campaign.

Clinical and epidemiological correlates of antibody response to human papillomaviruses (HPVs) as measured by a novel ELISA based on denatured recombinant HPV16 late (L) and early (E) antigens

BackgroundAt present, seroreactivity is not a valuable parameter for diagnosis of Human Papillomavirus (HPV) infection but, it is potentially valuable as marker of viral exposure in elucidating the natural history of this infection. More data are needed to asses the clinical relevance of serological response to HPV.ObjectivesThe objective was to assess the clinical and epidemiological correlates of HPV-seroreactivity in a cohort of HIV-negative and HIV-positive women.MethodsSeroreactivity of 96 women, evaluated in an ELISA test based on denatured HPV16 late (L) and early (E) antigens, was correlated with their clinical and epidemiological data previously collected for a multi-centre Italian study, HPV-PathogenISS study.ResultsNo significant correlation was found between HPV DNA detection and seroreactivity. Women, current smokers showed significantly less seroreactivity to L antigens as compared with the non-smokers. HIV-positive women showed significantly less (66.7%) antibody response as compared with HIV-negative women (89.3%), with particularly impaired response to L antigens. Women, HIV-positive and current smokers, showed by far the lowest seroprevalence (33.3%) as compared to 75.9% among all other women (OR = 0.158; 95%CI 0.036–0.695, p = 0.014; Fishers exact test). Importantly, this association did not loose its significance when controlled for confounding from age (continuous variable) in multivariate analysis or using Mantel-Haenszel test for age-groups.ConclusionIt is tempting to speculate that HIV-positive current smokers comprise a special high-risk group, with highly impaired immunological response that could prevent eradication of persistent HPV infections and thus contribute to development of CIN3/CC.

HPV, HIV infection, and risk of cervical intraepithelial neoplasia in former intravenous drug abusers

Humaa immmmdefíciency vims infection among patients in a gyaecology emergency department Lindsay M.K.; Grant J.; Peterson H.B.; Risby J.; Williams H.; Klein L. USA OBSTET GYNECOL 1993 81/6 (1012-1015) Objective: To determine the extent of human immunodeficiency virus (HIV) infection risk factors and the relationship to the clinical diagnosis in women seen in a busy inner-city gynecology emergency department. Methods: We performed a cross-sectional survey by offering routine voluntary HIV-1 antibody screening and obtaining HIV risk behavior profiles in 1033 (35%) of 2952 women seeking care in our gynecology emergency department during a 5-week period. Results: The HIV seroprevalence was 2%. Six (35%) of the infected women reported a history of intravenous drug use, tïve (29%) reported a history of crack cocaine use, and tïve (29%) reported no risk factors for infection. Seropositive women were more likely than were seronegative women to have clinical symptoms consistent with pelvic infiammatory disease (18 vs. 3%; P < 0.01). Conclusion: These data sugest that women attending the gpxoiogy emergency room in our hospita1 are at substantial risk for HIV infection.

Leiomyomatosis peritonealis disseminata: A case report of recurrent presentation and literature review

Highlights • Leiomyomatosis peritonealis disseminata can result from laparoscopic myomectomies.• Tumor morcellation should be probably reconsidered.• In young women hormonal therapy is probably the best approach.• Close follow-up is necessary due to the risk of malignant degeneration.