Breast cancer and human papillomavirus (HPV) infection: No evidence of a viral etiology in a group of Swiss women

There are controversial data on the meaning of viral induction of breast cancer. The aim of this study was to investigate the presence of human papillomavirus (HPV) DNA in patients with breast carcinoma and the correlation of viral infection with disease outcome. Paraffin-embedded sections from 81 patients with breast cancer were analyzed for HPV DNA by polymerase chain reaction (PCR) using the SPF1/2 primers covering about 40 different low-, intermediate- and high-risk types. We found all samples were negative for HPV DNA. Our analysis could not support a role of HPV in breast carcinoma. Controversial published data indicate a need for further, larger epidemiologic studies.

Impact of viral E2-gene status on outcome after radiotherapy for patients with human papillomavirus 16-positive cancer of the uterine cervix

PURPOSE: Integration of high-risk papillomavirus DNA has been considered an important step in oncogenic progression to cervical carcinoma. Disruption of the human papillomavirus (HPV) genome within the E2 gene is frequently a consequence. This study investigated the influence of episomal viral DNA on outcome in patients with advanced cervical cancer treated with primary radiotherapy. METHODS AND MATERIALS: Paraffin-embedded biopsies of 82 women with locally advanced cervical cancer could be analyzed for HPV infection by multiplex polymerase chain reaction (PCR) by use of SPF1/2 primers. E2-gene intactness of HPV-16-positive samples was analyzed in 3 separate amplification reactions by use of the E2A, E2B, E2C primers. Statistical analyses (Kaplan-Meier method; log-rank test) were performed for overall survival (OS), disease-free survival (DFS), local progression-free survival (LPFS), and distant metastases-free survival (DMFS). RESULTS: Sixty-one (75%) of 82 carcinomas were HPV positive, 44 of them for HPV-16 (72%). Seventeen of the 44 HPV-16-positive tumors (39%) had an intact E2 gene. Patients with a HPV-16-positive tumor and an intact E2 gene showed a trend for a better DFS (58% vs. 38%, p = 0.06) compared with those with a disrupted E2 gene. A nonsignificant difference occurred regarding OS (87% vs. 66%, p = 0.16) and DMFS (57% vs. 48%, p = 0.15). CONCLUSION: E2-gene status may be a promising new target, but more studies are required to elucidate the effect of the viral E2 gene on outcome after radiotherapy in HPV-positive tumors.

Prediction of outcome in patients with low-grade squamous intraepithelial lesions by fluorescence in situ hybridization analysis of human papillomavirus, TERC, and MYC

BACKGROUND Cytology is an excellent method with which to diagnose preinvasive lesions of the uterine cervix, but it suffers from limited specificity for clinically significant lesions. Supplementary methods might predict the natural course of the detected lesions. The objective of the current study was to test whether a multicolor fluorescence in situ hybridization (FISH) assay might help to stratify abnormal results of Papanicolaou tests. METHODS A total of 219 liquid-based cytology specimens of low-grade squamous intraepithelial lesions (LSIL), 49 atypical squamous cells of undetermined significance (ASCUS) specimens, 52 high-grade squamous intraepithelial lesion (HSIL) specimens, and 50 normal samples were assessed by FISH with probes for the human papillomavirus (HPV), MYC, and telomerase RNA component (TERC). Subtyping of HPV by polymerase chain reaction (PCR) was performed in a subset of cases (n=206). RESULTS There was a significant correlation found between HPV detection by FISH and PCR (P<.0001). In patients with LSILs, the presence of HPV detected by FISH was significantly associated with disease progression (P<.0001). An increased MYC and/or TERC gene copy number (>2 signals in>10% of cells) prevailed in 43% of ASCUS specimens and was more frequent in HSIL (85%) than in LSIL (33%) (HSIL vs LSIL: P<.0001). Increased TERC gene copy number was significantly correlated with progression of LSIL (P<.01; odds ratio, 7.44; area under the receiver operating characteristic curve, 0.73; positive predictive value, 0.30; negative predictive value, 0.94) CONCLUSIONS: The detection of HPV by FISH analysis is feasible in liquid-based cytology and is significantly correlated with HPV analysis by PCR. The analysis of TERC gene copy number may be useful for risk stratification in patients with LSIL.

Toward global prevention of sexually transmitted infections (STIs): The need for STI vaccines.

An estimated 499 million curable sexually transmitted infections (STIs; gonorrhea, chlamydia, syphilis, and trichomoniasis) occurred globally in 2008. In addition, well over 500 million people are estimated to have a viral STI such as herpes simplex virus type 2 (HSV-2) or human papillomavirus (HPV) at any point in time. STIs result in a large global burden of sexual, reproductive, and maternal-child health consequences, including genital symptoms, pregnancy complications, cancer, infertility, and enhanced HIV transmission, as well as important psychosocial consequences and financial costs. STI control strategies based primarily on behavioral primary prevention and STI case management have had clear successes, but gains have not been universal. Current STI control is hampered or threatened by several behavioral, biological, and implementation challenges, including a large proportion of asymptomatic infections, lack of feasible diagnostic tests globally, antimicrobial resistance, repeat infections, and barriers to intervention access, availability, and scale-up. Vaccines against HPV and hepatitis B virus offer a new paradigm for STI control. Challenges to existing STI prevention efforts provide important reasons for working toward additional STI vaccines. We summarize the global epidemiology of STIs and STI-associated complications, examine challenges to existing STI prevention efforts, and discuss the need for new STI vaccines for future prevention efforts.

Multibranched acquired periungual fibrokeratomas with confounding histopathologic findings resembling papillomavirus infection: a report of two cases

Acquired periungual fibrokeratomas are benign fibrous tissue tumors and are considered as the topographical variant of acquired digital fibrokeratoma. They usually present as solitary tumors. In some instance, the entity may appear in multibranched fashion. The main histopathologic features consist of acanthosis, thick collagen bundles mainly oriented in a vertical axis forming a central core, and numerous proliferating fibroblasts. In this article, we present two cases of acquired multibranched periungual fibrokeratoma and depict their varying clinical features over time. Binucleation and perinuclear halos of keratinocytes mimicking human papillomavirus (HPV) infection were detected microscopically, but there was no reactivity with HPV immunostaining. In context, anti-HPV immunostaining may be helpful in the differentiation of fibrokeratomas from HPV infection. On the other hand, it should be kept in mind that these histopathologic findings may be found in acral biopsies independent of viral effects.

Detection of Merkel cell polyomavirus in epidermodysplasia-verruciformis-associated skin neoplasms

BACKGROUNd: Epidermodysplasia verruciformis (EV) is a rare genodermatosis that is characterized by susceptibility to infection with specific human papillomavirus (HPV) genotypes. Among polyomaviruses, the novel Merkel cell polyomavirus (MCPyV) has been found in different epithelial skin neoplasias.

Putting the magic in magic bullets: top three global priorities for sexually transmitted infection control

Setting practical priorities for sexually transmitted infection (STI) control is a balance between idealism and pragmatism. Infections transmitted through unsafe sex (chlamydia, gonorrhoea, syphilis, HIV, hepatitis B and human papillomavirus (HPV) infections) rank in the top five causes of the global burden of disease.1 Their distribution in populations is driven by a complex mixture of individual behaviours, social and community norms and societal and historical context. Ideally, we would be able to reduce exposure to unsafe sex to its theoretical minimum level of zero and thus eliminate a significant proportion of the current global burden of disease, particularly in resource-poor settings.2 Ideally, we would have ‘magic bullets’ for diagnosing and preventing STI in addition to specific antimicrobial agents for specific infections.3 Arguably, we have ‘bullets’ that work at the individual level; highly accurate diagnostic tests and highly efficacious vaccines, antimicrobial agents and preventive interventions.4 Introducing them into populations to achieve similarly high levels of effectiveness has been more challenging.4 In practice, the ‘magic’ in the magic bullet can be seen as overcoming the barriers to sustainable implementation in partnerships, larger sexual networks and populations (figure 1).4 We have chosen three (pragmatic) priorities for interventions that we believe could be implemented and scaled up to control STI other than HIV/AIDS. We present these starting with the partnership and moving up to the population level.

[Cervical cancer screening in Switzerland - current practice and future challenges]

At the beginning of the 20th Century, cervical cancer was the leading cause of death from cancer in women. A marked decline in cervical cancer has been observed since the 1960s, in parallel with the introduction of the Papanicolau (Pap) test as a cytological screening method. Today, Pap smear screening is still the most widely used tool for cervical cancer prevention. Testing for human papillomavirus (HPV) in cervical specimens or a combination of Pap and HPV testing are also now available. In this article we compare current guidelines for cervical cancer screening in Switzerland with those in other European countries. In view of the opportunities offered by HPV testing and, since 2008, HPV vaccination, current guidelines for cervical cancer screening should be updated. Both the choice of screening tests and general organization of cervical cancer screening should be reviewed.

Risk factors for anal cancer in persons infected with HIV: a nested case-control study in the Swiss HIV Cohort Study

Although persons infected with human immunodeficiency virus (HIV), particularly men who have sex with men, are at excess risk for anal cancer, it has been difficult to disentangle the influences of anal exposure to human papillomavirus (HPV) infection, immunodeficiency, and combined antiretroviral therapy. A case-control study that included 59 anal cancer cases and 295 individually matched controls was nested in the Swiss HIV Cohort Study (1988-2011). In a subset of 41 cases and 114 controls, HPV antibodies were tested. A majority of anal cancer cases (73%) were men who have sex with men. Current smoking was significantly associated with anal cancer (odds ratio (OR) = 2.59, 95% confidence interval (CI): 1.25, 5.34), as were antibodies against L1 (OR = 4.52, 95% CI: 2.00, 10.20) and E6 (OR = ∞, 95% CI: 4.64, ∞) of HPV16, as well as low CD4+ cell counts, whether measured at nadir (OR per 100-cell/μL decrease = 1.53, 95% CI: 1.18, 2.00) or at cancer diagnosis (OR per 100-cell/μL decrease = 1.24, 95% CI: 1.08, 1.42). However, the influence of CD4+ cell counts appeared to be strongest 6-7 years prior to anal cancer diagnosis (OR for <200 vs. ≥500 cells/μL = 14.0, 95% CI: 3.85, 50.9). Smoking cessation and avoidance of even moderate levels of immunosuppression appear to be important in reducing long-term anal cancer risks.

The impact of smoking on HPV infection and the development of anogenital warts

PURPOSE: The worldwide prevalence of human papillomavirus (HPV) infection is estimated at 9-13 %. Persistent infection can lead to the development of malignant and nonmalignant diseases. Low-risk HPV types are mostly associated with benign lesions such as anogenital warts. In the present systematic review, we examined the impact of smoking on HPV infection and the development of anogenital warts, respectively. METHODS: A systematic literature search was performed using MEDLINE database for peer-reviewed articles published from January 01, 1985 to November 30, 2013. Pooled rates of HPV prevalence were compared using the χ (2) test. RESULTS: In both genders, smoking is associated with higher incidence and prevalence rates for HPV infection, whereas the latter responds to a dose-effect relationship. The overall HPV prevalence for smoking patients was 48.2 versus 37. 5 % for nonsmoking patients (p < 0.001) (odds ratio (OR) = 1.5, 95 % confidence interval (CI) 1.4-1.7). Smoking does also increase persistence rates for high-risk HPV infection, while this correlation is debatable for low-risk HPV. The incidence and recurrence rates of anogenital warts are significantly increased in smokers. CONCLUSIONS: Most current data demonstrate an association between smoking, increased anogenital HPV infection, and development of anogenital warts. These data add to the long list of reasons for making smoking cessation a keystone of patient health.

Recombinant human factor VIIa prevents hysterectomy in severe postpartum hemorrhage: single center study

Abstract Objective: To evaluate the effectiveness of human recombinant activated factor VII (rhFVIIa, NovoSeven) in avoiding hysterectomy postpartum in the management of severe postpartum hemorrhage (PPH). Methods: We performed a prospective cohort study at our university tertiary care center. Patients with severe post partum hemorrhage (blood loss >2000 mL) and failed medical and uterus-preserving surgical management, were treated with intravenous bolus administration of rhVIIa. Main outcome measures were cessation of bleeding, postpartum hysterectomy and thromboembolic events. Results: In 20/22 patients included, PPH was caused primarily by uterine atony, including 7 (32%) with additional lower genital tract lesion; in two women, it was due to pathologic placentation (placenta increta, 9%). One case of amniotic fluid embolism and one woman with uterine inversion were included. Recombinant hFVIIa was successful in stopping the PPH and in preventing a hysterectomy in 20/22 women (91%). The remaining two patients with persistent bleeding despite rhFVIIa treatment, who underwent postpartum hysterectomy, had placenta increta. No thromboembolic event was noticed. Conclusions: This study describes the largest single center series of rhFVIIa treatment for fertility preservation in severe postpartum hemorrhage published to date. Our data suggest that administration of rhFVIIa is effective in avoiding postpartum hysterectomy after conservative medical and surgical measures have failed. Although randomized studies are lacking, rhFVIIa should be considered as a second-line therapeutic option of life-threatening postpartal bleeding, in particular if preservation of fertility is warranted and hysterectomy is to be avoided.

Waddlia chondrophila induces systemic infection, organ pathology, and elicits Th1-associated humoral immunity in a murine model of genital infection

Waddlia chondrophila is a known bovine abortigenic Chlamydia-related bacterium that has been associated with adverse pregnancy outcomes in human. However, there is a lack of knowledge regarding how W. chondrophila infection spreads, its ability to elicit an immune response and induce pathology. A murine model of genital infection was developed to investigate the pathogenicity and immune response associated with a W. chondrophila infection. Genital inoculation of the bacterial agent resulted in a dose-dependent infection that spread to lumbar lymph nodes and successively to spleen and liver. Bacterial-induced pathology peaked on day 14, characterized by leukocyte infiltration (uterine horn, liver, and spleen), necrosis (liver) and extramedullary hematopoiesis (spleen). Immunohistochemistry demonstrated the presence of a large number of W. chondrophila in the spleen on day 14. Robust IgG titers were detected by day 14 and remained high until day 52. IgG isotypes consisted of high IgG2a, moderate IgG3 and no detectable IgG1, indicating a Th1-associated immune response. This study provides the first evidence that W. chondrophila genital infection is capable of inducing a systemic infection that spreads to major organs, induces uterus, spleen, and liver pathology and elicits a Th1-skewed humoral response. This new animal model will help our understanding of the mechanisms related to intracellular bacteria-induced miscarriages, the most frequent complication of pregnancy that affects one in four women.

The comprehensiveness of the ESHRE/ESGE classification of female genital tract congenital anomalies: a systematic review of cases not classified by the AFS system.

STUDY QUESTION How comprehensive is the recently published European Society of Human Reproduction and Embryology (ESHRE)/European Society for Gynaecological Endoscopy (ESGE) classification system of female genital anomalies? SUMMARY ANSWER The ESHRE/ESGE classification provides a comprehensive description and categorization of almost all of the currently known anomalies that could not be classified properly with the American Fertility Society (AFS) system. WHAT IS KNOWN ALREADY Until now, the more accepted classification system, namely that of the AFS, is associated with serious limitations in effective categorization of female genital anomalies. Many cases published in the literature could not be properly classified using the AFS system, yet a clear and accurate classification is a prerequisite for treatment. STUDY DESIGN, SIZE AND DURATION The CONUTA (CONgenital UTerine Anomalies) ESHRE/ESGE group conducted a systematic review of the literature to examine if those types of anomalies that could not be properly classified with the AFS system could be effectively classified with the use of the new ESHRE/ESGE system. An electronic literature search through Medline, Embase and Cochrane library was carried out from January 1988 to January 2014. Three participants independently screened, selected articles of potential interest and finally extracted data from all the included studies. Any disagreement was discussed and resolved after consultation with a fourth reviewer and the results were assessed independently and approved by all members of the CONUTA group. PARTICIPANTS/MATERIALS, SETTING, METHODS Among the 143 articles assessed in detail, 120 were finally selected reporting 140 cases that could not properly fit into a specific class of the AFS system. Those 140 cases were clustered in 39 different types of anomalies. MAIN RESULTS AND THE ROLE OF CHANCE The congenital anomaly involved a single organ in 12 (30.8%) out of the 39 types of anomalies, while multiple organs and/or segments of Müllerian ducts (complex anomaly) were involved in 27 (69.2%) types. Uterus was the organ most frequently involved (30/39: 76.9%), followed by cervix (26/39: 66.7%) and vagina (23/39: 59%). In all 39 types, the ESHRE/ESGE classification system provided a comprehensive description of each single or complex anomaly. A precise categorization was reached in 38 out of 39 types studied. Only one case of a bizarre uterine anomaly, with no clear embryological defect, could not be categorized and thus was placed in Class 6 (un-classified) of the ESHRE/ESGE system. LIMITATIONS, REASONS FOR CAUTION The review of the literature was thorough but we cannot rule out the possibility that other defects exist which will also require testing in the new ESHRE/ESGE system. These anomalies, however, must be rare. WIDER IMPLICATIONS OF THE FINDINGS The comprehensiveness of the ESHRE/ESGE classification adds objective scientific validity to its use. This may, therefore, promote its further dissemination and acceptance, which will have a positive outcome in clinical care and research. STUDY FUNDING/COMPETING INTERESTS None.