Jacob Bornstein

Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study

BACKGROUNDnKnowledge about the distribution of human papillomavirus (HPV) genotypes in invasive cervical cancer is crucial to guide the introduction of prophylactic vaccines. We aimed to provide novel and comprehensive data about the worldwide genotype distribution in patients with invasive cervical cancer.nnnMETHODSnParaffin-embedded samples of histologically confirmed cases of invasive cervical cancer were collected from 38 countries in Europe, North America, central South America, Africa, Asia, and Oceania. Inclusion criteria were a pathological confirmation of a primary invasive cervical cancer of epithelial origin in the tissue sample selected for analysis of HPV DNA, and information about the year of diagnosis. HPV detection was done by use of PCR with SPF-10 broad-spectrum primers followed by DNA enzyme immunoassay and genotyping with a reverse hybridisation line probe assay. Sequence analysis was done to characterise HPV-positive samples with unknown HPV types. Data analyses included algorithms of multiple infections to estimate type-specific relative contributions.nnnFINDINGSn22,661 paraffin-embedded samples were obtained from 14,249 women. 10,575 cases of invasive cervical cancer were included in the study, and 8977 (85%) of these were positive for HPV DNA. The most common HPV types were 16, 18, 31, 33, 35, 45, 52, and 58 with a combined worldwide relative contribution of 8196 of 8977 (91%, 95% CI 90-92). HPV types 16 and 18 were detected in 6357 of 8977 of cases (71%, 70-72) of invasive cervical cancer. HPV types 16, 18, and 45 were detected in 443 of 470 cases (94%, 92-96) of cervical adenocarcinomas. Unknown HPV types that were identified with sequence analysis were 26, 30, 61, 67, 69, 82, and 91 in 103 (1%) of 8977 cases of invasive cervical cancer. Women with invasive cervical cancers related to HPV types 16, 18, or 45 presented at a younger mean age than did those with other HPV types (50·0 years [49·6-50·4], 48·2 years [47·3-49·2], 46·8 years [46·6-48·1], and 55·5 years [54·9-56·1], respectively).nnnINTERPRETATIONnTo our knowledge, this study is the largest assessment of HPV genotypes to date. HPV types 16, 18, 31, 33, 35, 45, 52, and 58 should be given priority when the cross-protective effects of current vaccines are assessed, and for formulation of recommendations for the use of second-generation polyvalent HPV vaccines. Our results also suggest that type-specific high-risk HPV-DNA-based screening tests and protocols should focus on HPV types 16, 18, and 45.

Worldwide human papillomavirus genotype attribution in over 2000 cases of intraepithelial and invasive lesions of the vulva

BACKGROUNDnHuman papillomavirus (HPV) contribution in vulvar intraepithelial lesions (VIN) and invasive vulvar cancer (IVC) is not clearly established. This study provides novel data on HPV markers in a large series of VIN and IVC lesions.nnnMETHODSnHistologically confirmed VIN and IVC from 39 countries were assembled at the Catalan Institute of Oncology (ICO). HPV-DNA detection was done by polymerase chain reaction using SPF-10 broad-spectrum primers and genotyping by reverse hybridisation line probe assay (LiPA25) (version 1). IVC cases were tested for p16(INK4a) by immunohistochemistry (CINtec histology kit, ROCHE). An IVC was considered HPV driven if both HPV-DNA and p16(INK4a) overexpression were observed simultaneously. Data analyses included algorithms allocating multiple infections to calculate type-specific contribution and logistic regression models to estimate adjusted prevalence (AP) and its 95% confidence intervals (CI).nnnRESULTSnOf 2296 cases, 587 were VIN and 1709 IVC. HPV-DNA was detected in 86.7% and 28.6% of the cases respectively. Amongst IVC cases, 25.1% were both HPV-DNA and p16(INK4a) positive. IVC cases were largely keratinising squamous cell carcinoma (KSCC) (N=1234). Overall prevalence of HPV related IVC cases was highest in younger women for any histological subtype. SCC with warty or basaloid features (SCC_WB) (N=326) were more likely to be HPV and p16(INK4a) positive (AP=69.5%, CI=63.6-74.8) versus KSCC (AP=11.5%, CI=9.7-13.5). HPV 16 was the commonest type (72.5%) followed by HPV 33 (6.5%) and HPV 18 (4.6%). Enrichment from VIN to IVC was significantly high for HPV 45 (8.5-fold).nnnCONCLUSIONnCombined data from HPV-DNA and p16(INK4a) testing are likely to represent a closer estimate of the real fraction of IVC induced by HPV. Our results indicate that HPV contribution in invasive vulvar cancer has probably been overestimated. HPV 16 remains the major player worldwide.

Hyperinnervation and Mast Cell Activation May Be Used as Histopathologic Diagnostic Criteria for Vulvar Vestibulitis

Objective: Vestibulitis is currently diagnosed based only on clinical criteria. To achieve histopathological diagnostic criteria, we carried out a computerized image analysis method. Methods: Vestibular tissues removed from 40 women with severe vestibulitis were immunostained for mast cell count and degranulation by C-kit and mast cell tryptase, respectively. Vestibular nerve cells total area was evaluated after S-100 stain. Controls were 7 women aged 18–48. The images were converted to a digital signal, and analyzed using Image Proplus V4 software. Results: We found a significant increase in inflammatory infiltrate, number of mast cells and degranulated mast cells in vestibulitis compared to normal controls. The inflammatory cells were localized around the superficial minor vestibular glands. The total nerve fiber area was ten times higher in vestibulitis patients than in controls. A significant positive correlation was found between the total nerve fiber area and the number of mast cells in the vestibulitis group of patients. Conclusion: We documented two diagnostic histopathological criteria for vestibulitis: (1) the presence of eight or more mast cells per 10 × 10 microscopic field, and (2) the total calculated area of the nerve fibers is ten times higher than expected. These findings re-establish the inflammatory nature of the vestibulitis. It is speculated that the trigger for the local outburst of nerve fibers could be related to the activation of the mast cells by a topical agent.

EUROGIN 2011 roadmap on prevention and treatment of HPV-related disease

The EUROGIN 2011 roadmap reviews the current burden of human papillomavirus (HPV)‐related morbidity, as well as the evidence and potential practice recommendations regarding primary and secondary prevention and treatment of cancers and other disease associated with HPV infection. HPV infection causes ∼600,000 cases of cancer of the cervix, vulva, vagina, anus and oropharynx annually, as well as benign diseases such as genital warts and recurrent respiratory papillomatosis. Whereas the incidence of cervical cancer has been decreasing over recent decades, the incidence of anal and oropharyngeal carcinoma, for which there are no effective screening programs, has been rising over the last couple of decades. Randomized trials have demonstrated improved efficacy of HPV‐based compared to cytology‐based cervical cancer screening. Defining the best algorithms to triage HPV‐positive women, age ranges and screening intervals are priorities for pooled analyses and further research, whereas feasibility questions can be addressed through screening programs. HPV vaccination will reduce the burden of cervical precancer and probably also of invasive cervical and other HPV‐related disease in women. Recent trials demonstrated that prophylactic vaccination also protects against anogenital HPV infection, anogenital intraepithelial lesions and warts associated with vaccine types, in males; and anal HPV infection and anal intraepithelial neoplasia in MSM. HPV‐related oropharyngeal cancer could be treated less aggressively because of better survival compared to cancers of the oropharynx unrelated to HPV. Key findings in the field of cervical cancer prevention should now be translated in cost‐effective strategies, following an organized approach integrating primary and secondary prevention, according to scientific evidence but adapted to the local situation with particular attention to regions with the highest burden of disease.

Placental volume and three‐dimensional power Doppler analysis in prediction of pre‐eclampsia and small for gestational age between Week 11 and 13 weeks and 6 days of gestation

To assess three‐dimensional placental volume measurement and three‐dimensional power Doppler (3D‐PD) indices between 10 weeks and 6 days and 13 weeks and 6 days in predicting pregnancy‐induced hypertension (PIH) and small for gestational age (SGA).

2015 ISSVD, ISSWSH and IPPS Consensus Terminology and Classification of Persistent Vulvar Pain and Vulvodynia.

INTRODUCTIONnIn 2014, the Executive Council of the International Society for the Study of Vulvovaginal Disease (ISSVD), the Boards of Directors of the International Society for the Study of Womens Sexual Health (ISSWSH), and the International Pelvic Pain Society (IPPS) acknowledged the need to revise the current terminology of vulvar pain, based on the significant increase in high quality etiologic studies published in the last decade.nnnMETHODSnThe new terminology was achieved in four steps. The first involved a terminology consensus conference with representatives of the three societies, held in April 2015. Then, an analysis of the relevant published studies was used to establish a level of evidence for each factor associated with vulvodynia. The terminology was amended based on feedback from members of the societies. Finally, each societys board accepted the new terminology.nnnRESULTS AND CONCLUSIONnIn 2015, the ISSVD, ISSWSH, and IPPS adopted a new vulvar pain and vulvodynia terminology that acknowledges the complexity of the clinical presentation and pathophysiology involved in vulvar pain and vulvodynia, and incorporates new information derived from evidence-based studies conducted since the last terminology published inxa02003.

Topical Nifedipine for the Treatment of Localized Provoked Vulvodynia: A Placebo-Controlled Study

UNLABELLEDnTopical application of the calcium antagonist nifedipine has demonstrated effectiveness in treating chronic anal fissure, without adverse effects. Like chronic anal fissure, vulvodynia is associated with muscle hypertonicity and an inflammatory infiltrate. We conducted a double-blind placebo-controlled study to investigate the effectiveness of 2 concentrations of topical nifedipine cream in the treatment of vulvodynia. Thirty participants were alternately assigned to 3 topical treatment groups: .2% nifedipine, .4% nifedipine, and placebo. All administered the cream to the vestibule 4 times daily for 6 weeks. For all 3 treatment groups, mean pain intensity on vestibular touch, assessed by the Q-tipped cotton test, pain from speculum insertion, and reports of pain during sexual intercourse was reduced at post-treatment compared with pre-treatment. These improvements remained at 3 months follow-up. The effectiveness of nifedipine in treating vulvodynia did not exceed that of placebo.nnnPERSPECTIVEnThe topical application of both nifedipine and a placebo reduced pain in women with vulvodynia. This study highlights the need for controlled trials of treatments for vulvodynia and raises doubts about studies conducted without comparison to placebo.

Safety Profile of the 9-Valent HPV Vaccine: A Combined Analysis of 7 Phase III Clinical Trials

OBJECTIVES: The overall safety profile of the 9-valent human papillomavirus (9vHPV) vaccine was evaluated across 7 Phase III studies, conducted in males and females (nonpregnant at entry), 9 to 26 years of age. METHODS: Vaccination was administered as a 3-dose regimen at day 1, and months 2 and 6. More than 15u2009000 subjects received ≥1 dose of 9vHPV vaccine. In 2 of the studies, >7000 control subjects received ≥1 dose of quadrivalent HPV (qHPV) vaccine. Serious and nonserious adverse events (AEs) and new medical conditions were recorded throughout the study. Subjects testing positive for pregnancy at day 1 were not vaccinated; those who became pregnant after day 1 were discontinued from further vaccination until resolution of the pregnancy. Pregnancies detected after study start (n = 2950) were followed to outcome. RESULTS: The most common AEs (≥5%) experienced by 9vHPV vaccine recipients were injection-site AEs (pain, swelling, erythema) and vaccine-related systemic AEs (headache, pyrexia). Injection-site AEs were more common in 9vHPV vaccine than qHPV vaccine recipients; most were mild-to-moderate in intensity. Discontinuations and vaccine-related serious AEs were rare (0.1% and <0.1%, respectively). Seven deaths were reported; none were considered vaccine related. The proportions of pregnancies with adverse outcome were within ranges reported in the general population. CONCLUSIONS: The 9vHPV vaccine was generally well tolerated in subjects aged 9 to 26 years with an AE profile similar to that of the qHPV vaccine; injection-site AEs were more common with 9vHPV vaccine. Its additional coverage and safety profile support widespread 9vHPV vaccination.

The 2015 International Society for the Study of Vulvovaginal Disease (ISSVD) Terminology of Vulvar Squamous Intraepithelial Lesions

OBJECTIVES: The impact of terminology for vulvar intraepithelial lesions has been significant over the years, because it has affected diagnosis, treatment, and research. The introduction of the Lower Anogenital Squamous Terminology (LAST) in 2012 raised 2 concerns in relation to vulvar lesions: firstly, the absence of reference to “differentiated vulvar intraepithelial neoplasia” (differentiated VIN) could lead to its being overlooked by health care providers, despite its malignant potential. Secondly, including the term “low-grade squamous intraepithelial lesion” (LSIL) in LAST recreated the potential for overdiagnosis and overtreatment for benign, self-limiting lesions. MATERIALS AND METHODS: The International Society for the Study of Vulvovaginal Disease (ISSVD) assigned the terminology committee the task of developing a terminology to take these issues into consideration. The committee reviewed the development of terminology for vulvar SILs with the previous 2 concerns in mind and reviewed several new terminology options. RESULTS: The final version accepted by the ISSVD contains the following: 1) Low-grade SIL of the vulva or vulvar LSIL, encompassing flat condyloma or human papillomavirus effect. 2) High-grade SIL or vulvar HSIL (which was termed “vulvar intraepithelial neoplasia usual type” in the 2004 ISSVD terminology). 3) Vulvar intraepithelial neoplasia, differentiated type. CONCLUSION: The advantage of the new terminology is that it includes all types of vulvar SILs, it provides a solution to the concerns in relation to the application of LAST to vulvar lesion, and it is in accordance with the World Health Organization classification as well as the LAST, creating unity among clinicians and pathologists.

2015 ISSVD, ISSWSH, and IPPS Consensus Terminology and Classification of Persistent Vulvar Pain and Vulvodynia.

IntroductionIn 2014, the executive council of the International Society for the Study of Vulvovaginal Disease, the boards of directors of the International Society for the Study of Womens Sexual Health, and the International Pelvic Pain Society acknowledged the need to revise the current terminology of vulvar pain, on the basis of the significant increase in high-quality etiologic studies published in the last decade. Materials and MethodsThe new terminology was achieved in the following 4 steps. The first involved a terminology consensus conference with representatives of the 3 societies, held in April 2015. Then, an analysis of the relevant published studies was used to establish a level of evidence for each factor associated with vulvodynia. The terminology was amended on the basis of feedback from members of the societies. Finally, each societys board accepted the new terminology. Results and ConclusionsIn 2015, the International Society for the Study of Vulvovaginal Disease, International Society for the Study of Womens Sexual Health, and International Pelvic Pain Society adopted a new vulvar pain and vulvodynia terminology that acknowledges the complexity of the clinical presentation and pathophysiology involved in vulvar pain and vulvodynia, and incorporates new information derived from evidence-based studies conducted since the last terminology published in 2003.