Performance of p16INK4a ELISA as a primary cervical cancer screening test among a large cohort of HIV-infected women in western Kenya: a 2-year cross-sectional study.

ObjectiveA biomarker with increased specificity for cervical dysplasia compared with human papillomavirus (HPV) testing would be an attractive option for cervical cancer screening among HIV-infected women in resource-limited settings. p16(INK4a) has been explored as a biomarker for screening in general populations.DesignA 2-year cross-sectional study.Setting2 large HIV primary care clinics in western Kenya.Participants1054 HIV-infected women in western Kenya undergoing cervical cancer screening as part of routine HIV care from October 2010 to November 2012.InterventionsParticipants underwent p16(INK4a) specimen collection and colposcopy. Lesions with unsatisfactory colposcopy or suspicious for cervical intraepithelial neoplasia 2+ (CIN2+; including CIN2/3 or invasive cervical cancer) were biopsied. Following biopsy, disease status was determined by histopathological diagnosis.Primary and secondary outcome measuresWe measured the sensitivity, specificity and predictive values of p16(INK4a) ELISA for CIN2+ detection among HIV-infected women and compared them to the test characteristics of current screening methods used in general as well as HIV-infected populations.ResultsAverage p16(INK4a) concentration in cervical samples was 37.4 U/mL. After colposcopically directed biopsy, 127 (12%) women were determined to have CIN2+. Receiver operating characteristic analysis showed an area under the curve of 0.664 for p16(INK4a) to detect biopsy-proven CIN2+. At a p16(INK4a) cut-off level of 9 U/mL, sensitivity, specificity, positive and negative predictive values were 89.0%, 22.9%, 13.6% and 93.8%, respectively. The overall p16(INK4a) positivity at a cut-off level of 9 U/mL was 828 (78.6%) women. There were 325 (30.8%) cases of correct p16(INK4a) prediction to detect or rule out CIN2+, and 729 (69.2%) cases of incorrect p16(INK4a) prediction.Conclusionsp16(INK4a) ELISA did not perform well as a screening test for CIN2+ detection among HIV-infected women due to low specificity. Our study contributes to the ongoing search for a more specific alternative to HPV testing for CIN2+ detection

p16INK4a/Ki-67 dual stain cytology for cervical cancer screening in Thika district, Kenya

Background: The identification of suited early detection tests is one among the multiple requirements to reduce cervical cancer incidence in developing countries. Methods: We evaluated p16INK4a/Ki-67 dual-stain cytology in a screening population in Thika district, Kenya and compared it to high-risk human papillomavirus (HR-HPV) DNA testing and visual inspection by acetic acid (VIA) and Lugol’s iodine (VILI). Results: Valid results for all tests could be obtained in 477 women. 20.9 % (100/477) were tested positive for HR-HPV DNA, 3.1 % (15/477) had positive VIA/VILI and 8.2 % (39/477) positive p16INK4a/Ki-67 cytology. Of 22 women that showed up for colposcopy and biopsy, 6 women were diagnosed with CIN3 and two with CIN2. All women with CIN2/3 were negative in VIA/VILI screening and positive by HR-HPV DNA testing. But HPV was also positive in 91.7 % (11/12) of women with normal histology. p16INK4a/Ki-67 cytology was positive in all 6 women with CIN3, in one of the two CIN2 and in only 8.3 % (1/12) of women with normal histology. Conclusions: p16INK4a/Ki-67 cytology is an interesting test for further studies in developing countries, since our findings point to a lower fraction of false positive test results using p16INK4a/Ki-67 cytology compared to HPV DNA testing in a Kenyan screening population. VIA/VILI missed all histology-proven CIN2/3

Targeted deep sequencing of mucinous ovarian tumors reveals multiple overlapping RAS-pathway activating mutations in borderline and cancerous neoplasms

Background: Mucinous ovarian tumors represent a distinct histotype of epithelial ovarian cancer. The rarest (2-4 % of ovarian carcinomas) of the five major histotypes, their genomic landscape remains poorly described. We undertook hotspot sequencing of 50 genes commonly mutated in human cancer across 69 mucinous ovarian tumors. Our goals were to establish the overall frequency of cancer-hotspot mutations across a large cohort, especially those tumors previously thought to be “RAS-pathway alteration negative”, using highly-sensitive next-generation sequencing as well as further explore a small number of cases with apparent heterogeneity in RAS-pathway activating alterations. Methods: Using the Ion Torrent PGM platform, we performed next generation sequencing analysis using the v2 Cancer Hotspot Panel. Regions of disparate ERBB2-amplification status were sequenced independently for two mucinous carcinoma (MC) cases, previously established as showing ERBB2 amplification/overexpression heterogeneity, to assess the hypothesis of subclonal populations containing either KRAS mutation or ERBB2 amplification independently or simultaneously. Results: We detected mutations in KRAS, TP53, CDKN2A, PIK3CA, PTEN, BRAF, FGFR2, STK11, CTNNB1, SRC, SMAD4, GNA11 and ERBB2. KRAS mutations remain the most frequently observed alteration among MC (64.9 %) and mucinous borderline tumors (MBOT) (92.3 %). TP53 mutation occurred more frequently in carcinomas than borderline tumors (56.8 % and 11.5 %, respectively), and combined IHC and mutation data suggest alterations occur in approximately 68 % of MC and as many as 20 % of MBOT. Proven and potential RAS-pathway activating changes were observed in all but one MC. Concurrent ERBB2 amplification and KRAS mutation were observed in a substantial number of cases (7/63 total), as was co-occurrence of KRAS and BRAF mutations (one case). Microdissection of ERBB2-amplified regions of tumors harboring KRAS mutation suggests these alterations are occurring in the same cell populations, while consistency of KRAS allelic frequency in both ERBB2 amplified and non-amplified regions suggests this mutation occurred in advance of the amplification event. Conclusions: Overall, the prevalence of RAS-alteration and striking co-occurrence of pathway “double-hits” supports a critical role for tumor progression in this ovarian malignancy. Given the spectrum of RAS-activating mutations, it is clear that targeting this pathway may be a viable therapeutic option for patients with recurrent or advanced stage mucinous ovarian carcinoma, however caution should be exercised in selecting one or more personalized therapeutics given the frequency of non-redundant RAS-activating alterations

Human Papillomavirus Vaccine Impact and Effectiveness in Six High-Risk Populations: A Systematic Literature Review

Specific adult populations known to be at high risk for human papillomavirus (HPV)-related disease, such as men who have sex with men, are inconsistently included in national immunization programs. No compilation of the evidence on the real-world impact and effectiveness of HPV vaccines across these populations exists. This systematic literature review identifies and synthesizes the evidence of the real-world impact and effectiveness of the quadrivalent and nonavalent HPV vaccines in high-risk populations: women with prior/current HPV-related anogenital disease, men who have sex with men, immunocompromised/immunosuppressed individuals, female sex workers, transgender and non-binary individuals, and patients with recurrent respiratory papillomatosis (RRP). The outcomes included anogenital precancers/cancers, head and neck cancers, genital warts, and RRP recurrence. From the 2216 records identified, 30 studies (25 effectiveness and 5 impact studies) were included in this systematic literature review. The results, quantity, and quality of these studies were highly variable. The evidence for effectiveness was of high quality only in women with prior/current cervical disease and in individuals with RRP, the most frequently studied populations. No studies of transgender/non-binary individuals or female sex workers were identified. The real-world evidence supports HPV vaccination among women with prior cervical disease and individuals with RRP. Significant real-world data gaps remain in these high-risk populations

A systematic review of the HPV-attributable fraction of oropharyngeal squamous cell carcinomas in Germany

The prevalence of oropharyngeal squamous cell carcinoma (OPSCC) is increasing globally while the prevalence of other head and neck cancers is decreasing. The most likely reasons for this are a decreasing influence of smoking and the growing relevance of infections with the human papilloma virus (HPV) as a risk factor. A rise in the HPV-attributable fraction (HPV-AF) of OPSCC has been observed in many countries, yet a comprehensive review of prevalence rates and trends in Germany is lacking. To determine the current HPV-AF of OPSCC in Germany and to assess whether it has changed during the last decades, we performed a systematic literature review. We screened Medline and EMBASE for studies that reported the tumor HPV status of newly diagnosed OPSCC patients treated at medical centers in Germany by testing for both HPV DNA and p16(INK4a) overexpression to confirm involvement of HPV in tumorigenesis. Out of 287 screened studies, 14 studies with data from a total of 1819 OPSCC patients treated between 1988 and 2015 were included in the data synthesis. The reported average HPV-AF varied considerably between the studies, ranging from 11.5% (1988-2008) to 55.0% (2004-2009). Two of the included studies did not only provide the HPV-AF for the entire observed calendar period but also for separate years, allowing to more accurately assess changes over time. These studies reported increases in the HPV-AF from 21% in 2000 to 53% in 2015 and from 38% in 2004 to 71% in 2013, respectively

A Virtual Microscopy System to Scan, Evaluate and Archive Biomarker Enhanced Cervical Cytology Slides

Background: Although cytological screening for cervical precancers has led to a reduction of cervical cancer incidence worldwide it is a subjective and variable method with low single-test sensitivity. New biomarkers like p16 that specifically highlight abnormal cervical cells can improve cytology performance. Virtual microscopy offers an ideal platform for assisted evaluation and archiving of biomarker-stained slides

Performance of p16INK4a ELISA as a primary cervical cancer screening test among a large cohort of HIV-infected women in western Kenya: a 2-year cross-sectional study.

ObjectiveA biomarker with increased specificity for cervical dysplasia compared with human papillomavirus (HPV) testing would be an attractive option for cervical cancer screening among HIV-infected women in resource-limited settings. p16(INK4a) has been explored as a biomarker for screening in general populations.DesignA 2-year cross-sectional study.Setting2 large HIV primary care clinics in western Kenya.Participants1054 HIV-infected women in western Kenya undergoing cervical cancer screening as part of routine HIV care from October 2010 to November 2012.InterventionsParticipants underwent p16(INK4a) specimen collection and colposcopy. Lesions with unsatisfactory colposcopy or suspicious for cervical intraepithelial neoplasia 2+ (CIN2+; including CIN2/3 or invasive cervical cancer) were biopsied. Following biopsy, disease status was determined by histopathological diagnosis.Primary and secondary outcome measuresWe measured the sensitivity, specificity and predictive values of p16(INK4a) ELISA for CIN2+ detection among HIV-infected women and compared them to the test characteristics of current screening methods used in general as well as HIV-infected populations.ResultsAverage p16(INK4a) concentration in cervical samples was 37.4 U/mL. After colposcopically directed biopsy, 127 (12%) women were determined to have CIN2+. Receiver operating characteristic analysis showed an area under the curve of 0.664 for p16(INK4a) to detect biopsy-proven CIN2+. At a p16(INK4a) cut-off level of 9 U/mL, sensitivity, specificity, positive and negative predictive values were 89.0%, 22.9%, 13.6% and 93.8%, respectively. The overall p16(INK4a) positivity at a cut-off level of 9 U/mL was 828 (78.6%) women. There were 325 (30.8%) cases of correct p16(INK4a) prediction to detect or rule out CIN2+, and 729 (69.2%) cases of incorrect p16(INK4a) prediction.Conclusionsp16(INK4a) ELISA did not perform well as a screening test for CIN2+ detection among HIV-infected women due to low specificity. Our study contributes to the ongoing search for a more specific alternative to HPV testing for CIN2+ detection