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

Computed tomography for myocardial characterization in ischemic heart disease:a state-of-the-art review

This review provides an overview of the currently available computed tomography (CT) techniques for myocardial tissue characterization in ischemic heart disease, including CT perfusion and late iodine enhancement. CT myocardial perfusion imaging can be performed with static and dynamic protocols for the detection of ischemia and infarction using either single- or dual-energy CT modes. Late iodine enhancement may be used for the analysis of myocardial infarction. The accuracy of these CT techniques is highly dependent on the imaging protocol, including acquisition timing and contrast administration. Additionally, the options for qualitative and quantitative analysis and the accuracy of each technique are discussed

Frameshift mutations in coding repeats of protein tyrosine phosphatase genes in colorectal tumors with microsatellite instability

<p>Abstract</p> <p>Background</p> <p>Protein tyrosine phosphatases (PTPs) like their antagonizing protein tyrosine kinases are key regulators of signal transduction thereby assuring normal control of cellular growth and differentiation. Increasing evidence suggests that mutations in PTP genes are associated with human malignancies. For example, mutational analysis of the tyrosine phosphatase (PTP) gene superfamily uncovered genetic alterations in about 26% of colorectal tumors. Since in these studies tumors have not been stratified according to genetic instability status we hypothesized that colorectal tumors characterized by high-level of microsatellite instability (MSI-H) might show an increased frequency of frameshift mutations in those PTP genes that harbor long mononucleotide repeats in their coding region (cMNR).</p> <p>Results</p> <p>Using bioinformatic analysis we identified 16 PTP candidate genes with long cMNRs that were examined for genetic alterations in 19 MSI-H colon cell lines, 54 MSI-H colorectal cancers, and 17 MSI-H colorectal adenomas. Frameshift mutations were identified only in 6 PTP genes, of which PTPN21 show the highest mutation frequency at all in MSI-H tumors (17%).</p> <p>Conclusion</p> <p>Although about 32% of MSI-H tumors showed at least one affected PTP gene, and cMNR mutation rates in PTPN21, PTPRS, and PTPN5 are higher than the mean mutation frequency of MNRs of the same length, mutations within PTP genes do not seem to play a common role in MSI tumorigenesis, since no cMNR mutation frequency reached statistical significance and therefore, failed prediction as a Positive Selective Target Gene.</p

Cost-effectiveness analysis of alternative screening strategies for the detection of cervical cancer among women in rural areas of Western Kenya

While the incidence of cervical cancer has dropped in high-income countries due to organized cytology-based screening programs, it remains the leading cause of cancer death among women in Eastern Africa. Therefore, the World Health Organization(WHO) now urges providers to transition from widely prevalent but low-performance visual inspection with acetic acid (VIA) screening to primary human papillomavirus(HPV) DNA testing. Due to high HPV prevalence, effective triage tests are needed to identify those lesions likely to progress and so avoid over-treatment. To identify the optimal cost-effective strategy, we compared the VIA screen-and-treat approach to primary HPV DNA testing with p16/Ki67 dual-stain cytology or VIA as triage. We used a Markov model to calculate the budget impact of each strategy with incremental quality-adjusted life years and incremental cost-effectiveness ratios (ICER) as the main outcome. Deterministic cost-effectiveness analyses show that the screen-and-treat approach is highly cost-effective (ICER 2469 Int$), while screen, triage, and treat with dual staining is the most effective with favorable ICER than triage with VIA(ICER 9943 Int$ compared with 13,177 Int$). One-way sensitivity analyses show that the results are most sensitive to discounting, VIA performance, and test prices. In the probabilistic sensitivity analyses, the triage option using dual stain is the optimal choice above a willingness to pay threshold of 7115 Int$ being cost-effective as per WHO standards. The result of our analysis favors the use of dual staining over VIA as triage in HPV-positive women and portends future opportunities and necessary research to improve the coverage and acceptability of cervical cancer screening programs

Prevalence of Human Papillomavirus infection by age and cervical cytology in Thika, Kenya

Human papillomavirus (HPV) infections cause cervical cancer and premalignant dysplasia. Data on HPV and cervical cancer in Kenya are scarce. Type-specific HPV prevalence data provides a basis for assessing the impact of HPV vaccination programs on cervical cytology and how HPV based screening will influence cervical cancer prevention. To investigate HPV infections in a population in Kenya, we obtained cervical cells specimen from 498 women in a population in Thika district. We report HPV type specific prevalence and distribution data for 498 women (age range 18-74 years; mean age 36 years) recruited into the study in relation to age and cervical cytology. The study was conducted between January to May 2010. Pap smears were performed, HR HPV DNA were detected by Digene Hybrid capture 2® (hc2) test and HPV genotyping was performed with Multiplex Luminex HPV genotyping kit (Multimetrix, Progen, Germany). Samples from 106 women (21.3%) tested positive for HPV. Multiple HPV types were detected in 40 (37.7% of HC2-positive samples) and the rest had infection with single HPV type. The most common HR HPV type at all ages was HPV16, 52, 56, 66, and 18. There was a marked decline in the prevalence of HR-HPV with age. The pattern of HR HPV distribution in this population was slightly different from existing literature, which has important consequences for HPV vaccination and prevention programs

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

Framework for Evidence Assessment Based on Grade and Application to HPV Vaccination in Males in the European Health Care Context

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Molecular Alterations and Association with Clinical Parameters

Lynch syndrome is caused by germline mutations of DNA mismatch repair (MMR) genes, most frequently MLH1 and MSH2. Recently, MMR-deficient crypt foci (MMR- DCF) have been identified as a novel lesion which occurs at high frequency in the intestinal mucosa from Lynch syndrome mutation carriers, but very rarely progress to cancer. To shed light on molecular alterations and clinical associations of MMR-DCF, we systematically searched the intestinal mucosa from Lynch syndrome patients for MMR-DCF by immunohistochemistry. The identified lesions were characterised for alterations in microsatellite-bearing genes with proven or suspected role in malignant transformation. We demonstrate that the prevalence of MMR-DCF (mean 0.84 MMR-DCF per 1 cm2 mucosa in the colorectum of Lynch syndrome patients) was significantly associated with patients’ age, but not with patients’ gender. No MMR-DCF were detectable in the mucosa of patients with sporadic MSI-H colorectal cancer (n = 12). Microsatellite instability of at least one tested marker was detected in 89% of the MMR-DCF examined, indicating an immediate onset of microsatellite instability after MMR gene inactivation. Coding microsatellite mutations were most frequent in the genes HT001 (ASTE1) with 33%, followed by AIM2 (17%) and BAX (10%). Though MMR deficiency alone appears to be insufficient for malignant transformation, it leads to measurable microsatellite instability even in single MMR-deficient crypts. Our data indicate for the first time that the frequency of MMR-DCF increases with patients’ age. Similar patterns of coding microsatellite instability in MMR-DCF and MMR-deficient cancers suggest that certain combinations of coding microsatellite mutations, including mutations of the HT001, AIM2 and BAX gene, may contribute to the progression of MMR-deficient lesions into MMR-deficient cancers

Beta-2-microglobulin Mutations Are Linked to a Distinct Metastatic Pattern and a Favorable Outcome in Microsatellite-Unstable Stage IV Gastrointestinal Cancers

Immune checkpoint blockade (ICB) shows remarkable clinical effects in patients with metastatic microsatellite-unstable (MSI) cancer. However, markers identifying potential non-responders are missing. We examined the prevalence of Beta-2-microglobulin (B2M) mutations, a common immune evasion mechanism, in stage IV MSI gastrointestinal cancer and its influence on metastatic pattern and patients’ survival under ICB. Twentyfive patients with metastatic, MSI gastrointestinal adenocarcinoma were included. Eighteen patients received ICB with pembrolizumab and one patient with nivolumab/ ipilimumab. Sequencing was performed to determine B2M mutation status. B2M mutations and loss of B2M expression were detected in 6 out of 25 stage IV MSI cancers. B2M mutations were strongly associated with exclusively peritoneal/peritoneal and lymph node metastases (p=0.0055). However, no significant differences in therapy response (25% vs. 46.6%, p>0.99) and survival (median PFS: 19.5 vs 33.0 months, p=0.74; median OS 39 months vs. not reached, p>0.99) were observed between B2Mmutant and B2M-wild type tumor patients. Among metastatic MSI GI cancers, B2Mmutant tumors represent a biologically distinct disease with distinct metastatic patterns. To assess ICB response in B2M-mutant MSI cancer patients, future studies need to account for the fact that baseline survival of patients with B2M-mutant MSI cancer may be longer than of patients with B2M-wild type MSI cancer