Can human papillomavirus DNA testing of self-collected vaginal samples compare with physician-collected cervical samples and cytology for cervical cancer screening in developing countries?

Background: To determine human papillomavirus (HPV) types by polymerase chain reaction (PCR)-reverse line blot assay and examine the concordance between HPV by Hybrid Capture 2 (HC2) and PCR on self-collected vaginal and physician-collected cervical samples and cytology. Methods: This was a cross-sectional study of 546 sexually active women aged ≥30 years with persistent vaginal discharge, intermenstrual or postcoital bleeding or an unhealthy cervix. Participants self-collected vaginal samples (HPV-S) and physicians collected cervical samples for conventional Pap smear and HPV DNA (HPV-P) testing and performed colposcopy, with directed biopsy, if indicated. HPV testing and genotyping was done by HC2 and PCR reverse line blot assay. Concordance between HC2 and PCR results of self- and physician-collected samples was determined using a Kappa statistic (κ) and Chi-square test. Results: Complete data were available for 512 sets with 98% of women providing a satisfactory self-sample. PCR detected oncogenic HPV in 12.3% of self- and 13.0% of physician-collected samples. Overall, there was 93.8% agreement between physician-collected and self-samples (κ = 76.31%, 95% confidence interval [CI]: 64.97–82.29%, p = 0.04)—complete concordance in 473 cases (57 positive, 416 negative), partial concordance in seven pairs and discordance in 32 pairs. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of self-sampling for detection of cervical intraepithelial neoplasia (CIN)2+ disease were 82.5%, 93.6%, 52.4% and 98.4%, respectively; for physician-sampling they were 87.5%, 93.2%, 52.2% and 98.9%, respectively; and for cytology they were 77.5%, 87.3%, 34.1% and 97.9%, respectively. Concordance between HC2 and PCR was 90.9% for self-samples (κ = 63.7%, 95% CI: 55.2–72.2%) and 95.3% for physician-collected samples (κ = 80.4%, 95% CI: 71.8–89.0%). Conclusions: Self-HPV sampling compares favourably with physician-sampling and cytology. A rapid, affordable, HPV self-test kit can be used as the primary method of cervical cancer screening in low-resource situations.     

Liquid‐based cytology: is this the way forward for cervical screening?

Liquid-based cytology (LBC) is currently being marketed as an alternative methodology to replace the conventional PAP smear in cervical cytology. A substantial body of literature exists in support of LBC, some of which is at least partially sponsored by product manufacturers. The majority of published literature in support of LBC employs Bethesda reporting terminology. In this study we have analysed published raw data and presented this in NHSCSP terminology. Claims relating to sensitivity, specificity and smear adequacy have then been considered with reference to this data. Our analysis of existing data does not support the nationwide implementation of LBC at present. Further studies are recommended in order to evaluate the place of this technology within the NHSCSP.     

STI571 (Gleevec™) as a paradigm for cancer therapy

STI571 (Gleevec™, imatinib mesylate) exemplifies the successful development of a rationally designed, molecularly targeted therapy for the treatment of a specific cancer. This article reviews the identification of Bcr-Abl as a therapeutic target in chronic myelogenous leukemia and the steps in the development of an agent to inactivate this abnormality. Issues related to clinical trials of molecularly targeted agents are discussed, including dose and patient selection and possible mechanisms of resistance to STI571. Finally, the potential use of STI571 with different tumors and the translation of this paradigm to other malignancies are explored.     

European trends in cervical cancer mortality in relation to national screening programs, 1985–2014

BackgroundCervical cancer is the fourth leading oncological cause of death in women. Variable trends in cervical cancer mortality have been observed across Europe, despite the widespread adoption of screening programs. This variability has previously been attributed to heterogeneity in the quality of screening programs.MethodsAge-standardized cervical cancer death rates for European countries between 1985 and 2014 were analyzed using Joinpoint regression. Countries were dichotomized based on year of implementation and population invitational coverage of national population-based cervical cancer screening programs. National cervical cancer mortality trends during the study period were compared based on this classification.ResultsDecreasing trends in mortality were observed in all European countries with the specific exceptions of Bulgaria, Greece and Latvia. The highest rates of cervical cancer mortality throughout the study period were in Romania (16.0-14.9/100,000) and the lowest rates in Italy (1.4-1.2/100,000). The greatest percentage decline in mortality was observed in the United Kingdom and the greatest absolute reduction in mortality was seen in Hungary. European countries which implemented a national population-based cervical cancer screening program prior to 2009 demonstrated greater improvements in cervical cancer mortality outcomes compared to those that did not (p = 0.016).ConclusionCervical cancer mortality is improving in most European countries; however, substantial variation remains. Trends in mortality were associated with the time of implementation of national population-based cervical screening programs.     

Risk of significant gynaecological pathology in women with ?glandular neoplasia on cervical cytology

A. Talaat, D. Brinkmann, J. Dhundee, Y. Hana, J. Bevan, R. Irvine, S. Bailey and R. Woolas
Risk of significant gynaecological pathology in women with ?glandular neoplasia on cervical cytology Objective: To review the risk of pre‐invasive and invasive gynaecological pathology in women referred with cervical cytology reporting ?glandular neoplasia. Methods: Review of the case notes of all women referred with cervical cytology reported as ?glandular neoplasia between January 1999 and December 2008 at two UK hospitals: Portsmouth Hospitals NHS Trust and Queen Mary’s Hospital Sidcup. The category of ‘borderline nuclear change in endocervical cells’, result code 8 according to the national health service cancer screening programme (NHSCSP), was excluded from the study. Results: A total of 200 women were identified using the hospitals’ pathology computer systems. Invasive carcinoma was found in 48 women (24%): 28 endocervical adenocarcinomas, eight squamous cell carcinomas (SCC), ten endometrial and two ovarian adenocarcinomas. Pre‐invasive neoplasia was found in 115 (57.5%), including 14 cervical glandular intraepithelial neoplasia (CGIN), 31 cervical intraepithelial neoplasia (CIN) grade 2/3 and 70 concomitant CGIN and CIN2/3. CIN1/HPV was found in 25, simple endometrial hyperplasia in three and no histological abnormality in three. Thirty‐four (70.8%) of 48 invasive carcinomas (of which 23 were endocervical adenocarcinomas) were in asymptomatic women investigated for abnormal cytology. Fourteen of 34 (41.4%) of those with ?glandular neoplasia thought to be endometrial were CGIN or CIN2/3. Colposcopic appearances were normal in 47.6% of women with pure cervical glandular neoplasia (adenocarcinoma or CGIN) compared with 12.8% with squamous cell lesions (CIN2/3 or SCC): P = 0.0001. Thus, colposcopy was more sensitive for detecting squamous cell abnormalities than their glandular counterparts. Although cervical adenocarcinomas are less amenable to prevention by screening than cervical SCC, in our study cervical cytology predominantly detected these abnormalities at their early asymptomatic stages. Conclusion: At least CIN2 was found in 81.5% in women referred with cervical cytology reporting ?glandular neoplasia. A thorough evaluation of the whole genital tract is needed if colposcopy is negative.     

Comparison of cytology and histology results in English cervical screening laboratories before and after liquid‐based cytology conversion: do the data provide evidence for a single category of high‐grade dyskaryosis?

R. G. Blanks and R. S. Kelly
Comparison of cytology and histology results in English cervical screening laboratories before and after liquid‐based cytology conversion: do the data provide evidence for a single category of high‐grade dyskaryosis? Objective: To determine whether the difference between the positive predictive value (PPV) for cervical intraepithelial neoplasia (CIN) grade 2 or worse (CIN2+) of referral from moderate dyskaryosis and from severe dyskaryosis was reduced after laboratories converted from conventional to liquid‐based cytology (LBC). Furthermore, to explore the cytology/histology agreement after LBC conversion, and to determine post‐LBC whether there was increased support for the use of one single category of high‐grade dyskaryosis (equivalent to high‐grade squamous intraepithelial lesion). Methods: The association between cytology and histology has been examined using annual Korner return data (KC61 returns) collected by laboratories from the English National Health Service cervical screening programme. The study compares return data before and after LBC conversion. Results: The study examined data from 102 laboratories that converted from conventional cytology to LBC. Before conversion the PPV for CIN2+ of severe dyskaryosis was 88% and after increased to 90% (P = 0.003). For moderate dyskaryosis the PPV for CIN2+ increased from 70% to 72% (P = 0.06). The absolute difference of 18% between severe and moderate dyskaryosis was therefore the same pre‐ and post‐LBC conversion. The PPV of mild dyskaryosis for CIN2+ before and after conversion reduced from 23% to 19% (P < 0.001). The agreement between cytology and histology measured using a weighted Kappa statistic increased from 0.52 to 0.60 after conversion to LBC because of small increases in the proportions of severe dyskaryosis or worse with CIN3+ outcomes and mild dyskaryosis with CIN1 or less outcomes. Conclusions: Following LBC conversion there was evidence of a modest increase in the agreement between cytology and histology but no evidence of a change in the absolute difference in PPV for CIN2+ between moderate and severe dyskaryosis. The data support the conclusion that women referred with moderate dyskaryosis will on average have a lower risk of progression to invasive cancer than women referred with severe dyskaryosis. If the data were considered to support the categories of high‐grade dyskaryosis (moderate) and high‐grade dyskaryosis (severe) before LBC conversion then it can be strongly argued that they also support these categories after conversion.     

Will vaccinated women attend cervical screening? A population based survey of human papillomavirus vaccination and cervical screening among young women in Victoria,Australia

Objectives: To assess human papillomavirus (HPV) vaccination coverage and attitudes to vaccination and Pap screening in young women. Design: Population-based telephone survey. Setting: Victoria, Australia. Participants: 234 women resident in Victoria aged 18–28 years in May 2009. Main outcome measures: Self-reported HPV vaccination uptake, reasons for non-receipt or failure to complete vaccination, knowledge and attitudes about HPV vaccination and Pap screening, and cervical screening intentions. Results: The response rate for eligible households was 62.4%. Half of the women (56%, n = 131) had previously had a Pap test and 74% (age standardised estimate) had received HPV vaccine. Of the vaccinated women, 5% had received one dose only, 18% two doses and 76% had completed the course (1.7% unsure of number of doses). Vaccination uptake was highest in the youngest women (declining from 90% for at least one dose in women aged 18–38.5% in women aged 28; p for trend <0.001). Among women who had heard of the vaccine, 96% knew Pap tests were still needed after it, although 20% thought the vaccine could prevent all cervical cancers and 9% thought the vaccine could treat cervical abnormalities and cancer. Among vaccinated women, 8% of women agreed that having been vaccinated made them less likely to have Pap tests in the future. Conclusions: Self-reported coverage in this sample was higher than that recorded on the national vaccination register. Young women report the message that Pap tests are required after vaccination, but there are gaps in their knowledge about the limitations of the vaccine so it remains to be seen if they actually follow through with having Pap tests. Ongoing monitoring of cervical screening rates will be important as this cohort ages.     

Enantioanalysis of tryptophan in whole blood samples using stochastic sensors—A screening test for gastric cancer

Tryptophan is a key amino acid related to metabolomics in gastric cancer. To date, methods were developed only for the assay of l -tryptophan, the role of d -tryptophan being not yet established. Therefore, four stochastic sensors based on different graphene materials modified with β-cyclodextrins, 2,2-diphenyl-1-picrylhydrazyl, and protoporphyrin IX were designed and used for enantioanalysis of tryptophan in whole blood samples. High sensitivities, and reliabilities were recorded when the stochastic sensors were used for the enantioanalysis of tryptophan in whole blood samples. The paper opened a new chapter in early detection of gastric cancer, based on establishing the role of d -tryptophan in metabolomics, and in early diagnosis of gastric cancer.     

Could nuclear matrix protein 22 (NMP22) play a role with urine cytology in screening for bladder cancer? – experience at Kuwait University

Objectives:  This prospective study was undertaken to evaluate nuclear matrix protein (NMP22) compared to urine cytology in the detection of bladder cancer and also to determine whether indexing suspicious cytology to NMP22 could enhance the clinical utility of cytology.
Methods:  Cytological findings of voided urine collected prior to a cystoscopic biopsy were correlated with urine NMP22 assay in 46 patients attending the urology clinic in Mubarak Al-Kabeer Hospital. The patients were clinically categorized into newly diagnosed cases of transitional cell carcinoma (TCC), recurrent TCC, TCC in remission and controls.
Results:  Using histological diagnosis as the gold standard the sensitivity and specificity of NMP22 were 78% and 43% respectively and of cases with malignant urine cytology were 30% and 87% respectively. If suspicious and malignant cytology were combined as positive results the sensitivity increased significantly to 87% while the specificity decreased but not significantly to 74%. Suspicious or malignant cytology enhanced by positive NMP22 gave a sensitivity of 70% and specificity of 87% neither of which was significantly different from cytology alone. There were three false positive cases on cytology and 13 false positive cases on NMP22 assay. There were three false negative cytology and five false negative NMP22 cases but only one was false negative for both, resulting in a high sensitivity (96%) but low specificity (30%) if either positive NMP22 or malignant or suspicious cytology was taken as a positive result.
Conclusion:  Combining NMP22 with malignant or suspicious cytological result improved sensitivity for the detection of bladder cancer but with a major decrease in specificity, suggesting a potential role in screening rather than diagnosis.     

The azatryptophan-based fluorescent platform for in vitro rapid screening of inhibitors disrupting IKKβ-NEMO interaction

The nuclear factor-κB (NF-κB) plays an important role in inflammatory and immune responses. Aberrant NF-κB signaling is implicated in multiple disorders, including cancer. Targeting the regulatory scaffold subunit IκB kinase γ (IKKγ/NEMO) as therapeutic interventions could be promising due to its specific involvement in canonical NF-κB activation without interfering with non-canonical signaling. In this study, the use of unnatural amino acid substituted IKKβ with unique photophysical activity to sense water environment changes upon interaction with NEMO provides a powerful in vitro screening platform that would greatly facilitate the identification of compounds having the potential to disrupt IKKβ-NEMO interaction, and thus specifically modulate the canonical NF-κB pathway. We then utilized a competitive binding platform to screen the binding ability of a number of potential molecules being synthesized. Our results suggest that a lead compound (−)-PDC-099 is a potent agent with ascertained potency to disrupt IKKβ-NEMO complex for modulating NF-κB canonical pathway.     

Trends in socioeconomic inequalities in cervical,breast, and colorectal cancer screening participation among women in Japan, 2010–2019

BackgroundIt is known that socioeconomic status (SES) influences the outcome of cancer treatment and this could partly be explained by decreased use of cancer screening services by people of lower SES. Many studies have indicated that low SES, including low educational attainment or unstable employment, was related to nonparticipation in cancer screening. However, studies investigating trends in SES inequalities within cancer screening participation are limited. Our objective was to examine trends in SES inequalities in cervical, breast, and colorectal cancer screening participation among women in Japan between 2010 and 2019.MethodsWe analyzed 189,442, 168,571, 163,341, and 150,828 women in 2010, 2013, 2016, and 2019 respectively, using nationally representative cross-sectional surveys. The main outcome variables are participation in each cancer screening. We used educational attainment and employment status as measures for SES. Multivariable logistic regression analysis, adjusted for age, marital status, educational attainment, and employment status was performed to evaluate the associations between SES and nonparticipation in each cancer screening.ResultsOverall participation rates in each cancer screening increased between 2010 and 2019. Low educational attainment and non-permanent employment status were related to nonparticipation in each cancer screening and inequality according to employment status increased within each screening participation during the study period. For example, dispatched workers were more likely to not participate in cervical cancer screening than permanent workers: in 2010, [aOR 1.11 95 %CI: 1.01 –1.21], and in 2019, [aOR 1.46 95 %CI: 1.34–1.60]. The inequality was greatest in colorectal cancer screening nonparticipation, followed by breast and cervical screening.ConclusionsAlthough the participation rates in each cancer screening have increased, inequality in participation in terms of employment status widened among women in Japan between 2010 and 2019. Reducing inequalities in cancer screening participation is essential for cancer screening intervention policies.     

The untold story of IFN-γ in cancer biology

Interferon (IFN)-γ is the uppermost cytokine implicated in anti-tumor immunity. With its cytostatic, pro-apoptotic and immune-provoking effects, IFN-γ plays a central role in the recognition and elimination of transformed cells. Considering well-characterized anti-tumor effects of this cytokine, many clinical trials and immunotherapy approaches have been designed to reinforce IFN-γ-mediated immunity for different types of cancer. However, the outcomes were not satisfactory and leaded to questioning of alternative actions of IFN-γ. Many regulatory pathways can be induced by IFN-γ to protect the normal tissues from collateral damage and to facilitate the re-establishment of homeostasis. Nevertheless, malignant cells can take the advantage of IFN-γ as an inducer of mediators inhibiting anti-tumor immune reactions. In addition, under the influence of tumor-derived factors, certain types of immune cells are also licensed by IFN-γ to perform regulatory actions. This review focuses on the immune modulatory functions of IFN-γ in cancer as an alternative story to be told.     

High-throughput screening assay for sphingosine kinase inhibitors in whole blood using RapidFire® mass spectrometry

To facilitate discovery of compounds modulating sphingosine-1-phosphate (S1P) signaling, the authors used high-throughput mass spectrometry technology to measure S1P formation in human whole blood. Since blood contains endogenous sphingosine (SPH) and S1P, mass spectrometry was chosen to detect the conversion of an exogenously added 17-carbon-long variant of sphingosine, C17SPH, into C17S1P. The authors developed procedures to achieve homogeneous mixing of whole blood in 384-well plates and for a method requiring minimal manipulations to extract S1P from blood in 96- and 384-well plates prior to analyses using the RapidFire(?) mass spectrometry system.     

Fibronectin–integrin mediated signaling in human cervical cancer cells (SiHa)

Interaction between cell surface integrin receptors and extracellular matrix (ECM) components plays an important role in cell survival, proliferation, and migration, including tumor development and invasion of tumor cells. Matrix metalloproteinases (MMPs) are a family of metalloproteinases capable of digesting ECM components and are important molecules for cell migration. Binding of ECM to integrins initiates cascades of cell signaling events modulating expression and activity of different MMPs. The aim of this study is to investigate fibronectin–integrin-mediated signaling and modulation of MMPs. Our findings indicated that culture of human cervical cancer cell (SiHa) on fibronectin-coated surface perhaps sends signals via fibronectin–integrin-mediated signaling pathways recruiting focal adhesion kinase (FAK) extracellular signal regulated kinase (ERK), phosphatidyl inositol 3 kinase (PI-3K), integrin-linked kinase (ILK), nuclear factor-kappa B (NF-κB), and modulates expression and activation of mainly pro-MMP-9, and moderately pro-MMP-2 in serum-free culture medium.