Impact of HPV Vaccination on the Incidence of High-Grade Cervical Intraepithelial Neoplasia (CIN2+) in Women Aged 20-25 in the Northern Part of Norway: A 15-Year Study.

BACKGROUND: Human papillomavirus (HPV), the most prevalent sexually transmitted infection globally, is a key risk factor for high-grade cervical lesions and cervical cancer. Since 2009, HPV vaccination has been part of the national immunization program for girls in 7th grade in Norway (women born 1997 and later). This study aimed to assess the impact of HPV vaccination on the incidence of high-grade cervical precursors (CIN2+) among women aged 20-25 in Troms and Finnmark over a 15-year period. MATERIALS AND METHODS: In this time series study, we analyzed cervical screening data from 15,328 women aged 20-25 in Troms and Finnmark, collected between 2008 and 2022. Statistical methods, including linear and logistic regression, were employed to evaluate changes in cervical intraepithelial neoplasia grade 2 and worse (CIN2+) incidence and compare risks between vaccine-offered cohorts and pre-vaccine cohorts. RESULTS: The incidence of CIN2+ initially increased from 31 cases per year in 2008 to 110 cases in 2018, then significantly decreased to 44 cases per year by 2022 (p < 0.01). Women in pre-vaccine cohorts had a substantially higher risk of CIN2+ (OR 9.02, 95% CI 5.9-13.8) and CIN3+ (OR 19.6, 95% CI 7.3-52.6). Notably, no vaccinated women with CIN2+ tested positive for HPV types 16 or 18. Furthermore, none of the 13 cervical cancer cases recorded during the study were from the vaccinated cohorts. INTERPRETATION: The findings suggest a significant reduction in the incidence of high-grade cervical precursors following the introduction of the HPV vaccine in Norway's national immunization program, highlighting its effectiveness in cervical cancer prevention among young women in Northern Norway.

Enhancing Cervical Cancer Prevention in South African Women: Primary HPV mRNA Screening with Different Genotype Combinations.

BACKGROUND: Cervical cancer prevention in regions with limited access to screening and HPV vaccination necessitates innovative approaches. This study explored the potential of a test-and-treat strategy using mRNA HPV tests to impact cervical cancer prevention in a high-prevalence HIV population. METHODS: A cervical screening study was conducted at three South African hospitals involving 710 under-screened, non-pregnant women (25 to 65 years) without known cervical diseases. Cytology, HPV testing, colposcopy, and biopsies were performed concurrently. Histopathologists determined final histological diagnoses based on biopsy and LLETZ histology. mRNA-HPV-genotyping for 3 (16, 18, 45) to 8 (16, 18, 31, 33, 35, 45, 52, 58) high-risk types was performed on leftover liquid-based cytology material. The preventive potential of the test-and-treat approach was estimated based on published data, reporting the causative HPV types in cervical cancer tissue from South African women. Treatment was provided as needed. RESULTS: The HPV positivity rate more than doubled from 3-type (15.2%; 95% CI: 12.6-17.8) to 8-type mRNA (31.5%; 95% CI: 28.8-34.9) combinations, significantly higher among HIV-positive women. CIN3+ prevalence among HIV-positive women (26.4%) was double that of HIV-negative women (12.9%) (p < 0.01). The 6-type combination showed the best balance of sensitivity, specificity and treatment group size, and effectiveness to prevent cervical cancer. A 4-type combination (16, 18, 35, 45) could potentially prevent 77.6% (95% CI: 71.2-84.0) of cervical cancer burden by treating 20% and detecting 41.1% of CIN3 cases in the study group. Similarly, a 6-type combination (16, 18, 31, 33, 35, 45), treating 25% and including 62% of CIN3 cases, might prevent 85% of cervical cancer cases (95% CI: 79.6-90.6) among HIV-positive and negative women. CONCLUSION: Employing mRNA HPV tests within a test-and-treat approach holds huge promise for targeted cervical cancer prevention in under-screened populations. Testing for mRNA of the 6 highest-risk HPV types in this population and treating them all is projected to effectively prevent progression from CIN3 to invasive cervical cancer while reducing overtreatment in resource-constrained settings.

Risk of Intraepithelial Neoplasia Grade 3 or Worse (CIN3+) among Women Examined by a 5-Type HPV mRNA Test during 2003 and 2004, Followed through 2015.

BACKGROUND: The study's purpose was to evaluate the performance of a five-type HPV mRNA test to predict cervical intraepithelial neoplasia grade 3 or worse (CIN3+) during up to 12 years of follow-up. METHODS: Overall, 19,153 women were recruited by gynecologists and general practitioners in different parts of Norway between 2003 and 2004. The study population comprised 9582 women of these women, aged 25-69 years with normal cytology and a valid five-type HPV mRNA test at baseline. Follow-up for CIN3+ through 2015 was conducted in the Norwegian Cervical Cancer Screening Programme. RESULTS: The cumulative incidence of CIN3+ by baseline status for HPV mRNA-positive and mRNA-negative women were 20.8% and 1.1%, respectively (p < 0.001). Age did not affect the long-term ability of the HPV mRNA test to predict CIN3+ during follow-up. CONCLUSION: The low long-term risk of CIN3+ among HPV mRNA-negative women and the high long-term risk among HPV mRNA-positive women strengthen the evidence that the five-type HPV mRNA test is an appropriate screening test for women of all ages. Our findings suggest that women with a negative result may extend the screening interval up to 10 years.

13-Type HPV DNA Test versus 5-Type HPV mRNA Test in Triage of Women Aged 25-33 Years with Minor Cytological Abnormalities-6 Years of Follow-Up.

BACKGROUND: A specific, cost-effective triage test for minor cytological abnormalities is essential for cervical cancer screening among younger women to reduce overmanagement and unnecessary healthcare utilization. We compared the triage performance of one 13-type human papillomavirus (HPV) DNA test and one 5-type HPV mRNA test. METHODS: We included 4115 women aged 25-33 years with a screening result of atypical squamous cells of undetermined significance (ASC-US) or low-grade squamous intraepithelial lesions (LSIL) recorded in the Norwegian Cancer Registry during 2005-2010. According to Norwegian guidelines, these women went to triage (HPV testing and repeat cytology: 2556 were tested with the Hybrid Capture 2 HPV DNA test, which detects the HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68; and 1559 were tested with the PreTect HPV-Proofer HPV mRNA test, which detects HPV types 16, 18, 31, 33, and 45). Women were followed through December 2013. RESULTS: HPV positivity rates at triage were 52.8% and 23.3% among DNA- and mRNA-tested women (p < 0.001), respectively. Referral rates for colposcopy and biopsy and repeat testing (HPV + cytology) after triage were significantly higher among DNA-tested (24.9% and 27.9%) compared to mRNA-tested women (18.3% and 5.1%), as were cervical intraepithelial neoplasia grade 3 or worse (CIN3+) detection rates (13.1% vs. 8.3%; p < 0.001). Ten cancer cases were diagnosed during follow-up; eight were in DNA-tested women. CONCLUSION: We observed significantly higher referral rates and CIN3+ detection rates in young women with ASC-US/LSIL when the HPV DNA test was used at triage. The mRNA test was as functional in cancer prevention, with considerably less healthcare utilization.

Impact of HPV mRNA types 16, 18, 45 detection on the risk of CIN3+ in young women with normal cervical cytology.

BACKGROUND: Despite a well-established cervical cancer (CC) screening program in Norway, the incidence of CC in young women is increasing, peaking at 35 years of age. 25 percent of all women diagnosed with CC had normal cytology within 3 years prior to cancer diagnosis, addressing the need to improve the screening programme to further reduce cancer incidences missed by cytology. OBJECTIVE: We wanted to investigate the detection rate of CIN3+ in women 25-39 years with normal cytology by using a 3-type HPV mRNA test as a targeted quality assurance measure. The control group is women with normal cytology. METHODS: During 2014-2017, samples from 13,021 women 25-39 years of age attending cervical cancer screening were analysed at Nordlandssykehuset, Bodø, Norway, including 1,896 women with normal cytology and HPV mRNA test (intervention group), and 11,125 women with cytology only (control group). The HPV mRNA testing was performed using a 3-type HPV E6/E7 mRNA test (PreTect SEE; direct genotyping 16, 18 and 45). The women were followed-up according to national guidelines throughout December 2021. RESULTS: Of the 13,021 women, 429 women (3.3%) had CIN3+ confirmed by biopsy in the follow-up, including 13 cases of invasive cervical cancer. Of the 1,896 women with normal cytology and HPV mRNA test (intervention group), 49 women (2.6%) had a positive test. The risks of CIN3+ among women with either a positive or negative HPV mRNA test were 28.6% (14/49) and 0.8% (14/1847). None of the women in the intervention group developed cervical cancer during follow-up. Of the 11,125 women with cytology only (control group), 712 women (6.4%) had abnormal cytology (ASC-US+). The risks of CIN3+ among women with abnormal and normal cytology were 17.7% (126/712) and 2.6% (275/10,413). CONCLUSION: By testing women 25-39 years of age with a normal cytology result using a specific 3-type HPV mRNA test, an increase in screening programme sensitivity can be achieved without an excessive additional workload. Women with normal cytology and a negative HPV mRNA test have a very low risk of cervical cancer.

Helicobacter pylori resistance to antibiotics before and after treatment: Incidence of eradication failure.

BACKGROUND: Increasing prevalence of antibiotic resistance especially to clarithromycin and metronidazole has been observed in Helicobacter pylori (H. pylori). AIM: To characterize the antimicrobial resistance pattern of H. pylori before and after treatment in a cohort of patients accumulated over a period of 15 years after an unsuccessful eradication treatment had been given comparing sensitivity data from patients with newly diagnosed H. pylori infection. A specific objective was to look for resistance to levofloxacin. MATERIAL AND METHODS: Total of 50 patients newly diagnosed for H. pylori infection treated with omeprazole and amoxicillin/clarithromycin and 42 H pylori treatment-resistant patients treated with omeprazole and amoxicillin/levofloxacin were enrolled in this study. Cultures including antibiotic sensitivity testing were conducted according to standard laboratory routines and thus also in keeping with a European study protocol using E-test gradient strips or disc diffusion methods. RESULTS: Clarithromycin resistance was more frequently observed in the H. pylori resistant group than in newly diagnosed H. pylori group (39% versus 11%). Regarding metronidazole the distribution was 70% versus 38%, and 8% versus 12% were resistant to tetracycline. No resistance was observed for amoxicillin. After re-treatment of patients belonging to the H. pylori treatment-resistant group, just two patient strains were recovered of which one harbored metronidazole resistance. In the group of newly diagnosed H. pylori, seven patients were culture positive by control after treatment. Two and three patient strains showing resistance to clarithromycin and metronidazole, respectively. None of the strains in our material was classified as resistant to amoxicillin and levofloxacin. Whereas 12% was resistant to tetracycline in the newly diagnosed before treatment. CONCLUSION: Clarithromycin resistance was more frequent in the H. pylori treatment-resistant group than strains from patients with newly diagnosed H. pylori infection. No resistance was observed to amoxicillin and levofloxacin. In such cases Therefore levofloxacin may be used provided in vitro sensitivity testing confirms applicability. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05019586.

Risk of cervical intraepithelial neoplasia grade 3 or higher (CIN3+) among women with HPV-test in 1990-1992, a 30-year follow-up study.

BACKGROUND/OBJECTIVE: Having a 30-year follow-up of a cohort of women tested for HPV is a unique opportunity to further study long-term risk of CIN3+. The study objective was to compare HPV status at baseline with the risk of CIN3+ in the follow-up period of 30 years. METHODS: All women (n = 642) referred to the HPV outpatient clinic at the University Hospital of North Norway (UNN) in 1990-1992, with an HPV test at baseline, were included in a prospective cohort. HPV-testing was performed by two different HPV-DNA tests, and genotypes 6, 11, 16, 18, 31 and 33 were identified. High-risk (HR) HPV genotypes (16, 18, 31 and 33) were classified as HPV positive, whereas low-risk (LR) genotypes (6 and 11) in addition to absent HPV were classified as HPV negative. A single cohort in which women were classified for their HPV status underwent follow-up prospectively to the last time-point of observation of 30 years. RESULTS: During follow-up, 148 (148/642) cases of CIN3+ were detected, of whom 70.3% (104/148) were HPV positive and 29.7% (44/148) were HPV negative at baseline. The proportions of women who developed CIN3+ following a positive and a negative test were 46.6% (104/223) and 10.5% (44/419), respectively. Most cases of CIN3+ were seen shortly after the baseline HPV test, with 112 cases of CIN3+ diagnosed within the first year. In total, 48.6% (72/148) with HPV 16 and 57.6% (19/33) with HPV 33 developed CIN3+. Within the first year, CIN3+ was detected in 37.8% (56/148) with HPV 16, and 51.5% (17/33) with HPV 33. The long-term risk of CIN3+ was significantly lower than the short-term risk, and mainly associated with HPV 16. Overall, eight cases of cervical cancer were detected. Five were HPV positive, harboured HPV 16 at baseline and developed cervical cancer after 3, 4, 5, 11 and 24 years of follow-up. CONCLUSION AND CONSEQUENCES: HPV status at baseline is predictive for the subsequent risk of developing CIN3+. Women with a positive HPV test in 1990-1992 had a significantly higher risk of CIN3+ during 30 years of follow-up than those with a negative test. HPV 16 was associated with the greatest long-term risk of cervical cancer. All patients with a positive HPV test at baseline should be followed up until negative. TRIAL REGISTRATION: ISRCTN, ISRCTN10836802 . Registered 14 December 2020 - Retrospectively registered.

Long-term effectiveness of the nine-valent human papillomavirus vaccine in Scandinavian women: interim analysis after 8 years of follow-up.

A long-term follow-up (LTFU) of the nine-valent human papillomavirus (9vHPV) vaccine efficacy study in young women aged 16-26 years was initiated to evaluate if vaccine effectiveness for up to 14 years post-vaccination will remain above 90%. Vaccine effectiveness is measured as percent reduction in the incidence of HPV16/18/31/33/45/52/58-related high-grade cervical dysplasia in the LTFU cohort relative to expected incidence in a similar unvaccinated cohort. We report an interim analysis 8 years post-vaccination. Overall, 2029 participants from Denmark, Norway, and Sweden who received the 9vHPV vaccine during the clinical efficacy study continued into the LTFU study. National health registries were used to identify screening attendance and cervical pre-cancer/cancer diagnoses. Tissue samples were retrieved for HPV testing by PCR and pathology diagnosis adjudication. A control chart method was used to detect signals indicative of vaccine effectiveness waning below 90%. No new cases of HPV16/18/31/33/45/52/58-related high-grade cervical dysplasia were observed during the LTFU study period over 4084.2 person-years' follow-up (per-protocol effectiveness population; n = 1448). Thus, there were no signals indicative of vaccine effectiveness waning below 90%. These observations show that the 9vHPV vaccine provides continued statistically significant protection through at least 6 years, with indications of continued effectiveness through 8 years. TRIAL REGISTRATION: Clinicaltrials.gov: NCT00543543, NCT02653118.

Final analysis of a 14-year long-term follow-up study of the effectiveness and immunogenicity of the quadrivalent human papillomavirus vaccine in women from four nordic countries.

BACKGROUND: The quadrivalent human papillomavirus (qHPV) vaccine prevented vaccine HPV type-related infection and disease in young women in the 4-year FUTURE II efficacy study (NCT00092534). We report long-term effectiveness and immunogenicity at the end of 14 years of follow-up after enrollment in FUTURE II. METHODS: Young women (16-23 years of age) from Denmark, Iceland, Norway, and Sweden who received three qHPV vaccine doses during the randomized, double-blind, placebo-controlled FUTURE II base study were followed for effectiveness for an additional ≥10 years through national registries. Tissue samples including but not limited to those collected during organized cervical cancer screening programs were obtained from regional biobanks to be adjudicated for histopathology diagnosis and tested for HPV DNA. The observed incidence of HPV16/18-related high-grade cervical dysplasia (primary outcome) was compared with recent historical background incidence rates in an unvaccinated population. Serum was collected at years 9 and 14 to assess antibody responses. FINDINGS: No cases of HPV16/18-related high-grade cervical dysplasia were observed in the per-protocol effectiveness population (N = 2121; 24,099·0 person-years of follow-up) during the entire study. Vaccine effectiveness of 100% (95% CI 94·7-100) was demonstrated for ≥12 years, with a trend toward continued protection through 14 years post-vaccination. Seropositivity rates at study conclusion were >90% (HPV6/11/16) and 52% (HPV18) using competitive Luminex immunoassay, and >90% (all four HPV types) using the more sensitive IgG Luminex immunoassay. INTERPRETATION: Vaccination of young women with qHPV vaccine offers durable protection against HPV16/18-related high-grade cervical dysplasia for ≥12 years, with a trend toward continued protection through 14 years post-vaccination, and induces sustained HPV6/11/16/18 antibody responses for up to 14 years post-vaccination. There was no evidence of waning immunity, suggesting no need for a booster dose during that period. FUNDING: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Recurrent disease after treatment for cervical intraepithelial neoplasia-The importance of a flawless definition of residual disease and length of follow-up.

OBJECTIVE: To evaluate adherence to national guidelines for follow-up, and assess residual and recurrent disease after treatment for cervical intraepithelial neoplasia grade 2 or worse (CIN2+). STUDY DESIGN: In a case-series design women aged 25-69 years treated for primary CIN2+ in 2006-2011 (n = 752) were followed through August 9, 2019 for residual or recurrent disease, i.e., CIN2+ diagnosed before or after, respectively, two consecutive, normal post-treatment cytology results. We used the Chi-Square test to assess predictive factors of adherence to post-treatment follow-up and residual disease, and survival analyses to assess the cumulative incidence of residual and recurrent disease. RESULTS: Strict adherence to post-treatment follow-up was low . However, 702 (95 %) women attended at least one post-treatment follow-up visit within the suggested time window. Forty-two women (5.6%) were diagnosed with residual disease, 38 (91 %) of whom were diagnosed within 2 years of treatment. Among the 637 (85 %) women with two consecutive, normal post-treatment cytology results, cumulative incidence of recurrent disease was 1.0 (95 % confidence interval [CI]: 0.2-1.8) and 2.5 (95 % CI: 1.2-3.8) per 100 women-years within 42 and 78 months of treatment, respectively. Three women with residual and two with recurrent disease were diagnosed with cervical cancer within 78 months of treatment. Women with not-free resection margins at treatment had a significantly increased risk of residual and recurrent disease. Using a 2-year definition for residual disease would misclassify 3 of 5 cancer cases as recurrent disease when they were true cases of residual disease. CONCLUSIONS: This study emphasizes the importance of properly distinguishing between residual and recurrent disease after treatment for CIN2 + . Many women with residual disease could benefit from an earlier colposcopy, cervical biopsy, or diagnostic conization during post-treatment follow-up in order to detect occult cervical cancer. The cumulative incidence of recurrent disease within 78 months of treatment was low.

Fibrosis Mediators in the Colonic Mucosa of Acute and Healed Ulcerative Colitis.

OBJECTIVES: A healed intestinal mucosa is the aim of therapy in acute ulcerative colitis (UC). Disruption of mucosal wound healing may lead to severe complications including intestinal fibrosis. This study examined mucosal gene expression in the healing process of acute UC with a special focus on known mediators of fibrosis. METHODS: Endoscopic biopsies from patients with acute, moderate to severe UC were analyzed with a quantitative polymerase chain reaction array for 84 genes involved in fibrosis pathways. All patients were treated with infliximab (anti- tumor necrosis factor). Biopsies were taken before therapy and when disease remission was reached, defined as a Mayo score of ≤2, with an endoscopic subscore of 0 or 1. A healthy control group was included. Immunostaining of matrix metallopeptidase 9 and smooth muscle actin was performed. RESULTS: Mucosal biopsies from acute UC (n = 28), remission UC (n = 28), and healthy controls (n = 13) were analyzed. Fibrosis and extracellular matrix-associated genes were upregulated in the endoscopically healed UC mucosa vs controls, with collagen type III alpha 1 chain, actin alpha 2, lysyl oxidase, TIMP metallopeptidase inhibitor 3, and caveolin 1 uniquely showing no overlap with acute disease. Pro- and antifibrotic mediators (interleukin [IL]13 receptor subunit alpha 2, IL1B, IL10, tumor necrosis factor, snail family transcriptional repressor 1, and C-C motif chemokine ligand 2) were upregulated in both acute and healed UC compared with controls. An attenuated pattern of the canonical transforming growth factor beta (TGFB) pathway was observed in acute UC and to a lesser extent in the healed mucosa, except for TGFB2, which was enhanced. DISCUSSION: The endoscopically healed mucosa of UC showed a persisting dysregulation of fibrosis-associated mediators compared with controls, including extracellular matrix remodeling, profibrotic cytokines, and TGFB signaling pathways.

Ulcerative colitis: functional analysis of the in-depth proteome.

BACKGROUND: Ulcerative colitis (UC) is one major form of inflammatory bowel disease. The cause and the pathophysiology of the disease are not fully understood and we therefor aim in this study to identify important pathophysiological features in UC from proteomics data. METHODS: Colon mucosa biopsies from inflamed tissue of untreated UC patients at diagnosis and from healthy controls were obtained during colonoscopy. Quantitative protein data was acquired by bottom-up proteomics and furthermore processed with MaxQuant. The quantitative proteome data was analyzed with Perseus and enrichment data was analyzed by ClueGO for Cytoscape. RESULTS: The generated proteome dataset is to-date the deepest from colon mucosa biopsies with 8562 identified proteins whereof 6818 were quantified in > 70% of the samples. We report abundance differences between UC and healthy controls and the respective p values for all quantified proteins in the supporting information. From this data set enrichment analysis revealed decreased protein abundances in UC for metallothioneins, PPAR-inducible proteins, fibrillar collagens and proteins involved in bile acid transport as well as metabolic functions of nutrients, energy, steroids, xenobiotics and carbonate. On the other hand increased abundances were enriched in immune response and protein processing in the endoplasmic reticulum, e.g. unfolded protein response and signal peptidase complex proteins. CONCLUSIONS: This explorative study describes the most affected functions in UC tissue. Our results complemented previous findings substantially. Decreased abundances of signal peptidase complex proteins in UC are a new discovery.

The sensitivity of fecal calprotectin in predicting deep remission in ulcerative colitis.

BACKGROUND: Mucosal healing is proposed as treat-to-target in ulcerative colitis (UC), even though the definition of mucosal healing remains contested as it has been suggested to be assessed by either endoscopy, histology or both. However, all definitions require an endoscopic evaluation of the mucosa. As endoscopies are invasive and uncomfortable to the patient we aimed to calibrate noninvasive predictors of mucosal inflammatory status defined by both endoscopy and histology. METHODS: UC patients (n = 106) undergoing a sigmoid-/colonoscopy were prospectively included. Feces (fecal calprotectin, FC), blood samples (hemoglobin, C-reactive protein, orosomucoid, erythrocyte sedimentation rate, albumin) and symptom scores (Simple Clinical Colitis Activity Index, SSCAI) were collected and analyzed. The colonic mucosa was assessed by the Mayo endoscopic sub score and biopsies were obtained for a histologic grading by Geboes score. Predictive cutoff values were analyzed by receiver operating characteristics (ROC). A combined endoscopic and histologic assessment defined deep remission (Mayo =0 and Geboes ≤1) and activity (Mayo ≥2 and Geboes >3). RESULTS: Only FC showed a significant ROC curve (p < .05). We suggest FC (mg/kg) cutoffs for detection of following: Deep remission: FC ≤25; Indeterminate: FC 25-230 - an endoscopy is recommended if a comprehensive status of both endoscopic and histologic assessed activity is needed; Active disease: FC >230. The complete ROC data is presented, enabling extraction of an FC cutoff value's sensitivity and specificity. CONCLUSIONS: FC predicts endoscopic and histologic assessed deep remission and inflammatory activity of colon mucosa. Neither the markers in blood nor the SCCAI performed significant ROC results.

Risk for Cervical Intraepithelial Neoplasia Grade 3 or Higher in Follow-Up of Women With a Negative Cervical Biopsy.

OBJECTIVE: The Norwegian Cervical Cancer Screening Programme recommends follow-up of histologically confirmed normal/cervical intraepithelial neoplasia (CIN) 1 with combined cytology and human papillomavirus testing within 6 to 12 months. This study examines adherence to guidelines and subsequent risk for CIN 3+ within this subset of women. MATERIALS AND METHODS: Women aged 25 to 69 years attending the Norwegian Cervical Cancer Screening Programme in Norway's 2 northernmost counties were included. An exposed cohort with histologically confirmed normal/CIN 1 after an atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesion or atypical squamous cells - cannot exclude high-grade squamous intraepithelial lesion/high-grade squamous intraepithelial lesion enrolment cytology (n = 374) was compared with a nonexposed cohort with a normal enrolment cytology attending primary screening (N = 25,948). Risk calculations were stratified by outcomes of the first follow-up cytology. The study end point was CIN 3+ or censored at 78 months of follow-up. RESULTS: In the exposed cohort, the 42-month cumulative incidence of CIN 3+ was 9.4% (95% CI = 4.1-14.7) for women with an abnormal first follow-up cytology and 1.6% (95% CI = 0.0-3.4) for women with a normal first follow-up cytology versus 0.21% (95% CI = 0.15-0.27) in the nonexposed cohort (p < .01). The CIN 3+ risk was higher in the exposed cohort when the first follow-up cytology was abnormal (hazard ratio = 20.4, 95% CI = 11.2-37.1) compared with normal (hazard ratio = 4.7, 95% CI = 1.9-11.6) with the nonexposed cohort as reference. CONCLUSIONS: After a negative cervical biopsy, a normal first follow-up cytology provided a CIN 3+ risk considered acceptable to recommend return to routine screening in 3 years. Cytology and human papillomavirus co-testing in post-colposcopy follow-up of negative biopsies may improve risk stratification.

Can an inadequate cervical cytology sample in ThinPrep be converted to a satisfactory sample by processing it with a SurePath preparation?

BACKGROUND: The Norwegian Cervical Cancer Screening Program recommends screening every 3 years for women between 25 and 69 years of age. There is a large difference in the percentage of unsatisfactory samples between laboratories that use different brands of liquid-based cytology. We wished to examine if inadequate ThinPrep samples could be satisfactory by processing them with the SurePath protocol. MATERIALS AND METHODS: A total of 187 inadequate ThinPrep specimens from the Department of Clinical Pathology at University Hospital of North Norway were sent to Akershus University Hospital for conversion to SurePath medium. Ninety-one (48.7%) were processed through the automated "gynecologic" application for cervix cytology samples, and 96 (51.3%) were processed with the "nongynecological" automatic program. RESULTS: Out of 187 samples that had been unsatisfactory by ThinPrep, 93 (49.7%) were satisfactory after being converted to SurePath. The rate of satisfactory cytology was 36.6% and 62.5% for samples run through the "gynecology" program and "nongynecology" program, respectively. Of the 93 samples that became satisfactory after conversion from ThinPrep to SurePath, 80 (86.0%) were screened as normal while 13 samples (14.0%) were given an abnormal diagnosis, which included 5 atypical squamous cells of undetermined significance, 5 low-grade squamous intraepithelial lesion, 2 atypical glandular cells not otherwise specified, and 1 atypical squamous cells cannot exclude high-grade squamous intraepithelial lesion. A total of 2.1% (4/187) of the women got a diagnosis of cervical intraepithelial neoplasia 2 or higher at a later follow-up. CONCLUSIONS: Converting cytology samples from ThinPrep to SurePath processing can reduce the number of unsatisfactory samples. The samples should be run through the "nongynecology" program to ensure an adequate number of cells.

Accuracy of cervical cytology: comparison of diagnoses of 100 Pap smears read by four pathologists at three hospitals in Norway.

BACKGROUND: Cervical cancer can be prevented by early detection and treatment for precancerous lesions. Since 1995, there has been a national cervical cancer screening program in Norway, where women aged 25-69 years are recommended to take Pap smears every three years. There are 17 cytology laboratories covering a population of 5 million people. The detection rate of cervical abnormalities varies from laboratory to laboratory. We wanted to investigate the accuracy of cytology diagnoses by four different pathologists at three different hospitals in Norway. METHODS: One hundred Pap smears (20 Normal, 20 ASC-US, 20 LSIL, 20 ASC-H and 20 HSIL) screened at UNN in 2015 were evaluated by four pathologists at three hospitals in Norway. All patients were followed up through December 2016. Histologically confirmed high-grade dysplasia (CIN2+) was considered as study endpoint. RESULTS: The number of Pap smears evaluated as abnormal (ASC-US+) by the four pathologists varied from 61 to 85. The number of high-grade cytology (ASC-H+) varied from 26 to 50. There was moderate agreement (weighted kappa 0.45-0.58) between the observers. There were 32 women with high-grade histology (CIN2+) in the follow-up, including 19 CIN2, 12 CIN3 and one squamous cell carcinoma (SCC). Using high-grade cytology (ASC-H+) as cut-off, the sensitivity for CIN2+ varied from 68.8% to 93.8% (mean 77.4%) and specificity from 70.6% to 95.6% (mean 81.3%). The pathologist with the highest sensitivity for CIN2+ had the highest false positive rate and the lowest specificity (p<0.05). The accuracy for CIN2+ varied from 74.1% to 83.8% (mean 79.4%). The Pap smear from the woman with cervical cancer was diagnosed as high-grade (ASC-H+) by one of the four pathologists. CONCLUSIONS: Cervical cancer screening based on cytology has limited accuracy. The study revealed a moderate agreement between the observers, along with a trade-off between sensitivity and specificity. This might indicate that hospitals with high detection rates of cervical cytology have higher sensitivity for CIN2+ but lower specificity.

Microscopic colitis: a missed diagnosis among patients with moderate to severe irritable bowel syndrome.

OBJECTIVE: Irritable bowel syndrome (IBS) is a very common condition in general practise, affecting 10-20% of the population in the Western world. The clinical picture of diarrhoea-predominant IBS (IBS-D) resembles other chronic diarrhoeic conditions, such as microscopic colitis (MC). It is impossible to separate these by clinical examinations or lab-tests that can be done in general practise. The aim of this study was to detect any missed diagnoses when only using a symptom-based approach for the diagnosis of IBS. MATERIAL AND METHODOLOGY: We examined 87 participants diagnosed with IBS by the Rome III criteria. All the participants underwent full clinical examination, lab-tests and colonoscopy including mucosa biopsies for histological examination. RESULTS: The histological analysis revealed four cases of MC in participants who for years had been diagnosed with IBS. We found no biochemical or clinical markers that made it possible to differentiate between IBS and MC. MC was only found in the participants diagnosed with IBS-D. CONCLUSION: When long-lasting, unresolved diarrhoeic conditions are present in patients over 45-50 years of age, colonoscopy with biopsy should be performed to rule out MC and other pathologies before diagnosing IBS. In younger patients with pronounced watery diarrhoea, one should consider colonoscopy individually if there is no response to IBS-treatment.

HPV types in cervical cancer tissue in South Africa: A head-to-head comparison by mRNA and DNA tests.

Accurate identification of human papillomavirus (HPV)-types in cervical cancer tissue may be important for tailoring tests for primary screening and types to be included in a vaccine. The aim of this study was to compare test-performance of a 45-type HPV deoxyribonucleic acid (DNA)-test with a 9-type HPV messenger ribonucleic acid (mRNA)-test in cervical cancer tissues.In a case-series design 188 women with diagnosed cervical cancer during the period January 2008 to July 1, 2011 at the Gynaecological Oncology Unit, University of Pretoria, South Africa were recruited to the study. After cases with negative internal controls for DNA/mRNA detection (n = 18) and unconfirmed histology (n = 3) of cervical cancer were excluded, 167 women remained eligible for analysis. We compared 45 DNA-types detected through general primer (GP)5/6 polymerase chain reaction (PCR) and reverse line blot (RLB) genotyping with a modified version of the mRNA test PreTect HPV-Proofer detecting 9 genotypes (16, 18, 31, 33, 35, 45, 51, 52, 58).Histological types were 92.2% squamous cell carcinoma, 4.8% adenocarcinoma, and 3.0% adenosquamous carcinoma. Overall, HPV was detected in 95.2% (159/167) of specimens. The DNA- and mRNA tests each rendered 153/167 (91.6%) HPV positive results. When restricting the analysis to the 9 high-risk HPV-types included in the mRNA test, 91.6% (153/167) and 88.0% (147/167) were positive by the mRNA- and DNA-tests (P = .28), respectively. After hierarchical categorization of 9 comparable types, we found concordance in 66 of 67 specimens for HPV16, 25 of 27 specimens for HPV18, 19 of 21 specimens for HPV45, and only in 33 of 45 for HPV31, 33, 35, 51, 52, 58. The positivity rate for the HPV types 16, 18, and 45 and the positivity rate for HPV 16, 18, 45, 33 and 35 by both tests was 66% to 68% and 80% to 83%, respectively.Overall and when considering established high-risk types, the mRNA test has at least as high detection rate as the DNA test. The mRNA test can be an appropriate research tool to describe causative HPV-types in cervical cancer tissue for health care planning purposes.

Primary cervical cancer screening with an HPV mRNA test: a prospective cohort study.

OBJECTIVES: To assess the performance of a 5-type human papillomavirus (HPV) messenger RNA (mRNA) test in primary screening within the framework of the Norwegian population-based screening programme. DESIGN: Nationwide register-based cohort study. SETTING: In 2003-2004, general practitioners and gynaecologists recruited 18 852 women for participation in a primary screening study with a 5-type HPV mRNA test. PARTICIPANTS: After excluding women with a history of abnormal smears and with cervical intraepithelial neoplasia grade 2 (CIN2+) before or until 3 months after screening, 11 220 women aged 25-69 years were eligible for study participation. The Norwegian Cancer Registry completed follow-up of CIN2+ through 31 December 2009. INTERVENTIONS: Follow-up according to the algorithm for cytology outcomes in the population-based Norwegian Cervical Cancer Screening Programme. MAIN OUTCOME MEASURES: We estimated cumulative incidence of CIN grade 3 or worse (CIN3+) 72 months after the 5-type HPV mRNA test. RESULTS: 3.6% of the women were HPV mRNA-positive at baseline. The overall cumulative rate of CIN3+ was 1.3% (95% CI 1.1% to 1.5%) through 72 months of follow-up, 2.3% for women aged 25-33 years (n=3277) and 0.9% for women aged 34-69 years (n=7943). Cumulative CIN3+ rates by baseline status for HPV mRNA-positive and mRNA-negative women aged 25-33 years were 22.2% (95% CI 14.5% to 29.8%) and 0.9% (95% CI 0.4% to 1.4%), respectively, and 16.6% (95% CI 10.7% to 22.5%) and 0.5% (95% CI 0.4% to 0.7%), respectively, in women aged 34-69 years. CONCLUSIONS: The present cumulative incidence of CIN3+ is similar to rates reported in screening studies via HPV DNA tests. Owing to differences in biological rationale and test characteristics, there is a trade-off between sensitivity and specificity that must be balanced when decisions on HPV tests in primary screening are taken. HPV mRNA testing may be used as primary screening for women aged 25-33 years and 34-69 years.

5-type HPV mRNA versus 14-type HPV DNA test: test performance, over-diagnosis and overtreatment in triage of women with minor cervical lesions.

BACKGROUND: Repeat cytology and HPV testing is used in triage of women with minor cytological lesions. The objective of this study was to evaluate 14-type HPV DNA and 5-type HPV mRNA testing in delayed triage of women with ASC-US/LSIL. METHODS: We compared a DNA test (Roche Cobas 4800) and an 5-type mRNA test (PreTect HPV-Proofer). In total 564 women were included in the study. RESULTS: The sensitivity among solved cases for CIN3+ were 100 % (15/15) for both tests. The sensitivity for CIN2+ of the HPV DNA test was 100 % (38/38) relative to 79 % (30/38) for the 5-type HPV mRNA test. The corresponding estimates of specificity for CIN2+ among solved cases were 84 % (393/466; 95 % CI: 81-88) and 91 % (451/498; 95 % CI: 88-93). The positive predictive values for CIN3+ were 13.5 % (15/111) for DNA+ and 19.5 % (15/77) for 5-type mRNA+. Significantly more women screened with 5-type mRNA than DNA returned to screening (81 % vs 71 %, p < 0.01). Subsequently, significantly fewer women were referred for colposcopy/biopsies/treatment (19 % (105/564) vs 29 % (165/564), p < 0.01). CONCLUSIONS: 5-type HPV mRNA is more specific than 14-type HPV DNA in delayed triage of women with ASC-US/LSIL. The referral rate for colposcopy was 57 % higher for DNA+ relative to mRNA+ cases (165 vs 105), with the same detection rate of CIN3+, but the 5-type mRNA test had lower sensitivity for CIN2+. It is important to consider the trade-off between sensitivity and specificity of the diagnostic test when designing screening algorithms.