Enhancing Cervical Cancer Screening with 7-Type HPV mRNA E6/E7 Testing on Self-Collected Samples: Multicentric Insights from Mexico.

Cervical cancer remains a significant public health issue, particularly in regions with low screening uptake. This study evaluates the effectiveness of self-sampling and the 7-type HPV mRNA E6/E7 test in improving cervical cancer screening outcomes among a referral population in Mexico. A cohort of 418 Mexican women aged 25 to 65, referred for colposcopy and biopsy due to abnormal cytology results (ASC-US+), participated in this study. Self-samples were analyzed using both the 14-type HPV DNA test and the 7-type HPV mRNA E6/E7 test. The study assessed the sensitivity, specificity, positive predictive value (PPV), and the necessity of colposcopies to detect CIN3+ lesions. Participant acceptability of self-sampling was also evaluated through a questionnaire. The 7-type HPV mRNA E6/E7 test demonstrated equivalent sensitivity but significantly higher specificity (77.0%) and PPV for CIN3+ detection compared to the 14-type HPV DNA test (specificity: 45.8%, p < 0.001). The use of the HPV mRNA test as a triage tool reduced the number of colposcopies needed per CIN3+ case detected from 16.6 to 7.6 (p < 0.001). Self-sampling was highly accepted among participants, with the majority reporting confidence in performing the procedure, minimal discomfort, and willingness to undertake self-sampling at home. Self-sampling combined with the 7-type HPV mRNA E6/E7 testing offers a promising strategy to enhance cervical cancer screening by improving accessibility and ensuring precise diagnostics. Implementing these app roaches could lead to a significant reduction in cervical cancer morbidity and mortality, especially in underserved populations. Future research should focus on the long-term impact of integrating these methods into national screening programs and explore the cost-effectiveness of widespread implementation.

Post-Conization HPV Vaccination and Its Impact on Viral Status: A Retrospective Cohort Study in Troms and Finnmark, 2022.

Human papillomavirus (HPV) is associated with cellular changes in the cervix leading to cancer, which highlights the importance of vaccination in preventing HPV infections and subsequent cellular changes. Women undergoing the loop electrosurgical excision procedure (LEEP), a treatment for high-grade cervical intraepithelial neoplasia (CIN2+), remain at risk of recurrence. This study assessed the effect of post-conization HPV vaccination on the viral status of women at six months post-conization, aiming to evaluate the vaccine's effectiveness in preventing recurrence of CIN2+. A retrospective cohort study was conducted among women in Troms and Finnmark who underwent conization in 2022. Using the SymPathy database and the national vaccination register (SYSVAK), we analyzed the vaccination statuses and HPV test results of women born before 1991, who had not received the HPV vaccine prior to conization. Out of 419 women undergoing conization, 243 met the inclusion criteria. A significant association was found between post-conization HPV vaccination and a negative HPV test at six months of follow-up (ARR = 12.1%, p = 0.039). Post-conization HPV vaccination significantly reduced the risk of a positive HPV test at the first follow-up, suggesting its potential in preventing the recurrence of high-grade cellular changes. However, the retrospective design and the insufficient control of confounding variables in this study underscore the need for further studies to confirm these findings.

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.

May Women with a Negative Co-Test at First Follow-Up Visit Return to 3-Year Screening after Treatment for Cervical Intraepithelial Neoplasia?

BACKGROUND: The Norwegian Cervical Cancer Screening Programme recommends that women treated for cervical intraepithelial neoplasia (CIN) only be returned to 3-year screening after receiving two consecutive negative co-tests, 6 months apart. Here we evaluate adherence to these guidelines and assessed the residual disease, using CIN3+ as the outcome. METHODS: This cross-sectional study comprised 1397 women, treated for CIN between 2014 and 2017, who had their cytology, HPV, and histology samples analyzed by a single university department of pathology. Women who had their first and second follow-up at 4-8 and 9-18 months after treatment were considered adherent to the guidelines. The follow-up ended on 31 December 2021. We used survival analysis to assess the residual and recurrent CIN3 or worse among women with one and two negative co-tests, respectively. RESULTS: 71.8% (1003/1397) of women attended the first follow-up 4-8 months after treatment, and 38.3% were considered adherent at the second follow-up. Nearly 30% of the women had incomplete follow-up at the study end. None of the 808 women who returned to 3-year screening after two negative co-tests were diagnosed with CIN3+, whereas two such cases were diagnosed among the 887 women who had normal cytology/ASCUS/LSIL and a negative HPV test at first follow-up (5-year risk of CIN3+: 0.24, 95%, CI: 0.00-0.57 per 100 woman-years). CONCLUSIONS: The high proportion of women with incomplete follow-up at the end of the study period requires action. The risk of CIN3+ among women with normal cytology/ASCUS/LSIL and a negative HPV test at first follow-up is indicative of a return to 3-year screening.

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.

Prediction of long-term remission in patients following discontinuation of anti-TNF therapy in ulcerative colitis: a 10 year follow up study.

BACKGROUND: The long-term outcomes of Ulcerative colitis (UC) after discontinuation of biological therapy are largely unknown. There is also a lack of accurate and validated markers that can predict outcome after withdrawal accurately. The aims of this study were to describe the long-term outcomes in UC patients following cessation of anti-TNF therapy and explore potential biomarkers as an approach towards precision medicine. METHODS: Seventy-five patients with moderate to severe UC treated to remission with anti-tumor necrosis factor (TNF) were included in the study. This is a follow-up of previously reported UC outcomes. The patients were categorized as either "Remission" or "Relapse". The "Relapse" group was divided into subgroups determined by the highest treatment level needed to obtain remission the last 3 years of observation: non-biological therapy, biological therapy or colectomy. Remission were divided in long term remission (LTR), those using immunomodulating drugs (LTR + imids) and those using only 5-amino-salicylate (5-ASA) treatment (LTR) for the past 3 years. Analyses of mucosal gene expression by real-time PCR were performed. RESULTS: The median (IQR) observation time of all patients included was 121 (111-137) months. Of the 75 patients, 46 (61%) did not receive biological therapy, including 23 (31%) in LTR ± imids. Of these 23 patients, 16 (21%) were defined as LTR with a median observation time of (IQR) 95 (77-113) months. In total 14 patients (19%) underwent colectomy during the 10 years after first remission. Mucosal TNF copies/µg mRNA < 10 000 at anti-TNF discontinuation predicted long-term remission, biological free remission and lower risk of colectomy with a HR 0.36 (0.14-0.92) for long-term remission, HR 0.17 (0.04-0.78) for biological free remission and HR 0.12 (0.01-0.91) for colectomy. IL1RL1 was normalized in LTR phenotype and higher in relapsing UC. CONCLUSION: In this 10-year follow-up of UC of patients with moderate to severe disease, 61% of patients experience an altered phenotype to a milder disease course without need of biological therapy. Twenty-one percent of the patients were LTR without any medication except of 5-ASA. Mucosal TNF gene expression and IL1RL1- transcripts may be of clinical utility for long term prognosis in development of precision medicine in UC.

Population-based screening for celiac disease reveals that the majority of patients are undiagnosed and improve on a gluten-free diet.

The impact of a gluten-free diet (GFD) on screen-detected celiac disease (CD) is currently ambiguous. We aimed to identify the population-based prevalence of undiagnosed adult CD and examine the impact of a GFD on screen-detected CD. In total, 12,981 adults participated in a population-based health study in Tromsø, Norway. Participants with increased levels of anti-tissue transglutaminase-2 IgA or anti-deamidated gliadin peptide IgG were invited to undergo gastroduodenoscopy with both histological and immunohistochemical examination of small-bowel biopsies. The prevalence of previously diagnosed CD was 0.37%. Additionally, the prevalence of previously undiagnosed CD was 1.10%. Thus, 1.47% of the population had CD, of whom 75% were previously undiagnosed. A GFD resulted in significant improvements in overall gastrointestinal symptoms, diarrhea, and health-related quality of life, with reduced abdominal discomfort (76%) and improved levels of energy (58%). The large majority of patients with adult CD were undiagnosed and benefited from a GFD with reduced gastrointestinal symptoms and improved health-related quality of life. In clinical practice, there should be a low threshold for CD testing even in the absence of abdominal complaints because most adult patients appear to consider their symptoms a part of their normal state and therefore remain untested and undiagnosed.Trial registration: Clinical Trials. Gov Identifier: NCT01695681.

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.

Real-life evaluation of histologic scores for Ulcerative Colitis in remission.

BACKGROUND: Histological evaluation of ulcerative colitis (UC) patients has been debated ever since the first description of the disease and its role in follow-up has never been fully established. Recent evidence suggests an added benefit in accuracy when evaluating if the patient is in remission. Unfortunately, there are several different histological indices, and it is difficult to compare outcomes where different scores are applied. Histopathological evaluation is prone to subjective biases, despite the use of indices. In addition, these indices are developed by expert IBD pathologist, but applied at large, by general pathologist. Therefore, we evaluated the three most applied histological indices for UC on samples from patients in remission to compare test qualities and estimate their usefulness to identify remission by both general and GI specialized pathologist. METHOD: Mucosal biopsies from 41 UC patients in clinical and endoscopic remission were collected as part of a larger study on UC. Three pathologists blinded to the patients' clinical status evaluated them using Geboes score (GS), Nancy Index (NI) and Robarts Histopathological Index (RHI). We calculated the agreement between the pathologists using Inter-class correlation (ICC) and visualized it with ICC-plots and Bland-Altman plots. Association between clinical factors and histological category were analysed by Fisher's exact test. RESULTS: The ICC value for GS, RHI and NI were 0.85, 0.73 and 0.70 respectively. The limits of agreement were ±6.1, ±4.0 and ±1.4, for GS, RHI and NI, respectively. Mayo endoscopic subgrade and UC clinical score did not show association with any histological scores. Despite clinical and endoscopic remission 7-35% of the patients displayed histological inflammation on a level classified as active disease, depending on the index and cut-off. CONCLUSION: A substantial amount of UC patients in clinical and endoscopic remission display inflammation on a histological level, but the ability to classify these patients accurately and consistently could be improved.

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.

Transcriptional Signatures That Define Ulcerative Colitis in Remission.

BACKGROUND: This study addresses whether existing specific transcriptional profiles can improve and support the current status of the definition of ulcerative colitis (UC) remission apart from the existing endoscopic, histologic, and laboratory scoring systems. For that purpose, a well-stratified UC patient population in remission was compared to active UC and control patients and was investigated by applying the next-generation technology RNA-Seq. METHODS: Mucosal biopsies from patients in remission (n = 14), patients with active UC (n = 14), and healthy control patientss (n = 16) underwent whole-transcriptome RNA-Seq. Principal component analysis, cell deconvolution methods, gene profile enrichment, and pathway enrichment methods were applied to define a specific transcriptional signature of UC in remission. RESULTS: Analyses revealed specific transcriptional signatures for UC in remission with increased expression of genes involved in O-glycosylation (MUC17, MUC3A, MUC5AC, MUC12, SPON1, B3GNT3), ephrin-mediated repulsion of cells (EFNB2E, EFNA3, EPHA10, EPHA1), GAP junction trafficking (TUBA1C, TUBA4A, TUBB4B, GJB3, CLTB), and decreased expression of several toll-like receptors (TLR1, TLR3, TLR5, TLR6). CONCLUSIONS: This study reveals specific transcriptional signatures for remission. Partial restoration and improvement of homeostasis in the epithelial mucus layer and revival of immunological functions were observed. A clear role for bacterial gut flora composition can be implied. The results can be useful for the development of treatment strategies for UC in remission and may be useful targets for further investigations aiming to predict the outcome of UC in the future.

Discovery and validation of mucosal TNF expression combined with histological score - a biomarker for personalized treatment in ulcerative colitis.

BACKGROUND: There are no accurate markers that can predict clinical outcome in ulcerative colitis at time of diagnosis. The aim of this study was to explore a comprehensive data set to identify and validate predictors of clinical outcome in the first year following diagnosis. METHODS: Treatment naive-patients with ulcerative colitis were included at time of initial diagnosis from 2004 to 2014, followed by a validation study from 2014 to 2018. Patients were treated according to clinical guidelines following a standard step-up regime. Patients were categorized according to the treatment level necessary to achieve clinical remission: mild, moderate and severe. The biopsies were assessed by Robarts histopathology index (RHI) and TNF gene transcripts. RESULTS: We included 66 patients in the calibration cohort and 89 patients in the validation. Mucosal TNF transcripts showed high test reliability for predicting severe outcome in UC. When combined with histological activity (RHI) scores the test improved its diagnostic reliability. Based on the cut-off values of mucosal TNF and RHI scores from the calibration cohort, the combined test had still high reliability in the validation cohort (specificity 0.99, sensitivity 0.44, PPV 0.89, NPV 0.87) and a diagnostic odds-ratio (DOR) of 54. CONCLUSIONS: The combined test using TNF transcript and histological score at debut of UC can predict severe outcome and the need for anti-TNF therapy with a high level of precision. These validated data may be of great clinical utility and contribute to a personalized medical approach with the possibility of top-down treatment for selected patients.

Clinical characterization of Helicobacter pylori infected patients 15 years after unsuccessful eradication.

BACKGROUND AND AIMS: Patients that have failed therapy for Helicobacter pylori (H. pylori) infection are incompletely characterized. The aim of this study was to characterize a H. pylori treatment resistant cohort compared to the cohorts of newly diagnosed, earlier eradicated and non-infected. MATERIAL AND METHODS: Patients were selected from routine referrals to the Endoscopy units at three different Norwegian hospitals. In all four cohorts, gastric biopsies were scored according to the Sydney classification, and symptoms according to the Gastrointestinal Symptom Rating Scale score, including sub-scores for upper gastrointestinal symptoms and functional bowel symptoms. Patients in the H. pylori resistant group were treated with a triple therapy regimen that consisted of levofloxacin, amoxicillin and a proton pump inhibitor. RESULTS: We included 185 patients, 42 H. pylori treatment resistant, 50 newly diagnosed, 61 previously H. pylori eradicated and 32 never infected. The treatment-resistant cohort had higher scores for upper gastrointestinal symptoms and functional bowel symptoms compared to the other groups except for the group being never H. pylori infected. The H. pylori resistant patients had lower Sydney scores than patients with newly diagnosed H. pylori infection. The triple combination showed a high efficacy of 91% to eradicate H. pylori. CONCLUSIONS: Patients with treatment-resistant H. pylori infection had more gastrointestinal symptoms, but a lower Sydney score than patients with newly diagnosed infection. A treatment regimen including levofloxacin showed a high efficacy in eradicating H. pylori in patients that previously had failed eradication treatment.

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.

Intestinal inflammatory profile shows increase in a diversity of biomarkers in irritable bowel syndrome.

Background: It has been proposed that irritable bowel syndrome (IBS) is a low-grade mucosal inflammatory disease.Objective: To characterize the intestinal inflammatory profile in IBS patients with or without fructose intolerance.Design: Patients referred to colonoscopy with IBS complaints were screened for participation. IBS patients diagnosed according to the Rome II criteria and with no organic gastrointestinal disease were included in the study. One subgroup was patients included in a fructose-reduced diet study for 2 months with effects based on VAS symptom scores. Healthy controls were subjects under investigation of colorectal cancer screening with no IBS or other gastrointestinal diseases. All patients included had normal histology from rectum. Mucosal cytokines, chemokines and growth factors were measured by multiplex technology.Results: Of 27 inflammatory markers tested in the mucosal tissue, 13 were significantly increased and none was significantly decreased in IBS as compared to controls. Significantly increased were the proinflammatory cytokines tumor necrosis factor, the typical TH1 markers IFNγ, IL-1ß, IL-2 and RANTES, the typical TH2 markers IL-5 and IL-9, the TH17 marker IL-17, TNF, the pleiotropic IL-15, and the growth factors bFGF and GM-CSF. In IBS patients with fructose intolerance only IL-5 was significantly increased compared to patients without fructose intolerance.Conclusions: A dysregulated mucosal inflammatory profile with an increased level of TH1, TH2 and TH17 markers, and growth factors were observed in bowel mucosa in of IBS patients when compared to healthy controls.

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.