Human papillomavirus as a target for cancer prevention

If we would know more about virus causing cancer, we would have the possibility to prevent the disease. Human Papillomavirus (HPV) causes cervical cancer and is one of the world’s most common sexually transmitted diseases (STD). Cervical cancer is a preventable disease, nevertheless, still each year around 550 women are diagnosed, and almost 200 women lose their life to this disease in Sweden. This thesis aims to present: - an investigation on the cancer risk among immunosuppressed patients (I) - suggestions on how to, maintain a high-quality cervical cancer screening programme by annual clinical audits on HPV analysis (II), report quality indicators on cervical screening data (III), and use HPV genotype and viral load data to improve cervical cancer prediction in HPV primary screening (V) and, - how to use registry linkages over the Nordic borders to miminize loss to follow-up (IV). These population-based studies, and a follow-up study, utilized Nordic national and regional health-data and civil registries and a Belgium database to collect data on immunosuppressed patients, cancer outcomes, and cervical cancer screening and population data. We identified 43,912 immunosuppressed patients in Denmark and Sweden with 5,709 incident cancers (I). The overall standardized incidence ratio (SIR) varied between 1.6 in long-term dialysis patients in Denmark and 3.5 in the Swedish cohort of solid organ transplanted patients. The largest increase in SIR was observed in non-melanoma skin cancer in the Swedish cohort, 44.7 [n 994, 95% CI, 42–47.5]. Routine cytology has a method to estimate sensitivity to identify women diagnosed with cervical intraepithelial neoplasia grade 3 or worse. The HPV primary screening programme in Stockholm used similar method and estimated a sensitivity of 97 % (148/154 women) (II). Key quality indicators in the Swedish cervical screening programme in 2014-2016 presented a 69-70% population screening coverage and 96-97% of women who were followed-up with histology after abnormal cytology within 1 year (III). In a Belgian case-control cohort, including 2,230 LBC samples with HPV genotypes and viral load analysis results, HPV 16 and 18 (>0 copies/μl) and HPV31/33/45/52 (3000 >copies/μl) could predict 87% of invasive cervical cancer within a year. By adding 8 HPV types only 9 additional cases were predicted during a 7 year-period. (V). A registry-based follow-up study an HPV-vaccination trial used registry searches over the Nordic borders, Denmark, Iceland, Norway, and Sweden to gain completeness. In conclusion, we identified elevated cancer types in immunosuppressed patients that will need further investigations. We proposed strategies for quality assessment of HPV-analysis and cervical cancer screening, and how viral load and HPV-genotyping can improve prediction cervical cancer in a primary HPV screening

Targeting human papillomavirus to reduce the burden of cervical, vulvar and vaginal cancer and pre-invasive neoplasia: establishing the baseline for surveillance.

Infection with high-risk human papillomavirus (HPV) is causally related to cervical, vulvar and vaginal pre-invasive neoplasias and cancers. Highly effective vaccines against HPV types 16/18 have been available since 2006, and are currently used in many countries in combination with cervical cancer screening to control the burden of cervical cancer. We estimated the overall and age-specific incidence rate (IR) of cervical, vulvar and vaginal cancer and pre-invasive neoplasia in Denmark, Iceland, Norway and Sweden in 2004-2006, prior to the availability of HPV vaccines, in order to establish a baseline for surveillance. We also estimated the population attributable fraction to determine roughly the expected effect of HPV16/18 vaccination on the incidence of these diseases

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

Publisher's version (útgefin grein)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 for this research was provided by Merck Sharp &Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ,USA (MSD).The authors would like to thank the study participants and base-study investigators. In particular, the authors are grateful to SuzanneCampbell, Ragnhild Flingtorp, and Bo Terning Hansen for contribu-tions to the study; Sara Nordqvist Kleppe for data management; andJette Junge for contributions serving on the pathology panel. Chris-tine Shields of MSD provided clinical scientist support to thefinalanalysis and contributed to the clinical study report. Roshonda Flor-ence of ExecuPharm provided operational leadership and coordi-nated with the pathology panel and central laboratories; this wasfunded by MSD.Medical writing support, under the direction of the authors, wasprovided by Erin Bekes, PhD, of CMC AFFINITY, McCann Health Medi-cal Communications, and was funded by MSD, in accordance withGood Publication Practice (GPP3) guidelines.Peer Reviewe

Ledtidsreduktion på El-Björn AB - ur ett lönsamhets- och målkonfliktsperspektiv

Detta examensarbete har utförts vid El-Björn AB som är ett familjeföretag i Anderstorp, Småland. Deras produktsortiment består av mobila el-centraler, byggbelysning, avfuktare och värmefläktar. El-Björn AB har ungefär 60 anställda och en omsättning på cirka 170 MSEK. På grund av den ökande konkurrensen anser företaget att det är nödvändigt att effektivisera sin produktion för att göra den mer flexibel. Vårt angreppssätt för att uppnå flexibilitet är att studera möjligheten att reducera företagets ledtider. Målet med detta arbete är att presentera ett antal förslag på åtgärder för att korta ledtiden för en utvald produktgrupp och att visa på ett antal konsekvenser som dessa förslag får för ledtiden och lönsamheten samt vilka målkonflikter detta medför. Förslagen ska ses i relation till nuläget. Det finns i princip tre sätt att reducera ledtiden i ett produktionsflöde; operationstiden kan minskas, väntetiden mellan aktiviteter kan minskas och aktiviteter kan utföras parallellt. Olika metoder i enlighet med dessa principer har studerats. Eftersom El-Björn AB inte tillämpar parallella aktiviteter i utgångsläget har även batchstorleken stor betydelse för produktens ledtid genom flödet. Beräkningar av jämförande scenarier gällande utvalt flöde visar att minskade batchstorlekar i enlighet med EOQ (Economic Order Quantity) och införande av parallella aktiviteter medför kortare ledtider, lägre kapitalbindning och lagerhållningskostnad, samt ökad lönsamhet. Störst effekt ger den förändrade batchstorleken i jämförelsen. Införande av metoder för ledtidsreduktion medför ett antal målkonflikter. Dessa har identifierats och analyserats. Det är viktigt att företaget tar hänsyn till dem innan en förändring genomförs. En analys av lönsamheten visar att en ökning av vinstmarginalen ger större effekt på lönsamheten i jämförelse med ökad kapitalomsättningshastighet för El-Björn AB. Av arbetet har slutsatsen dragits att ett antal metoder för ledtidsreduktion är lämpliga att använda i företaget. Dessa är: reducering av icke värdeskapande aktiviteter, eliminering av slöseri av resurser enligt Lean Production, införande av parallella aktiviteter i flödet, koordinering av kommunikationen, arbete med flaskhalsreducering samt reducering av batchstorlekar. Metoder som inte anses tillämpbara är ställtidsreduktion enligt SMED samt införandet av ett pullsystem

Cervical cancer screening in Sweden 2014-2016.

BACKGROUND:To enable incremental optimization of screening, regular reporting of quality indicators is required. AIM:To report key quality indicators and basic statistics about cervical screening in Sweden. METHODS:We collected individual level data on all cervical cytologies, histopathologies, human papillomavirus tests and all invitations for cervical screening in Sweden during 2013-2016. RESULTS:There were over 2,278,000 cervical samples collected in Sweden in 2014-2016. Organized samples (resulting from an invitation) constituted 69% of samples. The screening test coverage of all resident women aged 23-60 was 82%. The coverage has slowly increased for >10 years. There is large variability between counties (from 71% to 92%) over time. There were 25,725 women with high-grade lesions in cytology during 2013-2015. Only 96% of these women had a follow-up histopathology within a year. Cervical cancer incidence showed an increasing trend. CONCLUSION:Key quality indicators such as population coverage and follow-up rates were stable or improving, but there was nevertheless an unexplained cervical cancer increase

Comparison of use of vaginal HPV self-sampling and offering flexible appointments as strategies to reach long-term non-attending women in organized cervical screening.

Many cervical cancers occur among women who have not attended cervical screening. Strategies to reach non-attending women may improve the effectiveness of cervical screening programmes

Viruses in case series of tumors: Consistent presence in different cancers in the same subject.

Studies investigating presence of viruses in cancer often analyze case series of cancers, resulting in detection of many viruses that are not etiologically linked to the tumors where they are found. The incidence of virus-associated cancers is greatly increased in immunocompromised individuals. Non-melanoma skin cancer (NMSC) is also greatly increased and a variety of viruses have been detected in NMSC. As immunosuppressed patients often develop multiple independent NMSCs, we reasoned that viruses consistently present in independent tumors might be more likely to be involved in tumorigenesis. We sequenced 8 different NMSCs from 1 patient in comparison to 8 different NMSCs from 8 different patients. Among the latter, 12 different virus sequences were detected, but none in more than 1 tumor each. In contrast, the patient with multiple NMSCs had human papillomavirus type 15 and type 38 present in 6 out of 8 NMSCs

Decline of HPV infections in Scandinavian cervical screening populations after introduction of HPV vaccination programs

Objective: To monitor the changes in prevalence of human papillomavirus (HPV) infections in women 12,000 women participating in cervical screening in the 3 Nordic countries before and after introduction of organized qHPV vaccination demonstrated a marked decline in HPV infection in the younger population in the 2 countries where qHPV vaccination programs started in 2008–2009, suggesting that organized HPV vaccination programs resulted in a decrease of HPV types circulating in the general population