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The objective of this study was to identify clinicopathologic parameters associated with disease outcome in FIGO stage I vulvar squamous cell carcinoma (vSqCC). The cohort consisted of 126 patients diagnosed with vSqCC in the period 2006-2016 who underwent primary vulvar surgery and evaluation of groin lymph node status. Tumors were reviewed by an experienced gynecologic pathologist. p16 and p53 protein expression by immunohistochemistry and HPV status were analyzed in 116 tumors. Clinicopathologic parameters, protein expression and HPV status were analyzed for association with progression-free and overall survival (PFS, OS). p16 expression and aberrant p53 were found in 49 (42%) and 61 (53%) tumors, respectively. Sixty-six tumors were HPV-associated (57%). Relapse was diagnosed in 35/126 (28%) of patients, and 23 (18%) died of disease. Tumor diameter > 4 cm (p = 0.013), lymphovascular space invasion (LVSI; p < 0.001), the presence of lichen sclerosus (p = 0.019), p16 expression (p = 0.007), p53 expression (p = 0.012), HPV status (p = 0.021), lymph node metastasis (p < 0.001) and post-operative radiotherapy (p < 0.001) were significantly related to OS in univariate analysis. Tumor diameter > 4 cm (p = 0.038), LVSI (p = 0.003), the presence of lichen sclerosus (p = 0.004), p16 expression (p = 0.004), HPV status (p = 0.039), lymph node metastasis (p < 0.001) and post-operative treatment (p < 0.001), were significantly related to PFS in univariate analysis. Age, BMI and surgical resection involvement were not significantly associated with OS or PFS. In multivariate Cox analysis, LVSI and p16 expression were independent prognosticators of OS (p < 0.001 and p = 0.02, respectively) and PFS (p = 0.018, p = 0.037). In conclusion, LVSI and p16 expression are independent prognostic factors in stage I vSqCC., (© 2023. The Author(s).)

Background: Few studies have been conducted on young people's attitudes to the COVID-19 vaccine during the pandemic. We wished to examine how young people with an ethnic minority background decided whether to have the COVID-19 vaccine, based on the concept of vaccine hesitancy. Vaccine hesitancy involves uncertainty with regard to vaccination, irrespective of the decision taken., Material and Method: Fourteen qualitative in-depth interviews with young people aged 16-25 years with an ethnic minority background and from the east side of Oslo were analysed and categorised into main themes. The participants also had links to the Middle East, South Asia and Africa., Results: Several of the study participants were hesitant to be vaccinated. Their hesitation was linked to the impression that the vaccine had been developed rapidly, false rumours, long travel times to vaccination centres and fear of adverse effects. A number called for better information. Vaccination through the school was described as a facilitating factor. Family and friends were less crucial in their assessment of whether to have the COVID-19 vaccine. The majority had trust in the authorities., Interpretation: Insufficient knowledge about the vaccine and fear of adverse effects, as well as practical barriers associated with undergoing vaccination, appears to contribute to vaccine scepticism among young people with an ethnic minority background. The authorities and healthcare personnel should provide young people with better vaccine information. Information should be provided by personnel they already trust, such as the school nurse.

Introduction: Approximately 25%-43% of all vulvar carcinomas are associated with human papillomavirus (HPV). In many countries, vulvar carcinoma incidence rates are increasing, possibly due to greater HPV exposure. However, studies exploring changes in HPV prevalence and genotype distribution in vulvar carcinoma over time are scarce. Our aim was to evaluate time trends in HPV prevalence and genotype distribution in vulvar squamous cell carcinoma in an unselected, nationwide sample of Norwegian women. Further, we explored clinical and histopathological aspects in relation to HPV status and investigated whether HPV status was associated with survival., Material and Methods: All vulvar squamous cell carcinoma cases from 1970-1975 and 2000-2005 were extracted from the Cancer Registry of Norway and corresponding tissue blocks were retrieved. After detailed histology review, HPV testing was conducted using real-time TaqMan PCR. Overall survival rates were calculated using the Kaplan-Meier method. Multivariable Cox regression analysis was performed to estimate hazard ratios adjusted for age at diagnosis, stage and diagnostic period., Results: Histological review was performed on 352 vulvar squamous cell carcinoma cases. We were able to obtain valid HPV analysis results for 282 cases, Overall, 29.8% (95% CI 24.5%-35.5%) of cases were high-risk HPV (hrHPV)-positive. When comparing the two periods, we found that the percentage of hrHPV-positive tumors increased significantly from 23% (95% CI 16.0%-31.4%) in 1970-1975 to 35.3% (95% CI 27.8%-43.3%) in 2000-2005 (P = 0.025). The predominant genotypes were HPV 16 (73%), HPV 33 (21%), and HPV 18 (6%), with similar distributions in both periods. In the more recent cohort, several additional genotypes were detected: HPV 6, 11, 39, 45, 52, 58 and 66 were found in smaller percentages, ranging from 1.8% to 3.6%. In univariate analysis, patients with HPV-positive tumors showed improved overall survival compared with patients with HPV-negative tumors (hazard ratio [HR] 0.65, 95% CI 0.48-0.86)., Conclusions: The prevalence of HPV in vulvar squamous cell carcinomas in Norway was significantly higher in 2000-2005 than in 1970-1975. The three predominant genotypes were HPV 16, 33 and 18 in both time periods. However, several other HPV genotypes have emerged over the last decades. HPV-positivity was associated with better overall survival., (© 2023 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Competing Interests: We declare no competing interests.

Bakgrunn: Smittesporing har fått ny aktualitet grunnet covid-19, men har lenge vært viktig i bekjempelsen av seksuelt overførbare infeksjoner. I denne artikkelen vil vi belyse hvordan smittesporingen ved seksuelt overførbare infeksjoner i Norge har endret seg de siste 120 årene., Materiale Og Metode: Kildegrunnlaget er årsberetninger fra Kristiania Sundhetskommission og Oslo Helseråd, årsrapporter fra Meldingssystem for smittsomme sykdommer ved Folkehelseinstituttet (MSIS), skjema for innkalling av pasienter, et originalt maskinskrevet manuskript av helseinspektør Harald Christian Gjessing (1896-1988) samt personlige meddelelser fra Øivind Jul Nilsen, seniorrådgiver ved Folkehelseinstituttet., Resultater Og Fortolkning: Smittesporing er i varierende grad dokumentert i årsberetningene fra Kristiania Sundhetskommission fra slutten av 1800-tallet og fram til dagens MSIS-rapporter. Politiet var sterkt involvert i kontrollen av kjønnssykdommene på slutten av 1800-tallet, men legene overtok mer av ansvaret ut over 1900-tallet. Under den annen verdenskrig ble igjen politiet mer involvert i kontroll og smittesporing. I 1947 kom lov om åtgjerder mot kjønnssykdommer, som stadfestet behandlende leges plikt til å utføre smittesporing. Denne loven ble erstattet av smittevernloven i 1995. Kvaliteten på smittesporingen over tid er noe vanskelig å vurdere, da datagrunnlaget for statistikken har endret seg. Fra å være et moralsk anliggende, med sterke elementer av tvang og hjelp fra sedelighetspolitiet, ble smittesporing etter hvert basert på frivillighet og samarbeid mellom lege og pasient.

The COVID-19 pandemic has largely been made sense of as a crisis However, using crisis as a temporal-analytical category arguably obscures the complexity of the different temporalities at work in the pandemic. In this article, we examine how the pandemic outbreak led to numerous acts of synchronisation and de-synchronisation-between humans and viruses, between social groups and even between historical ages. In order to make sense of the temporal consequences of an epidemic, we introduce the concept of 'temporal technologies', understood as a set of procedures that control, regulate, produce and assemble time in relational networks of both human and non-human actors. This article thus attempts to create a framework for understanding the epidemic experience in temporal terms by using 'temporal technologies' as an analytical tool., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: This study presents the clinical assessment of the Onclarity HPV Assay (Becton Dickinson) on the novel COR high-throughput instrument (Becton Dickinson) using the international guidelines in a routine setting., Methods: Screening samples collected in BD SurePath from women aged 30 years and older were used in this validation. Noninferiority of the Onclarity HPV Assay on the COR instrument (Onclarity-COR) was assessed with the comparator assay glycoprotein 5-positive (GP5+)/6+ enzyme immunoassay (GP-EIA) for clinical sensitivity on 122 cervical intraepithelial neoplasia 2 and greater samples. Specificity was assessed using 887 samples with twice-normal cytology. Inter- and intralaboratory reproducibility analysis was assessed using 525 samples. Finally, a time-and-motion study was performed to evaluate COR instrument performance characteristics., Results: The Onclarity-COR was noninferior to the GP-EIA for both sensitivity (P = .0016) and specificity (P < .0001). The intralaboratory reproducibility was 98.3% (κ = 0.96), and interlaboratory agreement was 98.5 % (κ = 0.96). The daily hands-on time for the COR instrument was 58 minutes, and walk-away time was 7 hours, 2 minutes per 8-hour day shift., Conclusions: The Onclarity-COR instrument fulfills international validation criteria on sensitivity, specificity, and laboratory reproducibility. The Onclarity assay's extended genotyping capability, together with its high-throughput characteristics, makes the COR instrument an excellent candidate for use in human papillomavirus primary cervical cancer screening., (© American Society for Clinical Pathology, 2021.)

FACBC (anti-1-amino-3- 18 F-fluorocyclobutane-1-carboxylic acid) is a FDA-approved PET-tracer in patients with suspected recurrent prostate cancer. In the diagnostic work-up of primary prostate cancer, accurate localization of the index tumor is needed for image-guidance of biopsies. We therefore assessed the performance of FACBC PET/CT to detect and localize the index tumor and compared it to multiparametric MRI (mpMRI) using whole-mount histopathology as reference standard. Twenty-three patients with biopsy-proven prostate cancer had FACBC PET/CT and mpMRI within two weeks prior to prostatectomy. FACBC PET/CT was acquired as 14 minutes list-mode and re-binned into seven 2-minutes intervals. Static FACBC was the acquired data from 4-6 minutes, whereas the dynamic FACBC included all seven intervals. Two radiologists and two nuclear medicine physicians independently interpreted the images and consensus was reached in case of discrepancy. Static PET detected 15 of 23 (65%) of the index tumors, dynamic PET detected 14 of 22 (64%), and MRI detected 20 of 23 (87%). To assess the extent of the tumor, the interpreters delineated the tumor in a 12-regions sector-based template. True positive, true negative, false positive and false negative sectors were recorded based on the template drawings and whole-mount histopathology. Both static and dynamic FACBC PET had sensitivity of 40% and specificity of 99%, whereas MRI had sensitivity of 81% and specificity of 100%. Our data indicate that FACBC PET/CT may be useful but that mpMRI is better for localizing the index tumor in patients with prostate cancer., Competing Interests: None., (AJNMMI Copyright © 2021.)

Background: Patient-accessible electronic health records (PAEHRs) enable patients to access their health records through a secure connection over the internet. Although previous studies of patient experiences with this kind of service have shown that a majority of users are positive toward PAEHRs, little is known about why some patients occasionally or regularly choose not to use them. A better understanding of why patients may choose not to make use of digital health services such as PAEHRs is important for further development and implementation of services aimed at having patients participate in digital health services., Objective: The objective of the study was to explore patients' rationales for not embracing online access to health records., Methods: Qualitative interviews were conducted with 40 patients in a department of internal medicine in a Norwegian hospital in 2018-2019. Interview transcripts were subjected to thematic content analysis. In this paper, we focus on the subject of nonuse of PAEHRs., Results: We identified 8 different rationales that study participants had for not embracing PAEHRs. When patients reflected on why they might not use PAEHRs, they variously explained that they found PAEHRs unnecessary (they did not feel they were useful), impersonal (they preferred oral dialogue with their doctor or nurse over written information), incomprehensible (the records contained medical terminology and explanations that were hard to understand), misery oriented (the records solely focused on disease), fear provoking (reading the records could cause unwanted emotional reactions), energy demanding (making sense of the records added to the work of being a patient), cumbersome (especially among patients who felt they did not have the necessary digital competence), and impoverishing (they were skeptical about the digital transformation of individual and social life)., Conclusions: It is often assumed that the barriers to PAEHR use are mostly practical (such as lack of hardware and access to the internet). In this study, we showed that patients may have many other valid reasons for not wanting to adopt this kind of service. The results can help guide how PAEHRs and other digital health services are promoted and presented to patients, and they may suggest that the goal of a given new digital health service should not necessarily be full uptake by all patients. Rather, one should recognize that different patients might prefer and benefit from different kinds of "analog" and digital health services., (©Hanne Støre Valeur, Anne Kveim Lie, Kåre Moen. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 28.05.2021.)

This article brings the social science concept of 'deservingness' to bear on clinical cases of transnational migrant patients. Based on the authors' medical social science research, health delivery practice and clinical work from multiple locations in Africa. Europe and the Americas, the article describes three clinical cases in which assumptions of deservingness have significant implications for the morbidity and mortality of migrant patients. The concept of deservingness allows us to maintain a critical awareness of the often unspoken presumptions of which categories of patients are more or less deserving of access to and quality of care, regardless of their formal legal eligibility. Many transnational migrants with ambiguous legal status who rely on public healthcare experience exclusion from care or poor treatment based on notions of deservingness held by health clinic staff, clinicians and health system planners. The article proposes several implications for clinicians, health professional education, policymaking and advocacy. A critical lens on deservingness can help global health professionals, systems and policymakers confront and change entrenched patterns of unequal access to and differential quality of care for migrant patients. In this way, health professionals can work more effectively for global health equity., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Effective antiviral therapy is important for tackling the coronavirus disease 2019 (COVID-19) pandemic. We assessed the efficacy and safety of combined interferon beta-1b, lopinavir-ritonavir, and ribavirin for treating patients with COVID-19., Methods: This was a multicentre, prospective, open-label, randomised, phase 2 trial in adults with COVID-19 who were admitted to six hospitals in Hong Kong. Patients were randomly assigned (2:1) to a 14-day combination of lopinavir 400 mg and ritonavir 100 mg every 12 h, ribavirin 400 mg every 12 h, and three doses of 8 million international units of interferon beta-1b on alternate days (combination group) or to 14 days of lopinavir 400 mg and ritonavir 100 mg every 12 h (control group). The primary endpoint was the time to providing a nasopharyngeal swab negative for severe acute respiratory syndrome coronavirus 2 RT-PCR, and was done in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT04276688., Findings: Between Feb 10 and March 20, 2020, 127 patients were recruited; 86 were randomly assigned to the combination group and 41 were assigned to the control group. The median number of days from symptom onset to start of study treatment was 5 days (IQR 3-7). The combination group had a significantly shorter median time from start of study treatment to negative nasopharyngeal swab (7 days [IQR 5-11]) than the control group (12 days [8-15]; hazard ratio 4·37 [95% CI 1·86-10·24], p=0·0010). Adverse events included self-limited nausea and diarrhoea with no difference between the two groups. One patient in the control group discontinued lopinavir-ritonavir because of biochemical hepatitis. No patients died during the study., Interpretation: Early triple antiviral therapy was safe and superior to lopinavir-ritonavir alone in alleviating symptoms and shortening the duration of viral shedding and hospital stay in patients with mild to moderate COVID-19. Future clinical study of a double antiviral therapy with interferon beta-1b as a backbone is warranted., Funding: The Shaw-Foundation, Richard and Carol Yu, May Tam Mak Mei Yin, and Sanming Project of Medicine., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Coercion and involuntary psychiatric admission have been the subject of heated debate in recent years. A new Act was proposed in the summer of 2019, the Act on limitation of coercion, which aims to collect all legislation on coercion within a single legislative Act. If the Act is adopted, the framework for the use of coercion will be the same for both somatic illness and psychiatry. Against this backdrop, we wished to investigate how involuntary admissions have been critically examined, debated and enshrined in law previously., Material and Method: We have examined the three main Acts (and the preparatory work on these) that have been adopted in the psychiatric healthcare service in Norway. We have paid particular attention to the criteria for involuntary admissions, which we have attempted to understand in light of their contemporary times., Results and Interpretation: The legislation on coercion retained many basic features from 1848, through 1961 until 1999, even though the attitudes to coercion changed. However, the change in legislation from 2017 shows a significant change in how coercion in the mental healthcare service is viewed. If the Act on limitation of coercion is adopted, coercive mental health care will no longer be regulated by separate legislation.

Background: Undocumented migrants probably fall outside the scope of public infectious disease control schemes. The article aims to describe the extent of undetected highly hazardous communicable diseases among patients at the Health Centre for Undocumented Migrants in Oslo., Material and Method: We reviewed the records of all patients who attended the Health Centre for the first time in 2016 or 2017, with a view to age, sex, period of stay in Norway, country category and infection test results from the period 1 January 2016-31 December 2017., Results: There were four new cases of hepatitis B among 139 patients tested, and four cases of chlamydia infection among 38 patients tested. There were no new cases of active pulmonary tuberculosis, syphilis, HIV infection or hepatitis C., Interpretation: There were fewer cases of highly hazardous communicable diseases than what might be expected based on the countries from which the patients originated.

Background: The policy on drug use is currently undergoing significant change. This article examines how the view of addiction to illegal drugs changed in the first 30 years after the advent of 'the drug problem' in Norway., Material and Method: We performed a search in Oria, bokhylla.no and various databases on the history of illegal drugs in Norway, with an emphasis on the period from 1960-90, with white papers from 1976 and 1986., Results: Until the mid-1960s, Norway had very few opiate abusers. This generally concerned abuse of medically prescribed drugs, and was perceived as an internal problem for the health services. The youth counterculture in the late 1960s brought the recreational use of illegal substances to Norway, leading to major concern on the part of the public authorities. 'The drug problem' was now perceived as a significant societal problem, with social and societal causal explanations, and was therefore the subject of a white paper (1976). The next white paper (1986) put forward the ideal of a 'drug-free society' for the first time, with the purpose of general deterrence and strict sentencing as important instruments., Interpretation: From the early 1960s until the late 1980s, the 'drug problem' was perceived in different ways. At the start of the period, it was formulated primarily as a medical problem. From the late 1960s, it was seen first and foremost as a social problem caused by changes in society, whereas from the late 1970s until the late 1980s, control measures constituted the most important instrument to address the problem.

Policy Points The current crisis of antibiotic resistance calls for policy reforms locally and globally. Historical insight in different regulatory systems can inform current decision making. A strong regulatory control implementing antimicrobial resistance concerns can ensure the combined objective of promoting access and limiting excess use by letting only certain drugs onto the market in compliance with public health needs. Regulation at this level also has powerful effects on consumption and needs to be considered as a tool for curbing antibiotic resistance. The Norwegian drug regulatory procedures was an example of how national drug regulatory authorities can promote innovation of new drugs that meet public health needs indirectly by accepting only drugs of added therapeutic value., Context: Antibiotic resistance is an increasingly serious threat to global health that requires coordinated action. Most current policy efforts address the lack of medicines. There is also a need for new thinking on promoting access to all who are in need of antibiotics, while simultaneously curbing inappropriate use. As the situation calls for new approaches, we examined one drug regulatory system in which antimicrobial resistance (AMR) has been on the agenda for a long time. The Norwegian drug regulatory system, and particularly its "need clause," has been invoked in international debates but not previously studied in detail., Methods: We conducted a historical review of the Norwegian drug regulatory system by examining the archives of the Norwegian health authorities, the Norwegian Medicines Agency, and policy debates in the period., Findings: The Norwegian drug regulatory system focused on the rational use of drugs, tied closely to public health needs. It was originally written to address unnecessary consumption of drugs, not consumer protection and safety. The most flexible element within this system stated that a drug must be "needed" in order to be registered. When antibiotic resistance became a concern, it limited the market entry of drugs considered to promote resistance, such as combination and broad-spectrum products. This was a powerful and flexible regulatory device that also influenced drug consumption., Conclusions: The need clause has lately been promoted as an alternative to address the current situation. The solutions to the problem of antibiotic resistance cannot be the same everywhere, and we do not argue that this drug regulatory system should be adopted globally. However, the current situation calls for consideration of many different aspects. This historical case demonstrates how regulatory procedures can be used to limit market entrance and promote appropriate use simultaneously., (© 2019 The Authors The Milbank Quarterly published by Wiley Periodicals, Inc. on behalf of The Millbank Memorial Fund.)

Background: Most primary prostate cancers are multifocal with individual tumors harboring different aggressiveness; however, the genomic heterogeneity among these tumors is poorly understood., Objective: To better understand the biological basis for clinical variability among different lesions, we sought to comprehensively characterize the heterogeneity of somatic gene mutations in multifocal prostate cancer., Design, Setting, and Participants: High-coverage whole-exome sequencing of 153 frozen tissue samples, taken from two to three distinct tumor foci and one non-cancerous area from each of 41 patients, covering a total of 89 tumor foci., Outcome Measurements and Statistical Analysis: State-of-the-art bioinformatics tools for mutation calling and copy number determination from whole-exome sequencing data., Results and Limitations: We found a very high degree of interfocal heterogeneity among tumors, that is, 76% of pairwise-compared tumor foci from the same prostatectomy specimen had no point mutations in common and DNA copy number changes were rarely shared across cancer foci. The few point mutations shared across tumor foci were seldom in cancer-critical genes., Conclusions: In this first large genomic heterogeneity study of primary prostate cancer, we observe that different tumor foci within the same patient are genetically distinct, only rarely sharing any somatic gene mutations, including those in cancer driver genes. This heterogeneity affects how genomics-based management of prostate cancer can be implemented, as information from all tumor foci is necessary to draw valid conclusions about the cancer's genomic alterations., Patient Summary: Most primary prostate cancers consist of multiple tumors within the same organ, but little is known about their relationships. We have compared the sets of gene mutations among such tumors and found that they only exceptionally have any in common. This will influence treatment decisions in the future as each tumor's mutations will render it unique and have to be considered to gain the best treatment results., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

When the patient applies for disability benefit in Norway, the general practitioner (GP) is required by the National Insurance Administration (NAV) to confirm that the patient is unfit for work due to disease. Considering the important social role of medical certificates, they have been given surprisingly little attention by the medical critique. They may make essential differences to peoples' lives, legitimise large social costs and, in addition, the GPs report that issuing certificates can be problematic. This article explores values, attitudes and persuasive language in a selection of medical certificates written by GPs. We direct attention to such texts as significant social actors using a mixed rhetoric including certain values and attitudes. When arguing for granting the patient disability benefit, some GPs emphasised the 'worthiness' of the patient by pointing to positive attitudes approved by the national insurance: a will to work and participate, to cooperate and be motivated. Others pointed out the patient's positive character in terms of universally accepted values, called for the reader's (the NAV official) sympathy , understanding and helpfulness or appealed to his/her willingness to be realistic and pragmatic and grant disability benefit (DB). The dialogic style varied: some certifiers-although they argued for disability benefit-showed openness to possible opposing or alternative voices by displaying their own uncertainty. Others addressed the reader to share responsibility, demanding or urging for DB. This shifting rhetoric, we believe, mirrors that the GPs see themselves as the patient's advocate, and that they may find themselves conflicted. We propose further studies within qualitative research to investigate the effect of this rhetoric on the reader, the decision-makers. In addition, to improve the quality and accuracy of these important documents, we suggest that medical schools introduce students to the making of text as a specific skill of medical practice., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Purpose: Multimodal imaging is increasingly included in the assessment of prostate cancer patients, and there is a need to study whether different techniques provide similar or complementary information. In the initial perfusion phase contrast agents and radioactive labelled tracers act as blood-pool agents and may show similar characteristics. The purpose of the current work was to compare time-activity- and time-concentration-curves (TCs) of dynamic 18 F-fluciclovine ( 18 F-anti-1-amino-2-[F]-fluorocyclobutane-1-carboxylic acid, FACBC) positron emission tomography (PET) and dynamic contrast-enhanced magnetic resonance imaging (DCE MRI)., Materials and Methods: Dynamic FACBC PET and DCE MRI were performed on 22 patients with intermediate or high-risk prostate cancer within 23 days prior to robot-assisted laparoscopic prostatectomy. Index tumour was delineated in the images using whole mount tissue sections as reference standard. Tumour TCs from PET and MRI were compared visually and quantitatively by calculating correlation coefficients between the curves at different time points after injection., Results: For the first minute post injection, the mean correlation coefficient between the TCs from PET and MRI was 0.92 (range; 0.75-0.99). After the first minute, MRI showed washout while PET showed plateau kinetics., Conclusion: Dynamic FACBC and DCE MRI showed similar wash-in time curve characteristics. At later time points, FACBC plateaued whereas MR contrast medium washed out. In DCE MRI, the usefulness of wash-in information is well documented. Whether wash-in information from dynamic FACBC can provide added value remains to be documented., (© 2018 The Authors. Published by Elsevier B.V. on behalf of European Society of Radiotherapy & Oncology.)

The established role of hypoxia-induced signaling in prostate cancer growth, metastasis, and response to treatment suggests that a method to image hypoxia in tumors could aid treatment decisions. Here, we present consumption and supply-based hypoxia (CSH) imaging, an approach that integrates images related to oxygen consumption and supply into a single image. This integration algorithm was developed in patients with prostate cancer receiving hypoxia marker pimonidazole prior to prostatectomy. We exploited the intravoxel incoherent motion (IVIM) signal in diagnostic diffusion-weighted (DW) magnetic resonance (MR) images to generate separate images of the apparent diffusion coefficient (ADC) and fractional blood volume (fBV). ADC and fBV correlated with cell density (CD) and blood vessel density (BVD) in histology and whole-mount sections from 35 patients, thus linking ADC to oxygen consumption and fBV to oxygen supply. Pixel-wise plots of ADC versus fBV were utilized to predict the hypoxia status of each pixel in a tumor and to visualize the predicted value in a single image. The hypoxic fraction (HF DWI ) of CSH images correlated strongly ( R 2 = 0.66; n = 41) with pimonidazole immunoscore (HS Pimo ); this relationship was validated in a second pimonidazole cohort ( R 2 = 0.54; n = 54). We observed good agreement between CSH images and pimonidazole staining in whole-mount sections. HF DWI correlated with tumor stage and lymph node status, consistent with findings for HS Pimo Moreover, CSH imaging could be applied on histologic CD and BVD images, demonstrating transferability to a histopathology assay. Thus, CSH represents a robust approach for hypoxia imaging in prostate cancer that could easily be translated into clinical practice. Significance: These findings present a novel imaging strategy that indirectly measures tumor hypoxia and has potential application in a wide variety of solid tumors and other imaging modalities. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/16/4774/F1.large.jpg Cancer Res; 78(16); 4774-85. ©2018 AACR ., (©2018 American Association for Cancer Research.)

We examine trends in incidence, mortality and survival of penile squamous cell carcinoma (SCC) in Norway over 60 years. Data on all cases of penile cancer diagnosed in Norway during 1956-2015 were obtained from the Cancer Registry of Norway. Trends in age-standardized rates of penile SCC incidence, mortality and 5-year relative survival were assessed by the annual percentage change statistic and joinpoint regression. A total of 1,596 penile cancer cases were diagnosed during 1956-2015, among which 1,474 (92.4%) were SCC. During 2011-2015, the age-standardized incidence and mortality of penile SCC were 0.91 (95% confidence interval (CI): 0.78; 1.05) and 0.50 (0.42; 0.60) per 100,000, respectively, and the 5-year relative survival was 61.6% (41.9; 76.4). The incidence of SCC increased during 1956-2015, with an average annual percentage change (AAPC) of 0.80% (0.46; 1.15). The increase was strongest among men diagnosed at a relatively early age (age<=64 years; AAPC: 1.47% (0.90; 2.05)). Mortality also increased over the study period (AAPC: 0.47% (0.10; 0.85)), whereas 5-year relative survival did not change (AAPC: 0.08% (-0.19; 0.36)). We conclude that the incidence of penile SCC has increased at a moderate and constant rate during 1956-2015, and that the most consistent increase occurred among younger men. Mortality also increased during the study period. However, survival did not change, thus changes in diagnostics and treatment had little impact on survival from penile SCC. Since a substantial proportion of penile SCC is caused by human papillomavirus (HPV), the incidence increase may in part be attributed to increased exposure to HPV in the population., (© 2017 The Authors International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Comparative data on different self-collection methods is limited., Objectives: To assess the impact of hrHPV testing of two self-collection devices for detection of cervical carcinoma and high-grade lesions., Study Design: Three hundred ten patients collected two cervicovaginal specimens using a brush (Evalyn ® Brush) and a swab (FLOQSwabs™), and filled a questionnaire at home. Then, a physician at the clinic took a cervical specimen into PreservCyt ® buffer for hrHPV testing and cytology. All specimens were tested using Anyplex™ II HPV28, Cobas ® 4800 HPV Test and Xpert ® HPV., Results: Performance comparison included 45 cervical carcinomas and 187 patients with premalignant lesions. Compared to the physician-specimen, hrHPV testing of Evalyn ® Brush showed non-inferior sensitivity for CIN3+ (relative sensitivity of Anyplex™ 0.99; Cobas ® 0.96; Xpert ® HPV 0.97) while hrHPV testing of FLOQSwabs™ showed inferior sensitivity (relative sensitivity of Anyplex™ 0.91; Cobas ® 0.92; Xpert ® HPV 0.93). Similar results were observed for invasive carcinomas albeit that FLOQSwabs™ was statistically non-inferior to the physician-specimen. Self-collection by either Evalyn ® Brush or FLOQSwabs™ was more sensitive for CIN3+ than LSIL or worse cytology. Significant decrease in sensitivity for CIN3+ were observed for FLOQSwabs™ when specimens were preprocessed for hrHPV testing after 28 days. Both devices were well accepted, but patients considered Evalyn ® Brush easier and more comfortable than FLOQSwabs™., Conclusions: Self-collection is comparable to current screening practice for detecting cervical carcinoma and CIN3+ but device and specimen processing effects exist. Only validated procedure including collection device, hrHPV assay and specimen preparation should be used., (Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: To explore the HPVgenotype profile in Norwegian women with ASC-US/LSIL cytology and the subsequent risk of high-grade cervical neoplasia (CIN 3+)., Methods: In this observational study delayed triage of ASC-US/LSIL of 6058 women were included from 2005 to 2010. High-risk HPV detection with Hybrid Capture 2 (HC2) was used and the HC2+ cases were genotyped with in-house nmPCR. Women were followed-up for histologically confirmed CIN3+ within three years of index HPV test by linkage to the screening databases at the Cancer Registry of Norway., Results: HC2 was positive in 45% (2756/6058) of the women. Within 3years CIN3+ was diagnosed in 26% of women<34year and in 15%≥34year. HC2 was positive at index in 94% of CIN3+ cases and negative in 64 cases including three women with cervical carcinomas. Women<34years with single infections of HPV 16, 35, 58 or 33 or multiple infections including HPV 16, 52, 33 or 31 were associated with highest proportions of CIN 3+. Older women with single infection with HPV 16, 33, 31 or 35 or multiple infections including HPV 16, 33, 31 or 18/39 were more likely to develop CIN 3+., Conclusions: HPV 16 and HPV 33 at baseline both as single or multiple infections, were associated with the highest risk for CIN3+. Among older women, all 13 high-risk genotypes as single infection were associated with >20% risk of CIN3+. Further studies are necessary to risk stratify the individual genotypes to reduce the number of colposcopies in Norway., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The objectives of this study were to assess the prevalence of high-risk human papillomavirus (HR HPV) and survival in all oropharyngeal cancer (OPSCC) patients in a Norwegian population cohort in 2010-2011. Clinical data were retrieved from hospital records. Biopsies from 166 patients were tested for the presence of HR HPV by qualitative polymerase chain reaction (qPCR). p16 immunohistochemistry was performed in 138 cases. Survival was compared between groups of patients with tumors positive for HPV16 and other HR HPV genotypes, and patients with HPV negative tumors. HR HPV was detected in 127 out of 166 cases (77%). HPV16 was the most prevalent genotype (n = 108), followed by HPV33 (n = 12), HPV18 (n = 3), and HPV31/35/56/59 (n = 1). There was a robust and significant association between p16 and HR HPV status. (Chi square 70.8; p < 0.0001). Among p16-positive/HR HPV-positive cases, the distribution of HPV16 and other HR HPV types was not significantly different [91% (88/97) versus 82% (14/17); p = 0.30]. HR HPV-negative patients had reduced overall survival compared to HR HPV-positive patients [hazard ratio 0.30; 95% confidence interval (CI) 0.16-0.56, p < 0.001]. Non-HPV16 HR HPV-positive patients had significantly poorer overall survival than HPV16-positive patients (hazard ratio 0.35; 95% CI 0.14-0.85, p = 0.02). Prevalence of HR HPV in OPSCC in Norway is high, and similar to the level reported in recent years from other countries in Northern Europe and in North America. HPV genotyping may be valuable in future risk-stratification algorithms for treatment of patients with HPV-positive OPSCC.

Objective: To explore trends in vulvar squamous cell carcinoma (SCC) incidence, age and stage at diagnosis, treatment and survival in Norway from 1961 to 2010., Methods: From 1961 to 2010, 2233 cases of vulvar SCC were extracted from the Cancer Registry of Norway. Data on age at diagnosis, tumor morphology, stage of the disease and treatment were analyzed. Age-standardized incidence rates, adjusted to the Norwegian standard population, were computed. Relative survival was calculated as a ratio of the observed survival in the study population over the expected survival in the background population. Multivariate Cox model was fitted to estimate hazard ratios., Results: The overall incidence of vulvar SCC increased >2.5 fold (from 1.70 to 4.66 per 100,000 women/year; P<0.01). Age-specific incidence rates increased among women aged ≤60years (by 150% in age group 0-39years, 175% in age group 40-49years and 68% in age group 50-59years). From 1971 to 2010, the percentage of patients receiving surgery as only treatment decreased from 81% to 61%, whereas the use of radiation and combination therapy (surgery and radiation) increased from 3% to 11% and 6% to 20%, respectively. 5-year relative survival increased significantly among women ≤80years (from 72% to 83% among women aged ≤60years and from 60% to 65% among women aged 61-80years)., Conclusions: The incidence of vulvar SCC has increased since the sixties, particularly among women younger than 60years. Despite less aggressive surgical treatment, survival has improved., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Medical certificates influence the distribution of economic benefits in welfare states; however, the qualitative aspects of these texts remain largely unexplored. The present study is the first systematic investigation done of these texts. Our aim was to investigate how GPs select and mediate information about their patients' health and how they support their conclusions about illness, functioning and fitness for work in medical certificates., Methods: We performed a textual analysis of thirty-three medical certificates produced by general practitioners (GP) in Norway at the request of the Norwegian Labour and Welfare Administration (NAV).The certificates were subjected to critical reading using the combined analytic methods of narratology and linguistics., Results: Some of the medical information was unclear, ambiguous, and possibly misleading. Evaluations of functioning related to illness were scarce or absent, regardless of diagnosis, and, hence, the basis of working incapacity was unclear. Voices in the text frequently conflated, obscuring the source of speaker. In some documents, the expert's subtle use of language implied doubts about the claimant's credibility, but explicit advocacy also occurred. GPs show little insight into their patients' working lives, but rather than express uncertainty and incompetence, they may resort to making too absolute and too general statements about patients' working capacity, and fail to report thorough assessments., Conclusions: A number of the texts in our material may not function as sufficient or reliable sources for making decisions regarding social benefits. Certificates as these may be deficient for several reasons, and textual incompetence may be one of them. Physicians in Norway receive no systematic training in professional writing. High-quality medical certificates, we believe, might be economical in the long term: it might increase the efficiency with which NAV processes cases and save costs by eliminating the need for unnecessary and expensive specialist reports. Moreover, correct and coherent medical certificates can strengthen legal protection for claimants. Eventually, reducing advocacy in these documents may contribute to a fairer evaluation of whether claimants are eligible for disability benefits or not. Therefore, we believe that professional writing skills should be validated as an important part of medical practice and should be integrated in medical schools and in further education as a discipline in its own right, preferably involving humanities professors.

In the period from 1891 - 1910, around 2000 patients with syphilis were admitted to the Department of Dermatology, Oslo University Hospital, Rikshospitalet. The head of the department, Cæsar Boeck (1845 - 1917), believed in allowing the disease to take its natural course and withheld treatment. He made detailed notes of the diagnosis and the clinical course of the disease for all his patients. Boeck's material is unique, and forms the basis for our current knowledge about the prognosis and course of syphilis infections. In 1928, the patients were scrutinised by Boeck's successor in the Department of Dermatology, Edvin Bruusgaard (1869 - 1934), and later by Trygve Gjestland (1911 - 1993). Gjestland's doctoral thesis from 1955 has remained as «The Oslo study of untreated syphilis.» This article presents a medical historical background for the study. Bruusgaard's and Gjestland's research was important for the Tuskegee Study in the USA, and the Oslo study gave implicit support to this research project, which posterity has emphatically condemned as ethically unacceptable.

Objectives: Hepatitis B core-related antigen (HBcrAg) is a novel serum marker that correlates with intrahepatic hepatitis B virus (HBV) activity. Its association with HBV reactivation in hepatitis B surface antigen (HBsAg)-negative antibody to hepatitis B core antigen (anti-HBc)-positive patients undergoing high-risk immunosuppressive therapy is undefined., Methods: HBcrAg was measured in HBsAg-negative, anti-HBc-positive Asian patients with undetectable HBV DNA, who participated in two prospective studies investigating HBV reactivation during rituximab-containing chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT). Patients were monitored every 4 weeks for up to 2 years, with entecavir started when HBV reactivation, defined as HBV DNA ≥10 IU ml -1 , developed., Results: One hundred and twenty-four HBsAg-negative, anti-HBc-positive patients (rituximab, N=62; allogeneic HSCT, N=62) with a median follow-up of 64 weeks (range: 4-104 weeks) were studied. HBV reactivation occurred in 31 patients, with a 2-year cumulative reactivation rate of 40.4%. Serum HBcrAg was detected in 43 (34.7%) patients. Baseline HBcrAg positivity was significantly associated with HBV reactivation (P=0.004, hazard ratio (HR): 2.94, 95% confidence interval (95% CI): 1.43-6.07). HBcrAg-positive patients had a significantly higher 2-year HBV reactivation rate than HBcrAg-negative patients (71.8 vs. 31%, P=0.002). In the rituximab cohort, the HRs for positive HBcrAg and negative antibody to HBsAg for HBV reactivation were 3.65 and 2.84, respectively (P=0.011, 95% CI: 1.35-9.86 and P=0.032, 95% CI: 1.10-7.37, respectively)., Conclusions: Serum HBcrAg positivity is a significant risk factor of HBV reactivation in HBsAg-negative, anti-HBc-positive patients undergoing high-risk immunosuppressive therapy and can potentially have a role in identifying patients who will best benefit from prophylactic nucleoside analogue treatment.

BACKGROUND This article examines two factors that helped to trigger and drive forward the debate about research ethics committees (now the Regional Committees for Medical and Health Research Ethics) in Norway in the 1970s: the revision of the Declaration of Helsinki by a Scandinavian working group, and the unfolding of the so-called Gro case in the Norwegian national media.METHOD We have used existing literature in the form of books and articles on the history of research ethics from the University Library of the University of Oslo, the National Library of Norway, the History of Science, Technology and Medicine database, and Retriever. We have manually reviewed issues of the Dagbladet daily newspaper from 1974, and relevant volumes of the Journal of the Norwegian Medical Association from the 1960s and 1970s. Finally, we have used the archives of the Norwegian Association of Higher Education Institutions, and the Faculty of Social Sciences at the University of Oslo.RESULTS The World Medical Association's revision of the Declaration of Helsinki in 1975 stipulated the use of independent ethics committees for the assessment and supervision of research projects. The Gro case, which concerned the testing of behavioural therapeutic treatment on a young girl resident in an institution and the ensuing public debate, led to a demand from the public for closer monitoring and ethical regulation of research activity.INTERPRETATION Both of the events mentioned were used actively in the argumentation and preparatory work for the establishment of research ethics committees.

Clinical outcome and mutations of 96 core-binding factor acute myeloid leukemia (AML) patients 18-60 years old were examined. Complete remission (CR) after induction was 94.6%. There was no significant difference in CR, leukemia-free-survival (LFS) and overall survival (OS) between t(8;21) (N=67) and inv(16) patients (N=29). Univariate analysis showed hematopoietic stem cell transplantation at CR1 as the only clinical parameter associated with superior LFS. Next-generation sequencing based on a myeloid gene panel was performed in 72 patients. Mutations in genes involved in cell signaling were associated with inferior LFS and OS, whereas those in genes involved in DNA methylation were associated with inferior LFS. KIT activation loop (AL) mutations occurred in 25 patients, and were associated with inferior LFS (P=0.003) and OS (P=0.001). TET2 mutations occurred in 8 patients, and were associated with significantly shorter LFS (P=0.015) but not OS. Patients negative for KIT-AL and TET2 mutations (N=41) had significantly better LFS (P<0.001) and OS (P=0.012) than those positive for both or either mutation. Multivariate analysis showed that KIT-AL and TET2 mutations were associated with inferior LFS, whereas age ⩾40 years and marrow blast ⩾70% were associated with inferior OS. These observations provide new insights that may guide better treatment for this AML subtype.

Chronic graft-versus-host disease (cGVHD) is an important complication after allogeneic hematopoietic stem cell transplantation (HSCT). To define the roles of T-cells and B-cells in cGVHD, a murine minor histocompatibility complex-mismatched HSCT model was used. Depletion of donor splenocyte CD4(+) T-cells and B220(+) B-cells alleviated cGVHD. Allogeneic recipients had significantly increased splenic germinal centers (GCs), with significant increases in follicular T-helper (Tfh) cells and GC B-cells. There were increased expressions in Tfh cells of inducible T-cell co-stimulator (ICOS), interleukin (IL)-4 and IL-17, and in GC B-cells of B-cell activating factor receptor and ICOS ligand. Depletion of donor splenocyte CD4(+) T-cells abrogated aberrant GC formation and suppressed Tfh cells and GC B-cells. Interestingly, depletion of donor splenocyte B200(+) B-cells also suppressed Tfh cells in addition to GC B-cells. These results suggested that in cGVHD, both Tfh and GC B-cells were involved, and their developments were mutually dependent. The mammalian target of rapamycin (mTOR) inhibitor everolimus was effective in suppressing cGVHD, Tfh cells, and GC B-cells, either as a prophylaxis or when cGVHD had established. These results implied that therapeutic targeting of both T-cells and B-cells in cGVHD might be effective. Signaling via mTOR may be another useful target in cGVHD.

Background: Serum lactate dehydrogenase (LDH) has been an adverse prognostic factor for myeloma but does not feature in the International Staging System (ISS). We examined whether elevated serum LDH at diagnosis remains an adverse risk factor independent of ISS for survivals transplant-eligible myeloma patients receiving early/frontline bortezomib-based induction, followed by autologous stem cell transplantation (ASCT)., Patients: Seventy-seven transplant-eligible Chinese patients received three induction regimens [staged approach (N = 25), PAD (N = 19), VTD (N = 33)], followed by ASCT and thalidomide maintenance., Results: Five-year overall (OS) and event-free (EFS) survivals were 66.4% and 36.2%. There was no difference in demographics, complete remission/near complete remission (CR/nCR rates postinduction or ASCT, and survivals among patients induced by the three induction regimens. Elevated LDH was associated with male gender (P = 0.006), ISS III (P = 0.042) and serum β2-microglobulin (P = 0.040). Univariate analysis showed that elevated LDH, ISS III, high β2-microglobulin, and failure to attain CR/nCR post-ACST were risk factors adversely impacting both OS and EFS. Multivariate analysis showed that elevated LDH was the only factor impacting both OS (P = 0.007) and EFS (P = 0.008)., Conclusion: In this uniformly treated cohort of transplant-eligible myeloma patients, elevated serum LDH is an adverse risk factor independent of ISS for both OS and EFS. Bortezomib-based induction/ASCT regimen had not abolished the adverse impact of elevated LDH., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The hypoxia marker pimonidazole is a candidate biomarker of cancer aggressiveness. We investigated the transcriptional programme associated with pimonidazole staining in prostate cancer., Methods: Index tumour biopsies were taken by image guidance from an investigation cohort of 52 patients, where 43 patients received pimonidazole before prostatectomy. Biopsy location within the index tumour was verified for 46 (88%) patients, who were included for gene expression profiling and immunohistochemistry. Two independent cohorts of 59 and 281 patients were used for validation., Results: Expression of genes in proliferation, DNA repair and hypoxia response was a major part of the transcriptional programme associated with pimonidazole staining. A signature of 32 essential genes was constructed and showed positive correlation to Ki67 staining, confirming the increased proliferation in hypoxic tumours as suggested from the gene data. Positive correlations were also found to tumour stage and lymph node status, but not to blood prostate-specific antigen level, consistent with the findings for pimonidazole staining. The association with aggressiveness was confirmed in validation cohorts, where the signature correlated with Gleason score and had independent prognostic impact, respectively., Conclusions: Pimonidazole staining reflects an aggressive hypoxic phenotype of prostate cancer characterised by upregulation of proliferation, DNA repair and hypoxia response genes.

Complete response (CR) predicts superior survivals in myeloma. To define the impact of duration of CR posttransplantation on survivals, 71 myeloma patients, who underwent an intended early (a staged approach) or frontline use of bortezomib-based induction, followed by autologous stem cell transplantation (ASCT) were studied. Achievement of CR was assessed every 4-weekly until maximal response after ASCT and then 6-weekly thereafter. All patients had follow-up time of ≥24 months from time of best response, of whom 27 failed to attain CR (non-CR) whereas 44 achieved CR. At 12, 18 and 24 months post-ASCT, 3 (4.2%), 6 (8.4%) and 11 (15.4%) patients lost CR, respectively, with maximal survival difference observed in the group with CR durations of ≥24 or <24 months. Patients with unsustained CR had survival inferior to those never achieving CR (p = 0.05). Unsustained CR of <24 months was associated with international staging system stage III (p = 0.007) and shorter postrelapse survival (p < 0.001). Both overall survival and event-free survival were superior in myeloma patients with CR of ≥24 months (p < 0.001). In multivariate analysis, international staging system stage I/II, CR/nCR post-ASCT and CR duration of ≥24 months remained favourable prognostic factors for both overall survival and event-free survival. In conclusion, CR of <24 months is an independent adverse risk factor for survival with a short postrelapse survival., (Copyright © 2014 John Wiley & Sons, Ltd.)