Impact of HPV in Oropharyngeal Cancer

The incidence of oropharyngeal cancers has increased in the western world and Human Papilloma Virus (HPV) has been recognised as a risk factor in the last decades. During the same period the prevalence of HPV in oropharyngeal tumours has increased and HPV has been suggested responsible for the increase. The HPV-positive tumours are today recognized as a distinct subset of head and neck cancers with its own clinopathological and risk profile and have a significantly improved prognosis regardless of treatment strategy. This review summarizes current knowledge regarding human papillomavirus biology, oncogenic mechanisms, risk factors, and impact of treatment

The process of transforming a non-digital game to a digital application

It is becoming more common to transform non-digital games into digital applications. The aim of this project was to explore this kind of transformation in detail, and to investigate what problems and opportunities that follow such a process. To be able to accomplish this, the team subjected itself to this transformation by taking an existing tabletop game, and transforming it into an application for the mobile medium. The design process was built around player experiences from the original tabletop game, and the goal throughout the transformation was to maintain as many player experiences as possible. This report covers the whole longevity of the design process, from the initial ideas and paper prototypes to a final digital prototype. The findings in this project were expressed as a list of seven recommendations covering important aspects of what to consider before attempting to transform a non-digital game into a digital application. In addition to the recommendations, the process also resulted in a functional and playable game prototype

Tumor Infiltrating CD8+ and Foxp3+ Lymphocytes Correlate to Clinical Outcome and Human Papillomavirus (HPV) Status in Tonsillar Cancer

BACKGROUND: Human papillomavirus (HPV) is a causative factor for tonsillar squamous cell carcinoma (TSCC) and patients with HPV positive (HPV(+)) TSCC have a better clinical outcome than those with HPV negative (HPV(-)) TSCC. However, since not all patients with HPV(+) TSCC respond to treatment, additional biomarkers are needed together with HPV status to better predict response to therapy and to individualize treatment. For this purpose, we examined whether the number of tumor infiltrating cytotoxic and regulatory T-cells in TSCC correlated to HPV status and to clinical outcome. METHODS: Formalin fixed paraffin embedded TSCC, previously analysed for HPV DNA, derived from 83 patients, were divided into four groups depending on the HPV status of the tumor and clinical outcome. Tumors were stained by immunohistochemistry and evaluated for the number of infiltrating cytotoxic (CD8(+)) and regulatory (Foxp3(+)) T-cells. RESULTS: A high CD8(+) T-cell infiltration was significantly positively correlated to a good clinical outcome in both patients with HPV(+) and HPV(-) TSCC patients. Similarly, a high CD8(+)/Foxp3(+) TIL ratio was correlated to a 3-year disease free survival. Furthermore, HPV(+) TSCC had in comparison to HPV(-) TSCC, higher numbers of infiltrating CD8(+) and Foxp3(+) T-cells. CONCLUSIONS: In conclusion, a positive correlation between a high number of infiltrating CD8(+) cells and clinical outcome indicates that CD8(+) cells may contribute to a beneficial clinical outcome in TSCC patients, and may potentially serve as a biomarker. Likewise, the CD8(+)/Foxp3(+)cell ratio can potentially be used for the same purpose

Energy smart ice arenas

This project has been regarding the ability to make Ice Arenas more Energy Smart. Using info and data from the A-hall in Gränby, Uppsala, different suggestions to make the arena better has been developed. There has also been taking under consideration whether the solutions are applicable in other Ice arenas in Sweden. The suggestions has focused on minimizing the energy usage, and if there is a realistic investment to install solar panels on the roof of the arena. The project has been based on theoretical studies, calculations, simulations and field trips. The project group has studied different areas of the arena in order to evaluate ways to improve the energy situation for each specific arena. The solutions has then been evaluated based on their respective applicability, energy saving capability, investment cost and payback time. Solutions found to be easy to apply with small investments were installing moving sensors for lights in dressing rooms and corridors and to make sure all doors to the arena are properly sealed. Some of the bigger investments included replacing glass in the windows, installing LED-tubes as light source and installing an airlock at the entrance. One conclusion to be drawn from the project is there are lots of ways to make an ice arena more energy smart, but the most important part is to anchor all the decisions with the working staff. If the new techniques are not properly taught and used, there will not be the required effect.Denna rapport skrivs som en sammanfattande slutrapport för kandidatarbetet ”Energismarta Ishallar” i kursen ”Självständigt arbete i Energisystem”. I projektet har gruppen studerat möjligheten att göra A-hallen i Gränby, Uppsala mer energismart genom att bland annat försöka minska energianvändningen och se över möjligheten att installera solceller. Under projektets gång har flera mindre områden av hallen studerats separat, och förändringsförslag har tagits fram och utvärderats. Projektet har baserats på teoristudier, beräkningar, simuleringar och studiebesök. Varje delområde har hanterats utifrån områdets karaktär. Under projektets gång har delrapporter skrivit och resultaten från dessa har resulterat i denna slutrapport. Gruppen har valt att värdera lösningarna efter hur enkla de är att tillämpa, hur stor energibesparing de skulle innebära, samt investeringskostnaden och återbetalningstiden. Enkla lösningar med kort återbetalning: • Se över samtliga dörrar så att de är ordentligt tätade och inte läcker värme. Detta kan spara upp till 5 000 kWh/år. • Installera rörelsevakter i serviceutrymmen, så som toaletter, omklädningsrum och korridorer. Dessa investeringar har en återbetalningstid på 2-6 år. • Installera en lågstrålningsduk i hallens tak. Detta kommer medföra minskade strålningsförlusterna genom taket. Lösningar som kräver lite större investeringar: • Investera i energifönster för att minska värme och kylläckage. Dessa har en återbetalningstid på cirka 12 år och kan spara cirka 7 000 kWh/år. • Byt ut lysrören mot LED-belysning i befintlig armatur. Detta ger en bättre ljusbild, påverkar isen positivt samt minskar den installerade effekten med 52%. Återbetalningstiden är drygt 2 år, dock ej installation inräknad. • Se till att ingången till hallen är utrustad med en entré som inskar energiläckage, till exempel en luftsluss. Större och mer omständliga lösningar som kräver större investeringar: • Se över hallens värmesystem och överväg att investera i en värmeanläggning som värmer underifrån sätena istället för ovanifrån. Utöver dessa åtgärder har projektet visat att det är viktigt att förankra beslut rörande ny teknik hos de i personalen som kommer jobba med den. Detta då det är viktigt att det finns en kunskap och en vilja att använda den nya tekniken. Det är oväsentligt hur bra en teknik är om den inte används på ett korrekt sätt

A crossover randomised controlled trial of oral mandibular advancement devices for obstructive sleep apnoea-hypopnoea (TOMADO)

Rationale Mandibular advancement devices (MADs) are used to treat obstructive sleep apnoea-hypopnoea syndrome (OSAHS) but evidence is lacking regarding their clinical and cost-effectiveness in less severe disease. Objectives To compare clinical- and cost-effectiveness of a range of MADs against no treatment in mild to moderate OSAHS. Measurements and methods This open-label, randomised, controlled, crossover trial was undertaken at a UK sleep centre. Adults with Apnoea-Hypopnoea Index (AHI) 5–<30/h and Epworth Sleepiness Scale (ESS) score ≥9 underwent 6 weeks of treatment with three nonadjustable MADs: self-moulded (SleepPro 1; SP1); semi-bespoke (SleepPro 2; SP2); fully-bespoke MAD (bMAD); and 4 weeks no treatment. Primary outcome was AHI scored by a polysomnographer blinded to treatment. Secondary outcomes included ESS, quality of life, resource use and cost. Main results 90 patients were randomised and 83 were analysed. All devices reduced AHI compared with no treatment by 26% (95% CI 11% to 38%, p=0.001) for SP1, 33% (95% CI 24% to 41%) for SP2 and 36% (95% CI 24% to 45%, p<0.001) for bMAD. ESS was 1.51 (95% CI 0.73 to 2.29, p<0.001, SP1) to 2.37 (95% CI 1.53 to 3.22, p<0.001, bMAD) lower than no treatment (p<0.001 for all). Compliance was lower for SP1, which was the least preferred treatment at trial exit. All devices were cost-effective compared with no treatment at a £20 000/quality-adjusted life year (QALY) threshold. SP2 was the most cost-effective up to £39 800/QALY. Conclusions Non-adjustable MADs achieve clinically important improvements in mild to moderate OSAHS and are cost-effective

Spatially resolved clonal copy number alterations in benign and malignant tissue

Publisher Copyright: © 2022, The Author(s).Defining the transition from benign to malignant tissue is fundamental to improving early diagnosis of cancer1. Here we use a systematic approach to study spatial genome integrity in situ and describe previously unidentified clonal relationships. We used spatially resolved transcriptomics2 to infer spatial copy number variations in >120,000 regions across multiple organs, in benign and malignant tissues. We demonstrate that genome-wide copy number variation reveals distinct clonal patterns within tumours and in nearby benign tissue using an organ-wide approach focused on the prostate. Our results suggest a model for how genomic instability arises in histologically benign tissue that may represent early events in cancer evolution. We highlight the power of capturing the molecular and spatial continuums in a tissue context and challenge the rationale for treatment paradigms, including focal therapy.Peer reviewe

Spatially resolved clonal copy number alterations in benign and malignant tissue

Publisher Copyright: © 2022, The Author(s).Defining the transition from benign to malignant tissue is fundamental to improving early diagnosis of cancer1. Here we use a systematic approach to study spatial genome integrity in situ and describe previously unidentified clonal relationships. We used spatially resolved transcriptomics2 to infer spatial copy number variations in >120,000 regions across multiple organs, in benign and malignant tissues. We demonstrate that genome-wide copy number variation reveals distinct clonal patterns within tumours and in nearby benign tissue using an organ-wide approach focused on the prostate. Our results suggest a model for how genomic instability arises in histologically benign tissue that may represent early events in cancer evolution. We highlight the power of capturing the molecular and spatial continuums in a tissue context and challenge the rationale for treatment paradigms, including focal therapy.Peer reviewe

Prognostic implications of p16 and HPV discordance in oropharyngeal cancer (HNCIG-EPIC-OPC): a multicentre, multinational, individual patient data analysis

Background p16(INK4a) (p16) immunohistochemistry is the most widely used biomarker assay for inferring HPV causation in oropharyngeal cancer in clinical and trial settings. However, discordance exists between p16 and HPV DNA or RNA status in some patients with oropharyngeal cancer. We aimed to clearly quantify the extent of discordance, and its prognostic implications. Methods In this multicentre, multinational individual patient data analysis, we did a literature search in PubMed and Cochrane database for systematic reviews and original studies published in English between Jan 1, 1970, and Sept 30, 2022. We included retrospective series and prospective cohorts of consecutively recruited patients previously analysed in individual studies with minimum cohort size of 100 patients with primary squamous cell carcinoma of the oropharynx. Patient inclusion criteria were diagnosis with a primary squamous cell carcinoma of oropharyngeal cancer; data on p16 immunohistochemistry and on HPV testing; information on age, sex, tobacco, and alcohol use; staging by TNM 7th edition; information on treatments received; and data on clinical outcomes and follow-up (date of last follow-up if alive, date of recurrence or metastasis, and date and cause of death). There were no limits on age or performance status. The primary outcomes were the proportion of patients of the overall cohort who showed the different p16 and HPV result combinations, as well as 5-year overall survival and 5-year disease-free survival. Patients with recurrent or metastatic disease or who were treated palliatively were excluded from overall survival and disease-free survival analyses. Multivariable analysis models were used to calculate adjusted hazard ratios (aHR) for different p16 and HPV testing methods for overall survival, adjusted for prespecified confounding factors. Findings Our search returned 13 eligible studies that provided individual data for 13 cohorts of patients with oropharyngeal cancer from the UK, Canada, Denmark, Sweden, France, Germany, the Netherlands, Switzerland, and Spain. 7895 patients with oropharyngeal cancer were assessed for eligibility. 241 were excluded before analysis, and 7654 were eligible for p16 and HPV analysis. 5714 (74middot7%) of 7654 patients were male and 1940 (25middot3%) were female. Ethnicity data were not reported. 3805 patients were p16-positive, 415 (10middot9%) of whom were HPV-negative. This proportion differed significantly by geographical region and was highest in the areas with lowest HPV-attributable fractions (r=-0middot744, p=0middot0035). The proportion of patients with p16+/HPV- oropharyngeal cancer was highest in subsites outside the tonsil and base of tongue (29middot7% vs 9middot0%, p<0middot0001). 5-year overall survival was 81middot1% (95% CI 79middot5-82middot7) for p16+/HPV+, 40middot4% (38middot6-42middot4) for p16-/HPV-, 53middot2% (46middot6-60middot8) for p16-/HPV+, and 54middot7% (49middot2-60middot9) for p16+/HPV-. 5-year disease-free survival was 84middot3% (95% CI 82middot9-85middot7) for p16+/HPV+, 60middot8% (58middot8-62middot9) for p16-/HPV-; 71middot1% (64middot7-78middot2) for p16-/HPV+, and 67middot9% (62middot5-73middot7) for p16+/HPV-. Results were similar across all European sub-regions, but there were insufficient numbers of discordant patients from North America to draw conclusions in this cohort. Interpretation Patients with discordant oropharyngeal cancer (p16-/HPV+ or p16+/HPV-) had a significantly worse prognosis than patients with p16+/HPV+ oropharyngeal cancer, and a significantly better prognosis than patients with p16-/HPV- oropharyngeal cancer. Along with routine p16 immunohistochemistry, HPV testing should be mandated for clinical trials for all patients (or at least following a positive p16 test), and is recommended where HPV status might influence patient care, especially in areas with low HPV-attributable fractions. Copyright (c) 2023 The Author(s). Published by Elsevier Ltd

Prognostic implications of p16 and HPV discordance in oropharyngeal cancer (HNCIG-EPIC-OPC): a multicentre, multinational, individual patient data analysis

Background: p16INK4a (p16) immunohistochemistry is the most widely used biomarker assay for inferring HPV causation in oropharyngeal cancer in clinical and trial settings. However, discordance exists between p16 and HPV DNA or RNA status in some patients with oropharyngeal cancer. We aimed to clearly quantify the extent of discordance, and its prognostic implications. Methods: In this multicentre, multinational individual patient data analysis, we did a literature search in PubMed and Cochrane database for systematic reviews and original studies published in English between Jan 1, 1970, and Sept 30, 2022. We included retrospective series and prospective cohorts of consecutively recruited patients previously analysed in individual studies with minimum cohort size of 100 patients with primary squamous cell carcinoma of the oropharynx. Patient inclusion criteria were diagnosis with a primary squamous cell carcinoma of oropharyngeal cancer; data on p16 immunohistochemistry and on HPV testing; information on age, sex, tobacco, and alcohol use; staging by TNM 7th edition; information on treatments received; and data on clinical outcomes and follow-up (date of last follow-up if alive, date of recurrence or metastasis, and date and cause of death). There were no limits on age or performance status. The primary outcomes were the proportion of patients of the overall cohort who showed the different p16 and HPV result combinations, as well as 5-year overall survival and 5-year disease-free survival. Patients with recurrent or metastatic disease or who were treated palliatively were excluded from overall survival and disease-free survival analyses. Multivariable analysis models were used to calculate adjusted hazard ratios (aHR) for different p16 and HPV testing methods for overall survival, adjusted for prespecified confounding factors. Findings: Our search returned 13 eligible studies that provided individual data for 13 cohorts of patients with oropharyngeal cancer from the UK, Canada, Denmark, Sweden, France, Germany, the Netherlands, Switzerland, and Spain. 7895 patients with oropharyngeal cancer were assessed for eligibility. 241 were excluded before analysis, and 7654 were eligible for p16 and HPV analysis. 5714 (74·7%) of 7654 patients were male and 1940 (25·3%) were female. Ethnicity data were not reported. 3805 patients were p16-positive, 415 (10·9%) of whom were HPV-negative. This proportion differed significantly by geographical region and was highest in the areas with lowest HPV-attributable fractions (r=–0·744, p=0·0035). The proportion of patients with p16+/HPV– oropharyngeal cancer was highest in subsites outside the tonsil and base of tongue (29·7% vs 9·0%, p<0·0001). 5-year overall survival was 81·1% (95% CI 79·5–82·7) for p16+/HPV+, 40·4% (38·6–42·4) for p16–/HPV–, 53·2% (46·6–60·8) for p16–/HPV+, and 54·7% (49·2–60·9) for p16+/HPV–. 5-year disease-free survival was 84·3% (95% CI 82·9–85·7) for p16+/HPV+, 60·8% (58·8–62·9) for p16–/HPV–; 71·1% (64·7–78·2) for p16–/HPV+, and 67·9% (62·5–73·7) for p16+/HPV–. Results were similar across all European sub-regions, but there were insufficient numbers of discordant patients from North America to draw conclusions in this cohort. Interpretation: Patients with discordant oropharyngeal cancer (p16–/HPV+ or p16+/HPV–) had a significantly worse prognosis than patients with p16+/HPV+ oropharyngeal cancer, and a significantly better prognosis than patients with p16–/HPV– oropharyngeal cancer. Along with routine p16 immunohistochemistry, HPV testing should be mandated for clinical trials for all patients (or at least following a positive p16 test), and is recommended where HPV status might influence patient care, especially in areas with low HPV-attributable fractions

Blood n-3 fatty acid levels and total and cause-specific mortality from 17 prospective studies.

The health effects of omega-3 fatty acids have been controversial. Here we report the results of a de novo pooled analysis conducted with data from 17 prospective cohort studies examining the associations between blood omega-3 fatty acid levels and risk for all-cause mortality. Over a median of 16 years of follow-up, 15,720 deaths occurred among 42,466 individuals. We found that, after multivariable adjustment for relevant risk factors, risk for death from all causes was significantly lower (by 15-18%, at least p < 0.003) in the highest vs the lowest quintile for circulating long chain (20-22 carbon) omega-3 fatty acids (eicosapentaenoic, docosapentaenoic, and docosahexaenoic acids). Similar relationships were seen for death from cardiovascular disease, cancer and other causes. No associations were seen with the 18-carbon omega-3, alpha-linolenic acid. These findings suggest that higher circulating levels of marine n-3 PUFA are associated with a lower risk of premature death.The EPIC Norfolk study (DOI 10.22025/2019.10.105.00004) has received funding from the Medical Research Council (MR/N003284/1 and MC-UU_12015/1) and Cancer Research UK (C864/A14136). NJW, NGF, and FI were supported by the Medical Research Council Epidemiology Unit core funding [MC_UU_12015/1 and MC_UU_12015/5]. NJW and NGF acknowledge support from the National Institute for Health Research Cambridge Biomedical Research Centre [IS-BRC-1215-20014] and NJW is an NIHR Senior Investigator