Mapping of human papilloma virus, p16, and epstein-barr virus in non-malignant tonsillar disease.

OBJECTIVES: Due to their location in the entrance of the aero-digestive tract, tonsils are steadily exposed to viruses. Human papilloma virus (HPV) and Epstein-Barr virus (EBV) are two potentially oncogenic viruses that tonsils encounter. The incidence of HPV positive tonsillar cancer is on the rise and it is unknown when infection with HPV occurs. AIM: To investigate if tonsils are infected with HPV and EBV, to study the co-expression of HPV and its surrogate marker p16, and to evaluate the number of EBV positive cells in benign tonsillar disease. MATERIALS AND METHODS: Tonsils from 40 patients in a university hospital were removed due to hypertrophy, chronic or recurrent infection. These were analyzed for presence of HPV, its surrogate marker p16, and EBV. HPV was studied using PapilloCheck (a PCR method), while p16 was identified in epithelial and lymphoid tissue with immunohistochemistry and EBV using EBER-ISH (Epstein-Barr encoding region-in situ hybridization). RESULTS: HPV was not detected, and p16 was present at low numbers in all epithelial samples as well as in 92.5% of the lymphoid tonsillar samples. At least one EBER-positive cell was seen in 65% of cases. Larger numbers of EBER-expressing cells were only seen in two cases. CONCLUSION: These findings demonstrate that EBV and HPV infect tonsils independently, but further studies are warranted to confirm their infectious relationship. LEVEL OF EVIDENCE: Cross-sectional study.

Did we see it Coming? An Evaluation of the Swedish Early Awareness and Alert System.

BACKGROUND: Early awareness and alert systems have been established in many countries but evidence on their ability to accurately prioritize new medicines (for early assessment) is limited. OBJECTIVE: The purpose of this study was to assess whether the Swedish Early Awareness and Alert System identified and prioritized (i.e., produced early assessment reports for) new medicines that would go on to have substantial economic impact. METHODS: We adapted a study design commonly used in the assessment of diagnostic test accuracy. The prioritization made by the Swedish Early Awareness and Alert System prior to marketing authorization comprised the index test and the national drug sales data in the second year post-authorization served as the reference standard. All initial marketing authorization applications for medicinal products processed by the European Medicines Agency between 2010 and 2015 (study population) were classified using the index test and the reference standard. RESULTS: Two hundred and fifty-three new medicinal products processed by the European Medicines Agency comprised the study population. Of these, 71 were prioritized by the Swedish Early Awareness and Alert System and 21 were classified as having substantial economic impact. The sensitivity and positive predictive value were 76.2% and 22.5%, respectively. Subgroup analyses showed that the accuracy of prioritization, in terms of sensitivity, was 100% for antineoplastic/immunomodulating agents. CONCLUSIONS: The Swedish Early Awareness and Alert System identified all new medicines that would go on to have substantial economic impact and prioritized most of these medicines. Our findings provide reassurance to decision makers who rely on the outputs of the Swedish Early Awareness and Alert System to keep informed about new medicines. Moreover, this study also provides valuable insights to stakeholders willing to establish or evaluate their own early awareness and alert activities and systems.

Real-World Use and Outcomes of Olaparib: a Population-Based Cohort Study.

BACKGROUND: Although olaparib, the first poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor approved, has been used in routine clinical practice for over three years, little has been published on its uptake, utilization patterns, and clinical outcomes. OBJECTIVE: To examine real-world use and outcomes of olaparib treatment in Swedish patients during the first three years following regulatory approval. PATIENTS AND METHODS: This is a population-based cohort study using data from the Swedish national registers. All individuals initiating olaparib treatment from regulatory approval to 31 December 2017 were included. The extent of off-label use was assessed based on recorded diagnoses. Ovarian cancer patients were followed until death or the end of the study period. Starting dose and dose adjustments were assessed. Time to olaparib discontinuation and overall survival were plotted using Kaplan-Meier survival curves. RESULTS: We identified 109 patients to whom olaparib was dispensed in Sweden during the study period. Nine of these were prescribed olaparib off-label for either breast or prostate cancer and were excluded from further analyses. Median age among the remaining 100 patients with ovarian cancer was 59 years (range: 42-83). Almost all patients (96%) started on the recommended dose (400 mg [eight capsules] taken twice daily). Dose reductions were explicitly recorded for 14% of patients. Median time to discontinuation was 289 days (95% confidence interval [CI]: 226; 338). Median overall survival from olaparib initiation was 1002 days (95% CI: 676; not calculable). CONCLUSIONS: To our knowledge, this is the first population-based study of olaparib real-world use and outcomes. During the first three years following regulatory approval, olaparib was mainly prescribed to ovarian cancer patients. Ovarian cancer patients stayed on olaparib for a median of 9.5 months and the treatment appeared to be well tolerated.

A prospective exploration of symptom burden clusters in women with breast cancer during chemotherapy treatment.

PURPOSE: The aim was to prospectively map symptom clusters in patients with stage I-IIIa breast cancer during standard chemotherapy treatment in a randomised study. METHODS: Participants completed the Memorial Symptom Assessment Scale (MSAS) at baseline, day 12 after the first and third cycle of FEC 75 or FEC 100, and day 12 after the last cycle of Taxotere. Cut-off values for symptom scores, a mean value based on each individual reporting a symptom including occurrence, frequency, severity and distress for inclusion in analysis, were determined. RESULTS: The symptom burden cluster analysis was conducted in two steps and included symptoms with high frequency and high levels of distress. The factor analysis revealed three symptom clusters; physical, gastro (phys/gastro) and emotional, with core symptoms that remained stable over time. The most prevalent symptoms for the total sample during all cycles were as follows: lack of energy (range between 48 and 90%), feeling sad (48-79%), difficulty sleeping (54-78%), difficulty concentrating (53-74%), worrying (54-74%) and pain (29-67%). CONCLUSION: In summary, we have prospectively established that symptom clusters remain stable over time with a basis of core symptoms. This knowledge will aid in the development of effective core symptom-focused interventions to minimise symptom burden for patients treated with chemotherapy for breast cancer.

Healthcare Utilisation and Drug Treatment in a Large Cohort of Patients with Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Crohn's disease [CD] and ulcerative colitis [UC] are chronic diseases associated with a substantial utilisation of healthcare resources. We aimed to estimate the prevalence of inflammatory bowel disease [IBD], CD, and UC and to describe and compare healthcare utilisation and drug treatment in CD and UC patients. METHODS: This was a cross-sectional study of all patients with a recorded IBD diagnosis in Stockholm County, Sweden. Data on outpatient visits, hospitalisations, surgeries, and drug treatment during 2013 were analysed. RESULTS: A total of 13 916 patients with IBD were identified, corresponding to an overall IBD prevalence of 0.65% [CD 0.27%, UC 0.35%, inflammatory bowel disease unclassified 0.04%]; 49% of all IBD patients were treated with IBD-related drugs. Only 3.6% of the patients received high-dose corticosteroids, whereas 32.4% were treated with aminosalicylates [CD 21.2%, UC 41.0%, p < 0.0001]. More CD patients were treated with biologicals compared with UC patients [CD 9.6%, UC 2.9%, p < 0.0001] and surgery was significantly more common among CD patients [CD 3.0%, UC 0.8%, p < 0.0001]. CONCLUSIONS: This study indicates that patients with CD are the group with the highest medical needs. Patients with CD utilised significantly more healthcare resources [including outpatient visits, hospitalisations, and surgeries] than UC patients. Twice as many CD patients received immunomodulators compared with UC patients and CD patients were treated with biologicals three times more often. These results highlight that CD remains a challenge and further efforts are needed to improve care in these patients.

Are new models needed to optimize the utilization of new medicines to sustain healthcare systems?

Medicines have made an appreciable contribution to improving health. However, even high-income countries are struggling to fund new premium-priced medicines. This will grow necessitating the development of new models to optimize their use. The objective is to review case histories among health authorities to improve the utilization and expenditure on new medicines. Subsequently, use these to develop exemplar models and outline their implications. A number of issues and challenges were identified from the case histories. These included the low number of new medicines seen as innovative alongside increasing requested prices for their reimbursement, especially for oncology, orphan diseases, diabetes and HCV. Proposed models center on the three pillars of pre-, peri- and post-launch including critical drug evaluation, as well as multi-criteria models for valuing medicines for orphan diseases alongside potentially capping pharmaceutical expenditure. In conclusion, the proposed models involving all key stakeholder groups are critical for the sustainability of healthcare systems or enhancing universal access. The models should help stimulate debate as well as restore trust between key stakeholder groups.

Application of human and animal viral microbial source tracking tools in fresh and marine waters from five different geographical areas.

Integrated river basin management planning to mitigate the impacts of economic, demographic and climate change is an important issue for the future protection of water resources. Identifying sources of microbial contamination via the emerging science of Microbial Source Tracking (MST) plays a key role in risk assessment and the design of remediation strategies. Following an 18-month surveillance program within the EU-FP7-funded VIROCLIME project, specific MST tools were used to assess human markers such as adenoviruses (HAdV) and JC polyomaviruses (JCPyV) and porcine and bovine markers such as porcine adenoviruses (PAdV) and bovine polyomaviruses (BPyV) via quantification with real-time PCR to analyze surface water collected from five sites within different climatic zones: the Negro River (Brazil), Glafkos River (Greece), Tisza River (Hungary), Llobregat River (Spain) and Umeälven River (Sweden). The utility of the viral MST tools and the prevalence and abundance of specific human and animal viruses in the five river catchments and adjacent seawater, which is impacted by riverine contributions from the upstream catchments, were examined. In areas where no sanitation systems have been implemented, sewage can directly enter surface waters, and river water exhibited high viral loads; HAdV and JCPyV could be detected at mean concentrations of 10(5) and 10(4) Genome Copies/Liter (GC/L), respectively. In general, river water samples upstream of urban discharges presented lower human viral loads than downstream sampling sites, and those differences appeared to increase with urban populations but decrease in response to high river flow, as the elevated river water volume dilutes microbial loads. During dry seasons, river water flow decreases dramatically, and secondary effluents can represent the bulk of the riverine discharge. We also observed that ice cover that formed over the river during the winter in the studied areas in North Europe could preserve viral stability due to the low temperatures and/or the lack of solar inactivation. Porcine and bovine markers were detected where intensive livestock and agricultural activities were present; mean concentration values of 10(3) GC/L indicated that farms were sometimes unexpected and important sources of fecal contamination in water. During spring and summer, when livestock is outdoors and river flows are low, animal pollution increases due to diffuse contamination and direct voiding of feces onto the catchment surface. The field studies described here demonstrate the dynamics of fecal contamination in all catchments studied, and the data obtained is currently being used to develop dissemination models of fecal contamination in water with respect to future climate change scenarios. The results concerning human and animal targets presented in this study demonstrate the specificity and applicability of the viral quantitative parameters developed to widely divergent geographical areas and their high interest as new indicators of human and animal fecal contamination in water and as MST tools.

Direct visualization of Propionibacterium acnes in prostate tissue by multicolor fluorescent in situ hybridization assay.

Prostate tissues from patients with prostate cancer and benign prostatic hyperplasia (BPH) frequently contain histological inflammation, and a proportion of these patients show evidence of Propionibacterium acnes infection in the prostate gland. We developed a multicolor fluorescent in situ hybridization (FISH) assay targeting P. acnes 23S rRNA along with a 14-kb region of the P. acnes genome. This assay was used to analyze prostate tissues from patients with prostate cancer and BPH. P. acnes infection of the prostate gland was demonstrated in prostatic tissue in 5 of 10 randomly selected prostate cancer patients. FISH analysis and confocal laser microscopy imaging revealed intracellular localization and stromal biofilm-like aggregates as common forms of P. acnes infection in prostate tissues from both prostate cancer and BPH patients. A sequential analysis of prostate tissue from individual patients suggested that P. acnes can persist for up to 6 years in the prostate gland. These results indicate that P. acnes can establish a persistent infection in the prostate gland. Further study is needed to clarify the link between this bacterium and prostatic inflammation which may contribute to the development of BPH and prostate cancer.