Benefits and harms of aspirin to reduce colorectal cancer risk: a cross-sectional study of methods to communicate risk in primary care.

BACKGROUND: New Australian guidelines recommend that GPs actively consider prescribing low-dose aspirin to patients aged 50-70 years to reduce their risk of developing colorectal cancer (CRC). Patients and GPs need to understand the relative benefits and harms to support informed decision making. AIM: To develop and examine different methods to communicate the benefits and harms of taking aspirin for CRC prevention. DESIGN AND SETTING: A cross-sectional, vignette study with patients aged 50-70 years consecutively recruited from general practices in Melbourne, Australia, between July and August 2018. METHOD: Summary estimates from meta-analyses of the effects of aspirin on the incidence of CRC, cardiovascular disease, gastrointestinal bleeding, and incidence rates in the Australian population to estimate outcomes in a hypothetical population of 10 000 people aged 50-70 years. These estimates were presented using four different risk communication formats. Participants were shown these different formats and asked if they would take aspirin to prevent CRC. RESULTS: A total of 313 participants were recruited (95.1% recruitment rate), of whom 304 completed the study. Most participants (71.7-75.3%) reported they would take aspirin irrespective of risk format presented. Bar charts (odds ratio [OR] 1.20, 95% confidence intervals [CI] = 1.01 to 1.44) and expected frequency trees (OR 1.18, 95% CI = 0.99 to 1.41) were more strongly associated with the intentions to take aspirin compared with icon arrays. Bar charts were most preferred for presenting risk information. CONCLUSION: A large proportion of participants in this study intended to take aspirin to reduce their CRC risk regardless of risk communication format. Bar charts and expected frequency trees were the preferred methods to present the benefits and harms of taking aspirin to prevent CRC.

Multidimensional, quantitative assessment of PD-1/PD-L1 expression in patients with Merkel cell carcinoma and association with response to pembrolizumab.

BACKGROUND: We recently reported a 56% objective response rate in patients with advanced Merkel cell carcinoma (MCC) receiving pembrolizumab. However, a biomarker predicting clinical response was not identified. METHODS: Pretreatment FFPE tumor specimens (n = 26) were stained for CD8, PD-L1, and PD-1 by immunohistochemistry/immunofluorescence (IHC/IF), and the density and distribution of positive cells was quantified to determine the associations with anti-PD-1 response. Multiplex IF was used to test a separate cohort of MCC archival specimens (n = 16), to identify cell types expressing PD-1. RESULTS: Tumors from patients who responded to anti-PD-1 showed higher densities of PD-1+ and PD-L1+ cells when compared to non-responders (median cells/mm2, 70.7 vs. 6.7, p = 0.03; and 855.4 vs. 245.0, p = 0.02, respectively). There was no significant association of CD8+ cell density with clinical response. Quantification of PD-1+ cells located within 20 µm of a PD-L1+ cell showed that PD-1/PD-L1 proximity was associated with clinical response (p = 0.03), but CD8/PD-L1 proximity was not. CD4+ and CD8+ cells in the TME expressed similar amounts of PD-1. CONCLUSIONS: While the binomial presence or absence of PD-L1 expression in the TME was not sufficient to predict response to anti-PD-1 in patients with MCC, we show that quantitative assessments of PD-1+ and PD-L1+ cell densities as well as the geographic interactions between these two cell populations correlate with clinical response. Cell types expressing PD-1 in the TME include CD8+ T-cells, CD4+ T-cells, Tregs, and CD20+ B-cells, supporting the notion that multiple cell types may potentiate tumor regression following PD-1 blockade.

Barriers to care for chronic hepatitis C in the direct-acting antiviral era: a single-centre experience.

BACKGROUND: Cure rates for chronic hepatitis C have improved dramatically with direct-acting antivirals (DAAs), but treatment barriers remain. We aimed to compare treatment initiation rates and barriers across both interferon-based and DAA-based eras. METHODS: We conducted a retrospective cohort study of all patients with chronic hepatitis C seen at an academic hepatology clinic from 1999 to 2016. Patients were identified to have chronic hepatitis C by the International Classification of Diseases, Ninth Revision codes, and the diagnosis was validated by chart review. Patients were excluded if they did not have at least one visit in hepatology clinic, were under 18 years old or had prior treatment with DAA therapy. Patients were placed in the DAA group if they were seen after 1 January 2014 and had not yet achieved virological cure with prior treatment. All others were considered in the interferon group. RESULTS: 3202 patients were included (interferon era: n=2688; DAA era: n=514). Despite higher rates of decompensated cirrhosis and medical comorbidities in the DAA era, treatment and sustained virological response rates increased significantly when compared with the interferon era (76.7% vs 22.3%, P<0.001; 88.8% vs 55%, P<0.001, respectively). Lack of follow-up remained a significant reason for non-treatment in both groups (DAA era=24% and interferon era=45%). An additional 8% of patients in the DAA era were not treated due to insurance or issues with cost. In the DAA era, African-Americans, compared with Caucasians, had significantly lower odds of being treated (OR=0.37, P=0.02). CONCLUSIONS: Despite higher rates of medical comorbidities in the DAA era, considerable treatment challenges remain including cost, loss to follow-up and ethnic disparities.

Development of a large-scale chemogenomics database to improve drug candidate selection and to understand mechanisms of chemical toxicity and action.

Successful drug discovery requires accurate decision making in order to advance the best candidates from initial lead identification to final approval. Chemogenomics, the use of genomic tools in pharmacology and toxicology, offers a promising enhancement to traditional methods of target identification/validation, lead identification, efficacy evaluation, and toxicity assessment. To realize the value of chemogenomics information, a contextual database is needed to relate the physiological outcomes induced by diverse compounds to the gene expression patterns measured in the same animals. Massively parallel gene expression characterization coupled with traditional assessments of drug candidates provides additional, important mechanistic information, and therefore a means to increase the accuracy of critical decisions. A large-scale chemogenomics database developed from in vivo treated rats provides the context and supporting data to enhance and accelerate accurate interpretation of mechanisms of toxicity and pharmacology of chemicals and drugs. To date, approximately 600 different compounds, including more than 400 FDA approved drugs, 60 drugs approved in Europe and Japan, 25 withdrawn drugs, and 100 toxicants, have been profiled in up to 7 different tissues of rats (representing over 3200 different drug-dose-time-tissue combinations). Accomplishing this task required evaluating and improving a number of in vivo and microarray protocols, including over 80 rigorous quality control steps. The utility of pairing clinical pathology assessments with gene expression data is illustrated using three anti-neoplastic drugs: carmustine, methotrexate, and thioguanine, which had similar effects on the blood compartment, but diverse effects on hepatotoxicity. We will demonstrate that gene expression events monitored in the liver can be used to predict pathological events occurring in that tissue as well as in hematopoietic tissues.