International journal of cancer. Journal international du cancer
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Multicenter Study
Circulating plasma phospholipid fatty acids and risk of pancreatic cancer in a large European cohort.
There are both limited and conflicting data on the role of dietary fat and specific fatty acids in the development of pancreatic cancer. In this study, we investigated the association between plasma phospholipid fatty acids and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. The fatty acid composition was measured by gas chromatography in plasma samples collected at recruitment from375 incident pancreatic cancer cases and375 matched controls. ⋯ Results were robust to a range of sensitivity analyses. Our findings suggest that higher circulating levels of saturated fatty acids with an odd number of carbon atoms and n-3 polyunsaturated fatty acids may be related to lower risk of pancreatic cancer. The influence of some fatty acids on the development of pancreatic cancer may be sex-specific and modulated by smoking.
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Lorlatinib (PF-06463922) is a promising oral anaplastic lymphoma kinase (ALK) and ROS1 inhibitor currently in Phase III clinical trials for treatment of non-small-cell lung cancer (NSCLC) containing an ALK rearrangement. With therapy-resistant brain metastases a major concern in NSCLC, lorlatinib was designed to have high membrane and blood-brain barrier permeability. We investigated the roles of the multidrug efflux transporters ABCB1 and ABCG2, and the multispecific drug-metabolizing enzyme CYP3A in plasma pharmacokinetics and tissue distribution of lorlatinib using genetically modified mouse strains. ⋯ Our data indicate that lorlatinib brain accumulation is substantially limited by P-glycoprotein/ABCB1 in the blood-brain barrier, but this can be effectively reversed by elacridar coadministration. Moreover, oral availability of lorlatinib is markedly restricted by CYP3A4 activity. These insights may be used in optimizing the therapeutic application of lorlatinib.
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Ultraviolet radiation (UVR) is a strong and ubiquitous risk factor for cutaneous melanoma, emitted naturally by the sun but also artificial sources. To shed light on the potential impact of interventions seeking to reduce exposure to UVR in both high and low risk populations, we quantified the number of cutaneous melanomas attributable to UVR worldwide. Population attributable fractions and numbers of new melanoma cases in adults due to ambient UVR were calculated by age and sex for 153 countries by comparing the current melanoma burden with historical data, i.e., the melanoma burden observed in a population with minimal exposure to UVR. ⋯ This burden was concentrated in very highly developed countries with 149,000 attributable cases and was most pronounced in Oceania, where 96% of all melanomas (representing 9.3% of the total cancer burden) were attributable to excess UVR. There would be approximately 151,000 fewer melanoma cases worldwide were incidence rates in every population equivalent to those observed in selected low-risk (dark-skinned, heavily pigmented) reference populations. These findings underline the need for public health action, an increasing awareness of melanoma and its risk factors, and the need to promote changes in behavior that decrease sun exposure at all ages.
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In patients with metastatic castrate-resistant prostate cancer (mCRPC), circulating tumor DNA (ctDNA) analysis offers novel opportunities for the development of non-invasive biomarkers informative of treatment response with novel agents targeting the androgen-receptor (AR) pathway, such as abiraterone or enzalutamide. However, the relationship between ctDNA abundance, detectable somatic genomic alterations and clinical progression of mCRPC remains unexplored. Our study aimed to investigate changes in plasma DNA during disease progression and their associations with clinical variables in mCRPC patients. ⋯ As we observed a wide variability of ctDNA levels, we evaluated ctDNA levels and their association with clinical parameters and included the second, larger cohort for these analyses. Employing altogether 428 longitudinal plasma samples from 148 patients, we identified the presence of bone metastases, increased lactate dehydrogenase and prostate-specific antigen (PSA) as having the strongest association with high ctDNA levels. In summary, ctDNA alterations are observable in the majority of patients with mCRPC and may eventually be useful to guide clinical decision-making in this setting.