There were an estimated 4.8 million new cases of gastrointestinal (GI) cancers and 3.4 million related deaths, worldwide, in 2018. GI cancers account for 26% of the global cancer incidence and 35% of ...all cancer-related deaths. We investigated the global burden from the 5 major GI cancers, as well as geographic and temporal trends in cancer-specific incidence and mortality.
Data on primary cancers of the esophagus, stomach, colorectum, liver, and pancreas were extracted from the GLOBOCAN database for the year 2018, as well as from the Cancer Incidence in 5 Continents series, and the World Health Organization mortality database from 1960 onward. Age-standardized incidence and mortality rates were calculated by sex, country, and level of human development.
We observed geographic and temporal variations in incidence and mortality for all 5 types of GI cancers. Esophageal, gastric, and liver cancers were more common in Asia than in other parts of the world, and the burden from colorectal and pancreatic cancers was highest in Europe and North America. There was a uniform decrease in gastric cancer incidence, but an increasing incidence of colorectal cancer in formerly low-incidence regions during the studied time period. We found slight increases in incidence of liver and pancreatic cancer in some high-income regions.
Although the incidence of some GI cancer types has decreased, this group of malignancies continues to pose major challenges to public health. Primary and secondary prevention measures are important for controlling these malignancies—most importantly reducing consumption of tobacco and alcohol, obesity control, immunizing populations against hepatitis B virus infection, and screening for colorectal cancer.
Observational studies and randomised controlled studies suggest that vitamin D plays a role in the prevention of acute respiratory tract infection (ARTI); however, findings are inconsistent and the ...optimal serum 25-hydroxyvitamin D (25(OH)D) concentration remains unclear. To review the link between 25(OH)D concentration and ARTI, we searched PubMed and EMBASE databases to identify observational studies reporting the association between 25(OH)D concentration and risk or severity of ARTI. We used random-effects meta-analysis to pool findings across studies. Twenty-four studies were included in the review, 14 were included in the meta-analysis of ARTI risk and five in the meta-analysis of severity. Serum 25(OH)D concentration was inversely associated with risk and severity of ARTI; pooled odds ratios (95% confidence interval) were 1.83 (1.42-2.37) and 2.46 (1.65-3.66), respectively, comparing the lowest with the highest 25(OH)D category. For each 10 nmol/L decrease in 25(OH)D concentration, the odds of ARTI increased by 1.02 (0.97-1.07). This was a non-linear trend, with the sharpest increase in risk of ARTI occurring at 25(OH)D concentration < 37.5 nmol/L. In conclusion, there is an inverse non-linear association between 25(OH)D concentration and ARTI.
Purpose
Variation in the human microbiome has been linked with a variety of physiological functions, including immune regulation and metabolism and biosynthesis of vitamins, hormones, and ...neurotransmitters. Evidence for extraskeletal effects of vitamin D has been accruing and it has been suggested that the effect of vitamin D on health is partially mediated through the microbiome. We aimed to critically evaluate the evidence linking vitamin D and the gastrointestinal microbiome.
Methods
We systematically searched the Embase, Web of Science, PubMed and CINAHL databases, including peer-reviewed publications that reported an association between a measure of vitamin D and the gastrointestinal microbiome in humans or experimental animals.
Results
We included 10 mouse and 14 human studies. Mouse studies compared mice fed diets containing different levels of vitamin D (usually high versus low), or vitamin D receptor knockout or
Cyp27B1
knockout with wild-type mice. Five mouse studies reported an increase in Bacteroidetes (or taxa within that phylum) in the low vitamin D diet or gene knockout group. Human studies were predominantly observational; all but two of the included studies found some association between vitamin D and the gut microbiome, but the nature of differences observed varied across studies.
Conclusions
Despite substantial heterogeneity, we found evidence to support the hypothesis that vitamin D influences the composition of the gastrointestinal microbiome. However, the research is limited, having been conducted either in mice or in mostly small, selected human populations. Future research in larger population-based studies is needed to fully understand the extent to which vitamin D modulates the microbiome.
Abstract
There is considerable debate regarding the role that 25-hydroxyvitamin D 25(OH)D concentrations play in cancer risk or mortality, with earlier studies drawing mixed conclusions. Using data ...from the UK Biobank (UKB), we evaluate whether genetically predicted 25(OH)D concentrations are associated with overall cancer susceptibility and cancer mortality using five 25(OH)D genetic markers. Data comprised 438 870 white British UKB participants aged 37-73, including 46 155 cancer cases and 6998 cancer-specific deaths. Participants with keratinocyte cancers and/or benign tumors were excluded from the analysis. Odds ratios were calculated per 20 nmol/L increase in genetically predicted 25(OH)D for cancer risk and cancer mortality. For individual cancer risks, estimates were meta-analyzed with publicly available data using a fixed-effect inverse-variance-weighted model. We demonstrated that genetically low plasma 25(OH)D concentrations were not associated with increased cancer risk nor cancer mortality. Stratification by sex or cancer types did not reveal any meaningful differences albeit wider confidence intervals. Fixed-effect meta-analysis of our individual cancer risk estimates with those derived from publicly available cancer consortia data and previous studies further reinforced our null Mendelian randomization findings on prostate, lung, colorectal and breast cancers with tight confidence intervals; for ovarian and pancreatic cancers, our estimates were less precise despite being not statistically significant. Taken altogether, our results provide no genetic evidence for an association between vitamin D and overall cancer outcomes, with tight confidence intervals to exclude all but very small effect sizes.
IMPORTANCE: Keratinocyte cancers (KCs), including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), are the most common cancers among fair-skinned populations worldwide. Although studies ...have indicated that the anatomical distribution of BCC and SCC differ, few have compared them directly in well-defined population samples. OBJECTIVES: To describe and compare the anatomical distribution of BCC and SCC in a population-based sample in Queensland, Australia. DESIGN, SETTING, AND PARTICIPANTS: This study was nested within the population-based QSkin Sun and Health Study in Queensland, Australia. Of 37 103 study participants linked to national medical insurance records, 3398 diagnosed with KCs from September 1, 2010, to September 30, 2012, were identified, and information about their KCs was extracted from pathology reports. Data were analyzed from January 1, 2013, to March 30, 2016. MAIN OUTCOMES AND MEASURES: The relative tumor densities (RTDs) on defined body sites, calculated by dividing the proportion of tumors occurring at a specified site by the proportion of skin area of that site. RESULTS: A total of 5150 KCs with complete data were identified in 2374 study participants (1339 men 56.4% and 1035 women 43.6%; mean SD age, 59.7 7.4 years). Of these, 3846 KCs (74.7%) were BCCs. Most BCCs were on the head and/or neck (1547 40.2%) and the trunk (1305 33.9%); most SCCs were on the head and/or neck (435 33.4%) and upper limbs (455 34.9%). The greatest differences in RTDs between BCC and SCC were on the hand (BCC:SCC ratio, 1:14) and the back and/or buttocks (BCC:SCC ratio, 8:1). Relative tumor densities of KCs were higher on the scalp and ear in men compared with women, and on the upper arm in women compared with men. The pattern of RTDs did not differ with age for BCC. Compared with younger adults (40-54 years), the RTDs in older adults (55-69 years) were 2-fold higher for SCC on the scalp (0.38 95% CI, 0.00-0.81 vs 1.07 95% CI, 0.75-1.38) and the back and/or buttocks (0.05 95% CI, 0.00-0.12 vs 0.12 95% CI, 0.07-0.16). CONCLUSIONS AND RELEVANCE: The high RTDs on sun-exposed body sites for BCC and SCC are in keeping with sun exposure as the primary etiologic factor for both tumors. However, for BCC, the low RTD on the hand and high RTDs on less sun-exposed sites suggest a complex association between sun exposure and occurrence of BCC. Knowledge about the anatomical distribution of BCC and SCC may provide insight into their diagnoses and causes.
The keratinocyte cancers (KC), basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most common cancers in fair-skinned people. KC treatment represents the second highest cancer ...healthcare expenditure in Australia. Increasing our understanding of the genetic architecture of KC may provide new avenues for prevention and treatment. We first conducted a series of genome-wide association studies (GWAS) of KC across three European ancestry datasets from Australia, Europe and USA, and used linkage disequilibrium (LD) Score regression (LDSC) to estimate their pairwise genetic correlations. We employed a multiple-trait approach to map genes across the combined set of KC GWAS (total N = 47 742 cases, 634 413 controls). We also performed meta-analyses of BCC and SCC separately to identify trait specific loci. We found substantial genetic correlations (generally 0.5-1) between BCC and SCC suggesting overlapping genetic risk variants. The multiple trait combined KC GWAS identified 63 independent genome-wide significant loci, 29 of which were novel. Individual separate meta-analyses of BCC and SCC identified an additional 13 novel loci not found in the combined KC analysis. Three new loci were implicated using gene-based tests. New loci included common variants in BRCA2 (distinct to known rare high penetrance cancer risk variants), and in CTLA4, a target of immunotherapy in melanoma. We found shared and trait specific genetic contributions to BCC and SCC. Considering both, we identified a total of 79 independent risk loci, 45 of which are novel.
A 2017 meta-analysis of data from 25 randomised controlled trials (RCTs) of vitamin D supplementation for the prevention of acute respiratory infections (ARIs) revealed a protective effect of this ...intervention. We aimed to examine the link between vitamin D supplementation and prevention of ARIs in an updated meta-analysis.
For this systematic review and meta-analysis, we searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, and the ClinicalTrials.gov registry for studies listed from database inception to May 1, 2020. Double-blind RCTs of vitamin D
, vitamin D
, or 25-hydroxyvitamin D (25OHD) supplementation for any duration, with a placebo or low-dose vitamin D control, were eligible if they had been approved by a research ethics committee, and if ARI incidence was collected prospectively and prespecified as an efficacy outcome. Studies reporting results of long-term follow-up of primary RCTs were excluded. Aggregated study-level data, stratified by baseline 25(OH)D concentration and age, were obtained from study authors. Using the proportion of participants in each trial who had one or more ARIs, we did a random-effects meta-analysis to obtain pooled odds ratios (ORs) and 95% CIs to estimate the effect of vitamin D supplementation on the risk of having one or more ARIs (primary outcome) compared with placebo. Subgroup analyses were done to estimate whether the effects of vitamin D supplementation on the risk of ARI varied according to baseline 25(OH)D concentration (<25 nmol/L vs 25·0-49·9 nmol/L vs 50·0-74·9 nmol/L vs >75·0 nmol/L), vitamin D dose (daily equivalent of <400 international units IU vs 400-1000 IU vs 1001-2000 IU vs >2000 IU), dosing frequency (daily vs weekly vs once per month to once every 3 months), trial duration (≤12 months vs >12 months), age at enrolment (<1·00 years vs 1·00-15·99 years vs 16·00-64·99 years vs ≥65·00 years), and presence versus absence of airway disease (ie, asthma only, COPD only, or unrestricted). Risk of bias was assessed with the Cochrane Collaboration Risk of Bias Tool. The study was registered with PROSPERO, CRD42020190633.
We identified 1528 articles, of which 46 RCTs (75 541 participants) were eligible. Data for the primary outcome were obtained for 48 488 (98·1%) of 49 419 participants (aged 0-95 years) in 43 studies. A significantly lower proportion of participants in the vitamin D supplementation group had one or more ARIs (14 332 61·3% of 23 364 participants) than in the placebo group (14 217 62·3% of 22 802 participants), with an OR of 0·92 (95% CI 0·86-0·99; 37 studies; I
=35·6%, p
=0·018). No significant effect of vitamin D supplementation on the risk of having one or more ARIs was observed for any of the subgroups defined by baseline 25(OH)D concentration. However, protective effects of supplementation were observed in trials in which vitamin D was given in a daily dosing regimen (OR 0·78 95% CI 0·65-0·94; 19 studies; I
=53·5%, p
=0·003), at daily dose equivalents of 400-1000 IU (0·70 0·55-0·89; ten studies; I
=31·2%, p
=0·16), for a duration of 12 months or less (0·82 0·72-0·93; 29 studies; I
=38·1%, p
=0·021), and to participants aged 1·00-15·99 years at enrolment (0·71 0·57-0·90; 15 studies; I
=46·0%, p
=0·027). No significant interaction between allocation to the vitamin D supplementation group versus the placebo group and dose, dose frequency, study duration, or age was observed. In addition, no significant difference in the proportion of participants who had at least one serious adverse event in the vitamin supplementation group compared with the placebo group was observed (0·97 0·86-1·07; 36 studies; I
=0·0%, p
=0·99). Risk of bias within individual studies was assessed as being low for all but three trials.
Despite evidence of significant heterogeneity across trials, vitamin D supplementation was safe and overall reduced the risk of ARI compared with placebo, although the risk reduction was small. Protection was associated with administration of daily doses of 400-1000 IU for up to 12 months, and age at enrolment of 1·00-15·99 years. The relevance of these findings to COVID-19 is not known and requires further investigation.
None.
To estimate the proportion and numbers of cancers occurring in Australia attributable to solar ultraviolet radiation (UVR) and the proportion and numbers prevented by regular sun protection factor ...(SPF) 15+ sunscreen use.
We estimated the population attributable fraction (PAF) and numbers of melanomas and keratinocyte cancers (i.e. basal cell carcinomas and squamous cell carcinomas) due to exposure to ambient UVR resulting from residing in Australia versus residing in the UK (for melanoma) or Scandinavia (for keratinocyte cancers). We also estimated the prevented fraction (PF): the proportion of cancers that would have occurred but were likely prevented by regular sunscreen use.
An estimated 7,220 melanomas (PAF 63%) and essentially all keratinocyte cancers occurring in Australia were attributable to high ambient UVR levels in Australia. We estimated that regular sunscreen use prevented around 14,190 (PF 9.3%) and 1,730 (PF 14%) people from developing SCC and melanoma, respectively.
Although our approach was conservative, a high proportion of skin cancers in Australia are attributable to high ambient levels of UVR. Prevailing levels of sunscreen use probably reduced skin cancer incidence by 10–15%.
Most skin cancers are preventable. Sunscreen should be a component of a comprehensive sun protection strategy.
Pancreatic cancer is a major cause of cancer-associated mortality, with a dismal overall prognosis that has remained virtually unchanged for many decades. Currently, prevention or early diagnosis at ...a curable stage is exceedingly difficult; patients rarely exhibit symptoms and tumours do not display sensitive and specific markers to aid detection. Pancreatic cancers also have few prevalent genetic mutations; the most commonly mutated genes are KRAS, CDKN2A (encoding p16), TP53 and SMAD4 - none of which are currently druggable. Indeed, therapeutic options are limited and progress in drug development is impeded because most pancreatic cancers are complex at the genomic, epigenetic and metabolic levels, with multiple activated pathways and crosstalk evident. Furthermore, the multilayered interplay between neoplastic and stromal cells in the tumour microenvironment challenges medical treatment. Fewer than 20% of patients have surgically resectable disease; however, neoadjuvant therapies might shift tumours towards resectability. Although newer drug combinations and multimodal regimens in this setting, as well as the adjuvant setting, appreciably extend survival, ∼80% of patients will relapse after surgery and ultimately die of their disease. Thus, consideration of quality of life and overall survival is important. In this Primer, we summarize the current understanding of the salient pathophysiological, molecular, translational and clinical aspects of this disease. In addition, we present an outline of potential future directions for pancreatic cancer research and patient management.
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