Global, regional, and national burden of colorectal cancer and its risk factors, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Funding: F Carvalho and E Fernandes acknowledge support from Fundação para a Ciência e a Tecnologia, I.P. (FCT), in the scope of the project UIDP/04378/2020 and UIDB/04378/2020 of the Research Unit on Applied Molecular Biosciences UCIBIO and the project LA/P/0140/2020 of the Associate Laboratory Institute for Health and Bioeconomy i4HB; FCT/MCTES through the project UIDB/50006/2020. J Conde acknowledges the European Research Council Starting Grant (ERC-StG-2019-848325). V M Costa acknowledges the grant SFRH/BHD/110001/2015, received by Portuguese national funds through Fundação para a Ciência e Tecnologia (FCT), IP, under the Norma Transitória DL57/2016/CP1334/CT0006.proofepub_ahead_of_prin

The global burden of cancer attributable to risk factors, 2010-19 : a systematic analysis for the Global Burden of Disease Study 2019

Background Understanding the magnitude of cancer burden attributable to potentially modifiable risk factors is crucial for development of effective prevention and mitigation strategies. We analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 to inform cancer control planning efforts globally. Methods The GBD 2019 comparative risk assessment framework was used to estimate cancer burden attributable to behavioural, environmental and occupational, and metabolic risk factors. A total of 82 risk-outcome pairs were included on the basis of the World Cancer Research Fund criteria. Estimated cancer deaths and disability-adjusted life-years (DALYs) in 2019 and change in these measures between 2010 and 2019 are presented. Findings Globally, in 2019, the risk factors included in this analysis accounted for 4.45 million (95% uncertainty interval 4.01-4.94) deaths and 105 million (95.0-116) DALYs for both sexes combined, representing 44.4% (41.3-48.4) of all cancer deaths and 42.0% (39.1-45.6) of all DALYs. There were 2.88 million (2.60-3.18) risk-attributable cancer deaths in males (50.6% [47.8-54.1] of all male cancer deaths) and 1.58 million (1.36-1.84) risk-attributable cancer deaths in females (36.3% [32.5-41.3] of all female cancer deaths). The leading risk factors at the most detailed level globally for risk-attributable cancer deaths and DALYs in 2019 for both sexes combined were smoking, followed by alcohol use and high BMI. Risk-attributable cancer burden varied by world region and Socio-demographic Index (SDI), with smoking, unsafe sex, and alcohol use being the three leading risk factors for risk-attributable cancer DALYs in low SDI locations in 2019, whereas DALYs in high SDI locations mirrored the top three global risk factor rankings. From 2010 to 2019, global risk-attributable cancer deaths increased by 20.4% (12.6-28.4) and DALYs by 16.8% (8.8-25.0), with the greatest percentage increase in metabolic risks (34.7% [27.9-42.8] and 33.3% [25.8-42.0]). Interpretation The leading risk factors contributing to global cancer burden in 2019 were behavioural, whereas metabolic risk factors saw the largest increases between 2010 and 2019. Reducing exposure to these modifiable risk factors would decrease cancer mortality and DALY rates worldwide, and policies should be tailored appropriately to local cancer risk factor burden. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.Peer reviewe

Does adding a cardia biopsy improve gastric intestinal metaplasia detection rate by the Sydney system protocol?

Background: The Sydney system offers a standard biopsy protocol for detection and follow-up of gastric preneoplastic lesions such as intestinal metaplasia (IM). The highest frequency of cardia-type gastric adenocarcinoma (GA) in Iran has been documented in the north-western part of the country. This study aims to investigate the effect of the addition of mucosal biopsies of gastric cardia to the standard Sydney protocol on the rate of detection of IM in the asymptomatic residents of this high-risk region for proximal gastric cancer. Methods: A retrospective new analysis was performed on the previous data obtained in cross-sectional endoscopic screening in 2000 as well as a biopsy study of 508 asymptomatic volunteer residents in Meshkinshahr district, Ardabil province. The screening study was conducted in a group of residents aged 40 years and older who did not have any previous GI or hemodynamic problems. Results: Intestinal metaplasia at the Sydney protocol sampling sites was detected in 107 samples belonging to 76 of the 508 (14.99%) volunteers. Twenty-one patients had IM at the cardia. Of these, five patients had IM-cardia (IM only at the cardia). Therefore, adding a cardia biopsy to the set of biopsies diagnosed five more IM cases which were not diagnosed on the standard Sydney protocol (P=0.062). Conclusion: The addition of a biopsy from the cardia to the Sydney protocol biopsy set does not seem to improve the frequency of detection of IM in the residents of this high-risk geographic area for proximal gastric carcinoma

Supplementary Figure S1 from Immune Marker Spatial Distribution and Clinical Outcome after PD-1 Blockade in Mismatch Repair–deficient, Advanced Colorectal Carcinomas

Supplementary Figure S1. PD-L1 (green) was expressed in (A) CD3+ T lymphocytes (magenta/pink), (B) CD68+ macrophages (red), panCK+ (cyan/light blue) tumor cells, and (C) tumor cells (red). PD-1 expression on CD8+ T lymphocytes was also observed.</p

Supplementary Table S1 from Immune Marker Spatial Distribution and Clinical Outcome after PD-1 Blockade in Mismatch Repair–deficient, Advanced Colorectal Carcinomas

Supplementary Table S1. Significant features in the univariable analysis for prediction of progression-free survival.</p

Supplementary Table S2 from Immune Marker Spatial Distribution and Clinical Outcome after PD-1 Blockade in Mismatch Repair–deficient, Advanced Colorectal Carcinomas

Supplementary Table S2. Significant features in the univariable analysis for prediction of tumor response.</p

Transcriptomic Signatures of MSI-High Metastatic Colorectal Cancer Predict Efficacy of Immune Checkpoint Inhibitors

Purpose: Microsatellite instability (MSI) is currently the only predictive biomarker of efficacy of immune checkpoint inhibitors (ICI) in metastatic colorectal cancers (mCRC). However, 10% to 40% of patients with MSI mCRC will experience a primary resistance to ICI.Experimental Design: In two cohorts of patients with MSI mCRC treated with ICI (exploratory, N = 103; validation, N = 35), 30 RNA sequencing was performed from primary tumors. Previously described single-cell transcriptomic signatures of tumor microenvironment (TME) were analyzed.Results: In the exploratory cohort, the unsupervised clustering allowed the identification of three clusters of tumors with distinct transcriptional profiles: cluster A ("stromal(HIGH)-proliferation(LOW)"), cluster B ("stromal(HIGH)-proliferation(MED)"), and cluster C ("stromal(LOW)-proliferation(HIGH)"), with an enrichment of patients progressing at first disease assessment under ICI in cluster A (30% vs. 12% in cluster B and 8.1% in cluster C; P = 0.074). Progressionfree survival (PFS) was also significantly shorter in patients belonging to cluster A, compared with clusters B or C (P &lt; 0.001) with 2-year PFS rates of 33.5%, 80.5%, and 78.3%, respectively. In multivariate analysis, PFS was still significantly longer in patients belonging to cluster B [HR, 0.19; 95% confidence interval (CI), 0.080.45; P &lt; 0.001] and cluster C (HR, 0.25; 95% CI, 0.10-0.59; P = 0.02), compared with patients belonging to cluster A. The association of this clustering with PFS under ICI was confirmed in the validation cohort. PFS related to non-ICI-based regimens was not significantly different according to cluster.Conclusions: This unsupervised transcriptomic classification identified three groups of MSI mCRCs with different compositions of TME cells and proliferative capacities of TME/tumor cells. The "stromalHIGH-proliferationLOW" cluster is associated with a poorer prognosis with ICI treatment

Supplemental Figure 2 from Transcriptomic Signatures of MSI-High Metastatic Colorectal Cancer Predict Efficacy of Immune Checkpoint Inhibitors

Kaplan Meier curves for progression-free survival according to the unsupervised clusters and the line of immune checkpoint inhibitor</p

Supplemental Figure 3 from Transcriptomic Signatures of MSI-High Metastatic Colorectal Cancer Predict Efficacy of Immune Checkpoint Inhibitors

Tumor mutational burden and diagnosed Lynch syndrome in patients with MSI-high status determined by only one method</p

Supplemental Figure 4 from Transcriptomic Signatures of MSI-High Metastatic Colorectal Cancer Predict Efficacy of Immune Checkpoint Inhibitors

Heatmap with unsupervised clustering in the validation cohort</p