Publications

ABSTRACT Importance Reliable estimates of COVID-19 mortality are crucial to aid control strategies and to assess the effectiveness of interventions. Objective Project COVID-19 mortality trends to October 1, 2020, in 12 countries or regions that constitute >90% of the global COVID-19 deaths reported as of April 12, 2020. Design, Setting, and Participants The Global COVID-19 Assessment of Mortality (GCAM) is an open, transparent, and continuously updated ( www.cghr.org/covid ) statistical model that combines actual COVID-19 mortality counts with Bayesian inference to forecast COVID-19 deaths, the date of peak deaths, and the duration of excess mortality. The analyses covered a total of 700 million population above age 20 in 12 countries or regions: USA; Italy; Spain; France; UK; Iran; Belgium; a province of China (Hubei, which accounted for 90% of reported Chinese deaths); Germany; the Netherlands; Switzerland; and Canada; and six US states: New York, New Jersey, Michigan, Louisiana, California, and Washington. Results Forecasted deaths across the 12 current high-burden countries sum 167,000 to 593,000 (median 253,000). The trajectory of US deaths (49,000-249,000 deaths; median 86,000)—over half of which are expected in states beyond the initial six states analysed in this study—will have the greatest impact on the eventual total. Mortality ranges are 25,000-109,000 (median 46,000) in the UK; 23,000-31,000 (median 26,000) in Italy; 21,000-37,000 (median 26,000) in France and 21,000-32,000 (median 25,000) in Spain. Estimates are most precise for Hubei, China—where the epidemic curve is complete—and least precise in California, where it is ongoing. New York has the highest cumulative median mortality rate per million (1135), about 12-fold that of Germany. Mortality trajectories are notably flatter in Germany, California, and Washington State, each of which took physical distancing and testing strategies seriously. Using past country-specific mortality as a guide, GCAM predicts surge capacity needs, reaching more than twice existing capacity in a number of places., In every setting, the results might be sensitive to undercounts of COVID-19 deaths, which are already apparent. Conclusion and Relevance Mortality from COVID-19 will be substantial across many settings, even in the best case scenario. GCAM will provide continually updated and increasingly precise estimates as the pandemic progresses. The coronavirus disease (COVID-19) pandemic has already caused over 115,000 deaths, with global deaths doubling every week. 1-3 Mortality is less biased than case reporting, which is affected by testing policies. However, the daily reporting of COVID-19 deaths is already known to undercount actual deaths, varying over time and place. 4-6 Reliable estimates of total COVID-19 mortality, the date of peak deaths, and of the duration of excess mortality are crucial to aid responses to the current and potential future pandemics. We have developed the Global COVID-19 Assessment of Mortality (GCAM), a statistical model to project COVID-19 mortality trends to October 1 2020 in 12 countries or regions that constitute >90% of the global COVID-19 deaths reported as of April 12 th . We report also on six US states that account for 70% of the American totals to date (Supplementary Appendix). 1 We quantify the COVID-19 mortality trajectory ranges in each setting. A semi-automated website ( www.cghr.org/covid ) provides daily updates. GCAM is open, transparent, and uses a reasonably simple method that employs publicly reported mortality data to make plausible projections. The method is designed to improve as more mortality data become available over longer time periods.

The role of diet, except for alcohol drinking and aflatoxin contamination, in the etiology of hepatocellular carcinoma (HCC) is unclear. A hospital-based case-control study was conducted in Italy in 1999-2002, including 185 incident, histologically-confirmed cases of HCC. Controls were 412 subjects admitted to hospitals for acute, nonneoplastic diseases unrelated to diet. Dietary habits were assessed using a validated food-frequency questionnaire. Odds ratios (ORs) and the corresponding 95% confidence intervals (CI) were computed using unconditional multiple logistic regression, adjusting for hepatitis B (HBV) and hepatitis C (HCV) virus infection and alcohol drinking. Energy adjustment was carried out by means of the residual model. A significant inverse relation was found between intakes of milk and yoghurt (OR = 0.28; 95% CI: 0.13-0.61), white meats (OR = 0.44; 95% CI: 0.20-0.95), eggs (OR = 0.31; 95% CI: 0.14-0.69), and fruits (OR = 0.48; 95% CI: 0.22-1.05) and HCC risk. The favourable effect of high intakes of milk and yoghurt, white meats, eggs and fruits was consistent across strata of HBV and HCV infections. The present study supports the hypothesis of a role of diet in HCC aetiology. Dietary modifications may be indicated in subjects at high-risk for HCC.

Although the protective role of dietary fiber on cancer risk has been reported in several epidemiological studies, the association of fiber intake on head and neck cancer (HNC) risk is still unclear. We investigated the association between fiber intake and the risk of HNC using data from the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial. Among 101,700 participants with complete dietary information, 186 participants developed HNC during follow-up (January 1998 to May 2011). Dietary data were collected using a self-administered food-frequency questionnaire (1998-2005). We estimated hazard ratios (HRs) and the corresponding 95% confidence intervals (CI), using the Cox proportional hazards model. Higher intake of total fiber, insoluble fiber and soluble fiber was associated with decreased HNC risks, with a significant trend. The HRs of highest vs. the lowest tertile of intake were 0.43 (95%CI: 0.25-0.76) for total fiber, 0.38 (95%CI: 0.22-0.65) for insoluble fiber, and 0.44 (95%CI: 0.25-0.79) for soluble fiber. These inverse association were consistent in oral cavity and pharyngeal cases, but the impact of fiber intake was weaker in laryngeal cases. We did not observe any significant interaction of potential confounders, including smoking and drinking, with total fiber intake on HNC risk. These findings support evidence of a protective role of dietary fiber on HNC risk.

If causal, eliminating industrial <i>trans</i>-fatty acids could offer a straightforward public health action for reducing ovarian cancer risk.

Cigar and pipe smoking are considered risk factors for head and neck cancers, but the magnitude of effect estimates for these products has been imprecisely estimated. By using pooled data from the International Head and Neck Cancer Epidemiology (INHANCE) Consortium (comprising 13,935 cases and 18,691 controls in 19 studies from 1981 to 2007), we applied hierarchical logistic regression to more precisely estimate odds ratios and 95% confidence intervals for cigarette, cigar, and pipe smoking separately, compared with reference groups of those who had never smoked each single product. Odds ratios for cigar and pipe smoking were stratified by ever cigarette smoking. We also considered effect estimates of smoking a single product exclusively versus never having smoked any product (reference group). Among never cigarette smokers, the odds ratio for ever cigar smoking was 2.54 (95% confidence interval (CI): 1.93, 3.34), and the odds ratio for ever pipe smoking was 2.08 (95% CI: 1.55, 2.81). These odds ratios increased with increasing frequency and duration of smoking (Ptrend ≤ 0.0001). Odds ratios for cigar and pipe smoking were not elevated among ever cigarette smokers. Head and neck cancer risk was elevated for those who reported exclusive cigar smoking (odds ratio = 3.49, 95% CI: 2.58, 4.73) or exclusive pipe smoking (odds ratio = 3.71, 95% CI: 2.59, 5.33). These results suggest that cigar and pipe smoking are independently associated with increased risk of head and neck cancers.

CHD and CVD mortality steadily declined in Europe, except in Russia, whose rates were 10 to 15-fold higher than those of France, Italy or Sweden. Hungary and Poland, and also Scotland, where CHD trends were less favourable than in other western European countries, also emerge as priorities for preventive interventions.

Mortality data, abstracted from the World Health Organization database, are presented in tabular form for 26 cancer sites or groups of sites, plus total cancer mortality, in 36 European countries during the period 1995-1999. Trends in mortality are also given in graphic form for 23 major countries plus the European Union as a whole over the period 1960-1999. In the European Union, total cancer mortality declined by 7% for both sexes over the last 5 years considered. The fall since the late 1980s was 10% in both sexes, corresponding to the avoidance of over 90000 deaths per year, as compared to the rates of the late 1980s. For the first time, over the last few years, some leveling of mortality was reported also in the Russian Federation, the Czech Republic, Poland, Hungary and other Eastern European countries, although cancer rates in those areas remain exceedingly high. The overall favorable pattern of cancer mortality over recent years is largely driven by the decline of tobacco-related cancer mortality in men. However, important components of the trends are also the persistence of substantial falls in gastric cancer, mainly in Russia and Eastern Europe, the recent decline in intestinal cancer in both sexes and of breast cancer in women, together with the long-term falls in uterine (cervical) cancer, leukemias, Hodgkin's disease and other neoplasms amenable to advancements in diagnosis and treatment. Female lung cancer mortality has been declining in the Russian Federation, but is still rising in other areas of the continent. Thus, urgent intervention is needed to bring under control the tobacco-related lung cancer epidemic in European women before it reaches the high level observed in North America. Supplementary material for this article can be found on the International Journal of Cancer website at http://www.interscience.wiley.com/jpages/0020-7136/suppmat/index.html

Aim. The aim of our study was to assess whether selected single nucleotide polymorphisms of CYP1A1 and 2E1, GSTM1, GSTT1, and SULT1A1 influence susceptibility towards HCC, considering their interaction with cigarette smoking. Methods. We recruited HCC cases and controls among patients admitted to the hospital "Agostino Gemelli," from January 2005 until July 2010. Odds ratios (OR) of HCC were derived from unconditional multiple logistic regression. Gene-gene and gene-smoking interaction were quantified by computing the attributable proportion (AP) due to biological interaction. Results. The presence of any CYP2E1 (*) 5B variant allele (OR: 0.23; 95% CI: 0.06-0.71) and CYP2E1 (*) 6 variant allele (OR: 0.08; 95% CI: 0.01-0.33) was inversely related to HCC. There was a borderline increased risk among carriers of combined CYP1A1 (*) 2A and SULT1A1 variant alleles (OR: 1.67; 95% CI: 0.97-3.24). A significant biological interaction was observed between GSTT1 and smoking (AP = 0.48; 95% CI: 0.001-0.815), with an OR of 3.13 (95% CI: 1.69-5.82), and borderline significant interaction was observed for SULT1A1 and smoking (AP = 0.36; 95% CI: -0.021-0.747), with an OR of 3.05 (95% CI: 1.73-5.40). Conclusion. CYP2E1 (*) 5B and CYP2E1 (*) 6 polymorphisms have a favourable effect on the development of HCC, while polymorphisms of GSTT1 and SULT1A1 might play role in increasing the susceptibility among smokers.

&lt;p&gt;Supplementary Figure 2: Pooled adjusted odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for the association between intake of proton-pump inhibitors and gastric cancer, by smoking status and alcohol drinking status.&lt;/p&gt;

Polatuzumab vedotin, an antibody-drug conjugate (ADC) targeting the B cell receptor (BCR) signaling subunit CD79B, has recently entered frontline therapy for diffuse large B cell lymphoma (DLBCL) and high-grade B cell lymphoma (HGBCL), achieving encouraging clinical results. However, MYC-driven B cell lymphomas, particularly HGBCL with MYC and BCL2 rearrangements, frequently silence surface BCR/CD79B expression, limiting the therapeutic reach of CD79B-directed ADCs and underscoring the need for complementary treatment strategies. To uncover drug vulnerabilities associated with BCR extinction in aggressive B cell lymphomas, we conditionally ablated surface BCR expression in the λ-MYC mouse B cell lymphoma model and screened 1475 small-molecule compounds, including clinically approved agents, on syngenic BCR-positive and BCR-negative tumor cells. This screening revealed compounds with comparable activity across both states as well as compounds with improved efficacy against BCR-deficient lymphomas. Notably, inhibitors of mTORC1/2 and CDK4/6 displayed robust and reproducible potency in BCR-negative lymphoma cells. Mechanistically, BCR loss impaired mTOR-dependent anabolic control, reducing protein synthesis, while diminished Cyclin D3 abundance sensitized tumor cells to pharmacological CDK4/6 blockade. Human BCR-negative HGBCL with MYC and BCL2 rearrangements similarly exhibited sub-micromolar sensitivity to mTORC1/2 and CDK4/6 inhibitors. Overall, our results uncover targetable vulnerabilities in MYC-driven B cell lymphomas, possibly extending to other aggressive B cell tumors silencing BCR expression. The data provide a rational basis for integrating CD79B-directed ADCs with mTOR or CDK4/6 inhibitors to prevent or overcome treatment resistance of aggressive B cell lymphomas.