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The aim of the study is to provide a comprehensive assessment of incidence and survival trends of epithelial ovarian cancer (EOC) by histological subtype across seven high income countries (Australia, Canada, Denmark, Ireland, New Zealand, Norway, and the United Kingdom). Data on invasive EOC diagnosed in women aged 15-99 years during 1995-2014 were obtained from 20 cancer registries. Age standardized incidence rates and average annual percentage change were calculated by subtype for all ages and age groups (15-64 and 65-99 years). Net survival (NS) was estimated by subtype, age group, and 5-year period using Pohar-Perme estimator. Our findings showed marked increase in serous carcinoma incidence was observed between 1995-2014 among women aged 65-99 years with average annual increase ranging between 2.2% and 5.8%. We documented a marked decrease in the incidence of adenocarcinoma 'not otherwise specified' with estimates ranging between 4.4% and 7.4% in women aged 15-64 years and between 2.0% and 3.7% among the older age group. Improved survival, combining all EOC subtypes, was observed for all ages combined over the 20-year study period in all countries with 5-year NS absolute percent change ranging between 5.0 in Canada and 12.6 in Denmark. Several factors such as changes in guidelines and advancement in diagnostic tools may potentially influence the observed shift in histological subtypes and temporal trends. Progress in clinical management and treatment over the past decades potentially plays a role in the observed improvements in EOC survival. This article is protected by copyright. All rights reserved.

Survival from lung cancer remains low, yet is the most common cancer diagnosed worldwide. With survival contrasting between the main histological groupings, small-cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), it is important to assess the extent that geographical differences could be from varying proportions of cancers with unspecified histology across countries. Lung cancer cases diagnosed 2010-2014, followed until 31st December 2015 were provided by cancer registries from seven countries for the ICBP SURVMARK-2 project. Multiple imputation was used to reassign cases with unspecified histology into SCLC, NSCLC, other. One- and three-year age-standardised net survival were estimated by histology, sex, age group and country. 404,617 lung cancer cases were included, 47,533 (11.7%) and 262,040 (64.8%) were SCLC and NSCLC. The proportion of unspecified cases varied, from 11.2% (Denmark) to 29.0% (U.K). Following imputation with unspecified histology, survival variations remained: 1-year SCLC survival ranged from 28.0% (New Zealand) to 35.6% (Australia) NSCLC survival from 39.4% (U.K.) to 49.5% (Australia). The largest survival change following imputation was for 1-year NSCLC (4.9 percentage point decrease). Similar variations were observed for 3-year survival. The oldest age group had lowest survival and largest decline following imputation. International variations in SCLC and NSCLC survival are only partially attributable to differences in the distribution of unspecified histology. While it is important that registries and clinicians aim to improve completeness in classifying cancers, it is likely that other factors play a larger role, including underlying risk factors, stage, comorbidity and care management which warrants investigation. This article is protected by copyright. All rights reserved.

Background: Over the last decade, studies unraveled the cancer-immune dialogue in the setting of immune checkpoint inhibitors (ICI) and influenced by the gut microbiota. The first evidence of the key role of the microbiota in ICI modulation was observed during antibiotics (ATB) treatment, where altering the microbiota composition by ATB inhibited ICI responses. DAV132 (DAV) is an orally administered colon-targeted ATB adsorbent capsules designed to prevent ATB-induced dysbiosis. We investigated whether DAV co-administered with ATB could prevent ATB-related dysbiosis and ICI response. Methods: 72 human healthy volunteers (HV) were randomized to receive either IV ceftazidime-avibactam (CZA) or Piperacillin tazobactam (PTZ) alone or in combination with oral DAV. CZA and PTZ plasmatic and fecal pharmacodynamic levels were measured using HPLC-MS/MS. Microbiome was profiled with metagenomics at different timepoints. FMT experiments in germ-free mice were performed using fecal samples from HV from the trial, before (D1) or after 6 days (D6) of CZA or PTZ+/-DAV; subsequently mice were inoculated with MCA205 or B16 tumors and treated with anti-PD-1. Tumor infiltrating lymphocytes (TILs) were analyzed by flow cytometry. Results: DAV did not impact plasmatic CZA or PTZ concentrations, but significantly reduced ceftazidime and piperacillin concentrations in feces compared to ATB groups alone. DAV significantly prevented the reduction in microbiota alpha-diversity at D6 and was associated with a rapid return to baseline microbiota. 50 and 43 metagenomics species were preserved in the CZA+DAV vs CZA, or PTZ-DAV vs PTZ such as Faecalibacterium praunistzii, Alistipes Spp and Blautia obeum. FMT in germ-free mice using feces collected at D1 exhibited a significant anti-PD-1 activity. This anti-tumor response was inhibited in two tumors models in mice transplanted with D6 feces from patients in the CZA or PTZ alone groups. Conversely, the anti-tumor response was maintained in mice transplanted with D6 feces from HV treated with CZA+DAV or PTZ+DAV groups. Flow cytometry on TILs demonstrated that CZA decreased CD8+T cell and CD8+/Treg ratio compared to CZA+DAV. Conclusions: DAV prevented ATB-induced dysbiosis in HV treated with CZA or PTZ without influencing plasmatic concentrations. In avatar mice FMT from HV treated with CZA+DAV was able to preserve anti-PD-1 efficacy. These results provide rationale to launch clinical trials combining DAV in patients on ATB amenable to ICI. Citation Format: Meriem Messaoudene, Nathalie Saint-Lu, Frédérique Sablier-Gallis, Stéphanie Ferreira, Mayra Ponce, Clément Le Bescop, Thomas Loppinet, Tanguy Corbel, Céline Féger, Fabien Vitry, Antoine Andremont, Jean de Gunzburg, Bertrand Routy. Prevention of antibiotic-induced dysbiosis in human volunteers by DAV132 and preservation of responsiveness to anti-PD-1 demonstrated by transplantation of human feces into tumor-bearing mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5882.

Background: Familial hypercholesterolemia (FH) is a monogenic disease characterized by a high concentration of low-density lipoprotein cholesterol. This population is considered to be at high cardiovascular risk; however, disease evolution remains heterogeneous among individuals. The coronary artery calcium (CAC) score is currently the best predictor of incidental major cardiovascular events in primary prevention in the general population. Few studies have described the CAC score in FH populations. Methods: The objective of our study was to determine the predictors of the CAC score in FH patients. We retrospectively studied FH patients followed at the Montreal Clinical Research Institute (IRCM) Lipid Clinic who had a cardiac scan for CAC score, using the Agatston method, between 2013 and 2019. Results: Final analysis included 62 FH patients. Mean age was 48 ± 14 years old, and 48% were men. Overall, 25 patients had a CAC score of 0 (40%), and 37 patients had a nonzero CAC score (60%). Sex, age, Montreal-FH-SCORE (MFHS), waist circumference, and statin exposure in years were significant predictors (P ≤ 0,05) of a nonzero CAC score in a univariate model. MFHS was the only factor that remained significant in a multivariate model (odds ratio 1.34, 95% confidence interval 1.11–1.61, P = 0.002). Conclusions: In conclusion, we found that MFHS, which includes traditional cardiovascular risk factors, was a predictor of a nonzero CAC score in FH patients. This finding suggests that MFHS may play a role in determining the cardiovascular risk and therefore the intensity of treatment in FH patients. Résumé: Contexte: L’hypercholestérolémie familiale (HF) est une maladie monogénique caractérisée par une forte concentration de cholestérol des lipoprotéines de basse densité. La population touchée est considérée comme étant exposée à un risque cardiovasculaire élevé; toutefois, l’évolution de la maladie demeure hétérogène d’une personne à l’autre. À l’heure actuelle, le score calcique coronaire (SCC) est le meilleur outil prédictif de manifestations cardiovasculaires majeures fortuites en prévention primaire dans la population générale. Peu d’études ont décrit le SCC dans des populations atteintes de HF. Méthodologie: L’objectif de notre étude était de déterminer les facteurs prédictifs du SCC chez les patients atteints de HF. Nous avons étudié de façon rétrospective des patients atteints de HF qui étaient suivis à la clinique de lipides de l’Institut de recherches cliniques de Montréal (IRCM) et chez qui le score SCC avait été mesuré pendant un examen de tomodensitométrie cardiaque, au moyen de la méthode d’Agatston, entre 2013 et 2019. Résultats: L’analyse finale a porté sur 62 patients atteints de HF. L’âge moyen était de 48 ± 14 ans et la proportion d’hommes était de 48 %. Dans l’ensemble, 25 patients avaient un SCC de 0 (40 %) et 37, un SCC différent de zéro (60 %). Le sexe, l’âge, le score MFHS (Montreal-FH-SCORE), le tour de taille et le nombre d’années d’exposition aux statines ont été des facteurs prédictifs significatifs (p ≤ 0,05) d’un SCC différent de zéro dans un modèle à une variable. Le score MFHS est le seul facteur qui est demeuré significatif dans un modèle à plusieurs variables (rapport de cotes : 1,34; intervalle de confiance à 95 % : 1,11 à 1,61; p = 0,002). Conclusions: En conclusion, nous avons observé que le score MFHS, qui englobe les facteurs classiques de risque cardiovasculaire, était un facteur prédictif d’un SCC différent de zéro chez les patients atteints de HF. Cette observation semble indiquer que le score MFHS pourrait jouer un rôle dans la détermination du risque cardiovasculaire et, par conséquent, dans l’intensité du traitement chez les patients atteints de HF.

BACKGROUND Leukaemias comprise a heterogenous group of haematological malignancies. In CONCORD-3, we analysed data for children (aged 0-14 years) and adults (aged 15-99 years) diagnosed with a haematological malignancy during 2000-14 in 61 countries. Here, we aimed to examine worldwide trends in survival from leukaemia, by age and morphology, in young patients (aged 0-24 years). METHODS We analysed data from 258 population-based cancer registries in 61 countries participating in CONCORD-3 that submitted data on patients diagnosed with leukaemia. We grouped patients by age as children (0-14 years), adolescents (15-19 years), and young adults (20-24 years). We categorised leukaemia subtypes according to the International Classification of Childhood Cancer (ICCC-3), updated with International Classification of Diseases for Oncology, third edition (ICD-O-3) codes. We estimated 5-year net survival by age and morphology, with 95% CIs, using the non-parametric Pohar-Perme estimator. To control for background mortality, we used life tables by country or region, single year of age, single calendar year and sex, and, where possible, by race or ethnicity. All-age survival estimates were standardised to the marginal distribution of young people with leukaemia included in the analysis. FINDINGS 164 563 young people were included in this analysis: 121 328 (73·7%) children, 22 963 (14·0%) adolescents, and 20 272 (12·3%) young adults. In 2010-14, the most common subtypes were lymphoid leukaemia (28 205 [68·2%] patients) and acute myeloid leukaemia (7863 [19·0%] patients). Age-standardised 5-year net survival in children, adolescents, and young adults for all leukaemias combined during 2010-14 varied widely, ranging from 46% in Mexico to more than 85% in Canada, Cyprus, Belgium, Denmark, Finland, and Australia. Individuals with lymphoid leukaemia had better age-standardised survival (from 43% in Ecuador to ≥80% in parts of Europe, North America, Oceania, and Asia) than those with acute myeloid leukaemia (from 32% in Peru to ≥70% in most high-income countries in Europe, North America, and Oceania). Throughout 2000-14, survival from all leukaemias combined remained consistently higher for children than adolescents and young adults, and minimal improvement was seen for adolescents and young adults in most countries. INTERPRETATION This study offers the first worldwide picture of population-based survival from leukaemia in children, adolescents, and young adults. Adolescents and young adults diagnosed with leukaemia continue to have lower survival than children. Trends in survival from leukaemia for adolescents and young adults are important indicators of the quality of cancer management in this age group. FUNDING Children with Cancer UK, the Institut National du Cancer, La Ligue Contre le Cancer, Centers for Disease Control and Prevention, Swiss Re, Swiss Cancer Research foundation, Swiss Cancer League, Rossy Family Foundation, US National Cancer Institute, and the American Cancer Society.

Background:\ud Greater understanding of international cancer survival differences is needed. We aimed to identify predictors and consequences of cancer diagnosis through emergency presentation in different international jurisdictions in six high-income countries.\ud \ud Methods:\ud Using a federated analysis model, in this cross-sectional population-based study, we analysed cancer registration and linked hospital admissions data from 14 jurisdictions in six countries (Australia, Canada, Denmark, New Zealand, Norway, and the UK), including patients with primary diagnosis of invasive oesophageal, stomach, colon, rectal, liver, pancreatic, lung, or ovarian cancer during study periods from Jan 1, 2012, to Dec 31, 2017. Data were collected on cancer site, age group, sex, year of diagnosis, and stage at diagnosis. Emergency presentation was defined as diagnosis of cancer within 30 days after an emergency hospital admission. Using logistic regression, we examined variables associated with emergency presentation and associations between emergency presentation and short-term mortality. We meta-analysed estimates across jurisdictions and explored jurisdiction-level associations between cancer survival and the percentage of patients diagnosed as emergencies.\ud \ud Findings:\ud In 857 068 patients across 14 jurisdictions, considering all of the eight cancer sites together, the percentage of diagnoses through emergency presentation ranged from 24·0% (9165 of 38 212 patients) to 42·5% (12 238 of 28 794 patients). There was consistently large variation in the percentage of emergency presentations by cancer site across jurisdictions. Pancreatic cancer diagnoses had the highest percentage of emergency presentations on average overall (46·1% [30 972 of 67 173 patients]), with the jurisdictional range being 34·1% (1083 of 3172 patients) to 60·4% (1317 of 2182 patients). Rectal cancer had the lowest percentage of emergency presentations on average overall (12·1% [10 051 of 83 325 patients]), with a jurisdictional range of 9·1% (403 of 4438 patients) to 19·8% (643 of 3247 patients). Across the jurisdictions, older age (ie, 75–84 years and 85 years or older, compared with younger patients) and advanced stage at diagnosis compared with non-advanced stage were consistently associated with increased emergency presentation risk, with the percentage of emergency presentations being highest in the oldest age group (85 years or older) for 110 (98%) of 112 jurisdiction-cancer site strata, and in the most advanced (distant spread) stage category for 98 (97%) of 101 jurisdiction-cancer site strata with available information. Across the jurisdictions, and despite heterogeneity in association size (I2=93%), emergency presenters consistently had substantially greater risk of 12-month mortality than non-emergency presenters (odds ratio >1·9 for 112 [100%] of 112 jurisdiction-cancer site strata, with the minimum lower bound of the related 95% CIs being 1·26). There were negative associations between jurisdiction-level percentage of emergency presentations and jurisdiction-level 1-year survival for colon, stomach, lung, liver, pancreatic, and ovarian cancer, with a 10% increase in percentage of emergency presentations in a jurisdiction being associated with a decrease in 1-year net survival of between 2·5% (95% CI 0·28–4·7) and 7·0% (1·2–13·0).\ud \ud Interpretation:\ud Internationally, notable proportions of patients with cancer are diagnosed through emergency presentation. Specific types of cancer, older age, and advanced stage at diagnosis are consistently associated with an increased risk of emergency presentation, which strongly predicts worse prognosis and probably contributes to international differences in cancer survival. Monitoring emergency presentations, and identifying and acting on contributing behavioural and health-care factors, is a global priority for cancer control.\ud \ud Funding:\ud Canadian Partnership Against Cancer; Cancer Council Victoria; Cancer Institute New South Wales; Cancer Research UK; Danish Cancer Society; National Cancer Registry Ireland; The Cancer Society of New Zealand; National Health Service England; Norwegian Cancer Society; Public Health Agency Northern Ireland, on behalf of the Northern Ireland Cancer Registry; the Scottish Government; Western Australia Department of Health; and Wales Cancer Network.

ObjectivesAs part of the International Cancer Benchmarking Partnership (ICBP) SURVMARK-2 project, we provide the most recent estimates of colon and rectal cancer survival in seven high-income countries by age and stage at diagnosis.MethodsData from 386 870 patients diagnosed during 2010–2014 from 19 cancer registries in seven countries (Australia, Canada, Denmark, Ireland, New Zealand, Norway and the UK) were analysed. 1-year and 5-year net survival from colon and rectal cancer were estimated by stage at diagnosis, age and country,Results(One1-year) and 5-year net survival varied between (77.1% and 87.5%) 59.1% and 70.9% and (84.8% and 90.0%) 61.6% and 70.9% for colon and rectal cancer, respectively. Survival was consistently higher in Australia, Canada and Norway, with smaller proportions of patients with metastatic disease in Canada and Australia. International differences in (1-year) and 5-year survival were most pronounced for regional and distant colon cancer ranging between (86.0% and 94.1%) 62.5% and 77.5% and (40.7% and 56.4%) 8.0% and 17.3%, respectively. Similar patterns were observed for rectal cancer. Stage distribution of colon and rectal cancers by age varied across countries with marked survival differences for patients with metastatic disease and diagnosed at older ages (irrespective of stage).ConclusionsSurvival disparities for colon and rectal cancer across high-income countries are likely explained by earlier diagnosis in some countries and differences in treatment for regional and distant disease, as well as older age at diagnosis. Differences in cancer registration practice and different staging systems across countries may have impacted the comparisons.

Background: Women attending mammography screening units (msus) and well women’s clinics (wwcs) represent a motivated cohort likely to engage in interventions aimed at primary breast cancer (bca) prevention. Methods: We used a feasibility questionnaire distributed to women (40–49 or 50–74 years of age) attending msus and wwcs in Halifax, Nova Scotia, to examine (1) women’s views about bca primary prevention and sources of health care information, (2) prevalence of lifestyle-related bca risk factors, and, (3) predictors of prior mammography encounters within provincial screening guidelines. Variables examined included personal profiling, comorbidities, prior mammography uptake, lifestyle behaviours, socioeconomic status, health information sources, and willingness to discuss or implement lifestyle modifications, or endocrine therapy, or both. A logistic regression analysis examined associations with prior mammography encounters. Results: Of the 244 responses obtained during 1.5 months from women aged 40–49 years (n = 75) and 50–74 years (n = 169), 56% and 75% respectively sought or would prefer to receive health information from within, as opposed to outside, health care. Lifestyle-related bca risk factors were prevalent, and most women were willing to discuss or implement lifestyle modifications (93%) or endocrine therapy (67%). Of the two age groups, 49% and 93% respectively had previously undergone mammography within guidelines. Increasing age and marital status (single, separated, or divorced vs. married or partnered) were independent predictors of prior mammography encounters within guidelines for women 40–49 years of age; no independent predictors were observed in the older age group. Conclusions: Women attending msus and wwcs seem to largely adhere to mammography guidelines and appear motivated to engage in bca primary prevention strategies, including lifestyle modifications and endocrine therapy. Women’s views as observed in this study provide a rationale for the potential incorporation of bca risk assessment within the “mammogram point of care” to engage motivated women in bca primary prevention strategies.

OBJECTIVE: The study aims to evaluate the differences in ovarian cancer survival by age and stage at diagnosis within and across seven high-income countries.METHODS: We analyzed data from 58,161 women diagnosed with ovarian cancer during 2010-2014, followed until 31 December 2015, from 21 population-based cancer registries in Australia, Canada, Denmark, Ireland, New Zealand, Norway, and United Kingdom. Comparisons of 1-year and 3-year age- and stage-specific net survival (NS) between countries were performed using the period analysis approach.RESULTS: Minor variation in the stage distribution was observed between countries, with most women being diagnosed with 'distant' stage (ranging between 64% in Canada and 71% in Norway). The 3-year all-ages NS ranged from 45 to 57% with Australia (56%) and Norway (57%) demonstrating the highest survival. The proportion of women with 'distant' stage was highest for those aged 65-74 and 75-99 years and varied markedly between countries (range:72-80% and 77-87%, respectively). The oldest age group had the lowest 3-year age-specific survival (20-34%), and women aged 65-74 exhibited the widest variation across countries (3-year NS range: 40-60%). Differences in survival between countries were particularly stark for the oldest age group with 'distant' stage (3-year NS range: 12% in Ireland to 24% in Norway).CONCLUSIONS: International variations in ovarian cancer survival by stage exist with the largest differences observed in the oldest age group with advanced disease. This finding endorses further research investigating international differences in access to and quality of treatment, and prevalence of comorbid conditions particularly in older women with advanced disease.

Regular cancer surveillance is crucial for understanding where progress is being made and where more must be done. We sought to provide an overview of the expected burden of cancer in Canada in 2022.We obtained data on new cancer incidence from the National Cancer Incidence Reporting System (1984-1991) and Canadian Cancer Registry (1992-2018). Mortality data (1984-2019) were obtained from the Canadian Vital Statistics - Death Database. We projected cancer incidence and mortality counts and rates to 2022 for 22 cancer types by sex and province or territory. Rates were age standardized to the 2011 Canadian standard population.An estimated 233 900 new cancer cases and 85 100 cancer deaths are expected in Canada in 2022. We expect the most commonly diagnosed cancers to be lung overall (30 000), breast in females (28 600) and prostate in males (24 600). We also expect lung cancer to be the leading cause of cancer death, accounting for 24.3% of all cancer deaths, followed by colorectal (11.0%), pancreatic (6.7%) and breast cancers (6.5%). Incidence and mortality rates are generally expected to be higher in the eastern provinces of Canada than the western provinces.Although overall cancer rates are declining, the number of cases and deaths continues to climb, owing to population growth and the aging population. The projected high burden of lung cancer indicates a need for increased tobacco control and improvements in early detection and treatment. Success in breast and colorectal cancer screening and treatment likely account for the continued decline in their burden. The limited progress in early detection and new treatments for pancreatic cancer explains why it is expected to be the third leading cause of cancer death in Canada.

BACKGROUND: The global burden of pancreatic cancer has steadily increased, while the prognosis after pancreatic cancer diagnosis remains poor. This study aims to compare the stage- and age-specific pancreatic cancer net survival (NS) for seven high-income countries: Australia, Canada, Denmark, Ireland, New Zealand, Norway, and United Kingdom. METHODS: The study included over 35,000 pancreatic cancer cases diagnosed during 2012–2014, followed through 31 December 2015. The stage- and age-specific NS were calculated using the Pohar-Perme estimator. RESULTS: Pancreatic cancer survival estimates were low across all 7 countries, with 1-year NS ranging from 21.1% in New Zealand to 30.9% in Australia, and 3-year NS from 6.6% in the UK to 10.9% in Australia. Most pancreatic cancers were diagnosed with distant stage, ranging from 53.9% in Ireland to 83.3% in New Zealand. While survival differences were evident between countries across all stage categories at one year after diagnosis, this survival advantage diminished, particularly in cases with distant stage. CONCLUSION: This study demonstrated the importance of stage and age at diagnosis in pancreatic cancer survival. Although progress has been made in improving pancreatic cancer prognosis, the disease is highly fatal and will remain so without major breakthroughs in the early diagnosis and management.

ObjectiveTo provide the first international comparison of oesophageal and gastric cancer survival by stage at diagnosis and histological subtype across high-income countries with similar access to healthcare.MethodsAs part of the ICBP SURVMARK-2 project, data from 28 923 patients with oesophageal cancer and 25 946 patients with gastric cancer diagnosed during 2012–2014 from 14 cancer registries in seven countries (Australia, Canada, Denmark, Ireland, New Zealand, Norway and the UK) were included. 1-year and 3-year age-standardised net survival were estimated by stage at diagnosis, histological subtype (oesophageal adenocarcinoma (OAC) and oesophageal squamous cell carcinoma (OSCC)) and country.ResultsOesophageal cancer survival was highest in Ireland and lowest in Canada at 1 (50.3% vs 41.3%, respectively) and 3 years (27.0% vs 19.2%) postdiagnosis. Survival from gastric cancer was highest in Australia and lowest in the UK, for both 1-year (55.2% vs 44.8%, respectively) and 3-year survival (33.7% vs 22.3%). Most patients with oesophageal and gastric cancer had regional or distant disease, with proportions ranging between 56% and 90% across countries. Stage-specific analyses showed that variation between countries was greatest for localised disease, where survival ranged between 66.6% in Australia and 83.2% in the UK for oesophageal cancer and between 75.5% in Australia and 94.3% in New Zealand for gastric cancer at 1-year postdiagnosis. While survival for OAC was generally higher than that for OSCC, disparities across countries were similar for both histological subtypes.ConclusionSurvival from oesophageal and gastric cancer varies across high-income countries including within stage groups, particularly for localised disease. Disparities can partly be explained by earlier diagnosis resulting in more favourable stage distributions, and distributions of histological subtypes of oesophageal cancer across countries. Yet, differences in treatment, and also in cancer registration practice and the use of different staging methods and systems, across countries may have impacted the comparisons. While primary prevention remains key, advancements in early detection research are promising and will likely allow for additional risk stratification and survival improvements in the future.

A good quality of life requires maintaining adequate skeletal muscle mass and strength, but therapeutic agents are lacking for this. We developed a bioassay-guided fractionation approach to identify molecules with hypertrophy-promoting effect in human skeletal muscle cells. We found that extracts from rosemary leaves induce muscle cell hypertrophy. By bioassay-guided purification we identified the phenolic diterpene carnosol as the compound responsible for the hypertrophy-promoting activity of rosemary leaf extracts. We then evaluated the impact of carnosol on the different signaling pathways involved in the control of muscle cell size. We found that activation of the NRF2 signaling pathway by carnosol is not sufficient to mediate its hypertrophy-promoting effect. Moreover, carnosol inhibits the expression of the ubiquitin ligase E3 Muscle RING Finger protein-1 that plays an important role in muscle remodeling, but has no effect on the protein synthesis pathway controlled by the protein kinase B/mechanistic target of rapamycin pathway. By measuring the chymotrypsin-like activity of the proteasome, we found that proteasome activity was significantly decreased by carnosol and Muscle RING Finger 1 inactivation. These results strongly suggest that carnosol can induce skeletal muscle hypertrophy by repressing the ubiquitin-proteasome system-dependent protein degradation pathway through inhibition of the E3 ubiquitin ligase Muscle RING Finger protein-1.

Multifactorial chylomicronemia syndrome (MCS) is a complex disease including a genetic component and the presence of lifestyle-related risk factors. We hypothesized that, in subjects with MCS, there would be a greater decrease in plasma triglycerides (TG) with a low-fat (F) diet than with a low-carbohydrate (C) diet. In secondary analyses, we tested the effect of both diets on TG concentration according to the presence or absence of a rare variant in the LPL gene. This randomized crossover dietary intervention included 12 adult subjects with MCS. Subjects followed 2 isocaloric diets, low-C (C, 35%; F, 45%) and low-F (F, 20%; C, 60%), in random order. Each diet lasted 3 weeks, followed by a 6-hour test meal. Diets were separated by a 2-week washout period. TG concentration in fasting subjects decreased by 55% during low-F diet (P = .002) and by 48% during low-C diet (P = .005). The difference between the 2 diets was not significant. However, we observed a more pronounced decrease in TG concentration (65% ± 17%) with the low-F diet compared with the low-C diet (46% ± 31%) (P = .06) in subjects carrying a rare variant in the LPL gene. This is the first study to show that dietary intervention is effective in MCS subjects. In addition, we highlighted the importance of the genetic profile in the choice of treatment by suggesting that subjects with a rare variant of the LPL gene have a greater reduction of TG concentration with a low-F diet than with a low-C diet.

International audience; A good quality of life requires maintaining adequate skeletal muscle mass and strength, but therapeutic agents are lacking for this. We developed a bioassay-guided fractionation approach to identify molecules with hypertrophy-promoting effect in human skeletal muscle cells. We found that extracts from rosemary leaves induce muscle cell hypertrophy. By bioassay-guided purification we identified the phenolic diterpene carnosol as the compound responsible for the hypertrophypromoting activity of rosemary leaf extracts. We then evaluated the impact of carnosol on the different signaling pathways involved in the control of muscle cell size. We found that activation of the NRF2 signaling pathway by carnosol is not sufficient to mediate its hypertrophy-promoting effect. Moreover, carnosol inhibits the expression of the ubiquitin ligase E3 Muscle RING Finger protein-1 that plays an important role in muscle remodeling, but has no effect on the protein synthesis pathway controlled by the protein kinase B/mechanistic target of rapamycin pathway. By measuring the chymotrypsin-like activity of the proteasome, we found that proteasome activity was significantly decreased by carnosol and Muscle RING Finger 1 inactivation. These results strongly suggest that carnosol can induce skeletal muscle hypertrophy by repressing the ubiquitin-proteasome system-dependent protein degradation pathway through inhibition of the E3 ubiquitin ligase Muscle RING Finger protein-1.

A healthy, intact gut microbiota is often resistant to colonization by gastrointestinal pathogens. During periods of dysbiosis, however, organisms such as Clostridioides difficile can thrive. We describe an optimized in vitro colonization resistance assay for C. difficile in stool (CRACS) and demonstrate the utility of this assay by assessing changes in colonization resistance following antibiotic exposure. Fecal samples were obtained from healthy volunteers (n = 6) and from healthy subjects receiving 5 days of moxifloxacin (n = 11) or no antibiotics (n = 10). Samples were separated and either not manipulated (raw) or sterilized (autoclaved or filtered) prior to inoculation with C. difficile ribotype 027 spores and anaerobic incubation for 72 h. Different methods of storing fecal samples were also investigated in order to optimize the CRACS. In healthy, raw fecal samples, incubation with spores did not lead to increased C. difficile total viable counts (TVCs) or cytotoxin detection. In contrast, increased C. difficile TVCs and cytotoxin detection occurred in sterilized healthy fecal samples or those from antibiotic-treated individuals. The CRACS was functional with fecal samples stored at either 4°C or −80°C but not with those stored with glycerol (12% or 30% [vol/vol]). Our data show that the CRACS successfully models in vitro the loss of colonization resistance and subsequent C. difficile proliferation and toxin production. The CRACS could be used as a proxy for C. difficile infection in clinical studies or to determine if an individual is at risk of developing C. difficile infection or other potential infections occurring due to a loss of colonization resistance.

Background Data from population-based cancer registries are often used to compare cancer survival between countries or regions. The ICBP SURVMARK-2 study is an international partnership aiming to quantify and explore the reasons behind survival differences across high-income countries. However, the magnitude and relevance of differences in cancer survival between countries have been questioned, as it is argued that observed survival variations may be explained, at least in part, by differences in cancer registration practice, completeness and the availability and quality of the respective data sources. Methods As part of the ICBP SURVMARK-2 study, we used a simulation approach to better understand how differences in completeness, the characteristics of those missed and inclusion of cases found from death certificates can impact on cancer survival estimates. Results Bias in 1- and 5-year net survival estimates for 216 simulated scenarios is presented. Out of the investigated factors, the proportion of cases not registered through sources other than death certificates, had the largest impact on survival estimates. Conclusion Our results show that the differences in registration practice between participating countries could in our most extreme scenarios explain only a part of the largest observed differences in cancer survival.

BACKGROUND: Population-based cancer registries strive to cover all cancer cases diagnosed within the population, but some cases will always be missed and no register is 100 % complete. Many cancer registries use death certificates to identify additional cases not captured through other routine sources, to hopefully add a large proportion of the missed cases. Cases notified through this route, who would not have been captured without death certificate information, are referred to as Death Certificate Initiated (DCI) cases. Inclusion of DCI cases in cancer registries increases completeness and is important for estimating cancer incidence. However, inclusion of DCI cases will generally lead to biased estimates of cancer survival, but the same is often also true if excluding DCI cases. Missed cases are probably not a random sample of all cancer cases, but rather cases with poor prognosis. Further, DCI cases have poorer prognosis than missed cases in general, since they have all died with cancer mentioned on the death certificates.METHODS: We performed a simulation study to estimate the impact of including or excluding DCI cases on cancer survival estimates, under different scenarios.RESULTS: We demonstrated that including DCI cases underestimates survival. The exclusion of DCI cases gives unbiased survival estimates if missed cases are a random sample of all cancer cases, while survival is overestimated if these have poorer prognosis.CONCLUSION: In our most extreme scenarios, with 25 % of cases initially missed, the usual practice of including DCI cases underestimated 5-year survival by at most 3 percentage points.

International audience; Lentinus edodes (=Lentinula edodes) is an edible mushroom grown and marketed for centuries due to its nutritional and medicinal properties. L. edodes has multiple pharmacological activities as antioxidant and anti-inflammatory. Few studies were performed taking into account the influence of culture conditions to optimize the biological properties of L. edodes on human health. Our work focused on the comparison of antioxidant capacity and anti-inflammatory activity of L. edodes fruit bodies cultivated by three mushroom producers in the French Occitanie region using the same strain in various growing conditions (orga nic and nonorganic). Sequential extraction was performed on freeze dried fungal materials. All extracts have a quantifiable but moderate antioxidant activity using the DPPH and ORAC tests. The antiinflammatory activity of the ethanol and aqueous extracts was evaluated on a model of inflammatory macrophages. The ethanol extracts inhibit NO production in a dose-dependent manner when the cells are pre-treated for 4 h with a 24 h stimulation time

Arsenic in drinking water impacts health. Highest levels of arsenic have been historically observed in Taiwan and Bangladesh but the contaminant has been affecting the health of people globally. Strong associations have been confirmed between exposure to high-levels of arsenic in drinking water and a wide range of diseases, including cancer. However, at lower levels of exposure, especially near the current World Health Organization regulatory limit (10μg/L), this association is inconsistent as the effects are mostly extrapolated from high exposure studies. This ecological study used Bayesian inference to model the relative risk of bladder and kidney cancer at these lower concentrations—0–2μg/L; 2–5μg/L and; ≥5μg/L of arsenic—in 864 bladder and 525 kidney cancers diagnosed in the study area, Nova Scotia, Canada between 1998 and 2010. The model included proxy measures of lifestyle (e.g. smoking) and accounted for spatial dependencies. Overall, bladder cancer risk was 16% (2–5μg/L) and 18% (≥5μg/L) greater than that of the referent group (

Spatial data on disease incidence locations are often aggregated to regional counts to preserve privacy, and spatio-temporal modelling of such can be problematic when there are boundary changes over the study period. Here an inhomogeneous Poisson process with intensity depending on variations in population (known a priori) and a smoothly varying relative risk is estimated with a local-Expectation–Maximization (or local-EM) algorithm. Using incidence data for male bladder cancer in Nova Scotia, Canada, the question of whether the data are consistent with spatially varying but temporally constant relative risk is examined. Areas where there is evidence that relative risk is substantially greater than 1 are identified with the intention of assessing the possible presence of environmental risk factors. This paper extends existing work by incorporating a temporally varying risk surface and an explicit data structure which contains a mixture of point locations and locations aggregated to non-nested areas. This added flexibility allows the modelling of data amalgamated from different sources and collected over many years. While local-EM leads naturally to an Expectation–Maximization–Smoothing algorithm, the extension to mixtures of aggregations leads to a modified algorithm that includes an additive term at every iteration to account for observed point locations.

The mechanisms underlying ryanodine receptor (RyR) dysfunction associated with Alzheimer disease (AD) are still not well understood. Here, we show that neuronal RyR2 channels undergo post-translational remodeling (PKA phosphorylation, oxidation, and nitrosylation) in brains of AD patients, and in two murine models of AD (3 × Tg-AD, APP +/− /PS1 +/−). RyR2 is depleted of calstabin2 (KFBP12.6) in the channel complex, resulting in endoplasmic reticular (ER) calcium (Ca2+) leak. RyR-mediated ER Ca2+ leak activates Ca2+-dependent signaling pathways, contributing to AD pathogenesis. Pharmacological (using a novel RyR stabilizing drug Rycal) or genetic rescue of the RyR2-mediated intracellular Ca2+ leak improved synaptic plasticity, normalized behavioral and cognitive functions and reduced Aβ load. Genetically altered mice with congenitally leaky RyR2 exhibited premature and severe defects in synaptic plasticity, behavior and cognitive function. These data provide a mechanism underlying leaky RyR2 channels, which could be considered as potential AD therapeutic targets.

Fluoroquinolone treatments induce dysbiosis of the intestinal microbiota, resulting in loss of resistance to colonization by exogenous bacteria such as Clostridioides difficile that may cause severe diarrhea in humans and lethal infection in hamsters. We show here that DAV131A, a charcoal-based adsorbent, decreases the intestinal levels of the fluoroquinolone antibiotics levofloxacin and ciprofloxacin in hamsters, protects their intestinal microbiota, and prevents lethal infection by C. difficile .

© 2019 World Health Organization Background: Population-based cancer survival estimates provide valuable insights into the effectiveness of cancer services and can reflect the prospects of cure. As part of the second phase of the International Cancer Benchmarking Partnership (ICBP), the Cancer Survival in High-Income Countries (SURVMARK-2) project aims to provide a comprehensive overview of cancer survival across seven high-income countries and a comparative assessment of corresponding incidence and mortality trends. Methods: In this longitudinal, population-based study, we collected patient-level data on 3·9 million patients with cancer from population-based cancer registries in 21 jurisdictions in seven countries (Australia, Canada, Denmark, Ireland, New Zealand, Norway, and the UK) for seven sites of cancer (oesophagus, stomach, colon, rectum, pancreas, lung, and ovary) diagnosed between 1995 and 2014, and followed up until Dec 31, 2015. We calculated age-standardised net survival at 1 year and 5 years after diagnosis by site, age group, and period of diagnosis. We mapped changes in incidence and mortality to changes in survival to assess progress in cancer control. Findings: In 19 eligible jurisdictions, 3 764 543 cases of cancer were eligible for inclusion in the study. In the 19 included jurisdictions, over 1995–2014, 1-year and 5-year net survival increased in each country across almost all cancer types, with, for example, 5-year rectal cancer survival increasing more than 13 percentage points in Denmark, Ireland, and the UK. For 2010–14, survival was generally higher in Australia, Canada, and Norway than in New Zealand, Denmark, Ireland, and the UK. Over the study period, larger survival improvements were observed for patients younger than 75 years at diagnosis than those aged 75 years and older, and notably for cancers with a poor prognosis (ie, oesophagus, stomach, pancreas, and lung). Progress in cancer control (ie, increased survival, decreased mortality and incidence) over the study period was evident for stomach, colon, lung (in males), and ovarian cancer. Interpretation: The joint evaluation of trends in incidence, mortality, and survival indicated progress in four of the seven studied cancers. Cancer survival continues to increase across high-income countries; however, international disparities persist. While truly valid comparisons require differences in registration practice, classification, and coding to be minimal, stage of disease at diagnosis, timely access to effective treatment, and the extent of comorbidity are likely the main determinants of patient outcomes. Future studies are needed to assess the impact of these factors to further our understanding of international disparities in cancer survival. Funding: Canadian Partnership Against Cancer; Cancer Council Victoria; Cancer Institute New South Wales; Cancer Research UK; Danish Cancer Society; National Cancer Registry Ireland; The Cancer Society of New Zealand; National Health Service England; Norwegian Cancer Society; Public Health Agency Northern Ireland, on behalf of the Northern Ireland Cancer Registry; The Scottish Government; Western Australia Department of Health; and Wales Cancer Network.

International audience; Quantitative data on fecal shedding of antimicrobial-resistant bacteria are crucial to assess the risk of ansmission from dogs to humans. Our first objective was to investigate the prevalence of quinolone/fluoroquinolone-resistant and beta-lactam-resistant Enterobacteriaceae in dogs in France and Spain. Due to the particular concern about possible transmission of extended-spectrum cephalosporin (ESC)-resistant isolates from dogs to their owners, we characterized the ESBL/pAmpC producers collected from dogs. Rectal swabs from 188 dogs, without signs of diarrhea and that had not received antimicrobials for 4 weeks before the study, were quantified for total and resistant Enterobacteriaceae on selective media alone or containing relevant antibiotic concentrations. Information that might explain antibiotic resistance was collected for each dog. Extended-spectrum cephalosporin-resistant isolates were subjected to bacterial species identification (API20E), genetic lineage characterization (MLST), ESBL/pAmpC genes identification (sequencing), and plasmid characterization (pMLST). Regarding beta-lactam resistance, amoxicillin- (AMX) and cefotaxime- (CTX) resistant Enterobacteriaceae were detected in 70 and 18% of the dogs, respectively, whereas for quinolone/fluoroquinolone-resistance, Nalidixic acid- (NAL) and ciprofloxacin- (CIP) resistant Enterobacteriaceae were detected in 36 and 18% of the dogs, respectively. Medical rather than preventive consultation was a risk marker for the presence of NAL and CIP resistance. CTX resistance was mainly due to a combination of specific ESBL/pAmpC genes and particular conjugative plasmids already identified in human patients: bla(CTX-M-1)/IncI1/ST3 (n = 4), bla(CMY-2)/IncI1/ST12 (n = 2), and bla(CTX-M-15)/IncI1/ST31 (n = 1). bla(SHV-12) ( n = 3) was detected in various plasmid lineages (InI1/ST3, IncI1/ST26, and IncFII). ESBL/pAmpC plasmids were located in different genetic lineages of E coil, with the exception of two strains in France (ST6998) and two in Spain (ST602). Our study highlights dogs as a potential source of Q/FQ-resistant and ESBL/pAmpC-producing bacteria that might further disseminate to humans, and notably a serious risk of future acquisition of CTX-M-1 and CMY-2 plasmids by the owners of dogs.

Background Aminopenicillins with or without a β-lactamase inhibitor are widely used in both human and veterinary medicine. However, little is known about their differential impact on the gut microbiota and development of antimicrobial resistance. Objectives To investigate changes in the faecal microbiota of dogs treated with amoxicillin or amoxicillin/clavulanic acid. Methods Faeces collected from 42 dogs (21 per treatment group) immediately before, during and 1 week after termination of oral treatment with amoxicillin or amoxicillin/clavulanic acid were analysed by culture and 16S rRNA gene sequence analysis. Results In both groups, bacterial counts on ampicillin selective agar revealed an increase in the proportion of ampicillin-resistant Escherichia coli during treatment, and an increased occurrence and proportion of ampicillin-resistant enterococci during and after treatment. 16S rRNA gene analysis showed reductions in microbial richness and diversity during treatment followed by a return to pre-treatment conditions approximately 1 week after cessation of amoxicillin or amoxicillin/clavulanic acid treatment. While no significant differences were observed between the effects of amoxicillin and amoxicillin/clavulanic acid on microbial richness and diversity, treatment with amoxicillin/clavulanic acid reduced the abundance of taxa that are considered part of the beneficial microbiota (such as Roseburia, Dialister and Lachnospiraceae) and enriched Escherichia, although the latter result was not corroborated by phenotypic counts. Conclusions Our results suggest a limited effect of clavulanic acid on selection of antimicrobial resistance and microbial richness when administered orally in combination with amoxicillin. However, combination with this β-lactamase inhibitor appears to broaden the spectrum of amoxicillin, with potential negative consequences on gut health.

Summary Background The overall incidence of colorectal cancer is decreasing in many high-income countries, yet analyses in the USA and other high-income countries such as Australia, Canada, and Norway have suggested increasing incidences among adults younger than 50 years. We aimed to examine longitudinal and generational changes in the incidence of colon and rectal cancer in seven high-income countries. Methods We obtained data for the incidence of colon and rectal cancer from 20 population-based cancer registries in Australia, Canada, Denmark, Norway, New Zealand, Ireland, and the UK for the earliest available year until 2014. We used age–period–cohort modelling to assess trends in incidence by age group, period, and birth cohort. We stratified cases by tumour subsite according to the 10th edition of the International Classification of Diseases. Age-standardised incidences were calculated on the basis of the world standard population. Findings An overall decline or stabilisation in the incidence of colon and rectal cancer was noted in all studied countries. In the most recent 10-year period for which data were available, however, significant increases were noted in the incidence of colon cancer in people younger than 50 years in Denmark (by 3·1%; per year), New Zealand (2·9% per year), Australia (2·9% per year), and the UK (1·8% per year). Significant increases in the average annual percentage change in the incidence of rectal cancer were also noted in this age group in Canada (by 3·4% per year), Australia (2·6% per year), and the UK (1·4% per year). Contemporaneously, in people aged 50–74 years, the average annual percentage change in the incidence of colon cancer decreased significantly in Australia (by 1·6% per year), Canada (1·9% per year), and New Zealand (3·4% per year) and of rectal cancer in Australia (2·4% per year), Canada (1·2% per year), and the UK (1·2% per year). Increases in the incidence of colorectal cancer in people younger than 50 years were mainly driven by increases in distal (left) tumours of the colon. In all countries, we noted non-linear cohort effects, which were more pronounced for rectal than for colon cancer. Interpretation We noted a substantial increase in the incidence of colorectal cancer in people younger than 50 years in some of the countries in this study. Future studies are needed to establish the root causes of this rising incidence to enable the development of potential preventive and early-detection strategies. Funding Canadian Partnership Against Cancer, Cancer Council Victoria, Cancer Institute New South Wales, Cancer Research UK, Danish Cancer Society, National Cancer Registry Ireland, the Cancer Society of New Zealand, NHS England, Norwegian Cancer Society, Public Health Agency Northern Ireland, Scottish Government, Western Australia Department of Health, and Wales Cancer Network.

International audience; The mechanical and cellular relationships between systole and diastole during left ventricular (LV) dysfunction remain to be established. LV contraction-relaxation coupling was examined during LV hypertrophy induced by chronic hypertension. Chronically instrumented pigs received angiotensin II infusion for4weeks to induce chronic hypertension (133 ± 7 mmHg vs 98 ± 5 mmHg for mean arterial pressure at Day 28 vs 0, respectively) and LV hypertrophy. LV function was investigated with the instrumentation and echocardiography for LV twist-untwist assessment before and after dobutamine infusion. The cellular mechanisms were investigated by exploring the intracellular Ca2+ handling. At Day 28, pigs exhibited LV hypertrophy with LV diastolic dysfunction (impaired LV isovolumic relaxation, increased LV end-diastolic pressure, decreased and delayed LV untwisting rate) and LV systolic dysfunction (impaired LV isovolumic contraction and twist) although LV ejection fraction was preserved. Isolated cardiomyocytes exhibited altered shortening and lengthening. Interestingly, contraction-relaxation coupling remained preserved both in vivo and in vitro during LV hypertrophy. LV systolic and diastolic dysfunctions were associated to post-translational remodeling and dysfunction of the type 2 cardiac ryanodine receptor/Ca2+ release channel (RyR2), i.e., PKA hyperphosphorylation of RyR2, depletion of calstabin 2 (FKBP12.6), RyR2 leak and hypersensitivity of RyR2 to cytosolic Ca2+ during both contraction and relaxation phases. In conclusion, LV contraction-relaxation coupling remained preserved during chronic hypertension despite LV systolic and diastolic dysfunctions. This implies that LV diastolic dysfunction is accompanied by LV systolic dysfunction. At the cellular level, this is linked to sarcoplasmic reticulum Ca2+ leak through PKA-mediated RyR2 hyperphosphorylation and depletion of its stabilizing partner.