Assessing predicted age-specific breast cancer mortality rates in 27 Europea countries by 2020

Background: We assessed differences in predicted breast cancer (BC) mortality rates, across Europe, by 2020, taking into account changes in the time trends of BC mortality rates during the period 2000-2010. Methods: BC mortality data, for 27 European Union (EU) countries, were extracted from the World Health Organization mortality database. First, we compared BC mortality data between time periods 2000-2004 and 2006-2010 through standardized mortality ratios (SMRs) and carrying out a graphical assessment of the age-specific rates. Second, making use of the base period 2006-2012, we predicted BC mortality rates by 2020. Finally, making use of the SMRs and the predicted data, we identified a clustering of countries, assessing differences in the time trends between the areas defined in this clustering. Results: The clustering approach identified two clusters of countries: the first cluster were countries where BC predicted mortality rates, in 2020, might slightly increase among women aged 69 and older compared with 2010 [Greece (SMR 1.01), Croatia (SMR 1.02), Latvia (SMR 1.15), Poland (SMR 1.14), Estonia (SMR 1.16), Bulgaria (SMR 1.13), Lithuania (SMR 1.03), Romania (SMR 1.13) and Slovakia (SMR 1.06)]. The second cluster was those countries where BC mortality rates level off or decrease in all age groups (remaining countries). However, BC mortality rates between these clusters might diminish and converge to similar figures by 2020. Conclusions: For the year 2020, our predictions have shown a converging pattern of BC mortality rates between European regions. Reducing disparities, in access to screening and treatment, could have a substantial effect in countries where a non-decreasing trend in age-specific BC mortality rates has been predicted

GCAT|Genomes for life: a prospective cohort study of the genomes of Catalonia

PURPOSE: The prevalence of chronic non-communicable diseases (NCDs) is increasing worldwide. NCDs are the leading cause of both morbidity and mortality, and it is estimated that by 2030, they will be responsible for 80% of deaths across the world. The Genomes for Life (GCAT) project is a long-term prospective cohort study that was designed to integrate and assess the role of epidemiological, genomic and epigenomic factors in the development of major chronic diseases in Catalonia, a north-east region of Spain. PARTICIPANTS: At the end of 2017, the GCAT Study will have recruited 20 000 participants aged 40-65 years. Participants who agreed to take part in the study completed a self-administered computer-driven questionnaire, and underwent blood pressure, cardiac frequency and anthropometry measurements. For each participant, blood plasma, blood serum and white blood cells are collected at baseline. The GCAT Study has access to the electronic health records of the Catalan Public Healthcare System. Participants will be followed biannually at least 20 years after recruitment. FINDINGS TO DATE: Among all GCAT participants, 59.2% are women and 83.3% of the cohort identified themselves as Caucasian/white. More than half of the participants have higher education levels, 72.2% are current workers and 42.1% are classified as overweight (body mass index ≥25 and <30 kg/m2). We have genotyped 5459 participants, of which 5000 have metabolome data. Further, the whole genome of 808 participants will be sequenced by the end of 2017. FUTURE PLANS: The first follow-up study started in December 2017 and will end by March 2018. Residences of all subjects will be geocoded during the following year. Several genomic analyses are ongoing, and metabolomic and genomic integrations will be performed to identify underlying genetic variants, as well as environmental factors that influence metabolites

Effect of a gum-based thickener on the safety of swallowing in patients with poststroke oropharyngeal dysphagia

Altres ajuts: This work has been supported by Danone Nutricia Research, Fundació Salut del Consorci Sanitari del Maresme, Furega (Fundació per a la Recerca en Gastroenterologia) and Centro de Investigación en Red en Enfermedades Hepáticas y Digestivas (CIBERehd).Background: Increasing viscosity with thickening agents is a valid therapeutic strategy for oropharyngeal dysphagia (OD). To assess the therapeutic effect of a xanthan gum-based thickener (Nutilis Clear) at six viscosities compared with thin liquid in poststroke OD (PSOD) patients. Methods: A total of 120 patients with PSOD were studied in this controlled, multiple-dose, fixed-order, and single-blind study using videofluoroscopy (VFSS). A series of boluses of 10 mL thin liquid and 2000, 1400, 800, 450, 250, and 150 mPa s viscosities were given in duplicate, interrupted in case of aspiration. We assessed the safety and efficacy of swallow and the kinematics of the swallow response. Key Results: A total of 41.2% patients had safe swallow at thin liquid which significantly increased for all viscosities from 71.9% at 150 mPa s to 95.6% at 1400 mPa s (P <.001). PAS score (3.7 ± 2.3) at thin liquid was also reduced by increasing bolus viscosity (P <.001). The prevalence of patients with aspiration at thin liquid was 17.5% and decreased at all viscosities (P <.01), except at 150 mPa s. Increasing viscosity shortened time to laryngeal vestibule closure (LVC) at all viscosities (P <.01) and reduced bolus velocity at ≥450 mPa s (P <.05). The prevalence of patients with pharyngeal residue at each viscosity 37.7%-44.7% was similar to that at thin liquid (41.2%). Conclusions and Inferences: The prevalence of unsafe swallow with thin liquids is very high in PSOD. Increasing shear bolus viscosity with this xanthan gum-based thickener significantly increased the safety of swallow in patients with PSOD in a viscosity-dependent manner without increasing the prevalence of pharyngeal residue

Phosphorylation at Ser-181 of oncogenic KRAS is required for tumor growth

KRAS phosphorylation has been reported recently to modulate the activity of mutant KRAS protein in vitro. In this study, we defined S181 as a specific phosphorylation site required to license the oncogenic function of mutant KRAS in vivo. The phosphomutant S181A failed to induce tumors in mice, whereas the phosphomimetic mutant S181D exhibited an enhanced tumor formation capacity, compared with the wild-type KRAS protein. Reduced growth of tumors composed of cells expressing the nonphosphorylatable KRAS S181A mutant was correlated with increased apoptosis. Conversely, increased growth of tumors composed of cells expressing the phosphomimetic KRAS S181D mutant was correlated with increased activation of AKT and ERK, two major downstream effectors of KRAS. Pharmacologic treatment with PKC inhibitors impaired tumor growth associated with reduced levels of phosphorylated KRAS and reduced effector activation. In a panel of human tumor cell lines expressing various KRAS isoforms, we showed that KRAS phosphorylation was essential for survival and tumorigenic activity. Furthermore, we identified phosphorylated KRAS in a panel of primary human pancreatic tumors. Taken together, our findings establish that KRAS requires S181 phosphorylation to manifest its oncogenic properties, implying that its inhibition represents a relevant target to attack KRAS-driven tumors

GCAT|Genomes for life : A prospective cohort study of the genomes of Catalonia

The prevalence of chronic non-communicable diseases (NCDs) is increasing worldwide. NCDs are the leading cause of both morbidity and mortality, and it is estimated that by 2030, they will be responsible for 80% of deaths across the world. The Genomes for Life (GCAT) project is a long-term prospective cohort study that was designed to integrate and assess the role of epidemiological, genomic and epigenomic factors in the development of major chronic diseases in Catalonia, a north-east region of Spain. Participants At the end of 2017, the GCAT Study will have recruited 20 000 participants aged 40-65 years. Participants who agreed to take part in the study completed a self-administered computer-driven questionnaire, and underwent blood pressure, cardiac frequency and anthropometry measurements. For each participant, blood plasma, blood serum and white blood cells are collected at baseline. The GCAT Study has access to the electronic health records of the Catalan Public Healthcare System. Participants will be followed biannually at least 20 years after recruitment. Findings to date Among all GCAT participants, 59.2% are women and 83.3% of the cohort identified themselves as Caucasian/white. More than half of the participants have higher education levels, 72.2% are current workers and 42.1% are classified as overweight (body mass index ≥25 and <30 kg/m 2). We have genotyped 5459 participants, of which 5000 have metabolome data. Further, the whole genome of 808 participants will be sequenced by the end of 2017. Future plans The first follow-up study started in December 2017 and will end by March 2018. Residences of all subjects will be geocoded during the following year. Several genomic analyses are ongoing, and metabolomic and genomic integrations will be performed to identify underlying genetic variants, as well as environmental factors that influence metabolites

Human Embryonic Stem Cell Derived Hepatocyte-Like Cells as a Tool for In Vitro Hazard Assessment of Chemical Carcinogenicity

Hepatocyte-like cells derived from the differentiation of human embryonic stem cells (hES-Hep) have potential to provide a human relevant in vitro test system in which to evaluate the carcinogenic hazard of chemicals. In this study, we have investigated this potential using a panel of 15 chemicals classified as noncarcinogens, genotoxic carcinogens, and nongenotoxic carcinogens and measured whole-genome transcriptome responses with gene expression microarrays. We applied an ANOVA model that identified 592 genes highly discriminative for the panel of chemicals. Supervised classification with these genes achieved a cross-validation accuracy of > 95%. Moreover, the expression of the response genes in hES-Hep was strongly correlated with that in human primary hepatocytes cultured in vitro. In order to infer mechanistic information on the consequences of chemical exposure in hES-Hep, we developed a computational method that measures the responses of biochemical pathways to the panel of treatments and showed that these responses were discriminative for the three toxicity classes and linked to carcinogenesis through p53, mitogen-activated protein kinases, and apoptosis pathway modules. It could further be shown that the discrimination of toxicity classes was improved when analyzing the microarray data at the pathway level. In summary, our results demonstrate, for the first time, the potential of human embryonic stem cell--derived hepatic cells as an in vitro model for hazard assessment of chemical carcinogenesis, although it should be noted that more compounds are needed to test the robustness of the assay

Ten-Year Probabilities of Death Due to Cancer and Cardiovascular Disease among Breast Cancer Patients Diagnosed in North-Eastern Spain

Mortality from cardiovascular disease (CVD), second tumours, and other causes is of clinical interest in the long-term follow-up of breast cancer (BC) patients. Using a cohort of BC patients (N = 6758) from the cancer registries of Girona and Tarragona (north-eastern Spain), we studied the 10-year probabilities of death due to BC, other cancers, and CVD according to stage at diagnosis and hormone receptor (HR) status. Among the non-BC causes of death (N = 720), CVD (N = 218) surpassed other cancers (N = 196). The BC cohort presented a significantly higher risk of death due to endometrial and ovarian cancers than the general population. In Stage I, HR- patients showed a 1.72-fold higher probability of all-cause death and a 6.11-fold higher probability of breast cancer death than HR+ patients. In Stages II-III, the probability of CVD death (range 3.11% to 3.86%) surpassed that of other cancers (range 0.54% to 3.11%). In Stage IV patients, the probability of death from any cancer drove the mortality risk. Promoting screening and preventive measures in BC patients are warranted, since long-term control should encompass early detection of second neoplasms, ruling out the possibility of late recurrence. In patients diagnosed in Stages II-III at an older age, surveillance for preventing late cardiotoxicity is crucial

Excess mortality among breast cancer patients in early stages in Tarragona and Gerona

Objetivo: analizar la supervivencia poblacional del cáncer de mama (CM) en estadios precoces, estimando la tendencia temporal del exceso de mortalidad (EM) a largo plazo en periodos anuales y quinquenales, y determinando, si es posible, una proporción de pacientes que puedan considerarse curadas. Método: Se incluyó la cohorte de pacientes diagnosticadas de CM en estadios I y II antes de los 60 anos de edad en Gerona y Tarragona (N = 2453). Se calcularon la supervivencia observada (SO) y la supervivencia relativa (SR) al CM hasta los 20 aaños de seguimiento. Para valorar el EM se estimó la SR a intervalos anuales (SRI) y quinquenales (SR5). Los resultados se presentan por grupos de edad (≤49 y 50-59), estadio (I/II) y periodo de diagnóstico (1985-1994 y 1995-2004). Resultados: en el estadio I, la SO y la SR fueron mayores en 1995-2004 que en 1985-1994: 3,5% a los 15 años de seguimiento y 4,5% a los 20 años. La SO superó el 80% en el estadio I y se mantuvo inferior al 70% en el estadio II. Sin embargo, el EM a largo plazo no desapareció (SRI <1) independientemente del grupo de edad, el estadio y el periodo de diagnóstico. A los 15 años de seguimiento, el EM a 5 años osciló entre el 1-5% en el estadio I (SR5 ≥0,95) y el 5-10% en el estadio II. Conclusiones: En nuestra cohorte, a los 15 años de seguimiento se detectó que el EM anual no desapareció y el quinquenal fue del 1-10%. Por ello, no se pudo determinar una proporción de curación del CM durante el periodo de estudio

Using population-based data to evaluate the impact of adherence to endocrine therapy on survival in breast cancer through the web-application BreCanSurvPred

We show how the use and interpretation of population-based cancer survival indicators can help oncologists talk with breast cancer (BC) patients about the relationship between their prognosis and their adherence to endocrine therapy (ET). The study population comprised a population-based cohort of estrogen receptor positive BC patients (N = 1268) diagnosed in Girona and Tarragona (Northeastern Spain) and classified according to HER2 status (+ / -), stage at diagnosis (I/II/III) and five-year cumulative adherence rate (adherent > 80%; non-adherent <= 80%). Cox regression analysis was performed to identify significant prognostic factors for overall survival, whereas relative survival (RS) was used to estimate the crude probability of death due to BC (PBC). Stage and adherence to ET were the significant factors for predicting all-cause mortality. Compared to stage I, risk of death increased in stage II (hazard ratio [HR] 2.24, 95% confidence interval [CI]: 1.51-3.30) and stage III (HR 5.11, 95% CI 3.46-7.51), and it decreased with adherence to ET (HR 0.57, 95% CI 0.41-0.59). PBC differences were higher in non-adherent patients compared to adherent ones and increased across stages: stage I: 6.61% (95% CI 0.05-13.20); stage II: 9.77% (95% CI 0.59-19.01), and stage III: 22.31% (95% CI 6.34-38.45). The age-adjusted survival curves derived from this modeling were implemented in the web application BreCanSurvPred (https://pdocomputation.snpstats.net/BreCanSurvPred). Web applications like BreCanSurvPred can help oncologists discuss the consequences of non-adherence to prescribed ET with patients