Occupational exposure to pesticides and endometrial cancer in the Screenwide case-control study.

BACKGROUND: Endometrial cancer is the most common gynaecological tumour in developed countries and disease burden is expected to increase over the years. Identifying modifiable risk factors may help developing strategies to reduce the expected increasing incidence of these neoplasms. OBJECTIVE: This study evaluates the association between occupational exposure to pesticides and endometrial cancer using data from a recent case-control study in Spain. METHODS: The analyses included data from 174 consecutive incident endometrial cancer cases and 216 hospital controls frequency-matched by age. Data were collected through structured epidemiological questionnaires and exposure to pesticides was assessed using a Spanish job-exposure matrix (MatEmESp). RESULTS: Overall, 12% of controls and 18% of cases were occupationally exposed to pesticides. We observed a positive association between occupational exposure to pesticides and endometrial cancer (OR = 2.08; 95% CI = 1.13-3.88 compared to non-exposed). In general, exposures that occurred farther in the past were significantly associated with endometrial cancer. Exposure to insecticides, fungicides and herbicides were positively associated with endometrial cancer (OR = 2.08; 95% CI = 1.13-3.88, OR = 4.40; 95% CI = 1.65-13.33, and OR = 5.25; 95% CI = 1.84-17.67, respectively). The agricultural, poultry and livestock activities scenario was associated with endometrial cancer (OR = 4.16; 95% CI = 1.59-12.32), while the cleaning exposure scenario was not (OR = 1.22; 95% CI = 0.55-2.67). CONCLUSIONS: Assessment of occupational exposure to pesticides assessed using a Spanish job-exposure matrix revealed a positive association with endometrial cancer. The elucidation of the role of pesticide compounds on endometrial cancer should shed a light on the aetiology of this tumour.

Cambios en parámetros masticatorios con prótesis parcial removible para dientes posteriores perdidos / Changes in masticatory parameters with removable partial dentures for missing posterior teeth

Introducción: el reemplazo de dientes perdidos aspira a mejorar la función masticatoria. Aunque hay diferentes opciones para ello, la conveniencia de la prótesis parcial removible (PPR) es su bajo costo. Objetivo: comparar el desempeño masticatorio (DM) después de 20 ciclos masticatorios y al umbral de la deglución (UD) en adultos de 50 a 70 años con dientes posteriores perdidos (DPP), con/sin PPR; y los ciclos hasta la deglución. Material y métodos: estudio transversal en 35 adultos con dientes anteriores y PPR bien ajustadas y utilizadas para comer. El lado de prueba fue el lado con más DPP. El DM se evaluó después de 20 ciclos y al UD utilizando un alimento prueba artificial (Optosil Comfort®) con/sin la PPR en orden aleatorizado. Las partículas se tamizaron para determinar el tamaño medio de partícula (TMP) como medida del DM. Los ciclos se contaron visualmente. Estadística descriptiva y comparaciones con SPSS-v23. Resultados: hubo diferencias significativas (p ≤ 0.05) al masticar con/sin PPR. El TMP fue más pequeño (mejor DM) con la PPR después de 20 ciclos y al UD (3.9 vs 4.4 mm y 3.2 vs 4.2 mm). Los ciclos para llegar al UD disminuyeron con la PPR (40 vs 47). Conclusión: a pesar de una mejora limitada de la función masticatoria, las PPR ayudan a preparar los alimentos en partículas más pequeñas antes de deglutirlas. La mejoría en DM con PPR es de 24% al UD, realizando menos ciclos antes de deglutir sus alimentos (AU)

Introduction: replacement of missing teeth should improve masticatory function. Although there are different options removable partial dentures (RPD) are used due to their lower cost. Objective: to compare masticatory performance (MP) after 20 chewing-cycles and swallowing-threshold (ST) in 50-70 year-old adults with missing posterior teeth (MPT) with and without their cast-metal RPD; chewing cycles until swallowing were also compared. Material and methods: 35 adults participated in this cross-sectional study. Subjects with anterior teeth and welladjusted RPDs, used for eating were included. The side with more MPT was selected as the test side. MP was evaluated after 20 cycles and ST using an artificial test-food (Optosil Comfort®) with/without the RPD (subject-own-control) (randomized order). Chewed particles were sieved to determine medium-particle-size (MPS) as a measure of MP. Chewing cycles were visually counted. Descriptive statistics and comparisons were run with SPSS v23. Results: there were significant differences (p ≤ 0.05) for all parameters when chewing with/without the RPD. MPS was smaller (better MP) with the RPD (3.9 vs 4.4 mm and 3.2 vs 4.2 mm) after 20 cycles and ST respectively. Cycles required to reach ST were less when chewing with the denture (40 vs 47). Conclusion: despite a limited improvement of masticatory function RPDs help patients prepare their food into smaller particles before swallowing. Improvement in MP with RPDs for patients with MPT is 24% at ST and they perform fewer chewing cycles before swallowing food (AU)

Adherence to Pro-Vegetarian Food Patterns and Risk of Oesophagus, Stomach, and Pancreas Cancers: A Multi Case-Control Study (The PANESOES Study).

We aimed to evaluate the association between three previously defined pro-vegetarian (PVG) food patterns and the cancers of the oesophagus, stomach, and pancreas in a multi case-control study. We analyzed data from a multi-case hospital-based study carried out in two Mediterranean provinces in Spain. A total of 1233 participants were included in the analyses: 778 incident cancer cases, histologically confirmed (199 oesophagus, 414 stomach, and 165 pancreas) and 455 controls. A dietary assessment was performed using a validated food frequency questionnaire (FFQ). Three PVG food patterns (general, healthful, and unhealthful) were estimated using 12 food groups for the general PVG (gPVG), scoring positive plant-based foods and negative animal-based foods, and 18 food groups, for the healthful (hPVG) and unhealthful (uPVG) food patterns. Multinomial logistic regression was used to estimate relative risk ratios (RRR) and confidence intervals (95% CI) for quintiles of adherence to PVG patterns and as a continuous variable. The RRR (95% CI) for the highest vs. the lowest quintile of gPVG were, RRR = 0.37 (0.32, 0.42) for the oesophagus, RRR = 0.34 (0.27, 0.43) for the stomach, and RRR = 0.43 (0.35, 0.52) for pancreas cancer. For the hPVG, the RRR were RRR = 0.72 (0.58, 0.90) for the oesophagus, RRR = 0.42 (0.34, 0.52) for the stomach, and RRR = 0.74 (0.59, 0.92) for pancreas cancer. The uPVG was associated with a higher risk of stomach cancer RRR = 1.76 (1.42, 2.18). Higher adherence to gPVG and hPVG food patterns is associated with a lower risk of oesophageal, stomach, and pancreas cancers, while a higher adherence to a uPVG food pattern is associated with a higher risk of stomach cancer.

Occupational Heat Exposure and Breast Cancer Risk in the MCC-Spain Study.

BACKGROUND: Mechanisms linking occupational heat exposure with chronic diseases have been proposed. However, evidence on occupational heat exposure and cancer risk is limited. METHODS: We evaluated occupational heat exposure and female breast cancer risk in a large Spanish case-control study. We enrolled 1,738 breast cancer cases and 1,910 frequency-matched population controls. A Spanish job-exposure matrix, MatEmEsp, was used to assign estimates of the proportion of workers exposed (P ≥ 25% for at least 1 year) and work time with heat stress (wet bulb globe temperature ISO 7243) for each occupation. We used three exposure indices: ever versus never exposed, lifetime cumulative exposure, and duration of exposure (years). We estimated ORs and 95% confidence intervals (CI), applying a lag period of 5 years and adjusting for potential confounders. RESULTS: Ever occupational heat exposure was associated with a moderate but statistically significant higher risk of breast cancer (OR 1.22; 95% CI, 1.01-1.46), with significant trends across categories of lifetime cumulative exposure and duration (P trend = 0.01 and 0.03, respectively). Stronger associations were found for hormone receptor-positive disease (OR ever exposure = 1.38; 95% CI, 1.12-1.67). We found no confounding effects from multiple other common occupational exposures; however, results attenuated with adjustment for occupational detergent exposure. CONCLUSIONS: This study provides some evidence of an association between occupational heat exposure and female breast cancer risk. IMPACT: Our results contribute substantially to the scientific literature. Further investigations are needed considering multiple occupational exposures.

Occupational Exposure to Pesticides and Chronic Lymphocytic Leukaemia in the MCC-Spain Study.

We aimed to study the association between occupational exposure to pesticides and chronic lymphocytic leukemia (CLL) in Spain. Occupational exposure to pesticides (four insecticides, four herbicides and two fungicides) was evaluated using a job-exposure matrix for the Spanish population (MatEmESp) among 302 CLL cases and 1567 population controls in five regions of Spain, 2010-2013. Cumulative exposure scores (CES) were obtained by summing across the exposed jobs the product of prevalence, intensity and duration of exposure to each active substance. Principal components analysis (PCA) and logistic regression models adjusted for age, sex, region, education and occupational exposure to solvents were used. Around 20% of controls and 29% of cases were exposed to one or more pesticides. Compared to non-exposed, subjects in the highest tertile (3rd tertile) of CES of insecticides, herbicides, fungicides were more likely to have CLL [OR (95% CI), P-trend; 2.10 (1.38; 3.19), 0.002; 1.77 (1.12; 2.80), 0.12; and 1.67 (1.06; 2.64), 0.10, respectively). Following PCA, the first component (PC1, explaining 70% of the variation) equally led by seven active substances (the insecticide pyrethrin, all herbicides, all fungicides) was associated with a 26% higher odds of having CLL for 1-standard deviation increase in PC1 (95% CI: 1.14 to 1.40). These results confirm previous associations between CLL and exposure to pesticides and provide additional evidence by application groups and active substance. However, more research is needed to disentangle independent effects of individual active substances.

Association of Human Papillomavirus Genotype 16 Viral Variant and Viral Load with Cervical High-grade Intraepithelial Lesions.

Human papillomavirus genotype 16 (HPV16) is by far the genotype most strongly associated with cervical cancer; viral variant and/or viral load of HPV16 could modulate this association. The objective was to determine the association between the viral variant and viral load of HPV16 and the presence of cervical high-grade lesions. This cross-sectional study included all women in whom HPV infection was found by cervical smear during routine gynecologic health checks. Women with single or multiple HPV16 infections (n = 176) were selected for viral variant and viral load analysis. Smear results were classified using the Bethesda system. HPV types were classified according to the International Agency for Research on Cancer. Odds ratios (OR) with their 95% confidence intervals (CI) were estimated by logistic regression, adjusted for age, immigrant status, and coinfection with other high-risk genotypes. No statistically significant associations were found regarding the detected viral variants. A viral load above the median (>1,367.79 copies/cell) was associated with a significant risk of high-grade epithelial lesion or carcinoma, after adjusting for age, immigrant status, coinfections, and viral variant: (adjusted OR 7.89; 95% CI: 2.75-22.68). This relationship showed a statistically significant dose-response pattern after categorizing by viral load tertiles: adjusted OR for a viral load greater than the third tertile was 17.23 (95% CI: 4.20-70.65), with adjusted linear P trend = 0.001. In patients infected with HPV16, viral load is associated with high-grade intraepithelial lesions or cervical carcinoma. This could be useful as prognostic biomarker of neoplastic progression and as screening for cervical cancer.

Vitamin D binding protein, but not vitamin D or vitamin D-related peptides, is associated with septic shock mortality.

BACKGROUND: The aim of this study was to assess the prognostic value of vitamin D, vitamin D binding protein (VDBP) and vitamin D-related peptides in septic shock patients in relation to hospital mortality. METHODS: This is a single-center, prospective, observational study that included all consecutive patients meeting criteria for septic shock who were admitted to the ICU. VDBP, 25-hydroxy vitamin D, 1,25-dihydroxy vitamin D, cathelicidin and beta-defensin levels were determined in blood samples obtained on admission to the ICU. RESULTS: Seventy-five patients were studied. The best area under the curve (AUC) for prediction of in-hospital mortality was for VDBP (0.78), with a negative predictive value of 85.45% for the optimal cut-off point. VDBP was also the only variable that had a statistically significant association with a higher risk of in-hospital mortality, regardless of other assessed variables and pre-determined confounders: adjusted odds ratio of 5.20 (95% confidence interval: 1.21-22.36). When restricted to patients with vitamin D insufficiency (n=54), the AUC was 0.77, and the adjusted OR 12.22 (95% CI: 1.46-102.14; p=0.021) for in-hospital mortality. CONCLUSIONS: VDBP levels showed a statistically significant association with in-hospital mortality, supporting the clinical utility of VDBP as a good prognostic marker in septic shock patients. Vitamin D and vitamin D-related peptides are not associated with in-hospital mortality. These results should be confirmed in a multicentre study with a larger sample size.

Applied diagnostics in liver cancer. Efficient combinations of sorafenib with targeted inhibitors blocking AKT/mTOR.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide. There is increasing interest in developing specific markers to serve as predictors of response to sorafenib and to guide targeted therapy. Using a sequencing platform designed to study somatic mutations in a selection of 112 genes (HepatoExome), we aimed to characterize lesions from HCC patients and cell lines, and to use the data to study the biological and mechanistic effects of case-specific targeted therapies used alone or in combination with sorafenib. We characterized 331 HCC cases in silico and 32 paired samples obtained prospectively from primary tumors of HCC patients. Each case was analyzed in a time compatible with the requirements of the clinic (within 15 days). In 53% of the discovery cohort cases, we detected unique mutational signatures, with up to 34% of them carrying mutated genes with the potential to guide therapy. In a panel of HCC cell lines, each characterized by a specific mutational signature, sorafenib elicited heterogeneous mechanistic and biological responses, whereas targeted therapy provoked the robust inhibition of cell proliferation and DNA synthesis along with the blockage of AKT/mTOR signaling. The combination of sorafenib with targeted therapies exhibited synergistic anti-HCC biological activity concomitantly with highly effective inhibition of MAPK and AKT/mTOR signaling. Thus, somatic mutations may lead to identify case-specific mechanisms of disease in HCC lesions arising from multiple etiologies. Moreover, targeted therapies guided by molecular characterization, used alone or in combination with sorafenib, can effectively block important HCC disease mechanisms.

Prevalence of high-risk HPV genotypes, categorised by their quadrivalent and nine-valent HPV vaccination coverage, and the genotype association with high-grade lesions.

BACKGROUND: The new nine-valent vaccine against human papillomavirus (HPV) includes the four HPV genotypes (6, 11, 16, and 18) that are targeted by the older quadrivalent HPV vaccine, plus five additional oncogenic types (31, 33, 45, 52, and 58) remain significantly associated with high grade lesions. We aimed to determine the prevalence of high-risk HPV genotypes in unvaccinated subjects and the association of these genotypes with the incidence of high-grade lesions. We also assessed which, if either, of these two HPV vaccines could have prevented these cases. METHODS: This cross-sectional study, conducted from 4 January 2010 to 30 December 2011, was composed of 595 women attending the Hospital General Universitario de Elche (Spain) gynaecology department who were positively screened for opportunistic cervical cancer by pap smears and HPV detection during a routine gynaecological health check. The pap smear results were classified using the Bethesda system. HPV genotyping was performed with the Linear Array HPV genotyping test, and viruses were classified by the International Agency for Research on Cancer assessment of HPV carcinogenicity. Odds ratios (ORs) with their 95% confidence intervals (95% CI) were estimated by logistic regression, adjusting for age and immigrant status. The prevented fraction among those exposed (PFe-adjusted) was determined as a measure of impact. RESULTS: At least one of the additional five high-risk HPV genotypes present in the nine-valent HPV vaccine was detected in 20.5% of subjects. After excluding women with genotype 16 and/or 18 co-infection, high-risk genotypes (31, 33, 45, 52, and 58) were associated with a higher risk of intraepithelial lesion or malignancy: adjusted OR = 3.51 (95% CI, 1.29-9.56), PFe-adjusted = 0.72 (95% CI, 0.22-0.90). Genotypes that are still non-vaccine-targeted were detected in 17.98% of the women, but these were not significantly associated with high-grade lesions. CONCLUSION: The greater protection of the nine-valent HPV vaccine is likely to have a positive impact because, in the absence of genotype 16 or 18 infection, these five genotypes on their own remained significantly associated with high-grade lesions.

Living with a peripherally inserted central catheter: the perspective of cancer outpatients-a qualitative study.

PURPOSE: The aim of this study was to describe the experience of using a peripherally inserted central catheter (PICC) in cancer sufferers receiving outpatient treatment. METHODS: A qualitative, phenomenological study was performed. Purposeful sampling methods were used. Data collection methods included semi-structured interviews and researcher field notes. Thematic analysis was used to analyze data. The study was conducted following the Consolidated Criteria for Reporting Qualitative Research guidelines. RESULTS: Eighteen patients (61% women, mean age 58 years) participated. They spent a mean duration of 155 days with the line in place. Two themes were identified with different subgroups. The theme "Living with a PICC line," including the subthemes "Benefits" and "Disadvantages," displays how the implantation is experienced by patients in a dichotomous manner. This highlighted both the beneficial and negative aspects of the implantation. The second theme was "Adapting to life with the catheter" and comprised three subthemes: "Advantages," "Lifestyle modifications," and "Overall assessment of the peripherally inserted central catheter," which shows how patients gradually accept the catheter by adapting their lifestyle. CONCLUSIONS: Over time, most patients considered having a PICC line to be a positive experience that they would recommend to other patients, as they found that it did not alter their quality of life. These results can be applied in Oncology Units for developing specific protocols for patients.

Helicobacter pylori serological biomarkers of gastric cancer risk in the MCC-Spain case-control Study.

BACKGROUND: Helicobacter pylori infection is one of the main risk factors for non-cardia gastric cancer. However, only a minority of infected persons develop the disease. This study aims at identifying H. pylori related serological biomarkers of risk for gastric cancer. METHODS: Incident gastric cancer cases and population controls (age, sex and region frequency-matched) from the MCC-Spain multicase-control Study were included. Seroreactivities against 16H. pylori proteins were determined using multiplex serology. Infection was defined as seropositivity against≥4 proteins. Relation of serological results to non-cardia and cardia gastric cancer was assessed using multivariable mixed logistic regression and principal components analysis. RESULTS: Seroprevalence was 88% among 2071 controls, 95% among 202 non-cardia gastric cancer cases (OR=1.9 (95% CI: 1.0-3.6)) and 85% among 62 cardia cancer cases (OR=0.5 (95% CI: 0.3-1.1)). In infected subjects, seropositivity for UreA, HP231, NapA and Cagδ was associated with lower non-cardia gastric cancer risk, while seropositivity for CagA and VacA was associated with higher risk. Seropositivity for CagA and seronegativity for Cagδ maintained the association after additional adjustment by serostatus of significant proteins. We identified two antibody reactivity patterns: the "virulent-pattern", related to a threefold higher risk of non-cardia gastric cancer and the "non-virulent pattern", related to a 60% decreased risk (4th vs. first quartile). CONCLUSIONS: In our population, people seropositive for H. pylori were characterized by two patterns of antibody reactivity against H. pylori proteins: 1) Combined high seroreactivity against several proteins, associated with a lower non-cardia gastric cancer risk, and 2) High seroreactivity against CagA and VacA, associated with an increased risk.

Association among presence of cancer pain, inadequate pain control, and psychotropic drug use.

INTRODUCTION: Pain is a common symptom in cancer patients, and its control and management are complex. Despite the high concomitant use of psychotropic drugs among such patients, the association among pain, inadequate pain control, and psychotropic drug use has not been fully determined. This study examined the prevalence of cancer pain and inadequate pain control and the association with psychotropic drug use. MATERIALS AND METHODS: In this cross-sectional study, we investigated 402 medical records obtained by simple random sampling of oncology patients at a hospital in northern Spain from July 2012 to July 2014. Adjusted odds ratios (ORs) were estimated together with their 95% confidence intervals (95% CIs) by unconditional logistic regression for each type of psychotropic drug (anxiolytics, hypnotics, and antidepressants). RESULTS: The mean patient age was 61.17 (standard deviation ± 13.14) years; 57.5% were women, 42.5% men. Pain was present in 18.4% of patients and inadequate pain control in 54.2%. We found a statistically significant association between the presence of cancer pain and anxiolytic use (adjusted OR, 3.15; 95% CI, 1.49-6.68) and hypnotic use (adjusted OR, 5.19; 95% CI, 1.77-15.25). Inadequate pain control was associated to a greater extent with the use of those drugs: adjusted OR for anxiolytic use, 4.74 (95% CI, 1.91-11.80); adjusted OR for hypnotic use, 6.09 (95% CI, 1.74-21.32). By contrast, no association was found between pain and antidepressant use (adjusted OR, 0.99). CONCLUSION: The presence of pain and (to a greater extent) poor pain control were associated with increased use of certain psychotropic drugs, such as anxiolytics and hypnotics. There appeared to be no association between pain and antidepressant use.

Molecular basis of targeted therapy in T/NK-cell lymphoma/leukemia: A comprehensive genomic and immunohistochemical analysis of a panel of 33 cell lines.

T and NK-cell lymphoma is a collection of aggressive disorders with unfavorable outcome, in which targeted treatments are still at a preliminary phase. To gain deeper insights into the deregulated mechanisms promoting this disease, we searched a panel of 31 representative T-cell and 2 NK-cell lymphoma/leukemia cell lines for predictive markers of response to targeted therapy. To this end, targeted sequencing was performed alongside the expression of specific biomarkers corresponding to potentially activated survival pathways. The study identified TP53, NOTCH1 and DNMT3A as the most frequently mutated genes. We also found common alterations in JAK/STAT and epigenetic pathways. Immunohistochemical analysis showed nuclear accumulation of MYC (in 85% of the cases), NFKB (62%), p-STAT (44%) and p-MAPK (30%). This panel of cell lines captures the complexity of T/NK-cell lymphoproliferative processes samples, with the partial exception of AITL cases. Integrated mutational and immunohistochemical analysis shows that mutational changes cannot fully explain the activation of key survival pathways and the resulting phenotypes. The combined integration of mutational/expression changes forms a useful tool with which new compounds may be assayed.

Shared Oncogenic Pathways Implicated in Both Virus-Positive and UV-Induced Merkel Cell Carcinomas.

Merkel cell carcinoma (MCC) is a highly malignant neuroendocrine tumor of the skin whose molecular pathogenesis is not completely understood, despite the role that Merkel cell polyomavirus can play in 55-90% of cases. To study potential mechanisms driving this disease in clinically characterized cases, we searched for somatic mutations using whole-exome sequencing, and extrapolated our findings to study functional biomarkers reporting on the activity of the mutated pathways. Confirming previous results, Merkel cell polyomavirus-negative tumors had higher mutational loads with UV signatures and more frequent mutations in TP53 and RB compared with their Merkel cell polyomavirus-positive counterparts. Despite important genetic differences, the two Merkel cell carcinoma etiologies both exhibited nuclear accumulation of oncogenic transcription factors such as NFAT or nuclear factor of activated T cells (NFAT), P-CREB, and P-STAT3, indicating commonly deregulated pathogenic mechanisms with the potential to serve as targets for therapy. A multivariable analysis identified phosphorylated CRE-binding protein as an independent survival factor with respect to clinical variables and Merkel cell polyomavirus status in our cohort of Merkel cell carcinoma patients.

Predictors of Hospitalized Exacerbations and Mortality in Chronic Obstructive Pulmonary Disease.

BACKGROUND AND AIM: Exacerbations of chronic obstructive pulmonary disease (COPD) carry significant consequences for patients and are responsible for considerable health-care costs-particularly if hospitalization is required. Despite the importance of hospitalized exacerbations, relatively little is known about their determinants. This study aimed to analyze predictors of hospitalized exacerbations and mortality in COPD patients. METHODS: This was a retrospective population-based cohort study. We selected 900 patients with confirmed COPD aged ≥35 years by simple random sampling among all COPD patients in Cantabria (northern Spain) on December 31, 2011. We defined moderate exacerbations as events that led a care provider to prescribe antibiotics or corticosteroids and severe exacerbations as exacerbations requiring hospital admission. We observed exacerbation frequency over the previous year (2011) and following year (2012). We categorized patients according to COPD severity based on forced expiratory volume in 1 second (Global Initiative for Chronic Obstructive Lung Disease [GOLD] grades 1-4). We estimated the odds ratios (ORs) by logistic regression, adjusting for age, sex, smoking status, COPD severity, and frequent exacerbator phenotype the previous year. RESULTS: Of the patients, 16.4% had ≥1 severe exacerbations, varying from 9.3% in mild GOLD grade 1 to 44% in very severe COPD patients. A history of at least two prior severe exacerbations was positively associated with new severe exacerbations (adjusted OR, 6.73; 95% confidence interval [CI], 3.53-12.83) and mortality (adjusted OR, 7.63; 95%CI, 3.41-17.05). Older age and several comorbidities, such as heart failure and diabetes, were similarly associated. CONCLUSIONS: Hospitalized exacerbations occurred with all grades of airflow limitation. A history of severe exacerbations was associated with new hospitalized exacerbations and mortality.

MAD2γ, a novel MAD2 isoform, reduces mitotic arrest and is associated with resistance in testicular germ cell tumors.

BACKGROUND: Prolonged mitotic arrest in response to anti-cancer chemotherapeutics, such as DNA-damaging agents, induces apoptosis, mitotic catastrophe, and senescence. Disruptions in mitotic checkpoints contribute resistance to DNA-damaging agents in cancer. MAD2 has been associated with checkpoint failure and chemotherapy response. In this study, a novel splice variant of MAD2, designated MAD2γ, was identified, and its association with the DNA damage response was investigated. METHODS: Endogenous expression of MAD2γ and full-length MAD2 (MAD2α) was measured using RT-PCR in cancer cell lines, normal foreskin fibroblasts, and tumor samples collected from patients with testicular germ cell tumors (TGCTs). A plasmid expressing MAD2γ was transfected into HCT116 cells, and its intracellular localization and checkpoint function were evaluated according to immunofluorescence and mitotic index. RESULTS: MAD2γ was expressed in several cancer cell lines and non-cancerous fibroblasts. Ectopically expressed MAD2γ localized to the nucleus and reduced the mitotic index, suggesting checkpoint impairment. In patients with TGCTs, the overexpression of endogenous MAD2γ, but not MAD2α, was associated with resistance to cisplatin-based chemotherapy. Likewise, cisplatin induced the overexpression of endogenous MAD2γ, but not MAD2α, in HCT116 cells. CONCLUSIONS: Overexpression of MAD2γ may play a role in checkpoint disruption and is associated with resistance to cisplatin-based chemotherapy in TGCTs.

Night shift work and stomach cancer risk in the MCC-Spain study.

OBJECTIVES: Night shift work has been classified as a probable human carcinogen by the International Agency for Research on Cancer, based on experimental studies and limited evidence on human breast cancer risk. Evidence at other cancer sites is scarce. We evaluated the association between night shift work and stomach cancer risk in a population-based case-control study. METHODS: A total of 374 incident stomach adenocarcinoma cases and 2481 population controls were included from the MCC-Spain study. Detailed data on lifetime night shift work were collected including permanent and rotating shifts, and their cumulative duration (years). Adjusted unconditional logistic regression models were used in analysis. RESULTS: A total of 25.7% of cases and 22.5% of controls reported ever being a night shift worker. There was a weak positive, non-significant association between ever having had worked for at least 1 year in permanent night shifts and stomach cancer risk compared to never having worked night shifts (OR=1.2, 95% CI 0.9 to 1.8). However, there was an inverse 'U' shaped relationship with cumulative duration of permanent night shifts, with the highest risk observed in the intermediate duration category (OR 10-20 years=2.0, 95% CI 1.1 to 3.6) (p for trend=0.19). There was no association with ever having had worked in rotating night shifts (OR=0.9, 95% CI 0.6 to 1.2) and no trend according to cumulative duration (p for trend=0.68). CONCLUSION: We found no clear evidence concerning an association between night shift work and stomach cancer risk.

Prevalence of Influenza Vaccination in Chronic Obstructive Pulmonary Disease Patients and Impact on the Risk of Severe Exacerbations.

OBJECTIVE: To determine the prevalence of influenza vaccination in chronic obstructive pulmonary disease (COPD) patients, and the effectiveness of the procedure. METHODS: Retrospective population-based cohort study. On 31 December 2011, influenza vaccination history was retrieved from 899 patients with confirmed COPD selected by simple random sampling from all COPD patients in Cantabria (northern Spain). Severe exacerbations (hospitalization due to COPD exacerbation) and overall mortality during 2012 were treated as dependent variables. Odds ratios (OR) were estimated by logistic regression, adjusting for age, sex, smoking status, severity of COPD, and frequency of exacerbations during the previous year. Prevented fraction among the exposed (PFe-adjusted) was determined as a measure of impact. RESULTS: Overall prevalence of influenza vaccination was 62.7%, but this rate fell in patients classified as more severe according to FEV1 (52.0%). Influenza vaccination showed a statistically significant protective effect against severe exacerbations in the following year: Ora: 0.54 (95%CI: 0.35-0.84); FPe-adjusted: 0.46 (95%CI: 0.16-0.65). A non-significant protective effect for overall mortality was observed: Ora: 0.76 (95%CI: 0.41-1.40). When stratified according to COPD severity (FEV1), the protective effect against risk of hospitalization was higher in more severe COPD patients: Ora: 0.23 (95%CI: 0.11-0.48); FPe-adjusted: 0.77 (95%CI: 0.52-0.89). CONCLUSIONS: We found that influenza vaccination has a protective effect and reduces the risk of hospitalization due to exacerbations in the following year. Despite the evidence for protection, prevalence of vaccination was not optimal, especially in more severe COPD patients.

Relationship between tobacco, cagA and vacA i1 virulence factors and bacterial load in patients infected by Helicobacter pylori.

BACKGROUND AND AIM: Several biological and epidemiological studies support a relationship between smoking and Helicobacter pylori (H. pylori) to increase the risk of pathology. However, there have been few studies on the potential synergistic association between specific cagA and vacA virulence factors and smoking in patients infected by Helicobacter pylori. We studied the relationship between smoking and cagA, vacA i1 virulence factors and bacterial load in H. pylori infected patients. METHODS: Biopsies of the gastric corpus and antrum from 155 consecutive patients in whom there was clinical suspicion of infection by H. pylori were processed. In 106 patients H. pylori infection was detected. Molecular methods were used to quantify the number of microorganisms and presence of cagA and vacA i1 genes. A standardized questionnaire was used to obtain patients' clinical data and lifestyle variables, including tobacco and alcohol consumption. Adjusted Odds Ratios (ORadjusted) were estimated by unconditional logistic regression. RESULTS: cagA was significantly associated with active-smoking at endoscope: ORadjusted 4.52. Evidence of association was found for vacA i1 (ORadjusted 3.15). Bacterial load was higher in active-smokers, although these differences did not yield statistical significance (median of 262.2 versus 79.4 copies of H. pylori per cell). CONCLUSIONS: The association between smoking and a higher risk of being infected by a virulent bacterial population and with higher bacterial load, support a complex interaction between H. pylori infection and environmental factors.

Significant clinical impact of recurrent BRCA1 and BRCA2 mutations in Mexico.

BACKGROUND: Frequent recurrent mutations in the breast and ovarian cancer susceptibility (BRCA) genes BRCA1 and BRCA2 among Hispanics, including a large rearrangement Mexican founder mutation (BRCA1 exon 9-12 deletion [ex9-12del]), suggest that an ancestry-informed BRCA-testing strategy could reduce disparities and promote cancer prevention by enabling economic screening for hereditary breast and ovarian cancer in Mexico. METHODS: In a multistage approach, 188 patients with cancer who were unselected for family cancer history (92 with ovarian cancer and 96 with breast cancer) were screened for BRCA mutations using a Hispanic mutation panel (HISPANEL) of 115 recurrent mutations in a multiplex assay (114 were screened on a mass spectroscopy platform, and a polymerase chain reaction assay was used to screen for the BRCA1 ex9-12del mutation). This was followed by sequencing of all BRCA exons and adjacent intronic regions and a BRCA1 multiplex ligation-dependent probe amplification assay (MLPA) for HISPANEL-negative patients. BRCA mutation prevalence was calculated and correlated with histology and tumor receptor status, and HISPANEL sensitivity was estimated. RESULTS: BRCA mutations were detected in 26 of 92 patients (28%) with ovarian cancer, in 14 of 96 patients (15%) with breast cancer overall, and in 9 of 33 patients (27%) who had tumors that were negative for estrogen receptor, progesterone receptor, and human epithelial growth factor 2 (triple-negative breast cancer). Most patients with breast cancer were diagnosed with locally advanced disease. The Mexican founder mutation (BRCA1 ex9-12del) accounted for 35% of BRCA-associated ovarian cancers and 29% of BRCA-associated breast cancers. At 2% of the sequencing and MLPA cost, HISPANEL detected 68% of all BRCA mutations. CONCLUSIONS: In this study, a remarkably high prevalence of BRCA mutations was observed among patients with ovarian cancer and breast cancer who were not selected for family history, and the BRCA1 ex9-12del mutation explained 33% of the total. The remarkable frequency of BRCA1 ex9-12del in Mexico City supports a nearby origin of this Mexican founder mutation and may constitute a regional public health problem. The HISPANEL mutation panel presents a translational opportunity for cost-effective genetic testing to enable breast and ovarian cancer prevention.