Seguridad alimentaria, consumo y COVID-19: un estudio observacional en estudiantes universitarios / Food Safety, Consumption and COVID-19: an Observational Study among University Students

Resumen: Objetivo: Determinar el grado de seguridad y de inseguridad alimentaria de estudiantes universitarios y sus hogares en período de pandemia por COVID-19. Materiales y métodos: Se realizó un estudio transversal, observacional con 110 estudiantes universitarios de la facultad de nutrición de la región Xalapa de la Universidad Veracruzana (UV), mediante una encuesta en línea en la que reportaron información individual y de los integrantes de sus hogares. La encuesta en línea se alojó en la plataforma del sistema de encuestas de la Coordinación Universitaria de Observatorios (CUO) de la UV y se aplicó durante el mes de noviembre de 2020. Resultados: Debido a la situación de pandemia, la mitad de los encuestados refirió que sus gastos en alimentación disminuyeron, esto también se vio afectado debido a que, en este período, en el 15.4% de los hogares, entre 1 y 2 integrantes del hogar perdieron su empleo o la fuente de ingresos. Se identificó una prevalencia de hogares en seguridad alimentaria de un 82.72 %, un 12.73% de inseguridad leve y 4.55 % de inseguridad moderada; 83.6% de los hogares presentaron alteraciones leves en su dieta; casi la mitad (45%) mantuvo el mismo patrón de consumo de alimentos procesados y ultra procesados. Conclusiones: Se necesita promover intervenciones educativas en el contexto universitario que favorezcan hábitos saludables de los estudiantes y un acceso a productos nutritivos y variados, y con ello procurar una mejor seguridad alimentaria.

Abstract: Objective: To determine the degree of security and food insecurity of university students and their homes in the period of the COVID-19pandemic. Materials and methods: A cross-sectional, observational study was carried out with 110 university students from the faculty of nutrition in the Xalapa region of the Universidad Veracruzana (UV), through an online survey in which they reported individual information and information on their household members. The online survey was hosted on the platform of the survey system of the University Coordination of Observatories (CUO) of the UV and was applied during november 2020. Results: Due to the pandemic situation, half of the respondents reported that their food expenses decreased,this was also affected because, in this period, in 15.4% of households, between 1 and 2 household members lost their job or source of income. A prevalence of households in food safety of 82.72% was identified, 12.73% mild insecurity and 4.55% moderate insecurity; 83.6% of the households presented slight alterations in their diet; almost half (45%) maintained the same pattern of consumption of processed and ultra-processed foods. Conclusions: It is necessary to promote educational interventions in the university context that favor healthy habits of students and access to nutritious and varied products, and with this, seek better food safety.

Catéter de arteria pulmonar en shock cardiogénico: novedades acerca de su valor pronóstico y marcadores derivados / Use of pulmonary artery catheter in patiens with cardiogenic shock: an upgrade

El uso del catéter de arteria pulmonar es un método eficaz para la monitorización de los pacientes críticos. Aunque ampliamente utilizado en las Unidades de Cuidados Críticos Cardiológicos, no se ha demostrado en estudios previos el beneficio de su uso. Registros recientes y numerosos en pacientes graves cursando shock cardiogénico muestran un beneficio en términos de mortalidad asociada, sobre todo relacionado con una adecuada interpretación. Además, nuevos parámetros relacionados con insuficiencia ventricular como son el poder cardíaco y el índice de pulsatilidad de arteria pulmonar, así como el conocimiento de las presiones de llenado ventriculares, tanto izquierdas, como derechas, ayudan en la toma de decisiones, las opciones de tratamiento y estimación del pronóstico. Complementando lo anterior, la modernización en la tecnología del catéter de arteria pulmonar permite la medición del gasto cardíaco de forma continua a través de un sistema termodilución integrada. Este sistema también permite la monitorización más precisa del ventrículo derecho por medio de la valoración continua de su fracción de eyección y volumen de fin de diástole. La información obtenida por medio del catéter de arteria pulmonar en shock cardiogénico ha llevado a que su uso comience a ser cada vez más frecuente en unidades de cuidados críticos cardiológicos y que se empleen estos valores por equipos de shock cardiogénico para la toma de decisiones complejas. La evidencia descrita sobre el valor pronóstico relacionada al uso del catéter de arteria pulmonar se resume en esta revisión.

The pulmonary artery catheter is an effective tool for monitoring critically ill patients; however, the evidence showed limited value and a posible increased risk. Recently, numerous registries in critical ill patients in cardiogenic shock have shown a benefit in mortality, especially related to an adequate interpretation of findings. In addition, new parameters related to ventricular failure, such as cardiac power output and pulmonary artery pulsatility index have shown to be useful for a better treatment and estimation of prognosis. Besides, determination of filling pressures (right and/or left side) have an important role in terms of prognosis and management. Advances in pulmonary artery catheter technology allows us to continuously measure cardiac output through an integrated thermodilution system. This system also allows the continuous assessment of right ventricular ejection fraction and end-diastolic volume. The information obtained has led to an increased use of the pulmonary artery catheter monitoring in cardiac Intensive Care Units allowing improvements in treatment and complex decision-making.

Influence of left ventricular systolic function on the long-term benefit of beta-blockers after ST-segment elevation myocardial infarction.

INTRODUCTION: Beta-blockers are recommended after ST-elevation myocardial infarction (STEMI), but their benefit in patients with preserved left ventricular ejection fraction (LVEF) is unclear. METHODS: Consecutive patients discharged in sinus rhythm after STEMI between January 2010 and April 2015 were followed until December 2017. Percutaneous coronary intervention (PCI) was performed in 969 (99.7%, including 112 with rescue PCI) and three (0.3%) received only thrombolytic therapy without rescue PCI. RESULTS: Of these 972 patients, mean age 62.6±13.5 years, 212 (21.8%) were women and 835 (85.9%) were prescribed beta-blockers at discharge. Patients who did not receive beta-blockers had more comorbidities than those who did, including chronic obstructive pulmonary disease (14.6% vs. 4.2%), anemia (8.0% vs. 3.7%), and cancer (7.3% vs. 2.8%), and more frequently had inferior STEMI (75.9% vs. 56.0%) and high-grade atrioventricular block (13.1% vs. 5.3%) (all p<0.01). After a mean follow-up of 49.6±24.9 months, beta-blocker treatment at discharge was independently associated with lower mortality (HR 0.61, 95% confidence interval [CI] 0.38-0.96, p=0.03). This effect was present in 192 patients with LVEF ≤40% (HR 0.57, 95% 95% CI 0.34-0.97, p=0.04) but was not clear in 643 patients with LVEF >40% (HR 0.67, 95% 95% CI 0.25-1.76, p=0.42). CONCLUSION: In the LVEF >40% group, the results raise reasonable doubts about the real benefit of systematic use of beta-blockers as treatment for these patients. These findings reinforce the need for large randomized clinical trials within this group of patients.

Effects of Somatic Methylation in Colonic Polyps on Risk of Developing Metachronous Advanced Colorectal Lesions.

The utility of molecular markers for predicting the risk of metachronous advanced colorectal lesions (MACLs) remains poorly investigated. We examined the relationship between somatic hypermethylation in polyps at baseline and the risk of developing MACL. This retrospective cohort study included 281 consecutive patients with colonic polyps who were enrolled between 2007 and 2009 and followed-up until 2014. MACLs were defined as adenomas of ≥10 mm, high-grade dysplasia, or with a villous component; and serrated lesions of ≥10 mm or with dysplasia. In total, 595 polyps were removed at baseline colonoscopy and analyzed for pathological characteristics and CpG island methylator phenotype (CIMP) using the MS-MLPA (Methylation-Specific -- Multiplex Ligation-dependent Probe Amplification) technique. Forty-five patients (16.0%) showed at least one CIMP+ polyp. MACL risk was higher in patients with CIMP+ polyps (odds ratio (OR), 4.50; 95% CI, 1.78-11.4; p = 0.002). Patients with CIMP+ polyps also exhibited shorter time to MACL development (33.8 months vs. 50.1 months; p < 0.001), even with adjustment for polyp size and number (OR, 2.40; 95% CI, 1.33-4.34). Adding CIMP analysis improved the sensitivity (57.0% to 70.9%), negative predictive value (71.1% to 77.3%), and overall accuracy (49.8% to 52.0%) for MACL risk estimation. These results highlight that CIMP may be a useful marker for endoscopic surveillance.

Increased Th17-Related Cytokine Serum Levels in Patients With Multiple Polyps of Unexplained Origin.

OBJECTIVES: Most patients with multiple colonic polyps do not have a known genetic or hereditary origin. Our aim was to analyze the presence of inflammatory cytokines and levels of glucose, insulin, and C-reactive protein (CRP) in patients with multiple colonic polyps. METHODS: Eighty-three patients with 10 or more adenomatous or serrated polyps and 53 control people with normal colonoscopy were included. Smoking habits were registered, and glucose, CRP, and basal insulin in the serum/blood were measured. Quantification of IL-2, IL-4, IL-6, IL-10, IL-11, IL-17A, and IL-23 cytokine levels in the serum was performed by a high-sensitivity enzyme-linked immunosorbent assay. RESULTS: Smoking and diabetes were more prevalent in those with colonic polyps than in the control people (67% vs 16%, P = 0.001; 11% vs 2%, P = 0.048). In addition, the cytokine serum levels were higher, i.e., IL-2 (P = 0.001), IL-4 (P = 0.001), IL-6 (P = 0.001), IL-17A (P = 0.001), IL-23 (P = 0.014), and CRP (P = 0.003). Adjusting for sex, smoking, and diabetes in a multivariate analysis, IL-2, IL-4, IL-6, IL-17A, and IL-23 remained independently elevated in cases with multiple polyps. DISCUSSION: These results indicate that immune responses mediated by Th17 cells may be involved in the pathogenesis of multiple colonic polyps.

Clinical profile, anatomical features and long-term outcome of acute coronary syndromes in human immunodeficiency virus-infected patients.

BACKGROUND: Long-term prognosis of acute coronary syndromes (ACS) in human immunodeficiency virus (HIV)-infected patients is unknown. AIMS: To compare outcomes after ACS in HIV-infected and uninfected patients. METHODS: Retrospective observational study. HIV cases were matched with two HIV-uninfected controls for age, sex and type of ACS. RESULTS: In 92 HIV patients (mean age 51.3 ± 9.0 years, 7.6% women), the prevalence of cardiovascular risk factors was high (smoking 71.7%; hypertension 41.3%; diabetes 14.1%); dyslipidaemia was more frequent (53 (57.6%) vs 79 (42.9%), P = 0.02) and obesity less common (8 (8.7%) vs 41 (22.3%), P = 0.002) than in controls. Eighty-seven (94.6%) HIV patients had undetectable viral load and 85 (92.4%) were under anti-retroviral therapy. Multivessel disease was more common in HIV patients than in controls (44 (47.8%) vs 71 (39.1%); P = 0.05) as was Killip class 3-4 on admission (9 (9.8%) vs 6 (3.3%); P = 0.04). The rate of in-hospital mortality was similar in both groups (2%), and there were no significant differences in 3-year mortality (10.2% vs 5.7%; P = 0.27). Non-cardiovascular readmissions at 3 years were more frequent in HIV patients than in controls (36.5% vs 7.4%; P < 0.001). Multivariate analysis identified previous coronary artery disease as the strongest predictor of mortality in HIV patients (hazard ratio 4.7, 95% confidence interval 1.4-15.7, P = 0.01), whereas HIV infection was not associated with prognosis. CONCLUSION: HIV patients with ACS had more frequent multivessel disease and heart failure than matched controls. However, in-hospital and long-term mortality was similar in both groups. Non-cardiovascular re-hospitalisations were more common in HIV patients.

Clinical characteristics of patients with sustained ventricular arrhythmias after sacubitril/valsartan initiation.

Our aim was to describe the clinical profile of patients presenting sustained ventricular arrhythmias after sacubitril/valsartan (SV) initiation. All cases of sustained ventricular arrhythmias in patients receiving SV were consecutively recorded in two centers. Nineteen patients had sustained ventricular arrhythmias after SV. All were men and were previously receiving angiotensin-converting enzyme inhibitors, or angiotensin II receptor blockers before SV initiation. Fifteen patients (78.9%) had electrical stability in the previous 6 months. Nine patients (47.4%) initiated SV at the lowest available dose (24/26 mg). Globally, in all but five patients alive at discharge, SV was discontinued after the event. Six patients presented new arrhythmic events after discontinuation of SV. Two deaths and three heart transplants occurred (one due to heart failure and the other two due to persistent ventricular arrhythmias). All patients had a high arrhythmic risk, and 17 (89.5%) had an implanted cardioverter defibrillator. No specific triggers for the arrhythmic event were found. Male sex and previous episodes of ventricular arrhythmias could be associated with an increased risk of sustained ventricular tachycardia after SV initiation. Discontinuation of the drug might be an additional approach to enable a better control of ventricular arrhythmias in some patients.

Colorectal cancer molecular classification using BRAF, KRAS, microsatellite instability and CIMP status: Prognostic implications and response to chemotherapy.

OBJECTIVE: The aim of this study was to validate a molecular classification of colorectal cancer (CRC) based on microsatellite instability (MSI), CpG island methylator phenotype (CIMP) status, BRAF, and KRAS and investigate each subtype's response to chemotherapy. DESIGN: This retrospective observational study included a population-based cohort of 878 CRC patients. We classified tumours into five different subtypes based on BRAF and KRAS mutation, CIMP status, and MSI. Patients with advanced stage II (T4N0M0) and stage III tumours received 5-fluoruracil (5-FU)-based chemotherapy or no adjuvant treatment based on clinical criteria. The main outcome was disease-free survival (DFS). RESULTS: Patients with the combination of microsatellite stable (MSS) tumours, BRAF mutation and CIMP positive exhibited the worst prognosis in univariate (log rank P<0.0001) and multivariate analyses (hazard ratio 1.75, 95% CI 1.05-2.93, P = 0.03) after adjusting for age, sex, chemotherapy, and TNM stage. Treatment with 5-FU-based regimens improved prognosis in patients with the combination of MSS tumours, KRAS mutation and CIMP negative (log rank P = 0.003) as well as in patients with MSS tumours plus BRAF and KRAS wild-type and CIMP negative (log-rank P<0.001). After adjusting for age, sex, and TNM stage in the multivariate analysis, only patients with the latter molecular combination had independently improved prognosis after adjuvant chemotherapy (hazard ratio 2.06, 95% CI 1.24-3.44, P = 0.005). CONCLUSION: We confirmed the prognostic value of stratifying CRC according to molecular subtypes using MSI, CIMP status, and somatic KRAS and BRAF mutation. Patients with traditional chromosomally unstable tumours obtained the best benefit from adjuvant 5-FU-based chemotherapy.

TFAP2E Methylation and Expression Status Does Not Predict Response to 5-FU-based Chemotherapy in Colorectal Cancer.

Purpose: A recent study reported that 5-fluorouracil (5-FU)-based chemotherapy is less effective in treating patients with advanced colorectal cancer demonstrating hypermethylation of the TFAP2E gene. The aim of our study was to confirm and validate these findings in large, uniformly treated, well-characterized patient cohorts.Experimental Design: Two cohorts of 783 patients with colorectal cancer: 532 from a population-based, multicenter cohort (EPICOLON I) and 251 patients from a clinic-based trial were used to study the effectiveness of TFAP2E methylation and expression as a predictor of response of colorectal cancer patients to 5-FU-based chemotherapy. DNA methylation status of the TFAP2E gene in patients with colorectal cancer was assessed by quantitative bisulfite pyrosequencing analysis. IHC analysis of the TFAP2E protein expression was also performed.Results: Correlation between TFAP2E methylation status and IHC staining was performed in 607 colorectal cancer samples. Among 357 hypermethylated tumors, only 141 (39.6%) exhibited loss of protein expression. Survival was not affected by TFAP2E hypermethylation in stage IV patients [HR, 1.21; 95% confidence interval (CI), 0.79-1.87; log-rank P = 0.6]. In stage II-III cases, disease-free survival was not influenced by TFAP2E hypermethylation status in 5-FU-treated (HR, 0.91; 95% CI, 0.52-1.59; log-rank P = 0.9) as well as in nontreated patients (HR, 0.88; 95% CI, 0.5-1.54; log-rank P = 0.7).Conclusions:TFAP2E hypermethylation does not correlate with loss of its protein expression. Our large, systematic, and comprehensive study indicates that TFAP2E methylation and expression may not play a major role in predicting response to 5-FU-based chemotherapy in patients with colorectal cancer. Clin Cancer Res; 24(12); 2820-7. ©2018 AACR.

KRAS and BRAF somatic mutations in colonic polyps and the risk of metachronous neoplasia.

BACKGROUND & AIMS: High-risk features of colonic polyps are based on size, number, and pathologic characteristics. Surveillance colonoscopy is often recommended according to these findings. This study aimed to determine whether the molecular characteristics of polyps might provide information about the risk of metachronous advanced neoplasia. METHODOLOGY: We retrospectively included 308 patients with colonic polyps. A total of 995 polyps were collected and tested for somatic BRAF and KRAS mutations. Patients were classified into 3 subgroups, based on the polyp mutational profile at baseline, as follows: non-mutated polyps (Wild-type), at least one BRAF-mutated polyp, or at least one KRAS-mutated polyp. At surveillance, advanced adenomas were defined as adenomas ≥ 10 mm and/or with high grade dysplasia or a villous component. In contrast, advanced serrated polyps were defined as serrated polyps ≥ 10 mm in any location, located proximal to the splenic flexure with any size or with dysplasia. RESULTS: At baseline, 289 patients could be classified as wild-type (62.3%), BRAF mutated (14.9%), or KRAS mutated (22.8%). In the univariate analysis, KRAS mutations were associated with the development of metachronous advanced polyps (OR: 2.36, 95% CI: 1.22-4.58; P = 0.011), and specifically, advanced adenomas (OR: 2.42, 95% CI: 1.13-5.21; P = 0.023). The multivariate analysis, adjusted for age and sex, also showed associations with the development of metachronous advanced polyps (OR: 2.27, 95% CI: 1.15-4.46) and advanced adenomas (OR: 2.23, 95% CI: 1.02-4.85). CONCLUSIONS: Our results suggested that somatic KRAS mutations in polyps represent a potential molecular marker for the risk of developing advanced neoplasia.

Increased Risk of Colorectal Cancer in Patients With Multiple Serrated Polyps and Their First-Degree Relatives.

BACKGROUND & AIMS: We investigated whether patients with multiple serrated polyps, but not meeting the World Health Organization criteria for serrated polyposis syndrome, and their relatives have similar risks for colorectal cancer (CRC) as those diagnosed with serrated polyposis. METHODS: We collected data from patients with more than 10 colonic polyps, recruited in 2008-2009 from 24 hospitals in Spain for a study of causes of multiple colonic polyps. We analyzed data from 53 patients who met the criteria for serrated polyposis and 145 patients who did not meet these criteria, but who had more than 10 polyps throughout the colon, of which more than 50% were serrated. We calculated age- and sex-adjusted standardized incidence ratios (SIRs) for CRC in both groups, as well as in their first-degree relatives. RESULTS: The prevalence of CRC was similar between patients with confirmed serrated polyposis and multiple serrated polyps (odds ratio, 1.35; 95% confidence interval [CI], 0.64-2.82; P = .40). The SIR for CRC in patients with serrated polyposis (0.51; 95% CI, 0.01-2.82) did not differ significantly from the SIR for CRC in patients with multiple serrated polyps (0.74; 95% CI, 0.20-1.90; P = .70). The SIR for CRC also did not differ significantly between first-degree relatives of these groups (serrated polyposis: 3.28, 95% CI, 2.16-4.77; multiple serrated polyps: 2.79, 95% CI, 2.10-3.63; P = .50). Kaplan-Meier analysis showed no differences in the incidence of CRC between groups during the follow-up period (log-rank, 0.6). CONCLUSIONS: The risk of CRC in patients with multiple serrated polyps who do not meet the criteria for serrated polyposis, and in their first-degree relatives, is similar to that of patients diagnosed with serrated polyposis.

Prognostic Impact of Age and Hemoglobin in Acute ST-Segment Elevation Myocardial Infarction Treated With Reperfusion Therapy.

Advanced age and low hemoglobin levels have been associated with a poor prognosis in ST-segment elevation myocardial infarction (STEMI). We studied 1,111 patients with STEMI who received reperfusion treatment (1,032 [92.9%] primary angioplasty and 79 [7.1%] fibrinolysis without rescue percutaneous coronary intervention). Mean age was 64.1 ± 14.0 years, and 23.2% were women. Patients in the last age quartile (>76 years) were more frequently women, presented more risk factors (except smoking), received thrombolysis less frequently, had less complete revascularization, and presented more complications and higher mortality. Hemoglobin level at admission was associated with age and ranged from 14.8 ± 1.5 g/dl in the first quartile to 13.2 ± 1.8 g/dl in the last, p <0.001. Multivariate analysis identified age as a predictor of in-hospital and long-term mortality (odds ratio 1.04, 95% confidence interval [CI] 1.00 to 1.07, hazard ratio 1.06, 95% CI 1.04 to 1.08). Hemoglobin levels were associated with better survival (odds ratio 0.8, 95% CI 0.6 to 0.9, hazard ratio 0.85, 95% CI 0.78 to 0.92). The other predictors of inhospital mortality were Killip class, chronic kidney disease, left ventricular ejection fraction, significant pericardial effusion, and ventricular arrhythmias. The association of hemoglobin with hospital mortality was seen in men and in women ≥65 years. In men ≥65 years, this association was also present in those with hemoglobin levels in the normal range. In conclusion, in patients with STEMI, hemoglobin is an independent predictor of inhospital and long-term mortality, especially in those aged ≥65 years. This association is also present in men ≥65 years with normal hemoglobin levels.

Sex differences in acute myocardial infarction: Is it only the age?

BACKGROUND: Several studies have shown that, after an acute myocardial infarction, women have worse prognosis than males. However, it is not clear if female sex is an independent predictor of mortality risk. Our aim was to analyse sex influence on the prognosis of these patients. METHODS: Retrospective registry of patients with ST segment elevation myocardial infarction (STEMI) from January 2010 to April 2015. RESULTS: From 1111 patients, 258 (23.2%) were women. Compared with men, they presented higher risk profiles with older age (70.1±14.4years vs. 62.3±13.4, P<0.001), more cardiovascular risk factors (except smoking), longer time from symptoms onset to hospital arrival (5.2±4.1h vs. 4.2±3.7), higher Killip classification (1.6±1.1 vs. 1.4±0.8), fewer complete revascularizations (175 [67.8%] vs. 662 [77.9%] in men) and higher in-hospital mortality (26 [10.1%] vs. 34 [4.0%]); all p values <0.003. At discharge, women less frequently received ACE inhibitors (189 [81.1%] vs. 702 [85.8%], p=0.045) and presented more major adverse events (death, bleeding, infection, myocardial infarction, stent thrombosis or heart failure) during the first month after discharge (10.5% vs. 4.5%, p<0.001) and higher long-term mortality (hazard ratio [HR] 1.6, 95% CI 1.1-2.2). After adjusting by age, most of the differences disappeared, and sex was not an independent factor of in-hospital (odds ratio 1.71, 95% CI 0.97-2.99) or long-term mortality (HR 1.0, 95% CI 0.7-1.5). CONCLUSIONS: In patients with acute STEMI, the association of female sex with poor prognosis is mainly explained by age. Sex does not seem to be an independent prognostic factor.

Serrated colorectal cancer: Molecular classification, prognosis, and response to chemotherapy.

Molecular advances support the existence of an alternative pathway of colorectal carcinogenesis that is based on the hypermethylation of specific DNA regions that silences tumor suppressor genes. This alternative pathway has been called the serrated pathway due to the serrated appearance of tumors in histological analysis. New classifications for colorectal cancer (CRC) were proposed recently based on genetic profiles that show four types of molecular alterations: BRAF gene mutations, KRAS gene mutations, microsatellite instability, and hypermethylation of CpG islands. This review summarizes what is known about the serrated pathway of CRC, including CRC molecular and clinical features, prognosis, and response to chemotherapy.

Endoscopic surveillance in patients with multiple (10-100) colorectal polyps.

BACKGROUND AND STUDY AIMS: Endoscopic surveillance in patients with multiple colorectal polyps aims to reduce colorectal cancer (CRC) incidence and mortality, as well as the need for colorectal surgery. The aim of this study was to determine the risk of developing CRC or the need for surgery during endoscopic surveillance in a cohort of patients with multiple (10 - 100) colorectal polyps. PATIENTS AND METHODS: This was a multicentrer, longitudinal, observational study in 15 CRC high risk clinics in Spain, carried out between January 2009 and December 2010. Patients who were included in the EPIPOLIP trial and had at least 1 year of follow-up were included in the study. The primary outcome of interest was the incidence of CRC at least 1 year following the initial colonoscopy. The secondary outcome was the need for colorectal surgery. RESULTS: A total of 265 patients were followed for a median of 3.8 years. Patients underwent a median of 5 colonoscopies, and 17 patients (6.4 %) were diagnosed with CRC. A total of 32 patients (12.1 %) underwent surgery, including 15 (5.7 %) for prophylaxis without a diagnosis of CRC. The corresponding incidence density rates for CRC and colorectal surgery were 1.4 (95 % confidence interval [CI] 0.7 to 2.1) and 2.7 (95 %CI 1.7 to 3.6) per 100 patient-years, respectively. Only the presence of symptoms at first colonoscopy was independently associated with CRC diagnosis (hazard ratio [HR] 7.7, 95 %CI 1.1 to 59.3) and colorectal surgery (HR 4.6, 95 %CI 1.02 to 20.6). CONCLUSIONS: Patients with more than 10 neoplastic polyps required frequent colonoscopies within a short follow-up period. More than 10 % of patients required colorectal surgery within 4 years, more than half for incident CRC.

Prevalence of MLH1 constitutional epimutations as a cause of Lynch syndrome in unselected versus selected consecutive series of patients with colorectal cancer.

BACKGROUND: The prevalence of MLH1 constitutional epimutations in the general population is unknown. We sought to analyse the prevalence of MLH1 constitutional epimutations in unselected and selected series of patients with colorectal cancer (CRC). METHODS: Patients with diagnoses of CRC (n=2123) were included in the unselected group. For comparison, a group of 847 selected patients with CRC who fulfilled the revised Bethesda guidelines (rBG) were also included. Somatic and constitutional MLH1 methylation was assayed via methylation-specific multiplex ligation-dependent probe amplification of cases lacking MLH1 expression. Germline alterations in mismatch-repair (MMR) genes were assessed via Sanger sequencing and methylation-specific multiplex ligation-dependent probe amplification. RESULTS: Loss of MLH1 expression occurred in 5.5% of the unselected series and 12.5% of the selected series (p<0.0001). No constitutional epimutations in MLH1 were detected in the unselected population (0/62); five cases from the selected series were positive for MLH1 epimutations (15.6%, 5/32; p=0.004). CONCLUSIONS: Our results suggest a negligible prevalence of MLH1 constitutional epimutations in unselected cases of CRC. Therefore, MLH1 constitutional epimutation analysis should be conducted only for patients who fulfil the rBG and who lack MLH1 expression with methylated MLH1.

New insights into POLE and POLD1 germline mutations in familial colorectal cancer and polyposis.

Germline mutations in DNA polymerase ɛ (POLE) and δ (POLD1) have been recently identified in families with multiple colorectal adenomas and colorectal cancer (CRC). All reported cases carried POLE c.1270C>G (p.Leu424Val) or POLD1 c.1433G>A (p.Ser478Asn) mutations. Due to the scarcity of cases reported so far, an accurate clinical phenotype has not been defined. We aimed to assess the prevalence of these recurrent mutations in unexplained familial and early-onset CRC and polyposis, and to add additional information to define the clinical characteristics of mutated cases. A total of 858 familial/early onset CRC and polyposis patients were studied: 581 familial and early-onset CRC cases without mismatch repair (MMR) deficiency, 86 cases with MMR deficiency and 191 polyposis cases. Mutation screening was performed by KASPar genotyping assays and/or Sanger sequencing of the involved exons. POLE p.L424V was identified in a 28-year-old polyposis and CRC patient, as a de novo mutation. None of the 858 cases studied carried POLD1 p.S478N. A new mutation, POLD1 c.1421T>C (p.Leu474Pro), was identified in a mismatch repair proficient Amsterdam II family. Its pathogenicity was supported by cosegregation in the family, in silico predictions, and previously published yeast assays. POLE and POLD1 mutations explain a fraction of familial CRC and polyposis. Sequencing the proofreading domains of POLE and POLD1 should be considered in routine genetic diagnostics. Until additional evidence is gathered, POLE and POLD1 genetic testing should not be restricted to polyposis cases, and the presence of de novo mutations, considered.

Prevalence and characteristics of MUTYH-associated polyposis in patients with multiple adenomatous and serrated polyps.

PURPOSE: The present study aimed to determine the prevalence of MUTYH mutations in patients with multiple colonic polyps and to explore the best strategy for diagnosing MUTYH-associated polyposis (MAP) in these patients. EXPERIMENTAL DESIGN: This study included 405 patients with at least 10 colonic polyps each. All cases were genetically tested for the three most frequent MUTYH mutations. Whole-gene analysis was performed in heterozygous patients and in 216 patients lacking the three most frequent mutations. Polyps from 56 patients were analyzed for the KRAS-Gly12Cys and BRAF V600E somatic mutations. RESULTS: Twenty-seven (6.7%) patients were diagnosed with MAP, of which 40.8% showed serrated polyps. The sensitivity of studying only the three common variants was 74.1%. Of 216 patients without any monoallelic mutation in common variants, whole-gene analysis revealed biallelic pathogenic mutation in only one. G396D mutation was associated with serrated lesions and older age at diagnosis. There was a strong association between germinal MUTYH mutation and KRAS Gly12Cys somatic mutation in polyps. BRAF V600E mutation was found in 74% of serrated polyps in MUTYH-negative patients and in none of the polyps of MAP patients. CONCLUSIONS: We observed a low frequency of MUTYH mutations among patients with multiple adenomatous and serrated polyps. The MAP phenotype frequently included patients with serrated polyps, especially when G396D mutation was involved. Our results show that somatic molecular markers of polyps can be useful in identifying MAP cases and support the need for the complete MUTYH gene analysis only in patients heterozygous for recurrent variants.

Clinical subtypes and molecular characteristics of serrated polyposis syndrome.

BACKGROUND & AIMS: We investigated clinical and molecular differences between the different phenotypes of serrated polyposis syndrome (SPS) and the frequency of mutations in BRAF or KRAS in polyps from patients with SPS. METHODS: We collected data on clinical and demographic characteristics of 50 patients who fulfilled the criteria for SPS. Polymerase chain reaction and sequence analysis were used to identify BRAF and KRAS mutations in 432 polyps collected from 37 patients; we analyzed CpG island methylator phenotypes in 272 of these polyps. RESULTS: Fifteen patients (30%) had type 1 SPS and 35 had type 2 SPS. There were no significant differences in age at diagnosis, sex, smoking frequency, body mass index, or colorectal cancer predisposition between groups of patients, or in the pathologic or molecular characteristics of their polyps. A familial history of colorectal cancer or colonic polyps was reported more frequently by patients with type 2 SPS. BRAF mutations were found in 63% of polyps and KRAS mutations were found in 9.9%; 43.4% of polyps had the CpG island methylator phenotype-high phenotype. A per-patient analysis revealed that all patients had a BRAF or KRAS mutation in more than 25% of their polyps; 84.8% of patients had a mutation in BRAF or KRAS in more than 50% of their polyps. CONCLUSIONS: Except for a greater likelihood of familial history of colorectal cancer or colonic polyps in patients with type 2 SPS, we found no significant demographic, pathologic, or molecular differences between types 1 and 2 SPS. All patients had a BRAF or KRAS mutation in at least 25% of their polyps.

Risk of cancer in cases of suspected lynch syndrome without germline mutation.

BACKGROUND & AIMS: Colorectal cancers (CRCs) with microsatellite instability (MSI) and a mismatch repair (MMR) immunohistochemical deficit without hypermethylation of the MLH1 promoter are likely to be caused by Lynch syndrome. Some patients with these cancers have not been found to have pathogenic germline mutations and are considered to have Lynch-like syndrome (LLS). The aim of this study was to determine the risk of cancer in families of patients with LLS. METHODS: We studied a population-based cohort of 1705 consecutive patients, performing MSI tests and immunohistochemical analyses of MMR proteins. Patients were diagnosed with Lynch syndrome when they were found to have pathogenic germline mutations. Patients with MSI and loss of MSH2 and/or MSH6 expression, isolated loss of PMS2 or loss of MLH1 without MLH1 promoter hypermethylation, and no pathogenic mutation were considered to have LLS. The clinical characteristics of patients and the age- and sex-adjusted standardized incidence ratios (SIRs) of cancer in families were compared between groups. RESULTS: The incidence of CRC was significantly lower in families of patients with LLS than in families with confirmed cases of Lynch syndrome (SIR for Lynch syndrome, 6.04; 95% confidence interval [CI], 3.58-9.54; SIR for LLS, 2.12; 95% CI, 1.16-3.56; P < .001). However, the incidence of CRC was higher in families of patients with LLS than in families with sporadic CRC (SIR for sporadic CRC, 0.48; 95% CI, 0.27-0.79; P < .001). CONCLUSIONS: The risk of cancer in families with LLS is lower that of families with Lynch syndrome but higher than that of families with sporadic CRC. These results confirm the need for special screening and surveillance strategies for these patients and their relatives.