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[Background]: Individuals with a non-syndromic family history of colorectal cancer are known to have an increased risk. There is an opportunity to prevent early-onset colorectal cancer (age less than 50 years) (EOCRC) in this population. The aim was to explore the proportion of EOCRC that is preventable due to family history of colorectal cancer. [Methods]: This was a retrospective multicentre European study of patients with non-hereditary EOCRC. The impact of the European Society of Gastrointestinal Endoscopy (ESGE), U.S. Multi-Society Task Force (USMSTF), and National Comprehensive Cancer Network (NCCN) guidelines on prevention and early diagnosis was compared. Colorectal cancer was defined as potentially preventable if surveillance colonoscopy would have been performed at least 5 years before the age of diagnosis of colorectal cancer, and diagnosed early if colonoscopy was undertaken between 1 and 4 years before the diagnosis. [Results]: Some 903 patients with EOCRC were included. Criteria for familial colorectal cancer risk in ESGE, USMSTF, and NCCN guidelines were met in 6.3, 9.4, and 30.4 per cent of patients respectively. Based on ESGE, USMSTF, and NCCN guidelines, colorectal cancer could potentially have been prevented in 41, 55, and 30.3 per cent of patients, and diagnosed earlier in 11, 14, and 21.1 per cent respectively. In ESGE guidelines, if surveillance had started 10 years before the youngest relative, there would be a significant increase in prevention (41 versus 55 per cent; P = 0.010). [Conclusion]: ESGE, USMSTF, and NCCN criteria for familial colorectal cancer were met in 6.3, 9.4, and 30.4 per cent of patients with EOCRC respectively. In these patients, early detection and/or prevention could be achieved in 52, 70, and 51.4 per cent respectively. Early and accurate identification of familial colorectal cancer risk and increase in the uptake of early colonoscopy are key to decreasing familial EOCRC., This study was funded by Instituto de Salud Carlos III through project PI20/0974 to J.P and PI19/01867 to F.B. (co-funded by European Regional Development Fund ‘A way to make Europe’); and Agència de Gestió d’Ajuts Universitaris i de Recerca (Generalitat de Catalunya, GRC 2017SGR653). Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas is funded by the Instituto de Salud Carlos III.

BACKGROUND & AIMS: Patients with early-onset colorectal cancer (eoCRC) are managed according to guidelines that are not age-specific. A multidisciplinary international group (DIRECt), composed of 69 experts, was convened to develop the first evidence-based consensus recommendations for eoCRC. METHODS: After reviewing the published literature, a Delphi methodology was used to draft and respond to clinically relevant questions. Each statement underwent 3 rounds of voting and reached a consensus level of agreement of ≥80%. RESULTS: The DIRECt group produced 31 statements in 7 areas of interest: diagnosis, risk factors, genetics, pathology-oncology, endoscopy, therapy, and supportive care. There was strong consensus that all individuals younger than 50 should undergo CRC risk stratification and prompt symptom assessment. All newly diagnosed eoCRC patients should receive germline genetic testing, ideally before surgery. On the basis of current evidence, endoscopic, surgical, and oncologic treatment of eoCRC should not differ from later-onset CRC, except for individuals with pathogenic or likely pathogenic germline variants. The evidence on chemotherapy is not sufficient to recommend changes to established therapeutic protocols. Fertility preservation and sexual health are important to address in eoCRC survivors. The DIRECt group highlighted areas with knowledge gaps that should be prioritized in future research efforts, including age at first screening for the general population, use of fecal immunochemical tests, chemotherapy, endoscopic therapy, and post-treatment surveillance for eoCRC patients. CONCLUSIONS: The DIRECt group produced the first consensus recommendations on eoCRC. All statements should be considered together with the accompanying comments and literature reviews. We highlighted areas where research should be prioritized. These guidelines represent a useful tool for clinicians caring for patients with eoCRC. publishedVersion

The original version of this Article did not contain details of Dutch Cancer Society (DCS) funding (grant number UL 2017-8223) in the Acknowledgements section. This has now been corrected in both the PDF and HTML versions of the Article.

SUMMARYFaithful segregation of bacterial chromosomes relies on the ParABS partitioning system and the SMC complex. In this work, we used single molecule techniques to investigate the role of cytidine triphosphate (CTP) binding and hydrolysis in the critical interaction between centromere-like parS DNA sequences and the ParB CTPase. Using a combined dual optical tweezers confocal microscope, we observe the specific interaction of ParB with parS directly. Binding around parS is enhanced 4-fold by the presence of CTP or the non-hydrolysable analogue CTPγS. However, ParB proteins are also detected at a lower density in distal non-specific regions of DNA. This requires the presence of a parS loading site and is prevented by roadblocks on DNA, consistent with one dimensional diffusion by a sliding clamp. Magnetic tweezers experiments show that the spreading activity, which has an absolute requirement for CTP binding but not hydrolysis, results in the condensation of parS-containing DNA molecules at low nanomolar protein concentrations. We propose a model in which ParB-CTP-Mg2+ complexes move along DNA following loading at parS sites and protein:protein interactions result in the localised condensation of DNA within ParB networks.

Colorectal cancer (CRC) is a complex disease that can be caused by a spectrum of genetic variants ranging from low to high penetrance changes, that interact with the environment to determine which individuals will develop the disease. In this study, we sequenced 20 early-onset CRC patients to discover novel genetic variants that could be linked to the prompt disease development. Eight genes, CHAD, CHD1L, ERCC6, IGTB7, PTPN13, SPATA20, TDG and TGS1, were selected and re-sequenced in a further 304 early onset CRC patients to search for rare, high-impact variants. Although we found a recurring truncating variant in the TDG gene shared by two independent patients, the results obtained did not help consolidate any of the candidates as promising CRC predisposing genes. However, we found that potential risk alleles in our extended list of candidate variants have a tendency to appear at higher numbers in younger cases. This supports the idea that CRC onset may be oligogenic in nature and may show molecular heterogeneity. Further, larger and robust studies are thus needed to unravel the genetics behind early-onset CRC development, coupled with novel functional analyses and omic approaches that may offer complementary insight. This research was supported by Grants from Instituto de Salud Carlos III /FEDER: PI11/00681 (CRP), PI16/01057 (AC), PI17/00509 (CRP), PI17/00878 (SCB), PI19/00179 (CFR), PI19/01316 (JMC-T), PI20/01113 (SCB), PI20/00226 (CRP); CIBERONC-CB16/12/00234 (LV); and Fundación Olga Torres (LV and CFR); CERCA Program and Agència de Gestió d’Ajuts Universitaris i de Recerca (Generalitat de Catalunya, GRPRE 2017SGR21, GRC 2017SGR653). AL-N is supported by a Predoctoral Fellowship (GAIN, Xunta de Galicia, 2018 call) and IQ is supported by the FPI program of the Spanish Ministry of Science and Innovation—FEDER (SAF2016-80888-R). This article is based upon work from COST Action TransColonCan CA17118, supported by European Cooperation in Science and Technology (COST—www.cost.eu; www.transcoloncan.eu).

Accumulating evidence supports the fact that the mere presence of mucinous differentiation in colorectal cancer (CRC), rather than its proportion, is a more accurate representative of a particular CRC subtype with distinct clinical and molecular features. In addition, the prognostic significance of the mucinous carcinoma (MC) subtype remains poorly understood and biomarkers have been barely explored in this disease. Herein, we have performed a systematic and comprehensive analysis in MCs and non-MCs and identified a panel of microRNAs (miRNAs) that are differentially expressed between these two subtypes of CRC. Next, we interrogated their clinical significance and demonstrated their robust diagnostic and prognostic clinical ability in CRCs with mucinous differentiation. Finally, we established an integrative risk-assessment model by combining the miRNA-based risk scores together with TNM staging, which was a superior predictor of prognosis in mucinous CRC patients. Collectively, we report a novel miRNA biomarker panel for the identification and predicting survival in CRC patients with mucinous differentiation.

ESGE recommends that individuals with hereditary gastrointestinal polyposis syndromes should be surveilled in dedicated units that provide monitoring of compliance and endoscopic performance measures. Strong recommendation, moderate quality of evidence, level of agreement 90 %.ESGE recommends performing esophagogastroduodenoscopy, small-bowel examination, and/or colonoscopy earlier than the planned surveillance procedure if a patient is symptomatic. Strong recommendation, low quality of evidence, level of agreement 100 %.

Ogławianie drzew optymalizuje pozyskiwanie biomasy odnawialnej i ułatwia lokalną produkcję drewna opałowego, zrębek, tarcicy i paszy. Zbiór odbywa się na przestrzeni dziesięcioleci, w zależności od wybranego cyklu zbioru i przeznaczenia materiału. Wiele gatunków drzew można poddać ogławianiu w celu uzyskania różnorodnych produktów. Ogławianie drzew wydłuża ich życie. Wskutek ograniczania ich wzrostu, są bardziej odporne na wiatry i susze, a to może być szczególnie ważne w warunkach zmian klimatu. Stare ogławiane drzewa separują żywe komórki (na zewnątrz) od martwych (w środku pnia), by ochronić je przed chorobami. Pnie drzew, a nawet ich korzenie są siedliskiem bioróżnorodności flory i fauny.

There is limited scientific evidence available to stratify the risk of developing metachronous colorectal cancer after resection of colonic polyps and to determine surveillance intervals and is mostly based on observational studies. However, while awaiting further evidence, the criteria of endoscopic follow-up needs to be unified in our setting. Therefore, the Spanish Association of Gastroenterology, the Spanish Society of Family and Community Medicine, the Spanish Society of Digestive Endoscopy, and the Colorectal Cancer Screening Group of the Spanish Society of Epidemiology, have written this consensus document, which is included in chapter 10 of the "Clinical Practice Guideline for Diagnosis and Prevention of Colorectal Cancer. 2018 Update". Important developments will also be presented as regards the previous edition published in 2009. First of all, situations that require and do not require endoscopic surveillance are established, and the need of endoscopic surveillance of individuals who do not present a special risk of metachronous colon cancer is eliminated. Secondly, endoscopic surveillance recommendations are established in individuals with serrated polyps. Finally, unlike the previous edition, endoscopic surveillance recommendations are given in patients operated on for colorectal cancer. At the same time, it represents an advance on the European guideline for quality assurance in colorectal cancer screening, since it eliminates the division between intermediate risk group and high risk group, which means the elimination of a considerable proportion of colonoscopies of early surveillance. Finally, clear recommendations are given on the absence of need for follow-up in the low risk group, for which the European guidelines maintained some ambiguity. (C) 2018 Elsevier Espana, S.L.U. All rights reserved.

There is limited scientific evidence available to stratify the risk of developing metachronous colorectal cancer after resection of colonic polyps and to determine surveillance intervals and is mostly based on observational studies. However, while awaiting further evidence, the criteria of endoscopic follow-up needs to be unified in our setting. Therefore, the Spanish Association of Gastroenterology, the Spanish Society of Family and Community Medicine, the Spanish Society of Digestive Endoscopy, and the Colorectal Cancer Screening Group of the Spanish Society of Epidemiology, have written this consensus document, which is included in chapter 10 of the "Clinical Practice Guideline for Diagnosis and Prevention of Colorectal Cancer. 2018 Update". Important developments will also be presented as regards the previous edition published in 2009. First of all, situations that require and do not require endoscopic surveillance are established, and the need of endoscopic surveillance of individuals who do not present a special risk of metachronous colon cancer is eliminated. Secondly, endoscopic surveillance recommendations are established in individuals with serrated polyps. Finally, unlike the previous edition, endoscopic surveillance recommendations are given in patients operated on for colorectal cancer. At the same time, it represents an advance on the European guideline for quality assurance in colorectal cancer screening, since it eliminates the division between intermediate risk group and high risk group, which means the elimination of a considerable proportion of colonoscopies of early surveillance. Finally, clear recommendations are given on the absence of need for follow-up in the low risk group, for which the European guidelines maintained some ambiguity.

Background Serrated polyposis syndrome (SPS) has been associated with an increased risk of colorectal cancer (CRC). Accordingly, intensive surveillance with annual colonoscopy is advised. The aim of this multicenter study was to describe the risk of advanced lesions in SPS patients undergoing surveillance, and to identify risk factors that could guide the prevention strategy. Methods From March 2013 to April 2015, 296 patients who fulfilled criteria I and/or III for SPS were retrospectively recruited at 18 centers. We selected patients in whom successful clearing colonoscopy had been performed and who underwent subsequent endoscopic surveillance. Advanced neoplasia was defined as CRC, advanced adenoma, or advanced serrated lesion that were >= 10 mm and/or with dysplasia. Cumulative incidence of advanced neoplasia was calculated and independent predictors of advanced neoplasia development were identified. Results In 152 SPS patients a total of 315 surveillance colonoscopies were performed (median 2, range 1-7). The 3-year cumulative incidence of CRC and advanced neoplasia were 3.1% (95% confidence interval [CI] 0-6.9) and 42.0% (95%CI 32.4-51.7), respectively. Fulfilling both I+III criteria and the presence of advanced serrated lesions at baseline colonoscopy were independent predictors of advanced neoplasia development (odds ratio [OR] 1.85, 95%CI 1.03-3.33, P = 0.04 and OR 2.62, 95%CI 1.18-5.81, P = 0.02, respectively). During follow-up, nine patients (5.9%) were referred for surgery for invasive CRC (n=4, 2.6%) or because of polyp burden (n=5, 3.3%). After total colectomy, 17.9% patients developed advanced neoplasia in the retained rectum. Conclusions Patients with SPS have a substantial risk of developing advanced neoplasia under endoscopic surveillance, whereas CRC incidence is low. Personalized endoscopic surveillance based on polyp burden and advanced serrated histology could help to optimize prevention in patients with SPS.

Agroleśnictwo jest zrównoważonym sposobem gospodarowania gruntami, który powinien być wspierany w ramach WPR. W obrębie I filara WPR, należy uwzględnić wsparcie do agroleśnictwa na gruntach ornych, pastwiskach trwałych i lasach w oparciu o plany zarządzania tymi gruntami, zarówno w perspektywie krótko- jak i długoterminowej. Filar II WPR powinien wspierać zakładanie oraz pielęgnację systemów rolno-leśnych zarówno na gruntach rolnych jak i leśnych. Należy zapewnić kwalifikowalność gruntów z zadrzewieniami do płatności bezpośrednich. Transformacja w kierunku agroleśnictwa powinna obejmować rozwój innowacji oraz dzielenie się wiedzą z wykorzystaniem usług doradztwa. - Agroforestry is a sustainable land use system that should be promoted by the CAP. Pillar I should support agroforestry on their 3 types of lands through the recognition of management plans at short and long term. Pillar II should support the establishment and maintenance of agroforestry in agricultural and forestry lands, and in the first case to ensure the land to remain eligible. Agroforestry transition should be promoted through the development of innovation and extension services.

Purpose: A recent study reported that 5 -fluorouracil (5-FU)based dientotherapy 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, wellcharacterized patient cohorts. Experimental Design: Two cohorts of 783 patients with colorectal cancer: 532 from a population-based, multicenter cohort (FPICOLON 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 hisulfite 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 PIK 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 TEAP2E hypermethylation status in 5-FU-treated (HR, 0.91; 95% Cl, 0.51 1.59; log-rank P = 0.9) as well as in nontreated patients (HR, 88; 95% CI, 0 5 - 1 .54; log-rank P = 0.7). Conclusions: TFAP2E hypemiethylation does nut correlate with loss of its protein expression. Our large, systematic, and comprehensive study indicates that TEAP2E methylation and expression may not play a major role in predicting response to 5-FU-based chemotherapy in patients with colorectal cancer. (C) 2018 AACR.

AFINET is one of the seventeen thematic networks that the European Union has financed under the H2020 framework and it is supervised by the EIP-Agri in order to foster innovation in Europe. The main topic of AFINET is agroforestry a practice of deliberately integrating woody vegetation with crops and/or animal systems and the promotion of this practice to foster climate changes. AFINET follows a multi-actor approach linked to the nine Regional Innovations Networks created to identify main challenges and develop main innovations about agroforestry. Main challenges were related to technical, economic, communication and policy issues.

Maria Liz Leoz, Sabela Carballal, Leticia Moreira, Teresa Ocaña, Francesc Balaguer Department of Gastroenterology, Hospital Clínic, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain Abstract: Familial adenomatous polyposis (FAP) is an inherited disorder that represents the most common gastrointestinal polyposis syndrome. Germline mutations in the APC gene were initially identified as responsible for FAP, and later, several studies have also implicated the MUTYH gene as responsible for this disease, usually referred to as MUTYH-associated polyposis (MAP). FAP and MAP are characterized by the early onset of multiple adenomatous colorectal polyps, a high lifetime risk of colorectal cancer (CRC), and in some patients the development of extracolonic manifestations. The goal of colorectal management in these patients is to prevent CRC mortality through endoscopic and surgical approaches. Individuals with FAP and their relatives should receive appropriate genetic counseling and join surveillance programs when indicated. This review is focused on the description of the main clinical and genetic aspects of FAP associated with germline APC mutations and MAP. Keywords: colorectal cancer, familial adenomatous polyposis, MAP, APC, MUTYH

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.

BACKGROUND & AIMS: We compared the ability of biennial fecal immunochemical testing (FIT) and one-time sigmoidoscopy to detect colon side-specific advanced neoplasms in a population-based, multicenter, nationwide, randomized controlled trial. METHODS: We identified asymptomatic men and women, 50-69 years old, through community health registries and randomly assigned them to groups that received a single colonoscopy examination or biennial FIT. Sigmoidoscopy yield was simulated from results obtained from the colonoscopy group, according to the criteria proposed in the UK Flexible Sigmoidoscopy Trial for colonoscopy referral. Patients who underwent FIT and were found to have >= 75 ng hemoglobin/mL were referred for colonoscopy. Data were analyzed from 5059 subjects in the colonoscopy group and 10,507 in the FIT group. The main outcome was rate of detection of any advanced neoplasm proximal to the splenic flexure. RESULTS: Advanced neoplasms were detected in 317 subjects (6.3%) in the sigmoidoscopy simulation group compared with 288 (2.7%) in the FIT group (odds ratio for sigmoidoscopy, 2.29; 95% confidence interval, 1.93-2.70; P = .0001). Sigmoidoscopy also detected advanced distal neoplasia in a higher percentage of patients than FIT (odds ratio, 2.61; 95% confidence interval, 2.20-3.10; P = .0001). The methods did not differ significantly in identifying patients with advanced proximal neoplasms (odds ratio, 1.17; 95% confidence interval, 0.78-1.76; P = .44). This was probably due to the lower performance of both strategies in detecting patients with proximal lesions (sigmoidoscopy detected these in 19.1% of patients and FIT in 14.9% of patients) vs distal ones (sigmoidoscopy detected these in 86.8% of patients and FIT in 33.5% of patients). Sigmoidoscopy, but not FIT, detected proximal lesions in lower percentages of women (especially those 50-59 years old) than men. CONCLUSIONS: Sigmoidoscopy and FIT have similar limitations in detecting advanced proximal neoplasms, which depend on patients' characteristics; sigmoidoscopy underperforms for women 50-59 years old. Screening strategies should be designed on the basis of target population to increase effectiveness and cost-effectiveness. ClinicalTrials.govnumber: NCT00906997

Colorectal cancer (CRC) is the second leading cause of cancer-related death among men and women in Western countries. Once a tumour develops, a differentiated prognosis could be determined by lifestyle habits or inherited and somatic genetic factors. Finding such prognostic factors will be helpful in order to identify cases with a shorter survival or at a higher risk of recurrence that may benefit from more intensive treatment and follow-up surveillance. Sixteen CRC genetic susceptibility variants were directly genotyped in a cohort of 1235 CRC patients recruited by the EPICOLON Spanish consortium. Univariate Cox and multivariate regression analyses were performed taking as primary outcomes overall survival (OS), disease-free survival and recurrence-free interval. Genetic variants rs9929218 at 16q22.1 and rs10795668 at 10p14 may have an effect on OS. The G allele of rs9929218 was linked with a better OS [GG genotype, genotypic model: hazard ratio (HR) 0.65, 95% confidence interval (CI) 0.450.93, P 0.0179; GG/GA genotypes, dominant model: HR 0.66, 95% CI 0.470.94, P 0.0202]. Likewise, the G allele of rs10795668 was associated with better clinical outcome (GG genotype, genotypic model: HR 0.73, 95% CI 0.531.01, P 0.0570; GA genotype, genotypic model: HR 0.66, 95% CI 0.470.92, P 0.0137; GG/GA genotypes, dominant model: HR 0.68, 95% CI 0.500.94, P 0.0194). In conclusion, CRC susceptibility variants rs9929218 and rs10795668 may exert some influence in modulating patients survival and they deserve to be further tested in additional CRC cohorts in order to confirm their potential as prognosis or predictive biomarkers.

Dans le chapitre 1 je donne des résultats dèjá connus, le premier ces résultats est, à vrai dire, une extension du résultat publié antérieurement. Dans le chapitre 2, à l'aide des propiétés des fonctions représentées par des séries de Taylor lacunaires , nous étudions, dans l'espace fonctionnel des fonctions entières d'ordre précise équivalent à $\rho(r)$, l'ensemble des fonctions qui ont une valeur exceptionelle et l'ensemble des fonctions qui appartiennent à la classe sinusoidal ,classe que nous définissons dans le même chapitre. Dans le chapitre 3 nous démontrons en premier lieu , que l'introductions d'une condition lacunaire fait disparaître la possible exceptions dans le théorème de Nevanlinna que, d'une forme abrégée, on peut énoncer comme suit: deux fonctions qui prennent quatre valeurs dans les mêmes points, sont identiques. en deuxième lien nous démontrons que moyennant une condition lacunaire , un autre téhorème d'unicité, dû aussi Nevalinna, peut s'étendre au cas de l'ordre entier ,mais uniquement pour les fonctions entières. Finalement, dans le chapitre 4 j'etablis une classification des valeurs asymptomatiques d'après la courbe décrite par la variable et d'après la rapidité avec laquelle la fonction tend vers le valeur asymtotique; je donne ensuite des conditions lacunaires suffisantes pour affirmer l'imposibilité de l'existence de valeurs asymtotiques de classe et de type déterminés.

An object-oriented design is presented for building dynamic three-dimensional applications. This design takes the form of the Fifth Dimension Toolkit consisting of a set of interrelated classes whose instances may be connected together in a variety of ways to form different applications. Animation is obtained by connecting graphical objects to dynamic variables, which are able to change their values over time by responding to events. The Fifth Dimension Toolkit is the core of the Fifth Dimension Project, a research project for animating synthetic actors in their environment. The design philosophy and methodology of the toolkit are also described, as well as some of the implementation issues for the Silicon Graphics Iris 4D workstation

Background: The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants (path_MMR) who are receiving medical follow-up, including colonoscopy surveillance, which aims to the achieve early diagnosis and treatment of cancers. Here we use the most recent PLSD cohort that is larger and has wider geographical representation than previous versions, allowing us to present mortality as an outcome, and median ages at cancer diagnoses for the first time.Methods: The PLSD is a prospective observational study without a control group that was designed in 2012 and updated up to October 2022. Data for 8500 carriers of path_MMR variants from 25 countries were included, providing 71,713 years of follow up. Cumulative cancer incidences at 65 years of age were combined with 10-year crude survival following cancer, to derive estimates of mortality up to 75 years of age by organ, gene, and gender.Findings: Gynaecological cancers were more frequent than colorectal cancers in path_MSH2, path_MSH6 and path_PMS2 carriers [cumulative incidence: 53.3%, 49.6% and 23.3% at 75 years, respectively]. Endometrial, colon and ovarian cancer had low mortality [8%, 13% and 15%, respectively] and prostate cancers were frequent in male path_MSH2 carriers [cumulative incidence: 39.7% at 75 years]. Pancreatic, brain, biliary tract and ureter and kidney and urinary bladder cancers were associated with high mortality [83%, 66%, 58%, 27%, and 29%, respectively]. Among path_MMR carriers undergoing colonoscopy surveillance, particularly path_MSH2 carriers, more deaths followed non-colorectal Lynch syndrome cancers than colorectal cancers.Interpretation: In path_MMR carriers undergoing colonoscopy surveillance, non-colorectal Lynch syndrome cancers were associated with more deaths than were colorectal cancers. Reducing deaths from non-colorectal cancers presents a key challenge in contemporary medical care in Lynch syndrome. Background: The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants (path_MMR) who are receiving medical follow-up, including colonoscopy surveillance, which aims to the achieve early diagnosis and treatment of cancers. Here we use the most recent PLSD cohort that is larger and has wider geographical representation than previous versions, allowing us to present mortality as an outcome, and median ages at cancer diagnoses for the first time. Methods: The PLSD is a prospective observational study without a control group that was designed in 2012 and updated up to October 2022. Data for 8500 carriers of path_MMR variants from 25 countries were included, providing 71,713 years of follow up. Cumulative cancer incidences at 65 years of age were combined with 10-year crude survival following cancer, to derive estimates of mortality up to 75 years of age by organ, gene, and gender. Findings: Gynaecological cancers were more frequent than colorectal cancers in path_MSH2, path_MSH6 and path_PMS2 carriers [cumulative incidence: 53.3%, 49.6% and 23.3% at 75 years, respectively]. Endometrial, colon and ovarian cancer had low mortality [8%, 13% and 15%, respectively] and prostate cancers were frequent in male path_MSH2 carriers [cumulative incidence: 39.7% at 75 years]. Pancreatic, brain, biliary tract and ureter and kidney and urinary bladder cancers were associated with high mortality [83%, 66%, 58%, 27%, and 29%, respectively]. Among path_MMR carriers undergoing colonoscopy surveillance, particularly path_MSH2 carriers, more deaths followed non-colorectal Lynch syndrome cancers than colorectal cancers. Interpretation: In path_MMR carriers undergoing colonoscopy surveillance, non-colorectal Lynch syndrome cancers were associated with more deaths than were colorectal cancers. Reducing deaths from non-colorectal cancers presents a key challenge in contemporary medical care in Lynch syndrome. Funding: We acknowledge funding from the Norwegian Cancer Society, contract 194751-2017.

Càncer en l’adult i pediatria; Síndromes hereditàries; Perfil genètic; Precisió Cáncer en el adulto y pediatría; Síndromes hereditarios; Perfil genético; Precisión Cancer in adults and pediatrics; Hereditary syndromes; Genetic profile; Accuracy En aquest estudi per a cadascuna de les síndromes es defineixen els criteris clínics d’estudi genètic que es basen en la probabilitat d’identificar variants patogèniques i en l’accionabilitat clínica. En alguns casos quan l’estudi es realitza per a una indicació terapèutica el criteri quedarà condicionat a l’aprovació d’aquesta indicació. En les síndromes en les quals els criteris són els de diagnòstic clínic (per exemple, síndromes endocrines) no s’especifiquen. Per a cada indicació clínica s’especifiquen els gens que s’han d’incloure i que s’han de fer constar en l’informe. En totes les indicacions s’inclou en l’assessorament genètic pretest oferir el cribratge oportunista dels gens BRCA1, BRCA2, MLH1, MSH2, MSH6. Per aquest motiu, aquests gens estan inclosos en tots els panels i no només en les síndromes relacionades.

Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods. Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results. Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion. Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.

Main RecommendationsESGE recommends that individuals with hereditary gastrointestinal polyposis syndromes should be surveilled in dedicated units that provide monitoring of compliance and endoscopic performance measures. Strong recommendation, moderate quality of evidence, level of agreement 90 %.ESGE recommends performing esophagogastroduodenoscopy, small-bowel examination, and/or colonoscopy earlier than the planned surveillance procedure if a patient is symptomatic. Strong recommendation, low quality of evidence, level of agreement 100 %.

Lynch syndrome (LS) results from pathogenic variants in the mismatch repair (MMR) genes and is the most common hereditary cancer syndrome, affecting an estimated 1 in 300 individuals. Pathogenic variants in each of the MMR genes path_MLH1, path_MSH2, path_MSH6, and path_PMS2 result in different risks for cancers in organs including the colorectum, endometrium, ovaries, stomach, small bowel, bile duct, pancreas, and upper urinary tract. Accurate estimates of these risks are essential for planning appropriate approaches to the prevention or early diagnosis of cancers but the robustness of previous studies has been limited by factors including retrospective design,1,2 lack of validation in independent cohorts,3-5 and inconsistent classification of genetic variants. Unexpected findings from previous studies have included path_MLH1 and path_MSH2 carriers appearing to have a lifetime risk of colorectal cancer (CRC) of approximately 50%, despite surveillance colonoscopy,6-8 and that shorter intervals between colonoscopies do not seem to reduce the incidence of CRC in LS.9,10 These findings challenge the assumptions that CRC in LS usually develops from a noninfiltrative adenoma precursor and that CRC can be prevented by colonoscopic detection and removal of adenomas in the colon and rectum. Additionally, previous studies in the Prospective Lynch Syndrome Database (PLSD) have shown no increase in cancer risk in path_PMS2 carriers before 40 years of age and, although observation years were limited in older path_PMS2 carriers, LS-associated cancers other than endometrial and prostate were not observed.6-8 In this study we collected prospective data from a new large cohort of path_MMR carriers to validate previous findings from PLSD. We also updated information on the original cohort to ensure consistent classification of pathogenicity of MMR gene variants. We then combined both data sets, providing larger numbers that allowed us to derive more precise risk estimates for cancers in LS categorized by gene and gender.

Microtubule-targeting agents (MTAs) are a class of clinically successful anti-cancer drugs. The emergence of multidrug resistance to MTAs imposes the need for developing new MTAs endowed with diverse mechanistic properties. Benzoxazepines were recently identified as a novel class of MTAs. These anticancer agents were thoroughly characterized for their antitumor activity, although, their exact mechanism of action remained elusive. Combining chemical, biochemical, cellular, bioinformatics and structural efforts we developed improved pyrrolonaphthoxazepines antitumor agents and their mode of action at the molecular level was elucidated. Compound 6j, one of the most potent analogues, was confirmed by X-ray as a colchicine-site MTA. A comprehensive structural investigation was performed for a complete elucidation of the structure-activity relationships. Selected pyrrolonaphthoxazepines were evaluated for their effects on cell cycle, apoptosis and differentiation in a variety of cancer cells, including multidrug resistant cell lines. Our results define compound 6j as a potentially useful optimized hit for the development of effective compounds for treating drug-resistant tumors., This work was supported in part by a grant from the Swiss National Science Foundation (31003A_166608; to M.O.S), grant BFU2016-75319-R (AEI/FEDER, EU) from Ministerio de Economia y Competitividad, Blueprint 282510, AIRC-17217. The authors acknowledge networking contribution by the COST Action CM1407 “Challenging organic syntheses inspired by nature - from natural products chemistry to drug discovery” (to M.O.S. and J.F.D.) and the COST Action EPICHEMBIO CM-1406 (to L.A. and G.C.). This work has also received partial funding from the European Union’s Horizon 2020 (EU) research and innovation programme under the Marie Sklodowska-Curie grant agreement No 721906. Finally, this work was partially funded by MIUR-PRIN project n. 2015Y3C5KP (to L.M.).

Knowledge of genetic susceptibility to gastrointestinal cancers is constantly evolving with identification of new genes. Similarly, a better understanding of the genotype/phenotype relationship in patients with Lynch syndrome (LS) or familial adenomatous polyposis (FAP) is leading to more individualised surveillance recommendations. In addition, molecular profiling of patients with cancer has been shown to guide targeted therapies, such as immunotherapy. Specialists involved in the care of patients with gastrointestinal cancer should be familiar with the main hereditary cancer syndromes and refer patients to specialised cancer genetic units for adequate genetic counselling and to address specific concerns associated to each genetic susceptibility. These guidelines aim to summarise the evidence-based data on hereditary colorectal cancer (CRC), gastric cancer (GC) and pancreatic cancer (PC) and provide useful clinical recommendations for identification and management of patients with hereditary gastrointestinal cancers.