Short-term preoperative radiotherapy reduces the risk of local recurrence in patients with rectal cancer who undergo a standardized total mesorectal excision.

Extensive epidemiologic studies have suggested that adult disease risk is associated with adverse environmental conditions early in development. Although the mechanisms behind these relationships are unclear, an involvement of epigenetic dysregulation has been hypothesized. Here we show that individuals who were prenatally exposed to famine during the Dutch Hunger Winter in 1944 -45 had, 6 decades later, less DNA methylation of the imprinted IGF2 gene compared with their unexposed, same-sex siblings. The association was specific for periconceptional exposure, reinforcing that very early mammalian development is a crucial period for establishing and maintaining epigenetic marks. These data are the first to contribute empirical support for the hypothesis that early-life environmental conditions can cause epigenetic changes in humans that persist throughout life.developmental origins ͉ DNA methylation ͉ insulin-like growth factor II ͉ nutrition ͉ periconception S uperimposed on the DNA sequence is a layer of epigenetic information that is heritable, particularly during mitosis, and controls the potential of a genomic region to be transcribed (1). Methyl groups coupled to cytosines in cytosine-guanine (CpG) dinucleotides and modifications of histones that package the DNA are the two main molecular marks that compose this information and regulate chromatin structure and DNA accessibility (2).Animal studies have indicated that certain transient environmental influences can produce persistent changes in epigenetic marks that have life-long phenotypic consequences (3, 4). Early embryonic development is of special interest in this respect, because this is a crucial period for establishing and maintaining epigenetic marks (5). Indeed, culturing of preimplantation mice embryos found that epigenetic marks are susceptible to nutritional conditions in the very early stages of mammalian development (6, 7). One of the rare opportunities for studying the relevance of such findings to humans is presented by individuals who were prenatally exposed to famine during the Dutch Hunger Winter (8). This period of famine was the consequence of a Germanimposed food embargo in the western part of The Netherlands toward the end of World War II in the winter of 1944-45. During this period, registries and health care remained intact, so that individuals who were prenatally exposed to this famine can be traced. Moreover, the period of famine was clearly defined, and official food rations were documented. These unique features allow us to assess whether prenatal exposure to famine is associated with persistent epigenetic differences in humans.One of the best-characterized epigenetically regulated loci is insulin-like growth factor II (IGF2). IGF2 is a key factor in human growth and development and is maternally imprinted (9). Imprinting is maintained through the IGF2 differentially methylated region (DMR), the hypomethylation of which leads to bi-allelic expression of IGF2 (10). We recently studied IGF2 DMR methylation in 372 twins (11). IGF2 D...

Standard survival data measure the time span from some time origin until the occurrence of one type of event. If several types of events occur, a model describing progression to each of these competing risks is needed. Multi-state models generalize competing risks models by also describing transitions to intermediate events. Methods to analyze such models have been developed over the last two decades. Fortunately, most of the analyzes can be performed within the standard statistical packages, but may require some extra effort with respect to data preparation and programming. This tutorial aims to review statistical methods for the analysis of competing risks and multi-state models. Although some conceptual issues are covered, the emphasis is on practical issues like data preparation, estimation of the effect of covariates, and estimation of cumulative incidence functions and state and transition probabilities. Examples of analysis with standard software are shown.

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Prenatal famine in humans has been associated with various later-life consequences, depending on the gestational timing of the insult and the sex of the exposed individual. Epigenetic mechanisms have been proposed to underlie these associations. Indeed, animal studies and our early human data on the imprinted IGF2 locus indicated a link between prenatal nutritional and DNA methylation. However, it remains unclear how common changes in DNA methylation are and whether they are sex- and timing-specific paralleling the later-life consequences of prenatal famine exposure. To this end, we investigated the methylation of 15 loci implicated in growth and metabolic disease in individuals who were prenatally exposed to a war-time famine in 1944-45. Methylation of INSIGF was lower among individuals who were periconceptionally exposed to the famine (n = 60) compared with their unexposed same-sex siblings (P = 2 x 10(-5)), whereas methylation of IL10, LEP, ABCA1, GNASAS and MEG3 was higher (all P < 10(-3)). A significant interaction with sex was observed for INSIGF, LEP and GNASAS. Next, methylation of eight representative loci was compared between 62 individuals exposed late in gestation and their unexposed siblings. Methylation was different for GNASAS (P = 1.1 x 10(-7)) and, in men, LEP (P = 0.017). Our data indicate that persistent changes in DNA methylation may be a common consequence of prenatal famine exposure and that these changes depend on the sex of the exposed individual and the gestational timing of the exposure.

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Purpose: Recommendations for adjuvant treatment for women with early-stage endometrial carcinoma are based on clinicopathologic features. Comprehensive genomic characterization defined four subgroups: p53-mutant, microsatellite instability (MSI), POLE-mutant, and no specific molecular profile (NSMP). We aimed to confirm the prognostic capacity of these subgroups in large randomized trial populations, investigate potential other prognostic classifiers, and integrate these into an integrated molecular risk assessment guiding adjuvant therapy.Experimental Design: Analysis of MSI, hotspot mutations in 14 genes including POLE, protein expression of p53, ARID1a, b-catenin, L1CAM, PTEN, ER, and PR was undertaken on 947 available early-stage endometrioid endometrial carcinomas from the PORTEC-1 and -2 trials, mostly high-intermediate risk (n ¼ 614). Prognostic value was determined using univariable and multivariable Cox proportional hazard models. AUCs of different risk stratification models were compared.Results: Molecular analyses were feasible in >96% of the patients and confirmed the four molecular subgroups: p53-mutant (9%), MSI (26%), POLE-mutant (6%), and NSMP (59%). Integration of prognostic molecular alterations with established clinicopathologic factors resulted in a stronger model with improved risk prognostication. Approximately 15% of highintermediate risk patients had unfavorable features (substantial lymphovascular space invasion, p53-mutant, and/or >10% L1CAM), 50% favorable features (POLE-mutant, NSMP being microsatellite stable, and CTNNB1 wild-type), and 35% intermediate features (MSI or CTNNB1-mutant).Conclusions: Integrating clinicopathologic and molecular factors improves the risk assessment of patients with early-stage endometrial carcinoma. Assessment of this integrated risk profile is feasible in daily practice, and holds promise to reduce both overtreatment and undertreatment.