A Diffusion-like Process Accommodates New Crypts During Clonal Expansion in Human Colonic Epithelium.

BACKGROUND & AIMS: Colorectal cancer (CRC) is thought to arise when the cumulative mutational burden within colonic crypts exceeds a certain threshold that leads to clonal expansion and ultimately neoplastic transformation. Therefore, quantification of the fixation and subsequent expansion of somatic mutations in normal epithelium is key to understanding colorectal cancer initiation. The aim of the present study was to determine how advantaged expansions can be accommodated in the human colon. METHODS: Immunohistochemistry was used to visualize loss of the cancer driver KDM6A in formalin-fixed paraffin-embedded (FFPE) normal human colonic epithelium. Combining microscopy with neural network-based image analysis, we determined the frequencies of KDM6A-mutant crypts and fission/fusion intermediates as well as the spatial distribution of clones. Mathematical modeling then defined the dynamics of their fixation and expansion. RESULTS: Interpretation of the age-related behavior of KDM6A-negative clones revealed significant competitive advantage in intracrypt dynamics as well as a 5-fold increase in crypt fission rate. This was not accompanied by an increase in crypt fusion. Mathematical modeling of crypt spacing identifies evidence for a crypt diffusion process. We define the threshold fission rate at which diffusion fails to accommodate new crypts, which can be exceeded by KRAS activating mutations. CONCLUSIONS: Advantaged gene mutations in KDM6A expand dramatically by crypt fission but not fusion. The crypt diffusion process enables accommodation of the additional crypts up to a threshold value, beyond which polyp growth may occur. The fission rate associated with KRAS mutations offers a potential explanation for KRAS-initiated polyps.

Teacher perceptions of sun protection practices in the secondary school setting: Barriers, enablers and recommendations for future.

OBJECTIVE: This qualitative study aimed to explore sun protection barriers and enablers in secondary schools in Victoria. METHODS: Five focus groups were conducted with nominated Health or Physical Education (PE) Coordinators (or other staff representatives) from schools in metropolitan and regional Victoria. Discussions were audio-recorded, transcribed and coded thematically. RESULTS: Participants identified the need for regulatory influences that included minimum standards for sun protection policy, training and shade in the built environment. Participants perceived that sun protection is not always acknowledged to be a duty of care in secondary schools. A crowded health and well-being curriculum, a focus on fostering independence, and challenges overcoming peer norms were perceived to be important contextual influences. At an organisational level, strong leadership and a united approach among staff were identified as critical ingredients for successful policy implementation and organisational change. Several potentially effective strategies were proposed, including increased shade, leveraging from student leaders, normalising sun protection practices and prioritising staff role modelling. CONCLUSIONS: A cultural shift is required for many schools to accept and act on sun protection as a duty of care. A comprehensive approach that includes regulatory action, healthy school policies and leading by example may help protect students and staff from harmful UV exposure during school hours. SO WHAT?: Without regulatory support, strong leadership is required to implement and enforce sun protection practices within schools. Health promotion programs could assist schools to trial and evaluate the sun protection strategies that involve student-led solutions, role modelling and increasing shade.

Intestinal label-retaining cells are secretory precursors expressing Lgr5.

The rapid cell turnover of the intestinal epithelium is achieved from small numbers of stem cells located in the base of glandular crypts. These stem cells have been variously described as rapidly cycling or quiescent. A functional arrangement of stem cells that reconciles both of these behaviours has so far been difficult to obtain. Alternative explanations for quiescent cells have been that they act as a parallel or reserve population that replace rapidly cycling stem cells periodically or after injury; their exact nature remains unknown. Here we show mouse intestinal quiescent cells to be precursors that are committed to mature into differentiated secretory cells of the Paneth and enteroendocrine lineage. However, crucially we find that after intestinal injury they are capable of extensive proliferation and can give rise to clones comprising the main epithelial cell types. Thus, quiescent cells can be recalled to the stem-cell state. These findings establish quiescent cells as an effective clonogenic reserve and provide a motivation for investigating their role in pathologies such as colorectal cancers and intestinal inflammation.

Not part of my routine: a qualitative study of use and understanding of UV forecast information and the SunSmart app.

BACKGROUND: The Ultraviolet (UV) Index provides a reliable means of monitoring the strength of UV radiation at the Earth's surface, which can be used to indicate the potential for skin damage. This qualitative study aims to examine public understanding of the UV Index among Australians who routinely use UV forecast information as well as those who do not. METHODS: Recent use of the SunSmart app (a popular mobile and tablet app that provides UV forecast information) served as a proxy for use of UV forecast information. Six focus groups were conducted with 'new users', who trialled the SunSmart app for the first time in the two weeks preceding the group discussion. In addition, 15 in-depth interviews were conducted with 'existing users', who routinely used the SunSmart app. Thematic discourse analysis was undertaken to compare views and experiences. RESULTS: Misperceptions about UV radiation were common. Participants learnt new information about UV radiation, the UV Index, and the times of the day that sun protection is recommended. Among adults who were using UV forecast information for the first time, this learning rarely translated to new behaviours; for these participants, the UV Index forecast information and recommendations were inconsistent with their own observation of the weather and subsequent judgement about their propensity to burn. Thus new users considered the UV forecast information to be overly cautious. In contrast, existing users recognised their inability to judge the UV Index level; for these participants, UV forecast information provided by the SunSmart app was incorporated into their daily routines and used to inform their sun protection behaviours. CONCLUSIONS/IMPLICATIONS: No matter how broadly UV forecast information is promoted, it is unlikely to improve sun protection behaviours across the Victorian population due to the low level of basic understanding of UV radiation. Public education strategies that correct the commonly held misperception that temperature and/or sunshine can reliably predict the potential for UV damage are required. Improved public awareness about UV radiation and how the UV Index can be used to prevent skin cancer may help Australians to develop more effective sun protection habits.

The Effect of Pack Warning Labels on Quitting and Related Thoughts and Behaviors in a National Cohort of Aboriginal and Torres Strait Islander Smokers.

INTRODUCTION: The high prevalence of smoking among Aboriginal and Torres Strait Islander people in Australia (39%) contributes substantially to health inequalities. This study assesses the impact of warning labels on quitting and related thoughts and behaviors for Aboriginal and Torres Strait Islander smokers. METHODS: Participants were recruited from communities served by 34 Aboriginal Community Controlled Health Services and communities in the Torres Strait, Australia, using quota sampling. A cohort of 642 daily/weekly smokers completed relevant questions at baseline (April 2012-October 2013) and follow-up (August 2013-August 2014). RESULTS: We considered three baseline predictor variables: noticing warning labels, forgoing cigarettes due to warning labels ("forgoing") and perceiving labels to be effective. Forgoing increased significantly between surveys only for those first surveyed prior to the introduction of plain packs (19% vs. 34%); however, there were no significant interactions between forgoing cigarettes and the introduction of new and enlarged graphic warning labels on plain packaging in any model. Forgoing cigarettes predicted attempting to quit (adjusted odds ratio [AOR]: 1.45, 95% confidence interval [CI]: 1.02-2.06) and, among those who did not want to quit at baseline, wanting to quit at follow-up (AOR: 3.19, 95% CI: 1.06-9.63). Among those less worried about future health effects, all three variables predicted being very worried at follow-up. Often noticing warning labels predicted correct responses to questions about health effects that had featured on warning labels (AOR: 1.84, 95% CI: 1.20-2.82) but not for those not featured. CONCLUSIONS: Graphic warning labels appear to have a positive impact on the understanding, concerns and motivations of Aboriginal and Torres Strait Islander smokers and, through these, their quit attempts. IMPLICATIONS: Graphic warning labels are likely to be effective for Aboriginal and Torres Strait Islander smokers as they are for the broader Australian population.

Predictors of wanting to quit in a national sample of Aboriginal and Torres Strait Islander smokers.

OBJECTIVE: To describe factors that predict wanting to quit smoking in a national sample of Aboriginal and Torres Strait Islander people. DESIGN, SETTING AND PARTICIPANTS: The Talking About The Smokes (TATS) project used a quota sampling design to recruit participants from communities served by 34 Aboriginal community-controlled health services and one community in the Torres Strait. Baseline survey data were collected from 1643 current smokers between April 2012 and October 2013. MAIN OUTCOME MEASURE: Wanting to quit smoking. RESULTS: More than two-thirds of smokers (70%) said they want to quit. Many factors were associated with wanting to quit, including past quitting activity. Interest in quitting was lower among men and smokers from economically disadvantaged areas, but there was no difference by age, remoteness or other measures of economic disadvantage. Attitudes and beliefs negatively associated with wanting to quit included enjoying smoking and believing quitting to be very difficult, and those positively associated included regretting ever starting to smoke, perceiving that local Aboriginal and Torres Strait Islander community leaders disapprove of smoking, believing non-smokers set a good example to children, worrying about future smoking-related health effects and believing quitting to be beneficial. Reporting support from family and friends was predictive of wanting to quit, but factors related to smoking in the social network were not. Associations with health and wellbeing were mixed. While most tobacco control policy exposure variables were positively associated with wanting to quit, two - receiving advice to quit from a health professional, and recall of targeted anti-tobacco advertising - appeared to have an effect that extended beyond influencing relevant attitudes and beliefs. CONCLUSION: Interest in quitting among Aboriginal and Torres Strait Islander smokers appears to be influenced by a broad range of factors, highlighting the importance of taking a comprehensive approach to tobacco control. Advice from health professionals and targeted advertising appear to be important intervention strategies.

Past quit attempts in a national sample of Aboriginal and Torres Strait Islander smokers.

OBJECTIVES: To describe past attempts to quit smoking in a national sample of Aboriginal and Torres Strait Islander people, and to compare their quitting activity with that in the general Australian population. DESIGN, SETTING AND PARTICIPANTS: The Talking About The Smokes (TATS) project used a quota sampling design to recruit participants from communities served by 34 Aboriginal community-controlled health services and one community in the Torres Strait. We surveyed 1643 smokers and 78 recent quitters between April 2012 and October 2013. Baseline results for daily smokers (n = 1392) are compared with results for daily smokers (n = 1655) from Waves 5 to 8.5 (2006-2012) of the Australian International Tobacco Control Policy Evaluation Project (ITC Project). MAIN OUTCOME MEASURES: Ever having tried to quit, tried to quit in the past year, sustained a quit attempt for 1 month or more. RESULTS: Compared with the general population, a smaller proportion of Aboriginal and Torres Strait Islander daily smokers had ever tried to quit (TATS, 69% v ITC, 81.4%), but attempts to quit within the past year were similar (TATS, 48% v ITC, 45.7%). More Aboriginal and Torres Strait Islander daily smokers than those in the general population reported sustaining past quit attempts for short periods only. Aboriginal and Torres Strait Islander smokers whose local health services had tobacco control resources were more likely to have tried to quit, whereas men and people who perceived they had experienced racism in the past year were less likely. Younger smokers, those who had gone without essentials due to money spent on smoking, and those who were often unable to afford cigarettes were more likely to have tried to quit in the past year, but less likely to have ever sustained an attempt for 1 month or more. Smokers who were unemployed, those who had not completed Year 12 and those from remote areas were also less likely to sustain a quit attempt. CONCLUSIONS: Existing comprehensive tobacco control programs appear to be motivating Aboriginal and Torres Strait Islander smokers to quit but do not appear to overcome challenges in sustaining quit attempts, especially for more disadvantaged smokers and those from remote areas.

Smoking-related knowledge and health risk beliefs in a national sample of Aboriginal and Torres Strait Islander people.

OBJECTIVES: To describe general knowledge and perceived risk of the health consequences of smoking among Aboriginal and Torres Strait Islander people; and to assess whether knowledge varies among smokers and whether higher knowledge and perceived risk are associated with quitting. DESIGN, SETTING AND PARTICIPANTS: The Talking About The Smokes project used quota sampling to recruit participants from communities served by 34 Aboriginal community-controlled health services and one community in the Torres Strait. Baseline survey data were collected from 2522 Aboriginal and Torres Strait Islander adults from April 2012 to October 2013. MAIN OUTCOME MEASURES: Knowledge of direct effects of smoking and harms of second-hand smoke (SHS), risk minimisation, health worry, and wanting and attempting to quit. RESULTS: Most Aboriginal and Torres Strait Islander participants who were daily smokers demonstrated knowledge that smoking causes lung cancer (94%), heart disease (89%) and low birthweight (82%), but fewer were aware that it makes diabetes worse (68%). Similarly, almost all daily smokers knew of the harms of SHS: that it is dangerous to non-smokers (90%) and children (95%) and that it causes asthma in children (91%). Levels of knowledge among daily smokers were lower than among non-daily smokers, ex-smokers and never-smokers. Among smokers, greater knowledge of SHS harms was associated with health worry, wanting to quit and having attempted to quit in the past year, but knowledge of direct harms of smoking was not. CONCLUSION: Lack of basic knowledge about the health consequences of smoking is not an important barrier to trying to quit for Aboriginal and Torres Strait Islander smokers. Framing new messages about the negative health effects of smoking in ways that encompass the health of others is likely to contribute to goal setting and prioritising quitting among Aboriginal and Torres Strait Islander people.

Personal attitudes towards smoking in a national sample of Aboriginal and Torres Strait Islander smokers and recent quitters.

OBJECTIVES: To describe attitudes towards smoking in a national sample of Aboriginal and Torres Strait Islander smokers and recent quitters and assess how they are associated with quitting, and to compare these attitudes with those of smokers in the general Australian population. DESIGN, SETTING AND PARTICIPANTS: The Talking About The Smokes project used a quota sampling design to recruit participants from communities served by 34 Aboriginal community-controlled health services and one community in the Torres Strait. We surveyed 1392 daily smokers, 251 non-daily smokers and 78 recent quitters from April 2012 to October 2013. MAIN OUTCOME MEASURES: Personal attitudes towards smoking and quitting, wanting to quit, and attempting to quit in the past year. RESULTS: Aboriginal and Torres Strait Islander daily smokers were less likely than daily smokers in the general Australian population to report enjoying smoking (65% v 81%) and more likely to disagree that smoking is an important part of their life (49% v 38%); other attitudes were similar between the two groups. In the Aboriginal and Torres Strait Islander sample, non-daily smokers generally held less positive attitudes towards smoking compared with daily smokers, and ex-smokers who had quit within the past year reported positive views about quitting. Among the daily smokers, 78% reported regretting starting to smoke and 81% reported spending too much money on cigarettes, both of which were positively associated with wanting and attempting to quit; 32% perceived smoking to be an important part of their life, which was negatively associated with both quit outcomes; and 83% agreed that smoking calms them down when stressed, which was not associated with the quitting outcomes. CONCLUSIONS: Aboriginal and Torres Strait Islander smokers were less likely than those in the general population to report positive reasons to smoke and held similar views about the negative aspects, suggesting that factors other than personal attitudes may be responsible for the high continuing smoking rate in this population.

Social acceptability and desirability of smoking in a national sample of Aboriginal and Torres Strait Islander people.

OBJECTIVES: To describe social normative beliefs about smoking in a national sample of Aboriginal and Torres Strait Islander people, and to assess the relationship of these beliefs with quitting. DESIGN, SETTING AND PARTICIPANTS: The Talking About The Smokes project used a quota sampling design to recruit participants from communities served by 34 Aboriginal community-controlled health services and one community in the Torres Strait. We surveyed 1392 daily smokers, 251 non-daily smokers, 311 ex-smokers and 568 never-smokers from April 2012 to October 2013. MAIN OUTCOME MEASURES: Eight normative beliefs about smoking; wanting and attempting to quit. RESULTS: Compared with daily smokers in the general Australian population, Aboriginal and Torres Strait Islander daily smokers were less likely to report that mainstream society disapproves of smoking (78.5% v 62%). Among Aboriginal and Torres Strait Islander daily smokers, 40% agreed that Aboriginal and Torres Strait Islander community leaders where they live disapprove of smoking, 70% said there are increasingly fewer places they feel comfortable smoking, and most (90%) believed non-smokers set a good example to children. Support for the government to do more to tackle the harm caused by smoking was much higher than in the general Australian population (80% v 47.2%). These five normative beliefs were all associated with wanting to quit. Non-smokers reported low levels of pressure to take up smoking. CONCLUSION: Tobacco control strategies that involve the leadership and participation of local Aboriginal and Torres Strait Islander community leaders, particularly strategies that emphasise protection of others, may be an important means of reinforcing beliefs that smoking is socially unacceptable, thus boosting motivation to quit.

Talking About The Smokes: a large-scale, community-based participatory research project.

OBJECTIVE: To describe the Talking About The Smokes (TATS) project according to the World Health Organization guiding principles for conducting community-based participatory research (PR) involving indigenous peoples, to assist others planning large-scale PR projects. DESIGN, SETTING AND PARTICIPANTS: The TATS project was initiated in Australia in 2010 as part of the International Tobacco Control Policy Evaluation Project, and surveyed a representative sample of 2522 Aboriginal and Torres Strait Islander adults to assess the impact of tobacco control policies. The PR process of the TATS project, which aimed to build partnerships to create equitable conditions for knowledge production, was mapped and summarised onto a framework adapted from the WHO principles. MAIN OUTCOME MEASURES: Processes describing consultation and approval, partnerships and research agreements, communication, funding, ethics and consent, data and benefits of the research. RESULTS: The TATS project involved baseline and follow-up surveys conducted in 34 Aboriginal community-controlled health services and one Torres Strait community. Consistent with the WHO PR principles, the TATS project built on community priorities and strengths through strategic partnerships from project inception, and demonstrated the value of research agreements and trusting relationships to foster shared decision making, capacity building and a commitment to Indigenous data ownership. CONCLUSIONS: Community-based PR methodology, by definition, needs adaptation to local settings and priorities. The TATS project demonstrates that large-scale research can be participatory, with strong Indigenous community engagement and benefits.

Recall of anti-tobacco advertising and information, warning labels and news stories in a national sample of Aboriginal and Torres Strait Islander smokers.

OBJECTIVES: To describe recall of anti-tobacco advertising (mainstream and targeted), pack warning labels, and news stories among a national sample of Aboriginal and Torres Strait Islander smokers, and to assess the association of these messages with attitudes that support quitting, including wanting to quit. DESIGN, SETTING AND PARTICIPANTS: A quota sampling design was used to recruit participants from communities served by 34 Aboriginal community-controlled health services and one community in the Torres Strait. We surveyed 1643 Aboriginal and Torres Strait Islander smokers from April 2012 to October 2013. MAIN OUTCOME MEASURES: Frequency of recall of advertising and information, warning labels and news stories; recall of targeted and local advertising; attitudes about smoking and wanting to quit. RESULTS: More smokers recalled often noticing warning labels in the past month (65%) than recalled advertising and information (45%) or news stories (24%) in the past 6 months. When prompted, most (82%) recalled seeing a television advertisement. Just under half (48%) recalled advertising that featured an Aboriginal or Torres Strait Islander person or artwork (targeted advertising), and 16% recalled targeted advertising from their community (local advertising). Frequent recall of warning labels, news stories and advertising was associated with worry about health and wanting to quit, but only frequent advertising recall was associated with believing that society disapproves of smoking. The magnitude of association with relevant attitudes and wanting to quit increased for targeted and local advertising. CONCLUSIONS: Strategies to tackle Aboriginal and Torres Strait Islander smoking should sustain high levels of exposure to anti-tobacco advertising, news stories and warning labels. More targeted and local information may be particularly effective to influence relevant beliefs and subsequently increase quitting.

Research methods of Talking About The Smokes: an International Tobacco Control Policy Evaluation Project study with Aboriginal and Torres Strait Islander Australians.

OBJECTIVE: To describe the research methods and baseline sample of the Talking About The Smokes (TATS) project. DESIGN: The TATS project is a collaboration between research institutions and Aboriginal community-controlled health services (ACCHSs) and their state and national representative bodies. It is one of the studies within the International Tobacco Control Policy Evaluation Project, enabling national and international comparisons. It includes a prospective longitudinal study of Aboriginal and Torres Strait Islander smokers and recent ex-smokers; a survey of non-smokers; repeated cross-sectional surveys of ACCHS staff; and descriptions of the tobacco policies and practices at the ACCHSs. Community members completed face-to-face surveys; staff completed surveys on paper or online. We compared potential biases and the distribution of variables common to the main community baseline sample and unweighted and weighted results of the 2008 National Aboriginal and Torres Strait Islander Social Survey (NATSISS). The baseline survey (Wave 1) was conducted between April 2012 and October 2013. SETTING AND PARTICIPANTS: 2522 Aboriginal and Torres Strait Islander people in 35 locations (the communities served by 34 ACCHSs and one community in the Torres Strait), and 645 staff in the ACCHSs. MAIN OUTCOME MEASURES: Sociodemographic and general health indicators, smoking status, number of cigarettes smoked per day and quit attempts. RESULTS: The main community baseline sample closely matched the distribution of the Aboriginal and Torres Strait Islander population in the weighted NATSISS by age, sex, jurisdiction and remoteness. There were inconsistent differences in some sociodemographic factors between our sample and the NATSISS: our sample had higher proportions of unemployed people, but also higher proportions who had completed Year 12 and who lived in more advantaged areas. In both surveys, similar percentages of smokers reported having attempted to quit in the past year, and daily smokers reported similar numbers of cigarettes smoked per day. CONCLUSION: The TATS project provides a detailed and nationally representative description of Aboriginal and Torres Strait Islander smoking behaviour, attitudes, knowledge and exposure to tobacco control activities and policies, and their association with quitting.

The stem cell organisation, and the proliferative and gene expression profile of Barrett's epithelium, replicates pyloric-type gastric glands.

OBJECTIVE: Barrett's oesophagus shows appearances described as 'intestinal metaplasia', in structures called 'crypts' but do not typically display crypt architecture. Here, we investigate their relationship to gastric glands. METHODS: Cell proliferation and migration within Barrett's glands was assessed by Ki67 and iododeoxyuridine (IdU) labelling. Expression of mucin core proteins (MUC), trefoil family factor (TFF) peptides and LGR5 mRNA was determined by immunohistochemistry or by in situ hybridisation, and clonality was elucidated using mitochondrial DNA (mtDNA) mutations combined with mucin histochemistry. RESULTS: Proliferation predominantly occurs in the middle of Barrett's glands, diminishing towards the surface and the base: IdU dynamics demonstrate bidirectional migration, similar to gastric glands. Distribution of MUC5AC, TFF1, MUC6 and TFF2 in Barrett's mirrors pyloric glands and is preserved in Barrett's dysplasia. MUC2-positive goblet cells are localised above the neck in Barrett's glands, and TFF3 is concentrated in the same region. LGR5 mRNA is detected in the middle of Barrett's glands suggesting a stem cell niche in this locale, similar to that in the gastric pylorus, and distinct from gastric intestinal metaplasia. Gastric and intestinal cell lineages within Barrett's glands are clonal, indicating derivation from a single stem cell. CONCLUSIONS: Barrett's shows the proliferative and stem cell architecture, and pattern of gene expression of pyloric gastric glands, maintained by stem cells showing gastric and intestinal differentiation: neutral drift may suggest that intestinal differentiation advances with time, a concept critical for the understanding of the origin and development of Barrett's oesophagus.

Identification of lineage-uncommitted, long-lived, label-retaining cells in healthy human esophagus and stomach, and in metaplastic esophagus.

BACKGROUND & AIMS: The existence of slowly cycling, adult stem cells has been challenged by the identification of actively cycling cells. We investigated the existence of uncommitted, slowly cycling cells by tracking 5-iodo-2'-deoxyuridine (IdU) label-retaining cells (LRCs) in normal esophagus, Barrett's esophagus (BE), esophageal dysplasia, adenocarcinoma, and healthy stomach tissues from patients. METHODS: Four patients (3 undergoing esophagectomy, 1 undergoing esophageal endoscopic mucosal resection for dysplasia and an esophagectomy for esophageal adenocarcinoma) received intravenous infusion of IdU (200 mg/m(2) body surface area; maximum dose, 400 mg) over a 30-minute period; the IdU had a circulation half-life of 8 hours. Tissues were collected at 7, 11, 29, and 67 days after infusion, from regions of healthy esophagus, BE, dysplasia, adenocarcinoma, and healthy stomach; they were analyzed by in situ hybridization, flow cytometry, and immunohistochemical analyses. RESULTS: No LRCs were found in dysplasias or adenocarcinomas, but there were significant numbers of LRCs in the base of glands from BE tissue, in the papillae of the basal layer of the esophageal squamous epithelium, and in the neck/isthmus region of healthy stomach. These cells cycled slowly because IdU was retained for at least 67 days and co-labeling with Ki-67 was infrequent. In glands from BE tissues, most cells did not express defensin-5, Muc-2, or chromogranin A, indicating that they were not lineage committed. Some cells labeled for endocrine markers and IdU at 67 days; these cells represented a small population (<0.1%) of epithelial cells at this time point. The epithelial turnover time of the healthy esophageal mucosa was approximately 11 days (twice that of the intestine). CONCLUSIONS: LRCs of human esophagus and stomach have many features of stem cells (long lived, slow cycling, uncommitted, and multipotent), and can be found in a recognized stem cell niche. Further analyses of these cells, in healthy and metaplastic epithelia, is required.

Field cancerization in the intestinal epithelium of patients with Crohn's ileocolitis.

BACKGROUND & AIMS: Tumors that develop in patients with Crohn's disease tend be multifocal, so field cancerization (the replacement of normal cells with nondysplastic but tumorigenic clones) might contribute to intestinal carcinogenesis. We investigated patterns of tumor development from pretumor intestinal cell clones. METHODS: We performed genetic analyses of multiple areas of intestine from 10 patients with Crohn's disease and intestinal neoplasia. Two patients had multifocal neoplasia; longitudinal sections were collected from 3 patients. Individual crypts were microdissected and genotyped; clonal dependency analysis was used to determine the order and timing of mutations that led to tumor development. RESULTS: The same mutations in KRAS, CDKN2A(p16), and TP53 that were observed in neoplasias were also present in nontumor, nondysplastic, and dysplastic epithelium. In 2 patients, carcinogenic mutations were detected in nontumor epithelium 4 years before tumors developed. The same mutation (TP53 p.R248W) was detected at multiple sites along the entire length of the colon from 1 patient; it was the apparent founder mutation for synchronous tumors and multiple dysplastic areas. Disruption of TP53, CDKN2A, and KRAS were all seen as possible initial events in tumorigenesis; the sequence of mutations (the tumor development pathway) differed among lesions. CONCLUSIONS: Pretumor clones can grow extensively in the intestinal epithelium of patients with Crohn's disease. Segmental resections for neoplasia in patients with Crohn's disease might therefore leave residual pretumor disease, and dysplasia might be an unreliable biomarker for cancer risk. Characterization of the behavior of pretumor clones might be used to predict the development of intestinal neoplasia.

Barrett's metaplasia glands are clonal, contain multiple stem cells and share a common squamous progenitor.

BACKGROUND: Little is known about the stem cell organisation of the normal oesophagus or Barrett's metaplastic oesophagus. Using non-pathogenic mitochondrial DNA mutations as clonal markers, the authors reveal the stem cell organisation of the human squamous oesophagus and of Barrett's metaplasia and determine the mechanism of clonal expansion of mutations. METHODS: Mutated cells were identified using enzyme histochemistry to detect activity of cytochrome c oxidase (CCO). CCO-deficient cells were laser-captured and mutations confirmed by PCR sequencing. Cell lineages were identified using immunohistochemistry. RESULTS: The normal squamous oesophagus contained CCO-deficient patches varying in size from around 30 µm up to about 1 mm. These patches were clonal as each area within a CCO-deficient patch contained an identical mitochondrial DNA mutation. In Barrett's metaplasia partially CCO-deficient glands indicate that glands are maintained by multiple stem cells. Wholly mutated Barrett's metaplasia glands containing all the expected differentiated cell lineages were seen, demonstrating multilineage differentiation from a clonal population of Barrett's metaplasia stem cells. Patches of clonally mutated Barrett's metaplasia glands were observed, indicating glands can divide to form patches. In one patient, both the regenerating squamous epithelium and the underlying glandular tissue shared a clonal mutation, indicating that they are derived from a common progenitor cell. CONCLUSION: In normal oesophageal squamous epithelium, a single stem cell clone can populate large areas of epithelium. Barrett's metaplasia glands are clonal units, contain multiple multipotential stem cells and most likely divide by fission. Furthermore, a single cell of origin can give rise to both squamous and glandular epithelium suggesting oesophageal plasticity.

'Radiation-induced pleomorphic sarcoma with rhabdomyoblastic differentiation of the lower limb following treatment of vaginal squamous cell carcinoma - A case report and review of the literature'.

We present the case of a 59-year-old woman who developed a right thigh pleomorphic sarcoma with rhabdomyoblastic differentiation 6 years following radiotherapy for a vaginal squamous cell carcinoma. The overall 5-year survival for a gynaecological malignancy is more than 80 % and as overall cancer survivorship and life expectancy improves, the incidence of radiation-induced malignancy is increasing (Bjerkehagen et al., 2013). As the prognosis of those malignancies is usually poor, clinicians must have a high index of suspicion to try to detect these cases early.

Prevalence and Correlates of Observed Sun Protection Behaviors Across Different Public Outdoor Settings in Melbourne, Australia.

Skin cancer prevention efforts in Australia have increasingly incorporated a focus on protection during incidental sun exposure. This complements the long-present messages promoting protection in high-risk settings and avoidance of acute intense bouts of sun exposure. Data from two waves of a cross-sectional direct observational survey was used to assess the prevalence and correlates of N = 12,083 adolescents' and adults' sun protection behavior (arm and leg cover, hat, sunglasses, and shade cover). Individuals were observed in public outdoor settings in Melbourne, Australia during peak ultraviolet (UV) times (11 a.m.-3 p.m.) on summer weekends. Settings included pools and beaches, parks and gardens, and for the first time in 2018, outdoor streets and cafés which may capture more incidental forms of sun exposure and represent another public setting where Australians commonly spend time outdoors. Females and older adults were consistently better protected than males and adolescents. Physical activity was strongly associated with low shade cover across settings. Weather was more strongly associated with sun protection at outdoor streets/cafes and parks/gardens than at pools/beaches but use of observed sun protection (particularly arm cover and covering hat) was low across settings. Continued public education about UV risk and its relation to weather and the seasons is needed to promote the routine use of multiple forms of sun protection during outdoor activities in peak UV times, especially among males and adolescents. Findings also highlight the importance of considering activity demands of public spaces in shade planning to optimize sun protection during outdoor activities in public spaces.

Acid reflux and oesophageal cancer.

Barrett's metaplasia is one of the commonest premalignant lesions in the western world following colorectal adenomas. One in 50 of the adult population develops Barrett's as a consequence of chronic gastro-oesophageal reflux. The mucosal inflammation seen within patients with gastro-oesophageal reflux seems likely to drive the growth of the metaplastic mucosa and also help direct further oncological change, yet the molecular events that characterize the pathway from inflammation to metaplasia to dysplasia and adenocarcinoma are poorly understood. There is hope that understanding the role of oesophageal inflammation will provide important insight into the development of Barrett's metaplasia and oesophageal cancer. This chapter will discuss the inflammation seen within context of Barrett's oesophagus and also clinical trials which hope to address this common premalignant disease. There are several ongoing clinical trials which are aiming to provide data using anti-inflammatory therapies to tackle this important premalignant condition. There is new data presented which suggests that data from the aspirin esomeprazole chemoprevention trial (AspECT) may hold the clue to disease treatment and that the cytokine TNF-α seems to be a key signalling molecule in the metaplasia-dysplasia-carcinoma sequence. Specifically it appears that both epigenetic and inherited genetics cooperate to modulate the prognosis.