Understanding of a negative bowel screening result and potential impact on future symptom appraisal and help-seeking behaviour: a focus group study.

This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1111/hex.12484BACKGROUND: Colorectal cancer (CRC) screening using a faecal occult blood test (FOBt) has the potential to reduce cancer-related mortality. Symptom vigilance remains crucial as a proportion of cancers will be diagnosed between screening rounds. A negative FOBt has the potential to influence how participants respond to future symptoms of CRC. OBJECTIVE: To explore (i) understanding of a negative FOBt and (ii) the potential impact of a negative FOBt upon future symptom appraisal and help-seeking behaviour. DESIGN: Qualitative methodology utilizing focus groups with participants who received a negative FOBt within the National Bowel Cancer Screening Programme in Coventry and Lothian. Topics explored included: experience of screening participation, interpretation and understanding of a negative result, symptom awareness and attitudes towards help-seeking. RESULTS: Four broad themes were identified: (i) emotional response to a negative FOBt, (ii) understanding the limitations of FOBt screening, (iii) symptom knowledge and interpretation and (iv) over-reassurance from a negative FOBt. Participants were reassured by a negative FOBt, but there was variability in the extent to which the result was interpreted as an "all clear". Some participants acknowledged the residual risk of cancer and the temporal characteristic of the result, while others were surprised that the result was not a guarantee that they did not have cancer. DISCUSSION AND CONCLUSIONS: Participants recognized that reassurance from a negative FOBt could lead to a short-term delay in help-seeking if symptoms developed. Screening programmes should seek to emphasize the importance of the temporal nature of FOBt results with key messages about symptom recognition and prompt help-seeking behaviour.This study was funded by the National Awareness and Early Diagnosis Initiative led by Cancer Research UK, the Department of Health, NHS England and Public Health England. Award number C12357/A12240

Find cancer early: Evaluation of a community education campaign to increase awareness of cancer signs and symptoms in people in regional Western Australians

Introduction: Cancer outcomes for people living in rural and remote areas are worse than for those living in urban areas. Although access to and quality of cancer treatment are important determinants of outcomes, delayed presentation has been observed in rural patients. Methods: Formative research with people from rural Western Australia (WA) led to the Find Cancer Early campaign. Find Cancer Early was delivered in three regions of WA, with two other regions acting as controls. Staff delivered the campaign using a community engagement approach, including promotion in local media. Television communications were not used to minimize contamination in the control regions. The campaign evaluation was undertaken at 20 months via a computer-assisted telephone interview (CATI) survey comparing campaign and control regions. The primary outcome variable was knowledge of cancer signs and symptoms. Results: Recognition and recall of Find Cancer Early and symptom knowledge were higher in the campaign regions. More than a quarter of those who were aware of the campaign reported seeing the GP as a result of their exposure. Conclusion: Despite limited use of mass media, Find Cancer Early successfully improved knowledge of cancer symptoms and possibly led to changes in behavior. Social marketing campaigns using community development can raise awareness and knowledge of a health issue in the absence of television advertising

The contribution of a negative colorectal screening test result to symptom appraisal and help-seeking behaviour among patients subsequently diagnosed with an interval colorectal cancer

Background: Colorectal cancer (CRC) screening programmes using a guaiac faecal occult blood test (gFOBt) reduce CRC mortality. Interval cancers are diagnosed between screening rounds: reassurance from a negative gFOBt has the potential to influence the pathway to diagnosis of an interval colorectal cancer. Methods: Twenty-six semi-structured face-to-face interviews were carried out in Scotland and England, with individuals diagnosed with an interval colorectal cancer following a negative gFOBt result. Results: Participants reported they were reassured by a negative gFOBt, interpreting their result as an "all clear". Therefore, most did not suspect cancer as a possible cause of symptoms and many did not recall their screening result during symptom appraisal. Among those who did consider cancer, and did think about their screening test result, reassurance from a negative gFOBt led some to "downplay" the seriousness of their symptoms with some interviewees explicitly stating that their negative test result contributed to a delayed decision to seek help. Conclusion: Screening participants need to be informed of the limitations of screening and the ongoing risk of developing colorectal cancer even when in receipt of a negative result: the importance of minimizing delay in seeking medical advice for colorectal symptoms should be emphasized

A Hidden Markov Model to estimate population mixture and allelic copy-numbers in cancers using Affymetrix SNP arrays

<p>Abstract</p> <p>Background</p> <p>Affymetrix SNP arrays can interrogate thousands of SNPs at the same time. This allows us to look at the genomic content of cancer cells and to investigate the underlying events leading to cancer. Genomic copy-numbers are today routinely derived from SNP array data, but the proposed algorithms for this task most often disregard the genotype information available from germline cells in paired germline-tumour samples. Including this information may deepen our understanding of the "true" biological situation e.g. by enabling analysis of allele specific copy-numbers. Here we rely on matched germline-tumour samples and have developed a Hidden Markov Model (HMM) to estimate allelic copy-number changes in tumour cells. Further with this approach we are able to estimate the proportion of normal cells in the tumour (mixture proportion).</p> <p>Results</p> <p>We show that our method is able to recover the underlying copy-number changes in simulated data sets with high accuracy (above 97.71%). Moreover, although the known copy-numbers could be well recovered in simulated cancer samples with more than 70% cancer cells (and less than 30% normal cells), we demonstrate that including the mixture proportion in the HMM increases the accuracy of the method. Finally, the method is tested on HapMap samples and on bladder and prostate cancer samples.</p> <p>Conclusion</p> <p>The HMM method developed here uses the genotype calls of germline DNA and the allelic SNP intensities from the tumour DNA to estimate allelic copy-numbers (including changes) in the tumour. It differentiates between different events like uniparental disomy and allelic imbalances. Moreover, the HMM can estimate the mixture proportion, and thus inform about the purity of the tumour sample.</p

Are microRNAs located in genomic regions associated with cancer?

We report on the location of 283 miRNAs in the human genome in relation to copy number changes in three distinct types of tumours: prostate, bladder and colon. In prostate and colon tumours, we find miRNAs over-represented in regions with copy number gain and under-represented in regions with copy number loss. Surprisingly this pattern appears to be reversed in bladder cancer. We compared our miRNA copy number data to published miRNA expression data; unexpectedly, we did not find a statistically significant relationship between miRNA copy number and expression level. This suggests that miRNA expression is regulated through different mechanisms than mRNA expression

Comprehensive prenatal diagnostics:Exome versus genome sequencing

OBJECTIVE: This study aimed to assess the diagnostic yield of prenatal genetic testing using trio whole exome sequencing (WES) and trio whole genome sequencing (WGS) in pregnancies with fetal anomalies, comparing the results to conventional chromosomal microarray (CMA) analysis.METHODS: A total of 40 pregnancies with fetal anomalies or increased nuchal translucency (NT≥5mm) were included between the 12th and 21st week of gestation. Trio WES/WGS and CMA were performed on all cases.RESULTS: The trio WES/WGS analysis increased the diagnostic yield by 25% in cases with negative CMA results. Furthermore, all six chromosomal aberrations identified by CMA were independently detected by WES/WGS analysis. In total, 16 out of 40 cases obtained a genetic sequence variant, copy number variant or aneuploidy explaining the phenotype, resulting in an overall WES/WGS diagnostic yield of 40%. WES analysis provided a more reliable identification of mosaic sequence variants than WGS due to higher sequencing depth.CONCLUSION: Prenatal WES/WGS proved to be powerful diagnostic tools for fetal anomalies, surpassing the diagnostic yield of CMA. They have the potential to serve as standalone methods for prenatal diagnosis. The study highlighted the limitations of WGS in accurately detecting mosaic variants, which is particularly relevant when analyzing chorionic villus samples. This article is protected by copyright. All rights reserved.</p

Safety of direct oral anticoagulants in patients with hereditary hemorrhagic telangiectasia

Background: Hereditary haemorrhagic telangiectasia (HHT) is a rare vascular dysplasia resulting in visceral arteriovenous malformations and smaller mucocutaneous telangiectasia. Most patients experience recurrent nosebleeds and become anaemic without iron supplementation. However, thousands may require anticoagulation for conditions such as venous thromboembolismand/or atrial fibrillation. Over decades,tolerance data has been publishedfor almost 200HHT-affected usersof warfarinand heparins, but there are no publisheddata forthe newer direct oralanticoagulants(DOACs)in HHT. Methods: To provide such data, aretrospective audit was conducted across the eight HHT centres of the European Reference Network for Rare Vascular Disorders (VASCERN),in Denmark, France, Germany, Italy, Netherlands and UK. Results: Although HHT Centreshad not specifically recommended the use of DOACs, 32treatment episodes had been initiated by other cliniciansin 28patients reviewed at the centres, at median age 65years(range 30-84). Indications were for atrial fibrillation (16 treatment episodes) and venous thromboembolism (16 episodes).The 32 treatment episodes used Apixaban (n=15), Rivaroxaban (n=14), and Dabigatran (n=3). HHT nosebleeds increased in severity in 24/32 treatment episodes (75%), leading to treatment discontinuation in 11 (34.4%). Treatment discontinuation was required for 4/15(26.7%) Apixabanepisodes and 7/14 (50%)Rivaroxaban episodes.By a 4 point scale of increasing severity,there was a trend for Rivaroxaban to be associated with a greaterbleeding riskboth including and excluding patients who had used more than one agent (age-adjusted coefficients 0.61 (95% confidence intervals 0.11, 1.20) and 0.74 (95% confidence intervals 0.12, 1.36) respectively. Associationswere maintained after adjustment for genderand treatment indication. Extreme haemorrhagic responses, worse thananything experienced previously, with individual nosebleedslasting hours requiring hospital admissions, blood transfusions and in all cases treatment discontinuation, occurred in5/14(35.7%) Rivaroxabanepisodes compared to 3/15(20%) Apixabanepisodes and published rates of ~5% for warfarin and heparin. Conclusions: Currently, conventional heparin and warfarin remain first choice anticoagulantsin HHT. If newer anticoagulants are considered,although study numbers are small, at this stage Apixaban appearsto be associated with lesser bleeding riskthan Rivaroxaban

Differential Effects of EGFR Ligands on Endocytic Sorting of the Receptor

Endocytic downregulation is a pivotal mechanism turning off signalling from the EGF receptor (EGFR). It is well established that whereas EGF binding leads to lysosomal degradation of EGFR, transforming growth factor (TGF)-α causes receptor recycling. TGF-α therefore leads to continuous signalling and is a more potent mitogen than EGF. In addition to EGF and TGF-α, five EGFR ligands have been identified. Although many of these ligands are upregulated in cancers, very little is known about their effect on EGFR trafficking

Impaired glucose-1,6-biphosphate production due to bi-allelic PGM2L1 mutations is associated with a neurodevelopmental disorder

We describe a genetic syndrome due to PGM2L1 deficiency. PGM2 and PGM2L1 make hexose-bisphosphates, like glucose-1,6-bisphosphate, which are indispensable cofactors for sugar phosphomutases. These enzymes form the hexose-1-phosphates crucial for NDP-sugars synthesis and ensuing glycosylation reactions. While PGM2 has a wide tissue distribution, PGM2L1 is highly expressed in the brain, accounting for the elevated concentrations of glucose-1,6-bisphosphate found there. Four individuals (three females and one male aged between 2 and 7.5 years) with bi-allelic inactivating mutations of PGM2L1 were identified by exome sequencing. All four had severe developmental and speech delay, dysmorphic facial features, ear anomalies, high arched palate, strabismus, hypotonia, and keratosis pilaris. Early obesity and seizures were present in three individuals. Analysis of the children's fibroblasts showed that glucose-1,6-bisphosphate and other sugar bisphosphates were markedly reduced but still present at concentrations able to stimulate phosphomutases maximally. Hence, the concentrations of NDP-sugars and glycosylation of the heavily glycosylated protein LAMP2 were normal. Consistent with this, serum transferrin was normally glycosylated in affected individuals. PGM2L1 deficiency does not appear to be a glycosylation defect, but the clinical features observed in this neurodevelopmental disorder point toward an important but still unknown role of glucose-1,6-bisphosphate or other sugar bisphosphates in brain metabolism.</p