Mutation prediction models in Lynch syndrome: evaluation in a clinical genetic setting

Background/aims: The identification of Lynch syndrome is hampered by the absence of specific diagnostic features and underutilization of genetic testing. Prediction models have therefore been developed, but they have not been validated for a clinical genetic setting. The aim of the present study was to evaluate the usefulness of currently available prediction models. METHODS: We collected data of 321 index probands who were referred to the department of Clinical Genetics of the Erasmus Medical Center because of a family history of colorectal cancer. These data were used as input for five previously published models. External validity was assessed by discriminative ability (AUC: area under the receiver operating characteristic curve) and calibration. For further insight, predicted probabilities were categorized with cut-offs of 5%, 10%, 20% and 40%. Furthermore, costs of different testing strategies were related to the number of extra detected mutation carriers. RESULTS: Of the 321 index probands, 66 harboured a germline mutation. All models discriminated well between high risk and low risk index probands (AUC: 0.82-0.84). Calibration was well for the Premm1,2 and Edinburgh model, but poor for the other models. Cut-offs could be found for the prediction models where costs could be saved while missing only few mutations. CONCLUSIONS: The Edinburgh and Premm1,2 model were the models with the best performance for an intermediate to high-risk setting. These models may well be of use in clinical practice to select patients for further testing of mismatch repair gene mutations

Genetic testing for Lynch syndrome: family communication and motivation

Current genetic counselling practice for Lynch syndrome (LS) relies on diagnosed index patients to inform their biological family about LS, referred to as the family-mediated approach. The objective of this study was to evaluate this approach and to identify factors influencing the uptake of genetic testing for LS. In 59 mutation carriers, 70 non carriers and 16 non-tested relatives socio-demographic characteristics, family communication regarding LS, experiences and attitudes towards the family-mediated approach and motivations for genetic testing, were assessed. The majority of all respondents (73 %) were satisfied with the family-mediated approach. Nevertheless, 59 % of the respondents experienced informing a family member and 57 % being informed by a family member as burdensome. Non-tested differed from tested respondents, in that they were younger, less closely related to the index patient and a lower proportion had children. The most important reasons for declining genetic testing were (1) anticipating problems with life insurance and mortgage, (

The value of computed tomography in detecting distal radioulnar joint instability after a distal radius fracture

This study evaluated the value of computed tomography scans for the diagnosis of distal radioulnar joint instability. A total of 46 patients, conservatively treated for a unilateral distal radius fracture, were evaluated. Clinical instability was tested using the stress test and clunk test. A computed tomography scan of both wrists was performed in pronation and supination. Two independent observers reviewed the computed tomography scans using: the radioulnar line, subluxation ratio, epicentre and radioulnar ratio methods. Radiological distal radioulnar joint instability was assessed by comparing the measurements of the injured wrist with those of the contralateral uninjured wrists. A

Somatic mosaicism by a de novo MLH1 mutation as a cause of Lynch syndrome

Background: Lynch syndrome (LS) is caused by germline mismatch repair (MMR) gene mutations. De novo MMR gene mutations are rare, and somatic mosaicism in LS is thought to be infrequent. We describe the first case of somatic mosaicism by a de novo MLH1 mutation for a patient diagnosed with a rectosigmoid adenocarcinoma at age 31. Methods: Twelve years after initial colorectal cancer diagnosis, tumor tissue of the patient was tested with sensitive next generation sequencing (NGS) analysis for the presence of somatic MMR mutations. Results: In tumor tissue, an inactivating MLH1 mutation (c.518_519del; p.(Tyr173Trpfs*18)) was detected, which was also present at low level in the blood of the patient. In both parents, as well as the patient's sisters, the mutation was not present. Conclusion: We show that low‐level mosaicism can be detected by using high‐coverage targeted NGS panels on constitutional and/or tumor DNA. This report illustrates that by using sensitive sequencing techniques, more cases of genetic diseases driven by mosaic mutations may be identified, with important clinical consequences for patients and family members

Omineca Herald, May, 23, 1924

Background: LKB1 mutations are the underlying genetic abnormality causing Peutz-Jeghers syndrome (PJS) and are a potential target for everolimus. In this phase II study, the efficacy of everolimus on polyp and tumor growth in PJS patients was investigated. Methods: Adult patients with a proven LKB1 mutation and who were suitable for everolimus treatment were included in two different PJS cohorts: (a) patients with unresectable malignancies and (b) patients with high-risk polyps. Treatment in both groups was oral everolimus, 10 mg daily. Response rates were primary endpoints for both cohorts. Results: Between October 2011 and April 2016, only two patients were enrolled, one in each cohort. A 49-year-old patient with advanced pancreatic cancer in cohort 1 was progressive after 2 months. A 52-year-old male patient in cohort 2 experienced severe toxicity and refused treatment after 4 months, even though endoscopy suggested stabilization of polyps. Adverse

Quality of life in participants of a CRC screening program

Background: Little is known about the effect of participating in a colorectal cancer (CRC) screening programme on quality of life (QOL), neither for participants with a negative nor for those with a positive test result. These findings, however, are important to evaluate the impact of CRC screening. Methods: Participants from CRC screening trials were sent a questionnaire, which included validated measures on generic health-related QOL, generic anxiety and screen-specific anxiety. Both faecal immunochemical test (FIT) and flexible sigmoidoscopy (FS) participants, either with negative or positive test results, were addressed. Results: The response rate was 73% (1289 out of 1772) for FIT and 78% (536 out of 689) for FS participants, with mean ages varying from 63-66 years. Positive FIT participants had worse physical (PCS-12, 47.1 vs 48.3, P=0.02), but equal mental QOL scores (MCS-12, 51.1 vs 51.6, P=0.26). Positive and negative FS participants had similar QOL scores. Both FIT and FS participants with a positive test result reported more screen-specific anxiety than negative FIT and FS participants. Positive and negative FS participants had similar generic anxiety scores. Conclusion: Our findings indicate that the burden of participating in CRC screening may be limited. Conducting a prospective study to confirm these results is recommended

Face-to-face vs telephone pre-colonoscopy consultation in colorectal cancer screening; A randomised trial

Background: A pre-colonoscopy consultation in colorectal cancer (CRC) screening is necessary to assess a screenees general health status and to explain benefits and risks of screening. The first option allows for personal attention, whereas a telephone consultation does not require travelling. We hypothesised that a telephone consultation would lead to higher response and participation in CRC screening compared with a face-to-face consultation. Methods:A total of 6600 persons (50-75 years) were 1: 1 randomised for primary colonoscopy screening with a pre-colonoscopy consultation either face-to-face or by telephone. In both arms, we counted the number of invitees who attended a pre-colonoscopy consultation (response) and the number of those who subsequently attended colonoscopy (participation), relative to the number invited for screening. A questionnaire regarding satisfaction with the consultation and expected burden of the colonoscopy (scored on five-point rating scales) was sent to invitees. Besides, a questionnaire to assess the perceived burden of colonoscopy was sent to participants, 14 days after the procedure.Results:In all, 3302 invitees were allocated to the telephone group and 3298 to the face-to-face group, of which 794 (24%) attended a telephone consultation and 822 (25%) a face-to-face consultation (P=0.41). Subsequently, 674 (20%) participants in the telephone group and 752 (23%) in the face-to-face group attended colonoscopy (P=0.018). Invitees and responders in the telephone group expected the bowel preparation to be more painful than those in the face-to-face group while perceived burden scores for the full screening procedure were comparable. More subjects in the face-to-face group than in the telephone group were satisfied by the consultation in general: (99.8% vs 98.5%, P=0.014).Conclusion:Using a telephone rather than a face-to-face consultation in a population-based CRC colonoscopy screening progr

What determines individuals' preferences for colorectal cancer screening programmes? A discrete choice experiment.

INTRODUCTION: In many countries uptake of colorectal cancer (CRC) screening remains low. AIM: To assess how procedural characteristics of CRC screening programmes determine preferences for participation and how individuals weigh these against the perceived benefits from participation in CRC screening. METHODS: A discrete choice experiment was conducted among subjects in the age group of 50-75 years, including both screening-naive subjects and participants of a CRC screening programme. Subjects were asked on their preferences for aspects of CRC screening programmes using scenarios based on pain, risk of complications, screening location, preparation, duration of procedure, screening interval a

Interpretation and adherence to the updated risk-stratified guideline for colonoscopy surveillance after polypectomy - a nationwide survey

Background and study aims Low adherence to the Dutch guideline for colonoscopy surveillance after polypectomy led to release of a new guideline in 2013. This new guideline was risk-stratified at a more detailed level than the previous one to achieve more efficient use of colonoscopy resources. This study assessed the feasibility of the risk-stratified guideline by evaluating correct interpretation of and adherence to this guideline. Methods Based on semi-structured interviews with 10 gastroenterologists, we developed an online survey to evaluate gastroenterologists’ recommendations for surveillance in 15 example cases of patients with polyps. If recommended intervals differed from the new guideline, respondents were asked to indicate their motives for doing so. Results Ninety-one of 592 (15.4 %) invited gastroenterologists responded to at least one case, of whom 84 (14.2 %) completed the survey. Gastroenterologists gave a correct recommendation in a median of 10 of 15 cases and adherence per case ranged from 14 % to 95 % (median case 76 %). The two cases that addressed management of serrated polyps were least often answered correctly (14 % and 28 % correct answers). Discrepancies were mainly due to misinterpretation of the guideline with respect to serrated polyps (48 %) or misreading of the questions (30 %). Conclusions Median adherence to the updated colonoscopy surveillance guideline of 76 % seems reasonable, and is higher than adherence to the previous guideline (range: 22 %-80 %, median 59 %). This shows that detailed (more complex) risk stratification for designation of a surveillance interval is feasible. Adherence could potentially be improved by clarifying correct interpretation of serrated polyps

Substantial and sustained improvement of serrated polyp detection after a simple educational intervention: Results from a prospective controlled trial

Objective: Serrated polyps (SPs) are an important cause of postcolonoscopy colorectal cancers (PCCRCs), which is likely the result of suboptimal SP detection during colonoscopy. We assessed the long-term effect of a simple educational intervention focusing on optimising SP detection. Design: An educational intervention, consisting of two 45 min training sessions (held 3 years apart) on serrated polyp detection, was given to endoscopists from 9 Dutch hospitals. Hundred randomly selected and untrained endoscopists from other hospitals were selected as control group. Our primary outcome measure was the proximal SP detection rate (PSPDR) in trained versus untrained endoscopists who participated in our faecal immunochemical test (FIT)-based population screening programme. Results: Seventeen trained and 100 untrained endoscopists were included, who performed 11 305 and 51 039 colonoscopies, respectively. At baseline, PSPDR was equal between the groups (9.3% vs 9.3%). After training, the PSPDR of trained endoscopists gradually increased to 15.6% in 2018. This was significantly higher than the PSPDR of untrained endoscopists, which remained stable around 10% (p=0.018). All below-average (ie, PSPDR ≤6%) endoscopists at baseline improved their PSPDR after training session 1, as did 57% of endoscopists with average PSPDR (6%-12%) at baseline. The second training session further improved the PSPDR in 44% of endoscopists with average PSPDR after the first training. Conclusion: A simple educational intervention was associated with substantial long-term improvement of PSPDR in a prospective controlled trial within FIT-based population screening. Widespread implementation of such interventions might be an easy way to improve SP detection, which may ultimately result in fewer PCCRCs. Trial registration number: NCT03902899