In addition to stenosis grading, magnetic resonance imaging (MRI) may provide valuable information about plaque 'status', e.g. hyperintense vulnerable carotid plaque, associated with higher morbidity ...and mortality. In the present study, we investigated the prevalence, clinical and radiological correlates of hyperintense carotid plaques on T(1)-weighted turbo-field echo (T(1)w-TFE) MRI in patients with ischemic symptoms.
A total of 153 patients presenting with transient ischemic attack or ischemic infarct, studied with contrast-enhanced magnetic resonance angiography (CEMRA), were retrospectively examined. Stenosis grade was obtained from CEMRA images, presence or absence of hyperintense carotid plaque from T(1)w-TFE MRI. Stenosis grade and baseline characteristics were compared between patients with and without a hyperintense plaque.
Twenty-eight patients (18%) showed one or more hyperintense internal carotid (ICA) plaques. Hyperintense plaques were found in patients with <50% stenosis (6 of 158 ICAs), 50-70% stenosis (4 of 11), >70% stenosis (14 of 74) and carotid occlusion (4 of 28). Presence of hyperintense plaque was associated with older age (70 vs. 62 years; p < 0.05), higher prevalence of cardiac disease (61 vs. 28%; p < 0.01), ischemic infarct as presenting symptom (37 vs. 14%; p < 0.01), ischemic cerebral lesions on MRI (63 vs. 32%; p < 0.01), and the ICA on the patients' symptomatic side (70 vs. 42%; p < 0.01).
More than one third of patients with 50-70% stenosis present with a hyperintense plaque. This subgroup of patients could in the future possibly benefit from more aggressive medicinal therapy or revascularization.
In approximately 10% of all gastric cancer (GC) cases, a heritable cause is suspected. A subset of these cases have a causative germline
mutation; however, in most cases the cause remains unknown. ...Our objective was to assess to what extent these remaining cases may be explained by germline mutations in the novel candidate GC predisposing genes
,
or
.
We sequenced a large cohort of unexplained young and/or familial patients with GC (n=286) without a
germline mutation for germline variants affecting
,
and
using a targeted next-generation sequencing approach based on single-molecule molecular inversion probes.
Predicted deleterious germline variants were not encountered in
, but recurrently observed in
(n=2) and
(n=3) in our cohort of patients with GC. In contrast to deleterious variants in
, deleterious variants in
also occur frequently in the general population.
Based on our results
should no longer be considered a GC predisposition gene, whereas deleterious
variants are confirmed as an infrequent cause of GC susceptibility. Biallelic
germline mutations are at most a very rare cause of GC susceptibility as no additional cases were identified.
Background & Aims Germline mutations in the cadherin 1, type 1, E-cadherin gene ( CDH1 ) cause a predisposition to gastric cancer. We evaluated the ability of the internationally accepted hereditary ...diffuse gastric cancer (HDGC) criteria to identify individuals with pathogenic mutations in CDH1 , and assessed their outcomes. The criteria were as follows: families with 2 or more cases of gastric cancer, with at least 1 patient diagnosed with diffuse gastric cancer (DGC) before age 50; families with 3 or more cases of DGC; families with 1 DGC before the age of 40; and families with a history of DGC and lobular breast cancer, with 1 diagnosis before the age of 50. Methods We collected results of a CDH1 mutation analysis of 578 individuals from 499 families tested in The Netherlands between 1999 and 2014 (118 families met the HDGC criteria for testing and 236 did not; there were 145 families with incomplete data and/or availability of only first-degree relatives). Data were linked with family histories and findings from clinical and pathology analyses. The Kaplan–Meier method and Cox regression analysis were used to evaluate the overall survival of patients with and without CDH1 mutations. Results In a cohort study in The Netherlands, the HDGC criteria identified individuals with a germline CDH1 mutation with a positive predictive value of 14% and 89% sensitivity. There were 18 pathogenic CDH1 mutations in 499 families (4%); 16 of these mutations were detected in the 118 families who met the HDGC criteria for testing. One pathogenic CDH1 mutation was detected in the 236 families who did not meet HDGC criteria and 1 in the 145 families with incomplete data and/or availability of only first-degree relatives. No CDH1 mutations were found in the 67 families whose members developed intestinal-type gastric cancer, or in the 22 families whose families developed lobular breast cancer. Among patients who fulfilled the HDGC criteria and had pathogenic CDH1 mutations, 36% survived for 1 year and 4% survived for 5 years; among patients who fulfilled the HDGC criteria but did not carry pathogenic CDH1 mutations, 48% survived for 1 year and 13% survived for 5 years ( P = .014 for comparative survival analysis between patients with and without a CDH1 mutation). Conclusions All individuals with a CDH1 mutation had a personal or family history of diffuse gastric cancer. Patients with gastric cancer and germline CDH1 mutations had shorter survival times than patients who met the HDGC criteria but did not have CDH1 mutations.
IntroductionThe INflammation and Small Vessel Disease (INSVD) study aims to investigate whether peripheral inflammation, immune (dys)regulation and blood–brain barrier (BBB) permeability relate to ...disease progression in cerebral small vessel disease (SVD). This research aims to pinpoint specific components of the immune response in SVD relating to disease progression. This could identify biomarkers of SVD progression, as well as potential therapeutic targets to inform the development and repurposing of drugs to reduce or prevent SVD, cognitive decline and vascular dementia.Methods and analysisINSVD is a prospective observational multicentre cohort study in individuals with symptomatic SVD. This longitudinal study combines comprehensive immunophenotyping of the peripheral blood immune compartment with advanced neuroimaging markers of SVD and BBB permeability. The main SVD marker of interest is white matter microstructure as determined by diffusion tensor imaging, a valuable marker of disease progression owing to its sensitivity to early alterations to white matter integrity. The research is being conducted in two sites—in the UK (Cambridge) and the Netherlands (Nijmegen)—with each site recruiting 100 participants (total n=200). Participants undergo clinical and cognitive assessments, blood draws, and brain MRI at baseline and 2-year follow-up.Ethics and disseminationThis study received ethical approval from the local ethics boards (UK: East of England—Cambridge Central Research Ethics Committee (REC) ref: 22/EE/00141, Integrated Research Application System (IRAS) ID: 312 747. Netherlands: Medical Research Ethics Committee (MREC) Oost-Nederland, ref: 2022-13623, NL-number: NL80258.091.22). Written informed consent was obtained from all subjects before the study. Any participant-derived benefits resulting from this research, such as new insights into disease mechanisms or possible novel therapies, will be disseminated to study participants, patient groups and members of the public.Trial registration numberNCT05746221.
Pre-test counseling about multigene panel testing involves many uncertainties. Ideally, counselees are informed about uncertainties in a way that enables them to make an informed decision about panel ...testing. It is presently unknown whether and how uncertainty is discussed during initial cancer genetic counseling. We therefore investigated whether and how counselors discuss and address uncertainty, and the extent of shared decision-making (SDM), and explored associations between counselors’ communication and their characteristics in consultations on panel testing for cancer. For this purpose, consultations of counselors discussing a multigene panel with a simulated patient were videotaped. Simulated patients represented a counselee who had had multiple cancer types, according to a script. Before and afterwards, counselors completed a survey. Counselors’ uncertainty expressions, initiating and the framing of expressions, and their verbal responses to scripted uncertainties of the simulated patient were coded by two researchers independently. Coding was done according to a pre-developed coding scheme using The Observer XT software for observational analysis. Additionally, the degree of SDM was assessed by two observers. Correlation and regression analyses were performed to assess associations of communicated uncertainties, responses and the extent of SDM, with counselors’ background characteristics. In total, twenty-nine counselors, including clinical geneticists, genetic counselors, physician assistants-in-training, residents and interns, participated of whom working experience varied between 0 and 25 years. Counselors expressed uncertainties mainly regarding scientific topics (94%) and on their own initiative (95%). Most expressions were framed directly (77%), e.g.
We don’t know
, and were emotionally neutral (59%; without a positive/negative value). Counselors mainly responded to uncertainties of the simulated patient by explicitly referring to the uncertainty (69%), without providing space for further disclosure (66%). More experienced counselors provided less space to further disclose uncertainty (
p
< 0.02), and clinical geneticists scored lower on SDM compared with other types of counselors (
p
< 0.03). Our findings that counselors mainly communicate scientific uncertainties and use space-reducing responses imply that the way counselors address counselees’ personal uncertainties and concerns during initial cancer genetic counseling is suboptimal.
Lynch syndrome (LS) patients are at high risk of developing colorectal cancer (CRC). Phenotypic variability might in part be explained by common susceptibility loci identified in Genome Wide ...Association Studies (GWAS). Previous studies focused mostly on
MLH1, MSH2
and
MSH6
carriers, with conflicting results. We aimed to determine the role of GWAS SNPs in
PMS2
mutation carriers. A cohort study was performed in 507
PMS2
carriers (124 CRC cases), genotyped for 24 GWAS SNPs, including SNPs at 11q23.1 and 8q23.3. Hazard ratios (HRs) were calculated using a weighted Cox regression analysis to correct for ascertainment bias. Discrimination was assessed with a concordance statistic in a bootstrap cross-validation procedure. Individual SNPs only had non-significant associations with CRC occurrence with HRs lower than 2, although male carriers of allele A at rs1321311 (6p21.31) may have increased risk of CRC (HR = 2.1, 95% CI 1.2–3.0). A polygenic risk score (PRS) based on 24 HRs had an HR of 2.6 (95% CI 1.5–4.6) for the highest compared to the lowest quartile, but had no discriminative ability (c statistic 0.52). Previously suggested SNPs do not modify CRC risk in
PMS2
carriers. Future large studies are needed for improved risk stratification among Lynch syndrome patients.
Recognition of individuals with a genetic predisposition to gastric cancer (GC) enables preventive measures. However, the underlying cause of genetic susceptibility to gastric cancer remains largely ...unexplained. We performed germline whole-exome sequencing on leukocyte DNA of 54 patients from 53 families with genetically unexplained diffuse-type and intestinal-type GC to identify novel GC-predisposing candidate genes. As young age at diagnosis and familial clustering are hallmarks of genetic tumor susceptibility, we selected patients that were diagnosed below the age of 35, patients from families with two cases of GC at or below age 60 and patients from families with three GC cases at or below age 70. All included individuals were tested negative for germline CDH1 mutations before or during the study. Variants that were possibly deleterious according to in silico predictions were filtered using several independent approaches that were based on gene function and gene mutation burden in controls. Despite a rigorous search, no obvious candidate GC predisposition genes were identified. This negative result stresses the importance of future research studies in large, homogeneous cohorts.
Gastric cancer is caused by both genetic and environmental factors. A woman who suffered from recurrent candidiasis throughout her life developed diffuse-type gastric cancer at the age of 23 years. ...Using whole-exome sequencing we identified a germline homozygous missense variant in
MYD88
. Immunological assays on peripheral blood mononuclear cells revealed an impaired immune response upon stimulation with
Candida albicans
, characterized by a defective production of the cytokine interleukin-17. Our data suggest that a genetic defect in
MYD88
results in an impaired immune response and may increase gastric cancer risk.
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