Patient-reported burden of intensified surveillance and surgery in high-risk individuals under pancreatic cancer surveillance

In high-risk individuals participating in a pancreatic cancer surveillance program, worrisome features warrant for intensified surveillance or, occasionally, surgery. Our objectives were to determine the patient-reported burden of intensified surveillance and/or surgery, and to assess post-operative quality of life and opinion of surgery. Participants in our pancreatic cancer surveillance program completed questionnaires including the Cancer Worry Scale (CWS) and the Hospital Anxiety and Depression Scale (HADS). For individuals who underwent intensified surveillance, questionnaires before, during, and ≥ 3 weeks after were analyzed. In addition, subjects who underwent intensified surveillance in the past 3 years or underwent surgery at any time, were invited for an interview, that included the Short-Form 12 (SF-12). A total of 31 high-risk individuals were studied. During the intensified surveillance period, median CWS scores were higher (14, IQR 7), as compared to before (12, IQR 9, P = 0.007) and after (11, IQR 7, P = 0.014), but eventually returned back to baseline (P = 0.823). Median HADS scores were low: 5 (IQR 6) for anxiety and 3 (IQR 5) for depression, and they were unaff

Long-term yield of pancreatic cancer surveillance in high-risk individuals

Objective We aimed to determine the long-term yield of pancreatic cancer surveillance in hereditary predisposed high-risk individuals. Design From 2006 to 2019, we prospectively enrolled asymptomatic individuals with an estimated 10% or greater lifetime risk of pancreatic ductal adenocarcinoma (PDAC) after obligatory evaluation by a clinical geneticist and genetic testing, and subjected them to annual surveillance with both endoscopic ultrasonography (EUS) and MRI/cholangiopancreatography (MRI/MRCP) at each visit. Results 366 individuals (201 mutation-negative familial pancreatic cancer (FPC) kindreds and 165 PDAC susceptibility gene mutation carriers; mean age 54 years, SD 9.9) were followed for 63 months on average (SD 43.2). Ten individuals developed PDAC, of which four presented with a symptomatic interval carcinoma and six underwent resection. The cumulative PDAC incidence was 9.3% in the mutation carriers and 0% in the FPC kindreds (p<0.001). Median PDAC survival was 18 months (range 1-32). Surgery was performed in 17 individuals (4.6%), whose pathology revealed 6 PDACs (3 T1N0M0), 7 low-grade precursor lesions, 2 neuroendocrine tumours <2 cm, 1 autoimmune pancreatitis and in 1 individual no abnormality. There was no surgery-related mortality. EUS detected more solid lesions than MRI/MRCP (100% vs 22%, p<0.001), but less cystic lesions (42% vs 83%, p<0.001). Conclusion The diagnostic yield of PDAC was substantial in established high-risk mutation carriers, but non-existent in the mutation-negative proven FPC kindreds. Nevertheless, timely identification of resectable lesions proved challenging despite the concurrent use of two imaging modalities, with EUS outperforming MRI/MRCP. Overall, surveillance by imaging yields suboptimal results with a clear need for more sensitive diagnostic markers, including biomarkers

Recurrent candidiasis and early-onset gastric cancer in a patient with a genetically defined partial MYD88 defect

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

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

Genetisch onderzoek bij prostaatkanker: nieuwe ontwikkelingen

Contains fulltext : 229429.pdf (Publisher’s version ) (Open Access)Op dit moment wordt kiembaan genetisch onderzoek bij prostaatkanker zelden aangevraagd. Bij mannen met gemetastaseerd prostaatcarcinoom wordt echter relatief vaak een mutatie in een borstkankergen gevonden (met name in BRCA2). In dit artikel worden criteria voor genetisch onderzoek voorgesteld. De uitslag van genetisch onderzoek kan van belang zijn voor familieleden die preventieve maatregelen kunnen nemen om kanker te voorkomen of tijdig op te sporen. De uitslag kan daarnaast ook van belang zijn voor de behandeling van de ziekte. De tijd is rijp om multidisciplinair een werkwijze in te richten waarbij genetisch onderzoek door het behandelteam met de patiënt wordt besproken, de patiënt goed geïnformeerd een keuze kan maken, en de uitslagen in nauwe samenwerking met de klinische genetica worden teruggekoppeld. Voor deze nieuwe werkwijze (mainstreaming van genetisch onderzoek) is adequate scholing nodig van urologen, oncologen en verpleegkundig specialisten

Counselee participation in follow-up breast cancer genetic counselling visits and associations with achievement of the preferred role, cognitive outcomes, risk perception alignment and perceived personal control

Item does not contain fulltextThe purpose of the study was to assess the counselee participation in the follow-up visits, compared to the first visits, for breast cancer genetic counselling and to explore associations with counselees' achievement of their preferred role in decision making, information recall, knowledge, risk perception alignment and perceived personal control. First and follow-up visits for breast cancer genetic counselling of 96 counselees of a Dutch genetics center were videotaped (2008-2010). Counselees completed questionnaires before counselling (T1), after the follow-up visit (T2) and one year after the follow-up visit (T3). Consultations were rated with the Roter Interaction Analysis System (RIAS). Counselee participation was measured as the percentage of counselee utterances, the percentage of counselee questions and the interactivity (number of turns per minute). Follow-up visits had higher levels of counselee participation than first visits as assessed by the percentage of counselee talk, the interactivity and counselee questions. More counselee talk in the follow-up visit was related to higher achievement of the preferred role (T2) and higher perceived personal control (T3). Higher interactivity in the follow-up visit was related to lower achievement of the preferred role in decision making and lower information recall (T2). There were no significant associations with the percentage of questions asked and none of the participation measures was related to knowledge, risk perception alignment and perceived personal control (T2). In line with the interviewing admonishment 'talk less and listen more', the only assessment of counselee participation associated to better outcomes is the percentage of counselee talk. High interactivity might be associated with lower recall in breast cancer genetic counselees who are generally highly educated. However, this study was limited by a small sample size and a heterogeneous group of counselees. Research is needed on the interactions causing interactivity and its relationships with involvement in decision making and recall

Who is being referred to cancer genetic counseling? Characteristics of counselees and their referral

Item does not contain fulltextBoth physician and patient play a role in the referral process for cancer genetic counseling. Access to such counseling is not optimal because some eligible patients are not being reached by current referral practice. We aimed to identify factors associated with the initiator of referral. During a 7-month period, we recorded demographic characteristics like gender, personal and family history of cancer, ethnicity and eligibility for genetic testing for 406 consecutive counselees using a specially designed questionnaire. Counselees were seen in a university hospital or a community hospital (n = 7) in the Netherlands. We also recorded educational level of each counselee, clinical setting and who initiated referral. Descriptive statistics were used to describe the counselees' general characteristics. We analysed the association between counselee characteristics and the initiator of referral by logistic regression. The majority of counselees seemed to have initiated referral themselves but were indeed eligible for genetic testing. In comparison to the general population in the Netherlands, the counselees had a higher level of education, and there were fewer immigrants, although a higher level of education was not found to be a facilitating factor for referral. The clinical setting where a counselee was seen was associated with initiator of referral, although this relationship was not straightforward. There is a complex interaction between clinical setting and initiator of referral, which warrants further research to elucidate the factors involved in this relationship. Patients seen in cancer genetic counseling do not reflect the general population in terms of educational level or ethnicity

Risk communication in completed series of breast cancer genetic counseling visits.

Purpose: There is no consensus on how best to communicate risk in breast cancer genetic counseling. We studied risk communication in completed series of counseling visits and assessed associations with counselees' postcounseling risk perception and satisfaction. Methods: Pre- and postcounseling questionnaires and videorecordings of all visits were available for 51 affected and unaffected women from families with no known BRCA1/2 mutation, who fulfilled criteria for DNA testing. We developed a checklist for assessing risk communication and counselors' behaviors. Results: General risks were mainly communicated in initial visits, while counselee-specific risks were discussed mainly in concluding visits. The risks discussed most often were conveyed only numerically or qualitatively, and most were only stated positively or negatively. Counselors regularly helped counselees to understand the information, but seldom built on counselees' pre-existing perspective. Counselees' breast cancer risk perception after counseling was unrelated to whether this risk had been explicitly stated. The number of general risks discussed was negatively associated with counselees' satisfaction about counseling. Conclusion: Findings suggest that counselors' authority prevails over mutuality with individual counselees, in their communication about risks.(aut. ref.

Prophylactic Laparoscopic Total Gastrectomy with Jejunal Pouch Reconstruction in Patients Carrying a CDH1 Germline Mutation

Contains fulltext : 152623.pdf (publisher's version ) (Open Access)BACKGROUND: For patients with an identified germline E-cadherin-1 (CDH1) mutation, prophylactic gastrectomy is the treatment of choice to eliminate the high risk of developing diffuse gastric cancer. Laparoscopic total gastrectomy with jejunal pouch reconstruction is a novel approach that may be especially suitable in these patients. METHODS: Patients with a germline CDH1 mutation who underwent prophylactic laparoscopic total gastrectomy with jejunal pouch were included in our prospective database. RESULTS: A total of 11 patients with a median age of 40 (22-61) years were included. The average operative time was 4:26 +/- 0:49 h and the average blood loss was 219 +/- 155 ml. Median length of hospital stay was 10 (7-27) days. In two patients, an esophagojejunal anastomotic leakage occurred (grade 4). The leakages were seen in patient numbers 2 and 3, which may be a result of a learning curve. The latter eight patients did not develop anastomotic leakage. Pulmonary complications occurred in one patient with atelectasis and in one patient with pneumonia (grade 2). The 60-day mortality rate was 0 %. Multiple foci of intramucosal diffuse gastric signet ring cell carcinoma were found in the resection specimen of 9/11 (82 %) patients. All 11/11 (100 %) resections were microscopically radical. CONCLUSIONS: Prophylactic laparoscopic total gastrectomy with jejunal pouch reconstruction in patients with a CDH1 germline mutation is feasible and safe. In 82 % of patients, foci of intramucosal diffuse gastric signet ring cell carcinoma in the resection specimen were found