Current and new frontiers in hereditary cancer surveillance: Opportunities for liquid biopsy.

At least 5% of cancer diagnoses are attributed to a causal pathogenic or likely pathogenic germline genetic variant (hereditary cancer syndrome-HCS). These individuals are burdened with lifelong surveillance monitoring organs for a wide spectrum of cancers. This is associated with substantial uncertainty and anxiety in the time between screening tests and while the individuals are awaiting results. Cell-free DNA (cfDNA) sequencing has recently shown potential as a non-invasive strategy for monitoring cancer. There is an opportunity for high-yield cancer early detection in HCS. To assess clinical validity of cfDNA in individuals with HCS, representatives from eight genetics centers from across Canada founded the CHARM (cfDNA in Hereditary and High-Risk Malignancies) Consortium in 2017. In this perspective, we discuss operationalization of this consortium and early data emerging from the most common and well-characterized HCSs: hereditary breast and ovarian cancer, Lynch syndrome, Li-Fraumeni syndrome, and Neurofibromatosis type 1. We identify opportunities for the incorporation of cfDNA sequencing into surveillance protocols; these opportunities are backed by examples of earlier cancer detection efficacy in HCSs from the CHARM Consortium. We seek to establish a paradigm shift in early cancer surveillance in individuals with HCSs, away from highly centralized, regimented medical screening visits and toward more accessible, frequent, and proactive care for these high-risk individuals.

SARS-CoV-2 ORF8 modulates lung inflammation and clinical disease progression.

The virus severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, is the causative agent of the current COVID-19 pandemic. It possesses a large 30 kilobase (kb) genome that encodes structural, non-structural, and accessory proteins. Although not necessary to cause disease, these accessory proteins are known to influence viral replication and pathogenesis. Through the synthesis of novel infectious clones of SARS-CoV-2 that lack one or more of the accessory proteins of the virus, we have found that one of these accessory proteins, ORF8, is critical for the modulation of the host inflammatory response. Mice infected with a SARS-CoV-2 virus lacking ORF8 exhibit increased weight loss and exacerbated macrophage infiltration into the lungs. Additionally, infection of mice with recombinant SARS-CoV-2 viruses encoding ORF8 mutations found in variants of concern reveal that naturally occurring mutations in this protein influence disease severity. Our studies with a virus lacking this ORF8 protein and viruses possessing naturally occurring point mutations in this protein demonstrate that this protein impacts pathogenesis.

ARIH2 is essential for embryogenesis, and its hematopoietic deficiency causes lethal activation of the immune system.

The E3 ligase ARIH2 has an unusual structure and mechanism of elongating ubiquitin chains. To understand its physiological role, we generated gene-targeted mice deficient in ARIH2. ARIH2 deficiency resulted in the embryonic death of C57BL/6 mice. On a mixed genetic background, the lethality was attenuated, with some mice surviving beyond weaning and then succumbing to an aggressive multiorgan inflammatory response. We found that in dendritic cells (DCs), ARIH2 caused degradation of the inhibitor IκBß in the nucleus, which abrogated its ability to sequester, protect and transcriptionally coactivate the transcription factor subunit p65 in the nucleus. Loss of ARIH2 caused dysregulated activation of the transcription factor NF-κB in DCs, which led to lethal activation of the immune system in ARIH2-sufficent mice reconstituted with ARIH2-deficient hematopoietic stem cells. Our data have therapeutic implications for targeting ARIH2 function.

Next generation of free? Points to consider when navigating sponsored genetic testing.

Genetics has been integrated into patient care across many subspecialties. However, genetic and genomic testing (GT) remain expensive with disparities in access both within Canada and internationally. It is, therefore, not surprising that sponsored GT has emerged as one alternative. Sponsored GT, for the purpose of this document, refers to clinical-grade GT partially or fully subsidised by industry. In return, industry sponsors-usually pharmaceutical or biotechnology companies-may have access to patients' genetic data, practitioner information, DNA and/or other information. The availability of sponsored GT options in the Canadian healthcare landscape has appeared to simplify patient and practitioner access to GT, but the potential ethical and legal considerations, as well as the nuances of a publicly funded healthcare system, must also be considered. This document offers preliminary guidance for Canadian healthcare practitioners encountering sponsored GT in practice. Further research and dialogue is urgently needed to explore this issue to provide fulsome considerations that one must be aware of when availing such options.

Risk-reducing mastectomy and breast cancer mortality in women with a BRCA1 or BRCA2 pathogenic variant: an international analysis.

BACKGROUND: Risk-reducing mastectomy (RRM) is offered to women with a BRCA1 or BRCA2 pathogenic variant, however, there are limited data on the impact on breast cancer mortality. METHODS: Participants were identified from a registry of women with BRCA1/2 pathogenic variants. We used a pseudo-randomised trial design and matched one woman with a RRM to one woman without a RRM on year of birth, gene, and country. We estimated the hazard ratio (HR) and 95% confidence intervals (CI) for dying of breast cancer in the follow-up period. RESULTS: There were 1654 women included; 827 assigned to the RRM arm and 827 assigned to the control arm. After a mean follow-up of 6.3 years, there were 20 incident breast cancers (including 15 occult cancers) and two breast cancer deaths in the RRM arm, and 100 incident breast cancers and 7 breast cancer deaths in the control arm (HR = 0.26; 95% CI 0.05-1.35; p = 0.11). The probability of dying of breast cancer within 15 years after RRM was 0.95%. CONCLUSIONS: In women with a BRCA1 or BRCA2 pathogenic variant, RRM reduces the risk of breast cancer, and the probability of dying of breast cancer is low.

Active narcotic use and post-peroral endoscopic myotomy outcomes in esophageal motility disorders.

BACKGROUND AND AIMS: Peroral endoscopic myotomy (POEM) is a minimally invasive technique used to treat esophageal motility disorders. Opioid use has been demonstrated to adversely affect esophageal dysmotility and is associated with an increased prevalence of esophageal motility disorders. Our aim was to investigate the effect of narcotic use on success rates in patients undergoing POEM. METHODS: This was a single-center, retrospective study of patients undergoing POEM between February 2017 and September 2021. Primary outcomes were post-POEM Eckardt score (ES), distensibility index, and length of procedure. Secondary outcomes included technical success, myotomy length, length of stay, adverse events, reintervention rates, and postprocedure GERD. RESULTS: During the study period, 90 patients underwent POEM for treatment of esophageal dysmotility disorders. Age, sex, race, indications for POEM, and body mass index were not significant between those with or without narcotic use. There were no differences in procedure time, preprocedure ESs, or length of stay. Postprocedure ESs were higher in the group with active narcotic use compared to the group with no prior history (2.73 vs 1.2, P = .004). Distensibility indexes measured with EndoFLIP (Medtronic, Minneapolis, Minn, USA) were not different in patients using narcotics compared with opioid-naïve patients. CONCLUSION: Active narcotic use negatively affects symptom improvement after POEM for the treatment of esophageal motility disorders.

Peroral endoscopic myotomy for spastic esophageal dysmotility among opioid users: a multicenter propensity score matching study.

BACKGROUND AND AIMS: Opioid-induced esophageal dysfunction (OIED) often presents as spastic esophageal disorders (SEDs) and esophagogastric junction outflow obstruction (EGJOO). The aim of this study was to evaluate and compare clinical outcomes of peroral endoscopic myotomy (POEM) for SEDs and EGJOO among opioid users and nonusers. METHODS: This propensity score (PS) matching study included consecutive opioid users and nonusers who underwent POEM for SEDs and EGJOO between January 2018 and September 2022. The following covariates were used for the PS calculation: age, sex, duration of symptoms, Eckardt score, type of motility disorder, and length of myotomy during POEM. Clinical response was defined as a post-POEM Eckardt score ≤3. RESULTS: A total of 277 consecutive patients underwent POEM during the study period. PS matching resulted in the selection of 64 pairs of patients strictly matched 1:1 (n = 128) with no statistically significant differences in demographic, baseline, or procedural characteristics or in the parameters considered for the PS between the 2 groups. Clinical response to POEM was significantly lower among opioid users (51 of 64 [79.7%]) versus nonusers (60 of 64 [93.8%]) (P = .03) at a median follow-up of 18 months. Among opioid users, higher opioid dose (>60 morphine milligram equivalents per day) was associated with a higher likelihood of failure to respond to POEM (odds ratio, 4.59; 95% confidence interval, 1.31-3.98; P = .02). CONCLUSIONS: Clinical response to POEM for SEDs and EGJOO is significantly lower among opioid users versus nonusers. There was a dose-relationship between opioids and response to POEM, with higher daily opioid usage associated with a higher likelihood of treatment failure.

Evaluating no fixation, endoscopic suture fixation, and an over-the-scope clip for anchoring fully covered self-expanding metal stents in benign upper gastrointestinal conditions: a comparative multicenter international study (with video).

BACKGROUND AND AIMS: Fully covered self-expandable metal stents (FCSEMSs) are widely used in benign upper gastrointestinal (GI) conditions, but stent migration remains a limitation. An over-the-scope clip (OTSC) device (Ovesco Endoscopy) for stent anchoring has been recently developed. The aim of this study was to evaluate the effect of OTSC fixation on SEMS migration rate. METHODS: A retrospective review of consecutive patients who underwent FCSEMS placement for benign upper GI conditions between 1/2011 and 10/2022 at 16 centers. The primary outcome was rate of stent migration. The secondary outcomes were clinical success and adverse events. RESULTS: A total of 311 (no fixation 122, OTSC 94, endoscopic suturing 95) patients underwent 316 stenting procedures. Compared to the no fixation (NF) group (n=49, 39%), the rate of stent migration was significantly lower in the OTSC (SF) (n=16, 17%, p=0.001) and endoscopic suturing (ES) group (n=23, 24%, p=0.01). The rate of stent migration was not different between the SF and ES groups (p=0.2). On multivariate analysis, SF (OR 0.34, CI 0.17-0.70, p<0.01) and ES (OR 0.46, CI 0.23-0.91, p=0.02) were independently associated with decreased risk of stent migration. Compared to the NF group (n=64, 52%), there was a higher rate of clinical success in the SF (n=64, 68%; p=0.03) and ES group (n=66, 69%; p = 0.02). There was no significant difference in the rate of adverse events between the three groups. CONCLUSION: Stent fixation using OTSC is safe and effective at preventing stent migration and may also result in improved clinical response.

Incidence of endometrial cancer in BRCA mutation carriers.

OBJECTIVE: Whether or not women who harbor a germline pathogenic variant ('mutation') in the BRCA1 or BRCA2 genes are at elevated risk of developing endometrial cancer is yet to be determined. METHODS: We conducted a prospective analysis of 4959 BRCA mutation carriers with no prior history of cancer (except for breast or melanoma) and an intact uterus. RESULTS: After a mean of 6.7 years of follow-up there were 38 incident cases of endometrial cancer diagnosed; 30 among BRCA1 carriers and eight among BRCA2 carriers. The mean age at diagnosis was 58.4 years (range 46.8-76.1). The majority were of the endometrioid subtype (n = 16), followed by mixed endometroid and serous (n = 4), serous (n = 3) or clear cell (n = 1) (missing = 13). The cumulative incidence from age 40 to age 70 was 3.4% for BRCA1 carriers and was 1.6% for BRCA2 mutation carriers. Prior tamoxifen use was associated with a significant two-fold increased risk (HR = 2.24; 95% CI 1.10-4.55). There was no significant association between exogenous hormone use, oophorectomy, smoking or BMI at age 40 and risk (P ≥ 0.32). CONCLUSIONS: Compared to the general population, we observed higher rates of endometrial cancer among young BRCA1 mutation carriers; however, lifetime risks were similar. Women with prior tamoxifen exposure were at a significantly increased risk. These findings were based. on a small number of incident cases and require confirmation with additional follow-up of our aging cohort.

Endoscopic Ultrasound-guided Transmural Biliary Drainage With 6 mm and 8 mm Cautery-enhanced Lumen-apposing Metal Stents: A Multicenter Collaborative Study.

OBJECTIVE: Endoscopic retrograde cholangiopancreatography (ERCP) may be unsuccessful in patients with duodenal stenosis or malignant ampullary infiltration. Endoscopic ultrasound-guided biliary drainage (EUS-BD) has been proposed as an alternative. We aimed to assess the efficacy and safety of EUS-BD for malignant distal bile duct obstruction using the newly introduced smaller caliber 6 or 8 mm cautery-enhanced lumen-apposing metal stent. METHODS: A multicenter retrospective study was performed on patients with unresectable malignant distal bile duct obstruction who underwent EUS-BD between 2021 and 2022 after unsuccessful ERCP. RESULTS: Thirty-two patients were included [7 (53.13%) males], with a mean age of 72.2 ± 12.5 years. The technical success rate was 100%. Altered anatomy was present in 2 (6.25%). The indication for drainage was biliary obstruction from pancreatic cancer in 26 patients (84.5%), cholangiocarcinoma in 3 (9.4%), and ampullary mass in 3 (9.4%). The procedure was performed mostly in an outpatient setting (n = 19, 59.38%). The clinical success rate was 92.3% [bilirubin: 14.1 (SD: 8.9) preprocedure vs 4.9 (SD: 1.1) postprocedure; P = 0.0001]. There was one early adverse event of a perforation, which was closed endoscopically and drained percutaneously. Delayed adverse events included food impaction of the stent (n = 1), which was resolved with a repeat procedure and insertion of a double pigtail stent. CONCLUSION: This study demonstrates the feasibility of EUS-BD drainage using smaller caliber 6 or 8 mm lumen-apposing metal stent to relieve malignant distal bile duct obstruction in patients who fail conventional ERCP.

Development of a comprehensive approach to adult hereditary cancer testing in Ontario.

BACKGROUND: Genetic testing for hereditary cancer susceptibility has advanced over time due to the discovery of new risk genes, improved technology and decreased cost. In the province of Ontario, testing eligibility criteria were initially developed to include hereditary breast, ovarian and colorectal cancer syndromes. The rapid evolution of genetic technologies has facilitated the ability to interrogate a large number of genes concurrently. This, coupled with new knowledge about risk genes, necessitated a coordinated approach to expanding the scope of genes and indications tested and synchronisation of access and test utilisation across the province as required in a publicly funded universal healthcare system. METHODS: Ontario Health-Cancer Care Ontario convened expert working groups to develop a standardised and comprehensive cancer gene list for adults and accompanying hereditary cancer testing (HCT) criteria using an evidence-based framework and broad laboratory and clinical genetics engagement. RESULTS: A standardised 76-cancer-gene panel, organised into 13 larger disease site panels and 25 single/small gene panels, was developed and endorsed by the working groups. Provincial genetic testing eligibility criteria were updated to align with the new panels and to guide clinical decision-making. In the first year following the implementation of these changes, 10 564 HCT panels were performed with an overall mutation detection rate of 12.2%. CONCLUSION: Using an evidence framework and broad clinical engagement to develop and endorse an updated guidance document, cancer genetic testing for adults in Ontario is now standardised and coordinated across the province.

A model for the return and referral of all clinically significant secondary findings of genomic sequencing.

Secondary findings (SFs) identified through genomic sequencing (GS) can offer a wide range of health benefits to patients. Resource and capacity constraints pose a challenge to their clinical management; therefore, clinical workflows are needed to optimise the health benefits of SFs. In this paper, we describe a model we created for the return and referral of all clinically significant SFs, beyond medically actionable results, from GS. As part of a randomised controlled trial evaluating the outcomes and costs of disclosing all clinically significant SFs from GS, we consulted genetics and primary care experts to determine a feasible workflow to manage SFs. Consensus was sought to determine appropriate clinical recommendations for each category of SF and which clinician specialist would provide follow-up care. We developed a communication and referral plan for each category of SFs. This involved referrals to specialised clinics, such as an Adult Genetics clinic, for highly penetrant medically actionable findings. Common and non-urgent SFs, such as pharmacogenomics and carrier status results for non-family planning participants, were directed back to the family physician (FP). SF results and recommendations were communicated directly to participants to respect autonomy and to their FPs to support follow-up of SFs. We describe a model for the return and referral of all clinically significant SFs to facilitate the utility of GS and promote the health benefits of SFs. This may serve as a model for others returning GS results transitioning participants from research to clinical settings.

Diffuse myocardial fibrosis is uncommon in people with perinatally acquired human immunodeficiency virus infection.

BACKGROUND: Cardiovascular disease (CVD) remains a leading cause of death in people living with HIV. Myocardial fibrosis is well-described in HIV infection acquired in adulthood. We evaluate the burden of fibrosis by cardiac magnetic resonance in people with perinatal HIV infection. METHODS: Individuals with perinatally acquired HIV (pnHIV) diagnosed before 10 years-old and on antiretroviral treatment for ≥ 6 months were matched with uninfected controls. Patients with significant cardiometabolic co-morbidities and pregnancy were excluded. Diffuse fibrosis was assessed by cardiac magnetic resonance (CMR) with native T1 mapping for calculation of extracellular volume fraction (ECV). Viability was assessed with late gadolinium enhancement. The normality of fibrosis was assessed using the Komogrov-Smirnov test. Fibrosis between the groups was analyzed using a Mann-Whitney U test, as the data was not normally distributed. Statistical significance was defined as a p-valve < 0.05. RESULTS: Fourteen adults with pnHIV group and 26 controls (71% female and 86% Black race) were assessed. The average (± standard deviation) age in the study group was 29 (± 4.3) years-old. All pnHIV had been on ART for decades. Demographic data, CMR functional/volumetric data, and pre-contrast T1 mapping values were similar between groups. Diastolic function was normal in 50% of pnHIV patients and indeterminate in most of the remainder (42%). There was no statistically significant difference in ECV between groups; p = 0.24. CONCLUSION: Perinatally-acquired HIV was not associated with diffuse myocardial fibrosis. Larger prospective studies with serial examinations are needed to determine whether pnHIV patients develop abnormal structure or function more often than unaffected controls.

Psychological distress following multi-gene panel testing for hereditary breast and ovarian cancer risk.

Advances in our understanding of the genetic landscape of hereditary breast and ovarian cancer (HBOC) have led to the clinical adoption of multi-gene panel testing. Panel testing introduces new sources of genetic uncertainty secondary to the inclusion of moderate- and low-penetrance genes, as well as the increased likelihood of identifying a variant of uncertain significance (VUS). This cross-sectional study explored the post-test psychological functioning of women who underwent multi-gene panel testing for HBOC susceptibility genes. Two hundred and ninety-five women who underwent panel testing within the previous 2 years completed a study questionnaire to measure levels of cancer-related and genetic testing-related distress using the Impact of Events Scale (IES) and the Multidimensional Impact of Cancer Risk Assessment (MICRA), respectively. Multiple regression analyses were conducted to evaluate the relationship between genetic test results and levels of psychological distress captured by the IES and MICRA. In this cohort, a pathogenic variant (PV) was identified in 41 (14%) of participants, and 77 (26%) participants were found to have a VUS. In the multi-variate model, higher mean levels of genetic testing-related distress were observed in individuals with a PV (p < 0.001) or a VUS (p = 0.007) compared to those with a negative result. Furthermore, participants with a PV in a moderate-penetrance gene were found to have higher levels of genetic testing-related distress compared to those with a PV in a high-risk gene (p = 0.03). Overall, participants were highly satisfied with their genetic testing experience, with 92% of individuals reporting they would recommend testing to others. Our findings highlight differences in psychological outcomes based on both variant pathogenicity and gene penetrance, which contribute to our understanding of the impact of panel testing and sources of both cancer-related and genetic testing-related distress secondary to testing.

The Anaesthetic Efficacy of Tetracaine and Oxymetazoline Compared With Co-Phenylcaine in Healthy Individuals.

OBJECTIVES: Nasal anaesthetic-decongestant sprays are commonly used prior to nasal instrumentation, such as flexible and rigid nasal endoscopy. Co-phenylcaine (lignocaine 5%, phenylephrine 0.5%, ENT Technologies Pty Ltd., Melbourne, VIC, Australia) is a combination spray commonly used for this purpose. However, lignocaine is less potent than other local anaesthetics, and both active constituents of Co-phenylcaine have a bitter taste. It was hypothesised that a combination spray containing tetracaine and oxymetazoline would both offer more potent topical anaesthesia and have a better taste. METHODS: Four anaesthetic-decongestant nasal sprays were tested in 10 healthy participants (Co-phenylcaine, and tetracaine 0.5%, 1% and 2% with oxymetazoline 0.05%). Sensory thresholds were sequentially measured at the head of the inferior turbinate using Semmes-Weinstein monofilaments over the following hour. Participants also rated taste on a Likert-style scale, and reported whether they experienced subjective numbness of the maxillary teeth. RESULTS: A median peak sensory threshold of 60 g (the maximum tested) was observed with Co-phenylcaine, but this threshold was exceeded by all the tetracaine-based sprays. Tetracaine 2% with oxymetazoline 0.05% had a significantly more rapid onset than Co-phenylcaine (4 min vs. 6 min, p < 0.05) and a longer duration of action. Eight participants reported dental numbness after administration of tetracaine 2% with oxymetazoline 0.05%, but only one participant after Co-phenylcaine. Tetracaine-based sprays were generally perceived to taste less unpleasant than Co-phenylcaine. CONCLUSION: Tetracaine 2% with oxymetazoline 0.05% is a more potent and rapidly acting anaesthetic-decongestant spray than Co-phenylcaine, with a longer duration of action.

Decoding the Prevalent High-Risk Breast Cancers: Demographics, Pathological, Imaging Insights, and Long-Term Outcome.

Objective: To investigate the features and outcomes of breast cancer in high-risk subgroups. Materials and Methods: REB approved an observational study of women diagnosed with breast cancer from 2010 to 2019. Three radiologists, using the BI-RADS lexicon, blindly reviewed mammogram and MRI screenings without a washout period. Consensus was reached with 2 additional reviewers. Inter-rater agreement was measured by Fleiss Kappa. Statistical analysis included Mann-Whitney U, Chi-square tests for cohort analysis, and Kaplan-Meier for survival rates, with a Cox model for comparative analysis using gene mutation as a reference. Results: The study included 140 high-risk women, finding 155 malignant lesions. Significant age differences noted: chest radiation therapy (median age 44, IQR: 37.0-46.2), gene mutation (median age 49, IQR: 39.8-58.0), and familial risk (median age 51, IQR: 44.5-56.0) (P = .007). Gene mutation carriers had smaller (P = .01), higher-grade tumours (P = .002), and more triple-negative ER- (P = .02), PR- (P = .002), and HER2- (P = .02) cases. MRI outperformed mammography in all subgroups. Substantial to near-perfect inter-rater agreement observed. Over 10 years, no deaths occurred in chest radiation group, with no significant survival difference between gene mutation and familial risk groups, HR = 0.93 (95% CI: 0.27, 3.26), P = .92. Conclusion: The study highlights the importance of age and specific tumour characteristics in identifying high-risk breast cancer subgroups. MRI is confirmed as an effective screening tool. Despite the aggressive nature of cancers in gene mutation carriers, early detection is crucial for survival outcomes. These insights, while necessitating further validation with larger studies, advocate for a move toward personalized medical care, strengthening the existing healthcare guidelines.

SCIP: software for efficient clinical interpretation of copy number variants detected by whole-genome sequencing.

Copy number variants (CNVs) represent major etiologic factors in rare genetic diseases. Current clinical CNV interpretation workflows require extensive back-and-forth with multiple tools and databases. This increases complexity and time burden, potentially resulting in missed genetic diagnoses. We present the Suite for CNV Interpretation and Prioritization (SCIP), a software package for the clinical interpretation of CNVs detected by whole-genome sequencing (WGS). The SCIP Visualization Module near-instantaneously displays all information necessary for CNV interpretation (variant quality, population frequency, inheritance pattern, and clinical relevance) on a single page-supported by modules providing variant filtration and prioritization. SCIP was comprehensively evaluated using WGS data from 1027 families with congenital cardiac disease and/or autism spectrum disorder, containing 187 pathogenic or likely pathogenic (P/LP) CNVs identified in previous curations. SCIP was efficient in filtration and prioritization: a median of just two CNVs per case were selected for review, yet it captured all P/LP findings (92.5% of which ranked 1st). SCIP was also able to identify one pathogenic CNV previously missed. SCIP was benchmarked against AnnotSV and a spreadsheet-based manual workflow and performed superiorly than both. In conclusion, SCIP is a novel software package for efficient clinical CNV interpretation, substantially faster and more accurate than previous tools (available at https://github.com/qd29/SCIP , a video tutorial series is available at https://bit.ly/SCIPVideos ).

Great expectations: patients' preferences for clinically significant results from genomic sequencing.

We aimed to describe patient preferences for a broad range of secondary findings (SF) from genomic sequencing (GS) and factors driving preferences. We assessed preference data within a trial of the Genomics ADvISER, (SF decision aid) among adult cancer patients. Participants could choose from five categories of SF: (1) medically actionable; (2) polygenic risks; (3) rare diseases; (4) early-onset neurological diseases; and (5) carrier status. We analyzed preferences using descriptive statistics and drivers of preferences using multivariable logistic regression models. The 133 participants were predominantly European (74%) or East Asian or mixed ancestry (13%), female (90%), and aged > 50 years old (60%). The majority chose to receive SF. 97% (129/133) chose actionable findings with 36% (48/133) choosing all 5 categories. Despite the lack of medical actionability, participants were interested in receiving SF of polygenic risks (74%), carrier status (75%), rare diseases (59%), and early-onset neurologic diseases (53%). Older participants were more likely to be interested in receiving results for early-onset neurological diseases, while those exhibiting lower decisional conflict were more likely to select all categories. Our results highlight a disconnect between cancer patient preferences and professional guidelines on SF, such as ACMG's recommendations to only return medically actionable secondary findings. In addition to clinical evidence, future guidelines should incorporate patient preferences.

How do members of the public expect to use variants of uncertain significance in their health care? A population-based survey.

PURPOSE: Genomic sequencing can generate complex results, including variants of uncertain significance (VUS). In general, VUS should not inform clinical decision-making. This study aimed to assess the public's expected management of VUS. METHODS: An online, hypothetical survey was conducted among members of the Canadian public preceded by an educational video. Participants were randomized to 1 of 2 arms, VUS or pathogenic variant in a colorectal cancer gene, and asked which types of health services they expected to use for this result. Expected health service use was compared between randomization arms, and associations between participants' sociodemographic characteristics, attitudes, and medical history were explored. RESULTS: Among 1003 respondents (completion rate 60%), more participants expected to use each type of health service for a pathogenic variant than for a VUS. However, a considerable proportion of participants expected to request monitoring (73.4%) and consult health care providers (60.9%) for a VUS. There was evidence to support associations between expectation to use health services for a VUS with family history of genetic disease, family history of cancer, education, and attitudes toward health care and technology. CONCLUSION: Many participants expected to use health services for a VUS in a colorectal cancer predisposition gene, suggesting a potential disconnect between patients' expectations for VUS management and guideline-recommended care.

Comparing clinical success and procedural difficulty between treatment-naïve and treatment-refractory patients with esophageal motility disorders during peroral endoscopic myotomy.

BACKGROUND AND AIMS: Peroral endoscopic myotomy (POEM) can successfully treat patients with achalasia. Prior therapy with Botox (Allergan, Madison, NJ, USA) injections, pneumatic dilation (PD), and/or laparoscopic Heller myotomy (LHM) is believed to increase the difficulty of POEM procedures. We aimed to determine if prior treatment methods were associated with longer procedure times or lower clinical success. METHODS: In this single-center retrospective study, consecutive patients who underwent POEM for achalasia between February 2017 and September 2021 were studied. Collected data were patient demographics, prior treatment, pre- and postprocedure Eckardt score (ES), distensibility indices (DIs), and procedure times. Primary outcomes were clinical success and procedure difficulty. RESULTS: Of 95 patients (mean age, 55.6 years; 45% women), 25 patients underwent POEM for type I achalasia, 31 for type II achalasia, and 33 for spastic esophageal pathologies. Thirty-three patients (34.7%) were treated for achalasia before POEM with onabotulinumtoxinA injections (n = 18), PD (n = 17), and LHM (n = 3). There were no significant differences in post-treatment ESs or technical success between the 2 groups (P = .98 and P = .66, respectively). Multivariate analysis showed that prior treatment was associated with decreased case time and easier tunneling during POEM. CONCLUSIONS: Prior treatment did not impact the clinical success rate of POEM and led to decreased case times and easier tunneling difficulty, likely because of persistent lower esophageal sphincter changes and differences in diagnostic indications. POEM should be considered for patients with treatment-refractory symptoms as a safe and feasible option. Further large-scale studies are needed to validate our findings.