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Background: General practitioners (GP) and community pharmacists need information about hospital discharge patients' medicines to continue their management in the community. This necessitates effective communication, collaboration, and reliable information-sharing. However, such handover is inconsistent, and whilst digital systems are in place to transfer information at transitions of care, these systems are passive and clinicians are not prompted about patients' transitions. There are also gaps in communication between community pharmacists and GPs. These issues impact patient safety, leading to hospital readmissions and increased healthcare costs., Methods: A three-phased, multi-method study design is planned to trial a multifaceted intervention to reduce 30-day hospital readmissions. Phase 1 is the co-design of the intervention with stakeholders and end-users; phase 2 is the development of the intervention; phase 3 is a stepped wedge cluster randomised controlled trial with 20 clusters (community pharmacies). Expected intervention components will be a hospital pharmacist navigator, primary care medication management review services, and a digital solution for information sharing. Phase 3 will recruit 10 patients per pharmacy cluster/month to achieve a sample size of 2200 patients powered to detect a 5% absolute reduction in unplanned readmissions from 10% in the control group to 5% in the intervention at 30 days. The randomisation and intervention will occur at the level of the patient's nominated community pharmacy. Primary analysis will be a comparison of 30-day medication-related hospital readmissions between intervention and control clusters using a mixed effects Poisson regression model with a random effect for cluster (pharmacy) and a fixed effect for each step to account for secular trends., Trial Registration: This trial is registered with the Australian New Zealand Clinical Trials Registry: ACTRN12624000480583p , registered 19 April 2024., (© 2024. Crown.)

We report a case of Mismatch Repair Deficiency (MMRD) caused by germline homozygous EPCAM deletion leading to tissue-specific loss of MSH2. Through the use of patient-derived cells and organoid technologies, we performed stepwise in vitro differentiation of colonic and brain organoids from reprogrammed EPCAM del iPSC derived from patient fibroblasts. Differentiation of iPSC to epithelial-colonic organoids exhibited continuous increased EPCAM expression and hypermethylation of the MSH2 promoter. This was associated with loss of MSH2 expression, increased mutational burden, MMRD signatures and MS-indel accumulation, the hallmarks of MMRD. In contrast, maturation into brain organoids and examination of blood and fibroblasts failed to show similar processes, preserving MMR proficiency. The combined use of iPSC, organoid technologies and functional genomics analyses highlights the potential of cutting-edge cellular and molecular analysis techniques to define processes controlling tumorigenesis and uncovers a new paradigm of tissue-specific MMRD, which affects the clinical management of these patients., (© 2024. The Author(s).)

Hereditary cancer syndromes (HCS) predispose individuals to a higher risk of developing multiple cancers. However, current screening strategies have limited ability to screen for all cancer risks. Circulating tumour DNA (ctDNA) detects DNA fragments shed by tumour cells in the bloodstream and can potentially detect cancers early. This study aimed to explore patients' perspectives on ctDNA's utility to help inform its clinical adoption and implementation. We conducted a qualitative interpretive description study using semi-structured phone interviews. Participants were purposively sampled adult HCS patients recruited from a Canadian HCS research consortium. Thirty HCS patients were interviewed (n = 19 women, age range 20s-70s, n = 25 were white). Participants were highly concerned about developing cancers, particularly those without reliable screening options for early detection. They "just wanted more" than their current screening strategies. Participants were enthusiastic about ctDNA's potential to be comprehensive (detect multiple cancers), predictive (detect cancers early) and tailored (lead to personalized clinical management). Participants also acknowledged ctDNA's potential limitations, including false positives/negatives risks and experiencing additional anxiety. However, they saw ctDNA's potential benefits outweighing its limitations. In conclusion, participants' belief in ctDNA's potential to improve their care overshadowed its limitations, indicating patients' support for using ctDNA in HCS care., (© 2023. The Author(s), under exclusive licence to European Society of Human Genetics.)

People with Li-Fraumeni syndrome (LFS) harbor a germline pathogenic variant in the TP53 tumor suppressor gene, face a near 100% lifetime risk of cancer, and routinely undergo intensive surveillance protocols. Liquid biopsy has become an attractive tool for a range of clinical applications, including early cancer detection. Here, we provide a proof-of-principle for a multimodal liquid biopsy assay that integrates a targeted gene panel, shallow whole-genome, and cell-free methylated DNA immunoprecipitation sequencing for the early detection of cancer in a longitudinal cohort of 89 LFS patients. Multimodal analysis increased our detection rate in patients with an active cancer diagnosis over uni-modal analysis and was able to detect cancer-associated signal(s) in carriers prior to diagnosis with conventional screening (positive predictive value = 67.6%, negative predictive value = 96.5%). Although adoption of liquid biopsy into current surveillance will require further clinical validation, this study provides a framework for individuals with LFS., Significance: By utilizing an integrated cell-free DNA approach, liquid biopsy shows earlier detection of cancer in patients with LFS compared with current clinical surveillance methods such as imaging. Liquid biopsy provides improved accessibility and sensitivity, complementing current clinical surveillance methods to provide better care for these patients. See related commentary by Latham et al., p. 23. This article is featured in Selected Articles from This Issue, p. 5., (©2023 The Authors; Published by the American Association for Cancer Research.)

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., Competing Interests: Declaration of interests William D. Foulkes has research funding from AstraZeneca. Sophie Sun has a consulting and advisory relationship with Novartis, Bristol-Myers Squibb, Pfizer, Purdue, Takeda, and AstraZeneca. Kasmintan A. Schrader has a consulting and advisory relationship with and has received honoraria from AstraZeneca Canada and Pfizer and research funding from AstraZeneca Canada. Dean Regier has a consulting/advisory relationship with Roche Canada and AstraZeneca. Trevor J. Pugh has a consulting and advisory relationship with Chrysalis Biomedical Advisors and the Canadian Pension Plan Investment Board, is on the scientific advisory board for Illumina, has received honoraria from AstraZeneca, Merck, PACT Pharma, and SAGA Diagnostics, and has research funding from Roche (Genentech), the National Institutes of Health, and the US Department of Defense. Yvonne Bombard has ownership interests and intellectual property rights as an inventor and patent holder with Genetics Adviser. The other authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the use of blood cell-free DNA (cfDNA) to identify emerging mechanisms of resistance to PARP inhibitors (PARPi) in high-grade serous ovarian cancer (HGSOC)., Experimental Design: We used targeted sequencing (TS) to analyze 78 longitudinal cfDNA samples collected from 30 patients with HGSOC enrolled in a phase II clinical trial evaluating cediranib (VEGF inhibitor) plus olaparib (PARPi) after progression on PARPi alone. cfDNA was collected at baseline, before treatment cycle 2, and at end of treatment. These were compared with whole-exome sequencing (WES) of baseline tumor tissues., Results: At baseline (time of initial PARPi progression), cfDNA tumor fractions were 0.2% to 67% (median, 3.25%), and patients with high ctDNA levels (>15%) had a higher tumor burden (sum of target lesions; P = 0.043). Across all timepoints, cfDNA detected 74.4% of mutations known from prior tumor WES, including three of five expected BRCA1/2 reversion mutations. In addition, cfDNA identified 10 novel mutations not detected by WES, including seven TP53 mutations annotated as pathogenic by ClinVar. cfDNA fragmentation analysis attributed five of these novel TP53 mutations to clonal hematopoiesis of indeterminate potential (CHIP). At baseline, samples with significant differences in mutant fragment size distribution had shorter time to progression (P = 0.001)., Conclusions: Longitudinal testing of cfDNA by TS provides a noninvasive tool for detection of tumor-derived mutations and mechanisms of PARPi resistance that may aid in directing patients to appropriate therapeutic strategies. With cfDNA fragmentation analyses, CHIP was identified in several patients and warrants further investigation., (©2023 The Authors; Published by the American Association for Cancer Research.)

Purpose: Global increases in cancer, coupled with a shortage of cancer specialists, has led to an increasing role for primary care providers (PCP) in cancer care. This review aimed to examine all extant cancer curricula for PCPs and to analyze the motivations for curriculum development., Methods: A comprehensive literature search was conducted from inception to October 13, 2021, with no language restrictions. The initial search yielded 11,162 articles and 10,902 articles underwent title and abstract review. After full-text review, 139 articles were included. Numeric and thematic analyses were conducted and education programs were evaluated using Bloom's taxonomy., Results: Most curricula were developed in high-income countries (HICs), with 58% in the United States. Cancer-specific curricula focused on HIC priority cancers, such as skin/melanoma, and did not represent the global cancer burden. Most (80%) curricula were developed for staff physicians and 73% focused on cancer screening. More than half (57%) of programs were delivered in person, with a shift toward online delivery over time. Less than half (46%) of programs were codeveloped with PCPs and 34% did not involve PCPs in the program design and development. Curricula were primarily developed to improve cancer knowledge, and 72 studies assessed multiple outcome measures. No studies included the top two levels of Bloom's taxonomy of learning (evaluating; creating)., Conclusion: To our knowledge, this is the first review to assess the current state of cancer curricula for PCPs with a global focus. This review shows that extant curricula are primarily developed in HICs, do not represent the global cancer burden, and focus on cancer screening. This review lays a foundation to advance the cocreation of curricula that are aligned to the global cancer burden.

Background: We explored health professionals' views on the utility of circulating tumor DNA (ctDNA) testing in hereditary cancer syndrome (HCS) management., Materials and Methods: A qualitative interpretive description study was conducted, using semi-structured interviews with professionals across Canada. Thematic analysis employing constant comparison was used for analysis. 2 investigators coded each transcript. Differences were reconciled through discussion and the codebook was modified as new codes and themes emerged from the data., Results: Thirty-five professionals participated and included genetic counselors (n = 12), geneticists (n = 9), oncologists (n = 4), family doctors (n = 3), lab directors and scientists (n = 3), a health-system decision maker, a surgeon, a pathologist, and a nurse. Professionals described ctDNA as "transformative" and a "game-changer". However, they were divided on its use in HCS management, with some being optimistic (optimists) while others were hesitant (pessimists). Differences were driven by views on 3 factors: (1) clinical utility, (2) ctDNA's role in cancer screening, and (3) ctDNA's invasiveness. Optimists anticipated ctDNA testing would have clinical utility for HCS patients, its role would be akin to a diagnostic test and would be less invasive than standard screening (eg imaging). Pessimistic participants felt ctDNA testing would add limited utility; it would effectively be another screening test in the pathway, likely triggering additional investigations downstream, thereby increasing invasiveness., Conclusions: Providers anticipated ctDNA testing will transform early cancer detection for HCS families. However, the contrasting positions on ctDNA's role in the care pathway raise potential practice variations, highlighting a need to develop evidence to support clinical implementation and guidelines to standardize adoption., (© The Author(s) 2022. Published by Oxford University Press.)

Context: There is growing recognition of the value to patients, families, society, and health systems in providing healthcare, including end-of-life care, that is consistent with both patient preferences and clinical guidelines., Objectives: Identify the core domains and subdomains that can be used to evaluate the performance of end-of-life care within and across health systems., Methods: PubMed/MEDLINE (NCBI), PsycINFO (ProQuest), and CINAHL (EBSCO) databases were searched for peer-reviewed journal articles published prior to February 22, 2020. The SPIDER tool was used to determine search terms. A priori criteria were followed with independent review to identify relevant articles., Results: A total of 309 eligible articles were identified out of 2728 discrete results. The articles represent perspectives from the broader health system (11), patients (70), family and informal caregivers (65), healthcare professionals (43), multiple viewpoints (110), and others (10). The most common condition of focus was cancer (103) and the majority (245) of the studies concentrated on high-income country contexts. The review identified five domains and 11 subdomains focused on structural factors relevant to end-of-life care at the broader health system level, and two domains and 22 subdomains focused on experiential aspects of end-of-life care from the patient and family perspectives. The structural health system domains were: 1) stewardship and governance, 2) resource generation, 3) financing and financial protection, 4) service provision, and 5) access to care. The experiential domains were: 1) quality of care, and 2) quality of communication., Conclusion: The review affirms the need for a people-centered approach to managing the delicate process and period of accepting and preparing for the end of life. The identified structural and experiential factors pertinent to the "quality of death" will prove invaluable for future efforts aimed to quantify health system performance in the end-of-life period., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Von Hippel-Lindau disease (VHL) is an autosomal dominant, inherited syndrome with variants in the VHL gene causing predisposition to multi-organ benign and malignant neoplasms. A germline VHL variant is identified in 95-100% of individuals with a clinical diagnosis of VHL. Here, we present the case of an individual with a clinical diagnosis of VHL disease where peripheral blood DNA analysis did not detect a VHL variant. Sequencing of four tumor tissues (ccRCC, pheochromocytoma, lung via sputum, liver) revealed a VHL c.593 T > C (p.Leu198Pro) variant at varying allele fractions (range: 10-55%) in all tissues. Re-examination of the peripheral blood sequencing data identified this variant at 6% allele fraction. Tumor analysis revealed characteristic cytomorphological, immunohistochemical reactivity for alpha-inhibin, and CAIX, and reduced pVHL reactivity supported VHL-related pseudohypoxia. This report of a rare case of VHL mosaicism highlights the value of tissue testing in VHL variant negative cases., (© 2022. The Author(s).)

Whole-genome sequencing of primary breast tumors enabled the identification of cancer driver genes and noncoding cancer driver plexuses from somatic mutations. However, differentiating driver from passenger events among noncoding genetic variants remains a challenge. Herein, we reveal cancer-driver cis -regulatory elements linked to transcription factors previously shown to be involved in development of luminal breast cancers by defining a tumor-enriched catalogue of approximately 100,000 unique cis -regulatory elements from 26 primary luminal estrogen receptor (ER) + progesterone receptor (PR) + breast tumors. Integrating this catalog with somatic mutations from 350 publicly available breast tumor whole genomes, we uncovered cancer driver cistromes, defined as the sum of binding sites for a transcription factor, for ten transcription factors in luminal breast cancer such as FOXA1 and ER, nine of which are essential for growth in breast cancer with four exclusive to the luminal subtype. Collectively, we present a strategy to find cancer driver cistromes relying on quantifying the enrichment of noncoding mutations over cis -regulatory elements concatenated into a functional unit. IMPLICATIONS: Mapping the accessible chromatin of luminal breast cancer led to discovery of an accumulation of mutations within cistromes of transcription factors essential to luminal breast cancer. This demonstrates coopting of regulatory networks to drive cancer and provides a framework to derive insight into the noncoding space of cancer., (©2021 The Authors; Published by the American Association for Cancer Research.)

Clinical testing for mismatch repair (MMR) deficiency often entails serial testing of tumor and constitutional DNA using multiple assays. To minimize cost and specimen requirements of MMR testing, we developed an integrated targeted sequencing protocol (termed MultiMMR) that tests for promoter methylation, mutations, copy number alterations, copy neutral loss of heterozygosity, and microsatellite instability from a single aliquot of DNA. Hybrid capture of DNA-sequencing libraries constructed with methylated adapters was performed on 142 samples (60 tumors and 82 constitutional samples) from 82 patients with MMR-associated colorectal, endometrial, and brain cancers as well as a synthetic DNA mix with 11 known mutations. The captured material was split to enable parallel bisulfite and conventional sequence analysis. The panel targeted microsatellite regions and 13 genes associated with MMR, hypermutation, and hereditary colorectal cancer. MultiMMR recapitulated clinical testing results in 23 of 24 cases, was able to explain MMR loss in an additional 29 of 48 patients with incomplete or inconclusive testing, and identified all 11 MMR variants within the synthetic DNA mix. Promoter methylation and microsatellite instability analysis found 95% and 97% concordance with clinical testing, respectively. We report the feasibility for amalgamation of the current stepwise and complex clinical testing workflow into an integrated test for hereditary and somatic causes of MMR deficiency., (Copyright © 2021. Published by Elsevier Inc.)

This study evaluates spatiotemporal variability in the behavior of septic system derived nutrients in a sandy nearshore aquifer and their discharge to a large lake. A groundwater nutrient-rich plume was monitored over a two-year period with the septic system origin of the plume confirmed using artificial sweeteners. High temporal variability in NO 3 -N attenuation in the nearshore aquifer prior to discharge to the lake (42-96%) reveals the complex behavior of NO 3 -N and potential importance of changing hydrological and geochemical conditions in controlling NO 3 -N discharge to the lake. While PO 4 -P was retarded in the nearshore aquifer, the PO 4 -P plume extended over 90 m downgradient of the septic system. It was estimated that the PO 4 -P plume may reach the lake within 10 years and represents a legacy issue whereby PO 4 -P loads to the lake may increase over time. To provide broader assessment of the contribution of septic systems to P and N loads to a large lake, a regional scale geospatial model was developed that considers the locations of individual septic systems along the Canadian Lake Erie shoreline. The estimated P and N loads indicate that septic systems along the shoreline are only a minor contributor to the annual P and N loads to Lake Erie. However, it is possible that nutrients from septic systems may contribute to localized algal blooms in shoreline areas with high septic system density. In addition, disproportionate P and N loads in discharging groundwater may change the N:P ratio in nearshore waters and promote growth of harmful cyanobacteria. The study provides new insights into factors controlling the function of the reaction zone near the groundwater-lake interface including its impact on groundwater-derived nutrient inputs to large lakes. Further, the study findings are needed to inform septic system and nutrient management programs aimed at reducing lake eutrophication., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest epithelial malignancies. Improvements in our understanding of PDAC carcinogenesis will hopefully improve its detection, management, and outcomes, as has been achieved with other malignancies. Here we review the literature on the natural history of PDAC, including its cell of origin, the initiating somatic mutational events, pathways deranged in the mature tumor, its biological heterogeneity, and the relationship of the primary tumor with metastases. We also suggest areas for further research and highlight translatable findings that are beginning to make clinical inroads., (Copyright © 2017 Elsevier Inc. All rights reserved.)