Clonal Decomposition and DNA Replication States Defined by Scaled Single-Cell Genome Sequencing.

Accurate measurement of clonal genotypes, mutational processes, and replication states from individual tumor-cell genomes will facilitate improved understanding of tumor evolution. We have developed DLP+, a scalable single-cell whole-genome sequencing platform implemented using commodity instruments, image-based object recognition, and open source computational methods. Using DLP+, we have generated a resource of 51,926 single-cell genomes and matched cell images from diverse cell types including cell lines, xenografts, and diagnostic samples with limited material. From this resource we have defined variation in mitotic mis-segregation rates across tissue types and genotypes. Analysis of matched genomic and image measurements revealed correlations between cellular morphology and genome ploidy states. Aggregation of cells sharing copy number profiles allowed for calculation of single-nucleotide resolution clonal genotypes and inference of clonal phylogenies and avoided the limitations of bulk deconvolution. Finally, joint analysis over the above features defined clone-specific chromosomal aneuploidy in polyclonal populations.

Evaluation of the Association Between Sociodemographic Status and Breast Screening Volumes During the COVID-19 Pandemic in a Provincial, Population-Based Organized Breast Screening Program.

OBJECTIVES: We sought to evaluate the association between patient sociodemographic status and breast screening volumes (BSVs) during the COVID-19 pandemic in a large, population-based breast screening program that serves a provincial population of over 5 million. METHODS: All patients who completed breast screening between April 1st, 2017 and March 31st, 2021 were eligible to participate. An average of 3 annual periods between April 1st, 2017 and March 31st, 2020 were defined as the pre-COVID period while the period between April 1st, 2020 and March 31st, 2021 was defined as the COVID-impacted period. The Postal CodeOM Conversion File Plus was applied to map patient residential postal codes to 2016 census standard geographical areas, which provided information on community size, income quintile and dissemination areas. Dissemination areas were subsequently linked to the Canadian Index of Multiple Deprivation (CIMD). RESULTS: Overall BSV was reduced by 23.0% during the COVID-impacted period as compared to the pre-COVID period. Percent reductions in BSVs were greatest among younger patients aged 40 to 49 years (31.3%) and patients residing in communities with a population of less than 10,000 (27.0%). Percent reduction in BSV was greatest among patients in the lowest income quintile (28.1%). Percent reductions in BSVs were greatest for patients in the most deprived quintiles across all 4 dimensions of the CIMD. CONCLUSION: Disproportionate reductions in BSVs were observed during the COVID-19 pandemic among younger patients, patients residing in rural communities, patients in lower income quintiles, and patients in the most deprived quintiles across all 4 dimensions of the CIMD.

Intra-individual comparison of 18F-sodium fluoride PET-CT and 99mTc bone scintigraphy with SPECT in patients with prostate cancer or breast cancer at high risk for skeletal metastases (MITNEC-A1): a multicentre, phase 3 trial.

BACKGROUND: Detection of skeletal metastases in patients with prostate cancer or breast cancer remains a major clinical challenge. We aimed to compare the diagnostic performance of 99mTc-methylene diphosphonate (99mTc-MDP) single-photon emission CT (SPECT) and 18F-sodium fluoride (18F-NaF) PET-CT for the detection of osseous metastases in patients with high-risk prostate or breast cancer. METHODS: MITNEC-A1 was a prospective, multicentre, single-cohort, phase 3 trial conducted in ten hospitals across Canada. Patients aged 18 years or older with breast or prostate cancer with a WHO performance status of 0-2 and with high risk or clinical suspicion for bone metastasis, but without previously documented bone involvement, were eligible. 18F-NaF PET-CT and 99mTc-MDP SPECT were done within 14 days of each other for each participant. Two independent reviewers interpreted each modality without knowledge of other imaging findings. The primary endpoint was the overall accuracy of 99mTc-MDP SPECT and 18F-NaF PET-CT scans for the detection of bone metastases in the per-protocol population. A combination of histopathological, clinical, and imaging follow-up for up to 24 months was used as the reference standard to assess the imaging results. Safety was assessed in all enrolled participants. This study is registered with ClinicalTrials.gov, NCT01930812, and is complete. FINDINGS: Between July 11, 2014, and March 3, 2017, 290 patients were screened, 288 of whom were enrolled (64 participants with breast cancer and 224 with prostate cancer). 261 participants underwent both 18F-NaF PET-CT and 99mTc-MDP SPECT and completed the required follow-up for statistical analysis. Median follow-up was 735 days (IQR 727-750). Based on the reference methods used, 109 (42%) of 261 patients had bone metastases. In the patient-based analysis, 18F-NaF PET-CT was more accurate than 99mTc-MDP SPECT (84·3% [95% CI 79·9-88·7] vs 77·4% [72·3-82·5], difference 6·9% [95% CI 1·3-12·5]; p=0·016). No adverse events were reported for the 288 patients recruited. INTERPRETATION: 18F-NaF has the potential to displace 99mTc-MDP as the bone imaging radiopharmaceutical of choice in patients with high-risk prostate or breast cancer. FUNDING: Canadian Institutes of Health Research.

Dynamics of genomic clones in breast cancer patient xenografts at single-cell resolution.

Human cancers, including breast cancers, comprise clones differing in mutation content. Clones evolve dynamically in space and time following principles of Darwinian evolution, underpinning important emergent features such as drug resistance and metastasis. Human breast cancer xenoengraftment is used as a means of capturing and studying tumour biology, and breast tumour xenografts are generally assumed to be reasonable models of the originating tumours. However, the consequences and reproducibility of engraftment and propagation on the genomic clonal architecture of tumours have not been systematically examined at single-cell resolution. Here we show, using deep-genome and single-cell sequencing methods, the clonal dynamics of initial engraftment and subsequent serial propagation of primary and metastatic human breast cancers in immunodeficient mice. In all 15 cases examined, clonal selection on engraftment was observed in both primary and metastatic breast tumours, varying in degree from extreme selective engraftment of minor (<5% of starting population) clones to moderate, polyclonal engraftment. Furthermore, ongoing clonal dynamics during serial passaging is a feature of tumours experiencing modest initial selection. Through single-cell sequencing, we show that major mutation clusters estimated from tumour population sequencing relate predictably to the most abundant clonal genotypes, even in clonally complex and rapidly evolving cases. Finally, we show that similar clonal expansion patterns can emerge in independent grafts of the same starting tumour population, indicating that genomic aberrations can be reproducible determinants of evolutionary trajectories. Our results show that measurement of genomically defined clonal population dynamics will be highly informative for functional studies using patient-derived breast cancer xenoengraftment.

Development and Evaluation of a Competency-Based Anatomy Rotation for Diagnostic Radiology Residents During Internship Year: A Canadian Experience.

RATIONALE AND AIM: As medical schools reduce the hours of anatomy teaching, residents in anatomy-intensive residency programs like radiology must independently acquire the anatomy knowledge needed to achieve competency. The purpose of this study was to develop and evaluate a 4-week competency-based self-directed anatomy rotation for junior residents. METHODS: Seven post-graduate year 1 (PGY-1) radiology residents completed a 4-week rotation of radiologic anatomy. The objectives were developed from standards, senior residents, and expert opinion, and the competency-based curriculum included self-directed modules. Pre-course and post-course tests were administered and test scores were compared using an unpaired t test. In addition, PGY-1 residents completed a course evaluation and survey regarding their anatomy knowledge and anatomy exposure prior to completing the course. RESULTS: Out of the 25 points available, the average pre-test score was 10.79 ± 2.78 (range 8-16.5), and the average post-test score was 21.64 ± 2.23 (range 18.5-25). This difference was statistically significant (P < .0001). The PGY-1 residents reported receiving < 10% of dedicated radiologic anatomy teaching prior to residency and felt unprepared for the anatomy required in residency. Overall, residents felt more confident in looking at images after completing the self-directed radiologic anatomy course. CONCLUSION: This study demonstrates the feasibility of creating a self-directed course for radiology residents that significant improves their anatomy knowledge. Given the trend in medical undergraduate education away from dedicated anatomy teaching, residency programs should consider addressing anatomy education more formally for junior residents to ensure that trainees receive the foundational knowledge required for residency.

Sink or Night Float: University of British Columbia Radiology Residents' Experience With Overnight Call.

PURPOSE: In July 2012, in response to residents' concerns regarding the impact of the traditional 24-hour call system on their personal well-being and educational experience, the University of British Columbia Radiology residency program adopted a 12-hour night float system. This shift takes place in the context of increasing concerns, both across Canada and internationally, about resident well-being and the impact of prolonged duty hours on patient care. METHODS: An anonymous survey was distributed to all 25 postgraduate years 2-5 University of British Columbia radiology residents 12 months after the introduction of night float. This study sought to solicit residents' feedback about these changes and to identify potential future changes to optimize the call system. RESULTS: The response rate was 100%; 96% of residents were in favor of continuing with night float rather than the traditional call system; 72% of residents reported that their judgement was affected secondary to being on night float. Although most residents described varying degrees of impairment, the rate of acute discrepancies between resident preliminary and attending radiologist final reports decreased by more than half, from 2% to less than 1%. CONCLUSIONS: The vast majority of our residents were in favor of maintaining the night float call system. Night float had a beneficial effect on the resident educational experience: by eliminating the pre-call morning and post-call day off rotation, residents gained an additional 24 days per year on other clinical rotations.

Accurate determination of CRISPR-mediated gene fitness in transplantable tumours.

Assessing tumour gene fitness in physiologically-relevant model systems is challenging due to biological features of in vivo tumour regeneration, including extreme variations in single cell lineage progeny. Here we develop a reproducible, quantitative approach to pooled genetic perturbation in patient-derived xenografts (PDXs), by encoding single cell output from transplanted CRISPR-transduced cells in combination with a Bayesian hierarchical model. We apply this to 181 PDX transplants from 21 breast cancer patients. We show that uncertainty in fitness estimates depends critically on the number of transplant cell clones and the variability in clone sizes. We use a pathway-directed allelic series to characterize Notch signaling, and quantify TP53 / MDM2 drug-gene conditional fitness in outlier patients. We show that fitness outlier identification can be mirrored by pharmacological perturbation. Overall, we demonstrate that the gene fitness landscape in breast PDXs is dominated by inter-patient differences.

The cost-effectiveness of adding tomosynthesis to mammography-based breast cancer screening: an economic analysis.

BACKGROUND: Observational studies show that digital breast tomosynthesis (DBT) combined with digital mammography (DM) can reduce recall rates and increases rates of breast cancer detection. The objective of this study was to examine the cost-effectiveness of DBT plus DM versus DM alone in British Columbia and to identify parameters that can improve the efficiency of breast cancer screening programs. METHODS: We conducted an economic analysis based on data from a cohort of screening participants in the BC Cancer Breast Screening Program. The decision model simulated lifetime costs and outcomes for participants in breast cancer screening who were aged 40-74 years between 2012 and 2017. We analyzed rates of health care resource utilization, health state costs and estimated incremental cost-effectiveness ratios (ICERs), to measure incremental cost differences per quality-adjusted life years (QALYs) gained from the addition of DBT to DM-based screening, from the government payer's perspective. RESULTS: The model simulated economic outcomes for 112 249 screening participants. We found that the ICER was highly sensitive to recall rate reductions and insensitive to parameters related to cancer detection. If DBT plus DM can reduce absolute recall rates by more than 2.1%, the base-case scenario had an ICER of $17 149 per QALY. At a willingness-to-pay threshold of $100 000 per QALY, more than 95% of the probabilistic simulations favoured the adoption of DBT plus DM versus DM alone. The ICER depended heavily on the ability of DBT plus DM to reduce recall rates. INTERPRETATION: The addition of DBT to DM would be considered cost-effective owing to the low positive predictive value of screening with DM alone. Reductions in false-positive recall rates should be monitored closely.

Rethinking the PGY-1 Basic Clinical Year: A Canadian National Survey of Its Educational Value for Diagnostic Radiology Residents.

RATIONALE AND OBJECTIVES: Recently, the relevance of the postgraduate year 1 (PGY-1) Basic Clinical Year for radiology residents has been questioned. The purpose of this study was to determine the attitude of radiologists and trainees toward this year and which clinical rotations they perceived as most valuable to clinical practice. MATERIALS AND METHODS: Following institutional review board approval, an anonymous online survey was administered to Canadian radiologists and radiology trainees. In addition to reporting demographic information, respondents were asked to rank the usefulness of individual rotations on a five-point Likert scale. To assess whether there are differences in the ratings and therefore rankings of the rotations by gender, position, and level of training, the Kruskal-Wallis one-way analysis of variance test was used with significance defined as P < .05. The Schulze method was used to rank the perceived usefulness of clinical rotations considered. RESULTS: Of the 275 respondents, 73.1% were male and 47.3% were trainees. A total of 71.3% of respondents were in favor of the basic clinical year, whereas 16.4% opposed. There was a statistically significant difference between the responses of staff radiologists and trainees, with the staff more strongly favoring the Basic Clinical Year (84.1%) than the trainees (56.9%) (P < .0001). As a whole, the respondents favored general surgery rotations as most relevant to their clinical practice (agreement rate of 48.3%). Interventional radiologists found general and subspecialty surgical rotations to be equally relevant. The rotations deemed to be "essential" were emergency medicine (48.7%) and general surgery (46.6%), and the rotations deemed to be "very useful" were orthopedics (45.8%), trauma (44.4%), neurosurgery (43.3%), neurology (42.2%), and hepatobiliary surgery (38.9%). There was no statistical difference between the respondents' choices based on their level of experience and scope of practice. CONCLUSIONS: Most radiologists and radiology trainees were in favor of completing the PGY-1 Basic Clinical Year. However, programs should maximize the education value of this year by including more of the top-ranked rotations. As the practice of radiology evolves, it is important to ensure that training paradigms continue to prepare residents for independent practice.

Breast screening participation and retention among immigrants and nonimmigrants in British Columbia: A population-based study.

Breast cancer screening programs operate across Canada providing mammography to women in target age groups with the goal of reducing breast cancer mortality through early detection of tumors. Disparities in breast screening participation among socio-demographic groups, including immigrants, have been reported in Canada. Our objectives were to: (1) assess breast screening participation and retention among immigrant and nonimmigrant women in British Columbia (BC), Canada; and (2) to characterize factors associated with screening among screening-age recent immigrant women in BC. We examined 2 population-based cohorts of women eligible for breast screening participation (537 783 women) and retention (281 052 women) using linked health and immigration data. Breast screening rates were presented according to socio-demographic and health-related variables stratified by birth country. Factors associated with screening among recent immigrant women were explored using Poisson regression. We observed marked variation in screening participation across birth country cohorts. Eastern European/Central Asian women showed low participation (37.9%) with rates from individual countries ranging from 35.0% to 49.0%. Participation rates for immigrant women from the most common birth countries, such as China/Macau/Hong Kong/Taiwan (45.7%), India (44.5%), the Philippines (45.9%), and South Korea (39.0%), were lower than the nonimmigrant rates (51.2%). Retention rates showed less variation by birth country; however, some disparities between immigrant and nonimmigrant groups persisted. Associations between screening indicators and study factors varied considerably across immigrant groups. Primary care physician visits were consistently positively associated with screening participation; this variable was also the only predictor associated with screening within each of the groups of recent immigrants. Our study provides unique data on both screening participation and retention among Canadian immigrant women compiled by individual country of birth. Our results are further demonstration that screening disparities exist among immigrant populations as well as in comparison with nonimmigrant women.

Implementation of a Longitudinal Introduction to Radiology Course During Internship Year Improves Diagnostic Radiology Residents' Academic and Clinical Skills: A Canadian Experience.

RATIONALE AND OBJECTIVES: In order to ease the transition from internship to diagnostic radiology residency, a year-long didactic introduction to radiology course was offered to post-graduate year one (PGY-1) diagnostic radiology residents during their internship, which consisted of 27 hours of lecture over 9 months. The purpose of this study was to determine the quantitative and qualitative educational value of this course and its effect with respect to on-call preparedness. MATERIALS AND METHODS: Two consecutive cohorts of Diagnostic Radiology residents were included: the first cohort (PGY-1s in 2011-2012) did not participate in the new course (Old Curriculum Residents) and the second cohort (PGY-1s in 2012-2013) completed the new course (New Curriculum Residents). These two cohorts were compared both qualitatively and quantitatively. Scores were compared from the standardized Canadian National Pre-Call Observed Standardized Clinical Examination and American College of Radiology Diagnostic Radiology In-Training examination, which are taken in the PGY-2 year, at months 5 and 7, respectively. In addition, staff observation of on-call resident performance and resident self-reported preparedness were considered. Cohorts were compared using Mann-Whitney U test with significance defined as P value <0.05. P values from 0.05 to 0.10 were noted as possibly significant and further analyzed using a Cohen d test where the difference was determined to be small (0.2), medium (0.5), or large (0.8). RESULTS: New Curriculum Residents reported that the content of the PGY1 curriculum was more appropriate than the old curriculum to prepare them for call in PGY2 (P = 0.013). New Curriculum Residents scored better than the Old Curriculum Residents on the Diagnostic Radiology In-Training examination (P = 0.039) and on the emergency cases of the Canadian National Pre-Call Observed Standardized Clinical Examination (P = 0.035). Staff radiologists, who were not blinded, reported that the New Curriculum Residents were better prepared for daytime (P = 0.006) and overnight (P = 0.008) independent call were better prepared to perform common ultrasound examinations alone (P = 0.049), and required less guidance while on call for nine competency areas. There was, however, no statistical difference between the residents' self-reported preparedness for independent call. CONCLUSIONS: Participation in a lecture-based introductory radiology curriculum during the PGY-1 internship year improved both radiology residents' preparedness for call and their performance in PGY-2.

Remedial training for the radiology resident: a template for optimization of the learning plan.

All radiology residency programs should strive for the early identification of individuals in need of remedial training and have an approach ready to address this situation. This article provides a template for a step-by-step approach which is team based. It includes definition of the learning or performance issues, creation of suitable learning objectives and learning plan, facilitation of feedback and assessment, and definition of outcomes. Using such a template will assist the resident in returning to the path toward a safe and competent radiologist.

Lessons learned from the application of whole-genome analysis to the treatment of patients with advanced cancers.

Given the success of targeted agents in specific populations it is expected that some degree of molecular biomarker testing will become standard of care for many, if not all, cancers. To facilitate this, cancer centers worldwide are experimenting with targeted "panel" sequencing of selected mutations. Recent advances in genomic technology enable the generation of genome-scale data sets for individual patients. Recognizing the risk, inherent in panel sequencing, of failing to detect meaningful somatic alterations, we sought to establish processes to integrate data from whole-genome analysis (WGA) into routine cancer care. Between June 2012 and August 2014, 100 adult patients with incurable cancers consented to participate in the Personalized OncoGenomics (POG) study. Fresh tumor and blood samples were obtained and used for whole-genome and RNA sequencing. Computational approaches were used to identify candidate driver mutations, genes, and pathways. Diagnostic and drug information were then sought based on these candidate "drivers." Reports were generated and discussed weekly in a multidisciplinary team setting. Other multidisciplinary working groups were assembled to establish guidelines on the interpretation, communication, and integration of individual genomic findings into patient care. Of 78 patients for whom WGA was possible, results were considered actionable in 55 cases. In 23 of these 55 cases, the patients received treatments motivated by WGA. Our experience indicates that a multidisciplinary team of clinicians and scientists can implement a paradigm in which WGA is integrated into the care of late stage cancer patients to inform systemic therapy decisions.

Patterns of spread of clear cell ovarian cancer: Case report and case series.

•Although patterns of metastases in ovarian clear cell cancer are not well described, patients may initially present with bone metastases.•Clear cell carcinoma with bone metastases is responsive to radiation therapy.•Bone metastases are not common in patients with ovarian high grade serous cancer.