Publications by authors named "K L Chan"

10,781 Publications

Analysis of Rates of Brain Metastases and Association With Breast Cancer Subtypes in Ontario, Canada.

JAMA Netw Open 2022 Aug 1;5(8):e2225424. Epub 2022 Aug 1.

Institute of Medical Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.

Importance: Approximately 1 in 7 patients with metastatic breast cancer (MBC) will receive radiotherapy for brain metastases (BRM). Significant differences in cumulative incidence of BRM by breast cancer subtype may inform future BRM screening protocols.

Objective: To describe cumulative incidence of BRM among patients with de novo MBC.

Design, Setting, And Participants: In this population-based cohort study, population health administrative databases in Ontario, Canada, held at the ICES were used to identify patients diagnosed with de novo MBC between 2009 and 2018. Given that a code for BRM does not exist within ICES, we analyzed the incidence of radiotherapy for BRM. The median (IQR) follow-up was 19.3 (6.2-39.5) months. A total of 100 747 patients with a new diagnosis of breast cancer between January 2009 and December 2018 were identified. Of these patients, 17 955 were excluded because they had previous or subsequent malignant neoplasms, 583 were excluded because they were younger than 18 years, 974 were excluded because there was an invalid Ontario Health Insurance Plan number or a date of death on or before the index date. Among 81 235 remaining patients, 3916 were identified as having de novo MBC.

Exposures: Treatment with radiotherapy for breast cancer BRM.

Main Outcomes And Measures: Cumulative incidence of radiotherapy for BRM accounting for the competing risk of death, and time from MBC diagnosis to brain radiotherapy. Kaplan-Meier analyses were performed for time-to-event end points. Logistic regression was used to account for confounding variables.

Results: Among 3916 patients with MBC, 1215 (31.0%) had HR-positive/ERBB2 (formerly HER2)-negative cancer, 310 (7.9%) had ERBB2-positive/HR-positive cancer, 200 (5.1%) had ERBB2-positive/HR-negative cancer, 258 (6.6%) had TNBC, and the remaining 1933 patients (49.4%) had an unknown breast cancer subtype. The median (IQR) age at diagnosis was 63 (52-75). A total of 549 (14.0%) underwent stereotactic radiosurgery or whole brain radiotherapy for breast cancer BRM. Cumulative incidence of BRM was higher among patients with ERBB2-positive/HR-negative breast cancer (34.7%), ERBB2-positive/HR-positive breast cancer (28.1%), and triple-negative breast cancer (21.9%) compared to those with HR-positive/ERBB2-negative breast cancer (12.1%). The median (IQR) time from MBC diagnosis to brain radiotherapy ranged from 7.5 (2.3-17.4) months for patients with TNBC to 19.8 (12.2-35.1) months for those with ERBB2-positive/HR-positive breast cancer.

Conclusions And Relevance: Incidence and time to development of BRM vary significantly by breast cancer subtype. A better understanding of the biology of intracranial metastatic disease may help inform potential screening programs or preventative interventions.
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http://dx.doi.org/10.1001/jamanetworkopen.2022.25424DOI Listing
August 2022

Pharmacogenomic profiling of pediatric acute myeloid leukemia to identify therapeutic vulnerabilities and inform functional precision medicine.

Blood Cancer Discov 2022 Aug 12. Epub 2022 Aug 12.

Sun Yat-sen University, China, China, China.

Despite the expanding portfolio of targeted therapies for adults with acute myeloid leukemia (AML), direct implementation in children is challenging due to inherent differences in underlying genetics. Here we established the pharmacological profile of pediatric AML by screening myeloblast sensitivity to approved and investigational agents, revealing candidates of immediate clinical relevance. Drug responses ex vivo correlated with patient characteristics, exhibited age-specific alterations, and concorded with activities in xenograft models. Integration with genomic data uncovered new gene-drug associations, suggesting actionable therapeutic vulnerabilities. Transcriptome profiling further identified gene expression signatures associated with on- and off-target drug responses. We also demonstrated the feasibility of drug screening-guided treatment for children with high-risk AML, with two evaluable cases achieving remission. Collectively, this study offers a high-dimensional gene-drug-clinical dataset that could be leveraged to research the unique biology of pediatric AML, and sets the stage for realizing functional precision medicine for clinical management of the disease.
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http://dx.doi.org/10.1158/2643-3230.BCD-22-0011DOI Listing
August 2022

Identifying cell receptors for the nanoparticle protein corona using genome screens.

Nat Chem Biol 2022 Aug 11. Epub 2022 Aug 11.

Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.

Nanotechnology provides platforms to deliver medical agents to specific cells. However, the nanoparticle's surface becomes covered with serum proteins in the blood after administration despite engineering efforts to protect it with targeting or blocking molecules. Here, we developed a strategy to identify the main interactions between nanoparticle-adsorbed proteins and a cell by integrating mass spectrometry with pooled genome screens and Search Tool for the Retrieval of Interacting Genes analysis. We found that the low-density lipoprotein (LDL) receptor was responsible for approximately 75% of serum-coated gold nanoparticle uptake in U-87 MG cells. Apolipoprotein B and complement C8 proteins on the nanoparticle mediated uptake through the LDL receptor. In vivo, nanoparticle accumulation correlated with LDL receptor expression in the organs of mice. A detailed understanding of how adsorbed serum proteins bind to cell receptors will lay the groundwork for controlling the delivery of nanoparticles at the molecular level to diseased tissues for therapeutic and diagnostic applications.
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http://dx.doi.org/10.1038/s41589-022-01093-5DOI Listing
August 2022

A cross-sectional retrospective study comparing handwritten operation notes with electronic operation notes.

Ann R Coll Surg Engl 2022 Aug 11. Epub 2022 Aug 11.

Darent Valley Hospital, UK.

Introduction: Electronically completed medical notes have been shown to be superior in legibility and completeness to handwritten ones. Despite this, surgeons continue to use handwritten operation notes. This paper aims to compare the quality of handwritten versus electronic operation notes.

Methods: This is a retrospective cross-sectional single-centre study done at Darent Valley Hospital, a district general hospital at Dartford, UK. We looked at 405 operation notes of patients who had general surgery procedures between 1 January 2020 to 31 January 2021 checking for legibility and completeness of operation note criteria as given by the Royal College of Surgeons of England's . Data were collated using an app that populates comparison criteria in an Excel sheet and were analysed using SPSS (Statistical Package for the Social Sciences). The results are presented in bar graphs and frequency table.

Results: In 17 out of the 18 criteria in RCS England's , electronic notes were better completed than handwritten ones (<0.001). Signature as a criterion had comparable level of completeness in both handwritten and electronic notes, 95% versus 91% respectively. There was 8.3% illegibility in the handwritten note and none in the electronic ones.

Conclusions: Electronic notes are far better completed than handwritten notes in 17 out of the 18 criteria of a good operation note by RCS England. The difference between both forms of notes is far too much; we propose a complete shift in practice from handwritten to electronic format.
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http://dx.doi.org/10.1308/rcsann.2022.0066DOI Listing
August 2022

Patterns of care for non-metastatic castration-resistant prostate cancer: A population-based study.

BJUI Compass 2022 Sep 18;3(5):383-391. Epub 2022 May 18.

St. Joseph's Healthcare McMaster University Hamilton Ontario Canada.

Objectives: To describe patterns of practice of PSA testing and imaging for Ontario men receiving continuous ADT for the treatment of non-metastatic castration-resistant prostate cancer (nmCRPC).

Patients And Methods: This was a retrospective, longitudinal, population-based study of administrative health data from 2008 to 2019. Men 65 years and older receiving continuous androgen deprivation therapy (ADT) with documented CRPC were included. An administrative proxy definition was applied to capture patients with nmCRPC and excluded those with metastatic disease. Patients were indexed upon progression to CRPC and were followed until death or end of study period to assess frequency of monitoring with PSA tests and conventional imaging. A 2-year look-back window was used to assess patterns of care leading up to CRPC as well as baseline covariates.

Results: At a median follow-up of 40.1 months, 944 patients with nmCRPC were identified. Their median time from initiation of continuous ADT to CRPC was 26.0 months. 60.7% of patients had their PSA measured twice or fewer in the year prior to index, and 70.7% patients did not receive any imaging in the year following progression to CRPC. Throughout the study period, 921/944 (97.6%) patients with CRPC progressed to high-risk (HR-CRPC) with PSA doubling time ≤ 10 months, of which more than half received fewer than three PSA tests in the year prior to developing HR-CRPC, and 30.9% received no imaging in the subsequent year.

Conclusion: PSA testing and imaging studies are underutilized in a real-world setting for the management of nmCRPC, including those at high risk of developing metastatic disease. Infrequent monitoring impedes proper risk stratification, disease staging and detection of treatment failure and/or metastases, thereby delaying the necessary treatment intensification with life-prolonging therapies. Adherence to guideline recommendations and the importance of timely staging should be reinforced to optimize patient outcomes.
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http://dx.doi.org/10.1002/bco2.158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9349587PMC
September 2022
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