Exploring The Prognostic Significance of SET-Domain Containing 2 (SETD2) Expression in Advanced and Castrate-Resistant Prostate Cancer.

SET-domain containing 2 (SETD2) is a histone methyltransferase and an epigenetic modifier with oncogenic functionality. In the current study, we investigated the potential prognostic role of SETD2 in prostate cancer. A cohort of 202 patients' samples was assembled on tissue microarrays (TMAs) containing incidental, advanced, and castrate-resistant CRPCa cases. Our data showed significant elevated SETD2 expression in advanced and castrate-resistant disease (CRPCa) compared to incidental cases (2.53 ± 0.58 and 2.21 ± 0.63 vs. 1.9 ± 0.68; p < 0.001, respectively). Interestingly, the mean intensity of SETD2 expression in deceased vs. alive patients was also significantly different (2.31 ± 0.66 vs. 2 ± 0.68; p = 0.003, respectively). Overall, high SETD2 expression was found to be considered high risk and was significantly associated with poor prognosis and worse overall survival (OS) (HR 1.80; 95% CI: 1.28-2.53, p = 0.001) and lower cause specific survival (CSS) (HR 3.14; 95% CI: 1.94-5.08, p < 0.0001). Moreover, combining high-intensity SETD2 with PTEN loss resulted in lower OS (HR 2.12; 95% CI: 1.22-3.69, p = 0.008) and unfavorable CSS (HR 3.74; 95% CI: 1.67-8.34, p = 0.001). Additionally, high SETD2 intensity with ERG positive expression showed worse prognosis for both OS (HR 1.99, 95% CI 0.87-4.59; p = 0.015) and CSS (HR 2.14, 95% CI 0.98-4.68, p = 0.058). We also investigated the protein expression database TCPA, and our results showed that high SETD2 expression is associated with a poor prognosis. Finally, we performed TCGA PRAD gene set enrichment analysis (GSEA) data for SETD2 overexpression, and our data revealed a potential association with pathways involved in tumor progression such as the AMPK signaling pathway, the cAMP signaling pathway, and the PI3K-Akt signaling pathway, which are potentially associated with tumor progression, chemoresistance, and a poor prognosis.

Feature-specific quantile normalization and feature-specific mean-variance normalization deliver robust bi-directional classification and feature selection performance between microarray and RNAseq data.

BACKGROUND: Cross-platform normalization seeks to minimize technological bias between microarray and RNAseq whole-transcriptome data. Incorporating multiple gene expression platforms permits external validation of experimental findings, and augments training sets for machine learning models. Here, we compare the performance of Feature Specific Quantile Normalization (FSQN) to a previously used but unvalidated and uncharacterized method we label as Feature Specific Mean Variance Normalization (FSMVN). We evaluate the performance of these methods for bidirectional normalization in the context of nested feature selection. RESULTS: FSQN and FSMVN provided clinically equivalent bidirectional model performance with and without feature selection for colon CMS and breast PAM50 classification. Using principal component analysis, we determine that these methods eliminate batch effects related to technological platforms. Without feature selection, no statistical difference was identified between the performance of FSQN and FSMVN of cross-platform data compared to within-platform distributions. Under optimal feature selection conditions, balanced accuracy was FSQN and FSMVN were statistically equivalent to the within-platform distribution performance in multivariable linear regression analysis. FSQN and FSMVN also provided similar performance to within-platform distributions as the number of selected genes used to create models decreases. CONCLUSIONS: In the context of generating supervised machine learning classifiers for molecular subtypes, FSQN and FSMVN are equally effective. Under optimal modeling conditions, FSQN and FSMVN provide equivalent model accuracy performance on cross-platform normalization data compared to within-platform data. Using cross-platform data should still be approached with caution as subtle performance differences may exist depending on the classification problem, training, and testing distributions.

Association of Cabozantinib Dose Reductions for Toxicity With Clinical Effectiveness in Metastatic Renal Cell Carcinoma (mRCC): Results From the Canadian Kidney Cancer Information System (CKCis).

BACKGROUND: Cabozantinib, an oral multi-targeted tyrosine kinase inhibitor (TKI), has demonstrated efficacy in metastatic renal cell carcinoma (mRCC). The association between toxicity and therapeutic effectiveness has been established with other TKIs. We investigated whether cabozantinib dose reductions, a surrogate for toxicity and adequate drug exposure, were associated with improved clinical outcomes in mRCC. METHODS: Employing the CKCis database, we analyzed patients treated with cabozantinib in the second line or later between 2011 to 2021. The cohort was stratified into those needing dose reductions (DR) during treatment and those not (no-DR). Outcomes, including objective response rate (ORR), time to treatment failure (TTF), and overall survival (OS), were compared based on dose reduction status. The influence of the initial dose on outcomes was also explored. RESULTS: Among 319 cabozantinib-treated patients, 48.3% underwent dose reductions. Response rates exhibited no significant difference between the DR and no-DR groups (15.1% vs. 18.2%, P = .55). Patients with DR had superior median OS (26.15 vs. 15.47 months, P = .019) and TTF (12.74 vs. 6.44 months, P = .022) compared to no-DR patients. These differences retained significance following adjustment for IMDC risk group (OS HR = 0.67, P = .032; TTF HR = 0.65, P = .008). There was no association between the initial dose and ORR, OS, or TTF. CONCLUSION: This study highlights the link between cabozantinib dose reductions due to toxicity and improved survival and time to treatment failure in mRCC patients. These findings underscore the potential of using on-treatment toxicity as an indicator of adequate drug exposure to individualize dosing and optimize treatment effectiveness. Larger studies are warranted to validate these results and develop individualized strategies for cabozantinib when given alone or in combination with immunotherapy.

A population-based analysis of the impact of 1 vs. 2 doses of mitomycin on patterns of failure of anal cancer patients treated with concurrent chemoradiotherapy.

PURPOSE: We report the impact of 1 vs. 2 doses of mitomycin-C (MMC) based chemoradiation (CRT) on patterns of treatment failure and long-term patient outcomes in anal squamous cell carcinoma (ASCC) and the predictors for locoregional failure (LRF) and distant metastasis (DM). METHODS: In this population-based study, we identified all patients with anal cancer in our province treated radically with radiation and concurrent 5-Fluorouracil (5FU) and 1 vs. 2 doses of MMC between the years 2000-2019. The primary outcomes analyzed were locoregional recurrence (LRR), disease free survival (DFS), ASCC cancer-specific survival (ASCC-CSS) and overall survival (OS). RESULTS: 451 patients were identified. 272 (60%) patients received 1 cycle of MMC (MMC1) and 179 (40%) received 2 cycles (MMC2) as part of the CRT regimen. The median follow-up was 57 (36-252) and 97 (38-239) months for MMC1 and MMC2, respectively. Cox Regression analysis showed stage IIIb and IIIc were associated with worse locoregional recurrence free survival (RFS) (HR=2.851, p=<0.001) and distant RFS (HR=3.391, p=<0.001). Similarly, stage IIIb and IIIc patients had poorer DFS (HR 3.439, p=<0.001), ASCC-SS (HR 3.729, p=<0.001) and OS (2.230, p=<0.001). The use of MMC2 showed a positive impact on improved ASCC-SS (HR 0.569, p=0.029) and distant RFS (HR 0.555, p=0.040) in patients with stage IIIb and IIIc. CONCLUSIONS: Our analysis showed that 1 vs. 2 cycles of MMC along with 5FU and radiation is associated with comparable treatment outcomes in general. However, in patients with stage IIIb and IIIc cancer, 2 doses of MMC were associated with improved ASCC-SS and distant DFS.

Individual Survival Distributions Generated by Multi-Task Logistic Regression Yield a New Perspective on Molecular and Clinical Prognostic Factors in Gastric Adenocarcinoma.

Recent advances in our understanding of gastric cancer biology have prompted a shift towards more personalized therapy. However, results are based on population-based survival analyses, which evaluate the average survival effects of entire treatment groups or single prognostic variables. This study uses a personalized survival modelling approach called individual survival distributions (ISDs) with the multi-task logistic regression (MTLR) model to provide novel insight into personalized survival in gastric adenocarcinoma. We performed a pooled analysis using 1043 patients from a previously characterized database annotated with molecular subtypes from the Cancer Genome Atlas, Asian Cancer Research Group, and tumour microenvironment (TME) score. The MTLR model achieved a 5-fold cross-validated concordance index of 72.1 ± 3.3%. This model found that the TME score and chemotherapy had similar survival effects over the entire study time. The TME score provided the greatest survival benefit beyond a 5-year follow-up. Stage III and Stage IV disease contributed the greatest negative effect on survival. The MTLR model weights were significantly correlated with the Cox model coefficients (Pearson coefficient = 0.86, p < 0.0001). We illustrate how ISDs can accurately predict the survival time for each patient, which is especially relevant in cases of molecular subtype heterogeneity. This study provides evidence that the TME score is principally associated with long-term survival in gastric adenocarcinoma. Additional external validation and investigation into the clinical utility of this ISD model in gastric cancer is an area of future research.

Incidence of Nonmelanoma Skin Cancers in Alberta, Canada, From 2007 to 2018.

BACKGROUND: Nonmelanoma skin cancer (NMSC) is the most common malignancy affecting Caucasian populations and has been seeing steady increases in incidence globally for decades. Our previous study (from Alberta, Canada) had shown a plateau in the incidence rates for NMSC. This contrasts with data from other regions within Canada and throughout the world that indicated a continued increase in incidence rates of NMSCs. OBJECTIVES: The objective of this study was to provide an update on the trends in incidence of NMSC in Alberta, Canada, from 2007 to 2018. METHODS: A retrospective analysis of patients from Alberta diagnosed with NMSC from 2007 to 2018 inclusive was conducted with data retrieved from Alberta Cancer Registry. Sex-, age-, anatomical location-, NMSC subtype-, stage-specific incidence rates and trends were examined. RESULTS: From 2007 to 2018, overall incidence rates of NMSC increased by 36%. Invasive squamous cell carcinoma (SCC) and in situ SCC demonstrated the most significant increase, invasive SCC [annual percentage change (APC) 3.48, P = .014] and in situ SCC (APC 5.61, P = .0001). In addition, we were able to determine that females had the most significant increases in NMSC incidence rates from 2007 to 2018 particularly invasive SCC (APC 3.03, P = <.0001) and in situ SCC (APC 5.08, P = <.0001). CONCLUSIONS: After initial levelling of NMSC incidence in Alberta in the early part of 21st century, the incidence of NMSC continues to increase over the past decade. The reasons for this change are not clear and likely multifactorial.

The effects of TGF-ß1 and IFN-α2b on decorin, decorin isoforms and type I collagen in hypertrophic scar dermal fibroblasts.

Hypertrophic scars (HTS) develop from an excessive synthesis of structural proteins like collagen and a decreased expression of proteoglycans such as decorin. Previous research has demonstrated that decorin expression is significantly down-regulated in HTS, deep dermal tissue, and thermally injured tissue, reducing its ability to regulate pro-fibrotic transforming growth factor-beta 1 (TGF-ß1) and normal fibrillogenesis. However, treatment of HTS fibroblasts with interferon-alpha 2b (IFN-α2b) has been shown to reduce excessive collagen synthesis and improve HTS by reducing serum TGF-ß1 levels. The expression of decorin isoforms in HTS is currently unknown and the effects of TGF-ß1 and IFN-α2b on decorin, decorin isoform expression and type 1 collagen are of great interest to our group. Dermal fibroblasts were treated with TGF-ß1 and/or IFN-α2b, for 48 h. The expression and secretion of decorin, decorin isoforms and type 1 collagen were quantified with reverse transcription-quantitative polymerase chain reaction, immunofluorescence staining and enzyme-linked immunosorbent assays. The mRNA expression of decorin and each isoform was significantly reduced in HTS fibroblasts relative to normal skin. TGF-ß1 decreased the mRNA expression of decorin and decorin isoforms, whereas IFN-α2b showed the opposite effect. IFN-α2b significantly inhibited TGF-ß1's effect on the mRNA expression of type I collagen alpha 1 in papillary dermal fibroblasts and overall showed relative effects of inhibiting TGF-ß1. These data support that a further investigation into the structural and functional roles of decorin isoforms in HTS pathogenesis is warranted and that IFN-α2b is an important agent in reducing fibrotic outcomes.

An Analysis of Clinical and Systemic Factors Associated with Palliative Radiotherapy Delivery and Completion at the End of Life in Alberta, Canada.

Radiotherapy (RT) is often utilized for symptom control at the end of life. Palliative RT (pRT) may not be taken to completion by patients, thus decreasing clinical benefits and adversely impacting resource allocation. We determined rates of incomplete pRT and examined predictors of non-completion using an electronic questionnaire. Methods: A questionnaire was embedded within the RT electronic prescribing system for all five cancer centers of Alberta, Canada, between 2017 and 2020. Prescribing radiation oncologists (ROs) were tasked with completing the questionnaire. Treatment variables were collected for 2040 patients prescribed pRT. Details on pRT courses delivered and completed were used to determine rates of incomplete RT. Electronic medical records of a subset of 367 patients randomly selected from the 2040 patients were then analyzed to examine for association of non-completion of RT with patient, disease, and therapy-related factors. Results: Overall, 10% of patients did not complete pRT. The rate of single fractions prescribed as a proportion of all RT fractions increased from 18% (pre-2017: pre-study era) to 29% (2017-2020: study era) (p < 0.0001). After conducting multivariate analysis on the overall group, multiple lifetime malignancies (OR:0.64) or increasing the number of pRT fractions (OR:0.08-0.17) were associated with non-completion. Being selected for stereotactic RT (OR:3.75) or survival > 30 days post-RT prescription (OR:2.20-5.02) were associated with greater rates of RT completion. The ROs' estimates of life expectancy at the time of RT prescription were not predictive of RT completion. In the multivariate analysis of the 367-patient subset, the presence of hepatic metastases (OR 2.59), survival 30-59 days (OR 6.61) and survival 90+ days (OR 8.18) post-RT prescription were associated with pRT completion. Only increasing pRT fractionation (OR:0.05-0.2) was associated with non-completion. Conclusion: One in ten patients prescribed pRT did not complete their treatment course. Decreasing pRT fractionation and improving prognostication in patients near the end of life may decrease rates of incomplete RT courses.

Durvalumab-Associated Pneumonitis in Patients with Locally Advanced Non-Small Cell Lung Cancer: A Real-World Population Study.

The PACIFIC trial led to a new standard of care for patients with locally advanced lung cancer, but real-world practice has demonstrated that immune checkpoint inhibitor (ICI) pneumonitis can lead to significant clinical complications. This study aimed to examine the clinical predictors, outcomes, and healthcare utilization data in patients who received consolidation durvalumab. Using the Alberta Immunotherapy Database, NSCLC patients who received durvalumab in Alberta, Canada, from January 2018 to December 2021 were retrospectively evaluated. We examined incidence and predictive values of severe pneumonitis, with overall survival (OS) and time-to-treatment failure (TTF) using exploratory multivariate analyses. Of 189 patients, 91% were ECOG 0-1 and 85% had a partial response from chemoradiation prior to durvalumab. Median TTF and OS were not reached; 1-year OS was 82%. An amount of 26% developed any grade of pneumonitis; 9% had ≥grade 3 pneumonitis. Male gender and a pre-existing autoimmune condition were associated with severe pneumonitis. V20 was associated with any grade of pneumonitis. Pneumonitis development was found to be an independent risk factor for worse OS (p = 0.038) and TTF (p = 0.007). Our results suggest clinical and dosimetric predictive factors of durvalumab-associated pneumonitis. These results affirm the importance of careful patient selection for safe completion of consolidation durvalumab in real-world LA-NSCLC population.

High-dose chemotherapy with autologous stem-cell transplantation for relapsed metastatic germ cell tumors: The Alberta experience.

INTRODUCTION: High-dose chemotherapy with autologous stem-cell transplantation (HDCASCT) is standard therapy for metastatic germ cell tumors (mGCTs) in patients whose disease progresses during or after conventional chemotherapy. We conducted a retrospective review of HDC-ASCT in relapsed mGCT patients in the province of Alberta, Canada over the past two decades. METHODS: Patients with mGCTs who received HDC-ASCT at two provincial cancer referral centers from 2000-2018 were identified from institutional databases. Baseline clinical and treatment characteristics were collected, as well as overall survival (OS) and disease-free survival (DFS). Relevant prognostic variables were analyzed. RESULTS: Forty-three patients were identified. The median age was 28 years (range 19-56). A majority (95%) had non-seminoma histology and testis/retroperitoneal primary (84%). Twenty patients (47%) had poor-risk disease, as per The International Germ Cell Consensus Classification (IGCCC), at start of first-line chemotherapy. HDC-ASCT was used as second-line therapy in 65% of patients, and 58% of ASCT patients received tandem transplants. Median followup after ASCT was 22 months (range 2-181). At last followup, 42% of patients were alive without disease, including 3/7 (43%) of patients with primary mediastinal disease. Two-year and five-year DFS/OS ratios were 44%/65% and 38%/45%, respectively. Median OS and DFS for all patients were 30.0 months (13.3-46.6) and 8.0 months (0.9-15.1), respectively. CONCLUSIONS: We found that HDC-ASCT is an effective salvage therapy in mGCT, consistent with existing literature. Patients appeared to benefit regardless of primary site. Though limited by small sample size, we found a numerical difference in DFS and OS between second- and third-line HDC-ASCT and single vs. tandem ASCT.

Trends of Utilization of Systemic Therapies for Metastatic Renal Cell Carcinoma in the Canadian Health Care System.

PURPOSE: Standard-of-care therapies for metastatic renal cell carcinoma (mRCC) have greatly evolved. However, the availability of emerging options in global health care systems can vary. We sought to describe the integration and usage of systemic therapies for mRCC in Canada since 2011. METHODS: We included patients with mRCC enrolled in the Canadian Kidney Cancer Information System, a prospective cohort of patients from 14 Canadian academic centers, who received systemic therapy from January 1, 2011, to December 31, 2021. Patients were stratified by treatment era (cohort 1: 2011-2015, cohort 2: 2016-2021). Stacked bar charts were used to present treatment proportions; Sankey diagrams were used to show the evolution of treatment sequencing between the two cohorts. RESULTS: Four thousand one hundred seven patients were diagnosed with mRCC, of whom 2,752 (67%) received systemic therapy. Among these patients, mean age was 64 years, 74% were male, 75% had clear cell histology, and International Metastatic RCC Database Consortium risk classification was favorable, intermediate, and poor in 16%, 56%, and 28%, respectively. Utilization of immune checkpoint inhibition (ICI)-based treatments has increased in Canada and reflects global and local patterns of approval and adoption. The use of therapies after doublet ICI has mostly shifted toward vascular endothelial growth factor-tyrosine kinase inhibitors (VEGF-TKIs) that were previously used in first line with subsequent treatments reflecting approved and available agents after previous VEGF-TKI. Clinical trial participation among patients who received systemic therapy was 18% in first, 21% in second, and 24% in third line. CONCLUSION: In Canada's publicly funded health care system, availability of standard mRCC therapies broadly reflects access from government-funded clinical trials and compassionate access program sources. In an evolving therapeutic landscape, ongoing advocacy is required to continue to facilitate patient access to efficacious therapies.

Changes in the outcomes of patients with anaplastic thyroid carcinoma over the past two decades.

OBJECTIVE: To assess the changes in survival outcomes among patients with anaplastic thyroid carcinoma in the US over the past two decades. METHODS: Surveillance, Epidemiology, and End Results (SEER) database research data were reviewed, and patients with anaplastic thyroid carcinoma, who were diagnosed from 2004 to 2020 were evaluated. Kaplan-Meier survival estimates were conducted to examine differences in overall survival between three year-of-diagnosis groups (2004 to 2010; 2011 to 2016; and 2017 to 2020). Multivariable Cox regression analysis was then performed to explore the factors affecting overall survival. RESULTS: A total of 1804 patients with anaplastic thyroid carcinoma were included. Using Kaplan-Meier survival estimates, overall survival was better among patients diagnosed from 2017 to 2020 versus those diagnosed at earlier periods (P < 0.001). One-year survival estimates were 25% among patients diagnosed from 2017 to 2020 versus 15% for patients diagnosed from 2011 to 2016, and 19%, for patients diagnosed from 2004 to 2010. Using the multivariable Cox regression model, an earlier year of diagnosis was associated with worse overall survival compared to the diagnosis year 2017 to 2020 (HR for diagnosis 2004 to 2010 versus diagnosis 2017 to 2020: 1.170; 95% CI: 1.029 to 1.331, and HR for diagnosis 2011 to 2016 versus diagnosis 2017 to 2020: 1.251; 95% CI: 1.103 to 1.419). CONCLUSIONS: While anaplastic thyroid carcinoma remains a deadly cancer, survival seems to be improving for the last few years compared to earlier years. There is still additional work to be done to improve the outcomes of those patients.

Genomic Biomarker Discovery in Disease Progression and Therapy Response in Bladder Cancer Utilizing Machine Learning.

Cancer in all its forms of expression is a major cause of death. To identify the genomic reason behind cancer, discovery of biomarkers is needed. In this paper, genomic data of bladder cancer are examined for the purpose of biomarker discovery. Genomic biomarkers are indicators stemming from the study of the genome, either at a very low level based on the genome sequence itself, or more abstractly such as measuring the level of gene expression for different disease groups. The latter method is pivotal for this work, since the available datasets consist of RNA sequencing data, transformed to gene expression levels, as well as data on a multitude of clinical indicators. Based on this, various methods are utilized such as statistical modeling via logistic regression and regularization techniques (elastic-net), clustering, survival analysis through Kaplan-Meier curves, and heatmaps for the experiments leading to biomarker discovery. The experiments have led to the discovery of two gene signatures capable of predicting therapy response and disease progression with considerable accuracy for bladder cancer patients which correlates well with clinical indicators such as Therapy Response and T-Stage at surgery with Disease Progression in a time-to-event manner.

Muscle and Adipose Wasting despite Disease Control: Unaddressed Side Effects of Palliative Chemotherapy for Pancreatic Cancer.

Muscle and adipose wasting during chemotherapy for advanced pancreatic cancer (aPC) are associated with poor outcomes. We aimed to quantify the contributions of chemotherapy regimen and tumour progression to muscle and adipose wasting and evaluate the prognostic value of each tissue loss. Of all patients treated for aPC from 2013-2019 in Alberta, Canada (n = 504), computed-tomography (CT)-defined muscle and adipose tissue index changes (∆SMI, ∆ATI, cm2/m2) were measured for patients with CT images available both prior to and 12 ± 4 weeks after chemotherapy initiation (n = 210). Contributions of regimen and tumour response to tissue change were assessed with multivariable linear regression. Survival impacts were assessed with multivariable Cox's proportional hazards models. Tissue changes varied widely (∆SMI: -17.8 to +7.3 cm2/m2, ∆ATI: -106.1 to +37.7 cm2/m2) over 116 (27) days. Tumour progression contributed to both muscle and adipose loss (-3.2 cm2/m2, p < 0.001; -12.4 cm2/m2, p = 0.001). FOLFIRINOX was associated with greater muscle loss (-1.6 cm2/m2, p = 0.013) and GEM/NAB with greater adipose loss (-11.2 cm2/m2, p = 0.002). The greatest muscle and adipose losses were independently associated with reduced survival (muscle: HR 1.72, p = 0.007; adipose: HR 1.73, p = 0.012; tertile 1 versus tertile 3). Muscle and adipose losses are adverse effects of chemotherapy and may require regimen-specific management strategies.

Design and Implementation of a Multidisciplinary High-Fidelity Simulation Course for the Management of Malignant Spinal Cord Compression.

High-fidelity simulation (HFS) training is suited to high-stakes, uncommon situations such as malignant spinal cord compression (MSCC), allowing for rare hands-on practice. This pilot study was created as the first of its kind to examine educational outcomes of a radiation therapist (RTT)-led multidisciplinary radiation oncology (RO) emergency simulation course. A multidisciplinary course design team composed of RO residents, radiation oncologists, RTT course instructors, and medical physicists created a high-fidelity MSCC simulation course using collaboratively developed learning goals. Fifteen learners including RO residents, senior RTT students, and a medical physics (MP) resident participated in a live, RTT-facilitated simulation. Participants completed anonymized pre- and post-simulation standard interdisciplinary education perception (IEP) scales and a course evaluation assessing educational outcomes. Standard IEP questionnaire results showed highly favorable perceptions of respondents' own specialty and other allied specialties, with mean total pre-simulation scores of 91.76 and post-simulation scores of 94.23. The course evaluation assessed 10 learning objective domains, with significant improvements seen in self-rated post-course knowledge in 9 domains. Pre-course evaluations showed that 6/15 participants agreed or strongly agreed that they felt comfortable in their knowledge of all included domains; after course completion, 14/15 participants agreed or strongly agreed they felt comfortable in all domains. Collaboratively designed and led HFS courses are not only viable but can be an effective means of improving learning outcomes for RO residents, RTT students, and MP residents.

Impact of a Powdered Meal Replacement on Metabolism and Gut Microbiota (PREMIUM) in individuals with excessive body weight: a study protocol for a randomised controlled trial.

INTRODUCTION: Excess body weight is associated with a state of low-grade chronic inflammation and alterations of the gut microbiome. Powdered meal replacements (PMR) have been shown to be an effective strategy for weight management; however, their effect on inflammation and the gut microbiome remains unclear. The aim of this 12-week randomised control clinical trial is to investigate the effects of PMR consumption, here given as a soy-yoghurt-honey formula, on inflammation, gut microbiome and overall metabolism in individuals with excessive body weight. METHODS AND ANALYSIS: Healthy adults with excess body weight (n=88) are being recruited and randomly assigned to one of the following groups: (1) Control group (CON): maintaining usual diet for 12 weeks, or (2) PMR group: replacing morning and afternoon snacks daily with a PMR for 12 weeks. Participants are asked to maintain body weight throughout the study and fill out a journal with information about PMR consumption, body weight, food intake, appetite sensations and medications. Three study visits are required: baseline, week 6 and week 12. Outcome measures include systemic inflammatory biomarkers, gut microbiome composition, metabolic blood markers, host energy metabolism, body composition, appetite sensations and host gene expression profile. ETHICS AND DISSEMINATION: This research protocol was approved by the University of Alberta Ethics Board (Pro00070712) and adheres to the Canadian Tri-Council Policy statement on the use of human participants in research. Procedures and potential risks are fully discussed with participants. Study findings will be disseminated in peer-reviewed journals, conference presentations and social media. TRIAL REGISTRATION NUMBER: NCT03235804.

Effect of transversus abdominis plane block on postoperative outcomes in gynecologic oncology patients managed on an Enhanced Recovery After Surgery pathway.

OBJECTIVES: To characterize the effect of transversus abdominis plane (TAP) blocks on post-operative outcomes in patients undergoing laparotomy for gynecologic malignancy. METHODS: This retrospective cohort study assessed patients undergoing laparotomy in 2016-2017 and 2020 in Alberta, Canada. The primary outcome was opioid consumption in oral morphine milligram equivalent (MME). Secondary outcomes included maximum pain scores, length of stay, and patient-controlled analgesia (PCA) use. Outcomes were compared using t-test with subgroup analysis by NSAID use. Multivariate regression modelling was performed for potential confounders. RESULTS: Data was collected on 956 patients; 828 received a TAP block, 128 did not. Opioid use in the first 24 h was lower in the TAP block group (35.9 mg MME vs 44.5 mg MME, p = 0.0294), without any increase in pain scores, this did not remain significant after regression analysis. Patients with TAP blocks had significant reduced mean length of stay (3.2 days vs. 5.0 days, p < 0.0001), and PCA use (19.9% vs. 56.25%, p < 0.0001). On subgroup analysis of patients that did not receive NSAIDs (n = 160), mean opioid use was decreased in those patients with TAP blocks compared to those without TAP blocks in the first 24 h (36.1 mg vs. 61.2 mg, p = 0.0017), and at 24 to 48 h (16.3 mg vs. 51.0 mg, p < 0.0001). CONCLUSIONS: Surgeon-administered TAP blocks were associated with decreased length of stay and post-operative opioid use in patients not receiving scheduled NSAIDs. This decrease in opioid use was not associated with any increase in average or maximum pain scores.

Cleavage and Polyadenylation-Specific Factor 4 (CPSF4) Expression Is Associated with Enhanced Prostate Cancer Cell Migration and Cell Cycle Dysregulation, In Vitro.

Potential oncogene cleavage and polyadenylation specific factor 4 (CPSF4) has been linked to several cancer types. However, little research has been conducted on its function in prostate cancer (PCa). In benign, incidental, advanced, and castrate resistant PCa (CRPCa) patient samples, protein expression of CPSF4 was examined on tissue microarray (TMAs) of 353 PCa patients using immunohistochemistry. Using the 'The Cancer Genome Atlas' Prostate Adenocarcinoma (TCGA PRAD) database, significant correlations were found between high CPSF4 expression and high-risk genomic abnormalities such as ERG-fusion, ETV1-fusion, and SPOP mutations. Gene Set Enrichment Analysis (GSEA) of CPSF4 revealed evidence for the increase in biological processes such as cellular proliferation and metastasis. We further examined the function of CPSF4 in vitro and confirmed CPSF4 clinical outcomes and its underlying mechanism. Our findings showed a substantial correlation between Gleason groups and CPSF4 protein expression. In vitro, CPSF4 knockdown reduced cell invasion and migration while also causing G1 and G2 arrest in PC3 cell lines. Our findings demonstrate that CPSF4 may be used as a possible biomarker in PCa and support its oncogenic function in cellular proliferation and metastasis.

Prevalence of palliative radiotherapy abstracts presented at the annual scientific meetings of the Canadian Association of Radiation Oncology: 2003-2021.

PURPOSE: Approximately half of all radiotherapy (RT) is delivered with palliative intent. Clinical research in palliative RT aims to manage symptoms, improve quality of life (QoL), evaluate supportive care, and determine optimal dose-fractionation schedules. Our aim was to describe the prevalence of palliative research at the Canadian Association of Radiation Oncology (CARO) Annual Scientific Meeting (ASM) over time and compare this analysis to previously published work which evaluated the years 1992-2002. METHODS: Published abstracts (2003-2021) were independently reviewed by two authors who categorized each as curative-intent; palliative-intent; pertaining to both populations; or neither. Abstracts were considered palliative if they described incurable malignancy and interventions primarily for symptom control or QoL. Type of study, primary, site treated, and symptoms palliated were recorded. Descriptive and summary statistics were calculated including one-way ANOVA test for trend. RESULTS: Three hundred thirty-nine out of 4566 abstracts (7.4%, range 2.4-13.9% per year) were classified as palliative. 7.7% (26/339) described phase I-III trials. The main primary site was the lung (39/339) and the most common metastatic site was the bone (34.2%). QoL, symptom and toxicity outcomes were reported in 31.6% (107/339), 37.8% (128/339) and 17.7% (60/339), respectively. The most common symptom investigated was pain (38/339). The proportion of abstracts classified as curative, palliative or reporting toxicity endpoints demonstrated significant change over time (all p<0.0001). CONCLUSION: While proportion of palliative themed abstracts has increased with time, there remains a significant gap before equivalence with the prevalence of palliative RT in clinical practice is achieved.

A prospective Canadian gastroesophageal cancer database: What have we learned?

BACKGROUND: Minimal literature exists on outcomes for Canadian patients with gastroesophageal adenocarcinoma (GEA). The objective of our study was to establish a prospective clinical database to evaluate demographic characteristics, presentation and outcomes of patients with GEA. METHODS: Patients diagnosed with GEA were recruited from Jan. 30, 2017, to Aug. 30, 2020. Data collected included demographic characteristics, presentation, treatment and survival. A multivariable model for overall survival in patients treated with curative intent was created using sex, lymph node status, resection margin status, age and tumour location as variables. RESULTS: A total of 122 patients with adenocarcinoma of the stomach or gastroesophageal junction were included. Median age was 65 years (interquartile range [IQR] 59-74), 70% of patients were male and 26% were born outside of Canada. Median follow-up time was 14.5 (IQR 8.0-31.0) months. Following staging computed tomography scanning, 88% of patients were deemed to have potentially resectable disease. Eighty-one (76%) received staging laparoscopy and 74 (61%) were treated with curativeintent surgery. Forty-six (62%) patients had nodal metastases. The median number of nodes harvested was 22 (IQR 18-30). The R0 resection margin rate was 82%. The 3-year overall survival for patients who received curative-intent treatment was 63% and 38% for all patients. On multivariable analysis, female sex (hazard ratio [HR] 3.88, p = 0.01), positive nodal status (HR 3.58, p = 0.02), positive margins (HR 3.11, p = 0.03) and tumour location (HR 3.00, p = 0.03) were associated with decreased overall survival. CONCLUSION: Many of the patients with GEA in this study presented with advanced disease, and only 61% were offered curative-intent surgery. A prospective multicentre national GEA database is now being established.