The Princess Margaret Hospital

Background: Prior studies have demonstrated that the overall density of T cells in colorectal tumors is favorably associated with colorectal cancer (CRC) survival; however, few studies have considered the potentially distinct roles of heterogeneous T cell subsets in different tissue regions in relation to CRC outcomes. Methods: Including 1,113 CRC tumors from three observational studies, we conducted in-situ T cell profiling using a customized 9-plex [CD3, CD4, CD8, CD45RA, CD45RO, FOXP3, KRT (keratin), MKI67 (Ki-67), and DAPI] multispectral immunofluorescence assay. Multivariable-adjusted Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of T cell subset densities in both epithelial and stromal tissue areas in CRC with disease-specific survival. Results: Higher CD3+CD4+ and CD3+CD8+ naive, memory, and regulatory T cell densities were significantly associated with better CRC-specific survival in both epithelial and stromal tissue areas (HRs highest quantile versus lowest quantile ranging 0.41-0.68). These associations persisted in models further adjusted for stage at diagnosis and were largely consistent when stratified by microsatellite instability (MSI) status. However, the further stratification into CD4+ or CD8+ T cell subsets beyond CD3+ subsets did not significantly improve how well our model explains CRC prognosis. Conclusions: The density of T cells in CRC tissue, both overall and for several T cell subset populations, is significantly associated with CRC-specific survival independent of MSI status and stage at diagnosis. Impact: Higher levels of T cell densities in different locations with different functions are associated with better CRC-specific survival.

Purpose There is currently a lack of evidence regarding antibiotic use for adult cancer patients presenting with non-neutropenic fever. This study evaluated broad-spectrum antibiotics use among adult cancer patients who presented to the Emergency Department (ED) with non-neutropenic fever or/and suspected infection. Methods A retrospective cohort study was completed that included adult patients with solid malignancies who presented to Juravinski Hospital ED with non-neutropenic fever or suspected infection from July 1 to December 31, 2020. The primary outcome was the proportion of patients who received one or more dose(s) of broad-spectrum antibiotics. Additionally, a multivariate logistic regression was completed to assess factors associated with an increased likelihood of clinicians prescribing broad-spectrum antibiotics. Results Of 275 patients analyzed, broad-spectrum intravenous antibiotics were used in 47% (109/230) of the cohort, and most of the time (78%) was the first antibiotic type given after arrival in ED. Age, gender, comorbidities, and receiving systemic treatment were not significantly associated with increased broad-spectrum antibiotic use. There were higher rates of broad-spectrum antibiotics prescribed to patients with stage IV cancer (OR 2.8, p = 0.002) and genitourinary cancer (OR 6.7, p < 0.001). Conclusion In our single-center study, nearly half of adult cancer patients received broad-spectrum intravenous antibiotics. With a few exceptions, there was generally no consistent criteria on which clinician prescribes broad-spectrum antibiotics. These data suggest a need for quality improvement strategies to improve antibiotic stewardship for cancer patients presenting with non-neutropenic fever.

Clonal haematopoiesis arises when a haematopoietic stem cell (HSC) acquires a mutation that confers a competitive advantage over wild-type HSCs, resulting in its clonal expansion. Individuals with clonal haematopoiesis are at increased risk of developing haematologic neoplasms and other age-related inflammatory illnesses1, 2, 3–4. Suppressing the expansion of mutant HSCs may prevent these outcomes; however, such interventions have not yet been identified. The most common clonal haematopoiesis driver mutations are in the DNMT3A gene, with arginine 882 (R882) being a mutation hotspot1, 2–3,5, 6–7. Here we show that mouse haematopoietic stem and progenitor cells (HSPCs) carrying the Dnmt3aR878H/+ mutation, equivalent to human DNMT3AR882H/+, have increased mitochondrial respiration compared with wild-type cells and are dependent on this metabolic reprogramming for their competitive advantage. Treatment with metformin, an anti-diabetic drug that inhibits mitochondrial respiration⁸, reduced the competitive advantage of Dnmt3aR878H/+ HSCs. Through a multi-omics approach, we found that metformin acts by enhancing methylation potential in Dnmt3aR878H/+ HSPCs and reversing the aberrant DNA CpG methylation and histone H3 K27 trimethylation profiles in these cells. Metformin also reduced the competitive advantage of human DNMT3AR882H HSPCs generated by prime editing. Our findings provide preclinical rationale for investigating metformin as a preventive intervention against DNMT3A R882 mutation-driven clonal haematopoiesis in humans.

Purpose Nasopharyngeal carcinoma (NPC) is endemic in Southeast Asia, requiring precise imaging for personalized treatment. This review highlights key imaging challenges and updates from recent literature, emphasizing findings that impact oncological management. Methods We discuss common and uncommon clinical entities, detailing salient imaging features and diagnostic distinctions to aid accurate interpretation. Results In the pre-treatment setting, leveraging the characteristic MR signals and spread patterns of NPC aids in defining the tumor volume for accurate staging and radiotherapy contouring. Key diagnostic challenges include differentiating tumor from benign hyperplasia, skull base osteomyelitis, and other skull base tumors. Perineural tumor spread, radiological extranodal extension and nodal necrosis further refine primary tumor and nodal assessment. In the post-treatment setting, the key question is whether tumor recurrence exists. Diagnostic challenges involve distinguishing tumor recurrence from scar tissue, post-radiation nasopharyngeal necrosis, or hypertrophied cervical ganglia. For recurrences, endoscopic nasopharyngectomy has emerged as the preferred approach over open surgery or re-irradiation. The text highlights characteristic post-treatment appearances and emphasizes recognizing these patterns to avoid misinterpretation and guide appropriate management. Conclusion Imaging plays a pivotal role in NPC precision oncology. Mastering imaging pearls and pitfalls empowers radiologists to provide clinicians with reliable, actionable guidance.

Tandem duplicator phenotype (TDP) consists of distinct genomic rearrangements where tandem duplications are randomly distributed. In this study, we characterized the prevalence and outcomes of TDP in a large series of prospectively sequenced tumors from patients with pancreatic ductal adenocarcinomas (PDAC). Whole-genome sequencing (WGS) was performed in 530 PDAC cases from the PanCuRx Initiative, COMPASS and PanGen/POG trials in Canada. Of 530 cases, 52 were identified as TDP (9.8%; 13 resected, 39 advanced). Etiological subgroups of TDP included BRCA1 (n = 9), CCNE1 (n = 4), and unknown (n = 39). Presence of TDP was not prognostic in resected specimens (p = 0.77) compared with non-HRD and non-TDP cases, described as typicals. In advanced cases, when stratified for only classical subtype cases, platinum therapy was correlated with longer response in non-BRCA1 TDP vs. typicals (p = 0.0036). There was no difference in overall survival between TDP and typicals (p = 0.5).TDP represents a potential novel targetable subgroup for chemotherapy selection in PDAC.

Inflammation is increasingly recognized as a critical factor in acute myeloid leukemia (AML) pathogenesis. We performed blood-based proteomic profiling of 251 inflammatory proteins in 543 newly diagnosed AML patients. Using a machine learning model, we derived an eight-protein prognostic score termed Leukemia Inflammatory Risk Score (LIRS). Individual proteins were evaluated in multivariable cox models and model performance was assessed by cumulative concordance index. Findings were validated in internal and external cohorts across two institutions. Blood-based LIRS significantly outperformed the European LeukemiaNet (ELN) 2022 risk model and was independently prognostic of overall survival after accounting for known clinical and molecular prognostic factors. OSMR was uniquely identified as the strongest independent predictor of survival, early mortality, and induction chemotherapy response, and further validated in an independent assay. These blood-based biomarkers could have significant clinical implications for risk stratification and prognostication in patients with newly diagnosed AML.

PURPOSE Cetuximab (CET), targeting the epidermal growth factor receptor, is a systemic treatment option for patients with colorectal cancer. One known predictive factor for CET efficacy is the presence of CET-related rash; other putative toxicity factors include fatigue and nausea. Analysis of early CET-associated toxicities may reveal patient subpopulations that clinically benefit from long-term CET treatment. METHODS We analyzed data from CO.20 (ClinicalTrials.gov identifier: NCT00640471 ) trial arms, CET + brivanib alaninate (BRIV) (n = 376) and CET + placebo (n = 374), and CO.17 (ClinicalTrials.gov identifier: NCT00079066 ) trial arms, CET (+best supportive care [BSC]; n = 287) and BSC only (n = 285). Patients were clustered into subpopulations using KmL3D, a machine learning method, to analyze 14 joint longitudinal toxicity trajectories from weeks 0 to 8 of treatment. Landmark survival analyses were performed from 8 weeks after treatment initiation. Regression analyses assessed the relationship between subpopulations and plasma CET concentrations. Three supervised machine learning models were developed to assign patients in the CO.20-CET trial arm into subpopulations, which were then validated using CO.20-CET-BRIV and CO.17-CET trial arm data. RESULTS Joint longitudinal toxicity clustering revealed dichotomous high- and low-toxicity clusters, with all CET-containing arms showing consistent toxicity trajectories and characteristics. High-toxicity clusters were associated with male predilection, fewer metastatic sites, fewer colon-only primaries, and higher body mass indices. In CO.20 trial samples, higher toxicity clusters were associated with improved overall survival and progression-free survival outcomes (adjusted hazard ratios ranging from 2.21 to 4.36) and higher CET concentrations ( P = .003). The random forest predictive model performed the best, with an AUC of 0.981 (0.963-0.999). CONCLUSION We used an innovative machine learning approach to analyze longitudinal joint drug toxicities, demonstrating their role in predicting patient outcomes through a putative pharmacokinetic mechanism.

Background and Aim Liver transplant (LT) recipients may succumb to graft‐related pathologies, contributing to graft fibrosis (GF). Current methods to diagnose GF are limited, ranging from procedural‐related complications to low accuracy. With recent advances in machine learning (ML), we aimed to develop a noninvasive tool using demographic, clinical, laboratory, and B‐mode ultrasound (US) features to predict significant fibrosis (METAVIR≥F2). Methods We used a nested 10‐fold cross‐validation approach with grid‐search for hyperparameter fine‐tuning to train an artificial neural network (ANN) and a support vector machine (SVM) to classify mild fibrosis (F0‐F1) and significant fibrosis (F2‐F4) on 1131 patients. We calculated Shapley values to identify top‐ranked features, determining the contribution of each feature to model predictions. For the imaging‐based model, we used 4819 images with 892 studies trained on the residual network 18 (ResNet18) model to classify F0‐F1 versus F3‐F4. Results We determined the ANN performed the best when compared to the SVM and standard biomarkers, with an AUC ranging from 0.77 to 0.81. The ResNet18 model was unable to diagnose advanced GF, leading to the training AUCs ranging from 0.89 to 0.97, while the validation and testing AUCs were 0.43–0.63. Shapley analysis highlighted the following top‐ranked features associated with significant GF: hepatitis C at transplant, recipient age, recipient sex, and certain blood markers such as creatinine and hemoglobin. Conclusion Noninvasive approaches using ML for predicting significant GF perform well when considering demographic, clinical, and laboratory data; however, this performance is not enhanced with the use of US images.

Early midlife bilateral salpingo‐oophorectomy (BSO) is associated with greater Alzheimer's disease risk compared to spontaneous/natural menopause. Previously, we found that participants with BSO had lower volume in the hippocampal dentate gyrus and cornu ammonis 2/3 composite subfield (DG‐CA2/3). We sought to extend those hippocampal subfield findings by assessing whether BSO affected volumes along the anteroposterior hippocampal axis, anterolateral entorhinal cortex, and perirhinal cortex subregions (Brodmann area (BA) 35 and 36). We also correlated volumes with key demographic and wellbeing‐related factors (age, depressive mood, education), hormone therapy characteristics, and recognition memory performance. Early midlife participants with BSO (with and without 17β‐estradiol therapy (ET)) and age‐matched control participants with intact ovaries (AMC) completed high‐resolution T2‐weighted structural magnetic resonance imaging (MRI). Medial temporal lobe volumes and Remember‐Know task recognition memory performance were compared between groups—BSO ( n = 23), BSO + ET ( n = 28), AMC ( n = 34) using univariate analyses. Multivariate Partial Least Squares (PLS) analyses were used to examine how volumes related to demographic and wellbeing‐related factors, as well as hormone therapy characteristics. Relative to BSO + ET, BSO had lower posterior hippocampal and DG‐CA2/3 volumes but greater perirhinal BA 36 volumes. Compared to age, depressive mood, and education, ET was the strongest positive predictor of hippocampal volumes and negative predictor of perirhinal BA 36 volumes. For BSO + ET, hippocampal volumes were negatively related to ET duration and positively related to concurrent progestogen therapy. Relative to AMC, BSO had greater anterolateral entorhinal cortex and perirhinal BA 35 and BA 36 volumes. BSO groups (with and without ET) relied more on familiarity than recollection for successful recognition memory. BSO and ET may have distinct effects on medial temporal lobe volumes, with potential implications for memory processes affected by Alzheimer's disease risk.

Introduction Immune checkpoint inhibitors (ICIs) can yield remarkable clinical responses in subsets of patients with solid tumors, but they also commonly cause immune-related adverse events (irAEs). The predictive features of clinically severe irAEs leading to cessation of ICIs have yet to be established. Given the similarities between irAEs and autoimmune diseases, we sought to investigate the association of a germline polygenic risk score for autoimmune disease and discontinuation of ICIs due to irAEs. Methods The Genetics of immune-related adverse events and Response to Immunotherapy (GeRI) cohort comprises 1302 patients with non-small cell lung cancer (NSCLC) who received ICI therapy between 2009 and 2022 at four academic medical centers. We used a published polygenic risk score for autoimmune diseases (PRS AD ) in the general population and validated it in the All of Us. We then assessed the association between PRS AD and cessation of ICI therapy due to irAEs in the GeRI cohort, using cause-specific and Fine-Gray subdistribution hazard models. To further understand the differential effects of type of therapy on the association between PRS AD and cessation of ICI due to irAEs, we conducted a stratified analysis by type of ICI therapy. Results Using a competing risk model, we found an association between PRS AD and ICI cessation due to irAEs (HR per SD=1.24, p=0.004). This association was particularly strong in patients who had ICI cessation due to irAEs within 3 months of therapy initiation (HR per SD=1.40, p=0.005). Individuals in the top quintile of PRS AD had 4.8% ICI discontinuation for irAEs by 3 months, compared with 2% discontinuation by 3 months among patients in the bottom quintile (log-rank p=0.03). In addition, among patients who received combination programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors and cytotoxic T-lymphocyte associated protein 4 (CTLA4) inhibitors, ICI discontinuation for irAEs by 3 months occurred in 4 of the 13 patients (30.8%) with high PRS AD genetic risk (top quintile) versus 3 of 21 patients (14.3%) with low PRS AD genetic risk (bottom quintile). Conclusions We demonstrate an association between a polygenic risk score for autoimmune disease and early ICI discontinuation for irAEs. Our results suggest that germline genetics may be used as an adjunctive tool for risk stratification around ICI clinical decision-making in solid tumor oncology.

Endocrine therapy (ET) has been underexplored in endometrial cancer. Emerging data suggest that combining ET with cyclin-dependent kinase 4/6 inhibitors improves outcomes in endometrial cancer. This commentary complements a recent CCR article and reviews the opportunities to improve precision ET and the potential to overcome resistance mechanisms associated with ET failure. See related article by Green et al., p. XX

Objectives Most patients with small cell lung cancer present with extensive-stage (ES-SCLC) disease. An international randomised trial demonstrated a survival benefit in patients treated with consolidative thoracic radiotherapy (cTRT). We report our institutional experience with this regimen. Methods A retrospective review was conducted on patients with ES-SCLC who were candidates for cTRT at our institution between 2013 and 2022. The patients included in our study had biopsy-proven ES-SCLC, received ≥4 cycles of chemotherapy and achieved complete response, partial response or stable disease as per Response Evaluation Criteria in Solid Tumors V.1.1. Overall survival, progression-free survival (PFS) and recurrence patterns were compared between patients who received cTRT and those who did not. For patients who received cTRT, treatment tolerability was assessed. Results We identified 123 patients with ES-SCLC who received ≥4 cycles of chemotherapy and were candidates for cTRT. Of those, 49 patients received cTRT, and 74 patients did not. From the end of chemotherapy, the control group had a median OS of 0.6 years with a 1- and 2-year OS of 23.5% and 11.0%. Within the cTRT group, the median OS was 0.9 years with a 1- and 2-year OS of 46.7% and 26.3%. Within the control group, the median PFS was 0.2 years compared with 0.4 years within the cTRT group. Intrathoracic failures in the cTRT group were lower compared with the control group (16.3% vs 29.7%). cTRT was well tolerated with no grade 3+ toxicities. Conclusion The improved clinical outcomes of cTRT for patients with ES-SCLC were comparable to the reported the Chest Radiotherapy Extensive-Stage Small Cell Lung Cancer Trial (CREST) outcome, with a low rate of side effects in our study cohort.

Radiation therapy (RT) is a cornerstone in the management of pediatric central nervous system (CNS) tumors. Recent advancements in RT delivery and techniques aim to enhance therapeutic effectiveness while minimizing both acute and long-term complications associated with pediatric brain RT. This paper highlights innovative developments in the field, including the clinical indications, benefits, and challenges of proton therapy and stereotactic radiotherapy. The ongoing refinement of risk-adapted RT volumes is highlighted, with examples of newly proposed germinoma RT volumes and hippocampal-sparing RT. Additionally, emerging experimental approaches, including FLASH therapy and theranostics, are also discussed as promising future directions. Further prospective, multi-institutional collaborative studies are essential to validate and expand upon the benefits outlined in this review.