Plasma Lipidomic Profiling Identifies Elevated Triglycerides as Potential Risk Factor in Chemotherapy-Induced Peripheral Neuropathy.

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect of cytotoxic cancer treatment, often necessitating dose reduction (DR) or chemotherapy discontinuation (CD). Studies on peripheral neuropathy related to chemotherapy, obesity, and diabetes have implicated lipid metabolism. This study examined the association between circulating lipids and CIPN. METHODS: Lipidomic analysis was performed on plasma samples from 137 patients receiving taxane-based treatment. CIPN was graded using Total Neuropathy Score-clinical version (TNSc) and patient-reported outcome measure European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-CIPN (EORTC-QLQ-CIPN20). RESULTS: A significant proportion of elevated baseline lipids were associated with high-grade CIPN defined by TNSc and EORTC-QLQ-CIPN20 including triacylglycerols (TGs). Multivariable Cox regression on lipid species, adjusting for BMI, age, and diabetes, showed several elevated baseline TG associated with shorter time to DR/CD. Latent class analysis identified two baseline lipid profiles with differences in risk of CIPN (hazard ratio, 2.80 [95% CI, 1.50 to 5.23]; P = .0013). The higher risk lipid profile had several elevated TG species and was independently associated with DR/CD when modeled with other clinical factors (diabetes, age, BMI, or prior numbness/tingling). CONCLUSION: Elevated baseline plasma TG is associated with an increased risk of CIPN development and warrants further validation in other cohorts. Ultimately, this may enable therapeutic intervention.

A New δ-Globin Gene Variant: Hb A2-Yulin [δ46(CD5)Gly→Arg,HBD: C.139G > A].

We report a new δ-chain hemoglobin (Hb) variant observed in a 5-year-old female living in Yulin, Guangxi, China. Capillary electrophoresis revealed splitting of the Hb A2 peak into two fractions (Hb A2 and Hb A2 variant), and the Hb A2 variant was also detected by high-performance liquid chromatography. However, it could not be detected using matrix-assisted laser desorption lonization-time of flight mass spectrometry. CD41-42 (-TCTT) heterozygosity was observed on the HBB gene by PCR and reverse dot-blot hybridization. Sanger sequencing showed a new transition (G > A) at codon 46 of the HBD gene, resulting in glycine changing to arginine. Based on the patient's place of residence, the new variant was named Hb A2-Yulin [δ46(CD5)Gly→Arg,HBD:c.139G > A].

Lessons Learned in Building Expertly Annotated Multi-Institution Datasets and Hosting the RSNA AI Challenges.

The Radiological Society of North America (RSNA) has held artificial intelligence competitions to tackle real-world medical imaging problems at least annually since 2017. This article examines the challenges and processes involved in organizing these competitions, with a specific emphasis on the creation and curation of high-quality datasets. The collection of diverse and representative medical imaging data involves dealing with issues of patient privacy and data security. Furthermore, ensuring quality and consistency in data, which includes expert labeling and accounting for various patient and imaging characteristics, necessitates substantial planning and resources. Overcoming these obstacles requires meticulous project management and adherence to strict timelines. The article also highlights the potential of crowdsourced annotation to progress medical imaging research. Through the RSNA competitions, an effective global engagement has been realized, resulting in innovative solutions to complex medical imaging problems, thus potentially transforming health care by enhancing diagnostic accuracy and patient outcomes. Keywords: Use of AI in Education, Artificial Intelligence © RSNA, 2024.

Clinical validation of circulating GDF15/MIC-1 as a marker of response to docetaxel and survival in men with metastatic castration-resistant prostate cancer.

BACKGROUND: Elevated circulating growth differentiation factor (GDF15/MIC-1), interleukin 4 (IL4), and IL6 levels were associated with resistance to docetaxel in an exploratory cohort of men with metastatic castration-resistant prostate cancer (mCRPC). This study aimed to establish level 2 evidence of cytokine biomarker utility in mCRPC. METHODS: IntVal: Plasma samples at baseline (BL) and Day 21 docetaxel (n = 120). ExtVal: Serum samples at BL and Day 42 of docetaxel (n = 430). IL4, IL6, and GDF15 levels were measured by ELISA. Monocytes and dendritic cells were treated with 10% plasma from men with high or low GDF15 or recombinant GDF15. RESULTS: IntVal: Higher GDF15 levels at BL and Day 21 were associated with shorter overall survival (OS) (BL; p = 0.03 and Day 21; p = 0.004). IL4 and IL6 were not associated with outcomes. ExtVal: Higher GDF15 levels at BL and Day 42 predicted shorter OS (BL; p < 0.0001 and Day 42; p < 0.0001). Plasma from men with high GDF15 caused an increase in CD86 expression on monocytes (p = 0.03), but was not replicated by recombinant GDF15. CONCLUSIONS: Elevated circulating GDF15 is associated with poor prognosis in men with mCRPC receiving docetaxel and may be a marker of changes in the innate immune system in response to docetaxel resistance. These findings provide a strong rationale to consider GDF15 as a biomarker to guide a therapeutic trial of drugs targeting the innate immune system in combination with docetaxel in mCRPC.

Machine Learning Detection and Characterization of Splenic Injuries on Abdominal Computed Tomography.

BACKGROUND: Multi-detector contrast-enhanced abdominal computed tomography (CT) allows for the accurate detection and classification of traumatic splenic injuries, leading to improved patient management. Their effective use requires rapid study interpretation, which can be a challenge on busy emergency radiology services. A machine learning system has the potential to automate the process, potentially leading to a faster clinical response. This study aimed to create such a system. METHOD: Using the American Association for the Surgery of Trauma (AAST), spleen injuries were classified into 3 classes: normal, low-grade (AAST grade I-III) injuries, and high-grade (AAST grade IV and V) injuries. Employing a 2-stage machine learning strategy, spleens were initially segmented from input CT images and subsequently underwent classification via a 3D dense convolutional neural network (DenseNet). RESULTS: This single-centre retrospective study involved trauma protocol CT scans performed between January 1, 2005, and July 31, 2021, totaling 608 scans with splenic injuries and 608 without. Five board-certified fellowship-trained abdominal radiologists utilizing the AAST injury scoring scale established ground truth labels. The model achieved AUC values of 0.84, 0.69, and 0.90 for normal, low-grade injuries, and high-grade splenic injuries, respectively. CONCLUSIONS: Our findings demonstrate the feasibility of automating spleen injury detection using our method with potential applications in improving patient care through radiologist worklist prioritization and injury stratification. Future endeavours should concentrate on further enhancing and optimizing our approach and testing its use in a real-world clinical environment.

Vision Transformer-based Decision Support for Neurosurgical Intervention in Acute Traumatic Brain Injury: Automated Surgical Intervention Support Tool.

Purpose To develop an automated triage tool to predict neurosurgical intervention for patients with traumatic brain injury (TBI). Materials and Methods A provincial trauma registry was reviewed to retrospectively identify patients with TBI from 2005 to 2022 treated at a specialized Canadian trauma center. Model training, validation, and testing were performed using head CT scans with binary reference standard patient-level labels corresponding to whether the patient received neurosurgical intervention. Performance and accuracy of the model, the Automated Surgical Intervention Support Tool for TBI (ASIST-TBI), were also assessed using a held-out consecutive test set of all patients with TBI presenting to the center between March 2021 and September 2022. Results Head CT scans from 2806 patients with TBI (mean age, 57 years ± 22 [SD]; 1955 [70%] men) were acquired between 2005 and 2021 and used for training, validation, and testing. Consecutive scans from an additional 612 patients (mean age, 61 years ± 22; 443 [72%] men) were used to assess the performance of ASIST-TBI. There was accurate prediction of neurosurgical intervention with an area under the receiver operating characteristic curve (AUC) of 0.92 (95% CI: 0.88, 0.94), accuracy of 87% (491 of 562), sensitivity of 87% (196 of 225), and specificity of 88% (295 of 337) on the test dataset. Performance on the held-out test dataset remained robust with an AUC of 0.89 (95% CI: 0.85, 0.91), accuracy of 84% (517 of 612), sensitivity of 85% (199 of 235), and specificity of 84% (318 of 377). Conclusion A novel deep learning model was developed that could accurately predict the requirement for neurosurgical intervention using acute TBI CT scans. Keywords: CT, Brain/Brain Stem, Surgery, Trauma, Prognosis, Classification, Application Domain, Traumatic Brain Injury, Triage, Machine Learning, Decision Support Supplemental material is available for this article. © RSNA, 2024 See also commentary by Haller in this issue.

Performance of the Winning Algorithms of the RSNA 2022 Cervical Spine Fracture Detection Challenge.

Purpose To evaluate and report the performance of the winning algorithms of the Radiological Society of North America Cervical Spine Fracture AI Challenge. Materials and Methods The competition was open to the public on Kaggle from July 28 to October 27, 2022. A sample of 3112 CT scans with and without cervical spine fractures (CSFx) were assembled from multiple sites (12 institutions across six continents) and prepared for the competition. The test set had 1093 scans (private test set: n = 789; mean age, 53.40 years ± 22.86 [SD]; 509 males; public test set: n = 304; mean age, 52.51 years ± 20.73; 189 males) and 847 fractures. The eight top-performing artificial intelligence (AI) algorithms were retrospectively evaluated, and the area under the receiver operating characteristic curve (AUC) value, F1 score, sensitivity, and specificity were calculated. Results A total of 1108 contestants composing 883 teams worldwide participated in the competition. The top eight AI models showed high performance, with a mean AUC value of 0.96 (95% CI: 0.95, 0.96), mean F1 score of 90% (95% CI: 90%, 91%), mean sensitivity of 88% (95% Cl: 86%, 90%), and mean specificity of 94% (95% CI: 93%, 96%). The highest values reported for previous models were an AUC of 0.85, F1 score of 81%, sensitivity of 76%, and specificity of 97%. Conclusion The competition successfully facilitated the development of AI models that could detect and localize CSFx on CT scans with high performance outcomes, which appear to exceed known values of previously reported models. Further study is needed to evaluate the generalizability of these models in a clinical environment. Keywords: Cervical Spine, Fracture Detection, Machine Learning, Artificial Intelligence Algorithms, CT, Head/Neck Supplemental material is available for this article. © RSNA, 2024.

PCPro: a clinically accessible, circulating lipid biomarker signature for poor-prognosis metastatic prostate cancer.

BACKGROUND: Using comprehensive plasma lipidomic profiling from men with metastatic castration-resistant prostate cancer (mCRPC), we have previously identified a poor-prognostic lipid profile associated with shorter overall survival (OS). In order to translate this biomarker into the clinic, these men must be identifiable via a clinically accessible, regulatory-compliant assay. METHODS: A single regulatory-compliant liquid chromatography-mass spectrometry assay of candidate lipids was developed and tested on a mCRPC Discovery cohort of 105 men. Various risk-score Cox regression prognostic models of OS were built using the Discovery cohort. The model with the highest concordance index (PCPro) was chosen for validation and tested on an independent Validation cohort of 183 men. RESULTS: PCPro, the lipid biomarker, contains Cer(d18:1/18:0), Cer(d18:1/24:0), Cer(d18:1/24:1), triglycerides and total cholesterol. Within the Discovery and Validation cohorts, men who were PCPro positive had significantly shorter OS compared to those who were PCPro negative (Discovery: median OS 12.0 months vs 24.2 months, hazard ratio (HR) 3.75 [95% confidence interval (CI) 2.29-6.15], p < 0.001, Validation: median OS 13.0 months vs 25.7 months, HR = 2.13 [95% CI 1.46-3.12], p < 0.001). CONCLUSIONS: We have developed PCPro, a lipid biomarker assay capable of prospectively identifying men with mCRPC with a poor prognosis. Prospective clinical trials are required to determine if men who are PCPro positive will benefit from therapeutic agents targeting lipid metabolism.

Interrater Agreement of CT Grading of Blunt Splenic Injuries: Does the AAST Grading Need to Be Reimagined?

Introduction: The Revised Organ Injury Scale (OIS) of the American Association for Surgery of Trauma (AAST) is the most widely accepted classification of splenic trauma. The objective of this study was to evaluate inter-rater agreement for CT grading of blunt splenic injuries. Methods: CT scans in adult patients with splenic injuries at a level 1 trauma centre were independently graded by 5 fellowship trained abdominal radiologists using the AAST OIS for splenic injuries - 2018 revision. The inter-rater agreement for AAST CT injury score, as well as low-grade (IIII) versus high-grade (IV-V) splenic injury was assessed. Disagreement in two key clinical scenarios (no injury versus injury, and high versus low grade) were qualitatively reviewed to identify possible sources of disagreement. Results: A total of 610 examinations were included. The inter-rater absolute agreement was low (Fleiss kappa statistic 0.38, P < 0.001), but improved when comparing agreement between low and high grade injuries (Fleiss kappa statistic of 0.77, P < .001). There were 34 cases (5.6%) of minimum two-rater disagreement about no injury vs injury (AAST grade ≥ I). There were 46 cases (7.5%) of minimum two-rater disagreement of low grade (AAST grade I-III) versus high grade (AAST grade IV-V) injuries. Likely sources of disagreement were interpretation of clefts versus lacerations, peri-splenic fluid versus subcapsular hematoma, application of adding multiple low grade injuries to higher grade injuries, and identification of subtle vascular injuries. Conclusion: There is low absolute agreement in grading of splenic injuries using the existing AAST OIS for splenic injuries.

Machine Learning Classification of Body Part, Imaging Axis, and Intravenous Contrast Enhancement on CT Imaging.

Purpose: The development and evaluation of machine learning models that automatically identify the body part(s) imaged, axis of imaging, and the presence of intravenous contrast material of a CT series of images. Methods: This retrospective study included 6955 series from 1198 studies (501 female, 697 males, mean age 56.5 years) obtained between January 2010 and September 2021. Each series was annotated by a trained board-certified radiologist with labels consisting of 16 body parts, 3 imaging axes, and whether an intravenous contrast agent was used. The studies were randomly assigned to the training, validation and testing sets with a proportion of 70%, 20% and 10%, respectively, to develop a 3D deep neural network for each classification task. External validation was conducted with a total of 35,272 series from 7 publicly available datasets. The classification accuracy for each series was independently assessed for each task to evaluate model performance. Results: The accuracies for identifying the body parts, imaging axes, and the presence of intravenous contrast were 96.0% (95% CI: 94.6%, 97.2%), 99.2% (95% CI: 98.5%, 99.7%), and 97.5% (95% CI: 96.4%, 98.5%) respectively. The generalizability of the models was demonstrated through external validation with accuracies of 89.7 - 97.8%, 98.6 - 100%, and 87.8 - 98.6% for the same tasks. Conclusions: The developed models demonstrated high performance on both internal and external testing in identifying key aspects of a CT series.

The RSNA Cervical Spine Fracture CT Dataset.

This dataset is composed of cervical spine CT images with annotations related to fractures; it is available at https://www.kaggle.com/competitions/rsna-2022-cervical-spine-fracture-detection/.

Multi-Omic Integration of Blood-Based Tumor-Associated Genomic and Lipidomic Profiles Using Machine Learning Models in Metastatic Prostate Cancer.

PURPOSE: To determine prognostic and predictive clinical outcomes in metastatic hormone-sensitive prostate cancer (mHSPC) and metastatic castrate-resistant prostate cancer (mCRPC) on the basis of a combination of plasma-derived genomic alterations and lipid features in a longitudinal cohort of patients with advanced prostate cancer. METHODS: A multifeature classifier was constructed to predict clinical outcomes using plasma-based genomic alterations detected in 120 genes and 772 lipidomic species as informative features in a cohort of 71 patients with mHSPC and 144 patients with mCRPC. Outcomes of interest were collected over 11 years of follow-up. These included in mHSPC state early failure of androgen-deprivation therapy (ADT) and exceptional responders to ADT; early death (poor prognosis) and long-term survivors in mCRPC state. The approach was to build binary classification models that identified discriminative candidates with optimal weights to predict outcomes. To achieve this, we built multi-omic feature-based classifiers using traditional machine learning (ML) methods, including logistic regression with sparse regularization, multi-kernel Gaussian process regression, and support vector machines. RESULTS: The levels of specific ceramides (d18:1/14:0 and d18:1/17:0), and the presence of CHEK2 mutations, AR amplification, and RB1 deletion were identified as the most crucial factors associated with clinical outcomes. Using ML models, the optimal multi-omics feature combination determined resulted in AUC scores of 0.751 for predicting mHSPC survival and 0.638 for predicting ADT failure; and in mCRPC state, 0.687 for prognostication and 0.727 for exceptional survival. The models were observed to be superior than using a limited candidate number of features for developing multi-omic prognostic and predictive signatures. CONCLUSION: Using a ML approach that incorporates multiple omic features improves the prediction accuracy for metastatic prostate cancer outcomes significantly. Validation of these models will be needed in independent data sets in future.

Development a novel nomogram model for predicting significant hepatic histological changes in chronic hepatitis B virus carriers.

A proportion of chronic hepatitis B virus (HBV) carriers with normal alanine transaminase (ALT) present with significant liver histological changes (SLHC). To construct a noninvasive nomogram model to identify SLHC in chronic HBV carriers with different upper limits of normal (ULNs) for ALT. The training cohort consisted of 732 chronic HBV carriers who were stratified into four sets according to different ULNs for ALT: chronic HBV carriers I, II, III, and IV. The external validation cohort comprised 277 chronic HBV carriers. Logistic regression and least absolute shrinkage and selection operator analyses were applied to develop a nomogram model to predict SLHC. A nomogram model-HBGP (based on hepatitis B surface antigen, gamma-glutamyl transpeptidase, and platelet count) demonstrated good performance in diagnosing SLHC with area under the curve (AUCs) of 0.866 (95% confidence interval [CI]: 0.839-0.892) and 0.885 (95% CI: 0.845-0.925) in the training and validation cohorts, respectively. Furthermore, HBGP displayed high diagnostic values for SLHC with AUCs of 0.866 (95% CI: 0.839-0.892), 0.868 (95% CI: 0.838-0.898), 0.865 (95% CI: 0.828-0.901), and 0.853 (95% CI: 0.798-0.908) in chronic HBV carriers I, II, III, and IV, respectively. Additionally, HBGP showed greater ability in predicting SLHC compared with the existing predictors. HBGP has shown high predictive performance for SLHC, and thus may lead to an informed decision on the initiation of antiviral treatment.

Augmentation of the RSNA Pulmonary Embolism CT Dataset with Bounding Box Annotations and Anatomic Localization of Pulmonary Emboli.

Supplemental material is available for this article. Keywords: CT, Pulmonary Arteries, Embolism/Thrombosis, Feature Detection © RSNA, 2023.

The mediating effect of psychological empowerment on the relationship between work environment and clinical decision-making among midwives: a multicentre cross-sectional study.

BACKGROUND: Clinical decision-making is considered an essential behaviour in clinical practice. However, no research has been done to examine the associations among midwives' clinical decision-making, work environment and psychological empowerment. Thus, this study aimed to determine the influence of work environment on midwives' clinical decision-making and confirm the mediating role of psychological empowerment. METHOD: This study was designed as a multicentre cross-sectional study, and included 602 registered midwives from 25 public hospitals in China. A sociodemographic questionnaire, Work Environment Scale, Psychological Empowerment Scale and Clinical decision-making Scale were applied. A structural equation model was conducted to estimate the hypothesis model of the clinical decision-making among midwives and explore the potential mediating mechanism of midwives' clinical decision-making. This model was employed maximum likelihood estimation method and bootstrapping to examine the statistical significance. RESULTS: The mean score of clinical decision-making among midwives was 143.03 ± 14.22, at an intermediate level. The data of this hypothesis model fitted well, and the results showed that work environment positively affected psychological empowerment, which in turn positively affected clinical decision-making; psychological empowerment partly mediated the relationship between work environment and clinical decision-making among midwives. CONCLUSIONS: Midwives' clinical decision-making could be promoted directly or indirectly by providing a healthy work environment and improving psychological empowerment. It is essential for hospital managers to pay attention to the assessment of the midwives' work environment and actively improve it, such as establishing a supportive, fair and just workplace, and maintaining effective communication with midwives. Furthermore, managers can also promote midwives' clinical decision-making behaviour by enhancing their psychological empowerment via enhancing job autonomy.

Modulation of Plasma Lipidomic Profiles in Metastatic Castration-Resistant Prostate Cancer by Simvastatin.

Elevated circulating sphingolipids are associated with shorter overall survival and therapeutic resistance in metastatic castration-resistant prostate cancer (mCRPC), suggesting that perturbations in sphingolipid metabolism promotes prostate cancer growth. This study assessed whether addition of simvastatin to standard treatment for mCRPC can modify a poor prognostic circulating lipidomic profile represented by a validated 3-lipid signature (3LS). Men with mCRPC (n = 27) who were not on a lipid-lowering agent, were given simvastatin for 12 weeks (40 mg orally, once daily) with commencement of standard treatment. Lipidomic profiling was performed on their plasma sampled at baseline and after 12 weeks of treatment. Only 11 men had the poor prognostic 3LS at baseline, of whom five (45%) did not retain the 3LS after simvastatin treatment (expected conversion rate with standard treatment = 19%). At baseline, the plasma profiles of men with the 3LS displayed higher levels (p < 0.05) of sphingolipids (ceramides, hexosylceramides and sphingomyelins) than those of men without the 3LS. These plasma sphingolipids were reduced after statin treatment in men who lost the 3LS (mean decrease: 23−52%, p < 0.05), but not in men with persistent 3LS, and were independent of changes to plasma cholesterol, LDL-C or triacylglycerol. In conclusion, simvastatin in addition to standard treatment can modify the poor prognostic circulating lipidomic profile in mCRPC into a more favourable profile at twice the expected conversion rate.

Harnessing the Heterogeneity of Prostate Cancer for Target Discovery Using Patient-Derived Explants.

Prostate cancer is a complex and heterogeneous disease, but a small number of cell lines have dominated basic prostate cancer research, representing a major obstacle in the field of drug and biomarker discovery. A growing lack of confidence in cell lines has seen a shift toward more sophisticated pre-clinical cancer models that incorporate patient-derived tumors as xenografts or explants, to more accurately reflect clinical disease. Not only do these models retain critical features of the original tumor, and account for the molecular diversity and cellular heterogeneity of prostate cancer, but they provide a unique opportunity to conduct research in matched tumor samples. The challenge that accompanies these complex tissue models is increased complexity of analysis. With over 10 years of experience working with patient-derived explants (PDEs) of prostate cancer, this study provides guidance on the PDE method, its limitations, and considerations for addressing the heterogeneity of prostate cancer PDEs that are based on statistical modeling. Using inhibitors of the molecular chaperone heat shock protein 90 (Hsp90) as an example of a drug that induces robust proliferative response, we demonstrate how multi-omics analysis in prostate cancer PDEs is both feasible and essential for identification of key biological pathways, with significant potential for novel drug target and biomarker discovery.

Combined impact of lipidomic and genetic aberrations on clinical outcomes in metastatic castration-resistant prostate cancer.

BACKGROUND: Both changes in circulating lipids represented by a validated poor prognostic 3-lipid signature (3LS) and somatic tumour genetic aberrations are individually associated with worse clinical outcomes in men with metastatic castration-resistant prostate cancer (mCRPC). A key question is how the lipid environment and the cancer genome are interrelated in order to exploit this therapeutically. We assessed the association between the poor prognostic 3-lipid signature (3LS), somatic genetic aberrations and clinical outcomes in mCRPC. METHODS: We performed plasma lipidomic analysis and cell-free DNA (cfDNA) sequencing on 106 men with mCRPC commencing docetaxel, cabazitaxel, abiraterone or enzalutamide (discovery cohort) and 94 men with mCRPC commencing docetaxel (validation cohort). Differences in lipid levels between men ± somatic genetic aberrations were assessed with t-tests. Associations between the 3LS and genetic aberrations with overall survival (OS) were examined using Kaplan-Meier methods and Cox proportional hazard models. RESULTS: The 3LS was associated with shorter OS in the discovery (hazard ratio [HR] 2.15, 95% confidence interval [CI] 1.4-3.3, p < 0.001) and validation cohorts (HR 2.32, 95% CI 1.59-3.38, p < 0.001). Elevated plasma sphingolipids were associated with AR, TP53, RB1 and PI3K aberrations (p < 0.05). Men with both the 3LS and aberrations in AR, TP53, RB1 or PI3K had shorter OS than men with neither in both cohorts (p ≤ 0.001). The presence of 3LS and/or genetic aberration was independently associated with shorter OS for men with AR, TP53, RB1 and PI3K aberrations (p < 0.02). Furthermore, aggressive-variant prostate cancer (AVPC), defined as 2 or more aberrations in TP53, RB1 and/or PTEN, was associated with elevated sphingolipids. The combination of AVPC and 3LS predicted for a median survival of ~12 months. The relatively small sample size of the cohorts limits clinical applicability and warrants future studies. CONCLUSIONS: Elevated circulating sphingolipids were associated with AR, TP53, RB1, PI3K and AVPC aberrations in mCRPC, and the combination of lipid and genetic abnormalities conferred a worse prognosis. These findings suggest that certain genotypes in mCRPC may benefit from metabolic therapies.

Overcoming enzalutamide resistance in metastatic prostate cancer by targeting sphingosine kinase.

BACKGROUND: Intrinsic resistance to androgen receptor signalling inhibitors (ARSI) occurs in 20-30% of men with metastatic castration-resistant prostate cancer (mCRPC). Ceramide metabolism may have a role in ARSI resistance. Our study's aim is to investigate the association of the ceramide-sphingosine-1-phosphate (ceramide-S1P) signalling axis with ARSI resistance in mCRPC. METHODS: Lipidomic analysis (∼700 lipids) was performed on plasma collected from 132 men with mCRPC, before commencing enzalutamide or abiraterone. AR gene aberrations in 77 of these men were identified by deep sequencing of circulating tumour DNA. Associations between circulating lipids, radiological progression-free survival (rPFS) and overall survival (OS) were examined by Cox regression. Inhibition of ceramide-S1P signalling with sphingosine kinase (SPHK) inhibitors (PF-543 and ABC294640) on enzalutamide efficacy was investigated with in vitro assays, and transcriptomic and lipidomic analyses of prostate cancer (PC) cell lines (LNCaP, C42B, 22Rv1). FINDINGS: Men with elevated circulating ceramide levels had shorter rPFS (HR=2·3, 95% CI=1·5-3·6, p = 0·0004) and shorter OS (HR=2·3, 95% CI=1·4-36, p = 0·0005). The combined presence of an AR aberration with elevated ceramide levels conferred a worse prognosis than the presence of only one or none of these characteristics (median rPFS time = 3·9 vs 8·3 vs 17·7 months; median OS time = 8·9 vs 19·8 vs 34·4 months). SPHK inhibitors enhanced enzalutamide efficacy in PC cell lines. Transcriptomic and lipidomic analyses indicated that enzalutamide combined with SPHK inhibition enhanced PC cell death by SREBP-induced lipotoxicity. INTERPRETATION: Ceramide-S1P signalling promotes ARSI resistance, which can be reversed with SPHK inhibitors. FUNDING: None.