Cardiotoxicity detection tool for breast cancer chemotherapy: a retrospective study.

Background: Patients with breast cancer undergoing biological therapy and/or chemotherapy perform multiple radionuclide angiography (RNA) or multigated acquisition (MUGA) scans to assess cardiotoxicity. The association between RNA imaging parameters and left ventricular (LV) ejection fraction (LVEF) remains unclear. Objectives: This study aimed to extract and evaluate the association of several novel imaging biomarkers to detect changes in LVEF in patients with breast cancer undergoing chemotherapy. Methods: We developed and optimized a novel set of MATLAB routines called the "RNA Toolbox" to extract parameters from RNA images. The code was optimized using various statistical tests (e.g., ANOVA, Bland-Altman, and intraclass correlation tests). We quantitatively analyzed the images to determine the association between these parameters using regression models and receiver operating characteristic (ROC) curves. Results: The code was reproducible and showed good agreement with validated clinical software for the parameters extracted from both packages. The regression model and ROC results were statistically significant in predicting LVEF (R2 = 0.40, P < 0.001) (AUC = 0.78). Some time-based, shape-based, and count-based parameters were significantly associated with post-chemotherapy LVEF (ß = 0.09, P < 0.001), LVEF of phase image (ß = 4, P = 0.030), approximate entropy (ApEn) (ß = 11.6, P = 0.001), ApEn (diastolic and systolic) (ß = 39, P = 0.002) and LV systole size (ß = 0.03, P = 0.010). Conclusions: Despite the limited sample size, we observed evidence of associations between several parameters and LVEF. We believe that these parameters will be more beneficial than the current methods for patients undergoing cardiotoxic chemotherapy. Moreover, this approach can aid physicians in evaluating subclinical cardiac changes during chemotherapy, and in understanding the potential benefits of cardioprotective drugs.

Development and Validation of Prognostic Models Using Radiomic Features from Pre-Treatment Positron Emission Tomography (PET) Images in Head and Neck Squamous Cell Carcinoma (HNSCC) Patients.

High-dimensional radiomics features derived from pre-treatment positron emission tomography (PET) images offer prognostic insights for patients with head and neck squamous cell carcinoma (HNSCC). Using 124 PET radiomics features and clinical variables (age, sex, stage of cancer, site of cancer) from a cohort of 232 patients, we evaluated four survival models-penalized Cox model, random forest, gradient boosted model and support vector machine-to predict all-cause mortality (ACM), locoregional recurrence/residual disease (LR) and distant metastasis (DM) probability during 36, 24 and 24 months of follow-up, respectively. We developed models with five-fold cross-validation, selected the best-performing model for each outcome based on the concordance index (C-statistic) and the integrated Brier score (IBS) and validated them in an independent cohort of 102 patients. The penalized Cox model demonstrated better performance for ACM (C-statistic = 0.70, IBS = 0.12) and DM (C-statistic = 0.70, IBS = 0.08) while the random forest model displayed better performance for LR (C-statistic = 0.76, IBS = 0.07). We conclude that the ML-based prognostic model can aid clinicians in quantifying prognosis and determining effective treatment strategies, thereby improving favorable outcomes in HNSCC patients.

Comparison of semi-automatic and manual segmentation methods for tumor delineation on head and neck squamous cell carcinoma (HNSCC) positron emission tomography (PET) images.

Objective. Accurate and reproducible tumor delineation on positron emission tomography (PET) images is required to validate predictive and prognostic models based on PET radiomic features. Manual segmentation of tumors is time-consuming whereas semi-automatic methods are easily implementable and inexpensive. This study assessed the reliability of semi-automatic segmentation methods over manual segmentation for tumor delineation in head and neck squamous cell carcinoma (HNSCC) PET images.Approach. We employed manual and six semi-automatic segmentation methods (just enough interaction (JEI), watershed, grow from seeds (GfS), flood filling (FF), 30% SUVmax and 40%SUVmax threshold) using 3D slicer software to extract 128 radiomic features from FDG-PET images of 100 HNSCC patients independently by three operators. We assessed the distributional properties of all features and considered 92 log-transformed features for subsequent analysis. For each paired comparison of a feature, we fitted a separate linear mixed effect model using the method (two levels; manual versus one semi-automatic method) as a fixed effect and the subject and the operator as the random effects. We estimated different statistics-the intraclass correlation coefficient agreement (aICC), limits of agreement (LoA), total deviation index (TDI), coverage probability (CP) and coefficient of individual agreement (CIA)-to evaluate the agreement between the manual and semi-automatic methods.Main results. Accounting for all statistics across 92 features, the JEI method consistently demonstrated acceptable agreement with the manual method, with median values of aICC = 0.86, TDI = 0.94, CP = 0.66, and CIA = 0.91.Significance. This study demonstrated that JEI method is a reliable semi-automatic method for tumor delineation on HNSCC PET images.

A systematic review and meta-analysis of predictive and prognostic models for outcome prediction using positron emission tomography radiomics in head and neck squamous cell carcinoma patients.

BACKGROUND: Positron emission tomography (PET) images of head and neck squamous cell carcinoma (HNSCC) patients can assess the functional and biochemical processes at cellular levels. Therefore, PET radiomics-based prediction and prognostic models have the potentials to understand tumour heterogeneity and assist clinicians with diagnosis, prognosis and management of the disease. We conducted a systematic review of published modelling information to evaluate the usefulness of PET radiomics in the prediction and prognosis of HNSCC patients. METHODS: We searched bibliographic databases (MEDLINE, Embase, Web of Science) from 2010 to 2021 and considered 31 studies with pre-defined inclusion criteria. We followed the CHARMS checklist for data extraction and performed quality assessment using the PROBAST tool. We conducted a meta-analysis to estimate the accuracy of the prediction and prognostic models using the diagnostic odds ratio (DOR) and average C-statistic, respectively. RESULTS: Manual segmentation method followed by 40% of the maximum standardised uptake value (SUVmax ) thresholding is a commonly used approach. The area under the receiver operating curves of externally validated prediction models ranged between 0.60-0.87, 0.65-0.86 and 0.62-0.75 for overall survival, distant metastasis and recurrence, respectively. Most studies highlighted an overall high risk of bias (outcome definition, statistical methodologies and external validation of models) and high unclear concern in terms of applicability. The meta-analysis showed the estimated pooled DOR of 6.75 (95% CI: 4.45, 10.23) for prediction models and the C-statistic of 0.71 (95% CI: 0.67, 0.74) for prognostic models. CONCLUSIONS: Both prediction and prognostic models using clinical variables and PET radiomics demonstrated reliable accuracy for detecting adverse outcomes in HNSCC, suggesting the prospect of PET radiomics in clinical settings for diagnosis, prognosis and management of HNSCC patients. Future studies of prediction and prognostic models should emphasise the quality of reporting, external model validation, generalisability to real clinical scenarios and enhanced reproducibility of results.

Metabolic alterations in a rat model of takotsubo syndrome.

AIMS: Cardiac energetic impairment is a major finding in takotsubo patients. We investigate specific metabolic adaptations to direct future therapies. METHODS AND RESULTS: An isoprenaline-injection female rat model (vs. sham) was studied at Day 3; recovery assessed at Day 7. Substrate uptake, metabolism, inflammation, and remodelling were investigated by 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography, metabolomics, quantitative PCR, and western blot (WB). Isolated cardiomyocytes were patch-clamped during stress protocols for redox states of NAD(P)H/FAD or [Ca2+]c, [Ca2+]m, and sarcomere length. Mitochondrial respiration was assessed by seahorse/Clark electrode (glycolytic and ß-oxidation substrates). Cardiac 18F-FDG metabolic rate was increased in takotsubo (P = 0.006), as was the expression of GLUT4-RNA/GLUT1/HK2-RNA and HK activity (all P < 0.05), with concomitant accumulation of glucose- and fructose-6-phosphates (P > 0.0001). Both lactate and pyruvate were lower (P < 0.05) despite increases in LDH-RNA and PDH (P < 0.05 both). ß-Oxidation enzymes CPT1b-RNA and 3-ketoacyl-CoA thiolase were increased (P < 0.01) but malonyl-CoA (CPT-1 regulator) was upregulated (P = 0.01) with decreased fatty acids and acyl-carnitines levels (P = 0.0001-0.02). Krebs cycle intermediates α-ketoglutarate and succinyl-carnitine were reduced (P < 0.05) as was cellular ATP reporter dihydroorotate (P = 0.003). Mitochondrial Ca2+ uptake during high workload was impaired on Day 3 (P < 0.0001), inducing the oxidation of NAD(P)H and FAD (P = 0.03) but resolved by Day 7. There were no differences in mitochondrial respiratory function, sarcomere shortening, or [Ca2+] transients of isolated cardiomyocytes, implying preserved integrity of both mitochondria and cardiomyocyte. Inflammation and remodelling were upregulated-increased CD68-RNA, collagen RNA/protein, and skeletal actin RNA (all P < 0.05). CONCLUSION: Dysregulation of glucose and lipid metabolic pathways with decreases in final glycolytic and ß-oxidation metabolites and reduced availability of Krebs intermediates characterizes takotsubo myocardium. The energetic deficit accompanies defective Ca2+ handling, inflammation, and upregulation of remodelling pathways, with the preservation of sarcomeric and mitochondrial integrity.

Standardization of Preclinical PET/CT Imaging to Improve Quantitative Accuracy, Precision, and Reproducibility: A Multicenter Study.

Preclinical PET/CT is a well-established noninvasive imaging tool for studying disease development/progression and the development of novel radiotracers and pharmaceuticals for clinical applications. Despite this pivotal role, standardization of preclinical PET/CT protocols, including CT absorbed dose guidelines, is essentially nonexistent. This study (1) quantitatively assesses the variability of current preclinical PET/CT acquisition and reconstruction protocols routinely used across multiple centers and scanners; and (2) proposes acquisition and reconstruction PET/CT protocols for standardization of multicenter data, optimized for routine scanning in the preclinical PET/CT laboratory. Methods: Five different commercial preclinical PET/CT scanners in Europe and the United States were enrolled. Seven different PET/CT phantoms were used for evaluating biases on default/general scanner protocols, followed by developing standardized protocols. PET, CT, and absorbed dose biases were assessed. Results: Site default CT protocols were the following: greatest extracted Hounsfield units (HU) were 133 HU for water and -967 HU for air; significant differences in all tissue equivalent material (TEM) groups were measured. The average CT absorbed doses for mouse and rat were 72 mGy and 40 mGy, respectively. Standardized CT protocol were the following: greatest extracted HU were -77 HU for water and -990 HU for air; TEM precision improved with a reduction in variability for each tissue group. The average CT absorbed dose for mouse and rat decreased to 37 mGy and 24 mGy, respectively. Site default PET protocols were the following: uniformity was substandard in one scanner, recovery coefficients (RCs) were either over- or underestimated (maximum of 43%), standard uptake values (SUVs) were biased by a maximum of 44%. Standardized PET protocols were the following: scanner with substandard uniformity improved by 36%, RC variability decreased by 13% points, and SUV accuracy improved to 10%. Conclusion: Data revealed important quantitative biases in preclinical PET/CT and absorbed doses with default protocols. Standardized protocols showed improvements in measured PET/CT accuracy and precision with reduced CT absorbed dose across sites. Adhering to standardized protocols generates reproducible and consistent preclinical imaging datasets, thus augmenting translation of research findings to the clinic.

Design, synthesis, in vitro characterization and preliminary imaging studies on fluorinated bile acid derivatives as PET tracers to study hepatic transporters.

With the aim of identifying a fluorinated bile acid derivative that could be used as [18F]-labeled Positron Emission Tomography (PET) tracer for imaging the in vivo functioning of liver transporter proteins, and particularly of OATP1B1, three fluorinated bile acid triazole derivatives of cholic, deoxycholic and lithocholic acid (CATD, DCATD and LCATD 4a-c, respectively) were synthesized and labeled with tritium. In vitro transport properties were studied with cell-based assays to identify the best substrate for OATP1B1. In addition, the lead compound, LCATD (4c), was tested as a substrate of other liver uptake transporters OATP1B3, NTCP and efflux transporter BSEP to evaluate its specificity of liver transport. The results suggest that 4c is a good substrate of OATP1B1 and NTCP, whereas it is a poor substrate of OATP1B3. The efflux transporter BSEP also appears to be involved in the excretion of 4c from hepatocytes. The automated radiosynthesis of [18F]-4c was accomplished in a multi-GBq scale and a pilot imaging experiment in a wild type rat was performed after i.v. administration to assess the biodistribution and clearance of the tracer. PET imaging revealed that radioactivity was primarily located in the liver (tmax=75s) and cleared exclusively through the bile, thus allowing to image the hepatobiliary excretion of bile acids in the animal model. These findings suggest that [18F]-LCATD 4c is a promising PET probe for the evaluation of hepatic transporters OATP1B1, NTCP and BSEP activity with potential for studying drug-drug interactions and drug-induced toxicity involving these transporters.

Neuronal human BACE1 knockin induces systemic diabetes in mice.

AIMS: ß-Secretase 1 (BACE1) is a key enzyme in Alzheimer's disease pathogenesis that catalyses the amyloidogenic cleavage of amyloid precursor protein (APP). Recently, global Bace1 deletion was shown to protect against diet-induced obesity and diabetes, suggesting that BACE1 is a potential regulator of glucose homeostasis. Here, we investigated whether increased neuronal BACE1 is sufficient to alter systemic glucose metabolism, using a neuron-specific human BACE1 knockin mouse model (PLB4). METHODS: Glucose homeostasis and adiposity were determined by glucose tolerance tests and EchoMRI, lipid species were measured by quantitative lipidomics, and biochemical and molecular alterations were assessed by western blotting, quantitative PCR and ELISAs. Glucose uptake in the brain and upper body was measured via (18)FDG-PET imaging. RESULTS: Physiological and molecular analyses demonstrated that centrally expressed human BACE1 induced systemic glucose intolerance in mice from 4 months of age onward, alongside a fatty liver phenotype and impaired hepatic glycogen storage. This diabetic phenotype was associated with hypothalamic pathology, i.e. deregulation of the melanocortin system, and advanced endoplasmic reticulum (ER) stress indicated by elevated central C/EBP homologous protein (CHOP) signalling and hyperphosphorylation of its regulator eukaryotic translation initiation factor 2α (eIF2α). In vivo (18)FDG-PET imaging further confirmed brain glucose hypometabolism in these mice; this corresponded with altered neuronal insulin-related signalling, enhanced protein tyrosine phosphatase 1B (PTP1B) and retinol-binding protein 4 (RBP4) levels, along with upregulation of the ribosomal protein and lipid translation machinery. Increased forebrain and plasma lipid accumulation (i.e. ceramides, triacylglycerols, phospholipids) was identified via lipidomics analysis. CONCLUSIONS/INTERPRETATION: Our data reveal that neuronal BACE1 is a key regulator of metabolic homeostasis and provide a potential mechanism for the high prevalence of metabolic disturbance in Alzheimer's disease.

Glucose uptake by the brain on chronic high-protein weight-loss diets with either moderate or low amounts of carbohydrate.

Previous work has shown that hunger and food intake are lower in individuals on high-protein (HP) diets when combined with low carbohydrate (LC) intakes rather than with moderate carbohydrate (MC) intakes and where a more ketogenic state occurs. The aim of the present study was to investigate whether the difference between HPLC and HPMC diets was associated with changes in glucose and ketone body metabolism, particularly within key areas of the brain involved in appetite control. A total of twelve men, mean BMI 34·9 kg/m², took part in a randomised cross-over trial, with two 4-week periods when isoenergetic fixed-intake diets (8·3 MJ/d) were given, with 30% of the energy being given as protein and either (1) a very LC (22 g/d; HPLC) or (2) a MC (182 g/d; HPMC) intake. An ¹8fluoro-deoxyglucose positron emission tomography scan of the brain was conducted at the end of each dietary intervention period, following an overnight fast (n 4) or 4 h after consumption of a test meal (n 8). On the next day, whole-body ketone and glucose metabolism was quantified using [1,2,3,4-¹³C]acetoacetate, [2,4-¹³C]3-hydroxybutyrate and [6,6-²H2]glucose. The composite hunger score was 14% lower (P= 0·013) for the HPLC dietary intervention than for the HPMC diet. Whole-body ketone flux was approximately 4-fold greater for the HPLC dietary intervention than for the HPMC diet (P< 0·001). The 9-fold difference in carbohydrate intakes between the HPLC and HPMC dietary interventions led to a 5% lower supply of glucose to the brain. Despite this, the uptake of glucose by the fifty-four regions of the brain analysed remained similar for the two dietary interventions. In conclusion, differences in the composite hunger score observed for the two dietary interventions are not associated with the use of alternative fuels by the brain.

Mapping changes in mouse brain metabolism with PET/CT.

UNLABELLED: Because preclinical imaging offers challenges and opportunities, we set out to investigate and optimize image processing techniques to measure changes in mouse brain metabolism with preclinical (18)F-FDG PET/CT. In particular, we considered the effects of scan length, image registration methods, image quantification methods, and smoothing during statistical parametric mapping (SPM). METHODS: A cohort of 12 wild-type mice was scanned on 3 occasions at an average age of 6, 10, and 14 mo. The impact of the scan length (10, 20, 30, or 40 min) was determined, and images were registered to a template based on either the PET or the CT image. Analysis was performed using SPM or predefined regions of interest (ROIs). Data were expressed in units of standardized uptake value or percentage injected dose per gram of tissue for absolute values; images were also normalized to whole-brain activity. RESULTS: Significant variability was observed in global brain (18)F-FDG uptake between animals. Normalizing images to the whole-brain activity significantly improved detection of regional changes in metabolism. Registration based on CT images provided greater power for detecting changes in metabolism than did registration based on PET images only. In line with an age-dependent decline in brain metabolism, both ROI and SPM-based methods revealed significant changes; SPM, however, was generally more sensitive and region-specific. For example, small clusters of voxels within an ROI differed significantly between ages even in the absence of significant changes in average uptake over the whole region. Finally, and contrary to expectation, we found little benefit from longer scan times yet a marked reduction in uptake from 45 to 85 min after injection and regional variations in the rate of washout. CONCLUSION: With appropriate processing, preclinical PET/CT provides a highly sensitive method for reliable identification of metabolic changes in the mouse brain.