Combining Dynamic Contrast-Enhanced Magnetic Resonance Imaging and Apparent Diffusion Coefficient Maps for a Radiomics Nomogram to Predict Pathological Complete Response to Neoadjuvant Chemotherapy in Breast Cancer Patients.

OBJECTIVE: The objective of this study was to develop a nomogrom for prediction of pathological complete response (PCR) to neoadjuvant chemotherapy in breast cancer patients. METHODS: Ninety-one patients were analyzed. A total of 396 radiomics features were extracted from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and apparent diffusion coefficient (ADC) maps. The least absolute shrinkage and selection operator was selected for data dimension reduction to build a radiomics signature. Finally, the nomogram was built to predict PCR. RESULTS: The radiomics signature of the model that combined DCE-MRI and ADC maps showed a higher performance (area under the receiver operating characteristic curve [AUC], 0.848) than the models with DCE-MRI (AUC, 0.750) or ADC maps (AUC, 0.785) alone in the training set. The proposed model, which included combined radiomics signature, estrogen receptor, and progesterone receptor, yielded a maximum AUC of 0.837 in the testing set. CONCLUSIONS: The combined radiomics features from DCE-MRI and ADC data may serve as potential predictor markers for predicting PCR. The nomogram could be used as a quantitative tool to predict PCR.

Interspecies Variation in NCMN-O-Demethylation in Liver Microsomes from Various Species.

NCMN (N-(3-carboxy propyl)-4-methoxy-1,8-naphthalimide), a newly developed ratiometric two-photon fluorescent probe for human Cytochrome P450 1A (CYP1A), shows the best combination of specificity and reactivity for real-time detection of the enzymatic activities of CYP1A in complex biological systems. This study aimed to investigate the interspecies variation in NCMN-O-demethylation in commercially available liver microsomes from human, mouse, rat, beagle dog, minipig and cynomolgus monkey. Metabolite profiling demonstrated that NCMN could be O-demethylated in liver microsomes from all species but the reaction rate varied considerably. CYP1A was the major isoform involved in NCMN-O-demethylation in all examined liver microsomes based on the chemical inhibition assays. Furafylline, a specific inhibitor of mammalian CYP1A, displayed differential inhibitory effects on NCMN-O-demethylation in all tested species. Kinetic analyses demonstrated that NCMN-O-demethylation in liver microsomes form rat, minipig and cynomolgus monkey followed biphasic kinetics, while in liver microsomes form human, mouse and beagle dog obeyed Michaelis-Menten kinetics, the kinetic parameters from various species are much varied, while NCMN-O-demethylation in MLM exhibited the highest similarity of specificity, kinetic behavior and intrinsic clearance as that in HLM. These findings will be very helpful for the rational use of NCMN as a practical tool to decipher the functions of mammalian CYP1A or to study CYP1A associated drug-drug interactions in vivo.

Development of a CT image analysis-based scoring system to differentiate gastric schwannomas from gastrointestinal stromal tumors.

Purpose: To develop a point-based scoring system (PSS) based on contrast-enhanced computed tomography (CT) qualitative and quantitative features to differentiate gastric schwannomas (GSs) from gastrointestinal stromal tumors (GISTs). Methods: This retrospective study included 51 consecutive GS patients and 147 GIST patients. Clinical and CT features of the tumors were collected and compared. Univariate and multivariate logistic regression analyses using the stepwise forward method were used to determine the risk factors for GSs and create a PSS. Area under the receiver operating characteristic curve (AUC) analysis was performed to evaluate the diagnostic efficiency of PSS. Results: The CT attenuation value of tumors in venous phase images, tumor-to-spleen ratio in venous phase images, tumor location, growth pattern, and tumor surface ulceration were identified as predictors for GSs and were assigned scores based on the PSS. Within the PSS, GS prediction probability ranged from 0.60% to 100% and increased as the total risk scores increased. The AUC of PSS in differentiating GSs from GISTs was 0.915 (95% CI: 0.874-0.957) with a total cutoff score of 3.0, accuracy of 0.848, sensitivity of 0.843, and specificity of 0.850. Conclusions: The PSS of both qualitative and quantitative CT features can provide an easy tool for radiologists to successfully differentiate GS from GIST prior to surgery.

Radiomics analysis of contrast-enhanced CT predicts lymphovascular invasion and disease outcome in gastric cancer: a preliminary study.

BACKGROUND: To determine whether radiomics features based on contrast-enhanced CT (CECT) can preoperatively predict lymphovascular invasion (LVI) and clinical outcome in gastric cancer (GC) patients. METHODS: In total, 160 surgically resected patients were retrospectively analyzed, and seven predictive models were constructed. Three radiomics predictive models were built from radiomics features based on arterial (A), venous (V) and combination of two phase (A + V) images. Then, three Radscores (A-Radscore, V-Radscore and A + V-Radscore) were obtained. Another four predictive models were constructed by the three Radscores and clinical risk factors through multivariate logistic regression. A nomogram was developed to predict LVI by incorporating A + V-Radscore and clinical risk factors. Kaplan-Meier curve and log-rank test were utilized to analyze the outcome of LVI. RESULTS: Radiomics related to tumor size and intratumoral inhomogeneity were the top-ranked LVI predicting features. The related Radscores showed significant differences according to LVI status (P < 0.01). Univariate logistic analysis identified three clinical features (T stage, N stage and AJCC stage) and three Radscores as LVI predictive factors. The Clinical-Radscore (namely, A + V + C) model that used all these factors showed a higher performance (AUC = 0.856) than the clinical (namely, C, including T stage, N stage and AJCC stage) model (AUC = 0.810) and the A + V-Radscore model (AUC = 0.795) in the train cohort. For patients without LVI and with LVI, the median progression-free survival (PFS) was 11.5 and 8.0 months (P < 0.001),and the median OS was 20.2 and 17.0 months (P = 0.3), respectively. In the Clinical-Radscore-predicted LVI absent and LVI present groups, the median PFS was 11.0 and 8.0 months (P = 0.03), and the median OS was 20.0 and 18.0 months (P = 0.05), respectively. N stage, LVI status and Clinical-Radscore-predicted LVI status were associated with disease-specific recurrence or mortality. CONCLUSIONS: Radiomics features based on CECT may serve as potential markers to successfully predict LVI and PFS, but no evidence was found that these features were related to OS. Considering that it is a single central study, multi-center validation studies will be required in the future to verify its clinical feasibility.

[Expression of CYP3A29 mRNA in Chinese experimental miniature pig's livers quantitated with real-time reverse transcription polymerase chain reaction].

CYP3A29 is the most important key enzyme for drug metabolism in pig's liver. Research of the characters of CYP3A29 mRNA expression in Chinese experimental miniature pig's livers is significant for evaluating it whether suitable for experimental model for drug metabolism mediated by human CYP3A4 enzyme. In this study, the levels of CYP3A29 mRNA expression in livers of Bama miniature pigs, Guizhou miniature pigs and Rongchang pigs were studied by TaqMan-mediated quantitative RT-PCR. Results indicated that the CYP3A29 mRNA expression levels in livers of these species were close to literatures of human. Levels of CYP3A29 mRNA expression were similar among livers of Bama miniature pigs, Guizhou miniature pigs and Rongchang pigs, but interindividual variations were quite large. It was suggested that Bama miniature pigs and Guizhou miniature pigs were both feasible for experimental animal model for evaluating drug metabolism in some degree.

Comparative metabolism of DDAO benzoate in liver microsomes from various species.

DDAB (6,8-dichloro-9,9-dimethyl-7-oxo-7,9-dihydroacridin-2-yl benzoate) is a newly developed near-infrared fluorescent probe for human carboxylesterase 2 (hCE2), exhibiting high specificity and good reactivity for real-time monitoring the enzymatic activities of hCE2 in complex biological systems. In order to explore the applicability of DDAB in commonly used animal species, the interspecies difference in DDAB hydrolysis was carefully investigated by using liver microsomes from human and five experimental animals including mouse, rat, dog, minipig and monkey. Metabolite profiling demonstrated that DDAB hydrolysis could be catalyzed by all tested liver microsomes from different animals but displayed significant difference in the reaction rate. Chemical inhibition assays demonstrated that carboxylesterases (CEs) were the major enzymes involved in DDAB hydrolysis in all tested liver microsomes, indicating that DDAB was a selective substrate of CEs in a variety of mammals. However, the differential effects of loperamide (LPA, a specific inhibitor against hCE2) on DDAB hydrolysis among various species were observed. The apparent kinetic parameters and the maximum intrinsic clearances (CLmax) for DDAB hydrolysis in liver microsomes from different animals were determined, and the order of CLmax values for the formation of DDAO was CyLM>MLM≈PLM>RLM>HLM≈DLM. These findings were helpful for the rational use of DDAB as an imaging tool for CE2 in different mammals, as well as for translational researches on the function of mammalian CEs and CE2-associated drug-drug interactions.

Constitutive expression of CYP3A mRNA in Bama miniature pig tissues.

The pig, particularly the miniature pig (minipig), is becoming an important animal model due to its physiological and anatomical similarities to humans. Bama minipigs (Sus scrofa domestica), a Chinese natural minipig breed, are a promising animal model. The pig is a useful model for drug metabolism and pharmacological studies due to the similar properties of cytochrome P450 (CYP)3A between pigs and humans. However, a detailed investigation regarding the abundance and expression of CYP3A in porcine tissues, particularly in minipig tissues, has not been performed. The present study investigated constitutive expression of CYP3A mRNA in Bama minipig tissues using real-time reverse transcriptase-polymerase chain reaction (RT-PCR). We found that the expression of CYP3A mRNAs relative to the endogenous control, ß-actin (ACTB), was lower than when compared to the expression of the endogenous control, TATA-binding protein (TBP), except for the expression of CYP3A29 mRNA in the spleen, adrenal gland, testis, and epididymis, and CYP3A46 in the spleen. Expression levels of all three CYP3As were highest in the liver amongst all the tissues tested, and the order of relative mRNA expression level of the three CYP3As was different between other tissues. We also analyzed the relative expression of the three CYP3A mRNAs in each tissue. CYP3A46 had the highest expression in all extrahepatic tissues, whereas CYP3A22 had the highest expression in the liver, and CYP3A29 had the lowest expression in all tissues except in the duodenum, where it had higher expression than CYP3A22. Because CYP3A22 and CYP3A46 were the most highly expressed isoforms, it could follow that they are probably important functional CYP3A genes for Bama miniature pig. Our present work will broaden the understanding of the physiological functions of CYP3As in the Bama minipig and promote its application in drug metabolism and pharmacological studies. Our results also indicate that the breed, age, and castration status of the pig should be considered when using the pig as an animal model in pharmacological applications.