Hepatic ketone body regulation of renal gluconeogenesis.

OBJECTIVES: During fasting, liver pivotally regulates blood glucose levels through glycogenolysis and gluconeogenesis. Kidney also produces glucose through gluconeogenesis. Gluconeogenic genes are transactivated by fasting, but their expression patterns are chronologically different between the two organs. We find that renal gluconeogenic gene expressions are positively correlated with the blood ß-hydroxybutyrate concentration. Thus, we herein aim to investigate the regulatory mechanism and its physiological implications. METHODS: Gluconeogenic gene expressions in liver and kidney were examined in hyperketogenic mice such as high-fat diet (HFD)-fed and ketogenic diet-fed mice, and in hypoketogenic PPARα knockout (PPARα-/-) mice. Renal gluconeogenesis was evaluated by rise in glycemia after glutamine loading in vivo. Functional roles of ß-hydroxybutyrate in the regulation of renal gluconeogenesis were investigated by metabolome analysis and RNA-seq analysis of proximal tubule cells. RESULTS: Renal gluconeogenic genes were transactivated concurrently with blood ß-hydroxybutyrate uprise under ketogenic states, but the increase was blunted in hypoketogenic PPARα-/- mice. Administration of 1,3-butandiol, a ketone diester, transactivated renal gluconeogenic gene expression in fasted PPARα-/- mice. In addition, HFD-fed mice showed fasting hyperglycemia along with upregulated renal gluconeogenic gene expression, which was blunted in HFD-fed PPARα-/- mice. In vitro experiments and metabolome analysis in renal tubular cells showed that ß-hydroxybutyrate directly promotes glucose and NH3 production through transactivating gluconeogenic genes. In addition, RNA-seq analysis revealed that ß-hydroxybutyrate-induced transactivation of Pck1 was mediated by C/EBPß. CONCLUSIONS: Our findings demonstrate that ß-hydroxybutyrate mediates hepato-renal interaction to maintain homeostatic regulation of blood glucose and systemic acid-base balance through renal gluconeogenesis regulation.

Predicting the in vivo developmental toxicity of fenarimol from in vitro toxicity data using PBTK modelling-facilitated reverse dosimetry approach.

In vitro methods are widely used in modern toxicological testing; however, the data cannot be directly employed for risk assessment. In vivo toxicity of chemicals can be predicted from in vitro data using physiologically based toxicokinetic (PBTK) modelling-facilitated reverse dosimetry (PBTK-RD). In this study, a minimal-PBTK model was constructed to predict the in-vivo kinetic profile of fenarimol (FNL) in rats and humans. The model was verified by comparing the observed and predicted pharmacokinetics of FNL for rats (calibrator) and further applied to humans. Using the PBTK-RD approach, the reported in vitro developmental toxicity data for FNL was translated to in vivo dose-response data to predict the assay equivalent oral dose in rats and humans. The predicted assay equivalent rat oral dose (36.46 mg/kg) was comparable to the literature reported in vivo BMD10 value (22.8 mg/kg). The model was also employed to derive the chemical-specific adjustment factor (CSAF) for interspecies toxicokinetics variability of FNL. Further, Monte Carlo simulations were performed to predict the population variability in the plasma concentration of FNL and to derive CSAF for intersubject human kinetic differences. The comparison of CSAF values for interspecies and intersubject toxicokinetic variability with their respective default values revealed that the applied uncertainty factors were adequately protective.

Data-driven disease progression model of Parkinson's disease and effect of sex and genetic variants.

As Parkinson's disease (PD) progresses, there are multiple biomarker changes, and sex and genetic variants may influence the rate of progression. Data-driven, long-term disease progression model analysis may provide precise knowledge of the relationships between these risk factors and progression and would allow for the selection of appropriate diagnosis and treatment according to disease progression. To construct a long-term disease progression model of PD based on multiple biomarkers and evaluate the effects of sex and leucine-rich repeat kinase 2 (LRRK2) mutations, a technique derived from the nonlinear mixed-effects model (Statistical Restoration of Fragmented Time course [SReFT]) was applied to datasets of patients provided by the Parkinson's Progression Markers Initiative. Four biomarkers, including the Unified PD Rating Scale, were used, and a covariate analysis was performed to investigate the effects of sex and LRRK2-related mutations. A model of disease progression over ~30 years was successfully developed using patient data with a median of 6 years. Covariate analysis suggested that female sex and LRRK2 G2019S mutations were associated with 21.6% and 25.4% significantly slower progression, respectively. LRRK2 rs76904798 mutation also tended to delay disease progression by 10.4% but the difference was not significant. In conclusion, a long-term PD progression model was successfully constructed using SReFT from relatively short-term individual patient observations and depicted nonlinear changes in relevant biomarkers and their covariates, including sex and genetic variants.

Exercise training outcomes in patients with chronic heart failure with reduced ejection fraction depend on patient background.

Background: The aim of this study was to identify significant factors affecting the effectiveness of exercise training using information of the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) study. Methods: Background factors influencing the effect of exercise training were comprehensively surveyed for 2,130 patients by multivariable Cox regression analysis with the stepwise variable selection, and only significant factors were selected that were statistically distinguished from dummy noise factors using the Boruta method. Results: The analysis suggested that the use of beta-blockers, pulse pressure, hemoglobin level, electrocardiography findings, body mass index, and history of stroke at baseline potentially influenced the exercise effect on all-cause death (AD). Therefore, a hypothetical score to estimate the effect of exercise training was constructed based on the analysis. The analysis suggested that the score is useful in identifying patients for whom exercise training may be significantly effective in reducing all-caused death and hospitalization (ADH) as well as AD. Such a subpopulation accounted for approximately 40% of the overall study population. On the other hand, in approximately 45% of patients, the effect of exercise was unclear on either AD or ADH. In the remaining 15% of patients, it was estimated that the effect of exercise might be unclear for ADH and potentially rather increase AD. Conclusions: This study is the first analysis to comprehensively evaluate the effects of various factors on the outcome of exercise training in chronic heart failure, underscoring the need to carefully consider the patient's background before recommending exercise training. However, it should be noted that exercise training can improve many outcomes in a wide variety of diseases. Therefore, given the limitations involved in post-hoc analyses of a single clinical trial, the characteristics of patients to whom the results of this analysis can be applied need attention, and also further research is necessary on the relationship between the degree of exercise and the outcomes. A new clinical trial would be needed to confirm the factors detected and the appropriateness of the score.

Involvement of multiple cytochrome P450 isoenzymes in drug interactions between ritonavir and direct oral anticoagulants.

Herein, we aimed to determine the significance of drug interactions (DIs) between ritonavir and direct oral anticoagulants (DOACs) and identify the involved cytochrome P450 (CYP) isoenzymes. Using an in vitro cocktail method with human liver microsomes (HLM), we observed that ritonavir strongly inhibited CYPs in the following order: CYP3A, CYP2C8, CYP2D6, CYP2C9, CYP2C19, CYP2B6, and CYP2J2 (IC50: 0.023-6.79 µM). The degree of CYP2J2 inhibition was inconclusive, given the substantial discrepancy between the HLM and human expression system. Selective inhibition of CYP3A decreased the O-demethylation of apixaban by only 13.4%, and the involvement of multiple CYP isoenzymes was suggested, all of which were inhibited by ritonavir. Multiple CYP isoenzymes contributed also to the metabolism of rivaroxaban. Replacement of the incubation medium with phosphate buffer instead of HEPES enhanced apixaban hydroxylation. On surveying the FDA Adverse Event Reporting System, we detected that the signal of the proportional reporting ratio of "death" and found increase for "hemoglobin decreased" (12.5-fold) and "procedural hemorrhage" (201.9-fold) on administering apixaban with ritonavir; these were far less significant for other CYP3A inhibitors. Overall, these findings suggest that co-administration of ritonavir-boosted drugs with DOACs may induce serious DIs owing to the simultaneous inhibition of multiple CYP isoenzymes.

BRCA2 Frameshift Mutation in de novo Small-Cell Neuroendocrine Carcinoma of the Prostate: A Case Report.

A 66-year-old male was diagnosed with cT4N0M1b small-cell neuroendocrine carcinoma of the prostate. Four months after the administration of combined androgen blockade, multiple novel metastatic regions in the lung and liver and progression of bone metastasis were observed. The patient was referred to our hospital because of biochemical and radiographic progression after four cycles of docetaxel as a first-line therapy for castration-resistant prostate cancer. Transurethral resection of the prostate and hepatic biopsy revealed small-cell carcinoma with positive expression of neuroendocrine markers. The FoundationOne CDx next-generation sequencing test revealed several pathogenic variants, including BRCA2 (W1692fs*3), KEAP1 (R320W), and TP53 (C2385) mutation. After four cycles of chemotherapy with carboplatin plus etoposide (CE), the metastatic regions regressed markedly. The prostate-specific antigen (PSA) and neuron-specific enolase (NSE) level decreased by 96.9% and 91.6%, respectively. However, 2 months after the completion of four cycles of CE, elevation of tumor marker levels, and re-growth of the metastatic regions were observed. Although olaparib, a poly (ADP-ribose) polymerase inhibitor (PARPi), achieved a 45.2% decrease in NSE, the patient rejected to continue therapy because of G2 adverse events. After receiving an additional two cycles of CE and one cycle of cabazitaxel, the patient died because of cancer progression 24 months after the initial treatment for prostate cancer. Here, we present a case of BRCA2-altered small-cell neuroendocrine prostate cancer treated with both platinum-containing chemotherapy and PARPi. Both therapies achieved an initial response; however, durable responses were not obtained. Additional discussion regarding the optimal treatment strategy for BRCA-altered small-cell/neuroendocrine prostate cancer is required.

The Current Trend of Radiation Therapy for Patients with Localized Prostate Cancer.

A recent approach to radiotherapy for prostate cancer is the administration of high doses of radiation to the prostate while minimizing the risk of side effects. Thus, image-guided radiotherapy utilizes advanced imaging techniques and is a feasible strategy for increasing the radiation dose. New radioactive particles are another approach to achieving high doses and safe procedures. Prostate brachytherapy is currently considered as a combination therapy. Spacers are useful to protect adjacent organs, specifically the rectum, from excessive radiation exposure.

VGLL3 confers slow-twitch muscle differentiation via PGC-1α expression in C2C12 myocytes.

Vestigial-like family member 3 (VGLL3) is a cofactor for the TEA-domain transcription factor (TEAD) family. Although VGLL3 influences myogenic differentiation, its involvement in slow- and fast-twitch fiber specification remains unknown. In this study, we established a cell line stably overexpressing VGLL3 and analyzed effects of VGLL3 on the myogenic differentiation of murine myoblast C2C12 cells. We found that VGLL3 expression promotes slow-twitch muscle differentiation. Mechanistically, VGLL3 expression induced the expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), a master transcriptional regulator of slow-twitch muscle development. We also found that VGLL3 proteins are degraded by the proteasome, which causes switching of TEAD cofactors from VGLL3 to Yes-associated protein (YAP) and transcriptional coactivator with a PDZ-binding motif (TAZ). These results suggest that the balance between the two kinds of TEAD cofactors VGLL3 and YAP/TAZ controls muscle fiber-type specification.

Model-based meta-analysis of ethnic differences and their variabilities in clearance of oral drugs classified by clearance mechanism.

In this study, the ethnic ratios (ERs) of oral clearance between Japanese and Western populations were subjected to model-based meta-analysis (MBMA) for 81 drugs evaluated in 673 clinical studies. The drugs were classified into eight groups according to the clearance mechanism, and the ER for each group was inferred together with interindividual variability (IIV), interstudy variability (ISV), and inter-drug variability within a group (IDV) using the Markov chain Monte Carlo (MCMC) method. The ER, IIV, ISV, and IDV were dependent on the clearance mechanism, and, except for particular groups such as drugs metabolized by polymorphic enzymes or their clearance mechanism is not confirmative, the ethnic difference was found to be generally small. The IIV was well-matched across ethnicities, and the ISV was approximately half of the IIV as the coefficient of variation. To adequately assess ethnic differences in oral clearance without false detections, phase I studies should be designed with full consideration of the mechanism of clearance. This study suggests that the methodology of classifying drugs based on the mechanism that causes ethnic differences and performing MBMA with statistical techniques such as MCMC analysis is helpful for a rational understanding of ethnic differences and for strategic drug development.

Ultra High-plex Spatial Proteogenomic Investigation of Giant Cell Glioblastoma Multiforme Immune Infiltrates Reveals Distinct Protein and RNA Expression Profiles.

A deeper understanding of complex biological processes, including tumor development and immune response, requires ultra high-plex, spatial interrogation of multiple "omes". Here we present the development and implementation of a novel spatial proteogenomic (SPG) assay on the GeoMx Digital Spatial Profiler platform with next-generation sequencing readout that enables ultra high-plex digital quantitation of proteins (>100-plex) and RNA (whole transcriptome, >18,000-plex) from a single formalin-fixed paraffin-embedded (FFPE) sample. This study highlighted the high concordance, R > 0.85 and <15% change in sensitivity between the SPG assay and the single-analyte assays on various cell lines and tissues from human and mouse. Furthermore, we demonstrate that the SPG assay was reproducible across multiple users. When used in conjunction with advanced cellular neighborhood segmentation, distinct immune or tumor RNA and protein targets were spatially resolved within individual cell subpopulations in human colorectal cancer and non-small cell lung cancer. We used the SPG assay to interrogate 23 different glioblastoma multiforme (GBM) samples across four pathologies. The study revealed distinct clustering of both RNA and protein based on pathology and anatomic location. The in-depth investigation of giant cell glioblastoma multiforme (gcGBM) revealed distinct protein and RNA expression profiles compared with that of the more common GBM. More importantly, the use of spatial proteogenomics allowed simultaneous interrogation of critical protein posttranslational modifications alongside whole transcriptomic profiles within the same distinct cellular neighborhoods. Significance: We describe ultra high-plex spatial proteogenomics; profiling whole transcriptome and high-plex proteomics on a single FFPE tissue section with spatial resolution. Investigation of gcGBM versus GBM revealed distinct protein and RNA expression profiles.

In vitro-based prediction of human plasma concentrations of food-related compounds.

Efforts have been made to replace animal experiments in safety evaluations, including in vitro-based predictions of human internal exposures, such as predicting peak plasma concentration (Cmax) values for xenobiotics and comparing these values with in vitro-based toxicity endpoints. Herein, the authors predicted the Cmax values of food-related compounds in humans based on existing and novel in vitro techniques. In this study, 20 food-related compounds, which have been previously reported in human pharmacokinetic or toxicokinetic studies, were evaluated. Human induced pluripotent stem cell-derived small intestinal epithelial cells (hiPSC-SIEC) and Caco-2 cells, HepaRG cells, equilibrium dialysis of human plasma, and LLC-PK1 cell monolayer were used to assess intestinal absorption and availability, hepatic metabolism, unbound plasma fraction, and secretion and reabsorption in renal tubular cells, respectively. After conversion of these parameters into human kinetic parameters, the plasma concentration profiles of these compounds were predicted using in silico methods, and the obtained Cmax values were found to be between 0.017 and 183 times the reported Cmax values. When the in silico-predicted parameters were modified with in vitro data, the predicted Cmax values came within 0.1-10 times the reported values because the metabolic activities of hiPSC-SIECs, such as uridine 5'-diphospho-glucuronosyl transferase, are more similar to those of human primary enterocytes. Thus, combining in vitro test results with the plasma concentration simulations resulted in more accurate and transparent predictions of Cmax values of food-related compounds than those obtained using in silico-derived predictions alone. This method facilitates accurate safety evaluation without the need for animal experiments.

Rapidly Moving Vanishing Tumor of the Lung After Open-heart Surgery.

Vanishing tumor of the lung, also known as phantom tumor, is uncommonly observed in congestive heart failure. We report a case of a vanishing tumor that rapidly disappeared and reappeared in just a few minutes due to repositioning in a patient after open-heart surgery.

Discontinuation of Intravenous Catecholamine by Oral Ivabradine in a Patient with Decompensated Heart Failure with Low Cardiac Output Syndrome.

Ivabradine has been shown to improve heart failure with sinus tachycardia by reducing the heart rate without affecting left ventricular systolic function or blood pressure. Here we report a case of a catecholaminedependent patient, New York Heart Association (NYHA) class IV, LVEF of 18%, and low cardiac output, who was able to discontinue intravenous catecholamine by oral administration of ivabradine.

Integrated Use of In Vitro and In Vivo Information for Comprehensive Prediction of Drug Interactions Due to Inhibition of Multiple CYP Isoenzymes.

BACKGROUND: Mechanistic static pharmacokinetic (MSPK) models are simple, have fewer data requirements, and have broader applicability; however, they cannot use in vitro information and cannot distinguish the contributions of multiple cytochrome P450 (CYP) isoenzymes and the hepatic and intestinal first-pass effects appropriately. We aimed to establish a new MSPK analysis framework for the comprehensive prediction of drug interactions (DIs) to overcome these disadvantages. METHODS: Drug interactions that occurred by inhibiting CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A in the liver and CYP3A in the intestine were simultaneously analyzed for 59 substrates and 35 inhibitors. As in vivo information, the observed changes in the area under the concentration-time curve (AUC) and elimination half-life (t1/2), hepatic availability, and urinary excretion ratio were used. As in vitro information, the fraction metabolized (fm) and the inhibition constant (Ki) were used. The contribution ratio (CR) and inhibition ratio (IR) for multiple clearance pathways and hypothetical volume (VHyp) were inferred using the Markov Chain Monte Carlo (MCMC) method. RESULT: Using in vivo information from 239 combinations and in vitro 172 fm and 344 Ki values, changes in AUC, and t1/2 were estimated for all 2065 combinations, wherein the AUC was estimated to be more than doubled for 602 combinations. Intake-dependent selective intestinal CYP3A inhibition by grapefruit juice has been suggested. By separating the intestinal contributions, DIs after intravenous dosing were also appropriately inferred. CONCLUSION: This framework would be a powerful tool for the reasonable management of various DIs based on all available in vitro and in vivo information.

A J-shaped Relationship between Sleep Duration and the Risk of Insulin Resistance in a General Japanese Population.

Objective Data on the role of sleep in the risk of insulin resistance (IR) are lacking. We therefore examined the association between sleep duration and IR in a general Japanese population. Methods Data of 1,344 individuals 34 to 89 years old from the Tanushimaru Study were analysed. IR was calculated using the fasting plasma glucose level×fasting insulin level/405, i.e. the homeostasis model assessment of IR (HOMA-IR). IR was defined as a HOMA-IR ≥1.73 based on the diagnostic criteria used in Japan. Information regarding sleep duration was collected via questionnaire. Results The frequencies of IR and metabolic syndrome (MetS) were 36.7% and 26.9%, respectively. A J-shaped relationship between sleep duration and IR was observed, and the same relationship was also shown between sleep duration and MetS; however, the relationship with MetS disappeared after adjusting for age, sex, and other confounding factors. Conclusion A J-shaped relationship was observed between sleep duration and the risks of IR in a general Japanese population.

Significance of Basal Membrane Permeability of Epithelial Cells in Predicting Intestinal Drug Absorption.

Drug absorption from the gastrointestinal tract is often restricted by efflux transport by P-glycoprotein (P-gp) and metabolism by CYP3A4. Both localize in the epithelial cells, and thus, their activities are directly affected by the intracellular drug concentration, which should be regulated by the ratio of permeability between apical (A) and basal (B) membranes. In this study, using Caco-2 cells with forced expression of CYP3A4, we assessed the transcellular permeation of A-to-B and B-to-A directions and the efflux from the preloaded cells to both sides of 12 representative P-gp or CYP3A4 substrate drugs and obtained the parameters for permeabilities, transport, metabolism, and unbound fraction in the enterocytes (fent) using simultaneous and dynamic model analysis. The membrane permeability ratios for B to A (RBA) and fent varied by 8.8-fold and by more than 3000-fold, respectively, among the drugs. The RBA values for digoxin, repaglinide, fexofenadine, and atorvastatin were greater than 1.0 (3.44, 2.39, 2.27, and 1.90, respectively) in the presence of a P-gp inhibitor, thus suggesting the potential involvement of transporters in the B membrane. The Michaelis constant for quinidine for P-gp transport was 0.077 µM for the intracellular unbound concentration. These parameters were used to predict overall intestinal availability (FAFG) by applying an intestinal pharmacokinetic model, advanced translocation model (ATOM), in which permeability of A and B membranes accounted separately. The model predicted changes in the absorption location for P-gp substrates according to its inhibition, and FAFG values of 10 of 12 drugs, including quinidine at varying doses, were explained appropriately. SIGNIFICANCE STATEMENT: Pharmacokinetics has improved predictability by identifying the molecular entities of metabolism and transport and by using mathematical models to appropriately describe drug concentrations at the locations where they act. However, analyses of intestinal absorption so far have not been able to accurately consider the concentrations in the epithelial cells where P-glycoprotein and CYP3A4 exert effects. In this study, the limitation was removed by measuring the apical and basal membrane permeability separately and then analyzing these values using new appropriate models.

Improvement of physical activity significantly reduced serum hepatocyte growth factor levels in a general population: 10 year prospective study.

Hepatocyte growth factor (HGF) is an adipocytokine elevated in obese subjects. We have previously reported that serum HGF levels were significantly associated with insulin resistance or components of the metabolic syndrome. However, it has been unknown how physical activity (PA) affects HGF levels after a long-term follow-up. Our aim was to clarify the association between PA changes and HGF levels as well as cerebro-cardiovascular disease (CVD) development, during a 10 year follow-up period in a Japanese general population. Of 1320 subjects who received a health check-up examination in Tanushimaru town in 1999, 903 subjects (341 males and 562 females), who received the examination both in 1999 and 2009 were enrolled. We evaluated their PA levels by Baecke questionnaire in 1999 and by a simple questionnaire in 2009. We measured the HGF levels by ELISA method in 1999 and 2009. We divided the subjects into four PA groups, stable low PA, increased PA, decreased PA, and stable high PA. Using these questionnaires, we compared their PA and HGF levels after an interval of 10 years. A significant inverse association was found between PA changes and HGF levels at 10 years, after adjustment for age and sex. The HGF levels of the increased PA group were significantly lower than stable low PA (p = 0.038), and the increased PA group showed reduced CVD development compared to the stable low PA group after adjustment for age and sex (p = 0.012). Our data demonstrated that improvement of PA levels was associated with reduced HGF levels and CVD development.

Effect of light source distances and illuminances on the gloss perception of papers.

This study examines the human gloss perception of printing papers at various illuminances and distances from a light source to the object's surface. Gloss is evaluated based on not only the intensity of reflected light but also the sharpness of specular highlights. The apparent spread of the reflected light source image, which is also used for gloss evaluations, depends on the distance between the light source and the object's surface. Unlike physical variation of specular image properties, the perception of gloss may exhibit constancy similar to color perception. Our results reveal that illuminance has a strong effect on gloss perception. We found cases where low-gloss samples looked glossier than high-gloss ones-the gloss reversal phenomenon. These results suggest that there is a case in which gloss constancy may not work in every condition.

High-plex imaging of RNA and proteins at subcellular resolution in fixed tissue by spatial molecular imaging.

Resolving the spatial distribution of RNA and protein in tissues at subcellular resolution is a challenge in the field of spatial biology. We describe spatial molecular imaging, a system that measures RNAs and proteins in intact biological samples at subcellular resolution by performing multiple cycles of nucleic acid hybridization of fluorescent molecular barcodes. We demonstrate that spatial molecular imaging has high sensitivity (one or two copies per cell) and very low error rate (0.0092 false calls per cell) and background (~0.04 counts per cell). The imaging system generates three-dimensional, super-resolution localization of analytes at ~2 million cells per sample. Cell segmentation is morphology based using antibodies, compatible with formalin-fixed, paraffin-embedded samples. We measured multiomic data (980 RNAs and 108 proteins) at subcellular resolution in formalin-fixed, paraffin-embedded tissues (nonsmall cell lung and breast cancer) and identified >18 distinct cell types, ten unique tumor microenvironments and 100 pairwise ligand-receptor interactions. Data on >800,000 single cells and ~260 million transcripts can be accessed at http://nanostring.com/CosMx-dataset .

Real-world outcomes and risk stratification in patients with metastatic castration-sensitive prostate cancer treated with upfront abiraterone acetate and docetaxel.

PURPOSE: We assessed clinical outcomes in patients with metastatic castration-sensitive prostate cancer (mCSPC) treated with two upfront therapies. METHODS: The medical records of 301 patients with mCSPC treated with androgen deprivation therapy plus upfront abiraterone acetate (ABI) or docetaxel (DOC) between 2014 and 2021 were retrospectively reviewed. Propensity score matching (PSM) was performed to compare survival outcomes. Subgroup analyses of risk factors for second progression were conducted. RESULTS: A total of 95 patients received upfront DOC, whereas 206 received upfront ABI. After PSM, the ABI group had a significantly better castration-resistant prostate cancer (CRPC)-free survival than the DOC group [hazard ratio (HR), 0.53; 95% confidence interval (CI), 0.34-0.82]. Second progression-free survival (PFS2) tended to be longer in the ABI group than in the DOC group, but the difference was not statistically significant (HR, 0.64; 95% CI, 0.33-1.22). No significant difference in overall survival (OS) was found between the two groups (HR, 0.92; 95% CI, 0.42-2.03). In the subgroup analysis, upfront ABI had significantly favorable PFS2 in patients aged ≥ 75 years compared with upfront DOC (p = 0.038). Four risk factors for second progression (primary Gleason 5, liver metastasis, high serum alkaline phosphatase level, and high serum lactate dehydrogenase level) successfully stratified patients into three risk groups. CONCLUSIONS: Upfront ABI provided better CRPC-free survival than upfront DOC; however, no significant differences in PFS2 or OS were observed between the two groups. Personalized management based on prognostic risk factors may benefit patients with mCSPC treated with upfront intensified therapies.