Multicenter propensity score-matched analysis to compare perioperative morbidity after laparoscopic or robotic complex hepatectomy for solitary hepatocellular carcinoma.

BACKGROUND: Postoperative complications are vital factors affecting the prognosis of patients with hepatocellular carcinoma (HCC), especially for complex hepatectomy. The present study aimed to compare perioperative complications between laparoscopic and robotic complex hepatectomy (LCH vs. RCH). METHODS: Patients with solitary HCC after complex hepatectomy were collected from a multicenter database. Propensity score-matched (PSM) analysis was adopted to control confounding bias. Multivariable analysis was performed to determine the prognostic factors. RESULTS: 436 patients were included. After PSM, 43 patients were included in both the LCH and RCH groups. The results showed that compared to LCH, RCH had lower rates of blood loss and transfusion, and lower postoperative 30-day and major morbidity, and post-hepatectomy liver failure (PHLF) (all P < 0.05). Additionally, the length of hospital stay was shorter in the RCH group (P = 0.026). Multivariable analysis showed RCH is an independent protective factor for reducing the 30-day morbidity, major morbidity and PHLF. CONCLUSION: RCH has advantages over LCH in the minimally invasive treatment of complex HCC, as it can reduce the incidence of postoperative morbidity. Therefore, RCH should be considered for patients with HCC who require complex hepatectomy.

Prognostic value of the Naples prognostic score in patients with intrahepatic cholangiocarcinoma after hepatectomy.

BACKGROUND: The Naples Prognostic Score (NPS), integrating inflammatory and nutritional biomarkers, has been reported to be associated with the prognosis of various malignancies, but there is no report on intrahepatic cholangiocarcinoma (ICC). This study aimed to explore the prognostic value of NPS in patients with ICC. METHODS: Patients with ICC after hepatectomy were collected, and divided into three groups. The prognosis factors were determined by Cox regression analysis. Predictive efficacy was evaluated by the time-dependent receiver operating characteristic (ROC) curves. RESULTS: A total of 174 patients were included (Group 1: 33 (19.0%) patients; Group 2: 83 (47.7%) patients; and Group 3: 58 (33.3%) patients). The baseline characteristics showed the higher the NPS, the higher the proportion of patients with cirrhosis and Child-Pugh B, and more advanced tumors. The Kaplan-Meier curves reflect higher NPS were associated with poor survival. Multivariable analysis showed NPS was an independent risk factor of overall survival (NPS group 2 vs. 1: HR = 1.671, 95% CI: 1.022-3.027, p = 0.009; NPS group 3 vs. 1: HR = 2.208, 95% CI: 1.259-4.780, p = 0.007) and recurrence-free survival (NPS group 2 vs. 1: HR = 1.506, 95% CI: 1.184-3.498, p = 0.010; NPS group 3 vs. 1: HR = 2.141, 95% CI: 2.519-4.087, P = 0.001). The time ROC indicated NPS was superior to other models in predicting prognosis. CONCLUSIONS: NPS is a simple and effective tool for predicting the long-term survival of patients with ICC after hepatectomy. Patients with high NPS require close follow-up, and improving NPS may prolong the survival time.

Survival benefit from adjuvant TACE combined with Lenvatinib for patients with hepatocellular carcinoma and microvascular invasion after curative hepatectomy.

BACKGROUND AND AIMS: The prognosis of patients with hepatocellular carcinoma (HCC) undergoing hepatectomy is unsatisfactory, especially for those with microvascular invasion (MVI). This study aimed to determine the impact of adjuvant transcatheter arterial chemoembolization (TACE) and Lenvatinib on the prognosis of patients with HCC and MVI after hepatectomy. METHODS: Patients diagnosed with HCC and MVI were reviewed, and stratified into four groups according to adjuvant TACE and/or Lenvatinib. Multivariate Cox regression analyses are used to determine independent risk factors. RESULTS: 346 patients were included, and divided into four groups (Group I, TACE+ Lenvatinib; Group II, Lenvatinib; Group III, TACE; Group IV, without adjuvant therapy). Multivariable analysis showed that compared to Group IV, Group I had the best effect on improving the overall survival (OS, HR 0.321, 95%CI 0.099-0.406, P = 0.001) and recurrence-free survival (RFS, HR 0.319, 95%CI 0.129-0.372, P = 0.001). Additionally, compared with Group II or Group III, Group I also can significantly improve the OS and RFS. There is no significant difference between Group II and Group III in OS and RFS. CONCLUSION: The combination of TACE and Lenvatinib should be considered for anti-recurrence therapy for patients with HCC and MVI after hepatectomy.

Preoperative Antiviral Therapy and Long-Term Outcomes for Hepatitis B Virus-Related Hepatocellular Carcinoma After Curative Liver Resection: A Multicenter Analysis.

Background & Aims: To examine the association of the history of preoperative antiviral therapy (AVT) with the tumor recurrence and overall survival in HBV-related HCC patients undergoing curative-intent hepatectomy. Methods: Patients who underwent curative-intent hepatectomy for HBV-related HCC between 2014 and 2019 at 4 Chinese hospitals were analyzed. Patients were categorized as having undergone preoperative antiviral therapy (AVT) > 1 year or without antiviral therapy (non-AVT). Patient clinical features, short-term outcomes, overall survival (OS), and time-to-recurrence (TTR) were also compared. Multivariate Cox regression analysis was performed to identify the impact of preoperative AVT on the OS and TTR. Results: Among the 565 patients, 190 (33.6%) underwent continuous AVT > 1 year before surgery. Patients in the non-AVT group were more likely to have worse liver function and more advanced tumor pathological characteristics than those in the AVT group. Postoperative morbidity and mortality rates were comparable between the two groups. Multivariate analyses revealed that a preoperative HBV viral level ≥ 2000 IU/mL was independently associated with poorer TTR (hazard ratio, 1.328; 95% CI, 1.049-1.682) and preoperative AVT was a protective factor for OS (hazard ratio, 0.691; 95% CI, 0.484-0.986). Conclusion: A high preoperative HBV DNA level was an independent risk factor for tumor recurrence. Preoperative AVT > 1 year was associated with better OS and a reduced incidence of tumor recurrence by inhibiting the preoperative level of HBV DNA.

Lysine-Specific Demethylase 1 Inhibitors: A Comprehensive Review Utilizing Computer-Aided Drug Design Technologies.

Lysine-specific demethylase 1 (LSD1/KDM1A) has emerged as a promising therapeutic target for treating various cancers (such as breast cancer, liver cancer, etc.) and other diseases (blood diseases, cardiovascular diseases, etc.), owing to its observed overexpression, thereby presenting significant opportunities in drug development. Since its discovery in 2004, extensive research has been conducted on LSD1 inhibitors, with notable contributions from computational approaches. This review systematically summarizes LSD1 inhibitors investigated through computer-aided drug design (CADD) technologies since 2010, showcasing a diverse range of chemical scaffolds, including phenelzine derivatives, tranylcypromine (abbreviated as TCP or 2-PCPA) derivatives, nitrogen-containing heterocyclic (pyridine, pyrimidine, azole, thieno[3,2-b]pyrrole, indole, quinoline and benzoxazole) derivatives, natural products (including sanguinarine, phenolic compounds and resveratrol derivatives, flavonoids and other natural products) and others (including thiourea compounds, Fenoldopam and Raloxifene, (4-cyanophenyl)glycine derivatives, propargylamine and benzohydrazide derivatives and inhibitors discovered through AI techniques). Computational techniques, such as virtual screening, molecular docking and 3D-QSAR models, have played a pivotal role in elucidating the interactions between these inhibitors and LSD1. Moreover, the integration of cutting-edge technologies such as artificial intelligence holds promise in facilitating the discovery of novel LSD1 inhibitors. The comprehensive insights presented in this review aim to provide valuable information for advancing further research on LSD1 inhibitors.

Extreme temperature events and dementia mortality in Chinese adults: a population-based, case-crossover study.

BACKGROUND: The effect of exposure to extreme temperature events (ETEs) on dementia mortality remains largely unknown. We aimed to quantify the association of ETE exposure with dementia mortality. METHODS: We conducted a population-based, case-crossover study among 57 791 dementia deaths in Jiangsu province, China, during 2015-20. Daily mean temperatures were extracted from a validated grid dataset at each subject's residential address, and grid-specific exposures to heat wave and cold spell were assessed with a combination of their intensity and duration. We applied conditional logistic regression models to investigate cumulative and lag effects for ETE exposures. RESULTS: Exposure to ETE with each of all 24 definitions was associated with an increased odds of dementia mortality, which was higher when exposed to heat wave. Exposure to heat wave (daily mean temperature ≥95th percentile, duration ≥3 days (d); P95_3d) and cold spell (≤5th percentile, duration ≥3 d; P5_3d) was associated with a 75% (95% CI: 61%, 90%) and 30% (19%, 43%) increase in odds of dementia mortality, respectively. Definitions with higher intensity were generally associated with a higher odds of dementia mortality. We estimated that 6.14% of dementia deaths were attributable to exposure to heat wave (P90_2d) and cold spell (P10_2d). No effect modifications were observed by sex or age, except that the association for heat wave was stronger among women. CONCLUSIONS: Exposure to both heat wave and cold spell was associated with an increased odds of dementia mortality. Our findings highlight that reducing individual ETE exposures may be helpful in preventing deaths from dementia, especially among women in summer.

Prediction of T staging in PI-RADS 4-5 prostate cancer by combination of multiparametric MRI and 68Ga-PSMA-11 PET/CT.

BACKGROUND: In this study, we explored the diagnostic performances of multiparametric magnetic resonance imaging (mpMRI), 68 Ga-PSMA-11 PET/CT and combination of 68 Ga-PSMA-11 PET/CT and mpMRI (mpMRI + PET/CT) for extracapsular extension (ECE). Based on the analyses above, we tested the feasibility of using mpMRI + PET/CT results to predict T staging in prostate cancer patients. METHODS: By enrolling 75 patients of prostate cancer with mpMRI and 68 Ga-PSMA-11 PET/CT before radical prostatectomy, we analyzed the detection performances of ECE in mpMRI, 68 Ga-PSMA-11 PET/CT and mpMRI + PET/CT on their lesion images matched with their pathological sample images layer by layer through receiver operating characteristics (ROC) analysis. By inputting the lesion data into Prostate Imaging Reporting and Data System (PI-RADS), we divided the lesions into different PI-RADS scores. The improvement of detecting ECE was analyzed by net reclassification improvement (NRI). The predictors for T staging were evaluated by using univariate and multivariable analysis. The Kappa test was used to evaluate the prediction ability. RESULTS: One hundred three regions of lesion were identified from 75 patients. 50 of 103 regions were positive for ECE. The ECE diagnosis AUC of mpMRI + PET/CT is higher than that of mpMRI alone (ΔAUC = 0.101; 95% CI, 0.0148 to 0.1860; p < 0.05, respectively). Compared to mpMRI, mpMRI + PET/CT has a significant improvement in detecting ECE in PI-RADS 4-5 (NRI 36.1%, p < 0.01). The diagnosis power of mpMRI + PET/CT was an independent predictor for T staging (p < 0.001) in logistic regression analysis. In patients with PI-RADS 4-5 lesions, 40 of 46 (87.0%) patients have correct T staging prediction from mpMRI + PET/CT (κ 0.70, p < 0.01). CONCLUSION: The prediction of T staging in PI-RADS 4-5 prostate cancer patients by mpMRI + PET/CT had a quite good performance.

Yiqi Yangjing recipe stimulates apoptosis while suppressing the energy metabolism via under-expression of PFKFB3 in A549 cells.

Background: Lung cancer is a malignant tumor associated with high morbidity and mortality. Yiqi Yangjing recipe (YYR) is a formula of traditional Chinese medicine (TCM) that is commonly used for the treatment of lung cancer with good clinical efficacy. The specific anti-cancer mechanism of YYR is still unknown. We need to embark on a more in-depth pharmacological study of YYR to determine the complex compound ingredients, which could be promoted in clinical practice to achieve efficacy in prolonging recurrent metastasis of lung cancer. Methods: The cytotoxic effects of YYR on A549 cells were evaluated by Cell Counting Kit-8 (CCK-8) assay. The PFKFB3-under-expressed and overexpressed A549 cell lines were constructed via PFK15 treatment and transfection, respectively. The effects of YYR on PFKFB3 messenger RNA (mRNA) and protein expression were detected by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot. The pro-apoptotic and anti-glycolytic abilities of YYR were measured using flow cytometry assay and hippocampal XF96 extracellular flux analyzer. An in vivo tumorigenicity assay was performed on nude mice to confirm the anti-cancer effects of YYR. Results: YYR has a noticeable cytotoxic activity on A549 cells, with the treatment with both YYR and PFK15 significantly inducing apoptosis. YYR and PFK15 treatment reduced the extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) in A549 cells. Similar to PFK15, YYR can down-regulate PFKFB3 expression, and PFKFB3 overexpression suppressed the apoptosis, which was reversed by YYR. Animal experiments confirmed that YYR was able to inhibit tumor growth, induce tumor cell apoptosis, and down-regulate PFKFB3 in tumor tissues. Conclusions: This study demonstrated that YYR promoted lung cancer cell apoptosis and inhibited energy metabolism by targeting PFKFB3. Furthermore, we believe that YYR may be a suitable supplement or alternative drug for lung cancer treatment.

Naples Prognostic Score is an Independent Prognostic Factor in Patients Undergoing Hepatectomy for Hepatocellular Carcinoma.

Background: Nutritional and inflammatory status has been reported to be associated with the prognosis of hepatocellular carcinoma (HCC), but many studies did not include all biomarkers simultaneously. The present study aimed to determine the impact of Naples prognostic score (NPS) on the long-term survival in patients undergoing hepatectomy for HCC. Methods: Patients with HCC after curative resection were eligible. Then, all patients were stratified into three groups according to the NPS. Clinical features and survival outcomes were compared among the three groups. Independent prognostic factors were determined by COX analysis. The time dependent receiver operating characteristic (ROC) curves were used to compare prognostic performance with other immunonutrition scoring systems. Results: A total of 476 patients were enrolled eventually. Baseline characteristics showed that patients with higher NPS had a higher proportion of poor liver function and advanced tumor features. Accordingly, Kaplan-Meier survival curves showed that patients with higher NPS had a lower rate of overall survival (OS) and recurrence-free survival (RFS). Multivariable COX analysis demonstrated that NPS was an independent risk factor of OS (NPS group 2 vs 1: HR=1.958, 95% CI: 1.038-3.369, p = 0.038; NPS group 3 vs 1: HR=2.608, 95% CI: 1.358-5.008, p=0.004, respectively) and RFS (NPS group 2 vs 1: HR=2.014, 95% CI: 1.299-2-3.124, p=0.002; NPS group 3 vs 1: HR=2.002, 95% CI: 1.262-3.175, p=0.003, respectively). The time-dependent ROC curve showed that NPS was superior to other models in prognostic performance and discriminatory power for long-term survival (median AUC 0.675, 95% CI: 0.586-0.712, P < 0.05). Conclusion: The NPS is a simple tool strongly associated with long-term survival in patients undergoing curative hepatectomy for HCC.

Microplastics in the Lung Tissues Associated with Blood Test Index.

Microplastics (MPs) have received a lot of attention and have been detected in multiple environmental matrices as a new environmental hazard, but studies on human internal exposure to MPs are limited. Here, we collected lung tissue samples from 12 nonsmoking patients to evaluate the characteristics of MPs in human lung tissues using an Agilent 8700 laser infrared imaging spectrometer and scanning electron microscopy. We detected 108 MPs covering 12 types in the lung tissue samples, with a median concentration of 2.19 particles/g. Most of the MPs (88.89%) were sized between 20 to 100 µm. Polypropylene accounts for 34.26% of the MPs in the lung tissues, followed by polyethylene terephthalate (21.30%) and polystyrene (8.33%). Compared with males and those living far from a major road (≥300 m), females and those living near the main road (<300 m) had higher levels of MPs in lung tissues, which positively correlated with platelet (PLT), thrombocytocrit, fibrinogen (FIB), and negatively related with direct bilirubin (DB). These findings help confirm the presence in the respiratory system and suggest the potential sources and health effects of inhaled MPs.

Long-term exposure to ambient fine particulate matter-bound polycyclic aromatic hydrocarbons and cancer mortality: A difference-in-differences approach.

The association of ambient fine particulate matter (PM2.5) exposure with cancer mortality was controversial, which may ascribe to the difference in PM2.5 constituents. Polycyclic aromatic hydrocarbons (PAHs) are carcinogenic constituents in PM2.5, which are suspected to account for PM2.5-induced cancer mortality but are yet to be investigated. We aimed to assess the association between long-term exposure to PM2.5-bound PAHs and cancer mortality and estimate the attributable mortality. A difference-in-differences approach was used to investigate the causal effect of long-term exposure to PM2.5-bound PAHs on cancer mortality. We divided Jiangsu province, China into 53 spatial units and summarized the annual number of cancer deaths in each spatial unit during 2016-2020. Annual population-weighted exposure to PM2.5-bound PAHs of each spatial unit was assessed by an inverse distance weighting method. The association between PM2.5-bound PAHs exposures and cancer mortality was evaluated by controlling spatial differences, temporal trends, PM2.5 mass exposures, temperatures, and socioeconomic status. Records of 793,269 cancer deaths were identified among 84.7 million population. Each ln-unit increase of exposure to total benzo[a]pyrene equivalents (∑BaPeq), total carcinogenic PAHs (∑PAH7c), and total PAHs (∑PAHs) was significantly associated with a 3.21%, 3.48%, and 2.64% increased risk of cancer mortality, respectively; the risk increased monotonically at low-level exposures but attenuated or flattened afterward (all p for nonlinearity <0.05). Similar exposure-response associations were identified for specific PAHs except that the associations for both fluoranthene and benzo[a]anthracene were linear. We estimated that exposure to ∑BaPeq, ∑PAH7c, and ∑PAHs contributed to 5.73%, 8.73%, and 7.33% of cancer deaths, respectively. In conclusion, long-term exposure to PM2.5-bound PAHs was associated with an increased risk of cancer mortality and contributed to substantial cancer deaths. Our findings highlight the importance to prevent deaths from cancer by reducing PM2.5-bound PAHs exposures and the necessity to take into consideration specific constituents in particulate pollution management in future.

Preoperative prediction model for microvascular invasion in HBV-related intrahepatic cholangiocarcinoma.

BACKGROUND AND AIMS: Preoperative prediction of microvascular invasion (MVI) using a noninvasive method remain unresolved, especially in HBV-related in intrahepatic cholangiocarcinoma (ICC). This study aimed to build and validate a preoperative prediction model for MVI in HBV-related ICC. METHODS: Patients with HBV-associated ICC undergoing curative surgical resection were identified. Univariate and multivariate logistic regression analyses were performed to determine the independent risk factors of MVI in the training cohort. Then, a prediction model was built by enrolling the independent risk factors. The predictive performance was validated by receiver operator characteristic curve (ROC) and calibration in the validation cohort. RESULTS: Consecutive 626 patients were identified and randomly divided into the training (418, 67%) and validation (208, 33%) cohorts. Multivariate analysis showed that TBIL, CA19-9, tumor size, tumor number, and preoperative image lymph node metastasis were independently associated with MVI. Then, a model was built by enrolling former fiver risk factors. In the validation cohort, the performance of this model showed good calibration. The area under the curve was 0.874 (95% CI: 0.765-0.894) and 0.729 (95%CI: 0.706-0.751) in the training and validation cohort, respectively. Decision curve analysis showed an obvious net benefit from the model. CONCLUSION: Based on clinical data, an easy model was built for the preoperative prediction of MVI, which can assist clinicians in surgical decision-making and adjuvant therapy.

New Evidence of Microplastics in the Lower Respiratory Tract: Inhalation through Smoking.

To investigate the relation of smoking and microplastic inhalation, we conducted a prospective study combining population-based and experimental work. Bronchoalveolar lavage fluid (BALF) samples from 17 smokers and 15 nonsmokers were collected in Zhuhai City, China. We simulated an active smoking model to explore the contribution of smoking to inhaled microplastics. The characteristics of microplastics in BALF samples and cigarette smoke were determined using laser direct infrared spectroscopy. We compared the differences between smokers and nonsmokers as well as between cigarette smoke and control groups. Microplastics were identified positive in all BALF samples. Smokers had higher concentrations of total microplastics (25.86 particles/g), polyurethane (11.34 particles/g), and silicone (1.15 particles/g) than nonsmokers. In the cigarette smoking simulation model, higher concentrations of total microplastics (9.99 particles/L), polyurethane (4.66 particles/L), and silicone (2.78 particles/L) were present in the cigarette smoke than those in the control group. We confirmed and extended the evidence on the presence of microplastics in the lower respiratory tract. These findings also provide new evidence on the relation between cigarette smoking and microplastic inhalation.

Survival Benefits From Adjuvant Lenvatinib for Patients With Hepatocellular Carcinoma and Microvascular Invasion After Curative Hepatectomy.

Background: The long-term prognosis of patients with hepatocellular carcinoma (HCC) after surgery remains far from satisfactory, especially in patients with microvascular invasion (MVI). This study aimed to evaluate the potential survival benefit from adjuvant lenvatinib for patients with HCC and MVI. Methods: Patients with HCC after curative hepatectomy were reviewed. All patients were divided into 2 groups according to adjuvant lenvatinib. Propensity score matching (PSM) analysis was used to reduce selection bias and make the results more robust. Survival curves are shown by the Kaplan-Meier (K-M) analysis and compared by the Log-rank test. Univariate and multivariate Cox regression analyses were performed to determine the independent risk factors. Results: Of 179 patients enrolled in this study, 43 (24%) patients received adjuvant lenvatinib. After PSM analysis, 31 pairs of patients were enrolled for further analysis. Survival analysis before and after PSM analysis showed a better prognosis in the adjuvant lenvatinib group (all P < .05). The adverse events associated with oral lenvatinib were acceptable. Multivariate Cox regression analysis showed that adjuvant lenvatinib was an independent protective factor for improving overall survival (OS) (hazard ratio [HR] = 0.455, 95% confidence interval [CI] = 0.249-0.831, P = .001) and recurrence-free survival (RFS) (HR = 0.523, 95% CI = 0.308-0.886, P = .016). Conclusions: Postoperative adjuvant targeted therapy can improve the long-term prognosis of patients with HCC and MVI. Therefore, in clinical practice, oral lenvatinib should be recommended for patients with HCC and MVI to decrease tumor recurrence and improve long-term survival.

Chromosome 11q13 amplification correlates with poor response and prognosis to PD-1 blockade in unresectable hepatocellular carcinoma.

Background & aims: Little is known about molecular biomarkers that predict the response and prognosis in unresectable hepatocellular carcinoma (HCC) treated with programmed death (PD)-1 inhibitors. Methods: A total of 62 HCC patients who underwent next-generation sequencing were retrospectively included in our department for this study. Patients with unresectable disease were subjected to systemic therapy. PD-1 inhibitors intervention (PD-1Ab) group and nonPD-1Ab group included 20 and 13 patients, respectively. Primary resistance was defined as initial on-treatment progression or progression with an initial stable disease of less than 6 months. Results: Chromosome 11q13 amplification (Amp11q13) was the most common copy number variation in our cohort. Fifteen (24.2%) patients harbored Amp11q13 in our dataset. Patients with Amp11q13 showed higher level of Des-γ-carboxy-prothrombin (DCP), tumor number and were more prone to be combined with portal vein tumor thrombosis (PVTT). In the PD-1Ab group, the proportion of progressive disease (PD) in patients with Amp11q13 was significantly higher than that in patients with nonAmp11q13 (100% vs 33.3%, P=0.03). In the nonPD-1Ab group, the proportion of PD in patients with Amp11q13 and nonAmp11q13 had no significant difference (0% vs 11.1%, P>0.99). In the PD-1Ab group, the median progression-free survival (PFS) was 1.5 months in Amp11q13 patients vs 16.2 months in non-Amp11q13 patients (HR, 0.05; 95% CI 0.01-0.45; P = 0.0003). No significant difference was observed in the nonPD-1Ab group. Notably, we found that hyperprogressive disease (HPD) might be associated with Amp11q13. The increased density of Foxp3+ Treg cells in HCC patients with Amp11q13 might be one of potential mechanisms. Conclusion: HCC patients with Amp11q13 are less likely to benefit from PD-1 blockade therapies. These findings may help guide the use of immunotherapy for HCC in routine clinical practice.

Discovery of novel, potent, and orally bioavailable HDACs inhibitors with LSD1 inhibitory activity for the treatment of solid tumors.

Histone deacetylases (HDACs) and lysine-specific demethylase 1 (LSD1) are attractive targets for epigenetic cancer therapy. There is an intimate interplay between the two enzymes. HDACs inhibitors have shown synergistic anticancer effects in combination with LSD1 inhibitors in several types of cancer. Herein, we describe the discovery of compound 5e, a highly potent HDACs inhibitor (HDAC1/2/6/8; IC50 = 2.07/4.71/2.40/107 nM) with anti-LSD1 potency (IC50 = 1.34 µM). Compound 5e exhibited marked antiproliferative activity in several cancer cell lines. 5e effectively induced mitochondrial apoptosis with G2/M phase arrest, inhibiting cell migration and invasion in MGC-803 and HCT-116 cancer cells. It also showed good liver microsomal stability and acceptable pharmacokinetic parameters in SD rats. More importantly, orally administered compound 5e demonstrated higher in vivo antitumor efficacy than SAHA in the MGC-803 (TGI = 71.5%) and HCT-116 (TGI = 57.6%) xenograft tumor models accompanied by good tolerability. This study provides a novel lead compound with dual inhibitory activity against HDACs and LSD1 to further develop epigenetic drugs for solid tumor therapy. Further optimization is needed to improve the LSD1 activity to achieve dual inhibitors with balanced potency on LSD1 and HDACs.

Targeted therapy for intractable cancer on the basis of molecular profiles: An open-label, phase II basket trial (Long March Pathway).

Purpose: We evaluated he effects of molecular guided-targeted therapy for intractable cancer. Also, the epidemiology of druggable gene alterations in Chinese population was investigated. Materials and methods: The Long March Pathway (ClinicalTrials.gov identifier: NCT03239015) is a non-randomized, open-label, phase II trial consisting of several basket studies examining the molecular profiles of intractable cancers in the Chinese population. The trial aimed to 1) evaluate the efficacy of targeted therapy for intractable cancer and 2) identify the molecular epidemiology of the tier II gene alterations among Chinese pan-cancer patients. Results: In the first stage, molecular profiles of 520 intractable pan-cancer patients were identified, and 115 patients were identified to have tier II gene alterations. Then, 27 of these 115 patients received targeted therapy based on molecular profiles. The overall response rate (ORR) was 29.6% (8/27), and the disease control rate (DCR) was 44.4% (12/27). The median duration of response (DOR) was 4.80 months (95% CI, 3.33-27.2), and median progression-free survival (PFS) was 4.67 months (95% CI, 2.33-9.50). In the second stage, molecular epidemiology of 17,841 Chinese pan-cancer patients demonstrated that the frequency of tier II gene alterations across cancer types is 17.7%. Bladder cancer had the most tier-II alterations (26.1%), followed by breast cancer (22.4%), and non-small cell lung cancer (NSCLC; 20.2%). Conclusion: The Long March Pathway trial demonstrated a significant clinical benefit for intractable cancer from molecular-guided targeted therapy in the Chinese population. The frequency of tier II gene alterations across cancer types supports the feasibility of molecular-guided targeted therapy under basket trials.

Survival benefit of adjuvant transcatheter arterial chemoembolization for patients with hepatocellular carcinoma after anatomical hepatectomy.

BACKGROUND & AIMS: Although anatomical hepatectomy (AH) is widely used in the treatment of hepatocellular carcinoma (HCC), the prognosis is still unsatisfactory. The present study aimed to evaluate the survival benefit of adjuvant transcatheter arterial chemoembolization (TACE) for patients with HCC after AH. METHODS: A total of 832 patients were stratified into with adjuvant TACE (443, 53.2%) and without adjuvant TACE group (389, 46.8%) AH. Propensity score matching (PSM) was performed to control for confounding factors, and multivariable Cox regression was performed to determine the independent risk factors. RESULTS: After PSM, the results showed that the adjuvant TACE group had better overall survival (OS) and recurrence-free survival (RFS). Among the patients with tumor recurrence, adjuvant TACE was associated with a high rate of early-stage tumor at recurrence, a lower recurrence rate around the frontal margin and extrahepatic metastases, and a higher rate of receiving curative treatment. Multivariable Cox regression analysis showed that adjuvant TACE was an independent prognostic factor for OS (HR 0.673, P = 0.001) and RFS (HR 0.650, P = 0.001). CONCLUSIONS: Patients with HCC after AH can benefit from postoperative adjuvant TACE. Therefore, adjuvant TACE should be considered for patients with a high risk of recurrence.