Prognoses of Patients Treated With Surgical Therapy Versus Continuation of Local-Plus-Systemic Therapy Following Successful Down-Staging of Intermediate-Advanced Hepatocellular Carcinoma: A Multicenter Real-World Study.

BACKGROUND: The difference in the prognoses between treatment with surgical therapy and continuation of local-plus-systemic therapy following successful down-staging of intermediate-advanced hepatocellular carcinoma (HCC) remains unclear. METHODS: Data of 405 patients with intermediate-advanced HCC treated at 30 hospitals across China from January 2017 to July 2022 were retrospectively reviewed. All patients received local-plus-systemic therapy and were divided into the surgical (n = 100) and nonsurgical groups (n = 305) according to whether they received surgical therapy. The differences between long-term prognoses of the 2 groups were compared. Subgroup analysis was performed in 173 HCC patients who met the criteria for surgical resection following down-staging. RESULTS: Multivariable analysis of all patients showed that surgical therapy, hazard ratio (HR): 0.289, 95% confidence interval, CI, 0.136-0.613) was a protective factor for overall survival (OS), but not for event-free survival (EFS). Multivariable analysis of 173 intermediate-advanced HCC patients who met the criteria for surgical resection after conversion therapy showed that surgical therapy (HR: 0.282, 95% CI, 0.121-0.655) was a protective factor for OS, but not for EFS. Similar results were obtained after propensity score matching. For patients with Barcelona Clinic Liver Cancer stage B (HR: 0.171, 95% CI, 0.039-0.751) and C (HR: 0.269, 95% CI, 0.085-0.854), surgical therapy was also a protective factor for OS. CONCLUSIONS: Overall, for patients with intermediate-advanced HCC who underwent local-plus-systemic therapies, surgical therapy is a protective factor for long-term prognosis and can prolong OS, and for those who met the surgical resection criteria after conversion therapy, surgical therapy is recommended.

Intratumoral microbial heterogeneity affected tumor immune microenvironment and determined clinical outcome of HBV-related HCC.

BACKGROUND AND AIMS: The intratumoral microbiome has been reported to regulate the development and progression of cancers. We aimed to characterize intratumoral microbial heterogeneity (IMH) and establish microbiome-based molecular subtyping of HBV-related HCC to elucidate the correlation between IMH and HCC tumorigenesis. APPROACH AND RESULTS: A case-control study was designed to investigate microbial landscape and characteristic microbial signatures of HBV-related HCC tissues adopting metagenomics next-generation sequencing. Microbiome-based molecular subtyping of HCC tissues was established by nonmetric multidimensional scaling. The tumor immune microenvironment of 2 molecular subtypes was characterized by EPIC and CIBERSORT based on RNA-seq and verified by immunohistochemistry. The gene set variation analysis was adopted to explore the crosstalk between the immune and metabolism microenvironment. A prognosis-related gene risk signature between 2 subtypes was constructed by the weighted gene coexpression network analysis and the Cox regression analysis and then verified by the Kaplan-Meier survival curve.IMH demonstrated in HBV-related HCC tissues was comparably lower than that in chronic hepatitis tissues. Two microbiome-based HCC molecular subtypes, defined as bacteria- and virus-dominant subtypes, were established and significantly correlated with discrepant clinical-pathologic features. Higher infiltration of M2 macrophage was detected in the bacteria-dominant subtype with to the virus-dominant subtype, accompanied by multiple upregulated metabolism pathways. Furthermore, a 3-gene risk signature containing CSAG4 , PIP4P2 , and TOMM5 was filtered out, which could predict the clinical prognosis of HCC patients accurately using the Cancer Genome Atlas data. CONCLUSIONS: Microbiome-based molecular subtyping demonstrated IMH of HBV-related HCC was correlated with a disparity in clinical-pathologic features and tumor microenvironment (TME), which might be proposed as a biomarker for prognosis prediction of HCC.

A Single-Cell Atlas of Tumor-Infiltrating Immune Cells in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with limited treatment options. To guide the design of more effective immunotherapy strategies, mass cytometry was employed to characterize the cellular composition of the PDAC-infiltrating immune cells. The expression of 33 protein markers was examined at the single-cell level in more than two million immune cells from four types of clinical samples, including PDAC tumors, normal pancreatic tissues, chronic pancreatitis tissues, and peripheral blood. Based on the analyses, we identified 23 distinct T-cell phenotypes, with some cell clusters exhibiting aberrant frequencies in the tumors. Programmed cell death protein 1 (PD-1) was extensively expressed in CD4+ and CD8+ T cells and coexpressed with both stimulatory and inhibitory immune markers. In addition, we observed elevated levels of functional markers, such as CD137L and CD69, in PDAC-infiltrating immune cells. Moreover, the combination of PD-1 and CD8 was used to stratify PDAC tumors from The Cancer Genome Atlas database into three immune subtypes, with S1 (PD-1+CD8+) exhibiting the best prognosis. Further analysis suggested distinct molecular mechanisms for immune exclusion in different subtypes. Taken together, the single-cell protein expression data depicted a detailed cell atlas of the PDAC-infiltrating immune cells and revealed clinically relevant information regarding useful cell phenotypes and targets for immunotherapy development.

Single-Cell DNA Sequencing Reveals Punctuated and Gradual Clonal Evolution in Hepatocellular Carcinoma.

BACKGROUND & AIMS: Copy number alterations (CNAs), elicited by genome instability, are a major source of intratumor heterogeneity. How CNAs evolve in hepatocellular carcinoma (HCC) remains unknown. METHODS: We performed single-cell DNA sequencing (scDNA-seq) on 1275 cells isolated from 10 patients with HCC, ploidy-resolved scDNA-seq on 356 cells from 1 additional patient, and single-cell RNA sequencing on 27,344 cells from 3 additional patients. Three statistical fitting models were compared to investigate the CNA accumulation pattern. RESULTS: Cells in the tumor were categorized into the following 3 subpopulations: euploid, pseudoeuploid, and aneuploid. Our scDNA-seq analysis revealed that CNA accumulation followed a dual-phase copy number evolution model, that is, a punctuated phase followed by a gradual phase. Patients who exhibited prolonged gradual phase showed higher intratumor heterogeneity and worse disease-free survival. Integrating bulk RNA sequencing of 17 patients with HCC, published datasets of 1196 liver tumors, and immunohistochemical staining of 202 HCC tumors, we found that high expression of CAD, a gene involved in pyrimidine synthesis, was correlated with rapid tumorigenesis and reduced survival. The dual-phase copy number evolution model was validated by our single-cell RNA sequencing data and published scDNA-seq datasets of other cancer types. Furthermore, ploidy-resolved scDNA-seq revealed the common clonal origin of diploid- and polyploid-aneuploid cells, suggesting that polyploid tumor cells were generated by whole genome doubling of diploid tumor cells. CONCLUSIONS: Our work revealed a novel dual-phase copy number evolution model, showed HCC with longer gradual phase was more severe, identified CAD as a promising biomarker for early recurrence of HCC, and supported the diploid origin of polyploid HCC.

Radiographic and α-fetoprotein response predict pathologic complete response to immunotherapy plus a TKI in hepatocellular carcinoma: a multicenter study.

BACKGROUND: Pathologic complete response (pCR) following preoperative systemic therapy is associated with improved outcomes after subsequent liver transplant/resection in hepatocellular carcinoma (HCC). However, the relationship between radiographic and histopathological response remains unclear. METHODS: We retrospectively examined patients with initially unresectable HCC who received tyrosine kinase inhibitor (TKI) plus anti-programmed death 1 (PD-1) therapy before undergoing liver resection between March 2019 and September 2021 across 7 hospitals in China. Radiographic response was evaluated using mRECIST. A pCR was defined as no viable tumor cells in resected samples. RESULTS: We included 35 eligible patients, of whom 15 (42.9%) achieved pCR after systemic therapy. After a median follow-up of 13.2 months, tumors recurred in 8 non-pCR and 1 pCR patient. Before resection, there were 6 complete responses, 24 partial responses, 4 stable disease cases, and 1 progressive disease case, per mRECIST. Predicting pCR by radiographic response yielded an area under the receiver operating characteristic curve (AUC) of 0.727 (95% CI: 0.558-0.902), with an optimal cutoff value of 80% reduction in the enhanced area in MRI (called major radiographic response), which had a 66.7% sensitivity, 85.0% specificity, and a 77.1% diagnostic accuracy. When radiographic response was combined with α-fetoprotein response, the AUC was 0.926 (95% CI: 0.785-0.999); the optimal cutoff value was 0.446, which had a 91.7% sensitivity, 84.6%, specificity, and an 88.0% diagnostic accuracy. CONCLUSIONS: In patients with unresectable HCC receiving combined TKI/anti-PD 1 therapy, major radiographic response alone or combined with α-fetoprotein response may predict pCR.

A Bayesian Network Prediction Model for Microvascular Invasion in Patients with Intrahepatic Cholangiocarcinoma: A Multi-institutional Study.

BACKGROUND: Microvascular invasion (MVI) has been reported to be an independent prognostic factor of recurrence and poor overall survival in patients with intrahepatic cholangiocarcinoma (ICC). This study aimed to explore the preoperative independent risk factors of MVI and establish a Bayesian network (BN) prediction model to provide a reference for surgical diagnosis and treatment. METHODS: A total of 531 patients with ICC who underwent radical resection between 2010 and 2018 were used to establish and validate a BN model for MVI. The BN model was established based on the preoperative independent variables. The ROC curves and confusion matrix were used to assess the performance of the model. RESULTS: MVI was an independent risk factor for relapse-free survival (RFS) (P < 0.05). MVI has a correlation with postoperative recurrence, early recurrence (< 6 months), median RFS and median overall survival (all P < 0.05). The preoperative independent risk variables of MVI included obstructive jaundice, prognostic nutritional index, CA19-9, tumor size, and major vascular invasion, which were used to establish the BN model. The AUC of the BN model was 78.92% and 83.01%, and the accuracy was 70.85% and 77.06% in the training set and testing set, respectively. CONCLUSION: The BN model established based on five independent risk variables for MVI is an effective and practical model for predicting MVI in patients with ICC.

Sintilimab, bevacizumab biosimilar, and HAIC for unresectable hepatocellular carcinoma conversion therapy: a prospective, single-arm phase II trial.

We assessed the efficacy and safety of sintilimab [an anti-programmed death (PD-1)] plus bevacizumab biosimilar (IBI305), and hepatic arterial infusion chemotherapy (HAIC) in patients with unresectable hepatocellular carcinoma (HCC). The patients received sintilimab (200 mg) plus IBI305 (7.5 mg/kg) and HAIC (FOLFOX for 23 h) and were treated every 3 weeks. The primary endpoint was the objective response rate (ORR) assessed by an independent review committee (IRC) per mRECIST v1.1. Twenty-nine patients were enrolled in our clinical trial (1 patient voluntarily withdrew due to adverse events after the initial treatment). Objective response was reached in 17/29 (58.6%) patients per mRECIST. A total of 19/29 (65.5%) patients became eligible for further treatment; 14 of them completed surgical resection; 1 (5.3%) achieved pathological complete response (pCR); and 5 (26.3%) reached major partial response (mPR). The 1-year OS rate was better in the PR or pCR+mPR+PR group than in the PD+SD group by either mRECIST or pathological assessment (p=0.039 and 0.006). The 1-year EFS rate was better in the PR group than in the PD+SD group by pathological assessment (p=0.007). The most common treatment-related adverse events (TEAEs) in 30 HCC patients included thrombocytopenia (40.0%), hypertension (23.3%), and leukopenia (23.3%). The grade 3-5 TEAEs that were observed were hypertension (10%), diarrhea (6.7%), asthenia (3.3%), and ascites (3.3%). Sintilimab plus IBI305 and HAIC showed promising efficacy and manageable safety in patients with unresectable HCC. It might represent a novel treatment option for these patients.

Recurrence and prognosis in intrahepatic cholangiocarcinoma patients with different etiology after radical resection: a multi-institutional study.

OBJECTIVE: We aimed to evaluate the prognosis and adjuvant chemotherapy (ACT) in intrahepatic cholangiocarcinoma (ICC) patients with different etiology after radical resection. METHODS: A total of 448 patients with ICC who underwent radical resection between 2010 and 2018 at ten Chinese tertiary hospitals were analyzed in the study. These patients were divided into conventional ICC (Con-ICC, n = 261, 58.2%), hepatitis B virus ICC (HBV-ICC, n = 102, 22.8%) and hepatolithiasis (Stone-ICC, n = 85,19.0%) subtypes according to different etiology. Propensity score matching (PSM) was conducted to mitigate the baseline differences between Con-ICC and HBV-ICC, Con-ICC and Stone-ICC, HBV-ICC and Stone-ICC subtypes. RESULTS: Univariate and multivariate analysis showed that different etiology was a prognostic factor for overall survival and relapse-free survival, and different etiology was an independent risk factor for overall survival in ICC patients, respectively (P < 0.05). In addition, there was a statistical difference for overall survival in early recurrence patients among the three etiological subtypes (P < 0.05). After PSM, the overall survival of patients with Stone-ICC was worse than those of Con-ICC and HBV-ICC subtypes (P < 0.05), while the relapse-free survival of patients with Stone-ICC was equivalent to patients with Con-ICC and HBV-ICC (P > 0.05). In Stone-ICC patients, the median overall survival was 16.0 months and 29.7 months, and the median relapse-free survival was 9.0 months and 20.0 months for non-ACT and ACT patients, respectively (P < 0.05). CONCLUSION: The prognosis of Stone-ICC patients was significantly worse than those of Con-ICC and HBV-ICC patients. Interestingly, postoperative adjuvant chemotherapy can improve the prognosis of Stone-ICC patients effectively.

PRMT5 confers lipid metabolism reprogramming, tumour growth and metastasis depending on the SIRT7-mediated desuccinylation of PRMT5 K387 in tumours.

The protein arginine methyltransferase 5 (PRMT5), which is highly expressed in tumour tissues, plays a crucial role in cancer development. However, the mechanism by which PRMT5 promotes cancer growth is poorly understood. Here, we report that PRMT5 contributes to lipid metabolism reprogramming, tumour growth and metastasis depending on the SIRT7-mediated desuccinylation of PRMT5 K387 in tumours. Mass spectrometric analysis identified PRMT5 lysine 387 as its succinylation site. Moreover, the desuccinylation of PRMT5 K387 enhances the methyltransferase activity of PRMT5. SIRT7 catalyses the desuccinylation of PRMT5 in cells. The SIRT7-mediated dessuccinylation of PRMT5 lysine 387 fails to bind to STUB1, decreasing PRMT5 ubiquitination and increasing the interaction between PRMT5 and Mep50, which promotes the formation of the PRMT5-Mep50 octamer. The PRMT5-Mep50 octamer increases PRMT5 methyltransferase activity, leading to arginine methylation of SREBP1a. The symmetric dimethylation of SREBP1a increases the levels of cholesterol, fatty acid, and triglyceride biogenesis in the cells, escaping degradation through the ubiquitin-proteasome pathway. Functionally, the desuccinylation of PRMT5 K387 promotes lipid metabolism reprogramming, tumour growth and metastasis in vitro and in vivo in tumours.

Imbalance of TGF-ß1/BMP-7 pathways induced by M2-polarized macrophages promotes hepatocellular carcinoma aggressiveness.

The transforming growth factor-beta (TGF-ß) signaling pathway is the predominant cytokine signaling pathway in the development and progression of hepatocellular carcinoma (HCC). Bone morphogenetic protein (BMP), another member of the TGF-ß superfamily, has been frequently found to participate in crosstalk with the TGF-ß pathway. However, the complex interaction between the TGF-ß and BMP pathways has not been fully elucidated in HCC. We found that the imbalance of TGF-ß1/BMP-7 pathways was associated with aggressive pathological features and poor clinical outcomes in HCC. The induction of the imbalance of TGF-ß1/BMP-7 pathways in HCC cells could significantly promote HCC cell invasion and stemness by increasing inhibitor of differentiation 1 (ID1) expression. We also found that the microRNA (miR)-17-92 cluster, originating from the extracellular vesicles (EVs) of M2-polarized tumor-associated macrophages (M2-TAMs), stimulated the imbalance of TGF-ß1/BMP-7 pathways in HCC cells by inducing TGF-ß type II receptor (TGFBR2) post-transcriptional silencing and inhibiting activin A receptor type 1 (ACVR1) post-translational ubiquitylation by targeting Smad ubiquitylation regulatory factor 1 (Smurf1). In vivo, short hairpin (sh)-MIR17HG and ACVR1 inhibitors profoundly attenuated HCC cell growth and metastasis by rectifying the imbalance of TGF-ß1/BMP-7 pathways. Therefore, we proposed that the imbalance of TGF-ß1/BMP-7 pathways is a feasible prognostic biomarker and recovering the imbalance of TGF-ß1/BMP-7 pathways might be a potential therapeutic strategy for HCC.

Chinese expert recommendations on management of hepatocellular carcinoma during COVID-19 pandemic: a nationwide multicenter survey.

BACKGROUND: This study aimed to investigate the work status of clinicians in China and their management strategy alteration for patients with hepatocellular carcinoma (HCC) during the COVID-19 pandemic. METHODS: A nationwide online questionnaire survey was conducted in 42 class-A tertiary hospitals across China. Experienced clinicians of HCC-related specialties responded with their work status and management suggestions for HCC patients during the pandemic. RESULTS: 716 doctors responded effectively with a response rate of 60.1%, and 664 were included in the final analysis. Overall, 51.4% (341/664) of clinicians reported more than a 60% reduction of the regular workload and surgeons declared the highest proportion of workload reduction. 92.5% (614/664) of the respondents have been using online medical consultation to substitute for the "face-to-face" visits. Adaptive adjustment for the treatment strategy for HCC was made, including the recommendations of noninvasive and minimally invasive treatments such as transcatheter arterial chemoembolization for early and intermediate stage. Targeted therapy has been the mainstay for advanced stage and also as a bridge therapy for resectable HCC. DISCUSSION: During the COVID-19 pandemic, online medical consultation is recommended to avoid social contact. Targeted therapy as a bridge therapy is recommended for resectable HCC considering the possibility of delayed surgery.

Next-generation sequencing-guided molecular-targeted therapy and immunotherapy for biliary tract cancers.

BACKGROUND: Chemotherapy is a standard regimen for advanced or relapsed biliary tract cancer (BTC) with a 5-year overall survival (OS) rate of approximately 5% and a median OS of less than a year. Targeted therapies and immunotherapy aimed at providing more personalized treatments for BTCs have been tested. The objective of this study was to evaluate the effects of targeted therapy and immunotherapy on advanced BTC patients. METHODS: Twenty-four advanced/relapsed BTC patients were enrolled and examined with next-generation sequencing (NGS). Eight of them received NGS-guided targeted or immunotherapy, and the other 16 patients underwent routine chemotherapy. Comparison analysis of OS and objective response rate (ORR) was performed. RESULTS: IDH1, BRCA2, MAP2K1, and BRAF (V600E) were the major actionable genes mutated in this cohort. Patients who received NGS-guided therapy exhibited higher OS (not achieved vs. 6.5 months, p < 0.001) and ORR (87.5% vs. 25%, p < 0.001) than those without targetable mutations and who received first-line chemotherapy. BTCs harboring mutations in IDH1, ATM/BRCA2, or MAP2K1/BRAF (V600E) received treatment with dasatinib, olaparib, or trametinib, respectively. Three of the patients had high tumor mutation burden (TMB-H) and were treated with immune-checkpoint inhibitors and chemotherapy. All these patients achieved complete response or partial response. CONCLUSIONS: NGS-guided targeted therapy and immunotherapy are promising personalized therapies for advanced or relapsed BTCs. TMB is a useful biomarker for predicting immunotherapy efficacy.

Perioperative Enteral Nutrition Improves Postoperative Recovery for Patients with Primary Liver Cancer: A Randomized Controlled Clinical Trial.

OBJECTIVE: The role of perioperative protein-enriched enteral nutrition for patients with primary liver cancer is unclear. We investigated the efficacy of perioperative protein-enriched enteral nutrition for patients with primary liver cancer followed hepatectomy. METHODS: Patients with primary liver cancer that underwent hepatectomy between January 2016 and 2018 were enrolled. Patients in the treatment group was given enteral nutrition (TP-MCT) in addition to the regular diet. The primary outcome measures were duration of hospital stay and length of postoperative hospital stay. Secondary outcome measures included time to first flatus and time to first defecation. RESULTS: There was a significant reduction of time to first flatus and time to first defecation in the treatment group, when compared with the control group (time to first flatus: P = 0.001, time to first defecation: P < 0.001). CONCLUSIONS: It is found that addition of protein-enriched enteral nutrition (TP-MCT) improved postoperative recovery for patients with primary liver cancer following hepatectomy, with a significant reduction in time to first flatus and time to first defecation.

Prolonged siRNA expression in mammalian cells using an Epstein-Barr virus-based plasmid expression system.

RNA interference (RNAi) is a powerful tool in gene function analysis and disease treatment, especially diseases that are 'undruggable' by classical small molecules. However, the RNAi applications are limited due to some defects, such as short duration and toxic side effects. New strategies are still needed to improve RNAi applications. Previous studies have illustrated that Epstein-Barr virus nuclear antigen 1 (EBNA-1) and the origin of plasmid replication (oriP) are critical factors for EBV latent gene expression, which can keep the replication of the EBV genome as an extrachromosomal element for a relatively long time. Here we report a plasmid expression system on the base of oriP and EBNA-1, which could produce protein as well as short interfering RNAs(siRNAs) for a long time in mammalian cells. siRNA expression mediated by this system causes efficient and specific down-regulation of gene expression. Except for analyzing gene function, this study also provided a new optional and practical way for protein and/or RNAi-based therapies that require enduring effect.

Distinct clinical and prognostic implication of IDH1/2 mutation and other most frequent mutations in large duct and small duct subtypes of intrahepatic cholangiocarcinoma.

BACKGROUND: Isocitrate dehydrogenase 1/2 (IDH1/2), BAP1, ARID1A and PBRM1 have been reported as the most frequent mutant genes in intrahepatic cholangiocarcinoma (ICC), and their relationships with clinicopathological features and prognosis were researched in this study. METHODS: We collected clinical data of 130 ICC patients from January 2012 to December 2017. The IDH1/2 mutation and loss of BAP1, ARID1A and PBRM1 expressions were detected by DNA sequencing or immunohistochemical methods, and histological subtype of ICCs was determined by hematoxylin-eosin, Alcian blue and S100P staining. RESULTS: IDH1/2 mutation was related to decreased preoperative serum total bilirubin (P = 0.039), ferritin (P = 0.000) and higher histological differentiation (P = 0.024), and was associated with prolonged disease-free survival (P = 0.009) and a trend toward increased overall survival (P = 0.126) in small duct type of ICCs. Immunohistochemical staining results of MsMab-1 were generally consistent with DNA sequencing for IDH1/2 mutant in ICCs (κ = 0.691). Only BAP1 expression loss was correlated to prolonged disease-free survival (P = 0.031) and overall survival (P = 0.041) in large duct type of ICCs. CONCLUSIONS: IDH1/2 mutation is a favorable predictor and may be related to iron metabolism in small duct type of ICCs. Furthermore, we suggest that the detection of IDH1/2 mutation is indispensable to determine targeted therapy in small duct type ICCs, while it is not necessary in large duct of ICCs. MsMab-1 is a relatively effective multi-specific antibody against IDH1/2 mutant in ICCs. BAP1 expression loss was correlated with improved prognosis only in large duct type ICCs.

Characterization of propiconazole field-resistant isolates of Ustilaginoidea virens.

The plant-pathogenic fungus Ustilaginoidea virens (Cooke) Takah causes rice false smut (RFS), which is responsible for significant quantitative and qualitative losses in rice industry. Propiconazole is a triazole fungicide which belongs to Demethylation inhibitors (DMIs). It is used to control RFS in China. We previously screened 158 isolates of U. virens collected in the fields in 2015 in Jiangsu province of China, and found two of them were highly resistant to propiconazole (named 82 and 88, respectively). In this study, we have analyzed the physiological and biochemical characters of six field-sensitive isolates and the two field-resistant isolates, including mycelial growth and cell wall integrity. We found there was cross-resistance between different DMIs fungicides, but was no cross-resistance between DMIs and QoIs fungicides. We also analyzed the fitness, and found the pathogenicity in 88 was stronger than the field-sensitive isolates, but was completely lost in 82. Sequence analyses of CYP51 and the 1000-bp upstream of CYP51 coding region showed no mutation in 82 compared to the field-sensitive strains, but two more bases CC were identified at 154-bp upstream of the coding region in the field-resistant isolate 88. Moreover, the expression of CYP51 gene in all tested isolates was significantly induced by propiconazole. However, the up-regulation expression level in both 82 and 88 was much higher than that in the field-sensitive isolates. We also found propiconazole could inhibit the ergosterol biosynthesis in the field-sensitive isolates, but stimulated it in both field-resistant isolates 82 and 88. Given the high level of U. virens developing propiconazole resistance and the good fitness of the field-resistant isolate 88, the resistance of U. virens to DMIs must be monitored and managed in rice fields.

Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: There are no systemic treatments for patients with hepatocellular carcinoma (HCC) whose disease progresses during sorafenib treatment. We aimed to assess the efficacy and safety of regorafenib in patients with HCC who have progressed during sorafenib treatment. METHODS: In this randomised, double-blind, parallel-group, phase 3 trial done at 152 sites in 21 countries, adults with HCC who tolerated sorafenib (≥400 mg/day for ≥20 of last 28 days of treatment), progressed on sorafenib, and had Child-Pugh A liver function were enrolled. Participants were randomly assigned (2:1) by a computer-generated randomisation list and interactive voice response system and stratified by geographical region, Eastern Cooperative Oncology Group performance status, macrovascular invasion, extrahepatic disease, and α-fetoprotein level to best supportive care plus oral regorafenib 160 mg or placebo once daily during weeks 1-3 of each 4-week cycle. Investigators, patients, and the funder were masked to treatment assignment. The primary endpoint was overall survival (defined as time from randomisation to death due to any cause) and analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01774344. FINDINGS: Between May 14, 2013, and Dec 31, 2015, 843 patients were screened, of whom 573 were enrolled and randomised (379 to regorafenib and 194 to placebo; population for efficacy analyses), and 567 initiated treatment (374 received regorafenib and 193 received placebo; population for safety analyses). Regorafenib improved overall survival with a hazard ratio of 0·63 (95% CI 0·50-0·79; one-sided p<0·0001); median survival was 10·6 months (95% CI 9·1-12·1) for regorafenib versus 7·8 months (6·3-8·8) for placebo. Adverse events were reported in all regorafenib recipients (374 [100%] of 374) and 179 (93%) of 193 placebo recipients. The most common clinically relevant grade 3 or 4 treatment-emergent events were hypertension (57 patients [15%] in the regorafenib group vs nine patients [5%] in the placebo group), hand-foot skin reaction (47 patients [13%] vs one [1%]), fatigue (34 patients [9%] vs nine patients [5%]), and diarrhoea (12 patients [3%] vs no patients). Of the 88 deaths (grade 5 adverse events) reported during the study (50 patients [13%] assigned to regorafenib and 38 [20%] assigned to placebo), seven (2%) were considered by the investigator to be related to study drug in the regorafenib group and two (1%) in the placebo group, including two patients (1%) with hepatic failure in the placebo group. INTERPRETATION: Regorafenib is the only systemic treatment shown to provide survival benefit in HCC patients progressing on sorafenib treatment. Future trials should explore combinations of regorafenib with other systemic agents and third-line treatments for patients who fail or who do not tolerate the sequence of sorafenib and regorafenib. FUNDING: Bayer.

The efficacy of combination of induction chemotherapy and irreversible electroporation ablation for patients with locally advanced pancreatic adenocarcinoma.

BACKGROUND AND OBJECTIVES: Irreversible electroporation (IRE) is a non-thermal focal therapy that utilizes high voltage electric pulses to permanently rupture the cellular membrane and induce cell death. In this multi-center study, we evaluated the safety and efficacy of IRE in patients with locally advanced pancreatic cancer (LAPC). METHODS: From 2012 to 2015, we performed laparotomic and laparoscopic IRE in a total of 70 patients with stage III LAPC. Either gemcitabine-based or TS-1 (Tegafur, Gimeracil, and Oteracil) chemotherapy was applied for at least 3 months before the IRE. RESULTS: No IRE-related deaths occurred. A median follow-up of 28.1 months showed that six patients (8.6%) experienced local recurrence and 24 (34%) experienced distant progression. The overall median survival from the time of treatment was 22.6 months, and the progression-free survival (PFS) was 15.4 months. The overall survival in the patients who used gemcitabine-based reagents was 19.1 months and that of those who used TS-1 was 28.7 months. The PFS for these two groups were 13.2 months and 26.4 months; the difference is significant. CONCLUSIONS: Our study suggests that IRE is safe and effective for the control of LAPC. We surmise that the addition of IRE to a chemotherapy regimen may provide a survival advantage.

[Recent progress in nanomedicine for hepatocellular carcinoma therapy].

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, with insidious onset, insensitive to chemotherapy and poor prognosis, which make its clinical treatment face an enormous challenge. In recent years, with the rapid development of nanotechnology, increasing kinds of nanomedicine come to the forefront in biomedical fields. Through rational design, nanomedicine can be prepared in suitable size and modified with specific liver targeting ligands. Moreover, various therapeutic agents of different mechanisms can be co-loaded into the same nanosystem, thus achieving the synergistic therapeutic effects towards HCC. Nanomedicine is able to enhance drug bioavailability and liver-targeting effect as well as reduce the side effects to normal tissues, which provide a great potential in HCC therapy. This review summarizes the recent progress in the application of nanomedicine for HCC therapy from two aspects: their liver-targeting design strategies and the recent progress in combination therapy of HCC.

Decreased expression of acetyl-CoA synthase 2 promotes metastasis and predicts poor prognosis in hepatocellular carcinoma.

Metastasis is a serious risk that may occur during the treatment of hepatocellular carcinoma (HCC), preventing many patients from being surgical candidates and contributing to poor prognosis. Hypoxia has been proved an important factor of metastasis through the epithelial-mesenchymal transition (EMT) pathway. Acetyl-CoA synthase 2 (ACSS2) provides an acetyl group for the acetylation of hypoxia-inducible factor (HIF)-2α, and this epigenetic modification affects the activity of HIF-2α and the subsequent EMT process. Here, we showed that ACSS2 expression was negatively correlated with HCC malignancy. Knockdown of ACSS2 increased the invasion and migration ability of HCC cells and promoted EMT without increasing the total protein level of HIF-2α, even in hypoxic conditions. The immunoprecipitation assay revealed downregulated acetylation levels of HIF-2α after ACSS2 knockdown in hypoxic conditions, which resulted in enhanced HIF-2α activity. Finally, decreased expression of ACSS2 was found to be related to advanced stage and poor overall survival and disease-free survival rates in a cohort of patients with HCC. In conclusion, ACSS2 plays an important role in the acetylation process of HIF-2α, which effectively modifies the activity of HIF-2α under hypoxic conditions and greatly impacts on the prognosis of patients with HCC.