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The FLT3-ITD (internal tandem duplication) mutant has been a promising target for acute myeloid leukemia (AML) drug discovery but is now facing the challenge of resistance due to point mutations. Herein, we have discovered a type II FLT3 inhibitor, SILA-123 . This inhibitor has shown highly potent inhibitory effects against FLT3-WT (IC 50 = 2.1 nM) and FLT3-ITD (IC 50 = 1.0 nM), tumor cells with the FLT3-ITD mutant such as MOLM-13 (IC 50 = 0.98 nM) and MV4-11 (IC 50 = 0.19 nM), as well as BaF3 cells associated with the FLT3-ITD mutant and point mutations like BaF3-FLT3-ITD-G697R (IC 50 = 3.0 nM). Moreover, SILA-123 exhibited promising kinome selectivity against 310 kinases (S score (10) = 0.06). In in vivo studies, SILA-123 significantly suppressed the tumor growth in MV4-11 (50 mg/kg/d, TGI = 87.3%) and BaF3-FLT3-ITD-G697R (50 mg/kg/d, TGI = 60.0%) cell-inoculated allograft models. Our data suggested that SILA-123 might be a promising drug candidate for FLT3-ITD-positive AML.

Introduction: Trauma is the leading cause of paediatric mortality and morbidity. Stay-home regulations for coronavirus disease 2019 (COVID-19) reportedly changed trauma severity, yet data from Hong Kong were lacking. This study examined Hong Kong's spectrum of paediatric trauma and addressed knowledge gaps concerning epidemiological changes during COVID-19., Methods: Children with traumatic injuries who attended a tertiary trauma centre from January 2010 to March 2022 were included in this retrospective, cross-sectional study. We analysed demographic and clinical data and conducted unadjusted bivariate analyses of injury patterns before and after the pandemic., Results: In total, 725 children attended the Accident and Emergency Department due to trauma, 585 before and 140 during COVID-19. The male-to-female ratio was 1.84:1. The 90-day trauma-related mortality was 0.7%. The overall Injury Severity Score was 3.52 ± 5.95. The paediatric trauma incidence was similar before and after social-distancing policies (both 5.8 cases monthly). Gender, ISS distribution, intensive care unit stay length, and hospital stay length values were similar (p > 0.05). Trauma call activation (8.4% vs. 5.7%, p = 0.002) and road traffic accidents (10.6% vs. 5.7%, p = 0.009) significantly decreased, yet younger-patient injuries (< 10 years old; 85.7% vs. 71%, p < 0.001), burns (28% vs. 45.7%, p < 0.001), and domestic injuries (65.5% vs. 85.7%, p < 0.001) significantly increased. No significant self-harm, assault, or abuse increases were found., Conclusions: The paediatric trauma incidences were similar before and during the pandemic. However, domestic and burn injuries significantly increased, highlighting the importance of injury prevention., (© 2024. The Author(s).)

Kinases, a class of enzymes controlling various substrates phosphorylation, are pivotal in both physiological and pathological processes. Although their conserved ATP binding pockets pose challenges for achieving selectivity, this feature offers opportunities for drug repositioning of kinase inhibitors (KIs). This study presents a cost-effective in silico prediction of KIs drug repositioning via analyzing cross-docking results. We established the KIs database (278 unique KIs, 1834 bioactivity data points) and kinases database (357 kinase structures categorized by the DFG motif) for carrying out cross-docking. Comparative analysis of the docking scores and reported experimental bioactivity revealed that the Atypical, TK, and TKL superfamilies are suitable for drug repositioning. Among these kinase superfamilies, Olverematinib, Lapatinib, and Abemaciclib displayed enzymatic activity in our focused AKT-PI3K-mTOR pathway with IC 50 values of 3.3, 3.2 and 5.8 μM. Further cell assays showed IC 50 values of 0.2, 1.2 and 0.6 μM in tumor cells. The consistent result between prediction and validation demonstrated that repositioning KIs via in silico method is feasible., (© 2024 Wiley-VCH GmbH.)

In this study, the effects of four types of amendments on effective Cd and Cd content in different parts of prickly ash soil and soil enzyme activity were studied, which provided scientific basis for acidification improvement of purple soil and heavy metal pollution control. A field experiment was conducted. Six treatments were set up:no fertilizer (CK), only chemical fertilizer (F), lime + chemical fertilizer (SF), organic fertilizer + chemical fertilizer (OM), biochar + chemical fertilizer (BF), and vinasse biomass ash + chemical fertilizer (JZ). Soil pH; available Cd (DTPA-Cd); Cd content in branches, leaves, shells, and seeds of Zanthoxylum; as well as the activities of catalase (S-CAT), acid phosphatase (S-ACP), and urease (S-UE) in different treatments were studied, and their relationships were clarified. The results showed following:① The two treatments of vinasse biomass ash + chemical fertilizer and lime + chemical fertilizer significantly increased soil pH ( P &lt; 0.05) to 3.39 and 2.25 units higher than that in the control, respectively. Compared with that in the control treatment, the content of available Cd in soil under vinasse biomass ash + chemical fertilizer and lime + chemical fertilizer treatment decreased by 28.91 % and 20.90 %, respectively. ② The contents of Cd in leaves, shells, and seeds of Zanthoxylum were decreased by 31.33 %, 30.24 %, and 34.01 %, respectively. The Cd enrichment ability of different parts of Zanthoxylum was different, with the specific performances being leaves &gt; branches &gt; seeds &gt; shells. Compared with that of the control, the enrichment coefficient of each part of Zanthoxylum treated with vinasse biomass ash + chemical fertilizer decreased significantly( P &lt; 0.05)by 27.54 %-40.0 %. ③ The changes in catalase and urease activities in soil treated with amendments were similar. Compared with those in the control group, the above two enzyme activities were significantly increased by 191.26 % and 199.50 %, respectively, whereas the acid phosphatase activities were decreased by 16.45 %. Correlation analysis showed that soil available Cd content was significantly negatively correlated with soil pH value( P &lt; 0.01), S-CAT and S-UE enzyme activities were significantly positively correlated with soil pH( P &lt; 0.01), and the soil available Cd content was significantly negatively correlated ( P &lt; 0.01); the S-ACP enzyme showed the complete opposite trends. The application of lime and vinasse biomass ash to acidic purple soil had the most significant effect on neutralizing soil acidity. It was an effective measure to improve acidic purple soil and prevent heavy metal pollution by reducing the effective Cd content in soil and improving the soil environment while inhibiting the absorption and transfer of Cd in various parts of Zanthoxylum.

Melanoma is the most lethal skin malignancy. Fucoxanthin is a marine carotenoid with significant anticancer activities. Intriguingly, Fucoxanthin's impact on human melanoma remains elusive. Signal Transducer and Activator of Transcription 3 (STAT3) represents a promising target in cancer therapy due to its persistent activation in various cancers, including melanoma. Herein, we revealed that Fucoxanthin is cytotoxic to human melanoma cell lines A2758 and A375 while showing limited cytotoxicity to normal human melanocytes. Apoptosis is a primary reason for Fucoxanthin's melanoma cytotoxicity, as the pan-caspase inhibitor z-VAD-fmk drastically abrogated Fucoxanthin-elicited clonogenicity blockage. Besides, Fucoxanthin downregulated tyrosine 705-phosphorylated STAT3 (p-STAT3 (Y705)), either inherently present in melanoma cells or inducible by interleukin 6 (IL-6) stimulation. Notably, ectopic expression of STAT3-C, a dominant-active STAT3 mutant, abolished Fucoxanthin-elicited melanoma cell apoptosis and clonogenicity inhibition, supporting the pivotal role of STAT3 blockage in Fucoxanthin's melanoma cytotoxicity. Moreover, Fucoxanthin lowered BCL-xL levels by blocking STAT3 activation, while ectopic BCL-xL expression rescued melanoma cells from Fucoxanthin-induced killing. Lastly, Fucoxanthin was found to diminish the levels of JAK2 with dual phosphorylation at tyrosine residues 1007 and 1008 in melanoma cells, suggesting that Fucoxanthin impairs STAT3 signaling by blocking JAK2 activation. Collectively, we present the first evidence that Fucoxanthin is cytotoxic selectively against human melanoma cells while sparing normal melanocytes. Mechanistically, Fucoxanthin targets the JAK2/STAT3/BCL-xL antiapoptotic axis to provoke melanoma cell death. This discovery implicates the potential application of Fucoxanthin as a chemopreventive or therapeutic strategy for melanoma management., (© 2024 Wiley Periodicals LLC.)

Background: Intraoperative indocyanine green (ICG) fluorescence imaging has been shown to be a new and innovative way to illustrate the optimal resection margin in hepatectomy for hepatocellular carcinoma. This study investigated its accuracy in resection margin determination by looking into the correlation of ICG intensity gradients with pathological examination results of resected specimens., Methods: This was a prospective, single-center, non-randomized controlled study. Patients who had liver tumors indicating liver resection were recruited. The hypothesis was that the use of intraoperative near-infrared/ICG fluorescence imaging would be a promising guiding tool for removing hepatocellular carcinoma with a better resection margin. Patients were given ICG (0.25 mg/kg) 1 day before operation. Resected specimens were inspected under a fluorescent imaging system. Biopsies were taken from tumors and normal tissue. Color signals obtained from ICG fluorescence imaging were compared with biopsies for analysis., Results: Twenty-two patients were recruited for study. The median size of their tumors was 2.25 cm. One patient had resection margin involvement. Under ICG fluorescence, the tumors typically lighted up as yellow color, wrapped by a zone of green color. Tumors of 17 patients (77.3%) displayed yellow color and were confirmed malignancy, while tumors of 12 patients (54.5%) displayed green color and were confirmed malignancy. Receiver operating characteristic curve was used to measure the sensitivity and specificity of the green color to look for a clear resection margin. The area under the curve was 85.3% (p = 0.019, 95% confidence interval 0.696-1.000), with a sensitivity of 0.706 and specificity of 1.000., Conclusion: The use of ICG fluorescence can be helpful in determining resection margins. Resection of tumor should include complete resection of the green zone shown in the fluorescence image., (© 2024. The Author(s).)

Biochar and modified biochar have been widely used as remediation materials in heavy metal-contaminated agricultural soils. In order to explore economical and effective materials for the remediation of cadmium (Cd)-contaminated acidic purple soil, distillers 'grains were converted into distillers' grains biochar (DGBC) and modified using nano-titanium dioxide (Nano-TiO 2 ) to produce two types of modified DGBCs:TiO 2 /DGBC and Fe-TiO 2 /DGBC. A rice pot experiment was used to investigate the effects of different biochar types and application rates (1%, 3%, and 5%) on soil properties, nutrient content, Cd bioavailability, Cd forms, rice growth, and Cd accumulation. The results showed that:① DGBC application significantly increased soil pH, cation exchange capacity (CEC), and nutrient content, with TiO 2 /DGBC and Fe-TiO 2 /DGBC exhibiting better effects. ② DGBC and modified DGBCs transformed Cd from soluble to insoluble forms, increasing residual Cd by 1.22% to 18.46% compared to that in the control. Cd bioavailability in soil decreased significantly, with available cadmium being reduced by 11.81% to 23.67% for DGBC, 7.64% to 43.85% for TiO 2 /DGBC, and 19.75% to 55.82% for Fe-TiO 2 /DGBC. ③ DGBC and modified DGBCs increased rice grain yield, with the highest yields observed at a 3% application rate:30.60 g·pot -1 for DGBC, 37.85 g·pot -1 for TiO 2 /DGBC, and 39.10 g·pot -1 for Fe-TiO 2 /DGBC, representing 1.13, 1.40, and 1.44 times the control yield, respectively. Cd content in rice was significantly reduced, with grain Cd content ranging from 0.24 to 0.30 mg·kg -1 for DGBC, 0.16 to 0.26 mg·kg -1 for TiO 2 /DGBC, and 0.14 to 0.24 mg·kg -1 for Fe-TiO 2 /DGBC. Notably, Cd content in rice grains fell below the food safety limit of 0.2 mg·kg -1 (GB2762-2022) at 5% for TiO 2 /DGBC and 3% and 5% for Fe-TiO 2 /DGBC. In conclusion, Nano-TiO 2 modified DGBC effectively reduced the bioavailability of soil Cd through its own adsorption and influence on soil Cd forms distribution, thus reducing the absorption of Cd by rice and simultaneously promoting rice growth and improving rice yield. It is a type of Cd-contaminated soil remediation material with a potential application prospect. The results can provide scientific basis for farmland restoration and agricultural safety production of Cd-contaminated acidic purple soil.

Multiple myeloma (MM), a cancer of plasma cells, is the second most common hematological malignancy which is characterized by aberrant plasma cells infiltration in the bone marrow and complex heterogeneous cytogenetic abnormalities. Over the past two decades, novel treatment strategies such as proteasome inhibitors, immunomodulators, and monoclonal antibodies have significantly improved the relative survival rate of MM patients. However, the development of drug resistance results in the majority of MM patients suffering from relapse, limited treatment options and uncontrolled disease progression after relapse. There are urgent needs to develop and explore novel MM treatment strategies to overcome drug resistance and improve efficacy. Here, we review the recent small molecule therapeutic strategies for MM, and introduce potential new targets and corresponding modulators in detail. In addition, this paper also summarizes the progress of multi-target inhibitor therapy and protein degradation technology in the treatment of MM., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Over the past decades, the role of rearranged during transfection (RET) alterations in tumorigenesis has been firmly established. RET kinase inhibition is an essential therapeutic target in patients with RET-altered cancers. In clinical practice, initial efficacy can be achieved in patients through the utilization of multikinase inhibitors (MKIs) with RET inhibitory activity. However, the effectiveness of these MKIs is impeded by the adverse events associated with off-target effects. Recently, many RET-selective inhibitors, characterized by heightened specificity and potency, have been developed, representing a substantial breakthrough in the field of RET precision oncology. This Perspective focuses on the contemporary understanding of RET mutations, recent advancements in next-generation RET inhibitors, and the challenges associated with resistance to RET inhibitors. It provides valuable insights for the development of next-generation MKIs and selective RET inhibitors.

The aim of this study was to explore the effects of four amendments on soil fertility and labile carbon fraction characteristics of acid purple soil, so as to provide scientific basis for nutrient management and carbon storage stability in purple soil. Field experiments were carried out, and six treatments were set up:no fertilization (CK), only chemical fertilizer (F), lime + chemical fertilizer (SF), organic fertilizer + chemical fertilizer (OM), biochar + chemical fertilizer (BF), and vinasse biomass ash + chemical fertilizer (JZ). The contents of soil organic matter, pH, available nutrients, soil integrated fertility index (IFI), dissolved organic carbon (DOC), microbial biomass carbon (MBC), particulate organic carbon (POC), their effective rates, and soil carbon pool management index (CPMI) under different treatments were studied to clarify their relationships. The results showed that:① the application of amendments significantly increased soil pH and the contents of organic matter, alkali-hydrolyzed nitrogen, available phosphorus, and available potassium ( P <0.05). The OM and JZ treatments had the most significant increase in soil comprehensive fertility index ( P <0.05), with increases of 1.96 and 0.77 and 170.43% and 66.96%, respectively. ② Compared with those in the control treatment, the contents of POC, MBC, and DOC in JZ and OM increased by 110.30% and 84.81%, 61.08% and 46.56%, and 195.87% and 141.67%, respectively. The application of amendments significantly increased the soil carbon pool index (CPI) and CMPI ( P <0.05), in which the OM treatment showed the most significant increase, with soil CPI and CMPI values increasing by 107.34% and 90.75% compared with those of the control, respectively. ③ Soil organic carbon and its labile fractions were positively correlated with IFI ( P <0.05), and redundancy analysis showed that there were significant differences among different treatments. The interpretation rates of soil IFI, pH, and available potassium to organic carbon and its components reached significant levels, and the order of interpretation rates was IFI(74.6%)>pH (11.7%)>AK(6.5%). The application of vinasse biomass ash and organic fertilizer to acid purple soil had the most significant effect on improving soil fertility and soil quality and was conducive to promoting the accumulation and activation of soil carbon fractions.

Objective: This study is to examine the impact of perioperative (intraoperative/postoperative) blood transfusion on the outcomes of curative hepatectomy for hepatocellular carcinoma. Hepatectomy is a well-established curative treatment for hepatocellular carcinoma, and blood transfusion cannot always be avoided in treating the disease., Methods: A retrospective study of patients having curative hepatectomy for hepatocellular carcinoma from January 2010 to December 2019 at a single center was conducted. The patients were stratified by their disease stage. Patients with and without perioperative blood transfusion were matched by propensity-score matching and compared for each disease stage. Univariate and multivariate analyses were performed to identify prognostic factors for overall survival for each stage., Results: A total of 846 patients were studied. Among them, 125 received perioperative blood transfusion and 720 did not. Patients with blood transfusion had worse disease-free and overall survival. After stratification and matching, the ratios of transfusion to non-transfusion were 33:165 (stage 1), 28:140 (stage 2), and 45:90 (stage 3). Perioperative blood transfusion was associated with a higher incidence of postoperative complications in all three disease stages (p = 0.004/0.006/0.017), and hence longer hospitalization (p < 0.001 in all stages), but had no significant impact on hospital mortality (p = 0.119/0.118/0.723), 90-day mortality (p = 0.259/0.118/0.723), disease-free survival (p = 0.128/0.826/0.511), or overall survival (p = 0.869/0.122/0.122) in any disease stage. Prognostic factors for overall survival included tumor size, tumor number, alpha-fetoprotein level, and postoperative complication of grade ≥ 3A., Conclusion: Perioperative blood transfusion was associated with a higher incidence of complications but had no significant impact on survival after curative hepatectomy for hepatocellular carcinoma., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Acute myeloid leukemia (AML) is the most common type of blood cancer and has been strongly correlated with the overexpression of Fms-like tyrosine kinase 3 (FLT3), a member of the class III receptor tyrosine kinase family. With the emergence of FLT3 internal tandem duplication alteration (ITD) and tyrosine kinase domain (TKD) mutations, the development of FLT3 small molecule inhibitors has become an effective medicinal chemistry strategy for AML. Herein, we have designed and synthesized two series of 1H-pyrrolo[2,3-b]pyridine derivatives CM1-CM24, as FLT3 inhibitors based on F14, which we previously reported, that can target the hydrophobic FLT3 back pocket. Among these derivates, CM5 showed significant inhibition of FLT3 and FLT3-ITD, with inhibitory percentages of 57.72 % and 53.77 % respectively at the concentration of 1 μΜ. Furthermore, CM5 demonstrated potent inhibition against FLT3-dependent human AML cell lines MOLM-13 and MV4-11 (both harboring FLT3-ITD mutant), with IC 50 values of 0.75 μM and 0.64 μM respectively. In our cellular mechanistic studies, CM5 also effectively induces apoptosis by arresting cell cycle progression in the G0/G1 phase. In addition, the amide and urea linker function were discussed in detail based on computational simulations studies. CM5 will serve as a novel lead compound for further structural modification and development of FLT3 inhibitors specifically targeting AML with FLT3-ITD mutations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The therapeutic benefits of available FLT3 inhibitors for AML are limited by drug resistance, which is related to mutations, as well toxicity caused by off-target effects. In this study, we introduce a new small molecule FLT3 inhibitor called danatinib, which was designed to overcome the limitations of currently approved agents. Danatinib demonstrated greater potency and selectivity, resulting in cytotoxic activity specific to FLT3-ITD and/or FLT3-TKD mutated models. It also showed a superior kinome inhibition profile compared to several currently approved FLT3 inhibitors. In diverse FLT3-TKD models, danatinib exhibited substantially improved activity at clinically relevant doses, outperforming approved FLT3 inhibitors. In vivo safety evaluations performed on the granulopoiesis of transgenic myeloperoxidase (MPO) zebrafish and mice models proved danatinib to have an acceptable safety profile. Danatinib holds promise as a new and improved FLT3 inhibitor for the treatment of AML, offering long-lasting remissions and improved overall survival rates., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interest. No disclosures were reported by all the authors., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Treatment options for pregnant women with immune thrombocytopenia (ITP) who do not respond to first-line treatment are limited. Few studies have reported the use of recombinant human thrombopoietin (rhTPO) for this subset of patients., Aims: To investigate the efficacy and safety of rhTPO in ITP during pregnancy and determine obstetric outcomes and predictors of treatment response., Methods: From July 2013 to October 2022, the data of 81 pregnant women with ITP and a platelet count < 30 × 10 9 /L who did not respond to steroids and/or intravenous immunoglobulin were retrospectively analysed. Of these patients, 33 received rhTPO treatment (rhTPO group) while 48 did not (control group). Baseline characteristics, haematological disease outcomes before delivery, obstetric outcomes, and adverse events were compared between groups. In the rhTPO group, a generalised estimating equation (GEE) was used to investigate the factors influencing the response to rhTPO treatment., Results: The baseline characteristics were comparable between both groups (P > 0.05, both). Compared with controls, rhTPO patients had higher platelet counts (median [interquartile range]: 42 [21.5-67.5] vs. 25 [19-29] × 10 9 /L, P = 0.002), lower bleeding rate (6.1% vs. 25%, P = 0.027), and lower platelet transfusion rate before delivery (57.6% vs. 97.9%, P < 0.001). Gestational weeks of delivery (37.6 [37-38.4] vs 37.1 [37-37.2] weeks, P = 0.001) were longer in the rhTPO group than in the control group. The rates of caesarean section, postpartum haemorrhage, foetal or neonatal complications, and complication types in both groups were similar (all P > 0.05). No liver or renal function impairment or thrombosis cases were observed in the rhTPO group. GEE analysis revealed that the baseline mean platelet volume (MPV) (odds ratio [OR]: 0.522, P = 0.002) and platelet-to-lymphocyte ratio (PLR) (OR: 1.214, P = 0.025) were predictors of response to rhTPO treatment., Conclusion: rhTPO may be an effective and safe treatment option for pregnancies with ITP that do not respond to first-line treatment; it may have slightly prolonged the gestational age of delivery. Patients with a low baseline MPV and high baseline PLR may be more responsive to rhTPO treatment. The present study serves as a foundation for future research., (© 2023. The Author(s).)

Objective: To explore the value of the aMAP risk score (age, male, albumin - bilirubin, and platelets) to predict early recurrence within one year after microwave ablation in patients with small hepatocellular carcinoma. Methods: This was a retrospective study that enrolled 142 patients diagnosed with hepatocellular carcinoma who were treated with microwave ablation in the Department of Hepatology Unit of Nanfang Hospital, Southern Medical University from July 2016 to July 2021. The cohort enrolled 121 male and 21 female patients, including 110 patients that were <60 years old. All the patients were followed-up after microwave ablation to evaluate residual tumor and recurrence of tumor by computed tomography or magnetic resonance imaging. The observation indices mainly included general data and imaging data of patients. Using the X-tile tools, patients were divided into two groups: a high aMAP score group and a low aMAP score group. Multivariate Cox regression analysis was conducted for comparison of independent risk factors. Results: Multivariate Cox regression showed that high aMAP score, maximum tumor diameter >20 mm, and high AFP were the independent risk factors of early recurrence (all P <0.05). Kaplan-Meier survival curves showed that the median recurrence-free survival was 25.5 months in the low aMAP score group and 6.1 months in the high aMAP score group ( P =0.001). Conclusions: The aMAP score could predict the early recurrence within 1 year of small hepatocellular carcinoma after microwave ablation. Patients with high aMAP score should undergo rigorous postoperative follow-up evaluations..

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with few treatment options. A promising TNBC treatment approach is targeting the oncogenic signaling pathways pivotal to TNBC initiation and progression. Deregulated activation of signal transducer and activator of transcription 3 (STAT3) is fundamental to driving TNBC malignant transformation, highlighting STAT3 as a promising TNBC therapeutic target. Methoxyhispolon Methyl Ether (MHME) is an analog of Hispolon, an anti-cancer polyphenol found in the medicinal mushroom Phellinus linteus . Still, MHME's anti-cancer effects and mechanisms remain unknown. Herein, we present the first report about MHME's anti-TNBC effect and its action mechanism. We first revealed that MHME is proapoptotic and cytotoxic against human TNBC cell lines HS578T, MDA-MB-231, and MDA-MB-463 and displayed a more potent cytotoxicity than Hispolon's. Mechanistically, MHME suppressed both constitutive and interleukin 6 (IL-6)-induced activation of STAT3 represented by the extent of tyrosine 705-phosphorylated STAT3 (p-STAT3). Notably, MHME-evoked apoptosis and clonogenicity impairment were abrogated in TNBC cells overexpressing a dominant-active mutant of STAT3 (STAT3-C); supporting the blockade of STAT3 activation is an integral mechanism of MHME's cytotoxic action on TNBC cells. Moreover, MHME downregulated BCL-2 in a STAT3-dependent manner, and TNBC cells overexpressing BCL-2 were refractory to MHME-induced apoptosis, indicating that BCL-2 downregulation is responsible for MHME's proapoptotic effect on TNBC cells. Finally, MHME suppressed SRC activation, while v-src overexpression rescued p-STAT3 levels and downregulated apoptosis in MHME-treated TNBC cells. Collectively, we conclude that MHME provokes TNBC cell apoptosis through the blockade of the SRC/STAT3/BCL-2 pro-survival axis. Our findings suggest the potential of applying MHME as a TNBC chemotherapy agent.

Background & Aims: Although non-alcoholic fatty liver disease (NAFLD) remains an uncommon indication for liver transplantation (LT) in the Chinese, the prevalence of NAFLD is increasing. We aimed to determine the prevalence of de novo steatosis and metabolic dysfunction-associated fatty liver disease (MAFLD) after LT., Methods: Transient elastography assessment for liver stiffness and controlled attenuation parameter (CAP) were performed after LT in 549 patients at median time of 77 months from LT. CAP was compared with implant liver biopsy, and also validated in 42 patients with post-LT liver biopsy. Longitudinal history including diabetes mellitus (DM), dyslipidemia, hypertension, and immunosuppressive regimen were recorded., Results: The optimal cut-off level of CAP for diagnosing at least mild (≥ S1) and moderate-to-severe steatosis (≥ S2/3) was 266 and 293 dB/m respectively, with AUROC of 0.740 and 0.954 respectively. Using this newly derived cut-off, 28.9% patients have de novo NAFLD, of which 95.6% fulfilled the criteria for MAFLD. After multivariate analysis, BMI (HR 1.34), DM (HR 2.01), hypertension (HR 2.03), HDL-cholesterol (HR 0.25), LDL-cholesterol (HR 1.5) and cryptogenic cirrhosis (HR 4.85) were associated with the development of S2/3 graft steatosis. de novo NAFLD was associated with higher incidence of new-onset hypertension (p < 0.001), graft dysfunction (defined as ALT > 40 U/L; p = 0.008), but not associated with graft fibrosis (defined as liver stiffness > 12 kPa; p = 0.761)., Conclusion: Although NAFLD remains an uncommon primary liver disease indication for LT in Chinese patients, post-transplant de novo graft steatosis is common and the majority is classified as MAFLD. Development of graft steatosis is not associated with an increase in graft fibrosis but was associated with worse metabolic control and graft dysfunction. Routine CAP measurement to detect de novo graft steatosis should be considered after LT regardless of the primary indication of LT., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Small molecule covalent drugs have proved to be desirable therapies especially on drug resistance related to point mutations. Secondary mutations of FLT3 have become the main mechanism of FLT3 inhibitors resistance which further causes the failure of treatment. Herein, a series of 4-(4-aminophenyl)-6-phenylisoxazolo[3,4-b]pyridine-3-amine covalent derivatives were synthesized and optimized to overcome the common secondary resistance mutations of FLT3. Among these derivatives, compound F15 displayed potent inhibition activities against FLT3 (IC 50  = 123 nM) and FLT3-internal tandem duplication (ITD) by 80% and 26.06%, respectively, at the concentration of 1 μM. Besides, F15 exhibited potent activity against FLT3-dependent human acute myeloid leukemia (AML) cell lines MOLM-13 (IC 50  = 253 nM) and MV4-11 (IC 50  = 91 nM), as well as BaF3 cells with variety of secondary mutations. Furthermore, cellular mechanism assays indicated that F15 inhibited phosphorylation of FLT3 and its downstream signaling factors. Notably, F15 could be considered for further development as potential drug candidate to treat AML., (© 2023 Wiley Periodicals LLC.)

Background: The synergy between locoregional therapies and immune checkpoint inhibitors has not been investigated as conversion therapy for unresectable hepatocellular carcinoma. We aimed to investigate the activity of sequential transarterial chemoembolisation (TACE) and stereotactic body radiotherapy followed by avelumab (an anti-PD-L1 drug) for locally advanced, unresectable hepatocellular carcinoma., Methods: START-FIT was a single-arm, phase 2 trial in patients with locally advanced hepatocellular carcinoma who were not suitable for curative treatment, conducted in two hospitals in Hong Kong and one in Shenzhen, China. Eligible patients were those aged 18 years or older with an Eastern Cooperative Oncology Group performance status 0-1, Child-Pugh liver function score A5 to B7, tumour size of at least 5 cm, a maximum of three tumour lesions, and adequate hepatic, renal, and bone marrow function. Participants received TACE on day 1, followed by stereotactic body radiotherapy (27·5-40·0 Gy in five fractions) at day 28. Avelumab (10 mg/kg) was administered 14 days following stereotactic body radiotherapy and every 2 weeks thereafter. The primary endpoint was the proportion of patients deemed amenable to curative treatment, defined as those who had a sustained complete or partial treatment response for at least 2 months and if curative treatment could be performed (ie, resection, radiofrequency ablation, or transplantation), analysed by intention to treat. Safety was also analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT03817736) and has been completed., Findings: Between March 18, 2019, and Jan 27, 2021, 33 patients (32 [97%] men and one [3%] woman) were enrolled. The median sum of the largest diameters of lesions was 15·1 cm (IQR 8·3-14·9). 21 (64%) patients had macrovascular invasion (hepatic vein [n=13], branched portal vein [n=3], or both [n=5]). Median follow-up was 17·2 months (IQR 7·8-25·8). 18 (55%) patients were deemed amenable to curative treatment: four (12%) of 33 patients had curative treatment (resection [n=2] or radiofrequency ablation [n=2]), and 14 (42%) had a radiological complete response and opted for close surveillance. 11 (33%) of 33 patients had treatment-related adverse events that were grade 3 or worse. The most common treatment-related grade 3 or worse adverse event was transient increase in alanine aminotransferase or aspartate aminotransferase (five [15%]) after TACE. Five (15%) patients developed immune-related adverse events of grade 3 or worse (three had hepatitis, two had dermatitis)., Interpretation: To our knowledge, this is the first prospective trial using the combination of immunotherapy and locoregional treatment as conversion therapy for locally advanced unresectable hepatocellular carcinoma, with promising results. Future randomised trials with larger cohorts of patients are warranted., Funding: Merck., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Surgical resection is indicated for resectable colorectal liver metastases (CLM), but it is controversial for non-colorectal liver metastases (NCLM). This study aimed to compare survival outcomes of patients with resection of NCLM versus CLM and to identify prognostic factors for resection of NCLM., Methods: Consecutive patients who underwent surgical resection of liver metastases at Queen Mary Hospital, Hong Kong from January 1989 to December 2019 were retrospectively reviewed. Patients with resected NCLM were compared to those with CLM. Overall and recurrence-free survival were determined. Subgroup analyses with patients grouped according to the year of liver resection, from 1989 to 2004 and from 2005 to 2019, were conducted. Univariate and multivariate analyses were performed to identify prognostic factors., Results: Among 674 patients included, 151 (22.4%) had NCLM while 523 (77.6%) had CLM. There were no statistically significant differences in median overall survival (65.2 vs 43.6 months, p = 0.555) and recurrence-free survival (12.5 vs 11.7 months, p = 0.425). The 1-year, 3-year, 5-year and 10-year overall survival rates were 89.8% vs 91.5%, 59.4% vs 58.8%, 50.6% vs 38.7% and 34.1% vs 26.3% in NCLM and CLM groups, respectively. Subgroup analyses demonstrated no statistically significant difference in overall survival between resection of NCLM versus CLM in both time intervals. In the NCLM group, better overall survival was found in liver metastasis of gastrointestinal stromal tumour (GIST) origin (hazard ratio (HR) 0.138, p = 0.003) and with a longer time interval from resection of primary tumour to resection of NCLM (HR 0.982, p = 0.042). Poor prognostic factors were presence of blood transfusion (HR 5.588, p = 0.013) and post-operative complications of Clavien-Dindo Grade IIIa or above (HR 74.853, p = 0.003)., Conclusions: Surgical resection of NCLM had comparable survival outcomes with CLM. With appropriate patient selection, the indication of liver resection could be expanded to NCLM., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aim: The clinical benefits of FLT3 inhibitors against acute myeloid leukemia (AML) have been limited by selectivity and resistance mutations. Thus, to identify FLT3 inhibitors possessing high selectivity and potency is of necessity. Methods & results: The authors used computational methods to systematically compare pocket similarity with 269 kinases. Subsequently, based on these investigations and beginning with in-house compound 10 , they synthesized a series of 6-methyl-isoxazol[3,4- b ]pyridine-3-amino derivatives and identified that compound 45 (IC 50 : 103 nM) displayed gratifying potency in human AML cell lines with FLT3-internal tandem duplications mutation as well as FLT3-internal tandem duplications-tyrosine kinase domain-transformed BaF3 cells. Conclusion: The integrated biological activity results indicated that compound 45 deserves further development for therapeutic remedies for AML.

Introduction: Liver resection is the best treatment option for patients with resectable colorectal liver metastasis (CRLM). A 10-year follow-up can reflect the true curative potential of resection. This retrospective study investigated factors for long-term survival of CRLM patients., Method: Data of patients who underwent liver resection for CRLM without extrahepatic disease from 1990 to 2012 at our hospital were reviewed. Patients who survived for > 10 years were compared with those who survived for < 10 years., Results: Totally, 315 patients were included in the study. They were divided into 2 groups: < 10-year group and > 10-year group. Patients in the < 10-year group had more tumor nodules (P = 0.016), more bilobar involvement (P = 0.004), narrower resection margin (P < 0.001), and worse disease-free and overall survival (P < 0.001). On multivariate analysis, low preoperative hemoglobin level, large number of tumor nodules, and bilobar involvement were poor prognostic factors for overall survival, while adjuvant chemotherapy was a favorable factor. Further analysis of patients with bilobar disease showed that perioperative blood transfusion was a poor prognostic factor for overall survival while adjuvant chemotherapy was a favorable one. In patients with multiple bilobar tumor nodules, adjuvant chemotherapy had a positive impact on disease-free survival and overall survival., Conclusions: Patients who survived for > 10 years after liver resection for CRLM tended to have normal preoperative hemoglobin level, unilobar disease, fewer tumor nodules, and have received adjuvant chemotherapy. Adjuvant chemotherapy favorably affected long-term survival of CRLM patients., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To explore the effect of curcumin on the insulin receptor substrate 1 (IRS1)/phosphatidylinositol-3-kinase (PI3K)/endometrial expression of glucose 4 (GLUT4) signalling pathway and its regulator, phosphatase and tensin homolog (PTEN), in a rat model of polycystic ovarian syndrome (PCOS)., Methods: PCOS model was induced by letrozole intragastric administration. Sprague-Dawley rats were randomized into 4 groups according to a random number table: (1) control group; (2) PCOS group, which was subjected to PCOS and received vehicle; (3) curcumin group, which was subjected to PCOS and treated with curcumin (200 mg/kg for 2 weeks); and (4) curcumin+LY294002 group, which was subjected to PCOS, and treated with curcumin and LY294002 (a specific PI3K inhibitor). Serum hormone levels (17 β-estradiol, follicle stimulating hormone, luteinizing hormone, progesterone, and testosterone) were measured by enzyme linked immunosorbent assay, and insulin resistance (IR) was assessed using the homeostasis model assessment of IR. Ovarian tissues were stained with haematoxylin and eosin for pathological and apoptosis examination. Expression levels of key transcriptional regulators and downstream targets, including IRS1, PI3K, protein kinase B (AKT), GLUT4, and PTEN, were measured via reverse transcription polymerase chain reaction and Western blot, respectively., Results: The PCOS group showed impaired ovarian morphology and function. Compared with the PCOS group, curcumin treatment exerted ovarioprotective effects, down-regulated serum testosterone, restored IR, inhibited inflammatory cell infiltration in ovarian tissues, decreased IRS1, PI3K, and AKT expressions, and up-regulated GLUT4 and PTEN expressions in PCOS rats (P<0.05 or P<0.01). In contrast, IRS1, PI3K, AKT, and PTEN expression levels were not significantly different between PCOS and curcumin+LY294002 groups (P>0.05)., Conclusion: The beneficial effects of curcumin on PCOS rats included the alteration of serum hormone levels and recovery of morphological ovarian lesions, in which, PTEN, a new target, may play a role in regulating the IRS1/PI3K/GLUT4 pathway., (© 2022. The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The impact of three-dimensional (3D) visualization on laparoscopic hepatectomy for hepatocellular carcinoma is largely unknown., Methods: A retrospective review with propensity-score matched analysis of 3D and two-dimensional (2D) laparoscopic hepatectomy performed in a tertiary hepatobiliary surgery center., Results: Since the availability of 3D laparoscopy, the proportion of laparoscopic major hepatectomies has significantly expanded (1.7% vs. 24.0%, p < 0.0001) and the percentage of difficult resections among patients who underwent laparoscopic hepatectomy has also increased (12.6% vs. 40.0%, p = 0.0001). A total of 305 patients (92 in the 3D group and 213 in the 2D group) underwent laparoscopic hepatectomy between 2002 and 2019. The 3D group had better liver function, larger tumors at more difficult locations, more major resections, and more difficult surgeries. After propensity score matching, 144 patients were analyzed (72 in both the 3D and 2D groups). Patients were comparable in terms of liver status, tumor status, and complexity of liver surgery. Operative time (218 vs. 218 mins, p = 0.50) and blood loss (0.2 vs. 0.2L, p = 0.49) were comparable between the two groups, however overall complications were higher in the 2D group (1.4 vs. 11.1%, p = 0.03). Patients who underwent 3D laparoscopic major hepatectomy had a shorter hospital stay than their comparable counterparts operated through an open approach (7 vs. 6 days, p = 0.003)., Conclusions: 3D visualization enhanced the feasibility of laparoscopic major hepatectomy and difficult laparoscopic liver resection. 3D resection was potentially associated with fewer operative morbidities and the 3D laparoscopic approach did not jeopardize the outcome of major hepatectomy., (© 2022. Society of Surgical Oncology.)

Fms-like tyrosine kinase 3 (FLT3) mutation has been strongly associated with increased risk of relapse, and the irreversible covalent FLT3 inhibitors had the potential to overcome the drug-resistance. In this study, a series of simplified 4-(4-aminophenyl)-6-methylisoxazolo[3,4-b] pyridin-3-amine derivatives containing two types of Michael acceptors (vinyl sulfonamide, acrylamide) were conveniently synthesized to target FLT3 and its internal tandem duplications (ITD) mutants irreversibly. The kinase inhibitory activities showed that compound C14 displayed potent inhibition activities against FLT3 (IC 50  = 256 nM) and FLT3-ITD by 73 % and 25.34 % respectively, at the concentration of 1 μM. The antitumor activities indicated that C14 had strong inhibitory activity against the human acute myeloid leukemia (AML) cell lines MOLM-13 (IC 50  = 507 nM) harboring FLT3-ITD mutant, as well as MV4-11 (IC 50  = 325 nM) bearing FLT3-ITD mutation. The biochemical analyses showed that these effects were related to the ability of C14 to inhibit FLT3 signal pathways, and C14 could induce apoptosis in MV4-11 cell as demonstrated by flow cytometry. Fortunately, C14 showed very weak potency against FLT3-independent human cervical cancer cell line HL-60 (IC 50  > 10 μM), indicating that it might have no off-target toxic effects. In light of these data, compound C14 represents a novel covalent FLT3 kinase inhibitor for targeted therapy of AML., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

In 2016, the World Health Organization set an ambitious goal of reducing viral hepatitis-related deaths by 65% by 2030. The key to this goal is to reduce viral hepatitis-related HCC deaths. Liver cancer is the fourth most common malignant tumor and the second leading cause of cancer death in China. The onset of HCC is insidious, and most patients are already in the middle and late stage when diagnosed. Despite the great progress on management of HCC, the therapeutic effect and prognosis of HCC are still unsatisfactory. Therefore, multi-dimensional and comprehensive analysis of the mechanism of liver cancer, improving the early screening, diagnosis and treatment rate of liver cancer are the key points of reducing the harm of liver cancer in China. In recent years, multi-omics studies have been widely applied in the field of liver cancer, providing a basis for the pathogenesis of liver cancer, early detection and diagnosis, development of individual treatment strategies and prognosis assessment. This issue will focus on the application of genomics, proteomics, metabolomics and imaging omics in early screening, diagnosis and treatment of liver cancer.

Primary liver cancer is the second leading cause of death from malignant tumors in China, and hepatocellular carcinoma (HCC) is the main type. The disease stage at the time of HCC diagnosis largely determines the efficacy of subsequent treatment. Due to the HCC screening among high-risk population has not yet popularized, and the current diagnose method of early HCC is not satisfactory, the early HCC diagnosis rate is less than 30% in China. Metabolomics research emerging in recent years has promoted the research progress of HCC in many fields, such as elaborating the mechanism of occurrence and development, early prevention and diagnosis, exploring drug treatment targets. At the same time, a large number of serum metabolites with excellent sensitivity and specificity were discovered, which made up for the deficiency of traditional serological indicators and helped the early screening and early diagnosis of HCC. This review will summarize the studies on serum metabolomic markers of HCC in recent 5 years, explore the role of metabolomics in the early prediction and diagnosis of HCC and its application prospect.

It is uncertain whether tumour biology affects radical treatment for post-transplant hepatocellular carcinoma (HCC) oligo-recurrence, i.e. recurrence limited in numbers and locations amendable to radical therapy. We conducted a retrospective study on 144 patients with post-transplant HCC recurrence. Early recurrence within one year after transplant (HR 2.53, 95% CI 1.65−3.88, p < 0.001), liver recurrence (HR 1.74, 95% CI 1.12−2.68, p = 0.01) and AFP > 200 ng/mL upon recurrence (HR 1.62, 95% CI 1.04−2.52, p = 0.03) predicted mortality following recurrence. In patients with early recurrence and liver recurrence, radical treatment was associated with improved post-recurrence survival (early recurrence: median 18.2 ± 1.5 vs. 9.2 ± 1.5 months, p < 0.001; liver recurrence: median 28.0 ± 4.5 vs. 11.6 ± 2.0, p < 0.001). In patients with AFP > 200 ng/mL, improvement in survival did not reach statistical significance (median 18.2 ± 6.5 vs. 8.8 ± 2.2 months, p = 0.13). Survival benefits associated with radical therapy were reduced in early recurrence (13.6 vs. 9.0 months) and recurrence with high AFP (15.4 vs. 9.3 months) but were similar among patients with and without liver recurrence (16.9 vs. 16.4 months). They were also diminished in patients with multiple biological risk factors (0 risk factor: 29.0 months; 1 risk factor: 19.7 months; 2−3 risk factors: 3.4 months): The survival benefit following radical therapy was superior in patients with favourable biological recurrence but was also observed in patients with poor tumour biology. Treatment decisions should be individualised considering the oncological benefits, quality of life gain and procedural morbidity.

Objective: To test the hypothesis that ICG fluorescence cholangiography (ICG-FC) helps to identify critical structures during laparoscopic cholecystectomy (LC) and hence reduce biliary injuries and conversions. In LC, biliary injury and conversion often happen if the biliary anatomy is misidentified., Methods: This was a single-center randomized controlled trial from 2017 to 2019. Patients with acute cholecystitis requiring LC were assessed for eligibility for the trial. Patients in the trial were randomized to undergo either conventional LC (conventional arm) or LC with ICG-FC (ICG arm). Conversion rate and biliary injury incidence were outcome measures., Results: Totally 92 patients participated (46 patients in each arm). The median age was 61 years in both arms (p = 0.472). The conventional arm had 22 men and 24 women; the ICG arm had 24 men and 22 women (p = 0.677). The two arms were comparable in all perioperative parameters. The time from ICG injection to surgery was 67 (16-1150) min. Both arms had an 8.7% conversion rate (p = 1.000). The median operative time was 140.5 min in the conventional arm and 149.5 min in the ICG arm (p = 0.086). The complication rate was 15.2% in the former and 10.9% in the latter (p = 0.536), and both had a 2.2% bile leakage rate. The median hospital stay was 3.5d in the former and 4.0d in the latter (p = 0.380)., Conclusion: ICG-FC did not make any difference in conversion or complication rate. Its routine use in LC is questionable. However, it may be helpful in difficult cholecystectomies and may be used as an adjunct., Trial Registration: The trial was registered with the Institutional Review Board of University of Hong Kong/Hospital Authority Hong Kong West Cluster ( http://www.med.hku.hk/en/research/ethics-and-integrity/human-ethics )., Registration Number: UW17-492., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background/Aim: Alpha-fetoprotein (AFP) had been used as a prognostic factor in hepatocellular carcinoma but it was unknown what level of AFP could predict the survival of patients with ruptured hepatocellular carcinoma (rHCC) after resection. This retrospective study was to identify the best cutoff value of AFP for this prediction. Methods: Data of patients having hepatectomy for rHCC from 1989 to 2015 were reviewed. The receiver operating characteristic curve and Youden's index were used to identify the cutoff value of AFP affecting survival. The patients were then divided into two groups by the cutoff for comparison. Results: Totally 114 patients were included. An AFP level of 256 ng/ml was found to affect survival (area under curve 63.1%, 95% confidence interval 0.514-0.748, p = 0.027; sensitivity 0.6, specificity 0.706). The 114 patients were divided into Group A (AFP < 256 ng/ml, n = 56) and Group B (AFP ≥ 256 ng/ml, n = 58). The median AFP level was 13.0 ng/ml (range, 2-253 ng/ml) in Group A and 11206.5 ng/ml (range, 259-481,000 ng/ml) in Group B (p < 0.001). Group A had a larger proportion of patients receiving transarterial embolization at the time of rupture, and the time to hepatectomy was longer in this group. Patients in Group B had more blood loss, more complications, larger tumors, and more cases of macrovascular/microvascular invasion. Overall survival (p = 0.013) and disease-free survival (p = 0.024) were significantly better in Group A. On multivariate analysis, AFP ≥ 256 ng/ml was an independent risk factor for overall survival. Conclusion: AFP ≥ 256 ng/ml had an adverse impact on the survival of patients with rHCC after resection.

Background: Salvage liver transplantation (SLT) is the ideal treatment for patients with recurrent hepatocellular carcinoma (HCC) and liver cirrhosis. The optimal timing for offering SLT was controversial. This study aimed at investigating the impact of time to recurrence and other prognostic factors on survival outcome after SLT., Methods: Between May 2000 and April 2019, patients who had undergone hepatectomy or ablation for HCC and later received SLT in Queen Mary Hospital were included. Clinico-pathological data during primary treatment and SLT were retrospectively reviewed. Kaplan-Meier analysis and log-rank test were used to determine overall and disease-free survival after SLT. Prognostic factors affecting overall and disease-free survival were determined by multivariate analysis using Cox regression analysis. P-value of less than 0.05 was considered statistically significant., Results: Fifty-three patients were identified within the specified period including 22 patients in early recurrence group (ER group, time to recurrence within 1 year) and 31 patients in late recurrence group (LR group, time to recurrence more than 1 year). The 1-, 5-, and 10-year overall survival after primary treatment was 100%, 76.6%, and 61.1% in the ER group and 100%, 90%, and 76.4% in the LR group (p = 0.59). There were no statistical differences in overall survival (p = 0.84) and disease-free survival (p = 0.85) after SLT between ER and LR group. Pre-transplant alpha-fetoprotein >  = 400 ng/mL (p = 0.007) and macrovascular invasion in explant (p = 0.002) were independent risk factors for shorter overall survival after primary treatment., Conclusion: Time to recurrence after primary treatment of HCC did not affect survival outcome after SLT. With careful patient selection, SLT could be offered to patient with early or late tumor recurrence., (© 2021. The Society for Surgery of the Alimentary Tract.)

Background/objective: Complete resection is the most effective treatment of hilar cholangiocarcinoma (HC) but may result in high morbidity and mortality. Most HC patients have jaundice, and preoperative biliary drainage may reduce their risk of obstructive jaundice. ERCP and PTBD have been advocated for this purpose. This retrospective study investigated the influence of ERCP versus PTBD versus their combination on the short-term outcomes of curative HC resection., Methods: Patients having curative HC resection with preoperative biliary drainage in a span of 26 years were reviewed and divided into groups according to drainage modality. Drainage-related and surgical complications and hospital mortality were compared between groups. Intention-to-treat analysis using a separate set of initial drainage data was performed., Results: Eighty-six patients were divided into: Group A, ERCP only, n = 32 (32/86 = 37.2%); Group B, PTBD only, n = 10 (10/86 = 11.6%); Group C, ERCP + PTBD, n = 44 (44/86 = 51.2%). International normalized ratio was significantly higher in Group B (p = 0.008). The three groups were comparable in operative details, hospital stay, and mortality. Fifty-two patients had postoperative complications. Significantly more patients in Groups A and C had subphrenic abscess (A: 25%, B: 0%, C: 9.1%; p = 0.035) and subsequent radiological drainage. Group A had insignificantly more patients with wound infection (31.3% vs 10% vs 22.7%, p = 0.334), chest infection (28.1% vs 20% vs 11.4%, p = 0.178), and urinary tract infection (6.3% vs 0% vs 0%, p = 0.133). The three groups had similar rates of major complications (p = 0.501). They also had comparable survival outcomes (overall, p = 0.370; disease-free, p = 0.569). Fifteen and 71 patients received PTBD and ERCP respectively as first drainage mode. These two groups were comparable in liver function, preoperative comorbidity, intraoperative details, and postoperative outcomes., Conclusion: In the preoperative management of HC, the use of ERCP, PTBD or their combination is acceptable and can optimize patients' condition for curative HC resection., Competing Interests: Declaration of competing interest Nil., (Copyright © 2021. Published by Elsevier Taiwan LLC.)

Background and Aims: Hepatectomy is a well-established curative treatment for hepatocellular carcinoma. However, the role of adjuvant therapy is controversial. This study examines the efficacy of adjuvant transarterial chemotherapy for hepatocellular carcinoma., Methods: The data of hepatocellular carcinoma patients undergoing curative hepatectomy was reviewed. Those with adjuvant transarterial chemotherapy were matched with those without using propensity score analysis, by tumour size and number, indocyanine green retention rate, disease staging and Child-Pugh grading. The groups were compared., Results: Eighty-seven patients with hepatocellular carcinoma who underwent hepatectomy received adjuvant transarterial chemotherapy (TAC group), and were matched with 870 patients who did not (no-TAC group). The groups were largely comparable in patient and disease characteristics, but the TAC group experienced more blood loss, higher transfusion rates, narrower margins and more positive margins. The two groups were found to be comparable in disease-free and overall survival rates. In margin-positive patients, those given TAC survived longer than those without, and margin-positive patients in the TAC group had overall survival rates similar to margin-negative patients in the no-TAC group., Conclusions: Margin involvement is an adverse factor for survival in HCC. Adjuvant transarterial chemotherapy may offer survival benefits to hepatocellular carcinoma patients with positive surgical margins., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

This study verified whether radical treatment for hepatocellular carcinoma (HCC) oligo-recurrence after liver transplantation conveys survival benefits. A retrospective study of 144 patients with posttransplant HCC recurrence was performed. Propensity score matching was performed to adjust for baseline covariates between patients who received radical and palliative treatments. The primary endpoint was postrecurrence survival. A total of 50 patients (35%) received radical treatment for recurrence, and 76 (53%) and 18 (13%) patients received palliative and supportive treatments, respectively. Compared with the radical group, patients who received palliative treatment had more early recurrences (time from transplant 17 versus 11 months; P = 0.01) and more extensive disease in terms of tumor numbers (1 versus 4; P < 0.001), size of largest tumor (1.8 versus 2.5 cm; P = 0.046), numbers of involved organs (interquartile range [IQR], 1-1 versus 1-2; P = 0.02), and alpha-fetoprotein (AFP) level (7 versus 40 ng/mL; P = 0.01). Multivariate Cox regression analysis revealed that early recurrence (time from transplant hazard ratio [HR], 1.02; 95% confidence interval [CI], 1.01-1.03; P = 0.001), larger recurrent tumor (HR, 1.12; 95% CI, 1.03-1.23; P = 0.01), liver recurrence (HR, 1.84; 95% CI, 1.17-2.90; P = 0.01), and log 10 AFP level at recurrence (HR, 1.27; 95% CI, 1.07-1.52; P = 0.01) predicted poor survival. Mammalian target of rapamycin inhibitor (HR, 0.331; 95% CI, 0.213-0.548; P < 0.001) and radical treatment (HR, 0.342; 95% CI, 0.213-0.548; P < 0.001) were associated with improved survival. After 2-to-1 propensity score matching for covariates, the 50 patients who received curative treatment survived significantly longer than the 25 matched patients who received palliative treatment (median survival time, 30.9 ± 2.4 versus 19.5 ± 3.0 months; P = 0.01). Radical treatment conveys survival benefits to HCC oligo-recurrence after liver transplantation., (Copyright © 2021 American Association for the Study of Liver Diseases.)

Purpose: This retrospective, single-center study aimed to investigate the importance of chemotherapy and to come up with the optimal liver resection margin length for patients with resectable colorectal liver metastasis (CRLM)., Methods: Patients who had undergone any form of liver resection for CRLM were reviewed and analyzed. The analyses were broken down into three parts: (1) overall effect of chemotherapy, (2) effect of chemotherapy with positive/negative resection margin, and (3) result of discriminative analysis with optimal margin length analysis., Results: In total, 381 patients were studied. Among them, 279 received chemotherapy whereas 102 did not. Survival was significantly better in patients with chemotherapy (5-year, 43.6% vs. 25.8%) (p < 0.001). Patients who received chemotherapy (n = 93) with negative margins had better survival than patients (n = 8) with positive margins (5-year, 28.1% vs. 0%) (p = 0.019). On multivariate analysis, margin involvement was the poor prognostic factor for survival. Patients who had chemotherapy (n = 238) with negative margin showed a trend of better survival than patients (n = 41) with positive margins (5-year, 45.7% vs. 29.3%) (p = 0.085). Patients (n = 93) with negative margin and no chemotherapy and patients (n = 41) with positive margin and chemotherapy had comparable survival at 5 years (p = 0.422). On multivariate analysis, tumor number was the prognostic factor for survival. By the discriminant method, 1.09 cm (sensitivity 0.242, specificity 0.718) was determined as the cut-off for optimal margin length. Patients who had margin ≥ 1.09 cm (n = 81) enjoyed significantly better survival (5-year, 54.3% vs. 33.5%) (p = 0.041). On multivariate analysis, margin length ≥ 1.09 cm was the prognostic factor for favorable survival., Conclusion: The results demonstrated the important effect of perioperative chemotherapy and negative margin liver resection in management of patients suffered from CRLM., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Precise staging is essential in the management of patients with recurrent hepatocellular carcinoma (HCC) after liver transplantation. There is no current consensus on the optimal staging strategy. We conducted this study to evaluate the performance of dual-tracer positron emission tomography-computed tomography (PET-CT) for this purpose and to investigate whether the results of dual-tracer PET-CT affected patient management., Methods: A retrospective study was conducted. Patients who underwent dual-tracer PET-CT for suspected or confirmed HCC recurrence after liver transplant were included. The lesion-based sensitivity and positive predictive value of dual-tracer PET-CT were determined., Results: Fifty-six patients and 189 recurrent tumors were included. The lesion-based sensitivity and positive predictive value of dual-tracer PET-CT were 94.7% and 90.4%, respectively. The sensitivity of dual-tracer PET-CT was better than the standard imaging in the surveillance protocol (82.5% versus 94.7%, P < 0.001), especially for detecting liver recurrence (71.0% versus 96.8%, P < 0.001). Half of the dual-tracer PET-CT detected additional recurrence (n = 26, 46.4%) and one-third led to a change in management (n = 19, 33.9%). Ten patients (17.9%) with inconclusive standard imaging had metabolic recurrence confirmed on PET-CT and treatment was commenced early. Four patients (7.1%) had revised locoregional treatment, and 5 (8.9%) had to withdraw from locoregional treatment after the detection of additional metastatic disease., Conclusions: Dual-tracer PET-CT is effective for staging posttransplant HCC recurrence. It often provides valuable information to guide clinical management., (Copyright © 2021 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Background: Hepatocellular carcinoma (HCC) with portal vein tumour thrombus (PVTT) signifies advanced disease, whether LT confers any survival superiority over resection remains uncertain., Methods: A propensity score matched (PSM) analysis of liver transplantation (LT) and liver resection (LR) for HCC with PVTT was performed., Results: A consecutive series of 88 patients who received either LT (10 DDLTs and 3 LDLTs) or LR (n=75) respectively were recruited. Before PSM, the LT group has a higher MELD score (17.3 vs. 7.8, P<0.001), lower serum AFP levels (96 vs. 2,164 ng/mL, P=0.017) and smaller tumour size (4 vs. 10 cm, P<0.001). The 5-year overall survival for LT and LR were 55.4% and 15.9% respectively (P=0.007). After matching for serum AFP levels and tumour size, 1-, 3- and 5-year overall survival for LT were 81 ng/mL, 3.9 cm, 80%, 70% and 70% and the corresponding rates for LR were 1,417 ng/mL, 5.3 cm, 51.8%, 19,6% and 9.8% (P value =0.12, 0.27 and 0.009 respectively)., Conclusions: LT is associated with significantly better oncological outcomes in HCC patients with PVTT involving the lobar or segmental level. A modest expansion of selection criteria to include small HCC with segmental PVTT should be considered., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/hbsn.2020.03.09). Dr. ACYC and Dr. CML serve as unpaid editorial board members of Hepatobiliary Surgery and Nutrition. The other authors have no conflicts of interest to declare., (2021 Hepatobiliary Surgery and Nutrition. All rights reserved.)

Background: We aimed to identify predictive factors for positron emission tomography (PET)-detected hepatocellular carcinoma (HCC) metastasis and a cost-effective approach to preoperative PET-computed tomography (CT) for detecting metastasis., Methods: Clinicopathological and survival data of HCC patients having PET-CT with 18F-fludeoxyglucose (FDG) and 11C-acetate (ACT) following contrast-enhanced CT/magnetic resonance imaging (MRI) for preoperative tumor staging were reviewed. Binary logistic regression was performed to identify predictive factors for PET-detected metastasis. A cost-benefit analysis model was built for the incurred costs and the impact of PET-CT findings on treatment strategy was studied., Results: Totally 152 patients were analyzed. Dual-tracer PET-CT detected metastasis in 17 patients (11%). By multivariate analysis, alpha-fetoprotein (AFP) ≥400 ng/mL [relative risk (RR): 4.30, 95% confidence interval (CI): 1.41-13.15, P=0.011] and bilobar disease (RR: 3.94, 95% CI: 1.24-12.52, P=0.014) were independent predictive factors for PET-detected metastasis. PET-CT findings altered the treatment strategy for 12 patients (7.9%); three partial hepatectomies, eight episodes of transarterial chemoembolization (TACE) and one episode of ablation were avoided, with an estimated cost-saving of US $91,000, $150,000 and $10,600 respectively. Had the PET-CT been performed only for patients with AFP ≥400 ng/mL or bilobar disease (n=74), metastasis would have been confirmed in 14 patients (18.9%), and the cost-saving per patient was estimated at US $1,070., Conclusions: Dual-tracer PET-CT is cost-effective and useful for preoperative HCC staging in patients with AFP ≥400 ng/mL or bilobar disease. Its routine use in preoperative workup for all HCC patients is not recommended. Unilobar disease with AFP <400 ng/mL can achieve good negative predictive value for PET-detected metastasis. Screening patients with either factor can avoid unnecessary procedures and is thus cost-effective for preoperative HCC workup., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/hbsn.2019.11.09). Dr. CML and Dr. ACYC serve as the unpaid editorial board members of Hepatobiliary Surgery and Nutrition. The other authors have no conflicts of interest to declare., (2021 Hepatobiliary Surgery and Nutrition. All rights reserved.)

Background: The 8 th edition of the American Joint Committee on Cancer tumor-node-metastasis staging system (AJCC 8 th ) has been launched with modifications in T staging. The University of Hong Kong liver cancer staging system (HKUSS) has been proven to better categorize hepatocellular carcinoma (HCC) into different T stages. This study aimed to compare the two systems' predictive ability for HCC recurrence after primary surgical resection., Methods: Patients who had primary, curative resection for HCC between 1989 and 2017 were reviewed. The Kaplan-Meier plot was used to estimate disease-free survival (DFS), and the log-rank test was used for survival comparison between subgroups. The two systems' prediction of recurrence was evaluated by the Cox regression model., Results: Totally 1,815 patients were included. With AJCC 8 th , the 5-year DFS was 58.9% for T1a, 52.3% for T1b, 30% for T2, 16.9% for T3, and 14.4% for T4. No survival difference was demonstrated between T1a and T1b (P=0.668) or between T3 and T4 (P=0.562). With HKUSS, the 5-year DFS was 57.7% for T1, 43.4% for T2, 28.9% for T3, and 15.7% for T4. The T staging in HKUSS showed significant survival differences (T1 vs. T2, T2 vs. T3, and T3 vs. T4; P<0.001). Using receiver operating characteristic curves to show the recurrence status in the two systems, HKUSS had the largest area under curve (AUC) (HKUSS: AUC =0.655, SE 0.014, P<0.001, 95% CI, 0.628-0.681; AJCC 8 th : AUC =0.652, SE 0.013, P<0.001, 95% CI, 0.625-0.677)., Conclusions: HKUSS showed better categorization of HCC. In the context of primary surgical resection, HKUSS may be more appropriate for stratification of patients with HCC with various T stages, and thus the choice of staging system when primary surgical resection is considered for patients of HCC., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-7611). The authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Objective: To evaluate the roles between two different HIV self-testing models in promoting HIV-testing among men who have sex with men (MSM). Methods: This paper focuses on two HIV self-testing service models. The first; is the online self-testing model (HIV self-testing conventional model) with the sexual health promotion network platform. The other one is an innovative HIV self-testing model (secondary distribution model), based on the previous program. The two different self-testing models, including the number of indexes and alters, the positive rate, and the demographics of indexes and alters, are compared. The influence of volunteers with or without leadership on the number of HIV self-test kits distributed or self-use is analyzed through the leadership survey scale. Results: The return rates of HIV self-testing results in the two models are 94.7%(323/341) and 99.2%(1 141/1 150), respectively, within 30 days. The proportion of alters in the secondary distribution is significantly higher (45.9%,281/612) than the conventional HIV self-testing (6.3%,20/318). In the secondary distribution model, the difference between the number of indexes and alters indicators including age, marital status, residence, sex orientation, anal sex with men in the past six months, and HIV test are statistically significant ( χ 2 test, all P <0.05). The opinion leader of MSM has significantly impacted the promotion of HIV self-testing ( P <0.05). Conclusions: Both models can promote HIV self-testing, result return, and HIV positive detection among MSM. In terms of expanding the testing and detection of HIV positive, the secondary distribution mode shows more obvious advantages, which significantly promotes a large number of MSM who have never been tested for HIV to undergo HIV testing. Influential indexes have a significant effect on increasing the HIV testing rate and promoting HIV testing among MSM.

Reaction of aryl 2-pyridyl ethers with arylzinc reagents under catalysis of NiCl 2 (PCy 3 ) 2 affords aryl-aryl cross-coupling products via selective cleavage of C Ar -OPy bonds. The reaction features a wide substrate range and good compatibility of functional groups. β-H-free alkylzinc reagents are also applicable as the nucleophiles in the transformation, whereas β-H-containing alkylzinc reagents lead to a mixture of cross-coupling and hydrogenation products.

Background: /Aim: Laparoscopic hepatectomy has been gaining popularity but its evidence in major hepatectomy for cirrhotic liver is lacking. We studied the long-term outcomes of the pure laparoscopic approach versus the open approach in major hepatectomy without Pringle maneuver in patients with hepatocellular carcinoma (HCC) and cirrhosis using the propensity score analysis., Methods: We reviewed patients diagnosed with HCC and cirrhosis who underwent major hepatectomy as primary treatment. The outcomes of patients who received the laparoscopic approach were compared with those of propensity-case-matched patients (ratio, 4:1) who received the open approach. The matching was made on the following factors: tumor size, tumor number, age, sex, hepatitis serology, HCC staging, comorbidity, and liver function., Results: Twenty-four patients underwent pure laparoscopic major hepatectomy for HCC with cirrhosis. Ninety-six patients who underwent open major hepatectomy were matched by propensity scores. The laparoscopic group had less median blood loss (300 ml vs 645 ml, p = 0.001), shorter median hospital stay (6 days vs 10 days, p = 0.002), and lower rates of overall complication (12.5% vs 39.6%, p = 0.012), pulmonary complication (4.2% vs 25%, p = 0.049) and pleural effusion (p = 0.026). The 1-year, 3-year and 5-year overall survival rates in the laparoscopic group vs the open group were 95.2%, 89.6% and 89.6% vs 87.5%, 72.0% and 62.8% (p = 0.211). Correspondingly, the disease-free survival rates were 77.1%, 71.2% and 71.2% vs 75.8%, 52.7% and 45.5% (p = 0.422)., Conclusions: The two groups had similar long-term survival. The laparoscopic group had favorable short-term outcomes. Laparoscopic major hepatectomy without routine Pringle maneuver for HCC with cirrhosis is a safe treatment option at specialized centers., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background . Endoscopic ultrasound (EUS) and fine-needle aspiration (FNA) are commonly used for assessing pancreatic lesions. This study aimed to evaluate the diagnostic yield and accuracy of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) in a single tertiary institution. Methods . Consecutive patients who underwent EUS-FNA of the pancreas at Queen Mary Hospital, Hong Kong, from January 2015 to March 2016 were retrospectively reviewed. Endoscopic findings and FNA results were analysed. For patients who subsequently underwent surgical resection of pancreatic lesion, EUS-FNA diagnoses were compared to histopathological findings of surgical specimens to determine its diagnostic accuracy. Results . One hundred twelve EUS-FNA were performed in 99 patients within the study time period and were included for analysis. Sixty-six (66.7%) pancreatic lesions were solid in nature and 33 (33.3%) were cystic. The overall diagnostic yield of EUS-FNA was 70.5% (n = 79). On multivariate analysis, more passes of needle were associated with a higher diagnostic yield (odds ratio = 2.000, P = .049). 57.1% (n = 64) of EUS-FNA results had an impact on management. Sixteen patients with diagnostic EUS-FNA subsequently underwent surgery for resection of the pancreatic lesion. Upon correlation to the histopathological findings of surgical specimens, there were 12 true-positive, 2 true-negative, 0 false-positive, and 2 false-negative cases. Sensitivity was 85.7%, specificity was 100%, positive predictive value was 100%, and negative predictive value was 50%. The diagnostic accuracy of EUS-FNA was 87.5%. Conclusion . EUS-FNA is accurate and reliable for diagnosing pancreatic lesions.

Background: In the management of operable hilar cholangiocarcinoma (HC) patients with hyperbilirubinemia, preoperative biliary drainage is a measure to bring down the bilirubin to a certain level so as to avoid adverse postoperative outcomes that would otherwise result from hyperbilirubinemia. A cutoff value of bilirubin level in this context is needed but has not been agreed upon without controversy. This retrospective study aimed to identify a cutoff of preoperative bilirubin level that would minimize postoperative morbidity and mortality., Methods: Data of patients having hepatectomy with curative intent for HC were analyzed. Discriminative analysis was performed to identify the preoperative bilirubin level that would make a survival difference. The identified level was used as the cutoff to divide patients into two groups. The groups were compared., Results: Ninety patients received hepatectomy with curative intent for HC. Their median preoperative bilirubin level was 23 μmol/L. A cutoff preoperative bilirubin level of 75 μmol/L was derived from Youden's index (sensitivity 0.333; specificity 0.949) and confirmed to be optimal by logistic regression (relative risk 9.250; 95% confidence interval 1.932-44.291; p = 0.005), with mortality shown to be statistically different at 90 days (p = 0.008). Patients were divided into Group A (≤75 μmol/L; n = 82) and Group B (> 75 μmol/L; n = 8). Group B had a higher preoperative bilirubin level (p < 0.001), more intraoperative blood loss (3.12 vs 1.4 L; p = 0.008), transfusion (100% vs 42.0%; p = 0.011) and replacement (2.45 vs 0.0 L; p < 0.001), more postoperative renal complications (p = 0.036), more in-hospital deaths (50% vs 8.5%; p = 0.004), and more 90-day deaths (50% vs 9.8%; p = 0.008). Group A had a longer follow-up period (p = 0.008). The groups were otherwise comparable. Disease-free survival was similar between groups (p = 0.142) but overall survival was better in Group A (5-year, 25.2% vs 0%; p < 0.001). On multivariate analysis, preoperative bilirubin level and intraoperative blood replacement were risk factors for 90-day mortality., Conclusion: A cutoff value of preoperative bilirubin level of 75 μmol/L is suggested, as the study showed that a preoperative bilirubin level ≤ 75 μmol/L resulted in significantly less blood replacement necessitated by blood loss during operation and significantly better patient survival after surgery.

Background: The aggressive approach of vascular resection plus reconstruction in curative resection of hilar cholangiocarcinoma (HC) remains controversial. This retrospective study investigated its short- and long-term outcomes., Methods: Data of HC patients from 1989 to 2016 were reviewed. Operated patients were divided into two groups (with and without vascular resection) and compared in terms of perioperative results. Patients who had unresectable HC were also compared with patients who had been operated., Results: Ninety patients underwent curative HC resection. They were divided into group A (without aggressive approach, n = 68) and group B (with aggressive approach, n = 22). The groups were comparable in all parameters including rates of overall and major complication and in-hospital, 30-day and 90-day mortality except that group B had more patients with more advanced disease (P = 0.008), more patients with tumour invasion of the vasculature (40.9% versus 7.4%, P = 0.001), and fewer patients with blood transfusion (27.3% versus 52.9%, P = 0.036). The groups had similar disease-free survival (group A: median, 17.9 months, 5 years, 27.4%; group B: median, 11.7 months, 5 years, 14.3%; P = 0.427) and overall survival (group A: median, 22.0 months, 5 years, 26.5%; group B: median, 26.5 months, 5 years, 14.7%; P = 0.90). Two hundred patients with unresectable HC were compared with patients who had received operation and found to have worse survival outcomes (P < 0.001)., Conclusions: Vascular resection plus reconstruction in HC resection was feasible and safe and might improve the long-term survival of patients with advanced HC. This aggressive approach should be adopted if the expertise is available and the patient's condition allows., (© 2020 Royal Australasian College of Surgeons.)