Neoadjuvant therapy for hepatocellular carcinoma is the frontier and hot topic in the current field of liver cancer research.The fundamental purpose is to reduce the risk of postoperative recurrence through standardized preoperative treatment methods.From the attempts of Transcatheter Arterial Chemoembolization monotherapy for neoadjuvant therapy for hepatocellular carcinoma to systematic treatment represented by"targeted combined with immunotherapy",the latter has become the most promising neoadjuvant strategy due to its high objective response rate and potential to induce pathological complete remission.However,the field still faces challenges such as lack of evidence of overall survival benefit in Phase Ⅲ randomized controlled trials,treatment-related adverse reactions that may lead to delay in surgery,optimal population screening,and timing of surgery.This article aims to briefly discuss the current research status of the application of neoadjuvant therapy in resectable hepatocellular carcinoma,explore relevant diagnosis and treatment concepts,and further understand neoadjuvant therapy.

Background and Aims:Currently,the treatment of hepatocellular carcinoma(HCC)faces significant challenges due to recurrence and metastasis,with tumor immune evasion being one of the key mechanisms underlying these issues.Signal transducer and activator of transcription 3(STAT3),an important transcription factor,is overactivated in many malignancies and is involved in both tumorigenesis and progression,closely associated with immune evasion.Programmed cell death ligand 1(PD-L1),a key immune checkpoint,helps tumor cells evade immune surveillance when its expression is upregulated,thereby suppressing anti-tumor immunity.Studies have shown that STAT3 may activate the MYC signaling pathway through interaction with DNA-activated protein kinase(PRKDC),thereby promoting PD-L1 expression and inducing immune evasion.However,the specific mechanism of the STAT3/PRKDC/MYC axis in HCC remains unclear.This study aims to elucidate the molecular mechanism by which STAT3 regulates PD-L1 expression through the PRKDC/MYC signaling pathway,potentially inducing immune evasion in HCC,with the goal of providing potential targets for HCC immunotherapy.Methods:The expressions of STAT3 in human normal liver cells(HL-7702)and human HCC cells(HuH-7,HepG2)were detected by qRT-PCR and Western blot.Plasmids with STAT3 knockdown(si-STAT3)and PRKDC overexpression(oe-PRKDC),along with their respective negative controls(si-NC,oe-NC),were constructed and transfected into HCC cells(HuH-7)according to the experimental design,with untreated HuH-7 cells as the blank control.Western blot was used to analyze the expression of STAT3,PRKDC,PD-L1,and MYC pathway-related proteins.Cell proliferation,invasion,migration,and apoptosis of HCC cells were assessed by CCK-8,Transwell,wound healing assay,and flow cytometry.After co-culturing HuH-7 cells with human peripheral blood mononuclear cells(hPBMCs),ELISA was used to detect the secretion of the immune regulatory factor interferon γ(IFN-γ).Co-immunoprecipitation and immunofluorescence co-localization were performed to verify the interaction between STAT3 and PRKDC proteins.Results:Results of qRT-PCR and Western blot showed that the mRNA and protein levels of STAT3 were significantly elevated in HCC cells(both P＜0.05).Functional experiments demonstrated that in the si-STAT3 group,HCC cell proliferation,migration,and invasion were significantly weakened,and cell apoptosis was notably increased;the expression of PD-L1 and MYC pathway-related proteins was significantly downregulated;the secretion of IFN-γ was significantly increased after co-culturing with hPBMCs(all P＜0.05).After co-culturing with oe-PRKDC plasmids,the effects of STAT3 knockdown on HCC cells were significantly reversed(all P＜0.05).Scansite 4.0 database analysis revealed that STAT3 and PRKDC have binding sites,and co-immunoprecipitation and immunofluorescence co-localization experiments confirmed the interaction between STAT3 and PRKDC proteins.Conclusion:STAT3 is highly expressed in HCC cells and can promote HCC cell proliferation,migration,invasion,and immune evasion through interaction with PRKDC,suppress cell apoptosis,activate the MYC pathway,and increase PD-L1 expression.The STAT3/PRKDC/MYC axis may serve as a potential target for HCC immunotherapy.

Neoadjuvant therapy for hepatocellular carcinoma is the frontier and hot topic in the current field of liver cancer research.The fundamental purpose is to reduce the risk of postoperative recurrence through standardized preoperative treatment methods.From the attempts of Transcatheter Arterial Chemoembolization monotherapy for neoadjuvant therapy for hepatocellular carcinoma to systematic treatment represented by"targeted combined with immunotherapy",the latter has become the most promising neoadjuvant strategy due to its high objective response rate and potential to induce pathological complete remission.However,the field still faces challenges such as lack of evidence of overall survival benefit in Phase Ⅲ randomized controlled trials,treatment-related adverse reactions that may lead to delay in surgery,optimal population screening,and timing of surgery.This article aims to briefly discuss the current research status of the application of neoadjuvant therapy in resectable hepatocellular carcinoma,explore relevant diagnosis and treatment concepts,and further understand neoadjuvant therapy.

Background and Aims:Currently,the treatment of hepatocellular carcinoma(HCC)faces significant challenges due to recurrence and metastasis,with tumor immune evasion being one of the key mechanisms underlying these issues.Signal transducer and activator of transcription 3(STAT3),an important transcription factor,is overactivated in many malignancies and is involved in both tumorigenesis and progression,closely associated with immune evasion.Programmed cell death ligand 1(PD-L1),a key immune checkpoint,helps tumor cells evade immune surveillance when its expression is upregulated,thereby suppressing anti-tumor immunity.Studies have shown that STAT3 may activate the MYC signaling pathway through interaction with DNA-activated protein kinase(PRKDC),thereby promoting PD-L1 expression and inducing immune evasion.However,the specific mechanism of the STAT3/PRKDC/MYC axis in HCC remains unclear.This study aims to elucidate the molecular mechanism by which STAT3 regulates PD-L1 expression through the PRKDC/MYC signaling pathway,potentially inducing immune evasion in HCC,with the goal of providing potential targets for HCC immunotherapy.Methods:The expressions of STAT3 in human normal liver cells(HL-7702)and human HCC cells(HuH-7,HepG2)were detected by qRT-PCR and Western blot.Plasmids with STAT3 knockdown(si-STAT3)and PRKDC overexpression(oe-PRKDC),along with their respective negative controls(si-NC,oe-NC),were constructed and transfected into HCC cells(HuH-7)according to the experimental design,with untreated HuH-7 cells as the blank control.Western blot was used to analyze the expression of STAT3,PRKDC,PD-L1,and MYC pathway-related proteins.Cell proliferation,invasion,migration,and apoptosis of HCC cells were assessed by CCK-8,Transwell,wound healing assay,and flow cytometry.After co-culturing HuH-7 cells with human peripheral blood mononuclear cells(hPBMCs),ELISA was used to detect the secretion of the immune regulatory factor interferon γ(IFN-γ).Co-immunoprecipitation and immunofluorescence co-localization were performed to verify the interaction between STAT3 and PRKDC proteins.Results:Results of qRT-PCR and Western blot showed that the mRNA and protein levels of STAT3 were significantly elevated in HCC cells(both P＜0.05).Functional experiments demonstrated that in the si-STAT3 group,HCC cell proliferation,migration,and invasion were significantly weakened,and cell apoptosis was notably increased;the expression of PD-L1 and MYC pathway-related proteins was significantly downregulated;the secretion of IFN-γ was significantly increased after co-culturing with hPBMCs(all P＜0.05).After co-culturing with oe-PRKDC plasmids,the effects of STAT3 knockdown on HCC cells were significantly reversed(all P＜0.05).Scansite 4.0 database analysis revealed that STAT3 and PRKDC have binding sites,and co-immunoprecipitation and immunofluorescence co-localization experiments confirmed the interaction between STAT3 and PRKDC proteins.Conclusion:STAT3 is highly expressed in HCC cells and can promote HCC cell proliferation,migration,invasion,and immune evasion through interaction with PRKDC,suppress cell apoptosis,activate the MYC pathway,and increase PD-L1 expression.The STAT3/PRKDC/MYC axis may serve as a potential target for HCC immunotherapy.

Objective:To investigate the value of the extrahepatic bile duct and main pancreatic duct segment patterns on magnetic resonance cholangiopancreatography (MRCP) for differentiating the periampullary carcinoma (PAC).Methods:The clinicopathologic data of 125 patients with PAC who were admitted to Wuxi No.2 People’s Hospital from June 2013 to December 2021 were retrospectively analyzed, including 72 males and 53 females, aged (64.9±8.6) years. According to its anatomy, the extrahepatic bile duct (B) was divided into suprapancreatic and intrapancreatic (including ampullary) segments, and the main pancreatic duct (P) was divided into tail-body and head segments. MRCP patterns: i. the extrahepatic bile duct or main pancreatic duct visible without dilatation, ii. cutoff of the distal extrahepatic bile duct or main pancreatic duct with upstream dilatation, iii. cutoff of the intrapancreatic or head segment with upstream dilatation and remnant intrapancreatic or head segments invisible, iv. cutoff of the intrapancreatic or head segment with upstream dilatation and nondilated remnant intrapancreatic or head segments, were represented as 0, 1, 2, and 3, respectively. Segment patterns of B1/P0+ B1/P1, B0/P2+ B0/P3+ B2/P2+ B2/P3+ B3/P3, B3/P0, and B0/P0+ B2/P0 on MRCP were compared in PAC patients.Results:Of the 125 patients, there were 57 (45.6%) with pancreatic head carcinoma, 36 (28.8%) with ampullary carcinoma, 20 (16.0%) with distal cholangiocarcinoma, and 12 (9.6%) with periampullary duodenal carcinoma. Segment patterns of B0/P2+ B0/P3+ B2/P2+ B2/P3+ B3/P3 were found in 52 patients with pancreatic head carcinoma (91.2%, 52/57), with a significant difference between PAC (χ 2=110.66, P<0.001). Segment patterns of B1/P0+ B1/P1were found in 36 patients with ampullary carcinoma (100.0%, 36/36), fallowed by 11 (91.7%, 11/12) with periampullary duodenal carcinoma, with a significant difference between PAC (χ 2=129.95, P<0.001). Segment pattern of B3/P0 presented in 16 patients with distal cholangiocarcinoma (80.0%, 16/20), with a significant difference between PAC (χ 2=62.45, P<0.001). The segment patterns of B0/P0+ B2/P0 were only seen in 3 of 57(5.3%) patients with pancreatic head carcinoma. Conclusion:On MRCP, cutoff of the head segment with upstream dilatation and remnant head segment invisible or nondilated indicates the pancreatic head carcinoma. Cutoff of the intrapancreatic segment with upstream dilatation, remnant intrapancreatic segment visible, and main pancreatic duct nondilated, indicates the distal cholangiocarcinoma. And cutoff of the distal extrahepatic segment with upstream dilatation and main pancreatic duct dilatation or not, indicates the ampullary or periampullary duodenal carcinoma.

BACKGROUND: Coronary artery disease (CAD) is the commonest cause of heart failure (HF), whereas pulmonary hypertension (PH) has not been established or reported in this patient population. Therefore, we assessed the prevalence, risk factors, and survival in CAD-associated HF (CAD-HF) complicated with PH. METHODS: Symptomatic CAD-HF patients were continuously enrolled in this prospective, multicenter registry study. Echocardiography, coronary arteriography, left and right heart catheterization (RHC), and other baseline clinical data were recorded. Patients were followed up and their survival was recorded. RESULTS: One hundred and eighty-two CAD-HF patients were enrolled, including 142 with HF with a preserved ejection fraction (heart failure with preserved ejection fraction [HFpEF]; left ventricular ejection fraction [LVEF] ≥50%) and 40 with a reduced ejection fraction (heart failure with reduced ejection fraction [HFrEF]; LVEF < 50%). PH was diagnosed with RHC in 77.5% of patients. Patients with PH showed worse hemodynamic parameters and higher mortality. HFrEF-PH patients had worse survival than HFpEF-PH patients. CAD-HF patients with an enlarged left ventricular end-diastolic diameter and reduced hemoglobin were at higher risk of PH. Nitrate treatment reduced the risk of PH. Elevated creatinine and mean pulmonary arterial pressure (mPAP), diastolic pressure gradient (DPG) ≥7 mmHg, and previous myocardial infarction (MI) entailed a higher risk of mortality in CAD-HF patients with PH. CONCLUSIONS: PH is common in CAD-HF and worsens the hemodynamics and survival in these patients. Left ventricle enlargement and anemia increase the risk of PH in CAD-HF. Patients may benefit from nitrate medications. Renal impairment, elevated mPAP, DPG ≥7 mmHg, and previous MI are strong predictors of mortality in CAD-HF-PH patients. TRIAL REGISTRATION ClinicalTrials.gov, NCT02164526.
Coronary Artery Disease/epidemiology* ; Creatinine ; Heart Failure/complications* ; Humans ; Hypertension, Pulmonary/complications* ; Nitrates ; Prevalence ; Prognosis ; Prospective Studies ; Registries ; Risk Factors ; Stroke Volume ; Ventricular Function, Left

Objective:To investigate the clinical application value of computed tomography (CT) and magnetic resonance imaging (MRI) examination in preoperative evaluation of adjacent organ invasion for periampullary carcinomas (PACs).Methods:The retrospective and descriptive study was conducted. The clinicopathological data of 81 patients with PACs who were admitted to the Affiliated Wuxi No.2 People′s Hospital of Nanjing Medical University from September 2013 to June 2019 were collected. There were 52 males and 29 females, aged from 41 to 80 years, with an average age of 62 years. Observation indicators: (1) surgical and pathological outcomes; (2) evaluation of adjacent organ invasion on CT and MRI examination for PACs; (3) comparison of diagnostic accuracy between CT and MRI examination in assessing adjacent organ invasion for PACs; (4) auxiliary and feature images of adjacent organ invasion for PACs; (5) comparison between CT and MRI examination in assessing adjacent organ invasion for PACs. Measurement data with skewed distribution were represented as M (range), and count data were described as absolute numbers or percentages. Comparison between groups was analyzed using the Mann-Whitney U test.The receiver operating characteristic curve and area under curve were used to evaluate diagnostic accuracy between CT and MRI examination in assessing adjacent organ invasion for PACs. Consistency was compared using the κ test. Results:(1) Surgical and pathological outcomes: of the 81 patients, 76 underwent pancreatoduodenectomy, 5 underwent palliative gastrojejunostomy or biliary drainage combined with biopsy, including the pancreas, duodenum, or lymph nodes. Of the 81 patients, 35 had pancreatic head carcinoma including 26 with duodenal invasion and 9 without duodenal invasion; 23 had ampullary carcinoma including 17 with duodenal invasion, 4 with both duodenal invasion and pancreatic invasion, and 2 without duodenal invasion or pancreatic invasion; 17 had distal bile duct carcinoma (including papillary type in 4 patients and periductal infiltrative type in 13 patients), of which 8 had duodenal invasion, 1 had duodenal invasion and pancreatic invasion (pathological classification of the 9 patients was periductal infiltrative type), 8 had neither duodenal invasion nor pancreatic invasion; 6 had duodenal carcinoma including 4 with pancreatic invasion and 2 without pancreatic invasion. (2) Evaluation of adjacent organ invasion on CT and MRI examination for PACs: of the 35 patients with pancreatic head carcinoma, duodenal invasion was identified in 25 patients and no duodenal invasion in 10 patients on both CT and MRI examination. Of the 23 patients with ampullary carcinoma, duodenal invasion, pancreatic invasion, both duodenal invasion and pancreatic invasion, and neither duodenal invasion nor pancreatic invasion were identified in 17, 1, 4, and 1 patients on CT examination, respectively; the above indicators were identified in 15, 2, 4, and 2 patients on MRI examination. Of the 17 patients with distal bile duct carcinoma, pancreatic invasion, both duodenal invasion and pancreatic invasion, and neither duodenal invasion nor pancreatic invasion were identified in 8, 1, and 8 patients on CT examination, respectively; the above indicators were identified in 9, 1, and 7 patients on MRI examination. Of the 6 patients with duodenal carcinoma, pancreatic invasion and no pancreatic invasion were identified in 3 and 3 patients on both CT and MRI examination.(3) Comparison of diagnostic accuracy between CT and MRI examination in assessing adjacent organ invasion for PACs: two reviewers had good agreement in assessing adjacent organ invasion on CT examination for pancreatic head carcinoma, ampullary carcinoma, and distal bile duct carcinoma ( κ=0.868, 0.701, 0.881, P<0.05), but they had poor agreement for duodenal carcinoma ( κ=0.333, P>0.05). Meanwhile, two reviewers had good agreement in assessing adjacent organ invasion on MRI examination for pancreatic head carcinoma and ampullary carcinoma( κ=0.860, 0.747, P<0.05), and moderate agreement for distal bile duct carcinoma ( κ=0.643, P<0.05), but they had poor agreement for duodenal carcinoma ( κ=0.333, P>0.05). (4) Auxiliary and feature images of adjacent organ invasion for PACs: for the 25 patients who had pancreatic head carcinoma with duodenal invasion on CT and MRI examination, based on well filling in duodenum, 12 patients showed locally morphological change of lumen and flattened or disappeared duodenal mucosal folds on negative contrast CT cholangiopancreatography; 14 patients showed similar signs on T2 weighted imaging or magnetic resonance cholangiopancreatography. The 17 patients who had distal bile duct carcinoma with pancreatic invasion on CT and MRI examination were periductal infiltrative type. Pancreatic invasion manifested as local thickenness of ductal wall with marked enhancement and narrowed ductal lumen, which was indistinguishable from the pancreas, and the pancreatic parenchyma showed hyperdense or hyperintense signs similar with the lesion, like a "transmural" sign. One patient with both duodenal invasion and pancreatic invasion showed locally thickened and enhanced duodenal wall on both CT and MRI examination. Four patients, who had papillary type distal bile duct carcinoma with neither duodenal invasion nor pancreatic invasion, showed intraductal growing mass which had a discernible boundary to the pancreas and slighter enhancement than infiltrative type on both CT and MRI examination. (5) Comparison between CT and MRI examination in assessing adjacent organ invasion for PACs: CT examination evaluating adjacent organ invasion for pancreatic head carcinoma, ampullary carcinoma, distal bile duct carcinoma, and duodenal carcinoma had a sensibility of 92.3%, 90.5%, 88.9%, 75.0%, a specificity of 88.9%, 50.0%, 87.5%, 100.0%, an accuracy of 0.906, 0.702, 0.882, 0.875, respectively. MRI examination evaluating adjacent organ invasion for pancreatic head carcinoma, ampullary carcinoma, distal bile duct carcinoma, and duodenal carcinoma had a sensibility of 88.5%, 85.7%, 88.9%, 75.0%, a specificity of 77.8%, 50.0%, 75.0%, 100.0%, an accuracy of 0.831, 0.679, 0.819, 0.875. There was no significant difference in sensibility for pancreatic head carcinoma, distal bile duct carcinoma, or duodenal carcinoma between CT and MRI examination( χ2=3.140, 0.141, 0.444, P>0.05), while there was a significant difference in sensibility for ampullary carcinoma ( χ2=13.263, P<0.05). There was no significant difference in specificity for pancreatic head carcinoma, ampullary carcinoma, or distal bile duct carcinoma between CT and MRI examination( χ2=0.321, 2.000, 3.429, P>0.05). There was no significant difference in accuracy for pancreatic head carcinoma, ampullary carcinoma, distal bile duct carcinoma, or duodenal carcinoma between CT and MRI examination( Z=0.967, 0.273, 0.559, 0.000, P>0.05). Conclusion:CT and MRI examination can be used for preoperative evaluation of adjacent organ invasion for periampullary carcinoma, with similar performance in specificity and accuracy, however, CT examination has a higher sensibility for ampullary carcinoma.

Objective To explore the mechanism of mTOR-mediated liver cancer cell invasion.Methods q-PCR was used to check the expression of miR-27a and GP73;miR-27a mimics were transfected into GP73-high expressing M97H cells and miR-27a inhibitors were transfected into GP73-low expressing HepG2 cells,q-PCR and Western blot were performed to observe the expression of GP73;Dual-luciferase assay was also performed to verify the binding sites of miR-27a in GP73 3'UTR;miR-27a mimics were transfected into M97H cells and miR-27a inhibitors were transfected into HepG2 cells,Transwell assay was used to measure cell invasion.Results mTOR downregulated miR-27a and upregulated GP73;GP73 was downregulated by miR-27a and upregulated by miR-27a suppression;GP73 was a target gene of miR-27a;miR-27a inhibited the invasion of M97H cells rather than HepG2 cells.Conclusions miR-27a is negatively regulated by mTOR and inhibits liver cancer cell invasion via targeting GP73.

Objective:To explore characteristics and interventional treatment of the elderly patients with chronic total occlusion of coronary artery. Methods:According to the age,146 cases of coronary heart disease received interventional treatment of chronic total occlusion from Feb 2012 to Mar 2016 were divided into elderly group and youth group. Comparative analysis of characteristics and prognosis between the two groups was done. Results:The proportion of family history of coronary heart disease in elderly group was significantly lower than that in the young group (P<0.05), the incidence rate of occlusive vascular calcification or tortuosity and surgical intervention time were significantly higher than those in the young group (P<0.05) . After interventional treatment, LVEDD in elderly group was significantly lower than that in the young group (P<0.05),and LVEF,left ventricular aneurysm and wall motion abnormality rate had no significant differences (P>0.05) . Conclusions:Elderly patients with chronic total occlusion of coronary artery prone to calcification or tortuosity, interventional treatment takes a long time, success rate and adverse cardiovascular events had no difference compared with the young, postoperative cardiac function of elderly patients improved more obviously.

Objective To study the right ventricular function of patients with pulmonary thromboembolism by using color Doppler ultrasound.Methods 31 patients with acute pulmonary thromboembolism,compared with 31 vohnteers,were enrolled in this study.The right ventricular anterior wall movement,right ventricular end diastolic volume,right ventricular ejection fraction,and myocardial performance index were observed by echocardiography.Resuits The right atrium diameter,right ventricles diameter,right ventrieular end diastolic volume and pulmonary artery inner diameter in study group were much larger than that in control group (P<0.01),and the right ventricular anterior wall movement and right ventrieular ejection fraction decreased in study group (P<0.01).Tricuspidal annular E peak velocity tended to be decreased,isovolumie relaxation time and isovolumic contraction time were prolonged and myocardial performance index was increased (P<0.01).Right ventricular myocardial performance index showed significant correlation with right ventrieular ejection fraction (r=0.78,P<0.01),isovolumic relaxation time and isovolumic contraction time(rl=0.88,r2=0.57,P<0.01).Conclusion The right ventricular function in patients with pulmonary thromboembelism is decreased and myocardial performance index is a sensitive index which can be used to reflect right ventricular function in pulmonary thromboembolism.