Immune checkpoint blockade (ICB) represents an important therapeutic approach for hepatocellular carcinoma (HCC). However, resistance to ICB treatment remains challenging. Here, we identified protein phosphatase magnesium-dependent 1δ (PPM1D) as a driver of HCC immunotherapy resistance. PPM1D expression was significantly upregulated in tumor tissues, and tumor cells elevated PPM1D expression in response to effector CD8+ T lymphocyte activation via TNFα-NF-κB signaling. Genetic or pharmacological inhibition of PPM1D inhibited HCC progression by enhancing CD8+ T-cell cytotoxicity. Mechanistically, PPM1D maintained tumor cell mitochondrial homeostasis and limited mitochondrial DNA leakage-triggered cGAS-STING-IFN activity by directly dephosphorylating mitochondrial outer membrane component VDAC2 at Ser 115, preventing VDAC2 oligomerization. Inhibiting PPM1D synergized with PD-1 inhibition in preclinical HCC models with minimal toxicity. Together, this study provides insights into targeting PPM1D to improve immunotherapy efficacy in HCC.

This study aimed to develop an optimal alternative site for islet transplantation, addressing the limitations of the current clinical standard, the intrahepatic site. In this study, prevascularized muscle sinus tracts (MSTs) in mice were created by implanting and then removing polyamide rods, leveraging a controlled foreign body reaction to generate a highly vascularized, porous collagen matrix. Transplantation of 350 syngeneic islets into these MSTs consistently reversed diabetes in mice, achieving long-term normoglycemia for over 180 days, with efficacy comparable with kidney capsule transplantation. The approach also supported the survival of human islets in immunodeficient mice and demonstrated feasibility in a porcine autotransplantation model. This work establishes the MST as a simple, effective, and clinically promising strategy that enhances islet engraftment through localized prevascularization, potentially improving the therapeutic outcomes of islet transplantation.

Abstract Background Lenvatinib and programmed cell death-1 (PD-1) inhibitors have emerged as a novel treatment for patients with BTC. This study aimed to compare the efficacy and safety of triple therapy with lenvatinib, PD-1 inhibitors plus chemotherapy (LenP + C) and dual therapy with lenvatinib plus PD-1 inhibitors (LenP) in patients with unresectable or recurrent BTC. Methods BTC patients receiving LenP + C or LenP treatment between June 2020 and March 2022 were retrospectively analyzed. The primary outcome was progression-free survival (PFS). The secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS) and safety. Results Ninety-eight patients were included in the present study, and they were divided into the LenP + C group (n = 40) and LenP group (n = 58). The median PFS was 8.3 months in the LenP + C group, significantly longer than 4.5 months in the LenP group (HR = 0.471; 95% CI, 0.271–0.817; P = 0.007). Although no difference was found in ORR between the two groups (LenP + C, 42.5% vs. LenP, 27.6%, P = 0.125), the DCR was higher in the LenP + C group than in the LenP group (95.0% vs. 75.9%, P = 0.012). The median OS was comparable between the two groups (13.7 vs. 12.4 months, P = 0.749). Treatment-related adverse events were more frequently observed in the LenP + C group. The incidence of neutropenia (grade ⩾3) was higher in patients receiving triple therapy (15% vs. 2%, P = 0.035). Conclusions This study showed that treatment with lenvatinib and PD-1 inhibitors is safe and effective for advanced BTC. The combination of chemotherapy with lenvatinib and PD-1 inhibitors showed improved anti-tumor efficacy compared with lenvatinib and anti-PD-1 therapy, yet with more toxic effects.

PurposeTo evaluate the efficacy of ultrasound-guided percutaneous microwave ablation (PMA) combined with portal vein embolization (PVE) for planned hepatectomy.MethodsWe retrospectively reviewed data of 18 patients with multiple right liver tumors or hilar tumor of liver invades the surrounding tissue and insufficient future liver remnant (FLR) for hepatectomy from July 2015 to March 2017. Ultrasound-guided PMA was performed by using PMCT cold circulation microwave treatment apparatus. PVE was performed after PMA. The increase of FLR was evaluated by computed tomography (CT) 6-22 days after PVE. The proportion of FLR, increase in the amplitude of FLR, procedure-related complications, perioperative morbidity and mortality, and overall survival (OS) rates, the median survival time were analyzed.ResultsThe median volume of FLR before PMA and PVE was 369.7 ml (range: 239.4-493.1 ml). After a median waiting period of 11.5 days (range: 6-22 days), the median volume of FLR was increased to 523.4 ml (range: 355.4-833.3 ml). The changes in FLR before and after PMA and PVE were statistically significant (p<0.001). No serious perioperative complications or mortality were found. After a median follow-up time of 51.0 months (range: 2-54 months), the 6-month, 1-year, 2-year, 3-year and 4-year survival rates were 88.9%, 72.2%, 44.4%, 33.3%, 22.2%, respectively, and the median survival time was 15.0 ± 7.1 months.ConclusionPMA combined with PVE increases FLR rapidly, avoids touching malignant tumors, and produces fewer procedure-related complications. It appears safe and efficacious for planned hepatectomy.

Duodenum-preserving pancreatic head resection (DPPHR) is very complicated due to its difficulty to find the lower common bile duct (CBD), and to preserve the blood supply of the duodenum and CBD. Recently, indocyanine green (ICG) has been widely applied for navigation during biliary system and liver surgery. However, the application of ICG-guided laparoscopic DPPHR has not been established. Herein, we report an intraoperative angiography technique using ICG fluorescence imaging to visualise blood flow, tissue perfusion, CBD navigation and bile leakage assessment.

本研究回顾性分析2016年1月至2018年12月在浙江省人民医院肝胆胰外科接受腹腔镜解剖性右半肝切除的42例原发性肝癌患者的临床资料。其中19例采用循中肝静脉和肝后下腔静脉平面法（肝静脉组），23例采用阻断入右肝血流后按缺血线法（缺血线组）。肝静脉组在手术时间［（234.21±50.59）min比（276.52±76.19）min］、术中出血量［（388.42±125.05）ml比（479.13±149.15）ml］、术后住院时间［（7.53±2.86）d比（9.48±3.15）d］较缺血线组有显著优势（均 P<0.05）。两组术后总并发症发生率无明显差异，围手术期均无死亡病例发生。术后中位随访时间31个月，肝静脉组复发8例，死亡3例，缺血线组复发10例，死亡4例。本研究显示腹腔镜循中肝静脉和肝后下腔静脉平面右半肝切除减少术中出血、缩短手术及住院时间，是一种安全、有效的肝切除术式。

Long non-coding RNAs are associated with cancer progression. Long intergenic non-protein coding RNA (linc)-regulator of reprogramming (ROR) enhances tumor development in hepatocellular carcinoma (HCC). However, the effect of chemoresistance and its underlying mechanisms in HCC are not completely understood. The present study aimed to identify the effect of ROR on sensitivity to doxorubicin (DOX) in HCC cells. In the present study, Cell Counting Kit-8 and EdU assays were performed to assess cell viability and proliferation, respectively. In addition, E-cadherin and vimentin protein expression levels were assessed via western blotting and immunofluorescence. The results of the present study demonstrated that HCC cells with high linc-ROR expression levels were more resistant to DOX, and linc-ROR knockdown increased HCC cell DOX sensitivity compared with the control group. The results indicated that compared with the NC siRNA group, linc-ROR knockdown notably suppressed epithelial-mesenchymal transition by downregulating twist family bHLH transcription factor 1 (TWIST1) expression. TWIST1 knockdown displayed a similar effect on HCC cell DOX sensitivity to linc-ROR knockdown. Moreover, linc-ROR knockdown-induced HCC cell DOX sensitivity was inhibited by TWIST1 overexpression. The present study provided evidence that linc-ROR promoted HCC resistance to DOX by inducing EMT via interacting with TWIST1. Therefore, linc-ROR might serve as a therapeutic target for reducing DOX resistance in HCC.

探讨吲哚菁绿荧光技术用于腹腔镜保留十二指肠胰头切除术(DPPHR)的相关经验。回顾性分析浙江省人民医院2019年12月至2020年4月行吲哚菁绿荧光导航腹腔镜DPPHR的3例患者临床资料。3例患者均完成腹腔镜DPPHR，年龄分别为26、36、48岁，男性1例，女性2例。手术时间分别为220、270、310 min，术中出血量分别为150、300、200 ml。1例患者术后发生生化漏，1例无术后并发症，另1例患者术后B级胰瘘合并腹腔出血及感染。3例患者术后住院时间分别为20、9、8 d。3例患者均无胆漏、胃瘫并发症。术后病理提示胰腺神经内分泌肿瘤(G2)1例，慢性胰腺炎伴胰管扩张及结石形成1例，胰腺导管内乳头状粘液性肿瘤1例。吲哚菁绿荧光导航腹腔镜DPPHR是一种安全有效的手术方式，可能有效防止胆道的损伤和胆漏发生，值得进一步推广。

Objective:To study the causes of hemorrhage after laparoscopic pancreaticoduodenectomy (LPD) and to develop countermeasures in its prevention.Methods:The clinical data of 215 patients who underwent LPD at the Department of Hepatobiliary and Pancreatic Surgery of Zhejiang Provincial People's Hospital from December 2013 to May 2020 were reviewed. The patients’ clinical data including gender, age, comorbidities and postoperative complications such as bleeding, pancreatic fistula, biliary fistula and intraperitoneal infection were studied, with the aims to analyze the causes, clinical manifestations and treatment results of post-pancreaticoduodenectomy hemorrhage (PPH) after LPD.Results:Of 215 patients, there were 132 males and 83 females, aged (60.7±10.3) years. PPH occurred in 20 patients, incidence rate was 9.30%(20/215). Early hemorrhage was mainly caused by inadequate hemostasis or loosening of vascular clips, while delayed hemorrhage was mainly caused by gastrointestinal fistula with vascular erosion, arterial injury by intraoperative energy instruments or pseudoaneurysms. Among the 20 patients, 6 patients had early hemorrhage and 14 delayed hemorrhage. There was 1 patient with grade A, 10 with grade B and 9 with grade C hemorrhage. Thirteen patients developed pancreatic fistula, 1 biliary fistula, and 2 intraperitoneal infection. One patient responded well to conservative treatment. Hemostasis was successfully achieved by gastroscopy ( n=1) and interventional therapy ( n=7). Eleven patients required laparotomy for hemostasis. In this study, 14 of 20 patients survivied PPH and 6 patients died. The mortality rate was 30% (6 of 20 patients with PPH). Conclusions:Early hemorrhage was caused by inadequate hemostasis or loosening vascular clips, while delayed hemorrhage was related to gastrointestinal fistula with vascular erosion, arterial injury by intraoperative energy instrument or pseudoaneurysm. Careful hemostasis, adequate protection of blood vessels, and accurate anastomosis should be performed in LPD. DSA angiography should be used for arterial hemorrhage which progressed very rapidly. Interventional therapy including embolism and stenting were means to control arterial bleeding in PPH. Decisive surgical exploration when interventional therapy failed was important in reducing the mortality rate of these patients.

Objective:To study the technical and essential steps in laparoscopic selective devascularization with paraesophageal veins-preservation.Methods:To retrospectively analyze the clinical data of 13 cirrhotic patients who underwent laparoscopic selective pericardial devascularization for portal hypertension at the Department of Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People's Hospital from January 2019 to March 2020. There were 9 males and 4 females with age ranging from 41 to 83 years (median 51 years). The operative time, intraoperative blood loss, postoperative complications and follow-up data were analyzed.Results:All the 13 patients completed theoperation, no patient stopped the operation or transferred to laparotomy. The operation time was (170±32) min.The intraoperative bleeding was (160±30) ml. The postoperative hospital stay was (6.1±1.1) days. There were no complications, including pancreatic leakage and intra-abdominal infection. On follow-up which ranged from 1 to 15 months, one patient developed portal vein thrombosis, no upper gastrointestinal rebleeding.Conclusions:Preservation of esophageal veins in laparoscopic selective devascularization is an accurate surgery which requires close teamwork and rich experience in laparoscopic surgery. The preservation of the main trunk of the gastric coronary vein and integrity of the esophageal veins are the keys to the surgery which is safe and feasible.

The safety and feasibility of laparoscopic versus open liver resection (LLR vs. OLR) associated lymphadenectomy for intrahepatic cholangiocarcinoma (ICC) are still controversial. The aim of the present study was to compare short and long-term outcomes. We reviewed data on 43 consecutive patients who underwent curative liver resection with associated lymphadenectomy for ICC. The short-term outcomes including postoperative morbidity and mortality, and the long-term outcomes including overall survival (OS) and recurrence-free survival (RFS) were compared. The median survival, 1- and 3-year OS in LLR and OLR groups were 22.5 months, 76.9% and 47.1%, and 12.1 months, 43.1% and 20.0%, respectively. The median survival, 1- and 3-year RFS in LLR and OLR groups were 10.3 months, 27.8% and 0%, and 8.1 months, 24.0% and 4.0%, respectively. The results showed that LLR obviously reduced intraoperative blood loss (median, 375 vs. 500ml, p = 0.016) and postoperative hospital stay (median, 6 vs. 9 days, p = 0.016). Moreover, there was no significant difference in short-term outcomes including postoperative morbidity (including wound infection, bile leakage, liver failure and pneumonia) and mortality within 30 days, and long-term outcomes including OS and RFS between LLR and OLR. (all p > 0.05). Multivariate analysis showed that CA19-9 level, TNM stage, and tumor differentiation were independent risk factors for OS and RFS. LLR for ICC is safety and feasibility compared with OLR. The advantage of LLR was to reduce intraoperative blood loss and postoperative hospital stay.

Objective: To investigate the application of proximal splenic vein (SV) ligation in laparoscopic splenectomy plus pericardial devascularization (LSPD) surgery.

本文回顾分析了2013年6月至2017年4月浙江省人民医院(杭州医学院附属人民医院)肝胆胰外科及微创外科小肝癌合并门静脉高压症8例患者资料.患者男性6例,女性2例,年龄(51.6±6.7)岁,均行超声引导微波消融(PMAT)联合腹腔镜脾切除加贲门周围血管离断术(LSPD)治疗.8例患者均顺利完成手术,无中转开腹.手术时间(195.6±62.4) min,其中消融时间(9.6±2.2) min,术中出血量(228.7±101.9)ml,术后住院时间(12.1±4.6)d.无术后严重并发症.肝脏肿瘤消融完全,无消化道再出血.随访2 ～36个月,1例随访7个月肝癌复发再次消融,随访至今未见复发转移.其余肝癌患者无复发.

目的 总结分析腹腔镜半肝联合全尾状叶整块切除(en-bloc)治疗肝门胆管癌的治疗经验.方法 回顾性分析2017年4月和2017年9月浙江省人民医院肝胆胰外科行腹腔镜半肝联合全尾状叶en-bloc治疗肝门胆管癌的2例病人临床资料.结果 2例病例Bismuth-Corlette分型分别为ⅢA型和Ⅳ型.分别行右半肝联合全尾状叶切除术和左半肝联合全尾状叶切除术.无中转开放手术,无围手术期死亡.手术时间分别为520 min和680 min:出血量为800 mL和500 mL,未行血管重建,行胆肠端侧吻合.2例术中冰冻病理学检查均提示胆管切缘阴性.术后病理学检查结果均为腺癌,上下切缘均阴性,淋巴结阳性(0/12)及(1/9).术后分别随访11、16个月,无复发,无术后胆肠吻合口狭窄.1例术后发生胆漏,经保守治疗治愈,无术后出血等其他并发症.结论 腹腔镜半肝联合全尾状叶整块切除治疗肝门部胆管癌根治术在有经验的腹腔镜中心选择合适的病人是可以尝试施行的,但须临床数据进一步验证.

Resistance to chemotherapy drugs remains a significant problem for the treatment of many types of cancer. Fascin-1 (FSCN-1) is an actin-bundling protein involved in the invasion and metastasis of a variety of tumors. However, its involvement in drug resistance in hepatocellular carcinoma (HCC) remains unclear. The present study aimed to investigate the function of FSCN-1 in HCC resistance to doxorubicin (DOX). FSCN-1 expression was increased in DOX-resistant HCC cell lines (SNU449 and SNU387) compared with DOX-sensitive cell lines (Huh7 and Hep3B). The resistance of HCC cells to DOX was decreased following FSCN-1 knockdown with small interfering RNA. FSCN-1 knockdown also significantly altered the expression of key markers of epithelial-mesenchymal transition (EMT). Notably, vimentin expression was reduced and epithelial-cadherin expression was increased. Furthermore, when EMT was suppressed through knockdown of Twist, an essential pathway of DOX-induced EMT, the viability of HCC cells following treatment with DOX was not affected by FSCN-1 expression. Furthermore, FSCN-1 knockdown eliminated hypoxia-induced doxorubicin resistance and EMT. The results of the present study indicated that FSCN-1 expression increased DOX resistance in HCC cells via the promotion of EMT, and this phenomenon was maintained in a hypoxic environment. FSCN-1 potentially represents a novel target to overcome resistance to DOX in HCC.

Objective To analyze the initial experience of total laparoscopic radical resection for patients with Bismuth type Ⅲa hilar cholangiocarcinoma.Methods A retrospective study was conducted to analyze the clinical data of three patients with Bismuth type Ⅲa hilar cholangiocarcinomatotal who underwent laparoscopic radical resection in Zhejiang Provincial People's Hospital from February to May in 2017.Results The three patients all underwent the operations successfully.The operation time ranged from 490.0 to 580.0 min.The intraoperative blood loss ranged from 300.0 ml to 1 200.0 ml.There was no severe perioperatire complication or death.One patient developed biliary leakage which responded to drainage without reoperation.Another patient developed pleural effusion treated with minimal invasive drainage.The length of postoperative hospital stay ranged from 10.0 to 18.0 days.Histopathology showed two patients with well-differentiated adenocarcinomas and one patient with poorly differentiated adenocarcinoma.The number of lymph nodes harvested ranged from 8 ～ 13.Two patients had no regional lymph node metastasis and one patient had regional lymph node metastasis (1/13).The hilar bile duct resection margins of the three patients were all negative.There was no evidence of tumor recurrence on following up for 7 ～ 10 months.Conclusions It was safe and feasible to carry out total laparoscopic radical resection in selected patients with Bismuth type Ⅲa hilar cholangiocarcinoma.More patients and longer follow-up are required to study the long term oncological results.

目的 探讨脾血管优先技术在腹腔镜保留脾脏胰体尾切除术中的应用.方法 回顾性分析2011年6月至2017年12月浙江省人民医院和浙江省长兴县人民医院采用腹腔镜保留脾脏胰体尾切除术治疗的58例胰体尾良性或交界性占位病变患者的临床资料.结果 中转开腹2例;余56例均顺利完成手术,其中保留脾动、静脉的保脾胰体尾切除术(Kimura法)53例,离断脾血管、保留胃短血管的保脾胰体尾切除术(Warshaw法)3例.手术时间65～220 (160±30) min,出血量30～500 (100±25) mL,术后住院时间5～21(8±5)d.术后并发生化瘘15例,B级胰瘘2例,C级胰瘘1例,腹腔出血1例,腹腔脓肿2例,肺部感染2例.术后病理诊断为胰腺内分泌肿瘤8例,胰腺导管内乳头状黏液瘤10例,胰腺实性假乳头状瘤12例,黏液性囊腺瘤10例,浆液性囊腺瘤13例,慢性胰腺炎肿块5例.结论 脾血管优先技术具有简便、安全的特点,有助于主动选择术式和规划手术路径,提高腹腔镜胰尾切除术的安全性和保脾成功率.

Objective To investigate the value of laparoscopic total pancreastectomy for the treatment of noncancerous pancreatic lesions.Methods Clinical data of 3 cases of noncancerous pancreatic lesions undergoing laparoscopic total pancreatectomy in Zhejiang Provincial People's Hospital were reviewed retrospectively.Results One patient underwent laparoscopic total pancreatectomy,one patient underwent laparoscopic resection with robotic reconstruction and one did laparoscopic resection with open reconstruction.All were spleen preserving surgery.The operation time was 310 (280-350) minutes,estimated blood loss was 483 ml(250-700)ml and postoperative hospital stay was 27 (14-38) days.One patient had postoperative bile leakage.Insulin was used to control blood glucose level in all postoperative cases.As showed by pathology there were intraductal papillary mucinous neoplasms in two patients and multiple neurocndocrine tumor in one patient.Conclusion Laparoscopic total pancreatectomy is safe and minimally invasive for the treatment of noncancerous pancreatic diseases.

BACKGROUND: Splenectomy and pericardial devascularization (SPD) is an effective treatment of upper gastrointestinal bleeding and hypersplenism in cirrhotic patients with portal hypertension. Indocyanine green retention at 15 minutes (ICGR15) was reported to offer better sensitivity and specificity than the Child-Pugh classification in hepatectomy, but few reports describe ICGR15 in SPD. The present study was to evaluate the prognostic value of ICGR15 for cirrhotic patients with portal hypertension who underwent SPD.METHODS: From January 2012 to January 2015, 43 patients with portal hypertension and hypersplenism caused by liver cirrhosis were admitted in our center and received SPD. The ICGR15, Child-Pugh classification, model for end-stage liver disease (MELD) score, and perioperative characteristics were analyzed retrospectively.RESULTS: Preoperative liver function assessment revealed that 34 patients were Child-Pugh class A with ICGR15 of 13.6%-43.0% and MELD score of 7-20; 8 patients were class B with ICGR15 of 22.8%-40.7% and MELD score of 7-17; 1 patient was class C with ICGR15 of 39.7% and MELD score of 22. The optimal ICGR15 threshold for liver function compensation was 31.2%, which offered a sensitivity of 68.4% and a specificity of 70.8%. Univariate analysis showed preoperative ICGR15, MELD score, surgical procedure, intraoperative blood loss, and autologous blood transfusion were significantly different between postoperative liver function compensated and decompensated groups. Multivariate regression analysis revealed that ICGR15 was an independent risk factor of postoperative liver function recovery (P=0.020).CONCLUSIONS: ICGR15 has outperformed the Child-Pugh classification for assessing liver function in cirrhotic patients with portal hypertension. ICGR15 may be a suitable prognostic indicator for cirrhotic patients after SPD.

Objective To evaluate the prognostic value of preoperative neutrophil-to-lymphocyte ratio (NLR) on recurrence after hepatectomy for AFP negative hepatocellular carcinoma (HCC).Methods Clinical data of 68 AFP negative HCC patients undergoing radical hepatectomy from September 2010 to January 2013 were analyzed retrospectively.According to preoperative NLR,patients were divided into low NLR group (NLR ＜ 2.78) and high NLR group (NLR ≥ 2.78),respectively.Univariate analysis was performed to assess for a significant difference in clinicopathological characteristics influencing disease-free suvival after hepatectomy.A multivariate analysis was performed by Cox regression for variables significant on univariate analysis.Kaplan-Meier method was used to assess disease-free survival rate.Results The overall 1,2,and 3-year disease-free survival rate was 79.7％,37.5％,and 18.2％ respectively.The disease-free survival of high NLR group was significantly lower than the low NLR group (1,2,and 3-year overall survival were 70.3％,35.1％,and 13.5％ vs 85.2％,40.7％,and 18.5％,respectively,P =0.042).Preoperative NLR ≥2.78,tumor size (＞ 5 cm),microvascular invasion and liver cirrhosis were risk factors of poor disease-free survival.Cox regression analysis revealed that all of these four factors were independent predictors of poorer disease-free survival.Conclusions Preoperative NLR≥2.78 was one of independent adverse predictors for disease-free survival in AFP negative HCC patients after hepatectomy.