Full laparoscopic liver resection has been performed widely since it was introduced in the early 1990s.It has been expanded from initial for partial resection of the anterolateral segments to non-restriction of area of the liver [1-3].Anatomical liver resection is considered to have potential superiority than non-anatomic resection in terms of tumor prognosis,thus it is more often recommended in the treatment of hepatocellular carcinoma [4,5].

To the Editor: Choledochocele, also known as type Ⅲ choledochal cysts in the classification by Todani et al. [1], is a congenital abnormality of the biliary system. It is characterized by a cystic dilation of intramural segment of the distal common bile duct（CBD） protruding into the descending duodenum. Choledochocele makes up about 0.5%-4% of choledochal cysts [1,2]. Compared with other subtypes,

Background: Hepatosplenic candidiasis is a rare but severe complication in immunocompromised patients undergoing chemotherapy. Antifungal agents are widely accepted as the first choices for therapy. However, resistance to or side-effect of antifungal agents may comxpromise its effi-ciency. Splenectomy has also been rarely performed as treatment for this disease.Methods: We present two cases of splenectomy for treating hepatosplenic candidiasis after failure of the initial drug therapy. Literatures on splenectomy as treatment for hepatosplenic candidiasis were searched in Pubmed and summarized.Results: Two leukemia patients developed hepatosplenic candidiasis after received chemotherapy for their primary diseases. Various antifungal agents including amphotericin B were all demon-strated failure to cure fever and the Candida abscesses due to resistance or intractable side-effect. Laparoscopic splenectomy were finally performed and resolved the candidiasis successfully. A total of 12 splenectomy cases for treating hepatosplenic candidiasis had been previously reported in literature. All the cases showed either resistance or unimproved to initial antifungal therapies. Splenectomy provided salvage therapeutic value in all cases.Conclusion: Splenectomy has therapeutic effect and may change the traditional concept in most surgeons. The present study may expand an alternative strategy in clinical practice guideline for the management of hepatosplenic candidiasis.

Sorafenib resistance is a major challenge in the treatment of patients with advanced hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) are a large family of non-coding RNA molecules, which is an important mechanism of drug resistance. We previously found that knockdown of miR-25 increased the sensitivity of TRAIL-induced apoptosis in liver cancer stem cells. We aimed to study the effects of miR-25 on sorafenib resistance of HCC and the underlying mechanisms. In the present study, we analyzed the expression of miR-25 between HCC and normal tissues and predicted miR-25 target genes through databases. After transfecting miR-25 mimics, inhibitor or FBXW7 Plasmid, CCK-8 and flow cytometry assay was performed to determine the sorafenib resistance. We performed LC3-dual-fluorescence assay and Western blotting to detect the autophagy levels. The expression of miR-25 was upregulated in human HCC tissues and was associated with tumor pathological grade, clinic staging, and lymphatic metastasis. MiR-25 enhanced sorafenib resistance of HCC cells and autophagy. FBXW7 is the direct target of miR-25. Overexpression of FBXW7 could reverse the increase of sorafenib resistance caused by miR-25 mimics. Our results suggested that miR-25 increased the sorafenib resistance of HCC via inducing autophagy. In addition, miR-25 decreases the expression of FBXW7 protein to regulate autophagy. Therefore, miR-25 may represent a novel therapeutic target for the treatment of HCC.

Objective We aimed to develop and validate a nomogram for preoperatively estimating the risk of microvascular invasion (MVI) in hepatocellular carcinoma (HCC) within the Milan criteria. Methods The clinical data of 312 HCC patients who underwent liver surgery at the xxx from Jan 2017 to Dec 2019 were retrospectively collected. Then, the study population was categorized into the training and validation group based on the date of surgery. To identify risk factors related to MVI, we conducted a series of logistic regression analyses. By combining these risk factors, a nomogram was then established. We further clarified the usability of our model through the area under the ROC curve (AUC), decision curve analysis (DCA), and calibration curve. Results Pathological examination revealed MVI in 108 patients with HCC (34.6%). Three independent predictors were identified: level of alpha-fetoprotein (AFP) exceeds 194 ng/mL (OR = 2.20, 95% CI: 1.13-4.31, p = 0.021), size of tumor (OR = 1.59; 95% CI: 1.18-2.12; P < 0.001) and number of tumors (OR = 3.37, 95% CI: 1.64-7.28, p < 0.001). A nomogram was subsequently built with an AUC of 0.73 and 0.74 respectively in the training cohort and validation cohort. The calibration curve showed a relatively high consistency between predicted probability and observed outcomes. Besides, the DCA revealed that the model was clinically beneficial for preoperatively predicting MVI in HCC. Conclusions A model for evaluating the risk of MVI HCC patients was developed and validated. The model could provide clinicians with a relatively reliable basis for optimizing treatment decisions.

Background and Aim Donor shortage has become worldwide limitation in liver transplantation (LT). Use of hepatitis B virus surface antigen positive (HBsAg+) donors could be an alternative source of donor organs. This study aims to investigate the safety and efficacy of LT using HBsAg+ liver grafts and associated long-term outcome. Methods This was a retrospective study of adults LT registered in the database of the China Liver Transplant Registry between January 2015 and September 2018. By propensity score matching (1:1), 503 eligible patients who received HBsAg+ liver grafts were compared with 503 matched patients who received HBsAg- liver grafts. Results The 1-, 3-, and 5-year patient survival rates were 81.52%, 72.04%, and 66.65% in HBsAg+ donor group, which were comparable with 83.93%, 77.27%, and 65.73% in HBsAg- donor group (P = 0.222). The 1-, 3-, and 5-year graft survival rates were also comparable between the two groups (81.49%, 71.45%, and 67.26% vs 83.62%, 77.11%, and 65.81%, respectively, P = 0.243). Most main complications were not increased in HBsAg+ donor group except for the retaining of HBsAg positivity after LT. Furthermore, transplanting HBsAg+ liver grafts did not result in inferior outcomes either in HBsAg+ or HBsAg- recipients. The risk of tumor recurrence after LT was not increased in hepatocellular carcinoma patients. Conclusions The outcomes of using HBsAg+ liver grafts were comparable with those of HBsAg- liver grafts. Our study provided strong evidence for the safe use of HBsAg+ grafts in LT to expand the donor liver pool.

Cutaneous metastases as an extrahepatic metastasis from hepatomas (HCC) is extremely rare and always carry a poor prognosis and less survival time. Previously, there has been a limited number of literature that reported skin metastasis in a large number of cases, which has rarely been discussed in the empirical treatment and therapy of cutaneous metastasis, especially for non-iatrogenic implantation. It is necessary to discuss this kind of metastasis. We summarize cases from our medical center from 2013 to 2021, there are 12 patients diagnosed with non-iatrogenic implantation of cutaneous metastasis after HCC. We conducted the investigation of the clinical prognosis, pathological characteristics, and treatment of those patients. All patients were male, the age ranged from 21 to 71 years old, the average size of primary HCC was over 5 cm, there was four patient’s cutaneous metastasis from the skin of head (including scalp and occipital region), followed by right abdominal (2 patients), right chest wall (2 patients), back (2 patients), umbilical (1 patient), gluteal region (1 patient). The cutaneous metastases presented as solitary or multiple nodules, papules, and erythema without ulcers with sizes between 0.5 cm and 5 cm. 7 patients died after being diagnosed with cutaneous metastasis within 2–19 months. The rate of non-iatrogenic implantation cutaneous metastasis is low, but the prognosis is poor, combining with histopathological analysis and history of diseases can be helpful in diagnosis. For large HCC (> 5 cm), systematic treatment is recommended to prevent the occurrence of cutaneous metastasis and improve the prognosis after hepatectomy.

BACKGROUND AND AIMS:Perivascular epithelioid cell neoplasms (PEComas) are a rare type of mesenchymal neoplasm and their preoperative diagnosis is challenging. In this study, we summarized the experience from a single medical center to study the examinations, clinical presentations, and pathological and histological characteristics of PEComas in the liver in order to optimize overall understanding of the diagnosis and treatment of these neoplasms.METHODS:We conducted a retrospective analysis to investigate the clinical and pathological characteristics as well as imaging presentations of 75 patients diagnosed with hepatic PEComa in The First Affiliated Hospital of Zhejiang University between April 2010 and April 2020.RESULTS:Among the 75 patients, 52 were women, and the median age was 48 years. Most patients had no specific symptoms, and two were admitted to the hospital for a second time owing to relapse. All patients underwent surgical resection. Histologically, 38 patients had classical angiomyolipoma (AML) and 37 had epithelioid AML. The PEComas were accompanied by positive immunohistochemical expression of HMB45, Melan-A, and smooth muscle actin. Follow-up data were obtained from 47 of the total 75 patients, through October 2020. Two patients had metastasis after surgery.CONCLUSIONS:AML is the most common type of hepatic PEComa. There are no specific symptoms of hepatic PEComa, and serological examinations and imaging modalities for accurate preoperative diagnosis are lacking. Epithelioid AML should be considered a tumor of uncertain malignant potential; however, the prognosis of PEComa after resection is promising.

To the Editor : Liver transplantation （LT） has become a major and effective therapeutic approach for end-stage liver disease [1] . However, 10- year graft and patient survival rates remained low with 54% and 61%, respectively [2] . Improving the outcome of long-term LT has become a major focus of the transplantation community.

Background Small nonfunctional pancreatic neuroendocrine tumors (NF-PNETs) ≤2 cm have variable biological features, and there is no gold standard treatment for their management. The present study aimed to evaluate the risk of malignancy of small NF-PNETs and their outcomes following curative resection. Methods Patients with NF-PNETs undergoing surgical resection at the First Affiliated Hospital, College of Medicine, Zhejiang University, between 2012 and 2017 were included. Clinicopathological characteristics, perioperative results, and prognosis were retrospectively analyzed. Results A total of 73 patients were identified, including 28 with small NF-PNETs and 45 large PNETs; 32.1% of NF-PNETs ≤2 cm underwent a parenchyma-sparing pancreas surgery, which was >6.7% in large NF-PNETs. No statistically significant differences in perioperative results, postoperative complications, and long-term outcomes were found between small tumors undergoing standard and parenchyma-sparing pancreatectomy. Eighteen small tumors (64.3%) developed a perioperative complication, with a clinically significant pancreatic fistula rate of 25%; however, only 2 patient needed reintervention. Small NF-PNETs in 3 patients were malignant. Multivariate logistic regression showed that grade ≥3 and lymphovascular invasion were independently related to malignancy in NF-PNETs. Conclusions Small NF-PNETs (≤2 cm) are not immune from potential malignancy. Surgical resection may be considered for small tumors and can provide favorable postoperative and long-term outcomes. Parenchyma-sparing pancreatectomy may be an alternative surgery for selected small local NF-PNETs.

Background Sorafenib is a multi-target kinase inhibitor that has been approved as a unique target drug for the treatment of advanced hepatocellular carcinoma (HCC). However, due to the frequent occurrence of drug resistance, its treatment efficacy is often limited. The aim of this study was to explore the function of HOX transcript antisense intergenic RNA (HOTAIR) for the treatment of HCC with sorafenib, and its underlying mechanism. Methods A cell counting kit-8 (CCK-8) assay and Edu assay were used to examine the viability and proliferation of HCC cells. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression of HOTAIR and miR-217 in HCC cells. Small interfering (si) RNA was transfected to knockdown HOTAIR to explore its biological function. A Western blot and immunofluorescence were performed to detect the level of E-cadherin and Vimentin expression. Results Sorafenib resistance was increased in HCC cells with high HOTAIR expression. Moreover, a knockdown of HOTAIR could improve the therapeutic effect of sorafenib on HCC via increasing E-cadherin and decreasing Vimentin expression. Additionally, a HOTAIR knockdown could increase the sensitivity of sorafenib for HCC treatment by up-regulating miR-217. Conclusions Lnc HOTAIR could increase sorafenib resistance in HCC by inhibiting miR-217. Our research attempts to elucidate a more effective treatment and provides novel insight into potential clinical treatment for HCC.

Background Synchronous renal cell carcinoma metastasizing to the pancreas and subcutaneous tissue is very rare. Unusual metastatic sites require attention during follow-up of renal cell carcinoma. It is extremely rare for renal cell carcinoma to metastasize to the pancreas; it is also very rare for it to metastasize to the subcutaneous tissue and extremely rare for it to synchronously metastasize to the pancreas and subcutaneous tissue almost a decade after radical nephrectomy. It is well known that most pancreatic tumors are primary pancreatic adenocarcinoma. However, the pancreas can also be an uncommon site for metastasis. We present a rare case of synchronous metastasis of renal cell carcinoma to the pancreas and subcutaneous tissue; we believe it to be only the second such case reported to date. Case presentation We describe a case of a 74-year-old Chinese man who was diagnosed with metastatic renal cell carcinoma to the pancreas and subcutaneous tissue at the same time, 10 years after left radical nephrectomy. He received distal pancreatectomy with spleen preservation plus resection of the subcutaneous tissue lesions on the left side of the anterior abdominal wall and right waist. Pathology showed that all resected metastatic tumors were of the clear cell type. The patient was seen in regular follow-up afterward. Conclusion Synchronous metastatic renal cell carcinoma to the pancreas and subcutaneous tissue is very rare, and it might occur after primary tumor resection. Patients must undergo lifelong monitoring and follow-up with regular examination so that any possible metastasis can be detected early. The optimal resection strategy should involve adequate resection margins and maximal tissue preservation of the pancreas, because renal cell carcinoma metastasizing to the pancreas and subcutaneous tissue has a good prognosis with long-term survival.

BACKGROUND:Hepatic ischemia reperfusion injury (IRI) is a primary cause of organ dysfunction occurring during liver resection surgery and transplantation. Galectin-1, an endogenous lectin expressed on lymphoid organs, plays an important role in governing innate and adaptive immunity. This study was designed to determine the therapeutic role of galectin-1 and underlying mechanism in hepatic IRI.METHODS:Male C57BL/6 mice were subjected to 90 min of partial hepatic ischemia followed by reperfusion with or without treatment with recombinant galectin-1 (rGal-1) or neutralizing anti-IL-10 antibody. Mice were sacrificed at 6 and 24 h following reperfusion. Liver damage related enzymes were determined and cytokines/chemokines were measured by qPCR and ELISA.RESULTS:Administration of rGal-1 significantly attenuated hepatic IRI, including a remarkable reduction in serum ALT/AST levels and an improved liver histology score compared to controls. rGal-1 treatment reduced TUNEL positive apoptotic hepatocytes, attenuated proinflammatory cytokines (TNF-α, IL-6, IL-1β, IL-12, IFN-γ, IL-17) and chemokines (CXCL-1, CXCL-10) levels, but upregulated IL-10 expression, compared with controls. In addition, rGal-1 increased the production of IL-10 in hepatic macrophages in vivo and in vitro. Blockade of IL-10 using neutralizing anti-IL-10 antibody reversed the protection of galectin-1 in hepatic IRI in mice.CONCLUSION:These data suggest that galectin-1 may attenuate hepatic IRI via an IL-10-dependent mechanism, which is a promising therapeutic target.

BACKGROUND:Reduced-size liver transplantation (LT) was invented to overcome the shortage of donor livers; however, it has proven to be more susceptible to ischemia-reperfusion injury. Bone marrow-derived mesenchymal stem cell infusion has been shown to be protective following LT. Optimization of MSC infusion has been performed, among which hypoxia preconditioning and miRNA modulation have shown promise. MiR-199a inhibition was reported to induce angioneogenesis; however, whether mir-199a inhibition enhances the protective effect of Bone marrow-derived mesenchymal stem cells in LT remains unknown. In this study, we combined antagomiR-199a with hypoxia-preconditioned MSC (H-MSC) infusion to discuss their effect and mechanism in a rat model of reduced-size LT.METHODS:A reduced-size LT model was constructed and H-MSCs were intraportally injected during operation. AgomiR-199a and antagomir-199a were injected through the caudal vein once a day after LT. The level of apoptosis and proinflammatory cytokines were measured. An anti-vascular endothelial growth factor (VEGF) antibody was injected to further explore the underlying mechanism.RESULTS:AntagomiR-199a plus H-MSC not only significantly decreased ALT and AST 72 h after LT but also ameliorated the level of apoptosis and inhibited inflammatory reactions. On the contrary, agomir-199a reduced the protective effect of the H-MSC infusion. In terms of mechanism, the liver protective effect of miR-199a inhibition was abolished by treatment with a VEGF-neutralizing antibody.CONCLUSIONS:AntagomiR-199a enhanced the protective effect of H-MSCs infusion via activation of the hypoxia induction factor 1α/VEGF axis.

Abstract Background Hepatic epithelioid hemangioendothelioma (HEHE) is a rare angiogenic tumor with no recognized effective treatment. Treatment options used worldwide include liver transplantation (LT), liver resection (LR), radiofrequency ablation (RFA), chemotherapy, and observation. The aim of this study was to describe the efficacy of different treatment options used for HEHE at our center. Methods The medical charts of 12 patients with HEHE (9 women and 3 men) who were diagnosed and treated at the First Affiliated Hospital of Zhejiang University, China, between January 2011 and December 2017 were retrospectively reviewed. Results The patients were diagnosed by postoperative histopathology or fine needle aspiration biopsy. Two patients with diffuse lesions received LT and were alive without recurrence at the last follow-up. Three patients received LR as the initial treatment, and all of them developed recurrence during the follow-up period. One patient received RFA and remained free of disease, while the remaining six patients opted for simple observation rather than treatment. One of the patients who received LR passed away because of tumor recurrence within 32 months after surgery; the other patients showed no significant disease activity after treatments for their recurrent lesions. As of April 2018, the mean follow-up duration was 39.6 ± 20.1 months (15–82 months). Conclusions There are multiple strategies for HEHE. Considering its indolent course, initial observation for assessment of the lesion behavior may aid in the selection of appropriate treatment. Surgery or LT is suitable for patients with disease progression during the observation period. However, our sample size was small, and further studies are required to gather more information that can aid in optimal treatment selection.

BACKGROUND:New-onset diabetes after transplantation (NODAT) has become one of the major factors that affect the overall survival and long-term life quality in liver transplantation (LT) recipients. Previous studies found that the serum adiponectin concentration of diabetic patients is significantly lower than that of healthy subjects. Adiponectin regulates the blood glucose level by increasing body sensitivity to insulin through various mechanisms. In this study, we aimed to investigate the impact of diabetes related gene polymorphisms on the development of NODAT in liver recipients.METHODS:A total of 256 LT patients in a single-center were selected retrospectively for the study. Genomic DNA was extracted from explanted liver tissues, and tested for twelve diabetes mellitus associated single nucleotide polymorphisms by Sequenom MassARRAY. Modified clinical models in predicting NODAT were established and evaluated.RESULTS:The GG genotype of ADIPOQ rs1501299 gene polymorphism was significantly more frequent in NODAT than non-NODAT LT patients (56% vs 39%, P=0.014). Dominant model (GG vs GT+TT, P=0.030) and recessive model (GT+GG vs TT, P=0.005) also confirmed the genotype distribution difference between NODAT and non-NODAT groups. Age (OR=1.048, P=0.004), BMI (OR=1.107, P=0.041), and blood tacrolimus level at 1-month LT (OR=1.170, P=0.003) were clinical independent risk factors of NODAT. Furthermore, rs1501299 could improve the ability of clinical model in predicting NODAT (AUROC=0.743, P<0.001).CONCLUSION:ADIPOQ rs1501299 gene polymorphism is associated with an increased risk of NODAT, which should be added to the clinical models in predicting the occurrence of NODAT in LT recipients.

BACKGROUND: The Milan criteria are widely accepted among many centers. However, patients with hepatocellular carcinoma beyond the Milan criteria might still benefit from liver transplantation (LT) when tumor itself is not aggressive. [F-18] fluorodeoxyglucose positron emission tomography/computed tomography imaging could provide useful information of tumor behaviors, which is helpful to predict the prognosis for many tumors.METHOD: In order to determine its role in candidate selection for LT, we therefore retrospectively analyzed 103 recipients with preoperative positron emission tomography (PET) findings.RESULTS: Positive PET findings (PET+) were significantly associated with tumor nodule numbers (P=0.013), tumor grade (P=0.025), macro- (P=0.002) and micro-vascular invasion (P=0.002), as well as the Milan criteria (P=0.018). PET+ patients had significantly increased risk of tumor recurrence post-LT compared to PET negative (PET-) patients (P=0.007). The 1-, 3-, and 5-year overall survival rate of PET- patients were 96.0%, 87.2% and 76.2%, compared to 74.7%, 55.4% and 49.9% in PET+ patients, respectively (P<0.05). The 1-, 3-, and 5-year recurrence-free survival rate of PET- patients were 91.8%, 81.9% and 76.0%, compared to 70.1%, 39.3% and 21.9% in PET+ patients, respectively (P<0.05). Recipients within the Milan criteria showed comparable 1-, 3-, and 5-year survival rates in comparison with those beyond the Milan criteria with a PET- findings (1-, 3-, and 5-year overall survival rates, 97.5%, 83.3%, and 83.3% vs 90.0%, 80.0%, and 66.7%, P= 0.123; 1-, 3-, and 5-year recurrence-free survival rates, 95.1%, 73.1%, and 73.1% vs 90.0%, 78.8%, and 65.6%, P=0.148).CONCLUSIONS: Certain patients with hepatocellular carcinoma and negative PET findings, who have exceeded the Milan criteria, are also eligible candidates for LT. Preoperative PET/CT imaging is an important marker, which should be incorporated in extended candidate selection criteria for LT.

Background Ischemia-reperfusion injury after liver transplantation (LT) impairs graft function and affects prognosis of recipients. Isoglycyrrhizinate magnesium (Iso) is a hepatoprotective drug usually used after liver injury. In this study, we intended to explore whether Iso alone have protective effect after ischemia-reperfusion injury in a rat model of liver transplantation. We also aimed to study whether Iso could enhance the hepatoprotective effect of FK506 (tacrolimus) and underlying mechanism. Methods Rats after LT were treated with different concentration of FK506 with or without, Iso or lower-dose FK506 plus Iso. Alanine transaminase, aspartate transaminase, and albumin level were measured after 48 hours, 72 hours, and 7 days. A cell ischemic/reperfusion model was established to further study the mechanism of hepatoprotective effect of FK506 and Iso. Results Iso treatment alone had no effect on liver grafts after LT, but lower-dose FK506 + Iso was better for maintenance of liver function than lower-dose FK506 alone at 48 hours, 72 hours, and 7 days after LT. In terms of mechanism, FK506 induced autophagy which resulted in significantly reduced apoptosis and maintained proliferative potential. However, autophagy induced by FK506 also lead to high-mobility group box (HMGB) 1 release from nuclei, resulting in hepatocyte injury through triggering of p38 phosphorylation and chemokine release. Iso effectively inhibited the release of HMGB1 and downstream inflammatory cytokines. Conclusions Iso could inhibit release of HMGB1 by FK506 and enhance the hepatoprotective effect of FK506 in rat LT. Combining Iso with FK506 would be promising for the patients after LT.