Conversion therapy in liver transplantation for hepatocellular carcinoma:What's new in the era of molecular and immune therapy?

Background:Hepatocellular carcinoma(HCC)is the sixth most common cancer globally,with limited therapies and unsatisfactory prognosis once in the advanced stages.With promising advances in locoregional and systematic treatments,fast development of targeted drugs,the success of immunotherapy,as well as the emergence of the therapeutic alliance,conversion therapy has recently become more well developed and an effective therapeutic strategy.This article aimed to review recent developments in conversion therapy in liver transplantation(LT)for HCC.Data sources:We searched for relevant publications on Pub Med before September 2022,using the terms“HCC”,“liver transplantation”,“downstaging”,“bridging treatment”and“conversion therapy.”Results:Conversion therapy was frequently represented as a combination of multiple treatment modalities to downstage HCC and make patients eligible for LT.Although combining various local and systematic treatments in conversion therapy is still controversial,growing evidence has suggested that multimodal combined treatment strategies downstage HCC in a shorter time,which ultimately increases the opportunities for LT.Moreover,the recent breakthrough of immunotherapy and targeted therapy for HCC also benefit patients with advanced-stage tumors.Conclusions:In the era of targeted therapy and immunotherapy,applying the thinking of transplant oncology to benefit HCC patients receiving LT is a new topic that has shed light on advanced-stage patients.With the expansion of conversion therapy concepts,further investigation and research is required to realize the full potential of conversion treatment strategies,including accurately selecting candidates,determining the timing of surgery,improving the conversion rate,and guaranteeing the safety and long-term efficacy of treatment.

Effect of glial cells on remyelination after spinal cord injury

Remyelination plays a key role in functional recovery of axons after spinal cord injury.Glial cells are the most abundant cells in the central nervous system.When spinal cord injury occurs,many glial cells at the lesion site are immediately activated,and different cells differentially affect inflammatory reactions after injury.In this review,we aim to discuss the core role of oligodendrocyte precursor cells and crosstalk with the rest of glia and their subcategories in the remyelination process.Activated astrocytes influence proliferation,differentiation,and maturation of oligodendrocyte precursor cells,while activated microglia alter remyelination by regulating the inflammatory reaction after spinal cord injury.Understanding the interaction between oligodendrocyte precursor cells and the rest of glia is necessary when designing a therapeutic plan of remyelination after spinal cord injury.

Hepatic epithelioid hemangioendothelioma:Update on diagnosis and therapy

With an estimated incidence of only 1-2 cases in every 1 million people,hepatic epithelioid hemangioendothelioma(HEHE)is a rare vascular endothelial cell tumor occurring in the liver and consisting of epithelioid and histiocyte-like vascular endothelial cells in mucus or a fibrotic matrix.HEHE is characterized as a low-to-moderate grade malignant tumor and is classified into three types:solitary,multiple,and diffuse.Both the etiology and characteristic clinical manifestations of HEHE are unclear.However,HEHE has a characteristic appearance on imaging including ultrasound,magnetic resonance imaging,and positron emission tomography/computerized tomography.Still,its diagnosis depends mainly on pathological findings,with immunohistochemical detection of endothelial markers cluster of differentiation 31(CD31),CD34,CD10,vimentin,and factor VIII antigen as the basis of diagnosis.Hepatectomy and/or liver transplantation are the first choice for treatment,but various chemotherapeutic drugs are reportedly effective,providing a promising treatment option.In this review,we summarize the literature related to the diagnosis and treatment of HEHE,which provides future perspectives for the clinical management of HEHE.

Drainage fluid and serum amylase levels accurately predict development of postoperative pancreatic fistula

AIM To investigate potential biomarkers for predicting postoperative pancreatic fistula( POPF) after pancreaticoduodenectomy(PD).METHODS We prospectively recruited 83 patients to this study. All patients underwent PD(Child's procedure) at the Division of Hepatobiliary and Pancreas Surgery at the First Bethune Hospital of Jilin University between June 2011 and April 2015. Data pertaining to demographic variables, clinical characteristics, texture of pancreas, surgical approach, histopathological results, white blood cell count, amylase and choline levels in the serum, pancreatic/gastric drainage fluid, and choline and amylase levels in abdominal drainage fluid were included in the analysis. Potential correlations between these parameters and postoperative complications such as, POPF, acute pancreatitis, hemorrhage, delayed gastric emptying, and biliary fistula, were assessed. RESULTS Twenty-eight out of the 83(33.7%) patients developed POPF. The severity of POPF was classified as Grade A in 8(28%) patients, grade B in 16(58%), and grade C in4(14%), according to the pancreatic fistula criteria. On univariate and multivariate logistic regression analyses, higher amylase level in the abdominal drainage fluid on postoperative day(POD)1 and higher serum amylase levels on POD4 showed a significant correlation with POPF(P < 0.05). On receiver operating characteristic curve analysis, amylase cut-off level of 2365.5 U/L in the abdominal drainage fluid was associated with a 78.6% sensitivity and 80% specificity [area under the curve(AUC): 0.844; P = 0.009]. A cut-off serum amylase level of 44.2 U/L was associated with a 78.6% sensitivity and 70.9% specificity(AUC: 0.784; P = 0.05).CONCLUSION Amylase level in the abdominal drainage fluid on POD1 and serum amylase level on POD4 represent novel biomarkers associated with POPF development.

Intra-arterial thrombolysis for early hepatic artery thrombosis after liver transplantation

BACKGROUND Early hepatic artery thrombosis(E-HAT)is a serious complication after liver transplantation(LT),which often results in graft failure and can lead to patient deaths.Treatments such as re-transplantation and re-anastomosis are conventional therapeutic methods which are restricted by the shortage of donors and the patient’s postoperative intolerance to re-laparotomy.Due to the advances in interventional techniques and thrombolytics,endovascular treatments are increasingly being selected by more and more centers.This study reviews and reports our single-center experience with intra-arterial thrombolysis as the first choice therapy for E-HAT after deceased donor LT.AIM To evaluate the feasibility and reasonability of intra-arterial thrombolysis for EHAT after deceased donor LT.METHODS A total of 147 patients who underwent deceased donor LT were retrospectively reviewed in our hospital between September 2011 and December 2016.Four patients were diagnosed with E-HAT.All of these patients underwent intraarterial thrombolysis with alteplase as the first choice therapy after LT.The method of arterial anastomosis and details of the diagnosis and treatment of EHAT were collated.The long-term prognosis of E-HAT patients was also recorded.The median follow-up period was 26 mo(range:23 to 30 mo).RESULTS The incidence of E-HAT was 2.7%(4/147).E-HAT was considered when Doppler ultrasonography showed no blood flow signals and a definite diagnosis was confirmed by immediate hepatic arterial angiography when complete occlusion of the hepatic artery was observed.The patients were given temporary thrombolytics(mainly alteplase)via a 5-Fr catheter which was placed in the proximal part of the thrombosed hepatic artery followed by continuous alteplase using an infusion pump.Alteplase dose was adjusted according to activated clotting time.The recanalization rate of intra-arterial thrombolysis in our study was 100%(4/4)and no thrombolysis-related mortality was observed.During the follow-up period,patient survival rate was 75%(3/4),and biliary complications were present in 50%of patients(2/4).CONCLUSION Intra-arterial thrombolysis can be considered first-line treatment for E-HAT after deceased donor LT.Early diagnosis of E-HAT is important and follow-up is necessary even if recanalization is successful.

Sclerosing angiomatoid nodular transformation of the spleen: A case report and literature review

BACKGROUND Sclerosing angiomatoid nodular transformation(SANT)is a rare disease of the spleen.It has unique pathological features and mimics splenic tumor on radiological imaging.CASE SUMMARY A 47-year-old woman was incidentally found to have a splenic mass on abdominal ultrasound.She had a 10-cm postoperative scar in the lower abdomen due to previous cesarean sections.The patient had a past history of anemia of unknown etiology for 20 years.The patient underwent laparoscopic splenectomy.The postoperative course was uneventful,with a hospital stay of 7 d.The histopathological examination of the spleen revealed SANT.At the 6-mo followup,the patient remained disease-free.CONCLUSION SANT is a rare benign disease mimicking a malignant tumor.A definitive diagnosis can be made only on histopathology.

Details determining the success in establishing a mouse orthotopic liver transplantation model

Liver transplantation(LT)is currently the only effective treatment option for endstage liver disease.The importance of animal models in transplantation is widely recognized among researchers.Because of the well-characterized mouse genome and the greater diversity and availability of both genetically modified animals and research reagents,mouse orthotopic LT(MOLT)has become an ideal model for the investigation of liver biology,tissue injury,regulation of alloimmunity and tolerance induction,and the pathogenesis of specific liver diseases.However,due to its complicated and technically demanding procedure,the model has merely been used by only a few research groups in the world for years.For a new learner,training lasting at least a couple of months or even years is required.Most of the investigators have emphasized the importance of elaborate techniques and dedicated instruments in establishing a MOLT model,but some details are often neglected.The nontechnical details are also significant,especially for researchers who have little experience in mouse microsurgery.Here,we review and summarize the crucial technical and nontechnical details in establishing the model of MOLT based on scientific articles and our experience in six aspects:animal selection,anesthesia,perioperative management,organ procurement,back-table preparation,and implantation surgery.We aim to enable research groups to shorten the learning curve and implement the mouse LT procedure with high technical success.

Efficacy and safety of sirolimus early conversion protocol in liver transplant patients with hepatocellular carcinoma:A single-arm, multicenter, prospective study

Mammalian target of rapamycin(m TOR) inhibitor as an attractive drug target with promising antitumor effects has been widely investigated. High quality clinical trial has been conducted in liver transplant(LT) recipients in Western countries. However, the pertinent studies in Eastern world are paucity. Therefore, we designed a clinical trial to test whether sirolimus can improve recurrence-free survival(RFS) in hepatocellular carcinoma(HCC) patients beyond the Milan criteria after LT. This is an open-labeled, single-arm, prospective, multicenter, and real-world study aiming to evaluate the clinical outcomes of early switch to sirolimus-based regimens in HCC patients after LT. Patients with a histologically proven HCC and beyond the Milan criteria will be enrolled. The initial immunosuppressant regimens are center-specifc for the frst 4-6 weeks. The following regimens integrated sirolimus into the regimens as a combination therapy with reduced calcineurin inhibitors based on the condition of patients and centers. The study is planned for 4 years in total with a 2-year enrollment period and a 2-year follow-up. We predict that sirolimus conversion regimen will provide survival benefts for patients particular in the key indicator RFS as well as better quality of life. If the trial is conducted successfully, we will have a continued monitoring over a longer follow-up time to estimate indicator of overall survival. We hope that the outcome will provide better evidence for clinical decision-making and revising treatment guidelines based on Chinese population data.

Pediatric living donor liver transplantation using liver allograft after ex vivo backtable resection of hemangioma: A case report

BACKGROUND Use of liver allograft with hepatic hemangioma after in vivo resection of hemangioma in living donor liver transplantation(LDLT)has been previously reported.However,there are few reports describing ex vivo backtable resection of hemangioma from liver allografts in LDLT.CASE SUMMARY A 55-year-old male was evaluated as a donor for an 8-month-year old patient with acute hepatic failure due to biliary atresia.Pre-operative contrast enhanced computed tomography revealed a 9 cm hemangioma in segment 4 with vascular variations in the donor.During LDLT,an intra-operative intrahepatic cholangiography was performed to ensure no variation in the anatomy of the intrahepatic bile duct.After intra-operative pathological diagnosis,ex vivo backtable resection of the hemangioma was performed and the liver allograft was transplanted into the recipient.The donor’s and recipient’s post-operative course were uneventful.At the 2-year follow-up,the liver allograft showed good regeneration without any recurrence of hemangioma.CONCLUSION Liver allografts with hemangiomas are an acceptable alternative strategy for LDLT.Ex vivo backtable resection of hemangioma from the donor liver during pediatric LDLT is safe and feasible,and can effectively reduce the operative time and intra-operative bleeding for the donor.

Surgical treatment of abnormal systemic artery to the left lower lobe: A case report

BACKGROUND Abnormal systemic artery to the left lower lobe is a rare congenital abnormality characterized by anomalous communication between the systemic and pulmonary circulation.Owing to its rarity,there is limited clinical experience with respect to the diagnosis and treatment of this disease.CASE SUMMARY We report a 60-year-old man who presented with a history of hemoptysis for 20 d.Contrast-enhanced computed tomography of the chest confirmed the diagnosis of abnormal systemic artery to the left lower lobe,and surgical treatment was performed.The aberrant artery arising from the descending thoracic aorta was ligated,followed by removal of the left lower lobe.The patient showed good recovery and was discharged 6 d after the surgery.At the 1-year follow-up,the patient had recovered completely,and lung CT showed no abnormal findings.CONCLUSION We present a case of abnormal systemic artery to the left lower lobe that was successfully managed by surgical resection of the aberrant artery and the left lower lobe.This case report adds to the clinical experience of diagnosing and treating this rare entity.

Feasible management of median arcuate ligament syndrome in orthotopic liver transplantation recipients

BACKGROUND In orthotopic liver transplantation(OLT)recipients,median arcuate ligament syndrome(MALS)is considered a risk factor for hepatic arterial thrombosis(HAT),which is dreadful for OLT recipients.Different alternative surgical procedures have been proposed to overcome the impact of MALS on transplantation,but clinical evidence is still scarce.AIM To evaluate the feasible surgical management of MALS to reduce complications in OLT patients.METHODS Data for 288 consecutive patients who underwent OLT at The First Hospital of Jilin University between January 2017 and July 2020 were retrospectively reviewed.The surgical management of median arcuate ligament(MAL)and modifications to the arterial anastomosis were recorded.The perioperative and long-term prognosis of MALS recipients were noted.Detailed preoperative and postoperative data of patients were analyzed in a descriptive manner.RESULTS Eight patients with MALS were included in this study.The first patient with MALS received no intervention during the primary surgery and developed postoperative HAT.Salvage liver transplantation with MAL division was successfully performed.Gastroduodenal artery(GDA)preservation with splenic artery ligation was performed on three patients,only GDA preservation was performed on two patients,and no intervention was performed on two patients.No patient developed HAT after surgery and postoperative recovery was satisfactory.CONCLUSION The preservation of collateral circulation between the superior mesenteric artery and celiac trunk via the GDA with or without splenic artery ligation is a safe and feasible alternative to MAL division.