Liver transplantation as an alternative for the treatment of neuroendocrine liver metastasis: Appraisal of the current evidence

Background:Liver transplantation(LT)for neuroendocrine liver metastases(NELM)is still in debate.Studies comparing LT with liver resection(LR)for NELM are scarce,as patient selection is heterogeneous and experience is limited.The goal of this review was to provide a critical analysis of the evidence on LT versus LR in the treatment of NELM.Data sources:A scoping literature search on LT and LR for NELM was performed with PubMed,including English articles up to March 2023.Results:International guidelines recommend LR for NELM in resectable,well-differentiated tumors in the absence of extrahepatic metastatic disease with superior results of LR compared to systemic or liver-directed therapies.Advanced liver surgery has extended resectability criteria whilst entailing increased perioperative risk and short disease-free survival.In highly selected patients(based on the Milan criteria)with unresectable NELM,oncologic results of LT are promising.Prognostic factors include tumor biology(G1/G2)and burden,waiting time for LT,patient age and extrahepatic spread.Based on low-level evi-dence,LT for low-grade NELM within the Milan criteria resulted in improved disease-free survival and overall survival compared to LR.The benefits of LT were lost in patients beyond the Milan NELM-criteria.Conclusions:With adherence to strict selection criteria especially tumor biology,LT for NELM is becoming a valuable option providing oncologic benefits compared to LR.Recent evidence suggests even stricter selection criteria with regard to tumor biology.

Ex vivo liver resection and auto-transplantation and special systemic therapy in perihilar cholangiocarcinoma treatment

This editorial contains comments on the article“Systematic sequential therapy for ex vivo liver resection and autotransplantation:A case report and review of li-terature”in the recent issue of World Journal of Gastrointestinal Surgery.It points out the actuality and importance of the article and focuses primarily on the role and place of ex vivo liver resection and autotransplantation(ELRAT)and systemic therapy,underlying molecular mechanisms for targeted therapy in perihilar cho-langiocarcinoma(pCCA)management.pCCA is a tough malignancy with a high proportion of advanced disease at the time of diagnosis.The only curative option is radical surgery.Surgical excision and reconstruction become extremely com-plicated and not always could be performed even in localized disease.On the other hand,ELRAT takes its place among surgical options for carefully selected pCCA patients.In advanced disease,systemic therapy becomes a viable option to prolong survival.This editorial describes current possibilities in chemotherapy and reveals underlying mechanisms and projections in targeted therapy with ki-nase inhibitors and immunotherapy in both palliative and adjuvant settings.Fi-broblast grow factor and fibroblast grow factor receptor,human epidermal grow-th factor receptor 2,isocitrate dehydrogenase,and protein kinase cAMP activated catalytic subunit alpha(PRKACA)and beta(PRKACB)pathways have been ac-tively investigated in CCA in last years.Several agents were introduced and approved by the Food and Drug Administration.They all demonstrated mean-ingful activity in CCA patients with no global change in outcomes.That is why every successfully treated patient counts,especially those with advanced disease.In conclusion,pCCA is still hard to treat due to late diagnosis and extremely complicated surgical options.ELRAT also brings some hope,but it could be performed in very carefully selected patients.Advanced disease requires systemic anticancer treatment,which is supposed to be individualized according to the genetic and molecular features of cancer cells.Targeted therapy in combination with chemo-immunotherapy could be effective in susceptible patients.

Radiofrequency ablation is an inferior option to liver resection for solitary hepatocellular carcinoma≤5 cm without cirrhosis:A population-based study with stratification by tumor size

Background:About 10%-20%of all individuals who develop hepatocellular carcinoma(HCC)do not have cirrhosis.Comparisons are rarely reported regarding the effectiveness of radiofrequency ablation(RFA)and liver resection(LR)in survival of HCC without cirrhosis and stratification by tumor size≤5 cm.Methods:We used the Surveillance,Epidemiology,and End Results(SEER)database and identified 1505 patients with a solitary HCC tumor≤5 cm who underwent RFA or LR during 2004-2015.Patients were classified into non-cirrhosis and cirrhosis groups and each group was categorized into three subgroups,according to tumor size(≤30 mm,31-40 mm,41-50 mm).Results:In patients without cirrhosis,LR showed better 5-year HCC cancer-specific survival than RFA in all tumor size subgroups(≤30 mm:82.51%vs.56.42%;31-40 mm:71.31%vs.46.83%;41-50 mm:74.7%vs.37.5%;all P<0.05).Compared with RFA,LR was an independent protective factor for HCC cancer-specific survival in multivariate Cox analysis[≤30 mm:hazard ratio(HR)=0.533,95%confidence interval(CI):0.313-0.908;31-40 mm:HR=0.439,95%CI:0.201-0.957;41-50 mm:HR=0.382;95%CI:0.159-0.916;all P<0.05].In patients with cirrhosis,for both tumor size≤30 mm and 31-40 mm groups,there were no significant survival differences between RFA and LR in multivariate analysis(all P>0.05).However,in those with tumor size 41-50 mm,LR showed significantly better 5-year HCC cancer-specific survival than RFA in both univariate(54.72%vs.23.06%;P<0.001)and multivariate analyses(HR=0.297;95%CI:0.136-0.648;P=0.002).Conclusions:RFA is an inferior treatment option to LR for patients without cirrhosis who have a solitary HCC tumor≤5 cm.

Liver transplantation in the management of cholangiocarcinoma:Evolution and contemporary advances

Cholangiocarcinoma(CCA)is an aggressive malignancy arising from the biliary epithelium.It may occur at any location along the biliary tree with the perihilar area being the most common.Prognosis is poor with 5-year overall survival at less than 10%,typically due to unresectable disease at presentation.Radical surgical resection with clear margins offers a chance of cure in patients with resectable tumours,but is frequently not possible due to locally advanced disease.On the other hand,orthotopic liver transplantation(LT)allows for a radical and potentially curative resection for these patients,but has been historically controversial due to the limited supply of donor grafts and previously poor outcomes.In patients with perihilar CCA,within specific criteria and following the implementation of a protocol combining neoadjuvant chemoradiation and LT,excellent results have been achieved in the last decades,resulting in its increasing acceptance as an indication for LT and the standard of care in several centres with significant experience.However,in intrahepatic CCA,the role of LT remains controversial and owing to dismal previous results it is not an accepted indication.Nevertheless,more recent studies have demonstrated favourable results with LT in early intrahepatic CCA,indicating that,under defined criteria,its role may increase in the future.This review highlights the history and contemporary advances of LT in CCA,with particular focus on the improving outcomes of LT in intrahepatic and perihilar CCA and future perspectives.

Liver-specific therapies for metastases of neuroendocrine pancreatic tumors

The presence or development of liver metastases in patients with neuroendocrine pancreatic tumors is the most important prognostic factor.Liver resection,transplantation and many different therapeutic approaches are discussed in this special review.

Macrophage inflammatory protein-2 contributes to liver resection-induced acceleration of hepatic metastatic tumor growth

瞄准：学习巨噬细胞的角色在在一只老鼠的肿瘤生长的导致切除术的加速肝的转移建模的肝的煽动性的蛋白质(MIP )-2。方法：在 50% 肝切除术以后， 1x10 (5 ) CT26.WT 房间被植入进 syngeneic balb/c 老鼠(PHx ) 的左肝脑叶。另外的动物与抵销 MIP-2 (PHx+mAB ) 的单音的同种细胞的抗体(MAB452 ) 被对待。将切除得非并且 non-mAB-treated 老鼠(反对) 用作控制。在 7 d 以后，象房间增长，肿瘤生长，和 CXCR-2 表示一样的肿瘤血管生成和微循环用生活期内萤光显微镜检查，组织学，免疫组织化学，和流动被分析血细胞计数。结果：增加的部分肝切除术(P【0.05 ) 肿瘤房间上的 MIP-2 受体 CXCR-2 的表示什么时候与将切除得非的控制相比，并且显著地加速了(P【0.05 ) 血管生成和转移瘤生长。(P【0.05 ) 由 MAB452 处理的 MIP-2 的中立化显著地压抑 CXCR-2 表示。进一步， MIP-2 的封锁减少了 angiogenic 反应(P【0.05 ) 并且禁止了肿瘤生长(P【0.05 ) 。兴趣，肝导致切除术的 hepatocyte 增长没被 anti-MIP-2 处理完成。结论：MIP-2 显著地贡献肝颜色的导致切除术的加速表面的 CT26.WT 肝的转移生长。

Laparoscopic liver resection for the treatment of hepatocellular carcinoma

Accumulation of experiences and technological advances after the first report of laparoscopic liver resection(LLR) are now revealing the characteristics and specific advantages of this approach, especially for hepatocellular carcinoma(HCC) patients with chronic liver diseases(CLD). Inlaparoscopic approach, there are minimum needs for:(1) laparotomy and dissection of the attachments and adhesion which may cause destructions in the collateral blood and lymphatic flows; and(2) compression of the liver which may cause parenchymal damage for the liver resection(LR). These are especially beneficial for the patients with CLD. LLR results in minimal postoperative ascites and the other complications, which could potentially lead to lowering the risk of fatal liver failure. These characteristics of LLR facilitate surgical treatment application to the patients of HCC with background CLD. Laparoscopic approach also results in improved vision and manipulation in a small operative field under several conditions, including the cases where it is necessary to perform repeat LR between adhesions. These characteristics make LLR safer and more accessible to the repeat treatment, such as multicentric and metachronous lesions in the cirrhotic liver. These advantages of LLR indicate it is a superior method than open LR under certain conditions in patients of HCC with background CLD.

Repeat resection of liver metastases from gastrointestinal stromal tumor

A 44-year-old man, who was diagnosed with a gastrointestinal stromal tumor incidentally during emergency laparotomy for treatment of acute obstruction of small intestine at another hospital in 1999, was referred to our hospital due to a solitary metastasis in the liver in November 2002. A right segmentectomy (Segment 6, Couinaud's system) of liver was carried out. Half and one years later, a recurrent metastasis with involvement of the inferior vena cava was detected in posterior region of the liver. He underwent the third surgery in May 2004. Three another small metastases in greater omentum were found and removed. The tumor in posterior sector of the liver was en bloc resected with portion of involved inferior vena cava and diaphragm. The resected vena cava is repaired primarily through a lateral venorraphy.However, local recurrence was detected one year later, he recieved the fourth surgery in July 2005. He is now in Gleevec therapy. At present, he is in good health and free of recurrence.

THE TECHNIQUE OF THE NORMOTHERMIC AND HYPOTHERMIC TOTAL HEPATIC VASCULAR EXCLUSION FOR RESECTION OF THE LIVER TUMORS

The technique for bloodless hepatic resection using the total hepatic vascular isolation under the normothermic or hypothermic perfusion was reported to deal with the large liver tumor involving in the liver hilum,the main hepatic veins or the retrohepatic vena cava.The original Heaney's and Fortner's methods were modified so that the technique could be simpler and more practicable to perform otherwise hazardous liver resection.During the past 4 year,major hepatic resection with the normothermic or hypothermic total vascular exclusion technique was successfully performed on 19 patients with liver tumors in our department.Among the 19 cases,16 underwent hepatic resection with the normothermic selective total vascular exclusion(extended right lobectomy in 5 cases,extended left lobectomy in 3 cases;right lobectomy in 5 cases;central segmentectomy in 3 cases)and 3 with the total vascular isolation and in situ cold perfusion(extended left lobectomy in 2 case,extended right lobectong in 1case).We believe that the technique of normothermic vascular exclusion may be indicated to deal with the lesion close to the hepatic veins and the retrohepatic vena cava.However,for more complicated hepatic resection,the hypothermic perfusion technique should be considered to prolong the safety of ischemic tune of the liver.The preliminary experience in the clinical application using the above technique is reported.

Malignant solitary fibrous tumor involving the liver

Solitary fibrous tumors are predominantly benign and are most commonly found in the thoracic cavity and pleura; while reports exist in the literature of malignant solitary fibrous tumors and those located in extrathoracic organs, these cases are considered extremely rare. Herein, a case is reported of a malignant solitary fibrous tumor involving the liver that was diagnosed and treated in a 62-year-old woman. The patient presented with complaints of upper abdominal pain and unintentional weight loss. Computed tomography scan of the abdomen revealed a remarkably large mass, measuring 15 cm × 10 cm × 20 cm, which appeared to be unrelated to any particular organ. The intraoperative finding of a wide communication with the left liver suggested hepatic origin, and served as an indicator for tumor resection via left hemihepatectomy. The diagnosis of solitary fibrous tumor and its malignant nature was confirmed by histological and immunohistochemical examination of the resected tissues. Hepatic solitary fibrous tumor is very rare, and surgery remains the mainstay of treatment. Due to limited reports of such tumors in the literature, little can be said about the benefit of adjuvant therapy and prognosis for the rare cases with malignant histological findings.

Aggressive behaviour of solid-pseudopapillary tumor of the pancreas in adults:A case report and review of the literature

Solid-pseudopapillary tumor (SPT) is a rare neoplasm of the pancreas that usually occurs in young females. It is generally considered a low-grade malignant tumor that can remain asymptomatic for several years. The occurrence of infiltrating varieties of SPT is around 10%-15%. Between 1986 and 2006, 282 cystic tumors of the pancreas were observed. Among them a SPT was diagnosed in 8 patients (2.8%) with only one infiltrating variety. This was diagnosed in a 49-year-old female 13 years after the sonographic evidence of a small pancreatic cystic lesion interpreted as a pseudocyst. The tumor invaded a long segment of the portal- mesenteric vein confluence, and was removed with a total pancreatectomy, resection of the portal vein and reconstruction with the internal jugular vein. Histological examination confirmed the R-0 resection of the primary SPT, although a vascular invasion was demonstrated. The postoperative course was uneventful, but 32 mo after surgery the patient experienced diffuse liver metastases. Chemotherapy with different drugs was started. The patient is alive and symptom-free, with stable disease, 75 mo after surgery. Twenty-five patients with invasion of the portal vein and/or of mesenteric vessels were retrieved from the literature, 16 recent patients with tumor relapse after potentially curative resection were also retrieved. The best treatment remains a radical resection whenever possible, even in locally advanced or metastatic disease. The role of chemotherapy, and/or radiotherapy, is still to be defined.

Surgical resection of adrenal metastasis from primary liver tumors:a report of two cases

BACKGROUND:Although the treatment of extrahepatic metastases from primary liver tumors is essentially palliative,solitary metastasis from such tumors offers a possibility of cure by surgical resection.The adrenal gland is an uncommon site for metastasis from primary liver tumors. METHOD:We report two cases of adrenalectomy for solitary adrenal metastasis:one from intrahepatic cholangiocarcinoma and the other from hepatocellular carcinoma. RESULTS:The patient with intrahepatic cholangiocar- cinoma had a synchronous adrenal metastasis and underwent simultaneous liver resection and adrenalectomy. However,he developed recurrent disease 17 months following surgery for which he is presently on palliative chemotherapy.The other patient underwent adrenalectomy for adrenal metastasis 3 months following liver transplantation for hepatocellular carcinoma.He is presently alive and disease-free 27 months after adrenalectomy. CONCLUSION:Carefully selected patients with solitary metastasis from primary liver tumors may be considered for resection.

A three-factor preoperative scoring model predicts risk of recurrence after liver resection or transplantation in hepatocellular carcinoma patients with preserved liver function

BACKGROUND： No staging systems of hepatocellular carcinoma（HCC） are tailored for assessing recurrence risk. We sought to establish a recurrence risk scoring system to predict recurrence of HCC patients receiving surgical curative treatment（liver resection or transplantation）.METHODS： We retrospectively studied 286 HCC patients with preserved liver function receiving liver resection（n=184） or transplantation（n=102）. Independent risk factors were identified to construct the recurrence risk scoring model. The recurrence free survival and discriminatory ability of the model were analyzed. RESULTS： Total tumor volume, HBs Ag status, plasma fibrinogen level were included as independent prognostic factors for recurrence-free survival and used for constructing a 3-factor recurrence risk scoring model. The scoring model was as follows： 0.758×HBs Ag status（negative： 0; positive： 1）＋0.387×plasma fibrinogen level（≤3.24 g/L： 0; 〉3.24 g/L： 1）＋0.633×total tumor volume（≤107.5 cm3： 0; 〉107.5 cm3： 1）. The cutoff value was set to 1.02, and we defined the patients with the score ≤1.02 as a low risk group and those with the score 〉1.02 as a high risk group. The 3-year recurrence-free survival rate was significantly higher in the low risk group compared with that in the high risk group（67.9% vs 41.3%, P〈0.001）. In the subgroup analysis, liver transplantation patients had a better3-year recurrence-free survival rate than the liver resection patients in the low risk group（80.0% vs 64.0%, P〈0.01）. Additionally for patients underwent liver transplantation, we compared the recurrence risk model with the Milan criteria in the prediction of recurrence, and the 3-year recurrence survival rates were similar（80.0% vs 79.3%, P=0.906）.CONCLUSION： Our recurrence risk scoring model is effective in categorizing recurrence risks and in predicting recurrencefree survival of HCC before potential surgical curative treatment.

Single hepatocellular carcinoma ≤ 3 cm in left lateral segment:Liver resection or radiofrequency ablation?

AIM:To evaluate the long-term results of radiofrequency ablation(RFA)compared to left lateral sectionectomy(LLS)in patients with Child-Pugh class A disease for the treatment of single and small hepatocellular carcinoma(HCC)in the left lateral segments.METHODS:We retrospectively reviewed the data of133 patients with single HCC(≤3 cm)in their left lateral segments who underwent curative LLS(n=66)or RFA(n=67)between 2006 and 2010.RESULTS:The median follow-up period was 33.5mo in the LLS group and 29 mo in the RFA group(P=0.060).Most patients had hepatitis B virus-related HCC.The hospital stay was longer in the LLS group than in the RFA group(8 d vs 2 d,P<0.001).The 1-,2-,and 3-year disease-free survival and overall survival rates were 80.0%,68.2%,and 60.0%,and 95.4%,92.3%,and 92.3%,respectively,for the LLS group;and 80.8%,59.9%,and 39.6%,and 98.2%,92.0%,and 74.4%,respectively,for the RFA group.The disease-free survival curve and overall survival curve were higher in the LLS group than in the RFA group(P=0.012 and P=0.013,respectively).Increased PIVKA-Ⅱlevels and small tumor size were associated with HCC recurrence in multivariate analysis.CONCLUSION:Liver resection is suitable for single HCC≤3 cm in the left lateral segments.

Review of the literature laparoscopic surgery for metastatic hepatic leiomyosarcoma associated with smooth muscle tumor of uncertain malignant potential: Case report

Metastatic hepatic leiomyosarcoma is a rare malignant smooth muscle tumor.We report a case of metastatic hepatic leiomyosarcoma associated with smooth muscle tumor of uncertain malignant potential(STUMP).A 68-year-old female presented with a liver mass(60 mm × 40 mm, Segment 4).She underwent left salpingooophorectomy for an ovary tumor with STUMP in a broad ligament 6 years ago.Though FDG-PET showed obvious metabolically active foci, abnormal metabolically active foci other than the lesion were not detected.A malignant liver tumor was strongly suspected and laparoscopic partial liver resection was performed with vessel-sealing devices using the crush clamping method and Pringle maneuver.Immunohistochemical findings revealed metastatic liver leiomyosarcoma associated with STUMP in a broad ligament.This case is an extremely rare case of malignant transformation from primary STUMP to metastatic hepatic leiomyosarcoma.It provides important evidence regarding the treatment for metastatic hepatic leiomyosarcoma associated with STUMP.

Expression of regulating apoptosis gene and apoptosis index in primary liver cancer

INTRODUCTIONProgramed cell death plays an important role in thegenesis of cancer.Certain cancer genes canregulate apoptosis.Recently,several proteins thatare structurally related to Bcl-2,an inhibitor ofapoptosis,have been identified.Therefore,novel strategies and agents that target specificmolecular pathways,as well as triggering a

Current position of ALPPS in the surgical landscape of CRLM treatment proposals

The Authors summarize problems,criticisms but also advantages and indications regarding the recent surgical proposal of associating liver partition and portal vein ligation(PVL)for staged hepatectomy(ALPPS)for the surgical management of colorectal liver metastases.Looking at published data,the technique,when compared with other traditional and well established methods such as PVL/portal vein embolisation(PVE),seems to give real advantages in terms of volumetric gain of future liver remnant.However,major concerns are raised in the literature and some questions remain unanswered,preliminary experiences seem to be promising.The method has been adopted all over the world over the last 2 years,even if oncological long-term results remain unknown,and benefit for patients is questionable.No prospective studies comparing traditional methods(PVE,PVL or classical 2 staged hepatectomy)with ALPPS are available to date.Technical reinterpretations of the original method were also proposed in order to enhance feasability and increase safety of the technique.More data about morbidity and mortality are also expected.The real role of ALPPS is,to date,still to be established.Large clinical studies,even if,for ethical reasons,in well selected cohorts of patients,are expected to better define the indications for this new surgical strategy.

Neoadjuvant therapy in the treatment of hilar cholangiocarcinoma:Review of the literature

Cholangiocarcinoma(CCA)is a malignant tumor of the biliary system and includes,according to the anatomical classification,intra hepatic CCA(iCCA),hilar CCA(hCCA)and distal CCA(dCCA).Hilar CCA is the most challenging type in terms of diagnosis,treatment and prognosis.Surgery is the only treatment possibly providing long-term survival,but only few patients are considered resectable at the time of diagnosis.In fact,tumor’s extension to segmentary or subsegmentary biliary ducts,along with large lymph node involvement or intrahepatic metastases,precludes the surgical approach.To achieve R0 margins is mandatory for the disease-free survival and overall survival.In case of unresectable locally advanced hCCA,radiochemotherapy(RCT)as neoadjuvant treatment demonstrated to be a therapeutic option before either hepatic resection or liver transplantation.Before liver surgery,RCT is believed to enhance the R0 margins rate.For patients meeting the Mayo Clinic criteria,RCT prior to orthotopic liver transplant(OLT)has proved to produce acceptable 5-years survivals.In this review,we analyze the current role of neoadjuvant RCT before resection as well as before OLT.

Current therapy of hilar cholangiocarcinoma

BACKGROUND: Hilar cholangiocarcinoma (HC) is an adeno-carcinoma of the extrahepatic biliary tree arising from the main left or right hepatic ducts or their confluence. This tumor is still considered to be difficult to treat or to cure. DATA SOURCES: We reviewed the medical literature on HC. Relevant and updated information on this tumor was analyzed in a concise and easy-to-read manner. The article is not intended to be a systematic review, but an extensive search was conducted on PubMed and MEDLINE using the keywords 'hilar cholangiocarcinoma' and 'Klatskin tumor' until July 2011. RESULTS: The selection and the timing of management options for patients with HC are determined by the degree of certainty of the diagnosis, the general condition of the patients, the underlying liver function and the stage of the disease. Current treatment of HC can be divided into curative and palliative treatment. For the curative treatment, local excision should only be used on small tumors which are confined to the bile duct wall and Bismuth I papillary carcinoma. Partial hepatectomy should be combined with caudate lobe resection and porta-hepatis lymph node dissection. The results of these major resections can be improved with portal vein embolization, and staging laparoscopy and laparoscopic ultrasound. The role of preoperative biliary drainage is controversial. Autotransplantation for HC gave disappointing results while the Mayo Protocol of chemoradiation for selecting patients with unresectable HC for orthotopic liver transplantation has been widely accepted. Palliative treatment included bypass surgery, endoscopic or percutaneous stenting, photodynamic therapy, intraluminal brachytherapy, and external radiation and systemic therapy. CONCLUSIONS: Adequate surgery with R0 resection should be the main goal of treatment. For patients with unresectable HC, treatment aims to improve the quality and quantity of their survival.

Evolving role of Sorafenib in the management of hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is one of the most common malignant diseases worldwide and comes third in cancer-related mortality.Although there is a broad spectrum of treatment options to choose from,only a few patients are eligible candidates to receive a curative therapy according to their stage of disease,and thus palliative treatment is implemented in the majority of the patients suffering from liver cancer.Sorafenib,a multikinase inhibitor,is the only currently approved agent for systemic therapy in patients with advanced stage HCC and early stage liver disease.It has been shown to improve the overall survival,but with various side effects,while its cost is not negligible.Sorafenib has been in the market for a decade and has set the stage for personalized targeted therapy.Its role during this time has ranged from monotherapy to neoadjuvant and adjuvant treatment with surgical resection,liver transplantation and chemoembolization or even in combination with other chemotherapeutic agents.In this review our aim is to highlight in depth the current position of Sorafenib in the armamentarium against HCC and how that has evolved over time in its use either as a single agent or in combination with other therapies.