Toxicity of targeted anticancer treatments on the liver in myeloproliferative neoplasms

The liver has a central role in metabolism,therefore,it is susceptible to harmful effects of ingested medications(drugs,herbs,and nutritional supplements).Druginduced liver injury(DILI)comprises a range of unexpected reactions that occur after exposure to various classes of medication.Even though most cases consist of mild,temporary elevations in liver enzyme markers,DILI can also manifest as acute liver failure in some patients and can be associated with mortality.Herein,we briefly review available data on DILI induced by targeted anticancer agents in managing classical myeloproliferative neoplasms:Chronic myeloid leukemia,polycythemia vera,essential thrombocythemia,and myelofibrosis.

Neoplastic disease after liver transplantation: focus on de novo neoplasms

De novo neoplasms account for almost 30% of deaths 10 years after liver transplantation and are the most common cause of mortality in patients surviving at least 1 year after transplant. The risk of malignancy is two to four times higher in transplant recipients than in an age- and sex-matched population, and cancer is expected to surpass cardiovascular complications as the primary cause of death in transplanted patients within the next 2 decades. Since exposure to immunosuppression is associated with an increased frequency of developing neoplasm, long-term immunosuppression should be therefore minimized. Promising results in the prevention of hepatocellular carcinoma(HCC) recurrence have been reported with the use of m TOR inhibitors including everolimus and sirolimus and the ongoing open-label prospective randomized controlled SILVER. Study will provide more information on whether sirolimus-containing vs m TOR-inhibitorfree immunosuppression is more efficacious in reducing HCC recurrence.

Simultaneous liver mucinous cystic and intraductal papillary mucinous neoplasms of the bile duct:A case report

Cystic hepatic neoplasms are rare tumors,and are classified into two separate entities:mucinous cystic neoplasms(MCNs)and intraductal papillary mucinous neoplasms of the bile duct(IPMN-B).We report the case of a 56-year-old woman who presented with abdominal pain and jaundice due to the presence of a large hepatic multilocular cystic tumor associated with an intraductal tumor.Partial hepatectomy with resection of extrahepatic bile ducts demonstrated an intrahepatic MCN and an intraductal IPMN-B.This is the first report of the simultaneous occurrence of these two histologically distinct entities in the liver.

Application of two-phase helical CT in liver neoplasms

Objective: To assess the value of helical CT in the di-agnosis of liver diseases.Methods: 59 patients with different liver diseaseswere examined by two-phase or multi-phase dynamichelical CT.Results: Small hepatocellular carcinoma showed ahigher density in the arterial phase, and a lower den-sity in the portal vein phase. Large hepatic carcino-ma showed a mixed pattern of higher-density in thearterial phase, and a lower density in the portal veinphase. Metastasis carcinoma showed an "oxeye sign"in the portal vein phase. Hemangioma was not obvi-ously enhanced in the early arterial phase, marginal-ly enhanced in the arterial phase, and equally-densedin the balanced phase.Conclusion: Two-phase helical CT is of value in im-proving the detection rate of or determining the fea-tures of hepatic diseases by two-phase helical dyna-mic scan (2.0-3.0 ml/s speed, and delay time 25-30 s and 70-85 s).

Spontaneous rupture of a mucinous cystic neoplasm of the liver resulting in a huge biloma in a pregnant woman:A case report

BACKGROUND Mucinous cystic neoplasm of the liver(MCN-L)and intraductal papillary neoplasm of the bile duct(IPN-B)are two different types of mucin-producing bile duct tumour that may complicate the course of pregnancy.To the best of our knowledge,we describe herein the first case of MCN-L with spontaneous rupture during pregnancy necessitating complex surgical treatment.CASE SUMMARY A 24-year-old woman was initially admitted to another hospital in October 2018 with signs of jaundice(serum bilirubin level 12 mg/dL)and upper abdominal pain radiating to the left shoulder.Initial magnetic resonance imaging(MRI)of the abdominal cavity revealed a multilocular cystic tumour of the liver hilum(37 mm×40 mm in diameter)located between segments 3 and 4 of the left liver lobe.Six weeks later(December 2018),the patient was found to be 12 wk pregnant and was referred to our institution for further diagnostics and treatment.At admission,a soft,palpable,and tender mass in the left upper abdomen was found.It was determined via MRI(with no intravenous contrast in view of the first-trimester pregnancy)to be a large collection of fluid(19 cm×17 cm×10 cm)located close to the liver hilum and below the left liver lobe.The patient did not undergo any diagnostic or therapeutic procedures nor did they have any abdominal trauma in the preceding weeks.The fluid collection proved to be of biliary origin following percutaneous drainage.Therefore,we concluded this was a spontaneous rupture of an MCN-L with the formation of a biloma.The MRI study also revealed the previously found cystic tumour of the liver hilum communicating with the left hepatic duct,which,together with left hepatic duct dilatation,suggested the diagnosis of IPN-B.The follow-up MRI with intravenous gadolinium contrast performed in the second trimester of pregnancy(week 14)showed,in turn,some features of MCN-L,including enhancement of the internal septations within the cystic liver mass.A precise preoperative differential diagnosis between IPN-B and MCN-L was therefore not possible.The patient was submitted to surgery in the second trimester of pregnancy(week 18).Surgery included a cholecystectomy,left hepatectomy,and concomitant resection of the extrahepatic bile ducts followed by anastomosis of the right hepatic duct with the Roux limb of the jejunum.The post-operative period was uneventful and the patient was discharged 8 days after surgery.The histopathological examination of the resected specimen revealed a final diagnosis of MCN-L with low-grade dysplasia and epithelium surrounded by ovarian-type stromal tissue.The patient delivered a healthy baby girl and both remain well at present,after 2 years of follow-up since surgery.CONCLUSION The differential diagnosis and management of MCN-L and IPN-B may be very challenging,particularly in the setting of pregnancy.When indications for surgery are obvious,the final diagnosis is based on histopathological examination,with ovarian-type stroma being pathognomonic for MCN-L.We believe that the growth of this subepithelial stroma secondary to the high levels of sex hormones produced during pregnancy might have been the main causative factor leading to the tumour rupture with the formation of a biloma in our patient.

Liver-directed therapies for liver metastases from neuroendocrine neoplasms:Can laser ablation play any role?

Aggressive cytoreduction can prolong survival in patients with unresectable liver metastases(LM)from neuroendocrine neoplasms(NEN),and minimally invasive,liver-directed therapies are gaining increasing interest.Catheter-based treatments are used in disseminated disease,whereas ablation techniques are usually indicated when the number of LM is limited.Although radiofrequency ablation(RFA)is by far the most used ablative technique,the goal of this opinion review is to explore the potential role of laser ablation(LA)in the treatment of LM from NEN.LA uses thinner needles than RFA,and this is an advantage when the tumors are in at-risk locations.Moreover,the multi-fiber technique enables the use of one to four laser fibers at once,and each fiber provides an almost spherical thermal lesion of 12-15 mm in diameter.Such a characteristic enables to tailor the size of each thermal lesion to the size of each tumor,sparing the liver parenchyma more than any other liver-directed therapy,and allowing for repeated treatments with low risk of liver failure.A recent retrospective study reporting the largest series of LM treated with LA documents both safety and effectiveness of LA,that can play a useful role in the multimodality approach to LM from NEN.

Neuroendocrine neoplasms of liver-A 5-year retrospective clinico-pathological study applying World Health Organization 2010 classification

AIM To study the clinicopathological characteristics of neuroendocrine neoplasms(NEN) on liver samples and apply World Health Organization(WHO) 2010 grading of gastroenteropancreatic(GEP) NEN.METHODS Clinicopathological features of 79 cases of NEN of the liver diagnosed between January 2011 to December 2015 were analyzed. WHO 2010 classification of GEP NEN was applied and the tumors were graded as G1, G2 or G3. Two more categories, D1/2(discordant 1/2) and D2/3(discordant 2/3) were also applied. The D1/2 grade tumors had a mitotic count of G1 and Ki-67 index of G2. The D2/3 tumors had a mitotic count of G2 and Ki-67 index of G3. The follow up details which were available till the end of the study period(December 2015) were collected.RESULTS Of the 79 tumors, 16 each were G1 and G2, and 18 were G3 tumors. Of the remaining 29 tumors, 13 were assigned to D1/2 and 16 were D2/3 grade. Male preponderance was noted in all tumors except for G2 neoplasms, which showed a slight female predilection. The median age at presentation was 47 years(range 10-82 years). The most common presentation was abdominal pain(81%). Pancreas(49%) was the most common site of primary followed by gastrointestinal tract(24.4%) and lungs(18%). Radiologically, 87% of the patients had multiple liver lesions. Histopathologically, necrosis was seen in only D2/3 and G3 tumors. Microvascular invasion was seen in all grades. Metastasis occurred in all grades of primary NEN and the grades of the metastatic tumors and their corresponding primary tumors were similar in 67% of the cases. Of the 79 patients, 36 had at least one follow up visit with a median duration of follow up of 8.5 mo(range: 1-50 mo). This study did not show any impact of the grade of tumor on the short term clinical outcome of these patients.CONCLUSION Liver biopsy is an important tool for clinicopathological characterization and grading of NEN, especially when the primary is not identified. Eighty-seven percent of the patients had multifocal liver lesions irrespective of the WHO grade, indicating a higher stage of disease at presentation. Follow up duration was inadequate to derive any meaningful conclusion on long term outcome in our study patients.

Update on surgical treatment of pancreatic neuroendocrine neoplasms

Pancreatic neuroendocrine neoplasms(PNENs) are rare and account for only 2%-4% of all pancreatic neoplasms. All PNENs are potential(neurendocrine tumors PNETs) or overt(neuroendocrine carcinomas PNECs) malignant,but a subset of PNETs is low-risk. Even in case of low-risk PNETs surgical resection is frequently required to treat hormone-related symptoms and to obtain an appropriate pathological diagnosis. Low-risk PNETs in the body and the tail are ideal for minimallyinvasive approaches which should be tailored to the individual patient. Generally,surgeons must aim for parenchyma sparing in these cases. In high-risk and malignant PNENs,indications for tumor resection are much wider than for pancreatic adenocarcinoma,in many cases due to the relatively benign tumor biology. Thus,patients with locally advanced and metastatic PNETs may benefit from extensive resection. In experienced hands,even multi-organ resections are accomplished with acceptable perioperative morbidity and mortality rates and are associated with excellent long term survival. However,poorly differentiated neoplasms with high proliferation rates are associated with a dismal prognosis and may frequently only be treated with chemotherapy. The evidence on surgical treatment of PNENs stems from reviews of mostly singlecenter series and some analyses of nation-wide tumor registries. No randomized trial has been performed to compare surgical and non-surgical therapies in potentially resectable PNEN. Though such a trial would principally be desirable,ethical considerations and the heterogeneity of PNENs preclude realization of such a study. In the current review,we summarize recent advances in the surgical treatment of PNENs.

FEASIBILITY STUDY OF AN ULTRASOUND CONTRAST AGENT(LEVOVIST) IN COLOR DOPPLER IMAGING OF LIVER NEOPLASMS

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Liver transplantation as an alternative for the treatment of intrahepatic cholangiocarcinoma: Past, present, and future directions

Intrahepatic cholangiocarcinoma(iCCA)is a rare biliary tract cancer with high mortality rate.Complete resection of the iCCA lesion is the first choice of treatment,with good prognosis after margin-negative resection.Unfortunately,only 12%-40% of patients are eligible for resection at presentation due to cirrhosis,portal hypertension,or large tumor size.Liver transplantation(LT)offers margin-negative iCCA extirpation for patients with unresectable tumors.Initially,iCCA was a contraindication for LT until size-based selection criteria were introduced to identify patients with satisfied post-LT outcomes.Recent studies have shown that tumor biology-based selection can yield high post-LT survival in patients with locally advanced iCCA.Another selection criterion is the tumor response to neoadjuvant therapy.Patients with response to neoadjuvant therapy have better outcomes after LT compared with those without tumor response to neoadjuvant therapy.Another index that helps predict the treatment outcome is the biomarker.Improved survival outcomes have also opened the door for living donor LT for iCCA.Patients undergoing LT for iCCA now have statistically similar survival rates as patients undergoing resection.The combination of surgery and locoregional and systemic therapies improves the prognosis of iCCA patients.

Liver transplantation as an alternative for the treatment of perihilar cholangiocarcinoma: A critical review

Background:Perihilar cholangiocarcinoma(phCCC)is a dismal malignancy.There is no consensus regard-ing the best treatment for patients with unresectable phCCC.The present review aimed to gather the current pieces of evidence for liver transplantation and liver resection as a treatment for phCCC and to build better guidance for clinical practice.Data sources:The search was conducted in PubMed,Embase,Cochrane,and LILACS.The related references were searched manually.Inclusion criteria were:reports in English or Portuguese literature that a)patients with confirmed diagnosis of phCCC;b)patients treated with a curative intent;c)patients with the outcomes of liver resection and liver transplantation.Case reports,reviews,letters,editorials,conference abstracts and papers with full-text unavailability were excluded from the analysis.Results:Most of the current literature is based on observational retrospective studies with low grades of evidence.Liver resection has better long-term outcomes than systemic chemotherapy or palliation ther-apy and liver transplantation is a good alternative for selected patients with unresectable phCCC.All candidates for resection or transplantation should be medically fit and free of intrahepatic or extrahep-atic diseases.As a general rule,patients presenting with a tumor having a longitudinal size>3 cm or extending below the cystic duct,lymph node disease,confirmed extrahepatic dissemination;intraoper-atively diagnosed metastatic disease;a history of other malignancies within the last five years,and did not complete chemoradiation regimen and were medically unfit should not be considered for transplan-tation.Some of these criteria should be individually assessed.Liver transplantation or resection should only be considered in highly experienced hepatobiliary centers,and any decision-making must be based on a multidisciplinary evaluation.Conclusions:phCCC is a complex condition with high morbidity.Surgical therapies,including hepatec-tomy and liver transplantation,are the best option for better long-term disease-free survival.

Prevalence and outcomes of pancreatic cystic neoplasms in liver transplant recipients

AIM To determine the prevalence,characteristics and clinical course of pancreatic cystic neoplasms(PCNs) in liver transplantation(LT) recipients.METHODS We retrospectively studied consecutive patients who underwent LT between January 1998 to April 2016. Clinical and laboratory data were obtained from patient medical records. Imaging findings on computed tomography and magnetic resonance cholangiopancreatography were reviewed by two radiologists.RESULTS During the study period,872 patients underwent cadaveric LT. Pancreatic cysts were identified in 53/872(6.1%) and 31/53(58.5%) were PCNs [28 intraductal papillary mucinous neoplasm(IPMN),2 mucinous cystic neoplasm(MCN),1 serous cystadenoma]. Patients with PCNs exhibited less male predominance(55% vs 73%,P = 0.03) compared to patients without pancreatic cysts. Thirteen patients(42%) were diagnosed with PCN pre-LT while 18 patients(58%) developed PCN post-LT. The median size of PCNs was 13 mm [interquartile range(IQR) 10-20 mm]. All IPMNs were side-branch type. Most PCNs were found in the head and body of pancreas(37% each),followed by the tail(25%). Five patients underwent further evaluation with endoscopic ultrasound. Progress imaging was performed on 81% of patients. PCNs remained stable in size and number in all but 2 patients. During a median follow up of 39 mo(IQR 26-58 mo),the 2(6%) patients with MCN underwent pancreatectomy. No PCN patient developed pancreatic adenocarcinoma,while 5 died from illnesses unrelated to the PCN. Among patients without PCN,1/841(0.1%) developed pancreatic adenocarcinoma.CONCLUSION The prevalence of PCNs in LT recipients was similar to the general population(3.6%,31/872). Side-branch IPMNs do not appear to have accelerated malignant potential in post-LT patients,indicating the current surveillance guidelines are applicable to this group.

Current status of surgical management of patients with gastroenteropancreatic neuroendocrine neoplasms

Neuroendocrine neoplasms(NENs)of the gastroenteropancreatic system are rare and heterogeneous tumours,yet with increasing prevalence.The most frequent primary sites are the small intestine,rectum,pancreas,and stomach.For a localized disease,surgical resection with local lymph nodes is usually curative with good overall and disease free survival.More complex situation is the treatment of locally advanced lesions,liver metastases,and,surprisingly,small asymptomatic tumours of the rectum and pancreas.In this review,we focus on the current role of surgical management of gastroenteropancreatic NENs.We present surgical approach for the most frequent primary sites.We highlight the role of endoscopic surgery and the watch-and-wait strategy for selected cases.As liver metastases pose an important clinical challenge,we present current indications and contraindications for liver resection and a role of liver transplantation for metastatic NENs.

Role of surgical treatments in high-grade or advanced gastroenteropancreatic neuroendocrine neoplasms

Over the last 40 years,the incidence and prevalence of gastroenteropancreatic neuroendocrine neoplasms(GEP-NENs)have continued to increase.Compared to other epithelial neoplasms in the same organ,GEP-NENs exhibit indolent biological behavior,resulting in more chances to undergo surgery.However,the role of surgery in high-grade or advanced GEP-NENs is still controversial.Surgery is associated with survival improvement of well-differentiated highgrade GEP-NENs,whereas poorly differentiated GEP-NENs that may benefit from resection require careful selection based on Ki67 and other tissue biomarkers.Additionally,surgery also plays an important role in locally advanced and metastatic disease.For locally advanced GEP-NENs,isolated major vascular involvement is no longer an absolute contraindication.In the setting of metastatic GEP-NENs,radical intended surgery is recommended for patients with low-grade and resectable metastases.For unresectable metastatic disease,a variety of surgical approaches,including cytoreduction of liver metastasis,liver transplantation,and surgery after neoadjuvant treatment,show survival benefits.Primary tumor resection in GEP-NENs with unresectable metastatic disease is associated with symptom control,prolonged survival,and improved sensitivity toward systemic therapies.Although there is no established neoadjuvant or adjuvant strategy,increasing attention has been given to this emerging research area.Some studies have reported that neoadjuvant therapy effectively reduces tumor burden,improves the effectiveness of subsequent surgery,and decreases surgical complications.

SULT1C2在肝癌中表达及其与预后关系生信分析

目的研究磺基转移酶1C2(SULT1C2)基因在肝癌中的表达情况及其与病人临床预后的关系,探讨SULT1C2基因在肝癌中作用的分子机制。方法从癌症基因组图谱(TCGA)和基因表达综合(GEO)数据库下载泛癌和肝癌原始RNA测序数据及病人的临床资料,利用R4.0.2提取SULT1C2基因表达值并在肝癌分子图谱数据库(HCCDB)和肝癌组织中验证,结合临床肝癌样本分析SULT1C2基因在肝癌组织中表达及其与病人预后的关系。通过基因富集分析(GSEA)分析SULT1C2基因相关的生物学功能和信号通路,采用Pearson相关性分析检验SULT1C2与信号通路间的相关性。结果TCGA、GEO和HCCDB数据集以及临床肝癌样本检测结果显示,SULT1C2在泛癌和肝癌组织中表达水平显著上调(P<0.05);Kapalan-Meier生存分析显示,SULT1C2表达与病人不良预后相关(P<0.05)。GSEA分析显示,SULT1C2在不同肿瘤中发挥抑癌或促癌的双重作用。在肝癌组织中,SULT1C2表达的同时可激活转录因子E2因子(E2F)、G2M检查点和MYC信号通路。结论SULT1C2基因在肝癌中高表达,它可能通过激活E2F、G2M检查点和MYC信号通路诱导肝癌病人的不良预后,有望成为肝癌潜在的诊断和治疗新靶点。

Progress in research of liver surgery in China

INTRODUCTIONLiver surgery,was started in the late 1950s in Chinaand has developed rapidly in the past 40 years.The study on the diagnosis and treatment of primaryliver cancer in China underwent four stages:①Inthe 1950s,the anatomical study of the liver lay asolid foundation for liver resection.①In

Expression of insulin-like growth factor Ⅱ and its receptor in liver cells of chronic liver diseases

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Prognosis of acute-on-chronic liver failure patients treated with artificial liver support system

AIM: To establish a new model for predicting survival in acute-on-chronic liver failure(ACLF) patients treated with an artificial liver support system. METHODS: One hundred and eighty-one ACLF patients who were admitted to the hospital from January 1, 2012 to December 31, 2014 and were treated with an artificial liver support system were enrolled in this retrospective study, including a derivation cohort(n = 113) and a validation cohort(n = 68). Laboratory parameters at baseline were analyzed and correlatedwith clinical outcome. In addition to standard medical therapy, ACLF patients underwent plasma exchange(PE) or plasma bilirubin adsorption(PBA) combined with plasma exchange. For the derivation cohort, KaplanMeier methods were used to estimate survival curves, and Cox regression was used in survival analysis to generate a prognostic model. The performance of the new model was tested in the validation cohort using a receiver-operator curve.RESULTS: The mean overall survival for the derivation cohort was 441 d(95%CI: 379-504 d), and the 90- and 270-d survival probabilities were 70.3% and 58.3%, respectively. The mean survival times of patients treated with PBA plus PE and patients treated with PE were 531 d(95%CI: 455-605 d) and 343 d(95%CI: 254-432 d), respectively, which were significantly different(P = 0.012). When variables with bivariate significance were selected for inclusion into the multivariate Cox regression model, number of complications, age, scores of the model for end-stage liver disease(MELD) and type of artificial liver support system were defined as independent risk factors for survival in ACLF patients. This new prognostic model could accurately discriminate the outcome of patients with different scores in this cohort(P < 0.001). The model also had the ability to assign a predicted survival probability for individual patients. In the validation cohort, the new model remained better than the MELD.CONCLUSION: A novel model was constructed to predict prognosis and accurately discriminate survival in ACLF patients treated with an artificial liver support system.

Codon 249 mutations of p53 gene in non-neoplastic liver tissues

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