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.

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.

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 diseases were examined by two-phase or multi-phase dynamic helical CT. Results: Small hepatocellular carcinoma showed a higher 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 the arterial phase, and a lower density in the portal vein phase. 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-densed in 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).

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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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.

Molecular targets and mechanisms of different aberrant alternative splicing in metastatic liver cancer

Metastasis remains a major challenge in the successful management of malignant diseases.The liver is a major site of metastatic disease and a leading cause of death from gastrointestinal malignancies such as colon,stomach,and pancreatic cancers,as well as melanoma,breast cancer,and sarcoma.As an important factor that influences the development of metastatic liver cancer,alternative splicing drives the diversity of RNA transcripts and protein subtypes,which may provide potential to broaden the target space.In particular,the dysfunction of splicing factors and abnormal expression of splicing variants are associated with the occurrence,progression,aggressiveness,and drug resistance of cancers caused by the selective splicing of specific genes.This review is the first to provide a detailed summary of the normal splicing process and alterations that occur during metastatic liver cancer.It will cover the role of alternative splicing in the mechanisms of metastatic liver cancer by examining splicing factor changes,abnormal splicing,and the contribution of hypoxia to these changes during metastasis.

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.

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

Transarterial chemoembolization for liver metastases from solid pseudopapillary epithelial neoplasm of pancreas: A case report

Solid pseudo-papillary epithelial neoplasm(SPEN) is a rare epithelial tumor of pancreas with a low malignant potential occurs most commonly in young females. We report a case of 40 years old woman presented withextensive liver metastasis from SPEN of pancreatic body for which she was operated four years ago. Due to the extensive nature of metastatic disease she was offered Transarterial chemoembolisation(TACE) using gemcitabine as chemotherapeutic agent. Short term follow up after a month of TACE with multiphase computed tomography showed > 90% resolution in the viable tumor with significant clinical improvement. TACE ensures targeted delivery of chemotherapeutic drugs in higher doses with least systemic toxicity and is more effective and safe than systemic chemotherapy. TACE with gemcitabine was found to be very effective in our patient with numerous liver metastasis.

Current surgical management of pancreatic endocrine tumor liver metastases

BACKGROUND: The management of metastatic disease in pancreatic endocrine tumors (PETs) demands a multidisciplinary approach and the cooperation of several medical specialties. The role of surgery is critical, even when a radical excision cannot always be achieved. DATA SOURCES: A PubMed search of relevant articles published up to February 2011 was performed to identify current information about PET liver metastases regarding diagnosis and management, with an emphasis on surgery. RESULTS: The early diagnosis of metastases and their accurate localization, most commonly in the liver, is very important. Surgical options include radical excision, and palliative excision to relieve symptoms in case of failure of medical treatment. The goal of the radical excision is to remove the primary tumor bulk and all liver metastases at the same time, but unfortunately it is not feasible in most cases. Palliative excisions include aggressive tumor debulking surgeries in well-differentiated carcinomas, trying to remove at least 90% of the tumor mass, combined with other additional destructive techniques such as hepatic artery embolization or chemoembolization to treat metastases or chemoembolization to relieve symptoms in cases of rapidly growing tumors. The combination of chemoembolization and systemic chemotherapy results in better response and survival rates. Other local destructive techniques include ethanol injection, cryotherapy and radiofrequency ablation. CONCLUSION: It seems that the current management of PETs can achieve important improvements, even in advanced cases.

Feasibility of laparoscopic isolated caudate lobe resection for rare hepatic mesenchymal neoplasms

BACKGROUND Mesenchymal tumors such as perivascular epithelioid cell neoplasm(PEComa)and inflammatory pseudotumor-like follicular dendritic cell sarcoma(IPT-like FDC sarcoma)are relatively uncommon in the liver and are particularly rare in the caudate lobe.The clinical manifestations and available imaging tests lack specificity for hepatic mesenchymal tumors.To the best of our knowledge,no caudate PEComa or IPT-like FDC sarcoma has been completely resected by laparoscopy.The standard laparoscopic technique,surgical approaches,and tumor margins for potentially malignant or malignant caudate mesenchymal tumors are still being explored.AIM To assess both the safety and feasibility of laparoscopic resection for rare caudate mesenchymal neoplasms.METHODS Eleven patients who underwent isolated caudate lobe resection from 2003 to 2017 were identified from a prospective database.Three consecutive patients with rare caudate mesenchymal tumors underwent laparoscopic resection.Patient demographic data,intraoperative parameters,and postoperative outcomes were assessed and compared with the open surgery group.RESULTS All procedures for the three resection patients with caudate mesenchymal tumors were completed using a total laparoscopic technique by two different approaches.The average operative time was 226 min,and the estimated blood loss was 133 mL.The average length of postoperative hospital stay was 6.3±0.3 d for the laparoscopy group and 15.5±2.3 d for the open surgery group(P<0.05).There were no perioperative complications or patient deaths in this series.CONCLUSION Laparoscopic isolated caudate lobe resection for rare mesenchymal neoplasms is a feasible and curative surgical option in selected patients.

Mixed neuroendocrine–nonneuroendocrine neoplasms of the gastrointestinal system:An update

Mixed neuroendocrine-nonneuroendocrine neoplasms(Mi NENs)of the digestive tract are a rare heterogeneous group of tumors that present many challenges in terms of diagnosis and treatment.Over the years,the diagnostic criteria,classification,and clinical behavior of these tumors have been the subjects of ongoing debate,and the various changes in their nomenclature have strengthened the challenges associated with Mi NENs.This review is performed to provide an understanding of the key factors involved in the evolution of the designation of these tumors as Mi NEN,highlight the current diagnostic criteria,summarize the latest data on pathogenesis and provide information on available treatments.Moreover,this work seeks to increase the awareness about these rare neoplasms by presenting the clinicopathological features and prognostic factors that play important roles in their behavior and discussing their different regions of origin in the gastrointestinal system(GIS).Currently,the Mi NEN category also includes tumors in the GIS with a nonneuroendocrine component and epithelial tumors other than adenocarcinoma,depending on the organ of origin.Diagnosis is based on the presence of both morphological components in more than 30%of the tumor.However,this value needs to be reconfirmed with further studies and may be a limiting factor in the diagnosis of Mi NEN by biopsy.Furthermore,available clinicopathological data suggest that the inclusion of amphicrine tumors in the definition of Mi NEN is not supportive and warrants further investigation.The diagnosis of these tumors is not solely based on immunohistochemical findings.They are not hybrid tumors and both components can act independently;thus,careful grading of each component separately is required.In addition to parameters such as the metastatic state of the tumor at the time of diagnosis and the feasibility of surgical resection,the aggressive potential of both components has paramount importance in the choice of treatment.Regardless of the organ of origin within the GIS,almost Mi NENs are tumors with poor prognosis and are frequently encountered in the elderly and men.They are most frequently reported in the colorectum,where data from molecular studies indicate a monoclonal origin;however,further studies are required to provide additional support for this origin.

Laparoscopic resection of synchronous intraductal papillary mucinous neoplasms:A case report

We describe herein a 68-year-old woman who was diagnosed with a quite rare entity of intraductal papillary mucinous neoplasms(IPMNs) occurring simultaneously in the left lateral lobe of liver and the tail of pancreas.Abdominal computed tomography and magnetic resonance cholangiopancreatography showed a cystic dilatation of the pancreatic duct in the pancreatic tail,which suggested an IPMN,and multiple intrahepatic duct stones in the left lateral lobe.The patient underwent a laparoscopic left lateral hepatolobectomy and spleenpreserving distal pancreatectomy.Intra-operative finding of massive mucin in the dilated bile duct implied an intraductal mucinous tumor in the liver.The diagnosis of synchronous IPMNs in the liver and pancreas was confirmed by pathological examination.The patient was followed up for 6 mo without signs of recurrence.Although several cases of IPMN of liver without any pancreatic association have been reported,the simultaneous occurrence of IPMNs in the liver and pancreas is very rare.To the best of our knowledge,it is the first reported case treated by laparoscopic resection.