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Survey Results of the Expert Meeting on Laparoscopic Living Donor Hepatectomy and Literature Review.

Tue, 10/17/2017 - 12:45
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Survey Results of the Expert Meeting on Laparoscopic Living Donor Hepatectomy and Literature Review.

Dig Surg. 2017 Oct 14;:

Authors: Cho JY, Han HS, Kaneko H, Wakabayashi G, Okajima H, Uemoto S, Soubrane O, Yong CC, Chen CL, Cheung TT, Belli G, Kubo S, Wu YM, Chen KH, Troisi RI, Kwon CHD, Suh KS, Soin AS, Kim KH, Cherqui D

Abstract
BACKGROUND: Because laparoscopic donor surgery has been successful in pediatric living donor liver transplantation, its application is expanding to right hepatectomy. However, there is no consensus on the indications for laparoscopic donor hepatectomy or on the details of the surgical technique.
OBJECTIVE: To evaluate the current status of laparoscopic donor hepatectomy and to summarize the expert opinion on it.
METHODS: Before the expert meeting on September 8, 2016, in Seoul, Korea, a survey was undertaken from expert liver surgeons from around the world.
RESULTS: Fifteen of 17 (88.2%) surgeons responded to the survey. The selection criteria for laparoscopic donor surgery are stricter than for open surgery in terms of the anatomy, remnant liver volume, and recipient's condition. There is no consensus on the instruments or equipment used. A literature review of laparoscopic donor hepatectomy showed that the use of this method is increasing and the short-term outcomes are similar to those of open surgery.
CONCLUSIONS: This survey and literature review show that laparoscopic donor hepatectomy is performed by experienced surgeons in selected cases, and that its incidence is increasing worldwide.

PMID: 29032378 [PubMed - as supplied by publisher]

The ALPPS Approach for Colorectal Liver Metastases: Impact of KRAS Mutation Status in Survival.

Tue, 10/17/2017 - 12:45
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The ALPPS Approach for Colorectal Liver Metastases: Impact of KRAS Mutation Status in Survival.

Dig Surg. 2017 Oct 14;:

Authors: Serenari M, Alvarez FA, Ardiles V, de Santibañes M, Pekolj J, de Santibañes E

Abstract
BACKGROUND/AIMS: Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations influence survival after hepatectomy for colorectal liver metastases (CRLM). However, their prognostic significance has never been evaluated in patients who undergo Associating Liver Partition and Portal vein occlusion for Staged hepatectomy (ALPPS).
METHODS: Between June 2011 and March 2016, 26 patients underwent ALPPS for CRLM. Complications were classified according to the Clavien-Dindo classification. Bi- and multivariate cox analyses were performed to evaluate variables potentially associated with survival.
RESULTS: Overall, morbidity grade ≥3a and 90-day mortality were 38.5 and 0%, respectively. The median follow-up from the time of discharge was 21.5 months (interquartile range 9.6-35.6). One- and 3-year overall survival (OS) was 83.4 and 48.9%, respectively. Patients with mutated (MT) KRAS had a median OS of 15.3 vs. 38.3 months for those with wild-type (WT) KRAS (p < 0.0001). Median disease-free survival was 7.9, 5.6 vs. 12.3 months for MT and WT KRAS, respectively (p = 0.023). KRAS mutation was found to be an independent risk factor for OS (hazard ratio 7.15, 95% CI 1.50-34.11; p = 0.014).
CONCLUSION: KRAS mutation is an independent predictor of poor survival after ALPPS. This finding will help to optimize patient selection, both avoiding futile surgical indication and maximizing the benefit for patients with extensive disease who are otherwise subjected to high-risk aggressive surgery.

PMID: 29032374 [PubMed - as supplied by publisher]

Advanced oxidation protein products induce S-phase arrest of hepatocytes via the ROS-dependent, β-catenin-CDK2-mediated pathway.

Tue, 10/17/2017 - 12:45
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Advanced oxidation protein products induce S-phase arrest of hepatocytes via the ROS-dependent, β-catenin-CDK2-mediated pathway.

Redox Biol. 2017 Oct 06;14:338-353

Authors: Sun S, Xie F, Xu X, Cai Q, Zhang Q, Cui Z, Zheng Y, Zhou J

Abstract
Liver regeneration has important clinical importance in the setting of partial hepatectomy (PH). Following PH, quiescent hepatocytes can reenter cell cycle to restore liver mass. Hepatocyte cell cycle progression, as the basic motivations of liver regeneration, can be disrupted by multiple pathological factors such as oxidative stress. This study aimed to evaluate the role of advanced oxidation protein products (AOPP) in S-phase arrest in hepatocytes. Serum AOPP level were measured during the perioperative period of PH in 33 patients with hepatocellular carcinoma (HCC). Normal Sprague Dawley rats, human and murine liver cell line (HL-7702 and AML-12) were challenged with AOPP prepared by incubation of rat serum albumin (RSA) with hypochlorous acid, and the effect of AOPP on hepatocytes cell cycle progression and liver regeneration was studied after PH. AOPP levels were increased following partial hepatectomy (PH) in patients with primary liver cancer. AOPP treatment impaired liver regeneration in rats following 70% partial hepatectomy. S-phase arrest was induced by AOPP administration in hepatocytes derived from the remnant liver at controlled times following partial hepatectomy in rats, and in HL-7702 and AML-12 cells. The effect of AOPP on hepatocyte S phase arrest was mainly mediated by a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent reactive oxygen species (ROS) generation, downregulation of downstream β-catenin signaling and decreased cyclin-dependent kinase 2 (CDK2) expression, which inhibited S-phase progression in hepatocytes. This study provides preliminary evidence that AOPP can induce S-phase arrest in hepatocytes via the ROS-dependent, β-catenin-CDK2-mediated pathway. These findings suggest a novel pathogenic role of AOPP contributing to the impaired liver regeneration and may provide the basis for developing new strategies to improve liver regeneration in patients undergoing PH.

PMID: 29032312 [PubMed - as supplied by publisher]

Schistosoma Japonicum Presenting as Colon Polyps.

Tue, 10/17/2017 - 12:45
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Schistosoma Japonicum Presenting as Colon Polyps.

Am J Med. 2017 Oct 12;:

Authors: Kiyani A, Walia A, Chuang KY

PMID: 29032231 [PubMed - as supplied by publisher]

An update on the physiopathology and therapeutic management of cholestatic pruritus in children.

Tue, 10/17/2017 - 12:45
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An update on the physiopathology and therapeutic management of cholestatic pruritus in children.

Clin Res Hepatol Gastroenterol. 2017 Oct 11;:

Authors: Thébaut A, Debray D, Gonzales E

Abstract
Pruritus is a disabling symptom accompanying chronic cholestasis. In extreme cases, the refractory nature of pruritus can result in a need for invasive therapies including liver transplantation. The pathogenesis of pruritus in cholestatic disease is poorly understood. It may involve a specific neural pathway (similar to that associated with pain) regulated by several pruritogenic substances such as bile acids, opioids, serotonin, and the more recently identified lysophosphatidic acid. While the therapeutic management of cholestatic pruritus is well established in adults, there is no consensus in children, in light of the difficulty of conducting controlled clinical studies. The currently recommended strategy to manage cholestatic pruritus in children is based on several lines of specific therapies that should be associated with skin hydration and with non-specific treatment of cholestasis including ursodeoxycholic acid. Pruritus should be assessed as objectively as possible between each line of therapy. Rifampicin, a potent CYP3A4 inducer, is the first-line treatment of cholestatic pruritus. Second-line therapies require evaluation of the child in an expert center and are discussed on a case-by-case basis depending on the underlying disease and the experience of the center. These include inhibitors of serotonin reuptake (sertraline), opioid antagonists (naloxone), or ASBT inhibitors. Invasive therapies such as biliary diversion or liver transplantation can also be proposed in the most severe cases. The aim of the current update is to review the physiopathologic mechanisms implicated in cholestatic pruritus and to propose potential therapeutic strategies in children.

PMID: 29031874 [PubMed - as supplied by publisher]

Percutaneous treatment of hepatocellular carcinoma: state of the art and innovations.

Tue, 10/17/2017 - 12:45
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Percutaneous treatment of hepatocellular carcinoma: state of the art and innovations.

J Hepatol. 2017 Oct 12;:

Authors: Nault JC, Sutter O, Nahon P, Ganne-Carrié N, Séror O

Abstract
Percutaneous treatment of hepatocellular carcinoma (HCC) encompasses a vast range of techniques, including monopolar radiofrequency ablation (RFA), multibipolar RFA, microwave ablation, cryoablation and irreversible electroporation. RFA is considered to be one of the main curative treatments for HCC of less than 5 cm developing on cirrhosis, together with surgical resection and liver transplantation. However, controversies exist concerning the respective roles of ablation and liver resection for HCC of less than 3 to 5 cm on cirrhosis. In line with the therapeutic algorithm of early HCC, percutaneous ablation could also be used as a bridge to liver transplantation or in a sequence of upfront percutaneous treatment, followed by transplantation if tumor relapses. Moreover, several innovations in ablation methods may help to efficiently treat early HCC initially considered as "non-ablatable", and might, in some cases, extend ablation criteria beyond early HCC in order to treat the largest number of patients using a curative approach.

PMID: 29031662 [PubMed - as supplied by publisher]

Genetics of Acute Rejection after Kidney Transplantation.

Tue, 10/17/2017 - 12:45
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Genetics of Acute Rejection after Kidney Transplantation.

Transpl Int. 2017 Oct 14;:

Authors: Dorr CR, Oetting WS, Jacobson PA, Israni AK

Abstract
Treatment of acute rejection (AR) following kidney transplantation has improved in recent years, but there are still limitations to successful outcomes. This review article covers literature in regards to recipient and donor genetics of AR kidney and secondarily of liver allografts. Many candidate gene and some genome wide association studies (GWAS) have been conducted for AR in kidney transplantation. Genetic associations with AR in kidney and liver are mostly weak and in most cases the associations have not been reproducible. A limitation in the study of AR is the lack of sufficiently large populations, which are often not stratified, to study the AR phenotype which in this era occurs in <10% of transplants. Furthermore, the AR phenotype has been difficult to define and the definitions of classifications have evolved over time. Literature related to the pharmacogenomics of TAC is robust and has been validated in many studies. Associations between gene expression and AR are emerging as markers of outcomes and AR classification. In the future, combinations of pre-transplant genotype for AR risk prediction, genotype-based immune suppressant dosing, pharmacogenomic markers to select AR maintenance or treatment and expression markers from biopsies may provide valuable clinical tools for guiding treatment. This article is protected by copyright. All rights reserved.

PMID: 29030886 [PubMed - as supplied by publisher]

Nationwide survey for acute liver failure and late-onset hepatic failure in Japan.

Tue, 10/17/2017 - 12:45
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Nationwide survey for acute liver failure and late-onset hepatic failure in Japan.

J Gastroenterol. 2017 Oct 13;:

Authors: Nakao M, Nakayama N, Uchida Y, Tomiya T, Ido A, Sakaida I, Yokosuka O, Takikawa Y, Inoue K, Genda T, Shimizu M, Terai S, Tsubouchi H, Takikawa H, Mochida S

Abstract
BACKGROUND: A nationwide survey was performed to clarify the recent status of acute liver failure (ALF) and late-onset hepatic failure (LOHF) in Japan.
METHODS: Two-step surveys for patients with ALF and LOHF meeting the Japanese diagnostic criteria were performed annually in 782 hospitals. The clinical features of the patients were then compared to those reported in previous surveys.
RESULTS: In total, 1554 and 49 patients with ALF and LOHF, respectively, who were seen between 2010 and 2015 were enrolled. The subjects were classified into 1280 patients with hepatitis (642 non-comatose and 638 comatose) and 323 patients without hepatitis (190 non-comatose and 133 comatose). Compared with patients seen between 1998 and 2009, an older patient age and a higher percentage of underlying extrahepatic disease were observed. Although hepatitis virus infection was the most frequent etiology, the percentage of patients with this etiology had decreased, compared with previous cohorts, while the percentages of patients with drug-induced liver injuries, autoimmune hepatitis, and an indeterminate etiology had increased. Liver transplantation was performed in 170 patients (10.6%), whereas artificial liver support with plasmapheresis and/or hemodiafiltration were performed for most of the comatose patients. The outcomes of comatose patients were unfavorable, similar to previous surveys, especially the outcomes of hepatitis B virus carriers, including those with de novo hepatitis B (survival rate of 5.4% without liver transplantation).
CONCLUSION: Although the clinical features, including the etiologies, of patients with ALF and LOHF have changed, the outcomes of patients have not improved in recent years.

PMID: 29030713 [PubMed - as supplied by publisher]

Prematurity and biliary atresia: a 30-year observational study.

Tue, 10/17/2017 - 12:45
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Prematurity and biliary atresia: a 30-year observational study.

Pediatr Surg Int. 2017 Oct 13;:

Authors: Durkin N, Deheragoda M, Davenport M

Abstract
AIM OF STUDY: The diagnosis of biliary atresia (BA) remains challenging and delay can lead to significant morbidity with time to surgery a key factor in determining outcome. Prematurity may impact on outcome potentially delaying diagnosis. We sought to assess whether the premature BA infants (PBA) have a delayed time to surgery and as such, worse outcomes?
METHODS: Review of a single-centre prospectively maintained database. Prematurity was defined as delivery < 37/40 gestation. PBA was compared with date-matched term biliary atresia controls on a 2:1 basis. Primary outcomes were clearance of jaundice (< 20 μmol/L) and native liver survival. A retrospective assessment of liver fibrosis was made on biopsies at diagnosis and at Kasai portoenterostomy (KPE) in both premature and term cohorts. Data are quoted as median (range) unless indicated. A P value of ≤ 0.05 was considered statistically significant.
RESULTS: 21 (female n = 14, 67%) premature infants with BA were treated in the period Jan. 1988-Dec. 2016 and compared with 41 contemporaneous term BA controls. Median gestation was 33 (29-36) weeks and birth weight 1930 (948-4230)g. Twin pregnancy (n = 10) was the leading cause for prematurity and significantly higher than the controls (48 vs. 0%; P < 0.0001). Maternal co-morbidity was high (n = 10, 48%) including pre-eclampsia (19%) and diabetes (14%). Liver biopsy was performed in 19 (90%) patients (all diagnostic) at a median of 57 (4-266) days. Delayed diagnosis (> 50 days) was seen in n = 13 but not associated with parenteral nutrition use (46 vs. 33%, P = 0.59) or phototherapy (50 vs. 83%, P = 0.19). Both BASM (33 vs. 7.5%; P = 0.01) and duodenal atresia (19 vs. 0%; P = 0.01) were seen more frequently in the PBA cohort. Mean fibrosis scores (Ishak) from diagnostic biopsies were lower in the premature group than the control group (2.71 vs. 3.53, P = 0.043) indicating less fibrosis but this equalized by time of subsequent KPE (P = 0.17). Primary surgery was Kasai portoenterostomy (n = 20) at an older median age than controls (65 vs. 56 days; P = 0.06). Liver transplantation was the primary procedure in one late-presenting child. There was an increased but non-significant clearance of jaundice in the PBA group [n = 12/20 (60%) vs 20/41 (48%); P = 0.23] post-KPE. Native liver survival and true survival were not different (P = 0.58 and 0.23).
CONCLUSIONS: PBA infants have similar outcomes to term infants, despite delayed diagnosis and higher frequency of the syndromic form. The high incidence of discordant twins supports the theory that epigenetic modifications could contribute to the pathogenesis of BA.
LEVEL OF EVIDENCE: IIIc Retrospective Matched Cohort Study.

PMID: 29030699 [PubMed - as supplied by publisher]

Biliary atresia and liver transplantation: results and thoughts for primary liver transplantation in select patients.

Tue, 10/17/2017 - 12:45
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Biliary atresia and liver transplantation: results and thoughts for primary liver transplantation in select patients.

Pediatr Surg Int. 2017 Oct 13;:

Authors: Superina R

Abstract
Biliary atresia (BA) is one of the most common indications for liver transplantation in children. Despite advances in biliary atresia surgical techniques, most children will ultimately require liver transplantation. Possible pre-operative predictors of outcome after the Kasai operation are: 1. Age at operation 2. Presence of the biliary atresia splenic malformation syndrome (BASM) 3. Center specific factors 4. Liver histology and 5. Anatomic pattern of bile ducts found at surgery.Age at surgery is considered a strong predictor of success after portoenterostomy. In a recent study, age of 75 days or more at surgery was associated with less frequent resolution of jaundice and decreased transplant free survival. Similarly, the Ohi type II or III anatomy was associated with a higher risk of transplantation or death than type I. Inflammatory findings on pre-operative biopsy predicted a pooreroutcome after a Kasai procedure than obstructive changes. Nodularity of the liver at surgery as well as ascites was associated with a poorer prognosis.Primary transplantation is rarely done despite excellent outcome. Deaths on the waiting list also have improved with routine use of split and live donor transplantation. The Kasai operation has the highest failure rate in its stated objective than any other operation in pediatric surgery. Failure to achieve any improvement in jaundice occurs in over 30% of all cases, even in the best of hands, and transplantation or listing for transplantation occurs in over half the children with type II and III BA by one year of age in countries where liver transplantation is readily available.There are almost no studies in children with BA that compare the outcome after liver transplantation for BA with or without a prior Kasai procedure. It is postulated that a prospective trial in children predicted to have a poor prognosis after the Kasai procedure based on anatomic pattern, liver histology and presence of BASM, would yield improved care, spare some infants needless surgery, and quite possibly result in diminished morbidity and mortality following liver transplant.

PMID: 29030698 [PubMed - as supplied by publisher]

Imaging Findings Within the First 12 Months of Hepatocellular Carcinoma Treated With Stereotactic Body Radiation Therapy.

Tue, 10/17/2017 - 12:45
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Imaging Findings Within the First 12 Months of Hepatocellular Carcinoma Treated With Stereotactic Body Radiation Therapy.

Int J Radiat Oncol Biol Phys. 2017 Aug 24;:

Authors: Mendiratta-Lala M, Gu E, Owen D, Cuneo KC, Bazzi L, Lawrence TS, Hussain HK, Davenport MS

Abstract
PURPOSE: To correlate the imaging findings of treated hepatocellular carcinoma (HCC) after stereotactic body radiation therapy (SBRT) with explant pathology and alpha-fetoprotein (AFP) response.
METHODS AND MATERIALS: From 2007 to 2015, of 146 patients treated with liver SBRT for Barcelona Clinic Liver Cancer stage A hepatocellular carcinoma, 10 were identified with inclusion criteria and had regular interval follow-up magnetic resonance imaging/triple phase computed tomography and explant pathology or declining AFP values for radiology-pathology response correlation. Reference standards for successful response were >90% necrosis on explant pathology or pretreatment AFP >75 ng/mL normalizing to <10 ng/mL within 1 year after SBRT without other treatment. Subjects were treated with 24 to 50 Gy in 3 to 5 fractions. Multiphasic magnetic resonance imaging or computed tomography performed at 3, 6, 9, and 12 months after SBRT was compared with pretreatment imaging by 2 expert radiologists. Descriptive statistics were calculated.
RESULTS: There were 10 subjects with 10 treated HCCs, classified as 3 Organ Procurement and Transplantation Network (OPTN) 5a, 4 OPTN 5b, and 3 OPTN 5x. All had successfully treated HCCs, according to explant pathology or declining AFP. Four of 10 HCCs had persistent central arterial hyperenhancement 3 to 12 months after SBRT; persistent wash-out was common up to 12 months (9 of 10). Of 10 treated HCCs, 9 exhibited decreased size at 12 months. Liver parenchyma adjacent to the lesion showed early (3-6 months) hyperemia followed by late (6-12 months) capsular retraction and delayed enhancement. No patient had a significant decline in liver function.
CONCLUSIONS: In the absence of increasing size, persistent central arterial hyperenhancement and wash-out can occur within the first 12 months after SBRT in successfully treated HCCs and may not represent residual viable tumor. Liver parenchyma adjacent to the treated lesion showed inflammation followed by fibrosis, without significant change in hepatic function. Until a radiologic signature of tumor control is determined, freedom from local progression seems to be the best measure of HCC control after SBRT.

PMID: 29029891 [PubMed - as supplied by publisher]

Society for the Advancement of Transplant Anesthesia: Liver Transplant Anesthesia Fellowship-White Paper Advocating Measurable Proficiency in Transplant Specialties Training.

Tue, 10/17/2017 - 12:45
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Society for the Advancement of Transplant Anesthesia: Liver Transplant Anesthesia Fellowship-White Paper Advocating Measurable Proficiency in Transplant Specialties Training.

Semin Cardiothorac Vasc Anesth. 2017 Oct 01;:1089253217737043

Authors: Chadha RM, Crouch C, Zerillo J, Pretto EA, Planinsic R, Kim S, Nicolau-Raducu R, Adelmann D, Elia E, Wray CL, Srinivas C, Mandell MS

Abstract
The anesthesia community has openly debated if the care of transplant patients was generalist or specialist care ever since the publication of an opinion paper in 1999 recommended subspecialty training in the field of liver transplantation anesthesia. In the past decade, liver transplant anesthesia has become more complex with a sicker patient population and evolving evidence-based practices. Transplant training is currently not required for accreditation or certification in anesthesiology, and not all anesthesia residency programs are associated with transplant centers. Yet there is evidence that patient outcome is affected by the experience of the anesthesiologist with liver transplants as part of a multidisciplinary care team. Requests for a formal review of the inequities in training opportunities and requirements led the Society for the Advancement for Transplant Anesthesia (SATA) to begin the task of developing post-graduate fellowship training recommendations. In this article, members of the SATA Working Group on Transplant Anesthesia Education present their reasoning for specialized education and conclusions about which pathways can better prepare trainees to care for complex transplant patients.

PMID: 29029588 [PubMed - as supplied by publisher]

Metadherin promotes metastasis by supporting putative cancer stem cell properties and epithelial plasticity in pancreatic cancer.

Tue, 10/17/2017 - 12:45
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Metadherin promotes metastasis by supporting putative cancer stem cell properties and epithelial plasticity in pancreatic cancer.

Oncotarget. 2017 Sep 12;8(39):66098-66111

Authors: Suzuki K, Takano S, Yoshitomi H, Nishino H, Kagawa S, Shimizu H, Furukawa K, Miyazaki M, Ohtsuka M

Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a high metastatic potential. However, the mechanism of metastatic colonization in PDAC remains poorly understood. Metadherin (MTDH) has emerged in recent years as a crucial mediator of metastasis in several cancer types, although the biological role of MTDH in PDAC has not been investigated. Here, we demonstrated the functional roles of MTDH in PDAC progression, especially focusing on the metastatic cascade. In vitro studies showed that MTDH provides cancer stem cell (CSC) properties in metastatic PDAC cells and contributes to anoikis resistance with epithelial characteristics in PDAC cells. We also performed in vivo studies using both orthotopic transplantation and intra-portal vein injection as experimental models of liver metastasis to examine the function of MTDH at the metastatic site. MTDH knockdown dramatically reduced the incidence of liver metastases along with epithelial features in both experimental mouse models. Collectively, MTDH facilitates metastatic colonization with putative CSC and epithelial properties in PDAC cells. PDAC cells were transiently treated with TGF-β1 to investigate the roles of MTDH on epithelial plasticity. Intriguingly, MTDH expression was negatively correlated with Twist1 expression during the Mesenchymal-Epithelial transition (MET) induction in metastatic PDAC cells. These results suggest that MTDH may contribute to MET induction via downregulation of Twsit1. Lastly, immunohistochemistry indicated that MTDH overexpression is closely associated with hematogenous metastasis and predicts poor prognosis in patients with PDAC. This is the first demonstration of MTDH function in PDAC metastatic colonization. Our data suggest that MTDH targeting therapy could be applied to control PDAC metastasis.

PMID: 29029495 [PubMed]

Curcumin protects against hepatic ischemia/reperfusion induced injury through inhibiting TLR4/NF-κB pathway.

Tue, 10/17/2017 - 12:45
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Curcumin protects against hepatic ischemia/reperfusion induced injury through inhibiting TLR4/NF-κB pathway.

Oncotarget. 2017 Sep 12;8(39):65414-65420

Authors: Wang L, Li N, Lin D, Zang Y

Abstract
The TLR4/NF-κB pathway had important roles in hepatic ischemia/reperfusion (I/R) injury. In this study, we reported a protective effect of curcumin against hepatic I/R injury via TLR4/NF-κB pathway. Curcumin significantly inhibited cell apoptosis, and decreased levels of LDH and production of TNF-a, IL-1b, and IL-6 in the cell supernatant. In addition, curcumin ameliorated elevated TLR4 and NF-κB caused by hypoxia/reoxygenation stimulation in BRL-3A cells. In vivo assays revealed that curcumin reduce levels of ALT and AST, and reversed TLR4/NF-κB signaling pathway caused by hepatic I/R stimulation in liver tissues. These results suggested that curcumin ameliorates hepatic I/R injury, which may be mediated in part via the TLR4/NF-κB signaling pathway.

PMID: 29029441 [PubMed]

Peripheral Tr1 and Foxp3(+) Treg as Markers of Recurrent Malignancies in Patients with Hepato-Biliary Pancreatic Cancers.

Tue, 10/17/2017 - 12:45
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Peripheral Tr1 and Foxp3(+) Treg as Markers of Recurrent Malignancies in Patients with Hepato-Biliary Pancreatic Cancers.

Anticancer Res. 2017 10;37(10):5541-5552

Authors: Ikemoto T, Shimada M, Ishikawa D, Kawashita Y, Teraoku H, Yoshikawa M, Yamada S, Saito YU, Morine Y, Imura S

Abstract
BACKGROUND/AIM: Recently CD4(+)CD49b(+) LAG3(+)regulatory T (Tr1) cells are reported to be IL-10 driven, have strong regulatory activities. Thus, this study aimed to investigate whether Treg and Tr1 cells participate in immunological status against cancer.
PATIENTS AND METHODS: Peripheral blood was withdrawn from patients (n=78), and healthy volunteers as controls (n=23). The peripheral blood mononuclear cells were subjected to FACScan analysis after labeling with anti-CD4, -CD25, - Foxp3, -CD49b and -LAG3 antibodies. Resected specimens were stained for IL-10. Patients' clinical course and clinicopathological factors were compared.
RESULTS: Tr1 was significantly higher in patients with cancer (p=0.02). Among patients who underwent R0 resection, those with early recurrence had a significantly higher pre-/post-operative Tr1 ratio (p<0.05). Median pre-/post-operative ratios of Foxp3Tregs and Tr1s predicted early recurrence with 85.6% sensitivity and 93.3% specificity. Disease-free survival was significantly lower in patients with high IL-10 expression in resected specimens.
CONCLUSION: Peripheral Tregs and Tr1 indicate immunological state against cancer.

PMID: 28982868 [PubMed - indexed for MEDLINE]

Angiotensin II subtype 1a receptor signaling in resident hepatic macrophages induces liver metastasis formation.

Tue, 10/17/2017 - 12:45
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Angiotensin II subtype 1a receptor signaling in resident hepatic macrophages induces liver metastasis formation.

Cancer Sci. 2017 Sep;108(9):1757-1768

Authors: Shimizu Y, Amano H, Ito Y, Betto T, Yamane S, Inoue T, Nishizawa N, Matsui Y, Kamata M, Nakamura M, Kitasato H, Koizumi W, Majima M

Abstract
Liver metastases from colorectal cancer (CRC) are a clinically significant problem. The renin-angiotensin system is involved in tumor growth and metastases. This study was designed to evaluate the role of angiotensin II subtype receptor 1a (AT1a) in the formation of liver metastasis in CRC. A model of liver metastasis was developed by intrasplenic injection of mouse colon cancer (CMT-93) into AT1a knockout mice (AT1aKO) and wild-type (C57BL/6) mice (WT). Compared with WT mice, the liver weight and liver metastatic rate were significantly lower in AT1aKO. The mRNA levels of CD31, transforming growth factor- β1 (TGF-β1), and F4/80 were suppressed in AT1aKO compared with WT. Double immunofluorescence analysis showed that the number of accumulated F4/80(+) cells expressing TGF-β1 in metastatic areas was higher in WT than in AT1aKO. The AT1aKO bone marrow (BM) (AT1aKO-BM)→WT showed suppressed formation of liver metastasis compared with WT-BM→WT. However, the formation of metastasis was further suppressed in WT-BM→AT1aKO compared with AT1aKO-BM→WT. In addition, accumulated F4/80(+) cells in the liver metastasis were not BM-derived F4/80(+) cells, but mainly resident hepatic F4/80(+) cells, and these resident hepatic F4/80(+) cells were positive for TGF-β1. Angiotensin II enhanced TGF-β1 expression in Kupffer cells. Treatment of WT with clodronate liposomes suppressed liver metastasis by diminishing TGF-β1(+) F4/80(+) cells accumulation. The formation of liver metastasis correlated with collagen deposition in the metastatic area, which was dependent on AT1a signaling. These results suggested that resident hepatic macrophages induced liver metastasis formation by induction of TGF-β1 through AT1a signaling.

PMID: 28660748 [PubMed - indexed for MEDLINE]

Acquired Inhibitors to Multiple Coagulation Factors (V, IX, and XII) Identified in a Unique Patient with Hepatocellular Carcinoma.

Tue, 10/17/2017 - 12:45
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Acquired Inhibitors to Multiple Coagulation Factors (V, IX, and XII) Identified in a Unique Patient with Hepatocellular Carcinoma.

Intern Med. 2017;56(10):1203-1206

Authors: Imataki O, Arai T, Uemura M

Abstract
An acquired formation of inhibitors to coagulation factors is a rare type of coagulopathy. The development of inhibitors for multiple coagulation factors has never been reported. A 75-year-old Japanese female underwent interventional therapy for hepatocellular carcinoma. Five days after the last intervention, her prothrombin time decreased to 10%, and her activated partial thromboplastin time (APTT) lengthened to 265.1 sec. The activities for coagulation factors showed significantly reduced activities (<10%) of factors V, IX, and XII. A cross-mixing test demonstrated an inhibitor pattern, and inhibitory antibodies against factors V, IX, and XII were detected. We discuss our patient's etiology and pathogenesis.

PMID: 28502937 [PubMed - indexed for MEDLINE]

Antimicrobial Prophylaxis for Full-Face Laser Resurfacing in Transplant Recipients.

Tue, 10/17/2017 - 12:45
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Antimicrobial Prophylaxis for Full-Face Laser Resurfacing in Transplant Recipients.

Dermatol Surg. 2017 04;43(4):599-604

Authors: Hibler BP, Saylor DK, Chin-Hong P, Arron ST

PMID: 28291061 [PubMed - indexed for MEDLINE]

MAN2A1-FER Fusion Gene Is Expressed by Human Liver and Other Tumor Types and Has Oncogenic Activity in Mice.

Tue, 10/17/2017 - 12:45
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MAN2A1-FER Fusion Gene Is Expressed by Human Liver and Other Tumor Types and Has Oncogenic Activity in Mice.

Gastroenterology. 2017 Oct;153(4):1120-1132.e15

Authors: Chen ZH, Yu YP, Tao J, Liu S, Tseng G, Nalesnik M, Hamilton R, Bhargava R, Nelson JB, Pennathur A, Monga SP, Luketich JD, Michalopoulos GK, Luo JH

Abstract
BACKGROUND & AIMS: Human tumors and liver cancer cell lines express the product of a fusion between the first 13 exons in the mannosidase α class 2A member 1 gene (MAN2A1) and the last 6 exons in the FER tyrosine kinase gene (FER), called MAN2A1-FER. We investigated whether MAN2A1-FER is expressed by human liver tumors and its role in liver carcinogenesis.
METHODS: We performed reverse transcription polymerase chain reaction analyses of 102 non-small cell lung tumors, 61 ovarian tumors, 70 liver tumors, 156 glioblastoma multiform samples, 27 esophageal adenocarcinomas, and 269 prostate cancer samples, as well as 10 nontumor liver tissues and 20 nontumor prostate tissues, collected at the University of Pittsburgh. We also measured expression by 15 human cancer cell lines. We expressed a tagged form of MAN2A1-FER in NIH3T3 and HEP3B (liver cancer) cells; Golgi were isolated for analysis. MAN2A1-FER was also overexpressed in PC3 or DU145 (prostate cancer), NIH3T3 (fibroblast), H23 (lung cancer), and A-172 (glioblastoma multiforme) cell lines and knocked out in HUH7 (liver cancer) cells. Cells were analyzed for proliferation and in invasion assays, and/or injected into flanks of severe combined immunodeficient mice; xenograft tumor growth and metastasis were assessed. Mice with hepatic deletion of PTEN were given tail-vein injections of MAN2A1-FER.
RESULTS: We detected MAN2A1-FER messenger RNA and fusion protein (114 kD) in the hepatocellular carcinoma cell line HUH7, as well as in liver tumors, esophageal adenocarcinoma, glioblastoma multiforme, prostate tumors, non-small cell lung tumors, and ovarian tumors, but not nontumor prostate or liver tissues. MAN2A1-FER protein retained the signal peptide for Golgi localization from MAN2A1 and translocated from the cytoplasm to Golgi in cancer cell lines. MAN2A1-FER had tyrosine kinase activity almost 4-fold higher than that of wild-type FER, and phosphorylated the epidermal growth factor receptor at tyrosine 88 in its N-terminus. Expression of MAN2A1-FER in 4 cell lines led to epidermal growth factor receptor activation of BRAF, MEK, and AKT; HUH7 cells with MAN2A1-FER knockout had significant decreases in phosphorylation of these proteins. Cell lines that expressed MAN2A1-FER had increased proliferation, colony formation, and invasiveness and formed larger (>2-fold) xenograft tumors in mice, with more metastases, than cells not expressing the fusion protein. HUH7 cells with MAN2A1-FER knockout formed smaller xenograft tumors, with fewer metastases, than control HUH7 cells. HUH7, A-172, and PC3 cells that expressed MAN2A1-FER were about 2-fold more sensitive to the FER kinase inhibitor crizotinib and the epidermal growth factor receptor kinase inhibitor canertinib; these drugs slowed growth of xenograft tumors from MAN2A1-FER cells and prevented their metastasis in mice. Hydrodynamic tail-vein injection of MAN2A1-FER resulted in rapid development of liver cancer in mice with hepatic disruption of Pten.
CONCLUSIONS: Many human tumor types and cancer cell lines express the MAN2A1-FER fusion, which increases proliferation and invasiveness of cancer cell lines and has liver oncogenic activity in mice.

PMID: 28245430 [PubMed - indexed for MEDLINE]

Rational approach to transfusion in liver transplantation.

Sun, 10/15/2017 - 18:48

Rational approach to transfusion in liver transplantation.

Minerva Anestesiol. 2017 Oct 12;:

Authors: Saner FH, Abeysundara L, Hartmann M, Mallett SV

Abstract
For over 50 years patients with liver cirrhosis were considered to be at markedly increased risk of bleeding. This dogma was seemingly supported by abnormalities in standard laboratory tests (SLTs), such as the prothrombin time, that were interpreted as indicating a bleeding diathesis. However, publications from the last decade have revealed SLTs to be poor predictors of bleeding and it is now understood that stable patients with cirrhosis have a rebalanced haemostatic system and preserved thrombin generation. Viscoelastic tests (VETs), such as ROTEM® or TEGTM allow dynamic assessment of the entire coagulation process and provide a better illustration of the interactions between pro- and anticoagulants as well as platelets. Despite their documented success in reducing transfusion rates in liver transplantation more than 30 years ago, the adoption of VETs has been met with some resistance and has only recently gained significant momentum. Bleeding risk should be assessed in every patient undergoing invasive intervention and must consider markers of disease severity, underlying coagulation incompetence, anaemia and surgical factors. The recognition that bleeding in this patient cohort is predominantly linked to mechanistic factors such as portal hypertension, rather than primary coagulopathy, has led to a paradigm shift in their peri-operative management. Cognizant of their detrimental effect, the use of large volumes of FFP to correct derangements in SLTs has given way to more refined haemostatic management with specific factor concentrates guided by VETs, coupled with measures to minimize portal venous pressure and meticulous surgical haemostasis.

PMID: 29027774 [PubMed - as supplied by publisher]

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