Skip directly to content

PubMed Liver Transplant

Subscribe to PubMed Liver Transplant feed PubMed Liver Transplant
NCBI: db=pubmed; Term=liver transplant
Updated: 1 hour 10 min ago

Risk of Post-transplant Hepatocellular Carcinoma Recurrence Is Higher in Recipients of Livers From Male Than Female Living Donors.

Tue, 06/20/2017 - 12:45
Related Articles

Risk of Post-transplant Hepatocellular Carcinoma Recurrence Is Higher in Recipients of Livers From Male Than Female Living Donors.

Ann Surg. 2017 Jun 16;:

Authors: Han S, Yang JD, Sinn DH, Kim JM, Choi GS, Jung G, Ahn JH, Kim S, Ko JS, Gwak MS, Kwon CHD, Leise MD, Gwak GY, Heimbach JK, Kim GS

Abstract
OBJECTIVE: To evaluate the relationship between donor sex and hepatocellular carcinoma (HCC) recurrence after living donor liver transplantation.
BACKGROUND: HCC shows a male predominance in incidence and recurrence after tumor resection due to sex differences in hepatic sex hormone receptors. There have been no studies evaluating the importance of donor sex on post-transplant HCC recurrence.
METHODS: Of 384 recipients of livers, from living donors, for HCC: 104/120 who received grafts from female donors were matched with 246/264 who received grafts from male donors using propensity score matching, with an unfixed matching ratio based on factors like tumor biology. Survival analysis was performed with death as a competing risk event. The primary outcome was overall HCC recurrence.
RESULTS: The median follow-up time was 39 months. Before matching, recurrence probability at 1/2/5 years after transplantation was 6.1/9.7/12.7% in recipients with female donors and 11.7/19.2/25.3% in recipients with male donors. Recurrence risk was significantly higher with male donors in univariable analysis (hazard ratio [HR] = 2.04 [1.15-3.60], P = 0.014) and multivariable analysis (HR=2.10 [1.20-3.67], P = 0.018). In the matched analysis, recurrence risk was also higher with male donors (HR=1.92 [1.05-3.52], P = 0.034): both in intrahepatic recurrence (HR=1.92 [1.05-3.51], P = 0.034) and extrahepatic recurrence (HR=1.93 [1.05-3.52], P = 0.033). Multivariable analysis confirmed the significance of donor sex (HR=2.08 [1.11-3.91], P = 0.023). Interestingly, the significance was lost when donor age was >40 years. Two external cohorts validated the significance of donor sex.
CONCLUSIONS: Donor sex appears to be an important graft factor modulating HCC recurrence after living donor liver transplantation.

PMID: 28628564 [PubMed - as supplied by publisher]

Interactions between primary sclerosing cholangitis and inflammatory bowel disease: implications in the adult liver transplant setting.

Tue, 06/20/2017 - 12:45
Related Articles

Interactions between primary sclerosing cholangitis and inflammatory bowel disease: implications in the adult liver transplant setting.

Expert Rev Gastroenterol Hepatol. 2017 Jun 19;:

Authors: Liu K, Strasser SI, Koorey DJ, Leong RW, Solomon M, McCaughan GW

Abstract
INTRODUCTION: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease which is associated with inflammatory bowel disease (IBD) in most cases. As there is currently no medical therapy which alters the natural history of PSC, liver transplantation may be required. Areas covered: We searched for articles in PubMed and critically reviewed current literature on the interrelationship between PSC and IBD with a specific focus on considerations for patients in the liver transplant setting. Expert commentary: PSC is an uncommon disease which limits available studies to be either retrospective or contain relatively small numbers of patients. Based on observations from these studies, the behavior and complications of PSC and IBD impact on each other both before and after a liver transplant. Both these autoimmune conditions and their associated cancer risk also influence patient selection for transplantation and may be impacted by immunosuppression use post-transplant. Hence, a complex interplay exists between PSC, IBD and liver transplantation which requires clarification with ongoing research.

PMID: 28627935 [PubMed - as supplied by publisher]

Accepting Hearts From Hepatitis C Positive Donor: Can We Expand the Donor Pool?

Tue, 06/20/2017 - 12:45
Related Articles

Accepting Hearts From Hepatitis C Positive Donor: Can We Expand the Donor Pool?

J Card Fail. 2017 Jun 13;:

Authors: Grinstein J, Lourenco LM, Te HS, Renz JF, Jeevanandam V, Uriel N

Abstract
BACKGROUND: Until recently, transplantation from hepatitis C positive donors was relatively contraindicated as eradication of active hepatitis C previously required an interferon-based regimen which has been associated with rejection in solid organ transplantation. New interferon-free treatment regimens for hepatitis C have fewer adverse events and higher cure rates than interferon-based regimens. Interferon-free regimens have been shown to be safe in the liver transplantation literature but little is known about the safety and efficacy of treatment in heart transplantation.
CASE DESCRIPTION AND DISCUSSION: Here we report a case of successful eradication of hepatitis C with a non-interferon based regimen using Ledipasvir-sofosbuvir following combined orthotopic heart and liver transplantation. Based on the prevalence of hepatitis C in the general population, inclusion of hepatitis C positive donors for heart transplantation can expand this component of the donor pool 3-6 fold.
CONCLUSIONS: In carefully selected patients and recipients, inclusion of hepatitis C positive donors may allow for expansion of the donor pool.

PMID: 28627403 [PubMed - as supplied by publisher]

"Spectrum of hepatitis B and renal involvement".

Tue, 06/20/2017 - 12:45
Related Articles

"Spectrum of hepatitis B and renal involvement".

Liver Int. 2017 Jun 19;:

Authors: Shah AS, Amarapurkar DN

Abstract
Renal involvement in hepatitis B occurs in various spectrums and its knowledge is important for clinicians in management of patients. The renal diseases most commonly associated with hepatitis B virus (HBV) infection include membranous nephropathy, membranoproliferative glomerulonephritis, and Polyarteritis nodosa. The widespread use of hepatitis B vaccination has decreased the incidence of HBV-related renal diseases. The incidence of HBV infection in dialysis patients has significantly decreased over the past few decades due to screening of blood products for hepatitis B surface antigen (HBsAg) and hepatitis B core antibody, implementation of infection control measures and hepatitis B vaccination. The definition of acute kidney injury has been recently modified in cirrhotic population, helping in prognosis and prediction of mortality. The most common etiologies of acute kidney injury in this cirrhotic population, which account for 80% to 90% of all cases, include volume depletion, acute tubular necrosis, and hepatorenal syndrome. Treatment with oral nucleoside/tide analogues (NA) brought a new paradigm in the management of HBsAg positive glomerulonephritis, kidney transplant recipients and dialysis patients, resulting in effective viral suppression, reduced hepatic complications, and improved patient survival, without compromising renal allograft outcome. NAs are cleared by the kidneys and therefore their dosage has to be adjusted in all patients with impaired renal function. This article reviews the recent knowledge of the pathogenesis and treatment of HBV-related glomerulonephritis and discusses the management of hepatitis B in patients on dialysis, kidney transplant recipients and cirrhotics, which is continuously evolving. This article is protected by copyright. All rights reserved.

PMID: 28627094 [PubMed - as supplied by publisher]

Unique clinical conditions associated with different acinar regions of fibrosis in long-term surviving pediatric liver grafts.

Tue, 06/20/2017 - 12:45
Related Articles

Unique clinical conditions associated with different acinar regions of fibrosis in long-term surviving pediatric liver grafts.

Pediatr Transplant. 2017 Jun 18;:

Authors: Baas M, Gouw ASH, van den Heuvel MC, Hepkema BG, Peeters PMGJ, Verkade H, Scheenstra R

Abstract
In the majority of long-term survivors after PLTx, graft fibrosis has been identified. Recently, subtypes of graft fibrosis have been described based on their predominant acinar localization. We aimed to evaluate whether the development of portal, perisinusoidal, and centrilobular distribution of graft fibrosis is related to patient or transplantation-related parameters. We reviewed the histological features in protocol liver biopsies taken at 1 and 5 years after PLTx of 47 children on a tacrolimus-based immunosuppressive regimen. Fibrosis was assessed according to the LAFSc. The prevalence of portal fibrosis increased from 31% to 62%, sinusoidal from 68% to 79%, and centrilobular from 76% to 85%. The presence of portal fibrosis was associated with total bilirubin and γGT levels (each P<.02) and tended to be associated with biliary complications (P=.06). Sinusoidal fibrosis was associated with prior rejection episodes (P<.02) and centrilobular fibrosis with the presence of HLA mismatches (P=.02). In conclusion, using the LAFSc, we found a high incidence of progressive fibrosis in the 1-year and 5-year protocol biopsies after PLTx. Progression of fibrosis was observed in all acinar compartments, and each of the three locations is associated with different clinical conditions.

PMID: 28627016 [PubMed - as supplied by publisher]

Successful liver transplantation for non-resectable desmoplastic nested spindle cell tumor complicated by Cushing's syndrome.

Tue, 06/20/2017 - 12:45
Related Articles

Successful liver transplantation for non-resectable desmoplastic nested spindle cell tumor complicated by Cushing's syndrome.

Pediatr Transplant. 2017 Jun 18;:

Authors: Tehseen S, Rapkin L, Schemankewitz E, Magliocca JF, Romero R

Abstract
Desmoplastic spindle cell tumors of liver are rare tumors of low malignant potential characterized by well-demarcated nests of spindle and epithelioid cells in a dense desmoplastic stroma. While surgery remains the definitive treatment, there have been reports of tumor recurrence locally and metastasis which respond poorly to chemotherapy. Hepatic transplant has been attempted in cases of recurrence or large size of primary tumor. Long-term follow-up and imaging surveillance are required as these tumors have shown a tendency for recurrence many years after initial therapy.

PMID: 28626929 [PubMed - as supplied by publisher]

A successful living donor liver re-transplantation for graft failure within seven days due to acute de novo donor-specific anti-HLA antibody-mediated rejection.

Tue, 06/20/2017 - 12:45
Related Articles

A successful living donor liver re-transplantation for graft failure within seven days due to acute de novo donor-specific anti-HLA antibody-mediated rejection.

Hepatol Res. 2017 Jun 19;:

Authors: Yamada Y, Hoshino K, Mori T, Kawaida M, Abe K, Ishihama H, Shimizu T, Takahashi N, Matsubara K, Hibi T, Abe Y, Yagi H, Shimojima N, Shinoda M, Kitago M, Obara H, Fuchimoto Y, Kameyama K, Kitagawa Y, Kuroda T

Abstract
Growing evidence suggests a relationship between antibody-mediated rejection (AMR) and early graft failure due to a previously unknown etiology in liver transplantation (LTx). We herein report a three-year-old boy who developed rapid graft failure due to de novo donor-specific antibody (DSA)-driven AMR a week after living donor LTx, requiring a second transplant on the 10th day after the first LTx. The pathology of the first graft showed massive necrosis in zone 3 along with positive C4d and inflammatory cell infiltrates in portal areas. The mean fluorescence intensity (MFI) against HLA-DR15, which was possessed by both the first and the second donor, peaked at 12945 on the day before the second LTx. Anti-thymocyte globulin, plasma exchange along with intravenous immunoglobulin, rituximab and the local infusion of prostaglandin E1, steroids and mesilate gabexiate via portal catheter were provided to save the second graft. To our knowledge, this is the first report to demonstrate a clear association between de novo DSA and acute AMR within seven days after a LTx. Furthermore, we successfully rescued the recipient with a second graft despite possessing the same targeted-HLA. The rapid decision to carry out re-transplantation and specific strategies overcoming AMR were crucial to achieving success in this case of immunologically high-risk LTx.

PMID: 28626871 [PubMed - as supplied by publisher]

The incidence of chylous ascites after liver transplantation and the proposal of a diagnostic and management protocol.

Tue, 06/20/2017 - 12:45
Related Articles

The incidence of chylous ascites after liver transplantation and the proposal of a diagnostic and management protocol.

J Pediatr Surg. 2017 Jun 11;:

Authors: Matsuura T, Yanagi Y, Hayashida M, Takahashi Y, Yoshimaru K, Taguchi T

Abstract
BACKGROUND: No protocol has been established for the diagnosis and management of chylous ascites after liver transplantation (LT). In this study, we retrospectively reviewed our cases of posttransplant chylous ascites (PTCA) and aimed to propose a diagnostic and management protocol.
PATIENTS AND METHODS: We retrospectively reviewed the clinical records of 96 LT recipients who underwent LT at our department. The incidence of PTCA and the associated risk factors were analyzed and our protocol for chylous ascites was evaluated.
RESULTS: PTCA occurred in 6 (6.3%) patients (mean age: 10.7±11.0years) at a mean of 10.8±3.6days after LT. The primary disease in all of PTCA cases was biliary atresia (BA). The periportal lymphadnopathy was an independent risk factor for PTCA. In all cases PTCA successfully resolved according to our protocol. Octreotide was administered in 4 of our 6 PTCA cases. The mean postoperative hospital stay was 40.2±8.4days, which was similar to that of cases without PTCA.
CONCLUSIONS: The incidence of PTCA in LT patients, especially in those with BA, is relatively high. Our diagnostic criteria and our management protocol were helpful for patients with refractory ascites after LT.
TYPE OF STUDY: Diagnostic test: Level II. Treatment study: Level III.

PMID: 28625694 [PubMed - as supplied by publisher]

Multifaceted Therapeutic Benefits of Factors Derived From Dental Pulp Stem Cells for Mouse Liver Fibrosis.

Tue, 06/20/2017 - 12:45
Related Articles

Multifaceted Therapeutic Benefits of Factors Derived From Dental Pulp Stem Cells for Mouse Liver Fibrosis.

Stem Cells Transl Med. 2016 10;5(10):1416-1424

Authors: Hirata M, Ishigami M, Matsushita Y, Ito T, Hattori H, Hibi H, Goto H, Ueda M, Yamamoto A

Abstract
: Chronic liver injury from various causes often results in liver fibrosis (LF). Although the liver possesses endogenous tissue-repairing activities, these can be overcome by sustained inflammation and excessive fibrotic scar formation. Advanced LF leads to irreversible cirrhosis and subsequent liver failure and/or hepatic cancer. Here, using the mouse carbon tetrachloride (CCl4)-induced LF model, we showed that a single intravenous administration of stem cells derived from human exfoliated deciduous teeth (SHEDs) or of SHED-derived serum-free conditioned medium (SHED-CM) resulted in fibrotic scar resolution. SHED-CM suppressed the gene expression of proinflammatory mediators, such as TNF-α, IL-1β, and iNOS, and eliminated activated hepatic stellate cells by inducing their apoptosis, but protected parenchymal hepatocytes from undergoing apoptosis. In addition, SHED-CM induced tissue-repairing macrophages that expressed high levels of the profibrinolytic factor, matrix metalloproteinase 13. Furthermore, SHED-CM suppressed the CCl4-induced apoptosis of primary cultured hepatocytes. SHED-CM contained a high level of hepatocyte growth factor (HGF). Notably, HGF-depleted SHED-CM (dHGF-CM) did not suppress the proinflammatory response or resolve fibrotic scarring. Furthermore, SHED-CM, but not dHGF-CM, inhibited CCl4-induced hepatocyte apoptosis. These results suggest that HGF plays a central role in the SHED-CM-mediated resolution of LF. Taken together, our findings suggest that SHED-CM provides multifaceted therapeutic benefits for the treatment of LF.
SIGNIFICANCE: This study demonstrated that a single intravenous administration of stem cells from human exfoliated deciduous teeth (SHEDs) or of the serum-free conditioned medium (CM) derived from SHEDs markedly improved mouse liver fibrosis (LF). SHED-CM suppressed chronic inflammation, eliminated activated hepatic stellate cells by inducing their apoptosis, protected hepatocytes from undergoing apoptosis, and induced differentiation of tissue-repairing macrophages expressing high levels of the profibrinolytic factor matrix metalloproteinase 13. Furthermore, hepatocyte growth factor played a central role in the SHED-CM-mediated resolution of LF. This is the first report demonstrating the multifaceted therapeutic benefits of secreted factors derived from SHEDs for LF.

PMID: 27280796 [PubMed - indexed for MEDLINE]

CRISPR-Cas9 Targeting of PCSK9 in Human Hepatocytes In Vivo-Brief Report.

Tue, 06/20/2017 - 12:45
Related Articles

CRISPR-Cas9 Targeting of PCSK9 in Human Hepatocytes In Vivo-Brief Report.

Arterioscler Thromb Vasc Biol. 2016 May;36(5):783-6

Authors: Wang X, Raghavan A, Chen T, Qiao L, Zhang Y, Ding Q, Musunuru K

Abstract
OBJECTIVE: Although early proof-of-concept studies of somatic in vivo genome editing of the mouse ortholog of proprotein convertase subtilisin/kexin type 9 (Pcsk9) in mice have established its therapeutic potential for the prevention of cardiovascular disease, the unique nature of genome-editing technology-permanent alteration of genomic DNA sequences-mandates that it be tested in vivo against human genes in normal human cells with human genomes to give reliable preclinical insights into the efficacy (on-target mutagenesis) and safety (lack of off-target mutagenesis) of genome-editing therapy before it can be used in patients.
APPROACH AND RESULTS: We used a clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated (Cas) 9 genome-editing system to target the human PCSK9 gene in chimeric liver-humanized mice bearing human hepatocytes. We demonstrated high on-target mutagenesis (approaching 50%), greatly reduced blood levels of human PCSK9 protein, and minimal off-target mutagenesis.
CONCLUSIONS: This work yields important information on the efficacy and safety of CRISPR-Cas9 therapy targeting the human PCSK9 gene in human hepatocytes in vivo, and it establishes humanized mice as a useful platform for the preclinical assessment of applications of somatic in vivo genome editing.

PMID: 26941020 [PubMed - indexed for MEDLINE]

Liver epithelioid progenitor cells derived from fetal Luxi bovine alleviate liver fibrosis.

Mon, 06/19/2017 - 12:45

Liver epithelioid progenitor cells derived from fetal Luxi bovine alleviate liver fibrosis.

Cytotechnology. 2017 Jun 17;:

Authors: Wang K, Liu H, Yang J, Ma C, Zhang Z, Zheng D, Guan W

Abstract
Liver epithelioid progenitor cells (LEPCs) have important roles in liver therapy because of their hepatic differentiation potency in vitro and in vivo. Despite many researches on humans, mice, and rats, equivalent progenitor cells derived from bovine are relatively rare. The purpose of our current study is to characterize bovine LEPCs, and research on the cure potency of this heteroplastic progenitor cells on mice liver fibrosis. We have used collagenase IV digesting and differential adhesion method to isolate slabstone shape, EpCAM, LGR5, NCAM1 and SOX9 positive progenitor cells from fetal Luxi bovine liver. When cultured in hepatic differentiation media containing 20 ng/ml Oncostatin M, LEPCs can differentiate into hepatocytes in vitro. After 4 weeks of intravenous tail vein injection into CCl4-injured mouse liver, LEPCs engrafted into liver parenchyma, differentiated into ALB positive hepatocytes, and could alleviate liver fibrosis through down regulating fibrosis genes-Tgfb1 and α-SMA as well as decreasing expression of collagen gene Col1a1, Col3a1, and Col4a1, and regain liver function by recovering ALT and AST. Our findings provided a useful tool for studying liver development in vitro, new cell resource for heterograft on mouse liver diseases, and a new platform for researches on immune rejection of heterogeneous cell transplantation.

PMID: 28625011 [PubMed - as supplied by publisher]

Steady-state pharmacokinetics of mycophenolic acid in renal transplant patients: exploratory analysis of the effects of cyclosporine, recipients' and donors' ABCC2 gene variants, and their interactions.

Mon, 06/19/2017 - 12:45

Steady-state pharmacokinetics of mycophenolic acid in renal transplant patients: exploratory analysis of the effects of cyclosporine, recipients' and donors' ABCC2 gene variants, and their interactions.

Eur J Clin Pharmacol. 2017 Jun 18;:

Authors: Božina N, Lalić Z, Nađ-Škegro S, Borić-Bilušić A, Božina T, Kaštelan Ž, Trkulja V

Abstract
PURPOSE: The study aims to evaluate the impact of recipients' and donors' polymorphisms in multidrug resistance-associated protein 2 (MRP2) gene ABCC2 -24C>T and 1249G>A on disposition of mycophenolic acid (MPA) and their interaction with cyclosporine (CsA) (compared to tacrolimus, TAC) in stable de novo adult renal transplant patients of Croatian origin.
METHODS: A total of 68 recipient-donor pairs were genotyped. Steady-state pharmacokinetics of MPA was assessed by the model-independent method.
RESULTS: Adjusted for MPA formulation, renal function, type of calcineurin inhibitor and recipients' and donors' genotypes at the two loci, donors' A-allele at 1249G>A was associated with a reduced peak (29%) and early (AUC0-2, 33%) exposure and increased MPA clearance (26%). Donors' A-allele combined with CsA was associated with 78% higher MPA clearance, 49% lower early and 48% lower total exposure as compared to wild type homozygosity + TAC. Recipients' SNPs per se did not reflect on MPA disposition. However, A-allele at 1249G>A + CsA (compared to wild type + TAC) was associated with a numerically greater increase in MPA clearance (59 vs. 41%), reduction in total exposure (36 vs. 27%) and increase in absorption rate (C max/AUC) (56 vs. 37%) than observed for the main effect of CsA. Less pronounced effects were observed for the combination of variant allele at -24C>T and CsA.
CONCLUSION: Considering MPA disposition, data indicate: donors' ABCC2 1249G>A polymorphism increases clearance and reduces exposure; CsA increases clearance and reduces exposure by inhibiting MRP2 in the gut, the liver, and the kidney; donors' ABCC2 1249G>A polymorphism enhances the renal CsA effect, while recipients' polymorphism seems to enhance the liver and the gut CsA effects.

PMID: 28624888 [PubMed - as supplied by publisher]

Efficacy and optimal duration of metallic stent in the management of refractory anastomotic stricture after liver transplantation.

Mon, 06/19/2017 - 12:45

Efficacy and optimal duration of metallic stent in the management of refractory anastomotic stricture after liver transplantation.

Clin Gastroenterol Hepatol. 2017 Jun 14;:

Authors: Jang S, Parsi MA, Lopez R, Bhatt A, Vargo JJ

Abstract
BACKGROUND: Anastomotic bile duct stricture (ABS) remains as one of the most common complications in liver transplant patients. Current practice of endoscopic retrograde cholangiopancreatography (ERCP) with insertion of plastic stent (PS) often requires multiple procedures before achieving stricture resolution. To date, studies utilizing covered self-expandable metallic stent (cSEMS) in ABS management reported varying degree of efficacy. The aim of this study was to analyze long term efficacy of cSEMS in patients with ABS, and identifying factor(s) influencing the probability of stricture resolution.
METHODS: Liver transplant patients with ABS who received cSEMS were identified by query of our endoscopic database. The Rate of stricture resolution, duration of stricture free interval, factors associated with stricture resolution, and adverse outcomes were analyzed.
RESULTS: Among 44 liver transplant patients with refractory ABS who underwent ERCP-cSEMS, stricture resolution was observed in 33 patients (75%). Longer duration of cSEMS insertion was the only variable associated with increasing probability of stricture resolution. There was 20% increase in odds of stricture resolution for every additional week cSEMS was in place. Among 33 patients with initial stricture resolution, 26 patients (78.8%) maintained bile duct patency throughout the follow up period. The most common adverse outcome was internal migration of cSEMS which occurred in 11 patients (25%).
CONCLUSION: The rate of ABS resolution observed with cSEMS placement in a single ERCP session appears to be comparable to that of multiple ERCPs with PS placement reported previously. Longer stent insertion period is associated with higher likelihood of ABS resolution.

PMID: 28624651 [PubMed - as supplied by publisher]

Identification of an Immune-specific Class of Hepatocellular Carcinoma, Based on Molecular Features.

Mon, 06/19/2017 - 12:45

Identification of an Immune-specific Class of Hepatocellular Carcinoma, Based on Molecular Features.

Gastroenterology. 2017 Jun 14;:

Authors: Sia D, Jiao Y, Martinez-Quetglas I, Kuchuk O, Villacorta-Martin C, Castro de Moura M, Putra J, Camprecios G, Bassaganyas L, Akers N, Losic B, Waxman S, Thung SN, Mazzaferro V, Esteller M, Friedman SL, Schwartz M, Villanueva A, Llovet JM

Abstract
BACKGROUND AND AIMS: Agents that induce an immune response against tumors by altering T-cell regulation have increased survival times of patients with advanced-stage tumors, such as melanoma or lung cancer. We aimed to characterize molecular features of immune cells that infiltrate hepatocellular carcinomas (HCCs) to determine whether these types of agents might be effective against liver tumors.
METHODS: We analyzed HCC samples from 956 patients. We separated gene expression profiles from tumor, stromal, and immune cells using a non-negative matrix factorization algorithm. We then analyzed the gene expression pattern of inflammatory cells in HCC tumors samples. We correlated expression patterns with the presence of immune cell infiltrates and immune regulatory molecules, determined by pathology and immunohistochemical analyses, in a training set of 228 HCC samples. We validated the correlation in a validation set of 728 tumor samples. Using data from 190 tumors in the Cancer Genome Atlas, we correlated immune cell gene expression profiles with numbers of chromosomal aberrations (based on single-nucleotide polymorphism array) and mutations (exome sequence data).
RESULTS: We found approximately 25% of HCCs to have markers of an inflammatory response, with high expression levels of the CD274 molecule (PD-L1) and programmed cell death 1 (PD-1), markers of cytolytic activity, and fewer chromosomal aberrations. We called this group of tumors the Immune class. It contained 2 subtypes, characterized by markers of an adaptive T-cell response or exhausted immune response. The exhausted immune response subclass expressed many genes regulated by transforming growth factor beta 1 (TGFB) that mediate immunosuppression. We did not observe any differences in numbers of mutations or expression of tumor antigens between the immune-specific class and other HCCs.
CONCLUSIONS: In an analysis of HCC samples from 956 patients, we found almost 25% to express markers of an inflammatory response. We identified 2 subclasses, characterized by adaptive or exhausted immune responses. These findings indicate that some HCCs might be susceptible to therapeutic agents designed to block the regulatory pathways in T cells, such as PD-L1, PD-1, or TGFB inhibitors.

PMID: 28624577 [PubMed - as supplied by publisher]

Intestinal Fungal Dysbiosis Associates With Visceral Hypersensitivity in Patients With Irritable Bowel Syndrome and Rats.

Mon, 06/19/2017 - 12:45

Intestinal Fungal Dysbiosis Associates With Visceral Hypersensitivity in Patients With Irritable Bowel Syndrome and Rats.

Gastroenterology. 2017 Jun 14;:

Authors: Botschuijver S, Roeselers G, Levin E, Jonkers DM, Welting O, Heinsbroek SE, de Weerd HH, Boekhout T, Fornai M, Masclee AA, Schuren FHJ, de Jonge WJ, Seppen J, van den Wijngaard RM

Abstract
BACKGROUND & AIMS: Visceral hypersensitivity is one feature of irritable bowel syndrome (IBS). Bacterial dysbiosis might be involved in activation of nociceptive sensory pathways, but there have been few studies of the role of the mycobiome (the fungal microbiome) in development of IBS. We analyzed intestinal mycobiomes of patients with IBS and a rat model of visceral hypersensitivity.
METHODS: We used internal transcribed spacer 1-based metabarcoding to compare fecal mycobiomes of 18 healthy volunteers with those of 39 patients with IBS (with visceral hypersensitivity or normal levels of sensitivity). We also compared the mycobiomes of Long Evans rats separated from their mothers (hypersensitive) with non-handled (normally sensitive) rats. We investigated whether fungi can cause visceral hypersensitivity using rats exposed to fungicide (fluconazole and nystatin). The functional relevance of the gut mycobiome was confirmed in fecal transplantation experiments: adult maternally separated rats were subjected to water avoidance stress (to induce visceral hypersensitivity), then given fungicide and donor cecum content via oral gavage. Other rats subjected to water avoidance stress were given soluble β-glucans, which antagonize C-type lectin domain family 7 member A (CLEC7A or DECTIN1) signaling via spleen associated tyrosine kinase (SYK), a SYK inhibitor to reduce visceral hypersensitivity, or vehicle (control). The sensitivity of mast cells to fungi was tested with mesenteric windows (ex vivo) and the human mast cell line HMC-1.
RESULTS: α diversity (Shannon index) and mycobiome signature (stability selection) of both groups of IBS patients differed from healthy volunteers, and the mycobiome signature of hypersensitive patients differed from that of normally sensitive patients. We observed mycobiome dysbiosis in rats that had been separated from their mothers compared with non-handled rats. Administration of fungicide to hypersensitive rats reduced their visceral hypersensitivity to normal levels of sensitivity. Administration of cecal mycobiomes from rats that had been separated from their mothers (but not non-handled mycobiome) restored hypersensitivity to distension. Administration of soluble β-glucans or a SYK inhibitor reduced visceral hypersensitivity, compared with controls. Particulate β-glucan (a DECTIN-1 agonist) induced mast cell degranulation in mesenteric windows and HMC-1 cells responded to fungal antigens by release of histamine.
CONCLUSIONS: In an analysis of patients with IBS and controls, we associated fungal dysbiosis with IBS. In studies of rats, we found fungi to promote visceral hypersensitivity, which could be reduced by administration of fungicides, soluble β-glucans, or a SYK inhibitor. The intestinal fungi might therefore be manipulated for treatment of IBS-related visceral hypersensitivity.

PMID: 28624575 [PubMed - as supplied by publisher]

Safety and feasibility of electrochemotherapy in patients with unresectable colorectal liver metastases: A pilot study.

Mon, 06/19/2017 - 12:45

Safety and feasibility of electrochemotherapy in patients with unresectable colorectal liver metastases: A pilot study.

Int J Surg. 2017 Jun 14;:

Authors: Coletti L, Battaglia V, De Simone P, Turturici L, Bartolozzi C, Filipponi F

Abstract
BACKGROUND AND OBJECTIVES: Electrochemotherapy is a novel ablation technique combining chemotherapeutic agents with reversible cell membrane electroporation. Previous experiences have shown its efficacy for cutaneous tumors. Its application for deep-seated malignancies is under investigation. We performed a prospective, pilot study to evaluate the feasibility, safety, and efficacy of intraoperative electrochemotherapy for otherwise unresectable colorectal liver metastases.
METHODS: Electrochemotherapy with bleomycin was combined with open liver resection and performed with linear or hexagonal needle electrodes according to an individualized pretreatment plan. The primary endpoints were: feasibility, as ratio of completed to planned treatments; safety, and efficacy, as per response assessed at 30 days with MRI and according to RECIST. The secondary endpoint was overall and progression-free survival at month 6.
RESULTS: A total of 9 colorectal liver metastases were treated in 5 patients with 20 electrode applications. No intraoperative complications were observed. At day 30, complete response was 55.5% and stable disease 45.5%. All (5) patients reached a 6 months overall survival, and 4 out of 5 patients had 6 months progression free survival.
CONCLUSIONS: Electrochemotherapy is a feasible and safe adjunct to open surgery for treatment of unresectable colorectal liver metastases. Larger studies and longer follow-ups are favored to better define its role in the treatment of secondary liver malignancies.

PMID: 28624558 [PubMed - as supplied by publisher]

Low-Dose Gene Therapy for Murine PKU Using Episomal Naked DNA Vectors Expressing PAH from Its Endogenous Liver Promoter.

Mon, 06/19/2017 - 12:45

Low-Dose Gene Therapy for Murine PKU Using Episomal Naked DNA Vectors Expressing PAH from Its Endogenous Liver Promoter.

Mol Ther Nucleic Acids. 2017 Jun 16;7:339-349

Authors: Grisch-Chan HM, Schlegel A, Scherer T, Allegri G, Heidelberger R, Tsikrika P, Schmeer M, Schleef M, Harding CO, Häberle J, Thöny B

Abstract
Limited duration of transgene expression, insertional mutagenesis, and size limitations for transgene cassettes pose challenges and risk factors for many gene therapy vectors. Here, we report on physiological expression of liver phenylalanine hydroxylase (PAH) by delivery of naked DNA/minicircle (MC)-based vectors for correction of homozygous enu2 mice, a model of human phenylketonuria (PKU). Because MC vectors lack a defined size limit, we constructed a MC vector expressing a codon-optimized murine Pah cDNA that includes a truncated intron and is under the transcriptional control of a 3.6-kb native Pah promoter/enhancer sequence. This vector, delivered via hydrodynamic injection, yielded therapeutic liver PAH activity and sustained correction of blood phenylalanine comparable to viral or synthetic liver promoters. Therapeutic efficacy was seen with vector copy numbers of <1 vector genome per diploid hepatocyte genome and was achieved at a vector dose that was significantly lowered. Partial hepatectomy and subsequent liver regeneration was associated with >95% loss of vector genomes and PAH activity in liver, demonstrating that MC vectors had not integrated into the liver genome. In conclusion, MC vectors, which do not have a defined size-limitation, offer a favorable safety profile for hepatic gene therapy due to their non-integration in combination with native promoters.

PMID: 28624210 [PubMed - in process]

Liver transplantation in patients with liver metastases from neuroendocrine tumors: A systematic review.

Mon, 06/19/2017 - 12:45

Liver transplantation in patients with liver metastases from neuroendocrine tumors: A systematic review.

Surgery. 2017 Jun 14;:

Authors: Moris D, Tsilimigras DI, Ntanasis-Stathopoulos I, Beal EW, Felekouras E, Vernadakis S, Fung JJ, Pawlik TM

Abstract
BACKGROUND: Liver transplantation to treat neuroendocrine tumors, especially in the setting of diffuse liver involvement not amenable to operative resection remains controversial. We sought to perform a systematic review of the current literature to summarize data on patients undergoing liver transplantation with neuroendocrine tumors liver metastases as the indication.
METHODS: A systematic review was conducted in accordance to the Preferred Reporting Items for Systematic reviews and Meta-Analysis guidelines. Eligible studies were identified using 3 distinct databases through March 2017: Medline (PubMed), ClinicalTrials.gov, and Cochrane library, Cochrane Central Register of Controlled Trials using a search algorithm: "(neuroendocrine or NET) and transplantation and liver."
RESULTS: From the 1,216 records retrieved, 64 studies were eligible. Overall, 4 studies presented data from registries, namely the European Liver Transplant Registry and the United Network for Organ Transplantation/Organ Procurement and Transplantation Network databases, 3 were multicenter studies. The largest cohort of data on patients undergoing liver transplantation for neuroendocrine tumors liver metastasis indication were from single center studies comprising a total of 279 patients. Pancreas was the primary tumor site for most patients followed by the ileum. Several studies reported that more than half of patients presented with synchronous disease (55.9% and 57.7%); in contrast, metachronous neuroendocrine tumors liver metastasis ranged from 17.7% to 38.7%. Overall, recurrence after liver transplantation ranged from 31.3% to 56.8%. Reported 1-, 3-, and 5-year overall survival was 89%, 69%, and 63%, respectively. Several prognostic factors associated with worse long-term survival including transplantation >50% liver tumor involvement, high Ki67, as well as a pancreatic neuroendocrine tumors versus gastrointestinal neuroendocrine tumors tumor location.
CONCLUSION: Liver transplantation may provide a survival benefit among patients with diffuse neuroendocrine tumors metastases to the liver. However, due to high recurrence rates, strict selection of patients is critical. Due to the scarcity of available grafts and the lack of level 1 evidence, the recommendations to endorse liver transplantation for extensive liver neuroendocrine tumors metastases warrants ongoing deliberations.

PMID: 28624178 [PubMed - as supplied by publisher]

Biliary complications after liver transplantation; recent developments in etiology, diagnosis and endoscopic treatment.

Mon, 06/19/2017 - 12:45

Biliary complications after liver transplantation; recent developments in etiology, diagnosis and endoscopic treatment.

Best Pract Res Clin Gastroenterol. 2017 Apr;31(2):227-235

Authors: Roos FJM, Poley JW, Polak WG, Metselaar HJ

Abstract
Biliary complications are considered to be the Achilles' heel of liver transplantation. The most common complications are leaks and bile duct strictures. Strictures can arise at the level of the anastomosis (anastomotic strictures; AS) or at other locations in the biliary tree (non-anastomotic strictures; NAS). Endoscopic treatment via endoscopic retrograde cholangiopancreatography (ERCP) is considered to be the preferred therapy for these complications. This review will focus on the diagnostic modalities, new insights in etiology of biliary complications and outcomes after different endoscopic therapies, in both deceased donor transplantation and living-donor liver transplantations. Advances in recent therapies, such as the use of self-expendable metal stents (SEMS) and endoscopic therapy for patients with a bilio-digestive anastomosis will be discussed.

PMID: 28624111 [PubMed - in process]

Interferon-free antiviral therapy for chronic hepatitis C among patients in the liver transplant setting.

Mon, 06/19/2017 - 12:45

Interferon-free antiviral therapy for chronic hepatitis C among patients in the liver transplant setting.

Best Pract Res Clin Gastroenterol. 2017 Apr;31(2):219-225

Authors: van Tilborg M, Maan R, van der Meer AJ, de Knegt RJ

Abstract
Chronic hepatitis C (HCV) infection remains a major public health problem with many infected individuals worldwide. The revolutionary discovery of highly effective direct-acting antivirals (DAAs) makes chronic HCV infection a curable disease, even in patients with advanced liver disease. Liver function may improve shortly after initiation of antiviral therapy in patients on the waiting list and could even obviate the need for transplantation. However, whether these short term benefits also result in a favorable prognosis on the long-term remains to be seen and this fuels the discussion whether DAAs should be used prior to liver transplantation in all patients. Following liver transplantation, DAA treatment is also highly effective so that postponing antiviral treatment to the post-transplant setting may be better for certain patients. Furthermore, the discussion whether HCV positive organ donors should be used now viral eradication is achieved in almost all patients has regained interest.

PMID: 28624110 [PubMed - in process]

Pages