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Synchronous colorectal liver metastases: focus on the elderly : An Effectiveness Study from Routine Care.

Tue, 08/15/2017 - 12:45
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Synchronous colorectal liver metastases: focus on the elderly : An Effectiveness Study from Routine Care.

Langenbecks Arch Surg. 2017 Aug 12;:

Authors: Albertsmeier M, Engel A, Guba MO, Stintzing S, Schiergens TS, Schubert-Fritschle G, Hölzel D, Werner J, Angele MK, Engel J

Abstract
PURPOSE: The goal of this study was to analyze the use and the effectiveness of both surgery and different chemotherapies in patients with synchronous colorectal liver metastases (CLMs) ≥70 years compared to younger patients.
METHODS: Survival was analyzed in 456 patients (24.3% ≥70 years) treated for CLM in a single center using Kaplan-Meier estimation of overall survival (OS), calculation of relative survival as estimate for disease-specific survival, and a Cox regression model.
RESULTS: Complete surgical resections were achieved more often in patients aged <70 years (39.2 vs. 28.1%, P = 0.056), and young patients more frequently received irinotecan or platin-based chemotherapies (70.3 vs. 41.6%, P < 0.001). Three-year OS and relative survival of patients ≥70 years were significantly lower compared to younger patients (OS 34.3 vs. 43.5%, P = 0.0114). In a Cox regression model, complete surgical removal of liver metastases was the most effective treatment (HR 0.313, P < 0.001) followed by chemotherapy (irinotecan/platin-based: HR 0.371, 5-FU only: HR 0.673, P < 0.001). Having >5 liver metastases, the presence of extrahepatic metastases, high grading, and a nodal positive primary but not age ≥70 years were associated with an increased risk of death.
CONCLUSIONS: Our data support radical resection and highly effective chemotherapy in selected elderly patients with CLM.

PMID: 28803383 [PubMed - as supplied by publisher]

Declining mortality in critically ill patients with cirrhosis in Australia and New Zealand between 2000 and 2015.

Tue, 08/15/2017 - 12:45
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Declining mortality in critically ill patients with cirrhosis in Australia and New Zealand between 2000 and 2015.

J Hepatol. 2017 Aug 09;:

Authors: Majumdar A, Bailey M, Kemp WM, Bellomo R, Roberts SK, Pilcher D

Abstract
BACKGROUND AND AIMS: Few studies have described the outcomes of patients with cirrhosis receiving intensive care unit (ICU) admission at a population level. We aimed to describe trends in the mortality of such patients in Australia and New Zealand (ANZ), and to investigate the relationship with associated organ failures.
METHODS: We studied patients admitted to 172 ICUs on a non-elective basis, with and without cirrhosis between January 1(st) 2000 and December 31(st) 2015 as recorded by the ANZ Intensive Care Society Centre for Outcome and Resource Evaluation Adult Patient Database. We assessed severity of illness on admission using organ failure models and acute physiology scores. The primary outcome was hospital mortality.
FINDINGS: Patients with cirrhosis accounted for 17,044 of 776,873 non-elective ICU admissions (2.2%). Cirrhosis hospital mortality was 32.4% compared to 16.9% in the non-cirrhotic group (p<0.0001). After adjustment for key confounders, cirrhosis had an independent effect on mortality with an odds ratio (OR) of 1.10 (1.06-1.15). There was no difference in the adjusted annual decline in mortality between cirrhotic and non-cirrhotic patients (OR 0.96 [0.95-0.97] vs 0.96 [0.96-0.96], p=0.67). No difference was seen in the adjusted decline in mortality of cirrhotic patients when stratified by mechanical ventilation (p=0.92), liver transplant centre status (p=0.27) or presence of sepsis (p=0.09). Mortality increased with number of organ failures, however, the presence of cirrhosis was not found to affect this relationship (p=0.33).
CONCLUSIONS: The mortality of patients with cirrhosis admitted to ICU on a non-elective basis has declined significantly over time, similar to non-cirrhotic patients and is predominantly governed by the number of organ failures. Outcomes are comparable between non-liver transplant ICUs and liver transplant centres.
LAY SUMMARY: The outcomes of patients with liver cirrhosis receiving intensive care unit (ICU) admission have been previously regarded to be poor. We have demonstrated that in Australia and New Zealand, annual in-hospital death rates following ICU admission in this patient group are lower than previously reported, have improved over 16 years to 29% and at a rate similar to patients without cirrhosis. Our data justify recommendations that advocate better access to intensive care for patients with cirrhosis.

PMID: 28802877 [PubMed - as supplied by publisher]

Primary sclerosing cholangitis - a comprehensive review.

Tue, 08/15/2017 - 12:45
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Primary sclerosing cholangitis - a comprehensive review.

J Hepatol. 2017 Aug 09;:

Authors: Karlsen TH, Folseraas T, Thorburn D, Vesterhus M

Abstract
Primary sclerosing cholangitis (PSC) is a rare disorder characterized by multi-focal bile duct strictures and progressive liver disease. Inflammatory bowel disease (IBD) is usually present and there is a high risk of cholangiocarcinoma and colorectal cancer. With no effective medical therapy, most patients ultimately require liver transplantation, after which disease recurrence may occur. With limited therapeutic options and lack of proven surveillance strategies, patients experience significant unmet needs. In the present seminar, we provide a comprehensive review of the current status of the field. We emphasize developments related to patient stratification and disease behavior, and provide an overview of management options in a practical, patient-centered perspective. We survey advances made in the understanding of PSC pathogenesis, and summarize the ongoing efforts to develop an effective therapy based on these insights.

PMID: 28802875 [PubMed - as supplied by publisher]

Recombinant Human Elafin Promotes Alveologenesis in Newborn Mice Exposed to Chronic Hyperoxia.

Tue, 08/15/2017 - 12:45
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Recombinant Human Elafin Promotes Alveologenesis in Newborn Mice Exposed to Chronic Hyperoxia.

Int J Biochem Cell Biol. 2017 Aug 09;:

Authors: Han W, Li X, Zhang H, Yu B, Guo C, Deng C

Abstract
BACKGROUND/AIMS: Elastase inhibitors reverse elastin degradation and abnormal alveologenesis and attenuate the lung structural abnormalities induced by mechanical ventilation with O2-rich gas. The potential of these molecules to improve endothelial function and to ameliorate severe bronchopulmonary dysplasia (BPD) during lung development is not yet understood. We sought to determine whether the intratracheal treatment of newborn mice with the elastase inhibitor elafin would prevent hyperoxia-induced lung elastin degradation and the cascade of events that cause abnormal alveologenesis.
METHODS: Newborn mice were exposed to 85% O2 for 3, 7, 14 or 21 days. Recombinant human elafin was administered administered by intratracheal instillation from the first day every two days for 20 days. We next used morphometric analyses, quantitative RT-PCR, immunostaining, Western blotting, and ELISA methods to assess the key variables involved in elastogenesis disruption and the potential signaling pathways noted below in recombinant human elafin-treated mouse pups that had been exposed to 85% O2.
RESULTS: We found that impaired alveolar development and aberrant elastin production were associated with elevations in whole lung elastase levels in 85% O2-exposed lungs. Elafin attenuated the structural disintegration that developed in the hyperoxia-damaged lungs. Furthermore, elafin prevented the elastin degradation, neutrophil influx, activation of TGF-β1 and apoptosis caused by 85% O2 exposure.
CONCLUSIONS: Pulmonary elastase plays an important role in disrupting elastogenesis during O2-induced damage, which is the result of a pulmonary inflammatory response. Elafin prevents these changes by inhibiting elastase and the TGF-β1 signalling cascade and may be a new therapeutic target for preventing O2-induced lung injury in neonates.

PMID: 28802561 [PubMed - as supplied by publisher]

HIV persistence in tissue macrophages of humanized myeloid-only mice during antiretroviral therapy.

Tue, 08/15/2017 - 12:45
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HIV persistence in tissue macrophages of humanized myeloid-only mice during antiretroviral therapy.

Nat Med. 2017 May;23(5):638-643

Authors: Honeycutt JB, Thayer WO, Baker CE, Ribeiro RM, Lada SM, Cao Y, Cleary RA, Hudgens MG, Richman DD, Garcia JV

Abstract
Despite years of fully suppressive antiretroviral therapy (ART), HIV persists in its hosts and is never eradicated. One major barrier to eradication is that the virus infects multiple cell types that may individually contribute to HIV persistence. Tissue macrophages are critical contributors to HIV pathogenesis; however, their specific role in HIV persistence during long-term suppressive ART has not been established. Using humanized myeloid-only mice (MoM), we demonstrate that HIV infection of tissue macrophages is rapidly suppressed by ART, as reflected by a rapid drop in plasma viral load and a dramatic decrease in the levels of cell-associated viral RNA and DNA. No viral rebound was observed in the plasma of 67% of the ART-treated animals at 7 weeks after ART interruption, and no replication-competent virus was rescued from the tissue macrophages obtained from these animals. In contrast, in a subset of animals (∼33%), a delayed viral rebound was observed that is consistent with the establishment of persistent infection in tissue macrophages. These observations represent the first direct evidence, to our knowledge, of HIV persistence in tissue macrophages in vivo.

PMID: 28414330 [PubMed - indexed for MEDLINE]

Suppression of murine tumour growth through CD8(+) cytotoxic T lymphocytes via activated DEC-205(+) dendritic cells by sequential administration of α-galactosylceramide in vivo.

Tue, 08/15/2017 - 12:45
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Suppression of murine tumour growth through CD8(+) cytotoxic T lymphocytes via activated DEC-205(+) dendritic cells by sequential administration of α-galactosylceramide in vivo.

Immunology. 2017 Jul;151(3):324-339

Authors: Kogo H, Shimizu M, Negishi Y, Uchida E, Takahashi H

Abstract
Cancer immunity is mediated through the effective priming and activation of tumour-specific class I MHC molecule-restricted CD8(+) cytotoxic T lymphocytes (CTLs). DEC-205(+) dendritic cells (DCs) can cross-present the epitope(s) of captured tumour antigens associated with class I MHC molecules alongside co-stimulatory molecules to prime and activate tumour-specific CD8(+) CTLs. Immunosuppressive tolerogenic DCs with reduced co-stimulatory molecules may be a cause of impaired CTL induction. Hepa1-6-1 cells were established from the mouse hepatoma cell line Hepa1-6; these cells grow continuously after subcutaneous implantation into syngeneic C57BL/6 (B6) mice and do not prime CD8(+) CTLs. In this study, we show that the growth of ongoing tumours was suppressed by activated CD8(+) CTLs with tumour-specific cytotoxicity through the administration of the glycolipid α-galactosylceramide (α-GalCer), which is a compound known to stimulate invariant natural killer T (iNKT) cells and selectively activate DEC-205(+) DCs. Moreover, we demonstrated that sequential repetitive intraperitoneal inoculation with α-GalCer every 48 hr appeared to convert tolerogenic DEC-205(+) DCs into immunogenic DCs with a higher expression of co-stimulatory molecules and a stronger cross-presentation capacity, which primed CTL precursors and induced tumour-specific CD8(+) CTLs within the tumour environment without activating iNKT cells. These findings provide a new basis for cancer immunotherapy to convert tolerogenic DEC-205(+) DCs within tumours into immunogenic DCs through the sequential administration of an immuno-potent lipid/glycolipid, and then activated immunogenic DCs with sufficient expression of co-stimulatory molecules prime and activate tumour-specific CD8(+) CTLs within the tumour to control tumour growth.

PMID: 28294313 [PubMed - indexed for MEDLINE]

Predictors of poor outcomes in patients with wild mushroom-induced acute liver injury.

Tue, 08/15/2017 - 12:45
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Predictors of poor outcomes in patients with wild mushroom-induced acute liver injury.

World J Gastroenterol. 2017 Feb 21;23(7):1262-1267

Authors: Kim T, Lee D, Lee JH, Lee YS, Oh BJ, Lim KS, Kim WY

Abstract
AIM: To identify early predictive markers of poor outcomes in patients with acute liver injury from wild mushroom intoxication.
METHODS: This observational, retrospective record review involved adults aged ≥ 18 years admitted to emergency department with mushroom intoxication from January 2005 to December 2015. The diagnosis of mushroom intoxication was based on the following: (1) a positive history of recent wild mushroom intake (either raw or cooked); (2) the onset of gastrointestinal symptoms, such as watery diarrhea, vomiting, and/or abdominal pain, after ingestion; and (3) the exclusion of other possible causes of acute liver injury. Acute liver injury was defined by a > 5-fold elevation of liver enzymes or moderate coagulopathy [international normalized ratio (INR) > 2.0]. Clinical and laboratory findings were compared in survivors and non-survivors.
RESULTS: Of 93 patients with mushroom intoxication, 23, 11 men (47.8%) and 12 women (52.2%), of median age 61 years, developed acute liver injury. The overall in-hospital mortality rate was 43.5% (10/23). Among the laboratory variables, mean serum alkaline phosphatase (73.38 ± 10.89 mg/dL vs 180.40 ± 65.39 mg/dL, P < 0.01), total bilirubin (2.312 ± 1.16 mg/dL vs 7.16 ± 2.94 mg/dL, P < 0.01) concentrations and indirect/direct bilirubin (2.45 ± 1.39 mg/dL vs 0.99 ± 0.45 mg/dL, P < 0.01) ratio as well as prothrombin time (1.88 ± 0.83 mg/dL vs 10.43 ± 4.81 mg/dL, P < 0.01), and activated partial thromboplastin time (aPTT; 32.48 ± 7.64 s vs 72.58 ± 41.29 s, P = 0.01), were significantly higher in non-survivors than in survivors. Logistic regression analysis showed that total bilirubin concentration (OR = 3.58, 95%CI: 1.25-10.22), indirect/direct bilirubin ratio (OR = 0.14, 95%CI: 0.02-0.94) and aPTT (OR = 1.30, 95%CI: 1.04-1.63) were significantly associated with mortality. All patients with total bilirubin > 5 mg/dL or aPTT > 50 s on day 3 died.
CONCLUSION: Monitoring of bilirubin concentrations and aPTT may help in predicting clinical outcomes in patients with acute liver injury from wild mushroom intoxication.

PMID: 28275306 [PubMed - indexed for MEDLINE]

Gut-Specific Delivery of T-Helper 17 Cells Reduces Obesity and Insulin Resistance in Mice.

Tue, 08/15/2017 - 12:45
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Gut-Specific Delivery of T-Helper 17 Cells Reduces Obesity and Insulin Resistance in Mice.

Gastroenterology. 2017 Jun;152(8):1998-2010

Authors: Hong CP, Park A, Yang BG, Yun CH, Kwak MJ, Lee GW, Kim JH, Jang MS, Lee EJ, Jeun EJ, You G, Kim KS, Choi Y, Park JH, Hwang D, Im SH, Kim JF, Kim YK, Seoh JY, Surh CD, Kim YM, Jang MH

Abstract
BACKGROUND & AIMS: Obesity and metabolic syndrome have been associated with alterations to the intestinal microbiota. However, few studies examined the effects of obesity on the intestinal immune system. We investigated changes in subsets of intestinal CD4(+) T-helper (TH) cells with obesity and the effects of gut-tropic TH17 cells in mice on a high-fat diet (HFD).
METHODS: We isolated immune cells from small intestine and adipose tissue of C57BL/6 mice fed a normal chow diet or a HFD for 10 weeks and analyzed the cells by flow cytometry. Mice fed a vitamin A-deficient HFD were compared with mice fed a vitamin A-sufficient HFD. Obese RAG1-deficient mice were given injections of only regulatory T cells or a combination of regulatory T cells and TH17 cells (wild type or deficient in integrin β7 subunit or interleukin 17 [IL17]). Mice were examined for weight gain, fat mass, fatty liver, glucose tolerance, and insulin resistance. Fecal samples were collected before and after T cell transfer and analyzed for microbiota composition by metagenomic DNA sequencing and quantitative polymerase chain reaction.
RESULTS: Mice placed on a HFD became obese, which affected the distribution of small intestinal CD4(+) TH cells. Intestinal tissues from obese mice had significant reductions in the proportion of TH17 cells but increased proportion of TH1 cells, compared with intestinal tissues from nonobese mice. Depletion of vitamin A in obese mice further reduced the proportion of TH17 cells in small intestine; this reduction correlated with more weight gain and worsening of glucose intolerance and insulin resistance. Adoptive transfer of in vitro-differentiated gut-tropic TH17 cells to obese mice reduced these metabolic defects, which required the integrin β7 subunit and IL17. Delivery of TH17 cells to intestines of mice led to expansion of commensal microbes associated with leanness.
CONCLUSIONS: In mice, intestinal TH17 cells contribute to development of a microbiota that maintains metabolic homeostasis, via IL17. Gut-homing TH17 cells might be used to reduce metabolic disorders in obese individuals.

PMID: 28246016 [PubMed - indexed for MEDLINE]

The Spleen Is an Ideal Site for Inducing Transplanted Islet Graft Expansion in Mice.

Tue, 08/15/2017 - 12:45
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The Spleen Is an Ideal Site for Inducing Transplanted Islet Graft Expansion in Mice.

PLoS One. 2017;12(1):e0170899

Authors: Itoh T, Nishinakamura H, Kumano K, Takahashi H, Kodama S

Abstract
Alternative islet transplantation sites have the potential to reduce the marginal number of islets required to ameliorate hyperglycemia in recipients with diabetes. Previously, we reported that T cell leukemia homeobox 1 (Tlx1)+ stem cells in the spleen effectively regenerated into insulin-producing cells in the pancreas of non-obese diabetic mice with end-stage disease. Thus, we investigated the spleen as a potential alternative islet transplantation site. Streptozotocin-induced diabetic C57BL/6 mice received syngeneic islets into the portal vein (PV), beneath the kidney capsule (KC), or into the spleen (SP). The marginal number of islets by PV, KC, or SP was 200, 100, and 50, respectively. Some plasma inflammatory cytokine levels in the SP group were significantly lower than those of the PV group after receiving a marginal number of islets, indicating reduced inflammation in the SP group. Insulin contents were increased 280 days after islet transplantation compared with those immediately following transplantation (p<0.05). Additionally, Tlx1-related genes, including Rrm2b and Pla2g2d, were up-regulated, which indicates that islet grafts expanded in the spleen. The spleen is an ideal candidate for an alternative islet transplantation site because of the resulting reduced inflammation and expansion of the islet graft.

PMID: 28135283 [PubMed - indexed for MEDLINE]

Comparative effectiveness of first-line radiofrequency ablation versus surgical resection and transplantation for patients with early hepatocellular carcinoma.

Tue, 08/15/2017 - 12:45
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Comparative effectiveness of first-line radiofrequency ablation versus surgical resection and transplantation for patients with early hepatocellular carcinoma.

Cancer. 2017 May 15;123(10):1817-1827

Authors: Kutlu OC, Chan JA, Aloia TA, Chun YS, Kaseb AO, Passot G, Yamashita S, Vauthey JN, Conrad C

Abstract
BACKGROUND: Significant controversy exists as to which treatment modality is most effective for small, solitary hepatocellular carcinomas (HCCs): radiofrequency ablation (RFA), surgical resection (RXN), or transplantation (TXP). Size cutoff values ranging from 20 to 50 mm have been proposed to achieve complete ablation. The current study compares outcomes between RFA, RXN, and TXP as first-line therapy for patients with HCC tumors measuring as large as 50 mm.
METHODS: The Surveillance, Epidemiology, and End Results database was queried for patients with HCC tumors measuring up to 50 mm who were treated with RFA, RXN, or TXP between 2004 and 2013. Overall survival (OS) and disease-specific survival (DSS) were examined in patients with tumors measuring ≤20 mm, 21 to 30 mm, or 31 to 50 mm. The impact of an increase in tumor size of only 5 mm beyond 30 mm was evaluated by also examining outcomes in patients with tumors measuring 31 to 35 mm.
RESULTS: Of 1894 cases, patients with HCC tumors measuring ≤20 mm and 21 to 30 mm demonstrated no difference in OS or DSS regardless of whether RFA and RXN was used. RFA was associated with a worse OS and DSS than TXP, whereas there was no difference in OS observed between RXN and TXP. In patients with tumors measuring 31 to 50 mm, OS and DSS were worse with RFA compared with RXN or TXP. Most important, the inferior DSS and OS noted with RFA were observed with only a 5-mm increase in tumors measuring >30 mm.
CONCLUSIONS: Although RFA frequently is used as first-line treatment of HCC tumors measuring as large as 50 mm, it is associated with worse results than RXN or TXP for tumors measuring >30 mm. To the best of the authors' knowledge, the results of the current study are the first to demonstrate that although RFA is an appropriate option for patients with HCC tumors measuring ≤30 mm, its use for tumors even slightly larger than 30 mm is associated with inferior outcomes. Cancer 2017;123:1817-1827. © 2017 American Cancer Society.

PMID: 28085184 [PubMed - indexed for MEDLINE]

Generation of patient-derived xenografts from fine needle aspirates or core needle biopsy.

Tue, 08/15/2017 - 12:45
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Generation of patient-derived xenografts from fine needle aspirates or core needle biopsy.

Surgery. 2017 May;161(5):1246-1254

Authors: Roife D, Kang Y, Wang L, Fang B, Swisher SG, Gershenwald JE, Pretzsch S, Dinney CP, Katz MHG, Fleming JB

Abstract
BACKGROUND: Patient-derived xenografts have recently become a powerful tool for cancer research and may be used to guide personalized therapy. Thus far, patient-derived xenografts have been grown from tumor tissue obtained after operative resection; however, many cancer patients never undergo operative intervention for a variety of reasons. We hypothesized that xenograft tumors could be grown from smaller volumes of patient tissue, such as those obtained during diagnostic biopsies.
METHODS: Surgical specimens were obtained after resection of primary or metastatic lesions of the following cancers: pancreatic carcinoma, non-small cell lung cancer, bladder (urothelial) carcinoma, and melanoma. At least 10 cases of each cancer were included in this study. To mimic clinical biopsies, small fragments of the surgical specimens were biopsied with a 22-gauge needle, and the needle contents were injected subcutaneously in immunocompromised mice. The tumor fragment from which the biopsy was taken was also implanted subcutaneously in the contralateral side of the same mouse as a control.
RESULTS: Success rates of the traditional method of xenograft implantation ranged from 27.3%-70%. Success rates of the fine needle aspirate technique ranged from 0%-36.4%. An attempt to engraft a percutaneous core needle liver biopsy of a metastatic pancreatic adenocarcinoma also was successful.
CONCLUSION: We have found that it is possible to engraft fine needle aspirates and core biopsies of solid tumors in order to generate patient-derived xenografts. This may open up xenografting to a wider cancer patient population than previously possible.

PMID: 28081955 [PubMed - indexed for MEDLINE]

A Portal Vein Injection Model to Study Liver Metastasis of Breast Cancer.

Tue, 08/15/2017 - 12:45
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A Portal Vein Injection Model to Study Liver Metastasis of Breast Cancer.

J Vis Exp. 2016 Dec 26;(118):

Authors: Goddard ET, Fischer J, Schedin P

Abstract
Breast cancer is the leading cause of cancer-related mortality in women worldwide. Liver metastasis is involved in upwards of 30% of cases with breast cancer metastasis, and results in poor outcomes with median survival rates of only 4.8 - 15 months. Current rodent models of breast cancer metastasis, including primary tumor cell xenograft and spontaneous tumor models, rarely metastasize to the liver. Intracardiac and intrasplenic injection models do result in liver metastases, however these models can be confounded by concomitant secondary-site metastasis, or by compromised immunity due to removal of the spleen to avoid tumor growth at the injection site. To address the need for improved liver metastasis models, a murine portal vein injection method that delivers tumor cells firstly and directly to the liver was developed. This model delivers tumor cells to the liver without complications of concurrent metastases in other organs or removal of the spleen. The optimized portal vein protocol employs small injection volumes of 5 - 10 μl, ≥ 32 gauge needles, and hemostatic gauze at the injection site to control for blood loss. The portal vein injection approach in Balb/c female mice using three syngeneic mammary tumor lines of varying metastatic potential was tested; high-metastatic 4T1 cells, moderate-metastatic D2A1 cells, and low-metastatic D2.OR cells. Concentrations of ≤ 10,000 cells/injection results in a latency of ~ 20 - 40 days for development of liver metastases with the higher metastatic 4T1 and D2A1 lines, and > 55 days for the less aggressive D2.OR line. This model represents an important tool to study breast cancer metastasis to the liver, and may be applicable to other cancers that frequently metastasize to the liver including colorectal and pancreatic adenocarcinomas.

PMID: 28060292 [PubMed - indexed for MEDLINE]

Utility of rapid whole exome sequencing in the diagnosis of neonatal Niemann Pick disease type C presenting with fetal hydrops and liver failure.

Sun, 08/13/2017 - 12:45
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Utility of rapid whole exome sequencing in the diagnosis of neonatal Niemann Pick disease type C presenting with fetal hydrops and liver failure.

Cold Spring Harb Mol Case Stud. 2017 Aug 11;:

Authors: Rohanizadegan M, El-Almery S, O'Donnell-Luria A, Mihalek I, Chen P, Sanders M, Leeman K, Cho M, Hung C, Bodamer O

Abstract
Rapid whole exome sequencing (rWES) is increasingly used in critically ill newborn infants to inform about diagnosis, clinical management and prognosis. Here we report a male newborn infant with hydrops, pancytopenia and acute liver failure who was listed for liver transplantation. Given the acuity of the presentation, the procedure related morbidity and mortality and lack of diagnosis we employed rWES in the proband and both parents with a turn-around time of 10 business days. rWES returned one maternally inherited, likely pathogenic and one paternally inherited, likely pathogenic variant in NPC1 suggestive of a diagnosis of Niemann Pick disease type C (NPC). Interestingly, a diagnosis of NPC was entertained prior to rWES, but deemed unlikely in light of absent cholesterol storage on liver biopsy and near normal oxysterol levels in dried blood. The diagnosis of NPC was confirmed on filipin stain in fibroblasts demonstrating defective cholesterol trafficking. NPC is a slowly progressive neurodegenerative disorder that may also affect the liver with overall poor prognosis. It was decided to take the infant off the transplant list and transfer to palliative care where he died after 4 weeks. This case highlights the utility of rWES in an acute clinical setting for several domains of precision medicine including (1) diagnosis; (2) prognosis and outcome; (3) management and therapy and (4) utilization of resources.

PMID: 28802248 [PubMed - as supplied by publisher]

Targeting senescent cholangiocytes and activated fibroblasts with Bcl-xL inhibitors ameliorates fibrosis in Mdr2(-/-) mice.

Sun, 08/13/2017 - 12:45
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Targeting senescent cholangiocytes and activated fibroblasts with Bcl-xL inhibitors ameliorates fibrosis in Mdr2(-/-) mice.

Hepatology. 2017 Aug 12;:

Authors: Moncsek A, Al-Suraih MS, Trussoni CE, O'Hara SP, Splinter PL, Zuber C, Patsenker E, Valli PV, Fingas CD, Weber A, Zhu Y, Tchkonia T, Kirkland JL, Gores GJ, Müllhaupt B, LaRusso NF, Mertens JC

Abstract
Cholangiocyte senescence has been linked to primary sclerosing cholangitis (PSC). Persistent secretion of growth factors by senescent cholangiocytes leads to the activation of stromal fibroblasts (ASF), which are drivers of fibrosis. The activated phenotype of ASF is characterized by an increased sensitivity to apoptotic stimuli. Here, we examined the mechanisms of apoptotic priming in ASF and explored a combined targeting strategy to deplete senescent cholangiocytes and ASF from fibrotic tissue to ameliorate liver fibrosis. Using a co-culture system, we determined that senescent cholangiocytes promoted quiescent mesenchymal cell activation in a PDGF-dependent manner. We also identified Bcl-xL as a key survival factor in PDGF-activated human and mouse fibroblasts. Bcl-xL was also upregulated in senescent cholangiocytes. In vitro, inhibition of Bcl-xL by the small molecule BH3 mimetic A-1331852 or Bcl-xL-specific siRNA induced apoptosis in PDGF-activated fibroblasts but not in quiescent fibroblasts. Likewise, inhibition of Bcl-xL reduced the survival and increased apoptosis of senescent cholangiocytes, compared to non-senescent cells. Treatment of Mdr2(-/-) mice with A-1331852 resulted in an 80% decrease in senescent cholangiocytes, a reduction of fibrosis-inducing growth factors and cytokines, decrease of αSMA-positive ASF and finally in a significant reduction of liver fibrosis.
CONCLUSIONS: Bcl-xL is a key survival factor in ASF as well as in senescent cholangiocytes. Treatment with the Bcl-xL-specific inhibitor A-1331852 reduces liver fibrosis, possibly by a dual effect on activated fibroblasts and senescent cholangiocytes. This novel mechanism represents an attractive therapeutic strategy in biliary fibrosis. This article is protected by copyright. All rights reserved.

PMID: 28802066 [PubMed - as supplied by publisher]

Hepatitis B virus pregenomic RNA in hepatocellular carcinoma: A nosological and prognostic determinant.

Sun, 08/13/2017 - 12:45
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Hepatitis B virus pregenomic RNA in hepatocellular carcinoma: A nosological and prognostic determinant.

Hepatology. 2017 Aug 12;:

Authors: Halgand B, Desterke C, Rivière L, Fallot G, Sebagh M, Calderaro J, Bioulac-Sage P, Neuveut C, Buendia MA, Samuel D, Féray C

Abstract
Hepatitis B virus (HBV) is a major cause of hepatocellular carcinoma (HCC). However, very little is known about the replication of HBV in HCC tissues.
PATIENTS AND METHODS: We analysed viral and cellular parameters in HCC (T) and non-tumor liver (NT) samples from 99 HBsAg-positive, virologically suppressed patients treated by tumour resection or liver transplantation. We examined total HBV DNA and RNA as well as covalently closed circular DNA (cccDNA) and pregenomic RNA (pgRNA), which are considered as markers of active HBV replication.
RESULTS: Total HBV DNA and RNA were detected in both T and NT samples in a majority of cases, but only a subset of tumors harboured detectable levels of HBV cccDNA and pgRNA (39% and 67%) compared to NT livers (66% and 90%) (p<0.01). Further evidence for HBV replication in tumor tissues was provided by sequencing of the X gene derived from episomal forms, showing that HBV genotypes differed between T and matched NT samples in 11 cases. The detection of pgRNA and cccDNA in tumours was correlated to the absence of tumorous microvascular invasion and to better patient survival. Analysis of gene expression profiles by Agilent microarrays revealed that pgRNA-positive HCCs were characterized by low levels of cell cycle and DNA repair markers, and expression of the HBV receptor: sodium taurocholate cotransporting polypeptide (NTCP), indicating well-differentiated tumors.
CONCLUSION: HCC replicating HBV represents a subtype of weakly invasive HCC with a transcriptomic signature. PgRNA originating from non-integrated, complete HBV genomes is a sensitive marker for viral replication and prognosis. This article is protected by copyright. All rights reserved.

PMID: 28802063 [PubMed - as supplied by publisher]

Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease.

Sun, 08/13/2017 - 12:45
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Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease.

Hepatology. 2017 Aug 12;:

Authors: Estes C, Razavi H, Loomba R, Younossi Z, Sanyal AJ

Abstract
BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) and resulting nonalcoholic steatohepatitis (NASH) are highly prevalent in the US, where they are a growing cause of cirrhosis and hepatocellular carcinoma (HCC), and increasingly, an indicator for liver transplantation.
METHODS: A Markov model was used to forecast NAFLD disease progression. Incidence of NAFLD was based on historical and projected changes in adult prevalence of obesity and type 2 diabetes mellitus (DM). Assumptions were derived from published literature where available, and validated using national surveillance data for incidence of NAFLD-related HCC. Projected changes in NAFLD-related cirrhosis, advanced liver disease, and liver-related mortality were quantified through 2030.
RESULTS: Prevalent NAFLD cases are forecasted to increase 21%, from 83.1 (2015) to 100.9 million (2030), while prevalent NASH cases will increase 63% from 16.52 to 27.00 million cases. Overall NAFLD prevalence among the adult population (aged ≥15 years) is projected at 33.5% in 2030, and the median age of the NAFLD population will increase from 50 to 55 years during 2015-2030. In 2015, approximately 20% of NAFLD cases were classified as NASH, increasing to 27% by 2030, a reflection of both disease progression and an aging population. Incidence of decompensated cirrhosis will increase 168% to 105,430 cases by 2030, while incidence of HCC will increase by 137% to 12,240 cases. Liver deaths will increase 178% to an estimated 78,300 deaths in 2030. During 2015-2030, there are nearly 800,000 excess liver deaths.
CONCLUSIONS: With continued high rates of adult obesity and DM, and an aging population, NAFLD-related liver disease and mortality will increase in the US. Strategies to slow the growth of NAFLD cases and therapeutic options are necessary to mitigate disease burden. This article is protected by copyright. All rights reserved.

PMID: 28802062 [PubMed - as supplied by publisher]

Anesthetic Management for Intestinal Transplantation: a Decade of Experience.

Sun, 08/13/2017 - 12:45
Related Articles

Anesthetic Management for Intestinal Transplantation: a Decade of Experience.

Clin Transplant. 2017 Aug 12;:

Authors: Zerillo J, Kim S, Hill B, Shapiro D, Lin HM, Burnham A, Moon J, Iyer K, DeMaria S

Abstract
BACKGROUND: Intestinal transplantation (ITx) is the definitive therapy for patients suffering from intestinal failure. Previous published reports suggest that these cases should be managed peri-operatively with the same intensive monitors and techniques as in liver transplantation.
METHODS: We retrospectively reviewed the anesthetic management of sixty-seven isolated intestinal, intestinal-pancreas and intestinal-kidney transplants over the previous decade (2005-2015) in our tertiary care institution.
RESULTS: Patients were typically managed with a single arterial line, a single central venous catheter and rarely intensive modalities such as a pulmonary artery catheter, a transesophageal echocardiography, a second arterial catheter or central venous catheter, a rapid infusion system, a cell salvage device or viscoelastic testing. Significant hemodynamic derangements were rare and the rate of post reperfusion syndrome (PRS) was 8.96%. Our fluid administration type and volume and transfusion type and volume were similar to previous reports in which more intensive anesthetic management was employed.
CONCLUSION: We demonstrate that intestinal transplantation can safely occur without utilizing the intensive resources requisite for a liver transplant. This article is protected by copyright. All rights reserved.

PMID: 28801969 [PubMed - as supplied by publisher]

Response to "Minimization of Ischemic Cholangiopathy in Donation after Cardiac Death Liver Transplantation: Is it Thrombolytic Therapy or Warm Ischemic Time Stringency and Donor Bile Duct Flush?

Sun, 08/13/2017 - 12:45
Related Articles

Response to "Minimization of Ischemic Cholangiopathy in Donation after Cardiac Death Liver Transplantation: Is it Thrombolytic Therapy or Warm Ischemic Time Stringency and Donor Bile Duct Flush?

Am J Transplant. 2017 Aug 12;:

Authors: Bohorquez H, Loss GE

Abstract
We thank Giorgakis and colleagues for their interest in our recent published article (1, 2). Since the etiology of ischemic cholangiopathy (IC) in Donation after Cardiac Death (DCD) for Liver Transplantation (LT) is not well defined, hypotheses include ischemia-reperfusion injury, microvascular thrombosis, cytotoxic injury, and impaired biliary epithelial regeneration (3-5), adopting a multifaceted protocol to optimize perioperative conditions is essential. We concur with their observation that fast organ recovery with rapid decompression, in-situ aortic and portal flushing, biliary tree flushing -and in our institution, retrograde venous flushing-, keep short ischemic times, careful donor-recipient selection and pristine technical implantation are imperative to good outcomes. This article is protected by copyright. All rights reserved.

PMID: 28801953 [PubMed - as supplied by publisher]

In-situ split liver splitting under extra-corporeal membrane oxygenation in brain-dead donor.

Sun, 08/13/2017 - 12:45
Related Articles

In-situ split liver splitting under extra-corporeal membrane oxygenation in brain-dead donor.

Am J Transplant. 2017 Aug 12;:

Authors: Michela A, Majno P, Toso C, Berney T, Giraud R, Dutkowski P, Andres A, Wildhaber B, Elkrief L

Abstract
Hemodynamic instability is generally considered as a contraindication to liver splitting, in particular when using an in-situ technique. We describe the cases of two young donors with brain death in whom refractory cardiac arrest and hemodynamic instability were supported by veno-arterial extracorporeal membrane oxygenation (VA-ECMO), allowing uneventful in situ splitting. Two adult and two pediatric liver recipients were successfully transplanted with immediate graft function. Favorable outcomes were also observed for the other transplanted organs, including one heart, two lungs and four kidneys. Refractory cardiac arrest and hemodynamic instability corrected by VA-ECMO should not be considered as a contraindication to in-situ liver splitting. This article is protected by copyright. All rights reserved.

PMID: 28801937 [PubMed - as supplied by publisher]

Right hepatic artery 'caterpillar hump' and dual cystic arteries: relevance of critical view of safety in a 'straightforward' cholecystectomy.

Sun, 08/13/2017 - 12:45
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Right hepatic artery 'caterpillar hump' and dual cystic arteries: relevance of critical view of safety in a 'straightforward' cholecystectomy.

BMJ Case Rep. 2017 Aug 11;2017:

Authors: Zefelippo A, Fornoni G

PMID: 28801516 [PubMed - in process]

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