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Controlled donation after circulatory death in the Netherlands: more organs, more efforts.

Fri, 08/11/2017 - 12:45
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Controlled donation after circulatory death in the Netherlands: more organs, more efforts.

Neth J Med. 2016 Aug;74(7):285-91

Authors: Leiden H, Haase-Kromwijk B, Hoitsma A, Jansen N

Abstract
BACKGROUND: The Netherlands was one of the first countries in Europe to stimulate controlled donation after circulatory death (cDCD) at a national level in addition to donation after brain death (DBD). With this program the number of organ transplants increased, but it also proved to have challenges as will be shown in this 15-year review.
METHODS: Data about deceased organ donation in the Netherlands, from 2000 until 2014, were analysed taking into account the whole donation process from donor referral to the number of organs transplanted.
RESULTS: Donor referral increased by 58%, from 213 to 336 donors per year, and the number of organs transplanted rose by 42%. Meanwhile the contribution of cDCD donors increased from 14% in 2000 to 54% in 2014 among all referrals. The organs were transplanted from 92-99% of referred DBD donors, but this percentage was significantly lower for cDCD donors and also decreased from 86% in 2000-2002 to 67% in 2012-2014. In 16% of all referred cDCD donors, organs were not recovered because donors did not die within the expected two-hour time limit after withdrawal of life- upporting treatment. Furthermore, cDCD is more often performed at a higher donor age, which is associated with a lower percentage of transplanted organs.
CONCLUSION: Although cDCD resulted in more transplants, the effort in donor recruitment is considerably higher. Important challenges in cDCD that need further attention are the time limit after withdrawal of life-supporting treatment and donor age, as well as the possibilities to stimulate non-renal transplants including the heart by machine preservation.

PMID: 27571943 [PubMed - indexed for MEDLINE]

3K3A-activated protein C stimulates postischemic neuronal repair by human neural stem cells in mice.

Fri, 08/11/2017 - 12:45
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3K3A-activated protein C stimulates postischemic neuronal repair by human neural stem cells in mice.

Nat Med. 2016 Sep;22(9):1050-5

Authors: Wang Y, Zhao Z, Rege SV, Wang M, Si G, Zhou Y, Wang S, Griffin JH, Goldman SA, Zlokovic BV

Abstract
Activated protein C (APC) is a blood protease with anticoagulant activity and cell-signaling activities mediated by the activation of protease-activated receptor 1 (F2R, also known as PAR1) and F2RL1 (also known as PAR3) via noncanonical cleavage. Recombinant variants of APC, such as the 3K3A-APC (Lys191-193Ala) mutant in which three Lys residues (KKK191-193) were replaced with alanine, and/or its other mutants with reduced (>90%) anticoagulant activity, engineered to reduce APC-associated bleeding risk while retaining normal cell-signaling activity, have shown benefits in preclinical models of ischemic stroke, brain trauma, multiple sclerosis, amyotrophic lateral sclerosis, sepsis, ischemic and reperfusion injury of heart, kidney and liver, pulmonary, kidney and gastrointestinal inflammation, diabetes and lethal body radiation. On the basis of proof-of-concept studies and an excellent safety profile in humans, 3K3A-APC has advanced to clinical trials as a neuroprotectant in ischemic stroke. Recently, 3K3A-APC has been shown to stimulate neuronal production by human neural stem and progenitor cells (NSCs) in vitro via a PAR1-PAR3-sphingosine-1-phosphate-receptor 1-Akt pathway, which suggests the potential for APC-based treatment as a strategy for structural repair in the human central nervous (CNS) system. Here we report that late postischemic treatment of mice with 3K3A-APC stimulates neuronal production by transplanted human NSCs, promotes circuit restoration and improves functional recovery. Thus, 3K3A-APC-potentiated neuronal recruitment from engrafted NSCs might offer a new approach to the treatment of stroke and related neurological disorders.

PMID: 27548576 [PubMed - indexed for MEDLINE]

Liver tissue fragments obtained from males are the most promising source of human hepatocytes for cell-based therapies - Flow cytometric analysis of albumin expression.

Thu, 08/10/2017 - 12:45
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Liver tissue fragments obtained from males are the most promising source of human hepatocytes for cell-based therapies - Flow cytometric analysis of albumin expression.

PLoS One. 2017;12(8):e0182846

Authors: Zakrzewska KE, Samluk A, Wencel A, Dudek K, Pijanowska DG, Pluta KD

Abstract
Cell-based therapies that could provide an alternative treatment for the end-stage liver disease require an adequate source of functional hepatocytes. There is little scientific evidence for the influence of patient's age, sex, and chemotherapy on the cell isolation efficiency and metabolic activity of the harvested hepatocytes. The purpose of this study was to investigate whether hepatocytes derived from different sources display differential viability and biosynthetic capacity. Liver cells were isolated from 41 different human tissue specimens. Hepatocytes were labeled using specific antibodies and analyzed using flow cytometry. Multiparametric analysis of the acquired data revealed statistically significant differences between some studied groups of patients. Generally, populations of cells isolated from the male specimens had greater percentage of biosynthetically active hepatocytes than those from the female ones regardless of age and previous chemotherapy of the patient. Based on the albumin staining (and partially on the α-1-antitrypsin labeling) after donor liver exclusion (6 out of 41 samples), our results indicated that: 1. samples obtained from males gave a greater percentage of active hepatocytes than those from females (p = 0.034), and 2. specimens from the males after chemotherapy greater than those from the treated females (p = 0.032).

PMID: 28793328 [PubMed - in process]

Mixed adenoneuroendocrine carcinoma derived from the cystic duct: A case report.

Thu, 08/10/2017 - 12:45
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Mixed adenoneuroendocrine carcinoma derived from the cystic duct: A case report.

Int J Surg Case Rep. 2017 Jul 13;39:29-33

Authors: Takemoto YK, Abe T, Amano H, Hanada K, Okazaki A, Minami T, Kobayashi T, Nakahara M, Yonehara S, Ohdan H, Noriyuki T

Abstract
INTRODUCTION: Mixed adenoneuroendocrine carcinomas (MANECs) derived from cystic duct are extremely rare.
PRESENTATION OF CASE: An 80-year-old woman was admitted to the department of surgery, Onomichi general hospital with abnormal liver function and jaundice. Enhanced abdominal computed tomography (CT) detected a well-enhanced papillary tumor in the cystic duct, which protruded into the common bile duct. The intrahepatic bile duct was dilated due to tumor obstruction. The entire tumor showed high intensity in T2-weighted magnetic resonance imaging (MRI) imaging. Endoscopic retrograde cholangiopancreatography (ERCP) showed that the tumor ranged from part of communication of three ducts (cystic, common hepatic and common bile duct), to the middle of common bile duct. Biliary cytology determined a class V malignancy (adenocarcinoma). Endoscopic ultrasound determined that the tumor was primarily at the cystic duct with heterogeneous echoic pattern, which extended into the common bile duct. The preoperative diagnosis was cystic duct carcinoma (T3N0M0, StageIIIA). An extended cholecystectomy with regional lymph nodes dissection was performed. Histologically, the tumor had components of both well-differentiated tubular adenocarcinoma and neuroendocrine carcinoma, which is classified as MANECs according to the 2010 WHO classification of endocrine tumors. Eight months after surgery, multiple liver metastases were discovered, and treatment with adjuvant chemotherapy was initiated.
DISSCUSION: We present a rare case of MANECs derived from cystic duct. Until now, an established adjuvant systemic chemotherapy has not emerged, and curative resection, with poor long-term prognosis, remains the only treatment option.
CONCLUSION: Though standards of treatment for MANECs have not been established,multidisciplinary theraphy is necessary to improve outcome.

PMID: 28793278 [PubMed - as supplied by publisher]

O-(2-(18)F-fluoroethyl)-l-tyrosine ((18)F-FET) uptake in insulinoma: first results from a xenograft mouse model and from human.

Thu, 08/10/2017 - 12:45
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O-(2-(18)F-fluoroethyl)-l-tyrosine ((18)F-FET) uptake in insulinoma: first results from a xenograft mouse model and from human.

Nucl Med Biol. 2017 Jul 12;53:21-28

Authors: Imperiale A, Boisson F, Kreutter G, Goichot B, Namer IJ, Bachellier P, Laquerriere P, Kessler L, Marchand P, Brasse D

Abstract
INTRODUCTION: Herein we have evaluated the uptake of O-(2-(18)F-fluoroethyl)-l-tyrosine ((18)F-FET) in insulinoma in comparison with those of 6-(18)F-fluoro-3,4-dihydroxy-l-phenylalanine ((18)F-FDOPA) providing first data from both murine xenograft model and one patient with proved endogenous hyperinsulinemic hypoglycemia.
METHODS: Dynamic (18)F-FET and carbidopa-assisted (18)F-FDOPA PET were performed on tumor-bearing nude mice after subcutaneous injection of RIN-m5F murine beta cells and on a 30-year-old man with type-1 multiple endocrine neoplasia and hyperinsulinemic hypoglycemia defined by a positive fasting test.
RESULTS: Seven and three nude mice bearing a RIN-m5F insulinoma xenograft were respectively studied by (18)F-FET and (18)F-FDOPA μPET. Insulinoma xenograft was detected in all the imaged animals. Xenograft was characterized by an early but moderate increase of (18)F-FET uptake followed by a slight decline of uptake intensity during the 20 min dynamic acquisition. Tumoral radiotracer peak intensity and the highest tumor-to-background contrast were reached about 5 minutes after (18)F-FET iv. injection (mean SUV: 1.21 ± 0.10). The biodistribution of (18)F-FET and (18)F-FDOPA and their dynamic tumoral uptake profile and intensity were similar. In the examined patient, (18)F-FDOPA and (18)F-FET PET/CT showed one concordant focal area of well-defined increased uptake in the pancreatic tail corresponding to 11 mm histologically proved insulinoma. The SUVmax tumor to liver ratio was 1.5, 1.1 for (18)F-FDOPA, 1.1, 1 for (18)F-FET at early (0-5 min post injection) and delayed (5-20 min post injection) PET/CT acquisition, respectively. Despite the relatively low tumoral uptake intensity, insulinoma was clearly identified due to the low background in the pancreas. At the contrary, no (18)F-FDOPA or (18)F-FET tumoral uptake was revealed on whole-body PET/CT images performed about 30 min after radiotracer administration. Note of worth, the dynamic uptake pattern of (18)F-FET and (18)F-FDOPA were similar between human insulinoma and mice xenograft tumor.
CONCLUSION: (18)F-FET PET compared equally to (18)F-FDOPA PET in a preclinical RIN-m5F murine model of insulinoma and in one patient with insulinoma-related hypoglycemia. However, in both cases, the tumoral uptake intensity was moderate and the tumor was only visible until 20 min after radiotracer injection. Hence, caution should be taken before asserting the translational relevance of our results in the clinical practices. However, the structural analogies between (18)F-FET and (18)F-FDOPA as well as the limited pancreatic uptake of (18)F-FET in human, encourage evaluating (18)F-FET as diagnostic radiotracer for insulinoma detection in further prospective studies involving large cohorts of patients.

PMID: 28793277 [PubMed - as supplied by publisher]

Proliferative capacity exhibited by human liver-resident CD49a+CD25+ NK cells.

Thu, 08/10/2017 - 12:45
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Proliferative capacity exhibited by human liver-resident CD49a+CD25+ NK cells.

PLoS One. 2017;12(8):e0182532

Authors: Martrus G, Kautz T, Lunemann S, Richert L, Glau L, Salzberger W, Goebels H, Langeneckert A, Hess L, Poch T, Schramm C, Oldhafer KJ, Koch M, Tolosa E, Nashan B, Altfeld M

Abstract
The recruitment and retention of Natural Killer (NK) cells in the liver are thought to play an important role during hepatotropic infections and liver cirrhosis. The aims of this study were to determine differences between liver-derived and peripheral blood-derived NK cells in the context of liver inflammation and cirrhosis. We conducted a prospective dual-center cross-sectional study in patients undergoing liver transplantation or tumor-free liver resections, in which both liver tissue and peripheral blood samples were obtained from each consenting study participants. Intrahepatic lymphocytes and PBMCs were stained, fixed and analyzed by flow cytometry. Our results showed that, within cirrhotic liver samples, intrahepatic NK cells were particularly enriched for CD49a+ NK cells when compared to tumor-free liver resection samples. CD49a+ liver-derived NK cells included populations of cells expressing CD25, CD34 and CXCR3. Moreover, CD49a+CD25+ liver-derived NK cells exhibited high proliferative capacity in vitro in response to low doses of IL-2. Our study identified a specific subset of CD49a+CD25+ NK cells in cirrhotic livers bearing functional features of proliferation.

PMID: 28792982 [PubMed - in process]

Mutations in the novel gene FOPV are associated with familial autosomal dominant and non-familial obliterative portal venopathy.

Thu, 08/10/2017 - 12:45
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Mutations in the novel gene FOPV are associated with familial autosomal dominant and non-familial obliterative portal venopathy.

Liver Int. 2017 Aug 09;:

Authors: Besmond C, Valla D, Hubert L, Poirier K, Grosse B, Guettier C, Bernard O, Gonzales E, Jacquemin E

Abstract
BACKGROUND AND AIMS: Obliterative portal venopathy (OPV) is characterized by lesions of portal vein intrahepatic branches and is thought to be responsible for many cases of portal hypertension in absence of cirrhosis or obstruction of large portal or hepatic veins. In most cases the cause of OPV remains unknown. The aim was to identify a candidate gene of OPV.
METHODS: Whole exome sequencing was performed in two families, including 6 patients with OPV. Identified mutations were confirmed by Sanger sequencing and expression of candidate gene transcript was studied by real time qPCR in human tissues.
RESULTS: In both families, no mutations were identified in genes previously reported to be associated with OPV. In each family, we identified a heterozygous mutation (c.1783G>A, p.Gly595Arg and c.4895C>T, p.Thr1632Ile) in a novel gene located on chromosome 4, that we called FOPV (Familial Obliterative Portal Venopathy), and having a cDNA coding for 1793 amino acids. The FOPV mutations segregated with the disease in families and the pattern of inheritance was suggestive of autosomal dominant inherited OPV, with incomplete penetrance and variable expressivity. In silico analysis predicted a deleterious effect of each mutant and mutations concerned highly conserved amino acids in mammals. A deleterious heterozygous FOPV missense mutation (c.4244T>C, p.Phe1415Ser) was also identified in a patient with non-familial OPV. Expression study in liver veins showed that FOPV transcript was mainly expressed in intrahepatic portal vein.
CONCLUSIONS: This report suggests that FOPV mutations may have a pathogenic role in some cases of familial and non-familial OPV. This article is protected by copyright. All rights reserved.

PMID: 28792652 [PubMed - as supplied by publisher]

Cost-effectiveness analysis of potentially curative and combination treatments for hepatocellular carcinoma with person-level data in a Canadian setting.

Thu, 08/10/2017 - 12:45
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Cost-effectiveness analysis of potentially curative and combination treatments for hepatocellular carcinoma with person-level data in a Canadian setting.

Cancer Med. 2017 Aug 08;:

Authors: Thein HH, Isaranuwatchai W, Qiao Y, Wong K, Sapisochin G, Chan KKW, Yoshida EM, Earle CC

Abstract
Patients with early-stage hepatocellular carcinoma (HCC) are potential candidates for curative treatments such as radiofrequency ablation (RFA), surgical resection (SR), or liver transplantation (LT), which have demonstrated a significant survival benefit. We aimed to estimate the cost-effectiveness of curative and combination treatment strategies among patients diagnosed with HCC during 2002-2010. This study used Ontario Cancer Registry-linked administrative data to estimate effectiveness and costs (2013 USD) of the treatment strategies from the healthcare payer's perspective. Multiple imputation by logistic regression was used to handle missing data. A net benefit regression approach of baseline important covariates and propensity score adjustment were used to calculate incremental net benefit to generate incremental cost-effectiveness ratio (ICER) and uncertainty measures. Among 2,222 patients diagnosed with HCC, 10.5%, 14.1%, and 10.3% received RFA, SR, and LT monotherapy, respectively; 0.5-3.1% dual treatments; and 0.5% triple treatments. Compared with no treatment (53.2%), transarterial chemoembolization (TACE) + RFA (average $2,465, 95% CI: -$20,000-$36,600/quality-adjusted life years [QALY]) or RFA monotherapy ($15,553, 95% CI: $3,500-$28,500/QALY) appears to be the most cost-effective modality with lowest ICER value. The cost-effectiveness acceptability curve showed that if the relevant threshold was $50,000/QALY, RFA monotherapy and TACE+ RFA would have a cost-effectiveness probability of 100%. Strategies using LT delivered the most additional QALYs and became cost-effective at a threshold of $77,000/QALY. Our findings found that TACE+ RFA dual treatment or RFA monotherapy appears to be the most cost-effective curative treatment for patients with potential early stage of HCC in Ontario. These findings highlight the importance of identifying and measuring differential benefits, costs, and cost-effectiveness of alternative HCC curative treatments in order to evaluate whether they are providing good value for money in the real world.

PMID: 28791798 [PubMed - as supplied by publisher]

The Role of Bariatric Surgery in Abdominal Organ Transplantation-the Next Big Challenge?

Thu, 08/10/2017 - 12:45
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The Role of Bariatric Surgery in Abdominal Organ Transplantation-the Next Big Challenge?

Obes Surg. 2017 Aug 08;:

Authors: Dziodzio T, Biebl M, Öllinger R, Pratschke J, Denecke C

Abstract
Obesity is linked to inferior transplant outcome. Bariatric surgery (BS) is an established treatment of morbid obesity. We provide an overview on BS in the field of kidney (KT) and liver transplantation (LT). In end-stage renal disease (ESRD) and KT patients, BS seems safe and feasible. Complication rates were slightly higher compared to the non-transplant population, whereas weight loss and improvement of comorbidities were comparable. Sleeve gastrectomy (SG) was the preferred procedure before KT and superior to gastric bypass (GB) in regard to mortality and morbidity. If conducted after KT, both procedures showed comparable results. BS before LT was associated with high complication rates, in particular after GB. Albeit distinct complications, SG conducted after LT showed the best results. Immunosuppression (IS) changes after BS were rare.

PMID: 28791580 [PubMed - as supplied by publisher]

Metabolic crosstalk between fatty pancreas and fatty liver: effects on local inflammation and insulin secretion.

Thu, 08/10/2017 - 12:45
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Metabolic crosstalk between fatty pancreas and fatty liver: effects on local inflammation and insulin secretion.

Diabetologia. 2017 Aug 08;:

Authors: Gerst F, Wagner R, Kaiser G, Panse M, Heni M, Machann J, Bongers MN, Sartorius T, Sipos B, Fend F, Thiel C, Nadalin S, Königsrainer A, Stefan N, Fritsche A, Häring HU, Ullrich S, Siegel-Axel D

Abstract
AIMS/HYPOTHESIS: Obesity-linked ectopic fat accumulation is associated with the development of type 2 diabetes. Whether pancreatic and liver steatosis impairs insulin secretion is controversial. We examined the crosstalk of human pancreatic fat cells with islets and the role of diabetogenic factors, i.e. palmitate and fetuin-A, a hepatokine released from fatty liver.
METHODS: Human pancreatic resections were immunohistochemically stained for insulin, glucagon, somatostatin and the macrophage/monocyte marker CD68. Pancreatic adipocytes were identified by Oil Red O and adiponectin staining. Primary pancreatic pre-adipocytes and differentiated adipocytes were co-cultured with human islets isolated from organ donors and the metabolic crosstalk between fatty liver and fatty pancreas was mimicked by the addition of palmitate and fetuin-A. Insulin secretion was evaluated by ELISA and RIA. Cytokine expression and secretion were assessed by RT-PCR and multiplex assay, respectively. Subcellular distribution of proteins was examined by confocal microscopy and protein phosphorylation by western blotting.
RESULTS: In human pancreatic parenchyma, highly differentiated adipocytes were detected in the proximity of islets with normal architecture and hormone distribution. Infiltration of adipocytes was associated with an increased number of CD68-positive cells within islets. In isolated primary pancreatic pre-adipocytes and differentiated adipocytes, palmitate and fetuin-A induced IL6, CXCL8 and CCL2 mRNA expression. Cytokine production was toll-like receptor 4 (TLR4)-dependent and further accentuated in pre-adipocytes when co-cultured with islets. In islets, IL6 and CXCL8 mRNA levels were also increased by fetuin-A and palmitate. Only in macrophages within the isolated islets, palmitate and fetuin-A stimulated the production of the cytotoxic cytokine IL-1β. Palmitate, but not fetuin-A, exerted pro-apoptotic effects in islet cells. Instead, fetuin-A impaired glucose-induced insulin secretion in a TLR4-independent, but c-Jun N-terminal kinase- and Ca(2+)-dependent, manner.
CONCLUSIONS/INTERPRETATION: These results provide the first evidence that fetuin-A-mediated metabolic crosstalk of fatty liver with islets may contribute to obesity-linked glucose blindness of beta cells, while fatty pancreas may exacerbate local inflammation.

PMID: 28791439 [PubMed - as supplied by publisher]

Combination of sofosbuvir and daclatasvir in the treatment of genotype 3 chronic hepatitis C virus infection in patients on maintenance hemodialysis.

Thu, 08/10/2017 - 12:45
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Combination of sofosbuvir and daclatasvir in the treatment of genotype 3 chronic hepatitis C virus infection in patients on maintenance hemodialysis.

Ther Clin Risk Manag. 2017;13:733-738

Authors: Sperl J, Frankova S, Kreidlova M, Merta D, Tothova M, Spicak J

Abstract
Chronic hepatitis C virus infection (HCV) has a negative impact on the long-term survival of recipients of kidney transplants. HCV should be treated in hemodialyzed patients before their enlistment for kidney transplantation in order to avoid the reactivation of virus after transplantation. Direct-acting antivirals represent the current standard of care in hemodialyzed patients with HCV genotypes 1 and 4; in patients with genotypes 2 or 3, the optimal regimen is yet to be established. Sofosbuvir (SOF) and daclatasvir (DCV) represent an antiviral pangenotypic regimen with favorable pharmacokinetics in hemodialyzed patients. We retrospectively evaluated safety and efficacy of the combination of SOF and DCV in the treatment of genotype 3a chronic HCV in six male patients (mean age of 39 years, range 25-53 years) with end-stage renal disease on maintenance hemodialysis; these patients were treated with a reduced dose of SOF (one half of a 400 mg tablet) and 60 mg of DCV once daily. The anticipated treatment duration was 12 weeks. Initial HCV RNA ranged from 120,000 to 11,000,000 IU/mL. Two of the six patients had compensated liver cirrhosis based on shear-wave elastography result. All of the patients completed a 12-week treatment. Viremia became negative on treatment and remained negative 12 weeks after the end of therapy in all the patients. All of them (6/6, 100%) achieved sustained virological response, including two with cirrhosis and two with HCV RNA >6,000,000 IU/mL. The treatment was well tolerated: none of the patients presented with a serious adverse event requiring hospital admission and none had anemia or any significant changes in blood count. One patient had a short period of diarrhea, which was resolved with antibiotic treatment. The combination of reduced-dose SOF and full-dose DCV, daily, was a safe and effective treatment in our group of hemodialyzed patients infected with HCV genotype 3.

PMID: 28790832 [PubMed]

Hydrogen peroxide test for intraoperative bile leak detection.

Thu, 08/10/2017 - 12:45
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Hydrogen peroxide test for intraoperative bile leak detection.

Med J Armed Forces India. 2017 Jul;73(3):256-260

Authors: Trehan V, Rao PP, Naidu CS, Sharma AK, Singh AK, Sharma S, Gaur A, Kulkarni SV, Pathak N

Abstract
BACKGROUND: Bile leakage (BL) is a common complication following liver surgery, ranging from 3 to 27% in different series. To reduce the incidence of post-operative BL various BL tests have been applied since ages, but no method is foolproof and every method has their own limitations. In this study we used a relatively simpler technique to detect the BL intra-operatively. Topical application of 1.5% diluted hydrogen peroxide (H2O2) was used to detect the BL from cut surface of liver and we compared this with conventional saline method to know the efficacy.
METHODS: A total of 31 patients included all patients who underwent liver resection and donor hepatectomies as part of Living Donor Liver Transplantation. After complete liver resection, the conventional saline test followed by topical diluted 1.5% H2O2 test was performed on all.
RESULTS: A BL was demonstrated in 11 patients (35.48%) by the conventional saline method and in 19 patients (61.29%) by H2O2 method. Statistically compared by Wilcoxon signed-rank test showed significant difference (P = 0.014) for minor liver resections group and (P = 0.002) for major liver resections group.
CONCLUSION: The topical application of H2O2 is a simple and effective method of detection of BL from cut surface of liver. It is an easy, non-invasive, cheap, less time consuming, reproducible, and sensitive technique with no obvious disadvantages.

PMID: 28790783 [PubMed]

[Critical Care Managements after Lung Transplantation].

Thu, 08/10/2017 - 12:45
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[Critical Care Managements after Lung Transplantation].

Kyobu Geka. 2017 Jul;70(8):701-707

Authors: Anraku M

Abstract
Lung transplantation is a viable treatment option for patients with end-stage lung diseases such as interstitial pneumonia/pulmonary fibrosis, emphysema, pulmonary hypertension, and so on. Collecting available clinical, physiological, serological, and surgical information of both donor and recipient is vital when planning relevant postoperative managements. The goal of the managements is to keep the transplanted lung (s) functional while preventing/treating infection, rejection, and ischemiareperfusion lung injury. Immunosuppressive therapy, anti-mycobacterial/viral therapy, and cardio-pulmonary supports should be optimized without causing unfavorable side-effects that can lead to kidney, liver, digestive and neurological malfunction. During the post-transplant intensive care period, satisfying the endorgan oxygen requirement is the key to maintain vital organ stability. Aggressive rehabilitation should be utilized as soon as the hemodynamic status allows it. Deep venous thrombosis and subsequent pulmonary embolism should be prevented by giving anti-coagulants and active mobilization, because the incidence could be underrecognized. Avoiding multifactorial allograft injuries can improve not only short-term graft function, but also long-term patients' outcome after lung transplantation.

PMID: 28790293 [PubMed - in process]

Non selective beta blockers in cirrhosis.

Thu, 08/10/2017 - 12:45
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Non selective beta blockers in cirrhosis.

J Hepatol. 2017 Aug 05;:

Authors: Thalheimer U, Giannelli V, Maimone S

PMID: 28789879 [PubMed - as supplied by publisher]

Prognostic value of Rho GDP dissociation inhibitors in patients with hepatocellular carcinoma following liver transplantation.

Thu, 08/10/2017 - 12:45
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Prognostic value of Rho GDP dissociation inhibitors in patients with hepatocellular carcinoma following liver transplantation.

Oncol Lett. 2017 Aug;14(2):1395-1402

Authors: Lai MC, Zhu QQ, Owusu-Ansah KG, Zhu YB, Yang Z, Xie HY, Zhou L, Wu LM, Zheng SS

Abstract
Rho GDP dissociation inhibitors (GDIs) are pivotal regulators of Rho GTPases, which are essential for tumor progression, yet their role in hepatocellular carcinoma (HCC) remains poorly understood. The purpose of the present study was to assess the role of RhoGDIs in the invasiveness and migration of liver cancer, and to determine their clinical prognostic significances in HCC following liver transplantation (LT). In the present study, the expression of RhoGDIs was assessed using reverse transcription-quantitative polymerase chain reaction and confirmed by western-blot analysis and immunohistochemistry. Their prognostic values were also analyzed, and determined in patients treated with LT. In addition, the functions of RhoGDIs in liver cancer cell line were studied in vitro. As a result, the downregulation of RhoGDI1 and RhoGDI2 at mRNA and protein levels were detected in HCC when compared with that of adjacent noncancerous tissues (P<0.05). However, the level of RhoGDI3 was identified to be similar in tumor and para-carcinoma tissues. Additionally, Kaplan-Meier curves demonstrated that patients with lower expression of RhoGDI1 or RhoGDI2 exhibited significantly increased risk of tumor recurrence following LT (P=0.007 and P=0.006, respectively). Cox proportional hazards model analysis revealed that the decreased expression level of RhoGDI2 was an unfavorable independent prognostic factor (hazard ratio, 3.306; P=0.001). In vitro studies involving the silencing of RhoGDI1 or RhoGDI2 demonstrated a significant increase in the migratory and invasive ability of tumor cells upon the silencing of these genes. Results from the present study indicate that RhoGDI dysregulation is a frequent event in human HCC, and that it promotes cancer progression by stimulating cell migration and invasion. RhoGDI2 may be a prognostic biomarker for patients with HCC following LT, and act as a potential therapeutic target.

PMID: 28789355 [PubMed]

Appearance of New Cutaneous Superficial Basal Cell Carcinomas during Successful Nivolumab Treatment of Refractory Metastatic Disease: Implications for Immunotherapy in Early Versus Late Disease.

Thu, 08/10/2017 - 12:45
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Appearance of New Cutaneous Superficial Basal Cell Carcinomas during Successful Nivolumab Treatment of Refractory Metastatic Disease: Implications for Immunotherapy in Early Versus Late Disease.

Int J Mol Sci. 2017 Jul 31;18(8):

Authors: Cohen PR, Kato S, Goodman AM, Ikeda S, Kurzrock R

Abstract
Metastatic basal cell carcinoma may be treated with hedgehog pathway inhibitors, including vismodegib and sonidegib. However, patients can demonstrate resistance to these agents. We describe a man with metastatic basal cell carcinoma who did not respond well to vismodegib and sonidegib. Next generation sequencing of his metastatic liver tumor demonstrated a high tumor mutational burden (103 mutations per megabase) and the genomic amplification of PD-L1, both of which are features that predict response to anti-PD1/PD-L1 immunotherapy. Treatment with nivolumab, an anti-PD1 checkpoint inhibitor, resulted in near complete remission. Yet, he developed new primary cutaneous basal cell carcinomas while receiving immunotherapy and while his metastatic disease showed an ongoing response. His new superficial skin cancer had a lower tumor mutational burden (45 mutations per megabase) than the metastatic disease. Since immunotherapy response rates are higher in patients with more genomically complex tumors, our observations suggest that, in contrast with the premise of earlier treatment is better, which holds true for targeted and cytotoxic therapies, immunotherapy may be better suited to more advanced disease.

PMID: 28788102 [PubMed - in process]

Improvement of Local Cell Delivery Using Helix Transendocardial Delivery Catheter in a Porcine Heart.

Thu, 08/10/2017 - 12:45
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Improvement of Local Cell Delivery Using Helix Transendocardial Delivery Catheter in a Porcine Heart.

Int Heart J. 2017 May 31;58(3):435-440

Authors: Mitsutake Y, Pyun WB, Rouy D, Foo CWP, Stertzer SH, Altman P, Ikeno F

Abstract
Cardiac regeneration strategies using stem cells have shown variable and inconsistent results with respect to patient cardiac function and clinical outcomes. There has been increasing consensus that improving the efficiency of delivery may improve results. The Helix transendocardial delivery system (BioCardia Inc.) has been developed to enable percutaneous transendocardial biotherapeutic delivery. Therefore, we evaluated cell retention using this unique system compared with direct transepicardial injection and intracoronary infusion in an animal model.Twelve healthy swine were used in this study. (18)Fluorodeoxyglucose (FDG)-labeled bone marrow mononuclear cells were delivered via percutaneous transendocardial route using the Helix system (TE group, n = 5), via direct transepicardial injection using a straight 27-gauge needle in an open chest procedure (TP group, n = 4), or via percutaneous intracoronary (IC) infusion (IC group, n = 3). One hour after cell delivery, the distribution of injected cells within the myocardium was assessed by PET-CT. Regions of interest were defined and their signals were compared in each group. Retention rates were calculated as a percentage of the comparing signal.The distribution of injected cells in the myocardium was higher in the TE group (17.9%) than in the TP group (6.0%, versus TE, P < 0.001) and the IC group (1.0%, versus TE, P < 0.001). Consistent with previous reports, there were signal distributions in the lungs, liver, and kidneys in qualitative whole body PET assessment.TE cell delivery using a helical infusion catheter is more efficient in cell retention than either TP delivery or IC delivery using PET-CT analysis.

PMID: 28539564 [PubMed - indexed for MEDLINE]

Epithelial calcineurin controls microbiota-dependent intestinal tumor development.

Thu, 08/10/2017 - 12:45
Related Articles

Epithelial calcineurin controls microbiota-dependent intestinal tumor development.

Nat Med. 2016 May;22(5):506-15

Authors: Peuker K, Muff S, Wang J, Künzel S, Bosse E, Zeissig Y, Luzzi G, Basic M, Strigli A, Ulbricht A, Kaser A, Arlt A, Chavakis T, van den Brink GR, Schafmayer C, Egberts JH, Becker T, Bianchi ME, Bleich A, Röcken C, Hampe J, Schreiber S, Baines JF, Blumberg RS, Zeissig S

Abstract
Inflammation-associated pathways are active in intestinal epithelial cells (IECs) and contribute to the pathogenesis of colorectal cancer (CRC). Calcineurin, a phosphatase required for the activation of the nuclear factor of activated T cells (NFAT) family of transcription factors, shows increased expression in CRC. We therefore investigated the role of calcineurin in intestinal tumor development. We demonstrate that calcineurin and NFAT factors are constitutively expressed by primary IECs and selectively activated in intestinal tumors as a result of impaired stratification of the tumor-associated microbiota and toll-like receptor signaling. Epithelial calcineurin supports the survival and proliferation of cancer stem cells in an NFAT-dependent manner and promotes the development of intestinal tumors in mice. Moreover, somatic mutations that have been identified in human CRC are associated with constitutive activation of calcineurin, whereas nuclear translocation of NFAT is associated with increased death from CRC. These findings highlight an epithelial cell-intrinsic pathway that integrates signals derived from the commensal microbiota to promote intestinal tumor development.

PMID: 27043494 [PubMed - indexed for MEDLINE]

Pure Laparoscopic Living Donor Hepatectomy: Focus on 55 Donors Undergoing Right Hepatectomy.

Wed, 08/09/2017 - 12:45

Pure Laparoscopic Living Donor Hepatectomy: Focus on 55 Donors Undergoing Right Hepatectomy.

Am J Transplant. 2017 Aug 08;:

Authors: Suh KS, Hong SK, Lee KW, Yi NJ, Kim HS, Ahn SW, Yoon KC, Choi JY, Oh D, Kim H

Abstract
Although laparoscopic donor hepatectomy is increasingly common, few centers with substantial experience have reported the results of pure laparoscopic donor right hepatectomy (PLDRH). Here, we report the experiences of 60 consecutive liver donors undergoing pure laparoscopic donor hepatectomy (PLDH), with most undergoing right hepatectomy. None of the 60 donors who underwent PLDH had intraoperative complications and none required transfusions, reoperation, or conversion to open hepatectomy. Forty-five donors who underwent PLDRH between November 2015 and December 2016 were compared with 42 who underwent conventional donor right hepatectomy (CDRH) between May 2013 and February 2014. The total operation time was longer (330.7 vs. 280.0 minutes; P<0.001) and the percentage with multiple bile duct openings was higher (53.3% vs. 26.2%; P=0.010) in the PLDRH group. However, the length of postoperative hospital stay (8.4 vs. 8.2 days; P=0.495) and rate of complications (11.9% vs. 8.9%; P=0.733) and re-hospitalizations (4.8% vs. 4.4%; P=1.000) were similar in both groups. PLDH, including PLDRH, is feasible when performed by a highly experienced surgeon and transplant team. Further evaluation, including long-term results, may support these preliminary findings of comparative outcomes for donors undergoing PLDRH and CDRH. This article is protected by copyright. All rights reserved.

PMID: 28787763 [PubMed - as supplied by publisher]

A different perspective on sofosbuvir-ledipasvir treatment of patients with HCV genotype 1b cirrhosis: the ITAL-C network study.

Wed, 08/09/2017 - 12:45

A different perspective on sofosbuvir-ledipasvir treatment of patients with HCV genotype 1b cirrhosis: the ITAL-C network study.

J Viral Hepat. 2017 Aug 08;:

Authors: Barone M, Iannone A, Shahini E, Ippolito AM, Brancaccio G, Morisco F, Milella M, Messina V, Smedile A, Conti F, Gatti P, Santantonio T, Tundo P, Lauletta G, Napoli N, Masetti C, Termite AP, Francavilla R, Di Leo A, Pesce F, Andriulli A

Abstract
The effectiveness of a 12-week course of sofosbuvir-ledipasvir in treatment-experienced HCV genotype 1b-infected patients with cirrhosis is still under debate. Our primary endpoint was to compare the sustained virological response at post-treatment week 12 (SVR12) of sofosbuvir-ledipasvir in combination with ribavirin for 12 weeks, and sofosbuvir-ledipasvir alone for 24 weeks. This was a prospective observational study that enrolled 424 (195 naive, 229 experienced; 164 treated for 12 weeks with Ribavirin and 260 with sofosbuvir-ledipasvir alone for 24 weeks) consecutive HCV genotype 1b-infected patients with cirrhosis. The SVR12 rates were 93.9% and 99.2% in patients treated for 12 and 24 weeks, respectively (p=0.002). The baseline characteristics of patients treated for 12 weeks were significantly different from those treated for 24 weeks as regards their younger age (p=0.002), prevalence of Child-Pugh class A (p=0.002), lower MELD scores (p=0.001) and smaller number of non-responders (p=0.04). The shorter treatment was significantly associated with a lower SVR12 in univariate and multivariate analysis (p=0.007 and p=0.008, respectively). The SVR rate was unaffected by age, gender, BMI, Child-Pugh class, MELD score or previous antiviral treatment. Patients receiving ribavirin experienced more episodes of ascites and headache but less recurrence of hepatocellular carcinoma (HCC), and were prescribed more diuretics and cardiopulmonary drugs. No patient discontinued treatment. The therapeutic regimen of sofosbuvir-ledipasvir plus ribavirin administered for 12 weeks was less effective than sofosbuvir-ledipasvir alone given for 24 weeks. At odds with European guidelines, the recommended 12-week treatment with sofosbuvir-ledipasvir alone might be suboptimal for this setting of patients. This article is protected by copyright. All rights reserved.

PMID: 28787102 [PubMed - as supplied by publisher]

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