In the nervous system, areas of concentration include the periaqueductal gray matter, rostral ventral medulla (RVM), locus ceruleus, and dorsal horn regions of the spinal cord. Side effects of opioids are numerous and presumably related to systems that contain these receptors (Table 1). Supraspinal effects include euphoria, sedation, sleep disturbance, Palbociclib research buy respiratory depression, cough suppression, pupillary constriction, truncal

rigidity, nausea and vomiting, and temperature dysregulation (hyperthermia or hypothermia). They can also lower seizure threshold by some as yet unknown mechanism. Peripheral effects include bradycardia (although meperidine causes tachycardia), hypotension, constipation and gastroparesis, renal function depression, and pruritus.[3] There is also ample evidence that there is an effect by many opioids on the endocrine and immune systems.[4, 5] Interestingly, unlike the analgesic and euphoric properties, some of these effects do not seem to abate with continued use, including gastrointestinal dysfunction, miosis, and, to some extent, respiratory depression.[3] In the United States, recreational use of opioids was not common until the Civil War years (1861-1865) and became even more widespread when heroin was synthesized in 1874 and marketed as a tonic for many symptoms

including pain. Intravenous heroin use blossomed after World War II, which became most problematic in the 1950s, 60s, and 70s. There has been a resurgence in opioid overuse and addiction because in part of the selleck kinase inhibitor increased use of opioids in the management of non-malignant chronic pain as promoted by Portenoy, Foley, and others since the late 1980s.[6] Opioids clearly lead to tolerance that then often leads to overuse, further tolerance, 上海皓元医药股份有限公司 and addictive behavior. The mechanism of tolerance was initially thought to involve receptor downregulation and/or receptor population/location changes. The process probably revolves around changes in receptor

linkage to second messengers and resulting ion channel effects. In particular, the N-methyl-D-aspartate (NMDA) ion channel complex seems very important because NMDA blockers (eg, ketamine) reduce tolerance (they also seem to reduce central sensitization). Tolerance to analgesic, euphoric, and relaxing effects seems to be inevitable for most patients taking opioids chronically. Depending on the specific opioid medication, tolerance generally occurs after 2 weeks or so of continued use, and potency reduction can eventually be as great as 35-fold.[3] And it is essential to remember that cross-tolerance is the rule in the opioid family – ie, tolerance to 1 opioid generalized to virtually all others with the possible exception of some effects of mixed agonist-antagonist agents. Tolerance to constipation and slowing of gastrointestinal function generally does not seem to happen.

These pigments have characteristic optical properties selleck that result in their variable contribution to the survival of the organism over a range of light conditions. Chlorophyll is an essential molecule in photosynthesis because it harvests light energy and drives electron transfer in the photosystems. Photosynthetic organisms have acquired various chlorophyll molecules during evolution. Most of the oxygenic cyanobacteria use chlorophyll a, but some cyanobacterial groups have acquired chlorophyll b, chlorophyll d, and chlorophyll f in addition to

chlorophyll a (e.g., Chen and Blankenship 2011). Chlorophyll b is used in green plants (Tanaka et al. 1998), and some prasinophytes use an intermediate chlorophyll molecule, Mg-2,4-divinyl-phaeoporphyrin a5 monomethyl ester as their Protein Tyrosine Kinase inhibitor photosynthetic pigment (Six et al. 2005). The heterokontophytes, haptophytes, cryptophytes, and dinoflagellates use chlorophyll c as the accessory pigment of their light-harvesting systems (e.g., Jeffery 1980). The enzymes and pathways for the biosynthesis of chlorophyll, except chlorophylls c, d (Chen and Blankenship 2011) and f, have been elucidated in cyanobacteria and eukaryotic cells. The chlorophyll degradation pathway has been extensively studied and characterized in higher plants. According to a recent study, the first step of chlorophyll degradation is the removal of the Mg ion from the chlorophyll molecule, resulting in the production of pheophytin a

(Hörtensteiner and Kräutler 2011). Pheophytin a is dephytilated to photoporbide a and then the ring is oxidatively opened to form the catabolite, red chlorophyll. However, little is known about the chlorophyll degradation pathway in microalgae because they lack the corresponding chlorophyll degradation enzymes found in higher plants. On the other hand, some degradation products of chlorophylls have been found in marine herbivores feeding on microalgae. 132,173-cyclopheophorbide a enol (cPPB-aE) is one of these degradation products, and produced from pyropheophorbide a by dehydration, which is produced from pheophytin a (Louda et al. 2000, 2008). Kashiyama et al. (2012) 上海皓元 provided

the evidence that cPPB-aE was generated as a detoxified derivative in heterotrophic protists. In this study, we isolated six species of dinoflagellates from various environments and analyzed the composition of the photosynthetic pigments by HPLC. In all six of these species, we detected the chlorophyll a derivative, cPPB-aE, not found in other photosynthetic organisms. Dinoflagellates are interesting photosynthetic organisms from the view point of chloroplast evolution. Most of the dinoflagellates possess red alga-derived chloroplasts (Zhang et al. 1999) and this type of chloroplast is often referred to as the peridinin-type chloroplast, because of the possession of a unique xanthophyll, peridinin (e.g., Strain et al. 1971). Other types of dinoflagellate chloroplasts include the green algal type (Watanabe et al.

On the basis of regression results, we calculated incident rate ratios (IRR), which is the ratio of the incidence rate of impaired ADLs (or IADLs) in individuals with cirrhosis relative to the rate of impairment among individuals without cirrhosis. An IRR > 1 indicates that cirrhosis is associated with increased impairment in functional status compared to their age-matched controls. The model was Autophagy inhibitor adjusted for potential confounders known to be associated with cirrhosis and independently associated with poor functional status (age, sex, race, ethnicity, schooling, net worth, living arrangement, comorbidities, and insurance other than Medicare/Medicaid). Comorbidities

were entered into the model as seven separate binary indicators, one for each comorbid condition. Cognitive

SP600125 impairment was intentionally excluded from this model, because neurocognitive dysfunction may directly result from cirrhosis and thus be a pathway to disability rather than a confounder. To determine whether health care utilization confounded the association between cirrhosis and disability, a sensitivity analysis was performed by creating an interaction variable between presence of cirrhosis and number of physician visits (over the duration of 2 years) and including it as a covariate in the regression model. All analyses were carried out using SAS version 9.1.3 (SAS Institute, Cary, NC) and were adjusted for the matched case–comparator design. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the appropriate institutional review committee. We identified 317 cases with cirrhosis and

951 comparators in the linked HRS–Medicare data. Relative to the comparison group, individuals with cirrhosis were more likely to be Hispanic (P < 0.001), have less education (P = 0.001), and have lower net worth (P = 0.040) (Table 1). The two groups were similar with respect 上海皓元 to the proportion of individuals with insurance other than Medicare/Medicaid (P = 0.091). Individuals with cirrhosis had a greater number of medical comorbidities (P < 0.001) than those in the comparison group, worse perceived health status (P < 0.001), and more severe cognitive impairment (P = 0.001) (Table 2). They also required more than double the health care services (hospitalizations, nursing home stays, and physician visits; P < 0.001 for all) and had significantly higher out-of-pocket medical expenses (P = 0.001) compared to those without cirrhosis, yet only 25% reported receiving home health services. One-quarter of individuals with cirrhosis reported their health status as “poor”, compared to only 11% of those without cirrhosis (P < 0.001 for the trend; Table 2). Individuals with cirrhosis had greater impairment of ADLs compared to the comparison group (P < 0.001), with 38% indicating at least one impaired ADL (Table 3). Overall, 14% of individuals with cirrhosis could perform only 0-2 of their ADLs (i.e., 4-6 impaired ADLs).

Disclosures: Paolo Angeli – Advisory Committees or Review Panels: Sequana Medica Hydroxychloroquine mw The following people have nothing to disclose: Alberto Ferrarese, Alberto

Zanetto, Edoardo Casiglia, Silvano Fasolato, Giovanni Boschetti, Kryssia I. Rodriguez, Elena Nadal, Ilaria Bortoluzzi, Francesco P. Russo, Giacomo Germani, Patrizia Burra, Marco Senzolo BACKGROUND In presence of bacterial resistance and/or failure of first-line antibiotic therapy, ceftriaxone, has poor outcome in patients with SBP. Carbepenems, are often used emperically and may lead to unwarranted drug resistance. The comparative efficacy & safety of Cefepime, compared to car-bepenems is not known in such difficult to treat SBP (DTT-SBP) patients. Such data may prevent emergence of carbanemase resistant strains and develop practice guidelines. PATIENTS Panobinostat clinical trial & METHODS This open label randomized trial (September 2012-December 2013) [Clinical trials- NCT01852630] included decompensated cirrhotics with DTT-SBP, defined as i). hospital acquired SBP (> 48 h of admission), ii). microbial resistance or inadequate response to first-line antibiotic (reduction in ANC by < 25% at 48 h), or iii). recurrence of SBP. These patients were randomized to

Cefepime IV 1g t.i.d (Gr A) or Imipenem IV 1g t.i.d (Gr. B). Diagnostic paracentesis was done at baseline and response tap at 48 h & 5 days for early response (reduction in ANC by > 25% and negative cultures at 48 h) or resolution of SBP (< 250 cu/mm. ANC at day 5) [primary end point]. Persistence of SBP at day 5 constituted treatment failure. Secondary end-point was survival at 3 month. RESULTS Of 957 diagnostic paracentesis among 1200 admitted decompensated cirrhotics, 253 (26.4%) had SBP. 175 (69.2%) with DTT-SBP received Cefepime (Gr..A;n-88) or Imipenem (Gr. B;n-87). Their baseline demographics, etiology, clinical, disease severity and ascitic fluid parameters

MCE were comparable. Main cause of DTT-SBP was resistance to first-line antibiotics (39% Gr.A and 48% Gr.B). Both early response (58.6% Gr. A vs. 51.7% Gr. B; p-0.36) and SBP resolution rates (65.5% vs. 60.9%; p-0.53) were comparable, no difference in mortality at week 2, month 1 & 3 (38.6% vs. 37.9%; p-0.92). Early response at 48 h (associated with absence of AKI & septic shock) was only independent predictor of SBP resolution(Odd’s ratio-18.95). Progression of HE & progressive /persistant AKI predicted high mortality & treatment failure. Hospital acquired DTT-SBP had higher mortality than others (39.7% vs.17.3%;p<0.01). Septic shock was main pretermi-nal event (32.3% Gr.A vs.35.6% Gr.B). Patients who died had higher MELD (28 vs 24) and lower SBP resolution rate (p-0.001). Baseline AKI (OR-5.3), pneumonia(OR-7.1),septic shock (OR-6.4) and failure of SBP resolution (OR-14.3) were independent predictors of 3 month mortality.

Our outcome data provide population-based confirmation of most findings from prior single-center experiences

with PSC and ASC and perhaps a broader view of outcomes from a less severe population with AIH. We used available histology and cholangiography data to isolate cases of ASC and compare them to their PSC and AIH peers. In ASC patients, the prevalence of comorbid IBD, positive ANCA serology, and elevated gamma-glutamyl transpeptidase find more levels most closely mirrored that in PSC patients, whereas the prevalence of positive ANA, F-actin, and LKM serologies and non-IBD comorbid autoimmune diseases in ASC patients most closely matched that in AIH patients. Outcomes were similar in the PSC and ASC groups, Acalabrutinib manufacturer with 38% and 42% of the patients, respectively, progressing to complicated liver disease. Among AIH patients, only 18% developed these complications. Some of the differences in PSC, ASC, and AIH did not reach statistical significance, however, likely because of the low power from the small sample size, which is inherent in studies of rare pediatric diseases. At a major referral center, cholangiography was performed prospectively in all pediatric patients who met the criteria for AIH, and ASC was diagnosed in 49% of cases.[4] Similarly to our data, ASC patients were more likely to be ANCA-positive and to have IBD than AIH patients. The

10-year transplant-free survival rate 上海皓元 was 65% for the ASC patients and 100% for

the AIH patients, and this demonstrated a trend toward poorer outcomes in patients with cholangiopathy that was similar to the results of our study. Our outcome data support the hypothesis that the risk of progression to complicated liver disease may depend most on the severity of cholangiopathy present rather than the specific underlying diagnosis. We feel that the characterization of patients as having ASC rather than PSC with overlap features or AIH with overlap features is important. Few studies of IMLDs have included a separate category of ASC, and a reliable consensus diagnostic definition does not exist.[27, 28] Traditionally, in studies that include patients with overlap features, the diagnosis (PSC or AIH) that is primary and the diagnosis that represents the overlap portion of the phenotype are based on whichever is discovered first. We do not believe that this method is valid. As other authors have shown, screening all patients for cholangiopathy in AIH,[4] as recommended for pediatric patients,[29] or IBD[30-32] reveals cases that are not evident on the basis of laboratory studies or symptoms. This suggests that the sclerosing cholangitis portion of the phenotype may be present from the outset and is not yet clinically apparent. Additionally, we are not aware of a way of distinguishing a patient with AIH and overlap from a patient with both AIH and PSC if the full diagnostic criteria can be met for both diseases.

HCV recurrence after LT is almost universal and severity depends on several host, viral, donor, and transplant factors. Graft and patient survival are significantly reduced after LT in HCV-positive recipients.[1-4]

A subset of patients (2%) may develop Dabrafenib molecular weight post-LT cholestatic hepatitis C, which is characterized by persistent cholestasis of at least 4 weeks in duration, high HCV RNA levels, hepatocyte ballooning, rapid progression to graft failure, and, in the absence of biliary and hepatic artery complications, sepsis and drug-related cholestasis.[5] The overall outcome of antiviral therapy in this group of patients is suboptimal, although it can be successfully pursued in select patients. The unique challenges of HCV treatment in this population include management of AEs, adjusting immunosuppressive regimens because of

DDIs in those on direct-acting antivirals (DAAs), and monitoring for graft rejection. Although selection criteria for treatment of chronic HCV in LT patients is variable, antiviral therapy is generally considered in those who develop significant or progressive recurrent HCV disease, as defined by moderate-to-severe necroinflammatory activity (grade 3-4) and/or significant fibrosis (stage 2-4) on histologic evaluation.[6] Treatment of recurrent HCV in LT recipients, particularly with successful viral eradication, is associated with increased graft and patient survival.[7] In various experiences published, the majority of patients included VX-770 nmr were genotype 1, had a reduced dose of RBV (400-800 mg/day) and/or PEG-IFN, and had use of ESAs. The pooled estimate of sustained viral response (SVR) from prospective

studies was 24%-40%, and virologic relapse was 21%-43%. Biochemical and histological responses were observed in approximately 50% of treated patients.[8, 9] Two thirds of 上海皓元医药股份有限公司 patients required dose reductions of either PEG-IFN or RBV and one fourth discontinued treatment early.[2] The approval of two protease inhibitors, telaprevir and boceprevir, has ushered in a new era of HCV treatment. In those with chronic HCV, one of these have been used in combination with PEG-IFN and RBV, and the regimens have enhanced response rates and shortened duration of therapy, whereas they have added to the side-effect profile.[10] Cost of treatment for boceprevir triple therapy is variable, and in instances of treatment duration similar to this case, the expense of therapy is approximately $71,000.[11] However, there are other expenses of close monitoring and frequently following immunosuppression drug levels, which then increase the cost relative to a patient who has not had LT. An incremental rate and degree of anemia has been observed with both TT regimens, which does present a challenge in the transplant recipients who are prone to anemia.

, MD (AASLD Postgraduate Course, Early Morning Workshops, Parallel Session) Consulting: GlaxoSmithKline, tibotec Grant/Research Support: Gilead, vertex, Ocera Forcione,

David G., MD (AASLD/ASGE Endoscopy Course) Nothing to disclose Content of the presentation does not include discussion of off-label/investigative use of medicine(s), medical devices or procedure(s) Forns, Xavier, MD (Early Morning Workshops) Consulting: Tibotec/Jansen, MSD, Boheringher Ingelheim Grant/Research Support: Roche, MSD, Gilead Content of the presentation does not include discussion of off-label/investigative use of medicine(s), medical devices or procedure(s) Fox, Ira J., MD (AASLD/NASPGHAN Pediatric Symposium) Advisory Committees or Review Panels: Regenerative learn more Medical Solutions Content of the presentation does not include discussion of off-label/investigative use of medicine(s), medical devices or procedure(s) Franco, Jose, MD (Meet-the-Professor Luncheon) Nothing to disclose Content of the presentation

does not include discussion of off-label/investigative use of medicine(s), medical devices or procedure(s)

Frenette, DAPT Catherine T., MD (Meet-the-Professor Luncheon) Speaking and Teaching: Onyx, Salix, Gilead Content of the presentation does not include discussion of off-label/investigative use of medicine(s), medical devices or procedure(s) Fried, Michael W. MCE (Parallel Session) Consulting: Genentech, Merck, Abbvie, Vertex, Janssen, Bristol Myers Squibb, Gilead Grant/Research Support: Genentech, Merck, AbbVie, Vertex, Janssen, Bristol Myers Squibb, Gilead Patent Held/Filed: HCCPlex Fried, Michael W., MD (AASLD Postgraduate Course, HCV Symposium) Advisory Committees or Review Panels: GlaxoSmithKline Consulting: Roche/Genentech, Janssen, Vertex, Merck, Bristol Myers Squibb, Abbott, Merck, Gilead, Novartis Grant/Research Support: Roche/Genentech, Janssen, Vertex, Merck, Bristol Myers Squibb, Abbott, Merck, Gilead Friedland, Shai, MD (AASLD/ASGE Endoscopy Course) Nothing to disclose Content of the presentation does not include discussion of off-label/investigative use of medicine(s), medical devices or procedure(s) Friedman, Joshua, MD, PhD (Early Morning Workshops, Parallel Session) Nothing to disclose Friedman, Lawrence S.

Therefore, primary cholangiocytes from the double-transgenic mice are capable of adopting a myofibroblast phenotype in vitro, as has been reported for mouse and human cholangiocytes by others.7, 34, 35 To determine whether EMT occurs in vivo, we induced liver fibrosis http://www.selleckchem.com/products/Maraviroc.html in Alfp-Cre × Rosa26-YFP mice by BDL. Sirius Red staining demonstrated progressively increasing hepatic fibrosis at 2, 4, and 8 weeks post-BDL (Fig. 3; Supporting Information Fig. 2). At these timepoints (Figs. 4, 5; Supporting Information Fig. 3), there was no evidence of YFP colocalization with the mesenchymal markers S100A4, vimentin, α-SMA, or procollagen 1α2,

despite significant peribiliary staining for these markers compared with untreated controls (Supporting Information Figs. 1C, 5). Occasional YFP-negative, S100A4-positive cells appeared to infiltrate bile ducts (Fig. 5D); these may be lymphocytes or monocytes, which are known to express S100A4.36-38 Despite significant hepatic stellate cell accumulation by 8 weeks post-BDL, no YFP colocalization with the HSC marker desmin was noted (Fig. 7). These data indicate that EMT does not occur at these timepoints in the mouse BDL model. To corroborate these findings, we exposed mice to CCl4, a hepatotoxin that induces hepatic (though nonbiliary-specific) fibrosis. Although

progenitor cell proliferation has been described in this model, the phenotype depends mostly on hyperplasia of mature cholangiocytes.39, 40 After 3 weeks of Selleckchem Dorsomorphin treatment the increase in fibrosis compared to controls was modest but statistically significant (Supporting Information Fig. 2). There was no evidence of YFP costaining with mesenchymal markers noted in any of the animals despite significant peribiliary staining (Fig. 7; Supporting Information Figs. 4, 5). Neither the CCl4 model nor the BDL model produced evidence of marker colocalization in YFP-labeled hepatocytes, consistent with a recent study suggesting that hepatocyte EMT does not occur.8 BDL is the most widely used rodent model of biliary

fibrosis, although it is an imperfect model for many human diseases because the phenotype results from marked proliferation MCE of mature cholangiocytes (primarily from the large bile ducts) rather than a ductular reaction, which is proposed to involve activation of bipotential progenitor cell populations (oval cells).39, 41, 42 The ductular reaction is a dominant feature of several fibrosing biliary diseases, including biliary atresia.43, 44 To assess the possibility that EMT occurs in cholangiocyte precursors, before the expression of K19, we used the DDC dietary model, which results in an oval cell response with a marked ductular reaction and sclerosing cholangitis.45, 46 Mice fed the DDC diet for 2 weeks developed moderate fibrosis (data not shown) compared to mice fed normal chow. At 3 weeks of treatment, fibrosis was more marked and roughly equivalent by Sirius Red staining to mice 2 weeks post-BDL (Fig. 3).

Augusta and Oscar ‘S’ were related and both had a history of nose bleeds, especially when they were younger; in both their families there had been ‘bleeders’. Augusta had already given birth to 11 children when Dr von Willebrand first saw her in 1924. By then, three daughters had died of bleeding complications (two from gastrointestinal bleeds at 2 years old and one at age 4 after a tongue bite). Hjördis, at that time aged 5 years, had among other bleeding problems been in bed for 10 weeks after a laceration to her lip and had also experienced a bad ankle bleed. She had a much prolonged Duke’s bleeding time

(according to Duke), while her coagulation time and clot retraction PF-6463922 order were normal. Her capillary fragility test was positive and platelet numbers were normal. von Willebrand ended his paper by stating the finding of a positive capillary resistance test does not necessarily mean that there is an alteration in the capillary vessel walls. He thought the pathogenesis of the bleeding was caused by platelet dysfunction, in combination with a general lesion of the vessel wall. Hjördis

bled to death at her fourth menstrual bleeding when she was 14 years old (Figs 3 and 4). When we first met the family in 1957, Åland was a poor country recovering from the Second World War. Professor Inga Marie Nilsson, from Malmö, was a guest researcher Rapamycin at Professor Erik Jorpe’s Medical Chemistry laboratory at Karolinska Institutet and I was employed at the laboratory. We had by then already investigated six Swedish families with pseudo-haemophilia and found that the probands and one parent, as well as several family members, had decreased levels of factor VIII, (FVIII) (at that time called AHG) and most had a prolonged bleeding time [2,3]. The probands had a

very prolonged bleeding time and an AHG level between 1% and 10% of normal. Infusion of human fraction I-0 (a purified fraction of Cohn Fraction I) corrected both the bleeding time and AHG deficiency and the capillary bleedings. We deduced by different in vivo experiments that there must be a new factor [4–7]. I thought the probands were homozygotes for the trait, but it was not until Zimmerman and co-workers developed a rabbit antibody to the FVIII/VWF PAK5 (FVIIIR:Ag) complex that real progress could be made. Many authors had by this time described similar patients with a severe haemorrhagic disorder (low AHG level and prolonged bleeding time) and had tried to find out if it was the same condition as that described by von Willebrand. Larrieu and Soulier suggested the name von Willebrand’s syndrome, which later became VWD. We, however, considered it distinguishable from von Willebrand’s thrombopathy or von Willebrand-Jurgens thrombopathy, as the German researchers preferred to call it [3]. However, Professor Jorpes came from Kökar (Fig. 1), another island in the Åland archipelago and he wanted us to investigate the Åland patients.

Most patients (n = 77, 72%) were treated with chemoembolization (cTACE versus DEB-TACE: n = 56 versus 21), while 28% patients (n = 30) received TAE only. Between TACE 1 and TACE 2, 32 patients suffered from a Child-Pugh score increase by at least 1 point, while 59 patients showed no change and 16 patients showed a decrease of the Child-Pugh

score by at least 1 point. Prior to the second TACE, the majority of patients (n = 72, 67%) had Child-Pugh A cirrhosis. Overall, the median number of TACE interventions was 3 (range 2-12). The median time interval between the first and second TACE was 45 days (range 13-90). Wnt inhibitor In the validation cohort (n = 115), the majority of patients were at BCLC stage B (n = 79, 69%) and 9 patients

(8%) had received an antitumor therapy prior the first TACE including liver resection (n = 7) and RFA (n = 2). In all, 114 patients were treated with cTACE with lipiodol and epirubicin, and one Deforolimus patient received DEB-TACE. Between TACE 1 and TACE 2, 27 patients suffered from a Child-Pugh score increase by at least 1 point, while 66 patients showed no change and 18 patients showed a decrease of the Child-Pugh score by at least 1 point. Prior the second TACE, most patients had Child-Pugh A cirrhosis (n = 69, 62%). Overall, the median number of TACE interventions was 3 (range 2-20). The median time interval between the first and second TACE was 42 days (range 26-85). In the training cohort (n = 107), 88% of the patients (n = 94) died during the observational period between January 1999 and December 2011, and 12% patients (n = 13) were still alive (n = 8) or lost to follow-up (n = 5). The median OS of the whole training population was 16.2 months (95% CI, 13.4-19.0) (Table 2). The median time of follow-up was 70.5 months. Of the patient characteristics (Table 1), only Child-Pugh stage (pre-TACE 2, P = 0.004), Loperamide tumor extent (pre-TACE 1, P = 0.047), and CRP-levels (pre-TACE 2, P = 0.001) had a significant impact

on OS (Table 2). Tumor response variables like radiologic tumor response (median OS: response versus nonresponse: 18.8 versus 9.3 months [95% CI: 14.2-23.4 versus 7.3-11.4 months], P = 0.001), as well as an AFP decrease >50% (median OS: AFP response versus no AFP response versus baseline AFP <200 kU/L: 16.7 versus 8.5 versus 16.7 months [95% CI: 12.1-21.3 versus 3.4-13.6 versus 12.5-20.9 months], P = 0.005) from baseline were significantly associated with a better outcome. We next evaluated the impact of liver function deterioration between pre-TACE-1 and pre-TACE-2 on patient outcome. Of all liver function-related laboratory parameters, only the quartiles of AST increase were associated with a worse survival (data not shown). Subsequent spline-based analysis of the influence of AST increase on the hazard ratio of death revealed a clear sigmoid shape (Supporting Fig. 1). An HR of 1.