A number of studies have shown that the limb-inducing signal originates in the axial mesoderm and is relayed from there to the LPM. In mouse, chick, and zebrafish, this signal is thought to be retinoic acid (RA), the bulk of which is synthesized by retinaldehyde dehydrogenase type2 (RALDH2) in early somites and the LPM.8–15 With respect to downstream effectors,

molecular studies have clearly shown that RA signaling from the zebrafish somitic mesoderm leads to the expression of the wnt2ba gene check details in the intermediate mesoderm, which then signals to the LPM and triggers tbx5 expression. Tbx5 is required for Fgf signaling in the fin bud that leads to prdm1 expression, which in turn triggers fgf10 and bmp2b expression.7, 16 In contrast, the identity of an initial hepatic inducer in vertebrates has yet to be validated genetically. In the first report to isolate a single gene regulating vertebrate liver Vadimezan in vivo specification, Ober et al.17 characterized an interesting zebrafish mutant called prometheus (prt). In prt embryos, the liver is absent or greatly reduced in size at 50 hours post-fertilization but may start to develop and “catch up” to normal size at a later stage. Positional cloning and further analysis revealed that the prt mutation

altered the wnt2bb gene (the second wnt2b gene) and that prt/wnt2bb was expressed in restricted bilateral domains in the LPM directly adjacent to the liver-forming endoderm. Subsequently, Shin et al.18 reported that Fgf and Bmp signaling pathways play important roles in zebrafish liver specification and raised the possibility that these molecules act downstream of Wnt2bb. However, the molecules that act upstream of Wnt2bb during liver specification 上海皓元 remain to be identified. In this study, we carried

out a detailed characterization of our medaka hio mutants, whose signature phenotypes are a small liver and no pectoral fins. Our results define hio as a missense mutation of the raldh2 gene, the expression of which likely results in a nonfunctional RALDH2 protein that cannot support fin development. We also show that the hio mutation causes a retardation of liver budding that resembles that observed in zebrafish prt mutants, and that wnt2bb expression is undetectable in hio LPM. Our data suggest that the role of RA signaling in the specification of both liver and fins is to induce expression of wnt2b family genes. AP, anteroposterior; atRA, all-trans retinoic acid; ck19, cytokeratin19; cp, ceruloplasmin; E, embryonic day; hio, hiohgi; LPM, lateral plate mesoderm; MO, Morpholino; mRNA, messenger RNA; nls, neckless; nof, no-fin; PED6, N-([6-(2,4-dinitro-phenyl)amino]hexanoyl)-1-palmitoyl-2-BODIPY-FL-pentanoyl-sn-glycero-3-phosphoethanolamine; prt, prometheus; RA, retinoic acid; RALDH2, Retinaldehyde dehydrogenase type2. Medaka were raised and maintained under standard laboratory conditions at approximately 27°C.

To decrease the burden of the cost on patient, family and the government, education plays the most important role. We suggest that we send a trained

team of physician and nurses to the deprived villages and cities instead of waiting for the patient to refer to our Care Center. “
“Summary.  Postauthorization safety surveillance of factor VIII (FVIII) concentrates is essential for assessing rare adverse event incidence. We determined safety and efficacy of ADVATE [antihaemophilic factor (recombinant), plasma/albumin-free method, (rAHF-PFM)] during routine clinical practice. Subjects with differing haemophilia A severities and medical histories were monitored during 12 months of prophylactic and/or on-demand therapy. Among 408 evaluable subjects, KPT-330 solubility dmso 386 (95%) received excellent/good efficacy ratings for all on-demand assessments; the corresponding number for subjects with previous FVIII inhibitors

was 36/41 (88%). Among 276 evaluable subjects receiving prophylaxis continuously in the study, 255 (92%) had excellent/good ratings for all prophylactic assessments; the corresponding Ipilimumab clinical trial number for subjects with previous FVIII inhibitors was 41/46 (89%). Efficacy of surgical prophylaxis was excellent/good in 16/16 evaluable procedures. Among previously treated patients (PTPs) with >50 exposure days (EDs) and FVIII ≤2%, three (0.75%) developed low-titre inhibitors. Two of these subjects had a positive inhibitor history; thus, the incidence of de novo inhibitor formation in PTPs with FVIII ≤2% and no inhibitor history was 1/348 (0.29%; 95% CI, 0.01–1.59%). A PTP with moderate haemophilia developed a low-titre inhibitor. High-titre inhibitors were reported in a PTP with mild disease (following surgery), a previously untreated patient (PUP) with moderate disease (following surgery) and a PUP with severe disease. The

favourable benefit/risk profile of rAHF-PFM previously documented in prospective clinical trials has been extended to include a broader range of haemophilia patients, many of whom would have been ineligible for registration studies. “
“Summary.  Although the funding of rare diseases such as haemophilia in developing countries MCE公司 remains a low priority, pressures on the funding of haemophilia treatment are also emerging in developed economies affected by the global economic downturn and the other demands on health care budgets. This is leading advisory bodies and payers alike to explore the tools of Health Technology Assessment (HTAs) in deriving recommendations for reimbursement policies. In particular, the use of cost utility analysis (CUA) in deriving costs per quality adjusted life year (QALY) for different interventions is being used to rank interventions in order of priorities relative to a threshold cost per QALY. In these exercises, rare chronic disorders such as haemophilia emerge as particularly unattractive propositions for reimbursement, as the accepted methodology of deriving a CUA. For e.g.

To decrease the burden of the cost on patient, family and the government, education plays the most important role. We suggest that we send a trained

team of physician and nurses to the deprived villages and cities instead of waiting for the patient to refer to our Care Center. “
“Summary.  Postauthorization safety surveillance of factor VIII (FVIII) concentrates is essential for assessing rare adverse event incidence. We determined safety and efficacy of ADVATE [antihaemophilic factor (recombinant), plasma/albumin-free method, (rAHF-PFM)] during routine clinical practice. Subjects with differing haemophilia A severities and medical histories were monitored during 12 months of prophylactic and/or on-demand therapy. Among 408 evaluable subjects, BI 2536 in vivo 386 (95%) received excellent/good efficacy ratings for all on-demand assessments; the corresponding number for subjects with previous FVIII inhibitors

was 36/41 (88%). Among 276 evaluable subjects receiving prophylaxis continuously in the study, 255 (92%) had excellent/good ratings for all prophylactic assessments; the corresponding selleck chemicals number for subjects with previous FVIII inhibitors was 41/46 (89%). Efficacy of surgical prophylaxis was excellent/good in 16/16 evaluable procedures. Among previously treated patients (PTPs) with >50 exposure days (EDs) and FVIII ≤2%, three (0.75%) developed low-titre inhibitors. Two of these subjects had a positive inhibitor history; thus, the incidence of de novo inhibitor formation in PTPs with FVIII ≤2% and no inhibitor history was 1/348 (0.29%; 95% CI, 0.01–1.59%). A PTP with moderate haemophilia developed a low-titre inhibitor. High-titre inhibitors were reported in a PTP with mild disease (following surgery), a previously untreated patient (PUP) with moderate disease (following surgery) and a PUP with severe disease. The

favourable benefit/risk profile of rAHF-PFM previously documented in prospective clinical trials has been extended to include a broader range of haemophilia patients, many of whom would have been ineligible for registration studies. “
“Summary.  Although the funding of rare diseases such as haemophilia in developing countries 上海皓元医药股份有限公司 remains a low priority, pressures on the funding of haemophilia treatment are also emerging in developed economies affected by the global economic downturn and the other demands on health care budgets. This is leading advisory bodies and payers alike to explore the tools of Health Technology Assessment (HTAs) in deriving recommendations for reimbursement policies. In particular, the use of cost utility analysis (CUA) in deriving costs per quality adjusted life year (QALY) for different interventions is being used to rank interventions in order of priorities relative to a threshold cost per QALY. In these exercises, rare chronic disorders such as haemophilia emerge as particularly unattractive propositions for reimbursement, as the accepted methodology of deriving a CUA. For e.g.

Eligibility for shortened treatment duration is based on achieving undetectable HCV RNA early during treatment. It is unclear whether a detected HCV RNA level that is below the assay lower limit of quantitation (detectable/BLOQ) is comparable to an undetectable HCV RNA level for RGT decision making. We analyzed data from boceprevir and telaprevir clinical trials to obtain a comprehensive understanding of the frequency and clinical relevance of detectable/BLOQ HCV RNA measurements. In Phase 3 trials P05216 (boceprevir), C216 (telaprevir), and 108 (telaprevir),

detectable/BLOQ levels were reported for approximately 10%-20% of all on-treatment HCV RNA measurements. In P05216 and C216, subjects with detectable/BLOQ HCV RNA, on average, had a reduced sustained virologic response (SVR) rate compared with subjects with undetectable HCV RNA at the same on-treatment timepoint. At key RGT timepoints (week check details 8 for boceprevir, week 4 for telaprevir), subjects with detectable/BLOQ HCV RNA had an approximately 20% lower SVR rate compared with subjects with undetectable HCV RNA, and this difference widened for later on-treatment timepoints. A similar trend was observed for Study 108, but the differences in SVR rates were modest, Pritelivir potentially explained by a higher frequency of reported detectable/BLOQ results. Analyses of Phase

2 boceprevir and telaprevir trials indicated subjects with detectable/BLOQ HCV RNA at RGT timepoints benefited from extended treatment duration. Conclusion: During boceprevir- and telaprevir-based treatment, subjects with detectable/BLOQ HCV RNA had a reduced virologic response compared with subjects with undetectable HCV RNA. Eligibility for shortened treatment duration should be based on achieving undetectable HCV RNA (i.e., HCV RNA not detected) at RGT decision timepoints. (Hepatology 2012) Analysis of hepatitis C virus (HCV) RNA levels in plasma or serum is critical for assessing the efficacy

of antiviral therapy for chronic HCV infection. The primary goal of anti-HCV therapy medchemexpress is achievement of a sustained virologic response (SVR), traditionally defined as undetectable serum or plasma HCV RNA 24 weeks following completion of treatment. The achievement of SVR is generally interpreted as a viral “cure” and is considered a validated surrogate of clinical efficacy because it predicts long-term clinical benefit.1, 2 The use of on-treatment HCV RNA measurements to guide treatment duration, termed response-guided therapy (RGT), has become a key component of patient management.3–5 During HCV treatment a rapid HCV RNA decline may justify a shorter treatment duration without significantly compromising efficacy. On the other hand, a slow HCV RNA decline may warrant an extended duration of treatment to maximize the chances of achieving SVR, and little or no HCV RNA decline may warrant early treatment cessation due to futility.

Eligibility for shortened treatment duration is based on achieving undetectable HCV RNA early during treatment. It is unclear whether a detected HCV RNA level that is below the assay lower limit of quantitation (detectable/BLOQ) is comparable to an undetectable HCV RNA level for RGT decision making. We analyzed data from boceprevir and telaprevir clinical trials to obtain a comprehensive understanding of the frequency and clinical relevance of detectable/BLOQ HCV RNA measurements. In Phase 3 trials P05216 (boceprevir), C216 (telaprevir), and 108 (telaprevir),

detectable/BLOQ levels were reported for approximately 10%-20% of all on-treatment HCV RNA measurements. In P05216 and C216, subjects with detectable/BLOQ HCV RNA, on average, had a reduced sustained virologic response (SVR) rate compared with subjects with undetectable HCV RNA at the same on-treatment timepoint. At key RGT timepoints (week Bioactive Compound Library 8 for boceprevir, week 4 for telaprevir), subjects with detectable/BLOQ HCV RNA had an approximately 20% lower SVR rate compared with subjects with undetectable HCV RNA, and this difference widened for later on-treatment timepoints. A similar trend was observed for Study 108, but the differences in SVR rates were modest, Cilomilast solubility dmso potentially explained by a higher frequency of reported detectable/BLOQ results. Analyses of Phase

2 boceprevir and telaprevir trials indicated subjects with detectable/BLOQ HCV RNA at RGT timepoints benefited from extended treatment duration. Conclusion: During boceprevir- and telaprevir-based treatment, subjects with detectable/BLOQ HCV RNA had a reduced virologic response compared with subjects with undetectable HCV RNA. Eligibility for shortened treatment duration should be based on achieving undetectable HCV RNA (i.e., HCV RNA not detected) at RGT decision timepoints. (Hepatology 2012) Analysis of hepatitis C virus (HCV) RNA levels in plasma or serum is critical for assessing the efficacy

of antiviral therapy for chronic HCV infection. The primary goal of anti-HCV therapy 上海皓元 is achievement of a sustained virologic response (SVR), traditionally defined as undetectable serum or plasma HCV RNA 24 weeks following completion of treatment. The achievement of SVR is generally interpreted as a viral “cure” and is considered a validated surrogate of clinical efficacy because it predicts long-term clinical benefit.1, 2 The use of on-treatment HCV RNA measurements to guide treatment duration, termed response-guided therapy (RGT), has become a key component of patient management.3–5 During HCV treatment a rapid HCV RNA decline may justify a shorter treatment duration without significantly compromising efficacy. On the other hand, a slow HCV RNA decline may warrant an extended duration of treatment to maximize the chances of achieving SVR, and little or no HCV RNA decline may warrant early treatment cessation due to futility.

Eligibility for shortened treatment duration is based on achieving undetectable HCV RNA early during treatment. It is unclear whether a detected HCV RNA level that is below the assay lower limit of quantitation (detectable/BLOQ) is comparable to an undetectable HCV RNA level for RGT decision making. We analyzed data from boceprevir and telaprevir clinical trials to obtain a comprehensive understanding of the frequency and clinical relevance of detectable/BLOQ HCV RNA measurements. In Phase 3 trials P05216 (boceprevir), C216 (telaprevir), and 108 (telaprevir),

detectable/BLOQ levels were reported for approximately 10%-20% of all on-treatment HCV RNA measurements. In P05216 and C216, subjects with detectable/BLOQ HCV RNA, on average, had a reduced sustained virologic response (SVR) rate compared with subjects with undetectable HCV RNA at the same on-treatment timepoint. At key RGT timepoints (week check details 8 for boceprevir, week 4 for telaprevir), subjects with detectable/BLOQ HCV RNA had an approximately 20% lower SVR rate compared with subjects with undetectable HCV RNA, and this difference widened for later on-treatment timepoints. A similar trend was observed for Study 108, but the differences in SVR rates were modest, Selleckchem Torin 1 potentially explained by a higher frequency of reported detectable/BLOQ results. Analyses of Phase

2 boceprevir and telaprevir trials indicated subjects with detectable/BLOQ HCV RNA at RGT timepoints benefited from extended treatment duration. Conclusion: During boceprevir- and telaprevir-based treatment, subjects with detectable/BLOQ HCV RNA had a reduced virologic response compared with subjects with undetectable HCV RNA. Eligibility for shortened treatment duration should be based on achieving undetectable HCV RNA (i.e., HCV RNA not detected) at RGT decision timepoints. (Hepatology 2012) Analysis of hepatitis C virus (HCV) RNA levels in plasma or serum is critical for assessing the efficacy

of antiviral therapy for chronic HCV infection. The primary goal of anti-HCV therapy medchemexpress is achievement of a sustained virologic response (SVR), traditionally defined as undetectable serum or plasma HCV RNA 24 weeks following completion of treatment. The achievement of SVR is generally interpreted as a viral “cure” and is considered a validated surrogate of clinical efficacy because it predicts long-term clinical benefit.1, 2 The use of on-treatment HCV RNA measurements to guide treatment duration, termed response-guided therapy (RGT), has become a key component of patient management.3–5 During HCV treatment a rapid HCV RNA decline may justify a shorter treatment duration without significantly compromising efficacy. On the other hand, a slow HCV RNA decline may warrant an extended duration of treatment to maximize the chances of achieving SVR, and little or no HCV RNA decline may warrant early treatment cessation due to futility.

Our results indicate that the physiological status of females (both moulting and reproductive status) influences the individual’s decisions, and thus, the outcome of pairing in the amphipod G. pulex. The degree

of size-assortative pairing is likely to vary across the female Dabrafenib moult cycle, being stronger when females are closer to the moult. Size-assortative pairing may be overestimated in pooling data procedures without any consideration of the female moulting status. Moulting and pairing decision could not be dissociated, and moulting should be controlled for when examining the behavioural ecology of mate choice decisions in crustaceans. We would like to thank A. Guvenatam for his help during the experiments, A. Godon for his help in figure designing and R. Elwood, V. Hayssen, M. Thiel and an anonymous referee for their constructive comments that helped selleck chemical to improve the paper. We are greatly indebted to F. Graf for the valuable discussions. This study complies with the current laws of France. “
“Egg features are key components

of egg quality that can influence future prospects of survival. Past studies have outlined the importance of egg size, but little is known about egg shape variation, differences among females, influence of external factors on shape and the importance of shape for hatchability. In this study of the grey partridge Perdix perdix, we examined shape characteristics (elongation and three indices derived from photographs). There was a significant individual difference in egg shape among females, and shape was influenced by the position in the laying order, with last-laid eggs being less elongated. Egg shape indices were not influenced by food

quality (experiment with two diets differing in β-carotene content), nor by an immune challenge (experiment with two groups differing in Newcastle disease virus vaccine treatment). Eggs laid by females in poorer health conditions were more asymmetric and more pointed. Egg hatchability was higher for intermediate egg elongation values. “
“School of Environmental and Life Sciences, University of Newcastle, Callaghan, NSW, Australia Hydrological regimes strongly influence ecological processes in river basins. Yet, the impacts of management regimes are unknown for 上海皓元医药股份有限公司 many freshwater taxa in highly regulated rivers. We used radio-telemetry to monitor the movement and activity of broad-shelled river turtles Chelodina expansa to infer the impact of current water management practices on turtles in Australia’s most regulated river – the Murray River. We radio-tracked C. expansa to (1) measure the range span and examine the effect of sex, size and habitat type on turtle movement, and (2) examine habitat use within the river channel and its associated backwaters. C. expansa occupied all macro habitats in the river (main channel, backwater, swamp and connecting inlets). Within these habitats, females occupied discrete home ranges, whereas males moved up to 25 km.

This has important implications for 3-dimensional cell cultures when estimating per cell performance in potential cell therapy applications. Disclosures: The following people have nothing to disclose:

Eloy Erro, Hyun Woo Yu, Dominic Davis, James T. Bundy, Aurelie Le lay, Humphrey Hodgson, Barry Fuller, Clare Selden Background. Though ammonia is implicated as a toxin central to the pathogenesis of hepatic encephalopathy (HE) and cerebral edema (CE) in acute liver failure (ALF), there is limited data on the clinical relevance of point of care (POC) measurement of its arterial concentration (AAC), and changes with therapeutic interventions. In a large cohort of patients with ALF we examined the clinical associations of AAC and utility in prediction of DMXAA nmr complications. Patients and Methods Patients with ALF admitted to a single intensive therapy unit (ITU) over a 10 year period were studied. AAC was measured on and after admission using the POC PocketChem BA Blood Ammonia Analyser. Its relation to development of HE, CE and survival was assessed. Changes

in AAC following introduction of hemofiltration for renal replacement and after liver transplan tation (LT) were examined, as was relation to progression of HE and development of CE. BIBW2992 manufacturer Results 729 patients of median age 37 years (IQR 28-49) were studied; 59% were female. 413 (57%) had acetaminophen (APAP) and 316 medchemexpress (43%) non- APAP etiologies. 496 (68%) had or developed HE grade ≥3 (high-grade), in 81 (16%) with evidence of CE. 400 survived with medical management alone, 176 underwent LT and 155 died without LT. Median AAC was 102 (66-156) in those with

high-grade HE and 73 (45-103) in those without (p<0.001). In those admitted without HE, AAC on admission was higher in those who progressed to high-grade (n=97) than those who did not (n=221) 88 (60-146) vs. 65 (43-89) (p<0.001). In patients with high grade HE who developed CE (n=81) AAC was higher than those who did not (n=396) on admission (132 (99-203) vs. 84 (64-144)) and on ITU day 2 (122 (71-156) vs. 82 (61-124)) (both p<0.001). AAC was the best laboratory measure for prediction of HE progression (AUROC 0.730) and development of CE (AUROC 0.660). In those with HE, admission AAC did not differ between survivors and non-survivors (87 (56-134) vs.93 (64-145) p=0.16) but did at day 3 (68 (49-101) vs. 98 (66-139) (p<0.001)) In those with high-grade HE, hemofiltration on admission was associated with a median 16% fall in AAC on day 2 and 25% on day 3 as compared to 5% and 13% when not treated in this way (p<0.03). LT was associated with a fall in AAC by 70% from 116 (77-170) to 38 (19-55) (p<0.0001). Conclusions Elevations of AAC, particularly if sustained, relate closely to the development and severity of cerebral complications of ALF.

This has important implications for 3-dimensional cell cultures when estimating per cell performance in potential cell therapy applications. Disclosures: The following people have nothing to disclose:

Eloy Erro, Hyun Woo Yu, Dominic Davis, James T. Bundy, Aurelie Le lay, Humphrey Hodgson, Barry Fuller, Clare Selden Background. Though ammonia is implicated as a toxin central to the pathogenesis of hepatic encephalopathy (HE) and cerebral edema (CE) in acute liver failure (ALF), there is limited data on the clinical relevance of point of care (POC) measurement of its arterial concentration (AAC), and changes with therapeutic interventions. In a large cohort of patients with ALF we examined the clinical associations of AAC and utility in prediction of Smoothened inhibitor complications. Patients and Methods Patients with ALF admitted to a single intensive therapy unit (ITU) over a 10 year period were studied. AAC was measured on and after admission using the POC PocketChem BA Blood Ammonia Analyser. Its relation to development of HE, CE and survival was assessed. Changes

in AAC following introduction of hemofiltration for renal replacement and after liver transplan tation (LT) were examined, as was relation to progression of HE and development of CE. selleck compound Results 729 patients of median age 37 years (IQR 28-49) were studied; 59% were female. 413 (57%) had acetaminophen (APAP) and 316 上海皓元医药股份有限公司 (43%) non- APAP etiologies. 496 (68%) had or developed HE grade ≥3 (high-grade), in 81 (16%) with evidence of CE. 400 survived with medical management alone, 176 underwent LT and 155 died without LT. Median AAC was 102 (66-156) in those with

high-grade HE and 73 (45-103) in those without (p<0.001). In those admitted without HE, AAC on admission was higher in those who progressed to high-grade (n=97) than those who did not (n=221) 88 (60-146) vs. 65 (43-89) (p<0.001). In patients with high grade HE who developed CE (n=81) AAC was higher than those who did not (n=396) on admission (132 (99-203) vs. 84 (64-144)) and on ITU day 2 (122 (71-156) vs. 82 (61-124)) (both p<0.001). AAC was the best laboratory measure for prediction of HE progression (AUROC 0.730) and development of CE (AUROC 0.660). In those with HE, admission AAC did not differ between survivors and non-survivors (87 (56-134) vs.93 (64-145) p=0.16) but did at day 3 (68 (49-101) vs. 98 (66-139) (p<0.001)) In those with high-grade HE, hemofiltration on admission was associated with a median 16% fall in AAC on day 2 and 25% on day 3 as compared to 5% and 13% when not treated in this way (p<0.03). LT was associated with a fall in AAC by 70% from 116 (77-170) to 38 (19-55) (p<0.0001). Conclusions Elevations of AAC, particularly if sustained, relate closely to the development and severity of cerebral complications of ALF.

[25] Such self-contradictory recommendations may be justified by the following concept that HCC metastasizes selleckchem into

the anatomical field (e.g. a segment or lobe) through the blood flow of the corresponding major portal branches, and therefore the width of the safety margin may not affect the peritumoral, locoregional curability; however, there is no direct evidence demonstrating this concept. Because these recommendations for HCC treatment are based on strict statistical processing, such self-contradiction in treatment guidelines is thought to result from data obtained through inappropriate study design. Optimal surgery (i.e. adequate safety margin of hepatectomy) for HCC has long been evaluated using survival or disease-free survival (DFS) as a surrogate outcome. However, the results of these survival rates are influenced by intrahepatic tumor recurrence caused not only by remaining IM lesions but also by non-metastatic MC lesions FGFR inhibitor developing from the underlying

diseased liver. These recurrent types of HCC have been commonly determined based on histopathological analysis according to the Liver Cancer Study Group of Japan.[29-31] Briefly, the criteria for IM have been defined as follows: (i) tumors clearly growing from portal vein tumor thrombi; (ii) tumors surrounding a large main tumor with multiple satellite nodules; and (iii) a small, solitary tumor consisting of moderately or poorly differentiated HCC with the same or a lesser degree of differentiation compared

with that of the primary tumor. The criteria for MC have also been defined as: (i) tumors consist of early, well-differentiated HCC; (ii) tumors contain regions of adenomatous hyperplasia in the peripheral areas; and (iii) tumor is of the “nodule-in-nodule” form, in which nodules of moderate or poorly differentiated HCC are contained in a nodule of well-differentiated HCC. Based on these histopathological criteria, Huang et al. observed MC recurrence in 45% of patients undergoing repeat hepatectomy for HCC.[31] In accordance with these findings, 上海皓元医药股份有限公司 Oikawa et al. demonstrated that MC develops frequently in patients with chronic hepatitis, particularly those with hepatitis C virus infection.[32] Various other studies, including genetic analysis, also revealed that MC plays a considerable role in tumor recurrence, comprising approximately 50% of intrahepatic recurrences.[33-41] Although the current analytical methods have some limitation in differentiating IM from MC,[30, 38, 42] these findings suggest that DFS is not a specific outcome for postoperative tumor recurrence due to IM. In addition, survival after surgery is greatly affected by liver function. Treatment effectiveness for tumor recurrences is also known to affect postoperative survival. Thus, survival or even DFS is greatly influenced by non-metastatic factors, and is not considered an appropriate surrogate outcome for locoregional curability (i.e.