Human liver afferent and efferent nerves revealed by 3-D/Airyscan super-resolution imaging.

Neural regulation of hepatic metabolism has long been recognized. However, the detailed afferent and efferent innervation of the human liver has not been systematically characterized. This is largely due to the liver's high lipid and pigment contents, causing false-negative (light scattering and absorption) and false-positive (autofluorescence) results in in-depth fluorescence imaging. Here, to avoid the artifacts in three-dimensional (3-D) liver neurohistology, we embed the bleached human liver in the high-refractive-index polymer for tissue clearing and antifade 3-D/Airyscan super-resolution imaging. Importantly, using the paired substance P (SP, sensory marker) and PGP9.5 (pan-neuronal marker) labeling, we detect the sensory nerves in the portal space, featuring the SP+ varicosities in the PGP9.5+ nerve bundles/fibers, confirming the afferent liver innervation. Also, using the tyrosine hydroxylase (TH, sympathetic marker) labeling, we identify 1) condensed TH+ sympathetic nerves in the portal space, 2) extension of sympathetic nerves from the portal to the intralobular space, in which the TH+ nerve density is 2.6 ± 0.7-fold higher than that of the intralobular space in the human pancreas, and 3) the TH+ nerve fibers and varicosities contacting the ballooning cells, implicating potential sympathetic influence on hepatocytes with macrovesicular fatty change. Finally, using the vesicular acetylcholine transporter (VAChT, parasympathetic marker), PGP9.5, and CK19 (epithelial marker) labeling with panoramic-to-Airyscan super-resolution imaging, we detect and confirm the parasympathetic innervation of the septal bile duct. Overall, our labeling and 3-D/Airyscan imaging approach reveal the hepatic sensory (afferent) and sympathetic and parasympathetic (efferent) innervation, establishing a clinically related setting for high-resolution 3-D liver neurohistology.NEW & NOTEWORTHY We embed the human liver (vs. pancreas, positive control) in the high-refractive-index polymer for tissue clearing and antifade 3-D/Airyscan super-resolution neurohistology. The pancreas-liver comparison reveals: 1) sensory nerves in the hepatoportal space; 2) intralobular sympathetic innervation, including the nerve fibers and varicosities contacting the ballooning hepatocytes; and 3) parasympathetic innervation of the septal bile duct. Our results highlight the sensitivity and resolving power of 3-D/Airyscan super-resolution imaging in human liver neurohistology.

Longitudinal analysis of liver transplant candidates for hepatocellular carcinoma in a single center.

BACKGROUND: Wailitst lost is an critical issue and we investigated the long-term effect of insufficient liver functional reserve at liver transplantation evaluation on waitlist outcomes in patients with hepatocellular carcinoma (HCC). METHODS: Clinical data of patients with HCC waitlisted for liver transplantation were retrospectively collected from a single hospital cohort during the period from 2014 to 2021. Parameters of liver reserve, including cirrhosis, Child-Pugh grade, and Model for End-Stage Liver Disease (MELD) scores, were analyzed for patient survival, after adjustment for tumor factors. RESULTS: Of 292 eligible patients, 94.2% had cirrhosis, 55.8% had Child-Pugh grade B or C, and the median MELD score was 13.2. The median follow-up time was 2.2 years, with a dropout rate of 62.7%. Eighty-nine candidates (30.5%) eventually received liver transplant, including 67 from live donors. The estimated 1-year mortality rate reached 40.6% in 203 patients who remained on the waitlist without receiving a transplant, of whom 143 died. Most deaths were attributed to liver failure (37.1%) and cancer death (35.7%). After we adjusted for tumor confounders, including alpha fetoprotein, primary HCC stage, tumor number at evaluation, and sequential cancer treatment before and while waiting, hazard ratios (HRs) for patient survival were 1.69 (95% confidence interval, 1.18-2.41) for cirrhotic stage B or C, 1.07 (1.04-1.10) for MELD scores, and 1.14 (1.04-1.25) for tumor size at transplant evaluation. Transplantation was a protective disease modifier with adjusted HR 0.22 (0.14-0.33). CONCLUSION: Insufficient liver functional reserve poses more risk than expected to liver transplant waitlist outcomes with HCC.

Hepatitis C treatment and long-term outcome of patients with hepatocellular carcinoma after resection.

BACKGROUND AND AIM: This study aimed to investigate the survival outcomes of antiviral agents (direct-acting antivirals [DAAs] or interferon [IFN]) in patients with hepatitis C virus who underwent liver resection for primary hepatocellular carcinoma. METHODS: This retrospective single-center study included 247 patients, between 2013 and 2020, being treated with DAAs (n = 93), IFN (n = 73), or no treatment (n = 81). Overall survival (OS), recurrence-free survival (RFS), and risk factors were analyzed. RESULTS: After a median follow-up time of 50.4 months, the rates of 5-year OS and RFS in the IFN, DAA, and no treatment groups were 91.5% and 55.4%, 87.2% and 39.8%, and 60.9% and 26.7%, respectively. One hundred and twenty-eight (51.6%) patients developed recurrence; recurrence was mostly (86.7%) intrahepatic, and 58 (23.4%) developed early recurrence, most of which received no antiviral treatment. The OS and RFS were similar between patients who received antiviral treatment before (50.0%) and after surgery, but longer survival was observed in patients achieving sustained virologic response. In multivariate analysis, antiviral treatment was protective for OS (hazard ratio [HR] 0.475, 95% confidence interval [CI]: 0.242-0.933) with significance but not RFS, in contrast to microvascular invasion (OS HR 3.389, 95% CI: 1.637-7.017; RFS HR 2.594, 95% CI: 1.520-4.008). In competing risk analysis, DAAs (subdistribution HR 0.086, 95% CI: 0.007-0.991) were protective against hepatic decompensation events but not recurrence events. CONCLUSION: In patients with hepatitis C virus, antiviral treatment suggested OS benefit for primary hepatocellular carcinoma after resection, and DAAs might be protective against hepatic decompensation. Following adjustment for oncological factors, IFN and DAA treatment was not significantly advantageous relative to the other.

Interval dynamics of transplantability for hepatocellular carcinoma after primary curative resection: risk factors for nontransplantable recurrence.

BACKGROUND: To investigate the changes in transplantability between primary and recurrent Hepatocellular carcinoma (HCC) after hepatic resection (HR) and the risk factors for nontransplantable recurrence (NTR). METHODS: Consecutive 3122 patients who received HR for primary HCC between 2001 and 2019 were analyzed for changes in transplantability. Predictors of survival and NTR were evaluated using a competing risk analysis. RESULTS: After a median follow-up of 78.3 months, the 5-year overall survival rate was 82.6%. Also, 58.2% of them developed recurrence after a median of 45.6 months. Recurrence occurred in 1205 and 611 patients with primary transplantable and nontransplantable HCC, respectively, of whom 26.1% and 63.2%, respectively, had NTR. Tumor diameter >3 cm [subdistribution hazard ratios (95% CI), 2.00 (1.62-2.48)], major resection [1.20 (1.00-1.43)], pathological grade >2 [1.28 (1.07-1.52)], microvascular invasion [1.74 (1.45-2.08)], and early recurrence (<1 year) [9.22 (7.83-10.87)] were associated with NTR. The overall transplantable pool increased from 72.3% to 77.5%. CONCLUSION: Microvascular invasion and early recurrence were risk factors for NTR. Nonetheless, the transplantable pool increased after HR, 41.8% of the patients had no recurrence and may not require liver transplantation. If the patient's liver function is acceptable, HR should be considered the treatment of choice for HCC.

State of the art treatment of hepatitis B virus hepatocellular carcinoma and the role of hepatitis B surface antigen post-liver transplantation and resection.

Chronic hepatitis B virus (HBV) infection is the major aetiology of hepatocellular carcinoma (HCC). The optimal goal of therapy, hepatitis B surface antigen (HBsAg) loss and anti-HBs production, is achieved rarely and HBsAg-associated HCC risk is well recognized. Here we review the role of HBsAg in HCC, the link between HBsAg and HCC recurrence post-liver transplantation or resection, and the implications for therapy. HBV-associated carcinogenesis is a multifactorial process. The observation that HBV-related HCC can occur in the absence of cirrhosis is compatible with a direct oncogenic effect of the virus, which may occur via multiple mechanisms, including those mediated by both mutated and unmutated HBsAg. HCC recurrence in HBsAg-positive patients post-liver transplantation has been reported in 10%-15% of patients and is likely to be because of expansion of residual HCC tumour cell populations containing integrated HBV DNA, which expand and independently replicate HBV, leading to the recurrence of both HCC and HBV. The direct role of HBsAg in HCC recurrence post-liver resection is less clear. Cirrhosis is the most important risk factor for HCC development, and precancerous cirrhotic liver remains after resection, with the potential to undergo malignant transformation regardless of the existence of HBV-derived oncogenic drivers. The role of HBsAg in the development of HCC and its recurrence post-surgical intervention has multiple implications for therapy and suggests a potential role for immunotherapy in the future management of HCC, in particular post-liver transplantation. Use of hepatitis B immunoglobulins that target HBsAg directly, alongside immune-oncology therapies, may be relevant in this setting.

Predictors of changes in preoperative tumor stage between dynamic computed tomography and gadoxetate disodium-enhanced magnetic resonance imaging for hepatocellular carcinoma.

BACKGROUND/PURPOSE: Gadoxetate disodium-enhanced magnetic resonance imaging (EOB-MRI) has a higher diagnostic accuracy for hepatocellular carcinoma (HCC) than computed tomography (CT). However, indications for performing EOB-MRI after dynamic CT are not well defined. Therefore, we investigated the clinical factors associated with changes in the preoperative tumor stage between dynamic CT and EOB-MRI. METHODS: A prospective cohort was conducted from January 2014 to December 2017. 156 adult patients with clinical suspicion of HCC before liver resection were enrolled and we retrospectively reviewed the images. The tumor staging was evaluated by dynamic CT and then EOB-MRI subsequently according to the TNM staging system. The changes in tumor stage between two modalities were identified, and the associated clinical factors were analyzed. RESULTS: A total of 99 patients were analyzed after excluding 57 patients. 20 patients (20.2%) had changes in tumor stage between dynamic CT and EOB-MRI. The change occurred only in early stage (T1 and T2 lesions) based on dynamic CT initially. Furthermore, in univariate and multivariate analyses, albumin-bilirubin (ALBI) grade 2 and log alpha-fetoprotein (AFP) levels were associated with changes in tumor staging by EOB-MRI than those without (50% vs. 9.9%, p < 0.001 and 2.04 ± 1.35 vs. 1.40 ± 1.16, p = 0.038, respectively). Patients with changes in tumor stage also exhibited higher 1-year recurrence rate and shorter recurrence-free survival. CONCLUSION: Changes in preoperative tumor stage between dynamic CT and EOB-MRI were associated with CT-defined early stage, ALBI grades, higher log AFP levels, and early recurrence.

Experience of applying threshold concepts in medical education.

BACKGROUND: Practical barriers exist in applying threshold-concept-based clinical teaching. We applied the practice model to the subject of acute liver failure and reported the experiences in teaching and learners' reactions. METHODS: The course comprised a 10-min online preclass video and a 1-h class with in-depth discussion. The video explained six extracted threshold concepts, which were labelled TC1-TC6. Three sets of feedback questionnaires were given to students. Questionnaires were provided after they watched the online video (Q1), after class (Q2), and before the end of the curriculum section (Q3). All the feedback questionnaires were analysed. RESULTS: Of the 136 attendees in the academic year 2018, 127 (93.4%), 69 (50.7%), and 112 (82.4%) completed the Q1, Q2, and Q3 questionnaires, respectively, and 48 (42.6%) provided comments. The degree of comprehension varied among threshold concepts and individual students. TC1 and TC2 were viewed as transformative for all three surveys. The threshold-concept-based learning process was satisfactory, and students could auto-reflect on the defining features of a threshold concept. Students became aware of their deficiencies in knowledge and acknowledged room for development with regard to their mindset for future patient management. CONCLUSION: Threshold-concept-based clinical teaching is a feasible strategy. Students' reflections indicate that thresholds were crossed, which does not guarantee that students' mindsets are ready for future clinical practice.

Minimally invasive surgery versus radiofrequency ablation for single subcapsular hepatocellular carcinoma ≤ 2 cm with compensated liver cirrhosis.

BACKGROUND: There is currently no consensus regarding the relative applicability of minimally invasive treatment, including radiofrequency ablation (RFA) and minimally invasive surgery (MIS) in patients with a single small peripheral hepatocellular carcinoma (HCC) and compensated cirrhosis. This study investigated the clinical outcomes of MIS and RFA for single subcapsular HCC ≤ 2 cm in patients with compensated cirrhosis. METHODS: In this retrospective study, we enrolled 75 patients who had a single subcapsular HCC ≤ 2 cm along with Child-Pugh class A cirrhosis and a preoperative platelet count ≥ 100 k/µl. These patients underwent RFA (n = 39) or MIS (n = 36) between 2010 and 2016. Clinical outcomes including disease-free survival (DFS), survival without recurrence beyond the Milan criteria (RBM), and overall survival (OS) were compared. RESULTS: The 7-year DFS rates in the MIS and RFA groups were 86.1% and 35.9% (p < 0.001), respectively, the 7-year RBM rates were 88.9% and 66.7% (p = 0.014), respectively, and the 7-year OS rates were 97.2% and 82.1% (p = 0.008), respectively. RFA was associated with more ipsilateral lobe recurrence (20% vs. 83.4%, p = 0.004), and 40% were in direct contact with the ablation penumbra. A Cox proportional hazard analysis identified RFA as an independent predictor of mortality (adjusted hazard ratio, 9.625, p = 0.038). No major complications occurred in either group. RFA patients had a shorter hospital stay (median of 2 vs. 6 days, p < 0.001) and operation time (median of 23.5 vs. 216 min, p = 0.001). CONCLUSIONS: MIS was associated with a better 7-year OS, RBM, and DFS among patients with single subcapsular HCC ≤ 2 cm, Child-Pugh A liver function, and no clinically significant portal hypertension when compared to those who underwent percutaneous RFA.

Roles of Epstein-Barr virus viral load monitoring in the prediction of posttransplant lymphoproliferative disorder in pediatric liver transplantation.

BACKGROUND/PURPOSE: This study is aimed to investigate the risk factors and clinical characteristics of posttransplant lymphoproliferative disorder (PTLD) after conducting Epstein-Barr virus (EBV) viral load monitoring in pediatric liver transplant (LT) patients in Taiwan, where EBV infection is endemic. METHODS: From 2007 to 2013, pediatric LT recipients who underwent EBV viral load monitoring within 3 months after LT were recruited in this study. The impact of clinical parameters-including age at LT, sex, peak EBV viral load and immunosuppressant levels after LT-on the risk of PTLD were assessed. RESULTS: A total 39 patients underwent LT at a median age of 1.3 years (range: 0.6-14.0 years), and 5 patients developed PTLD during follow-up. Cox's proportional-hazards model identified two predictors of PTLD: peak EBV viral load within 3 months of LT >4100 copies/µg peripheral blood mononuclear cells (PBMC) DNA and peak tacrolimus level within 3 months of LT >14.8 ng/mL (Hazard ratio = 17.14 and 11.54, P = 0.02 and 0.03, respectively). Kaplan-Meier survival analysis revealed significant higher cumulative incidence rates of PTLD (27.3% and 41.8% at 0.3 and 1.2 years after LT) in subjects with peak EBV viral load >4100 copies/µg PBMC DNA within 3 months after LT. (P = 0.001, log-rank test). CONCLUSION: Close monitoring of EBV viral load within 3 months after LT is helpful to predict a high risk of PTLD. Tapering of immunosuppressants is suggested if the EBV viral load is >4100 copies/µg PBMC DNA in LT children.

Comparative effectiveness of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in chemoprevention of hepatocellular carcinoma: a nationwide high-risk cohort study.

BACKGROUND: Research has revealed that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) may prevent cancers such as hepatocellular carcinoma (HCC). The comparative chemopreventive effects of ACEIs and ARBs in high-risk populations with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection have yet to be investigated. METHODS: From 2005 to 2014, high-risk HBV and HCV cohorts of hypertensive patients without HCC history were recruited from three linked national databases of Taiwan, and were classified into two groups based on the ACEI or ARB exposure within the initial six months after initiating antiviral agent. Intergroup differences in clinical characteristics and duration of drug exposure within study period were evaluated. HCC-free survival was compared using the log-rank test. Multivariate Cox regression including time-dependent variables for the use of ACEIs or ARBs and other medications was applied to adjust for confounders. RESULTS: Among the 7724 patients with HBV and 7873 with HCV, 46.3% and 42.5%, respectively, had an initial exposure to ACEIs or ARBs. The median durations of exposure were 36.4 and 38.9 months for the HBV and HCV cohorts, respectively. The median durations of ACEI or ARB use during study period between initial exposure and nonexposure groups were 41.8 vs. 18.3 months and 46.4 vs. 22.7 months for the HBV and HCV cohorts, respectively. No significant difference was observed in HCC risk within 7 years between the initial exposure and non-exposure groups. After adjustment for comorbidities, namely liver cirrhosis, diabetes mellitus (DM), and hyperlipidemia, and medications, namely aspirin, metformin, and statins, the hazard ratios (HRs) for ACEI or ARB exposure for HCC risk were 0.97 (95% confidence interval [CI]: 0.81-1.16) and 0.96 (0.80-1.16) in the HBV and HCV cohorts, respectively. In the HCV cohort, the increased HCC risk was associated with ACEI or ARB use in patients without cirrhosis, DM, and hyperlipidemia (HR: 4.53, 95% CI: 1.46-14.1). CONCLUSION: Compared with other significant risk and protective factors for HCC, ACEI or ARB use in the HBV and HCV cohorts was not associated with adequate protective effectiveness under standard dosages and may not be completely safe.

Efficient undergraduate learning of liver transplant: building a framework for teaching subspecialties to medical students.

BACKGROUND: Liver recipients may develop various diseases after transplant. However, because of inadequate study of liver transplant during undergraduate education, the quality of post-transplant care provided to these patients remains suboptimal. Herein, we introduce an innovative and integrated multimodal pedagogical approach to effectively disseminate key information regarding liver transplant to undergraduate students. The goal is to examine this approach through students' assessment in multiple dimensions. METHODS: This prospective observational study evaluated student reactions to our pedagogical approach. Fifth-year medical students during the academic year 2015-2016 attended a 2-h session on what nontransplant doctors should know about liver transplants. The pedagogical strategy consisted of an online preclass self-learning exercise, an in-class interactive discussion (facilitated by the class teacher who is a liver transplant specialist to avoid distractions within the short-time frame), and a postclass essay assignment (to integrate and apply concepts). After the class, questionnaires were distributed to individual students to collect data, if returned, concerning the students' learning experience and feedback to improve teaching quality. Descriptive statistics, Mann-Whitney U tests, chi-squared tests, and McNemar's tests were used to analyze quantitative data. Qualitative data were content-coded through a descriptive approach using thematic analysis. RESULTS: Of the 266 attendees, 263 (98.9%) completed the questionnaires and 182 (69.2%) provided comments. Student feedback indicated they "felt better" and "more satisfied" compared with problem-based learning (PBL) (51.0 and 63.1%, respectively) or large-lecture class (92.0 and 88.6%, respectively) approaches. Regarding confidently managing liver transplant patients in future, 80 (30.4%) and 246 (93.5%) students expressed preclass and postclass confidence, respectively (p < 0.001). The bell curve of the postclass self-assessment score of learning shifted toward right and became steeper compared with that of the preclass score (p < 0.001), suggesting students acquired considerable knowledge. The course was typically perceived to be cost-effective, practical, tension-free, and student-friendly. CONCLUSION: This pedagogical approach effectively propagated knowledge concerning liver transplant to medical students, who expressed considerable satisfaction with the approach.

Robotic Versus Open Hepatectomy for Hepatocellular Carcinoma: A Matched Comparison.

BACKGROUND: Robotic hepatectomy has been suggested to be a safe and effective approach for liver disease; however, studies comparing robotic hepatectomy with the conventional open approach regarding oncologic outcomes for hepatocellular carcinoma (HCC) are limited. Accordingly, we performed a matched comparison of surgical and oncological outcomes between robotic and open hepatectomy. METHODS: Between January 2012 and October 2015, a total of 183 patients underwent robotic hepatectomy and 275 patients underwent open hepatectomy by the same surgical team in our center. Eighty-one newly diagnosed HCC cases in each group were compared under propensity score matching (PSM) in a 1:1 ratio. RESULTS: With robotic hepatectomy, the conversion rate was 1.6 % and the complication rate was 4.4 %. On PSM, the groups had a comparable percentage of major liver resections (41.9 vs. 39.5 %) and liver cirrhosis (45.7 vs. 46.9 %). Compared with the open group, the robotic group required longer operation times (343 vs. 220 min), shorter hospital stays (7.5 vs. 10.1 days), and lower dosages of postoperative patient-controlled analgesia (350 vs. 554 ng/kg). The 3-year disease-free survival of the robotic group was comparable with that of the open group (72.2 % vs. 58.0 %; p = 0.062), as was the 3-year overall survival (92.6 vs. 93.7 %; p = 0.431). CONCLUSIONS: This is the first oncological study comparing robotic liver resection for HCC with open resection. Robotic hepatectomy can be applied for challenging major resections in patients with cirrhotic liver disease with less postoperative pain and shorter hospital stays without compromising oncological outcomes.

Robotic liver donor right hepatectomy: A pure, minimally invasive approach.

Right hepatectomy for a living liver donor via a pure minimally invasive approach is a challenging procedure and only a few cases have been reported. Between May 2013 and August 2015, 13 patients underwent robotic living donor right hepatectomy in our institute, and 54 patients received open surgery. In this series, no conversion was conducted for robotic donor right hepatectomy. The 2 groups shared similar blood loss (169 versus 146 mL), complication rates (7.7% versus 9.3%), and recovery of donor liver function (peak alanine aminotransferase, 269 versus 252 IU/mL). The robotic group needed longer operation time (596 versus 383 minutes) but less postoperative patient-controlled analgesia (0.58 versus 0.84 ng/kg) and a shorter period before returning to work/school (52.9 versus 100.0 days) and sex (100.0 versus 156.0 days). For recipient outcomes regarding the donor procedure, the robotic group shared similar experiences in early allograft dysfunction, complications, and 1-year recipient liver function with the open group. With respect to documented benefits of minimally invasive left-sided liver donor procedure, the development of right donor hepatectomy is slow. In conclusion, with substantial improvements in patient recovery after the minimally invasive approach, the robotic platform would be a big step toward completing pure minimally invasive liver donor surgery. Liver Transplantation 22 1509-1518 2016 AASLD.

RBMY, a novel inhibitor of glycogen synthase kinase 3ß, increases tumor stemness and predicts poor prognosis of hepatocellular carcinoma.

UNLABELLED: Male predominance of hepatocellular carcinoma (HCC) occurs particularly among young children aged 6-9 years, indicative of a possible role of the Y chromosome-encoded oncogene in addition to an androgenic effect. The discovery of oncogenic activation of RBMY (RNA-binding motif on Y chromosome), which is absent in normal hepatocytes but present in male HCC tissues, sheds light on this issue. Herein, we report on a critical hepatocarcinogenic role of RBMY and its ontogenic origin. During liver development, the Ser/Thr phosphorylated RBMY is expressed in the cytoplasm of human and rodent fetal livers. It is then silenced in mature hepatocytes and restricted to scarce expression in the bile ductular cells. Upon hepatocarcinogenesis, a noteworthy increase of cytoplasmic and nuclear RBMY is observed in HCC tissues; however, only the former is expressed dominantly in hepatic cancer stem cells and correlates significantly to a poor prognosis and decreased survival rate in HCC patients. Cytoplasmic expression of RBMY, which is mediated by binding to nuclear exporter chromosome region maintenance 1 and further enriched upon Wnt-3a stimulation, confers upon tumor cells the traits of cancer stem cell by augmenting self-renewal, chemoresistance, cell-cycle progression, proliferation, and xenograft tumor growth. This is achieved mechanistically through increasing Ser9 phosphorylation-inactivation of glycogen synthase kinase 3ß by RBMY, thereby impeding the glycogen synthase kinase 3ß-dependent degradation of ß-catenin and eventually inducing the nuclear entry of ß-catenin for the transcription of downstream oncogenes. CONCLUSION: RBMY is a novel oncofetal protein that plays a key role in attenuating glycogen synthase kinase 3ß activity, leading to aberrant activation of Wnt/ß-catenin signaling, which facilitates malignant hepatic stemness; because of its absence from normal human tissues except the testis, RBMY represents a feasible therapeutic target for the selective eradication of HCC cells in male patients.

Transplantation speed offers early hepatocyte engraftment in acute liver injured rats: A translational study with clinical implications.

The impact of the rate of intraportal hepatocyte transplantation on early engraftment and repopulation is unclear. The aim of this study was to address this and to improve the engraftment and repopulation efficiencies of hepatocyte transplantation for the treatment of a rat model of acute liver failure in a clinically useful way without preconditioning. Acute hepatic injury was induced into Sprague-Dawley rats with D-galactosamine. Hepatocytes were infused intraportally over a period of 30, 70, or 100 seconds to study early engraftment (2 days) and repopulation (7 days). Three groups had significant differences in hepatocyte engraftment (P = 0.018) and repopulation efficiencies (P = 0.037), and an infusion over a period of 70 seconds produced superior outcomes. After the 70-second infusion, the transplanted cells immediately transmigrated the sinusoidal endothelial layer and rarely accumulated in the portal venules, with liver function improving significantly. The mean first peak pressures, without significant differences, were 14.8 ± 6.5, 17.7 ± 3.7, and 13.6 ± 3.0 mm Hg in the 30-, 70-, and 100-second groups, respectively. Differential hepatocyte transfusion rates contributed to accelerated early engraftment and repopulation in rats with acute liver injury. These proof-of-concept findings are of clinical significance because they are easy to translate into practice.

Assessing hepatic fibrosis: comparing the intravoxel incoherent motion in MRI with acoustic radiation force impulse imaging in US.

OBJECTIVES: This study compared the diagnostic performance of intravoxel incoherent motion (IVIM) in magnetic resonance imaging (MRI) and acoustic radiation force impulse imaging (ARFI) in ultrasound (US) for liver fibrosis (LF) evaluation. METHODS: A total of 49 patients scheduled for liver surgery were recruited. LF in the non-tumorous liver parenchyma at the right lobe was estimated using a slow diffusion coefficient, fast diffusion coefficient (D fast), perfusion fraction (f) of the IVIM parameters, the total apparent diffusion coefficient of conventional diffusion-weighted imaging and the shear wave velocity (Vs) of ARFI. LF was graded using the Metavir scoring system on histological examination. The Spearman rank correlation coefficient for correlation and analysis of variance was used for determining difference. The diagnostic performance was compared using receiver operating characteristic curve analysis. RESULTS: LF exhibited significant correlation with the three parameters D fast, f, and Vs (r = -0.528, -0.337, and 0.481, respectively, P < 0.05). The D fast values in the F4 group were significantly lower than those in the F0, F1 and F2 groups. D fast exhibited a non-inferior performance for diagnosing all fibrosis grades compared with that of Vs. CONCLUSIONS: Both IVIM and ARFI provide reliable estimations for the noninvasive assessment of LF. KEY POINTS: • Liver fibrosis can be diagnosed and graded using noninvasive imaging modalities. • ARFI and IVIM can be incorporated into routine examinations. • IVIM can differentiate liver cirrhosis from none to moderate liver fibrosis. • The diagnostic performances of IVIM and ARFI are equal.

B cells and immunoglobulin in ABO-incompatible renal transplant patients receiving rituximab and double filtration plasmapheresis.

BACKGROUND/PURPOSE: The effect of rituximab on B cell and immunoglobulin production after therapeutic apheresis has not been studied in ABO-incompatible renal transplant patients. METHODS: Twenty consecutive ABO-incompatible renal transplant patients receiving rituximab induction and double filtration plasmapheresis were enrolled; one case was excluded because of repeated plasmapheresis and immunoglobulin therapy (Incompatible group). The B cell count of the Incompatible group was compared to another group of 18 ABO-compatible renal transplant patients who were operated on during the same period (Compatible group). In the Incompatible group, the total IgM, IgG, and IgG1-4 subclasses after transplantation were compared to those before desensitization. Tacrolimus, mycophenolate mofetil, and steroids were used for both groups. RESULTS: The B cell count of the Incompatible group was significantly lower than the Compatible group post-transplant from Month 1 to Month 11 only. The B cell count of the Compatible group also decreased for the first 6 months, suggesting that maintenance immunosuppressive agents suppress B cells. Total IgG and IgM levels after transplantation were significantly lower than before desensitization during the 24-month follow-up period. The post-transplant IgG3 level was significantly lower than before desensitization for only 3 months. CONCLUSION: With the aid of tacrolimus and mycophenolate mofetil, rituximab resulted in sustained suppression of B cell count and total IgG and IgM. Among the IgG subclasses, IgG3 was less sensitive to rituximab.

De novo cancer avoidance after renal transplantation: A case-control study on low-dose sirolimus combined with a calcineurin inhibitor.

BACKGROUND/PURPOSE: Full-dose sirolimus (SRL) therapy without a calcineurin inhibitor (CNI) reduces the incidence of malignancy after renal transplantation, but with significant side effects. We hypothesized that de novo therapy with low-dose SRL combined with a CNI could still prevent cancer in renal transplant recipients. METHODS: A retrospective case-control study was performed to assess the cancer incidence among renal transplant patients who had undergone surgery in our transplant centers between January 2000 and June 2012. Patients who received low-dose SRL and a CNI (SRL group, n = 189) were compared with patients receiving conventional CNI-based therapy in the same hospitals (Conventional group, n = 271). RESULTS: The 5-year graft and patient survival rates were comparable between the two groups. Seven patients in the SRL group and 24 patients in the Conventional group developed malignancies during mean follow-up periods of 68.2 ± 37.5 months and 81.7 ± 51.4 months, respectively. The cancer incidence at 5 years was significantly lower in the SRL group (1.9%), than that in the Conventional group (6.7%; p = 0.04). By multivariate analyses, SRL therapy (p = 0.04), male sex (p = 0.04), and younger age (p = 0.01) were significantly associated with a lower risk of malignancy after kidney transplantation. CONCLUSION: De novo therapy with low-dose SRL combined with a CNI was associated with reduced risk of post-transplant cancer in renal transplant recipients. De novo cancer prevention using a low-dose proliferation signal inhibitor such as SRL could be effective for renal transplant recipients.