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.

Unraveling the impact of cancer-associated fibroblasts on hypovascular pancreatic neuroendocrine tumors.

BACKGROUND: Pancreatic neuroendocrine tumors (PNETs) with low microvessel density and fibrosis often exhibit clinical aggressiveness. Given the contribution of cancer-associated fibroblasts (CAFs) to the hypovascular fibrotic stroma in pancreatic ductal adenocarcinoma, investigating whether CAFs play a similar role in PNETs becomes imperative. In this study, we investigated the involvement of CAFs in PNETs and their effects on clinical outcomes. METHODS: We examined 79 clinical PNET specimens to evaluate the number and spatial distribution of α-smooth muscle actin (SMA)-positive cells, which are indicative of CAFs. Then, the findings were correlated with clinical outcomes. In vitro and in vivo experiments were conducted to assess the effects of CAFs (isolated from clinical specimens) on PNET metastasis and growth. Additionally, the role of the stromal-cell-derived factor 1 (SDF1)-AGR2 axis in mediating communication between CAFs and PNET cells was investigated. RESULTS: αSMA-positive and platelet-derived growth factor-α-positive CAFs were detected in the hypovascular stroma of PNET specimens. A higher abundance of α-SMA-positive CAFs within the PNET stroma was significantly associated with a higher level of clinical aggressiveness. Notably, conditioned medium from PNET cells induced an inflammatory phenotype in isolated CAFs. These CAFs promoted PNET growth and metastasis. Mechanistically, PNET cells secreted interleukin-1, which induced the secretion of SDF1 from CAFs. This cascade subsequently elevated AGR2 expression in PNETs, thereby promoting tumor growth and metastasis. The downregulation of AGR2 in PNET cells effectively suppressed the CAF-mediated promotion of PNET growth and metastasis. CONCLUSION: CAFs drive the growth and metastasis of aggressive PNETs. The CXCR4-SDF1 axis may be a target for antistromal therapy in the treatment of PNET. This study clarifies mechanisms underlying PNET aggressiveness and may guide future therapeutic interventions targeting the tumor microenvironment.

The effects of double-filtration plasmapheresis on coagulation profiles and the risk of bleeding.

BACKGROUND/PURPOSE: Double-filtration plasmapheresis (DFPP) can be used to remove circulating pathogenic molecules. By reclaiming filtered albumin, DFPP reduces the need for albumin and plasma replacement. Large proteins, such as fibrinogen, are removed. Our institution adopts a DFPP treatment protocol consisting of active surveillance of coagulation profiles and prophylactic supplementation of blood products containing fibrinogen. This study aims to investigate the effects of consecutive DFPP treatments on serial coagulation profiles and the risk of bleeding under this protocol. METHODS: Serial laboratory data and bleeding events at a single tertiary medical center were prospectively collected. Prophylactic transfusion of cryoprecipitate or fresh frozen plasma (FFP) was instituted if significant coagulopathy or a clinically evident bleeding event was observed. RESULTS: After the first treatment session, plasma fibrinogen levels decreased from 332 ± 106 mg/dL to 96 ± 44 mg/dL in the 37 study patients. In the following sessions, plasma fibrinogen levels were maintained at around 100 mg/dL under prophylactic transfusion. No major bleeding events were recorded, but five (14%) patients experienced minor bleeding. CONCLUSION: DFPP treatment might be performed safely along with active monitoring of coagulation profiles and prophylactic transfusion of cryoprecipitate or FFP.

Prevention and management of cytomegalovirus infection and disease in kidney transplant: A consensus statement of the Transplantation Society of Taiwan.

Kidney transplant recipients have an increased risk of cytomegalovirus (CMV) infection and disease. A strategy for mitigating the risk of CMV infection in kidney transplant recipients has not yet been established in Taiwan. The Transplantation Society of Taiwan aimed to develop a consensus by expert opinion on the prevention and management of CMV infection. Based on the results of Consensus Conference, we suggested low-dose valganciclovir prophylaxis (450 mg once daily) for kidney transplant recipients. The prophylaxis duration was ≥6 months for high-risk (D+/R-) patients and 3 months for moderate-risk (R+) patients. Even for low-risk (D-/R-) patients, prophylaxis for at least 3 months is recommended because of the high seroprevalence of CMV in Taiwan. CMV prophylaxis was suggested after anti-thymocyte globulin treatment but not after methylprednisolone pulse therapy. Routine surveillance after prophylaxis, secondary prophylaxis after CMV disease treatment, and mTOR inhibitors for primary CMV prophylaxis were not recommended. Letermovir and marabavir are emerging CMV agents used for prophylaxis and refractory CMV disease. CMV immunoglobulins have been used to treat refractory CMV disease in Taiwan. We hope this consensus will help professionals manage patients with CMV in Taiwan to improve the quality of care.

IL-1ß-driven neutrophilia preserves antibacterial defense in the absence of the kinase IKKß.

Transcription factor NF-κB and its activating kinase IKKß are associated with inflammation and are believed to be critical for innate immunity. Despite the likelihood of immune suppression, pharmacological blockade of IKKß-NF-κB has been considered as a therapeutic strategy. However, we found neutrophilia in mice with inducible deletion of IKKß (Ikkß(Δ) mice). These mice had hyperproliferative granulocyte-macrophage progenitors and pregranulocytes and a prolonged lifespan of mature neutrophils that correlated with the induction of genes encoding prosurvival molecules. Deletion of interleukin 1 receptor 1 (IL-1R1) in Ikkß(Δ) mice normalized blood cellularity and prevented neutrophil-driven inflammation. However, Ikkß(Δ)Il1r1(-/-) mice, unlike Ikkß(Δ) mice, were highly susceptible to bacterial infection, which indicated that signaling via IKKß-NF-κB or IL-1R1 can maintain antimicrobial defenses in each other's absence, whereas inactivation of both pathways severely compromises innate immunity.

Protective Effect of Vaccine Doses and Antibody Titers Against SARS-CoV-2 Infection in Kidney Transplant Recipients.

Patients undergoing kidney transplantation have a poor response to vaccination and a higher risk of disease progression of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The effectiveness of vaccine doses and antibody titer tests against the mutant variant in these patients remains unclear. We retrospectively analyzed the risk of SARS-CoV-2 infection in a single medical center according to vaccine doses and immune responses before the outbreak. Among 622 kidney transplant patients, there were 77 patients without vaccination, 26 with one dose, 74 with two doses, 357 with three, and 88 with four doses. The vaccination status and infection rate proportion were similar to the general population. Patients undergoing more than three vaccinations had a lower risk of infection (odds ratio = 0.6527, 95% CI = 0.4324-0.9937) and hospitalization (odds ratio = 0.3161, 95% CI = 0.1311-0.7464). Antibody and cellular responses were measured in 181 patients after vaccination. Anti-spike protein antibody titer of more than 1,689.3 BAU/mL is protective against SARS-CoV-2 infection (odds ratio = 0.4136, 95% CI = 0.1800-0.9043). A cellular response by interferon-γ release assay was not correlated with the disease (odds ratio = 1.001, 95% CI = 0.9995-1.002). In conclusion, despite mutant strain, more than three doses of the first-generation vaccine and high antibody titers provided better protection against the omicron variant for a kidney transplant recipient.

Prevention and management of tuberculosis in solid organ transplantation: A consensus statement of the transplantation society of Taiwan.

Solid organ transplant recipients have an increased risk of tuberculosis (TB). Due to the use of immunosuppressants, the incidence of TB among solid organ transplant recipients has been consistently reported to be higher than that among the general population. TB frequently develops within the first year after transplantation when a high level of immunosuppression is maintained. Extrapulmonary TB and disseminated TB account for a substantial proportion of TB among solid organ transplant recipients. Treatment of TB among recipients is complicated by the drug-drug interactions between anti-TB drugs and immunosuppressants. TB is associated with an increased risk of graft rejection, graft failure and mortality. Detection and management of latent TB infection among solid organ transplant candidates and recipients have been recommended. However, strategy to mitigate the risk of TB among solid organ transplant recipients has not yet been established in Taiwan. To address the challenges of TB among solid organ transplant recipients, a working group of the Transplantation Society of Taiwan was established. The working group searched literatures on TB among solid organ transplant recipients as well as guidelines and recommendations, and proposed interventions to strengthen TB prevention and care among solid organ transplant recipients.

Long-term durability of sustained virologic response for hepatitis C virus infection in solid organ transplant recipients receiving direct-acting antivirals.

Data are limited regarding the long-term durability of sustained virologic response (SVR) in solid organ transplant recipients who achieve SVR12 with direct-acting antivirals (DAAs) for hepatitis C virus (HCV). We reported the virologic outcomes in 42 recipients who received DAAs for acute or chronic HCV infection after heart, liver, and kidney transplantation. After achieving SVR12, all recipients received HCV RNA surveys at SVR24, and biannually until the last visit. If HCV viremia was detected during the follow-up period, direct sequencing and phylogenetic analysis were performed to confirm late relapse or reinfection. Sixteen (38.1%), 11 (26.2%), and 15 (35.7%) patients underwent heart, liver and, kidney transplantation. Thirty-eight (90.5%) received sofosbuvir (SOF)-based DAAs. No recipients had late relapse or reinfection after a median (range) of post-SVR12 follow-up 4.0 (1.0-6.0) years. We demonstrate that the durability of SVR in solid organ transplant recipients is excellent once SVR12 is achieved with DAAs.

Multimodal 3-D/2-D human islet and duct imaging in exocrine and endocrine lesion environment: associated pancreas tissue remodeling.

Pancreatic intraepithelial neoplasia (PanIN) and islet cell microadenoma are exocrine and endocrine neoplasms of human pancreas that have been linked to pancreatic ductal adenocarcinoma (PDAC) and neuroendocrine tumor, respectively. However, in health and at the surgical margin of pancreatic cancer, it remains unresolved how to simultaneously characterize duct and islet remodeling to investigate the exocrine-endocrine association in the lesion microenvironment. Here, we develop a new vibratome-based approach to detect, confirm, and analyze the two types of pancreas remodeling via stereo/three-dimensional (3-D) and classic/two-dimensional (2-D) histology. Surgical margins of PDAC (n = 10, distal) and cadaveric donor pancreases (n = 10, consecutive cases) were fixed, sectioned by vibratome (350 µm), and surveyed for PanIN and microadenoma via stereomicroscopy. After lesion detection, PanIN and microadenoma were analyzed with 3-D fluorescence imaging and clinical microtome-based histology for confirmation and assessment of microenvironment. Multimodal imaging of PDAC surgical margins and cadaveric donor pancreases detected the peri-PanIN islet aggregation with duct-islet cell clusters. Organ-wide survey of cadaveric donor pancreases shows a marked 2.3-fold increase in the lesion size with the PanIN-islet association vs. without the association. In the survey, we unexpectedly detected the islet cell microadenoma adjacent to (<2 mm) PanIN. Overall, among the 53 early lesions in the cadaveric donor pancreases (PanINs and microadenomas), 81% are featured with the associated exocrine-endocrine tissue remodeling. Multimodal 3-D/2-D tissue imaging reveals local and simultaneous duct and islet remodeling in the cancer surgical margin and cadaveric donor pancreas. In the cadaveric donor pancreas, the peri-PanIN islet aggregation and PanIN-microadenoma association are two major features of pancreas remodeling in the early lesion microenvironment.NEW & NOTEWORTHY We develop a new multimodal 3-D/2-D imaging approach (matched stereomicroscopic, fluorescence, and H&E signals) to examine human duct-islet association in the PDAC surgical margin and cadaveric donor pancreas. In both conditions, peri-PanIN islet aggregation with duct-islet cell clusters was identified. The PanIN-islet cell microadenoma association was unexpectedly detected in the donor pancreas. Our work provides the technical and morphological foundations to simultaneously characterize human islets and ducts to study their association in health and disease.

The role of S100A9 in the interaction between pancreatic ductal adenocarcinoma cells and stromal cells.

BACKGROUND: A major feature of the microenvironment in pancreatic ductal adenocarcinoma (PDAC) is the significant amount of extracellular matrix produced by pancreatic stellate cells (PSCs), which have been reported to enhance the invasiveness of pancreatic cancer cells and negatively impact the prognosis. METHODS: We analyzed the data from two publicly available microarray datasets deposited in the Gene Expression Omnibus and found candidate genes that were differentially expressed in PDAC cells with metastatic potential and PDAC cells cocultured with PSCs. We studied the interaction between PDAC cells and PSCs in vitro and verified our finding with the survival data of patients with PDAC from the website of The Human Protein Atlas. RESULTS: We found that PSCs stimulated PDAC cells to secrete S100A9, which attracted circulatory monocytes into cancer tissue and enhanced the expression of programmed death-ligand 1 (PD-L1) on macrophages. When analyzing the correlation of S100A9 and PD-L1 expression with the clinical outcomes of patients with PDAC, we ascertained that high expression of S100A9 and PD-L1 was associated with poor survival in patients with PDAC. CONCLUSIONS: PSCs stimulated PDAC cells to secrete S100A9, which acts as a chemoattractant to attract circulatory monocytes into cancer microenvironment and induces expression of PD-L1 on macrophages. High expression of S100A9 and PD-L1 was associated with worse overall survival in a cohort of patients with PDAC.

Survey of factors associated with the willingness toward living kidney donation.

BACKGROUND: Living donor kidney transplantation (LDKT) is an important organ resource, especially in countries with low deceased donation rates. Strategies for expanding access to transplantation should be developed by identifying the modifiable factors. In this study, we evaluated these factors in the relatives of patients from both medical centers and dialysis clinics using questionnaires. METHODS: The questionnaires were anonymous and confidential. We collected questionnaires from previous donors, relatives of patients on the waitlist in the medical center, and relatives of dialysis patients in three nephrology clinics. The study groups were divided into three categories: donor group (n = 68), willing group (n = 43), and non-donor group (n = 65). RESULTS: Respondents in the clinics had lower cognition and willingness towards LDKT than those in the medical center. More knowledge of LDKT, better relationship with patients, more familial support, and female gender were positively related to donation. The non-donor group tended to want to maintain an intact body for the afterlife. There was no significant difference in age, educational degree, average monthly income, and medical compliance among the three groups. CONCLUSION: More efforts need to be made in dialysis clinics, where general nephrologists are important for the outreach of information. In addition, dealing with religious ambivalence and reestablishing cultural mindsets with health education programs are important issues in a non-Christian country.

Dynamics of cellular immune responses in recipients of renal allografts positive for hepatitis B surface antigen.

BACKGROUND/PURPOSE: Hepatitis B surface antigen (HBsAg)-positive renal transplantation recipients must take lifelong immunosuppressants and nucleotide analogues (NAs). We investigated the cellular immune responses of HBsAg-positive renal transplantation recipients taking immunosuppressants and NAs. METHODS: Blood samples were collected from HBsAg-positive individuals with end-stage renal disease on the transplant waiting list (Group 1) and renal transplantation recipients taking immunosuppressants and NAs (Group 2) or immunosuppressants without NAs (Group 3). Hepatitis B virus (HBV)-specific pentamers were used to quantify circulating HBV-specific CD8+ T cells. RESULTS: Groups 2 and 3 had higher cellular immune responses, as indicated by significantly lower regulatory T (Treg)/CD8+ T cell ratios than Group 1. With undetectable viral loads under both immunosuppressant and NAs, the CD8+ T cell and HBV-specific CD8+ T cell frequencies were similar in Group 2 and Group 1. Patients in Group 3 did not use NAs and had an elevated viral load and higher HBV-specific CD8+ T cell and IFN-γ-producing HBV-specific CD8+ T cell frequencies, but lower a frequency of programmed death-1 (PD-1)+ HBV-specific CD8+ T cells than the other groups. Increased viral replication in Group 3 resulted in significantly higher CD8+ T cell and IFN-γ-producing CD8+ T cell frequencies than Group 1. CONCLUSION: Immunosuppressant therapy increases viral replication in HBsAg-positive renal transplant recipients due to disabling or dysregulation of virus-specific CD8+ T cells. The higher cellular immune responses due to lower Treg/CD8+ T cell ratios in HBsAg-positive renal transplant recipients may be one of the reasons to induce liver pathology because of uncontrolled viral replication.

Local islet remodelling associated with duct lesion-islet complex in adult human pancreas.

AIMS/HYPOTHESIS: Islets are thought to be stably present in the adult human pancreas to maintain glucose homeostasis. However, identification of the pancreatic intraepithelial neoplasia (PanIN)-islet complex in mice and the presence of PanIN lesions in adult humans suggest that similar remodelling of islet structure and environment may occur in the human pancreas. To identify islet remodelling in a clinically related setting, we examine human donor pancreases with 3D histology to detect and characterise the human PanIN-islet complex. METHODS: Cadaveric donor pancreases (26-65 years old, n = 10) were fixed and sectioned (350 µm) for tissue labelling, clearing and microscopy to detect local islet remodelling for 3D analysis of the microenvironment. The remodelled microenvironment was subsequently examined via microtome-based histology for clinical assessment. RESULTS: In nine pancreases, we identified the unique peri-lobular islet aggregation associated with the PanIN lesion (16 lesion-islet complexes detected; size: 3.18 ± 1.34 mm). Important features of the lesion-islet microenvironment include: (1) formation of intra-islet ducts, (2) acinar atrophy, (3) adipocyte association, (4) inflammation (CD45+), (5) stromal accumulation (α-SMA+), (6) increase in Ki-67 proliferation index but absence of Ki-67+ alpha/beta cells and (7) in-depth and continuous duct-islet cell contacts, forming a cluster. The duct-islet cell cluster and intra-islet ducts suggest likely islet cell neogenesis but not replication. CONCLUSIONS/INTERPRETATION: We identify local islet remodelling associated with PanIN-islet complex in the adult human pancreas. The tissue remodelling and the evidence of inflammation and stromal accumulation suggest that the PanIN-islet complex is derived from tissue repair after a local injury.

Heterogeneity and neurovascular integration of intraportally transplanted islets revealed by 3-D mouse liver histology.

Intraportal islet transplantation has been clinically applied for treatment of unstable type 1 diabetes. However, in the liver, systematic assessment of the dispersed islet grafts and the graft-hepatic integration remains difficult, even in animal models. This is due to the lack of global and in-depth analyses of the transplanted islets and their microenvironment. Here, we apply three-dimensional (3-D) mouse liver histology to investigate the islet graft microstructure, vasculature, and innervation. Streptozotocin-induced diabetic mice were used in syngeneic intraportal islet transplantation to achieve euglycemia. Optically cleared livers were prepared to enable 3-D morphological and quantitative analyses of the engrafted islets. 3-D image data reveal the clot- and plaque-like islet grafts in the liver: the former are derived from islet emboli and associated with ischemia, whereas the latter (minority) resemble the plaques on the walls of portal vessels (e.g., at the bifurcation) with mild, if any, perigraft tissue damage. Three weeks after transplantation, both types of grafts are revascularized, yet significantly more lymphatics are associated with the plaque- than clot-like grafts. Regarding the islet reinnervation, both types of grafts connect to the periportal nerve plexus and develop peri- and intragraft innervation. Specifically, the sympathetic axons and varicosities contact the α-cells, highlighting the graft-host neural integration. We present the heterogeneity of the intraportally transplanted islets and the graft-host neurovascular integration in mice. Our work provides the technical and morphological foundation for future high-definitional 3-D tissue and cellular analyses of human islet grafts in the liver.NEW & NOTEWORTHY Modern 3-D histology identifies the clot- and plaque-like islet grafts in the mouse liver, which otherwise cannot be distinguished with the standard microtome-based histology. The two types of grafts are similar in blood microvessel density and sympathetic reinnervation. Their differences, however, are their locations, severity of associated liver injury, and access to lymphatic vessels. Our work provides the technical and morphological foundation for future high-definitional 3-D tissue/cellular analyses of human islet grafts in the liver.

Completion and Adverse Drug Events of Latent Tuberculosis Infection Treatment in Patients Receiving Dialysis: Predictors and Impacts of Different Regimens in a Prospective Cohort Study.

Although patients with end-stage renal disease receiving maintenance hemodialysis are at high risk for tuberculosis, the optimal treatment regimen for latent tuberculosis infection (LTBI) in this group has scarcely been studied for predictors of completion rate and adverse drug events (ADE). We prospectively enrolled dialysis patients for LTBI intervention from three medical centers in Taiwan. LTBI treatments were 3 months of weekly rifapentine plus isoniazid (3HP) and 9 months of daily isoniazid (9H). Completion rate, ADE, and reasons for treatment termination were recorded. Factors associated with treatment termination and ADE were analyzed using multivariate logistic regression. In all, 91 treatment courses (41 9H and 50 3HP) were surveyed. The completion rates were 61% for 9H and 82% for 3HP (P = 0.046). Use of 9H and development of ADE with a grade of ≥2 (≥grade 2 ADE) were associated with treatment termination. Hypersensitivity occurred in 29.2% of subjects in the 3HP group and 10.8% in the 9H group (P = 0.035) and independently correlated with 3HP regimen, diabetes mellitus (DM), and peritoneal dialysis (PD). Similarly, the independent predictors of ≥grade 2 ADE were use of 3HP regimen, presence of DM, and use of PD, whereas ≥grade 3 ADE were associated with eosinophil counts of >700/mm3 after 2 weeks of LTBI treatment even after adjustment for age and gender. In conclusion, for patients on dialysis, 3HP showed a higher rate of completion but also a higher rate of ≥grade 2 ADE than 9H. In addition, DM and PD were risk factors for ≥grade 2 ADE. Eosinophilia after 2-week treatment might be an alert for severe ADE.

Role of autophagy-related protein in the prognosis of combined hepatocellular carcinoma and cholangiocarcinoma after surgical resection.

BACKGROUND: Autophagy-related proteins may predict postresection overall survival (OS) and disease-free survival (DFS) in patients with combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CC). METHODS: We prospectively investigated how these proteins affect clinical prognosis in 40 patients who underwent hepatectomy for cHCC-CC from 2011 to 2019 at a Taiwanese hospital. Levels of autophagy-related proteins, namely LC3, Beclin-1, and p62, were immunohistochemically assessed in patient tumor and non-tumor tissues. RESULTS: We noted that LC3 expression was significantly correlated with mild clinicopathological characteristics, including macrovascular invasion, lymph node metastasis, American Joint Committee on Cancer and Barcelona Clinic Liver Cancer stages, recurrence, and mortality. Ten patient showed tumor recurrence, and 15 patients died. Postresection 5-year OS and DFS rates were 43.7 and 57.4%, respectively. Cox regression analysis showed that high intratumoral LC3 expression was significantly associated with improved OS [hazard ratio (HR; 95% confidence interval (CI)): (1.68-26.9), p = 0.007], but multiple tumors and microvascular invasion was significantly correlated with poor OS [HR (95% CI): 0.03 (0.01-0.34), p = 0.004, and 0.07 (0.01-0.46), p = 0.006, respectively]. Furthermore, high LC3 expression and cirrhosis had improved DFS [HR (95% CI): 51.3 (2.85-922), p = 0.008, and 17.9 (1.05-306), p = 0.046, respectively]. The 5-year OS and DFS rates were respectively 61.2 and 74.6% in high LC3 expression patients and 0 and 0% in those with low LC3 expression. CONCLUSION: High LC3 expression in tumors is significantly associated with mild clinicopathological characteristics and favorable clinical prognosis in patients with cHCC-CC after resection.

Surgical resection significantly promotes the overall survival of patients with hepatocellular carcinoma: a propensity score matching analysis.

BACKGROUND: The benefits of surgical resection (SR) for various Barcelona Clinic Liver Cancer (BCLC) stages of hepatocellular carcinoma (HCC) remain unclear. We investigated the risk factors of overall survival (OS) and survival benefits of SR over nonsurgical treatments in patients with HCC of various BCLC stages. METHODS: Overall, 2316 HCC patients were included, and their clinicopathological data and OS were recorded. OS was analyzed by the Kaplan-Meier method and Cox regression analysis. Propensity score matching (PSM) analysis was performed. RESULTS: In total, 66 (2.8%), 865 (37.4%), 575 (24.8%) and 870 (35.0%) patients had BCLC stage 0, A, B, and C disease, respectively. Furthermore, 1302 (56.2%) of all patients, and 37 (56.9%), 472 (54.6%), 313 (54.4%) and 480 (59.3%) of patients with BCLC stage 0, A, B, and C disease, respectively, died. The median follow-up duration time was 20 (range 0-96) months for the total cohort and was subdivided into 52 (8-96), 32 (1-96), 19 (0-84), and 12 (0-79) months for BCLC stages 0, A, B, and C cohorts, respectively. The risk factors for OS were (1) SR and cirrhosis; (2) SR, cirrhosis, and Child-Pugh (C-P) class; (3) SR, hepatitis B virus (HBV) infection, and C-P class; and (4) SR, HBV infection, and C-P class for the BCLC stage 0, A, B, and C cohorts, respectively. Compared to non-SR treatment, SR resulted in significantly higher survival rates in all cohorts. The 5-year OS rates for SR vs. non-SR were 44.0% versus 28.7%, 72.2% versus 42.6%, 42.6% versus 36.2, 44.6% versus 23.5%, and 41.4% versus 15.3% (all P values < 0.05) in the total and BCLC stage 0, A, B, and C cohorts, respectively. After PSM, SR resulted in significantly higher survival rates compared to non-SR treatment in various BCLC stages. CONCLUSIONS: SR conferred significant survival benefits to patients with HCC of various BCLC stages and should be considered a recommended treatment for select HCC patients, especially patients with BCLC stage B and C disease.

Two-year protocol biopsy after kidney transplantation in clinically stable recipients - a retrospective study.

The idea of protocol biopsy is to detect subclinical pathologies, including rejection, recurrent disease, or infection for early intervention and adjustment of immunosuppressants. Nevertheless, it is not adopted by most clinicians because of its low yield rate and uncertain long-term benefits. This retrospective study evaluated the impact of protocol biopsy on renal function and allograft survival. A two-year protocol biopsy was proposed for 190 stable patients; 68 of them accepted [protocol biopsy (PB) group], while 122 did not [nonprotocol biopsy (NPB) group]. The rejection diagnosis was made in 13 patients by protocol biopsy, and 11 of them had borderline rejection. In the following 5 years, graft survival was better in the PB group than in the NPB group (P = 0.0143). A total of 4 and 17 patients in the PB and NPB groups, respectively, had rejection events proven by indication biopsy. Renal function was better preserved in the PB group than in the NPB group (P = 0.0107) for patients with rejection events. Nevertheless, the survival benefit disappeared by a longer follow-up period (12-year, P = 0.2886). In conclusion, 2-year protocol biopsy detects subclinical pathological changes in rejection and preserves renal function by early intervention so as to prolong graft survival within 5 years.

Latent Tuberculosis Infection Increases in Kidney Transplantation Recipients Compared With Transplantation Candidates: A Neglected Perspective in Tuberculosis Control.

BACKGROUND: The prevalence and incidence of latent tuberculosis infection (LTBI) in patients with kidney transplantation remain unclear. METHODS: In this prospective study, we enrolled kidney transplantation candidates (KTCs) and recipients (KTRs) from 2014 to 2018. We defined LTBI as a positive result of QuantiFERON-TB Gold In-tube (QFT). We analyzed the predictors for LTBI acquisition and followed up on QFT assay test for 2 years among those initially without LTBI. RESULTS: Of 425 patients enrolled, 305 (71.8%) patients belonged to the KTC group and 120 (28.2%) to the KTR group. The initial QFT showed positive results in 32 (10.5%) and 24 (20.0%) patients in the KTC and KTR groups, respectively (P = .009). The QFT response value in patients with LTBI was higher in the KTR group than in the KTC group (1.85 vs 1.06 IU/mL, P = .046). Multivariate logistic regression showed that old age, absence of bacillus Calmette-Guérin (BCG) scar, presence of donor-specific antibody, and KTR group were independent factors for positive LTBI. For participants with initial negative QFT, positive QFT conversion within a 2-year follow-up was higher after kidney transplantation (20%) than in KTCs (5.5%) (P = .034). CONCLUSIONS: This study is the first cohort to follow up LTBI status in patients with kidney transplantation and shows its higher prevalence and incidence in KTRs. It indicates that surveillance of LTBI after renal transplantation is important. In addition to status of kidney transplantation, old age, no BCG vaccination, and positive donor-specific antibody are also positive predictors for LTBI.

Telbivudine for renal transplant recipients with chronic hepatitis B infection: a randomized controlled trial with early termination.

BACKGROUND: The aim of this study was to analyze changes in renal function in HBsAg-positive renal transplant recipients receiving lamivudine who did or did not switch to telbivudine. METHODS: In this prospective randomized clinical trial (RCT), HBsAg-positive renal transplant recipients who had received lamivudine prophylaxis for at least 6 months were 1:2 randomized to receive either lamivudine or telbivudine for another 24 months. Renal function was evaluated by creatinine level and estimated glomerular filtration rate (eGFR) at the time of randomization (baseline), 6, 12, 18, and 24 months respectively. RESULTS: This RCT was prematurely terminated after recruiting only 17 patients due to a high incidence (61.5%; 8/13) of clinical myalgia in the telbivudine group. Cox's proportional hazards model revealed that there was no independent predictor of myalgia. Based on intention-to-treat and per protocol analyses using generalized estimating equations, the patients in the randomized telbivudine group had a significantly increased eGFR and the patients in the lamivudine group had a significantly decreased eGFR at the end of follow-up compared to the values at study enrollment. However, there was no significant difference between the lamivudine and telbivudine groups. CONCLUSIONS: The renal protective effect of telbivudine for HBsAg positive renal transplant recipients was uncertain for high incidence of myalgia and only patients who were on telbivudine for 24 months had renal function maintenance.