There is a critical need for biomarkers of acute cellular rejection (ACR) in organ transplantation. We hypothesized that ACR leads to changes in donor-reactive T cell small extracellular vesicle (sEV) profiles in transplant recipient circulation that match the kinetics of alloreactive T cell activation. In rodent heart transplantation, circulating T cell sEV quantities (P < .0001) and their protein and mRNA cargoes showed time-specific expression of alloreactive and regulatory markers heralding early ACR in allogeneic transplant recipients but not in syngeneic transplant recipients. Next generation sequencing of their microRNA cargoes identified novel candidate biomarkers of ACR, which were validated by stem loop quantitative reverse transcription polymerase chain reaction (n = 10). Circulating T cell sEVs enriched from allogeneic transplant recipients mediated targeted cytotoxicity of donor cardiomyocytes by apoptosis assay (P < .0001). Translation of the concept and EV methodologies to clinical heart transplantation demonstrated similar upregulation of circulating T cell sEV profiles at time points of grade 2 ACR (n = 3 patients). Furthermore, T cell receptor sequencing of T cell sEV mRNA cargo demonstrated expression of T cell clones with intact complementarity determining region 3 signals. These data support the diagnostic potential of T cell sEVs as noninvasive biomarker of ACR and suggest their potential functional roles.

Objective: Surgery for ascending aneurysms in bicuspid aortic valve syndrome primarily includes Bentall root replacement, aortic valve replacement with supra-coronary ascending aorta replacement (AVRSCAAR), and valve-sparing root reimplantation (VSRR). Comparative analysis of long-term clinical and functional outcomes of these procedures is detailed. Methods: From 1997 to 2017, 635 patients with bicuspid aortic valve undergoing root complex-focused procedures electively were stratified by valvulopathy (ie, aortic stenosis vs aortic insufficiency) and substratified into ascending or root aneurysm phenotype. Inverse probability weights were calculated to adjust for baseline differences. Results: Kaplan-Meier curves for all-cause mortality demonstrated no difference between Bentall versus AVRSCAAR for aortic stenosis and aortic insufficiency presentations (log-rank P > .05). In patients with aortic stenosis, multivariable Cox regression showed significantly decreased risk of stroke for biologic AVRSCAAR (hazard ratio, 0.04; P = .013). Aortic reoperation rates were similar for biologic versus mechanical valves ( P = .353). In patients with aortic insufficiency, similar long-term mortality (hazard ratio, 0.95; P = .93), but lower stroke risk in biologic AVRSCAAR group by Cox regression, and lower aortic reoperation rate was noted (coefficient < 0.01; P < .001). Comparing Bentall to VSRR, mortality (hazard ratio, 0.12; P = .022) was significantly improved in patients undergoing VSRR, but recurrence of moderate or greater aortic insufficiency was higher in VSRR by multistate model (beta coefficient 2.63; P < .001). Conclusions: A tailored approach to heterogeneous ascending aneurysm pathologies in bicuspid aortic valve syndrome utilizing Bentall, AVRSCAAR, and VSRR procedures renders excellent long-term clinical and functional outcomes, with biologic conduits showing equivalent to improved clinical outcomes. (J Thorac Cardiovasc Surg 2024;167:2063-75)

BACKGROUND:There is a critical need for development of biomarkers to noninvasively monitor for lung transplant rejection. We investigated the potential of circulating donor lung-specific exosome profiles for time-sensitive diagnosis of acute rejection in a rat orthotopic lung transplant model. METHODS:Left lungs from Wistar transgenic rats expressing human CD63-GFP, an exosome marker, were transplanted into fully MHC-mismatched Lewis recipients or syngeneic controls. Recipient blood was collected between 4 h and 10 d after transplantation, and plasma was processed for exosome isolation by size exclusion column chromatography and ultracentrifugation. Circulating donor exosomes were profiled using antihuman CD63 antibody quantum dot on the nanoparticle detector and via GFP trigger on the nanoparticle flow cytometer. RESULTS:In syngeneic controls, steady-state levels of circulating donor exosomes were detected at all posttransplant time points. Allogeneic grafts lost perfusion by day 8, consistent with acute rejection. Levels of circulating donor exosomes peaked on day 1, decreased significantly by day 2, and then reached baseline levels by day 3. Notably, decrease in peripheral donor exosome levels occurred before grafts had histological evidence of acute rejection. CONCLUSIONS:Circulating donor lung-specific exosome profiles enable an early detection of acute rejection before histologic manifestation of injury to the pulmonary allograft. As acute rejection episodes are a major risk factor for the development of chronic lung allograft dysfunction, this biomarker may provide a novel noninvasive diagnostic platform that can translate into earlier therapeutic intervention for lung transplant patients.

Preeclampsia is a major cause of mortality and morbidity in expecting mothers and is one of the most common causes of pregnancy complications and premature birth [2]. Along with eclampsia, it is directly associated with 10-15% of maternal deaths [2]. Currently, it is diagnosed during the second or third trimester after clinical symptoms are displayed, but studies have attempted to understand the pathophysiologic mechanism underlying preeclampsia, noting its beginnings in the first trimester. Although there is no defined cause nor is there a cure for the disease, it is widely agreed that preeclampsia stems from the placenta and is related to a decrease in uteroplacental blood flow and hypoxia [3].

Preeclampsia is the most common placental pathology in pregnant females, with increased morbidity and mortality incurred on the mother and the fetus. There is a need for improved biomarkers for diagnosis and monitoring of this condition. Placental syncytiotrophoblasts at the maternal-fetal interface release nanoparticles, including extracellular microvesicles, into the maternal blood during pregnancy. Syncytiotrophoblast extracellular microvesicles (STEVs) are being studied for their diagnostic potential and for their potential physiologic role in preeclampsia. We hypothesized that STEV profiles in maternal circulation would be altered under conditions of preeclampsia compared to normal pregnancy. Extracellular vesicles (EVs) released by BeWo cells in vitro showed high expression of syncytin-1, but no plac1 expression, demonstrating that trophoblast cell EVs express syncytin-1 on their surface. Placental alkaline phosphatase also showed high expression on BeWo EVs, but due to concern for cross reactivity to highly prevalent isoforms of intestinal and bone alkaline phosphatase, we utilized syncytin-1 as a marker for STEVs. In vivo, syncytin-1 protein expression was confirmed in maternal plasma EVs from Control and Preeclampsia subjects by Western blot, and overall, lower expression was noted in samples from patients with preeclampsia (n = 8). By nanoparticle analysis, EV profiles from Control and Preeclampsia groups showed similar total plasma EV quantities (p = 0.313) and size distribution (p = 0.415), but STEV quantitative signal, marked by syncytin-1 specific EVs, was significantly decreased in the Preeclampsia group (p = 2.8 × 10−11). Receiver operating characteristic curve demonstrated that STEV signal threshold cut-off of <0.316 was 95.2% sensitive and 95.6% specific for diagnosis of preeclampsia in this cohort (area under curve = 0.975 ± 0.020). In conclusion, we report that the syncytin-1 expressing EV profiles in maternal plasma might serve as a placental tissue specific biomarker for preeclampsia.

OBJECTIVE:The durability of root repair for acute type A aortic dissection is not well studied in the context of aortic insufficiency and stability of the sinuses of Valsalva. We compared clinical and functional outcomes in patients undergoing root repair and replacement for acute type A aortic dissection. METHODS:Of 716 patients undergoing surgery for acute type A aortic dissection, 585 (81.7%) underwent root repair and 131 (18.3%) underwent root replacement. Survival, cumulative incidence of reoperation, aortic insufficiency, and sinuses of Valsalva dilation were compared between the 2 groups. RESULTS:Survival at 1, 5, and 10 years was 84.1% versus 77.3%, 70.8% versus 69.2%, 57.6% versus 58.0% in the root repair and replacement groups, respectively (P = .69). Cumulative incidence of reoperation at 1, 5, and 10 years was 0.0% versus 0.8%, 1.4% versus 3.8%, and 3.4% versus 8.6% in the root repair and root replacement groups, respectively (P = .011). Multivariable Cox regression identified sinuses of Valsalva diameter 45 mm or more as a risk factor for proximal aortic reoperation (hazard ratio, 9.06; 95% confidence interval, 1.26-65.24). In a repeated-measures, linear, mixed-effects model, root replacement was associated with smaller follow-up of sinuses of Valsalva dimensions (β = -0.66, P < .001). In an ordinal longitudinal mixed model, root replacement was associated with lower severity of postoperative aortic insufficiency (β = -3.10, P < .001). CONCLUSIONS:Survival is similar, but the incidence of aortic insufficiency and root dilation may be greater after root repair compared with root replacement for acute type A aortic dissection.

Background. Patients with acute type A aortic dissection (ATAAD) present with heterogeneous involvement of the aortic root complex. Despite this variation, the aortic root can usually be preserved the majority of the time by Teflon (WL Gore, Newark, DE) inlay patch reconstruction of the dissected sinuses of Valsalva (SOV). In this study, we report the long term anatomic, functional, and clinical outcomes associated with the preserved SOV after surgery for ATAAD. Methods. From 2002-2017, of 776 emergency ATAAD operations at a single institution, 558 (71.9%) underwent valve resuspension with SOV preservation. Echocardiography reports were reviewed to obtain postoperative SOV dimensions. Cumulative incidence of SOV dilation >= 4 5mm was calculated using the Fine-Gray method with death as a competing risk. Repeated-measures linear mixed effects model was used to determine risk factors for SOV growth over time. Results. During the follow-up period, 62 of 558 (11.1%) patients developed SOV diameter >= 45 mm. Cumulative incidence of SOV dilation >= 45mmat 1, 5, and 10 years was 5.5%, 12.4%, and 18.9% respectively. In amultivariable Cox regressionmodel, preoperative SOVdiameter >= 45mm was associated with a hazard ratio of 14.11 (95% confidence interval 7.03-31.62) for postoperative SOVdilation >= 45mm. In a repeated-measures linear mixed effects model, preoperative and discharg eSOV diameter were significant predictors of SOV dilation. Postoperative time course was also identified as significant indicating growth over time. Conclusions. The preserved sinuses of Valsalva after surgery for ATAAD may be prone to progressive dilatation over time. Closer echocardiographic surveillance may be warranted in these patients. (C) 2020 by The Society of Thoracic Surgeons

Background. Endomyocardial biopsy remains the gold standard for distinguishing types of immunologic injury—acute versus antibody-mediated rejection (AMR). Exosomes are tissue-specific extracellular microvesicles released by many cell types, including transplanted heart. Circulating transplant heart exosomes express donor-specific human leukocyte antigen (HLA) I molecules. As AMR is mediated by antibodies to donor HLAs, we proposed that complement deposition that occurs with AMR at tissue level would also occur on circulating donor heart exosomes. Methods. Plasma exosomes in 4 patients were isolated by column chromatography and ultracentrifugation. Donor heart exosomes were purified using anti-donor HLA I antibody beads and complement C4d protein expression was assessed in this subset as marker for AMR. Results. Three patients had no rejection episodes. Circulating donor heart exosomes showed troponin protein and mRNA expression at all follow-up time points. One patient developed AMR on day 14 endomyocardial biopsy that was treated with rituximab, IVIG/plasmapheresis. Time-specific detection of C4d protein was seen in donor heart exosome subset in this patient, which resolved with treatment. C4d was not seen in other 3 patients’ donor exosomes. Conclusions. Anti-donor HLA I specificity enables characterization of circulating donor heart exosomes in the clinical setting. Further characterization may open the window to noninvasively diagnose rejection type, such as AMR.

Objective: The incidence of elderly patients with acute type A aortic dissection is increasing. A recent analysis of the International Registry of Acute Aortic Dissection failed to show a mortality benefit with surgery compared with medical management in octogenarians. Therefore, we compared our institutional outcomes of emergency surgery for acute type A aortic dissection in octogenarians versus septuagenarians to understand the outcomes of surgical intervention in elderly patients. Methods: From 2002 to 2017, 70 octogenarians (aged >= 80 years) and 165 septuagenarians (70-79 years) underwent surgery for acute type A aortic dissection (N = 235, total). Quality of life was assessed by the RAND Short Form-36 quality of life survey. Midterm clinical and functional data were obtained retrospectively. Results: At baseline, septuagenarians had a higher prevalence of diabetes (20.6% vs 5.7%, P = .01). The prevalence of cardiopulmonary resuscitation was 4.8% versus 10.0% (P = .24) in septuagenarians and octogenarians. The prevalence of cardiogenic shock was 18.2% versus 27.1% (P = .17). Thirty-day/in-hospital mortality was 21.2% versus 28.6% (P = .29). Multivariable logistic regression identified cardiogenic shock as an independent risk factor for in-hospital mortality (odds ratio, 10.07; 95% confidence interval, 2.30-44.03) in octogenarians. Survival at 5 years was 49.7% (42.1%-58.6%) versus 34.2% (23.9%-48.8%) in septuagenarians and octogenarians, respectively. Responses to the quality of life survey were no different between septuagenarians and octogenarians across all 8 quality of life categories. Conclusions: Clinical outcomes after surgery for acute type A aortic dissection are similar in octogenarians and septuagenarians. For discharged survivors, quality of life remains favorable and does not differ between the 2 groups.

Islet cell transplantation is curative therapy for patients with complicated autoimmune type 1 diabetes (T1D). We report the diagnostic potential of circulating transplant islet–specific exosomes to noninvasively distinguish pancreatic β cell injury secondary to recurrent autoimmunity vs immunologic rejection. A T1D patient with hypoglycemic unawareness underwent islet transplantation and maintained normoglycemia until posttransplant day 1098 before requiring exogenous insulin. Plasma analysis showed decreased donor islet exosome quantities on day 1001, before hyperglycemia onset. This drop in islet exosome quantity signified islet injury, but did not distinguish injury type. However, analysis of purified transplant islet exosome cargoes showed decrease in insulin-containing exosomes, but not glucagon-containing exosomes, indicating selective destruction of transplanted β cells secondary to recurrent T1D autoimmunity. Furthermore, donor islet exosome cargo analysis showed time-specific increase in islet autoantigen, glutamic acid decarboxylase 65 (GAD65), implicated in T1D autoimmunity. Time-matched analysis of plasma transplant islet exosomes in 3 control subjects undergoing islet cell transplantation failed to show changes in islet exosome quantities or intraexosomal cargo expression of insulin, glucagon, and GAD65. This is the first report of noninvasive diagnosis of recurrent autoimmunity after islet cell transplantation, suggesting that transplant tissue exosome platform may serve as a biomarker in islet transplant diagnostics.

The stem cell field is hindered by its inability to noninvasively monitor transplanted cells within the target organ in a repeatable, time-sensitive, and condition-specific manner. We hypothesized that quantifying and characterizing transplanted cell-derived exosomes in the recipient plasma would enable reliable, noninvasive surveillance of the conditional activity of the transplanted cells. To test this hypothesis, we used a human-into-rat xenogeneic myocardial infarction model comparing two well-studied progenitor cell types: cardiosphere-derived cells (CDCs) and c-kit+ cardiac progenitor cells (CPCs), both derived from the right atrial appendage of adults undergoing cardiopulmonary bypass. CPCs outperformed the CDCs in cell-based and in vivo regenerative assays. To noninvasively monitor the activity of transplanted CDCs or CPCs in vivo, we purified progenitor cell-specific exosomes from recipient total plasma exosomes. Seven days after transplantation, the concentration of plasma CPC-specific exosomes increased about twofold compared to CDC-specific exosomes. Computational pathway analysis failed to link CPC or CDC cellular messenger RNA (mRNA) with observed myocardial recovery, although recovery was linked to the microRNA (miRNA) cargo of CPC exosomes purified from recipient plasma. We further identified mechanistic pathways governing specific outcomes related to myocardial recovery associated with transplanted CPCs. Collectively, these findings demonstrate the potential of circulating progenitor cell-specific exosomes as a liquid biopsy that provides a noninvasive window into the conditional state of the transplanted cells. These data implicate the surveillance potential of cell-specific exosomes for allogeneic cell therapies.

BACKGROUND & AIMS Growth, progression, and drug resistance of pancreatic ductal adenocarcinomas (PDACs) have been associated with increased levels and activity of glycogen synthase kinase 3 beta (GSK3B) and histone deacetylases (HDACs). We designed and synthesized molecules that simultaneously inhibit the activities of both enzymes. We tested the effects of one of these molecules, Metavert, in pancreatic cancer cells and mice with pancreatic tumors. METHODS We tested the ability of Metavert to bind GSK3B and HDACs using surface plasmon resonance. MIA PaCa-2, Bx-PC3, HPAF-II, and HPDE6 cell lines were incubated with different concentrations of Metavert, with or without paclitaxel or gemcitabine, or with other inhibitors of GSK3B and HDACs; cells were analyzed for apoptosis and migration and by immunoblotting, immunofluorescence, and real-time polymerase chain reaction. Krasþ/LSLG12D;Trp53þ/LSLR172H;Pdx-1-Cre (KPC) mice (2 months old) were given injections of Metavert (5 mg/kg, 3 times/week) or vehicle (control). B6.129J mice with tumors grown from UN-KPC961-Luc cells were given injections of Metavert or vehicle. Tumors and metastases were counted and pancreata were analyzed by immunohistochemistry. Glucose metabolism was measured using 13C-glucose tracer and mass spectroscopy and flow cytometry. Cytokine levels in blood samples were measured using multiplexing enzyme-linked immunosorbent assay. RESULTS Metavert significantly reduced survival of PDAC cells but not nontransformed cells; the agent reduced markers of the epithelial-to-mesenchymal transition and stem cells in PDAC cell lines. Cells incubated with Metavert in combination with irradiation and paclitaxel or gemcitabine had reduced survival compared with cells incubated with either agent alone; Metavert increased killing of drug-resistant PDAC cells by paclitaxel and gemcitabine. PDAC cells incubated with Metavert acquired normalized glucose metabolism. Administration of Metavert (alone or in combination with gemcitibine) to KPC mice or mice with syngeneic tumors significantly increased their survival times, slowed tumor growth, prevented tumor metastasis, decreased tumor infiltration by tumor-associated macrophages, and decreased blood levels of cytokines. CONCLUSIONS In studies of PDAC cells and 2 mouse models of PDAC, we found a dual inhibitor of GSK3B and HDACs (Metavert) to induce cancer cell apoptosis, reduce migration and expression of stem cell markers, and slow growth of tumors and metastases. Metavert had synergistic effects with gemcitabine.

Background. Annular stabilization techniques in bicuspid aortic valve (BAV) repair include valve-sparing root reimplantation (VSRR), external subannular aortic ring (ESAR), and subcommissural annuloplasty (SCA). Unlike VSRR that offers neoroot creation, ESAR and SCA offer annular reduction only. We compared long-term functional outcomes to understand BAV repair durability. Methods. From 2004 to 2017, 137 patients underwent Sievers type I BAV repair (VSRR, n = 54; ESAR, n = 22; SCA, n = 51). Prospectively maintained BAV repair database was queried for clinical and functional outcomes. Data were analyzed by logistic regression, threshold regression, multistate survival, and transition models for BAV repair durability. Results. VSRR patients had larger preoperative sinus dimensions (p < 0.001), but mean preoperative annulus size was similar for VSRR, ESAR, and SCA (29.3 +/- 3.7 mm, 29.8 +/- 3.8 mm, and 29.7 +/- 3.8mm, respectively; p = 0.807). Degree of annular reduction (p = 0.280) was comparable between the groups. Intraoperative postrepair freedom from aortic insufficiency (AI) 1+ or greater was 100% across the entire cohort. By logistic regression, important predictors of recurrent AI (1+ and >= 2+) were preoperative annulus of 30 mm or more for SCA. Threshold regression confirmed annulus of 30 mm or more as risk factor for recurrent AI of 1+ or greater for SCA. Risk to relapse from no AI to AI 1+ was equal between the groups; however, once AI 1+ was reached, there was a 2.5-fold increased risk for patients with annulus of 30 mm or more who underwent SCA to progress to recurrent AI of 2+ or greater. Conclusions. VSRR is associated with improved longitudinal BAV durability compared with SCA. Preoperative annulus diameter of 30 mm or more is associated with increased recurrent AI, especially for SCA patients. For annular indications, ESAR might offer comparable functional outcomes with VSRR; however, further follow-up is critical. (C) 2018 by The Society of Thoracic Surgeons

Curcumin, an aromatic phytoextract from the turmeric (Curcuma longa) rhizome, has been used for centuries for a variety of purposes, not the least of which is medicinal. A growing body of evidence suggests that curcumin has a broad range of potentially therapeutic pharmacological properties, including anti-inflammatory, anti-fibrotic, and anti-neoplastic effects, among others. Clinical applications of curcumin have been hampered by quality control concerns and limited oral bioavailability, although novel formulations appear to have largely overcome these issues. Recent in vitro and in vivo studies have found that curcumin's cytoprotective and other biological activities may play a role in an array of benign and malignant hepatobiliary conditions, including but not limited to non-alcoholic fatty liver disease, cholestatic liver disease (e.g. primary sclerosing cholangitis), and cholangiocarcinoma. Here we provide an overview of fundamental principles, recent discoveries, and potential clinical hepatobiliary applications of this pleiotropic phytocompound.

Smoking is a major risk factor for developing pancreatic adenocarcinoma (PDAC); however, little is known about the mechanisms involved.Here we employed a genetic animal model of early stages of PDAC that overexpresses oncogenic Kras in the pancreas to investigate the mechanisms of smoking-induced promotion of the disease in vivo. We confirmed the regulation of the interactions between the tumor microenvironment cells using in vitro cellular systems.Aerial exposure to cigarette smoke stimulated development of pancreatic intraepithelial neaoplasia (PanIN) lesions associated with a tumor microenvironment-containing features of human PDAC including fibrosis, activated stellate cells, M2-macrophages and markers of epithelial-mesenchymal transition (EMT). The pro-cancer effects of smoking were prevented by Histone Deacetylase HDAC I/II inhibitor Saha.Smoking decreased histone acetylation associated with recruitment of and phenotypic changes in macrophages; which in turn, stimulated survival and induction of EMT of the pre-cancer and cancer cells. The interaction between the cancer cells and macrophages is mediated by IL-6 produced under the regulation of HDAC3 translocation to the nucleus in the cancer cells. Pharmacological and molecular inhibitions of HDAC3 decreased IL-6 levels in cancer cells. IL-6 stimulated the macrophage phenotype change through regulation of the IL-4 receptor level of the macrophage.This study demonstrates a novel pathway of interaction between cancer cells and tumor promoting macrophages involving HDAC3 and IL-6. It further demonstrates that targeting HDAC3 prevents progression of the disease and could provide a strategy for treating the disease considering that the HDAC inhibitor we used is FDA approved for a different disease.

A 75-year-old woman was hospitalized with generalized weakness, malaise, nonproductive cough, and new-onset abdominal pain, for which inpatient gastroenterology consultation was requested. The patient’s medical history included long-standing hypertension and 55 pack-years of smoking. Physical examination revealed mild tachypnea, right upper quadrant tenderness, and a mass in the right lower quadrant extending below the level of the superior iliac crest, possibly contiguous with the liver. Laboratory investigation was notable for alkaline phosphatase of 236 U/L (normal, 35–105 U/L), aspartate aminotransferase of 239 U/L (normal, 8–43 U/L), alanine aminotransferase of 436 U/L (normal, 7–45 U/L), and total bilirubin of 3.3 mg/dL (normal, ≤1.2 mg/dL). Computed tomography of the abdomen and pelvis was obtained, demonstrating innumerable hepatic lesions and extension of the right hepatic lobe into the pelvis (Figure A). Positron emission tomography was performed, revealing a large, solitary, fluorodeoxyglucose-avid pulmonary mass (Figure B). Core biopsy of the mass was positive for small cells with a high nucleocytoplasmic ratio which stained positive for neurosecretory markers (Figure C),1Kalhor N. Zander D.S. Liu J. TTF-1 and p63 for distinguishing pulmonary small-cell carcinoma from poorly differentiated squamous cell carcinoma in previously pap-stained cytologic material.Mod Pathol. 2006; 19: 1117-1123Scopus (88) Google Scholar thus confirming a diagnosis of small cell lung carcinoma (SCLC). SCLC is an epithelial lung cancer that accounts for approximately 15% of all new lung cancer diagnoses and is strongly associated with cigarette smoking. SCLC preferentially metastasizes to the liver and less frequently to bone and brain. The presentation of metastatic SCLC varies widely, from asymptomatic (ie, incidental diagnosis) to nonspecific serum liver test abnormalities to acute liver failure with hepatomegaly, the latter of which can develop even before the onset of pulmonary symptoms.2Brown W.R. Dee E. Dysphagia in a patient with recurrent small-cell lung cancer.Gastroenterology. 2013; 144: 252-253Google Scholar Aside from SCLC, only ocular melanoma and neuroblastoma have been reported to present with metastatic massive hepatomegaly.3Rich N.E. Sanders C. Hughes R.S. et al.Malignant infiltration of the liver presenting as acute liver failure.Clin Gastroenterol Hepatol. 2015; 13: 1025-1028Google Scholar Accurate diagnosis in these cases is critical given that an established treatment for acute liver failure is liver transplantation, which is contraindicated in the presence of metastatic malignancy. Complicating accurate diagnosis is the observation that SCLC involving the liver can manifest without discrete lesions (ie, only hepatomegaly) on imaging, thus necessitating tissue acquisition. A recent study from a large, multicenter acute liver registry suggests that this scenario may in fact be more common than previously appreciated.3Rich N.E. Sanders C. Hughes R.S. et al.Malignant infiltration of the liver presenting as acute liver failure.Clin Gastroenterol Hepatol. 2015; 13: 1025-1028Google Scholar Our patient underwent biliary stenting via endoscopic retrograde cholangiography, after which combined chemotherapy with etoposide and cisplatin was initiated with concurrent radiotherapy. This case highlights the clinical pearl that for patients who present with hepatomegaly (with or without discrete hepatic lesions on imaging), metastatic SCLC should be included in the differential diagnosis; testing to rule out this entity, and the few others that can cause massive metastatic hepatomegaly, should be considered, along with the requisite diagnostic testing.

Kupffer cells play a central role in the pathogenesis of alcoholic hepatitis(AH). It is believed that alcohol increases the gut permeability that results in raised levels of serum endotoxins containing lipopolysaccharides(LPS). LPS binds to LPS-binding proteins and presents it to a membrane glycoprotein called CD14, which then activates Kupffer cells via a receptor called tolllike receptor 4. This endotoxin mediated activation of Kupffer cells plays an important role in the inflammatory process resulting in alcoholic hepatitis. There is no effective treatment for AH, although notable progress has been made over the last decade in understanding the underlying mechanism of alcoholic hepatitis. We specifically review the current research on the role of Kupffer cells in the pathogenesis of AH and the treatment strategies. We suggest that the imbalance between the pro-inflammatory and the anti-inflammatory process as well as the increased production of reactive oxygen species eventually lead to hepatocyte injury, the final event of alcoholic hepatitis.