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1.
Dig Dis Sci ; 2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31407130

RESUMO

BACKGROUND: Thrombocytopenia is a hallmark of advanced liver disease. Platelets, growth factors (GFs), and vascular integrity are closely linked factors in disease pathogenesis, and their relationship, particularly in early disease stages, is not entirely understood. The aim was to compare circulating platelets, growth factors, and vascular injury markers (VIMs) in hepatitis C-infected (HCV) patients with early fibrosis and cirrhosis. METHODS: Retrospective evaluation of serum GFs and VIMs by ELISA were evaluated from twenty-six HCV patients. Analytes from an earlier time-point were correlated with MELD at a later time-point. RESULTS: Platelets and GFs decreased, and VIMs increased with fibrosis. Platelets correlated positively with PDGF-AA, PDGF-BB, TGFB1, EGF, and P-selectin, and negatively with ICAM-3 and VCAM-1. P-selectin showed no correlations with VIMs but positively correlated with PDGF-AA, PDGF-BB, TGFB1, and EGF. Soluble VCAM-1 and ICAM-3 were linked to increasing fibrosis, liver enzymes, and synthetic dysfunction. Higher VCAM-1 and ICAM-3 and lower P-selectin at an earlier time-point were linked to higher MELD score at a later time-point. CONCLUSION: In chronic HCV, progressive decline in platelets and growth factors with fibrosis and their associations suggest that platelets are an important source of circulating GFs and influence GF decline with fibrosis. Enhanced markers of vascular injury in patients with early fibrosis suggest an earlier onset of endothelial dysfunction preceding cirrhosis. Associations of VIMs with platelets suggest a critical link between platelets and vascular homeostasis. Circulating markers of vascular injury may not only have prognostic importance but emphasize the role of vascular dysfunction in liver disease pathogenesis (NCT00001971).

2.
Hepatology ; 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31432525

RESUMO

We thank Drs. Huang and colleagues for the interest in our manuscript on the use of noninvasive markers to identify advance fibrosis in a cohort of HIV-HBV infected adults1 . One strength of our study was the central reading of liver histology and that only biopsies determined as adequate (i.e., representative) by the HBRN Pathology committee were included. As mentioned in our methods and limitations sections, we acknowledged the possibility that lack of portal triad counting and sampling error may have impacted our results,2 although it has been our experience that sample variation effects are mitigated in large cohorts, such as ours. This article is protected by copyright. All rights reserved.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31351862

RESUMO

BACKGROUND: The prognosis of metastatic colorectal cancer (mCRC) is poor. We assessed the feasibility, safety, and efficacy of the anti-programmed cell death 1 fusion protein AMP-224 in combination with low-dose cyclophosphamide and stereotactic body radiation (SBRT) treatment in patients with mCRC refractory to standard chemotherapy. PATIENTS AND METHODS: Fifteen patients were enrolled. Six received SBRT 8 Gy on day 0 (dose level 1), whereas 9 received 8 Gy on days -2 to day 0. All received cyclophosphamide 200 mg/m2 intravenously (I.V.) on day 0. On day 1, both groups received AMP-224 10 mg/kg I.V., repeated every 2 weeks for a total of 6 doses. Primary end points were feasibility and safety. RESULTS: Ten (67%) patients completed 6 doses of AMP-224; 5 patients (33%) discontinued treatment because of disease progression. No dose-limiting toxicity was observed; 9 patients (60%) experienced treatment-related adverse events, all Grade 1 or 2. No objective response was noted; 3 patients (20%) had stable disease. Median progression-free survival and overall survival were 2.8 months (95% confidence interval [CI], 1.2-2.8 months) and 6.0 months (95% CI, 2.8-9.6 months), respectively. M2 macrophage polarization was present in the pretreatment tumor biopsy samples, but not post-treatment samples. CONCLUSION: AMP-224 in combination with SBRT and low-dose cyclophosphamide was well tolerated, however, no significant clinical benefit was observed in patients with mCRC.

4.
Antivir Ther ; 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31359874

RESUMO

BACKGROUND: While acute changes in hepatic fibrosis are recognized shortly after achieving sustained virologic response (SVR) using direct acting antiviral therapies, long-term outcomes for the growing population of successfully treated patients with hepatitis C virus (HCV) remain uncertain. The aim of this study is to characterize long-term changes in fibrosis following SVR in patients with and without HIV and to identify potential factors associated with progression or regression of fibrosis. METHODS: We completed a prospective longitudinal study of 162 subjects with HCV (34% HIV-coinfected) with pre-treatment fibrosis stage determined by liver biopsy and post-SVR transient elastography. Progression of fibrosis was defined as a 2-stage or greater increase in fibrosis, while regression was defined as a 2-stage or greater decrease at last follow-up. The median duration of follow-up was 4.1 years. RESULTS: Fibrosis progression occurred in 4% of subjects while regression occurred in 7% and 89% were stable and did not differ by HIV coinfection. Fibrosis progression was associated with increased body mass index (BMI), hepatic steatosis, and smoking pack-years. In a multivariable logistic regression, HIV coinfection (p=0.009), lower steatosis score (p<0.05) and lower smoking pack-years (p=0.0007) were associated with a lower fibrosis score at last follow-up. CONCLUSION: We identify potentially important relationships between BMI, hepatic steatosis, and smoking and changes in hepatic fibrosis post-SVR in patients with and without HIV co-infection. Attention to modifiable risk factors such as body weight and smoking may reduce the risk of liver disease progression in the growing population of successfully treated chronic HCV patients.

5.
Hepatology ; 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31318454

RESUMO

Non-cirrhotic portal hypertension (NCPH) is a heterogenous group of liver disorders characterized by elevated portal pressures in the absence of cirrhosis. Nodular regenerative hyperplasia (NRH) is a common cause of NCPH and can be due to drugs, hematological, autoimmune, and neoplastic disorders.(1) Patients with NCPH appear clinically distinct from cirrhotic patients due to their age, lack of significant alcohol intake or metabolic syndrome, and often carry associated risk factors (i.e. primary immunodeficiency). Interestingly, NCPH, especially when due to NRH, often results in peri- or pre-sinusoidal portal hypertension and unlike cirrhotic disease, patients often have a normal or mildly elevated hepatic venous pressure gradient (HVPG) that does not accurately reflect their actual degree of portal hypertension. Thus, it is unclear if HVPG measurements are routinely needed in the evaluation of patients suspected to have NCPH. This article is protected by copyright. All rights reserved.

6.
J Pediatr Gastroenterol Nutr ; 69(2): 152-159, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31169665

RESUMO

OBJECTIVES: The aim of this study was to provide an overview of the presenting features, etiologies, and outcomes of children enrolled in the Drug-induced Liver Injury Network (DILIN) prospective and retrospective studies. METHODS: Consecutive definite, highly likely, or probable cases in children enrolled into the ongoing DILIN prospective and retrospective studies between September 2004 and February 2017 were reviewed. RESULTS: Fifty-seven cases were adjudicated as definite (14), highly likely (30), or probable (13) DILI. Median age was 14.3 years (1.7-17.9), 67% female, and 82% Caucasian. At DILI onset, 82% had hepatocellular injury with a median alanine aminotransferase of 411 U/L (33-4185), alkaline phosphatase 203 U/L (62-1177), and total bilirubin 3.3 mg/dL (0.2-33.9). The median duration of suspect medication use was 55 days (1-2789) and the most frequently implicated individual agents were minocycline (n = 11) and valproate (n = 6). Sixty-three percent were hospitalized and 3 (5%) underwent liver transplant within 1 month of DILI onset. Among 46 children followed for at least 6 months, 8 (17%) met criteria for chronic DILI with 6 of them having persistent liver injury at 24 months of follow-up. A genome-wide association study in 39 Caucasian children focusing on regions associated with pediatric cholestatic liver disease failed to demonstrate any single nucleotide polymorphism associated with DILI susceptibility or outcome. CONCLUSIONS: Antimicrobials (51%) and antiepileptic drugs (21%) are the most frequently implicated agents in pediatric DILI patients. Although the majority of cases are self-limited, there is potential for serious morbidity including acute liver failure, chronic liver injury, and death.

7.
Hepatology ; 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31220357

RESUMO

Noninvasive biomarkers are used increasingly to assess fibrosis in patients with chronic liver disease. We determined the utility of dual cutoffs for noninvasive biomarkers to exclude and confirm advanced fibrosis in hepatitis B virus (HBV)-human immunodeficiency virus (HIV) co-infected patients receiving combined antiretroviral therapy. Participants were anti-HIV/hepatitis B surface antigen-positive adults from eight clinical sites in the United States and Canada of the Hepatitis B Research Network. Fibrosis was staged by a central pathology committee using the Ishak fibrosis score (F). Clinical, laboratory, and vibration-controlled transient elastography (VCTE) data were collected at each site. Dual cutoffs for three noninvasive biomarkers (aspartate aminotransferase-to-platelet ratio index, Fibrosis-4 index [FIB-4], and liver stiffness by VCTE) with the best accuracy to exclude or confirm advanced fibrosis (F ≥ 3) were determined using established methodology. Of the 139 enrolled participants, 108 with a liver biopsy and having at least one noninvasive biomarker were included: 22% had advanced fibrosis and 54% had normal alanine aminotransferase. The median (interquartile range) of APRI (n = 106), FIB-4 (n = 106), and VCTE (n = 63) were 0.34 (0.26-0.56), 1.35 (0.99-1.89), and 4.9 (3.8-6.8) kPa, respectively. The area under the curve for advanced fibrosis was 0.69 for APRI, 0.66 for FIB-4, and 0.87 for VCTE. VCTE cutoffs of 5.0 kPa or less (to exclude) and 8.8 kPa or greater (to confirm) advanced fibrosis had a sensitivity of 92.3% and specificity of 96.0%, respectively, and accounted for 65.1% of participants. Among the 34.9% with values between the cutoffs, 26.1% had advanced fibrosis. Considering APRI or FIB-4 jointly with VCTE did not improve the discriminatory capacity. Conclusion: VCTE is a better biomarker of advanced fibrosis compared with APRI or FIB-4 in HBV/HIV co-infected adults on combined antiretroviral therapy. Using VCTE dual cutoffs, approximately two-thirds of patients could avoid biopsy to determine advanced fibrosis.

8.
Br J Haematol ; 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31218662

RESUMO

Vibration controlled transient elastography (VCTE) is validated for the evaluation of hepatic fibrosis in different liver diseases. Sickle cell liver disease (SCLD) results from a cumulative hepatic injury and its lifelong and progressive nature raises the need for a non-invasive tool for fibrosis evaluation. Fifty patients, aged between 23 and 59 years with sickle cell disease and suspected SCLD underwent a VCTE followed by a liver biopsy. Biopsies were evaluated for various scores of liver disease that were then correlated to VCTE score. 90% of our patients had an Ishak Fibrosis (IF) score between 0-2 (Group A-minimal to no fibrosis) and 10% of the patients had IF score between 3-6 (Group B-advanced fibrosis). The median Transient Elastography (TE) for patients in Groups A and B was 4·8 kilopascals (kPa) and 17·6 kPa, respectively. A positive correlation was shown between TE and IF score, R = 0·0·68 (P = <0·0001); a positive correlation was also shown with Histology Activity Index fibrosis score, R = 0·64 (P = <0·0001). This study emphasises the need for further studies of non-invasive tools and their utility in liver fibrosis evaluation of patients with SCLD.

9.
Sci Transl Med ; 11(495)2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31167928

RESUMO

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a monogenic disorder caused by AIRE mutations, presents with several autoimmune diseases. Among these, endocrine organ failure is widely recognized, but the prevalence, immunopathogenesis, and treatment of non-endocrine manifestations such as pneumonitis remain poorly characterized. We enrolled 50 patients with APECED in a prospective observational study and comprehensively examined their clinical and radiographic findings, performed pulmonary function tests, and analyzed immunological characteristics in blood, bronchoalveolar lavage fluid, and endobronchial and lung biopsies. Pneumonitis was found in >40% of our patients, presented early in life, was misdiagnosed despite chronic respiratory symptoms and accompanying radiographic and pulmonary function abnormalities, and caused hypoxemic respiratory failure and death. Autoantibodies against BPIFB1 and KCNRG and the homozygous c.967_979del13 AIRE mutation are associated with pneumonitis development. APECED pneumonitis features compartmentalized immunopathology, with accumulation of activated neutrophils in the airways and lymphocytic infiltration in intraepithelial, submucosal, peribronchiolar, and interstitial areas. Beyond APECED, we extend these observations to lung disease seen in other conditions with secondary AIRE deficiency (thymoma and RAG deficiency). Aire-deficient mice had similar compartmentalized cellular immune responses in the airways and lung tissue, which was ameliorated by deficiency of T and B lymphocytes. Accordingly, T and B lymphocyte-directed immunomodulation controlled symptoms and radiographic abnormalities and improved pulmonary function in patients with APECED pneumonitis. Collectively, our findings unveil lung autoimmunity as a common, early, and unrecognized manifestation of APECED and provide insights into the immunopathogenesis and treatment of pulmonary autoimmunity associated with impaired central immune tolerance.

10.
Antiviral Res ; 168: 61-67, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31125632

RESUMO

BACKGROUND: Fibrosis regression has been associated with nucleoside analogue (NA) treatment in chronic hepatitis B (CHB) patients. Although non-invasive fibrosis markers have been evaluated in CHB, their utility for monitoring on-treatment histologic regression has not been evaluated. AIMS: To characterize improvements in disease severity and the utility of non-invasive biomarkers in CHB NA treated patients. METHODS: Histology, labs, AST-to-platelet ratio index, and Fibrosis-4 (Fib-4) from treatment-naïve CHB patients were evaluated at baseline and longitudinally. Relative change from baseline to various time points during treatment were evaluated. Correlative analysis of APRI and Fib-4 with histology was performed longitudinally. RESULTS: 80 CHB patients (84% male, median age 45 (IQR 32, 54)) with histology up to 17 years (median 6(IQR 3.9, 8.0)) years were studied. Median baseline Ishak fibrosis was 3 (IQR 2, 4), histologic activity index (HAI) inflammation was 9 (IQR 7, 11), and AUROC of fibrosis markers for detecting cirrhosis (Ishak ≥ 5) was >0.64. HAI improved at a rate of 54% during year 1 and 37% in year 2, both greater than in the remaining follow-up periods. Within the first year, fibrosis improved by 35%, greater than all other time periods. Non-invasive biomarkers began to correlate with histology beyond 4 years (APRI: 4-6 years: r = 0.33, p = 0.03; ≥6 years: r = 0.41, p = 0.009; Fib-4: ≥6 years: r = 0.35, p = 0.03). CONCLUSION: Early dynamic changes in histology occur in CHB patients on NA followed by linear improvements. Non-invasive fibrosis biomarkers do not capture these dynamic changes and may demonstrate clinical utility beyond 4 years of treatment.

11.
Oncologist ; 24(9): 1259-1269, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30996010

RESUMO

BACKGROUND: The objective of this study was to characterize the clinicopathologic features of sicca syndrome associated with immune checkpoint inhibitor (ICI) therapy. SUBJECTS, MATERIALS, AND METHODS: Consecutive patients with new or worsening xerostomia in the setting of ICI treatment for benign or malignant neoplastic disease were evaluated, including labial salivary gland biopsy (LSGB). RESULTS: Twenty patients (14 male; median age 57 years) had metastatic melanoma (n = 10), metastatic carcinoma (n = 6), or recurrent respiratory papillomatosis (n = 4) and were being treated with avelumab (n = 8), nivolumab (n = 5), pembrolizumab (n = 4), nivolumab/ipilimumab (n = 2), and M7824, a biologic targeting programmed cell death ligand 1 (PD-L1) and transforming growth factor ß (n = 1). Four had pre-existing autoimmune disease. Nineteen had very low whole unstimulated saliva flow; six had new dry eye symptoms. The median interval between ICI initiation and dry mouth onset was 70 days. Rheumatoid factor and anti-Sjögren's Syndrome-related Antigen A (Anti-SSA) were both positive in two subjects. LSGB showed mild-to-severe sialadenitis with diffuse lymphocytic infiltration and architectural distortion. There were lymphocytic aggregates in eight patients, composed mainly of CD3+ T cells with a slight predominance of CD4+ over CD8+ T cells. ICI targets (e.g., programmed cell death 1 and PD-L1) were variably positive. In direct response to the advent of the sicca immune-related adverse event, the ICI was held in 12 patients and corticosteroids were initiated in 10. Subjective improvement in symptoms was achieved in the majority; however, salivary secretion remained very low. CONCLUSION: ICI therapy is associated with an autoimmune-induced sicca syndrome distinct from Sjögren's syndrome, often abrupt in onset, usually developing within the first 3 months of treatment, and associated with sialadenitis and glandular injury. Improvement can be achieved with a graded approach depending on severity, including withholding the ICI and initiating corticosteroids. However, profound salivary flow deficits may be long term. IMPLICATIONS FOR PRACTICE: Sicca syndrome has been reported as an immune-related adverse event (irAE) of immune checkpoint inhibitor therapy (ICI) for neoplastic diseases. Severe dry mouth (interfering with eating or sleeping) developed abruptly, typically within 90 days, after initiation of ICI therapy. Salivary gland biopsies demonstrated mild-to-severe sialadenitis distinct from Sjögren's syndrome, with diffuse T-cell lymphocytic infiltration and acinar injury. Recognition of the cardinal features of ICI-induced sicca will spur appropriate clinical evaluation and management, including withholding of the ICI and corticosteroid, initiation. This characterization should help oncologists, rheumatologists, and oral medicine specialists better identify patients that develop ICI-induced sicca to initiate appropriate clinical evaluation and therapy to reduce the likelihood of permanent salivary gland dysfunction.

12.
Aliment Pharmacol Ther ; 49(9): 1195-1204, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30934130

RESUMO

BACKGROUND: Bodybuilding supplements can cause a profound cholestatic syndrome. AIM: To describe the drug-Induced liver injury network's experience with liver injury due to bodybuilding supplements. METHODS: Liver injury pattern, severity and outcomes, potential genetic associations, and exposure to anabolic steroids by product analysis were analysed in prospectively enrolled subjects with bodybuilding supplement-induced liver injury with causality scores of probable or higher. RESULTS: Forty-four males (mean age 33 years) developed liver injury with a median latency of 73 days. Forty-one per cent presented with hepatocellular pattern of liver injury as defined by the R > 5 ([Fold elevation of ALT] ÷ [Fold elevation of Alk Phos] (mean, range = 6.4, 0.5-31.4, n = 42) despite all presenting with clinical features of cholestatic liver injury (100% with jaundice and 84% with pruritus). Liver biopsy (59% of subjects) demonstrated a mild hepatitis and profound cholestasis in most without bile duct injury, loss or fibrosis. Seventy-one per cent were hospitalised, and none died or required liver transplantation. In some, chemical analysis revealed anabolic steroid controlled substances not listed on the label. No enrichment of genetic variants associated with cholestatic syndromes was found, although mutations in ABCB11 (present in up to 20%) were significantly different than in ethnically matched controls. CONCLUSIONS: Patients with bodybuilding supplements liver injury uniformly presented with cholestatic injury, which slowly resolved. The ingested products often contained anabolic steroids not identified on the label, and no enrichment in genetic variants was found, indicating a need for additional studies.

13.
Viruses ; 11(4)2019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-31027244

RESUMO

Ground glass hepatocytes (GGHs), a histological hallmark of chronic hepatitis B virus (HBV) infection, contain excessive hepatitis surface antigen (HBsAg) in the endoplasmic reticulum (ER), which is linked to unfolded protein response (UPR). The mechanism by which HBV activates UPR has not been fully defined. To investigate this, HepG2-NTCP cells and primary human hepatocytes (PHHs) were either infected with HBV or transduced with adenoviral vectors expressing replication-competent HBV genome or individual HBV genes. UPR markers were evaluated by qPCR, Western blotting, and immunofluorescence. Apoptosis and cell viability were measured by Caspase-3/7 and ATPlite assay respectively. We found that UPR markers were induced by the overexpression of HBsAg in HepG2-NTCP cells and PHHs. Elevation of UPR-induced genes showed a dose-dependent correlation with HBsAg levels. In HBV-infected livers, GGHs also demonstrated excessive accumulation of HBsAg associated with increased BIP/GRP78 staining, a marker of UPR. Prolonged activation of UPR by HBsAg overexpression induced signs of apoptosis. Overexpression of HBsAg can induce ER stress through protein kinase RNA-like endoplasmic reticulum kinase (PERK) pathway in vitro, and may be linked to the appearance of GGHs. The activation of UPR by HBsAg may sensitize hepatocytes to cell death and result in possible subsequent cellular changes leading to a premalignant phenotype.

14.
Hepatology ; 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31034092

RESUMO

Identifying effective therapies for nonalcoholic steatohepatitis (NASH) with fibrosis is a pressing challenge, with 1-2% of the population in developed nations at risk of developing NASH cirrhosis and its complications. The design of NASH clinical therapeutic trials is hampered by the long period of minimally symptomatic disease that typically precedes the development of decompensated cirrhosis, and the accompanying uncertainties regarding the best pre-cirrhotic trial endpoints that reliably reflect a subsequent reduction in liver-related morbidity and mortality. The Liver Forum is a multi-stakeholder organization comprised of academic, industry, and regulatory experts working from a regulatory science perspective to identify barriers, prioritize research, and identify solutions to accelerate therapeutic development for NASH. Prior work of The Liver Forum has focused on recommendations for disease definitions and baseline parameters to be implemented in clinical trials that are designed to assess disease status and prevent progression to cirrhosis, liver transplantation, hepatocellular carcinoma, and death. The purpose of this summary is to review currently available clinical data to identify parameters that change in parallel with liver histology and are likely to reflect clinically meaningful reductions in the risk of developing cirrhosis and its complications. We review available data on exploratory histologic, blood-based and imaging pharmacodynamic biomarkers that may reflect meaningful treatment responses and provide recommendations regarding measurements to be considered in phase 2 and 3 trials as well as during post-marketing monitoring trials. This article is protected by copyright. All rights reserved.

15.
Clin Liver Dis ; 23(2): 263-277, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30947876

RESUMO

Cystic fibrosis liver disease (CFLD) remains the third leading cause of death in patients with cystic fibrosis. Although most patients with CFLD present in childhood, recent studies suggest a second wave of liver disease in adulthood. There are no clear guidelines for diagnosing CFLD. Treatment options for CFLD remain limited, and while UDCA is widely used, its long-term benefit is unclear. Those who develop hepatic decompensation or uncontrolled variceal bleeding may benefit from liver transplant, either alone, or in combination with lung transplant.

16.
Cell Rep ; 26(10): 2651-2666.e6, 2019 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-30840888

RESUMO

Intratumor mutational heterogeneity has been documented in primary non-small-cell lung cancer. Here, we elucidate mechanisms of tumor evolution and heterogeneity in metastatic thoracic tumors (lung adenocarcinoma and thymic carcinoma) using whole-exome and transcriptome sequencing, SNP array for copy-number alterations (CNAs), and mass-spectrometry-based quantitative proteomics of metastases obtained by rapid autopsy. APOBEC mutagenesis, promoted by increased expression of APOBEC3 region transcripts and associated with a high-risk APOBEC3 germline variant, correlated with mutational tumor heterogeneity. TP53 mutation status was associated with APOBEC hypermutator status. Interferon pathways were enriched in tumors with high APOBEC mutagenesis and IFN-γ-induced expression of APOBEC3B in lung adenocarcinoma cells, suggesting that the immune microenvironment may promote mutational heterogeneity. CNAs occurring late in tumor evolution correlated with downstream transcriptomic and proteomic heterogeneity, although global proteomic heterogeneity was significantly greater than transcriptomic and CNA heterogeneity. These results illustrate key mechanisms underlying multi-dimensional heterogeneity in metastatic thoracic tumors.

17.
Aliment Pharmacol Ther ; 49(9): 1205-1213, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30854694

RESUMO

BACKGROUND: Dyslipidaemia is frequent in non-alcoholic steatohepatitis (NASH); however, it is unclear if improvement in liver histology is associated with favourable changes in cardiovascular disease (CVD) risk. AIMS: To evaluate the relationship of NASH resolution and lipoprotein subfraction levels, markers of endothelial dysfunction, and macrophage activation. METHODS: One hundred and seventeen individuals with NASH who participated in the Pioglitazone vs Vitamin E vs Placebo for the Treatment of Nondiabetic Patients with NASH (PIVENS) trial with paired liver biopsies and serum samples available at baseline and after 96 weeks of treatment were included. Participants in the PIVENS trials received vitamin E, pioglitazone, or placebo for 96 weeks. Lipoprotein subfraction levels, intracellular adhesion molecule 1 (ICAM-1), vascular cellular adhesion molecule 1 (VCAM-1), E-selectin, and sCD163 levels were assessed at baseline and week 96 and their relationship with NASH resolution was examined. RESULTS: Fifty-seven individuals had NASH resolution and 60 individuals did not have resolution of NASH. NASH resolution was associated with favourable changes in lipoprotein subfraction levels compared to those without NASH resolution. Individuals with resolution of NASH had a significantly increased mean peak LDL diameter (ratio of geometric means [96 weeks vs baseline] 1.007 vs 0.996, P = 0.004), and higher frequency of LDL phenotype A (58% vs 33%, P = 0.003) at week 96, after adjustment for relevant co-variates including treatment group. No differences in VCAM, ICAM, E-selectin, or sCD163 levels by NASH resolution were found. CONCLUSIONS: NASH resolution is associated with favourable changes in a subset of serum lipoprotein levels. More studies are warranted to understand if these favourable changes are associated with decreased risk of CVD.

18.
Hepatology ; 69(6): 2579-2585, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30791107

RESUMO

Loss-of-function mutations in genes that encode for components of the telomere repair complex cause accelerated telomere shortening. Hepatic involvement has been recognized as a cause of morbidity in telomere diseases, but very few studies have characterized the nature and extent of liver involvement in affected patients. We report the prevalence and characteristics of liver involvement in a large cohort of patients with telomere disease evaluated serially at the National Institutes of Health. One hundred twenty-one patients with known or suspected telomere disease were screened; 40 patients with liver involvement were included in the current study. Median follow-up was 2.4 years. Data were collected regarding their demographic information, laboratory analysis, imaging, and histopathology. Forty patients (40% of the cohort) with a median age of 42 years were found to have liver involvement. Liver enzyme elevation was cholestatic in pattern; 8 (21%) had drug-related enzyme elevations. The most common imaging finding was increased hepatic echogenicity on ultrasound in 39% (9) of patients, followed by hepatomegaly in 26% (6). Biopsies were infrequent because of risk associated with thrombocytopenia, but in 6 patients, there were varying findings: nodular regenerative hyperplasia, steatohepatitis, hemosiderosis, cholestasis, and cirrhosis with hepatic steatosis. Almost half the cohort had pulmonary diffusion abnormalities, and 25% died during the follow-up period. Conclusion: In patients with telomere disease, hepatic involvement is common and can present in diverse ways, including elevated liver enzymes as well as histopathologic and imaging abnormalities. Liver disease has important implications for morbidity and mortality in patients with telomere disease.

19.
Transplantation ; 2019 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-30720689

RESUMO

BACKGROUND: An 11-year old girl with DOCK8 deficiency was proposed for potentially curative hematopoietic stem cell transplantation (HSCT), the donor being her haploidentical mother. However, end-stage liver disease, caused by chronic Cryptosporidium infection required liver transplantation before HSCT. METHODS: Consequently, a staged approach of a sequential liver transplant followed by a HSCT was planned, with her mother as the donor for both liver and HSCT. RESULTS: The patient successfully underwent a left lobe orthotopic liver transplant, however, she developed a biliary leak delaying the HSCT. Notably, the recipient demonstrated 3 percent donor lymphocyte chimerism in her peripheral blood immediately prior to HSCT. Haploidentical related donor HSCT performed two months after liver transplantation was complicated by the development of acyclovir-resistant HSV viremia, primary graft failure, and sinusoidal obstruction syndrome (SOS). The patient died from SOS associated multiorgan failure with Candida sepsis on day +40 following HSCT. CONCLUSIONS: We discuss the many considerations inherent to planning for HSCT preceded by liver transplant in patients with primary immunodeficiencies, including the role of prolonged immunosuppression and the risk of infection prior to immune reconstitution. We also discuss the implications of potential recipient sensitization against donor stem cells precipitated by exposure of the recipient to the donor lymphocytes from the transplanted organ.

20.
Cancer Immunol Immunother ; 68(4): 599-608, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30688989

RESUMO

BACKGROUND: Checkpoint inhibitors have recently been approved for the treatment of patients with hepatocellular carcinoma (HCC). However, biomarkers, which will help identify patients responding to therapy, are missing. We recently tested the combination of anti-CTLA4 treatment (tremelimumab) with loco-regional therapy in patients with HCC and reported a partial response rate of 26%. METHODS: Here, we report updated survival analyses and results from our immune monitoring studies on peripheral blood mononuclear cells (PBMCs) and tumors from these patients. RESULTS: Tremelimumab therapy increased CD4+-HLA-DR+, CD4+PD-1+, CD8+HLA-DR+, CD8+PD-1+, CD4+ICOS+ and CD8+ICOS+ T cells in the peripheral blood of the treated patients. Patients with higher CD4+PD1+ cell frequency at baseline were more likely to respond to tremelimumab therapy. PD-1 expression was increased on alpha fetal protein (AFP) and survivin-specific CD8 T cells upon tremelimumab treatment. An increase of tumor infiltrating CD3+ T cells were also seen in these patients. Immunosequencing of longitudinal PBMC showed that one cycle of tremelimumab significantly decreased peripheral clonality, while no additional effects were seen after loco-regional therapy. CONCLUSION: In summary, we observed a clear activation of T cell responses in HCC patients treated with tremelimumab and identified potential biomarkers which will help identify patients responding to immunotherapy with anti-CTLA4.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Antígeno CTLA-4/antagonistas & inibidores , Carcinoma Hepatocelular/imunologia , Neoplasias Hepáticas/imunologia , Linfócitos do Interstício Tumoral/imunologia , Adulto , Idoso , Biomarcadores , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Citotoxicidade Imunológica , Feminino , Genes Codificadores da Cadeia beta de Receptores de Linfócitos T , Humanos , Imunofenotipagem , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Projetos Piloto , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
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