Hepatitis E virus (HEV) is considered an agent responsible for acute hepatitis that does not progress to chronic hepatitis. We identified 14 cases of acute HEV infection in three patients receiving ...liver transplants, nine receiving kidney transplants, and two receiving kidney and pancreas transplants. All patients were positive for serum HEV RNA. Chronic hepatitis developed in eight patients, as confirmed by persistently elevated aminotransferase levels, serum HEV RNA, and histologic features of chronic hepatitis. The time from transplantation to diagnosis was significantly shorter and the total counts of lymphocytes and of CD2, CD3, and CD4 T cells were significantly lower in patients in whom chronic disease developed.
Abstract In contrast to other types of organ transplantation, liver-transplant recipients used to be considered highly resistant to donor-specific antibodies (DSAs). Consequently, most transplant ...programs did not consider the presence of DSAs at transplantation or during the follow-up. However, since the early 1990s, antibody-mediated pathological lesions have been recognized in ABO-incompatible liver-transplant recipients. Recent data confirm the detrimental effect of preformed and de novo DSAs in ABO-compatible liver transplantation, with inferior clinical outcomes in patients presenting with circulating antibodies. Acute antibody-mediated rejection (AMR), plasma-cell hepatitis, biliary stricture, but also long-term complications, such as chronic rejection, liver ductopenia, and graft fibrosis, are now recognized to be associated with DSAs. Moreover, some non-HLA DSAs are suspected to induce graft dysfunction. Clinical, biological, and histological patterns within AMR need to be clarified. Treatment of these complications has yet to be defined. This article summarizes recent advances concerning the impact of preformed and de novo DSAs in liver transplantation, it defines the complications associated with DSAs, and discusses the potential strategies to manage patients with such complications.
Colonic macrophages are considered to be major effectors of inflammatory bowel diseases (IBDs) and the control of gut inflammation through C-type lectin receptors is an emerging concept. We show that ...during colitis, the loss of dectin-1 on myeloid cells prevents intestinal inflammation, while the lack of mannose receptor (MR) exacerbates it. A marked increase in dectin-1 expression in dextran sulfate sodium (DSS)-exposed MR-deficient mice supports the critical contribution of dectin-1 to colitis outcome. Dectin-1 is crucial for Ly6ChighCCR2high monocyte population enrichment in the blood and their recruitment to inflamed colon as precursors of inflammatory macrophages. Dectin-1 also promotes inflammasome-dependent interleukin-1β (IL-1β) secretion through leukotriene B4 production. Interestingly, colonic inflammation is associated with a concomitant overexpression of dectin-1/CCL2/LTA4H and downregulation of MR on macrophages from IBD patients. Thus, MR and dectin-1 on macrophages are important mucosal inflammatory regulators that contribute to the intestinal inflammation.
Display omitted
•Colitis is attenuated in mice with dectin-1−/− macrophages and severe in mice with MR−/− macrophages•Dectin-1 on macrophages mediates recruitment of inflammatory classical monocytes in the gut•Dectin-1 positively controls inflammatory phenotype of intestinal macrophages during colitis•Gut inflammation in IBD patients is linked to dectin-1 induction and reduced MR
Rahabi et al. show a critical contribution of dectin-1 on macrophages in intestinal inflammation. Dectin-1 is involved in Ly6ChighCCR2high monocyte population enrichment in the blood and their recruitment to inflamed colon, macrophage differentiation toward inflammatory phenotype, and inflammasome-dependent IL-1β secretion through LTB4.
The role of inflammation in the pathogenesis of non-alcoholic steatohepatitis (NASH), a common cause of liver disease, is still poorly understood. This study aimed at assessing the involvement of a ...major inflammatory cytokine, IL-6, in NASH.
Steatohepatitis was induced by feeding wild-type or IL-6(-/-) mice for 5 weeks with a methionine and choline-deficient (MCD) diet.
Whereas MCD diet-induced weight loss and decreases in serum glucose, cholesterol and triglyceride levels were similar in both genotypes, serum alanine aminotransferase was less elevated in IL-6(-/-) mice than in wild-type animals. Despite having a comparable liver steatosis score, IL-6-deficient mice exhibited less lobular inflammation than their wild-type littermates. Liver gene expression of TGF-beta and MCP-1 was also strongly attenuated in mutant mice; a more modest reduction was observed for PPAR-gamma and F4/80 transcripts as well as proteins. Chromatographic analysis of liver lipids demonstrated that MCD diet induced in normal and mutant mice a similar decrease in the ratio of phosphatidylcholine to phosphatidylethanolamine. However, the diet-induced increase in the levels of sphingomyelin and ceramide was less important in IL-6(-/-) mice.
Altogether, these results indicate that IL-6 deficiency does not block the development of NASH; yet, IL-6 plays a critical role in the accompanying liver inflammation.
To investigate the role of tacrolimus intra-patient variability (IPV) in adult liver-transplant recipients.
We retrospectively assessed tacrolimus variability in a cohort of liver-transplant ...recipients and analyzed its effect on the occurrence of graft rejection and
donor-specific antibodies (
DSAs), as well as graft survival during the first 2 years posttransplantation. Between 02/08 and 06/2015, 116 patients that received tacrolimus plus mycophenolate mofetil (with or without steroids) were included.
Twenty-two patients (18.5%) experienced at least one acute-rejection episode (BPAR). Predictive factors for a BPAR were a tacrolimus IPV of > 35% OR = 3.07 95%CI (1.14-8.24),
= 0.03 or > 40% OR = 4.16 (1.38-12.50),
= 0.01), and a tacrolimus trough level of < 5 ng/mL OR=3.68 (1.3-10.4),
=0.014. Thirteen patients (11.2%) developed at least one
DSA during the follow-up. Tacrolimus IPV coded as a continuous variable: OR = 1.1, 95%CI (1.0-1.12),
= 0.006 of > 35% OR = 4.83, 95%CI (1.39-16.72),
= 0.01 and > 40% OR = 9.73, 95%CI (2.65-35.76),
= 0.001 were identified as predictors to detect
DSAs. IPV did not impact on patient- or graft-survival rates during the follow-up.
Tacrolimus-IPV could be a useful tool to identify patients with a greater risk of graft rejection and of developing a
DSA after liver transplantation.
Mutation of the KRAS oncogene is present in 75% to 95% of pancreatic cancer tissues. This study aimed to evaluate whether endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA), combined with ...analysis of the KRAS mutation, improves the diagnosis of pancreatic cancer in cases of inconclusive or doubtful cytopathologic analysis.
We prospectively included 186 patients with a pancreatic mass (103 men; mean age: 62 y). Cytopathology and KRAS mutations, using TaqMan MGB allelic discrimination, were performed on EUS-FNA material. A final diagnosis was obtained from EUS-FNA analysis and/or a subsequent biopsy if necessary, and/or surgery, and follow-up: these were pancreatic adenocarcinoma (n=104), other malignant pancreatic tumors (n=22), and benign lesions (n=60, including 35 cases of chronic pancreatitis).
Inconclusive or doubtful (low-grade dysplasia or atypia) cytopathology was found in 68 cases. Of these, 29 patients who had adenocarcinoma were subsequently diagnosed, including 19 cases with a former KRAS mutation. Sensitivity, specificity, positive and negative predictive values, and overall accuracy of cytopathology alone to diagnose adenocarcinoma were 73%, 100%, 100%, 75%, and 85%, respectively. When KRAS mutation analysis was combined with pathology, these values reached 88%, 99%, 99%, 89%, and 93%, respectively. The performance of EUS-FNA to diagnose malignancy was similarly improved after the KRAS-mutation assay (negative predictive value increased from 67% to 88%; accuracy increased from 85% to 94%).
EUS-FNA plus KRAS-mutation analysis, using allelic discrimination, is accurate and improves the diagnosis of pancreatic adenocarcinoma when pathology is inconclusive or doubtful.
The outcome of stage II-III colorectal cancer (CRC) is highly variable and therapeutic choice is currently based on TNM staging with a few additional biomarkers. However, studies show that some stage ...III patients have a better prognosis than some stage II patients. A promising consensus molecular (CMS) classification with prognostic relevance has been developed, but it is not used in daily practice. Our team developed CINSARC, a 67-gene expression prognostic signature, whose prognostic value has been demonstrated in many cancer types. It is applicable to formalin-fixed, paraffin-embedded (FFPE) blocks using NanoString® technology. We investigated whether it could predict outcome in stage II-III CRC. We established the CINSARC classification on the TCGA retrospective cohort comprising 297 stage II-III CRC patients using RNA sequencing and on a second independent cohort comprising 169 cases using NanoString® technology. We compared its recurrence-free and overall survival prognostic value with TNM staging and CMS classification. In the TCGA cohort, we showed that CINSARC significantly splits the population of stage II-III CRC into two groups with different progression-free interval (P = 1.68 × 10
; HR = 1.87 1.11-3.16) and overall survival (P = 3.73 × 10
; HR = 2.45 1.31-4.59) and is a strong prognostic factor in multivariate analysis, outperforming TNM staging and CMS classification. We validated these results in the second cohort by applying CINSARC on FFPE samples with Nanostring® technology. CINSARC is a ready-to-use tool with a robust independent prognostic value in stage II-III CRC.
Immunohistochemistry (IHC) and/or MSI-PCR (microsatellite instability-polymerase chain reaction) tests are performed routinely to detect mismatch repair deficiency (MMR-D). Classical MMR-D tumors ...present a loss of MLH1/PMS2 or MSH2/MSH6 with MSI-High. Other profiles of MMR-D tumors have been described but have been rarely studied. In this study, we established a classification of unusual MMR-D tumors and determined their frequency and clinical impact. All MMR-D tumors identified between 2007 and 2017 were selected. Any profile besides the classical MMR-D phenotype was defined as unusual. For patients with unusual MMR-D tumors, IHC, and PCR data were reviewed, the tumor mutation burden (TMB) was evaluated and clinical and genetic features were collected. Of the 4948 cases of MMR testing, 3800 had both the available IHC and MSI-PCR results and 585 of these had MMR-D. After reviewing the IHC and PCR, 21% of the cases initially identified as unusual MMR-D were reclassified, which resulted in a final identification of 89 unusual MMR-D tumors (15%). Unusual MMR-D tumors were more often associated with non-CRC than classical MMR-D tumors. Unusual MMR-D tumors were classified into four sub-groups: i) isolated loss of PMS2 or MSH6, ii) classical loss of MLH1/PMS2 or MSH2/MSH6 without MSI, iii) four MMR proteins retained with MSI and, iv) complex loss of MMR proteins, with clinical characteristics for each sub-group. TMB-high or -intermediate was shown in 96% of the cancers studied (24/25), which confirmed MMR deficiency. Genetic syndromes were identified in 44.9% (40/89) and 21.4% (106/496) of patients with unusual and classical MMR-D tumors, respectively (P < 0.001). Five patients treated with an immune checkpoint inhibitor (ICI) had a prolonged clinical benefit. Our classification of unusual MMR-D phenotype helps to identify MMR deficiency. Unusual MMR-D phenotype occurs in 15% of MMR-D tumors. A high frequency of genetic syndromes was noted in these patients who could benefit from ICI.
Primary intestinal lymphangiectasia is an unusual cause of protein losing enteropathy due to either congenital malformation or obstruction of lymphatics of intestine. The disease can affect all or ...only a small part of the small intestine. Peripheral lymphedema may be associated. The diagnosis is based on endoscopic and histopathological findings. A 30-year-old woman presents lower extremity edema with hypoproteinemia, hypoalbuminemia, and hypogammaglobulinemia. Tc-labeled human serum albumin nanocolloid lymphoscintigraphy of the lower extremity demonstrated a dermal backflow in the right extremity consistent with lymphedema and an unusual ileal uptake on SPECT/CT. Diagnosis is confirmed on histopathological evaluation of biopsy of ileum.
PDF
