Studies are needed to determine the long-term effects of bariatric surgery for patients with nonalcoholic steatohepatitis (NASH). We evaluated sequential liver samples, collected the time of ...bariatric surgery and 1 and 5 years later, to assess the long-term effects of bariatric surgery in patients with NASH.
We performed a prospective study of 180 severely obese patients with biopsy-proven NASH, defined by the NASH clinical research network histologic scores. The patients underwent bariatric surgery at a single center in France and were followed for 5 years. We obtained liver samples from 125 of 169 patients (76%) having reached 1 year and 64 of 94 patients (68%) having reached 5 years after surgery. The primary endpoint was the resolution of NASH without worsening of fibrosis at 5 years. Secondary end points were improvement in fibrosis (reduction of ≥1 stage) at 5 years and regression of fibrosis and NASH at 1 and 5 years.
At 5 years after bariatric surgery, NASH was resolved, without worsening fibrosis, in samples from 84% of patients (n = 64; 95% confidence interval, 73.1%-92.2%). Fibrosis decreased, compared with baseline, in samples from 70.2% of patients (95% CI, 56.6%-81.6%). Fibrosis disappeared from samples from 56% of all patients (95% CI, 42.4%-69.3%) and from samples from 45.5% of patients with baseline bridging fibrosis. Persistence of NASH was associated with no decrease in fibrosis and less weight loss (reduction in body mass index of 6.3 ± 4.1 kg/m2 in patients with persistent NASH vs reduction of 13.4 ± 7.4 kg/m2; P = .017 with resolution of NASH). Resolution of NASH was observed at 1 year after bariatric surgery in biopsies from 84% of patients, with no significant recurrence between 1 and 5 years (P = .17). Fibrosis began to decrease by 1 year after surgery and continued to decrease until 5 years (P < .001).
In a long-term follow-up of patients with NASH who underwent bariatric surgery, we observed resolution of NASH in liver samples from 84% of patients 5 years later. The reduction of fibrosis is progressive, beginning during the first year and continuing through 5 years.
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Background & Aims The effects of bariatric surgery in patients with nonalcoholic fatty liver disease (NASH) are not well established. We performed a prospective study to determine the biological and ...clinical effects of bariatric surgery in patients with NASH. Methods From May 1994 through May 2013, one hundred and nine morbidly obese patients with biopsy-proven NASH underwent bariatric surgery at the University Hospital of Lille, France (the Lille Bariatric Cohort). Clinical, biological, and histologic data were collected before and 1 year after surgery. Results One year after surgery, NASH had disappeared from 85% of the patients (95% confidence interval CI: 75.8%−92.2%). Compared with before surgery, patients had significant reductions in mean ± SD body mass index (BMI, from 49.3 ± 8.2 to 37.4 ± 7) and level of alanine aminotransferase (from 52.1 ± 25.7 IU/L to 25.1 ± 20 IU/L); mean levels of γ-glutamyltransferases were reduced from 51 IU/L before surgery (interquartile range IQR, 34−87 IU/L) to 23 IU/L afterward (IQR, 14−33 IU/L) and mean insulin resistance index values were reduced from 3.6 ± 0.5 to 2.9 ± 0.5 ( P < .01 for each comparison). NASH disappeared from a higher proportion of patients with mild NASH before surgery (94%) than severe NASH (70%) ( P < .05) according to Brunt score. In histologic analysis, steatosis was detected in 60% of the tissue before surgery (IQR, 40%−80%) but only 10% 1 year after surgery (IQR, 2.5%−21.3%); the mean nonalcoholic fatty liver disease score was reduced from 5 (IQR, 4−5) to 1 (IQR, 1−2) (each P < .001). Hepatocellular ballooning was reduced in 84.2% of samples (n = 69; 95% CI: 74.4−91.3) and lobular inflammation in 67.1% (n = 55; 95% CI: 55.8−77.1). According to Metavir scores, fibrosis was reduced in 33.8% of patients (95% CI: 23.6%−45.2%). Patients whose NASH persisted 1 year after surgery (n = 12) had lost significantly less weight (change in BMI, 9.1 ± 1.5) than those without NASH (change in BMI, 12.3 ± 0.6) ( P = .005). Patients who underwent laparoscopic gastric banding lost less weight (change in BMI, 6.4 ± 0.7) than those who underwent gastric bypass (change in BMI, 14.0 ± 0.5) ( P < .0001), and a higher proportion had persistent NASH (30.4% vs 7.6% of those with gastric bypass; P = .015). Conclusions Bariatric surgery induced the disappearance of NASH from nearly 85% of patients and reduced the pathologic features of the disease after 1 year of follow-up. It could be a therapeutic option for appropriate morbidly obese patients with NASH who do not respond to lifestyle modifications. More studies are needed to determine the long-term effects of bariatric surgery in morbidly obese patients with NASH.
To test the hypothesis that signet ring cell (SRC) histology has a negative prognostic value in patients with gastric adenocarcinoma (ADC).
In western countries, gastric ADC with SRC often occurs ...after the disease has advanced. Consequently, the prognosis of SRC is generally regarded as poor, although survival studies comparing SRC and non-SRC have yielded inconsistent results.
: An intent to treat analysis was performed among 215 patients with gastric ADC scheduled for surgical resection from 1996 to 2007. Of these, 180 patients underwent the resection and 35 were not resected due to diffuse metastatic illness. From 59 resected patients with SRC (SRC group), control non-SRC resected patients matched by age, gender, American Society of Anaesthesiologists (ASA) classification, tumoral location, and pTNM stage were randomly selected by computer (non-SRC group: n = 100) during the same study period.
The overall median survival was 21 months, which was significantly higher in resected compared to non-resected patients (31 vs. 5 months, P < 0.001). In non-resected patients, SRC histological subtype was associated with higher rates of diffuse peritoneal carcinomatosis (90.1% vs. 62.5%, P = 0.053) and neoplastic ascitis (63.6% vs. 34.7%, P = 0.059) and poorer median survival (5 vs. 7 months, P = 0.062). For resected patients, the 2 groups (SRC and non-SRC) were comparable regarding matching variables, demographic variables, and postoperative course. The median survival was significantly lower for SRC patients (21 vs. 44 months, P = 0.004). SRC resected patients exhibited higher rates of localized peritoneal carcinomatosis (P = 0.013) and lymph node involvement (P < 0.001) at diagnosis, lower R0 resection rate (P = 0.019) and earlier tumor relapse (P = 0.009), which was generally in a peritoneal carcinomatosis form (P = 0.011). By multivariate analysis, we concluded that SRC histology was independently associated with a dismal prognosis after adjustment on confounding variables (hazard ratio = 1.5, 95% confidence interval 1.1-2.0, P = 0.004). The prognostic role of SRC was maintained after exclusion of patients with advanced stage at initial diagnosis such as localized peritoneal carcinomatosis or lymph node invasion.
This study is currently the best evidence showing that SRC is a major and independent predictor of poor prognosis due to specific characteristics such as more infiltrating tumors showing affinity for lymphatic tissue accompanied by a higher rate of peritoneal carcinomatosis. Our results suggest the need for a specific therapeutic strategy for such tumors.
MUC1 is an oncogenic mucin overexpressed in several epithelial cancers, including pancreatic ductal adenocarcinoma, and is considered as a potent target for cancer therapy. To control cancer ...progression, miRNAs became very recently, major targets and tools to inhibit oncogene expression. Inhibiting MUC1 using miRNAs appears thus as an attractive strategy to reduce cancer progression. However, potent miRNAs and associated mechanisms regulating MUC1 expression remain to be identified. To this aim, we undertook to study MUC1 regulation by miRNAs in pancreatic cancer cells and identify those with tumor suppressive activity. MiRNAs potentially targeting the 3′-UTR, the coding region, or the 5′-UTR of MUC1 were selected using an in silico approach. Our invitro and invivo experiments indicate that miR-29a and miR-330-5p are strong inhibitors of MUC1 expression in pancreatic cancer cells through direct binding to MUC1 3′-UTR. MUC1 regulation by the other selected miRNAs (miR-183, miR-200a, miR-876-3p and miR-939) was found to be indirect. MiR-29a and miR-330-5p are also deregulated in human pancreatic cancer cell lines and tissues and in pancreatic tissues of KrasG12D mice. In vitro, miR-29a and miR-330-5p inhibit cell proliferation, cell migration, cell invasion and sensitize pancreatic cancer cells to gemcitabine. In vivo intra-tumoral injection of these two miRNAs in xenografted pancreatic tumors led to reduced tumor growth. Altogether, we have identified miR-29a and miR-330-5p as two new tumor suppressive miRNAs that inhibit the expression of MUC1 oncogenic mucin in pancreatic cancer cells.
•MUC1 is directly repressed by miR-29a and miR-330-5p in PDAC cells.•Expression of miR-29a and miR-330-5p is decreased in human PDAC.•Overexpression of miR-29a and miR-330-5p alters the biological properties of PDAC cell lines.•Overexpression of miR-29a and miR-330-5p sensitizesPDAC cell line to gemcitabine.
In alcoholic hepatitis (AH), development of targeted therapies is crucial and requires improved knowledge of cellular and molecular drivers in liver dysfunction. The unique opportunity of using ...explanted livers from patients with AH having undergone salvage liver transplantation allowed to perform more in-depth molecular translational studies.
We studied liver explants from patients with AH submitted to salvage transplantation (n=16), from patients with alcoholic cirrhosis without AH (n=12) and fragments of normal livers (n=16). Hepatic cytokine content was quantified. Hepatocyte function and proliferation and the presence of hepatic progenitor cells (HPCs) were evaluated by immunohistochemistry, western blot or quantitative PCR. Mitochondrial morphology was evaluated by electron microscopy.
Livers from patients with AH showed decreased cytokine levels involved in liver regeneration (tumour necrosis factor α and interleukin-6), as well as a virtual absence of markers of hepatocyte proliferation compared with alcoholic cirrhosis and normal livers. Electron microscopy revealed obvious mitochondrial abnormalities in AH hepatocytes. Importantly, livers from patients with AH showed substantial accumulation of HPCs that, unexpectedly, differentiate only into biliary cells. AH livers predominantly express laminin (extracellular matrix protein favouring cholangiocyte differentiation); consequently, HPC expansion is inefficient at yielding mature hepatocytes.
AH not responding to medical therapy is associated with lack of expression of cytokines involved in liver regeneration and profound mitochondrial damage along with lack of proliferative hepatocytes. Expansion of HPCs is inefficient to yield mature hepatocytes. Manoeuvres aimed at promoting differentiation of HPCs into mature hepatocytes should be tested in AH.
Background & Aims Severe obesity is implicated in development of nonalcoholic fatty liver disease (NAFLD). Bariatric surgery induces weight loss and increases survival time of obese patients, but ...little is known about its effects on liver damage. We performed a 5-year prospective study to evaluate fibrosis and nonalcoholic steatosis (NASH) in severely obese patients after bariatric surgery. Methods Bariatric surgery was performed on 381 patients. Clinical and biological data, along with liver biopsies, were collected before and at 1 and 5 years after surgery. Results Five years after surgery, levels of fibrosis increased significantly, but 95.7% of patients maintained a fibrosis score ≤ F1. The percentage of patients with steatosis decreased from 37.4% before surgery to 16%, the NAFLD score from 1.97 to 1, ballooning from 0.2 to 0.1. Inflammation remained unchanged. The percentage of patients with probable or definite NASH decreased significantly over 5 years, from 27.4% to 14.2%. The kinetics of insulin resistance (IR) paralleled that of steatosis and ballooning; the greatest improvements occurred within the first year and were sustained 5 years later. Steatosis and ballooning occurred more frequently in patients with a refractory IR profile. In multivariate analysis, the refractory IR profile independently predicted the persistence of steatosis and ballooning 5 years later. Conclusions Five years after bariatric surgery for severe obesity, almost all patients had low levels of NAFLD, whereas fibrosis slightly increased. Steatosis and ballooning were closely linked to IR; long-term effects could be predicted by early improvement in IR.
Merkel cell carcinoma is a rare neuroendocrine carcinoma of the skin mostly induced by Merkel cell polyomavirus integration. Cytokeratin 20 (CK20) positivity is currently used to distinguish Merkel ...cell carcinomas from other neuroendocrine carcinomas. However, this distinction may be challenging in CK20-negative cases and in cases without a primary skin tumor. The objectives of this study were first to evaluate the diagnostic accuracy of previously described markers for the diagnosis of Merkel cell carcinoma and second to validate these markers in the setting of difficult-to-diagnose Merkel cell carcinoma variants. In a preliminary set (n = 30), we assessed optimal immunohistochemical patterns (CK20, thyroid transcription factor 1 TTF-1, atonal homolog 1 ATOH1, neurofilament NF, special AT-rich sequence-binding protein 2 SATB2, paired box protein 5, terminal desoxynucleotidyl transferase, CD99, mucin 1, and Merkel cell polyomavirus-large T antigen) and Merkel cell polyomavirus load thresholds (real-time PCR). The diagnostic accuracy of each marker was then assessed in a validation set of 103 Merkel cell carcinomas (9 CK20-negative cases and 15 cases without a primary skin tumor) and 70 extracutaneous neuroendocrine carcinoma cases. The most discriminant markers for a diagnosis of Merkel cell carcinoma were SATB2, NF expression, and Merkel cell polyomavirus DNA detection (positive likelihood ratios: 36.6, 44.4, and 28.2, respectively). Regarding Merkel cell carcinoma variants, cases without a primary skin tumor retained a similar immunohistochemical profile and CK20-negative tumors displayed a different profile (decrease frequency of NF and SATB2 expression), but Merkel cell polyomavirus DNA remained detected (78% of cases by qPCR). Moreover, 8/9 (89%) CK20-negative Merkel cell carcinoma cases but only 3/61 (5%) CK20-negative extracutaneous neuroendocrine cases were positive for at least one of these markers. In conclusion, detection of SATB2 and NF expression and Merkel cell polyomavirus DNA helps distinguish between Merkel cell carcinoma classical and variant cases and extracutaneous neuroendocrine carcinomas.
Anaplastic thyroid carcinoma (ATC) is a rare tumor, with poorly defined oncogenic molecular mechanisms and limited therapeutic options contributing to its poor prognosis. The aims of this ...retrospective study were to determine the frequency of anaplastic lymphoma kinase (ALK) translocations and to identify the mutational profile of ATC including TERT promoter mutations.
One hundred and forty-four ATC cases were collected from 10 centers that are a part of the national French network for management of refractory thyroid tumors. Fluorescence in situ hybridization analysis for ALK rearrangement was performed on tissue microarrays. A panel of 50 genes using next-generation sequencing and TERT promoter mutations using Sanger sequencing were also screened.
Fluorescence in situ hybridization was interpretable for 90 (62.5%) cases. One (1.1%) case was positive for an ALK rearrangement with a borderline threshold (15% positive cells). Next-generation sequencing results were interpretable for 94 (65.3%) cases, and Sanger sequencing (TERT) for 98 (68.1%) cases. A total of 210 mutations (intronic and exonic) were identified. TP53 alterations were the most frequent (54.4%). Forty-three percent harbored a mutation in the (H-K-N)RAS genes, 13.8% a mutation in the BRAF gene (essentially p.V600E), 17% a PI3K-AKT pathway mutation, 6.4% both RAS and PI3K pathway mutations, and 4.3% both TP53 and PTEN mutations. Nearly 10% of the cases showed no mutations of the RAS, PI3K-AKT pathways, or TP53, with mutations of ALK, ATM, APC, CDKN2A, ERBB2, RET, or SMAD4, including mutations not yet described in thyroid tumors. Genes encoding potentially druggable targets included: mutations in the ATM gene in four (4.3%) cases, in ERBB2 in one (1.1%) case, in MET in one (1.1%) case, and in ALK in one (1.1%) case. A TERT promoter alteration was found in 53 (54.0%) cases, including 43 C228T and 10 C250T mutations. Three out of our cases did not harbor mutations in the panel of genes with therapeutic interest.
This study confirms that ALK rearrangements in ATC are rare and that the mutational landscape of ATC is heterogeneous, with many genes implicated in the follicular epithelial cell dedifferentiation process. This may explain the limited effectiveness of targeted therapeutic options tested so far.
Multiple intestinal atresia (MIA) is a rare cause of bowel obstruction that is sometimes associated with a combined immunodeficiency (CID), leading to increased susceptibility to infections. The ...factors underlying this rare disease are poorly understood. We characterized the immunological and intestinal features of 6 unrelated MIA-CID patients. All patients displayed a profound, generalized lymphocytopenia, with few lymphocytes present in the lymph nodes. The thymus was hypoplastic and exhibited an abnormal distribution of epithelial cells. Patients also had profound disruption of the epithelial barrier along the entire gastrointestinal tract. Using linkage analysis and whole-exome sequencing, we identified 10 mutations in tetratricopeptide repeat domain–7A (TTC7A), all of which potentially abrogate TTC7A expression. Intestinal organoid cultures from patient biopsies displayed an inversion of apicobasal polarity of the epithelial cells that was normalized by pharmacological inhibition of Rho kinase. Our data indicate that TTC7A deficiency results in increased Rho kinase activity, which disrupts polarity, growth, and differentiation of intestinal epithelial cells, and which impairs immune cell homeostasis, thereby promoting MIA-CID development.
Abstract
Tissue injury triggers activation of mesenchymal lineage cells into wound-repairing myofibroblasts, whose unrestrained activity leads to fibrosis. Although this process is largely controlled ...at the transcriptional level, whether the main transcription factors involved have all been identified has remained elusive. Here, we report multi-omics analyses unraveling Basonuclin 2 (BNC2) as a myofibroblast identity transcription factor. Using liver fibrosis as a model for in-depth investigations, we first show that
BNC2
expression is induced in both mouse and human fibrotic livers from different etiologies and decreases upon human liver fibrosis regression. Importantly, we found that
BNC2
transcriptional induction is a specific feature of myofibroblastic activation in fibrotic tissues. Mechanistically, BNC2 expression and activities allow to integrate pro-fibrotic stimuli, including TGFβ and Hippo/YAP1 signaling, towards induction of matrisome genes such as those encoding type I collagen. As a consequence,
Bnc2
deficiency blunts collagen deposition in livers of mice fed a fibrogenic diet. Additionally, our work establishes BNC2 as potentially druggable since we identified the thalidomide derivative CC-885 as a BNC2 inhibitor. Altogether, we propose that BNC2 is a transcription factor involved in canonical pathways driving myofibroblastic activation in fibrosis.
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