[Show abstract][Hide abstract] ABSTRACT: Chronic liver inflammation and immune/inflammatory response promote hepatocellular carcinoma. The aim of this study was to characterize the immune status of HCV-related cirrhosis in patients with hepatocellular carcinoma (HCV-HCC) as compared to HCV patients without hepatocellular carcinoma.
Immune markers (CD3, CD4, CD8, CD20, CD56, TCRγδ, FoxP3) and gene expression profiles (CD8α, CD8β, FoxP3, IL-6, IFN-γ, perforin, RANTES) were analyzed in a test cohort by immunohistochemistry and quantitative RT-PCR analysis on serial non-tumorous and tumorous tissues.
Immune micro-environment was more inflammatory in HCV-HCC than HCV cirrhotic livers. The number of CD3(+) , CD4(+) , CD8(+) and CD20(+) liver-infiltrating lymphocytes was significantly higher whereas the number of CD56(+) cells was significantly lower in HCV-HCC compared to HCV cirrhotic parenchyma. These differences were restricted to fibrous septa for CD4(+) and CD20(+) cells and to nodular parenchyma for CD8(+) cells. Gene expressions of CD8α, FoxP3 and RANTES were also significantly higher in HCV-HCC than in HCV cirrhosis. Interestingly, high density of CD8(+) cells in cirrhotic areas away from the tumor was an independent prognostic factor for tumor recurrence after resection, further validated in a large cohort of 63 HCV-HCC patients. The number of CD8(+) cells ≥100/field was associated with significant higher tumor recurrence (p=0.003) and lower overall survival (p=0.05) at 5 years.
High densities of liver-infiltrating lymphocytes in HCV-HCC cirrhotic parenchyma prevail inflammatory conditions and could contribute to tumorigenesis and tumor recurrence. These results could contribute towards better clinical evaluation of patients susceptible for HCC recurrence after curative surgery. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
Full-text · Article · Jul 2015 · Liver international: official journal of the International Association for the Study of the Liver
[Show abstract][Hide abstract] ABSTRACT: Several bacterial species have been implicated in the development of colorectal carcinoma (CRC), but CRC-associated changes of fecal microbiota and their potential for cancer screening remain to be explored. Here, we used metagenomic sequencing of fecal samples to identify taxonomic markers that distinguished CRC patients from tumor-free controls in a study population of 156 participants. Accuracy of metagenomic CRC detection was similar to the standard fecal occult blood test (FOBT) and when both approaches were combined, sensitivity improved > 45% relative to the FOBT, while maintaining its specificity. Accuracy of metagenomic CRC detection did not differ significantly between early- and late-stage cancer and could be validated in independent patient and control populations (N = 335) from different countries. CRC-associated changes in the fecal microbiome at least partially reflected microbial community composition at the tumor itself, indicating that observed gene pool differences may reveal tumor-related host–microbe interactions. Indeed, we deduced a metabolic shift from fiber degradation in controls to utilization of host carbohydrates and amino acids in CRC patients, accompanied by an increase of lipopolysaccharide metabolism.
Full-text · Article · Nov 2014 · Molecular Systems Biology
[Show abstract][Hide abstract] ABSTRACT: Background:
A KIT gain of function mutation is present in 70% of gastrointestinal stromal tumors (GISTs) and the wild-type (WT) allele is deleted in 5 to 15% of these cases. The WT KIT is probably deleted during GIST progression. We aimed to identify the mechanism of WT KIT loss and to determine whether other genes are involved or affected.
Whole-genome SNP array analyses were performed in 22 GISTs with KIT exon 11 mutations, including 11 with WT loss, to investigate the mechanisms of WT allele deletion. CGH arrays and FISH were performed in some cases. Common genetic events were identified by SNP data analysis. The 9p21.3 locus was studied by multiplex quantification of genomic DNA.
Chromosome instability involving the whole chromosome/chromosome arm (whole C/CA) was detected in 21/22 cases. The GISTs segregated in two groups based on their chromosome number: polyGISTs had numerous whole C/CA gains (mean 23, range [9 to 43]/3.11 [1 to 5]), whereas biGISTs had fewer aberrations. Whole C/CA losses were also frequent and found in both groups. There were numerous copy-neutral losses of heterozygosity (cnLOH) of whole C/CA in both polyGIST (7/9) and biGIST (9/13) groups. cnLOH were frequent on 4q, 11p, 11q, 1p, 2q, 3p and 10, and never involved 12p, 12q, 20p, 20q or 19q. Other genetic alterations included segmental chromosome abnormalities, complete bi-allelic deletions (homozygous deletions) and, more rarely, amplifications. Nine of 11 GISTs with homozygous KIT exon 11 mutations had cnLOH of chromosome 4.
The cnLOH of whole C/CA is a frequent genetic alteration in GISTs and is closely associated with homozygous mutations of KIT and WT allele deletion.
[Show abstract][Hide abstract] ABSTRACT: Purpose
To compare histopathologically the completeness of radiofrequency (RF) ablation to treat hepatocellular carcinoma (HCC) with monopolar or multipolar technique.
Materials and Methods
Thirty-five consecutive patients (mean age, 59 y) with cirrhosis and HCC (n = 59) within Milan criteria received RF ablation and subsequently underwent liver transplantation (LT) for tumor progression or liver failure. Data were extracted retrospectively from a prospective database. Thirty nodules were treated with a monopolar device with internally cooled (n = 17) or perfused (n = 13) electrodes, and 29 were treated with a multipolar technique with internally cooled electrodes based on the “no-touch” concept. This consisted of inserting two or three straight electrodes around the nodule to avoid intratumor puncture to the greatest extent possible. Effectiveness of the three devices was compared by histopathologic examination of explants. Fisher exact and χ2 tests and multivariate logistic regression analysis were performed.
Mean sizes of nodules ablated (25, 22, and 21.6 mm) and median times from ablation to LT (11, 7.5, and 8.4 months) for patients treated with the monopolar internally cooled electrode device (MoICD), monopolar perfused electrode device (MoPED), and multipolar internally cooled electrode device (MuICD), respectively, were similar (P = .8 and P = .9, respectively). Pathologic examination showed complete necrosis for eight of 17 and six of 13 nodules treated with the MoICD and MoPED, respectively, versus 26 of 29 treated with the MuICD (P = .0019). In multivariate analysis, RF technique remained the predictive factor for complete necrosis (P = .005).
Ablation of small HCCs with multipolar RF ablation based on the no-touch concept improves the rate of complete necrosis during pathologic examination compared with monopolar techniques.
No preview · Article · Apr 2014 · Journal of vascular and interventional radiology: JVIR
[Show abstract][Hide abstract] ABSTRACT: PurposeTo determine if intra-voxel incoherent motion diffusion-weighted imaging (IVIM-DWI) parameters, including free molecular-based (D) and perfusion-related (D*, f) diffusion parameters, correlate with the degree of tumor necrosis and viable tumor in colo-rectal cancer (CRC) metastasis. Materials and Methods
Fifteen patients referred for resection of liver metastases from CRC were retrospectively included in this Institutional Review Board approved study. An IVIM-DWI sequence was performed on a 1.5 Tesla MR imaging system, with 10 b factors (0, 10, 20, 30, 50, 80, 100, 200, 400 and 800 s/mm(2)). Mean D, D*, f and apparent diffusion coefficient (ADC) values were determined in metastases with a longest diameter above 10 mm. Correlations between the diffusion parameters and the degree of liver tumor necrosis and viable tissue were determined (Spearman). ResultsCorrelation between diffusion parameters and histopathological findings was performed in 35 hepatic metastases with a diameter of more than 10 mm (mean size of 17.9 mm; range, 1-68 mm). Both D (r=0.36; P=0.035) and ADC (r=0.4; P=0.02) correlated with the degree of tumor necrosis but not with viable tumor. ConclusionADC variation observed in CRC metastases following systemic chemotherapy reflects a specific increase in free-molecular diffusion (D), in itself correlated to the degree of metastasis necrosis. J. Magn. Reson. Imaging 2014;39:317-325. (c) 2013 Wiley Periodicals, Inc.
No preview · Article · Feb 2014 · Journal of Magnetic Resonance Imaging
[Show abstract][Hide abstract] ABSTRACT: Stevens-Johnson syndrome and toxic epidermal necrolysis are severe adverse cutaneous drug reactions characterized by widespread skin and mucous membrane detachments, including bronchial mucosa, which may be associated with respiratory failure requiring mechanical ventilation. The presentation and outcome of patients requiring mechanical ventilation and the characteristics of bronchial epithelial lesions among ventilated patients are reported. Predictors of mechanical ventilation available on hospital admission were identified using univariate and multivariate logistic regressions.
Retrospective cohort study.
Medical ICU and dermatology department of a tertiary care hospital, which hosts the French national referral center for toxic epidermal necrolysis.
Patients admitted for Stevens-Johnson syndrome/toxic epidermal necrolysis over a 14-year period were included.
Of the 221 patients included in the study, 56 patients (25.3%) required mechanical ventilation. None of the patients received noninvasive ventilation. Patients requiring mechanical ventilation had a larger baseline detached body surface area, higher Logistic Organ Dysfunction score, and Simplified Acute Physiology Score II, and they presented more often with shock, pulmonary infiltrates, and renal dysfunction (p < 0.0001 for all comparisons). Among patients receiving mechanical ventilation, 57% of the patients died; those having bronchial epithelial lesions (22 of 56) required intubation earlier than others (1 [1-4] vs 4 [1-6] d after hospital admission; p = 0.027). Variables associated with mechanical ventilation in multivariate analysis included serum bicarbonates less than 20 mM (odds ratio, 4.9 [95% CI, 1.1-22.7]; p = 0.041), serum urea greater than 10 mM (odds ratio, 7.0 [95% CI, 2.2-22.8]; p < 0.001), a detached body surface area between 10% and 29% (odds ratio, 3.7 [95% CI, 1.0-13.8]; p = 0.048) or greater than or equal to 30% (odds ratio, 19.7 [95% CI, 4.4-87.4]; p < 0.0001), WBCs more than 12,000/mm (odds ratio, 11.6 [95% CI, 2.8-48.1]; p < 0.001), blood hemoglobin less than 8 g/dL (odds ratio, 8.1 [95% CI, 1.2-55.2]; p = 0.032), and more extensive pulmonary infiltrates (odds ratio, 9.7 [95% CI, 3.6-25.9]; p < 0.0001).
Mechanical ventilation is required in one of four Stevens-Johnson syndrome/toxic epidermal necrolysis patients and is associated with a poor outcome. Prompt identification of Stevens-Johnson syndrome/toxic epidermal necrolysis patients at higher risk of intubation could help guide their early management, particularly for those having bronchial epithelial lesions.
Full-text · Article · Aug 2013 · Critical care medicine
[Show abstract][Hide abstract] ABSTRACT: Greater utilization of cross-sectional abdominal imaging has increased the diagnostic frequency of cystic neoplasms of the pancreas. The "International Consensus Guidelines 2012 for the Management of IPMN and MCN of the Pancreas" illustrates a diagnostic and therapeutic algorithm for these lesions based on current knowledge.
We present a case of a 49-year-old woman with two years of intermittent epigastric pain found to have an 8.5 cm head of the pancreas mass on CT. Evaluation was consistent with a mucinous cystic neoplasm for which she underwent an uneventful pancreaticoduodenectomy. Histology revealed a bronchogenic cyst of the head of the pancreas.
Bronchogenic cysts are congenital anomalies of the ventral foregut that can migrate into the abdomen prior to fusion of the diaphragm. They can easily be misdiagnosed for other benign and malignant retroperitoneal lesions. Similarly to mucinous cystic neoplasms, bronchogenic cysts have been reported to undergo malignant transformation. They can also become infected and hemorrhage. Therefore, resection should be performed in appropriate risk candidates. It is possible, with increased use of high resolution cross-sectional imaging, that these lesions may be identified with greater frequency in the abdomen and confused with other pancreatic neoplasms. The presence of ciliated respiratory epithelium and cartilage on pathology provides for definitive diagnosis.
Full-text · Article · Jul 2013 · JOP: Journal of the pancreas
[Show abstract][Hide abstract] ABSTRACT: Colorectal cancer (CRC) is posing an increasingly important burden on the health care system, with western countries seeing a growing incidence of the disease. Except for germline DNA mutations which have been attributed to less than 5% of patients, little is known about the main causes of CRC. However, environment factors such as food, lifestyle and medication are now suspected to have a major influence on inducing cancers. Today, exhaustive quantitative and qualitative evaluation of all environmental factors is not possible. Various environment-induced diseases have been characterized based on colon microflora, also called microbiota, analyses. Growing data have shown specific changes in microflora (i.e. dysbiosis) in the stools of patients with colon cancer or those adherent to the colonic mucosa. Thus, it appears that microbiota may be considered a platform offering host and environment interactions for studying CRCs. The hypothesis that colon cancer might be a bacteria-related disease is suggested and perspectives are discussed.
Full-text · Article · May 2013 · Therapeutic Advances in Gastroenterology
[Show abstract][Hide abstract] ABSTRACT: In Western countries there is a growing incidence in obesity, inflammatory bowel disease (IBD) and colorectal cancer (CRC), which places an increasingly important burden on the health care system. In the current decade, changes in intestinal microflora (i.e., dysbiosis) are likely the result of environment factors such as food, lifestyle, and medications which have been shown in obesity and IBD. In CRC, with the exception of germline DNA mutations which have been attributed to less than 5% of patients, little is still known about the main causes although the role of food is now suspected to have a major influence in the induction of cancer. Increasing data have shown specific changes in microflora m colon cancer patients' stools or adherent to the colonic mucosa, for which several mechanisms have been proposed using animal experiments. Thus, microbiota may be considered as a platform of host and environment interactions with which to study CRCs. Through new mechanisms in CRC pathophysiology including bacterial approach, the perspectives of screening, diagnostic and prognostic tests are discussed.
[Show abstract][Hide abstract] ABSTRACT: Background:
Liver stiffness measurement (LSM) by transient elastography (TE) (FibroScan) is a validated method of quantifying liver fibrosis in non-transplanted patients with hepatitis C virus (HCV). It could be useful in follow-up after liver transplantation (LT). The aim of this study was to assess the diagnostic accuracy of LSM in evaluating liver fibrosis after LT in patients with and without recurrent HCV.
Patients and methods:
Forty-three patients (mean age 57.6 ± 9.9 years), 28 (65.1%) HCV-positive patients and 15 (34.9%) HCV-negative patients underwent gold standard liver biopsy and TE 55.8 ± 4.9 months after transplantation. Liver fibrosis was scored on biopsy specimens according to METAVIR (F0-F4). Accuracy of TE and optimal stiffness cut-off values for fibrosis staging were determined by a receiver-operating characteristics (ROC) curve analysis.
Median stiffness values were significantly different for METAVIR score less than 2 (5.8 kPa) vs. METAVIR score greater to equal to 2 (9.6 kPa) (P<0.001). The area under the ROC curve was 0.83 for METAVIR score greater to equal to 2 (95%CI: 0.71-0.95). The optimal stiffness cut-off value was 7 kPa for METAVIR scores greater to equal to 2. The results were similar whether the patients had recurrent HCV infection or not.
These results indicate that transient elastography accurately identifies LT recipients with significant fibrosis, irrespective of HCV status. It is a promising non-invasive tool to assess graft fibrosis progression after LT in patients with HCV recurrence, as well as for screening of late graft fibrosis of other etiologies. Transient elastography could reduce the use of invasive protocol biopsies.
Full-text · Article · Jan 2013 · Gastroentérologie Clinique et Biologique
[Show abstract][Hide abstract] ABSTRACT: Inflammatory pseudotumor (IPT) of the liver is a rare benign lesion for which imaging diagnosis remains a challenge. We report the case of a 39-year-old Algerian woman, who presented epigastric pains combined with fever and jaundice. Ultrasound, CT scan and MRI showed the presence of a 10cm-long multi-septated cystic mass of the left lobe, with peripheral enhancement. A left-hepatectomy was performed and histopathology revealed an IPT of the liver. During the 4 following years, the patient had three other recurrences of liver IPT at various locations distinct from the original, revealed by the same clinical symptoms. During these relapses, the lesions did regress thanks to a medical treatment. This observation underlines the difficulty of the diagnosis and treatment of liver IPT.
No preview · Article · Dec 2012 · Gastroentérologie Clinique et Biologique
[Show abstract][Hide abstract] ABSTRACT: Background/aim:
Peripheral intrahepatic cholangiocarcinoma (ICC) occurring mainly in the absence of cirrhosis represents an increasing subgroup of primary liver tumors in Western countries. Histopathologic changes in the non-neoplastic liver in this context are not well characterized.
Patients and methods:
We assessed the clinical characteristics and histopathologic changes in the distant nontumoral liver of 57 consecutive White patients (34 men, mean age 59 years) referred to one medical and one surgical liver institution over a 16-year period who developed a peripheral ICC in the absence of cirrhosis or bile duct disease.
High alcohol consumption was observed in 11 patients (20%), 38 patients (66%) had a BMI of 25 kg/m or more, 22 patients (40%) had diabetes, two patients had hepatitis B virus infection, two others had hepatitis C virus infection, three patients had genetic hemochromatosis, and two patients had cutaneous porphyria tarda. The distant nontumoral liver was normal in 10 patients (18%). The two main histopathologic changes observed were macrovesicular steatosis (>10% of hepatocytes) in 38 patients (66%), including 11 patients (19%) with steatohepatitis, and moderate or intense hepatocyte iron overload in 22 patients (38%).
This study shows a high prevalence of macrovesicular steatosis associated or not with steatohepatitis and iron overload in patients who develop peripheral ICC in the absence of cirrhosis or bile duct disease.
No preview · Article · Oct 2012 · European journal of gastroenterology & hepatology
[Show abstract][Hide abstract] ABSTRACT: Phenotypic identification of focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA) subtypes using immunohistochemical markers has been developed from their molecular characteristics. Our objective was to evaluate the sensitivity of these markers in the definitive diagnosis of these lesions by core needle biopsies. A total of 239 needle biopsies paired with their surgical resection specimen (group A) or without an associated resection specimen (group B) were reviewed. Using a step-by-step algorithm after standard staining, appropriate immunostaining analyses were performed to determine the certainty of diagnosis of FNH, HNF1α-inactivated HCA, inflammatory HCA, β-catenin-activated HCA, or unclassified HCA. The diagnosis of FNH was certain or probable on routine stains in 53% of needle biopsies of group A, whereas after glutamine synthetase staining, the diagnosis was certain in 86.7% as compared with 100% on the corresponding surgical specimen (P=0.04). In needle biopsies of group A, the diagnosis of HCA was certain on routine stains in 58.6% as compared with 94.3% on surgical specimens. After specific immunostaining, diagnosis was established on biopsies with 74.3% certainty, including all HCA subtypes, with similar distribution in surgical specimens. For each "certain diagnosis" paired diagnostic test (biopsy and surgical specimen), a positive correlation was observed (P<0.001). No significant difference was observed between groups A and B for FNH (P=0.714) or for HCA subtypes (P=0.750). Compared with surgical specimens, immunohistochemical analysis performed on biopsies allowed the discrimination of FNH from HCA and the identification of HCA subtypes with good performance.
Full-text · Article · Oct 2012 · The American journal of surgical pathology
[Show abstract][Hide abstract] ABSTRACT: Background
Titanium dioxide (TiO2) and carbon black (CB) nanoparticles (NPs) have biological effects that could aggravate pulmonary emphysema. The aim of this study was to evaluate whether pulmonary administration of TiO2 or CB NPs in rats could induce and/or aggravate elastase-induced emphysema, and to investigate the underlying molecular mechanisms.
On day 1, Sprague-Dawley rats were intratracheally instilled with 25 U kg−1 pancreatic porcine elastase or saline. On day 7, they received an intratracheal instillation of TiO2 or CB (at 100 and 500 μg) dispersed in bovine serum albumin or bovine serum albumin alone. Animals were sacrificed at days 8 or 21, and bronchoalveolar lavage (BAL) cellularity, histological analysis of inflammation and emphysema, and lung mRNA expression of heme oxygenase-1 (HO-1), interleukin-1β (IL-1β), macrophage inflammatory protein-2, monocyte chemotactic protein-1, and matrix metalloprotease (MMP)-1, and -12 were measured. In addition, pulmonary MMP-12 expression was also analyzed at the protein level by immunohistochemistry.
TiO2 NPs per se did not modify the parameters investigated, but CB NPs increased perivascular/peribronchial infiltration, and macrophage MMP-12 expression, without inducing emphysema. Elastase administration increased BAL cellularity, histological inflammation, HO-1, IL-1β and macrophage MMP-12 expression and induced emphysema. Exposure to TiO2 NPs did not modify pulmonary responses to elastase, but exposure to CB NPs aggravated elastase-induced histological inflammation without aggravating emphysema.
TiO2 and CB NPs did not aggravate elastase-induced emphysema. However, CB NPs induced histological inflammation and MMP-12 mRNA and protein expression in macrophages.
Full-text · Article · Jul 2012 · BMC Pulmonary Medicine
[Show abstract][Hide abstract] ABSTRACT: The four and a half LIM-only protein 2 (FHL2) is upregulated in diverse pathological conditions. Here, we analyzed the effects of FHL2 overexpression in the liver of FHL2 transgenic mice (Apo-FHL2).
We first examined cell proliferation and apoptosis in Apo-FHL2 livers and performed partial hepatectomy to investigate high FHL2 expression in liver regeneration. Expression of FHL2 was then analyzed by real time PCR in human hepatocellular carcinoma and adjacent non-tumorous livers. Finally, the role of FHL2 in hepatocarcinogenesis was assessed using Apo-FHL2;Apc(lox/lox) mice.
Six-fold increase in cell proliferation in transgenic livers was associated with concomitant apoptosis, resulting in normal liver mass. In Apo-FHL2 livers, both cyclin D1 and p53 were markedly increased. Evidence supporting a p53-dependent cell death mechanism was provided by the findings that FHL2 bound to and activated the p53 promoter, and that a dominant negative p53 mutant compromised FHL2-induced apoptosis in hepatic cells. Following partial hepatectomy in Apo-FHL2 mice, hepatocytes displayed advanced G1 phase entry and DNA synthesis leading to accelerated liver weight restoration. Interestingly, FHL2 upregulation in human liver specimens showed significant association with increasing inflammation score and cirrhosis. Finally, while Apo-FHL2 mice developed no tumors, the FHL2 transgene enhanced hepatocarcinogenesis induced by liver-specific deletion of the adenomatous polyposis coli gene and aberrant Wnt/β-catenin signaling in Apc(lox/lox) animals.
Our results implicate FHL2 in the regulation of signaling pathways that couple proliferation and cell death machineries, and underscore the important role of FHL2 in liver homeostasis and carcinogenesis.
Full-text · Article · Jul 2012 · Journal of Hepatology