Mirelle E.E. Bröker

Tumor promotion through the mesenchymal stem cell compartment in human hepatocellular carcinoma

Although the infiltration of mesenchymal stem (stromal) cells (MSCs) into different tumors is widely recognized in animal models, the question whether these MSCs have a positive or negative effect on disease progression remains unanswered. The aim of this study is to investigate whether human hepatocellular carcinoma (HCC) harbors MSCs and whether these MSCs affect tumor growth. We observed that cells capable of differentiation into both adipocyte and osteocyte lineages and expressing MSC markers can be cultured from surgically resected HCC tissues. In situ staining of human HCC tissues with a STRO-1 antibody showed that the tumor and tumor-stromal region are significantly enriched with candidate MSCs compared with adjacent tissue (n = 12, P < 0.01). In mice, coengraftment of a human HCC cell line (Huh7) with MSCs resulted in substantially larger tumors compared with paired engraftment of Huh7 alone (n = 8, P < 0.01). Consistently, coculturing Huh7 with irradiated MSCs significantly increased the number and the size of colonies formed. This enhancement of Huh7 colony formation was also observed by treatment of MSC-conditioned medium (MSC-CM), suggesting that secreted trophic factors contribute to the growth-promoting effects. Genome-wide gene expression array and pathway analysis confirmed the upregulation of cell growth and proliferation-related processes and downregulation of cell death-related pathways by treatment of MSC-CM in Huh7 cells. In conclusion, these results show that MSCs are enriched in human HCC tumor compartment and could exert trophic effects on tumor cells. Thus, targeting of HCC tumor MSCs may represent a new avenue for therapeutic intervention.

Discriminating between simple and perforated appendicitis.

BACKGROUNDnSeveral studies have been performed in order to diagnose an acute appendicitis using history taking and laboratory investigations. The aim of this study was to create a model for the identification of a perforated appendicitis.nnnMETHODSnAll consecutive patients who have undergone an appendectomy in the Reinier de Graaf hospital between January 1, 2007 and July 31, 2009, were included in a retrospective cohort study. Baseline patient characteristics, history and laboratory data were collected. Variables discriminating perforated from non-perforated appendicitis were identified using univariate and multivariable analyses.nnnRESULTSnA total of 498 patients were included in the study. In the univariate analysis leukocyte count, C-Reactive Protein levels, Erythrocyte Sedimentation Rate levels, days of symptoms and temperature were identified as predictors of perforated appendicitis. The predicted probability (P) of a perforated appendicitis can be calculated from the following model: (P)=1/(1+e(-(-2.788+0.012 * CRP+0.207 * days with complaints))).nnnCONCLUSIONSnPerforation of appendicitis can be predicted from the CRP level and the duration of abdominal pain. These findings might influence the choice between conservative or surgical treatment of appendicitis, and could provide guidance in the early start of antibiotics.

The Management of Pregnancy in Women with Hepatocellular Adenoma: A Plea for an Individualized Approach

Because of the risk of hormone-induced growth and spontaneous rupture of hepatocellular adenoma (HCA) during pregnancy, special considerations are required. Due to the scarcity of cases, there is no evidence-based algorithm for the evaluation and management of HCA during pregnancy. We think it should be questioned if it is justified to discourage pregnancy in all women with HCA. The biological behavior of this benign lesion might be less threatening than presumed and a negative advice concerning pregnancy has great impact on the lives of these young female patients. The balance between the pros and cons of hepatic adenomas and pregnancy should be reconsidered. In our center, pregnancy in women with an HCA up to 5u2009cm is no longer discouraged in close consultation with the patient, her partner, and members of the liver expert team.

Pregnancy and liver adenoma management: PALM-study

BackgroundHepatocellular adenoma (HCA) in pregnant women requires special considerations because of the risk of hormone induced growth and spontaneous rupture, which may threaten the life of both mother and child. Due to scarcity of cases there is no evidence-based algorithm for the evaluation and management of HCA during pregnancy. Most experts advocate that women with HCA should not get pregnant or advise surgical resection before pregnancy. Whether it is justified to deny a young woman a pregnancy, as the biological behavior may be less threatening than presumed depends on the incidence of HCA growth and the subsequent clinical events during pregnancy.We aim to investigate the management and outcome of HCA during pregnancy and labor based on a prospectively acquired online database in the Netherlands.Methods/designThe Pregnancy And Liver adenoma Management (PALM) - study is a multicentre prospective study in three cohorts of pregnant patients. In total 50 pregnant patients, ≥ 18u2009years of age with a radiologically and/or histologically proven diagnosis of HCA will be included in the study. Radiological diagnosis of HCA will be based on contrast enhanced MRI. Lesions at inclusion must not exceed 5u2009cm. The study group will be compared to a healthy control group of 63 pregnant patients and a group of 63 pregnant patients with diabetes mellitus without HCA. During their pregnancy HCA patients will be closely monitored by means of repetitive ultrasound (US) at 14, 20, 26, 32 and 38u2009weeks of gestation and 6 and 12u2009weeks postpartum. Both control groups will undergo US of the liver at 14u2009weeks of gestation to exclude HCA lesions in the liver. All groups will be asked to fill out quality of life related questionnaires.DiscussionThe study will obtain information about the behaviour of HCA during pregnancy, the clinical consequences for mother and child and the impact of having a HCA during pregnancy on the health related quality of life of these young women. As a result of this study we will propose a decision-making model for the management of HCA during pregnancy.Trial registrationDutch trial register: NTR3034

Genotype-phenotype correlations in hepatocellular adenoma: an update of MRI findings.

Hepatocellular adenoma (HCA) is a generally benign liver tumor with the potential for malignancy and bleeding. HCAs are categorized into four subtypes on the basis of genetic and pathological features: hepatocyte nuclear factor 1α-mutated HCA, β-catenin-mutated HCA, inflammatory HCA, and unclassified HCA. Magnetic resonance imaging (MRI) plays an important role in the diagnosis, subtype characterization, and detection of HCA complications; it is also used to differentiate HCA from focal nodular hyperplasia. In this review, we present an overview of the genetic abnormalities, oncogenesis, and typical and atypical MRI findings of specific subtypes of HCA using contrast-enhanced MRI with or without hepatobiliary contrast agents (gadobenate dimeglumine and gadoxetate disodium). We also discuss their different management implications after diagnosis.

Hepatocellular adenoma: when and how to treat? Update of current evidence

Hepatocellular adenoma (HCA) is a rare, benign liver tumor. Discovery of this tumor is usually as an incidental finding, correlated with the use of oral contraceptives, or pregnancy. Treatment options have focused on conservative management for the straightforward, smaller lesions (<5 cm), with resection preferred for larger lesions (>5 cm) that pose a greater risk of hemorrhage or malignant progression. In recent years, a new molecular subclassification of HCA has been proposed, associated with characteristic morphological features and loss or increased expression of immunohistochemical markers. This subclassification could possibly provide considerable benefits in terms of patient stratification, and the selection of treatment options. In this review we discuss the decision-making processes and associated risk analyses that should be made based on lesion size, and subtype. The usefulness of this subclassification system in terms of the procedures instigated as part of the diagnostic work-up of a suspected HCA will be outlined, and suitable treatment schemes proposed.

A Model-Based Prediction of the Probability of Hepatocellular Adenoma and Focal Nodular Hyperplasia Based on Characteristics on Contrast-Enhanced Ultrasound

Contrast-enhanced ultrasound (CEUS) is an emerging imaging technique that is increasingly used to diagnose liver lesions. It is of the utmost importance to differentiate between the two most common solid focal liver lesions (i.e., hepatocellular adenoma [HCA] and focal nodular hyperplasia [FNH]), because their management and follow-up differ greatly. The main objective of this study was to determine how frequently the specific CEUS features of HCA and FNH are visible on CEUS and to define their predictive value for discrimination between HCA and FNH. We included 324 CEUS examinations performed on patients with FNH (nxa0=xa0181) or HCA (nxa0=xa0143). Patients with HCA and FNH significantly differed with respect to age and CEUS features of steatosis, echogenicity, homogeneity, the presence of a central scar, central artery, arterial enhancement pattern, necrosis or thrombus and enhancement in the late venous phase.

The Predictive Value of Golgi Protein 73 in Differentiating Benign from Malignant Liver Tumors

Introduction In the work up of primary solid liver lesions it is essential to differentiate correctly between benign and malignant tumors, such as hepatocellular adenoma (HCA) and hepatocellular carcinoma (HCC) respectively. A promising new marker to detect HCC is Golgi Protein 73 (GP73). Studies comparing patients with HCC and cirrhosis with normal controls suggested that GP73 is specific for patients with HCC; however, patients with other liver tumors were not included. We therefore studied the predictive value of GP73 in differentiating between solid benign and malignant liver tumors. Materials and Methods This study included 264 patients: 88 patients with HCC, 88 with hepatocellular adenoma (HCA), and 88 with focal nodal hyperplasia (FNH). A blood sample was collected from each patient to measure GP73 levels using a quantitative ELISA assay and differences in outcome between subgroups were compared. The receiver operating characteristic (ROC) curve, sensitivity and specificity of GP73 were calculated and compared to alpha-fetoprotein (AFP) levels. Results When comparing malignant and benign liver tumors the area under ROC was 0.701 and 0.912 for GP73 and AFP respectively. Test characteristics revealed a sensitivity of 60% for GP73 and 65% for AFP; in addition the specificity was 77% for GP73 and 96% for AFP. Conclusion Although the literature suggests that GP73 is a valuable serum marker in patients with HCC, the serum concentration may also be increased in patients with solid benign liver tumors. Therefore, a GP73 assay is less suitable for discriminating between primary malignant and benign tumors of the liver.

Inflammatory and multiple hepatocellular adenoma are associated with a higher BMI

Aim To identify patient and lesion characteristics associated with the occurrence of single or multiple hepatocellular adenoma (HCA). Patients and methods Using a tertiary centre database, we retrospectively collected information on patient and lesion characteristics, management and follow-up of all patients with HCA included between 2001 and 2016. Patients were classified into three groups; patients with a single HCA, 2–9 HCA and at least 10 HCA. Results A total of 458 patients were diagnosed with HCA, including 121 (26.4%) with single HCA, 235 (51.3%) with 2–9 HCA and 102 (22.3%) with at least 10 HCA. Significant differences in the mean BMI were found, with the highest BMI in patients with more than 10 HCA (P<0.05). The mean BMI was significantly higher in patients with inflammatory HCA compared with steatotic HCA (31 vs. 26, respectively, P<0.05). Steatotic HCA were more often single lesions (22/55, 40%), whereas patients with inflammatory HCA were often diagnosed with multiple lesions (122/166, 73%). Conclusion Our series show a significantly higher BMI and frequency of inflammatory HCA in patients with multiple HCA compared with single HCA.

Growth of Focal Nodular Hyperplasia is Not a Reason for Surgical Intervention, but Patients Should be Referred to a Tertiary Referral Centre

BackgroundWhen a liver lesion diagnosed as focal nodular hyperplasia (FNH) increases in size, it may cause doubt about the initial diagnosis. In many cases, additional investigations will follow to exclude hepatocellular adenoma or malignancy. This retrospective cohort study addresses the implications of growth of FNH for clinical management.MethodsWe included patients diagnosed with FNH based on ≥2 imaging modalities between 2002 and 2015. Characteristics of patients with growing FNH with sequential imaging in a 6-month interval were compared to non-growing FNH.ResultsGrowth was reported in 19/162 (12%) patients, ranging from 21 to 200%. Resection was performed in 4/19 growing FNHs; histological examination confirmed FNH in all patients. In all 15 conservatively treated patients, additional imaging confirmed FNH diagnosis. No adverse outcomes were reported. No differences were found in characteristics and presentation of patients with growing or non-growing FNH.ConclusionThis study confirms that FNH may grow significantly without causing symptoms. A significant increase in size should not have any implications on clinical management if confident diagnosis by imaging has been established by a tertiary benign liver multidisciplinary team. Liver biopsy is only indicated in case of doubt after state-of-the-art imaging. Resection is deemed unnecessary if the diagnosis is confirmed by multiple imaging modalities in a tertiary referral centre.