[Show abstract][Hide abstract] ABSTRACT: To evaluate risk factors associated with alterations in venous structures adjacent to an ablation zone after percutaneous irreversible electroporation (IRE) of hepatic malignancies at subacute follow-up (1 to 3 days after IRE) and to describe evolution of these alterations at mid-term follow-up.
43 patients (men/women, 32/11; mean age, 60.3 years) were identified in whom venous structures were located within a perimeter of 1.0 cm of the ablation zone at subacute follow-up after IRE of 84 hepatic lesions (primary/secondary hepatic tumors, 31/53). These vessels were retrospectively evaluated by means of pre-interventional and post-interventional contrast-enhanced magnetic resonance imaging or computed tomography or both. Any vascular changes in flow, patency, and diameter were documented. Correlations between vascular change (yes/no) and characteristics of patients, lesions, and ablation procedures were assessed by generalized linear models.
191 venous structures were located within a perimeter of 1.0 cm of the ablation zone: 55 (29%) were encased by the ablation zone, 78 (41%) abutted the ablation zone, and 58 (30%) were located between 0.1 and 1.0 cm from the border of the ablation zone. At subacute follow-up, vascular changes were found in 19 of the 191 vessels (9.9%), with partial portal vein thrombosis in 2, complete portal vein thrombosis in 3, and lumen narrowing in 14 of 19. At follow-up of patients with subacute vessel alterations (mean, 5.7 months; range, 0 to 14 months) thrombosis had resolved in 2 of 5 cases; vessel narrowing had completely resolved in 8 of 14 cases, and partly resolved in 1 of 14 cases. The encasement of a vessel by ablation zone (OR = 6.36, p<0.001), ablation zone being adjacent to a portal vein (OR = 8.94, p<0.001), and the usage of more than 3 IRE probes (OR = 3.60, p = 0.035) were independently associated with post-IRE vessel alterations.
Venous structures located in close proximity to an IRE ablation zone remain largely unaffected by this procedure, and thrombosis is rare.
PLoS ONE 08/2015; 10(8):e0135773. DOI:10.1371/journal.pone.0135773 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC) are referred to as autoimmune liver diseases. An association with other autoimmune diseases, so-called overlap syndromes is frequently described, whereby the overlap between autoimmune liver diseases themselves is the most frequently observed overlap. In well-defined groups of patients with classical autoimmune hepatitis, the frequency of overlap syndromes to PBC or PSC was estimated to occur in up to 19 %. Only a few case reports exist on overlap of PBC and PSC. No uniform criteria for the diagnosis of overlap syndromes have been established. However, it is important to characterize the clinically leading disease, since this may be important for treatment and prognosis. In this review, we summarize the current state of diagnosis and therapy of autoimmune liver diseases with special consideration of overlap syndromes.
[Show abstract][Hide abstract] ABSTRACT: Colorectal cancer is the third most common cancer and a major cause of morbidity and mortality worldwide. Adjuvant chemotherapy is considered the standard of care in patients with UICC stage III colon cancer after R0 resection. Adjuvant therapy was not shown to be beneficial in patients with UICC stage II colon cancer. However, there is an ongoing discussion as to whether adjuvant chemotherapy may be beneficial for a subgroup of UICC II patients in a "high-risk situation" (such as T4).
We investigated a Bavarian population-based (2.1 million inhabitants) cohort of 1937 patients with UICC II CRC treated between 2002 and 2012 in regard of the benefit of adjuvant chemotherapy for large (T4) tumors. Patients older than 80 years of age were excluded. Of 1937 patients, 240 had a T4 tumor (12 %); 77 of all T4 patients received postoperative chemotherapy (33 %). Kaplan-Meier analysis and Cox regression models were used for survival analyses.
Patients with a T4 tumor who received postoperative chemotherapy had a highly significant survival benefit in respect of overall survival (p < 0.001) and recurrence-free survival (p = 0.008). However, no difference was observed between oxaliplatin-containing and non-oxaliplatin-containing treatment regimens. G2 and G3 tumors were found to particularly benefit from adjuvant treatment. Chemotherapy, age at diagnosis, and tumor grading remained independent risk factors in the multivariate cox regression analysis.
Our retrospective study demonstrated the significant benefit of adjuvant chemotherapy in the T4 subgroup of patients with UICC II colon cancer. Our data suggest that adjuvant chemotherapy should be seriously considered in these patients.
BMC Cancer 05/2015; 15(1):419. DOI:10.1186/s12885-015-1404-9 · 3.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Inter-cellular communication with stromal cells is vital for cancer cells. Molecules involved in the communication are potential drug targets. To identify them systematically, we applied a systems level analysis that combined reverse network engineering with causal effect estimation. Using only observational transcriptome profiles we searched for paracrine factors sending messages from activated hepatic stellate cells (HSC) to hepatocellular carcinoma (HCC) cells. We condensed these messages to predict ten proteins that, acting in concert, cause the majority of the gene expression changes observed in HCC cells. Among the 10 paracrine factors were both known and unknown cancer promoting stromal factors, the former including Placental Growth Factor (PGF) and Periostin (POSTN), while Pregnancy-Associated Plasma Protein A (PAPPA) was among the latter. Further support for the predicted effect of PAPPA on HCC cells came from both in vitro studies that showed PAPPA to contribute to the activation of NFκB signaling, and clinical data, which linked higher expression levels of PAPPA to advanced stage HCC. In summary, this study demonstrates the potential of causal modeling in combination with a condensation step borrowed from gene set analysis [Model-based Gene Set Analysis (MGSA)] in the identification of stromal signaling molecules influencing the cancer phenotype.
[Show abstract][Hide abstract] ABSTRACT: Unlabelled:
Interleukin-33 (IL-33), a cytokine with pleiotropic functions, is elevated in serum of patients with hepatocellular carcinoma (HCC). This study investigated the effects of local IL-33 expression in resected HCC on patient survival and on the immunological and molecular tumor microenvironment. Tissue of resected HCCs was stained for hematoxylin and eosin, Masson trichrome, alpha-smooth muscle actin, IL-33, CD8, and IL-13 and analyzed by flow cytometry. Besides histomorphologic evaluation, the immunohistochemical stainings were analyzed for the respective cell numbers separately for tumor area, infiltrative margin, and distant liver stroma. These findings were correlated with clinical data and patient outcome. Further, gene expression of different HCC risk groups was compared using microarrays. In multivariable analysis, infiltration of HCCs by IL-33(+) cells (P = 0.032) and CD8(+) cells (P = 0.014) independently was associated with prolonged patient survival. Flow cytometry demonstrated that cytotoxically active subpopulations of CD8(+) cells, in particular CD8(+) CD62L(-) KLRG1(+) CD107a(+) effector-memory cells, are the main producers of IL-33 in these HCC patients. Using infiltration by IL-33(+) and CD8(+) cells as two separate factors, an HCC immune score was designed and evaluated that stratified patient survival (P = 0.0004). This HCC immune score identified high- and low-risk patients who differ in gene expression profiles (P < 0.001).
Infiltration of HCCs by IL-33(+) and CD8(+) cells is independently associated with prolonged patient survival. We suggest that this is due to an induction of highly effective, cytotoxically active CD8(+) CD62L(-) KLRG1(+) CD107a(+) effector-memory cells producing IL-33. Based on these two independent factors, we established an HCC immune score that provides risk stratification for HCC patients and can be used in the clinical setting.
[Show abstract][Hide abstract] ABSTRACT: TGF-β is cytostatic towards damage induced compensatory hepatocyte proliferation. This function is frequently lost during hepatocarcinogenesis, thereby switching the TGF-β role from tumor suppressor to tumor promoter. Here, we investigate Smad7 overexpression as pathophysiological mechanism for cytostatic TGF-β inhibition in liver damage and HCC. Transgenic hepatocyte specific Smad7 overexpression in damaged liver of fumarylacetoacetate hydrolase (FAH) deficient mice increased compensatory proliferation of hepatocytes. Similarly, modulation of Smad7 expression changed the sensitivity of Huh7, FLC-4, HLE and HLF HCC cell lines for cytostatic TGF-β effects. In our cohort of 140 HCC patients, Smad7 transcripts were elevated in 41.4% of HCC samples as compared to adjacent tissue, with significant positive correlation to tumor size, whereas low Smad7 expression levels were significantly associated with worse clinical outcome. Univariate and multivariate analyses indicate Smad7 levels as independent predictor for overall (p<0.001) and disease free survival (p=0.0123). Delineating a mechanism for Smad7 transcriptional regulation in HCC, we identified cold shock Y-box protein-1 (YB-1), a multifunctional transcription factor. YB-1 RNAi reduced TGF-β induced and endogenous Smad7 expression in Huh7 and FLC-4 cells, respectively. YB-1 and Smad7 mRNA expression levels correlated positively (p<0.0001). Furthermore, nuclear colocalization of Smad7 and YB-1 proteins was present in cancer cells of those patients. In summary, our study provides a YB-1/Smad7-mediated mechanism that interferes with anti-proliferative/tumor suppressive TGF-β actions in a subgroup of HCC cells, that may facilitate aspects of tumor progression.
[Show abstract][Hide abstract] ABSTRACT: Purpose: The purpose of this study was to identify clinical factors influencing Gd-EOB-DTPA liver uptake in patients with healthy liver parenchyma. Materials and Methods: A total of 124 patients underwent contrast-enhanced MRI with a hepatocyte-specific contrast agent at 3T. T1-weighted volume interpolated breath-hold examination (VIBE) sequences with fat suppression were acquired before and 20 minutes after contrast injection. The relative enhancement (RE) between plain and contrast-enhanced signal intensity was calculated. Simple and multiple linear regression analyses were performed to evaluate clinical factors influencing the relative enhancement. Patients were subdivided into three groups according to their relative liver enhancement (HRE, RE 100%; MRE, 100% > RE >50%; NRE, RE 50%) and were analyzed according to the relevant risk factors. Results: Simple regression analyses revealed patient age, transaminases (AST, ALT, GGT), liver, spleen and delta-liver volume (the difference between the volumetrically measured liver volume and the estimated liver volume based on body weight) as significant factors influencing relative enhancement. In the multiple analysis the transaminase AST, spleen and delta liver volume remained significant factors influencing relative enhancement. Delta liver volume showed a significant difference between all analyzed groups. Conclusion: Liver enhancement in the hepatobiliary phase depends on a variety of factors. Body weight-adapted administration of Gd-EOB-DTPA may lead to inadequate liver enhancement after 20 minutes especially when the actual liver volume differs from the expected volume.
RöFo - Fortschritte auf dem Gebiet der R 01/2015; 187(1):29-35. DOI:10.1055/s-0034-1385211 · 1.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Lately, advances in high throughput technologies in biomedical research have led to a dramatic increase in the accessibility of molecular insights at diverse biological levels in hepatology. Much of this information was collected from numerous publications but increasingly also large scale analyses and stored in various databases. Scope of these databases is very divergent and may range from large, more general databases collecting information on almost every known disease to very specialized databases covering only one specific liver disease or aspect of hepatology. Over recent years, these bioinformatics data repositories have rapidly developed into an essential aid for molecular hepatology. Many of these databases are publicly available through the internet. However, up to now they have not been summarized or connected and many of these databases are only known to a few experts in a very specific field. In this review, we summarize the publicly available databases and give short summaries of their focus and applications in hepatology.
Journal of Hepatology 10/2014; 62(3). DOI:10.1016/j.jhep.2014.10.036 · 11.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Liver test abnormalities have been described in up to 60% of patients with systemic lupus erythematodes (SLE) at some point during the course of their disease. Prior treatment with potentially hepatotoxic drugs or viral hepatitis is commonly considered to be the main cause of liver disease in SLE patients. However, in rare cases elevated liver enzymes may be due to concurrent autoimmune hepatitis (AIH). To distinguish whether the patient has primary liver disease with associated autoimmune clinical and laboratory features resembling SLE - such as AIH - or the elevation of liver enzymes is a manifestation of SLE remains a difficult challenge for the treating physician. Here, we present six female patients with complex autoimmune disorders and hepatitis. Patient charts were reviewed in order to investigate the complex relationship between SLE and AIH. All patients had coexisting autoimmune disease in their medical history. At the time of diagnosis of AIH, patients presented with arthralgia, abdominal complaints, cutaneous involvement and fatigue as common symptoms. All patients fulfilled the current diagnostic criteria of both, AIH and SLE. Remission of acute hepatitis was achieved in all cases after the initiation of immunosuppressive therapy. In addition to this case study a literature review was conducted.
World Journal of Gastroenterology 09/2014; 20(35):12662-7. DOI:10.3748/wjg.v20.i35.12662 · 2.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Motivation:
Co-regulated genes are not identified in traditional microarray analyses, but may theoretically be closely functionally linked [guilt-by-association (GBA), guilt-by-profiling]. Thus, bioinformatics procedures for guilt-by-profiling/association analysis have yet to be applied to large-scale cancer biology. We analyzed 2158 full cancer transcriptomes from 163 diverse cancer entities in regard of their similarity of gene expression, using Pearson's correlation coefficient (CC). Subsequently, 428 highly co-regulated genes (|CC| ≥ 0.8) were clustered unsupervised to obtain small co-regulated networks. A major subnetwork containing 61 closely co-regulated genes showed highly significant enrichment of cancer bio-functions. All genes except kinesin family member 18B (KIF18B) and cell division cycle associated 3 (CDCA3) were of confirmed relevance for tumor biology. Therefore, we independently analyzed their differential regulation in multiple tumors and found severe deregulation in liver, breast, lung, ovarian and kidney cancers, thus proving our GBA hypothesis. Overexpression of KIF18B and CDCA3 in hepatoma cells and subsequent microarray analysis revealed significant deregulation of central cell cycle regulatory genes. Consistently, RT-PCR and proliferation assay confirmed the role of both genes in cell cycle progression. Finally, the prognostic significance of the identified KIF18B- and CDCA3-dependent predictors (P = 0.01, P = 0.04) was demonstrated in three independent HCC cohorts and several other tumors. In summary, we proved the efficacy of large-scale guilt-by-profiling/association strategies in oncology. We identified two novel oncogenes and functionally characterized them. The strong prognostic importance of downstream predictors for HCC and many other tumors indicates the clinical relevance of our findings.
Supplementary data are available at Bioinformatics online.
Zeitschrift für Gastroenterologie 09/2014; 31(2). DOI:10.1093/bioinformatics/btu586 · 1.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background and aims:
Despite increasingly sensitive and accurate blood tests to detect liver disease, liver biopsy remains very useful in patients with atypical clinical features and abnormal liver tests of unknown etiology. The aim was to determine those elevated laboratory liver parameters that cause the clinician to order a biopsy, and whether laboratory tests are associated with pathological findings on histology.
504 patients with unclear hepatopathy, admitted to the outpatient clinic of a university hospital between 2007 and 2010, were analyzed with respect to laboratory results, clinical data, and the results of liver biopsies.
Aspartate aminotransferase (AST) and glutamate dehydrogenase (GLDH) levels above the normal range significantly increased the likelihood of recommending a liver biopsy by 81% [OR with 95% CI 1.81 (1.21-2.71), p = 0.004] and 159% [OR with 95% CI 2.59 (1.70-3.93), p < 0.001], respectively. AST values above normal were associated with fibrosis (63 vs. 40% for normal AST, p = 0.010). Elevated ferritin levels pointed to a higher incidence of steatosis (48 vs. 10% for normal ferritin, p < 0.001) and inflammation (87 vs. 62% for normal ferritin, p = 0.004).
Our results indicate that elevated AST and GLDH were associated with a greater likelihood of recommending liver biopsy. Elevated AST and ferritin levels were associated with steatosis, inflammation and fibrosis on liver biopsies. Thus, AST and ferritin may be useful non-invasive predictors of liver pathology in patients with unclear hepatopathy.