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ABSTRACT: Background and study aims: Molecular imaging has mainly been studied for detection of lesions using diagnostic probes. The aim of the current trial was to evaluate in vivo confocal laser endomicroscopy (CLE) with cetuximab, an antibody targeting the epidermal growth factor receptor (EGFR), for detection and moreover early prediction of response to molecular chemotherapy in models of human colorectal cancer (CRC).Methods: Xenografts with cetuximab-sensitive (HT29) and cetuximab-resistant (SW620) human CRC cell lines were induced in 44 mice. CLE was performed 48 h after injection of a fluorescently labelled cetuximab test dose, and compared with isotype antibody or untreated controls on d0, and d30 (HT29) or d15 (SW620). Initial fluorescence intensity was examined in relation to clinical readouts (tumor growth, thriving, mortality) during cetuximab treatment vs. controls. Results were validated in vivo with wide-field molecular imaging in three HT29 mice and ex vivo using fluorescence-activated cell sorting (FACS) and immunohistochemistry.Results: All HT29 xenografts showed specific fluorescence in vivo after cetuximab injection on d0 and d30. Fluorescence at d0 was significantly stronger in cetuximab-treated HT29 tumors than in HT29 controls (P = 0.0017) or cetuximab-treated SW620 tumors (P = 0.0027), and accorded with significantly slower tumor progression (P = 0.0009), better overall survival (P = 0.02), and better physical condition (P < 0.0001). Cetuximab sensitivity could be predicted from fluorescence intensity at d0 with high positive predictive value.Conclusions: Molecular CLE was for the first time linked to early prediction of response to targeted therapy in models of human CRC. Therapeutic antibodies can be used as molecular beacons in CLE and wide-field techniques. These results may indicate a promising principle for early patient stratification.
Endoscopy 04/2013; · 5.21 Impact Factor
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J M Kittner,
F Brokamp,
B Jäger,
W Wulff,
B Schwandt,
J Jasinski,
H Wedemeyer,
R E Schmidt,
J M Schattenberg, P R Galle,
M Schuchmann
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ABSTRACT: Abstract Disclosure is a prerequisite to receive disease-specific social support. However, in the case of a stigmatised disease, it can also lead to discrimination. We aimed to assess disclosure rates of HIV patients and the reactions they encountered in comparison to patients with chronic viral hepatitis or diabetes mellitus and patients' general perception of disease-specific discrimination. We constructed a self-report questionnaire, anonymously assessing the size of the social environment, the persons who had been informed, and the experienced reactions as perceived by the disclosing patients, to be rated on 1-4 point Likert scales. In addition, patients were asked whether they perceive general discrimination in Germany. One hundred and seventy-one patients were asked to participate. Five rejected, thus questionnaires from 83 patients with HIV, 42 patients with chronic viral hepatitis B (n=9) or C (n=33), and 41 patients with insulin-dependent diabetes mellitus (type I n=14, type II n=27) were analysed. Whereas the size of the social environment did not differ, HIV-infected patients were least likely to disclose their disease (60.7%, SD±31.9) to their social environment as compared to patients with chronic viral hepatitis (84.2±23.3%, p<0.0001), or diabetes mellitus (94.4 ±10.3%, p<0.0001), respectively. Within the HIV patient group, the mean disclosure rate was highest to partners (90.9%), followed by the public environment (65.2%), friends (59.4%) and family members (43.8%). HIV patients experienced supportive reactions after 79.3±26.4% of disclosures, which was the case in 91.4±19.6% and 75.7±36.1% of patients with hepatitis or diabetes mellitus, respectively. 69.5% of HIV patients stated to perceive general discrimination in Germany. We conclude that HIV patients had experienced supportive reactions after the majority of disclosures, but the low rate points out that their information strategy had been very selective. Societal discrimination of HIV patients is still an issue and needs to be further addressed.
AIDS Care 02/2013; · 1.60 Impact Factor
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ABSTRACT: Background:Melatonin induces apoptosis in many different cancer cell lines, including hepatocellular carcinoma cells. However, the responsible pathways have not been clearly elucidated. A member of the forkhead transcription factors' family, FoxO3a, has been implicated in the expression of the proapoptotic protein Bim (a Bcl-2-interacting mediator of cell death). In this study, we used human HepG2 liver cancer cells as an in vitro model to investigate whether melatonin treatment induces Bim through regulation by the transcription factor FoxO3a.Methods:Cytotoxicity of melatonin was compared in HepG2 hepatoblastoma cells and primary human hepatocytes. Proapoptotic Bim expression was analysed by reverse transcriptase-polymerase chain reaction and western blot. Reporter gene assays and chromatin immunoprecipitation assays were performed to analyse whether FoxO3a transactivates the Bim promoter. Small interfering RNA (siRNA) was used to study the role of FoxO3a in Bim expression. Immunofluorescence was performed to analyse FoxO3a localisation in HepG2 cells.Results:Melatonin treatment induces apoptosis in HepG2 cells, but not in primary human hepatocytes. The proapoptotic effect was mediated by increased expression of the BH3-only protein Bim. During melatonin treatment, we observed increased transcriptional activity of the forkhead-responsive element and could demonstrate that FoxO3a binds to a specific sequence within the Bim promoter. Furthermore, melatonin reduced phosphorylation of FoxO3a at Thr(32) and Ser(253), and induced its increased nuclear localisation. Moreover, silencing experiments with FoxO3a siRNA prevented Bim upregulation.Conclusion:This study shows that melatonin can induce apoptosis in HepG2 hepatocarcinoma cells through the upregulation of proapoptotic Bim mediated by nuclear translocation and activation of the transcription factor FoxO3a.British Journal of Cancer advance online publication, 20 December 2012; doi:10.1038/bjc.2012.563 www.bjcancer.com.
British Journal of Cancer 12/2012; · 5.04 Impact Factor
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ABSTRACT: The prognosis for patients with advanced esophageal cancer is poor. Proper risk assessment and knowledge of tumor biology may facilitate early diagnosis of adenocarcinomas and squamous cell cancer of the esophagus. New endoscopic techniques are available (e.g., (virtual) chromoendoscopy, autofluorescence, and endomicroscopy) for the early detection of cancer. Endoscopic therapy with complete resection of mucosal cancers offers long-term survival.En bloc resection combined with the removal of locoregional lymph nodes is the surgical option of choice for locally advanced cancer. In this respect, minimally invasive surgery offers the patient numerous advantages. Multimodal therapy results in better outcome for defined cancer stages and includes surgery, chemotherapy and chemoradiation. Multimodal treatment should always be individualized and requires cooperation of all subspecialties (tumor board conference). New chemotherapeutic strategies may offer improved survival but may also include new side effects. Patients with inoperable esophageal cancer also benefit from multimodal treatment.
Der Internist 10/2012; · 0.30 Impact Factor
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ABSTRACT: Abstract Anticoagulants play an important role in the prevention and treatment of a variety of acute and chronic thromboembolic disorders such as primary prevention and treatment of venous thromboembolism or prevention of stroke and systemic embolism in atrial fibrillation just to name of few. Within recent years, a promising new oral anticoagulant, the direct thrombin inhibitor dabigatran etexilate (dabigatran) successfully underwent clinical development and has emerged as an alternative to vitamin K antagonists according to a variety of recently revised and updated international guidelines referring to the indication of stroke prevention in atrial fibrillation. Considering the intensive clinical use of vitamin K antagonists in the mentioned indication as well as the widespread and increasing therapeutic need on one hand and the likely availability of a more efficacious alternative with fewer limitations in clinical practice on the other, there is good reason to assume that the use of dabigatran may be broad within the general medical community in the near future. Based on what is currently published in the public domain and clinical trial data it is suggested that dabigatran etexilate is associated with higher rates of dyspeptic symptoms compared to warfarin. Therefore, it is the authors' intent to review and discuss this potential dyspeptic side effect profile of dabigatran and potential counter measures from a gastroenterologist's perspective.
Scandinavian journal of gastroenterology 09/2012; · 2.08 Impact Factor
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ABSTRACT: IgG4-related disease has gained increased attention worldwide. While the initial focus was on autoimmune pancreatitis which was first described in Asian populations and turned out to be of relevance in Western populations too, the scope has recently broadened towards a notion of a multi-systemic disease with very diverse manifestations such as autoimmune pancreatitis, IgG4-related sclerosing cholangitis (IgG4-SC), retroperitoneal fibrosis and tubulointerstitial nephritis. IgG4-SC (also known as IgG4-associated cholangitis, IAC) represents a rare but clinically challenging differential diagnosis in patients with obstructive jaundice and proximal extra- or intrahepatic biliary strictures which can be mistaken for cholangiocarcinoma (CC). We present the case of a 79-year-old male patient who presented with obstructive jaundice and biliary strictures at the hepatic duct bifurcation without any evidence for autoimmune pancreatitis and without elevation of serum IgG4-concentrations who underwent hemihepatectomy for suspected CC. However, on histological examination of the resection specimen CC could not be confirmed. It was only after several episodes of obstructive jaundice had reoccurred that the diagnosis of IgG4-SC could be established by reexamination of the surgical specimen which showed extensive infiltration with IgG4-positive plasma cells. Appropriate medical treatment with steroids and azathioprine led to complete remission of the disease. Early recognition of IgG4-SC can save patients from potential harmful and unnecessary surgical interventions. Here we describe the clinical features of this rare case of IgG4-SC with extensive liver tissue infiltration with IgG4-positive cells but without elevated serum IgG4 concentration or evidence of autoimmune pancreatitis. We describe diagnostic criteria for IgG4-SC and review recent insights in pathophysiology and treatment options.
Zeitschrift für Gastroenterologie 09/2012; 50(9):1008-1012. · 0.90 Impact Factor
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ABSTRACT: The evaluation of liver histology is an important component of the diagnosis and staging of liver diseases. The most common technique employed to sample liver tissue for decades has been percutaneous liver biopsy. Although this is a relatively well tolerated technique in the early stages of liver disease, it carries a high risk of complications, particularly hemorrhage, in patients with advanced cirrhosis. Mini-laparoscopy allows macroscopic assessment and biopsy under direct vision and therefore is a well tolerated and effective technique.
The major advantages of this technique are direct visualization of the liver surface, thereby allowing inspection for morphologic changes of cirrhosis as well as targeted biopsies, the ability to immediately treat potential complications (bleeding and bile leakage), furthermore the peritoneal cavity can be visualized to stage gastrointestinal (GI) malignancies. Additionally, 'blind' percutaneous liver biopsy fails to establish a diagnosis in about 25% of cases, largely because of sampling error.
This technique presents the opportunity to visualize the surface of the liver and the peritoneal cavity, making it a valuable tool for liver biopsy. This review summarizes the technique of mini-laparoscopy and addresses its potential uses and limitations as a diagnostic modality.
Current opinion in gastroenterology 07/2012; 28(5):461-6. · 4.33 Impact Factor
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ABSTRACT: Lethal giant larvae proteins have key roles in regulating polarity in a variety of cell types and function as tumour suppressors. A transcriptional programme initiated by aberrant Snail expression transforms epithelial cells to potentially aggressive cancer cells. Although progress in defining the molecular determinants of this programme has been made, we have little knowledge as to how the Snail-induced phenotype can be suppressed. In our studies we identified the human lethal giant larvae homologue 2, Hugl-2, (Llgl2/Lgl2) polarity gene as downregulated by Snail. Snail binds E-boxes in the Hugl-2 promoter and represses Hugl-2 expression, whereas removal of the E-boxes releases Hugl-2 from Snail repression. We demonstrate that inducing Hugl-2 in cells with constitutive Snail expression reverses the phenotype including changes in morphology, motility, tumour growth and dissemination in vivo, and expression of epithelial markers. Hugl-2 expression reduced the nuclear localization of Snail and thus binding of Snail to its target promoters. Our results placing Hugl-2 within the Snail network as well as its ability to suppress Snail carcinogenesis identifies Hugl-2 as a target molecule driving cascades, which may have preventative and therapeutic promise to minimize cancer progression.Oncogene advance online publication, 14 May 2012; doi:10.1038/onc.2012.162.
Oncogene 05/2012; · 6.37 Impact Factor
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ABSTRACT: Das Budd-Chiari Syndrom ist eine seltene Manifestationsform der hereditären oder erworbenen Thrombophilie. Bei einer 30 jährigen
Patientin konnte, nach anfänglichen diagnostischen Schwierigkeiten, ein BCS diagnostiziert und erfolgreich, durch portocavalen
Seit-zu-Seit Shunt, behandelt werden. Bei der Chiari-Trias aus abdominellen Schmerzen, Hepatomegalie und Ascites muß das BCS
in die differentialdiagnostischen Überlegungen mit einbezogen und gegebenenfalls durch invasive Diagnostik ausgeschlossen
werden. Therapiemöglichkeiten sind die Anticoagulation und die Anlage eines portosystemischen Shunts (TIPS oder chirurgischer
Shunt). Eine Lebertransplantation kommt als ultima ratio bei Leberinsuffizienz oder Cirrhose in Betracht, dadurch wird auch
eine hereditäre Thrombophilie meist kausal therapiert.
Budd-Chiari syndrome is a rare manifestation of hereditary or acquired thrombophilia. We saw a case of Budd-Chiari syndrome
in a 30-year-old woman leading to initial diagnostic difficulties. She underwent surgical side-to-side shunt and 9 weeks later
an almost normal liver could be demonstrated on computerized tomography. Budd-Chiari syndrome should be considered if the
Chiari triad with abdominal pain, hepatomegaly and ascites occurs in a patient. If necessary, invasive diagnostic procedures
(e.g. angiography) must be performed. Therapeutic options are anticoagulative therapy and porto-systemic shunt, either as
a TIPS or a surgical shunt. If severe liver failure occurs or liver cirrhosis is present, orthotopic liver transplantation
is an additional option which also cures hereditary thrombophilia.
Der Chirurg 05/2012; 71(4):462-465. · 0.70 Impact Factor
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ABSTRACT: Untersuchungen der letzten 10 Jahre haben zu einem verbesserten Verständnis der Pathophysiologie von chronisch entzündlichen
Darmerkrankungen geführt. Neuere Studien belegen hierbei v. a. die funktionelle Bedeutung einer Aktivierung des mukosalen
Immunsystems durch bakterielle Antigene für die Pathogenese der chronisch entzündlichen Darmerkrankungen (CED). Neben Chemokinen
und Adhäsionsmolekülen scheinen vor allem Zytokine, die von antigenpräsentierenden Zellen und T-Lymphozyten produziert werden,
pathogenetisch für die CED von entscheidender Bedeutung zu sein. So konnte tierexperimentell gezeigt werden, dass Antikörper
gegen proinflammatorische Zytokine zu einer Suppression von chronisch intestinalen Entzündungsreaktionen führen können, was
durch eine Induktion von T-Zellapoptose bedingt ist. Basierend auf neuen Erkenntnissen zur Immunpathogenese der CED werden
klinisch zzt. innovative Therapiekonzepte getestet, die z. B. rekombinante antiinflammatorische Zytokine und neutralisierende
Antikörper gegen proinflammatorische Zytokine und ihre Rezeptoren umfassen. Trotz dieser Fortschritte im Verständnis der Pathophysiologie
und der Bedeutung des mukosalen Immunsystems bleiben jedoch zahlreiche Fragen über die molekulare Immunpathogenese der CED
offen und bedürfen weiterer Untersuchung.
Der Internist 04/2012; 43(11):1343-1353. · 0.30 Impact Factor
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ABSTRACT: A 35-year-old Kenian lady with advanced immunodeficiency due to HIV infection started on an antiretroviral therapy. Five months later, a severe colitis was diagnosed, however, no causal pathogen could be found. In order to avoid imminent perforation, a hemicolectomy became necessary, and immediately the symptoms and inflammation markers normalized rapidly. M. tuberculosis could be proven in culture in a draining abdominal lymph node. We assume that the severe inflammation was caused by an immune restoration inflammatory syndrome (IRIS). Essentials in diagnosis, pathogenesis and therapy of IRIS are discussed.
Zeitschrift für Gastroenterologie 04/2012; 50(4):382-5. · 0.90 Impact Factor
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ABSTRACT: Hepatocellular carcinomas rank among the most common cancers worldwide. They are characterized by phenotypic heterogeneity and poor response to treatment modalities. Although considerable progress in diagnosis and management of hepatocellular carcinomas has been made over the last decade, the exact biology of liver cancer remains poorly understood, overall hindering the development of new therapeutic strategies. The development of whole-genome analyses on different molecular levels greatly advanced our understanding of hepatocarcinogenesis by simultaneously investigating thousands of molecular targets. Although implementation of the results from these analyses in routine clinical practice is still limited, these next generation technologies offer unprecedented insights into the molecular mechanisms of the development of liver cancer. Overall, great promise rests on whole genomic approaches to improve the diagnostic testing and to identify novel targets for individualized treatment modalities in liver cancer.
DMW - Deutsche Medizinische Wochenschrift 04/2012; 137(16):855-60. · 0.53 Impact Factor
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ABSTRACT: Complete bowel cleansing is mandatory for effective colon cancer screening and surveillance. The aim of the current pilot study, which was conducted in humans, was to test the safety and efficiency of a newly developed disposable cleaning device, the MedJet, for intraprocedural bowel cleansing.
Patients with screening or surveillance colonoscopy after previous polypectomy were included. The colonoscope was first inserted to the cecum and the overall cleansing was assessed according to the Ottawa scale. The MedJet device was used if colon cleansing had been incomplete. The MedJet catheter was passed over the working channel of the colonoscope and the colon was cleaned during withdrawal. The MedJet device delivered controlled jets comprising compressed CO2 and minimal amounts of sterile water, which allowed disintegration and removal of residual stool. The efficiency of cleaning was assessed according to the Boston scale.
A total of 32 patients (16 female; mean age 61 years) were treated with the device. No device-related adverse or serious adverse events were noted. MedJet application during withdrawal provided effective and significant improvement in bowel cleansing (P = 0.005). Furthermore, 18 adenomas and 1 colon cancer, which were hidden behind stool remnants, could be identified in 11 patients following use of the MedJet device. However, the withdrawal times were prolonged (11.4±6.0 minutes) due to the additional cleaning procedure. All patients tolerated the procedure well.
The new MedJet device enabled highly effective and safe bowel cleansing during colonoscopy. The catheter-based system was easy to use and CO2 was applied for cleansing. The procedure was well tolerated by patients.
Endoscopy 03/2012; 44(8):767-71. · 5.21 Impact Factor
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DMW - Deutsche Medizinische Wochenschrift 02/2012; 137(5):210-3. · 0.53 Impact Factor
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ABSTRACT: In Germany the extent of organ donation is still low and not sufficent to duly address all patients on the waiting lists. It is likely that a lack of information and a consecutive uncertainty in the adult population relate to this imbalance. Virtually no data exist about teenagers' knowledge of the facts of organ donation.
4000 questionnaires were distributed in secondary schools in the state capital city Mainz, Germany. The students were asked to respond to 12 questions. The survey was voluntary and performed in class, without the students using any information sources.
Data from 1155 questionnaires were analysed. Overall 11.3 % of the teenagers carried an organ donor card. 48.9 % of the students had spoken about organ donation and brain death in their families. 37.0 % of the students declined organ donation. Of these, 72.4 % named a lack of education and informations as the primary reason for this statement. More non-German than German pupils declined organ donation (43.4 % vs. 36.2 %).
More than half of the pupils between 14 years and 20 years of age support the concept of organ transplantation as therapeutic option. Nevertheless the proportion of organ card holders is small among these students. These regional results identify an information deficit in young people in Germany as one of the main causes for inadequate acceptance of organ donation. Therefore, information and structured education should be intensified in German schools as possible measure to increase the number of future organ donor card holders in Germany.
DMW - Deutsche Medizinische Wochenschrift 01/2012; 137(3):69-73. · 0.53 Impact Factor
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ABSTRACT: Promoted by the decoding of the human genome as part of the human genome project, individualised therapy approaches have become a realistic perspective for therapies that are more effective, less prone to side effects and economically reasonable. This also applies to chronic liver disease. With the aim not only to expand the current knowledge base through basic research on the underlying disease processes and treatment options but also to identify and characterise biomarkers, the creation of genetic fingerprints for individualised diagnosis, prognosis and treatment of patients takes its place in the centre of translational hepatology. For certain liver diseases personalised therapy approaches are already existent. Examples are the determination of viral genotypes, viral kinetics and genotyping of the IL28B polymorphism to optimise the treatment of chronic hepatitis C. The challenges of the next few years relate to the broadening of the knowledge base, the establishment of reliable and standardised technologies, and the development of intelligent bioinformatics strategies for data analysis and data integration. The following review not only summarises the current state of progress and possibilities of personalised medicine in hepatological diseases, but also explains the technical background of the limitations that currently hinder a consistent clinical implementation.
Zeitschrift für Gastroenterologie 01/2012; 50(1):41-6. · 0.90 Impact Factor
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ABSTRACT: Loss of intestinal barrier function plays an important role in the pathogenesis of inflammatory bowel disease (IBD). Shedding of intestinal epithelial cells is a potential cause of barrier loss during inflammation. The objectives of the study were (1) to determine whether cell shedding and barrier loss in humans can be detected by confocal endomicroscopy and (2) whether these parameters predict relapse of IBD.
Confocal endomicroscopy was performed in IBD and control patients using intravenous fluorescein to determine the relationship between cell shedding and local barrier dysfunction. A grading system based on appearances at confocal endomicroscopy in humans was devised and used to predict relapse in a prospective pilot study of 47 patients with ulcerative colitis and 11 patients with Crohn's disease.
Confocal endomicroscopy in humans detected shedding epithelial cells and local barrier defects as plumes of fluorescein effluxing through the epithelium. Mouse experiments demonstrated inward flow through some leakage-associated shedding events, which was increased when luminal osmolarity was decreased. In IBD patients in clinical remission, increased cell shedding with fluorescein leakage was associated with subsequent relapse within 12 months after endomicroscopic examination (p<0.001). The sensitivity, specificity and accuracy for the grading system to predict a flare were 62.5% (95% CI 40.8% to 80.4%), 91.2% (95% CI 75.2 to 97.7) and 79% (95% CI 57.7 to 95.5), respectively.
Cell shedding and barrier loss detected by confocal endomicroscopy predicts relapse of IBD and has potential as a diagnostic tool for the management of the disease.
Gut 11/2011; 61(8):1146-53. · 10.11 Impact Factor
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T C Wehler,
C Graf,
K Altherr,
T Zimmermann,
W Brenner,
J W Thüroff,
S Biesterfeld,
I Gockel,
M Theobald, P R Galle,
C C Schimanski
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ABSTRACT: For several tumor entities, a significant correlation between the chemokine stromal cell-derived factor 1 (SDF1) and its receptor C-X-C chemokine receptor type 4 (CXCR4), metastasis and tumor proliferation, as well as prognosis, has been described. In this study, a series of 105 renal cell carcinoma patients were analyzed in terms of expression of SDF1α and SDF1β and infiltration by CD4+ and CD8+ T-cells and the data correlated with TNM category, grading and survival. While the splice variant SDF1α had no impact on tumor grading, T-cell invasion or overall survival, expression of SDF1β showed a significant correlation with tumor grading and also suggested a correlation with metastasis, as well as CD8+ T-cell invasion. These results indicate a potential T-cell-mediated antitumor response induced by SDF1β up-regulation. Therefore targeting the SDF1β-CXCR4 signaling pathway may be a promising means for new therapeutic strategies in advanced tumor stages.
Anticancer research 09/2011; 31(9):2797-803. · 1.73 Impact Factor
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ABSTRACT: Despite great progress in diagnosis and management of hepatocellular carcinoma (HCC), the exact biology of the tumor remains poorly understood overall limiting the patients' outcome. Detailed analysis and characterization of the molecular mechanisms and subsequently individual prediction of corresponding prognostic traits would revolutionize both diagnosis and treatment of HCC and is the key goal of modern personalized medicine. Over the recent years systematic approaches for the analysis of whole tumor genomes and transcriptomes as well as epigenomes became affordable tools in translational research. This includes simultaneous analyses of thousands of molecular targets using microarray-based technologies as well as next-generation sequencing. Although currently diagnosis and classification of hepatocellular cancers still rely on histological examination of tumor sections, these technologies show great promise to advance the current knowledge of hepatocarcinogenesis, complement diagnostic classification in a setting of microarray-aided pathology, and rationalize the individual drug selection. This review aims to summarize recent progress of system biological approaches in hepatocarcinogenesis and outline potential areas for translational application in a clinical setting. Further, we give an update about known signaling pathways active in HCC, summarize the historical application of whole genomic approaches in liver cancer and indicate ongoing experimental research utilizing novel technologies in diagnosis and treatment of this deadly disease. This will also include the discussion and characterization of new molecular and cellular targets such as Cancer Stem Cells (CSCs).
Journal of Hepatology 07/2011; 56(1):267-75. · 9.26 Impact Factor
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M Moehler,
A Mueller,
J T Hartmann,
M P Ebert,
S E Al-Batran,
P Reimer,
M Weihrauch,
F Lordick,
T Trarbach,
S Biesterfeld,
M Kabisch,
D Wachtlin, P R Galle
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ABSTRACT: Sunitinib monotherapy in pretreated patients with advanced gastric cancer (AGC) was investigated. Preplanned analyses of tumour biomarkers on treatment outcome were performed.
Patients received sunitinib 50mg/day for 4 weeks with 2 weeks rest until disease progression or unacceptable toxicity. The primary end-point was objective response rate (ORR). Secondary end-points included progression-free survival (PFS), overall survival (OS) and safety.
Fifty-two patients were enrolled and treated (safety population, SP). In the intention to treat population (n=51); the ORR was 3.9%, median PFS was 1.28 months [95% CI, 1.18-1.90], median OS was 5.81 months [95% CI, 3.48-12.32], the estimated one-year survival rate was 23.7% [95%CI: 12.8-36.5]. In subgroup analyses, tumour VEGF-C expression compared with no expression was associated with significantly shorter median PFS (1.23 versus 2.86 months, logrank p=0.0119) but there was no difference in tumour control rate (p=0.142). In the SP, serious adverse events occurred in 26 patients, leading to 13 deaths, all sunitinib unrelated. Thirty-eight patients died from progressive disease, nine died <60 days after treatment start.
Sunitinib monotherapy was associated with limited tumour response and good/moderate tolerability in this setting.
European journal of cancer (Oxford, England: 1990) 07/2011; 47(10):1511-20. · 4.12 Impact Factor
