[Successful intraductal radiofrequency ablation of residual adenoma tissue following endoscopic papillectomy]. / Erfolgreiche intraduktale Radiofrequenzablation residuellen Adenomgewebes nach endoskopischer Papillektomie.

Treatment of adenoma of the major duodenal papilla is often a challenge for the endoscopist. We report about two patients with papillary adenoma who had residual adenoma in the center of the ductus hepatocholedochus papillary region after endoscopic papillectomy. Due to missing possibility of further endoscopic resection we carried out endobiliary radiofrequency ablation instead of surgical treatment. In follow-up examination, there where no macroscopic or histological relapse, therefore endobiliary radiofrequency ablation needs to be discussed as an alternative to surgical therapy option.

[Diagnostic quality of transluminal biopsy in undetermined biliary duct stenosis by primary PTCD with "cross and push" technique - a prospective monocentric pilot study]. / Diagnostische Güte der transluminalen Biopsie bei unklaren Gallenwegstenosen im Rahmen der primären PTCD-Anlage mit der "Cross and Push"-Technik ­ eine prospektive monozentrische Pilotstudie.

BACKGROUND: Histological characterisation of a biliary duct stenosis can be essential for further therapeutic steps. Access to the stenosis is not given in every patient by endoscopic retrograde cholangiography. In these cases, a percutaneous transhepatic cholangiodrainage (PTCD) may be helpful. The optimal preparation and diagnostic precision of taking a biopsy by PTCD is not sufficiently evaluated. METHODS: After a training phase of 10 patients, PTCDs in 30 patients with a biliary duct stenosis and lack of adequate drainage by ERC were done in a time range of 24 months. The stenosis was passed with a wire and then a directed forceps-biopsy was performed in a "cross and push" technique (Transluminal Biliary Biopsy Forceps Set, Cook Medical™), using a wire-guided introducer (7 Fr. inner diameter). The result of the histological survey was then correlated with the definite diagnosis. The follow-up time was 18 months. RESULT: Out of 30 patients, there were 22 (73 %) with a malignant stenosis (10 biliary duct neoplasms, 12 non-biliary carcinoma/metastases/lymphomas). Eight (27 %) out of 30 patients had a benign stenosis. In case of all 30 patients, there was enough tissue gained by biopsy for histologic survey. Sub-group analysis was performed for biliary duct cancer and non-biliary cancer. Thereby, 8 out of 10 patients with biliary duct neoplasms were also classified as malignant by histology (sensitivity 80 %); whereas, only 8 out of 12 non-biliary cancers could be histologically classified as malignant (sensitivity 66.6 %, difference not significant, p = 0.0577). In all patients with benign stenosis, histological evaluation of biopsies revealed benign histology (specificity 100 %). There were no intervention-related complications. CONCLUSION: This prospective cohort-study shows a high diagnostic precision for the percutaneous transductal biopsy-set to evaluate an undetermined biliary duct stenosis-particularly in biliary processes. Because it can be difficult to gain histology in malignant biliary duct processes using different methods, the "cross and push" biopsy completes the spectrum of diagnostic procedures.

[Perforation as a delayed complication after endoscopic full-thickness resection in a recurrent adenoma of the sigmoid]. / Perforation als Spätkomplikation nach endoskopischer Vollwandresektion eines Rezidivadenoms im Colon sigmoideum.

The endoscopic full-thickness resection (EFTR) is established in ablation of recurrent colorectal adenomas, which cannot be removed by endoscopic resection in cases of fibrosis. The EFTR can be applied with low risk, in one step, with the use of special devices, such as the full-thickness resection device (FTRD®). The main risks described in literature are bleeding and perforations. The mentioned perforations were explained by previous defects of the device system or patient-related predisposed parameters for perforation.We report the case of a 55-year old woman who underwent an endoscopic full-thickness resection with the FTRD® due to a recurrent adenoma with high-grade intraepithelial neoplasm in the sigmoid. After primary uncomplicated development, she presented with a secondary perforation with purulent peritonitis seven days after intervention, so a sigmoid-resection was necessary. There were no signs of defects with the FTRD® system or patient-related predisposed parameters, which prefer a perforation.Our case-report demonstrates the necessity for clinical follow up, after primary uncomplicated endoscopic full-thickness resection, to recognize delayed complications.

A liver nodule in a patient transplanted for primary sclerosing cholangitis: an interdisciplinary diagnostic approach.

We report the case of a 53-year-old female patient who was transplanted with the liver of a 71-year-old male donor for advanced primary sclerosing cholangitis (PSC) and who additionally was diagnosed with a histologically non-classifiable colitis shortly before transplantation. Upon follow-up abdominal ultrasound 4 months after transplantation, a liver lesion measuring 16 × 23 mm was detected in the transplanted liver. This lesion had not been noticed immediately after transplantation and showed a pattern suspicious for malignancy in contrast-enhanced ultrasound. In line, a biopsy revealed the presence of a metastasis of an adenocarcinoma of colorectal origin, suggesting that a colitis- and PSC-associated colorectal cancer of the recipient might have been overseen upon the initial diagnostic workup. Despite two negative follow-up colonoscopies, this hypothesis was further supported by a strong positive signal in projection to the cecum in a subsequently performed PET/CT-scan. However, surgical resection of the right colon that was performed simultaneously with the atypical resection of the liver metastasis only revealed an inflamed diverticulum but no malignancy in the resected colon segment. Moreover, cytogenetic and molecular genetic testing on the resected specimens clearly attributed the metastasis to the male donor. On the one hand, this case underlines the necessity of endoscopic surveillance of patients with PSC and/or inflammatory bowel disease as well as the challenges in diagnosis of colitis-associated cancer. On the other hand, it shows that the acceptance of organs from elderly donors in times of organ shortage might be linked to an increased risk of donor transmitted malignancies.

Computer-based classification of small colorectal polyps by using narrow-band imaging with optical magnification.

BACKGROUND: Recent studies have shown that narrow-band imaging (NBI) is a powerful diagnostic tool for the differentiation between neoplastic and non-neoplastic colorectal polyps. OBJECTIVE: To develop a computer-based method for classification of colorectal polyps. DESIGN: A prospective study. SETTING: University hospital. PATIENTS: A total of 214 patients with colorectal polyps who underwent a zoom NBI colonoscopy. INTERVENTIONS: A total of 434 detected polyps 10 mm or smaller were imaged and subsequently removed for histological analysis. MAIN OUTCOME MEASUREMENTS: Diagnostic performance in polyp classification by 2 experts, 2 nonexperts, and a computer-based algorithm. RESULTS: The expert group and the computer-based algorithm achieved a comparable diagnostic performance (expert group: 93.4% sensitivity, 91.8% specificity, and 92.7% accuracy; computer-based algorithm: 95.0% sensitivity, 90.3% specificity, and 93.1% accuracy) and were both significantly superior to the nonexpert group (86.0% sensitivity, 87.8% specificity, and 86.8% accuracy) in terms of sensitivity, negative predictive value, and accuracy. Subgroup analysis of 255 polyps 5 mm or smaller revealed comparable results without significant differences in the overall analysis of all polyps. LIMITATIONS: No fully automatic classification system. CONCLUSIONS: The study demonstrates that computer-based classification of colon polyps can be achieved with high diagnostic performance.

Assessment of inflammatory and fibrotic stenoses in patients with Crohn's disease using contrast-enhanced ultrasound and computerized algorithm: a pilot study.

PURPOSE: The development of stenosis is a typical complication of Crohn's disease and represents a serious diagnostic and therapeutic challenge. The aim of the present study was to define objective quantitative measures of stricture characteristics (fibrostenotic/cicartricial vs. inflammatory) using contrast-enhanced ultrasound (CEUS) in patients with stenotic Crohn's disease. MATERIALS AND METHODS: During a period of 18 months, 18 consecutive patients with Crohn's disease and manifestation of a localized significant small bowel stenosis were prospectively recruited. Standardized ultrasound (US) examination, color-coded duplex sonography and CEUS using SonoVue® were performed. Quantitative measurements of bowel wall vascularity were determined using computerized algorithms (Bracco QONTRAST software). The quality of stenosis (fibrostenotic vs. inflammatory) was classified in a 4-point scale, and the diagnostic/prognostic power of the US and clinical tests upon initial presentation were compared. RESULTS: We established a novel standardized CEUS procedure using computerized algorithms to quantitatively examine stenoses in Crohn's disease. An inflammatory origin of stenosis correlated significantly with a high Crohn's Disease Activity Index (CDAI) (p < 0.01), the length of stenosis (p < 0.01) as well as the Limberg score (p < 0.01). There was no correlation between the type of stenosis and quantitative results of CEUS. CONCLUSION: Although bowel wall vascularity can be quantitatively assessed in stenotic areas by CEUS, this analysis does not improve the diagnostic power for the objective determination of the quality of stenosis at a single measurement. Semiquantitative analysis of bowel wall vascularity, length of stenosis, and CDAI may help to discriminate the origin of small bowel stenosis in Crohn's disease.

Glycoprotein 130-dependent pathways in host hepatocytes are important for liver repopulation in mice.

Hepatocyte transplantation (HT) is still restricted by the limited amount of transplantable cells. Therefore, a better understanding of the mechanisms involved in cellular engraftment, proliferation, and in vivo selection is important. Here we aimed to evaluate the role of the interleukin 6 (IL-6)/glycoprotein 130 (gp130) system for liver repopulation. Mice carrying a conditional hepatocyte-specific deletion of the common IL-6 signal transducer gp130 (gp130(Deltahepa)) were used for HT. First, we compared bone marrow transplantation (BMT), partial hepatectomy (PH), and retrorsine treatment of recipient mice to optimize the in vivo selection of transplanted hepatocytes. BMT combined with PH was sufficient to induce a 30-fold increase in the number of transplanted donor hepatocytes, whereas additional retrorsine pretreatment led to an up to 40-fold increase. Next, the influence of gp130 signaling in hepatocytes on cell selection was evaluated. Wild-type (WT) hepatocytes repopulated WT recipients at the same rate as gp130(Deltahepa) cells. In contrast, liver repopulation by transplanted cells was enhanced in gp130(Deltahepa) recipient mice. This was associated with higher proliferation of donor hepatocytes and enhanced apoptosis in gp130(Deltahepa) recipient livers. Additionally, the acute phase response was strongly induced after HT in WT recipients but blunted in gp130(Deltahepa) recipients. As a result, significantly more liver remodeling, evidenced by stronger hepatic stellate cell activation and collagen accumulation, was found in gp130(Deltahepa) mice after HT. In conclusion, the HT model established here can be efficiently applied to investigate cell-specific mechanisms in liver repopulation. Moreover, we have shown that gp130-dependent pathways in host hepatocytes are important for controlling liver repopulation.

Small intestinal mucosa expression of putative chaperone fls485.

BACKGROUND: Maturation of enterocytes along the small intestinal crypt-villus axis is associated with significant changes in gene expression profiles. fls485 coding a putative chaperone protein has been recently suggested as a gene involved in this process. The aim of the present study was to analyze fls485 expression in human small intestinal mucosa. METHODS: fls485 expression in purified normal or intestinal mucosa affected with celiac disease was investigated with a molecular approach including qRT-PCR, Western blotting, and expression strategies. Molecular data were corroborated with several in situ techniques and usage of newly synthesized mouse monoclonal antibodies. RESULTS: fls485 mRNA expression was preferentially found in enterocytes and chromaffine cells of human intestinal mucosa as well as in several cell lines including Rko, Lovo, and CaCo2 cells. Western blot analysis with our new anti-fls485 antibodies revealed at least two fls485 proteins. In a functional CaCo2 model, an increase in fls485 expression was paralleled by cellular maturation stage. Immunohistochemistry demonstrated fls485 as a cytosolic protein with a slightly increasing expression gradient along the crypt-villus axis which was impaired in celiac disease Marsh IIIa-c. CONCLUSIONS: Expression and synthesis of fls485 are found in surface lining epithelia of normal human intestinal mucosa and deriving epithelial cell lines. An interdependence of enterocyte differentiation along the crypt-villus axis and fls485 chaperone activity might be possible.

Longitudinal monocyte human leukocyte antigen-DR expression is a prognostic marker in critically ill patients with decompensated liver cirrhosis.

BACKGROUND: Critical illness in cirrhotic patients is associated with a poor prognosis and increased susceptibility to infections. Monocyte HLA-DR expression is decreased in cirrhotic patients, but its prognostic value has not been investigated prospectively. METHODS: Thirty-eight critically ill patients with decompensated liver cirrhosis were included in this prospective study. On admission to the intensive care unit (ICU), inflammatory parameters (C-reactive protein, procalcitonin and lipopolysaccharide-binding protein), interleukin (IL)-10, interferon (IFN)-gamma serum levels, tumour necrosis factor (TNF)-alpha ex vivo stimulation (whole blood assay) and HLA-DR expression on monocytes (FACS analysis) were determined. Immune parameters were furthermore measured every third day until discharge from the ICU or death of the patients. RESULTS: Intensive care unit mortality of the cirrhotic patients was 34.2%. During admission, TNF ex vivo, IFN-gamma and HLA-DR expression were lower in non-survivors (all P<0.05), while IL-10 levels were increased in non-survivors compared with survivors (P=0.001). However, individual values clearly overlapped between groups. Prospective analysis revealed that monocyte HLA-DR expression remained stable or increased in survivors, but decreased in non-survivors (P=0.002). A decrease in HLA-DR expression between admission and day 3 was strongly associated with decreased IFN-gamma levels and increased ICU mortality (hazard ratio 3.36, P=0.008), mostly owing to late sepsis. This association was independent of the sequential organ failure assessment and model for end-stage liver disease score. CONCLUSIONS: Here we establish the relative HLA-DR expression (admission/day 3) as a prognostic marker for ICU mortality in critically ill cirrhotic patients. These results may guide the evaluation of immune-modulating therapies in these patients.

Quest for the best endoscopic imaging modality for computer-assisted colonic polyp staging.

BACKGROUND: It was shown in previous studies that high definition endoscopy, high magnification endoscopy and image enhancement technologies, such as chromoendoscopy and digital chromoendoscopy [narrow-band imaging (NBI), i-Scan] facilitate the detection and classification of colonic polyps during endoscopic sessions. However, there are no comprehensive studies so far that analyze which endoscopic imaging modalities facilitate the automated classification of colonic polyps. In this work, we investigate the impact of endoscopic imaging modalities on the results of computer-assisted diagnosis systems for colonic polyp staging. AIM: To assess which endoscopic imaging modalities are best suited for the computer-assisted staging of colonic polyps. METHODS: In our experiments, we apply twelve state-of-the-art feature extraction methods for the classification of colonic polyps to five endoscopic image databases of colonic lesions. For this purpose, we employ a specifically designed experimental setup to avoid biases in the outcomes caused by differing numbers of images per image database. The image databases were obtained using different imaging modalities. Two databases were obtained by high-definition endoscopy in combination with i-Scan technology (one with chromoendoscopy and one without chromoendoscopy). Three databases were obtained by high-magnification endoscopy (two databases using narrow band imaging and one using chromoendoscopy). The lesions are categorized into non-neoplastic and neoplastic according to the histological diagnosis. RESULTS: Generally, it is feature-dependent which imaging modalities achieve high results and which do not. For the high-definition image databases, we achieved overall classification rates of up to 79.2% with chromoendoscopy and 88.9% without chromoendoscopy. In the case of the database obtained by high-magnification chromoendoscopy, the classification rates were up to 81.4%. For the combination of high-magnification endoscopy with NBI, results of up to 97.4% for one database and up to 84% for the other were achieved. Non-neoplastic lesions were classified more accurately in general than non-neoplastic lesions. It was shown that the image recording conditions highly affect the performance of automated diagnosis systems and partly contribute to a stronger effect on the staging results than the used imaging modality. CONCLUSION: Chromoendoscopy has a negative impact on the results of the methods. NBI is better suited than chromoendoscopy. High-definition and high-magnification endoscopy are equally suited.

Current diagnosis and management of primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is an important liver disease with major morbidity and mortality. The diagnosis of PSC is confirmed by magnetic resonance cholangiopancreaticography, and endoscopic retrograde cholangiopancreaticography is performed in patients needing therapeutic endoscopy. As a result of the unknown cause of the disease, current medical therapies are unsatisfactory. Nevertheless, high-dose ursodeoxycholic acid should be recommended for treatment of PSC patients because there is a trend toward increased survival. Dominant bile duct stenoses should be treated endoscopically. However, liver transplantation continues to be the only therapeutic option for patients with advanced disease. Estimation of prognosis and timing of liver transplantation should be determined individually for each PSC patient on the basis of all results. The diagnosis and treatment of cholangiocarcinoma (CC) still remain a challenge in PSC patients. Early diagnosis of CC certainly is a prerequisite for successful treatment with surgical resection or innovative strategies such as neoadjuvant radiochemotherapy with subsequent orthotopic liver transplantation. Therefore, endoscopic techniques such as cholangioscopy and/or intraductal ultrasound may be useful diagnostic tools in patients with stenoses suspicious for malignancy.

Perihilar lymph nodes in patients with primary sclerosing cholangitis with and without cholangiocellular carcinoma.

OBJECTIVE: Enlarged perihilar lymph nodes have been described in patients with primary sclerosing cholangitis (PSC). The aim of the study was to determine the clinical relevance of perihilar lymph nodes in PSC patients with and without cholangiocellular carcinoma (CCC). MATERIAL AND METHODS: The status of perihilar lymph nodes was investigated in 117 patients with PSC using "high-end" ultrasound. Thirty-five of the 117 PSC patients had histologically proven CCC. Lymph node status was correlated with the presence of CCC and inflammatory bowel disease (IBD). RESULTS: Seventy-three percent of PSC patients without CCC and 86% of patients with CCC had enlarged perihilar lymph nodes (NS). In CCC patients, the width of lymph nodes was significantly larger (12+/-6 mm versus 8+/-4 mm; p=0.0001), and the length:width ratio (2.15+/-0.7:1 versus 2.5+/-0.6:1; p=0.004) of the lymph nodes was significantly lower. Thirty-seven percent of PSC patients without CCC and 57% of patients with PSC and CCC had multiple perihilar lymph nodes (p=0.04). In all patients, the presence versus absence of IBD had no influence on the number (84% versus 74%,) and size of perihilar lymph nodes (length: 21+/-10 mm versus 19+/-7 mm). Lymph node status did not correlate with the number of episodes of cholangitis. CONCLUSIONS: Enlarged perihilar lymph nodes are characteristic of patients with PSC. Since perihilar lymph nodes are not predictive of the presence of complicating CCC, such patients should not be excluded from liver transplantation.

Primary sclerosing cholangitis: diagnosis and treatment.

BACKGROUND: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease that involves progressive destruction of the bile ducts. Its prevalence is 4 to 16 cases per 100,000 persons. Its incidence has risen over the last 20 years, with a more than 35% increase in the last 10 years alone. PSC tends to arise in patients with chronic inflammatory bowel diseases. It is associated with an increased risk of various types of cancer (13%-14%), most prominently cholangiocellular carcinoma (CCC). METHOD: This review is based on a selective search in PubMed for original articles, meta-analyses, and review articles about PSC that appeared from January 1980 to May 2013. RESULTS: The diagnosis is generally established with a bile duct imaging study--typically, magnetic resonance cholangiopancreaticography (MRCP): this test is more than 80% sensitive and more than 90% specific for the diagnosis of PSC. The time from diagnosis to death or liver transplantation is 12 to 18 years, and the risk that a patient with PSC will die of cancer is 40% to 58%. Options for drug treatment are limited. Randomized, controlled trials have not shown any improvement of outcomes from the administration of ursodeoxycholic acid (UDCA). Interventional endoscopy is used to treat dominant stenoses and cholangitis, even though this method of treatment is supported only by low-level evidence. Liver transplantation results in a 10-year survival rate above 80%. CONCLUSION: There is no causally directed treatment for PSC. Early diagnosis, complication management, and the evaluation of an optimally timed liver transplantation are the main determinants of outcome.

Response evaluation of chemotherapy in metastatic colorectal cancer by contrast enhanced ultrasound.

AIM: To evaluate whether contrast enhanced ultrasound (CEUS) might also be used for response prediction and early response evaluation in patients receiving bevacizumab based chemotherapy for metastasized colorectal cancer. METHODS: Thirty consecutive patients with non primary resectable liver metastases from colorectal cancer underwent CEUS before treatment (CEUS date 1) and before the second (CEUS date 2) and fourth (CEUS date 3) cycle of bevacizumab based chemotherapy. Three parameters [PEAK, Time to peak (TTP) and RISE RATE]were correlated with radiological response. RESULTS: For neoadjuvant purpose a reduction of tumour mass was required to assume clinical response. Based on these response criteria there was a significant (P < 0.001) correlation in TTP between metastases of responders (9.08 s) and non-responders (14.76 s) archived on CEUS date 1. By calculating a standardized quotient (metastases divided by normal liver tissue) we were able to define a cut off, predicting response with a sensitivity of 92.3 % and a specificity of 100 %. To reflect a palliative intention only those patients with progressive disease were classified as non-responders. In this stetting TTP was also significantly (P < 0.01) different between responders and non-responders. In contrast, Peak and Rise rate did not show any significant difference between responder and non-responder. CONCLUSION: CEUS might serve as a surrogate marker to predict treatment response in patients with metastasized colorectal cancer who receive antiangiogenic therapy.

Management of primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease with major morbidity and mortality. Therapeutic management is difficult, due to lack of conclusive data and individual disease progression. High-dose UDCA was used for years as a pharmacotherapeutic agent to prevent disease progression, based on a positive trend in pilot studies, but has recently been proven to have a negative effect in advanced disease. Immunosuppressants might be useful in patients with overlap syndromes. Dominant bile duct stenoses should be treated endoscopically, and cholangiocellular carcinoma (CCC) still remains a therapeutic challenge in PSC patients. Early diagnosis of CCC must be improved and new strategies such as neoadjuvant radiochemotherapy with subsequent liver transplantation in selected patients are further options to be considered.

Safe use of FOLFOX in two patients with metastatic colorectal carcinoma and severe hepatic dysfunction.

BACKGROUND: Chemotherapeutic options for patients with metastasised colorectal cancer and impaired liver function are limited. Although oxaliplatin and 5-FU are well tolerated as single therapeutic agents, data supporting their use as combination chemotherapy in the setting of severe hepatic dysfunction are insufficient. PATIENTS AND METHODS: Here, we report on 2 patients with colorectal cancer and severe liver dysfunction secondary to hepatic metastases. On admission both patients displayed a bilirubin of > 22 mg/dL and an alkaline phosphatase (AP) of > 350 U/L as signs of extensive hepatic tumor spread. We initiated a 5-FU/oxaliplatin-based combination chemotherapy in both patients. RESULTS: Liver function and clinical performance improved dramatically within the first cycles of therapy in both patients. On radiologic evaluation, we observed 1 partial response and one long-term (10 months) disease stabilization. The toxicity was acceptable in both patients. CONCLUSION: We concluded that oxaliplatin-based combination chemotherapies (eg FOLFOX4) may achieve good tumor response without significant side effects in patients with metastatic colorectal cancer and hepatic dysfunction.

[Anemia and severe thrombocytopenia in celiac disease]. / Anämie und schwere Thrombozytopenie bei Sprue.

BACKGROUND: The frequency of diagnosis of celiac disease has increased since the introduction of serologic testing. The number of patients in whom extraintestinal symptoms reflect the initial manifestation is rising. Common symptoms are changes in blood counts, which can arise from changes in all cell lineages. Among these, iron deficiency anemia is very common, but also thrombocytosis and thrombocytopenia have been reported to manifest themselves within the framework of celiac disease. CASE REPORT: The authors report on a patient with malnutrition, macrocytic anemia, and pronounced thrombocytopenia. Based on changes of peripheral blood smear and endoscopic result, celiac disease was suspected that could be confirmed by histology of duodenal biopsies. The thrombocytopenia was reversible after initiation of gluten-free diet and folic acid substitution. In addition, clinical symptoms resolved and hematologic reconstitution could be observed. CONCLUSION: Similar deficiencies have almost exclusively been observed in patients with increased folic acid requirements during pregnancy or intensive care. Celiac disease must be taken into consideration, if changes in blood counts occur associated with gastrointestinal symptoms.

Long-term survival of a HCC-patient with severe liver dysfunction treated with sorafenib.

Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver. Prognosis and treatment options are stage dependent. In general, prognosis of patients with unresectable HCC is poor, especially for those patients with impaired liver function. Whereas treatment with the novel molecular tyrosine kinase inhibitor sorafenib (Nexavar) was shown to result in prolonged survival in patients with preserved liver function, its' possible application in HCC-patients with strongly impaired liver function has not been clearly assessed. Here, we report on a 47-year-old male patient who presented with Child-Pugh class C liver cirrhosis and multifocal, non-resectable HCC. The patient was treated for 27 mo with Sorafenib, which was not associated with major drug-related side effects. During treatment, a reduction in tumour size of 24% was achieved, as assessed by regular CT scan. Moreover, within the 27 mo interval of stable tumour disease, liver function improved from Child-Pugh class C to class A.

Functional contribution of elevated circulating and hepatic non-classical CD14CD16 monocytes to inflammation and human liver fibrosis.

BACKGROUND: Monocyte-derived macrophages critically perpetuate inflammatory responses after liver injury as a prerequisite for organ fibrosis. Experimental murine models identified an essential role for the CCR2-dependent infiltration of classical Gr1/Ly6C(+) monocytes in hepatic fibrosis. Moreover, the monocyte-related chemokine receptors CCR1 and CCR5 were recently recognized as important fibrosis modulators in mice. In humans, monocytes consist of classical CD14(+)CD16(-) and non-classical CD14(+)CD16(+) cells. We aimed at investigating the relevance of monocyte subpopulations for human liver fibrosis, and hypothesized that 'non-classical' monocytes critically exert inflammatory as well as profibrogenic functions in patients during liver disease progression. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed circulating monocyte subsets from freshly drawn blood samples of 226 patients with chronic liver disease (CLD) and 184 healthy controls by FACS analysis. Circulating monocytes were significantly expanded in CLD-patients compared to controls with a marked increase of the non-classical CD14(+)CD16(+) subset that showed an activated phenotype in patients and correlated with proinflammatory cytokines and clinical progression. Correspondingly, CD14(+)CD16(+) macrophages massively accumulated in fibrotic/cirrhotic livers, as evidenced by immunofluorescence and FACS. Ligands of monocyte-related chemokine receptors CCR2, CCR1 and CCR5 were expressed at higher levels in fibrotic and cirrhotic livers, while CCL3 and CCL4 were also systemically elevated in CLD-patients. Isolated monocyte/macrophage subpopulations were functionally characterized regarding cytokine/chemokine expression and interactions with primary human hepatic stellate cells (HSC) in vitro. CD14(+)CD16(+) monocytes released abundant proinflammatory cytokines. Furthermore, CD14(+)CD16(+), but not CD14(+)CD16(-) monocytes could directly activate collagen-producing HSC. CONCLUSIONS/SIGNIFICANCE: Our data demonstrate the expansion of CD14(+)CD16(+) monocytes in the circulation and liver of CLD-patients upon disease progression and suggest their functional contribution to the perpetuation of intrahepatic inflammation and profibrogenic HSC activation in liver cirrhosis. The modulation of monocyte-subset recruitment into the liver via chemokines/chemokine receptors and their subsequent differentiation may represent promising approaches for therapeutic interventions in human liver fibrosis.