[Transarterial ablation of hepatocellular carcinoma. Status and developments]. / Transvaskuläre Ablation des hepatozellulären Karzinoms. Ist Chemotherapie alles?

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and represents the main cause of death among European patients with liver cirrhosis. Only 30-40% of patients diagnosed with HCC are candidates for curative treatment options (e.g. surgical resection, liver transplantation or ablation). The remaining majority of patients must undergo local regional and palliative therapies. Transvascular ablation of HCC takes advantage of the fact that the hypervascularized HCC receives most of its blood supply from the hepatic artery. In this context transvascular ablation describes different therapy regimens which can be assigned to four groups: cTACE (conventional transarterial chemoembolization), bland embolization (transarterial embolization TAE), DEB-TACE (TACE with drug-eluting beads, DEB) and SIRT (selective internal radiation therapy, radioembolization). Conventional TACE is the most common type of transvascular ablation and represents a combination of intra-arterial chemotherapy and embolization with occlusion of the arterial blood supply. However, there is no standardized regimen with respect to the chemotherapeutic drug, the embolic agent, the usage of lipiodol and the interval between the TACE procedures. Even the exact course of a cTACE procedure (order of chemotherapy or embolization) is not standardized. It remains unclear whether or not intra-arterial chemotherapy is definitely required as bland embolization using very small, tightly calibrated spherical particles (without intra-arterial administration of a chemotherapeutic drug) shows tumor necrosis comparable to cTACE. For DEB-TACE microparticles loaded with a chemotherapeutic drug combine the advantages of cTACE and bland embolization. Thereby, a continuing chemotherapeutic effect within the tumor might cause a further increase in intratumoral cytotoxicity and at the same time a decrease in systemic toxicity.

[Systemic amyloidoses]. / Systemische Amyloidosen.

Amyloidoses are rare protein folding disorders, in which proteins are deposited as insoluble fibrillar aggregates due to a conformational change. This can occur in a local or systemic form. Systemic amyloidoses are life-threatening complications of monoclonal gammopathy, chronic inflammatory diseases or within hereditary diseases. The causative treatment of amyloidosis is the reduction of the amyloid precursor protein by chemotherapy, anti-inflammatory treatment, or liver transplantation. Early diagnosis of the disease is essential in order to effectively treat patients and avoid further deterioration of organ functions.

Enhanced caspase-8 recruitment to and activation at the DISC is critical for sensitisation of human hepatocellular carcinoma cells to TRAIL-induced apoptosis by chemotherapeutic drugs.

Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) exhibits potent antitumour activity upon systemic administration in mice without showing the deleterious side effects observed with other apoptosis-inducing members of the TNF family such as TNF and CD95L. TRAIL may, thus, have great potential in the treatment of human cancer. However, about 60% of tumour cell lines are not sensitive to TRAIL. To evaluate the mechanisms of tumour resistance to TRAIL, we investigated hepatocellular carcinoma (HCC) cell lines that exhibit differential sensitivity to TRAIL. Pretreatment with chemotherapeutic drugs, for example, 5-fluorouracil (5-FU), rendered the TRAIL-resistant HCC cell lines sensitive to TRAIL-induced apoptosis. Analysis of the TRAIL death-inducing signalling complex (DISC) revealed upregulation of TRAIL-R2. Caspase-8 recruitment to and its activation at the DISC were substantially increased after 5-FU sensitisation, while FADD recruitment remained essentially unchanged. 5-FU pretreatment downregulated cellular FLICE-inhibitory protein (cFLIP) and specific cFLIP downregulation by small interfering RNA was sufficient to sensitise TRAIL-resistant HCC cell lines for TRAIL-induced apoptosis. Thus, a potential mechanism for TRAIL sensitisation by 5-FU is the increased effectiveness of caspase-8 recruitment to and activation at the DISC facilitated by the downregulation of cFLIP and the consequent shift in the ratio of caspase-8 to cFLIP at the DISC.

Radiological monitoring of the treatment of solid tumors in practice.

PURPOSE: Thanks to advances in cancer therapy, the diagnosis of "incurable cancer" is increasingly able to be changed to a chronic disease that is manageable over long periods, resulting in a change in the clinical management of cancer patients with solid tumors. New parameters are needed to measure the success of targeted therapy in clinical trials. MATERIALS AND METHODS: Review article on the basis of selective literature research. RESULTS: In order to assess how well solid tumors respond to treatment, size-based criteria called RECIST (Response Evaluation Criteria in Solid tumors) have been defined. These criteria have been validated in large oncology trials and are currently used most frequently. New molecular therapies often do not - or at least do not immediately - reduce the size of a tumor. Therefore, RECIST evaluation should be critically assessed especially in the case of modern therapies. Any additional available tumor biology information should be considered. In radiology new methods and developments of RECIST have been introduced to better assess the success of targeted therapy. CONCLUSION: Assessment according to RECIST has been proven for the follow-up of classic tumor therapy. For the monitoring of targeted therapies, new parameters are often required. Therefore, some specific tumor- and therapy-adapted criteria have already been defined to better evaluate treatment success in clinical trials.

Improvement in gastrointestinal and health-related quality of life outcomes after conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium in liver transplant recipients.

OBJECTIVE: To evaluate improvement in gastrointestinal (GI) symptoms and health-related quality of life (HRQoL) in liver transplant recipients switched from mycophenolate mofetil (MMF) to enteric-coated mycophenolate sodium (EC-MPS). METHODS: A multicenter, open-label, single-arm study was undertaken in maintenance liver transplant recipients who reported GI complications with MMF therapy. The patients were switched to equimolar doses of EC-MPS at baseline. The primary end point was the change in the Gastrointestinal Symptom Rating Scale (GSRS) total score after 6 to 8 weeks of treatment with EC-MPS. Other key assessments for GI symptoms and HRQoL included the GSRS subscores, the Gastrointestinal Quality of Life Index (GIQLI), the Psychological General Well-Being Index, and the Overall Treatment Effect (OTE). Paired t-test was used to assess the difference in the mean score changes over time. RESULTS: A total of 34 patients were enrolled and switched to equimolar doses of EC-MPS. After 6 to 8 weeks of EC-MPS treatment, mean GSRS total score improved significantly from 2.88 ± 0.66 to 2.10 ± 0.78. Mean improvement in GSRS total score (-0.77 score points; P = .001) exceeded the minimal clinically important difference. Significant improvements were observed in all GSRS subscales (P < .05), GIQLI total scores (P = .001), and GIQLI subscales "GI symptoms" (P < .001) and "physical function" (0.013). Patients who continued EC-MPS reported sustained benefits compared with patients who switched back to MMF after 6 to 8 weeks of treatment with EC-MPS. On the OTE scale, improvement in symptoms was reported in 76.5% and 61.8% of the patients as perceived by the physicians and the patients. Improvement in HRQoL was reported by 41.2% of the patients. No deaths, biopsy proven acute rejections, or graft losses were reported during the study. CONCLUSION: Conversion from MMF to EC-MPS was associated with a significant improvement in GI symptoms and HRQoL in liver transplant recipients.

Orthotopic liver transplantation in human-immunodeficiency-virus-positive patients in Germany.

Objectives. This summary evaluates the outcomes of orthotopic liver transplantation (OLT) of HIV-positive patients in Germany. Methods. Retrospective chart analysis of HIV-positive patients, who had been liver-transplanted in Germany between July 1997 and July 2011. Results. 38 transplantations were performed in 32 patients at 9 German transplant centres. The reasons for OLT were end-stage liver disease (ESLD) and/or liver failure due to hepatitis C (HCV) (n = 19), hepatitis B (HBV) (n = 10), multiple viral infections of the liver (n = 2) and Budd-Chiari-Syndrome. In July 2011 19/32 (60%) of the transplanted patients were still alive with a median survival of 61 months (IQR (interquartile range): 41-86 months). 6 patients had died in the early post-transplantation period from septicaemia (n = 4), primary graft dysfunction (n = 1), and intrathoracal hemorrhage (n = 1). Later on 7 patients had died from septicaemia (n = 2), delayed graft failure (n = 2), recurrent HCC (n = 2), and renal failure (n = 1). Recurrent HBV infection was efficiently prevented in 11/12 patients; HCV reinfection occurred in all patients and contributed considerably to the overall mortality. Conclusions. Overall OLT is a feasible approach in HIV-infected patients with acceptable survival rates in Germany. Reinfection with HCV still remains a major clinical challenge in HIV/HCV coinfection after OLT.

Sporadic cases of acute autochthonous hepatitis E virus infection in Southwest Germany.

Hepatitis E infection is usually a self-limiting disease and an important cause of acute hepatitis in tropical and subtropical regions where the virus is endemic. In industrialized countries, sporadic cases of acute hepatitis E virus (HEV) infections have been described and the number of documented autochthonous infections seems to be increasing. We report three sporadic cases of autochthonous hepatitis E infections in Southwestern Germany which presented at our university hospital within two years. All cases were men who presented with acute hepatitis, icterus and elevated liver. In case 1 and case 2, liver biopsy revealed acute hepatitis, both patients were positive for anti-HEV antibodies, case 1 was also positive for HEV RNA with a viral load of 3.0 x 10(3)copies/ml in serum. In case 3, anti-HEV antibodies were detectable and HEV RNA was detected in serum (4.3 x 10(3)copies/ml) and stool (1.4 x 10(6)copies/ml). None of the patients had a recent travel history outside Germany and close contact to animals has been denied. HEV sequence analysis of two patients revealed genotype 3 with homologies to other European isolates and isolates from swine. Thus the source of infection remains unclear. Hepatitis E should be considered in differential diagnosis in patients with unexplained hepatitis and patients with acute hepatitis, whatever their age or travel history might be, should be tested for HEV.

[[18F]-FDG-PET in the diagnostics of gastrointestinal tumors]. / [18F]-FDG-PET in der Diagnostik gastrointestinaler Tumoren.

Positron emission Tomography (PET) with 2-[(18)F]-fluoro-2-deoxy-d-glucose (FDG) is a functional imaging technique with increasing value in special diagnostic fields of gastrointestinal tumours. In the initial staging of esophageal and gastric cancer, FDG-PET is useful in the staging of patients with advanced but local resectable disease. The detection of distant metastases results in an up-staging, and these patients should not be treated by surgery. Furthermore, FDG-PET is sufficient for monitoring early therapy responses after neoadjuvant treatment and enables one to select non-responders who may benefit from therapy alterations. Major indications for FDG-PET in patients with rectal carcinoma are therapy monitoring and diagnosis of relapses, especially the differentiation between tumour and scar and also the localisation of tumour manifestations in cases with increasing tumour markers. FDG-PET is very efficient in the imaging of pulmonal and hepatic metastases of colorectal cancer but not in lymph node staging. In diagnostic procedures for pancreatic carcinoma, FDG-PET can be recommended to explore the dignity of pancreatic lesions and in the imaging of tumour relapses. For gastrointestinal stroma tumours, FDG-PET is useful for the monitoring of therapy and the initial staging. For imaging of hepatocellular carcinoma and carcinoma of the gall bladder, FDG-PET is not sufficient.

[Cellular mechanisms of tumor response: clinical demands]. / Zelluläre Mechanismen der Tumorresponse : Klinische Anforderungen.

Diseases caused by cancer have become more common due to an increase in life-expectation, but the probability of reaching an old age with or without a tumor disease is still increasing. According to the statistics of the German Cancer register, at present more than half of cancer patients survive for at least 5 years after cancer has been diagnosed. Many tumors can be cured using innovative neoadjuvant and adjuvant therapy regimes, but the options for palliative therapy have also been improved. This leads to an increasing importance of the evaluation of the tumor response using imaging techniques. Classically, tumor response is measured by imaging using the RECIST (response evaluation criteria in solid tumors) criteria, which define the changes in size of the tumor during therapy. However, there is increasingly more evidence that RECIST as the only measure of tumor response, does not document tumor response for all tumor entities and especially not for many medications known as targeted therapy. This article gives a review of the principles and mode of effect of various therapy regimes as well as the clinical demands on imaging techniques.

Helicobacter pylori-induced apoptosis in T cells is mediated by the mitochondrial pathway independent of death receptors.

BACKGROUND: Chronic infection with Helicobacter pylori is related to the pathogenesis of the noncardia carcinoma of the stomach. In this study we investigated the mechanisms of H. pylori-induced apoptosis in T lymphocytes, which could explain a mechanism of immune evasion facilitating chronic inflammation of the mucosa and gastric carcinogenesis. MATERIALS AND METHODS: The supernatant of H. pylori culture was used to study the mechanism of apoptosis induction in human leukaemia T cell lines Jurkat and CEM and in primary T cells. The cytotoxin associated gene A (CagA) and vacuolating cytotoxin A (Vac A) positive bacterial strain H. pylori 60190 (CagA(+), VacA(+)) and as a control the less toxic H. pylori strain Tx30a (CagA(-), VacA(-)) were used to produce the supernatant. Cell death was determined by DNA fragmentation and protein expression by Western blot. RESULTS: H. pylori 60190-induced apoptosis was neither blocked by inhibition of the death ligands TRAIL (TNF-related apoptosis-inducing ligand), CD95L/FasL and TNF-alpha (tumour necrosis factor-a) in wild type Jurkat cells nor in FADD(def) (Fas-associated death domain protein) and caspase-8(def) subclones of the Jurkat cell line. Yet, the pancaspase inhibitor zVAD-fmk could inhibit up to 90% of H. pylori-induced apoptosis. Stable transfection of Jurkat wild type cells with Bcl-x(L and) Bcl-2 resulted in marked reduction of H. pylori-induced apoptosis, showing that the mitochondrial pathway is the key regulator. This is supported by the finding that surviving primary human lymphocytes upregulate Bcl-2 when exposed to H. pylori supernatant. CONCLUSIONS: H. pylori-induced apoptosis of T cells is mediated by the mitochondrial pathway and could create a local environment that facilitates life-long infection by immune evasion.

Emergence of oligoclonal T cell populations following therapeutic T cell depletion in rheumatoid arthritis.

OBJECTIVE: To examine the compartment of CD4+ T cells in patients with rheumatoid arthritis (RA) who have developed persistent lymphopenia following antibody-mediated T cell depletion and to investigate why T cell depletion is of limited therapeutic efficacy. METHODS: Circulating T lymphocytes from 10 patients with seropositive RA treated with the monoclonal antibody (MAb) CAMPATH-1H were longitudinally monitored by fluorescence-activated cell sorter analysis with MAb. To assess the molecular diversity of repopulating T cells, random samples of T cell clones from the peripheral blood of 3 patients were analyzed by sequencing the T cell receptor (TCR) beta chains. At the time of recurring disease, the synovial tissue was examined by immunohistochemistry, and the repertoires of peripheral and synovial tissue T cells were compared by TCR beta-chain sequencing and by semiquantitative hybridization with oligonucleotides specific for the V-D-J beta junctional region of selected clones. RESULTS: The reconstitution of the peripheral T cell compartment was very slow. A mean CD4+ T cell count of 105/microliters was reached 34 weeks following MAb treatment. After treatment, the percentage of CD4+ T cells with the CD45RO+ phenotype was significantly increased (P = 0.001), indicating the expansion of antigen-primed memory T cells. TCR beta-chain sequences revealed a marked restriction in the diversity of repopulating T cells with the emergence of dominant clonotypes. Despite the low counts of peripheral CD4+ T cells, the synovial tissue was infiltrated by CD4+ T cells to a similar extent as that in RA patients not treated with MAb. Selected clonotypes that had emerged in the peripheral blood compartment dominated the repertoire of tissue-infiltrating T cells in the synovium. CONCLUSION: In patients with RA, T cell depletion induces a long-term imbalance in T cell homeostasis. Clonal proliferation of CD4+ T cells severely restricts the diversity of available T cell specificities and results in the emergence of dominant clonotypes, which accumulate in the synovial tissue despite peripheral lymphopenia.