Bendamustine--a new approach to the treatment of advanced hepatocellular carcinoma?

AIMS: Therapeutic options for advanced hepatocellular carcinoma (HCC) are limited. Bendamustine, a bifunctional cytostatic agent with mainly alkylating effect may be an alternative. METHODS: Five HCC cell lines were incubated in vitro with five different concentrations of bendamustine. In addition, cell lines Huh-7 and HepG2 were tested in a chimeric mouse model. RESULTS: In vitro treatment with bendamustine resulted in an IC( 50 )<6 microg/mL in two, <12 microg/mL in one, and 12-23 microg/mL in two cell lines. In vivo, bendamustine reduced significantly tumor volume in chimeric mice. CONCLUSION: Bendamustine demonstrated significant tumor growth inhibition both in vitro and in vivo at concentrations that can be reached in the plasma. The potential role of bendamustine therapy for HCC and its tolerability in impaired liver function is currently subject of a phase II study.

[Prevention of gastrointestinal malignancies]. / Prävention von Malignomen des Verdauungstrakts.

Malignancies of the gastrointestinal tract are the most common causes of cancer-related deaths in Germany. They also induce significant morbidity. Despite both surgical and medical therapeutic improvements, advanced stages of these cancers can rarely be cured. Preventive and screening measures are suitable to decrease gastrointestinal cancer-related mortality. Weight reduction and cessation of smoking are effective in preventing esophageal, pancreatic and colorectal cancer. Treatment of infections like chronic viral hepatitis and helicobacter pylori gastritis is able to protect from hepatocellular and gastric cancer, respectively. Colonoscopy is one of the best established screening methods. It allows early detection of colorectal neoplasia. Preneoplastic adenomas can be endoscopically removed during the same session. We here review simple prevention strategies and effective screening methods in gastrointestinal cancers of relevance in daily practice.

Capecitabine plus oxaliplatin (CapOx) versus capecitabine plus gemcitabine (CapGem) versus gemcitabine plus oxaliplatin (mGemOx): final results of a multicenter randomized phase II trial in advanced pancreatic cancer.

BACKGROUND: To compare the efficacy and safety of three different chemotherapy doublets in the treatment of advanced pancreatic cancer (PC). PATIENTS AND METHODS: At total of 190 patients were randomly assigned to receive capecitabine 1000 mg/m(2) twice daily on days 1-14 plus oxaliplatin 130 mg/m(2) on day 1 (CapOx), capecitabine 825 mg/m(2) twice daily on days 1-14 plus gemcitabine 1000 mg/m(2) on days 1 and 8 (CapGem) or gemcitabine 1000 mg/m(2) on days 1 and 8 plus oxaliplatin 130 mg/m(2) on day 8 (mGemOx). Treatment cycles were repeated every three weeks. The primary end point was progression-free survival (PFS) rate at 3 months; secondary end points included objective response rate, carbohydrate antigen 19-9 response, clinical benefit response, overall survival and toxicity. RESULTS: The PFS rate after 3 months was 51% in the CapOx arm, 64% in the CapGem arm and 60% in the mGemOx arm. Median PFS was estimated with 4.2 months, 5.7 months and 3.9 months, respectively (P = 0.67). Corresponding median survival times were: 8.1 months (CapOx), 9.0 months (CapGem) and 6.9 months (mGemOx) (P = 0.56). Grade 3/4 hematological toxicities were more frequent in the two Gem-containing arms; grade 3/4 non-hematological toxicity rates did not exceed 15% in any arm. CONCLUSION: CapOx, CapGem and mGemOx have similar clinical efficacy in advanced PC. Each regimen has a distinct but manageable tolerability profile.

Antireflux stents for palliation of malignant esophagocardial stenosis.

Placement of self-expanding metal stents (SEMS) for palliation of malignant stenoses at the gastroesophageal junction is often associated with stent migration and reflux symptoms. SEMS with an antireflux mechanism have been developed to overcome the latter problem. The aim of this study was to evaluate the safety and efficacy of antireflux Z-stents. Patients with advanced squamous cell or adenocarcinoma of the distal esophagus or cardia suffering from dysphagia received an antireflux Z-stent. Technical success, complications of the procedure, clinical symptoms before and after stent placement, reinterventions and survival were recorded. Follow-up was accomplished by patient interviews and a standardized questionnaire for primary care physicians. Eighteen consecutive patients received an antireflux Z-stent. Seventeen of 18 stents were placed technically successful in a single endoscopic procedure. Mean dysphagia score improved from 2.2 to 0.6. Four patients (22%) had permanent reflux symptoms, an additional nine (50%) were taking proton pump inhibitors on a regular basis. In 10 patients, a re-intervention was necessary mainly due to dislocation of the stent. To ensure adequate nutrition three and two patients received a percutaneous gastrostomy and a jejunostomy, respectively. Median survival from stent insertion was 54 days (range, 3-201). Although placement of an antireflux Z-stent is technically feasible, its application is hampered by frequent stent migration and insufficient prevention of gastroesophageal reflux. Further technical improvements of stents or alternative methods like brachytherapy are required for satisfactory palliation of malignant gastroesophageal stenosis.

TIPS for veno-occlusive disease following stem cell transplantation.

Hepatic veno-occlusive disease (VOD) is a complication of allogeneic blood stem cell transplantation (SCT). Duplex ultrasound has been proposed to predict the outcome of VOD. We report here the case of a 39-year-old female patient with VOD following allogeneic SCT for AML. Repeated Doppler ultrasound examinations did not indicate a high-risk profile. However, the patient's condition deteriorated and was refractory to medical therapy. Transjugular intrahepatic portosystemic shunting (TIPS) was performed 19 days after transplantation and VOD resolved subsequently. VOD often has an unpredictable course. Transjugular intrahepatic portosystemic shunts may prove beneficial for patients with refractory disease.

Predictive value of heparanase expression in the palliative therapy of pancreatic cancer.

BACKGROUND/AIMS: Patients with pancreatic ductal adenocarcinoma (PDA) have a median survival of less than six months from diagnosis. Palliative chemotherapy with the current standard gemcitabine does only marginally improve median survival. There may be subgroups of patients receiving palliative therapy that have a better prognosis. Factors predicting response to palliative therapy are ill-defined, though. Heparanase, an endoglycosidase degrading components of the extracellular matrix, promotes cell invasion, is involved in angiogenesis and plays a role in tumor metastases. It is expressed in PDA and its expression is associated with shorter postoperative survival after pancreatic resections. METHODS: 58 patients with inoperable PDA were treated with gemcitabine therapy. Tissue sections from primary or metastatic tumor were used for immunohistochemical analysis. Heparanase expression was determined and correlated to tumor response, time to progression and survival. RESULTS: Heparanase expression was detectable by immunohistochemistry in 36 out of 58 (62%) patients analyzed. Overall survival was 7.4 vs. 13.3 months (p = 0.006) in heparanase-positive and -negative tumors, respectively. Progression-free survival was 1.3 vs. 3.4 months, respectively (p = 0.47). CONCLUSION: Heparanase expression may be a useful marker to predict response to palliative therapy with gemcitabine in PDA.

[Current diagnostics and therapy for carcinomas of the biliary tree and gallbladder]. / Aktuelle Diagnostik und Therapie von Gallengangs- und Gallenblasenkarzinomen.

Carcinoma of the biliary tree are rare tumours of the gastrointestinal tract with a rising incidence during the last years. Biliary neoplasms are classified into intra- and extrahepatic cholangiocarcinoma (Klatskin tumour, middle and distal extrahepatic tumours), gallbladder cancer, and ampullary carcinoma. Transformation of normal into malignant bile duct tissue requires a chain of consecutive gene mutations, similar to the adenoma-dysplasia-carcinoma-sequence in colon cancer. Abdominal ultrasound, combined non-invasive magnetic resonance cholangiography/tomography (MRC/MRT), and facultatively endoscopic retrograde cholangiography (ERC) for unclear diagnosis, represent the gold standard for primary diagnosis. For ampullary carcinoma, endosonography and endoscopic biopsy are the diagnostic tools of choice. Cure is attainable only by formal curative radical surgical resection. Increasing surgical radicality within the last years enabled clearly improved 5-year survival rates. In contrast, there has been no clinical benefit for adjuvant and neoadjuvant therapies. For palliation, bile duct stenting and photodynamic therapy are established methods. Radio- and chemotherapy should be reserved for clinical studies. New therapeutic approaches include brachytherapy, the use of modern chemotherapeutics, COX-2- and tyrosine kinase-receptor-inhibitors.

[Best supportive care of pancreatic carcinoma]. / Pankreaskarzinom.

The incidence of pancreatic cancer is about 10,000 cases a year in Germany. The role of surgery as a curative modality is limited. The 5-year survival for all stages remains less than 5%. Pain, cachexia, jaundice, nausea, fatigue and depression are frequent symptoms which reduce the quality of life for affected patients. Therefore, amelioration of symptoms is a major goal of palliative care. Chemotherapy may yield a moderate survival benefit. Gemcitabine is the drug of choice in metastatic pancreatic cancer. In locally advanced disease, radiochemotherapy can be considered. Different treatment strategies against molecular targets are currently tested in clinical trials.

[Conservative and interventional endoscopic therapy of biliary tract carcinoma]. / Konservative und interventionelle endoskopische Therapie des Gallenwegskarzinoms.

Endoscopic therapy is central to the palliative treatment of bile duct carcinoma. In obstructive jaundice, biliary drainage has few complications and relieves symptoms reliably. It can prevent further complications and is indispensable to the treatment of cholangitis. The principal drawback of biliary stents is stent occlusion and cholangitis. Prophylactic antibiotics were not proven to be effective. Technical details concerning material, number and location of stents await further clarification. Photodynamic therapy is an emerging adjunct to palliative therapy of biliary cancer. Preoperative biliary drainage in obstructive jaundice is not warranted as a routine intervention. It may be indicated, though, as preoperative bridging or to allow liver function to recover before major hepatic surgery. Finally, stenting of postoperative bile duct stenosis is gaining increasing acceptance.

[Esophagus, stomach, liver, pancreas carcinoma. What recommendations for prevention?]. / Osophagus-, Magen-, Leber-, Pankreaskarzinom. Was raten Sie zur Vorbeugung?

A variety of carcinogens, in particular smoking, alcohol abuse and infections, are associated with an increased risk for the development of cancer of the upper gastrointestinal tract. Cancer prevention should start here, in particular since cessation of nicotine abuse, only moderate consumption of alcohol, and weight loss also have other positive effects on health. Where the indication is appropriate, H. pylori eradication, vaccination against hepatitis B and avoidance of exposure to hepatitis are well-founded prophylactic measures. Further screening measures make good sense only in high-risk groups, and are based on recommendations. It has, however, not yet been demonstrated that the screening of patients with Barrett's esophagus, liver cirrhosis, chronic hepatitis or gastric risk diseases actually can lower cancer-related deaths.

Heparanase expression is a prognostic indicator for postoperative survival in pancreatic adenocarcinoma.

Pancreatic ductal adenocarcinoma has a median survival of less than 6 months from diagnosis. This is due to the difficulty in early diagnosis, the aggressive biological behaviour of the tumour and a lack of effective therapies for advanced disease. Mammalian heparanase is a heparan-sulphate proteoglycan cleaving enzyme. It helps to degrade the extracellular matrix and basement membranes and is involved in angiogenesis. Degradation of extracellular matrix and basement membranes as well as angiogenesis are key conditions for tumour cell spreading. Therefore, we have analysed the expression of heparanase in human pancreatic cancer tissue and cell lines. Heparanase is expressed in cell lines derived from primary tumours as well as from metastatic sites. By immunohistochemical analysis, it is preferentially expressed at the invading edge of a tumour at both metastatic and primary tumour sites. There is a trend towards heparanase expression in metastasising tumours as compared to locally growing tumours. Postoperative survival correlates inversely with heparanase expression of the tumour reflected by a median survival of 34 and 17 month for heparanase negative and positive tumours, respectively. Our results suggest, that heparanase promotes cancer cell invasion in pancreatic carcinoma and could be used as a prognostic indicator for postoperative survival of patients.

Inhibition of T-cell acute lymphoblastic leukemia proliferation in vivo by re-expression of the p16INK4a tumor suppressor gene.

T-cell acute lymphoblastic leukemia (T-ALL) is characterized by the presence of differentiation-inhibited pro- and pre-T-cell blasts. The p16INK4a tumor suppressor gene has been shown to be frequently deleted in human T-ALL cases. Deletion of p16INK4a may be associated with poor prognosis and relapse of the disease. Radiation-induced murine T-ALL in C57B1/6 mice shares pathogenetic and molecular characteristics with the human disease. We used the murine disease as a model to study the status of the INK4/ARF gene locus and to examine the effect of p16INK4a-re-expression in T-ALL cells on their leukemic potential in vivo. In 9 of 17 radiation-induced murine T-ALL cell lines, the p16INK4a protein was not expressed as determined by immunoblotting. Southern blot analysis revealed homozygous deletions of the p16INK4a gene locus in three of the nine lines, along with the genes encoding p15INK4b and p19ARF. Transduction of p16INK4a-negative T-ALL lines with retrovirus encoding p16INK4a significantly inhibited their in vitro proliferation by inducing G1-arrest. Importantly, re-expression of p16INK4a in p16INK4a-negative T-ALL cells obliterated the induction of lethal disseminated leukemia in syngeneic mice. This is the first demonstration that re-establishment of p16INK4a expression is critical for in vivo growth regulation of T-ALL cells.

A phase II pilot trial of 13-cis retinoic acid and interferon-alpha in patients with advanced pancreatic carcinoma.

BACKGROUND: Advanced unresectable pancreatic adenocarcinoma has a dismal prognosis. The authors previously have shown that retinoic acid (RA) and interferon-alpha (IFN-alpha) inhibit growth and induce differentiation in human pancreatic carcinoma cells in vitro and in vivo. The purpose of this trial was to examine the feasibility and tolerability of a combination therapy of 13-cis RA and IFN-alpha in patients with advanced unresectable pancreatic carcinoma. METHODS: Twenty-two patients (median age, 62 years) with histologically confirmed, unresectable pancreatic adenocarcinoma classified as International Union Against Cancer Stage III (5 patients) or IV (17 patients) were included. Patients received 1 mg/kg body weight 13-cis RA orally and 6 million IU IFN-alpha subcutaneously daily. Restaging by ultrasound, computed tomography scan, and chest X-ray was performed every 2 months. RESULTS: No complete remission and 1 partial remission (PR) (4.5%) were observed. Fourteen patients (63.6%) demonstrated stable disease with a median duration of 5.0 months (range, 2.3-17.7+ months). Toxicity mainly was related to IFN-alpha and predominantly was hematologic (no toxicity was World Health Organization [WHO] Grade 4 and 13.6% were WHO Grade 3). Nonhematologic toxicities did not exceed Grade 2 (skin and oral mucosa) and mainly were related to 13-cis RA. The median survival of the patients with Stage III disease was 8.7 months (range, 6.8-23.9+ months) and was 7.4 months for patients with Stage IV disease (range, 0.9-19.2+ months), resulting in a median overall survival of 7.7 months (range, 0.9-23.9+ months). CONCLUSIONS: Combination therapy with 13-cis RA and IFN-alpha is feasible and well tolerated in patients with advanced pancreatic carcinoma. Based on the median survival rates observed in this study this combination should be investigated further in Phase III trials.

[Tumor suppressor gene p53--function and significance in gastroenterology]. / Das Tumorsuppressorgen p53--Funktion und Bedeutung in der Gastroenterologie.

The p53 gene is a tumor suppressor gene. The encoded p53 protein directly induces the expression of genes that are involved in cell cycle regulation. p53 was named "guardian of the genome" for its prevention of an otherwise fatal outcome under DNA damaging conditions. Under these conditions p53 inhibits cell cycle progression or induces apoptosis. The p53 protein has been structurally and functionally divided into four domains, two of which are of crucial importance: The sequence specific DNA-binding domain and the aminoterminal transactivation domain. They are both required to trigger the downstream processes following p53 expression. Mutations and inactivation of p53 by oncogenes are frequent events in the development of human neoplasia. That includes gastrointestinal tumors with their mutational spectra reflecting tissue-specific influences of endogenous and exogenous factors in carcinogenesis. Despite considerable progress in molecular biology, clinical applicability of p53 in both diagnostic and therapeutic strategies has not yet been validated.

Characterization of [3H]pentazocine binding sites in post-mortem human frontal cortex.

We investigated binding characteristics of [3H](+)-pentazocine in homogenates of post-mortem human frontal cortex. At equilibrium, specific binding was linear with protein concentration, was saturable, reversible, stereoselective, heat-labile and was nearly absent in the white matter. Saturation experiments revealed a KD of 3.68 +/- 0.46nM and a B(max) of 0.636 +/- 0.107 pmol/mg protein. The rank order of Ki values of competing substances was: haloperidol < N,N'-di(o-tolyl)guanidine (DTG) < (+)-SKF 10,047 < (-)-SKF 10,047. We also examined the influence of age, gender, hemisphere, post-mortem time and storage time of brain tissue at -80 degrees C on [3H](+)-pentazocine binding sites. Of these variables, only age was significantly related to [3H](+)-pentazocine binding (diminished binding with increasing age). Together, our results demonstrate the presence of specific [3H](+)-pentazocine binding sites in post-mortem human brain tissue. Furthermore, the binding sites decrease with increasing age and are apparently independent of gender, hemisphere, post-mortem time and storage time of brain tissue.

Amantadine and memantine are NMDA receptor antagonists with neuroprotective properties.

The pharmacological inhibition of excitatory amino acid neurotransmission has evolved to be a major topic in neuropharmacology since enhanced synaptic action of glutamate and possibly other related neurotransmitters has been suggested to play a role both in acute neurological conditions such as ischemia and epilepsy and in chronic degenerative neurological diseases including Parkinson's disease, Huntington's disease and Alzheimer's disease. While antagonists at N-methyl-D-aspartate (NMDA) type glutamate receptors include psychotomimetic and neurotoxic agents such as phencyclidine and MK-801, the aminoadamantanes represent a class of drugs which may be largely free of such actions and which have already been used clinically as antiviral and antiparkinsonian agents. Multiple in vitro studies have recently delineated the neuroprotective properties of amantadine, and of its more potent congener, memantine, which appear to mediate neuroprotection via inhibition of NMDA receptor-dependent glutamate activity. Thus, neuroprotection targeting glutamate receptors does apparently not have to be associated with prominent psychotogenicity, and the development and evaluation of new neuroprotective drugs will have to performed in consideration both of the relative safety and of the good clinical effect of the already known and established aminoadamantanes.

Affinity of 1-aminoadamantanes for the sigma binding site in post-mortem human frontal cortex.

The 1-aminoadamantanes memantine (1-amino-3,5-dimethyl-adamantane) and amantadine (1-amino-adamantane) are clinically used as anti-parkinsonian, anti-spasticity, anti-dementia and antiviral drugs. In the present investigation we have tested a series of 1-aminoadamantane derivatives including memantine and amantadine for their ability to compete with [3H](+)-pentazocine in homogenates of post-mortem human frontal cortex. The Ki values ranged from 0.237 +/- 0.019 microM for 1-N-dimethyl-amino-3,5-dimethyl-adamantane to 20.25 +/- 16.48 microM for amantadine. The Ki value of memantine was 19.98 +/- 3.08 microM and was thus very similar to that of amantadine. Memantine, at therapeutic concentrations, probably does not interact with the sigma binding site. Amantadine, at therapeutic concentrations, probably binds both to the sigma site and to the phencyclidine (PCP) binding site of the N-methyl-D-aspartate (NMDA) receptor.

[Experimental studies on the pathogenesis of coli enterotoxemia in swine. I. Comparison of toxin effect of 2 different E. coli serotypes following parenteral toxin administration]. / Experimentelle Untersuchungen zur Pathogenese der Kolienterotoxämie der Schweine. I. Vergleich der Wirkungen des Toxins von zwei unterschiedlichen E.-coli-Serotypen nach parenteraler Toxinapplikation

Broth culture filtrate containing endotoxin, prepared from serotype O 139:K82(?):H1 was given by the intra-enteric route with and without dimethyl sulphoxide, and with or without blockade of the RES by intravenous injection of trypan blue, using about five piglets for each of the four combinations. Clinical signs, blood pressure, ECG, respiration, temperature, haematology and pathological findings were recorded. Coli enterotoxaemia manifested by fatal endotoxin shock developed in all ten piglets given toxin plus dimethyl sulphoxide, and in 4 of 5 similarly treated after RES blockade. The sondrmoe did not develop in piglets given large amounts of toxin without dimethyl sulphoxide, whether the RES was blocked or not. When enteric absorption of toxin was promoted by dimethyl sulphoxide, RES blockade increased the sensitivity of the animal to toxin (shortening of the time till death). The results show that there are two functional barriers to endotoxin: - the intestinal barrier, which normally prevents large amounts of toxin from entering the circulation; and RES, which plays a part in detoxifying and eliminating endotoxin which has been absorbed. Application of these findings to the pathogenesis of coli, enterotoxaemia is discussed.