The transcription factor ZEB1 (deltaEF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity.

Epithelial to mesenchymal transition (EMT) is implicated in the progression of primary tumours towards metastasis and is likely caused by a pathological activation of transcription factors regulating EMT in embryonic development. To analyse EMT-causing pathways in tumourigenesis, we identified transcriptional targets of the E-cadherin repressor ZEB1 in invasive human cancer cells. We show that ZEB1 repressed multiple key determinants of epithelial differentiation and cell-cell adhesion, including the cell polarity genes Crumbs3, HUGL2 and Pals1-associated tight junction protein. ZEB1 associated with their endogenous promoters in vivo, and strongly repressed promotor activities in reporter assays. ZEB1 downregulation in undifferentiated cancer cells by RNA interference was sufficient to upregulate expression of these cell polarity genes on the RNA and protein level, to re-establish epithelial features and to impair cell motility in vitro. In human colorectal cancer, ZEB1 expression was limited to the tumour-host interface and was accompanied by loss of intercellular adhesion and tumour cell invasion. In invasive ductal and lobular breast cancer, upregulation of ZEB1 was stringently coupled to cancer cell dedifferentiation. Our data show that ZEB1 represents a key player in pathologic EMTs associated with tumour progression.

Achieving full-dose, on-schedule administration of ACE chemotherapy every 14 days for the treatment of patients with extensive small-cell lung cancer.

Extensive small-cell lung cancer (SCLC) is commonly treated with multiple cycles of chemotherapy. Reducing the time interval between cycles of chemotherapy (dose-dense chemotherapy) may improve outcomes in the treatment of extensive SCLC, as it has in other chemosensitive malignancies. To evaluate the feasibility of dose-dense chemotherapy in patients with extensive SCLC, this study evaluates a dose-dense doxorubicin/cyclophosphamide/etoposide (ACE) regimen, supported by the once-per-cycle administration of the hematopoietic growth factor pegfilgrastim. Patients received up to six 14-day cycles of ACE chemotherapy (doxorubicin 40 mg/m,(2) cyclophosphamide 1000 mg/m(2), etoposide 120 mg/m(2) on day 1 IV, plus oral etoposide 240 mg/m(2) daily on days 2-3). On day 4 of each cycle, patients received pegfilgrastim 6 mg by subcutaneous injection. Of 30 patients enrolled, 27 started chemotherapy and received pegfilgrastim. Full-dose, on-schedule chemotherapy was given to all 22 patients starting cycle 2, and in 107 (88%) of 121 cycles. Eighteen of the 27 patients (67%) received full-dose, on-schedule chemotherapy for all 6 cycles. The overall response rate was 17/27 (63%). Nine patients (33%) experienced hematologic toxicities that investigators considered severe or life-threatening. Four patients (15%) had febrile neutropenia. Full-dose, on-schedule dose-dense ACE chemotherapy is feasible with once-per-cycle pegfilgrastim support in extensive SCLC.

N-CPAP rejecters--a specific group of noncompliant patients with obstructive sleep apnea syndrome.

A large number of studies have been focused on patients with severe obstructive sleep apnea syndrome (OSAS) being non-compliant with N-CPAP therapy, but data concerning patients who reject N-CPAP therapy from the very start, without a day of N-CPAP home therapy, do not exist. The purpose of the study was to determine differences, if any, in the quality of life (QoL) between patients rejecting N-CPAP therapy from the start, untreated patients with severe OSAS waiting for N-CPAP titration, and controls. Qol was measured in terms of life satisfaction on the basis of the Munich life quality dimension list (MLDL), an instrument for cognitive assessment of elementary components (physical condition, psyche, social life, everyday life) of QoL. Untreated patients (n = 16) with severe OSAS have a significantly worse QoL in the dimension of psyche (p = 0.00022), social life (p = 0.00582) and everyday life (p = 0.01633) than do rejecters of therapy (n = 19). In the dimension of physical condition, no significant difference was seen (p = 0.47138). Compared with controls (n = 113), rejecters of therapy have a significantly lower QoL score in regard of physical condition (p = 0.00014) but not in terms of psyche, social life and everyday life. We conclude that a good QoL and the absence of the stress of suffering is one reason why patients with severe OSAS reject N-CPAP therapy in spite of physical impairment.

Stop-flow in mediastinum and thorax for resistant lymphoma.

BACKGROUND/AIMS: Management of patients with heavily pretreated malignant lymphoma failing frontline treatment and salvage high-dose chemotherapy and autologous peripheral stem cell rescue, is problematic. A pilot study was conducted to evaluate isolated thoracic perfusion of drugs by means of stopflow technique. METHODOLOGY: Six patients were enrolled in the study; diagnoses included 4 advanced Hodgkin's disease, 1 primary mediastinal B-cell lymphoma, and 1 anaplastic large cell lymphoma. Patients were aged 18-37 years; 4 presented with bulky mediastinum. They had never achieved a complete response since all had progressed from front-line treatment, and 3 had even failed salvage high-dose chemotherapy with autologous peripheral stem cell rescue. Cisplatin (100 mg/m2) and melphalan (35 mg/m2) were used. Carmustine (100 mg/m2) were added to these 2 drugs and cytarabine (2000 mg/m2) in patients not previously treated by carmustine, etoposide, cytarabine, and melphalan. Epidoxorubicin (70 mg/m2) was added in patients who previously received a suboptimal dosage of antracycline. Drugs were delivered monthly via aortic perfusion performed by means of Aigner's stop-flow technique. RESULTS: Overall 13 cycles of perfusional chemotherapy were administered with a median number of 2 cycles. During the procedures there were no technical, hemodynamic, or vascular complications, and no deaths occurred during surgery. After 1 month, 6 (100%) objective responses after isolated thoracic perfusion were recorded, 3 (50%) of which were complete. Tolerance to therapy was excellent. Hematological toxicity was mild and transfusional support was needed only in one course. At the last follow-up, 2 patients are alive (1 complete response and 1 very good partial response, maintained). CONCLUSIONS: This new therapeutical approach seems very active in recurrent/refractory malignant lymphoma and may play an important role in this setting.

[Brucellosis and Aujeszky's disease in a wild boar enclose. Case report]. / Brucellose und Aujeszky-Krankheit in einem Wildschweingatter. Fallbeschreibung.

In wild boars kept in a paddock of approximately 1.7 square miles Brucella suis biotype 2 was isolated and Aujeszky's disease was diagnosed by serological tests. To clear the paddock, the wild boars were lured by offered food and caught using specially built smaller pens. They were then transported to a location far off their original surroundings and euthanized. Of a total of 297 wild boars kept in the paddock, 71% were caught and 28% shot. Three wild boars (= 1%) were found trapped. The described method could also be used in case of epidemics to catch wild boars living outside existing paddocks. In order to avoid killing the boars which stayed in separate quarantine enclosures, a darting gun was used to anaesthetize the animals with tiletamine/zolazepam. Achieved sedation levels were deep enough to allow for blood samples to be taken from the jugular vein without any problems, i.e. without any defence reactions of the boars. The origin of infection could not be identified.

Pharmacokinetics of mitomycin C in pelvic stopflow infusion and hypoxic pelvic perfusion with and without hemofiltration: a pilot study of patients with recurrent unresectable rectal cancer.

This pilot study was conducted to evaluate the advantage in drug delivery for regional chemotherapy in patients with unresectable recurrent rectal carcinoma by different methods. For this research, the pharmacokinetic advantages of mitomycin C delivery by four different methods were compared: intraaortic infusion with aortic stopflow; intraaortic infusion with inferior vena cava stopflow; intraaortic infusion with aortic and inferior caval vein stopflow (hypoxic pelvic perfusion); and hypoxic pelvic perfusion with hemofiltration. The results of this study indicate that pelvic stopflow infusion followed by hypoxic pelvic perfusion significantly increases mitomycin C concentrations in the blood coming from the tumor site. Also, use of hemofiltration reduces mitomycin C levels in peripheral blood after high-dose regional chemotherapy. Further investigations involving more patients should be carried out in the future to validate these results.

Regional versus systemic chemotherapy for advanced pancreatic cancer: a randomized study.

BACKGROUND/AIMS: In an attempt to improve treatment protocols for advanced pancreatic cancer, the value of regional chemotherapy compared with systemic chemotherapy was investigated in this randomized study. METHODOLOGY: Fourteen patients with advanced non-resectable pancreatic adenocarcinoma were randomized receiving either systemic chemotherapy with mitomycin, mitoxanthrone and cisplatin (5pts.) or celiac axis infusion regional chemotherapy with SpherexR microembolization. In the systemic group one patient was stage III, four patients were stage IV, in the intraarterial group two patients were specified stage III and seven were stage IV. RESULTS: In the systemic group one stable disease and four progressive diseases were noted, in the regional group two stable diseases and seven partial responses were noted. Median survival was 11 weeks in the systemically treated patients versus 33 weeks in the patients treated with intraarterial infusion (p=0.001). One patient became resectable (R0). CONCLUSIONS: Performance status improved during regional chemotherapy whilst it steadily decreased in the patients treated systemically. The study was terminated at that point.

Impact of nasal continuous positive airway pressure treatment on quality of life in patients with obstructive sleep apnoea.

Quality-of-life (QoL) issues have become increasingly important in health care practice and research. Obstructive sleep apnoea syndrome (OSAS) results in an especially serious reduction in QoL. The purpose of this study was to measure the QoL (life satisfaction) of OSAS patients treated with nasal continuous positive airway pressure (nCPAP). We aimed to determine whether and to what extent the QoL of OSAS patients using nCPAP differs from that of randomly selected subjects without this disorder. The QoL of 67 patients treated for at least 3 months with nCPAP, 21 OSAS patients at the time of OSAS diagnosis, and 113 randomly selected persons visiting the hospital (controls) was investigated with the help of the Munich life-quality dimension list (MLDL), an instrument for cognitive assessment of elementary components (physical condition, psyche, social life, everyday life) of QoL. It was found that QoL of OSAS patients treated with nCPAP did not significantly differ from that of control subjects with regard to elementary components. The 21 untreated OSAS patients showed significantly lower scores in all four subcategories: physical condition (p<0.0005), psyche (p<0.01), social life (p<0.0005) and everyday life (p<0.007). Thus, it may be concluded that nasal continuous positive airway pressure therapy has an important impact on the quality of life of obstructive sleep apnoea syndrome patients, and signifies a further advantage in addition to clinical aspects. Treated patients are as satisfied or dissatisfied with their life as persons without this illness.

Intra-arterial infusion: overview and novel approaches.

Intra-arterial infusion includes a variety of treatment modalities, adjusted selectively to chemosensitivity and vascularization. For most drugs, response behaviour of different tumors is concentration dependent and requires improved modes of application of cytotoxics. In the treatment of liver metastases from colorectal cancer and hepatocellular carcinoma, blood flow reduction by micro-embolization with starch microspheres has brought significant advantage in response. Balloon stopflow infusion combined with micro-embolization induced 83% complete remissions in a study including 100 patients with locally recurrent breast cancer. Stepwise increased local exposure demonstrated concentration-dependent response. Stopflow infusion of the celiac axis combined with microspheres for advanced Stage III and IV pancreatic cancer induced a 96% remission rate (n = 24 patients) at a median survival of 10 months. This was confirmed in a series of consecutive studies including 242 patients. Quality of life was significantly improved in all responding patients. Overall pain response was 80%. A prospective randomized trial in this patient group, comparing systemic vs. regional chemotherapy in the form of intra-arterial infusion with tumor adjusted concentrations, was stopped in an early phase because median survival time was significantly prolonged (P = 0.001) in the arterial group.

Abdominal stop flow infusion breaks drug resistance in systemically pretreated progressive FIGO IIIc and IV ovarian cancer.

Fourty-five patients with progressive FIGO IIIc (36/45 pts.) and IV (9/45 pts.) ovarian cancer, who were in progression under prior cisplatin-based chemotherapy, were submitted to aortic infusion and stop flow infusion with the same drugs. 36/45 patients (80%) had four-quadrant and 9/45 patients (20%) had two-quadrant peritoneal carcinosis, 33/45 with severe ascites. Overall clinical response was 93%: 5/45 CR (11%), 21/45 PR (47%), 16/45 MR (35%). Complete resolution of ascites occurred in 9/33 patients (27%), a substantial reduction of ascites of more than 50% in 14/33 patients (43%). Median survival time was 12.5 months, median time to progression 8.6 months. Toxicity was minimal and in most patients performance and quality of life improved shortly after therapy.

Phase II trial of gemcitabine in advanced non-small-cell lung cancer.

Gemcitabine has shown activity in different solid tumors. In the present study we have evaluated its efficacy in 32 patients with advanced non-small-cell lung cancer in a phase II trial. Gemcitabine (1250 mg/m2) was given intravenously as a 30-minute infusion on days 1, 8 and 15. Cycles were repeated every 4 weeks. Twenty-nine patients were evaluable for response and all patients for toxicity. Partial remissions and stable disease were seen in 4 (14%) and 13 (45%) patients, respectively. Improvement of symptoms occurred in 54% of the patients. Side effects were mild and included predominantly leukopenia and thrombocytopenia. In conclusion, gemcitabine is active and well tolerated in patients with advanced non-small-cell lung cancer.

Adjunctive interferon-alpha-2c in stage IIIB/IV small-cell lung cancer: a phase III trial.

Preliminary studies have shown bioactivity of interferons (IFNs) in the treatment of small-cell lung cancer (SCLC). The aim of the present study was to determine whether, in patients with advanced SCLC, a combination of recombinant IFN-alpha-2c and standard induction chemotherapy would improve response rates and survival at acceptable toxicity. Of the 85 patients recruited by 11 centres in Austria, 77 were evaluable for response after induction therapy; of these, 43 were randomized to receive the combined treatment (three cycles each of cyclophosphamide/vincristine/doxorubicin and cisplatin/etoposide plus subcutaneous IFN-alpha-2c), and 34 received chemotherapy alone. After the induction phase, patients in the IFN arm had higher rates of complete (30 vs 15%) and partial remission (42 vs 29%) than those who received chemotherapy alone. Accordingly, there was a lower rate of progressive disease in the interferon arm (21 vs 44%; p < 0.05). Whilst there were no significant differences in time to progression (7.6 vs 5.4 months) patients in the IFN arm survived longer than those in the chemotherapy arm (p < 0.02). Six of the patients treated with IFN (14%) survived for more than 2 yrs, whereas none in the chemotherapy arm did. We conclude that the addition of interferon-alpha-2c to induction chemotherapy may improve response rates and survival in advanced small-cell lung cancer.

[Practicability, effectiveness and tolerance of a standardized prepared theophylline infusion]. / Praktikabilität, Wirksamkeit und Verträglichkeit einer standardisierten Theophyllin-Fertiginfusion.

The practicality, efficacy, and tolerance of a standardized, ready-to-use theophylline solution (Eloasthmin, Leopold Pharma, Graz) was studied on 33 patients with bronchial asthma and/or chronic obstructive bronchitis (COPD) (19 males, 14 females) aged 19 to 79 (median 50) years. Eloasthmin a ready-to-use pure theophylline solution containing no auxilliary substances, contains one gram theophyllin per liter in a hypotonic (2/3) NaCl solution. The infusion therapy was carried out in patients in an acute stage of their chronic obstructive ventilation dysfunction. The therapy was carried out for 2 to 4 days at a dose of 400 to 1000 mg theophylline per day, so that theophylline blood levels remained within the therapeutic range of 8 to 20 mg/ml. A highly significant improvement (p < 0.001) of lung function parameters was seen during treatment: VC before therapy = 2.46 l, after therapy = 3.36 l; FEV 1 before therapy = 1.34 l, after therapy = 2.04 l; and PEF before therapy = 3.48 l/s after therapy = 5.13 l/s. Since most patients also received concomittant medication (beta 2-sympathomimetica and/or glucocorticoids), it was difficult to differentiate the specific efficacy of the theophylline.

[Diagnostic process of alveolitis--state of the art]. / Diagnosegang der Alveolitis--Stand des Wissens.

Diagnosing of alveolitis is a puzzle of many pieces, based on clinical experience and keeping in mind the criteria of extrinsic allergic alveolitis. They are antigen-exposure, typical delayed postexpositional symptoms (cough, chills, fever, dyspnea, tiredness), and serological tests of precipitating antibodies. Helpful findings are X-ray of the chest, high resolution computer tomography, auscultation findings, lowered diffusing capacity, bronchoalveolar lavage with lymphocytes > 50% and low T4/T8-ratio, histology of periphere lung specimens, and occasional inhaled provocation. Differential diagnosis are toxic lung disorders, drug adverse effects, sarcoidosis, silicosis, autoimmune alveolitis, idiopathic fibrosing alveolitis. The most frequent failure in diagnosis are common viral cold, bronchopneumonia, sarcoidosis, chronic bronchitis, and miliar tuberculosis.

[Comparative computerized tomography cephalometric and pharyngometric studies of patients with severe and mild sleep apnea, and in a control group]. / Vergleichende computertomographische kephalometrische und pharyngometrische Untersuchungen bei Patienten mit schwerer und leichter Schlafapnoe, sowie einer Kontrollgruppe.

116 males were examined. Of these, 52 belonged to a control group, whereas 40 had severe obstructive sleep apnoea (apnoea index > 20 + clinical symptoms) and 24 mild obstructive sleep apnoea (apnoea index 5-20 + clinical symptoms) (in the following, OSA signifies obstructive sleep apnoea). Cephalometry and planimetric examinations of the pharynx were performed in recumbent position with the head in neutral position and with shallow respiration. The narrowest passage of the pharynx was measured; other measured sites were the areas of the nasopharynx, oropharynx (at the level of the tip of the palatine uvula) and of the hypopharynx (at the level of the base of the tongue). The sum of all the measured cross-sections was obtained. The cephalogram was evaluated to obtain the length and thickness of the soft palate, the distance between the mandible and hyoid bone, the posterior airspace (PAS), the nuchal subcutaneous fatty tissue at the level of the spine of the second cervical vertebra (also known as axis), the thickness of the posterior pharyngeal wall at the level of the second cervical vertebra, or axis, and the angles between the sella, nasion and superior maxilla and between the sella, nasion and mandible (SNA and SNB, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

[Hospital-acquired pneumonia]. / Im Krankenhaus erworbene Pneumonien.

Nosocomial pneumonia is sometimes preventable. In manifestation it is a challenge to the interdisciplinary cooperation to pneumologists, internal medicine, intensive care medicine, clinical microbiologists, nursing staff and physiotherapists. Preventive measurements are of special value.