Inhaled iloprost in patients with chronic thromboembolic pulmonary hypertension: effects before and after pulmonary thromboendarterectomy

BACKGROUND: In primary pulmonary hypertension, aerosolized prostanoids selectively reduce pulmonary vascular resistance and improve right ventricular function. In this study, hemodynamic effects of inhaled iloprost, a stable prostacyclin analogue, were evaluated in patients with chronic thromboembolic pulmonary hypertension (CTEPH) before and early after pulmonary thromboendarterctomy (PTE). METHODS: Ten patients (mean age 49 years old [32 to 70 years old], New York Heart Association functional class III and IV) received a dose of 33 micro g aerosolized iloprost immediately before surgery (T1), after intensive care unit admission (T2), and 12-hours postoperatively (T3). Effects on pulmonary and systemic hemodynamics and gas exchange were recorded and compared with preinhalation baseline values. RESULTS: Preoperatively, inhaled iloprost did not significantly change mean pulmonary artery pressure (mPAP), cardiac index (CI), or pulmonary vascular resistance (PVR). Postoperatively, inhaled iloprost induced a significant reduction of mPAP and PVR and a significant increase of CI at T2 and T3. Preinhalation versus postinhalation PVR was as follows: at T1, 847 versus 729 dynes. s. cm(-5), p = 0.45; at T2, 502 versus 316 dynes. s. cm(-5), p = 0.008; and at T3, 299 versus 227 dynes. s. cm(-5), p = 0.004. CONCLUSIONS: In patients with CTEPH, inhalation of iloprost elicits no significant pulmonary vasodilation before surgery, and may have detrimental effects on systemic hemodynamics. Postoperatively, it significantly reduces mPAP and PVR, and enhances CI. Following PTE, inhalation of iloprost is useful to improve early postoperative hemodynamics.     

Long-term survival in SCLC after treatment with paclitaxel,carboplatin and etoposide--a phase II study

PURPOSE: We evaluated the toxicity and feasibility of adding paclitaxel to a standard platinum/etoposide regimen in the first-line treatment of patients with small cell lung cancer (SCLC). PATIENTS AND METHODS: Eighty-nine patients with limited disease (LD) or extensive disease without distant metastases (ED I) were treated in this multi-centered phase II trial between April 1996 and June 1997. Paclitaxel administration (175 mg/m(2) by a 1 h intravenous infusion) was immediately followed by a 30 min infusion of carboplatin at an area under the concentration time curve (AUC) of 5 on day 1 and etoposide 50 mg orally twice daily (bid) was given on days 2-8. Courses were repeated every 21 days. Patients who had an objective response continued treatment for a maximum of 6 courses. RESULTS: Eighty-four patients were assessable for response. Overall response rate (RR) was 82.1% with 17.8% complete remissions and 64.3% partial remissions. Median survival for LD patients was 20.5 months with a 1 year survival rate of 71.4% and a 3 year survival rate of 21.4%. Median survival of ED I patients was 11 months with a 1 year survival rate of 31.3% and a 3 year survival rate of 3.1%. Overall median survival was 18.1 months with a 1 year survival rate of 56.8% and a 3 year survival rate of 14.8%. Median progression-free intervals were 12.3 months for patients with LD stage of the disease and 8 months with ED I stage. Grade 3/4 toxicity was primarily hematologic. Grade 3/4 leucopenia occurred in 16.0% of courses and febrile episodes were detected in 0.3% of courses. Non-hematologic toxicities were uncommon. Grade 3 GI-tract toxicities or peripheral neuropathy appeared in less than 1% of the courses. Toxicities were detected according to WHO toxicity criteria. CONCLUSION: Paclitaxel can be added at full dose (175 mg/m(2)) to a carboplatin/etoposide combination while maintaining a tolerable toxicity profile. Efficacy data, RR, progression-free interval and survival in both, extensive and limited stage patients compare favorably with other reported data. This new regimen will be further evaluated in comparison to standard regimens in a phase III trial.     

Induction of CD8 T-cell-Ifn-gamma response and positive clinical outcome after immunization with gene-modified allogeneic tumor cells in advanced non-small-cell lung carcinoma

Large tumor burdens in advanced non-small-cell lung carcinoma (NSCLC) are thought to be immunosuppressive. To determine whether CD8-mediated immune responses could be elicited in stage IIIB/IV NSCLC patients, 14 subjects were immunized several times with allogeneic NSCLC cells transfected with CD80 (B7.1) and HLA-A1 or A2. Patients enrolled were matched or unmatched at the HLA A1 or A2 locus and their immune response compared. Immunization significantly increased the frequencies of interferon-gamma secreting CD8 T cells in all but one patient in response to ex vivo challenge with NSCLC cells. The CD8 response of matched and unmatched patients was not statistically different. NSCLC reactive CD8 cells did not react to K562. Clinically, five of 14 patients responded to immunization with stable disease or partial tumor regression. The study demonstrates that CD8 Ifn-gamma responses against nonimmunogenic or immunosuppressive tumors can be evoked by cellular vaccines even at advanced stages of disease. The positive clinical outcome suggests that nonimmunogenic tumors may be highly susceptible to immune effector cells generated by immunization.     

Novel benzylidene-9(10H)-anthracenones as highly active antimicrotubule agents. Synthesis,antiproliferative activity,and inhibition of tubulin polymerization

A novel series of 10-benzylidene-9(10H)-anthracenones and 10-(phenylmethyl)-9(10H)-anthracenones were synthesized and evaluated for antiproliferative activity in an assay based on K562 leukemia cells. The 3-hydroxy-4-methoxybenzylidene analogue 9h was found to be the most active compound (IC(50) K562: 20 nM). Structure-activity relationships are also considered. The highly active compound 9h and the 2,4-dimethoxy-3-hydroxybenzylidene analogue 9l were tested against five tumor cell lines using the XTT assay, including multidrug resistant phenotypes. Induction of cell death in a variety of tumor cell lines was determined in a monolayer assay using propidium iodide. Noteworthy, all compounds within the series induced elongations in K562 cells similar to vinblastine-treated cells. The effect of the lead compound 9h on K562 cell growth was associated with cell cycle arrest in G2/M. Concentrations for 50% KB/HeLa cells arrested in G2/M after treatment with 9h and 9l were determined and found to be in the range of 0.2 microM. Additionally, we monitored the dose dependent caspase-3-like protease activity in K562 cells and MCF-7/Casp-3 cells treated with 9h, indicating induction of apoptosis. Western blotting analysis demonstrated that 9h caused a shift in tubulin concentration from the polymerized state found in the cell pellet to the unpolymerized state found in the cell supernatant. Seven compounds strongly inhibited tubulin polymerization with activities higher or comparable to those of the reference compounds such as colchicine, podophyllotoxin, and nocodazole. In general, the antiproliferative activity correlated with inhibition of tubulin polymerization. The most active compounds strongly displaced [(3)H]colchicine from its binding site in the tubulin, yielding IC(50) values 3- to 4-fold lower than that of colchicine. The novel benzylidene-9(10H)-anthracenones described in the present study constitute an interesting group of highly active and easily accessible antimitotic agents that inhibit tubulin polymerization.     

Impaired autonomic control of the heart by SOX10 mutation

The autonomic nervous system plays an important role in the generation of complex heart rate dynamics that enable an organism to adapt to stress. Little is known about genes influencing the development of this autonomic control of the heart. We suggest the SOX10 gene to be a candidate for this process.     

Transgenic pigs as models for translational biomedical research

The translation of novel discoveries from basic research to clinical application is a long, often inefficient, and thus costly process. Accordingly, the process of drug development requires optimization both for economic and for ethical reasons, in order to provide patients with appropriate treatments in a reasonable time frame. Consequently, “Translational Medicine” became a top priority in national and international roadmaps of human health research. Appropriate animal models for the evaluation of efficacy and safety of new drugs or therapeutic concepts are critical for the success of translational research. In this context rodent models are most widely used. At present, transgenic pigs are increasingly being established as large animal models for selected human diseases. The first pig whole genome sequence and many other genomic resources will be available in the near future. Importantly, efficient and precise techniques for the genetic modification of pigs have been established, facilitating the generation of tailored disease models. This article provides an overview of the current techniques for genetic modification of pigs and the transgenic pig models established for neurodegenerative diseases, cardiovascular diseases, cystic fibrosis, and diabetes mellitus.     

Using reagent-supported thromboelastometry (ROTEM((R))) to monitor haemostatic changes in congenital heart surgery employing deep hypothermic circulatory arrest

Objective: Cardiac surgery employing cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA) can induce coagulation disturbances and bleeding complications that may be especially severe in infants. A better understanding of the coagulopathy and a quick method for its evaluation would be helpful in the management of patients exposed to CPB and DHCA. This study aimed to monitor coagulation defects in congenital heart surgery using rotational thromboelastometry (ROTEM((R))), standard coagulation tests and platelet flow cytometry. Methods: The study comprised 10 infants undergoing surgery for congenital heart disease on CPB and DHCA. Blood was sampled at skin incision, after heparinisation during CPB (directly pre- and directly post-DHCA) and after protamine administration post-CPB. ROTEM((R)) using different reagents including a heparinase-containing assay to evaluate coagulation during heparinisation, APTT and INR, and flow cytometry to evaluate platelet activation were performed. Results: During CPB, the ROTEM((R)) indicated CPB-induced clotting factor depletion and platelet dysfunction that persisted after CPB and heparin neutralisation. ROTEM((R)) results were available within 15min and therefore much faster than standard tests. ROTEM((R))-guided specific blood product treatment resulted in satisfactory coagulatory function. The highest degree of platelet activation was found directly after DHCA. Conclusions: A major benefit of ROTEM((R)) is the quick detection of a developing coagulopathy already during CPB. ROTEM((R)) guides quick and specific blood product treatment after CPB, which may decrease bleeding complications in cardiac surgery. The finding of maximal platelet activation directly after DHCA suggests that not only CPB but also hypothermia activates platelets in vivo, thereby contributing to platelet dysfunction.     

Comparison of T-cell receptor repertoire restriction in blood and tumor tissue of colorectal cancer patients

Several immunotherapeutic approaches rely on antigen-specific T-cells. Restrictions in the T-cell receptor (TCR) repertoire were reported as indicator of anti-tumor cytotoxic T-lymphocyte (CTL) response in various tumor entities. It is unclear yet whether a TCR restriction in peripheral blood mirrors the tumor compartment. We compared the expression of TCR Vβ-families for the quantification of TCR repertoire alterations in blood and tissue samples from patients with colorectal carcinoma. Blood samples from patients with colorectal carcinoma and healthy volunteers and tissue samples of normal colonic mucosa and colorectal carcinoma were analyzed. Relative Vβ-family quantification was performed based on quantitative reverse transcribed PCR. Standard deviation and average mean of the single families were determined. Two variables describing the degree of Vβ-repertoire restriction were defined. Forty-eight blood samples and 37 tissue samples were analyzed. TCR repertoire restriction was higher in blood of tumor patients than in blood of healthy controls (p < 0.05). No difference in the degree of TCR repertoire restriction was found between carcinoma and unaffected colon tissue. We found no corresponding elevated TCR families among the different compartments blood, normal colon, and carcinoma tissue of the same patient. In conclusion, we observed a repertoire restriction in peripheral blood as well as in tumor tissue of cancer patients. However, in tumor tissue, repertoire alterations were comparable to normal mucosa, suggesting compartment-specific TCR distribution rather than alterations due to tumor-T-cell interaction questioning the presence of highly restricted clonal T-cell expansions in colorectal cancer as they have been described in other, assumingly more immunogenic tumor entities.