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N Suttorp

Publications and source records attributed to N Suttorp.

At least 19 recordsLinked to original sources
PubMed2006

Docetaxel/gemcitabine or cisplatin/gemcitabine followed by docetaxel in the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC): results of a multicentre randomized phase II trial.

BACKGROUND: Most patients (pts) with metastatic non-small cell lung cancer (NSCLC) receive either single agents or chemotherapy doublets. Recent studies have demonstrated that triple-agent therapies may improve the response rate, but are associated with significant toxicity, and frequently do not prolong survival. A sequential triple-agent schedule may combine acceptable tolerability and good efficacy. We therefore conducted a multicentre, prospectively randomized study that evaluates a sequential three-drug schedule and a platinum-free doublet regimen. PATIENTS AND METHODS: The pts with union international contre le cancer (UICC) stage IV NSCLC were randomized to one of two schedules: in arm Doc-Gem, they received gemcitabine (900 mg/m(2), 30 min infusion) on days 1 and 8, and docetaxel (75 mg/m(2), 1 h infusion) on day 1, repeated every 3 weeks up to six cycles. In arm Cis-Gem-->Doc, gemcitabine (900 mg/m(2), days 1 and 8) and cisplatin (70 mg/m(2), 1 h infusion, day 1) were given for three cycles, followed by three cycles of docetaxel (100 mg/m(2), day 1, repeated every 3 weeks). RESULTS: One hundred and thirteen pts were randomized to arms Doc-Gem (55 pts) and Cis-Gem-->Doc (58 pts). With Doc-Gem, 20.4% of pts responded to the treatment whereas 31.0% responded in arm Cis-Gem-->Doc (overall response, intent-to-treat, difference not significant). The median time to progression was 3.6 months in arm Doc-Gem [95% confidence interval (CI) 1.4, 5.9] and 5.2 months in arm Cis-Gem-->Doc (95% CI 3.1, 7.3). The median survival was 8.7 months with treatment Doc-Gem (95% CI 5.7, 11.6) and 9.4 months with treatment Cis-Gem-->Doc (95% CI 7.8, 11.0). The 1-year survival rates were 34 and 35%, respectively. Mild to moderate leukopenia was frequently seen with both schedules. Other common adverse events (AE) were nausea/vomiting, thrombocytopenia, anaemia, diarrhoea, and infections. No significant differences in AEs were observed between the schedules except for nausea/vomiting, which occurred more frequently with Cis-Gem-->Doc. CONCLUSION: The sequential therapy comprising cisplatin, gemcitabine, and docetaxel demonstrated promising tumour control whereas the platinum-free combination (docetaxel/gemcitabine) was very well tolerated. However, the schedules resulted in comparable survival to recent large trials in pts with advanced NSCLC. The present results do not justify further phase III investigation.

Adult↗
PubMed2006

Legionella pneumophila-induced NF-kappaB- and MAPK-dependent cytokine release by lung epithelial cells.

Legionella pneumophila causes community-acquired pneumonia with high mortality, but little is known about its interaction with the alveolar epithelium. The aim of this study was to investigate whether L. pneumophila infection of lung epithelial cells (A549) resulted in pro-inflammatory activation. L. pneumophila infection induced liberation of interleukin (IL)-2, -4, -6, -8 and -17, monocyte chemoattractant protein-1, tumour necrosis factor-alpha, IL-1beta, interferon-gamma and granulocyte colony-stimulating factor, but not of IL-5, -7, -10, -12 (p70) or -13 or granulocyte-macrophage colony-stimulating factor. The present study focused on IL-8 and found induction by L. pneumophila strains 130b, Philadelphia 1, Corby and, to a lesser extent, JR32. Knockout of dotA, a central gene involved in type IVB secretion, did not alter IL-8 induction, whereas lack of flagellin significantly reduced IL-8 release by Legionella. Moreover, p38 mitogen-activated protein kinase (MAPK) was activated and kinase inhibition reduced secretion of induced cytokines, with the exception of IL-2 and granulocyte colony-stimulating factor. In contrast, inhibition of the MAPK kinase 1/extracellular signal-regulated kinase pathway only reduced the expression of a few cytokines. L. pneumophila also induced binding of nuclear factor-kappaB subunit RelA/p65 and RNA polymerase II to the il8 promoter, and a specific inhibitor of the inhibitor of nuclear factor-kappaB complex dose-dependently lowered IL-8 expression. Taken together, Legionella pneumophila activated p38 mitogen-activated protein kinase- and nuclear factor-kappaB/RelA pathway-dependent expression of a complex pattern of cytokines by human alveolar epithelial cells, presumably contributing to the immune response in legionellosis.

Cell Culture Techniques↗
PubMed2006

Allergic lung inflammation induces pulmonary vascular hyperresponsiveness.

Pulmonary arterial vasoconstriction is an important early component of pulmonary hypertension. Inflammatory mechanisms play a prominent role in the pathogenesis of pulmonary hypertension. The present authors investigated the potential role of acute allergic lung inflammation for alterations in pulmonary haemodynamics. BALB/c mice were intraperitoneally sensitised to ovalbumin and challenged by ovalbumin inhalation. Subsequently, lungs were ventilated and perfused ex vivo, and pulmonary arterial pressure (P(pa)) was continuously monitored. Isolated perfused lungs of allergen-sensitised and -challenged mice showed five-fold enhanced P(pa) responses to serotonin, which is reported to be a significant contributor to pulmonary hypertension in humans. This increase in P(pa) was abolished by the serotonin receptor-2A antagonist ketanserin, but not the serotonin receptor-1B antagonist GR127935. Intracellular signalling to serotonin involved phosphatidylcholine-specific phospholipase C and protein kinase C, as well as Rho-kinase, as assessed by employing the specific inhibitors D609, bisindolylmaleimide and Y27632, respectively. In addition to serotonin, impressively enhanced P(pa) increases in allergic lungs were also evoked by the thromboxane receptor agonist U46619, angiotensin II and endothelin-1. In conclusion, allergic lung inflammation was accompanied by impressive pulmonary vascular hyperresponsiveness. These results suggest a possible role for allergic inflammation in the development of pulmonary arterial hypertension.

Animals↗
PubMed2006

[Brain metastases of lung cancer].

Cerebral metastases are a frequent complication of lung cancer. They often determine patients' prognosis and need urgent therapeutic intervention. Based on histologic type, former therapies, age and performance of the patient, the number of cerebral lesions and the extracerebral tumour activity, individualized treatments are applied. For patients who suffer from non-small cell lung cancer and a single CNS lesion the best results can be achieved if they are surgically resected or receive radiosurgery. Their survival time can be markedly increased in comparison to patients who undergo whole brain irradiation. If multiple metastases are seen in CT or MRI, whole brain irradiation is the therapy to choose. Furthermore it should be initiated if small cell lung cancer metastasizes to the brain. More aggressive local treatment options appear promising, but a clear role for them has not yet been defined. Systemic chemotherapy gains more attention in the treatment of small and non-small cell lung cancer with brain metastases. How to increase the efficacy through simultaneous application of chemo- and radiotherapy is tested in current trials. This article gives an overview on clinical presentation and diagnosis of cerebral metastases in lung cancer and reviews current treatment options.

Anticonvulsants↗
PubMed2006

[Pneumonia - pathogen-based or constellation-based therapy?].

Community-acquired pneumonia is one of the most frequent infectious diseases with high morbidity and mortality. Early and sufficient antibiotic treatment is crucial for the prognosis of the patient. The underlying pathogens are mostly unknown at the onset of symptoms. The choice of antibiotic treatment depends on the suspected pathogens, derived from the typical germs and the typical resistances in a certain area. In addition, individual risk factors, such as age, severity of the diseases, comorbidities, and previous antibiotic treatment have a major impact on the probability of dying for an individual patient. These factors must be considered at the beginning of any treatment. Pathogen-based treatment has to be switched to constellation-based treatment.

Anti-Bacterial Agents↗
PubMed2006

CRB-65 predicts death from community-acquired pneumonia.

OBJECTIVE: The study was performed to validate the CURB, CRB and CRB-65 scores for the prediction of death from community-acquired pneumonia (CAP) in both the hospital and out-patient setting. DESIGN: Data were derived from a large multi-centre prospective study initiated by the German competence network for community-acquired pneumonia (CAPNETZ) which started in March 2003 and were censored for this analysis in October 2004. SETTING: Out- and in-hospital patients in 670 private practices and 10 clinical centres. SUBJECTS: Analysis was done for n = 1343 patients (n = 208 out-patients and n = 1135 hospitalized) with all data sets completed for the calculation of CURB and repeated for n = 1967 patients (n = 482 out-patients and n = 1485 hospitalized) with complete data sets for CRB and CRB-65. INTERVENTION: None. 30-day mortality from CAP was determined by personal contacts or a structured interview. RESULTS: Overall 30-day mortality was 4.3% (0.6% in out-patients and 5.5% in hospitalized patients, P < 0.0001). Overall, the CURB, CRB and CRB-65 scores provided comparable predictions for death from CAP as determined by receiver-operator-characteristics (ROC) curves. However, in hospitalized patients, CRB misclassified 26% of deaths as low risk patients. Availability of the CRB-65 score (90%) was far superior to that of CURB (65%), due to missing blood urea nitrogen values (P < 0.001). CONCLUSIONS: Both the CURB and CRB-65 scores can be used in the hospital and out-patients setting to assess pneumonia severity and the risk of death. Given that the CRB-65 is easier to handle, we favour the use of CRB-65 where blood urea nitrogen is unavailable.

Adolescent↗
PubMed2006

Omalizumab decreased IgE-release and induced changes in cellular immunity in patients with allergic asthma.

BACKGROUND: Omalizumab, a recombinant monoclonal anti-immunoglobulin E (IgE) antibody, shows proven efficacy in the treatment of allergic diseases. A little is known about the immunological pathways affected by the decrease of circulating free IgE during omalizumab treatment. AIM OF THE STUDY: To investigate the immunological consequence of IgE withdrawal, we studied the influence of omalizumab on stimulated IgE-release of cultured peripheral blood mononuclear cells (PBMC) and on the relative number of lymphocytes in the peripheral blood (cellular immune status) in patients with allergic asthma. METHODS: Nineteen patients were enrolled and received omalizumab at a dose of at least 0.016 mg/kg/IgE (IU/ml) every 4 weeks. PBMC were isolated from peripheral blood. Cells were cultured and stimulated with IL-4 (5 ng/ml) and CD40 ligand (1 microg/ml) for 10 days. IgE release was detected in cell culture supernatants by enzyme-linked immunosorbent assay (ELISA). Cellular immune status was investigated by fluorescence-activated cell sorting. RESULTS: Omalizumab treatment induced significant inhibition of stimulated IgE release (median 1.38-0 ng/ml vs. 1.64-2.0 ng/ml in placebo group, P<0.05). B-lymphocyte counts were also significantly lower in the omalizumab group compared with placebo after 12 weeks of treatment (median 18.2-15.6% lymphocytes vs 12.7-13.7% lymphocytes after placebo, P<0.01). There were no significant differences in the other lymphocyte subpopulations between the groups. CONCLUSIONS: These findings provide evidence of immunological influences of omalizumab treatment, leading to a downregulation of IgE secretion and decrease of lymphocyte subpopulations (B-cells) indicating their anti-inflammatory potency.

Adult↗
PubMed2005

[New therapeutic strategies for community acquired pneumonia].

Community Acquired Pneumonia (CAP) is the most important infectious disease in Germany. In the acute phase, lethality is almost 10%, and in the six months follow up period following the acute infection, lethality is more than 15%. Problems with resistances had not been found in Germany, except for a decreasing susceptibility of S. pneumoniae against macrolides. The CRB-65 score allows a reliable discrimination between patients with a high and low risk of dying. The new S3 guideline for diagnosis and treatment of community acquired pneumonia recommends a risk adapted treatment. Low risk patients shall receive a monotherapy with e. g. amoxicillin, high risk patients should be treated with a broad spectrum combination therapy (beta-lactam and macrolide).

Anti-Bacterial Agents↗
PubMed2004

[Competence network "community acquired pneumonia" (CAPNETZ). A first interim report].

Community acquired pneumonia (CAP) is a disease with high morbidity and mortality in Germany. However, no reliable data are available about spectrum and resistance of pathogens, course of the disease, evidence based guidelines for treatment, and pathogen-host interactions. The German Ministry of Education and Research recognized these deficits and therefore decided to fund CAPNETZ, a network of competence for community acquired pneumonia. CAPNETZ integrates components of health research as well as clinical and basic research (horizontal network) on one hand and supports cooperation among general practitioners, community hospitals and universities (vertical network). Since October 2002, 1547 patients with CAP have been recruited within the network. First results indicate, that new observations made in terms of symptoms, spectrum of pathogens involved, and treatment modalities will impact on the formulation of new guidelines for the management of community acquired pneumonia.

Biomedical Research↗
PubMed2004

Differences in cell activation by Chlamydophila pneumoniae and Chlamydia trachomatis infection in human endothelial cells.

Seroepidemiological studies and demonstration of viable bacteria in atherosclerotic plaques have linked Chlamydophila pneumoniae infection to the development of chronic vascular lesions and coronary heart disease. In this study, we characterized C. pneumoniae-mediated effects on human endothelial cells and demonstrated enhanced phosphorylation and activation of the endothelial mitogen-activated protein kinase (MAPK) family members extracellular receptor kinase (ERK1/2), p38-MAPK, and c-Jun-NH2 kinase (JNK). Subsequent interleukin-8 (IL-8) expression was dependent on p38-MAPK and ERK1/2 activation as demonstrated by preincubation of endothelial cells with specific inhibitors for the p38-MAPK (SB202190) or ERK (U0126) pathway. Inhibition of either MAPK had almost no effect on intercellular cell adhesion molecule 1 (ICAM-1) expression. While Chlamydia trachomatis was also able to infect endothelial cells, it did not induce the expression of endothelial IL-8 or ICAM-1. These effects were specific for a direct stimulation with viable C. pneumoniae and independent of paracrine release of endothelial cell-derived mediators like platelet-activating factor, NO, prostaglandins, or leukotrienes. Thus, C. pneumoniae triggers an early signal transduction cascade in target cells that could lead to endothelial cell activation, inflammation, and thrombosis, which in turn may result in or promote atherosclerosis.

Chlamydia trachomatis↗
PubMed2003

[CAPNet--network of competence for community acquired pneumonia: structures and aims].

Community Acquired Pneumonia (CAP) is a disease with high morbidity and mortality in Germany. Apart from the importance of CAP, no reliable data is available about infective germs, resistance of germs, course of the disease, or evidence based treatment. Also basic research should be improved in this field. The German State Ministry for Research (BMBF) has recognised these deficits and supports CAPNet, the network of competence for Community Acquired Pneumonia since 2002.

Community-Acquired Infections↗
PubMed2002

Effectiveness of twice-weekly pyrimethamine-sulfadoxine as primary prophylaxis of Pneumocystis carinii pneumonia and toxoplasmic encephalitis in patients with advanced HIV infection.

The safety and efficacy of a fixed 25 mg pyrimethamine-500 mg sulfadoxine combination supplemented with 15 mg folinic acid twice a week as primary prophylaxis of Pneumocystis carinii pneumonia (PCP) and toxoplasmic encephalitis was evaluated in 106 patients infected with the human immunodeficiency virus. All patients had a CD4+ T-lymphocyte count of less than 100 cells/microl at study entry. Efficacy in this single-arm open-label prospective study was analyzed on an as-treated basis. No patient received highly active antiretroviral treatment, including protease inhibitors or non-nucleoside reverse transcriptase inhibitors, while on study medication. PCP developed in four patients, one of whom had been noncompliant. No PCP episode occurred in the first year. Probabilities of freedom from PCP were 0.97 (95%CI, 0.92-1) after 24 months and 0.93 (95%CI, 0.84-1) after 36 months. Of 74 (69.8%) patients positive for anti-toxoplasma IgG antibodies, one noncompliant patient developed toxoplasmic encephalitis after 24 months. Allergic reactions were observed in 18 (17%) patients and resulted in permanent discontinuation in 7 (6.6%) patients. One (0.9%) patient who had continued prophylaxis despite progressive hypersensitivity reactions developed a serious adverse reaction (Stevens-Johnson syndrome). The median survival of study participants was 29 months, with relentless progression of AIDS accounting for most deaths. The prophylaxis regimen studied appeared safe and effective for primary prophylaxis of PCP and toxoplasmic encephalitis. Severe adverse events can likely be prevented by discontinuation of prophylaxis at the time allergic reactions are noted. Rechallenge frequently results in tolerance. Efficacy and safety compare favorably with previously studied regimens. This simple prophylactic regimen may provide a convenient alternative for patients failing or intolerant to approved regimens.

AIDS-Related Opportunistic Infections↗
PubMed2001

Relative frequency of malaria pigment-carrying monocytes of nonimmune and semi-immune patients from flow cytometric depolarized side scatter.

BACKGROUND: Recently, it was observed that malaria can be detected by performing automated complete blood count analysis including depolarization measurement of scattered laser light. To explain large discrepancies in sensitivity and specificity observed in semi-immune and nonimmune malaria patients, we determined the relative frequencies of malaria pigment-carrying monocytes (PCM) by flow cytometric measurements combined with rare event analysis. METHODS: An experimental cell-sorting unit utilizing argon, krypton, and helium-neon lasers measured the relative frequencies of leukocytes of malaria patients. Single white blood cells showing high intensity in their depolarized side scatter were sorted for subsequent microscopic analysis. RESULTS: From microscopic inspection of sorted cells, we identified malaria PCM as a distinct cluster in scatter diagrams that is well separated from normal leukocytes. For nonimmune patients, the average relative frequency of PCM is 1.5 x 10(-4) (median), for semi-immune patients 8.8 x 10(-4), and for malaria-negative persons 4.4 x 10(-6). Results derived from depolarized side scatter at 488, 633, or 647 nm agree well. Furthermore, malaria pigment-carrying neutrophilic granulocytes were identified microscopically after sorting. We discuss briefly how pigment-carrying neutrophils might be differentiated from normal leukocytes and PCM by using flow cytometry and measuring depolarized side scatter at two wavelengths. CONCLUSION: Our results confirm the feasibility of malaria detection by flow cytometry for semi-immune patients and extend malaria detection to nonimmune patients with low frequencies of PCM. High sensitivity and specificity for malaria detection were obtained.

Cell Separation↗
PubMed2001

Homogeneous assay based on 52 primer sets to scan for mutations of the ABCA1 gene and its application in genetic analysis of a new patient with familial high-density lipoprotein deficiency syndrome.

Familial high-density lipoprotein (HDL)-deficiency syndromes are caused by mutations of the ABCA1 gene, coding for the ATP-binding cassette transporter 1. We have developed a homogeneous assay based on 52 primer sets to amplify all 50 ABCA1 exons and approximately 1 kb of its promoter. The assay allows for convenient amplification of the gene from genomic DNA and easy mutational analysis through automatic sequencing. It obviates the need to use mRNA preparations, which were difficult to handle and posed a risk to miss splice junction or promoter mutations. The application of the test to the molecular analysis of a new patient with familial HDL-deficiency (Tangier disease) led to a discovery of two novel ABCA1 mutations: C2665del and C4457T.

ATP Binding Cassette Transporter 1↗