NTPDase1/CD39 and aberrant purinergic signalling in the pathogenesis of COPD.

Purinergic receptor activation via extracellular ATP is involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). Nucleoside triphosphate diphosphohydrolase-1/CD39 hydrolyses extracellular ATP and modulates P2 receptor signalling.We aimed to investigate the expression and function of CD39 in the pathogenesis of cigarette smoke-induced lung inflammation in patients and preclinical mouse models. CD39 expression and soluble ATPase activity were quantified in sputum and bronchoalveolar lavage fluid (BALF) cells in nonsmokers, smokers and COPD patients or mice with cigarette smoke-induced lung inflammation. In mice, pulmonary ATP and cytokine concentrations, inflammation and emphysema were analysed in the presence or absence of CD39.Following acute cigarette smoke exposure CD39 was upregulated in BALF cells in smokers with further increases in COPD patients. Acute cigarette smoke exposure induced CD39 upregulation in murine lungs and BALF cells, and ATP degradation was accelerated in airway fluids. CD39 inhibition and deficiency led to augmented lung inflammation; treatment with ATPase during cigarette smoke exposure prevented emphysema.Pulmonary CD39 expression and activity are increased in COPD. CD39 deficiency leads to enhanced emphysema in mice, while external administration of a functional CD39 analogue partially rescues the phenotype. The compensatory upregulation of pulmonary CD39 might serve as a protective mechanism in cigarette smoke-induced lung damage.

6-year experience of concurrent radiochemotherapy with vinorelbine plus a platinum compound in multimorbid or aged patients with inoperable non-small cell lung cancer.

BACKGROUND AND PURPOSE: Although poor-risk patients represent no minority in inoperable non-small cell lung cancer (NSCLC), there is little experience with concurrent radiochemotherapy (RCT) in this group. Here, the authors report on the feasibility and efficacy of RCT with vinorelbine plus carboplatin or cisplatin in NSCLC patients with comorbidities and poor general health or advanced age. PATIENTS AND METHODS: A total of 66 patients (ten women, 56 men, median age 68 years) with inoperable NSCLC and an increased risk of treatment side effects (WHO performance score of 2-3; cardiac, pulmonary or renal failure or extensive weight loss before treatment, or an age of 71-78 years) were treated with vinorelbine 12.5 mg/m(2) on days 1, 8, 15, 29, 36, and 43 in combination with either carboplatin 70 mg/m(2) (n = 59) or cisplatin 20 mg/m(2) (n = 7) on days 1-5 and 29-33 in addition to receiving conventional fractionated radiotherapy with doses of up to 63 Gy (90% isodose). RESULTS: 62 of 66 patients (94%) reached the 90% level of the prescribed radiation dose, and 41/66 patient (62%) received at least two cycles of the platinum compound and four cycles of vinorelbine. The following hematologic side effects (CTC classification [Common Toxicity Criteria]) were observed: grade 3 (12%) and grade 4 (15%) thrombocytopenia, grade 3 (38%) and grade 4 (4%) leukocytopenia, and anemia requiring transfusion (26%). Other side effects (CTC) included grade 3 (3%) and grade 4 (2%) esophagitis and grade 3 pneumonitis (3%). The response rates were as follows: complete remission 18%, partial remission 56%, stable disease 21%, and progressive disease 5%. The cumulative survival rates were 53%, 24%, and 8% at 12 months, 24 months, and 5 years, respectively. CONCLUSION: After including a larger group of patients than in 2003 and following the patients for several years, the authors determine that concurrent RCT consisting of vinorelbine plus a platinum compound and conventional fractionated radiotherapy can be carried out with manageable toxicity, even in this negatively selected population of patients. Their survival rates were comparable to those achieved in other studies with simultaneous RCT.

Simultaneous chemoradiotherapy with irinotecan and cisplatin in limited disease small cell lung cancer: a phase I study.

INTRODUCTION: Early radiotherapy concurrent with chemotherapy appears to have prognostic benefits in patients with limited disease SCLC. Irinotecan/cisplatin have been shown to be superior to a standard treatment with etoposide/cisplatin in extensive disease SCLC. The present phase I study aims to assess the feasibility of irinotecan/cisplatin administered concurrently with radiotherapy. PATIENTS AND METHODS: Twelve patients were treated concurrently with conventional fractionated radiotherapy (1.8-45 Gy + 9 Gy (RP)) and two cycles of irinotecan (40/50/60 mg/m2, Day 1/8/15, 29/36/43) and cisplatin (20 mg/m2, Days 1-3, 29-31), and four cycles of consolidation chemotherapy (CT). In addition, patients in complete remission (CR) received prophylactic cranial irradiation (PCI). Dose-limiting toxicity (DLT) was defined as any case grade III/IV non-hematological toxicity (esophagitis grade IV), grade IV leukopenia or grades III/IV thrombopenia (CTC) during RCT. RESULTS: No DLT was observed; an irinotecan dose of 60 mg/m2 is recommended. 3/12 patients developed grade III leukopenia, one grade II pneumonitis. The predominant toxicity was esophagitis, grade II in 7/12 patients, grade III in 5/12. After RCT 7/12 patients were in CR, systemic progression was not observed during RCT. CONCLUSION: Concurrent RCT with irinotecan (60 mg/m2) and cisplatin followed by four cycles of CT can be safely administered.

Concurrent radiochemotherapy with vinorelbine plus cisplatin or carboplatin in patients with locally advanced non-small-cell lung cancer (NSCLC) and an increased risk of treatment complications. Preliminary results.

BACKGROUND: In elderly patients, patients with multiple morbidities, and patients with a reduced general condition, the standard treatment of inoperable non-small-cell lung cancer (NSCLC) consists of either chemotherapy or radiation therapy alone and is associated with an extremely poor prognosis. We therefore investigated the feasibility, toxicity, and efficacy of radiotherapy with concurrent chemotherapy using vinorelbine plus cisplatin or carboplatin in NSCLC patients at risk for treatment complications. PATIENTS AND METHODS: A total of 33 patients (six women, 27 men, median age 65 years) with locally advanced, functionally inoperable pulmonary carcinomas, recurrent lung cancer or postoperative macroscopic residual tumors (R2) with an increased risk of treatment complications (WHO performance status 2/3; cardiac, renal or pulmonary failure; marked pretherapeutic weight loss; age between 71-75 years) received 12.5 mg of vinorelbine per m(2) body surface area (BSA) on days 1, 8, 15, 29, 36 and 43 plus either cisplatin 20 mg/m(2) BSA (ten patients) or carboplatin 70 mg/m(2) BSA (23 patients) on days 1-5 and 29-33 together with conventionally fractionated radiotherapy. The tumor regions were irradiated with doses of up to 63 Gy (90% isodose), and potentially affected lymph nodes received doses of up to 45.0 or 50.4 Gy (90% isodose). RESULTS: Briefly, 31 of 33 patients successfully completed radiation therapy and 26 received four cycles of vinorelbine plus at least two cycles of cisplatin or carboplatin. Hematotoxic side effects included grade III leukocytopenia (n = 8), grade III thrombocytopenia (n = 5), and grade IV thrombocytopenia (n = 2). Other side effects consisted of peripheral neuropathy grade III (n = 1) and esophagitis grade IV (n = 1). Severe pneumonitis did not occur. Six patients had pneumonia before radiochemotherapy. 21 patients (63%) exhibited a complete (n = 7) or partial response (n = 14) to chemoradiation. The twelve nonresponders had either stable (n = 9) or progressive disease (n = 3). The survival rates plus standard deviations were as follows: 1-year survival: 60 +/- 8%, 2-year survival: 36 +/- 9%, 3-year survival: 24 +/- 9%, median survival time: 17 months (5;29 months; 95% confidence interval [CI]), median progression-free survival: 11 months (9;13 months; 95% CI). The median follow-up time was 14 months. CONCLUSION: Conventionally fractionated radiochemotherapy with vinorelbine plus a platinum derivative is feasible in patients with NSCLC and increased risk of treatment complications. Compared to patient populations described in the literature, the survival rates achieved by concurrent radiochemotherapy appear to be better than those achieved with radiotherapy alone.

Stimulation of P2 purinergic receptors induces the release of eosinophil cationic protein and interleukin-8 from human eosinophils.

1. Extracellular nucleotides are the focus of increasing attention for their role as extracellular mediators since they are released into the extracellular environment in a regulated manner and/or as a consequence of cell damage. 2. Here, we show that human eosinophils stimulated with different nucleotides release eosinophil cationic protein (ECP) and the chemokine interleukin 8 (IL-8), and that release of these two proteins has a different nucleotide requirement. 3. Release of ECP was triggered in a dose-dependent manner by ATP, UTP and UDP, but not by 2'-&3'-o-(4-benzoyl-benzoyl)adenosine 5'-triphosphate (BzATP), ADP and alpha,beta-methylene adenosine 5' triphosphate (alpha,beta-meATP). Release of IL-8 was triggered by UDP, ATP, alpha,beta-meATP and BzATP, but not by UTP or ADP. Pretreatment with pertussis toxin abrogated nucleotide-stimulated ECP but not IL-8 release. 4. Release of IL-8 stimulated by BzATP was fully blocked by the P2X(7) blocker KN-62, while release triggered by ATP was only partially inhibited. IL-8 secretion due to UDP was fully insensitive to KN-62 inhibition. 5. Priming of eosinophils with GM-CSF increased IL-8 secretion irrespectively of the nucleotide used as a stimulant. 6. It is concluded that extracellular nucleotides trigger secretion of ECP by stimulating a receptor of the P2Y subfamily (possibly P2Y(2)), while, on the contrary, nucleotide-stimulated secretion of IL-8 can be due to activation of both P2Y (P2Y(6)) and P2X (P2X(1) and P2X(7)) receptors.

Occlusal and skeletal effects of an oral appliance in the treatment of obstructive sleep apnea.

STUDY OBJECTIVE: s: Oral appliances (OAs) are considered to be a treatment option for patients with obstructive sleep apnea/hypopnea syndrome (OSAHS). Although the effectiveness of these appliances has been evaluated in a number of clinical trials, there are few follow-up studies concerning the dental and skeletal side effects that, theoretically, could be caused by OAs. We sought to examine the long-term skeletal and occlusal effects of a nocturnally worn activator in adult patients treated for OSAHS. DESIGN: We analyzed the dental casts and lateral radiographs of 34 patients (mean age, 52.9 years; SD, 9.6 years; range, 27.1 to 64.6 years) before initiating treatment and after at least 24 months of treatment (mean length of treatment, 29.6 months; range, 24.1 to 43.5 months; SD, 5.1 months). The OA was worn by each patient 6 to 8 h nightly for > 5 days per week. SETTING: Department of Orthodontics, Dental Medical School, Freiburg, Germany. MEASUREMENTS AND RESULTS: Follow-up polysomnography studies confirmed improved breathing parameters with the use of OAs. A statistically significant alteration in the occlusion was found. The anteroposterior position of the molars and the inclination of the upper and lower incisors were changed. No skeletal changes in the position of the mandible were noted. CONCLUSIONS: The data suggest that in addition to control polysomnographic examinations, regular dental follow-up visits are mandatory when lifelong OSAHS treatment with an OA is being considered for patients with obstructive sleep apnea/hypopnea.

A comparative study of two mandibular advancement appliances for the treatment of obstructive sleep apnoea.

Mandibular advancement appliances (MAAs) are accepted as a treatment option for snoring and mild obstructive sleep disorders. In the present clinical study two differently designed devices were examined for their effectiveness in treating obstructive sleep apnoea (OSA). The study was based on an assessment of 26 patients with a polysomnographic diagnosis of mild OSA [22 men, four women; mean body mass index 27.3 kg/m2 (SD 3.1); mean age 56.8 years (SD 5.2); mean respiratory disturbance index (RDI): 16.0 events/hour (SD 4.4)]. After insertion of the first MAA and a 6-8-week habituation period, a cardio-respiratory home-sleep study was carried out. Following a 2-3-week period with no treatment, the second appliance was inserted. The sequence of the devices was randomized. Once the patients had become accustomed to the second appliance, another somnographic registration was carried out. Daytime sleepiness, snoring, and sleep quality were assessed subjectively on a visual analogue scale. The results showed that a statistically significant improvement in the respiratory parameters was achieved with both appliances (P < 0.01). However, the activator [RDI: 5.5 events/hour, SD 3.3; apnoea index (AI): 3.4 events/hour, SD 2.1] was significantly more effective (P < 0.01) than the Silencor (RDI, 7.3 events/hour, SD 5.3; AI: 5.8 events/hour, SD 3.2). No difference was recorded in the subjective assessment of the therapeutic effects. Both appliances reduced daytime sleepiness and snoring and improved sleep quality, and both influenced the treatment outcome.