Background and Aims: In a retrospective study using stereotactic body radiotherapy (SBRT) in medically inoperable patients with stage I NSCLC we previously reported a local control rate of 88% utilizing a median dose of 15 Gy × 3. This report records the toxicity encountered in a prospective phase II trial, and its relation to coexisting chronic obstructive pulmonary disease (COPD) and cardio vascular disease (CVD). Material and methods: Sixty patients were entered in the study between August 2003 and September 2005. Fifty-seven patients (T1 65%, T2 35%) with a median age of 75 years (59-87 years) were evaluable. The baseline mean FEV1% was 64% and median Karnofsky index was 80. A total dose of 45 Gy was delivered in three fractions at the 67% isodose of the PTV. Clinical, pulmonary and radiological evaluations were made at 6 weeks, 3, 6, 9, 12, 18, and 36 months post-SBRT. Toxicity was graded according to CTC v2.0 and performance status was graded according to the Karnofsky scale. Results: At a median follow-up of 23 months, 2 patients had relapsed locally. No grade 4 or 5 toxicity was reported. Grade 3 toxicity was seen in 12 patients (21%). There was no significant decline of FEV1% during follow-up. Low grade pneumonitis developed to the same extent in the CVD 3/17 (18%) and COPD 7/40 (18%) groups. The incidence of fibrosis was 9/17 (53%) and pleural effusions was 8/17 (47%) in the CVD group compared with 13/40 (33%) and 5/40 (13%) in the COPD group. Conclusion: SBRT for stage I NSCLC patients who are medically inoperable because of COPD and CVD results in a favourable local control rate with a low incidence of grade 3 and no grade 4 or 5 toxicity. © 2008 Elsevier Ireland Ltd. All rights reserved.

Purpose The impact of stereotactic body radiotherapy (SBRT) on 3-year progression-free survival of medically inoperable patients with stage I non-small-cell lung cancer (NSCLC) was analyzed in a prospective phase II study. Patients and Methods Fifty-seven patients with T1NOMO (70%) and T2N0M0 (30%) were included between August 2003 and September 2005 at seven different centers in Sweden, Norway, and Denmark and observed up to 36 months. SBRT was delivered with 15 Gy times three at the 67% isodose of the planning target volume. Results Progression-free survival at 3 years was 52%. Overall- and cancer-specific survival at 1, 2, and 3 years was 86%, 65%, 60%, and 93%, 88%, 88%, respectively. There was no statistically significant difference in survival between patients with T1 or T2 tumors. At a median follow-up of 35 months (range, 4 to 47 months), 27 patients (47%) were deceased, seven as a result of lung cancer and 20 as a result of concurrent disease. Kaplan-Meier estimated local control at 3 years was 92%. Local relapse was observed in four patients (7%). Regional relapse was observed in three patients (5%). Nine patients (16%) developed distant metastases. The estimated risk of all failure (local, regional, or distant metastases) was increased in patients with T2 (41%) compared with those with T1 (18%) tumors (P = .027). Conclusion With a 3-year local tumor control rate higher than 90% with limited toxicity, SBRT emerges as state-of-the-art treatment for medically inoperable stage I NSCLC and may even challenge surgery in operable instances.

 Background: This phase III randomized trial compared pemetrexed 500 mg/m2 (P500) with pemetrexed 900 mg/m2 (P900) to determine whether higher dosing benefits non-small-cell lung cancer (NSCLC) patients as second-line therapy. Patients and methods: Patients with locally advanced or metastatic NSCLC, previously treated with platinum-based chemotherapy, were randomly assigned to receive i.v. P500 or P900 every 3 week. Results: Accrual was terminated with 588/600 patients enrolled because an interim analysis indicated a low probability of improved survival and numerically greater toxicity on the P900 arm. P900 patients were permitted to continue treatment at P500. No statistical difference was observed between the treatment arms (P500 versus P900) for median survival {6.7 versus 6.9 months, hazard ratio [HR] = 1.0132 [95% confidence interval (CI) 0.837-1.226]}, progression-free survival [2.6 versus 2.8 months, HR = 0.9681 (95% CI 0.817-1.147)], or best overall tumor response [7.1% versus 4.3% (P = 0.1616)]. The incidence of drug-related grade 3/4 toxicity was typically <5% on both treatment arms, but was numerically higher on the P900 arm for most toxicity categories. Conclusions: P900 did not improve any efficacy measure over P500. P500 i.v. every 3 week remains the standard pemetrexed dose for second-line treatment of platinum-pretreated advanced NSCLC.

The emergence of multidrug-resistant strains of Mycobacterium tuberculosis (MTB), the bacterium responsible for tuberculosis (TB), has rekindled the interest in the role of nutritional supplementation of micronutrients, such as vitamin D, as adjuvant treatment. Here, the growth of virulent MTB in macrophages obtained from the peripheral blood of patients with and without TB was studied. The H37Rv strain genetically modified to express Vibrio harveyi luciferase was used to determine the growth of MTB by luminometry in the human monocyte-derived macrophages (hMDMs) from study subjects. Determination of cytokine levels in culture supernatants was performed using a flow cytometry-based bead array technique. No differences in intracellular growth of MTB were observed between the different study groups. However, stimulation with 100 nM 1,25-dihydroxyvitamin D significantly enhanced the capacity of hMDMs isolated from TB patients to control the infection. This effect was not observed in hMDMs from the other groups. The interleukin (IL)-1β and IL-10 release by hMDMs was clearly increased upon stimulation with 1,25-dihydroxyvitamin D. Furthermore, the 1,25-dihydroxyvitamin D stimulation also led to elevated levels of TNF-α (tumor necrosis factor-alpha) and IL-12p40. It was concluded that vitamin D triggers an inflammatory response in human macrophages with enhanced secretion of cytokines, as well as enhancing the capacity of hMDMs from patients with active TB to restrict mycobacterial growth.

BACKGROUND: Pulmonary Langerhans cell histiocytosis (PLCH) is a rare interstitial lung disease associated with tobacco smoke exposure. New insights into its pathogenesis and how it differs from that of chronic obstructive pulmonary disease (COPD) may be provided by proteomic studies on bronchoalveolar lavage fluid (BALF).

CASE REPORT: We present the BALF proteome in a biopsy-proven case of PLCH and compare it with typical proteomes of COPD and of the healthy lung. The BALF proteins were separated by two-dimensional gel electrophoresis (2-DE) and the protein patterns were analyzed with a computerized 2-DE imaging system. As compared to the healthy subject and the COPD case, the PLCH case showed a strikingly different 2-DE pattern. There was much more IgG (heavy chain) and orosomucoid, and less α1-antitrypsin, surfactant protein-A, haptoglobin, cystatin-S, Clara cell protein 10, transthyretin and gelsolin. Moreover, no apolipoprotein-A1, pro-apolipoprotein-A1, amyloid P, calgranulin A, or calgranulin B was detected at all.

CONCLUSIONS: This case of PLCH presents with an extreme BALF proteome lacking significant amounts of protective and anti-inflammatory proteins. Thus, the intriguing BALF proteome opens up new lines of research into the pathophysiology of PLCH and how its pathogenesis differs from that in COPD.

Background: Several attempts to increase the locoregional control in locally advanced lung cancer including concurrent chemotherapy, accelerated fractionation and dose escalation have been made during the last years. As the EGFR directed antibody cetuximab has shown activity concurrent with radiotherapy in squamous cell carcinoma of the head and neck, as well as in stage IV NSCLC combined with chemotherapy, we wanted to investigate radiotherapy with concurrent cetuximab in locally advanced NSCLC, a tumour type often over expressing the EGF-receptor. Methods: Between February 2006 and August 2007 75 patients in stage Ill NSCLC with good performance status (PS 0 or 1) and adequate lung function (FEV1 andgt; 1.0) were enrolled in this phase II study at eight institutions. Treatment consisted of 2 cycles of induction chemotherapy, docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) with 3 weeks interval. An initial dose of cetuximab 400 mg/m(2) was given before start of 3D-CRT to 68 Gy with 2 Gy per fraction in 7 weeks concurrent with weekly cetuximab 250 mg/m(2). Toxicity was scored weekly during radiotherapy (CTC 3.0), and after treatment the patients were followed every third month with CT-scans, toxicity scoring and QLQ. Results: Seventy-one patients were eligible for analysis as four were incorrectly enrolled. Histology: adenocarcinoma 49%, squamous cell carcinoma 39% and other NSCLC 12%. The majority had PS 0 (62.5%), median age 62.2 (42-81), 50% were women and 37% had a pre-treatment weight loss andgt; 5%. Toxicity: esophagitis grade 1-2: 72%; grade 3:1.4%. Hypersensitivity reactions grade 3-4: 5.6%. Febrile neutropenia grade 3-4: 15.4%. Skin reactions grade 1-2: 74%; grade 3: 4.2%. Diarrhoea grade 1-2: 38%; grade 3: 11.3%. Pneumonitis grade 1-2: 26.8%; grade 3: 4.2%; grade 5:1.4%. The median follow-up was 39 months for patients alive and the median survival was 17 months with a 1-, 2- and 3-year OS of 66%, 37% and 29% respectively. Until now local or regional failure has occurred in 20 patients and 22 patients have developed distant metastases. Weight loss, PS and stage were predictive for survival in univariate as well as in multivariate analysis. Conclusion: Induction chemotherapy followed by concurrent cetuximab and RT to 68 Gy is clearly feasible with promising survival. Toxicity, e.g. pneumonitis and esophagitis is low compared to most schedules with concurrent chemotherapy. This treatment strategy should be evaluated in a randomised manner vs. concurrent chemoradiotherapy to find out if it is a valid treatment option.

Sequential administration of chemotherapeutic drugs might have advantages: additive toxicity is avoided and the individual drugs can be given in full dosages. The Swedish group earlier found the combination of gemcitabine and carboplatin to be effective and with acceptable toxicity. The group therefore decided to add docetaxel in a sequential way in a randomized phase II study. Patients were randomized to either gemcitabine or carboplatin for six cycles or the same regimen for three cycles followed by weekly single agent docetaxel. The primary objective was time to progression (UP). One hundred and twenty-three patients with performance status WHO 0-2 and with earlier un-treated non-small cell lung cancer with measurable stage IIIB disease, not amenable to curative treatment, or stage IV disease without known metastatic spread to the CNS, were enrolled. Hematological toxicity was more common in the GC group but clinically significant bleeding or leucopenic fever occurred only in a minority of patients. No complete responses were noted. Partial response (PR) was observed in 19.3% and 20.8% in the GC and GCD group, respectively. Progression-free survival was 5.6 and 4.8 months and overall survival time 10.6 and 10.1 months in the GC and GCD groups, respectively. Thus, sequential treatment with docetaxel after treatment with gemcitabine and carboplatin did not improve time to progression, response rates, or overall survival.

The prognosis for patients with lung cancer is poor with an average of 5-year overall survival rate of only 10-15 % taking all clinical stages together. The aim of this study was to elucidate the impact of the radiotherapy regimen on survival. Clinical data were collected from all the Swedish Oncology Departments for 1,287 patients with a diagnosed non-small cell lung cancer (NSCLC) subjected to curatively intended irradiation (andgt;= 50 Gy) during the years 1990 to 2000. The included patients were identified based on a manual search of all medical and radiation charts at the oncology departments from which the individual patient data were collected. Patients who did not have a histopathological diagnosis date and/or death date/last follow-up date as well as patients being surgically treated were excluded from the study (n = 592). Thus, 695 patients were included in the present study. Patients who received hyperfractionated radiotherapy (HR) had a higher local control rate compared with patients receiving conventional fractionation (CF) (38 vs. 49 % local relapse). The difference in survival between the two radiotherapy regimens was statistically significant in a univariate Cox analysis (p = 0.023) in favor of HR. This significance was, however, not retained in a multivariate Cox analysis (p = 0.56). Thus, the possible beneficial effects of hyperfractionation are still unclear and need to be further investigated in well-controlled prospective clinical trials, preferably including systemic treatment with novel drugs.

BACKGROUND: Increased expression of cyclooxygenase-2 (COX-2) is common in non-small cell lung cancer (NSCLC) and has been associated with poor prognosis. Experimental and clinical phase II trials have indicated that the addition of the COX-2 inhibitor celecoxib to palliative chemotherapy might increase survival time in patients with advanced NSCLC.

METHODS: We performed a double-blind, placebo-controlled multicentre phase III trial at 13 centres in Sweden. Three hundred and nineteen patients with advanced NSCLC stage IIIB-IV and performance status 0-2 were randomised to receive celecoxib 400mg b.i.d. or placebo in addition to palliative chemotherapy. The primary objective was to compare overall survival. Other end-points were quality of life, progression-free survival, toxicity, cardiovascular events and biological markers. The trial is registered with ClinicalTrials.gov, No. NCT00300729.

FINDINGS: Three hundred and sixteen patients were included in the analysis, 158 in each treatment group. Median survival time was 8.5months. There was no survival difference between the treatment arms. Small but not statistically significant differences in global quality of life and pain were seen favouring the celecoxib group. No increased incidence of cardiovascular events was observed in the celecoxib group.

INTERPRETATION: This study failed to demonstrate a survival benefit of the addition of celecoxib to palliative chemotherapy.

Cyclooxygenase-2 (COX-2) expression may be a prognostic factor in lung cancer. In previous studies, COX-2 expression has almost exclusively been evaluated with immunohistochemical methods performed on histology sections of tissue biopsies. However, in clinical practice, lung cancer is often diagnosed with cytological techniques only. We present methodology and results from analysis of COX-2 expression with immunochemistry on cytological material in 53 patients with lung cancer. Preparation and staining with the method established at our laboratory were easy to perform and resulted in good quality slides. The percentage COX-2-stained cells and the intensity of staining varied widely between and within the different cases. The proportion of positively stained tumor cells was as follows: <1% in 20 patients, 1-10% in 7 patients, 11-50% in 17 patients, and more than 50% in 9 patients. In 17 cases, groups of cells with different intensity of COX-2 staining were found in the same slide. In conclusion, immunocytochemical analysis of COX-2 expression is technically easy to perform with routine diagnostic procedures. There is a great variation in the proportion of COX-2-positive cells among patients and in the intensity of staining among individual cells in many single cases. Diagn. Cytopathol.2011;39:188-193. © 2010 Wiley-Liss, Inc.

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Background. In SBRT of lung tumours no established relationship between dose-volume parameters and the incidence of lung toxicity is found. The aim of this study is to compare the LQ model and the universal survival curve (USC) to calculate biologically equivalent doses in SBRT to see if this will improve knowledge on this relationship. Material and methods. Toxicity data on radiation pneumonitis grade 2 or more (RP2+) from 57 patients were used, 10.5% were diagnosed with RP2+. The lung DVHs were corrected for fractionation (LQ and USC) and analysed with the Lyman-Kutcher-Burman (LKB) model. In the LQ-correction alpha/beta = 3 Gy was used and the USC parameters used were: alpha/beta = 3 Gy, D-0 = 1.0 Gy, (n) over bar = 10, alpha = 0.206 Gy(-1) and d(T) = 5.8 Gy. In order to understand the relative contribution of different dose levels to the calculated NTCP the concept of fractional NTCP was used. This might give an insight to the questions of whether "high doses to small volumes" or "low doses to large volumes" are most important for lung toxicity. Results and Discussion. NTCP analysis with the LKB-model using parameters m = 0.4, D-50 = 30 Gy resulted for the volume dependence parameter (n) with LQ correction n = 0.87 and with USC correction n = 0.71. Using parameters m = 0.3, D-50 = 20 Gy n = 0.93 with LQ correction and n = 0.83 with USC correction. In SBRT of lung tumours, NTCP modelling of lung toxicity comparing models (LQ, USC) for fractionation correction, shows that low dose contribute less and high dose more to the NTCP when using the USC-model. Comparing NTCP modelling of SBRT data and data from breast cancer, lung cancer and whole lung irradiation implies that the response of the lung is treatment specific. More data are however needed in order to have a more reliable modelling.

BACKGROUND:Reduced ventilation in lung regions affected by chronic obstructive pulmonary disease (COPD), reflected as inhomogeneities in the single-photon emission computed tomography (SPECT) lung image, is correlated to disease advancement. An analysis method for measuring these inhomogeneities is proposed in this work. The first aim was to develop a quantitative analysis method that could discriminate between Monte Carlo simulated normal and COPD lung SPECT images. A second aim was to evaluate the ability of the present method to discriminate between human subjects with advanced COPD and healthy volunteers.

METHODS:In the simulated COPD study, different activity distributions in the lungs were created to mimic the healthy lung (normal) and different levels of COPD. Gamma camera projections were Monte Carlo simulated, representing clinically acquired projections of a patient who had inhaled 125 MBq 99mTc-Technegas followed by a 10-min SPECT examination. Reconstructions were made with iterative ordered subset expectation maximisation. The coefficient of variance (CV) was calculated for small overlapping volumes covering the 3D reconstructed activity distribution. A CV threshold value (CVT) was calculated as the modal value of the CV distribution of the simulated normal. The area under the distribution curve (AUC), for CV values greater than CVT, AUC(CVT), was then calculated. Moreover, five patients with advanced emphysema and five healthy volunteers inhaled approximately 75 MBq 99mTc-Technegas immediately before the 20-min SPECT acquisition. In the human study, CVT was based on the mean CV distribution of the five healthy volunteers.

RESULTS:A significant difference (p < 0.001) was found between the Monte-Carlo simulated normal and COPD lung SPECT examinations. The present method identified a total reduction of ventilation of approximately 5%, not visible to the human eye in the reconstructed image. In humans the same method clearly discriminated between the five healthy volunteers and five patients with advanced COPD (p < 0.05).

CONCLUSIONS:While our results are promising, the potential of the AUC(CVT) method to detect less advanced COPD in patients needs further clinical studies.

Background: A combination of chemotherapy and radiotherapy is the treatment base for locally advanced non-small cell lung cancer (NSCLC). However, both loco-regional and distant failure is frequent. Attempts to improve the loco-regional control were made in three separate phase 11 studies in Swedish University Hospitals, where accelerated radiotherapy or concurrent daily or weekly chemotherapy with conventional radiotherapy were tested. Comparatively good results from these studies lead to this national randomized phase 11 study, the RAKET-study, where the different concepts were investigated on a wider basis for further phase III studies. Methods: Inoperable stage III non-small cell lung cancer patients in good performance status (PS andlt; 2) were equally randomized to either of three arms in eight institutions. All arms started with two cycles of induction chemotherapy: paclitaxel 200 mg/m(2) and carboplatin AUC6. Arm A: a third identical cycle was given concomitant with start of accelerated radiotherapy, 1.7 Gy BID to 64.6 Gy in 4.5 weeks. Arm B consisted of daily concomitant paclitaxel 12 mg/m(2) with conventionally fractionated radiotherapy: 2 Gy to 60 Gy in 6 weeks. Arm C: weekly concomitant paclitaxel 60 mg/m2 and identical radiotherapy to 60 Gy. Primary endpoint: TTP. Secondary: OS, toxicity, QL and relapse pattern. Results: Between June 2002 and May 2005 152 patients were randomized and of them 151 were evaluable: 78 men and 73 women, median age 62 years (43-78), 55% had performance status 0 and 45% PS 1. Thirty-four percent had stage IIIa and 66% IIIb. Histology: adenocarcinoma 48%, squamous cell carcinoma 32% and 20% non-small cell carcinoma. The three arms were well balanced. Toxicity was manageable with 12% grades 3-4 esophagitis, 1% grades 3-4 pneumonitis and there was no clear difference between the arms. The QL data did not differ either. Median time to progression was 9.8 (8.3-12.7) months (8.8, 10.3 and 9.3 months for arms A, B and C, respectively). Median survival was 17.8 (14.4-23.7) months (17.7, 17.7 and 20.6 months for A, B and C, respectively). The 1-, 3- and 5-year overall survival was 63, 31 and 24%. Sixty-nine percent of the patients relapsed with distant metastases initially and 31% had loco-regional tumor progression, without significant differences between treatment arms. Thirty-four percent developed brain metastases. Conclusions: Treatment results are quite equal by intensifying the loco-regional treatment either by accelerated fractionated radiotherapy or daily or weekly concomitant chemo-radiotherapy both in terms of

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Background: The role of vitamin D supplementation as adjuvant treatment of tuberculosis (TB) has lately attracted increasing interest. Our aim was to investigate the capacity of alveolar macrophages (AMs) from patients with or without exposure to TB to control intracellular growth of virulent Mycobacterium tuberculosis (Mtb).

Methods: AMs were freshly harvested from the bronchoalveolar lavage fluid of 7 patients with a history of TB (4 patients with previous TB and 3 patients with current TB) and 4 non-TB subjects. The H37Rv strain, genetically modified to express Vibrio harveyi luciferase, was used to determine the growth of Mtb by luminometry in the AMs from study subjects. Cytokine levels in culture supernatants were determined using a flow cytometry-based bead array technique.

Results: AMs from patients with a TB history were less efficient in restricting Mtb growth. Stimulation with 100 nM1, 25-dihydroxyvitamin D (1,25D₃) did not significantly influence the capacity of AMs from any study subjects to control the infection. Out of the cytokines evaluated (TNF-α, IL-1β, IL-10 and IL-12p40) only TNF-α demonstrated detectable levels in culture supernatants, but did not respond to stimulation with 1,25D₃.

Conclusions: We conclude that AMs of TB-patients show reduced ability to control mycobacterial growth in vitro, and, that AMs in this pilot study do no respond to 1, 25D₃-stimulation. The former observation supports the concept that innate immunity is crucial for the control of TB infection.

Iron-catalyzed oxidative damage on the respiratory epithelium is prevented by alveolar macrophages depositing iron inside their lysosomes. Bound in an un-reactive state to various metalloproteins, e.g. ferritin, most lysosomal iron is kept separated from reactive oxygen species (ROS) by intracellular anti-oxidative enzyme systems. Some ROS may, however, escape this protective shield of antioxidants, react with small amounts of free redox-active iron within lysosomes, thereby causing peroxidative damage on lysosomes and possibly also ensuing cell death. Since macrophages, containing large amounts of lysosomal iron, are very resistant to TNF-alpha, we hypothesized that this cell type has developed specific defense mechanisms against TNF-alpha-induced ROS generation. Murine macrophages were exposed (or not) to non-toxic concentrations of TNF-alpha and/or iron and were then challenged with H2O2. Iron-exposed oxidatively stressed cells exhibited extensive lysosomal disruption resulting in pronounced cell death. In contrast, TNF-alpha stabilized lysosomes and protected cells, particularly those iron-exposed, by reducing cellular iron and increasing H-ferritin. Intracellular generation of H2O2 under oxidative stress was kept unchanged by TNF-alpha and/or iron. However, TNF-alpha increased basal levels of glutathione by up-regulating the synthesis of gamma-glutamylcystein synthetase, thereby strengthening the anti-oxidative capacity. TNF-alpha inhibitors would block this novel anti-oxidative defense system, possibly explaining their adverse effects on the lung.

Background: Lung allografts contain large amounts of iron (Fe), which inside lung macrophages may promote oxidative lysosomal membrane permeabilization (LMP), cell death and inflammation. The macrolide antibiotic azithromycin (AZM) accumulates 1000-fold inside the acidic lysosomes and may interfere with the lysosomal pool of Fe. Objective: Oxidative lysosomal leakage was assessed in lung macrophages from lung transplant recipients without or with AZM treatment and from healthy subjects. The efficiency of AZM to protect lysosomes and cells against oxidants was further assessed employing murine J774 macrophages. Methods: Macrophages harvested from 8 transplant recipients (5 without and 3 with ongoing AZM treatment) and 7 healthy subjects, and J774 cells pre-treated with AZM, a high-molecular-weight derivative of the Fe chelator desferrioxamine or ammonium chloride were oxidatively stressed. LMP, cell death, Fe, reduced glutathione (GSH) and H-ferritin were assessed. Results: Oxidant challenged macrophages from transplants recipients without AZM exhibited significantly more LMP and cell death than macrophages from healthy subjects. Those macrophages contained significantly more Fe, while GSH and H-ferritin did not differ significantly. Although macrophages from transplant recipients treated with AZM contained both significantly more Fe and less GSH, which would sensitize cells to oxidants, these macrophages resisted oxidant challenge well. The preventive effect of AZM on oxidative LMP and J774 cell death was 60 to 300 times greater than the other drugs tested. Conclusions: AZM makes lung transplant macrophages and their lysososomes more resistant to oxidant challenge. Possibly, prevention of obliterative bronchiolitis in lung transplants by AZM is partly due to this action.

Purpose: This phase III study compared overall survival in patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) when treated with single-agent gemcitabine versus gemcitabine/carboplatin. Secondary objectives were to compare response, time to progression, toxicity, and quality of life. Patients and Methods: Chemotherapy-naive patients received either gemcitabine alone (1,250 mg/m2 on days 1 and 8, gemcitabine arm) or with carboplatin (area under the curve 5 on day 1, GC arm) every 21 days. Results: Demographics and disease characteristics of 334 randomly assigned patients were comparable on both arms. An intent-to-treat analysis showed significantly better overall survival (log-rank P = .0205) and 2-year survival (15% v 5%, P = .009) favoring the GC arm. Per Cox multivariate analysis, only two covariates, treatment arm (GC v G) and baseline performance status (0 or 1 v 2), independently influenced survival. Per-protocol analyses showed significantly longer median time to progression (5.7 v 3.9 months, P = .0001) and significantly higher objective response rate (29.6 v 11.3%, P < .0001) in the GC arm. Grade 3 to 4 leucopenia and thrombocytopenia were significantly more pronounced in the GC arm (P for both variables < .001) but importantly without associated increases in fever, infection, bleeding, or hospitalizations. There was no discernible difference in global quality-of-life patterns between treatment arms. Conclusion: In advanced NSCLC, gemcitabine/carboplatin therapy resulted in significant survival benefit compared with single-agent gemcitabine without undue increase in toxicity. © 2005 by American Society of Clinical Oncology.

Objectives: To evaluate to what extent emphysema was evident, as identified by High Resolution Computed Tomography (HRCT), in smokers with normal lung function and to relate age, gender, smoking history, and body mass index (BMI) to the HRCT results. A secondary aim was to study to what extent emphysema was present in smokers with lower normal values of lung function defined as FEV1/FVC ratio percentage of predicted value (89-93% of predicted value for males and 90-93% for females) or FEF50 60% of predicted compared with smokers without this definition.

Methods: Fifty-nine smokers, with a mean age of 53 years and with normal lung function, were examined with HRCT.

Results: Emphysema evidenced visually by HRCT was present in 43% of the subjects. Using a 0-5 grade scale (0=normal finding; 5=emphysema in most slices), the degree of emphysema was almost exclusively 3-4. The type of emphysema was distributed as centrilobular emphysema predominant in 43.5%, paraseptal emphysema predominant in 43.5%, and as an equal mixture of these types in 13%. The presence of emphysema did not differ between the group of smokers with lower normal values of lung function and the rest of the smokers. Smokers with emphysema had significantly lower BMI than those devoid of emphysema, 24 and 27 respectively (p0.0011).

Conclusion: There was a high occurrence of visual emphysema in middle-aged smokers with normal lung function. The densitometric quantitative analysis method is inadequate for detecting mild emphysema. High prevalence of emphysema was associated with low BMI.

BACKGROUND: The incidence of chronic obstructive pulmonary disease (COPD) is increasing in developed countries, as is the mortality rate. The main cause of COPD is smoking, and COPD is usually diagnosed at a late stage. AIM: To evaluate a method to detect COPD at an early stage in smokers in a young age group (40-55 years).

DESIGN OF STUDY: Prospective descriptive study.

SETTING: The city of Motala (45,000 inhabitants) and its surrounding rural areas (43,000 inhabitants) in south-east Sweden. Nineteen thousand, seven hundred and fifty subjects were between 40 and 55 years of age. According to Swedish statistics, approximately 27% of this population are smokers.

METHOD: Smokers aged between 40 and 55 years were invited to have free spirometry testing in primary healthcare centres. Placards were placed in pharmacies and health centres and advertising was carried out locally twice a year.

RESULTS: A total of 512 smokers responded. The prevalence of COPD was 27% (n = 141). The COPD was classified as mild obstruction in 85% (n = 120), moderate in 13% (n = 18) and severe in 2% (n = 3) according to the European Respiratory Society classification. Knowledge of the disease COPD was acknowledged by 39% of the responders to the questionnaire. Logistic regression analysis showed that age, male sex, number of pack years, dyspnoea and symptoms of chronic bronchitis significantly increased the odds of having COPD. The adjusted odds ratio was significant for having > 30 pack years.

CONCLUSIONS: This method of inviting relatively young smokers selected a population of smokers with a high incidence of COPD, and may be one way of identifying smokers with COPD in the early stages.

BACKGROUND: Smoking cessation is the most important therapeutic intervention in patients with chronic obstructive pulmonary diseases (COPD) and the health benefits are immediate and substantial. Major efforts have been made to develop methods with high smoking cessation rates.

OBJECTIVES: To study whether a combination of spirometry and brief smoking cessation advice to smokers with COPD, annually for three years, increased their smoking cessation rate in comparison with groups of smokers with normal lung function.

METHOD: Prospective, randomized study in primary care. Smoking cessation rates were compared between smokers with COPD followed-up yearly over a period of three years and smokers with normal lung function followed-up yearly for three years or followed-up only once after three years.

RESULTS: The point-prevalence abstinence rate and prolonged abstinence rate at 6 and 12 months increased yearly and in smokers with COPD at year 3 was 29%, 28%, and 25%, respectively. The abstinence rates were significantly higher in smokers with COPD than in smokers with normal lung function. Smoking cessation rates among smokers with normal lung function did not increase with increasing number of follow-ups.

CONCLUSION: Smokers diagnosed with COPD stopped smoking significantly more often than those with normal lung function.

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Aim of the study: The primary purpose of this study is to investigate if pretreatment plasma levels of vascular endothelial growth factor (VEGF) are predictive of the effect of celecoxib on survival in advanced non-small cell lung cancer (NSCLC) treated with palliative chemotherapy. A secondary objective is to describe the course of plasma VEGF levels during and after treatment with cytotoxic chemotherapy combined with celecoxib or placebo. less thanbrgreater than less thanbrgreater thanMethods: In a previously published double-blind multicenter phase III trial, 316 patients with NSCLC stage IIIB or IV and World Health Organisation (WHO) performance status 0-2 were randomised to receive celecoxib 400 mg b.i.d. or placebo in combination with two-drug platinum-based chemotherapy. Chemotherapy cycle length was three weeks and planned duration of chemotherapy was four cycles. Celecoxib was given for a maximum of one year but was stopped earlier in case of disease progression or prohibitive toxicity. In a subset of patients, plasma VEGF levels were examined at onset of treatment and at 6, 12 and 20 weeks. less thanbrgreater than less thanbrgreater thanResults: VEGF levels at start of treatment were obtained in 107 patients at four study sites. The median value was 70 pg/ml. Mean values declined during the first 12 weeks and then increased at 20 weeks. A subpopulation treatment effect pattern plot (STEPP) analysis showed an inverse relationship between initial plasma VEGF and the impact of celecoxib on survival with zero effect at 200 pg/ml. The effect on survival by celecoxib in the whole subset of patients was positive (hazard ratio (HR)=0.64 [confidence interval (CI) 0.43-0.95], p=0.028). less thanbrgreater than less thanbrgreater thanConclusion: Low pretreatment plasma levels of VEGF appear to be predictive of a positive effect of celecoxib on survival.

Aim: To evaluate weekly, induction chemotherapy followed by weekly concomitant chemoradiotherapy in a multicentre phase II study of patients with wiresectable stage III non-small cell lung cancer (NSCLC; stage wet IIIB excluded). Patients (aid Methods: Eligible patients received three weekly cycles of paclitaxel 100 mg/m(2) and carboplatin AUC2 followed by six weekly cycles of paclitaxel 60 mg/m(2) and carboplatin AUC2 in combination with thoracic radiotherapy (2 Gy per fraction and day to a total (lose of 60 Gy), Results: Sixty-four patients (40 males and 24 females) with a median age of 63 Years (range, 43-79 years) entered the study. T and N stage were distributed as follows: T1 2 patients (3.2%). T2 10 patients (15.6%), T3 15 patients (23.4%). T4 37 patients (57.8%), N0 10 patients (15.6%). N1 1 patient (1.6%), N2 26 patients (40.6%), N3 26 patients (40.6%), and N missing I patient (1.6%). Seven patients (10.9%) suffered from grade 314 oesophagitis. Grade 112 oesophagitis occurred in 36 patients (56.3%) and pneumonitis grade 112 occurred in 10 patients (15.6%). Sixty-three patients were evaluated on an intent-to-treat basis. The overall response rate was 74.6%. The median time to progression was 247 days and median overall survival was 461 days. According to subgroup analyses, no statistically signicant differences were noted according to gender, age (<65 vs. >= 65 years), perfromance status, histology, or study centre. Conclusion: Induction chemotherapy followed by concurrent chemoradiotherapy with weekly cycles of paclitaxel and carboplatin is feasible and generates moderate toxicity. Efficacy is comparable to other recently published regimens. However, prognosis remains, ill general, poor for this group of patients and further work to develop better therapy is required.

The aim of this study was to investigate the reliability and validity of the Fatigue Impact Scale (FIS) among patients with chronic obstructive pulmonary disease (COPD) and shorten the questionnaire. The empirically developed FIS, which comprised three subscales (cognitive, physical and psychosocial), was tested originally on Pipers' theoretical framework of subjective manifestations of fatigue, including behavioural, physical, emotional and cognitive expressions. The data analysed here consisted of responses from 296 patients with COPD who reported fatigue. The dimensionality of the FIS was examined using confirmatory factor analysis. A reduction of 15 items from the original FIS was made based on theory, modification indices and factor loadings. The results indicate that a nested-factor model with one general behavioural factor and three specific factors, physical, emotional and cognitive, shows acceptable fit. A modified version of 25 items, FIS-25 was developed. The original FIS and the FIS-25 were able to discriminate between patients with differing duration of fatigue. Test - retest correlations ranged from .70 to .85 for items and .94 for the total scale. Due to modification, the FIS-25 needs to be validated on a new group of patients with COPD.

Objective: To test the effects of pulmonary rehabilitation on fatigue, functional status and health perceptions in patients with chronic obstructive pulmonary disease.

Design: Randomized controlled trial.

Setting: Pulmonary outpatient department.

Subjects: Thirty patients randomly assigned to a rehabilitation (3 men, 9 women, mean age 66 ( 2) years) or a control group (10 men, 4 women, mean age 64 ( 2) years).

Interventions: The patients in the rehabilitation group participated in a multidisciplinary rehabilitation programme comprising exercise training twice weekly, for a 12-week period, nutritional and self-care advice, and education about disease and energy conservation strategies.

Main measures: Fatigue, functional limitations due to fatigue, functional performance and satisfaction, six-minute walking distance, hand grip strength and health perception were assessed at baseline and after 12 weeks.

Results: At baseline there were no significant differences between the groups, except for gender. The six-minute walking distance was 312.6 (+/- 79.3) m for the rehabilitation group and 3603 (+/- 84.7) m for the control group. After 12 weeks, the rehabilitation group improved their walking distance by 40.6 (+/- 27.2) m (P<0.05). The rehabilitation group improved in performance (from 4.8 (12.0) to 6.0 (+/- 1.5) scores, P<0.01) and satisfaction (from 4.6 (+/- 2.2) to 6.0 (+/- 2.1) scores, P<0.001) with regard to own selected daily activities. No statistically significant differences were seen between the changes within the rehabilitation group and changes within the control group at the 12-week follow-up.

Conclusions: Although the pulmonary rehabilitation programme had an immediate effect, it was not sustained.

Fatigue is one of the most prevalent symptoms in patients with chronic obstructive pulmonary disease (COPD). In research as well as in clinical practise, fatigue and its influence on functioning and health has not been in focus. The aim of this study was to compare fatigue, functional limitations owing to fatigue and health between patients with COPD and individuals from the general population to assess the differences between patients experiencing no, moderate and severe fatigue. Patients with COPD (n = 151) and individuals from the general population (n = 95) answered questions about fatigue, the Fatigue Impact Scale and the Medical Outcomes Survey Short Form-36. The patients with COPD reported a higher frequency, longer daily duration and more severity of fatigue compared with individuals from the general population as well as more functional limitations and worse health. The patients who reported severe fatigue had more functional limitations and worse health compared with patients reporting moderate fatigue. These results indicate that fatigue severity should be screened for during the nursing care process with purpose to reduce the symptom burden.