Gh Koeter

Preoperative Staging of Non–Small-Cell Lung Cancer with Positron-Emission Tomography

BACKGROUND Determining the stage of non-small-cell lung cancer often requires multiple preoperative tests and invasive procedures. Whole-body positron-emission tomography (PET) may simplify and improve the evaluation of patients with this tumor. METHODS We prospectively compared the ability of a standard approach to staging (computed tomography [CT], ultrasonography, bone scanning, and, when indicated, needle biopsies) and one involving PET to detect metastases in mediastinal lymph nodes and at distant sites in 102 patients with resectable non-small-cell lung cancer. The presence of mediastinal metastatic disease was confirmed histopathologically. Distant metastases that were detected by PET were further evaluated by standard imaging tests and biopsies. Patients were followed postoperatively for six months by standard methods to detect occult metastases. Logistic-regression analysis was used to evaluate the ability of PET and CT to identify malignant mediastinal lymph nodes. RESULTS The sensitivity and specificity of PET for the detection of mediastinal metastases were 91 percent (95 percent confidence interval, 81 to 100 percent) and 86 percent (95 percent confidence interval, 78 to 94 percent), respectively. The corresponding values for CT were 75 percent (95 percent confidence interval, 60 to 90 percent) and 66 percent (95 percent confidence interval, 55 to 77 percent). When the results of PET and CT were adjusted for each other, only PET results were positively correlated with the histopathological findings in mediastinal lymph nodes (P<0.001). PET identified distant metastases that had not been found by standard methods in 11 of 102 patients. The sensitivity and specificity of PET for the detection of both mediastinal and distant metastatic disease were 95 percent (95 percent confidence interval, 88 to 100 percent) and 83 percent (95 percent confidence interval, 74 to 92 percent), respectively. The use of PET to identify the stage of the disease resulted in a different stage from the one determined by standard methods in 62 patients: the stage was lowered in 20 and raised in 42. CONCLUSIONS PET improves the rate of detection of local and distant metastases in patients with non-small-cell lung cancer.

Changes in bronchial hyperreactivity induced by 4 weeks of treatment with antiasthmatic drugs in patients with allergic asthma: A comparison between budesonide and terbutaline☆

We performed a double-blind crossover study to compare the effects of long-term treatment of inhaled budesonide and terbutaline on bronchial hyperreactivity in 17 patients with allergic asthma. Both drugs were administered for 4 weeks with a placebo-treatment period before and after each active-treatment period. To assess bronchial hyperreactivity, standardized inhalation provocation tests with histamine and propranolol were performed every 2 weeks. Before each inhalation provocation the drugs were withheld for at least 12 hours. Before the budesonide treatment the FEV1 value (percent predicted) was 85.3 +/- 4.1% (mean +/- SEM). After 2 and 4 weeks of treatment with this drug, the value increased significantly to 89.4 +/- 4.1% and 96.2 +/- 3.8%, respectively (p less than 0.05 and p less than 0.005). The histamine provocation concentrations causing a decrease in FEV1 of 20% (PC20) on the same days were 4.0, 7.2, and 9.5 mg/ml, respectively (both p less than 0.001). The PC20 values for propranolol, which were measured 1 hour after the histamine provocation, were 11.7, 13.3, and 14.0 mg/ml (ns). The FEV1 values before and after 2 and 4 weeks of treatment with terbutaline were 86.2 +/- 4.0%, 84.8 +/- 4.1%, and 87.0 +/- 4.6%, respectively. The histamine PC20 values on the same days were 4.7, 3.1 (p less than 0.05), and 3.8 mg/ml, respectively. The propranolol PC20 values were 14.2, 8.7, and 10.1 mg/ml (p less than 0.001 and p less than 0.05, respectively. We conclude that budesonide improves bronchial hyperreactivity, possibly by a dampening of late allergic reactions, whereas treatment with terbutaline may lead to a temporary increase of bronchial hyperreactivity, possibly as a result of beta-receptor desensitization.

Ongoing airway inflammation in patients with COPD who do not currently smoke

BACKGROUND Inflammatory changes in the airways in chronic obstructive pulmonary disease (COPD) are largely attributed to smoking, yet they may be present even if patients do not currently smoke. The differences in inflammatory cells and the factors contributing to these differences were examined in the airways of patients with COPD who do not currently smoke. METHODS Eighteen non-atopic subjects with COPD (14 men) of mean (SD) age 62 (8) years and forced expiratory volume in one second (FEV1) 59 (13)% predicted and 11 non-atopic healthy subjects (eight men) of mean (SD) age 58 (8) years, FEV1 104 (11)% predicted were studied. Sputum induction and bronchoscopy with bronchoalveolar lavage (BAL) and biopsies were performed. RESULTS Patients with COPD had more mucosal EG2+ cells (eosinophils) (median (range) 40 (0–190) versus 5 (0–40) cells/mm2, p = 0.049) and CD68+ cells (1115 (330–2920) versus 590 (450–1580) cells/mm2, p = 0.03), and a tendency towards more CD4+ but not CD8+ lymphocytes than healthy controls. Furthermore, patients with COPD had higher percentages of sputum neutrophils (77 (29–94) versus 36 (18–60)%, p = 0.001) and eosinophils (1.2 (0–8.5) versus 0.2 (0–3.1)%, p = 0.008), BAL fluid eosinophils (0.4 (0–1.7) versus 0.2 (0–0.5)%, p = 0.03), and higher concentrations of sputum eosinophilic cationic protein (ECP) (838 (115–23 760) versus 121 (35–218) ng/ml, p<0.001). Concentrations of ECP expressed per eosinophil were not higher. Patients with COPD with high mucosal EG2+ cell numbers also had high mucosal CD4+ cell numbers. Sputum eosinophilia was associated with a decrease in FEV1/VC and BAL fluid eosinophilia with a decrease in mucosal NP57+ cells (neutrophils). CONCLUSIONS Subjects with COPD who do not currently smoke have increased numbers of inflammatory cells. Eosinophils are increased in number in the airways in COPD but do not seem to be activated. The increased eosinophil numbers are probably due to recruitment as a result of ongoing inflammation. Macrophages and lymphocytes may play a part in this inflammation.

QUALITY-OF-LIFE IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY-DISEASE IMPROVES AFTER REHABILITATION AT HOME

We have developed a rehabilitation programme at home and have investigated its effects on quality of life (QOL), lung function, and exercise tolerance in patients with chronic obstructive pulmonary disease (COPD). We studied 43 patients with severe airflow obstruction: forced expiratory volume in one second (FEV1) 1.3 +/- 0.4 l (mean +/- SD), FEV1/inspiratory vital capacity (IVC) 37 +/- 7.9%. After stratification, 28 patients were randomly allocated in a home rehabilitation programme for 12 weeks. Fifteen patients in a control group received no rehabilitation. The rehabilitation group received physiotherapy by the local physiotherapist, and supervision by a nurse and a general practitioner. Quality of life was assessed by the four dimensions of the Chronic Respiratory Questionnaire (CRQ). We found a highly significant improvement in the rehabilitation group compared to the control group for the dimensions dyspnoea, emotion, and mastery. Lung function showed no changes in the rehabilitation group. The exercise tolerance improved significantly in the rehabilitation group compared to the control group. The improvement in quality of life was not correlated with the improvement in exercise tolerance. Rehabilitation of COPD patients at home may improve quality of life; this improvement is not correlated with an improvement in lung function and exercise tolerance.

Relation of lung function, maximal inspiratory pressure, dyspnoea, and quality of life with exercise capacity in patients with chronic obstructive pulmonary disease.

BACKGROUND--Several studies have shown that both objective and subjective measurements are related to exercise capacity in patients with chronic obstructive pulmonary disease (COPD). In this study the relative contribution of lung function, maximal inspiratory pressure, dyspnoea, and quality of life to the performance in a walking distance test and a bicycle ergometer test was investigated. METHODS--Static lung volumes, forced expiratory volume in one second (FEV1), inspiratory slow vital capacity (IVC), transfer factor for carbon monoxide (TLCO) divided by the alveolar volume (TLCO/VA), static compliance (Cst), and maximal inspiratory peak pressure (PImaxPOES) were measured in 40 patients with COPD with severe airways obstruction (mean FEV1 44% predicted, mean FEV1/IVC 37% predicted). Quality of life was assessed by the Chronic Respiratory Questionnaire (CRQ) and dyspnoea by the Borg category scale. Exercise capacity was measured by both a six minute walking distance (test) and a maximal work load of the bicycle ergometer test (Wmax). RESULTS--Spirometric values and maximal inspiratory pressure were modestly correlated with both the six minute walking test and Wmax, r values ranging from 0.50 to 0.58. The TLCO was strongly correlated with the six minute walking test (r = 0.62) and with Wmax (r = 0.78). Quality of life showed no correlation with exercise capacity, while there was a correlation between dyspnoea and the six minute walking test (r = -0.41). Backward linear regression analysis selected TLCO and PImaxPOES as the most significant determinants for exercise performance. They explained 54% and 69% of the variance in the six minute walking test and Wmax, respectively. CONCLUSIONS--The results show that exercise capacity in patients with COPD with severe airways obstruction is more strongly related to inspiratory muscle strength and lung function than to dyspnoea and quality of life. The significant correlation between dyspnoea and the six minute walking test suggests that subjective variables are more strongly related to walking tests than to bicycle ergometer tests.

Long term benefits of rehabilitation at home on quality of life and exercise tolerance in patients with chronic obstructive pulmonary disease.

BACKGROUND--Pulmonary rehabilitation has been shown to have short term subjective and objective benefits for patients with chronic obstructive pulmonary disease (COPD). However, appropriately controlled studies have not previously been performed, nor have the benefits of different types of continuation programme for rehabilitation been investigated. Both these problems have been addressed in a single study of the long term effects of once monthly physiotherapy versus once weekly physiotherapy at home after a comprehensive home rehabilitation programme on quality of life and exercise tolerance in patients with COPD. METHODS--Thirty six patients with severe airways obstruction (mean SD) forced expiratory volume in one second (FEV1) 1.3(0.4) 1, FEV1/inspiratory vital capacity (IVC) 37.2(7.9)%) were studied. Twenty three patients followed a rehabilitation programme at home for 18 months consisting of physiotherapy and supervision by a nurse and general practitioner. During the first three months all 23 patients visited the physiotherapist twice a week for a 0.5 hour session. Thereafter, 11 patients (group A) received a session of physiotherapy once weekly while 12 patients (group B) received a session of physiotherapy once a month. The control group C (13 patients) received no rehabilitation at all. Quality of life was assessed by the Chronic Respiratory Questionnaire, exercise tolerance by the six minute walking distance, and lung function by FEV1 and IVC. Outcome measures were assessed at baseline and at three, six, 12, and 18 months. RESULTS--Long term improvements in quality of life were found in patients in groups A and B, but not in those in group C compared with baseline, but these only reached significance in group B at all time points. Patients in group B had a higher quality of life than those in group C only at three and 12 months. There was a decrease in both six minute walking distance (at 12 and 18 months) and IVC (at three, 12, and 18 months) in patients in group C compared with the baseline measurement. Between groups analysis showed no differences for six minute walking distance, FEV1, and IVC. CONCLUSIONS--This study is the first to show that rehabilitation at home for three months followed by once monthly physiotherapy sessions improves quality of life over 18 months. The change in quality of life was not associated with a change in exercise tolerance.

Comparison of induced sputum with bronchial wash, bronchoalveolar lavage and bronchial biopsies in COPD

It is unclear how cellular and soluble inflammatory markers in induced sputum relate to markers in lavage fluid and biopsies in chronic obstructive pulmonary disease (COPD). This was investigated and also the possible differences between subjects with COPD and healthy controls assessed. Eighteen nonatopic subjects with COPD and 11 healthy controls were studied. Sputum was induced by inhalation of hypertonic saline. The airways were lavaged, using the first 50 mL for bronchial wash (BW) and the subsequent 150 mL for bronchoalveolar lavage (BAL), and biopsies were taken from subsegmental carinae. Neutrophils were the predominant cell type in sputum in COPD (median 77.3%) but not in BW (5.5%) and BAL fluid (1.7%). Differential cell counts in sputum did not correlate with the counts in BW or BAL fluid or biopsies, whereas sputum eosinophil cationic protein (ECP) levels correlated with BW fluid ECP levels (p=0.66, p=0.007) and sputum interleukin-8 (IL-8) concentration with BAL fluid IL-8 concentration (p= 0.52, p=0.026). Subjects with COPD had a higher percentage of sputum neutrophils and eosinophils and higher concentrations of ECP and IL-8 than healthy controls. The higher percentages of eosinophils and concentrations of ECP were also seen in BW and BAL fluid. Finally, higher numbers of macrophages and eosinophils were found in biopsies. In conclusion, induced sputum is derived from a different compartment from BW and BAL fluid and biopsies. Induced sputum may be useful for studying the contribution of luminal neutrophils and eosinophils in chronic obstructive pulmonary disease.

Reliability and validity of the chronic respiratory questionnaire (CRQ).

BACKGROUND--The Chronic Respiratory Questionnaire (CRQ) is frequently applied to assess quality of life in patients with chronic obstructive pulmonary disease (COPD). However, the reliability and validity of this questionnaire have not yet been determined. This study investigates the reliability and validity of the four separate dimensions of the CRQ. METHODS--The CRQ was administered on two consecutive days to 40 patients with COPD (mean FEV1 44% predicted, FEV1/IVC 37% predicted). Internal consistency reliability of each dimension was investigated by Cronbachs alpha reliability coefficient, test retest reliability by the Spearman-Brown reliability coefficient (p), and content validity by Pearsons correlation coefficient between the CRQ and the symptom checklist (SCL-90). RESULTS--Items of the fatigue, emotion, and mastery dimensions showed a high internal consistency reliability (alpha = 0.71-0.88) as well as a high test retest reliability (p above 0.90). These three dimensions correlated with comparable dimensions of the SCL-90. Items of the dyspnoea dimension showed a low internal consistency reliability (alpha = 0.53) and a test retest reliability of p = 0.73. CONCLUSIONS--Items of the dimensions fatigue, emotion, and mastery of the CRQ are reliable and valid and can be used to assess quality of life in patients with severe airways obstruction. Items of the dyspnoea dimension are less reliable and should not be included in the overall score of the CRQ in comparative research. However, by scoring the items of dyspnoea separately they may be useful for the evaluation of the effects of intervention in a specific patient.

Treatment of posttransplant lymphoproliferative disease with rituximab: the remission, the relapse, and the complication.

BACKGROUND Rituximab, a humanized anti-CD20 monoclonal antibody, is a promising new tool for the treatment of posttransplant lymphoproliferative disease (PTLD), especially for patients transplanted with rejection prone transplants of vital organs, such as patients after lung transplantation. Thus far, no major complications have been described. We treated three lung transplant recipients with Rituximab because of PTLD. METHODS Patients were treated with four weekly doses of 375 mg/m2 of Rituximab. Epstein-Barr virus (EBV) DNA was monitored with quantitative-competitive polymerase chain reaction and circulating B cells with flow cytometry. RESULTS Treatment with Rituximab resulted in a complete remission in all patients without signs of or progression of bronchiolitis obliterans syndrome. Patient 1 relapsed after 2 months with a partly CD20-negative PTLD but is in stable remission after radiotherapy. Patient 2 is in complete remission 16 months after treatment, but patient 3 developed a hypogammaglobulinemia and died of invasive aspergillosis after 6 months. EBV DNA was detectable in the blood samples of patients 2 and 3 before treatment with Rituximab and became negative instantly after Rituximab. In all three patients, B cells are absent in the peripheral blood 7 months (at death), 16 months, and 16 months after treatment with Rituximab. Antiproliferating agents, such as mycophenolate mofetil (MMF), might prolong B-cell depletion. CONCLUSIONS Rituximab was effective for the treatment of PTLD without progression of transplant dysfunction in our patients. Complications were a partly CD20-negative relapse of PTLD and a hypogammaglobulinemia. Attention should be paid to immunoglobulin G (IgG) levels, especially in patients treated with antiproliferating agents such as MMF.

Markers of nitric oxide metabolism in sputum and exhaled air are not increased in chronic obstructive pulmonary disease

BACKGROUND Nitric oxide (NO) is involved in inflammation and host defence of the lung. It has been found in increased concentrations in the airways in asthmatic subjects but its levels in patients with chronic obstructive pulmonary disease (COPD) have not been investigated. A study was undertaken to determine whether markers of NO metabolism (NO in exhaled air, iNOS expression in sputum cells, and nitrite + nitrate (NO2 –/NO3 –) in sputum supernatant) are increased in subjects with COPD, and whether they correlate with inflammatory indices in induced sputum. The associations of these markers with smoking were also assessed. METHODS Sixteen subjects with COPD (median age 66 years, median forced expiratory volume in one second (FEV1) 63% predicted, eight current smokers) and 16 healthy subjects (median age 63 years, median FEV1 113% predicted, eight current smokers) participated in the study. NO was measured during tidal breathing and sputum was induced by inhalation of hypertonic saline. RESULTS No differences were observed between subjects with COPD and healthy controls in exhaled NO excretion rate (median 5.15 and 6.25 nmol/min), sputum macrophage iNOS expression (14% and 12%), and sputum supernatant NO2 –/NO3 – (46 and 73 μM). NO in exhaled air correlated with the percentage of sputum eosinophils in patients with COPD (rho = 0.65, p = 0.009) but not in healthy individuals. Exhaled NO and supernatant NO2 –/NO3 – levels were lower in healthy smokers than in healthy non/ex-smokers. CONCLUSIONS Our findings indicate that NO metabolism is not increased in patients with stable COPD. The close association between exhaled NO levels and sputum eosinophils suggests a role for NO in airway inflammation in COPD. Studies performed during exacerbations may clarify this role.