Pulmonary Rehabilitation in Advanced Lung Cancer Patients During Chemotherapy.

The aim of this study was to investigate the utility of pulmonary rehabilitation for improving of exercises efficiency, dyspnea, and quality of life of patients with lung cancer during chemotherapy. After the enrollment selection, the study included 20 patients with newly diagnosed advanced lung cancer and performance status 0-2. There were 12 patients randomly allocated to the pulmonary rehabilitation group and another 8 constituted the control group that did not undergo physical rehabilitation. Both groups of patients had continual cycles of chemotherapy. Data were analyzed before and after 8 weeks of physical rehabilitation, and before and after 8 weeks of observation without rehabilitation in controls. The inpatient rehabilitation program was based on exercise training with ski poles and respiratory muscle training. We found a tendency for enhanced mobility (6 Minute Walk Test: 527.3 ± 107.4 vs. 563.9 ±64.6 m; p > 0.05) and a significant increase in forced expired volume in 1 s (66.9 ± 13.2 vs. 78.4 ± 17.7 %predicted; p = 0.016), less dyspnea (p = 0.05), and a tendency for improvement in the general quality of life questionnaire after completion of pulmonary rehabilitation as compared with the control group. This report suggests that pulmonary rehabilitation in advanced lung cancer patients during chemotherapy is a beneficial intervention to reduce dyspnea and enhance the quality of life and mobility.

Fatigue in sarcoidosis and exercise tolerance, dyspnea, and quality of life.

Fatigue is one of the major symptoms reported by sarcoidosis patients. The relationship between fatigue and clinical course of sarcoidosis remains unclear. The aim of the study was to evaluate the relationship between fatigue and lung function tests, exercise tolerance, dyspnea, and quality of life among sarcoidosis patients. One hundred eleven sarcoidosis patients completed the following questionnaires: Fatigue and Assessment Scale (FAS), Quality of Life Scale (SF-36), and dyspnea scales: Medical Research Council Questionnaire, Baseline Dyspnea Index, and Oxygen Cost Diagram. Clinical parameters (FVC, FEV1, DLCO, VO2, and VO2/AT, and work load) were derived from the patients' medical files. The exercise tolerance was the only clinical parameter associated with fatigue (Max. Work Load -0.65, VO2 -0.42, VO2/AT -0.51). No correlations were found between FAS and spirometry or diffusing tolerance. Fatigue correlated with all dyspnea domains by means of (r values ranging from 0.47 to 0.77 in multivariate regression analysis) and with quality of life in SF-36 questionnaire (r values ranging from -0.33 to -0.83). We conclude that FAS seems a reliable and valid indicator of dyspnea level, quality of life, and exercise tolerance in sarcoidosis patients.

High resolution computed tomography in 2-year follow-up of Stage I sarcoidosis.

There are as yet no markers known to predict the course of sarcoidosis. High resolution computed tomography (HRCT) is a tool that enables to visualize subtle parenchymal opacities in the lungs. Therefore, the aim of this study was to assess the prognostic role of HRCT at Stage I sarcoidosis. Fifty one patients (28 males and 23 females, aged 23-58) were studied. Based on HRCT examinations, two groups were distinguished: HRCT-positive (28 patients with pathologic changes in pulmonary parenchyma - mainly nodular opacities) and HRCT-negative (23 patients without parenchymal opacities). We found no significant differences between HRCT-negative and HRCT-positive groups in the mean values of pulmonary function tests (FEV1, FVC, FEV1/FVC, DLCO, and d(A-a)O2) between the starting and ending measurements of a 2-year long observation (check-up every 3 months). Likewise, there were no differences in the X-ray follow-up between the HRCT-positive and HRCT-negative groups. Nor were there significant differences in the percentage of patients showing stabilization, progression, or improvement between both groups (18 vs. 39 %, 21 vs. 4 %, and 61 vs. 57 %, respectively). We conclude that HRCT examination in stage I sarcoidosis has no significant prognostic role during a 2-year follow-up.

Pulmonary rehabilitation in patients referred for lung transplantation.

Effectiveness of pulmonary rehabilitation in patients with chronic obstructive lung diseases, cystic fibrosis, and interstitial lung disease is well documented but little is known about the results of pulmonary rehabilitation in patients referred for lung transplantation. The purpose of this study is to prospectively examine the efficacy of Nordic walking, a low cost, accessible, and proven beneficial form of physical exercise, as a form of pulmonary rehabilitation in patients referred for lung transplantation. Twenty-two male patients referred for lung transplantation at the Department of Lung Diseases and Tuberculosis in Zabrze, Poland, were invited to take part in the study. The rehabilitation program, which was conducted for 12 weeks, was based on Nordic walking exercise training with ski poles. Lung function tests (FVC, FEV1), mobility (6 min walking test (6MWT)), rating of dyspnea (Oxygen Cost Index, MRC and Baseline Dyspnea Index), and quality of life assessments (SF-36) were performed before and after the completion of the exercise program. No adverse events were observed after completing the pulmonary rehabilitation program in patients referred for lung transplantation. After 12 weeks of pulmonary rehabilitation with Nordic walking we observed a significant increase in the mean distance walked in the 6MWT (310.2 m vs. 372.1 m, p < 0.05). The results of lung function tests also showed improvement in FVC. There were no significant differences in the perception of dyspnea before and after completing the rehabilitation program. General health and quality of life questionnaire (SF-36) showed improvement in the domain of social functioning (p < 0.05). In conclusion, pulmonary rehabilitation with a Nordic walking program is a safe and feasible physical activity in end-stage lung disease patients referred for lung transplantation and results in improvements in patients' mobility and quality of life.

Osteoporosis in patients referred for lung transplantation.

OBJECTIVE: Osteoporosis may significantly impair the final result of lung transplantation. The purpose of study is to determine the prevalence of osteoporosis with the regard to risk factors for osteoporosis in patients awaiting lung transplantation. MATERIAL AND METHODS: We determined bone mineral density (BMD) in 48 patients (12 with idiopathic pulmonary fibrosis (IPF), 15 with other form idiopathic interstitial pneumonia (IIP), 5 with sarcoidosis and 16 with COPD) referred for lung transplantation (LT). BMD was performed on lumbar spine (LS), total hip (TH), and femoral neck (FN). Osteoporosis risk factors were analyzed with the consideration to principal diagnosis, lung function tests (FVC, FEV1) and mobility (6 MWT; six minute walking test). RESULTS: In osteoporosis group (50% of study population) the most affected was LS (mean T-score -3 ±1), with higher steroid consumption (cumulative steroid dose 40 ±28), lower FVC, FEV1 and mobility (6 MWT: 285 m) than in patients without osteoporosis. COPD patients presented the lowest BMD with the highest cumulative steroid dose (csd/kg: 0.6 ±0.6), lowest FEV1 (21 ±15% pred.) and 6 MWT (279 m). In patients with the lowest steroid consumption (IPF) the best results of BMD and FVC, FEV1 and 6 MWT were observed. No relation was found between BMD and sex and age in study group. CONCLUSIONS: Osteoporosis is very common in patients referred for lung transplantation, especially among COPD candidates. Steroid consumption is the mean risk factor. Therefore, early diagnosis and prevention of osteoporosis in lung transplant candidates should receive high priority.

Dyspnea and quality of life in patients referred for lung transplantation.

BACKGROUND: In the years 2007-2010 in the Department of Lung Diseases and Tuberculosis, Medical University of Silesia, 86 patients fulfilling ISHLT criteria qualified for lung transplantation. OBJECTIVES: The aim of the study was to assess the correlation between dyspnea and quality of life, and how it is related to clinical data in the examined group. MATERIAL AND METHODS: MRC, OCD, BDI and Borg scale were used for dyspnea evaluation, whereas quality of life was evaluated with SF-36 and SGRQ. A reference group consisted of 18 females and 68 males of the mean age 52 ±10 years and BMI 24 ±6. Thirty patients were diagnosed with IPF, 22 with COPD, and 34 with IIP. RESULTS: In the reference group, there was a significant correlation between dyspnea and quality of life: between MRC and Pf (SF-36 domain) r = -0.53; OCD and activity (SGRQ) r = 0.56; OCD and Pf r = -0.55; BDI and impact (SGRQ) r = 0.51; Borg scale and impact r = 0.47. In patients after lung transplantation, correlation between MRC and SF was r = -0.92; OCD and Pf, Bp, MH, PCS r = -0.97; OCD and RE r = -0.89; BDI and Pf r = -0.89; BDI and activity r=0.9; BDI and PCS r = -0.84. Depending on the diagnosis, the strongest correlation in IIP patients was found between OCD and activity (r = 0.62), in COPD patients - between BDI and impact (r = 0.79), and in IPF patients r = - 0.62 for OCD and Pf. Summing up the results, we can state that there is a significant correlation between dyspnea and quality of life. This correlation seems the strongest in patients after lung transplantation. CONCLUSIONS: The correlation found between the level of dyspnea and quality of life domains in lung transplant patients suggests that it would be worthwhile to add questions regarding dyspnea to assess the severity of the disease, clinical symptoms, and functional impairment during referring the patients for lung transplantation.

Right ventricular function in patients with severe interstitial lung disease: a Tissue Doppler imaging study.

Tissue Doppler imaging (TDI) can be useful in the evaluation of right ventricular (RV) regional dysfunction due to pulmonary diseases. The aim of the study was to assess RV dysfunction in patients with severe interstitial lung diseases (ILD), using both TDI and conventional transthoracic echocardiography (TTE). The study group consisted of 40 consecutive patients with end-stage ILD referred for lung transplantation (LT). Eighteen of them, mean age 47 +/-12 yr, who fulfilled the ATS/ERS criteria for LT (mean forced vital capacity (FVC) 1.4 +/-0.8 l, mean diffusing capacity for carbon dioxide (DLCO) <50% of predicted) constituted the active group, and 22 age-matched patients (mean age 49 +/-12 yr), who did not fulfill these criteria, were placed in the waiting group for LT. We found that among the TDI parameters, the longitudinal peak systolic strain rate (SR) measured at the RV outflow tract, was significantly more negative (-1.1 +/-0.3 vs. -3.2 +/-1.2 s(-1), P=0.03) and the time to peak velocity (TpVEL) in the medial and apical septal segments were shorter (129.9 +/-47.9 vs. 159.2 +/-38.1 ms, P=0.018 and 126.8 +/-44.3 vs. 154.6 +/-40.9 ms, P=0.019) in the patients from the active than those from the waiting group. TTE showed that patients from the active group had significantly lower values of tricuspid annulus plane systolic excursion (TAPSE) (14.3 +/-3.3 vs. 20.6 +/-6.2 mm, P=0.0003) and pulmonary artery acceleration time (PVAT) (70.3 +/-23.3 vs. 96.9 +/-12.4 ms, P=0.0001)compared with those from the waiting group. No other differences were found for other parameters of RV function between the examined groups. In conclusion, severity of lung disease in patients with ILD influences RV systolic dysfunction, which is reflected in both TDI and conventional echocardiographic parameters.

Induced sputum metalloproteinases and their inhibitors in relation to exhaled nitrogen oxide and sputum nitric oxides and other inflammatory cytokines in patients with chronic obstructive pulmonary disease.

The aim of this study was to assess sputum levels of the metalloproteinases MMP-1, MMP-2, MMP-3, TIMP-1, and TIMP-2, as well as MMPs/TIMPs ratios in relation to exhaled NO (eNO) and sputum NOs (nitrates and nitrites) and IL8 obtained from chronic obstructive pulmonery disease (COPD) patients, healthy non-smokers, and healthy smokers. We found higher levels of TIMP-1 (118.9 ng/ml) and TIMP-2 (3.75 ng/ml) in COPD patients than in healthy smokers (17.7 ng/ml, P<0.03; 0.51 ng/ml, P>0.05, respectively) and healthy non-smokers (84.6 ng/ml, P>0.05; 1.61 ng/ml, P>0.05, respectively). We also observed significant positive correlations between concentrations of NOs and MMP-1, MMP-2, MMP-3, and TIMP-2 (r=0.37, P<0.02; r=0.60, P<0.0001; r=0.56, P<0.0004 and r=0.47 P<0.004, respectively) in COPD patients. IL8, MMP-2, MMP-3, and TIMP-2 levels in induced sputum were negatively correlated with airway obstruction, i.e., FEV(1)/FVC (r=-0.61, P<0.00009; r=-0.41, P<0.01; r=-0.38, P<0.02; r=-0.49, P<0.002). Our study points to a potentially pathogenic role of stromelysin-1 (MMP-3) in COPD.

Left ventricular dysfunction in patients with interstitial lung diseases referred for lung transplantation.

The objective of this study was to determine the prevalence of left ventricular (LV) dysfunction in patients with advanced interstitial lung disease (ILD) and the relationship between LV function and factors limiting physical activity. In 2005-2006, 40 patients with end stage ILD were admitted with qualifications for lung transplantation (LT). From this group, 18 patients (7 women, 11 men) were referred for LT (active list), 22 patients (8 women, 14 men), who did not meet the ATS/ERS criteria for LT were excluded from this procedure (waiting list). All patients had echocardiography, spirometry, 6-min walking test (6MW), and gas exchange measurements. The following main echocariographic data that describe the LV function and morphology were taken into account: LVs, LVd, LVPWd, LVPWs, Ao, LA, ESV, EDV, and EF. We noted significant differences in LVPWd (P=0.01), ESV (P=0.01), and EDV (P=0.02), which presented lower values in patients on the active list compared with those on the waiting list. A positive correlation was found between 6MW and LVs (r=0.41), LA (r=0.45), ESV (r=0.62), and EDV (r=0.68). Correlations between spirometric, gas exchange, and left ventricle echocardiographic data were also observed. We conclude that patients on active list for lung transplantation present a decrease in the diameter and volume of the left ventricle. The latter change may influence the functional ability of interstitial lung disease patients.

Late consequences of respiratory system burns.

Burn inhalation has negative effects on pulmonary function and may result in whole airway damage. The consequences of a methane explosion are thermal injury of the respiratory tract, shock wave, and carbon monoxide intoxication. The aim of this study was to determine changes in the pulmonary function tests (PFTs) after six years of follow-up in miners who survived a methane explosion. Two groups were examined: 41 miners who fell victims to a methane explosion and had a documented thermal injury of the respiratory tract and 25 healthy miners who served as controls. Pulmonary function studies were repeated after six months and six years from the time of injury in 33 study subjects and at the same time intervals in 16 control subjects. The study included static and dynamic lung volumes and diffusing capacity for carbon monoxide (DLCO). The mean values of PFTs were within normal ranges in both groups examined six months and six years after the injury. A significant decrease in DLCO was observed in the victims (98.4% vs. 85.4%), but not in the control group, after a six years' observation. The decrease may be one of the reasons for a breathing discomfort emerging in these patients. In the control subjects we observed a significant decrease in FEV1 (96.4% vs. 83.4%)--over a six years' period. This finding is due likely to smoking and heavy pollution of the working environment.

Correlation of exhaled nitric oxide with nitrogen oxides and selected cytokines in induced sputum of chronic obstructive pulmonary disease patients.

Assessment of exhaled nitric oxide (eNO) in patients with chronic obstructive pulmonary disease (COPD) provides seemingly conflicting results and the relationships between eNO and other sputum inflammatory mediators are relatively weakly recognized. In the present study we measured eNO in 63 subjects (14 non-smoking healthy controls and 49 COPD stable patients--15 patients at stage 0, 9 patients at stage 1, 16 patients at stage 2, and 9 patients at stage 3). Additionally, concentrations of cytokines (IL-8, TNF-alpha, TGF-beta1, GM-CSF, Eotaxin) and nitrogen oxides (as nitrite or nitrate) (NOs) were measured in induced sputum in these patients. We found that there were no significant differences between the means of either eNO or NOs levels in COPD patients (stage 0-2) and controls. The only significant difference was noted for NOs between the COPD stage 3 patients and controls (9.0+/-1.7 microM vs. 21.1+/-4.8 microM). There was no significant correlation between eNO and sputum NOs. No relationships existed between eNO and the examined cytokine levels, except for a single negative correlation with GM-CSF (r=-0.38, P=0.02). In contrast, NOs correlated positively with IL-8 levels (r=0.51, P<0.01) and IL-8 levels correlated negatively (r=-0.47, P<0.01) with FEV1. We conclude that exhaled NO, sputum NOs, and other sputum cytokines offer separate and additive information about the pathophysiological condition in COPD.

Dyspnea and quality of life in patients with pulmonary fibrosis after six weeks of respiratory rehabilitation.

The aim of the study was to estimate the level of dyspnea and quality of life in patients with pulmonary fibrosis after 6 weeks' respiratory rehabilitation. The study comprised of 31 patients (F/M-12/19) with interstitial lung diseases (21 with idiopathic interstitial pneumonia, 4 with lung fibrosis due to allergic alveolitis, 4 with lung fibrosis due to collagenosis, 2 with lung fibrosis due to silicosis) who successfully finished the rehabilitation program. Each patient underwent an intensive (every day for 30 min) inpatient pulmonary rehabilitation program of an average length of 4 wk, continued later at home for up to 12 wk. The program consisted of respiratory muscle training and bicycle riding to the limits of the patient's tolerance. Dyspnea (MRC, OCD, BDI and Borg scale) and the quality of live (SF-36, St. George's Respiratory Questionnaire) were assessed at the time of admission and discharge. Rehabilitation caused dyspnea sensation to diminish (Borg scale: 2.97 before vs. 2.19 after). Some domains of the quality of life in SF-36 questionnaire (Role-Physical 40.6 vs. 60.2) and St. George's Respiratory Questionnaire (activity: 52 vs. 45, impact 47 vs. 40 and total 47 vs. 42) also were improved compared with the pre-rehabilitation results. We conclude that 12 weeks of combined inpatient and home-based rehabilitation programme improves the quality of live and sensation of dyspnea in patients with interstitial lung disease, despite changes in pulmonary function tests.

Potential confounding factors in measurement of exhaled nitric oxide.

Nitric oxide is present in the exhaled air. Factors affecting the level of exhaled nitric oxide (exNO), except for smoking, are not well defined. In this study we seek to determine whether age, gender, body mass index (BMI), part of the day, or time after a meal could modulate exNO levels. exNO was examined by the use of a chemiluminescence method in 100 subjects - 31 women (19 nonsmokers and 12 smokers) and 69 males (55 nonsmokers and 14 smokers). Forty four subjects took medications due to stable coronary disease, 22 were after heart transplantation, and 34 did not take any drugs. We found that exNO levels did not differ either between the whole groups of women and men or between smokers and nonsmokers of either respective group (4.91 +/-2.38 vs. 6.27 +/-4.23 ppb; 3.21 +/-1.16 vs. 3.71 +/-1.55 ppb; 5.98 +/-2.35 vs. 6.92 +/-4.45 ppb). The correlation of exNO with age in the whole population was weak (r=0.23; P=0.02) and insignificant in the smoking and nonsmoking subgroups. Likewise, correlations of exNO with BMI, part of the day, or time after a meal were insignificant in whole population as well as the subgroups. We conclude that the aforementioned factors are not able to confound the measurement of exNO in the population studied.

Quality of life during one-year observation of patients with idiopathic pulmonary fibrosis awaiting lung transplantation.

The aim of the study was to evaluate the quality of life and its changes in patients with idiopathic pulmonary fibrosis (IPF), waiting for lung transplantation. Sixteen IPF patients, who qualified for lung transplantation, and 14 chronic obstructive pulmonary disease (COPD) patients on long term oxygen therapy, taken as a reference group, were assessed. The quality of life was estimated twice, using an SF-36-questionnaire, at the time of qualification for lung transplantation and 12 months later. The IPF and reference patients had similarly profound disturbances in lung function and arterial blood gas content. The IPF patients had a statistically greater score in their physical functioning (PF; 45 vs. 18), the role of limitations due to physical problems (RP; 43 vs. 11), social functioning (SF; 58 vs. 30), and the role of emotional limitations in everyday life (RE; 65 vs. 12) than the reference ones. After a year's observation, there were no differences in SF-36 questionnaire results, except for the role of limitations due to physical problems (RP). A correlation was noted between spirometry and blood gas results and SF-36 questionnaire results in IPF patients qualified for lung transplantation. There was a positive correlation between the partial pressure of oxygen (PaO(2)), on one side, and mental and general health, on the other. There also were positive correlations between FEV1 and SF and FEV1 and the level of bodily pain (BP). We conclude that the SF-36 questionnaire is a sensitive tool to assess the quality of life in IPF patients qualified for lung transplantation. The information gained can help assess the severity of the disease, clinical symptoms, and functional impairment in these patients.

Prognostic risk factors in patients with interstitial lung disease referred for lung transplantation.

The aim of the study was to identify prognostic factors that would differentiate patients with interstitial lung disease between those with and without a chance to survive until lung transplantation. A retrospective study was performed in patients with interstitial lung disease referred for lung transplantation between September 1999 and April 2005. The analysis included the demographic data, the time from referral to transplantation, the functional tests (FVC, FEV1, FEV1%VC, the PaO(2) at rest and after oxygen supplementation via a nasal catheter), the count of NYHA functional classes, the left ventricular ejection fraction (EF), the distance covered during a 6-min walk test, and the pathogens in the respiratory tract. The patients were divided into two groups: Group 1 - lung transplant candidates who survived until the successful procedure and Group 2 - lung transplant candidates who died while on the waiting list. There were statistical differences between the two groups in PaO2 after supplementation (P=0.005), EF (P=0.002), and the 6-min walk distance (P=0.001). It appears that simple functional tests of the cardiorespiratory system may define survival of patients with interstitial lung disease waiting for lung transplantation.

Human cytomegalovirus DNA level in patients with idiopathic pulmonary fibrosis.

The objectives of the study were to estimate human cytomegalovirus (HCMV) DNA copy number in broncho-alveolar lavage cells, blood leukocytes, and serum of patients with idiopathic pulmonary fibrosis (IPF). The study groups consisted of 16 patients, newly diagnosed with IPF and never treated, (mean age 40.9 +/-11.0 yr; F/M-7/9) and in 16 adult healthy volunteers (mean age 36.8 +/-6.4 yr; F/M-4/12) used as controls. The HCMV DNA copy number was calculated by a Q-PCR method using TaqMan ABI PRISM 7700. We found that the prevalence of the HCMV DNA positive subjects in the patient group (75%) did not differ significantly from that in the control group (69%). We also found that in both patient and control groups the mean HCMV DNA copy number in BAL cells was significantly higher than that in blood leukocytes (log10=2.7 vs. 1.2 for patients and 2.8 vs. 0.9 for controls, respectively). However, a higher HCMV DNA copy number in blood serum was observed in IPF patients than in controls (log10=3.2 vs. 2.0, respectively). We conclude that the lungs play an important role in the human pathobiology of cytomegalovirus sustenance.

An increase in exhaled nitric oxide is not associated with activity in pulmonary sarcoidosis.

Exhaled nitric oxide (eNO) concentration measurement may permit the noninvasive estimation of the severity of airways inflammation in respiratory tract diseases. The aim of this study was to evaluate the correlation between eNO concentration and the activity of sarcoidosis, its radiographic staging and lung function abnormalities. eNO concentration was measured using a chemiluminescent analyser in 27 patients with sarcoidosis and 11 control subjects. The mean eNO concentration in patients with sarcoidosis was significantly higher (6.7+/-0.50 parts per billion (ppb)) than that in the control group (5.17+/-0.73 ppb). eNO concentration was similar in radiographic stage I, II and III patients (6.53, 7.32 and 6.24 ppb, respectively). No significant difference was found in eNO concentration between the patients with active and inactive disease. Nor did eNO concentration differ between the patients with and without indication for therapy. There was no significant correlation between eNO concentration and forced vital capacity or bronchoalveolar lavage fluid lymphocyte and macrophage counts. There was a weak correlation between eNO concentration and single-breath carbon monoxide diffusing capacity of the lung. Exhaled nitric oxide concentration is elevated in patients with sarcoidosis. This concentration does not depend on the radiographic staging, activity or progression of the disease.

Adult croup--a case report.

A case of a female adult patient with croup is described. Inflammation, as well as pseudomembranes, restricting the patency of trachea, developed within several hours after the first symptoms of infection were observed. Tracheostomy was performed Bronchofiberoscopies were repeated on a regular basis several times a day over a period of two weeks, with the removal of fibrinous casts and dense secretion being the only way to save the patient's life.

[Endometriosis of the lungs: analysis of diagnosis and therapy]. / Przypadek endometriozy plucnej--analiza diagnostyki, leczenie.

A casuistic case has been presented with endometriosis of the lung in an 18-year-old girl. Several diagnostic difficulties including haemoptysis accompanying changes in the hings and chest, suggesting a npl process. The final diagnosis has been made after the second thoracotomy and was confirmed by the histopathological examination of the lungs and pleurae. Because of the patient's age the a-GnRH therapy was not taken and the treatment with new progestin (dienogest) was administered. The 4-months therapy have appeared to be fully positive without any side effects.