Theodoros Kontakiotis

Management of malignant pleural effusion by suicide gene therapy in advanced stage lung cancer: a case series and literature review

Gene therapy can be defined as the transfer of genetic material into a cell for therapeutic purposes. Cytosine deaminase (CD) transferred into tumor cells by an adenoviral vector (Ad.CD), can convert the antifungal drug fluorocytosine (5-FC) to the antimetabolite 5-fluorouracil (5-FU), which kills not only the transfected tumor cells but also their neighbors by the so-called ‘bystander effect’. After testing a protocol for Ad.CD transfer and lung tumor burden control in a Lewis mouse model, we used this technique in the management of lung cancer patients with malignant pleural effusion (MPE): two cases are presented investigating the possible enhancement of anticancer effect in both non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) by local activation of the pro-drug 5-FC. Results were discussed in parallel to a literature review on the topic. 5-FC and Ad.CD were administered intratumorally to Lewis mouse lung carcinoma and the effect was monitored by tumor size and electromicroscopy. Two patients with advanced stage lung cancer (1SCLC, 1NSCLC), which developed MPE during first-line treatment were administered 1012 plaque-forming unit (pfu) Ad.CD by intrapleural instillation, in two doses (day1 and day7). Instillation was performed when the pleural fluid was ⩽200 ml. In addition, they received 5-FC 500 mg four times daily for 14 days. Lung tumor regression and successful transfer of adenoviral particles were observed in treated animals. Patients presented complete regression of pleural effusion as monitored by computerized tomography scan. Neutrapenia and anemia were the most severe adverse effect presented (grade III/grade IV 100%). The increased toxicity followed by the intrapleural gene therapy indicates the augmentation of anticancer effect of transformed pro-drug 5-FC to active 5-FU. The obtained data indicate that intrapleural gene therapy may be a useful tool, adjunct to chemotherapy, in the management of MPE related to lung cancer.

Serum Total Antioxidant Status in Severe Exacerbation of Asthma: Correlation with the Severity of the Disease

Oxidative processes, mediated by oxygen free radicals are recognized to contribute significantly to the inflammatory pathology of bronchial asthma. An imbalance between oxidants and antioxidants has also been proposed in this disease. This study examines the serum total antioxidant status (TAS) in asthmatic patients with severe exacerbation of their disease and the probable correlation with clinical or laboratory findings. The TAS was measured in 20 patients (10 men and 10 women, with a mean age of 41.95 ± 20.75 years), using a colorimetric method. On the days of admission and discharge, the forced expiratory volume in 1 sec (FEV1), the partial arterial oxygen pressure (PaO2), and severity criteria were recorded and correlated with TAS at the same time. The TAS was also measured in 10 healthy subjects (8 men and 2 women, mean age of 39 ± 9 years). A statistically significant decrease of TAS was observed on admission day compared to that on discharge day (0.98 ± 0.08 vs. 1.12 ± 0.17 mmol/L, p < 0.001, respectively, paired t‐test) suggesting the presence of oxidative stress during an asthma attack. The TAS on admission was also statistically significantly decreased compared to that of normal subjects (0.98 ± 0.08 vs. 1.19 ± 0.09 mmo/L, p < 0.001, respectively, paired t‐test). A statistically significant correlation was observed between FEV1change and TAS change, from admission to discharge day (r = 0.58, p = 0.007, Pearson correlation). Finally, a statistically significant correlation was found between FEV1change and TAS on discharge day (r = 0.65, p = 0.002). Decreased TAS was found during an asthma attack, probably as a consequence of increased oxidative stress. The TAS change was correlated with severity criteria, such as FEV1. Therefore, it seems that measurement of TAS could be a simple and useful tool in the evaluation of an asthma attack. The supplementary administration of antioxidants in future needs further clarification.

Anemia of Chronic Disease in Chronic Obstructive Pulmonary Disease: A Case-Control Study of Cardiopulmonary Exercise Responses

Background: Anemia may be present in patients with chronic obstructive pulmonary disease (COPD) and further impair their functional capacity. Objectives: This study investigated the prevalence of anemia of chronic disease (ACD) in COPD patients and its impact on dyspnea and exercise capacity, utilizing cardiopulmonary exercise testing (CPET). Methods: ACD prevalence was assessed in 283 consecutive patients with stable COPD (263 males, 60 females; age 60.31 ± 5.34 years; percent forced expiratory volume in 1 s 46.94 ± 6.12). ACD diagnosis was based on a combination of clinical and laboratory parameters [hemoglobin (Hb) <13 g/dl for males, <12 g/dl for females; ferritin >30 ng/ml; total iron-binding capacity <250 µg/dl, and transferrin saturation rate between 15 and 50%]. Twenty-seven patients who were identified with ACD (cases) and 27 matched nonanemic patients (controls) completed maximal CPET, and data were compared between the groups. Results: ACD was diagnosed in 29 patients, which represents a prevalence of 10.24%; the severity of anemia was generally mild (mean Hb: 12.19 ± 0.66 g/dl). Patients with ACD had a higher Medical Research Council dyspnea score compared to controls (2.78 ± 0.44 vs. 2.07 ± 0.55; p <0.001) and lower peak O2 uptake (VO2) (59.54 ± 17.17 vs. 71.26 ± 11.85% predicted; p <0.05), peak work rate (54.94 ± 21.42 vs. 68.72 ± 20.81% predicted; p <0.05) and peak VO2/heart rate (69.07 ± 17.26 vs. 82.04 ± 18.22% predicted; p <0.05). There was also a trend for a lower anaerobic threshold (48.48 ± 15.16 vs. 55.42 ± 9.99% predicted; p = 0.062). No exercise parameter indicative of respiratory limitation differed between the groups. Conclusions: ACD occurs in approximately 10% of stable COPD patients and has a negative impact on dyspnea and circulatory efficiency during exercise.

Difficult airway and difficult intubation in postintubation tracheal stenosis: a case report and literature review

Management of a “difficult airway” remains one of the most relevant and challenging tasks for anesthesiologists and pulmonary physicians. Several conditions, such as inflammation, trauma, tumor, and immunologic and metabolic diseases, are considered responsible for the difficult intubation of a critically ill patient. In this case report we present the case of a 46-year-old male with postintubation tracheal stenosis. We will focus on the method of intubation used, since the patient had a “difficult airway” and had to be intubated immediately because he was in a life-threatening situation. Although technology is of utter importance, clinical examination and history-taking remain invaluable for the appropriate evaluation of the critically ill patient in everyday medical life. Every physician who will be required to perform intubation has to be familiar with the evaluation of the difficult airway and, in the event of the unanticipated difficult airway, to be able to use a wide variety of tools and techniques to avoid complications and fatality.

Levels of inflammatory mediators in chronic obstructive pulmonary disease patients with anemia of chronic disease: a case–control study

BACKGROUND Although a subset of patients with chronic obstructive pulmonary disease (COPD) display anemia, the role of elevated pro-inflammatory cytokines in COPD-related anemia of chronic disease (ACD) has not been fully investigated. AIM To examine the levels of interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor-alpha (TNFα), interferon-gamma (IFNγ), C-reactive protein (CRP) and erythropoietin in stable COPD outpatients with and without ACD. DESIGN A case-control design was followed. METHODS Fifty-four patients with stable COPD were studied. Among them, 27 had ACD according to strict clinical and laboratory criteria (group of cases), while another 27 nonanemic COPD patients, carefully matched to cases for age, gender, height, lung function and smoking status represented the controls. Serum levels of IL-1β, IL-6, IL-10, TNFα, IFNγ, CRP and erythropoietin were measured in both groups. RESULTS Patients with ACD had significantly higher levels of IL-10 [25.6 (1.9-95.2) vs. 4.1 (1.9-31.9) pg/ml, P = 0.049] and IFNγ [15.2 (2.2-106.9) vs. 2 (1.2-18.3) pg/ml, P = 0.026] and had more frequently elevated CRP than controls. Levels of IL-1β [26.2 (9.8-96.4) vs. 7.9 (2.1-28.4) pg/ml, P = 0.073], IL-6 [20.3 (2.1-125.4) vs. 6.2 (1.2-33.8) pg/ml, P = 0.688] and TNFα [30.1 (3.2-107.5) vs. 10.1 (3.2-50.4) pg/ml, P = 0.131] were also higher in cases, but the differences did not reach statistical significance. Patients with ACD also displayed significantly higher erythropoietin levels than controls [(21.9 (8.4-101.7) vs. 9.7 (6.3-21.7) mIU/ml, P = 0.010], indicating erythropoietin resistance. CONCLUSION This study shows that in stable COPD outpatients with strictly defined ACD, levels of inflammatory mediators and erythropoietin are elevated compared to nonanemic controls.

A Phase II study of docetaxel and carboplatin in the treatment of non-small cell lung cancer.

We investigated the efficacy of docetaxel (D) in combination with carboplatin (C) in the treatment of non-small cell lung cancer (NSCLC) patients. Since 1996, 123 with inoperable NSCLC were enrolled in the study; 120 (108 males, 12 females; mean age 58.0+/-8.3 years) were evaluated. Of those, 46 patients had squamous carcinoma, 44 adenocarcinoma, 11 large cell carcinoma and 19 undifferentiated tumours. Eligibility criteria included, documented inoperable NSCLC, WHO performance status (PS) 0-1, age up to 70 years, and normal renal and hepatic function. A total of 622 cycles of chemotherapy (CHT) (median 7 (95% CI 6.2-7.47), courses per patient) were administered. Each cycle consisted of 100 mg/m(2) of docetaxel in a 2-h infusion with C at a dose of area under the curve (AUC) of 6 on day 1. This regimen was repeated every 28 days up to eight cycles. Of the patients, five (4%) achieved complete response, 49 (40%) partial response, 47 (39%) had stable disease and 19 (15%) had progressive disease. The median survival was 12 months for all patients, 12 for the four patients with stage IIb disease, 18 for the patients with stage IIIa disease, 20 for the 29 patients with stage IIIb disease, and 11 for the 65 stage IV patients. The median time to progression was 8 months (90 patients). Toxicity was, grade 3/4 neutropenia, 18 patients (15%); grade 3/4 anaemia, 6 patients (5%); and tolerable peripheral neuropathy, 16 patients (13.3%). Responders received radiotherapy (total dose, 50 Gy in 4 weeks) between the 6th and 8th cycle. Among responders with initial stage IIIb disease, 7 (5%) underwent surgical resection. Patients with early progression of the disease received the same dose of radiotherapy between 2nd and 3rd cycle. The study is ongoing, and six patients (5%) are still alive (after 3 years). Preliminary results indicate that the D/C combination is very active in the treatment of NSCLC with tolerable toxicity. It appears that this drug combination is also good as neoadjuvant therapy in inoperable NSCLC patients.

Experimentation with inhaled bronchodilators and corticosteroids

BACKGROUND Inhaled bronchodilators and corticosteroids have been used for decades with different production systems. MATERIALS AND METHODS The following jet-nebulizers: (a) Invacare, (b) Sunmist, (c) Maxineb and ultrasound nebulizers: (a) GIMA, (b) OMRON and (c) EASY NEB II were used as production systems. The jet-nebulizers were used with different residual cups and volume filling, while the ultrasound nebulizers with different volume fillings and face mask versus inlet. RESULTS Inhalation and ultrasound process detect significant differences between the factors and interactions considered, but each technique follows a specific pattern of magnitude effect. Thus the inhaled mechanism ranks the factor effects in decreasing order: residual cup>drug>nebulizer>loading (2, 3, 4 ml) and also drug>residual cup>nebulizer (loading 8 ml). The ultrasound mechanism orders as follows: nebulizer>drug>loading. In fact, varying micro environmental conditions created during the performance of the devices in both processes alternate the magnitude of factor significance allowing for unique capacities. CONCLUSIONS PULMICORT, MAXINEB, design cup J and loading 6 ml are the best options for the inhaled process. Optimal combinations are provided by FLIXOTIDE and cup B and also by MAXINEB and cup J. The incorporation of large residual cups suggests one out of six drugs, the SUNMIST nebulizer and design D as the best choices. Ultrasound performance informs for other optimal conditions: ZYLOREN, MAXINEB, 4 ml load and MAXINEB×loading 4 ml.

Solitary Papillomas of the Lower Airways: Epidemiological, Clinical, and Therapeutic Data during a 22-Year Period and Review of the Literature

Introduction: Solitary respiratory papillomas (SRPs) are considered uncommon yet benign neoplasms of the lower respiratory tract. Most of our understanding stems from single case reports or limited case series. Objective: To determine the incidence of solitary SRPs and more accurately describe the localization, distribution of subtypes of solitary SRPs, clinical features, and the risk of malignant transformation. This retrospective report is based on data collected in a busy single-center bronchoscopy practice during a 22-year period. Methods: Among 36,780 patients who underwent bronchoscopic procedures between 1986 and 2008, we identified 32 patients with SRPs. This patient group was compared with 69 patients with SRPs described in the English literature as case reports, case series, or diagnostic dilemmas. Results: Twenty-three patients were men (male/female ratio of 3:1), and 21 patients were former smokers (65.6%). The mean age of initial presentation in men and women was 56.9 ± 14.3 versus 53.3 ± 14.4 years, respectively. The presenting symptoms included cough in 18 patients (40.6%), hemoptysis in 11 (25%), dyspnea in seven (21.8%), and fever in five patients (15.7%). Two patients with papillomas in the subglottic region had wheezing and were on aerosolized bronchodilator therapy. In one patient, the papilloma was incidentally discovered on a chest computed tomography scan. The histologic analysis of lesions revealed squamous papillomas in 65.6%, a glandular subtype in 18.75%, and a mixed subtype in 15.6%. Malignant transformation was observed in five patients (15.7%). The malignancies consisted of squamous cell carcinoma in two patients, and single cases of small cell lung carcinoma, glandular carcinoma, and low-grade carcinoma. Conclusion: In our experience, the estimated incidence of SRPs is 3.95 cases/100,000 patients/yr. SRPs occur more commonly in men (ratio 3:1). Squamous papillomas occur commonly during the fifth decade of life, glandular papillomas predominate in the sixth decade, and the distribution of mixed type papillomas is from the third to the sixth decade of life. Malignant transformation was observed in a minority of patients.

Left ventricular diastolic dysfunction in idiopathic pulmonary fibrosis: a tissue Doppler echocardiographic study

It was hypothesised that, apart from right ventricular (RV) dysfunction, patients with idiopathic pulmonary fibrosis (IPF) also exhibit left ventricular (LV) impairment, which may affect disease progression and prognosis. The aim of the present study was to evaluate LV performance in a cohort of IPF patients using conventional and tissue Doppler echocardiography. IPF patients exhibiting mild-to-moderate pulmonary arterial hypertension (mean age 65±9 yrs; n = 22) and healthy individuals (mean age 61±6 yrs; n = 22) were studied. Conventional and tissue Doppler echocardiography were used for the evaluation of RV and LV systolic and diastolic function. In addition to the expected impairment in RV function, all patients showed a characteristic reversal of LV diastolic filling to late diastole compared with controls (early diastolic peak filling velocity (E)/late diastolic peak filling velocity 0.7±0.2 versus 1.5±0.1, respectively). Patients with IPF also exhibited lower peak myocardial velocities in early diastole (Em; 5.7±1.1 versus 10.3±1.6 cm·s−1, respectively), higher in late diastole (Am; 8.9±1.3 versus 5.5±0.8 cm·s−1, respectively), lower Em/Am ratio (0.6±0.1 versus 1.9±0.5, respectively) and higher E/Em ratio (10.8±3 versus 6±0.6, respectively), all indicative of LV diastolic dysfunction. Moreover, LV propagation velocity was significantly lower in IPF patients (46±13 versus 83±21 cm·s−1, respectively). Physicians should be aware that patients with idiopathic pulmonary fibrosis exhibit early impairment of left ventricular diastolic function.

Docetaxel-carboplatin in combination with erlotinib and/or bevacizumab in patients with non-small cell lung cancer

Background Bevacizumab and erlotinib have been demonstrated to prolong overall survival in patients with non-squamous non-small cell lung cancer (NSCLC). We designed a four-arm Phase III trial to evaluate the efficacy and toxicity of the combination of docetaxel, carboplatin, bevacizumab, and erlotinib in the first-line treatment of patients with NSCLC. Methods A total of 229 patients with stage IIIb/IV non-squamous NSCLC were treated with two cycles of carboplatin (area under the concentration-time curve 5.5) and docetaxel 100 mg/m2 as chemotherapy. After completion of two treatment cycles, patients were evaluated for response and divided into four groups: 61/229 continued with four more cycles of chemotherapy (control group), 52/229 received chemotherapy plus erlotinib 150 mg daily, 56/229 received chemotherapy plus bevacizumab 7.5 mg/kg, and 60/229 were treated with the combination of chemotherapy, erlotinib, and bevacizumab until disease progression. The primary endpoint was overall survival. Results Over 4 years of follow-up, there was no statistically significant difference in survival and time to progression between the four treatment groups. After two cycles of chemotherapy, responders and nonresponders were divided according to their response in order to examine the role of initial response as an independent factor in survival and response when a biological agent is combined with chemotherapy. Nonresponders, who received additional therapy with bevacizumab or combination therapy, had a survival benefit [657 days (95% confidence interval 349–970) and 681 days (95% confidence interval 315–912), respectively], which was statistically significant compared with continuation of cytotoxic chemotherapy (P < 0.001). The combination therapy had a safety profile comparable with that of bevacizumab and erlotinib taken individually. Conclusion Administration of bevacizumab and erlotinib in combination with first-line chemotherapy, followed by bevacizumab and erlotinib monotherapy as maintenance, showed promising results in patients with NSCLC, with reduced toxicity as compared with chemotherapy alone, but did not translate into longer overall survival.