Kostas Zarogoulidis

Macrolides: from in vitro anti-inflammatory and immunomodulatory properties to clinical practice in respiratory diseases

BackgroundMacrolides have long been recognised to exert immunomodulary and anti-inflammatory actions. They are able to suppress the “cytokine storm” of inflammation and to confer an additional clinical benefit through their immunomodulatory properties.MethodsA search of electronic journal articles was performed using combinations of the following keywords: macrolides, COPD, asthma, bronchitis, bronchiolitis obliterans, cystic fibrosis, immunomodulation, anti-inflammatory effect, diabetes, side effects and systemic diseases.ResultsMacrolide effects are time- and dose-dependent, and the mechanisms underlying these effects remain incompletely understood. Both in vitro and in vivo studies have provided ample evidence of their immunomodulary and anti-inflammatory actions. Importantly, this class of antibiotics is efficacious with respect to controlling exacerbations of underlying respiratory problems, such as cystic fibrosis, asthma, bronchiectasis, panbrochiolitis and cryptogenic organising pneumonia. Macrolides have also been reported to reduce airway hyper-responsiveness and improve pulmonary function.ConclusionThis review provides an overview on the properties of macrolides (erythromycin, clarithromycin, roxithromycin, azithromycin), their efficacy in various respiratory diseases and their adverse effects.

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.

Inhaled Insulin: Too Soon To Be Forgotten?

Inhalation is a potentially viable route of administration for numerous agents. In diabetes mellitus, the need for frequent injections to achieve ideal glycemic control remains a significant limitation for initiating and complying with insulin therapy in a large number of patients. To overcome this barrier, inhaled insulin was developed. The inhalation form of regular human insulin has been tested and administered in a large number of trials. Respiratory capacity was evaluated in patients with normal lung parenchyma in whom inhaled insulin was administered without complications. However, issues like cost, bulky device, fear for lung safety, and the small number of studies in subjects with underlying respiratory disease prevented widespread use of this new mode of delivery. In the present review, we will suggest a number of methods that could be applied in this form of administration to maximize drug absorption and fully exploit the advantages of this route of administration.

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.

Intensive care unit and lung cancer: when should we intubate?

Lung cancer still remains the leading cause of cancer death among males. Several new methodologies are being used in the everyday practise for diagnosis and staging. Novel targeted therapies are being used and others are being investigated. However; early diagnosis still remains the cornerstone for efficient treatment and disease management. Lung cancer patients requires in many situations intensive care unit (ICU) admission, either due to the necessity for supportive care until efficient disease symptom control (respiratory distress due to malignant pleural effusion) or disease adverse effect management (massive pulmonary embolism). In any case guidelines indicating the patient that has to be intubated have not yet been issued. In the current review we will present current data and finally present an algorithm based on the current published information for lung cancer patients that will probably benefit from admission to the ICU.

Efficacy and safety of erythromycin as sclerosing agent in patients with recurrent malignant pleural effusion.

Objectives:The aim of pleurodesis in malignant pleural effusions is to prevent reaccumulation of the fluid, symptoms, and avoid the need for repeated hospitalization for thoracentesis. The purpose of this study was to evaluate the efficacy and safety of erythromycin as a pleural sclerosing agent. Methods:Over a 2-year period, 34 patients with a symptomatic, recurrent, malignant pleural effusion who referred for chest tube drainage and pleurodesis were included. They had not received prior intrapleural therapy and had predicted survival of at least 1 month. All underwent pleural drainage and chemical pleurodesis with erythromycin. Complications and response to pleurodesis, according to clinical and radiographic criteria after 90 days, were recorded. Results:The overall response was 88.2%. Complete response (no reaccumulation of pleural fluid after 90 days) was observed in 27 patients (79.4%). Partial response (reaccumulation of fluid but without symptoms, not requiring drainage) was observed in 3 (8.8%). No response (symptomatic reaccumulation of fluid that required drainage) was observed in 4 (11.8%). All patients experienced pleurodynia that was treated with administration of paracetamol and/or dextropropoxyphene. Sinus tachycardia and concurrent mild systemic hypertension were observed 2 and 4 hours after pleurodesis. Both of them were attributed to pleurodynia as there was remission with analgesics. Conclusions:This study suggests that erythromycin is effective and safe as a sclerosing agent for pleurodesis in patients with recurrent malignant pleural effusions.

Anti-angiogenic-specific adverse events in patients with non-small cell lung cancer treated with nintedanib and docetaxel

OBJECTIVES LUME-Lung 1 was a randomized, placebo-controlled, Phase III trial investigating nintedanib+docetaxel versus placebo+docetaxel in patients with advanced NSCLC progressing after first-line chemotherapy. Progression-free survival was significantly improved with nintedanib+docetaxel in the overall population and overall survival was significantly improved in the pre-specified analysis of patients with adenocarcinoma. We evaluated the frequency of characteristic adverse events (AEs) commonly seen with existing anti-angiogenic agents. MATERIALS AND METHODS The incidence and intensity of AEs were evaluated in all patients who received at least one dose of study medication (N=1307) and for the two main histologies: adenocarcinoma (n=653) and squamous cell carcinoma (SCC; n=553). AEs of special interest were analyzed by category, preferred term, and worst CTCAE grade and included perforation, hypertension, bleeding, thromboembolic events, and skin disorders. RESULTS AND CONCLUSION The incidence of patients with all-grade gastrointestinal (GI) perforations was low and balanced between arms (0.5% in both) and across histologies; the incidence of non-GI perforations was 1.2% with nintedanib+docetaxel versus 0.2% with placebo+docetaxel. The incidence of some events was higher with nintedanib+docetaxel versus placebo+docetaxel; hypertension (3.5% vs 0.9%), rash (11.0% vs 8.1%), and cutaneous adverse reactions (13.0% vs 10.7%). Rash and cutaneous adverse reactions were predominantly Grade 1-2 with both treatments. The incidence of all-grade bleeding was also slightly higher in nintedanib+docetaxel-treated patients (14.1% vs 11.6%) driven by between-treatment differences in the SCC subpopulation; most events were Grade 1-2. The proportion of patients with a thromboembolic event was low and comparable between arms for all grades (5.1% vs 4.6%) and Grade ≥3 (2.1% vs 3.1%). Safety evaluation of the LUME-Lung 1 study showed that the frequency of AEs commonly associated with other anti-angiogenic agents was lower with nintedanib+docetaxel. Survival benefits from addition of nintedanib to docetaxel in patients with adenocarcinoma after first-line therapy can be achieved alongside a manageable safety profile.

Are there any differences in clinical and laboratory findings on admission between H1N1 positive and negative patients with flu-like symptoms?

BackgroundThe World Health Organization alert for the H1N1 influenza pandemic led to the implementation of certain measures regarding admission of patients with flu-like symptoms. All these instructions were adopted by the Greek National Health System. The aim of this study was to retrospectively examine the characteristics of all subjects admitted to the Unit of Infectious Diseases with symptoms indicating H1N1 infection, and to identify any differences between H1N1 positive or negative patients. Patients from the ED (emergency department) with flu-like symptoms (sore throat, cough, rhinorhea, or nasal congestion) and fever >37.5°C were admitted in the Unit of Infectious diseases and gave pharyngeal or nasopharyngeal swabs. Swabs were tested with real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR).FindingsPatients were divided into two groups. Group A comprised 33 H1N1 positive patients and Group B (control group) comprised of 27 H1N1 negative patients. The two groups did not differ in terms of patient age, co-morbidities, length of hospitalization, temperature elevation, hypoxemia, as well as renal and liver function. There were also no significant differences in severity on admission. C-reactive protein (CRP) (mean 12.8 vs. 5.74) and white blood count (WBC) (mean 10.528 vs. 7.114) were significantly higher in group B than in group A upon admission. Obesity was noted in 8 patients of Group A (mean 31.67) and 14 patients of Group B (mean 37.78). Body mass index (BMI) was lower in H1N1 positive than in H1N1 negative patients (mean 31.67 vs. 37.78, respectively; p = 0.009).ConclusionsThe majority of patients in both groups were young male adults. CRP, WBC and BMI were higher among H1N1 negative patients. Finally, clinical course of patients in both groups was mild and uneventful.

In vivo synergistic cytogenetic effects of aminophylline on lymphocyte cultures from patients with lung cancer undergoing chemotherapy

BACKGROUND The anti-cancer and cytogenetic effects of aminophylline (AM) have been demonstrated in several clinical trials. The aim of the present study was to investigate the in vivo cytogenetic effects of AM in newly diagnosed patients with small cell (SCLC) and non-small cell lung cancer (NSCLC), receiving chemotherapy for the first time. METHODS Sister chromatid exchanges (SCEs) and proliferation rate index (PRI) were evaluated in peripheral blood lymphocyte cultures from six patients with SCLC and six patients with NSCLC after the in vitro addition of AM and after the in vivo administration of AM in patients receiving chemotherapy. RESULTS The in vitro addition of AM significantly increased SCEs only in SCLC patients (p<0.001). The in vivo administration of AM after chemotherapy increased SCEs in both cancer types (SCLC: p<0.001, NSCLC: p=0.003) and this increase was synergistic, the rates of SCEs in the presence of AM were higher than the expected SCE values if the increases above background for chemotherapy and AM were independent and additive (SCLC: p<0.001, NSCLC: p=0.008). Although in both groups of patients cell division delays were observed after the combined chemotherapy plus in vivo AM treatment, the correlation between the magnitude of the SCE response and the PRI depression was not statistically significant (p>0.05). CONCLUSIONS These observations suggest that AM enhances the results of concurrently administered chemotherapy by synergistically increasing its cytogenetic effects in patients with lung cancer.

Community-acquired pneumonia due to Legionella pneumophila, the utility of PCR, and a review of the antibiotics used

Introduction There are at least 40 types of Legionella bacteria, half of which are capable of producing disease in humans. The Legionella pneumophila bacterium, the root cause of Legionnaires’ disease, causes 90% of legionellosis cases. Case presentation We describe the case of a 60-year-old woman with a history of diabetes mellitus and arterial hypertension who was admitted to our hospital with fever and symptoms of respiratory infection, diarrhea, and acute renal failure. We used real-time polymerase chain reaction (PCR) to detect L. pneumophila DNA in peripheral blood and serum samples and urine antigen from a patient with pneumonia. Legionella DNA was detected in all two sample species when first collected. Conclusion Since Legionella is a cause of 2% to 15% of all community-acquired pneumonias that require hospitalization, legionellosis should be taken into account in an atypical pulmonary infection and not be forgotten. Moreover, real-time PCR should be considered a useful diagnostic method.