Real-world Data and Economic Evaluation of Nivolumab in Previously Treated Non-small Cell Lung Cancer Greek Patients.

BACKGROUND/AIM: Nivolumab is an FDA-approved immune checkpoint inhibitor (ICI) for patients with advanced, pre-treated non-small cell lung cancer (NSCLC). However, treatment profiles and patient outcomes often differ in routine clinical practice while the financial impact of approved therapies is largely unknown. In this study, we investigated the efficacy, tolerability, and economic impact of nivolumab in real-world settings (RWS) in Greece. PATIENTS AND METHODS: Patients diagnosed with advanced pre-treated NSCLC, receiving nivolumab were recruited from October 2015 until November 2019 across 18 different clinical centers in Greece. Endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and safety. Cost analysis was conducted using a third-party public-payer perspective (National Organization for Healthcare Services Provision; EOPYY). RESULTS: A total of 346 patients, median age 66.5 years, were included. With 43.4 months median follow-up, median PFS was 7.8 months and median OS 15.8 months. The 1-year OS rate was 56.5%, 2-year OS 38.8%, and 3-year OS 27.3%. The ORR was 29.5% and DCR 58.7%, with a median response duration of 26.8 months. Patients with objective response were more likely to experience long-term survival (HR=0.14, p<0.001). Only 8.4% of patients experienced grade 3-4 adverse events. The presence of immune-related adverse events was associated with improved OS (HR=0.77, p=0.043). Nivolumab-associated economic burden accounted for €2,214.10 per cycle for each patient, mainly attributed to drug-acquisition costs. CONCLUSION: This is the first report of real-world efficacy, safety, and economic burden of nivolumab in pre-treated patients with NSCLC in Greece. Indirectly compared to clinical trials, nivolumab was associated with improved efficacy in RWS, further supporting its use in clinical practice and providing insights on clinical prognosticators. The main cost component affecting the nivolumab economic burden was drug-acquisition costs, while toxicity-associated cost was negligible.

Smoking-Induced Disturbed Sleep. A Distinct Sleep-Related Disorder Pattern?

The relationship between smoking and sleep disorders has not been investigated sufficiently yet. Many aspects, especially regarding non-obstructive sleep apnea−hypopnea (OSA)-related disorders, are still to be addressed. All adult patients who visited a tertiary sleep clinic and provided information about their smoking history were included in this cross-sectional study. In total, 4347 patients were divided into current, former and never smokers, while current and former smokers were also grouped, forming a group of ever smokers. Sleep-related characteristics, derived from questionnaires and sleep studies, were compared between those groups. Ever smokers presented with significantly greater body mass index (BMI), neck and waist circumference and with increased frequency of metabolic and cardiovascular co-morbidities compared to never smokers. They also presented significantly higher apnea−hypopnea index (AHI) compared to never smokers (34.4 ± 24.6 events/h vs. 31.7 ± 23.6 events/h, p < 0.001) and were diagnosed more frequently with severe and moderate OSA (50.3% vs. 46.9% and 26.2% vs. 24.8% respectively). Epworth sleepiness scale (ESS) (p = 0.13) did not differ between groups. Ever smokers, compared to never smokers, presented more frequent episodes of sleep talking (30.8% vs. 26.6%, p = 0.004), abnormal movements (31.1% vs. 27.7%, p = 0.021), restless sleep (59.1% vs. 51.6%, p < 0.001) and leg movements (p = 0.002) during sleep. Those were more evident in current smokers and correlated significantly with increasing AHI. These significant findings suggest the existence of a smoking-induced disturbed sleep pattern.

Electronic Cigarettes and Asthma: What Do We Know So Far?

Electronic cigarettes (EC) are a novel product, marketed as an alternative to tobacco cigarette. Its effects on human health have not been investigated widely yet, especially in specific populations such as patients with asthma. With this review, we use the existing literature in order to answer four crucial questions concerning: (1) ECs' role in the pathogenesis of asthma; (2) ECs' effects on lung function and airway inflammation in patients with asthma; (3) ECs' effects on asthma clinical characteristics in asthmatics who use it regularly; and (4) ECs' effectiveness as a smoking cessation tool in these patients. Evidence suggests that many EC compounds might contribute to the pathogenesis of asthma. Lung function seems to deteriorate by the use of EC in this population, while airway inflammation alters, with the aggravation of T-helper-type-2 (Th2) inflammation being the most prominent but not the exclusive effect. EC also seems to worsen asthma symptoms and the rate and severity of exacerbations in asthmatics who are current vapers, whilst evidence suggests that its effectiveness as a smoking cessation tool might be limited. Asthmatic patients should avoid using EC.

A multifactoral analysis of 1452 patients for smoking sensation. An outpatient lab experience.

Smoking habit is held responsible for several respiratory and metabolic diseases. Data from 1452 patients were recorded from our outpatient laboratory. The following parameters were recorded within several follow ups of our patients; smoking habit, respiratory functions, smoking cessation questionnaires, and administered drugs. The treatment administered to smokers throughout the period of inspection seems to also have a significant effect on dependence. In fact, varelicline causes a 50% reduction in smoking dependence in regards to nicotine substitutes (odds ratio: 0.48 (0.31-0,74), p=0.001) so displaying a substantial preponderance on the choice to fight smoking dependence.

Preoperative evaluation for lung cancer resection.

During the last decades lung cancer is the leading cause of death worldwide for both sexes. Even though cigarette smoking has been proved to be the main causative factor, many other agents (e.g., occupational exposure to asbestos or heavy metals, indoor exposure to radon gas radiation, particulate air pollution) have been associated with its development. Recently screening programs proved to reduce mortality among heavy-smokers although establishment of such strategies in everyday clinical practice is much more difficult and unknown if it is cost effective compared to other neoplasms (e.g., breast or prostate cancer). Adding severe comorbidities (coronary heart disease, COPD) to the above reasons as cigarette smoking is a common causative factor, we could explain the low surgical resection rates (approximately 20-30%) for lung cancer patients. Three clinical guidelines reports of different associations have been published (American College of Chest Physisians, British Thoracic Society and European Respiratory Society/European Society of Thoracic Surgery) providing detailed algorithms for preoperative assessment. In the current mini review, we will comment on the preoperative evaluation of lung cancer patients.

Airway inflammation in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is an inflammatory airway disease whose incidence and mortality increases every year. It is associated with an abnormal inflammatory response of the lung to toxic particles or gases (usually cigarette smoke). A central role in the pathophysiology has been shown to play a chronic inflammation of the airways that is expressed primarily by hypersecretion of mucus, stenosis of the smaller airways and the establishment of pulmonary emphysema. There is an increasing trend for assessing the inflammatory pattern of inflammatory airway diseases through mediators measured by noninvasive techniques. Markers in biological fluids and exhaled air have been the subject of intense evaluation over the past few years, with some of them reaching their introduction into clinical practice, while others remain as research tools. Of particular interest for the scientific community is the discovery of clinically exploitable biomarkers associated with specific phenotypes of the disease. Studying the effects of therapeutic interventions in these biomarkers may lead to targeted therapy based on phenotype and this is perhaps the future of therapeutics in COPD.

Clinical differences between H3N2 and H1N1 influenza 2012 and lower respiratory tract infection found using a statistical classification approach.

BACKGROUND: Influenza A H1N1 and H3N2 are two influenza waves that have been identified in past years. METHODS: Data from 77 inpatients from three tertiary hospitals were included and statistical analysis was performed in three different clusters. RESULTS: Thirty-four patients (44.2%) had respiratory distress upon admission, 31.2% had a smoking history or were active smokers, 37.7% manifested disease symptoms, and 7.8% were obese (body mass index >41). The mean age of patients was 51.1 years. Cough was the most common symptom observed in 77.9% of the patients, accompanied by sputum production (51.9%) and fatigue (42.9%). Hemoptysis and vomiting were rarely recorded in the patients (9.1% and 16.9%, respectively). Oseltamivir administration varied between 0 and 10 days, giving a mean value of 2.2 days. In particular, 19 patients received no drug, 31 patients received drug for only for 1 day, 19 patients for 5 days, and 8 patients from 2 to 10 days. CONCLUSION: Clusters of symptoms can be used to identify different types of influenza and disease severity. Patients with vaccination had pneumonia, whereas patients without vaccination had influenza A. Patients more than 54.5 years old had H3N2 and patients less than 54.5 years had H1N1. White blood cell count values increased from normal to elevated in H3N2 patients but still remained abnormal in lower tract infection and H1N1 patients.

Defense mechanisms of the respiratory system and aerosol production systems.

Aerosolized therapies have been used in everyday clinical practice for decades. Experimentation with different delivery systems have led to the creation of aerosolized insulin, antibiotics, gene therapy and chemotherapy. Several of these therapies are already clinically available while others are being investigated in active clinical trials. The main factors affecting the efficiency and safety of the aerosolized therapies are the production of the aerosol, distribution/deposition of the aerosol throughout the lung parenchyma, respiratory defense mechanisms and tissue/pharmaceutical molecule interactions. Current methods of aerosol production and distribution will be presented along with an overview of the respiratory defense mechanisms. In addition, methods of aerosol evaluation in conjunction with a future perspective of the potential development of aerosol therapies will be presented.

A 3D Polymer Model for Future Nutrition Design Novel Nutrition Approach for Cystic Fibrosis, Ulcerative Colitis and Crohn's Disease.

INTRODUCTION: Cystic Fibrosis (CF), Ulcerative Colitis (UC), and Crohn's Disease (CD) manifest as various, multiple symptoms from malfunctioning and/or damaged gastrointestinal tract, which plague the patients. These symptoms result from the dysfunctional expression products of the specific mutations of the genes, which either manifest upon birth (CF) or later in life in immuno-genetically susceptible individuals as inflammatory bowel diseases (IBD). They all may potentially lead to malnutrition of the patients. Since only correcting the mutated genes, may cure these diseases permanently, the works on the future safe gene therapies continue vigorously. However, provision of the necessary nutrients to the suffering patients is the requirement for an effective, supportive care at present. In this realm, we have developed a model of the diseased gastrointestinal tract aimed to guide designing and testing various nutritional therapies. MATERIALS AND METHODS: It is well known that inflammatory bowel diseases induce crypts within the patients' gastrointestinal tract. Therefore, we have bioengineered, a novel, three-dimensional model of the gastrointestinal tract to evaluate the rheology of different types of nutrients. The model was assembled out of the bio-inert polymer tube with openings leading to vials of different shapes and sizes, as the simulation of the gastrointestinal tract altered by the diseases to contain multiple crypts. RESULTS AND CONCLUSIONS: The newly developed three-dimensional model effectively simulates the structure and functions of the gastrointestinal tract of the patients with mild and severe Ulcerative Colitis, Crohn's Disease, and Cystic Fibrosis. This model should allow us to design and test different nutritional supplements, with properties complementing the pathologically altered by the diseases functionalities of the patients' gastrointestinal tracts. Therefore, it should help us to design the effective supportive therapies; thus to prevent the patients' malnutrition.

Molecular Targeted Drugs and Biomarkers in NSCLC, the Evolving Role of Individualized Therapy.

Lung cancer first line treatment has been directed from the non-specific cytotoxic doublet chemotherapy to the molecular targeted. The major limitation of the targeted therapies still remains the small number of patients positive to gene mutations. Furthermore, the differentiation between second line and maintenance therapy has not been fully clarified and differs in the clinical practice between cancer centers. The authors present a segregation between maintenance treatment and second line and present a possible definition for the term "maintenance" treatment. In addition, cancer cell evolution induces mutations and therefore either targeted therapies or non-specific chemotherapy drugs in many patients become ineffective. In the present work pathways such as epidermal growth factor, anaplastic lymphoma kinase, met proto-oncogene and PI3K are extensively presented and correlated with current chemotherapy treatment. Future, perspectives for targeted treatment are presented based on the current publications and ongoing clinical trials.

The role of second-line chemotherapy in small cell lung cancer: a retrospective analysis.

BACKGROUND: To evaluate the benefit of second-line chemotherapy with platinum-based treatment in patients with recurrent small cell lung cancer (SCLC). PATIENTS AND METHODS: A total of 535 patients continued with follow-up or best supportive care if needed, and 229 patients who progressed after the completion of first-line chemotherapy were treated with second-line chemotherapy at the time of progression. In total, 103/229 patients received paclitaxel 190 mg/m(2) and carboplatin 5.5 area under the curve while 126/229 patients received etoposide 200 mg/m(2) and carboplatin 5.5 area under the curve every 28 days. RESULTS: Patients administered second-line chemotherapy lived significantly longer, with a median survival of 422 days compared to 228 days in patients with best supportive care alone (P<0.001). Patients who received paclitaxel as second-line chemotherapy lived for an average of 462 days (95% confidence interval: 409-514), versus 405 days in the etoposide group (95% confidence interval: 371-438), which was not statistically significant (P=0.086). The overall response rate was 8% for the paclitaxel group and 6% for the etoposide group. Patients with progression of the disease in more than 3 months had significantly better survival compared with those that progressed in less than 3 months (P<0.001). CONCLUSION: Continuation with carboplatin/paclitaxel or carboplatin/etoposide as second-line chemotherapy has no significant survival impact, and it did not improve response rates.

Treatment of non-small cell lung cancer (NSCLC).

Radical surgery is the standard of care for fit stage I non-small cell lung cancer (NSCLC) patients. Adjuvant treatment should be offered only as part of an investigation trial. Stage II and IIIA adjuvant cisplatin-based chemotherapy remains the gold standard for completely resected NSCLC tumors. Additionally radiotherapy should be offered in patients with N2 lymph nodes. In advanced stage IIIB/IV or inoperable NSCLC pts, a multidisciplinary treatment should be offered consisted of 4 cycles of cisplatin-based chemotherapy plus a 3(rd) generation cytotoxic agent or a cytostatic (anti-EGFR, anti-VEGFR) drug.

Malignant pleural mesothelioma: current and future perspectives.

Mesothelioma still remains an occupational related cancer with severe outcome. It is usually diagnosed at advanced stage since it does not demonstrate early symptoms. Several efforts have been made towards removing all materials inducing mesothelioma in the work setting and new work protection measures have been applied. Although we have new targeted treatments and radical surgery as arrows in the quiver, the type of mesothelioma and early diagnosis still remain the best treatment approach. Novel treatment modalities have been explored and several others are already on the way. In the current review we will present current data for mesothelioma and future perspectives.

Malignant pleural effusion and algorithm management.

Involvement of the pleura in lung cancer is a common manifestation accompanying with reduced life expectancy. Symptoms relief and improvement of the quality of life are the primary goals of the management of malignant pleural effusion (MPE). Histological confirmation is essential for optimal patient management. Lung cancer patients, with life expectancy more than 3 months, resistant to chemotherapy should be treated with thoracentesis, intercoastal tube drainage and installation of a sclerosant agent or pleurodesis through thoracospopic procedures or placement of an indwelling pleura catheter. Talc pleurodesis (sterile asbestos-free graded, particle size >15 µm), as "poudrage" or "slurry" still remains the treatment of choice in patients with MPE resistant to chemotherapy.

Occupational exposure and lung cancer.

Lung cancer is the leading cause of cancer death for male and the second most usual cancer for women after breast cancer. Currently there are available several non-specific cytotoxic agents and several targeted agents for lung cancer therapy. However; early stage diagnosis is still unavailable and several efforts are being made towards this direction. Novel biomarkers are being investigated along with new biopsy techniques. The occupational and environmental exposure to carcinogenic agents is an everyday phenomenon. Therefore until efficient early diagnosis is available, avoidance of exposure to carcinogenic agents is necessary. In the current mini-review occupational and environmental carcinogenic agents will be presented.

Internal mouthpiece designs as a future perspective for enhanced aerosol deposition. Comparative results for aerosol chemotherapy and aerosol antibiotics.

BACKGROUND: In an effort to identify factors producing a finest mist from Jet-Nebulizers we designed 2 mouthpieces with 4 different internal designs and 1-3 compartments. MATERIALS AND METHODS: Ten different drugs previous used with their "ideal" combination of jet-nebulizer, residual-cup and loading were used. For each drug the mass median aerodynamic diameter size had been established along with their "ideal" combination. RESULTS: For both mouthpiece, drug was the most important factor due the high F-values (Flarge=251.7, p<0.001 and Fsmall=60.1, p<0.001) produced. The design affected the droplet size but only for large mouthpiece (Flarge=5.99, p=0.001, Fsmall=1.72, p=0.178). Cross designs create the smallest droplets (2.271) so differing from the other designs whose mean droplets were greater and equal ranging between 2.39 and 2.447. The number of compartments in the two devices regarding the 10 drugs was found not statistically significant (p-values 0.768 and 0.532 respectively). Interaction effects between drugs and design were statistically significant for both devices (Flarge=8.87, p<0.001, Fsmall=5.33, p<0.001). CONCLUSION: Based on our experiment we conclude that further improvement of the drugs intended for aerosol production is needed. In addition, the mouthpiece design and size play an important role in further enhancing the fine mist production and therefore further experimentation is needed.

Intratumoral chemotherapy for lung cancer: re-challenge current targeted therapies.

Strategies to enhance the already established doublet chemotherapy regimen for lung cancer have been investigated for more than 20 years. Initially, the concept was to administer chemotherapy drugs locally to the tumor site for efficient diffusion through passive transport within the tumor. Recent advances have enhanced the diffusion of pharmaceuticals through active transport by using pharmaceuticals designed to target the genome of tumors. In the present study, five patients with non-small cell lung cancer epidermal growth factor receptor (EGFR) negative stage IIIa-IV International Union Against Cancer 7 (UICC-7), and with Eastern Cooperative Oncology Group (ECOG) 2 scores were administered platinum-based doublet chemotherapy using combined intratumoral-regional and intravenous route of administration. Cisplatin analogues were injected at 0.5%-1% concentration within the tumor lesion and proven malignant lymph nodes according to pretreatment histological/cytological results and the concentration of systemic infusion was decreased to 70% of a standard protocol. This combined intravenous plus intratumoral-regional chemotherapy is used as a first line therapy on this short series of patients. To the best of our knowledge this is the first report of direct treatment of involved lymph nodes with cisplatin by endobronchial ultrasound drug delivery with a needle without any adverse effects. The initial overall survival and local response are suggestive of a better efficacy compared to established doublet cisplatin-based systemic chemotherapy in (higher) standard concentrations alone according to the UICC 7 database expected survival. An extensive search of the literature was performed to gather information of previously published literature of intratumoral chemo-drug administration and formulation for this treatment modality. Our study shows a favorable local response, more than a 50% reduction, for a massive tumor mass after administration of five sessions of intratumoral chemotherapy plus two cycles of low-dose intravenous chemotherapy according to our protocol. These encouraging results (even in very sick ECOG 2 patients with central obstructive non-small cell lung cancer having a worse prognosis and quality of life than a non-small cell lung cancer in ECOG 0 of the same tumor node metastasis [TNM]-stage without central obstruction) for a chemotherapy-only protocol that differs from conventional cisplatin-based doublet chemotherapy by the route, target site, and dose paves the way for broader applications of this technique. Finally, future perspectives of this treatment and pharmaceutical design for intratumoral administration are presented.

Measurement of exhaled alveolar nitrogen oxide in patients with lung cancer: a friend from the past still precious today.

Nitric oxide (NO) is a marker of airway inflammation and indirectly a general indicator of inflammation and oxidative stress. NO is a contributing factor in lung cancer at an early stage and also after chemotherapy treatment of lung cancer. We studied whether exhaled NO levels were altered by three cycles of chemotherapy at diagnosis and after chemotherapy, and whether, directly or indirectly, these changes were related to the course of disease. Also, a correlation of NO levels with other markers of inflammation was performed. We studied 42 patients diagnosed early: 26 men and 16 women with lung cancer. We analyzed blood tests for control of inflammatory markers, functional pulmonary tests, and alveolar exhaled NO. We recorded a decrease in exhaled NO after three cycles of chemotherapy in all patients, regardless of histological type and stage: there were 42 patients with mean 9.8 NO after three cycles (average 7.7). Also, a strong correlation appeared between NO measurements before and after chemotherapy and C-reactive protein (P < 0.05, r = 0.42, before) and (P < 0.045, r = 0.64, after). NO alveolar measurement as an indicator of airway inflammation indicates response to chemotherapy in lung cancer. Also, the inflammatory process in lung cancer was confirmed and indicated response to chemotherapy through an index that is sensitive to inflammatory disease of the airways.