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Background: The emergence of novel antiprogrammed cell death protein-1 (PD-1) inhibitors in non-small cell lung cancers (NSCLC) has revolutionized the therapeutic landscape of this disease. Although overall survival (OS) has improved in the first- and second-line therapy settings for advanced NSCLC, the benefit is not universal. In a climate of global scrutiny for healthcare costs and potential for toxicities related to immunotherapy, appropriate patient selection is crucial. The aim of this study was to evaluate potential prognostic and predictive biomarkers interferon-gamma (IFN-γ), tumour necrosis factor-alpha (TNF-α) and a panel of interleukins (ILs) in the peripheral blood, and assess any correlation with response to anti-PD-1 inhibition, progression-free survival and OS in NSCLC patients. Methods: We prospectively studied 26 NSCLC patients that received immunotherapy (either pembrolizumab or nivolumab). IFN-γ, TNF-α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10 and IL-12 were analyzed by flow cytometry at the time of diagnosis and at 3 months after initiation of anti-PD-1 inhibition. Results: Increased cytokine values (IFN-γ, TNF-α, IL-1β, IL-2, IL-4, IL-6 and IL-8) at the time of diagnosis and at 3 months after initiation of treatment were significantly correlated with improved response to immunotherapy and prolonged OS. There was no correlation between cytokine levels and programmed cell death ligand-1 (PD-L1) expression. Conclusions: Increased IFN-γ, TNF-α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10 and IL-12 levels resulted in better response to NSCLC anti-PD-1 inhibition and longer survival, and this could potentially play an important role in selecting patients that would benefit from anti-PD-1 inhibitors.

Background: Several preclinical and clinical studies have demonstrated that cyclooxygenase-2 (Cox-2) inhibitors have anti-tumor activity in the treatment of non-small-cell lung cancer. However, there is little data on the use of Cox2 inhibitors in patients with small cell carcinoma (SCLC). The aim of this prospective study was to evaluate the role of Rofecoxib , a selective Cox2 inhibitor in combination with conventional chemotherapy in SCLC treatment. Methods: Patients with extensive small-cell lung cancer and median age 62±11.7 years, were randomized to receive oral rofecoxib 12.5 mg twice daily every day plus cisplatin 25 mg/m(2) and etoposide 100 mg/m2 or chemotherapy alone. Both regimens were repeated every 4 weeks until disease progression. Primary end points of our study were survival and time to progression Results: 98 patients were enrolled. 44 pts were randomly assigned chemotherapy plus rofecoxib and 54 chemotherapy alone. Median OS was 14 months (95% CI, 11.5 to 16 mo) for the cox-2 arm and 7.7 months (95% CI, 6 to 9.4) for chemotherapy(control) arm, which is statistically significant (p= 0.001). Median time to progression was 9.2 months (95% CI, 7.4 to 11) for the cox-2 arm and 5 months (95% CI, 3.7 to 6.5) for the control arm (p= 0.004). The response rates were 48.0 and 29.6%, respectively. Toxicity was mild, and no increase in cardiovascular events was observed. Conclusion: In advanced SCLC, rofecoxib in combination with chemotherapy improves survival , but the results must be interpreted with caution due to the limited number of patients.

Konstantinos Zarogoulidis,1 Efimia Boutsikou,1 Paul Zarogoulidis,1,2 Kaid Darwiche,2 Lutz Freitag,2 Konstantinos Porpodis,1 Dimitrios Latsios,1 Theodoros Kontakiotis,1 Haidong Huang,3,4 Qiang Li,4 Wolfgang Hohenforst-Schmidt,5 Maria Kipourou,1 J Francis Turner,6 Dionysios Spyratos11Pulmonary Department, “G Papanikolaou” General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece; 2Department of Interventional Pneumology, Ruhrlandklinik, West German Lung Center, University Hospital, University Duisburg-Essen, Essen, Germany; 3Bronchoscopy and Interventional Pulmonology, Pulmonary and Critical Care Medicine, Henry Ford Hospital, Wayne State University, School of Medicine, Detroit, MI, USA; 4Department of Respiratory Diseases, Changhai Hospital/First Affiliated Hospital of the Second Military Medical University, Shanghai, People’s Republic of China; 5II Medical Clinic, “Coburg” Regional Hospital, University of Wuerzburg, Coburg, Germany; 6Pulmonary Medicine, University of Nevada School of Medicine, National Supercomputing Center for Energy and the Environment University of Nevada, Las Vegas, NV, USABackground: 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/m2 and carboplatin 5.5 area under the curve while 126/229 patients received etoposide 200 mg/m2 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

Konstantinos Zarogoulidis,1 Eftimios Ziogas,1 Efimia Boutsikou,1 Paul Zarogoulidis,1,2 Kaid Darwiche,2 Theodoros Kontakiotis,1 Kosmas Tsakiridis,3 Konstantinos Porpodis,1 Dimitrios Latsios,1 Olga Chatzizisi,4 Ilias Karapantzos,5 Qiang Li,6 Georgios Kyriazis21Pulmonary Department, "G Papanikolaou" General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece; 2Department of Interventional Pneumology, Ruhrlandklinik, West German Lung Center, University Hospital, University Duisburg-Essen, Essen, Germany; 3Thoracic Surgery Department, "Saint Luke" Private Hospital, Panorama, Thessaloniki, Greece; 4Immunology Department, "G Papanikolaou" General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece; 5Ear, Nose and Throat Department, "Saint Luke" Private Hospital, Panorama, Thessaloniki, Greece; 6Respiratory Diseases Department, Shanghai hospital, Second Military Medical University, Shanghai, People's Republic of ChinaPurpose: To evaluate the effect of immunotherapy on response, survival, and certain immune markers in patients with small cell lung cancer (SCLC) who are receiving chemotherapy.Patients and methods: Patients with SCLC (n = 164) were assigned to receive either chemotherapy alone (group A) or a combination of chemotherapy and immunotherapy as follows: interferon α (IFN-α; 3 million IU) 3 times per week (group B); IFN-γ (3 million IU) 3 times per week (group C); and IFN-α and IFN-γ (1.5 million IU of each) 3 times per week (group D). Chemotherapy was the same for all groups and consisted of eight cycles with carboplatin 5.5 mg/m2 intravenously on day 1, ifosfamide 3.5 mg/m2 intravenously on day 1, and etoposide 200 mg/m2 total dose taken orally on days 1 through 3, every 28 days. Patients completing chemotherapy were restaged, and those who were found to have limited disease received primary site and prophylactic cranial irradiation. Immunotherapy was continued throughout these treatments and during the follow-up period. Blood was taken before each course of chemotherapy and during follow-up to measure CD3+ lymphocytes, CD3+CD4+ lymphocytes, CD3+CD8+ lymphocytes, natural killer cells, and natural killer T cells.Results: Differences in response and survival were not significantly different when all patients were considered. However, among patients with limited disease, Kaplan–Meier analysis disclosed a survival benefit for group B (P < 0.05). The analysis of immunologic measurements revealed that the improvement of immune markers was always accompanied by clinical improvement, whereas deterioration of all markers was accompanied by disease progression (result not statistically significant except for group C; P < 0.05).Conclusion: Among cytokines used in the study, only IFN-α seems to confer a survival benefit to patients with SCLC with limited disease. However, immunotherapy remains a challenge in the treatment of lung neoplasms and should be further explored.Keywords: interferon, SCLC, lung cancer, immunomodifiers

Konstantinos Zarogoulidis,1 Dimitrios Latsios,1 Konstantinos Porpodis,1 Paul Zarogoulidis,1,2 Kaid Darwiche,2 Nick Antoniou,1 Wolfgang Hohenforst-Schmidt,3 Ellada Eleftheriadou,1 Efimia Boutsikou,1 Theodoros Kontakiotis11Pulmonary Department-Oncology Unit, “G Papanikolaou” General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece; 2University Pulmonary Department- Interventional Unit, Ruhrlandklinik, University, University of Duisburg-Essen, Essen, Germany; 3II Medical Clinic, Hospital of Coburg, University of Wuerzburg, Coburg, GermanyBackground: Many patients with limited disease (LD) behave similarly to those with extensive disease (ED) from a prognostic point of view. On the other hand, a proportion of patients with ED small-cell lung cancer (SCLC) behave similarly to those with LD.Patients and methods: In this retrospective study analysis, 764 patients with proven SCLC were included and managed with the same therapeutic protocols. Of these patients, 278 (36.4%) had LD, while 486 (63.6%) had ED.Results: No statistically significant difference was observed for survival for IA and IB disease stages (P = 0.254) and between IIA and IIB stages (P = 0.256) according to the new tumor, node, metastasis (TNM) staging classification classification. In addition, no statistical significant difference was observed for survival between patients with (IIA + IIB) and IIIA (P = 0.951), (IIA + IIIA, P = 0.658), and (IIB + IIIA, P = 0.573) stages. Statistical significant difference was observed for survival among the LD SCLC patients with (IA + IB), (IIA + IIB + IIIA), and IIIB stages (P < 0.001). Similarly, statistical significance was observed for ED SCLC patients with (IIA + IIB + IIIA), IIIB, and IV stages (P < 0.001).Conclusions: Although stratification of SCLC patients in LD and ED is generally satisfactory, the TNM staging system is recommended for more detailed prognostic information and treatment evaluation in these patients.Keywords: small-cell lung cancer, staging, lung cancer