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Kalliopi Domvri,1 Savvas Petanidis,2,3 Paul Zarogoulidis,4 Doxakis Anestakis,5 Charalampos Charalampidis,5 Drosos Tsavlis,6 Haidong Huang,7 Lutz Freitag,8 Wolfgang Hohenforst-Schmidt,9 Dimitris Matthaios,10 Theodora Katopodi,2 Konstantinos Porpodis3 1Pulmonary Department-Oncology Unit, “G. Papanikolaou” General Hospital, Aristotle University of Thessaloniki, Thessaloniki, 57010, Greece; 2Department of Medicine, Laboratory of Medical Biology and Genetics, Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece; 3Department of Pulmonology, I.M. Sechenov First Moscow State Medical University, Moscow, 119992, Russian Federation; 4Third Department of Surgery, “AHEPA” University Hospital, Aristotle University of Thessaloniki, Thessaloniki, 55236, Greece; 5Department of Anatomy, Medical School, University of Cyprus, Nicosia, 1678, Cyprus; 6Department of Medicine, Laboratory of Experimental Physiology, Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece; 7Department of Respiratory & Critical Care Medicine, Changhai Hospital, Second Military Medical University, Shanghai, 200433, People’s Republic of China; 8Department of Pulmonology, University Hospital Zurich, Zurich, 8091, Switzerland; 9Medical Clinic I, “Fuerth” Hospital, University of Erlangen, Fuerth, 91054, Germany; 10Oncology Department, General Hospital of Rodos, Rodos, 85133, GreeceCorrespondence: Savvas Petanidis, Department of Medicine, Laboratory of Medical Biology and Genetics, Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece, Tel +30-2310-999-205, Fax +30-2310-999-208, Email spetanid@auth.grIntroduction: Tumor immunotherapy is a key therapeutic paradigm for the treatment of several malignancies. However, in metastatic lung cancer, classical immunotherapy regimes are ineffective due to regulatory T cell (Treg)-related immunosuppression and tumor relapse.Materials: To address this issue, we designed specific biocompatible Treg-targeted nanocarriers (NCs) as a model of immune-based nanotherapy, in order to target Treg-related immunosuppression in the lung tumor microenvironment. This is achieved through the combination of Dasatinib and Epacadostat integrated into biodegradable nanosomes which can inhibit and reverse Treg-supporting immunosuppression. Flow cytometry and immunofluorescence analysis, PET/CT scan, PTT/PA imaging and the Balb/c tumor model were used to explore the anti-tumor effect of Treg-targeted NCs both in vitro and in vivo.Results: Findings reveal that NC treatment triggered substantial tumor cell apoptosis and drastically decreased tumor volume followed by downregulation of Ki-67 antigen expression, respectively. Drug circulation time was also increased as shown by biodistribution analysis accompanied by greater accumulation in lung and peripheral tissues. Intratumoral Th1 cytokines’ expression was also increased, especially TNF-A, IL-12 by 42%, and IL-6 by 18% compared to PBS treatment. In addition, the presence of mature CD80+/CD86+dendritic cells (DCs) revealed T cell enrichment and a decline in MDSC infiltration and myeloid subsets. Interestingly, a significant decline of Gr/CD11b myeloid cell population in blood and tissue samples was also observed. This immune activation can be attributed to the enhanced PTT efficiency and tumor targeting ability of the nanospheres which under near infrared (NIR) exposure can prompt highly efficient tumor ablation. We also demonstrated their therapeutic efficacy against 4T1 metastatic breast cancer model. Additionally, the photothermal therapy in combination with PD-L1 checkpoint blockade therapy exerted long-term tumor control over both primary and distant tumors.Discussion: Overall, our findings present a novel nano-enabled platform for the inhibition of Treg-dependent immunosuppression in NSCLC and provide a novel nanotherapeutic strategy for the treatment of metastatic neoplasia.Keywords: Tregs, nanosomes, metastasis, immunosuppression, T cells

Wolfgang Hohenforst-Schmidt,1 Paul Zarogoulidis,2 Michael Steinheimer,1 Thomas Schneider,1 Naim Benhassen,1 Holger Rupprecht,3 Lutz Freitag4 1Medical Clinic I, “Fuerth” Hospital, University of Erlangen, Fuerth, Germany; 2Pulmonary Department-Oncology Unit, “G Papanikolaou” General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece; 3Department of General, Vascular and Thoracical Surgery, “Fuerth” Hospital, University of Erlangen, Fuerth, 4Department of Interventional Pneumology, Ruhrlandklinik, University Hospital Essen, University of Essen-Duisburg, Essen, Germany Introduction: Stents have been used for quite some time for the treatment of benign and malignant airway stenosis. Silicon stents are preferred for benign situations, whereas metallic self-expanding stents are preferred for malignant comorbidities.Patient and methods: In general, stents can be placed in different approach directions, although in pulmonary medicine it is logical to apply only antegrade techniques – until now. A 63-year-old patient, 168 cm height and 53 kg weight on referral, suffered chronical diseases. The patient was diagnosed with a papillary thyroid carcinoma in 1989, which was treated by resection and radiotherapy. In the following years, she developed a stenosis of the esophagus. The decision to try endobronchial stenting was made upon the plan to close that fistula with a pedicled omentum majus replacement through the diaphragmal opening of the esophagus. This surgical plastic needed an abutment and a secured continuous airway replacement above the tracheostoma level. A Freitag stent (FS), 11 cm in length (110–25–40) and an inner diameter of 13 mm, was placed successfully retrograde into the trachea and completely bridged the big fistula. Unfortunately the patient passed away due to pulmonary infections after several weeks.Discussion: In this case report, a successful but unusual case of retrograde stent placement of a modified FS is presented. Keywords: stents, drug-eluting stents, cancer, benign stenosis

Christos Asteriou,1 Achilleas Lazopoulos,1 Thomas Rallis,1 Apostolos S Gogakos,1 Dimitrios Paliouras,1 Kosmas Tsakiridis,2 Athanasios Zissimopoulos,3 Drosos Tsavlis,4 Konstantinos Porpodis,4 Wolfgang Hohenforst-Schmidt,5 Ioannis Kioumis,4 John Organtzis,4 Konstantinos Zarogoulidis,4 Paul Zarogoulidis,4 Nikolaos Barbetakis1 1Department of Thoracic Surgery, Theagenio Cancer Hospital, Thessaloniki, Greece; 2Cardiothoracic Surgery Department, Saint Luke Private Hospital, Panorama, Thessaloniki, Greece; 3Nuclear Medicine Department, University General Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece; 4Pulmonary Department-Oncology Unit, “G Papanikolaou” General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece; 5Medical Clinic I, ‘‘Fuerth’’ Hospital, University of Erlangen, Fuerth, Germany Background: Video-assisted thoracic surgery (VATS) has been shown to effectively reduce postoperative pain, enhance mobilization of the patients, shorten in-hospital length of stay, and minimize postoperative morbidity rates. The aim of this prospective study is to evaluate neuroendocrine and respiratory parameters as stress markers in cancer patients who underwent lung wedge resections, using both mini muscle-sparing thoracotomy and VATS approach. Methods: The patients were randomly allocated into two groups: Group A (n=30) involved patients who were operated on using the VATS approach, while in group B (n=30), the mini muscle-sparing thoracotomy approach was used. Neuroendocrine and biological variables assessed included blood glucose levels, C-reactive protein (CRP) levels, cortisol, epinephrine, and adrenocorticotropic hormone (ACTH) levels. Arterial oxygen (Pao2) and carbon dioxide (Paco2) partial pressure were also evaluated. All parameters were measured at the following time points: 24 hours preoperatively (T1), 4 hours (T2), 24 hours (T3), 48 hours (T4), and 72 hours (T5), after the procedure. Results: Pao2 levels were significantly higher 4 and 24 hours postoperatively in group A vs group B, respectively (T2: 94.3 vs 77.9 mmHg, P=0.015, T3: 96.4 vs 88.7 mmHg, P=0.034). Blood glucose (T2: 148 vs 163 mg/dL, P=0.045, T3: 133 vs 159 mg/dL, P=0.009) and CRP ­values (T2: 1.6 vs 2.5 mg/dL, P=0.024, T3: 1.5 vs 2.1 mg/dL, P=0.044) were found increased in both groups 4 and 24 hours after the procedure. However, their levels were significantly lower in the VATS group of patients. ACTH and cortisol values were elevated immediately after the operation and became normal after 48 hours in both groups, without significant difference. Postoperative epinephrine levels measured in group A vs group B, respectively, (T2: 78.9 vs 115.6 ng/L, P=0.007, T3: 83.4 vs 122.5 ng/L, P=0.012, T4: 67.4 vs 102.6 ng/L, P=0.021). The levels were significantly higher in group B. Conclusion: This study confirmed that minimally invasive thoracic surgery, by means of VATS, significantly reduces the acute-phase response and surgical stress, while enables better postoperative oxygenation. Keywords: VATS, stress, markers, randomized controlled trial (RCT)

Wolfgang Hohenforst-Schmidt,1 Paul Zarogoulidis,2 Michael Steinheimer,1 Naim Benhassen,3 Chrysanthi Sardeli,4 Nikos Stalikas,2 Melpomeni Toitou,2 Haidong Huang5 1Sana Clinic Group Franken, Department of Cardiology/Pulmonology/Intensive Care/Nephrology, “Hof” Clinics, University of Erlangen, Hof, Germany; 2Pulmonary Department – Oncology Unit, “G Papanikolaou” General Hospital, Thessaloniki, Greece; 3Medical Clinic I, “Fuerth” Hospital, University of Erlangen, Fuerth, Germany; 4Department of Pharmacology & Clinical Pharmacology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece; 5Department of Respiratory and Critical Care Medicine, Changhai Hospital/First Affiliated Hospital of the Secondary Military Medical University, Shanghai, China Introduction: The majority of cases of lung cancer are still diagnosed at a late stage. At this stage, palliative therapeutic options including nonspecific cytotoxic drugs, targeted therapy, or immunotherapy can be utilized. In 2016, immunotherapy was approved in Europe for squamous cell carcinoma and adenocarcinoma. Moreover, afatinib was also approved as second-line therapy for squamous cell carcinoma. Case report: This article presents a case of a 76-year-old male with squamous cell carcinoma who received nab-paclitaxel as first-line therapy, and his treatment was switched to the tyrosine kinase inhibitor afatinib (40 mg) after disease progression with left lung atelectasis. After receiving afatinib for only 28 days, the atelectasis resolved. No adverse effects were observed from the afatinib therapy. Discussion: In this case, afatinib 40 mg proved to be an effective alternative treatment for an elderly patient. Treatment choice should be based on the performance status of the patient, cost-effectiveness, and drug treatment guidelines. Keywords: lung cancer, EGFR, afatinib

Dimitrios Paliouras,1 Apostolos Gogakos,1 Thomas Rallis,1 Fotios Chatzinikolaou,2 Christos Asteriou,1 Georgios Tagarakis,3 John Organtzis,4 Kosmas Tsakiridis,5 Drosos Tsavlis,4 Athanasios Zissimopoulos,6 Ioannis Kioumis,4 Wolfgang Hohenforst-Schmidt,7 Konstantinos Zarogoulidis,4 Paul Zarogoulidis,4 Nikolaos Barbetakis1 1Thoracic Surgery Department, Theagenio Cancer Hospital, 2Department of Forensic Medicine and Toxicology, Faculty of Medicine, 3Department of Cardiothoracic Surgery, AHEPA University Hospital, 4Pulmonary Department-Oncology Unit, “G. Papanikolaou” General Hospital, Aristotle University of Thessaloniki, 5Cardiothoracic Surgery Department, “Saint Luke” Private Hospital, Panorama, Thessaloniki, 6Nuclear Medicine Department, University General Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece; 7Medical Clinic I, “Fuerth” Hospital, University of Erlangen, Fuerth, Germany Background: Papillomatosis presents, most frequently, as multiple lesions of the respiratory tract, which are usually considered benign. Malignant degeneration into squamous cell carcinoma is quite common, although curative approaches vary a lot in modern literature.Case report: We report a case of a 66-year-old male patient with the coexistence of multiple squamous cell papilloma and carcinoma in the upper trachea with severe airway obstruction that was diagnosed through bronchoscopy and treated by performing an urgent tracheostomy, followed by concurrent chemotherapy and radiotherapy. There was no evidence of recurrence after a 12-month follow-up period.Conclusion: This study underlines the diagnostic and therapeutic value of bronchoscopy as well as multimodality palliative treatment in such cases. To the best of our knowledge, this is the first study to describe an immediate treatment protocol with tracheostomy and concurrent chemotherapy/radiotherapy in a patient with squamous cell tracheal papilloma and carcinoma. Keywords: papilloma, trachea, squamous cell carcinoma

Anastasios Kallianos,1 Paul Zarogoulidis,2 Fotini Ampatzoglou,2 Georgia Trakada,2,3 Elias Gialafos,4 Georgia Pitsiou,2 Athanasia Pataka,2 Lemonia Veletza,2 Konstantinos Zarogoulidis,2 Wolfgang Hohenforst-Schmidt,5 Dimitris Petridis,6 Ioannis Kioumis,2 Aggeliki Rapti112nd Pulmonary Department, Sotiria Chest Diseases Hospital, Athens, 2Pulmonary Department-Oncology Unit, “G Papanikolaou” General Hospital, Aristotle University of Thessaloniki, Thessaloniki, 3Pulmonary Laboratory, Therapeutic Clinic Alexandra Hospital, University of Athens, Athens, 4Heart Diseases Department Aiginitio Hospital, University of Athens, Athens, Greece; 5Medical Clinic I, “Fuerth” Hospital, University of Erlangen, Fuerth, Germany; 6Department of Food Technology, School of Food Technology and Nutrition, Alexander Technological Educational Institute, Thessaloniki, GreeceIntroduction: Pulmonary function tests (PFTs) do not always predict functional limitations during exercise in sarcoidosis. Cardiopulmonary exercise testing (CPET) may facilitate the recognition of exercise intolerance in these patients.Aim: As relevant data in sarcoid patients are limited, the aim of the study reported here was to assess exercise capacity impairment during a maximal CPET and to evaluate potential correlations with PFT measurements and radiological stages of the disease.Method: A total of 83 sarcoid patients consecutively referred for evaluation of exertional dyspnea over a 3-year period were studied retrospectively with PFTs, including spirometry, diffusing capacity of the lung for carbon monoxide (DLCO) and lung volumes, and CPET using standard protocol. Patients were grouped according to their radiological stages: Stage I (n=43), Stages II–III (n=31), and Stage IV (n=9).Results: Forced expiratory volume in 1 second, forced vital capacity, and total lung capacity were mildly impaired only in Stage IV (means ± standard deviation: 72.44±28.00, 71.33±26.70, and 59.78±21.72, respectively), while DLCO was mildly and moderately reduced in Stages II–III and IV (72.68±14.13 and 51.22±18.50, respectively) and differed significantly between all stages (I vs II–III: P=0.003, I vs IV: P=0.003, and II–III vs IV: P=0.009). Exercise capacity (as expressed by peak oxygen consumption

Wolfgang Hohenforst-Schmidt,1,9 Bernd Linsmeier,2 Paul Zarogoulidis,3 Lutz Freitag,4 Kaid Darwiche,4 Robert Browning,5 J Francis Turner,6 Haidong Huang,7 Qiang Li,7 Thomas Vogl,8 Konstantinos Zarogoulidis,3 Johannes Brachmann,9 Harald Rittger1 1Medical Clinic I, “Fuerth” Hospital, University of Erlangen, Fuerth, Germany; 2Department of Thoracic Surgery, Medinos Clinic Sonneberg, Sonnerberg, Germany; 3Pulmonary Department-Oncology Unit, “G. Papanikolaou” General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece; 4Department of Interventional Pneumology, Ruhrlandklinik, University Hospital Essen, University of Essen-Duisburg, Tueschener Weg, Essen, Germany; 5Pulmonary and Critical Care Medicine, Interventional Pulmonology, National Naval Medical Center, Walter Reed Army Medical Center, Bethesda, MD, USA; 6Division of Interventional Pulmonology and Medical Oncology, Cancer Treatment Centers of America, Western Regional Medical Center, Goodyear, AZ, USA; 7Department of Respiratory Diseases Shanghai Hospital, II Military University Hospital, Shanghai, People’s Republic of China; 8Department of Diagnostic and Interventional Radiology, Goethe University of Frankfurt, Frankfurt, Germany; 9II Medical Clinic, “Coburg” Hospital, University of Wuerzburg, Coburg, GermanyAbstract: Tracheomalacia or tracheobronchomalacia (TM or TBM) is a common problem especially for elderly patients often unfit for surgical techniques. Several surgical or minimally invasive techniques have already been described. Stenting is one option but in general long-time stenting is accompanied by a high complication rate. Stent removal is more difficult in case of self-expandable nitinol stents or metallic stents in general in comparison to silicone stents. The main disadvantage of silicone stents in comparison to uncovered metallic stents is migration and plugging. We compared the operation time and in particular the duration of a sufficient Dumon stent fixation with different techniques in a patient with severe posttracheotomy TM and strongly reduced mobility of the vocal cords due to Parkinson’s disease. The combined approach with simultaneous Dumon stenting and endoluminal transtracheal externalized suture under cone-beam computer tomography guidance with the Berci needle was by far the fastest approach compared to a (not performed) surgical intervention, or even purely endoluminal suturing through the rigid bronchoscope. The duration of the endoluminal transtracheal externalized suture was between 5 minutes and 9 minutes with the Berci needle; the pure endoluminal approach needed 51 minutes. The alternative of tracheobronchoplasty was refused by the patient. In general, 180 minutes for this surgical approach is calculated. The costs of the different approaches are supposed to vary widely due to the fact that in Germany 1 minute in an operation room costs on average approximately 50–60€ inclusive of taxes. In our own hospital (tertiary level), it is nearly 30€ per minute in an operation room for a surgical approach. Calculating an additional 15 minutes for patient preparation and transfer to wake-up room, therefore a total duration inside the investigation room of 30 minutes, the cost per flexible bronchoscopy is per minute on average less than 6€. Although the Dumon stenting requires a set-up with more expensive anesthesiology accompaniment, which takes longer than a flexible investigation estimated at 1 hour in an operation room, still without calculation of the costs of the materials and specialized staff that the surgical approach would consume at least 3,000€ more than a minimally invasive approach performed with the Berci needle. This difference is due to the longer time of the surgical intervention which is calculated at approximately 180 minutes in comparison to the achieved non-surgical approach of 60 minutes in the operation suite.Keywords: stent, airway, cone-beam computer tomography, Berci needle, Dumon stents, tracheobronchomalacia

Georgia Pitsiou,1 Paul Zarogoulidis,1 Dimitris Petridis,2 Ioannis Kioumis,1 Sofia Lampaki,1 John Organtzis,1 Konstantinos Porpodis,1 Antonis Papaiwannou,1 Theodora Tsiouda,3 Wolfgang Hohenforst-Schmidt,4 Stylianos Kakolyris,5 Konstantinos Syrigos,6 Haidong Huang,7 Qiang Li,7 J Francis Turner,8 Konstantinos Zarogoulidis1 1Pulmonary Department, G Papanikolaou General Hospital, Aristotle University of Thessaloniki, 2Department of Food Technology, School of Food Technology and Nutrition, Alexander Technological Educational Institute, 3Internal Medicine Department, Thegenio Anticancer Hospital, Thessaloniki, Greece; 4II Medical Department, Coburg Regional Hospital, Coburg, Germany; 5Oncology Department, Sotiria Hospital of Chest Diseases, University of Athens, Athens, 6Oncology Department, University General Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece; 7Department of Respiratory Diseases, Changhai Hospital/First Affiliated Hospital of the Second Military Medical University, Shanghai, People’s Republic of China; 8Division of Interventional Pulmonology and Medical Oncology, Cancer Treatment Centers of America, Western Regional Medical Center, Goodyear, AZ, USA Abstract: Pulmonary hypertension is a disease with severe consequences for the human body. There are several diseases and situations that induce pulmonary hypertension and are usually underdiagnosed. Treatments include conventional medical therapies and oral, inhaled, intravenous, and subcutaneous options. Depending on its severity, heart or lung transplant may also be an option. A possible novel treatment could be tyrosine kinase inhibitors. We conducted experiments with three jet nebulizers and three ultrasound nebulizers with erlotinib, gefitinib, and imatinib. Different residual cup designs and residual cup loadings were used in order to identify the best combination to produce droplets of less than 5 µm in mass median aerodynamic diameter. We found that gefitinib could not be transformed into a powder, so conversion to an aerosol form was not possible. Our experiments indicated that imatinib is superior to erlotinib with regard to small droplet size formation using both inhaled technologies (1.37 µm

Paul Zarogoulidis,1 Ioannis Kioumis,1 Sofia Lampaki,1 John Organtzis,1 Konstantinos Porpodis,1 Dionysios Spyratos,1 Georgia Pitsiou,1 Dimitris Petridis,2 Athanasia Pataka,1 Haidong Huang,3 Qiang Li,3 Lonny Yarmus,4 Wolfgang Hohenforst-Schmidt,5 Nikolaos Pezirkianidis,6 Konstantinos Zarogoulidis1 1Pulmonary Department-Oncology Unit, “G Papanikolaou” General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece; 2Department of Food Technology, School of Food Technology and Nutrition, Alexander Technological Educational Institute, Thessaloniki, Greece; 3Department of Respiratory Diseases, Shanghai Hospital, II Military University Hospital, Shanghai, People’s Republic of China; 4Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA; 5II Medical Department, “Coburg” Regional Hospital, Coburg, Germany; 6Surgery Department, Private Cabinet, Serres, Greece Background: At this time, several antibiotics have been investigated as possibilities for aerosol administration, but local therapy has been found to be more efficient in several diseases. Materials and methods: The drugs linezolid (Zyvox), vancomycin (Voncon), and daptomycin (Cubicin) were tested with three jet nebulizers with seven different residual cups and different loadings. Moreover, three ultrasound nebulizers were again tested with these drugs, with different loadings and mouthpiece attachments. Results: When drugs are combined with particular cup designs, they significantly lower the droplet size to 1.60 and 1.80 µm, which represents the best combination of Zyvox and cup G and Cubicin and cup D, respectively. Cup design D is suggested as the most effective cup for lowering the droplet size (2.30 µm) when considering a higher loading level (8 mL). Conclusion: Modification of current drugs from dry powder to solution is possible, and the residual cup design plays the most important role in droplet size production when the nebulization systems have the same properties. Keywords: vancomycin, linezolid, daptomycin, aerosol, jet nebulizers, ultrasound nebulizers

Wolfgang Hohenforst-Schmidt,1 Paul Zarogoulidis,2 Filiz Oezkan,3 Christian Mahnkopf,4 Gerhard Grabenbauer,5 Alfons Kreczy,6 Rolf Bartunek,7 Kaid Darwiche,3 Lutz Freitag,3 Qiang Li,8 Haidong Huang,8 Thomas Vogl,9 Patrick LePilvert,10 Theodora Tsiouda,11 Kosmas Tsakiridis,12 Konstantinos Zarogoulidis,2 Johannes Brachmann11II Medical Clinic, Coburg Clinic, University of Würzburg, Coburg, Germany; 2Pulmonary Department-Oncology Unit, G Papanikolaou General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece; 3Department of Interventional Pneumology, Ruhrlandklinik, West German Lung Center, University Hospital, University of Duisburg-Essen, Essen, Germany; 4II Medizinische Klinik, Klinik für Kardiologie, Angiologie, Pneumologie, Klinikum Coburg, 5Department of Radiotherapy, 6Department of Pathology, Cytology and Molecular Diagnostics, 7Institute of Diagnostic and Interventional Radiology, Coburg Clinic, University of Wüerzburg, Coburg, Germany; 8Department of Respiratory Diseases, Changhai Hospital/First Affiliated Hospital of the Second Military Medical University, Shanghai, People’s Republic of China; 9Department of Diagnostic and Interventional Radiology, Goethe University of Frankfurt, Frankfurt, Germany; 10Interventional Drug Delivery Systems and Strategies (ID2S2), Medical Cryogenics, Lakeland Court Jupiter, FL, USA; 11Internal Medicine Unit, Theagenio Cancer Hospital, Thessaloniki, 12Cardiothoracic Surgery Department, Saint Luke Private Hospital, Thessaloniki, GreeceAbstract: Vasointestinal peptide metabolism plays a key physiological role in multimodular levels of vasodilatory, smooth muscle cell proliferative, parenchymal, and inflammatory lung reactions. In animal studies, vasointestinal peptide relaxes isolated pulmonary arterial segments from several mammalian species in vitro and neutralizes the pulmonary vasoconstrictor effect of endothelin. In some animal models, it reduces pulmonary vascular resistance in vivo and in monocrotaline-induced pulmonary hypertension. A 58-year-old woman presented with dyspnea and mild edema of the lower extremities. A bronchoscopy was performed without any suspicious findings suggesting a central tumor or other infiltrative disease. Endobronchial ultrasound revealed enlarged pulmonary arteries containing thrombi, a few enlarged lymph nodes, and enlarged mediastinal tissue anatomy with suspicion for mediastinal infiltration of a malignant process. We estimated that less than 10% of the peripheral vascular bed of the lung was involved in direct consolidated fibrosis as demonstrated in the left upper lobe apex. Further, direct involvement of fibrosis around the main stems of the pulmonary arteries was assumed to be low from positron emission tomography and magnetic resonance imaging scans. Assuming a positive influence of low-dose radiation, it was not expected that this could have reduced pulmonary vascular resistance by over two thirds of the initial result. However; it was noted that this patient had idiopathic pulmonary arterial hypertension mixed with “acute” (mediastinal) fibrosis which could have contributed to the unexpected success of reduction of pulmonary vascular resistance. To the best of our knowledge, this is the first report of successful treatment of idiopathic pulmonary arterial hypertension, probably as a result of low-dose radiation to the pulmonary arterial main stems. The patient continues to have no specific complaints concerning her idiopathic pulmonary arterial hypertension.Keywords: radiation, pulmonary hypertension, denervatio

Dimitris Petridis,1 Paul Zarogoulidis,2,3 Anastasios Kallianos,4 Ioannis Kioumis,2 Georgia Trakada,5 Dionysios Spyratos,2 Antonis Papaiwannou,2 Konstantinos Porpodis,2 Haidong Huang,6 Aggeliki Rapti,4 Wolfgang Hohenforst-Schmidt,7 Konstantinos Zarogoulidis2 1Department of Food Technology, Alexander Technological Educational Institute of Thessaloniki, Thessaloniki, Greece; 2Pulmonary Department, "G Papanikolaou" General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece; 3Department of Interventional Pneumology, Ruhrlandklinik, West German Lung Center, University Hospital, University Duisburg-Essen, Essen, Germany; 42nd Pulmonary Department, "Sotiria" Hospital for Chest Diseases, Athens, Greece; 5Department of Clinical Therapeutics, Division of Pneumonology, Medical School, National University of Athens, Athens, Greece; 6Department of Respiratory Diseases, Changhai Hospital/First Affiliated Hospital of the Second Military Medical University, Shanghai, People's Republic of China; 7II Medical Department, "Coburg" Regional Clinic, University of Wüerzburg, Coburg, Germany 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. Keywords: H3N2, H1N1, influenza outbreak, respiratory infection, vaccination

Kaid Darwiche,1 Paul Zarogoulidis,1,2 Leslie Krauss,3 Filiz Oezkan,1 Robert Fred Henry Walter,1,4 Robert Werner,4 Dirk Theegarten,4 Leonidas Sakkas,5 Antonios Sakkas,5 Wolfgang Hohenforst-Scmidt,6 Konstantinos Zarogoulidis,1 Lutz Freitag11Department of Interventional Pneumology, Ruhrlandklinik, West German Lung Center, University Hospital, University Duisburg-Essen, Essen, Germany; 2Pulmonary Department, Oncology Unit, G Papanikolaou General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece; 3CytoViva, Inc, Auburn, AL, USA; 4Institute of Pathology and Neuropathology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany; 5Pathology Department, G Papanikolaou General Hospital, Thessaloniki, Greece; 6II Medical Department, Coburg Regional Clinic, University of Wuerzburg, Coburg, GermanyBackground: There are currently many techniques and devices available for the diagnosis of lung cancer. However, rapid on-site diagnosis is essential for early-stage lung cancer, and in the current work we investigated a new diagnostic illumination nanotechnology.Methods: Tissue samples were obtained from lymph nodes, cancerous tissue, and abnormal intrapulmonary lesions at our interventional pulmonary suites. The following diagnostic techniques were used to obtain the samples: endobronchial ultrasound bronchoscopy; flexible bronchoscopy; and rigid bronchoscopy. Flexible and rigid forceps were used because several of the patients were intubated using a rigid bronchoscope. In total, 30 tissue specimens from 30 patients were prepared. CytoViva® illumination nanotechnology was subsequently applied to each of the biopsy tissue slides.Results: A spectral library was created for adenocarcinoma, epidermal growth factor receptor mutation-positive adenocarcinoma, squamous cell carcinoma, usual interstitial pneumonitis, nonspecific interstitial pneumonitis, typical carcinoid tumor, sarcoidosis, idiopathic pulmonary fibrosis, small cell neuroendocrine carcinoma, thymoma, epithelioid and sarcomatoid mesothelioma, cryptogenic organizing pneumonia, malt cell lymphoma, and Wegener's granulomatosis.Conclusion: The CytoViva software, once it had created a specific spectral library for each entity, was able to identify the same disease again in subsequent paired sets of slides of the same disease. Further evaluation of this technique could make this illumination nanotechnology an efficient rapid on-site diagnostic tool.Keywords: lung cancer, endobronchial ultrasound, spectral imaging, diagnosis

Paul Zarogoulidis,1,2 Ioannis Kioumis,1 Konstantinos Porpodis,1 Dionysios Spyratos,1 Kosmas Tsakiridis,3 Haidong Huang,4 Qiang Li,4 J Francis Turner,5 Robert Browning,6 Wolfgang Hohenforst-Schmidt,7 Konstantinos Zarogoulidis1 1Pulmonary 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; 3Cardiothoracic Surgery Department, Saint Luke Private Hospital of Health Excellence, Thessaloniki, Greece; 4Department of Respiratory Diseases, Shanghai Hospital/First Affiliated Hospital of the Second Military Medical University, Shanghai, People’s Republic of China; 5Pulmonary Medicine, University of Nevada School of Medicine, National Supercomputing Center for Energy and the Environment University of Nevada, Las Vegas, NV, USA; 6Pulmonary and Critical Care Medicine, Interventional Pulmonology, National Naval Medical Center, Walter Reed Army Medical Center, Bethesda, MD, USA; 7II Medical Department, Regional Clinic of Coburg, University of Wuerzburg, Coburg, Germany Abstract: Currently almost all antibiotics are administered by the intravenous route. Since several systems and situations require more efficient methods of administration, investigation and experimentation in drug design has produced local treatment modalities. Administration of antibiotics in aerosol form is one of the treatment methods of increasing interest. As the field of drug nanotechnology grows, new molecules have been produced and combined with aerosol production systems. In the current review, we discuss the efficiency of aerosol antibiotic studies along with aerosol production systems. The different parts of the aerosol antibiotic methodology are presented. Additionally, information regarding the drug molecules used is presented and future applications of this method are discussed. Keywords: antibiotics, aerosol, nebulizers

Haidong Huang,1 Konstantinos Porpodis,2 Paul Zarogoulidis,2,3 Kalliopi Domvri,2 Paschalina Giouleka,2 Antonis Papaiwannou,2 Stella Primikyri,2 Efi Mylonaki,2 Dionysis Spyratos,2 Wolfgang Hohenforst-Schmidt,4 Ioannis Kioumis,2 Konstantinos Zarogoulidis2 1Department of Respiratory Diseases, Changhai Hospital/First Affiliated Hospital of the Second Military Medical University, Shanghai, People’s Republic of China; 2Pulmonary Department, “G Papanikolaou” General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece; 3Department of Interventional Pneumology, Ruhrlandklinik, West German Lung Center, University Hospital, University Duisburg–Essen, Essen, Germany; 4II Medical Clinic, “Coburg” Hospital, University of Würzburg, Coburg, Germany Abstract: Humans have the ability to synthesize vitamin D during the action of ultraviolet (UV) radiation upon the skin. Apart from the regulation of calcium and phosphate metabolism, another critical role for vitamin D in immunity and respiratory health has been revealed, since vitamin D receptors have also been found in other body cells. The term “vitamin D insufficiency” has been used to describe low levels of serum 25-hydroxyvitamin D that may be associated with a wide range of pulmonary diseases, including viral and bacterial respiratory infection, asthma, chronic obstructive pulmonary disease, and cancer. This review focuses on the controversial relationship between vitamin D and asthma. Also, it has been found that different gene polymorphisms of the vitamin D receptor have variable associations with asthma. Other studies investigated the vitamin D receptor signaling pathway in vitro or in experimental animal models and showed either a beneficial or a negative effect of vitamin D in asthma. Furthermore, a range of epidemiological studies has also suggested that vitamin D insufficiency is associated with low lung function. In the future, clinical trials in different asthmatic groups, such as infants, children of school age, and ethnic minorities are needed to establish the role of vitamin D supplementation to prevent and/or treat asthma. Keywords: vitamin D, asthma, immunomodulation, anti-inflammation

Wolfgang Hohenforst-Schmidt,1 Paul Zarogoulidis,2,3 Kaid Darwiche,3 Thomas Vogl,4 Eugene P Goldberg,5 Haidong Huang,6 Michael Simoff,7 Qiang Li,6 Robert Browning,8 J Francis Turner,9 Patrick Le Pivert,10 Dionysios Spyratos,2 Konstantinos Zarogoulidis,2 Seyhan I Celikoglu,11 Firuz Celikoglu,11 Johannes Brachmann11II Medical Clinic, Coburg Hospital, University of Wuerzburg, Coburg, Germany; 2Pulmonary Department-Oncology Unit, G Papanikolaou General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece; 3Department of Interventional Pneumology, Ruhrlandklinik, West German Lung Center, University Hospital, University Duisburg-Essen, Essen, Germany; 4Department of Diagnostic and Interventional Radiology, Goethe University of Frankfurt, Frankfurt, Germany; 5Biomaterials Science and Engineering, Department of Materials Science and Engineering, University of Florida, FL, USA; 6Department of Respiratory Diseases, Changhai Hospital/First Affiliated Hospital of the Second Military Medical University, Shanghai, People's Republic of China; 7Bronchoscopy and Interventional Pulmonology, Pulmonary and Critical Care Medicine, Henry Ford Hospital, Wayne State University, School of Medicine, MI, USA; 8Pulmonary and Critical Care Medicine, Interventional Pulmonology, National Naval Medical Center, Walter Reed Army Medical Center, Bethesda, USA; 9Pulmonary Medicine, University of Nevada School of Medicine, National Supercomputing Center for Energy and the Environment University of Nevada, Las Vegas, USA; 10Interventional Drug Delivery Systems and Strategies (ID2S2), Medical Cryogenics, Jupiter, FL, USA; 11Pulmonary Department, Cerrahpasa Medical Faculty, University of Istanbul, Istanbul, TurkeyAbstract: 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.Keywords: cisplatin, lymph nodes, chemotherapy, intratumoral, lung cancer

Wolfgang Hohenforst-Schmidt,1 Arndt Petermann,2 Aikaterini Visouli,3 Paul Zarogoulidis,4 Kaid Darwiche,5 Ioanna Kougioumtzi,6 Kosmas Tsakiridis,3 Nikolaos Machairiotis,6 Markus Ketteler,2 Konstantinos Zarogoulidis,4 Johannes Brachmann11II Medical Clinic, Coburg Clinic, University of Wuerzburg, Coburg, Germany; 2Division of Nephrology, Coburg Clinic, University of Wuerzburg, Coburg, Germany; 3Cardiothoracic Surgery Department, “Saint Luke” Private Hospital, Thessaloniki, Greece; 4Pulmonary Department, “G Papanikolaou” General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece; 5Department of Interventional Pneumology, Ruhrlandklinik, West German Lung Center, University Hospital, University of Duisburg-Essen, Essen, Germany; 6Surgery Department (National Health System), University General Hospital of Alexandroupolis, Alexandroupolis, GreeceAbstract: Extracorporeal membrane oxygenation (ECMO) is increasingly applied in adults with acute refractory respiratory failure that is deemed reversible. Bleeding is the most frequent complication during ECMO support. Severe pre-existing bleeding has been considered a contraindication to ECMO application. Nevertheless, there are cases of successful ECMO application in patients with multiple trauma and hemorrhagic shock or head trauma and intracranial hemorrhage. ECMO has proved to be life-saving in several cases of life-threatening respiratory failure associated with pulmonary hemorrhage of various causes, including granulomatosis with polyangiitis (Wegener’s disease). We successfully applied ECMO in a 65-year-old woman with acute life-threatening respiratory failure due to diffuse massive pulmonary hemorrhage secondary to granulomatosis with polyangiitis, manifested as severe pulmonary-renal syndrome. ECMO sustained life and allowed disease control, together with plasmapheresis, cyclophosphamide, corticoids, and renal replacement therapy. The patient was successfully weaned from ECMO, extubated, and discharged home. She remains alive on dialysis at 17 months follow-up.Keywords: ECMO, ARDS, polyangiitis, granulomatosis, hemorrhage

Wolfgang Hohenforst-Schmidt,1 Juergen Hornig,2 Norbert Friedel,3 Paul Zarogoulidis,1,4 Konstantinos Zarogoulidis,4 Johannes Brachmann11II Medical Clinic, Coburg Clinic, University of Würzburg, Coburg, Germany; 2Department of Cardiology, Bayreuth Clinic, University of Erlangen, Bayreuth, Germany; 3Department of Cardiac Surgery, “Bayreuth Clinic”, University of Erlangen, Bayreuth, Germany; 4Pulmonary Department, G Papanikolaou, General Hospital, Aristotle University of Thessaloniki, Thessaloniki, GreeceAbstract: Pulmonary hypertension is defined by 25 mmHg pressure at rest, and 35 mmHg pressure at exercise, in the pulmonary arteries. Hypertension either primary or secondary. The exact prevalence of all types of pulmonary hypertension is not yet known. We present a case of a 58-year-old female patient suffering from CREST syndrome, Raynaud’s syndrome, esophageal motility impairment, and severe pulmonary hypertension who had previously obtained a specially developed implantable pump, named Lenus Pro®, to facilitate continuous parenteral treatment of pulmonary arterial hypertension with treprostinil. Treprostinil is a prostanoid derivative with very stable physiochemical properties which allows subcutaneous treatment of pulmonary arterial hypertension in the outpatient. Treprostinil is normally dosed individually in a range of 0.6 to 50 ng/kg/minute. In the underlying case, a dose of more than 100 mg given over 1 minute is equivalent to a 1000 fold overdose. The patient’s critical condition required installment of a central venous access, full monitoring, sedation, oxygen nasal tube, fluid balance, and parenteral nutrition. The patient could be hemodynamically stabilized within 24 hours after the overdose. After 6 days of recovery, the patient left the hospital with no remaining health impairment.Keywords: pulmonary hypertension, ICU, overdose, treprostinil, Raynaud’s syndrome, CREST syndrome

Wolfgang Hohenforst-Schmidt,1 Andreas Riedel,1 Paul Zarogoulidis,2,3 Christian Franke,4 Andreas Gschwendtner,5 Haidong Huang,6 Nikolaos Machairiotis,2 Vasiliki Dramba,2 Konstantinos Zarogoulidis,2 Johnannes Brachmann11II Medical Clinic, Coburg Clinic, University of Würzburg, Coburg, Germany; 2Pulmonary Department, G Papanikolaou General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece; 3Pulmonary Department–Interventional Unit, University of Duisburg-Essen, Essen, Germany; 4Pulmonary Department, Sonneberg, Germany; 5Institute for Pathology, Coburg Clinic, University of Würzburg, Coburg, Germany; 6Department of Respiratory Diseases, Changhai Hospital, Second Military Medical University, Shanghai, ChinaAbstract: Pulmonary eosinophilia comprises a heterogeneous group of diseases that are defined by eosinophilia in pulmonary infiltrates or in tissue. Drugs can cause almost all histopathologic patterns of interstitial pneumonias, such as cellular and fibrotic nonspecific interstitial pneumonia, pulmonary infiltrates and eosinophilia, organizing pneumonia, lymphocytic interstitial pneumonia, desquamative interstitial pneumonia, a pulmonary granulomatosis-like reaction, and a usual interstitial pneumonia-like pattern. We present a very rare case of chronic eosinophilic pneumonia due to radiographic contrast infusion diagnosed with video-assisted thoracoscopy. The patient after 1 year is still under corticosteroid treatment with the disease stabilized.Keywords: interstitial lung disease, radiographic contrast, orphan disease

Paul Zarogoulidis1, Ekaterini Chatzaki2, Konstantinos Porpodis1, Kalliopi Domvri1, Wolfgang Hohenforst-Schmidt3, Eugene P Goldberg4, Nikos Karamanos5, Konstantinos Zarogoulidis11Pulmonary Department, "G Papanikolaou" General Hospital, Aristotle University of Thessaloniki, Greece; 2Pharmacology Laboratory, Medical School, Democritus University of Thrace, Alexandroupolis, Greece; 3II Medical Clinic, Hospital Coburg, University of Wurzburg, Coburg, Germany; 4Biomaterials Science and Engineering, Department of Materials Science and Engineering, University of Florida, FL; 5Biochemistry Laboratory, Department of Chemistry, University of Patra, GreeceAbstract: Regional chemotherapy was first used for lung cancer 30 years ago. Since then, new methods of drug delivery and pharmaceuticals have been investigated in vitro, and in animals and humans. An extensive review of drug delivery systems, pharmaceuticals, patient monitoring, methods of enhancing inhaled drug deposition, safety and efficacy, and also additional applications of inhaled chemotherapy and its advantages and disadvantages are presented. Regional chemotherapy to the lung parenchyma for lung cancer is feasible and efficient. Safety depends on the chemotherapy agent delivered to the lungs and is dose-dependent and time-dependent. Further evaluation is needed to provide data regarding early lung cancer stages, and whether regional chemotherapy can be used as neoadjuvant or adjuvant treatment. Finally, inhaled chemotherapy could one day be administered at home with fewer systemic adverse effects.Keywords: inhaled chemotherapy, carriers, transducers

Zarogoulidis P, Kioumis I, Porpodis K, Spyratos D, Tsakiridis K, Huang H, Li Q, Turner JF, Browning R, Hohenforst-Schmidt W, Zarogoulidis K. Drug Des Devel Ther. 2013;7:1115–1134.Throughout the paper Microsprayer should have been cited as MicroSprayer® Aerosolizer (Penn-Century, Inc., Wyndmoor, PA, USA).On page 1127 and 1128 the paragraph on Azithromycin should not have been included in the paper.Read the original article.