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Luca Gallelli,1,* Daniela Falcone,1,* Roberto Cannataro,2 Mariarita Perri,2 Raffaele Serra,3 Girolamo Pelaia,3 Rosario Maselli,3 Rocco Savino,1 Giuseppe Spaziano,4 Bruno D’Agostino4 1Department of Health Science, University of Catanzaro, Catanzaro, 2Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, 3Department of Medical and Surgical Sciences, University of Catanzaro, Catanzaro, 4Department of Experimental Medicine, School of Medicine, Section of Pharmacology, Second University of Naples, Naples, Italy *These authors contributed equally to this work Abstract: Theophylline is a natural compound present in tea. Because of its property to relax smooth muscle it is used in pharmacology for the treatment of airway diseases (ie, chronic obstructive pulmonary disease, asthma). However, this effect on smooth muscle is dose dependent and it is related to the development of side effects. Recently, an increasing body of evidence suggests that theophylline, at low concentrations, also has anti-inflammatory effects related to the activation of histone deacetylases. In this study, we evaluated the effects of theophylline alone and in combination with corticosteroids on human bronchial epithelial cells under inflammatory stimuli. Theophylline administrated alone was not able to reduce growth-stimulating signaling via extracellular signal-regulated kinases activation and matrix metalloproteases release, whereas it strongly counteracts this biochemical behavior when administered in the presence of corticosteroids. These data provide scientific evidence for supporting the rationale for the pharmacological use of theophylline and corticosteroid combined drug. Keywords: human bronchial epithelial cells, theophylline, corticosteroids, signal transduction

Girolamo Pelaia,1 Alessandro Vatrella,2 Maria Teresa Busceti,1 Luca Gallelli,3 Mariaimmacolata Preianò,3 Nicola Lombardo,1 Rosa Terracciano,3 Rosario Maselli1 1Department of Medical and Surgical Sciences, Section of Respiratory Diseases, University “Magna Græcia” of Catanzaro, Catanzaro, Italy; 2Department of Medicine and Surgery, Section of Respiratory Diseases, University of Salerno, Salerno, Italy; 3Department of Health Science, University “Magna Græcia” of Catanzaro, Catanzaro, Italy Abstract: Within the context of the heterogeneous phenotypic stratification of asthmatic population, many patients are characterized by moderate-to-severe eosinophilic asthma, not adequately controlled by relatively high dosages of inhaled and even oral corticosteroids. Therefore, these subjects can obtain significant therapeutic benefits by additional biologic treatments targeting interleukin-5 (IL-5), given the key pathogenic role played by this cytokine in maturation, activation, proliferation, and survival of eosinophils. In particular, reslizumab is a humanized anti-IL-5 monoclonal antibody that has been found to be an effective and safe add-on therapy, capable of decreasing asthma exacerbations and significantly improving disease control and lung function in patients experiencing persistent allergic or nonallergic eosinophilic asthma, despite the regular use of moderate-to-high doses of inhaled corticosteroids. These important therapeutic effects of reslizumab, demonstrated by several controlled clinical trials, have led to the recent approval by US Food and Drug Administration of its use, together with other antiasthma medications, for the maintenance treatment of patients suffering from severe uncontrolled asthma. Keywords: IL-5, eosinophilic asthma, reslizumab, chronic obstructive pulmonary disease, MAPK, Janus kinases

Girolamo Pelaia,1 Alessandro Vatrella,2 Maria Teresa Busceti,1 Luca Gallelli,3 Cecilia Calabrese,4 Rosa Terracciano,3 Nicola Lombardo,1 Rosario Maselli11Department of Medical and Surgical Sciences, Magna Græcia University of Catanzaro, Catanzaro, 2Department of Medicine and Surgery, University of Salerno, Salerno, 3Department of Health Science, Magna Græcia University of Catanzaro, Catanzaro, 4Department of Cardio-Thoracic and Respiratory Sciences, Second University of Naples, Naples, ItalyAbstract: Bronchodilators are the most important drugs used for the treatment of chronic obstructive pulmonary disease (COPD). In particular, these therapeutic agents are mostly long-acting compounds utilized via inhalation, and include LAMA (long-acting muscarinic receptor antagonists) and LABA (long-acting β2-adrenoceptor agonists). Because LAMA and LABA induce bronchodilation by distinct mechanisms of action, LABA/LAMA combinations provide a reciprocal potentiation of the pharmacological effects caused by each component. Hence, many COPD patients who do not achieve a satisfactory control of their symptoms using a single, either LAMA or LABA bronchodilator, can experience relevant benefits with the use of LAMA/LABA fixed combinations. Many different LAMA/LABA combinations have been recently developed and evaluated in randomized clinical trials. In this context, our review focuses on the pharmacological mechanisms underpinning the bronchodilation elicited by the LAMA tiotropium bromide and the LABA olodaterol. We also discuss the results of the most important clinical studies carried out in COPD patients to assess the efficacy and safety of tiotropium/olodaterol combinations.Keywords: LAMA, LABA, tiotropium, olodaterol, dual bronchodilation, tiotropium/olodaterol combinations

Alessandro Vatrella,1 Immacolata Fabozzi,1 Cecilia Calabrese,2 Rosario Maselli,3 Girolamo Pelaia3 1Department of Medicine and Surgery, University of Salerno, Salerno, 2Department of Cardiothoracic and Respiratory Sciences, Second University of Naples, Naples, 3Department of Medical and Surgical Sciences, University Magna Græcia, Catanzaro, Italy Abstract: Simultaneously with the steady progress towards a better knowledge of the pathobiology of asthma, the potential usefulness of anticytokine therapies is emerging as one of the key concepts in the newly developing treatments of this widespread airway disease. In particular, given the key role played by interleukin (IL)-4 and IL-13 in the pathophysiology of the most typical aspects of asthma, such as chronic airway inflammation, tissue remodeling, and bronchial hyperresponsiveness, these pleiotropic cytokines are now considered as suitable therapeutic targets. Among the recently developed antiasthma biologic drugs, the monoclonal antibody dupilumab is very promising because of its ability to inhibit the biological effects of both IL-4 and IL-13. Indeed, dupilumab prevents IL-4/13 interactions with the α-subunit of the IL-4 receptor complex. A recent trial showed that in patients with difficult-to-control asthma, dupilumab can markedly decrease asthma exacerbations and improve respiratory symptoms and lung function; these effects were paralleled by significant reductions in T-helper 2-associated inflammatory biomarkers. However, further larger and longer trials are required to extend and validate these preliminary results, and also to carefully study the safety and tolerability profile of dupilumab. Keywords: Th2-high asthma, interleukin-4, interleukin-13, dupilumab

Nicholas Eleftheriadis, Haruhiro Inoue, Haruo Ikeda, Manabu Onimaru, Akira Yoshida, Toshihisa Hosoya, Roberta Maselli, Shin-ei KudoDigestive Disease Center, Showa University Northern Yokohama Hospital, Yokohama, JapanAbstract: Peroral endoscopic myotomy (POEM) has been developed in the context of natural orifice transluminal endoscopic surgery (NOTES) as a minimally invasive endoscopic treatment for symptomatic esophageal achalasia, which is a chronic progressive benign disease with severe morbidity and difficult management. Since September 2008, POEM has been successfully performed in more than 200 consecutive patients with symptomatic achalasia at the Digestive Disease Center of Showa University, Northern Yokohama Hospital, Yokohama, Japan, with excellent short- and long-term results and absence of serious complications. International experience of POEM within clinical studies is also promising. According to these results, POEM is considered as a safe procedure that can be applied to all achalasia patients. However, the low incidence of achalasia (0.3%–1% per 100,000 population), in combination with the potential serious complications related to the technically demanding POEM procedure, has made training difficult. There is therefore an urgent need for an animal model for training to decrease the learning curve. Further, there are other ethical and training issues to address. The pig is the most appropriate animal model for training in POEM due to its anatomy being similar to that of humans. The porcine esophagus has the advantage of easy mobilization due to absence of tight junctions to surrounding organs. A non-survival porcine model would be a simple, inexpensive, and reproducible animal model for training in POEM, without the need for concern about complications. A possible training process might first involve observation of POEM performed by specialists, then training on non-survival and survival porcine models, followed by training in humans under specialist guidance and finally, performance of POEM in humans.Keywords: porcine organ model, non-survival, porcine esophagus, Heller myotomy

Girolamo Pelaia1, Luca Gallelli1, Teresa Renda1, Pasquale Romeo1, Maria Teresa Busceti1, Rosa Daniela Grembiale1, Rosario Maselli1, Serafino Antonio Marsico2, Alessandro Vatrella31Department of Experimental and Clinical Medicine, University Magna Græcia of Catanzaro, Catanzaro; 2Department of Cardiothoracic and Respiratory Sciences, Second University of Naples, Naples; 3Department of Respiratory Medicine, University of Salerno, Salerno, ItalyAbstract: Omalizumab is a humanized monoclonal anti-IgE antibody recently approved for the treatment of severe allergic asthma. This drug inhibits allergic responses by binding to serum IgE, thus preventing interaction with cellular IgE receptors. Omalizumab is also capable of downregulating the expression of high affinity IgE receptors on inflammatory cells, as well as the numbers of eosinophils in both blood and induced sputum. The clinical effects of omalizumab include improvements in respiratory symptoms and quality of life, paralleled by a reduction of asthma exacerbations, emergency room visits, and use of systemic corticosteroids and rescue bronchodilators. Omalizumab is relatively well-tolerated, and only rarely induces anaphylactic reactions. Therefore, this drug represents a valid option as add-on therapy for patients with severe persistent allergic asthma inadequately controlled by high doses of standard inhaled treatments.Keywords: omalizumab, anti-IgE, severe asthma

This article discusses the use of endoscopic submucosal dissection (ESD) as a treatment option for proximal colonic lesions. ESD is commonly used for rectal lesions due to the high risk of submucosal invasion, but its use for proximal lesions is not widely adopted. The study aimed to assess the technical and clinical outcomes of patients treated with ESD for lesions located proximally to the splenic flexure. The results showed that ESD and hybrid ESD were feasible for high-risk proximal colonic lesions, with a high rate of complete resection achieved. The study suggests that ESD may be a curative technique for patients with high-risk histological features. [Extracted from the article]

This article, published in the journal Endoscopy, presents the findings of a multicenter study conducted at six Italian referral centers. The study aimed to evaluate the efficacy and safety of endoscopic submucosal dissection (ESD) for lesions involving the ileocecal valve (ICV) compared to other right-side colon lesions. The results showed that ESD is a safe and effective treatment for right-side neoplasia involving the ICV when performed by expert endoscopists in Western referral centers. The study found no significant differences in en-bloc resection rate, R0 resection rate, procedure time, or rates of adverse events between the ICV group and the non-ICV group. [Extracted from the article]

This article discusses a new technique called saline immersion (SI) vessel pre-sealing that aims to reduce bleeding during third-space endoscopy (TSE) procedures. TSE procedures often require coagulation forceps to stop bleeding from large vessels, which can slow down the procedure and increase costs. The SI pre-sealing technique involves using electrocautery coagulation with the tip of the knife under saline solution to seal the vessel, eliminating the need for coagulation forceps. The study found that the SI pre-sealing technique reduced the need for coagulation retreatment and the use of dedicated hemostatic devices, without affecting procedural length or safety. The authors suggest that this technique could be beneficial for less experienced endoscopists. [Extracted from the article]

This article discusses the use of cold snare endoscopic mucosal resection (CS-EMR) as a new trend in treating large colorectal adenomas. The study aimed to assess the feasibility, safety, and efficacy of CS-EMR for proximal large adenomas. The results showed that CS-EMR had a 100% technical success rate with no adverse events. The recurrence rate at 6 months was 5.2%, but all recurrences were successfully re-treated in the same procedure. The study concludes that CS-EMR is both feasible and safe for treating large colorectal adenomas, but further research is needed to validate its efficacy. [Extracted from the article]

This article, published in the journal Endoscopy, presents a meta-analysis and systematic review of the use of Hybrid Argon Plasma Coagulation (H-APC) in the treatment of Barrett's esophagus. The study aimed to assess the safety and efficacy of H-APC compared to other techniques. The analysis of six studies involving 331 patients found that H-APC demonstrated promising efficacy and safety, with a high rate of complete eradication of intestinal metaplasia. The study also highlighted a favorable patient tolerability profile for H-APC. [Extracted from the article]

This article discusses a study that evaluated the effectiveness and safety of endoscopic submucosal dissection (ESD) for high-risk colorectal colitis-associated neoplasia (HR-CAN) in patients with inflammatory bowel disease (IBD). The study included 91 IBD patients who underwent ESD or hybrid-ESD for HR-CANs. The results showed that ESD was effective and safe, with high rates of en bloc and R0 resection. Adverse events occurred in 12.5% of cases but were managed endoscopically and conservatively. The study suggests that ESD can be a viable option for treating HR-CANs in IBD patients, but further research is needed to assess long-term outcomes. [Extracted from the article]

This article presents the initial results of a multicenter observational study on the Hybrid-APC (H-APC) technique for treating Barrett's esophagus (BE). The H-APC technique combines argon plasma coagulation (APC) with a saline injection for ablation therapy. The study collected data from 57 patients with BE who underwent H-APC ablation, with 38 patients completing the treatment so far. The results show that H-APC has high efficacy and safety, with a high tolerability profile and a limited number of treatment sessions required. However, further randomized comparative studies are needed to confirm its effectiveness. [Extracted from the article]

This article discusses a prospective study that aimed to evaluate the clinical efficacy and safety of endoscopic dilation with EsoFLIP in patients with benign esophageal strictures. EsoFLIP is a novel dilation balloon that uses high-resolution impedance planimetry to provide real-time visualization and monitoring of dilation. The study enrolled 10 patients with various types of esophageal strictures, and all dilation procedures were technically successful with no adverse events. After the procedure, there was a significant decrease in the severity and frequency of dysphagia, as well as an increase in stricture diameter and distensibility index. The authors conclude that endoscopic dilation with EsoFLIP is clinically effective and safe, and may potentially reduce fluoroscopy time exposure compared to traditional dilation methods. [Extracted from the article]

This article, published in the journal Endoscopy, examines the outcomes of different anesthesia techniques used in the endoscopic treatment of Zenker Diverticulum (ZD). The study, conducted at the Humanitas Research Hospital, analyzed data from January 2015 to November 2023 and compared outcomes between deep sedation (DS) and orotracheal intubation (IOT). The results showed that DS was non-inferior to IOT in terms of safety and efficacy, with similar rates of severe adverse events and recurrence. The study suggests that DS can be a viable option for ZD treatment in a tertiary setting with expertise in anesthesiology and therapeutic endoscopy. [Extracted from the article]