The Incredible Adventure of Omalizumab.

The basis of our current understanding of allergies begins with the discovery of IgE in the mid-1960s. The whole theory of the physiology and pathophysiology of allergic diseases, including rhinitis and asthma, dates from that period. Among the key regions of IgE identified were the FAB (fragment antigen binding) portion that has the ability to capture allergens, and the Cε3 domain, through which IgE binds to its membrane receptor. It was then postulated that blocking IgE at the level of the Cε3 domain would prevent it from binding to its receptor and thus set in motion the allergic cascade. This was the beginning of the development of omalizumab, a monoclonal antibody with an anti-IgE effect. In this article, we review the pathophysiology of allergic disease and trace the clinical development of omalizumab. We also review the benefits of omalizumab treatment that are apparently unrelated to allergies, such as its effect on immunity and bronchial remodeling.

Switching Biological Therapies in Severe Asthma.

Currently, three classes of monoclonal antibodies targeting type 2 inflammation pathways are available in Italy for the treatment of severe asthma: anti-IgE (Omalizumab), anti-IL-5/anti-IL-5Rα (Mepolizumab and Benralizumab), and anti-IL-4Rα (Dupilumab). Numerous randomized controlled trials (RCTs) and real-life studies have been conducted to define their efficacy and identify baseline patients' characteristics potentially predictive of favorable outcomes. Switching to another monoclonal antibody is recommended in case of a lack of benefits. The aim of this work is to review the current knowledge on the impact of switching biological therapies in severe asthma as well as on predictors of treatment response or failure. Almost all of the information about switching from a previous monoclonal antibody to another comes from a real-life setting. In the available studies, the most frequent initial biologic was Omalizumab and patients who were switched because of suboptimal control with a previous biologic therapy were more likely to have a higher baseline blood eosinophil count and exacerbation rate despite OCS dependence. The choice of the most suitable treatment may be guided by the patient's clinical history, biomarkers of endotype (mainly blood eosinophils and FeNO), and comorbidities (especially nasal polyposis). Due to overlapping eligibility, larger investigations characterizing the clinical profile of patients benefiting from switching to different monoclonal antibodies are needed.

Randomized clinical trials and real life studies: Comparison of baseline characteristics of patients in oral target therapies for renal cell carcinoma.

INTRODUCTION: Pivotal Randomized Controlled Trials (RCTs) constitute scientific evidence in support of therapeutic choices when a drug is authorized in the market. In RCTs, patients are selected in a rigorous manner, in order to avoid bias that may influence efficacy assessments. Therefore, patients who take the drug in Real Life Studies (RLSs) are not the same as those participating in RCTs, which, in turn, leads to low data transferability from RCTs to RLS. The objective of this study was to evaluate the differences between RCTs and RLS, in terms of patient baseline characteristics. MATERIALS AND METHODS: Our study includes all oral target therapies for RCC (Renal Cell Carcinoma) marketed in Europe before March 31, 2019. For each treatment, we considered both RCTs and RLSs, the former gathered from Summary of Product Characteristics published on the European Medicine Agency (EMA) website, and the latter yielded by our search in relevant literature. For each drug considered, we then compared the baseline characteristics of patients included in the RCT samples with those of the samples included in the RLSs using the Chi-squared and Mann-Whitney tests. RESULTS: We considered six medicines, for a total of 9 pivotal RCTs and 31 RLSs. RCTs reported the same type of patient baseline characteristics, whereas RLSs are more varied in reporting. Some patient baseline characteristics (metastases, previous treatments, etc.) were significantly different between RCTs and RLs. Other characteristics, such as ECOG Performance Status, brain metastases, and comorbidities, liver and kidney failure, are comprised in exclusion criteria of RCTs, though are included in RLS.Discussion and Conclusion: While evaluating equal treatments for the same indications, RCTs and RLSs do not always assess patients with the same characteristics. It would be necessary to produce evidence from RLSs so as to have an idea of treatment effectiveness in patients groups that are not eligible or underrepresented in RCTs.

Oral immunotherapy in severe cow's milk allergic patients treated with omalizumab: Real life survey from a Spanish registry.

BACKGROUND: Oral immunotherapy is a frequent treatment for the management of food allergies, but adverse events (AE) are common. This study assessed the outcome of cow's milk oral immunotherapy (MOIT) in severe cow`s milk-allergic patients treated with omalizumab in a real-life setting. METHODS: OmaBASE was a national, multicenter, open, and observational registry that collected clinical, immunologic, and treatment from patients with food allergy receiving omalizumab. RESULTS: Data derived from 58 patients aged 10.3 years (IQR 6.3-13.2) and median milk-specific IgE 100 kUA /L at the start of omalizumab treatment. Most had experienced anaphylaxis by accidental exposures (70.7%) and had asthma (81.0%). Omalizumab in monotherapy induced tolerance to ≥6000 mg of cow's milk protein (CMP) to 34.8% of patients tested by oral food challenge. Omalizumab combined with MOIT conferred desensitization to ≥6000 mg of CMP to 83.0% of patients. Omalizumab withdrawal triggered more AE (P = .013) and anaphylaxis (P = .001) than no discontinuation. Anaphylaxis was observed in 36.4% of patients who discontinued omalizumab, and more in those with sudden (50.0%) rather than progressive (12.5%) discontinuation. At database closure, 40.5% of patients who had completed follow-up tolerated CMP without omalizumab (7.2% 1500-4500 mg; 33.3% ≥6000 mg). CONCLUSION: Milk oral immunotherapy initiated under omalizumab allows the desensitization of subjects with severe cow's milk allergy even after omalizumab discontinuation. However, discontinuation of omalizumab can lead to severe AE and should be carefully monitored.

"Artificial intelligence": Which services, which applications, which results and which development today in clinical research? Which impact on the quality of care? Which recommendations?

Artificial intelligence (AI), beyond the concrete applications that have already become part of our daily lives, makes it possible to process numerous and heterogeneous data and knowledge, and to understand potentially complex and abstract rules in a manner human intelligence can but without human intervention. AI combines two properties, self-learning by the successive and repetitive processing of data as well as the capacity to adapt, that is to say the possibility for a scripted program to deal with multiple situations likely to vary over time. Roundtable experts confirmed the potential contribution and theoretical benefit of AI in clinical research and in improving the efficiency of patient care. Experts also measured, as is the case for any new process that people need to get accustomed to, its impact on practices and mindset. To maximize the benefits of AI, four critical points have been identified. The careful consideration of these four points conditions the technical integration and the appropriation by all actors of the life science spectrum: researchers, regulators, drug developers, care establishments, medical practitioners and, above all, patients and the civil society. 1st critical point: produce tangible demonstrations of the contributions of AI in clinical research by quantifying its benefits. 2nd critical point: build trust to foster dissemination and acceptability of AI in healthcare thanks to an adapted regulatory framework. 3rd critical point: ensure the availability of technical skills, which implies an investment in training, the attractiveness of the health sector relative to tech-heavy sectors and the development of ergonomic data collection tools for all health operators. 4th critical point: organize a system of governance for a distributed and secure model at the national level to aggregate the information and services existing at the local level. Thirty-seven concrete recommendations have been formulated which should pave the way for a widespread adoption of AI in clinical research. In this context, the French "Health data hub" initiative constitutes an ideal opportunity.

Randomized Controlled Trials and real life studies. Approaches and methodologies: a clinical point of view.

Randomized Controlled Trials (RCTs) are the "gold standard" for evaluating treatment outcomes providing information on treatments "efficacy". They are designed to test a therapeutic hypothesis under optimal setting in the absence of confounding factors. For this reason they have high internal validity. The strict and controlled conditions in which they are conducted, leads to low generalizability because they are performed in conditions very different from real life usual care. Conversely, real life studies inform on the "effectiveness" of a treatment, that is, the measure of the extent to which an intervention does what is intended to do in routine circumstances. At variance to RCTs, real life trials have high generalizability, but low internal validity. Recently the number of real life studies has been rapidly growing in different areas of respiratory medicine, particularly in asthma and COPD. The role of such studies is becoming a hot topic in respiratory medicine, attracting research interest and debate. In the first part of this review we discuss some of the advantages and disadvantages of different types of RCTs and analyze the strengths and weaknesses of real life trials, considering the recent examples of some studies conducted in COPD. We then discuss methodological approaches and options to overcome some of the limitations of real life studies. Comparing the conclusions of effectiveness and efficacy trials can provide important pieces of information. Indeed, these approaches can result complementary, and they can guide the interpretation of each other results.

Nivolumab in pretreated pleural mesothelioma: Results from an observational real-world study of patients treated within the AIFA 5% Fund.

BACKGROUND: Pleural mesothelioma is a rare cancer with a dismal prognosis and few therapeutic options, especially in the pretreated setting. Immunotherapy with checkpoint inhibitors as single agents yielded interesting results in refractory pleural mesothelioma, achieving a response rate between 10-20%, median progression-free survival of 2-5 months and median overall survival of 7-13 months. PATIENTS AND METHODS: A retrospective, multi-institutional study of pleural mesothelioma patients treated with nivolumab in second and further line was performed. The endpoints of the study are response rate, disease control rate, progression free survival and overall survival. RESULTS: Sixty-five patients with pleural mesothelioma treated with nivolumab in second and further line were enrolled at seven Italian institutions. The response rate was 8%, disease control rate was 37%, median progression free survival was 5.7 months (95% CI: 2.9-9.0) and median overall survival was 11.1 (95% CI 6.2-19.9) months. A higher neutrophils and neutrophils to lymphocytes ratio at baseline were associated with worse prognosis. CONCLUSION: Nivolumab as a single agent is fairly active in a cohort of unselected pretreated pleural mesothelioma patients. Further investigations on clinical and translational factors are needed to define which patient might benefit most from nivolumab treatment in pleural mesothelioma.

Clinical endpoints in allergen immunotherapy: State of the art 2022.

110 years after the classical study by Noon, numerous studies have confirmed the efficacy of allergen immunotherapy. A variety of clinical endpoints have been used in these trials. This review gives an overview of clinical endpoints for randomized clinical trials on allergen immunotherapy (AIT) in rhinitis and asthma. In addition, real-life studies have been carried out with the same kind of endpoints. In general, AIT studies are characterized by a lack of standardized and validated outcome measures. For allergic rhinoconjunctivitis, digital tools have been developed to monitor patients. Such tools are particularly useful to obtain real-world evidence for AIT. Finally, well-accepted outcome measures are available for cost-effectiveness studies.

Encorafenib plus cetuximab with or without binimetinib in patients with BRAF V600E-mutated metastatic colorectal cancer: real-life data from an Italian multicenter experience.

BACKGROUND: Encorafenib plus cetuximab with or without binimetinib showed increased objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) compared with chemotherapy plus anti-EGFR in previously treated patients with BRAF V600E-mutated (mut) metastatic colorectal cancer (mCRC). Although no formal comparison was planned, addition of binimetinib to encorafenib plus cetuximab did not provide significant efficacy advantage. PATIENTS AND METHODS: This real-life study was aimed at evaluating safety, activity, and efficacy of encorafenib plus cetuximab with or without binimetinib in patients with BRAF V600E-mut mCRC treated at 21 Italian centers within a nominal use program launched in May 2019. RESULTS: Out of 133 patients included, 97 (73%) received encorafenib plus cetuximab (targeted doublet) and 36 (27%) the same therapy plus binimetinib (targeted triplet). Most patients had Eastern Cooperative Group Performance Status (ECOG-PS) of 0 or 1 (86%), right-sided primary tumor (69%), and synchronous disease (66%). Twenty (15%) tumors were DNA mismatch repair deficiency (dMMR)/microsatellite instability (MSI)-high. As many as 44 (34%) patients had received two or more prior lines of therapy, 122 (92%) were previously exposed to oxaliplatin, and 109 (82%) to anti-vascular endothelial growth factor (anti-VEGF). Most frequent adverse events were asthenia (62%) and anti-EGFR-related skin rash (52%). Any grade nausea (P = 0.03), vomiting (P = 0.04), and diarrhea (P = 0.07) were more frequent with the triplet therapy, while melanocytic nevi were less common (P = 0.06). Overall, ORR and disease control rate (DCR) were 23% and 69%, respectively, with numerically higher rates in the triplet group (ORR 31% versus 17%, P = 0.12; DCR 78% versus 65%, P = 0.23). Median PFS and OS were 4.5 and 7.2 months, respectively. Worse ECOG-PS, peritoneal metastases, and more than one prior treatment were independent poor prognostic factors for PFS and OS. Clonality of BRAF mutation measured as adjusted mutant allele fraction in tumor tissue was not associated with clinical outcome. CONCLUSIONS: Our real-life data are consistent with those from the BEACON trial in terms of safety, activity, and efficacy. Patients in good general condition and not heavily pretreated are those more likely to derive benefit from the targeted treatment.

Efficacy and follow-up of anti-VEGF injections in diabetic macular edema in real-life practice at the Dijon university medical centre through the Save Sight Registries.

PURPOSE: To evaluate the efficacy of intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections (IVT) in diabetic macular edema (DME) in real-life practice using the Save Sight Registries (SSR). MATERIAL AND METHODS: We conducted an observational, single-centre, retrospective study in the department of ophthalmology of the Dijon University Hospital. We included treatment-naive patients who presented with DME between January 2016 and December 2017. Demographic and clinical data, follow-up visits, and treatments administered were entered into the SSR, an international online ophthalmic registry. Primary endpoints were the change in best-corrected visual acuity (BCVA) and central subfield thickness (CST) from baseline to 12 and 24 months. RESULTS: Fifty-eight eyes of 43 patients with a mean [standard deviation (SD)] age of 67.1 [9.5] years were included. Forty-one eyes completed 12 months of follow-up, and 17 eyes completed 24 months of follow up. Median [SD] baseline BCVA was 56.1 [22.9] ETDRS letters and the median [95% confidence interval (95% CI)] baseline CST was 447.9 [161.0] micrometers (µm). Median [95% CI] improvement in BCVA from baseline to months 12 and 24 were respectively, +5.6 [+0.5; +10.7] ETDRS letters and +7.7 [-2.8; +18.2] ETDRS letters. The median [95% CI] decrease in CST from baseline to months 12 and 24 were respectively, -110.9 [-154.5; -67.3] µm and -125.5 [-198.0; -53.0] µm. CONCLUSION: Our clinical practice can be evaluated easily with the SSR system. In real life, anti-VEGF IVT are an effective treatment for DME, which result in improved BCVA and decreased CST.

Palbociclib in metastatic breast cancer: current evidence and real-life data.

The purpose of this review is to summarize the background and latest evidence for the use of palbociclib, an oral, first-in-class, highly selective cyclin-dependent kinase 4/6 inhibitor, in advanced breast cancer, with a focus on some of the unanswered questions about the performance of this agent in clinical practice. The available clinical data from both controlled clinical trials and real-life experiences concerning palbociclib-based combinations in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic disease, including patient-reported outcomes and subgroup analyses, have been reviewed and discussed. Palbociclib significantly improved progression-free survival and clinical benefit rates when added to letrozole in postmenopausal women as initial endocrine-based therapy, and it prolonged progression-free survival and overall survival when added to fulvestrant in women who progressed on previous endocrine therapy in randomized clinical trials. Tolerability profile was manageable, with neutropenia occurring most commonly, without detrimental impact on quality of life. Available data from real-life experiences confirm the good performance of palbociclib in unselected, heavily pretreated populations. Palbociclib in combination with endocrine therapy is a valuable emerging option for patients with HR+/HER2- advanced or metastatic breast cancer. Further investigation is needed to provide solutions for palbociclib resistance and to identify the best sequence to use for the best patient benefit with a minimal toxicity.

Real-life studies of biologics used in asthma patients: key differences and similarities to trials.

Introduction: The precision medicine approach that is now mandatory for severe asthma management includes the use of novel biologic agents blocking specific immunological mechanisms that are responsible for disease phenotypes and endotypes: monoclonal antibodies blocking IgE, IL-5 and IL-4/IL-13 immunological pathways are so far available. Areas covered: Clinical trials involving a large number of patients proved their efficacy in reducing asthma exacerbations, improving lung function and quality of life, and reducing the need for systemic corticosteroid treatment. Since biologics have been available for routine use, a series of real-life experiences on severe asthmatics treated with them have been published: these studies confirmed the beneficial effects in a real-world setting (effectiveness) of these drugs and showed novel aspects that were not covered by clinical trials, such as their effect on particular subgroup of patients, unexpected adverse events, and potential novel indications. Expert opinion: Both clinical trials and real-life experiences are needed to establish robust data on biologic agents for severe asthma, with real-life studies giving more broader insights on different aspects related to the biologics themselves and to the disease.

Impact of Omalizumab on Food Allergy in Patients Treated for Asthma: A Real-Life Study.

BACKGROUND: The effects of omalizumab on food allergy thresholds have been little studied. OBJECTIVE: To assess the real-life effects of omalizumab on food threshold tolerability in children treated for severe asthma. METHODS: In this observational, real-life, efficacy study, we reviewed the food allergen thresholds of patients with severe asthma, as well as their immediate reactions to 2+ foods before and after a 4-month treatment with omalizumab. We also evaluated their control of asthma and their quality of life, as measured by Pediatric Quality of Life Inventory (PedsQL). RESULTS: Fifteen children, allergic to 37 foods, were evaluated. Omalizumab induced an increase in the allergen threshold for milk, egg, wheat, and hazelnut from a mean 1012.6 ± 1464.5 mg protein to 8727 ± 6463.3 eliciting dose (P < .001). A total of 70.4% of subjects tolerated the complete challenge dose after 4 months of treatment with omalizumab. These foods were reintroduced in the patients' diet without the need for any oral immunotherapy procedures. The remaining foods were partially tolerated. The number of reactions to the unintended ingestion of allergenic foods over 4 months dropped from 47 to 2. The PedsQL increased from 61 ± 5.32 to 87 ± 7.33 (parental judgment; P < .001) and from 65 ± 7.39 to 90 ± 4.54 (patients' judgment; P < .001). The mean cost of omalizumab was €1311.63 per month. CONCLUSIONS: During treatment with omalizumab for severe uncontrolled asthma, the food allergen threshold increases to 8.6 times its original value. The quality of life of patients also increased, due to a better asthma control and a reduction in dietary restrictions. The cost/benefit ratio of such treatment for selected cases of food allergy remains to be evaluated.

[Use of direct-acting oral anticoagulants in Primary Care in Spain. Positioning statement by SEMERGEN on the current situation]. / Utilización de los anticoagulantes orales de acción directa en Atención Primaria de España. Posicionamiento de SEMERGEN ante la situación actual.

The direct-acting oral anticoagulants (DOACs) are drugs that have been shown to have a safety profile superior to the vitaminK antagonists (VKA). The prescribing of DOACs in Spain is subject to approval in the form of an inspection visa. This sets out the clinical conditions defined in the Spanish Medicines Agency Therapeutic Positioning Report (TPR) of 2013, updated in 2016. These recommendations do not coincide with those of the European Cardiology Society (2016), restricting the use of DOACs to a second-line treatment in the majority of cases. Furthermore, this TPR is applied differently in the Regional Autonomous Communities and even in different health areas. This leads to a wide variation in the prescribing conditions, causing territorial inequalities in accessibility to these drugs by patients. The removal of the visa, and the appropriateness of the prescription to the recommendations of the Clinical Practice guidelines are key aspects to neutralise the current administrative and clinical barriers for the efficient use of DOACs in Primary Care. SEMERGEN supports the boosting of the clinical training and alliance with the patients in order to promote awareness and knowledge of atrial fibrillation.

Botulinum toxin for chronic migraine: Clinical trials and technical aspects.

OnabotulinumtoxinA has been approved for the prophylaxis of chronic migraine following the demonstration of efficacy in two large controlled trials. Data collected from pragmatic studies in the real-life setting have contributed important additional information useful for the management of this group of extremely disabled and challenging patients. The main findings from these studies are presented and discussed.

Abiraterone in chemotherapy-naive patients with metastatic castration-resistant prostate cancer: a systematic review of 'real-life' studies.

BACKGROUND: To assess the efficacy and safety of treatment with abiraterone acetate (AA) in chemotherapy-naïve men with metastatic castration-resistant prostate cancer (mCRPC) in the 'real-life' setting. METHODS: Data acquisition on the outcomes of the use of AA in chemotherapy-naive patients with mCRPC was performed by a MEDLINE comprehensive systematic literature search using combinations of the following key words: 'prostate cancer', 'metastatic', 'castration resistant', 'abiraterone', 'real life', and excluding controlled clinical trials (phase II and III studies). Identification and selection of the studies was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) criteria. Outcomes of interest were overall survival (OS), progression-free survival (PFS), 12-week 50% reduction in prostate-specific antigen (PSA), and grade 3 and higher adverse events. Data were narratively synthesized in light of methodological and clinical heterogeneity. RESULTS: Within the eight identified studies that fulfilled the criteria, a total of 801 patients were included in the meta-analysis. Baseline PSA ranged between 9.5 and 212.0 ng/ml. Most of the patients had bone metastases. Duration of treatment with AA was longer in the studies with lower baseline PSA levels. The median OS ranged between 14 and 36.4 months. The PFS, assessed according to different definitions, ranged from 3.9 to 18.5 months. A 50% PSA reduction at 12 weeks was reached by a variable percentage of patients ranging from 36.0% to 62.1%. Finally, the rate of grade 3 and higher adverse events was reported in three studies and ranged from 4.4% to 15.5%. CONCLUSIONS: Despite the high grade of heterogeneity among studies, treatment with AA seems to ensure good survival outcomes in the 'real-life' setting. However, prospective studies based on patients' characteristics being more similar to 'real-life' patients are necessary.

Smoking cessation effectiveness in smokers with COPD and asthma under real life conditions.

INTRODUCTION: Although smoking cessation is strongly indicated by international guidelines as an effective therapeutic tool for patients with COPD and Asthma, a large proportion of them do not quit smoking and they are regarded as a "difficult" target group. AIM: To study the effectiveness of an intensive smoking cessation program in smokers with COPD and asthma under real-life conditions. METHODS: 166 smokers with COPD, 120 smokers with asthma and 1854 control smokers attended the smoking cessation program in the out-patient patient Smoking Cessation Clinic of the Pulmonary Department in Athens University. Continuous Abstinence Rate (CAR) was evaluated in 3, 6, 9 and 12 months after the target quit date. RESULTS: Short-term CAR (in 3 months) was 49.4% for COPD smokers, 51.7% for asthmatic smokers and 48.0% for the control group of smokers. 12 months after the initial visit the CAR was 13.9%, 18.3% and 15.9%, respectively. No statistically significant differences between groups at any study period were found. Smokers with good compliance with the program had higher long-term CAR after 12 months: 37.7% in COPD smokers, 40.0% in asthmatic smokers and 39.3% in control smokers. High CAR was observed at all stages of COPD severity. CONCLUSION: The results support the view that smokers with respiratory obstructive airway diseases of any severity should be offered an intensive smoking cessation program with regular and long-term follow-up. This will help them to achieve high abstinence rates and prevent relapses.