Publications by authors named "Mario Cazzola"

635 Publications

Relationship between clone metrics and clinical outcome in clonal cytopenia.

Blood 2021 07 13. Epub 2021 Jul 13.

Department of Hematology Oncology, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy

Clonal cytopenia of undetermined significance (CCUS) is associated with an increased risk of developing a myeloid neoplasm with myelodysplasia (MN). To identify the features of the mutant clone(s) that are associated with clinical phenotype and progression, we studied the following cohorts of individuals: 311 patients with idiopathic cytopenia of undetermined significance (ICUS), 532 community-dwelling individuals without hematologic phenotype (n=355) or with unexplained anemia (n=177), and 592 patients with overt MN. Ninety-two of 311 (30%) ICUS patients carried a somatic genetic lesion that allowed diagnosis of CCUS. Clonal hematopoiesis (CH) was detected in 19.7% and 27.7% of non-anemic and anemic community-dwelling individuals, respectively (P=.045). Different mutation patterns and variant allele frequencies (VAF) (clone metrics parameters) were observed in the conditions studied (P<.001). Recurrent mutation patterns exhibited different VAF values associated with marrow dysplasia (0.17-0.48, P<.001), indicating variable clinical expressivity of mutant clones. Unsupervised clustering analysis based on mutation profiles identified two major clusters, characterized by isolated DNMT3A mutations (CH-like cluster) or combinatorial mutation patterns (MN-like cluster), and showing different overall survival (HR=1.8, P<.001). Within CCUS patients, the 2 clusters had different risk of progression into MN (HR=2.7, P<.001). Within the MN-like cluster, distinct subsets with different risk of progression into MN (P<.001) could be identified based on clone metrics. These findings unveil marked variability in the clinical expressivity of myeloid driver genes, and underline the limitations of morphologic dysplasia for clinical staging of mutant hematopoietic clones. Clone metrics appears to be critical to inform clinical decision-making in patients with clonal cytopenia.
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http://dx.doi.org/10.1182/blood.2021011323DOI Listing
July 2021

Ceiling effect of beclomethasone/formoterol/glycopyrronium triple fixed-dose combination in COPD: A translational bench-to-bedside study.

Pulm Pharmacol Ther 2021 Jun 12;69:102050. Epub 2021 Jun 12.

Department of Medicine and Surgery, Respiratory Disease and Lung Function Unit, University of Parma, Parma, Italy. Electronic address:

Background: Currently, data on the possible synergy of adding a LAMA to ICS/LABA combination are missing and no studies assessed whether triple therapy may induce ceiling bronchodilator effect. A translational study was performed to investigate the interaction between glycopyrronium bromide (GB) and beclomethasone dipropionate (BDP)/formoterol fumarate (FF) combination in human isolated airways and the effect on FEV and small airway resistance of BDP/FF/GB in COPD.

Methods: The interaction of adding GB to BDP/FF combination was tested in vitro in medium and small airways via Bliss, Loewe, and Highest Single Agent models. The peak and trough effect on FEV and R5-R19 of salbutamol on top of BDP/FF/GB 100/6/12.5 μg FDC via extrafine formulation was investigated in severe COPD patients after two weeks of treatment.

Results: GB plus BDP/FF elicited significant synergistic bronchorelaxation in medium and small isolated airways (overall maximal effect: +32% vs. additive effect). No significant (P > 0.05) improvement in R5-R19 was detected when salbutamol was administered on top of BDP/FF/GB 100/6/12.5 μg FDC (peak -0.12 ± 0.22 cmHO/L/s, trough -0.23 ± 0.25 cmHO/L/s). Salbutamol significantly (P < 0.01) increased FEV when administered on top of triple FDC (peak +145 ± 119 ml, trough +221 ± 111 ml).

Conclusion: The synergistic interaction detected in vitro when adding GB to BDP/FF combination may lead to ceiling bronchorelaxation of small airways in vivo, an effect that may improve hyperinflation in subjects with small airway disease and, thus, explain the substantial clinical benefits of triple combination therapy administered via extrafine formulation in severe COPD patients.

Study Registration: ISRCTN94089001.
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http://dx.doi.org/10.1016/j.pupt.2021.102050DOI Listing
June 2021

Step-up and step-down approaches in the treatment of asthma.

Expert Rev Respir Med 2021 Jun 7:1-10. Epub 2021 Jun 7.

Division of Respiratory Medicine, University Hospital "Tor Vergata", Rome, Italy.

Significant intraindividual and temporal variability in symptom control is a feature of asthma that requires careful monitoring and the need to periodically review and adjust therapy. Both NHLBI/NAEPP and GINA offer helpful algorithms for a stepping approach to asthma. The problems arisen in applying the stepwise approach to the treatment of asthma proposed by NHLBI/NAEPP and GINA algorithms and their possible alternatives. The current therapeutic stepping approach to asthma, which takes into account lung function, symptoms and quality of life, is certainly useful, but it does not consider the underlying mechanisms. Furthermore, patient's overestimation or underestimation of the severity of the disease and differences in the opinions on the level of asthma control required between patients and physicians and also between physicians in both primary care and specialist settings are common and may negatively affect asthma control and future risks. A reassessment of the conventional stepping approach to management of asthma is now needed. A pragmatic approach that sets therapeutic goals for each individual and associates them with the treatable traits of asthma which, when therapeutically targeted, will in many cases help to achieve the goals, seems more reasonable than the present stepping approach.
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http://dx.doi.org/10.1080/17476348.2021.1935245DOI Listing
June 2021

Preexisting cardiorespiratory comorbidity does not preclude the success of multidisciplinary rehabilitation in post-COVID-19 patients.

Respir Med 2021 08 15;184:106470. Epub 2021 May 15.

Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy. Electronic address:

Patients recovering from coronavirus disease 2019 (COVID-19) may not return to a pre-COVID functional status and baseline levels of healthcare needs after discharge from acute care hospitals. Since the long-term outcomes of COVID-19 can be more severe in patients with underlying cardiorespiratory diseases, we aimed at verifying the impact of a preexisting cardiorespiratory comorbidity on multidisciplinary rehabilitation in post-COVID-19 patients. We enrolled 95 consecutive patients referring to the Pulmonary Rehabilitation Unit of Istituti Clinici Scientifici Maugeri Spa SB, IRCCS of Telese Terme, Benevento, Italy after being discharged from the COVID-19 acute care ward and after recovering from acute COVID-19 pneumonia. Forty-nine of them were not suffering from underlying comorbidities, while 46 had a preexisting cardiorespiratory disease. Rehabilitation induced statistically significant improvements in respiratory function, blood gases and the ability to exercise both in patients without any preexisting comorbidities and in those with an underlying cardiorespiratory disease. Response to the rehabilitation cycle tended to be greater in those without preexisting comorbidities, but DLco%-predicted was the only parameter that showed a significant greater improvement when compared to the response in the group of patients with underlying cardiorespiratory comorbidity. This study suggests that multidisciplinary rehabilitation may be useful in post-COVID-19 patients regardless of the presence of preexisting cardiorespiratory comorbidities.
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http://dx.doi.org/10.1016/j.rmed.2021.106470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123366PMC
August 2021

Management of COPD patients during COVID: difficulties and experiences.

Expert Rev Respir Med 2021 May 19:1-9. Epub 2021 May 19.

Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.

: The role of COPD in COVID-19 is not yet well understood. However, there is increasing evidence showing that COPD patients with COVID-19 have a higher risk of presenting a serious infection, a greater likelihood of requiring ICU support, and a higher mortality than other groups.: In this article, we address some critical questions on COVID-19 as they pertain to COPD. In particular, we discuss whether the usual algorithms of pharmacological and non-pharmacological management in COPD still apply.: Patients with COPD must continue their regular therapy, regardless of whether they are affected by COVID-19. Corticosteroids reduce mortality in COVID-19 patients in need of supportive oxygen therapy or invasive mechanical ventilation. It is essential that a COPD patient who has tested positive for SARS-CoV-2 is closely followed over time because any delay in diagnosis and initiation of appropriate therapy could negatively affect his/her prognosis. However, we still do not know if COVID-19 infection occurs and evolves differently in each of the recognized COPD phenotypes and, therefore, whether it needs a different management. There are other open questions concerning COVID-19 and COPD that need to be considered. Future studies are absolutely necessary to answer these questions.
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http://dx.doi.org/10.1080/17476348.2021.1929176DOI Listing
May 2021

Classes of drugs that target the cellular components of inflammation under clinical development for COPD.

Expert Rev Clin Pharmacol 2021 May 17:1-13. Epub 2021 May 17.

Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy.

Introduction: The persistent inflammation that characterizes COPD and affects its natural course also impacting on symptoms has prompted research to find molecules that can regulate the inflammatory process but still available anti-inflammatory therapies provide little or no benefit in COPD patients. Consequently, numerous anti-inflammatory molecules that are effective in animal models of COPD have been or are being evaluated in humans.

Areas Covered: In this article we describe several classes of drugs that target the cellular components of inflammation under clinical development for COPD.

Expert Opinion: Although the results of many clinical trials with new molecules have often been disappointing, several studies are underway to investigate whether some of these molecules may be effective in treating specific subgroups of COPD patients. Indeed, the current perspective is to apply a more personalized treatment to the patient. This means being able to better define the patient's inflammatory state and treat it in a targeted manner. Unfortunately, the difficulty in translating encouraging experimental data into human clinical trials, the redundancy in the effects induced by signal-transmitting substances and the nonspecific effects of many classes that are undergoing clinical trials, do not yet allow specific inflammatory cell types to be targeted.
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http://dx.doi.org/10.1080/17512433.2021.1925537DOI Listing
May 2021

Disputes over the production and dissemination of misinformation in the time of COVID-19.

Respir Med 2021 06 29;182:106380. Epub 2021 Mar 29.

Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.

Ultimate coronavirus disease 2019 (COVID-19) mitigation and crisis resolution is dependent on trustworthy data and actionable information. At present time, there is still no cure for COVID-19, although some treatments are being used in severe illness. Regrettably, as the SARS-CoV-2 virus spreads, the lack of cure has been accompanied by an increasing amount of medical misinformation. In particular, there is a lot of misinformation about how to treat patients who have tested positive for SARS-CoV-2 and who are asymptomatic or have mild symptoms and for whom management at home is deemed appropriate. In this editorial, we highlight the risks deriving from this misinformation, which often arises from the publication of studies that are not conceptually and methodologically accurate.
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http://dx.doi.org/10.1016/j.rmed.2021.106380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006495PMC
June 2021

Bronchodilator reversibility testing in post-COVID-19 patients undergoing pulmonary rehabilitation.

Respir Med 2021 06 13;182:106401. Epub 2021 Apr 13.

Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy. Electronic address:

Background: The usefulness of bronchodilators in coronavirus diseases 2019 (COVID-19) survivors is still uncertain, especially for patients with a concomitant obstructive lung disease. We aimed at verifying the level of bronchodilator reversibility in COVID-19 patients undergoing multidisciplinary pulmonary rehabilitation after the acute phase.

Methods: We enrolled 105 consecutive patients referring to the Pulmonary Rehabilitation Unit of Istituti Clinici Scientifici Maugeri Spa SB, IRCCS of Telese Terme, Benevento, Italy after being discharged from the COVID-19 acute care ward and after recovering from acute COVID-19 pneumonia. All subjects performed a spirometry before and after inhalation of salbutamol 400 μg to determine the bronchodilation response within 48 h of admission to the unit.

Results: All patients had suffered from a moderate to severe COVID-19, classified 3 or 4 according to the WHO classification, Seventeen patients had concomitant obstructive lung disease (14 suffering from COPD and 3 from asthma). FEV after salbutamol improved on average by 41.7 mL in the entire examined sample, by 29.4 mL in subjects without concomitant obstructive lung diseases, by 59.3 mL in COPD patients and by 320.0 mL in asthma patients. Mean FVC after salbutamol improved by 65.7 mL in the entire examined sample, by 52.5 mL in subjects without concomitant obstructive lung diseases, by 120.0 mL in COPD patients, and by 200.0 mL in asthma patients.

Conclusions: This study suggests that a treatment with bronchodilators must always be taken into consideration in post-COVID-19 patients because it can induce a functional improvement that, even if small, can facilitate the breathing of these patients.
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http://dx.doi.org/10.1016/j.rmed.2021.106401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041746PMC
June 2021

SARS-CoV-2 Neutralizing Antibodies: A Network Meta-Analysis across Vaccines.

Vaccines (Basel) 2021 Mar 5;9(3). Epub 2021 Mar 5.

Respiratory Disease and Lung Function Unit, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy.

: There are no studies providing head-to-head comparison across SARS-CoV-2 vaccines. Therefore, we compared the efficacy of candidate vaccines in inducing neutralizing antibodies against SARS-CoV-2. : A network meta-analysis was performed to compare the peak levels of SARS-CoV-2 neutralizing antibodies across candidate vaccines. Data were reported as standardized mean difference (SMD) since the outcome was assessed via different metrics and methods across the studies. : Data obtained from 836 healthy adult vaccine recipients were extracted from 11 studies. BBIBP-CorV, AZD1222, BNT162b2, New Crown COVID-19, and Sputnik V induced a very large effect on the level of neutralizing antibodies (SMD > 1.3); CoVLP, CoronaVac, NVX-CoV2373, and Ad5-nCoV induced a large effect (SMD > 0.8 to ≤1.3); and Ad26.COV2.S induced a medium effect (SMD > 0.5 to ≤0.8). BBIBP-CorV and AZD122 were more effective ( < 0.05) than Ad26.COV2.S, Ad5-nCoV, mRNA-1237, CoronaVac, NVX-CoV2373, CoVLP, and New Crown COVID-19; New Crown COVID-19 was more effective ( < 0.05) than Ad26.COV2.S, Ad5-nCoV, and mRNA-1237; CoronaVac was more effective ( < 0.05) than Ad26.COV2.S and Ad5-nCoV; and Sputnik V and BNT162b2 were more effective ( < 0.05) than Ad26.COV2.S. In recipients aged ≤60 years, AZD1222, BBIBP-CorV, and mRNA-1237 were the most effective candidate vaccines. : All the candidate vaccines induced significant levels of SARS-CoV-2 neutralizing antibodies, but only AZD1222 and mRNA-1237 were certainly tested in patients aged ≥70 years. Compared with AZD1222, BNT162b and mRNA-1237 have the advantage that they can be quickly re-engineered to mimic new mutations of SARS-CoV-2.
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http://dx.doi.org/10.3390/vaccines9030227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999682PMC
March 2021

New Avenues for Phosphodiesterase Inhibitors in Asthma.

J Exp Pharmacol 2021 15;13:291-302. Epub 2021 Mar 15.

Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy.

Introduction: Phosphodiesterases (PDEs) are isoenzymes ubiquitously expressed in the lungs where they catalyse cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (GMP), which are fundamental second messengers in asthma, thereby regulating the intracellular concentrations of these cyclic nucleotides, their signaling pathways and, consequently, myriad biological responses. The superfamily of PDEs is composed of 11 families with a distinct substrate specificity, molecular structure and subcellular localization. Experimental studies indicate a possible role in asthma mainly for PDE3, PDE4, PDE5 and PDE7. Consequently, drugs that inhibit PDEs may offer novel therapeutic options for the treatment of this disease.

Areas Covered: In this article, we describe the progress made in recent years regarding the possibility of using PDE inhibitors in the treatment of asthma.

Expert Opinion: Many data indicate the potential benefits of PDE inhibitors as an add-on treatment especially in severe asthma due to their bronchodilator and/or anti-inflammatory activity, but no compound has yet reached the market as asthma treatment mainly because of their limited tolerability. Therefore, there is a growing interest in developing new PDE inhibitors with an improved safety profile. In particular, the research is focused on the development of drugs capable of interacting simultaneously with different PDEs, or to be administered by inhalation. CHF 6001 and RPL554 are the only molecules that currently are under clinical development but there are several new agents with interesting pharmacological profiles. It will be stimulating to assess the impact of such agents on individual treatable traits in specially designed studies.
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http://dx.doi.org/10.2147/JEP.S242961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979323PMC
March 2021

Gene expression profile correlates with molecular and clinical features in patients with myelofibrosis.

Blood Adv 2021 03;5(5):1452-1462

Center for Genome Research.

Myelofibrosis (MF) belongs to the family of classic Philadelphia-negative myeloproliferative neoplasms (MPNs). It can be primary myelofibrosis (PMF) or secondary myelofibrosis (SMF) evolving from polycythemia vera (PV) or essential thrombocythemia (ET). Despite the differences, PMF and SMF patients are currently managed in the same way, and prediction of survival is based on the same clinical and genetic features. In the last few years, interest has grown concerning the ability of gene expression profiles (GEPs) to provide valuable prognostic information. Here, we studied the GEPs of granulocytes from 114 patients with MF, using a microarray platform to identify correlations with patient characteristics and outcomes. Cox regression analysis led to the identification of 201 survival-related transcripts characterizing patients who are at high risk for death. High-risk patients identified by this gene signature displayed an inferior overall survival and leukemia-free survival, together with clinical and molecular detrimental features included in contemporary prognostic models, such as the presence of high molecular risk mutations. The high-risk group was enriched in post-PV and post-ET MF and JAK2V617F homozygous patients, whereas pre-PMF was more frequent in the low-risk group. These results demonstrate that GEPs in MF patients correlate with their molecular and clinical features, particularly their survival, and represent the proof of concept that GEPs might provide complementary prognostic information to be applied in clinical decision making.
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http://dx.doi.org/10.1182/bloodadvances.2020003614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948267PMC
March 2021

Comparative studies of dual bronchodilation in COPD.

Monaldi Arch Chest Dis 2021 Feb 12;91(1). Epub 2021 Feb 12.

Unit of Respiratory Disease and Lung Function, Department of Medicine and Surgery, University of Parma.

Dual bronchodilation therapy is becoming the cornerstone for the treatment of COPD because the clinical benefits of LABA/LAMA fixed-dose combinations (FDCs) are now extensively established. Therefore, it not surprising that a number of LAMA/LABA combinations in a single inhaler have now been approved for clinical use as treatments for patients with COPD. Regrettably, very few head-to-head studies between all of the available LABA/LAMA FDCs have been carried out. This makes choosing the most appropriate FDC difficult. Comparative effectiveness research that also uses conventional meta-analyses to compare different care strategies can help generate useful information. A bidimensional comparative analysis across LAMA/LABA FDCs has suggested constant superiority for tiotropium/olodaterol. However, considering that there is not an equivalent amount of evidence on efficacy outcomes for all LAMA/LABA FDCs, a proper comparison between the different LAMA/LABA FDCs cannot be made yet, and the information available is still rather inconsistent.
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http://dx.doi.org/10.4081/monaldi.2021.1625DOI Listing
February 2021

Treatable Mechanisms in Asthma.

Mol Diagn Ther 2021 03 11;25(2):111-121. Epub 2021 Feb 11.

Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.

Asthma is a heterogeneous condition, but firm identification of heterogeneity-focused treatments is still lacking. Dividing patients into subgroups of asthma pheno-/endotypes based on combined clinical and cellular biological characteristics and linking them to targeted treatments could be a potentially useful approach to personalize therapy for better outcomes. Nonetheless, there are still many problems related to the identification and validation of asthma phenotypes and endotypes. Alternatively, a precision-medicine strategy for the management of patients with airways disease that is free from the traditional diagnostic labels and based on identifying "treatable traits" in each patient might be preferable. However, it would represent a quite unsophisticated approach because the definition of a treatable trait is too imprecise. In fact, there is still no understanding of the mechanisms underlying treatable traits that allow directing any targeted therapies against any particular treatable trait. Fortunately, in-depth identification of underlying molecular pathways to guide targeted treatment in individual patients is in progress thanks to the improvement in big data management obtained from '-omic' sciences that is greatly increasing knowledge concerning asthma.
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http://dx.doi.org/10.1007/s40291-021-00514-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956930PMC
March 2021

Sex differences in COPD management.

Expert Rev Clin Pharmacol 2021 Mar 12;14(3):323-332. Epub 2021 Mar 12.

Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy.

: A growing body of evidence indicates that prevalence of chronic obstructive pulmonary disease (COPD) has been increasing more rapidly among women compared to men, but the available data on the differences between the sexes in the responses to the various COPD therapies are still scarce.: The aim of this narrative review is to provide an overview of current knowledge on sex differences in COPD management.: There is no solid evidence of sex differences in response to usual COPD treatments but there are sex-related differences in management of patients with a clinical diagnosis of COPD. It is difficult to explain the reason for these differences, but most likely they are due to local prescribing habits, rather than solid scientific reasons. However, there are also signals of different sex-related responses, the qualification and quantification of which is difficult with the information currently available. These signals should lead to the inclusion of more women in clinical trials, but also to the design of prospective clinical studies to assess the possible differences linked to sex in COPD treatment responses, whose identification is an important step toward the definition of personalized COPD therapy.
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http://dx.doi.org/10.1080/17512433.2021.1888713DOI Listing
March 2021

Long-acting muscarinic antagonists and small airways in asthma: Which link?

Allergy 2021 Jul 27;76(7):1990-2001. Epub 2021 Feb 27.

Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.

Involvement of small airways, those of <2 mm in internal diameter, is present in all stages of asthma and contributes substantially to its pathophysiologic expression. Therefore, small airways are a potential target to achieve optimal asthma control. Airway tone, which is increased in asthma, is mainly controlled by the vagus nerve that releases acetylcholine (ACh) and activates muscarinic ACh receptors (mAChRs) post-synaptically on airway smooth muscle (ASM). In small airways, M mAChRs are expressed, but there is no vagal innervation. Non-neuronal ACh released from the epithelial cells that may express choline acetyltransferase in response to inflammatory stimuli, as well as from other structural cells in the airways, including fibroblasts and mast cells, can activate mAChRs. By antagonizing M mAChR, the contraction of the ASM is prevented and, potentially, local inflammation can be reduced and the progression of remodeling may be averted. In fact, ACh also contributes to inflammation and remodeling of the airways and regulates the growth of ASM. Several experimental studies have demonstrated the potential benefit derived from the use of mAChR antagonists, mainly long-acting mAChR antagonists (LAMAs), on small airways in asthma. However, there are several confounding factors that may cause a wrong estimation of the relationship between LAMAs and small airways in asthma. Further studies are needed to differentiate broncholytic and anti-inflammatory effects of LAMAs and to better understand the interaction between LAMAs and corticosteroids, also in the context of a triple therapy that includes a β -AR agonist, at different levels of the bronchial tree.
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http://dx.doi.org/10.1111/all.14766DOI Listing
July 2021

Introduction to a How I Treat series on acquired hemolytic anemia.

Authors:
Mario Cazzola

Blood 2021 03;137(10):1269

Associate Editor, Blood.

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http://dx.doi.org/10.1182/blood.2020009747DOI Listing
March 2021

Triple Therapy Is Also Effective in Real-World When Used in Chronic Obstructive Pulmonary Disease Patients Who Are Frequent Exacerbators.

Respiration 2021;100(2):93-95. Epub 2021 Jan 15.

Pulmonary and Critical Care Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

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http://dx.doi.org/10.1159/000512728DOI Listing
January 2021

Pharmacokinetic/pharmacodynamic approaches to drug delivery design for inhalation drugs.

Expert Opin Drug Deliv 2021 Jul 19;18(7):891-906. Epub 2021 Jan 19.

Unit of Respiratory Medicine, Dept. Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy.

: Inhaled drugs are important in the treatment of many lung pathologies, but to be therapeutically effective they must reach unbound concentrations at their effect site in the lung that are adequate to interact with their pharmacodynamic properties (PD) and exert the pharmacological action over an appropriate dosing interval. Therefore, the evaluation of pharmacokinetic (PK)/PD relationship is critical to predict their possible therapeutic effect.: We review the approaches used to assess the PK/PD relationship of the major classes of inhaled drugs that are prescribed to treat pulmonary pathologies.: There are still great difficulties in producing data on lung concentrations of inhaled drugs and interpreting them as to their ability to induce the desired therapeutic action. The structural complexity of the lungs, the multiplicity of processes involved simultaneously and the physical interactions between the lungs and drug make any PK/PD approach to drug delivery design for inhalation medications extremely challenging. New approaches/methods are increasing our understanding about what happens to inhaled drugs, but they are still not ready for regulatory purposes. Therefore, we must still rely on plasma concentrations based on the axiom that they reflect both the extent and the pattern of deposition within the lungs.
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http://dx.doi.org/10.1080/17425247.2021.1873271DOI Listing
July 2021

Myelodysplastic Syndromes. Reply.

Authors:
Mario Cazzola

N Engl J Med 2020 12;383(26):2590

Fondazione IRCCS Policlinico San Matteo, Pavia, Italy

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http://dx.doi.org/10.1056/NEJMc2032391DOI Listing
December 2020

Co-mutation pattern, clonal hierarchy, and clone size concur to determine disease phenotype of SRSF2-mutated neoplasms.

Leukemia 2020 Dec 21. Epub 2020 Dec 21.

Department of Molecular Medicine, University of Pavia, Pavia, Italy.

Somatic mutations in splicing factor genes frequently occur in myeloid neoplasms. While SF3B1 mutations are associated with myelodysplastic syndromes (MDS) with ring sideroblasts, SRSF2 mutations are found in different disease categories, including MDS, myeloproliferative neoplasms (MPN), myelodysplastic/myeloproliferative neoplasms (MDS/MPN), and acute myeloid leukemia (AML). To identify molecular determinants of this phenotypic heterogeneity, we explored molecular and clinical features of a prospective cohort of 279 SRSF2-mutated cases selected from a population of 2663 patients with myeloid neoplasms. Median number of somatic mutations per subject was 3. Multivariate regression analysis showed associations between co-mutated genes and clinical phenotype, including JAK2 or MPL with myelofibrosis (OR = 26.9); TET2 with monocytosis (OR = 5.2); RAS-pathway genes with leukocytosis (OR = 5.1); and STAG2, RUNX1, or IDH1/2 with blast phenotype (MDS or AML) (OR = 3.4, 1.9, and 2.1, respectively). Within patients with SRSF2-JAK2 co-mutation, JAK2 dominance was invariably associated with clinical feature of MPN, whereas SRSF2 mutation was dominant in MDS/MPN. Within patients with SRSF2-TET2 co-mutation, clinical expressivity of monocytosis was positively associated with co-mutated clone size. This study provides evidence that co-mutation pattern, clone size, and hierarchy concur to determine clinical phenotype, tracing relevant genotype-phenotype associations across disease entities and giving insight on unaccountable clinical heterogeneity within current WHO classification categories.
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http://dx.doi.org/10.1038/s41375-020-01106-zDOI Listing
December 2020

Prospects for COPD treatment.

Curr Opin Pharmacol 2021 02 14;56:74-84. Epub 2020 Dec 14.

Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, London, UK.

The management of chronic obstructive pulmonary disease (COPD) is fundamentally still heavily dependent on the use of bronchodilators and corticosteroids. Therefore, there is a need for alternative, more effective and safer therapeutic approaches. In particular, since inflammation in COPD lungs is often poorly responsive to corticosteroid treatment, novel pharmacological anti-inflammatory approaches are needed to optimally treat COPD patients. There have been multiple attempts to develop drugs that inhibit recruitment and activation of inflammatory cells, such as macrophages, neutrophils and T-lymphocytes, in the lungs of patients with COPD or target inflammatory mediators that are important in the recruitment or activation of these inflammatory cells or released by such cells. This review article focuses on novel classes of anti-inflammatory drugs that have already been tested in humans as possible treatments for patients with COPD.
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http://dx.doi.org/10.1016/j.coph.2020.11.003DOI Listing
February 2021

Reply to Han et al.: impact on mortality of triple ICS/LABA/LAMA therapy in a population of COPD patients including also subjects with asthma-like profile.

Expert Rev Respir Med 2021 Apr 28;15(4):579-581. Epub 2020 Dec 28.

Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy.

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http://dx.doi.org/10.1080/17476348.2021.1866835DOI Listing
April 2021

Long-Acting Muscarinic Antagonists Under Investigational to Treat Chronic Obstructive Pulmonary Disease.

J Exp Pharmacol 2020 8;12:559-574. Epub 2020 Dec 8.

Division of Respiratory Medicine, University Hospital Tor Vergata, Rome, Italy.

Introduction: Bronchodilators are the cornerstone of chronic obstructive pulmonary disease (COPD) therapy and long-acting muscarinic antagonists (LAMAs) as a mono or combination treatment play a pivotal role. Several LAMAs are already available on the market in different formulations, but developing a new compound with a higher M3 receptor selectivity and a lower affinity to M2 receptors to increase the therapeutic effect and minimize the adverse effects is still a goal. Moreover, new formulations could improve adherence to therapy.

Areas Covered: This systematic review assesses investigational long-acting muscarinic antagonist in Phase I and II clinical trials over the last decade. It offers insights on whether LAMAs and/or their new formulations in clinical development can become effective treatments for COPD in the future.

Expert Opinion: Research on LAMA seems to have come to a standstill, the few new molecules under study do not show distinctive characteristics compared to the previous ones. Muscarinic antagonist/β2-agonist (MABAs) appear to be the major innovation currently under investigation, and they could theoretically open new research frontiers on the effect between adrenergic and muscarinic interaction in the same cell.
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http://dx.doi.org/10.2147/JEP.S259330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733406PMC
December 2020

Guidance on nebulization during the current COVID-19 pandemic.

Respir Med 2021 01 19;176:106236. Epub 2020 Nov 19.

Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.

Awareness of the risk of airborne transmission of SARS-CoV-2 makes patients hesitant about using inhaled medications that are considered as a potential source of viral transmission and immunosuppression. However, patients with asthma or COPD should continue all prescribed inhaled medications. Apparently, inhalers, including pMDIs, DPIs, or SMIs, have a low risk of contamination although characteristics of drug formulation can precipitate cough, whereas some researchers do not rule out the probability that nebulizer treatments may increase the risk of infection transmission via droplet nuclei and aerosols. Considering that aerosol therapy generates fugitive emissions that are not inhaled by the patient and are released from the device during expiration, several international professional bodies have provided recommendations for drug delivery via inhalers and in particular, nebulizers. Unfortunately, these recommendations are often in conflict with each other and do not clarify whether it is appropriate to use nebulizers during this COVID-19 pandemic. Considering what is available in literature, there are no known infection-related hazards to an uninfected patient and also a patient with COVID-19 that preclude the use of a nebulizer at home, but it fundamental that all patients, regardless of whether or not suffering from COVID-19, always follow some practical advices.
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http://dx.doi.org/10.1016/j.rmed.2020.106236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676318PMC
January 2021

ACE2: The Major Cell Entry Receptor for SARS-CoV-2.

Lung 2020 12 10;198(6):867-877. Epub 2020 Nov 10.

Dipartimento di Scienze Mediche Traslazionali, University of Campania "L. Vanvitelli", Naples, Italy.

Despite the unprecedented effort of the scientific community, the novel SARS-CoV-2 virus has infected more than 46 million people worldwide, killing over one million two hundred thousand. Understanding the mechanisms by which some individuals are more susceptible to SARS-CoV-2 infection and why a subgroup of them are prone to experience severe pneumonia, and death should lead to a better approach and more effective treatments for COVID-19. Here, we focus our attention on ACE2, a primary receptor of SARS-CoV-2. We will discuss its biology, tissue expression, and post-translational regulation that determine its potential to be employed by SARS-CoV-2 for cell entry. Particular attention will be given to how the ACE2 soluble form can have a great impact on disease progression and thus be used in a potential therapeutic strategy. Furthermore, we will discuss repercussions that SARS-CoV-2/ACE2 binding has on the renin-angiotensin system and beyond. Indeed, although mostly neglected, ACE2 can also act on [des-Arg 937]-bradykinin of the kinin-kallikrein system regulating coagulation and inflammation. Thorough comprehension of the role that ACE2 plays in different pathways will be the key to assess the impact that SARS-CoV-2/ACE2 binding has on organismal physiology and will help us to find better therapies and diagnostic tools.
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http://dx.doi.org/10.1007/s00408-020-00408-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653219PMC
December 2020
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