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Objectives: to date, no consensus has been reached on the surgical gold-standard in pleural mesothelioma (PM). We retrospectively reviewed our experience as a tertiary referral centre, to compare short- and long-term survival of PM patients undergoing different types of surgery., Methods: in retrospective, observational, single-centre study, we analysed all the patients histologically diagnosed with PM undergoing surgical procedures with palliative or curative intent at IRCCS Istituto Nazionale dei Tumori of Milan, Italy, from January 2003 to December 2020. The primary study endpoint was 10-year overall survival (OS) in three different types of resections: extra-pleural-pneumonectomy (EPP), pleurectomy/decortication (P/D), partial-pleurectomy/pleural-biopsy (PP/B). Secondary endpoints were postoperative hospital stay and postoperative 30-day and 90-day mortality rates. The survival function was estimated using Kaplan-Meier, and the Log-rank test was used for testing differences. Univariable and Multivariable Cox regression models were implemented to estimate Hazard Ratio (HR) for all variables of interest., Results: 243 consecutive patients were enrolled, EPP was performed in 49 (20.2%), P/D in 58 (23.8%), PP/B in 136 (56.0%) patients. The median follow-up time was 19.8 months. 10-year OS was significantly better for P/D group (16%, Log-Rank test p<0.0001) compared to PP/B (1.8%) and EPP (0%). No statistically significant differences were found among the 3 surgical groups in 30- and 90-day mortality rates. At multivariable analysis, gender (male, HR=1.58), type of resection (P/D, HR=0.55) and surgery date (recent years, HR=0.61) were found to be independent prognostic factors for OS., Conclusions: in PM, lung-sparing curative approach (e.g. P/D) should be preferred in highly selected patients and in highly experienced centres, whenever appropriate. Anyway, when P/D is not indicated, adopting palliative/conservative management (e.g. PP/B) could ensure comparable results as extremely aggressive surgeries (e.g. EPP). The aim of surgery in PM should not be reaching complete resection, but rather accomplishing significant resection allowing to complete the multimodality treatment in highly selected patients in experienced centers., Competing Interests: Disclosure The authors have no conflicts of interest to declare that are relevant to the content of this article., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Mesenchymal Stromal Cell (MSC) clinical applications have been widely reported and their therapeutic potential has been documented in several diseases. MSCs can be isolated from several human tissues and easily expanded in vitro, they are able to differentiate in a variety of cell lineages, and they are known to interact with most immunological cells, showing immunosuppressive and tissue repair properties. Their therapeutic efficacy is closely associated with the release of bioactive molecules, namely Extracellular Vesicles (EVs), effective as their parental cells. EVs isolated from MSCs act by fusing with target cell membrane and releasing their content, showing a great potential for the treatment of injured tissues and organs, and for the modulation of the host immune system. EV-based therapies provide, as major advantages, the possibility to cross the epithelium and blood barrier and their activity is not influenced by the surrounding environment. In the present review, we deal with pre-clinical reports and clinical trials to provide data in support of MSC and EV clinical efficacy with particular focus on neonatal and pediatric diseases. Considering pre-clinical and clinical data so far available, it is likely that cell-based and cell-free therapies could become an important therapeutic approach for the treatment of several pediatric diseases., Competing Interests: Declaration of Competing Interest We declare that the manuscript has not been published previously in print or electronic format and is not under consideration by another journal. All the authors have reviewed the manuscript, agree with its contents, and consent to its submission. No honorarium, grant or other form of payment, was given to anyone to produce this manuscript. Conflicts of interest: none to be declare., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Cytisine, a partial agonist-binding nicotine acetylcholine receptor, is a promising cessation intervention. We conducted a single-center, randomized, controlled trial (RCT) in Italy to assess the efficacy and tolerability of cytisine as a smoking cessation therapy among lung cancer screening participants., Methods: From July 2019 to March 2020, the Screening and Multiple Intervention on Lung Epidemics RCT enrolled 869 current heavy tobacco users in a low-dose computed tomography screening program, with a randomized comparison of pharmacologic intervention with cytisine plus counseling (N = 470) versus counseling alone (N = 399). The primary outcome was continuous smoking abstinence at 12 months, biochemically verified through carbon monoxide measurement., Results: At the 12-month follow-up, the quit rate was 32.1% (151 participants) in the intervention arm and 7.3% (29 participants) in the control arm. The adjusted OR of continuous abstinence was 7.2 (95% confidence interval: 4.6-11.2). Self-reported adverse events occurred more frequently in the intervention arm (399 events among 196 participants) than in the control arm (230 events among 133 participants, p < 0.01). The most common adverse events were gastrointestinal symptoms, comprising abdominal swelling, gastritis, and constipation., Conclusions: The efficacy and safety observed in the Screening and Multiple Intervention on Lung Epidemics RCT indicate that cytisine, a very low-cost medication, is a useful treatment option for smoking cessation and a feasible strategy to improve low-dose computed tomography screening outcomes with a potential benefit for all-cause mortality., (Copyright © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: The genetically engineered, humanized, bispecific monoclonal antibody emicizumab (Hemlibra) that mimics the cofactor activity of activated factor VIII (FVIII) has been approved for treatment of hemophilia A patients with and without inhibitor. In the pivotal premarketing clinical trials, emicizumab prophylaxis significantly reduced bleeding rates compared with previous treatments and was well tolerated. However, a consequence of this novel therapy may be the host immune response to a foreign protein., Objective: Characterization of the neutralizing anti-emicizumab antibody associated with the loss of treatment efficacy., Patient: A pediatric hemophilia A patient with inhibitor enrolled in the HAVEN2 (Study of Emicizumab Administered Subcutaneously (SC) in Pediatric Participants With Hemophilia A and Factor VIII (FVIII) Inhibitors) clinical trial., Methods: The anti-emicizumab antibody has been characterized with Western blot and enzyme-linked immunosorbent assay (ELISA). The antibody was affinity purified and sequenced. Binding affinity to full-length and papain-digested emicizumab was analyzed using surface plasmon resonance and byo-layer interferometry., Results: The neutralizing anti-emicizumab antibody was highly polyclonal with high-affinity binding mainly to the Fab portion of emicizumab with a small amount of binding to the Fc portion. Molecular interaction experiments between emicizumab and the purified antibody indicated the presence of at least two components with similar affinities., Conclusions: Although the incidence of neutralizing anti-emicizumab antibody is rare, this study highlights the importance of a close monitoring and the need of a simple laboratory assay to promptly detect these antibodies in patients with a history of poor drug efficacy., (© 2021 International Society on Thrombosis and Haemostasis.)

The development of anti-factor VIII (FVIII) neutralizing antibodies (inhibitors) is the major complication in hemophilia A. Nonneutralizing antibodies (NNAs) have been detected in hemophilia patients and also in unaffected individuals. The aim of this study was to assess the prevalence of NNAs and to evaluate whether their presence is associated with the development of inhibitors in a cohort of previously untreated or minimally treated patients with hemophilia A; plasma samples of 237 patients with severe hemophilia A enrolled in the SIPPET trial were collected before any exposure to FVIII concentrates and analyzed for the presence of anti-FVIII NNAs. Patients were observed for the development of neutralizing antibodies. NNAs were found in 18 (7.6%) of 237 patients at screening, and there was a clear age gradient. Of those with NNAs, 7 patients subsequently developed an inhibitor for a cumulative incidence of 45.4% (95% confidence interval [CI], 19.5% to 71.3%); among the 219 patients without NNAs, 64 (29%) developed an inhibitor (cumulative incidence, 34.0%; 95% CI, 27.1%-40.9%). In Cox regression analyses, patients with NNAs at screening had an 83% higher incidence of inhibitor development than patients without NNAs (hazard ratio [HR], 1.83; 95% CI, 0.84-3.99). For high-titer inhibitors, the incidence rate had an almost threefold increase (HR, 2.74; 95% CI, 1.23-6.12). These associations did not materially change after adjustment. The presence of anti-FVIII NNAs in patients with severe hemophilia A who were not previously exposed to FVIII concentrates is associated with an increased incidence of inhibitors., (© 2017 by The American Society of Hematology.)

Background: The formation of ADAMTS13-specific circulating immune complexes (CICs) may be a pathophysiologic mechanism in autoimmune thrombotic thrombocytopenic purpura (TTP), but has not been systematically investigated., Objectives: (a) To develop an assay for ADAMTS13-specific CICs; (b) to evaluate their prevalence in autoimmune TTP; and (c) to assess their association with ADAMTS13-related measurements and clinical features in autoimmune TTP patients., Patients/methods: We developed and validated an ELISA method for ADAMTS13-specific CICs. ADAMTS13-specific CICs were searched for in 55 patients with autoimmune TTP from the Milan TTP Registry (URL:http://www.ttpdatabase.org/) and 28 controls. The associations between ADAMTS13-specific CIC levels and ADAMTS13 activity, antigen, anti-ADAMTS13 IgGs and acute TTP clinical features were assessed by multivariate linear regression., Results: Intra- and inter-assay coefficients of variation of the new test were 5.3 and 9.6%. In 36 patients with severe ADAMTS13 deficiency and anti-ADAMTS13 autoantibodies, the prevalence of ADAMTS13-specific CICs was 47% (n = 17; 95% confidence interval [CI], 32-63%). ADAMTS13-specific CICs were detected also in seven of 19 (37%; 95% CI, 19-59%) patients with reduced ADAMTS13 activity, but apparently negative anti-ADAMTS13 autoantibodies. ADAMTS13-specific CICs were not associated with ADAMTS13 activity, antigen or anti-ADAMTS13 IgGs. In patients with acute TTP, increasing levels of ADAMTS13-specific CICs were associated with a higher number of plasma-exchange procedures required to attain remission (per 0.1 increase in normalized OD values, beta, 2.9; 95% CI, -0.7 to 6.5)., Conclusions: Approximately one to two-thirds of patients with autoimmune TTP display ADAMTS13-specific CICs. A thorough investigation of the prognostic relevance of ADAMTS13-specific CIC levels in autoimmune TTP is warranted., (© 2013 International Society on Thrombosis and Haemostasis.)

Background: The considerable genetic predisposition to deep vein thrombosis (DVT) is only partially accounted for by known genetic risk variants. Rare single-nucleotide variants (SNVs) of the coding areas of hemostatic genes may explain part of this missing heritability. The ADAMTS13 and VWF genes encode two interconnected proteins with fundamental hemostatic functions, the disruption of which may result in thrombosis., Objectives: To study the distribution and burden of rare coding SNVs of ADAMTS13 and VWF found by sequencing in cases and controls of DVT., Patients/methods: The protein-coding areas of 186 hemostatic/proinflammatory genes were sequenced by next-generation technology in 94 thrombophilia-negative patients with DVT and 98 controls. Gene-specific information on ADAMTS13 and VWF was used to study the association between DVT and rare coding SNVs of the two genes., Results: More than 70 billion base pairs of raw sequence data were produced to sequence the 700-kb target area with a median redundancy of × 45 in 192 individuals. Most of the 4366 SNVs identified were rare and non-synonymous, indicating pathogenetic potential. Rare (frequency of < 1%) and low-frequency (< 5%) coding SNVs of ADAMTS13 were associated with DVT (prevalence 17% vs. 4%; odds ratio [OR] 4.8 and 95% confidence interval [CI] 1.6-15.0 for rare coding; prevalence 36% vs. 23%, OR 1.9 and 95% CI 1.0-3.5 for low-frequency coding). Patients with rare coding SNVs of ADAMTS13 had lower plasma levels of ADAMTS-13 activity than patients without them. SNVs of VWF were not associated with DVT., Conclusions: We found an excess of rare coding SNVs of the ADAMTS13 gene in patients with DVT., (© 2013 International Society on Thrombosis and Haemostasis.)

Background: Thrombotic thrombocytopenic purpura (TTP) is a rare life-threatening disease. Of surviving patients, 45% develops an exacerbation or a late recurrence. Severe ADAMTS-13 deficiency, both during the acute episode and remission, is a well-established predictor of recurrence. The predictive value of anti-ADAMTS-13 antibodies, their inhibitory activity and Ig class subtype for disease recurrence is still to be established., Objectives: To analyze ADAMTS-13-related biomarkers (ADAMTS-13 and anti-ADAMTS-13 immunoglobulins, classes and subclasses) and their potential relationship with prognosis., Patients/methods: In 115 patients with TTP, we assessed the association between levels of these biomarkers and the severity of acute episodes; we analysed also the hazard ratio (HR) and 95% confidence interval (CI) of recurrence in association with biomarkers levels retrieved at the previous acute episode or during remission, using Cox regression models., Results: During the acute phase, higher IgA, IgG1 and IgG3 titers showed the strongest association with acute episode severity. In the survival analyzes, the only biomarker significantly associated with a high hazard of recurrence after an acute episode was the presence of IgG. Conversly, low ADAMTS-13 activity or antigen levels (<10%), the presence of ADAMTS-13 inhibitor or IgG during remission were all significantly associated with a higher hazard of recurrence., Conclusions: Both the Ig class and subclass are of predictive value for acute episode severity in patients with TTP. Although markers that could predict the risk of recurrence in the acute phase are limited, a thorough assessment of ADAMTS-13-related parameters during remission is warranted., (© 2012 International Society on Thrombosis and Haemostasis.)

The Drosophila Notch gene and its ligands, Delta and Serrate, are involved in cell fate determination in a variety of developing tissues. Recently, several Notch, Delta and Serrate homologues have been identified in vertebrates. We report here the cloning of the human and murine JAGGED2 (JAG2), a Serrate-like gene, and the analysis of its expression pattern during embryogenesis. Jag2 was found to be expressed as early as E9 in the surface ectoderm of the branchial arches and in the apical ectodermal ridge (AER) of the developing limb. At E12.5, Jag2 expression is upregulated in differentiated neurons of the central and peripheral nervous system and in the inner neuroblastic layer of the developing retina. Outside the nervous system, Jag2 is expressed in the developing vibrissae follicles, tooth buds, thymus, submandibular gland and stomach. Our findings suggest the involvement of Jagged2 in the development of the mammalian limb, branchial arches, central and peripheral nervous systems and several tissues whose development depends upon epithelial-mesenchymal interactions.

The abnormal multimeric composition of plasma von Willebrand factor in type IIB von Willebrand's disease is transiently corrected after infusion of 1-deamino-[8-D-arginine]-vasopressin. However, the larger multimers released into the circulation disappear more rapidly in these patients than in type I von Willebrand's disease or normals. We demonstrate that the larger multimers of normal von Willebrand factor transfused into a type IIB patient are cleared from the circulation more slowly than multimers of similar size endogenously released from tissue stores. The rate of disappearance of large von Willebrand factor multimers after infusion of cryoprecipitate is similar in IIB, IIA, and severe homozygous-like von Willebrand's disease. Platelets from the IIB patient exhibited normal ristocetin-induced binding of normal von Willebrand factor. However, like normal platelets, they bound IIB von Willebrand factor at lower ristocetin concentrations than required for normal von Willebrand factor. These findings provide evidence that absence of the larger multimers from IIB plasma is related to a molecular abnormality of von Willebrand factor rather than to enhanced affinity of abnormal tissue or cellular binding sites, as is the case in the recently described "pseudo" von Willebrand's disease and "platelet-type" von Willebrand's disease.