Search

During stressful conditions, the human body synthesizes catecholamine neurotransmitters such as dopamine and adrenaline, and cortisol. The monitoring of these three molecules levels is crucial for stress management and holds significant medical applications. Here we developed an analytical device that incorporates a biomimetic (tongue-mimic) associated with an optical physico-chemical transducer, able to detect simultaneously cortisol, dopamine and adrenaline in human saliva without pre-treatments, using an array sensor based on fluorescent chemical receptors (BODIPY, Rhodamine, and Naphthylamides) able to interact by non-covalent interaction with cortisol, adrenaline and dopamine, leading to a change of the emission. Calibration, recovery and selectivity have been performed to validate the device. In particular, the linear responses of the array to concentration range of 1 pM-1 mM of the three analytes were demonstrated by PLS analysis, as well as the high selectivity by PLS-DA analysis performed with artificial saliva samples. Analyses in real human saliva samples, compared to the validated analytical methods, demonstrated that our prototype represents the first point-of-care device able to quantify these three analytes in human saliva with one single analysis in a wider concentration range respect to the other standard methods., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Janus kinase inhibitors (JAKis) are a novel class of drugs interfering with intracellular signaling of type I and type II cytokines, which play a crucial role in immune dysregulation associated with several chronic inflammatory diseases. Filgotinib (FIL), in particular, is the newest member of the JAKi class and exerts its therapeutic effects by selectively targeting and inhibiting the kinase activity of JAK1. While the efficacy of FIL in rheumatoid arthritis (RA) has been confirmed in clinical trials, real-world evidence may provide better insights into its effectiveness and safety in routine clinical practice. Methods: We performed a multicenter, retrospective cohort study investigating the real-life effectiveness and safety of FIL in adult patients with RA. Demographic information, disease characteristics, prior treatment history, and comorbid conditions were retrieved from clinical records at baseline (M0) and after 3 (M3) and 6 months (M6) of treatment. Results: A total of 82 patients (63 women) agreed to participate in the study, of whom 39 (47.6%) were older than 65 years. The average RA duration was 13 ± 9 years; 19 patients (23.1%) were current or former smokers, and 4 patients (4.9%) had a history of cardiovascular events. Most patients had previously received at least one biologic disease-modifying antirheumatic drug (range: 1-6+); in addition, 11 patients (13.4%) had been already exposed to another JAKi. During the follow-up, 7 patients discontinued treatment due to primary failure ( n = 3) or adverse events ( n = 4). Significant reductions in pain and number of tender and swollen joints were observed at M3 and M6. A relevant proportion of patients achieved DAS28-CRP remission at M3 and M6 (46.3% and 66.2%, respectively). Conclusions: Our data provide additional insight into the effectiveness of filgotinib in a real-world setting, even among patients with difficult-to-treat RA and a high prevalence of cardiovascular risk factors.

Background: Therapeutic plasma exchange (TPE) is a highly effective rescue treatment for patients with acute exacerbation of neuroimmunological disease that removes circulating autoantibodies and inflammatory components from the bloodstream. The aims of this study are to explore the safety and the effectiveness of TPE in patients with autoimmune neurological disorders., Methods: We retrospectively evaluated the frequency of adverse events (AEs) and the effectiveness of TPE using the modified Ranking Scale (mRS) in patients with acute neurological flares who underwent TPE at the University Hospital of Palermo., Results: Of 59 patients, the majority underwent TPE due to multiple sclerosis (MS) relapse. In 23.7% of cases, TPE was performed before obtaining a definite diagnosis due to the severity of the clinical presentation. After TPE, the mRS score was globally reduced ( p < 0.0001), and this effect was marked in patients with MS, Guillain-Barré syndrome, and myasthenia gravis crisis but not in those with paraneoplastic syndromes. Circulating pathogenetic antibodies, younger age, and the early use of TPE were factors strongly associated with TPE effectiveness. The overall safety profile of TPE was satisfactory with an AE frequency of 15%., Conclusions: These results highlight the early use of TPE in patients with circulating pathogenetic antibodies as well as its favorable safety profile.

Myelin oligodendrocyte glycoprotein-immunoglobulin G associated disease (MOGAD) is an autoimmune demyelinating disorder of the central nervous system (CNS) which usually occurs with recurrent optic neuritis, transverse myelitis, acute disseminating encephalomyelitis, or brainstem encephalitis. To date, the anti-CD 20 drug rituximab (RTX) is employed in MOGAD although some authors reported the efficacy of Tocilizumab (TCZ) in refractory patients. We present the case of a woman affected by refractory MOGAD who was treated with TCZ after therapy with RTX had failed to prevent relapses. We also conducted a current literature review on TCZ use in MOGAD. A 57-year-old Caucasian woman affected by MOGAD with severe motor impairment and cognitive dysfunction was treated from 2020 to February 2022 with RTX. However, she experienced progressive clinical and cognitive worsening associated with white matter lesions mimicking leukodystrophy. In February 2022, the patient started therapy with TCZ administered with improvement of cognitive performance, walking ability, and brainstem functions. During TCZ, our patient reached the condition of NEDA-3 (no relapse, no increase in disability, no MRI activity on neuroimaging follow-up performed in September 2023). Moreover, the patient experienced paucisymptomatic SARS-CoV-2 infection that did not modify TCZ schedule. To date, there are few evidence on the efficacy and safety of TCZ in MOGAD. However, all the reviewed cases showed that TCZ represents an effective therapy in drug-resistant MOGAD. Our case highlights the efficacy of TCZ in drug resistant MOGAD and strengthens previous reports of TCZ safety and efficacy in MOGAD., (© 2023. The Author(s).)

Introduction: The impact of COVID-19 pandemic represents a serious challenge for 'frail' patients' populations with inflammatory autoimmune systemic diseases such as systemic sclerosis (SSc). We investigated the prevalence and severity of COVID-19, as well the effects of COVID-19 vaccination campaign in a large series of SSc patients followed for the entire period (first 38 months) of pandemic., Patients and Method: This prospective survey study included 1755 unselected SSc patients (186 M, 1,569F; mean age 58.7 ± 13.4SD years, mean disease duration 8.8 ± 7.3SD years) recruited in part by telephone survey at 37 referral centers from February 2020 to April 2023. The following parameters were carefully evaluated: i. demographic, clinical, serological, and therapeutical features; ii. prevalence and severity of COVID-19; and iii. safety, immunogenicity, and efficacy of COVID-19 vaccines., Results: The prevalence of COVID-19 recorded during the whole pandemic was significantly higher compared to Italian general population (47.3 % vs 43.3 %, p < 0.000), as well the COVID-19-related mortality (1.91 % vs 0.72 %, p < 0.001). As regards the putative prognostic factors of worse outcome, COVID-19 positive patients with SSc-related interstitial lung involvement showed significantly higher percentage of COVID-19-related hospitalization compared to those without (5.85 % vs 1.73 %; p < 0.0001), as well as of mortality rate (2.01 % vs 0.4 %; p = 0.002). Over half of patients (56.3 %) received the first two plus one booster dose of vaccine; while a fourth dose was administered to 35.6 %, and only few of them (1.99 %) had five or more doses of vaccine. Of note, an impaired seroconversion was recorded in 25.6 % of individuals after the first 2 doses of vaccine, and in 8.4 % of patients also after the booster dose. Furthermore, the absence of T-cell immunoreactivity was observed in 3/7 patients tested by QuantiFERON® SARSCoV-2 Starter Set (Qiagen). The efficacy of vaccines, evaluated by comparing the COVID-19-related death rate recorded during pre- and post-vaccination pandemic periods, revealed a quite stable outcome in SSc patients ( death rate from 2.54 % to 1.76 %; p = ns), despite the significant drop of mortality observed in the Italian general population (from 2.95 % to 0.29 %; p < 0.0001)., Conclusions: An increased COVID-19 prevalence and mortality rate was recorded in SSc patients; moreover, the efficacy of vaccines in term of improved outcomes was less evident in SSc compared to Italian general population. This discrepancy might be explained by concomitant adverse prognostic factors: increased rate of non-responders to vaccine in SSc series, low percentage of individuals with four or more doses of vaccine, ongoing immunomodulating treatments, disease-related interstitial lung disease, and/or reduced preventive measures in the second half of pandemic. A careful monitoring of response to COVID-19 vaccines together with adequate preventive/therapeutical strategies are highly recommendable in the near course of pandemic in this frail patients' population., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Alessandro Antonelli reports financial support was provided by Italian 10.13039/100009647Ministry of Health, Ricerca Finalizzata (RF-2021-12374986) Destinatario istituzionale: Regione Toscana. Unità Operative:U.O.1: Azienda Ospedaliero-Universitaria Pisana; U.O.2: Azienda Ospedaliero-Universitaria Aldo Moro Bari; U.O.3: Azienda Ospedaliero-Universitaria Modena, CUP Master: D55E22000670001., (© 2023 Published by Elsevier B.V.)

Purpose: Comparative outcome data after intraoperative radiation therapy and whole breast irradiation (WBI) for breast cancer at >10 years median follow-up are rare. We present a mature, single-institution, matched-pair comparison reporting survival and relapse rates in patients treated with either modality., Methods and Materials: Complete data sets for 258 intraoperative electron radiation therapy (IOERT) patients treated between 2000 and 2010 were matched with 258 patients postoperatively treated with WBI by age/histology/tumor size, grading/lymph-node-status/hormone receptors/type of adjuvant therapy/surgical margins, and treatment date. Relapse at surgical intervention site was classified as true local recurrence (LR). All recurrences in the treated breast (any quadrant) were classified as ipsilateral recurrence (IR)., Results: Median follow-up was 157 months (12-251) for the IOERT group and 154 months (31-246) for the WBI group. Cumulative incidence of IR at 5, 10, and 15 years was 2.4%, 7.9%, and 12.7% for IOERT and 1.2%, 4.1%, and 5.0% for WBI (P = .02). Cumulative incidence of LR at 5, 10, and 15 years was 1.6%, 5.1%, and 8.3% for IOERT and 0.4%, 2.1%, and 2.5% for WBI (P = .02). No differences in overall survival, disease-free survival, second cancer incidence, or cardiac events were recorded in either treatment group. Outcome was better in the accelerated partial breast irradiation (APBI)-suitable group than in the APBI-unsuitable group (2009 criteria) (cumulative incidence of IR at 5, 10, and 15 years was 0% vs 7.3%, 6.1% vs 13.3%, and 7.3% vs 19.9% for IOERT and 0% vs 1.8%, 2.0% vs 3.9%, and 3.1% vs 3.9% for WBI) and in the revised APBI-suitable group than in the APBI-cautionary group (2017 criteria) (cumulative incidence of IR at 5, 10, and 15 years was 1.1% vs 6.4%, 6.2% vs 13.3%, and 7.8% vs 27.5% for IOERT and 1.7% vs 0%, 4.1% vs 4.4%, and 5.4% vs 4.4% for WBI)., Conclusions: The IR and LR rate were higher after IOERT than after WBI for the American Society for Radiation Oncology suitable patient group, although without reaching statistical significance. Thus, IOERT could be an alternative to WBI upon stringent patient selection, but patients should be counseled carefully about the potential for increased IR rate with IOERT. Second cancer incidence and cardiac events did not differ between IOERT and WBI., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aims: During pregnancy, fetal cells can migrate to the mother via blood circulation. A percentage of these cells survive in maternal tissues for decades generating a population of fetal microchimeric cells (fMCs), whose biological role is unclear. The aim of this study was to investigate the association between the sex of offspring, an indirect marker of fMCs, and magnetic resonance imaging (MRI) features in women with multiple sclerosis (MS)., Methods: We recruited 26 nulliparous MS patients (NPp), 20 patients with at least one male son (XYp), and 8 patients with only daughters (XXp). Each patient underwent brain MR scan to acquire 3D-T2w FLAIR FatSat and 3D-T1w FSPGR/TFE. Lesion Segmentation Tool (LST) and FreeSurfer were used to obtain quantitative data from MRI. Additional data were collected using medical records. Multiple regression models were applied to evaluate the association between sex of offspring and MS data., Results: Comparing NPp and XXp, we found that NPp had larger 4th ventricle volume (2.02 ± 0.59 vs. 1.70 ± 0.41; p = 0.022), smaller left entorhinal volume (0.55 ± 0.17 vs. 0.68 ± 0.25; p = 0.028), and lower thickness in the following cortical areas: left paracentral (2.34 ± 0.16 vs. 2.39 ± 0.17; p = 0.043), left precuneus (2.27 ± 0.11 vs. 2.34 ± 0.16; p = 0.046), right lateral occipital (2.14 ± 0.11 vs. 2.25 ± 0.08; p = 0.006). NPp also had lower thickness in left paracentral cortex (2.34 ± 0.16 vs. 2.46 ± 0.17; p = 0.004), left precalcarine cortex (1.64 ± 0.14 vs. 1.72 ± 0.12; p = 0.041), and right paracentral cortex (2.34 ± 0.17 vs. 2.42 ± 0.14; p = 0.015) when compared to XYp. Comparing XYp and XXp, we found that XYp had higher thickness in left cuneus (1.80 ± 0.14 vs. 1.93 ± 0.10; p = 0.042) and left pericalcarine areas (1.59 ± 0.19 vs. 1.72 ± 0.12; p = 0.032) and lower thickness in right lateral occipital cortex (2.25 ± 0.08 vs. 2.18 ± 0.13; p = 0.027)., Discussion: Our findings suggested an association between the sex of offspring and brain atrophy. Considering the sex of offspring as an indirect marker of fMCs, we speculated that fMCs could accumulate in different brain areas modulating MS neuropathological processes., Competing Interests: GSa received grants outside of this study, for speaking or consultancies from: Almirall, Biogen, Merck, Novartis, Roche, and Sanofi Genzyme. PR received grants outside of this study for speaking or consultancies from: Biogen, Bristoll-Myers-Squibb, Merck, Novartis, Roche, and Sanofi Genzyme. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Bianchi, Aprile, Schirò, Gasparro, Iacono, Andolina, Marrale, Gattuso, La Tona, Midiri, Gagliardo, Salemi and Ragonese.)

Objective: Autoimmune systemic diseases (ASD) represent a predisposing condition to COVID-19. Our prospective, observational multicenter telephone survey study aimed to investigate the prevalence, prognostic factors, and outcomes of COVID-19 in Italian ASD patients., Methods: The study included 3,918 ASD pts (815 M, 3103 F; mean age 59±12SD years) consecutively recruited between March 2020 and May 2021 at the 36 referral centers of COVID-19 and ASD Italian Study Group. The possible development of COVID-19 was recorded by means of a telephone survey using a standardized symptom assessment questionnaire., Results: ASD patients showed a significantly higher prevalence of COVID-19 (8.37% vs. 6.49%; p<0.0001) but a death rate statistically comparable to the Italian general population (3.65% vs. 2.95%). Among the 328 ASD patients developing COVID-19, 17% needed hospitalization, while mild-moderate manifestations were observed in 83% of cases. Moreover, 12/57 hospitalized patients died due to severe interstitial pneumonia and/or cardiovascular events; systemic sclerosis (SSc) patients showed a significantly higher COVID-19-related death rate compared to the general population (6.29% vs. 2.95%; p=0.018). Major adverse prognostic factors to develop COVID-19 were: older age, male gender, SSc, pre-existing ASD-related interstitial lung involvement, and long-term steroid treatment. Of note, patients treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) showed a significantly lower prevalence of COVID-19 compared to those without (3.58% vs. 46.99%; p=0.000), as well as the SSc patients treated with low dose aspirin (with 5.57% vs. without 27.84%; p=0.000)., Conclusion: During the first three pandemic waves, ASD patients showed a death rate comparable to the general population despite the significantly higher prevalence of COVID-19. A significantly increased COVID-19- related mortality was recorded in only SSc patients' subgroup, possibly favored by preexisting lung fibrosis. Moreover, ongoing long-term treatment with csDMARDs in ASD might usefully contribute to the generally positive outcomes of this frail patients' population., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Autoimmune systemic diseases (ASD) may show impaired immunogenicity to COVID-19 vaccines. Our prospective observational multicenter study aimed to evaluate the seroconversion after the vaccination cycle and at 6-12-month follow-up, as well the safety and efficacy of vaccines in preventing COVID-19. The study included 478 unselected ASD patients (mean age 59 ± 15 years), namely 101 rheumatoid arthritis (RA), 38 systemic lupus erythematosus (SLE), 265 systemic sclerosis (SSc), 61 cryoglobulinemic vasculitis (CV), and a miscellanea of 13 systemic vasculitis. The control group included 502 individuals from the general population (mean age 59 ± 14SD years). The immunogenicity of mRNA COVID-19 vaccines (BNT162b2 and mRNA-1273) was evaluated by measuring serum IgG-neutralizing antibody (NAb) (SARS-CoV-2 IgG II Quant antibody test kit; Abbott Laboratories, Chicago, IL) on samples obtained within 3 weeks after vaccination cycle. The short-term results of our prospective study revealed significantly lower NAb levels in ASD series compared to controls [286 (53-1203) vs 825 (451-1542) BAU/mL, p < 0.0001], as well as between single ASD subgroups and controls. More interestingly, higher percentage of non-responders to vaccine was recorded in ASD patients compared to controls [13.2% (63/478), vs 2.8% (14/502); p < 0.0001]. Increased prevalence of non-response to vaccine was also observed in different ASD subgroups, in patients with ASD-related interstitial lung disease (p = 0.009), and in those treated with glucocorticoids (p = 0.002), mycophenolate-mofetil (p < 0.0001), or rituximab (p < 0.0001). Comparable percentages of vaccine-related adverse effects were recorded among responder and non-responder ASD patients. Patients with weak/absent seroconversion, believed to be immune to SARS-CoV-2 infection, are at high risk to develop COVID-19. Early determination of serum NAb after vaccination cycle may allow to identify three main groups of ASD patients: responders, subjects with suboptimal response, non-responders. Patients with suboptimal response should be prioritized for a booster-dose of vaccine, while a different type of vaccine could be administered to non-responder individuals., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The Covid-19 pandemic may have a deleterious impact on patients with autoimmune systemic diseases (ASD) due to their deep immune-system alterations., Objective: This study aims to investigate the prevalence of symptomatic Covid-19 and its correlations with both organ involvement and ongoing treatments in a large series of Italian ASD patients during the first wave of pandemic., Methods: Our multicenter telephone 6-week survey included 3,029 unselected ASD patients enrolled at 36 tertiary referral centers of northern, central, and southern Italian macro-areas with different diffusion of the pandemic. Symptomatic SARS-CoV-2 infection was classified as definite Covid-19 (presence of symptoms plus positive oral/nasopharyngeal swabs) or highly suspected Covid-19 (highly suggestive symptoms, in the absence of a swab testing)., Results: A significantly higher prevalence of definite plus highly suspected Covid-19 compared to the Italian general population was detected in the whole ASD series (p=.000), as well as in patients from the three macro-areas (p=.000 in all). Statistically higher prevalence of Covid-19 was also found in connective tissue diseases compared to chronic arthritis subgroup (p=.000) and in ASD patients with pre-existing interstitial lung involvement (p=.000). Patients treated with either conventional disease-modifying anti-rheumatic drugs (DMARDs) and/or biological DMARDs showed a significantly lower prevalence of Covid-19 (p=.000 in both). Finally, scleroderma patients undergoing low-dose aspirin showed a significantly lower rate of Covid-19 compared to those without (p=0.003)., Conclusion: The higher prevalence of Covid-19 in ASD patients, along with the significant correlations with important clinical features and therapeutic regimens, suggests the need to develop targeted prevention/management strategies during the current pandemic wave., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: Covid-19 infection poses a serious challenge for immune-compromised patients with inflammatory autoimmune systemic diseases. We investigated the clinical-epidemiological findings of 1641 autoimmune systemic disease Italian patients during the Covid-19 pandemic., Method: This observational multicenter study included 1641 unselected patients with autoimmune systemic diseases from three Italian geographical areas with different prevalence of Covid-19 [high in north (Emilia Romagna), medium in central (Tuscany), and low in south (Calabria)] by means of telephone 6-week survey. Covid-19 was classified as (1) definite diagnosis of Covid-19 disease: presence of symptomatic Covid-19 infection, confirmed by positive oral/nasopharyngeal swabs; (2) highly suspected Covid-19 disease: presence of highly suggestive symptoms, in absence of a swab test., Results: A significantly higher prevalence of patients with definite diagnosis of Covid-19 disease, or with highly suspected Covid-19 disease, or both the conditions together, was observed in the whole autoimmune systemic disease series, compared to "Italian general population" (p = .030, p = .001, p = .000, respectively); and for definite + highly suspected diagnosis of Covid-19 disease, in patients with autoimmune systemic diseases of the three regions (p = .000, for all comparisons with the respective regional general population). Moreover, significantly higher prevalence of definite + highly suspected diagnosis of Covid-19 disease was found either in patients with various "connective tissue diseases" compared to "inflammatory arthritis group" (p < .000), or in patients without ongoing conventional synthetic disease-modifying anti-rheumatic drugs treatments (p = .011)., Conclusions: The finding of a higher prevalence of Covid-19 in patients with autoimmune systemic diseases is particularly important, suggesting the need to develop valuable prevention/management strategies, and stimulates in-depth investigations to verify the possible interactions between Covid-19 infection and impaired immune-system of autoimmune systemic diseases. Key Points • Significantly higher prevalence of Covid-19 is observed in a large series of patients with autoimmune systemic diseases compared to the Italian general population, mainly due to patients' increased susceptibility to infections and favored by the high exposure to the virus at medical facilities before the restriction measures on individual movement. • The actual prevalence of Covid-19 in autoimmune systemic diseases may be underestimated, possibly due to the wide clinical overlapping between the two conditions, the generally mild Covid-19 disease manifestations, and the limited availability of virological testing. • Patients with "connective tissue diseases" show a significantly higher prevalence of Covid-19, possibly due to deeper immune-system impairment, with respect to "inflammatory arthritis group". • Covid-19 is more frequent in the subgroup of autoimmune systemic diseases patients without ongoing conventional synthetic disease-modifying anti-rheumatic drugs, mainly hydroxyl-chloroquine and methotrexate, which might play some protective role against the most harmful manifestations of Covid-19.

Background: Elderly breast cancer patients are frequently affected by significant comorbidities that make sophisticated radiotherapy treatments particularly challenging., Aims: We dosimetrically analyzed two different simple free-breathing external beam radiotherapy (EBRT) techniques for the hypofractionated treatment of the left breast in elderly patients with a low compliance, to compare target coverage, and heart and left anterior descending coronary artery (LADCA) sparing., Methods: We developed radiation plans for 24 elderly patients using 3D conformal (3DCRT) field-in-field tangential technique and intensity-modulated (IMRT) tangential beam technique. Dose-Volume-Histograms (DVHs) were used to provide a quantitative comparison between plans., Results: The median breast volume was 645 cm 3 . IMRT and 3DCRT plans comparison demonstrated no significant differences in terms of organ sparing for the heart. Regarding LADCA, mean dose (10.3 ± 9.5 Gy vs 11.9 ± 9.6 Gy, p = 0.0003), maximum dose (26.1 ± 16.1 Gy vs 29.1 ± 16.1 Gy, p = 0.004) and V 17 Gy (21.5% ± 26.9% vs 25.0% ± 27.2%, p = 0.002) significantly decreased using IMRT compared with 3DCRT. IMRT plans showed a better target coverage compared with 3DCRT (0.91 ± 0.05 vs 0.93 ± 0.04, p = 0.05)., Discussion: Comparing the two different EBRT techniques, we demonstrated few, although substantial, dosimetric differences in terms of doses to the organs at risk characterized by a statistically significant dose reduction of LADCA in the IMRT plans., Conclusions: Elderly patients with a low compliance to treatment might benefit from 3DCRT with field-in-field tangential arrangement or from a simple IMRT approach. IMRT should be preferred.

Purpose: To report criticisms and barriers to the "real-life" application of international guidelines and recent developments in the management of locally advanced non-small cell lung cancer (NSCLC) in Italy., Methods: Three 2-day courses were organized. During the first day, experts in different fields of thoracic oncology gave their lecture on diagnosis and therapy for locally advanced NSCLC. During the second day, all participants were divided into four groups to discuss on a clinical case as a multidisciplinary team (MDT). The aim was to stimulate the discussion on practical issues in the management of NSCLC patients in the real-life practice., Results: A total of 196 physicians were involved in the courses as learners. Invasive diagnosis of nodal disease for staging purposes, a priori definition of "surgical resectability" and a regular MDT with all crucial participants available were the three main key points identified for a good management of these patients. The main barriers to the clinical application of a good diagnostic and therapeutic approach to the patient were the absence of a regular and complete MDT in the South and Centre of Italy, while in the North of Italy, time for discussion of clinical cases in the MDT and waiting lists for staging and therapeutic interventions were deemed as the major concerns., Conclusion: The meetings showed that diagnosis and treatment of locally advanced NSCLC are still extremely variable between different Italian regions. Logistic issues, waiting lists, paucity of well-trained staff and expertise seem to be the main barriers to international guidelines application.

Introduction: Post-marketing surveillance activities (namely pharmacovigilance) are crucial to favor the early detection of unexpected adverse events (AEs) and/or serious adverse reactions (SAEs). Indeed, spontaneous reporting of AEs has been demonstrated to underestimate the number of events in different clinical settings. Aim of the present study is to report the preliminary data of a Regional (Calabria, Italy) Pharmacovigilance Program (CBPP) aimed at improving AEs' reporting associated with biologics use in rheumatology., Materials and Methods: We developed a simple, cost-effective pharmacovigilance program based on regular training sessions for physicians (stimulated reporting), periodical phone calls by a clinical pharmacologist aimed at identifying new events and stimulating self-awareness and encouraging reporting to the physician during the subsequent follow-up visit for minor AEs. To test this approach, all consecutive patients undergoing treatment with one biologic agent at eight rheumatology centers during a two-years period were invited to participate. Collected AEs were compared to the number of AEs spontaneously reported for the same molecules in the same centers before starting the protocol., Results: During the study period, 399 patients (245 females; mean age: 58 ± 11 years) were started on treatment with biologics for active RA (n = 211, 52.9%), PsA (n = 119, 29.8%) or AS (n = 69, 17.3%) at eight rheumatology centers. A total of 125 AEs (31.3%) and 9 SAEs (2.3%) were reported during the two-years study period. In the control cohort (comprising 368 consecutive patients started on treatment with bDMARDs during a two-years period before CBPP study) only 42 (11.4%) AEs and no SAEs were reported (p < 0.0001). The most common AEs were injection site reactions and skin disorders., Conclusions: In conclusion, our study provides further evidence of a critical role of active pharmacovigilance in detection, reporting and analysis of AEs in rheumatology., Competing Interests: The authors have declared that no competing interests exist.

T cells compete with malignant cells for limited nutrients within the solid tumor microenvironment. We found that effector memory CD4 T cells respond distinctly from other T cell subsets to limiting glucose and can maintain high levels of interferon-γ (IFN-γ) production in a nutrient-poor environment. Unlike naive (T N ) or central memory T (T CM ) cells, effector memory T (T EM ) cells fail to upregulate fatty acid synthesis, oxidative phosphorylation, and reductive glutaminolysis in limiting glucose. Interference of fatty acid synthesis in naive T cells dramatically upregulates IFN-γ, while increasing exogenous lipids in media inhibits production of IFN-γ by all subsets, suggesting that relative ratio of fatty acid metabolism to glycolysis is a direct predictor of T cell effector activity. Together, these data suggest that effector memory T cells are programmed to have limited ability to synthesize and metabolize fatty acids, which allows them to maintain T cell function in nutrient-depleted microenvironments., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Niemann Pick A disease causes a progressive accumulation of sphyngomyelin in several organs and the survival of the patients is usually limited to three years. We describe the outcome of a patient suffering from Niemann Pick A disease, who first underwent an haploidentical bone marrow transplantation, and then intrathecal and I.V injections of mesenchymal cells., Methods and Results: While the outcome of bone marrow transplantation was a complete failure, one month after the treatment with the mesenchymal cells the patient improved from the psychomotor and the parenchymal storage perspective. When hypersplenism was solved platelets rose quickly from 20,000 to 120,000/microliter., Conclusions: Therefore cellular therapy should be considered as a possible choice of treatment of NPA disease.

Background and Objectives: SMA1 is a genetic disease that leads to a progressive apoptosis of the second motoneuron and then to a complete paralysis. There are reports of efficacy of mesenchymal cells in the treatment of other neurological diseases; therefore we decided to treat some children with these cells., Methods and Results: Four children suffering from SMA1 were treated by means of intrathecal injections of mesenchymal cells. All patients improved their motility after three weeks. The effect was relevant at the distal muscles, while the proximal ones were less affected. The treatment was repeated once a month for 3∼ 8 months as the effect of the treatment lasted not more than 30 days. One patient who withdrew the treatment died after 45 days. Another patient resulted completely paralysed after two months after quitting the cell therapy but he regained the skills after a new injection. Two patients are stable after the first improvement., Conclusions: Intrathecal injections of mesenchymal cells improve the motility of children suffering from SMA1. We argue that an early treatment, before the onset of irreversible neurological damages, could result in the cure of this disease.

Background: Mesenchymal stromal cells (MSC) have been proven to have potent immunosuppressive action and hence have been proposed for the treatment of severe Graft Versus Host Disease. However, in most models, MSC were added at the same time of lymphocyte stimulation, which is quite different from what occurs in vivo., Aims: To investigate how the timing of lymphocyte activation and the exposure to activation-related cytokines (licensing) can influence the immunosuppressive action of Wharton's jelly stromal cells (WJSC)., Methods: WJSC, licensed or not with activation-related cytokines, were added lymphocytes the same time or 24 hours after their stimulation with phytohaemoagglutinin. Proliferation of lymphocytes and cytokines production was measured after three days co-culture., Results: Lymphocytes stimulated in the presence of WJSC displayed a dramatic decrease in proliferation and production of cytokines, in spite of normal expression of activation markers. The suppression was weakened when targeted lymphocytes were seperated by a membrane and partially rescued by the addition of exogenous l-tryptophan, suggesting a major role for indoleamine 2,3-dioxigenase with a probable paracrine effect. Licensing of WJSC increased the immunosuppressive effect, in both contact and non-contact settings. The timing of WJSC licensing was crucial for the immunosuppressive action. Lymphocytes pre-stimulated alone for 24 h, and added afterwards to non-licensed WJSC, showed normal or even increased proliferation. On the other hand, their proliferation was strongly inhibited by licensed WJSC., Conclusions: WJSC have a potent immunosuppressive function best realized with direct contact, and increased by licensing signals before and during lymphocyte stimulation. Our results could contribute to the set up of new WJSC-based therapies for severe autoimmuno disorders.

Over the last decade, hematopoietic stem cells transplantation (HSCT) has been increasingly used in the treatment of severe progressive autoimmune diseases. We report a retrospective survey of 183 multiple sclerosis (MS) patients, recorded in the database of the European Blood and Marrow Transplantation Group (EBMT). Transplant data were available from 178 patients who received an autologous graft. Overall, transplant related mortality (TRM) was 5.3% and was restricted to the period 1995-2000, with no further TRM reported since then. Busulphan-based regimens were significantly associated with TRM. Clinical status at the time of transplant and transplant techniques showed some correlations with toxicity. No toxic deaths were reported among the 53 patients treated with the BEAM (carmustine, etoposide, cytosine-arabinoside, melphalan)/antithymocyte globulin (ATG) regimen without graft manipulation, irrespective of their clinical condition at the time of the transplant. Improvement or stabilization of neurological conditions occurred in 63% of patients at a median follow-up of 41.7 months, and was not associated with the intensity of the conditioning regimen. In this large series, HSCT was shown as a promising procedure to slow down progression in a subset of patients affected by severe, progressive MS; the safety and feasibility of the procedure can be significantly improved by appropriate patient selection and choice of transplant regimen.

We report a long-lasting (8-month) reactivation of human herpesvirus 6 (HHV-6) infection in child who had undergone cord blood stem cell transplantation. The reactivation was characterized by high viral loads and by immediate-early mRNA positivity. HHV-6 infection was associated with a deep depletion of CD3, while the CD4/CD8 ratio remained substantially unchanged.

CD40 ligand (CD40L) deficiency causes recurrent sinopulmonary infection, Pneumocystis carinii pneumonia, and Cryptosporidium parvum infection. Approximately 40% to 50% of patients survive to the third decade: long-term survival is unclear. Hematopoietic stem cell transplantation (HSCT) is curative. We present a retrospective analysis of 38 European patients undergoing HSCT for CD40L deficiency in 8 European countries between 1993 and 2002. Donor stem cell source included 14 HLA-identical siblings, 22 unrelated donors, and 2 phenotypically matched parental stem cells (12 T-cell depleted). Of the patients, 34 engrafted and 26 (68%) survived; 3 had autologous reconstitution, 22 (58%) were cured, and 1 engrafted but has poor T-cell immune reconstitution. There were 18 evaluated patients who responded to vaccination. Of the patients, 12 (32%) died from infection-related complications, with severe cryptosporidiosis in 6. Grades 2 to 4 graft-versus-host disease (GvHD) associated with infection occurred in 6 of 12 fatal cases. HSCT cured 58% of patients, 72% of those without hepatic disease. Early T-cell function following whole marrow HSCT may limit cryptosporidial disease, but survival was similar after T-cell-depleted HSCT. Preexisting lung damage was the most important adverse risk factor. Further studies will determine optimal timing and type of HSCT.

Unlabelled: Among 94 osteopetrotic patients presenting with a severe clinical picture and diagnosed early in life, 12 bore mutations in the ClCN7 gene, but only 7 of them had the expected two recessive mutations. The remaining five patients seem to be heterozygous for a ClCN7 mutation, and significant variations were observed in the clinical manifestations of their disease, even within the same family., Introduction: Human osteopetroses are a heterogeneous group of diseases that include both infantile severe, autosomal recessive (ARO) and adult autosomal dominant (ADO) forms. Two genes, Atp6a3 (TCIRG1) and ClCN7, have been shown to be associated with human ARO, the latter of which is also thought to be responsible for ADO-II. However, patients with an intermediate phenotype have been described: the genetic basis of these observances is unknown., Materials and Methods: In this study, we report the clinical and molecular analysis of 94 patients in which a diagnosis of severe osteopetrosis was made within the first 2 years of age. Both TCIRG1 and CLCN7 genes were sequenced in all patients and the molecular findings were correlated to clinical parameters., Results and Conclusions: In 56 of 94 patients with a classical picture of ARO, TCIRG1-dependent recessive mutations were found. In contrast, ClCN7 mutations were found in 12 cases (13%) of severe osteopetrosis, but only 7 of them had two recessive mutations identified: in 6 of these 7 cases, central nervous system manifestations were noted, and these patients had a poor prognosis. The remaining five cases were heterozygous for a ClCN7 mutation, including two brothers from a large family with a history of ADO-II in which the presence of a second ClCN7 mutation was formally excluded. Despite an early and severe clinical presentation, these five patients all reached adulthood, suggesting that the degree of dominant interference with chloride channel function can vary widely. Our findings suggest that recessive ClCN7-dependent ARO may be associated with CNS involvement and have a very poor prognosis, whereas heterozygous ClCN7 mutations cause a wide range of phenotypes even in the same family, ranging from early severe to nearly asymptomatic forms. These findings have prognostic implications, might complicate prenatal diagnosis of human osteopetroses, and could be relevant to the management of these patients.

Human malignant infantile osteopetrosis (arOP; MIM 259700) is a genetically heterogeneous autosomal recessive disorder of bone metabolism, which, if untreated, has a fatal outcome. Our group, as well as others, have recently identified mutations in the ATP6i (TCIRG1) gene, encoding the a3 subunit of the vacuolar proton pump, which mediates the acidification of the bone/osteoclast interface, are responsible for a subset of this condition. By sequencing the ATP6i gene in arOP patients from 44 unrelated families with a worldwide distribution we have now established that ATP6i mutations are responsible for approximately 50% of patients affected by this disease. The vast majority of these mutations (40 out of 42 alleles, including seven deletions, two insertions, 10 nonsense substitutions and 21 mutations in splice sites) are predicted to cause severe abnormalities in the protein product and are likely to represent null alleles. In addition, we have also analysed nine unrelated arOP patients from Costa Rica, where this disease is apparently much more frequent than elsewhere. All nine Costa Rican patients bore either or both of two missense mutations (G405R and R444L) in amino acid residues which are evolutionarily conserved from yeast to humans. The identification of ATP6i gene mutations in two families allowed us for the first time to perform prenatal diagnosis: both fetuses were predicted not to be affected and two healthy babies were born. This study contributes to the determination of genetic heterogeneity of arOP and allows further delineation of the other genetic defects causing this severe condition.