Search

The clinical diagnosis of synucleinopathies, including Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), is challenging, especially at an early disease stage, due to the heterogeneous and often non-specific clinical manifestations. The discovery of reliable specific markers for synucleinopathies would consequently be of great aid to the diagnosis and management of these disorders. Real-Time Quaking-Induced Conversion (RT-QuIC) is an ultrasensitive technique that has been previously used to detect self-templating amyloidogenic proteins in the cerebrospinal fluid (CSF) and other biospecimens in prion disease and synucleinopathies. Using a wild-type recombinant α-synuclein as a substrate, we applied RT-QuIC to a large cohort of 439 CSF samples from clinically well-characterized, or post-mortem verified patients with parkinsonism or dementia. Of significance, we also studied patients with isolated REM sleep behavior disorder (iRBD) (n = 18) and pure autonomic failure (PAF) (n = 28), representing clinical syndromes that are often caused by a synucleinopathy, and may precede the appearance of parkinsonism or cognitive decline. The results show that our RT-QuIC assay can accurately detect α-synuclein seeding activity across the spectrum of Lewy Body (LB)-related disorders (LBD), including DLB, PD, iRBD, and PAF, with an overall sensitivity of 95.3%. In contrast, all but two patients with MSA showed no α-synuclein seeding activity in the applied experimental setting. The analysis of the fluorescence response reflecting the amount of α-synuclein seeds revealed no significant differences between the clinical syndromes associated with LB pathology. Finally, the assay demonstrated 98% specificity in a neuropathological cohort of 101 cases lacking LB pathology. In conclusion, α-synuclein RT-QuIC provides an accurate marker of synucleinopathies linked to LB pathology and may have a pivotal role in the early discrimination and management of affected patients. The finding of no α-synuclein seeding activity in MSA seems to support the current view that MSA and LBD are associated with different conformational strains of α-synuclein. Electronic supplementary material The online version of this article (10.1007/s00401-020-02160-8) contains supplementary material, which is available to authorized users.

Objective To analyze Italian Cardiac Surgery experience during the pandemic of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) identifying risk factors for overall mortality according to coronavirus disease 2019 (COVID‐19) status. Methods From February 20 to May 31, 2020, 1354 consecutive adult patients underwent cardiac surgery at 22 Italian Centers; 589 (43.5%), patients came from the red zone. Based on COVID‐19 status, 1306 (96.5%) were negative to SARS‐CoV‐2 (COVID‐N), and 48 (3.5%) were positive to SARS‐CoV‐2 (COVID‐P); among the COVID‐P 11 (22.9%) and 37 (77.1%) become positive, before and after surgery, respectively. Surgical procedures were as follows: 396 (29.2%) isolated coronary artery bypass grafting (CABG), 714 (52.7%) isolated non‐CABG procedures, 207 (15.3%) two associate procedures, and three or more procedures in 37 (2.7%). Heart failure was significantly predominant in group COVID‐N (10.4% vs. 2.5%, p = .01). Results Overall in‐hospital mortality was 1.6% (22 cases), being significantly higher in COVID‐P group (10 cases, 20.8% vs. 12, 0.9%, p

In recent decades, high income countries (HIC) have been exposed to huge human migratory flows. Consistent with this influx, there has been a dramatic increase in the number of chronic kidney disease (CKD) patients in the immigrant population. In Italy, comparisons between Italian and immigrant CKD patients are still lacking, thus we aimed to describe the baseline clinical characteristics and the main outcomes of CKD patients who immigrated to Italy and reside in the Emilia Romagna region. This is a retrospective cohort study based on CKD patients from the Prevenzione Insufficienza Renale Progressiva (PIRP) project, which included 963 (3.1%) immigrants among the 30,702 patients seen by nephrologists between April 1st, 2004 and June 30th, 2020. We sub-divided the immigrants into seven groups based on their area of origin, and compared their baseline characteristics, CKD progression and time to end-stage kidney disease (ESKD) to those of Italian CKD patients. At presentation, Italian subjects were on average older (73.1 years) and had less preserved kidney function (eGFR 34.3 ml/min), while South and East Asians had the highest proportion of diabetes and obesity (approximately 45% and 30%, respectively). At 4-year follow-up, about 20% of patients from South Asia, Eastern Europe and Arab Countries were diagnosed with ESKD, compared to only 11% of Italians and Latin Americans. We found important differences between Italian and immigrant CKD patients, as well as among immigrant subgroups. First clinical encounters with nephrologists revealed that immigrants had varied patterns of clinical presentation and of nephropathy. During follow-up, immigrants showed faster kidney function decline which led to a higher risk of disease evolution and progression towards ESKD.

ObjectiveTo investigate whether the CSF α-synuclein (α-syn) real-time quaking-induced conversion (RT-QuIC) assay accurately identifies patients with mild cognitive impairment (MCI) due to probable Lewy body (LB) disease.MethodsWe applied α-syn RT-QuIC to 289 CSF samples obtained from 2 independent cohorts, including 81 patients with probable MCI-LB (age 70.7 ± 6.6 years, 13.6% female, Mini-Mental State Examination [MMSE] score 26.1 ± 2.4), 120 with probable MCI due to Alzheimer disease (AD) (age 68.6 ± 7.4 years, 45.8% female, MMSE score 25.5 ± 2.8), and 30 with unspecified MCI (age 65.4 ± 9.3 years, 30.0% female, MMSE score 27.0 ± 3.0). Fifty-eight individuals with no cognitive decline or evidence of neurodegenerative disease and 121 individuals lacking brain α-syn deposits at the neuropathologic examination were used as controls.ResultsRT-QuIC identified patients with MCI-LB against cognitively unimpaired controls with 95% sensitivity, 97% specificity, and 96% accuracy and showed 98% specificity in neuropathologic controls. The accuracy of the test for MCI-LB was consistent between the 2 cohorts (97.3% vs 93.7%). Thirteen percent of patients with MCI-AD also had a positive test; of note, 44% of them developed 1 core or supportive clinical feature of dementia with Lewy bodies (DLB) at follow-up, suggesting an underlying LB copathology.ConclusionsThese findings indicate that CSF α-syn RT-QuIC is a robust biomarker for prodromal DLB. Further studies are needed to fully explore the added value of the assay to the current research criteria for MCI-LB.Classification of EvidenceThis study provides Class III evidence that CSF α-syn RT-QuIC accurately identifies patients with MCI-LB.

The current classification of sporadic Creutzfeldt–Jakob disease (sCJD) includes six major clinicopathological subtypes defined by the physicochemical properties of the protease-resistant core of the pathologic prion protein (PrPSc), defining two major PrPSc types (i.e., 1 and 2), and the methionine (M)/valine (V) polymorphic codon 129 of the prion protein gene (PRNP). How these sCJD subtypes relate to the well-documented phenotypic heterogeneity of genetic CJD (gCJD) is not fully understood. We analyzed molecular and phenotypic features in 208 individuals affected by gCJD, carrying 17 different mutations, and compared them with those of a large series of sCJD cases. We identified six major groups of gCJD based on the combination PrPSc type and codon 129 genotype on PRNP mutated allele, each showing distinctive histopathological characteristics, irrespectively of the PRNP associated mutation. Five gCJD groups, named M1, M2C, M2T, V1, and V2, largely reproduced those previously described in sCJD subtypes. The sixth group shared phenotypic traits with the V2 group and was only detected in patients carrying the E200K-129M haplotype in association with a PrPSc type of intermediate size (“i”) between type 1 and type 2. Additional mutation-specific effects involved the pattern of PrP deposition (e.g., a “thickened” synaptic pattern in E200K carriers, cerebellar “stripe-like linear granular deposits” in those with insertion mutations, and intraneuronal globular dots in E200K-V2 or -M”i”). A few isolated cases linked to rare PRNP haplotypes (e.g., T183A-129M), showed atypical phenotypic features, which prevented their classification into the six major groups. The phenotypic variability of gCJD is mostly consistent with that previously found in sCJD. As in sCJD, the codon 129 genotype and physicochemical properties of PrPSc significantly correlated with the phenotypic variability of gCJD. The most common mutations linked to CJD appear to have a variable and overall less significant effect on the disease phenotype, but they significantly influence disease susceptibility often in a strain-specific manner. The criteria currently used for sCJD subtypes can be expanded and adapted to gCJD to provide an updated classification of the disease with a molecular basis.

Background This group previously reported on the repair of a wide tracheoesophageal fistula with a bioabsorbable patch. The current study describes a consecutive series of patients operated on using the same technique. Methods Data of patients undergoing surgical closure of tracheoesophageal fistula at a single center from 2011 to 2018 were extracted and analyzed. Results An absorbable patch was used in 8 of 23 patients (34.8%) operated on for tracheoesophageal fistula during the study period. Causes of the fistulae included postintubation injury (n = 6), mediastinal radiotherapy (n = 1), and a complication of lung resection (n = 1). The median fistula size was 27.5 mm (range, 15 to 45 mm). In 3 patients, the surgical approach was through cervicotomy and in 5 it was through right thoracotomy. Prosthetic materials consisted of Gore Bio-A (W.L. Gore & Associates, Inc, Newark, DE) tissue reinforcement in 6 patients and polyglactin 910 knitted mesh in 2 patients. In every case, the prosthesis was covered with a pedicled muscle flap. The esophageal defect was treated by primary closure in 7 patients and by esophageal exclusion in 1. Fistula recurrence and postoperative death occurred in 1 patient (12.5%), whereas 7 patients experienced postoperative complications (87.5%). Five patients resumed oral intake, and 3 breathed without a tracheal appliance. Compared with the other patients, in those who underwent repair of their fistula using a prosthesis, the median size of the airway defect was larger, morbidity was greater, and the rate of resumption of oral intake was lower. Conclusions Repair of tracheoesophageal fistulae with synthetic prostheses is feasible and may be effective in complex cases. Further research is needed to identify the ideal prosthetic material.

Introduction Surrogate cerebrospinal fluid (CSF) biomarkers of neurodegeneration still have a central role in the first‐line screening of patients with suspected Creutzfeldt‐Jakob disease (CJD). Recently, CSF α‐synuclein, a marker of synaptic damage, showed a close to optimal performance in distinguishing between CJD and other neurodegenerative dementias. Methods We evaluated the diagnostic value of CSF α‐synuclein in patients with prion disease, non‐prion rapidly progressive dementias, and non‐neurodegenerative controls. Additionally, we studied its distribution across the different prion disease subtypes and evaluated its association with survival. Results CSF α‐synuclein levels were significantly higher in patients with prion disease than in the other groups but showed a lower diagnostic value than CSF total tau or 14‐3‐3. Moreover, CSF α‐synuclein was significantly associated with survival in the whole prion cohort and the most frequent clinicopathological subtypes. Discussion In the clinical setting, CSF α‐synuclein does not exceed the diagnostic performance of currently used surrogate markers, but it might constitute a robust prognostic indicator.

Background In neurodegenerative dementias (NDs) such as prion disease, Alzheimer’s disease (AD), and frontotemporal lobar degeneration (FTLD), protein misfolding leads to the tissue deposition of protein aggregates which, in turn, trigger neuroinflammation and neurodegeneration. Cerebrospinal fluid (CSF) biomarkers have the potential to reflect different aspects of these phenomena across distinct clinicopathological subtypes and disease stages. Methods We investigated CSF glial markers, namely chitotriosidase 1 (CHIT1), chitinase-3-like protein 1 (YKL-40) and glial fibrillary acidic protein (GFAP) in prion disease subtypes (n = 101), AD (n = 40), clinicopathological subgroups of FTLD (n = 72), and controls (n = 40) using validated, commercially available ELISA assays. We explored glial biomarker levels’ associations with disease variables and neurodegenerative CSF biomarkers and evaluated their diagnostic accuracy. The genotype of the CHIT1 rs3831317 polymorphic site was also analyzed. Results Each ND group showed increased levels of CHIT1, YKL-40, and GFAP compared to controls with a difference between prion disease and AD or FTLD limited to YKL-40, which showed higher values in the former group. CHIT1 levels were reduced in both heterozygotes and homozygotes for the CHIT1 24-bp duplication (rs3831317) in FTLD and controls, but this effect was less significant in AD and prion disease. After stratification according to molecular subgroups, we demonstrated (i) an upregulation of all glial markers in Creutzfeldt-Jakob disease VV2 compared to other disease subtypes, (ii) a difference in CHIT1 levels between FTLD with TAU and TDP43 pathology, and (iii) a marked increase of YKL-40 in FTLD with amyotrophic lateral sclerosis (ALS) in comparison with FTLD without ALS. In prion disease, glial markers correlated with disease stage and were already elevated in one pre-symptomatic case of Gerstmann-Sträussler-Scheinker disease. Regarding the diagnostic value, YKL-40 was the only glial marker that showed a moderate accuracy in the distinction between controls and NDs. Conclusions NDs share a CSF profile characterized by increased levels of CSF CHIT1, YKL-40, and GFAP, which likely reflects a common neuroinflammatory response to protein misfolding and aggregation. CSF glial markers of neuroinflammation demonstrate limited diagnostic value but have some potential for monitoring the clinical and, possibly, preclinical phases of NDs.

Environmental enrichment may slow cognitive decay possibly acting through an improvement in vascular function. Aim of the study was to assess the effects of a 7-month cognitive, social, and physical training program on cognitive and vascular function in patients with mild cognitive impairment. In a single-center, randomized, parallel-group study, 113 patients (age, 65–89 years) were randomized to multidomain training (n=55) or usual care (n=58). All participants underwent neuropsychological tests and vascular evaluation, including brachial artery flow-mediated dilation, carotid–femoral pulse wave velocity, carotid distensibility, and assessment of circulating hematopoietic CD34+ and endothelial progenitor cells. At study entry, an age-matched control group (n=45) was also studied. Compared with controls, patients had at study entry a reduced flow-mediated dilation (2.97±2.14% versus 3.73±2.06%; P =0.03) and hyperemic stimulus (shear rate area under the curve, 19.1±15.7 versus 25.7±15.1×10 −3 ; P =0.009); only the latter remained significant after adjustment for confounders ( P =0.03). Training improved Alzheimer disease assessment scale cognitive (training, 14.0±4.8 to 13.1±5.5; nontraining, 12.1±3.9 to 13.2±4.8; P for interaction visit×training=0.02), flow-mediated dilation (2.82±2.19% to 3.40±1.81%, 3.05±2.08% to 2.24±1.59%; P =0.006; P =0.023 after adjustment for diameter and shear rate area under the curve), and circulating hematopoietic CD34 + cells and prevented the decline in carotid distensibility (18.4±5.3 to 20.0±6.6, 23.9±11.0 to 19.5±7.1 Pa −1 ; P =0.005). The only clinical predictor of improvement of cognitive function after training was established hypertension. There was no correlation between changes in measures of cognitive and vascular function. In conclusion, a multidomain training program slows cognitive decline, especially in hypertensive individuals. This effect is accompanied by improved systemic endothelial function, mobilization of progenitor CD34 + cells, and preserved carotid distensibility. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01725178.

Spinal cord injury (SCI) is a neurological disorder that arises from a primary acute mechanical lesion, followed by a pathophysiological cascade of events that leads to further spinal cord tissue damage. Several preclinical and clinical studies have highlighted the ability of stem cell therapy to improve long‐term functional recovery in SCI. Previously, we demonstrated that moringin (MOR) treatment accelerates the differentiation process in mesenchymal stem cells inducing an early up‐regulation of neural development associated genes. In the present study, we investigated the anti‐inflammatory, anti‐apoptotic, and regenerative effects of gingival mesenchymal stem cells (GMSCs) pretreated with nanostructured liposomes enriched with MOR in an animal model of SCI. SCI was produced by extradural compression of the spinal cord at levels T6–T7 in ICR (CD‐1) mice. Animals were randomly assigned to the following groups: Sham, SCI, SCI + GMSCs (1 × 106 cell/i.v.), SCI + MOR‐GMSCs (1 × 106 cell/i.v.). Our data show that MOR‐treated GMSCs exert anti‐inflammatory and anti‐apoptotic activities. In particular, MOR‐treated GMSCs are able to reduce the spinal cord levels of COX‐2, GFAP, and inflammatory cytokines IL‐1β and IL‐6 and to restore spinal cord normal morphology. Also, MOR‐treated GMSCs influenced the apoptotic pathway, by reducing Bax, caspase 3, and caspase 9 expressions.

About 15% of patients with myasthenia gravis are affected by thymoma. Precise tumor staging is necessary to plan the appropriate operation. In early stages, complete surgical resection is the mainstay of treatment. Minimally invasive approaches can be safely performed by highly trained surgeons, and may be preferred in myasthenic patients because they can ensure optimal results from the oncological, neurologic, and surgical point of views, avoiding the complications of open approach. For advanced stage thymoma in myasthenic patients, a careful, multidisciplinary planning of the therapeutic approach must be undertaken, particularly for extended resections involving the lung and great vessels.

BACKGROUND: Chronic lung allograft dysfunction remains an obstacle to long-term survival after lung transplantation. Two phenotypes have been described: obliterative bronchiolitis and restrictive allograft syndrome. Preclinical models are essential to analyze chronic lung allograft dysfunction pathophysiology. METHODS: Orthotopic lung transplants from 38 Lewis into Fischer 344 (Lew→F344) and 67 Brown-Norway into Lewis (BN→Lew) rats were performed in our center in the last decade. We carefully reviewed and quantified all grafts with chronic rejection (40 cases) (18 Lew→F344, 22 BN→Lew) with the aim to investigate if histological changes of chronic lung allograft dysfunction could be also detected in rat grafts. RESULTS: All animals showed human reminiscent histological lesions. Early chronic rejection lesions were detected in BN→Lew. End-stage chronic rejection with features of obliterative bronchiolitis was observed in 33% of Lew→F344; end-stage with restrictive allograft syndrome chronic rejection in 67% and 80% of Lew→F344 and BN→Lew, respectively. BN→Lew showed higher grades of endotheliitis, vascular fibrosis, and lower grades of lymphoid aggregates than Lew→F344 (P=0.007, P=0.043, P=0.004, respectively). CONCLUSIONS: Chronic rejection lesions in rat lung allografts mimic those in humans. The frequent occurrence of restrictive allograft syndrome-like lesions in BN→Lew may be related to a higher degree of mismatch in this strain combination. These animal models could allow future mechanistic studies to better understand chronic lung allograft dysfunction pathogenesis.

In this paper we aimed to address the role of pulmonary metastasectomy (PM) in patients affected by Lung Metastases (LM) from Renal Cell Carcinoma (RCC) and to analyse prognostic factors affecting overall survival (OS), disease-free interval (DFI) between primary RCC and first LM, and disease-free survival (DFS) after PM and before lung recurrence. Medical records of 210 patients who underwent PM from RCC in 4 Italian Thoracic Centres, from January 2000 to September 2019, were collected and analysed. All patients underwent RCC resection before lung surgery. The main RCC histology was clear cells (188, 89.5%). The 5- and 10-year OS from the first lung operation were 60% and 34%, respectively. LM synchronous with RCC (p = 0.01) and (Karnofsky Performance Status Scale) KPSS &lt, 80% (p &lt, 0.001) negatively influenced OS. Five- and 10-year DFI were 54% and 28%, respectively. The main factors negatively influencing DFI were: male gender (p = 0.039), KPSS &lt, 80% (p = 0.009) and lactate dehydrogenase &gt, 1.5 times 140 U/L (p = 0.001). Five- and 10-year disease-free survival were 54% and 28%, respectively, multiple LM (p = 0.036), KPSS &lt, 80% (p = 0.001) and histology of RCC other than clear cells negatively influenced disease-free survival. Conclusions: patients with KPSS &gt, 80%, single metachronous LM with a long DFI from RCC diagnosis, and clear cell histology, benefit from pulmonary metastasectomy.

Purpose Bronchial stenoses are challenging complications after lung transplantation and are associated with high rates of morbidity and mortality. We report a series of patients who underwent bronchoplasty or sleeve resection for bronchial stenoses that did not resolve with endoscopic treatment after lung transplantation. Methods Between 1995 and 2020, 497 patients underwent lung transplantation at our Institution. 35 patients (7.0%) experienced bronchial stenoses with a median time from transplantation of 3 months. Endoscopic management was effective in 28 cases (5.6%) while 1 patient required re-transplantation. Six patients (1.2%) underwent bronchoplasty or sleeve resection. Results The procedures of the six patients who underwent bronchoplasty or sleeve resection were as follows: lower sleeve bilobectomy (n = 3), wedge bronchoplasty of the bronchus intermedius (n = 1), isolated sleeve resection of the bronchus intermedius (n = 1), and isolated sleeve resection of the bronchus intermedius (n = 1), associated with a middle lobectomy. All patients were discharged after a median time of 11 days. At a median of 12 months from surgery, two patients remain alive with a preserved pulmonary function. Four patients died after a median time of 56 months from bronchoplasty of causes that were not related to surgery. Conclusions Bronchial reconstructions are challenging procedures that can be performed in highly specialized centers. Despite this, they can be considered a good strategy to obtain a definitive resolution of stenosis after lung transplantation.

Simple Summary The involvement of mediastinal great vessels is common in advanced stage thymic tumors, which makes their surgical resection challenging. Moreover, the impact of vascular involvement on the oncological prognosis is still unclear. The aim of our retrospective, single-center study is to investigate surgical and oncological in a population of patients operated for advanced stage thymic tumors, dividing them in two groups according to the presence or absence of vascular involvement. We demonstrated that resection of thymic tumors with vascular involvement can be performed with optimal surgical results in a high-volume center and that the involvement of the great vessels seems to be associated with a higher recurrence rate, without affecting long-termsurvival. Abstract Background: The involvement of mediastinal great vessels is common in advanced stage thymic tumors, which makes their surgical resection challenging. Moreover, the impact of vascular involvement on the oncological prognosis is still unclear. The aim of this study is to investigate the surgical and oncological outcomes and the impact of vascular involvement in a population of patients operated for advanced stage thymic tumors. Methods: A retrospective analysis on four hundred and sixty-five patients undergoing resection for advanced stage (Masaoka III–IV) thymic tumors in a single high-volume center was performed. One hundred forty-four patients met the inclusion criteria and were eligible for the study. Patients were divided in two groups according to the presence or absence of vascular involvement. Results: the two groups did not differ for the baseline characteristics and showed comparable surgical outcomes. Vascular involvement was not associated with worse overall survival but with an increased recurrence rate (p = 0.03). Multivariable analysis demonstrated a higher risk of recurrence in patients without R0 resection (HR 0.11, 0.02–0.54, p = 0.006) and with thymic carcinoma (HR 2.27, 1.22–4.24, p = 0.01). Conclusions: resection of thymic tumors with vascular involvement can be performed with optimal surgical results in a high volume center. From the oncological point of view, the involvement of the great vessels seems to be associated with a higher recurrence rate without affecting long-term survival.

Prion real-time quaking-induced conversion (RT-QuIC) is emerging as the most potent assay for the in vivo diagnosis of Creutzfeldt–Jakob disease (CJD), but its full application, especially as a screening test, is limited by suboptimal substrate availability, reagent costs, and incomplete assay standardization. Therefore, the search for the most informative cerebrospinal fluid (CSF) surrogate biomarker is still of primary importance. We compared the diagnostic accuracy of CSF protein 14-3-3, measured with both western blot (WB) and enzyme-linked immunosorbent assay (ELISA), total (t)-tau and neurofilament light chain protein (NfL) alone or in combination with RT-QuIC in 212 subjects with rapidly progressive dementia in which we reached a highly probable clinical diagnosis at follow-up or a definite neuropathological diagnosis. T-tau performed best as surrogate CSF biomarker for the diagnosis of CJD (91.3% sensitivity and 78.9% specificity). The 14-3-3 ELISA assay demonstrated a slightly higher diagnostic value compared to the WB analysis (76.9% vs. 72.2%), but both methods performed worse than the t-tau assay. NfL was the most sensitive biomarker for all sCJD subtypes (>95%), including those with low values of t-tau or 14-3-3, but showed the lowest specificity (43.1%). When ELISA-based biomarkers were adopted as screening tests followed by RT-QuIC, t-tau correctly excluded a higher number of non-CJD cases compared to NfL and 14-3-3 ELISA. Our study showed that among the CSF surrogate biomarkers of potential application for the clinical diagnosis of CJD, t-tau performs best either alone or as screening test followed by RT-QuIC as a second-level confirmatory test.

Background and aims: Cognitive impairments associated with aging and dementia are major sources of neuropsychiatric symptoms (NPs) and deterioration in quality of life (QoL). Preventive measures to both reduce disease and improve QoL in those affected are increasingly targeting individuals with mild cognitive impairment (MCI) at early disease stage. However, NPs and QoL outcomes are too commonly overlooked in intervention trials. The purpose of this study was to test the effects of physical and cognitive training on NPs and QoL in MCI. Methods: Baseline data from an MCI court (N = 93, mean age 74.9 ± 4.7) enrolled in the Train the Brain (TtB) study were collected. Subjects were randomized in two groups: a group participated to a cognitive and physical training program, while the other sticked to usual standard care. Both groups underwent a follow-up re-evaluation after 7months from baseline. NPs were assessed using the Neuropsychiatric Inventory (NPI) and QoL was assessed using Quality of Life-Alzheimer’s Disease (QOL-AD) scale. Results: After 7months of training, training group exhibited a significant reduction of NPs and a significant increase in QOL-AD with respect to no-training group (p = 0.0155, p = 0.0013, respectively). Our preliminary results suggest that a combined training can reduce NPs and improve QoL. Conclusions: Measuring QoL outcomes is a potentially important factor in ensuring that a person with cognitive deficits can ‘live well’ with pathology. Future data from non-pharmacological interventions, with a larger sample and a longer follow-up period, could confirm the results and the possible implications for such prevention strategies for early cognitive decline. Background and aims: Cognitive impairments associated with aging and dementia are major sources of neuropsychiatric symptoms (NPs) and deterioration in quality of life (QoL). Preventive measures to both reduce disease and improve QoL in those affected are increasingly targeting individuals with mild cognitive impairment (MCI) at early disease stage. However, NPs and QoL outcomes are too commonly overlooked in intervention trials. The purpose of this study was to test the effects of physical and cognitive training on NPs and QoL in MCI. Methods: Baseline data from an MCI court (N = 93, mean age 74.9 ± 4.7) enrolled in the Train the Brain (TtB) study were collected. Subjects were randomized in two groups: a group participated to a cognitive and physical training program, while the other sticked to usual standard care. Both groups underwent a follow-up re-evaluation after 7 months from baseline. NPs were assessed using the Neuropsychiatric Inventory (NPI) and QoL was assessed using Quality of Life-Alzheimer’s Disease (QOL-AD) scale. Results: After 7 months of training, training group exhibited a significant reduction of NPs and a significant increase in QOL-AD with respect to no-training group (p = 0.0155, p = 0.0013, respectively). Our preliminary results suggest that a combined training can reduce NPs and improve QoL. Conclusions: Measuring QoL outcomes is a potentially important factor in ensuring that a person with cognitive deficits can ‘live well’ with pathology. Future data from non-pharmacological interventions, with a larger sample and a longer follow-up period, could confirm the results and the possible implications for such prevention strategies for early cognitive decline.

Uveal melanoma (UM) is the most common primary intraocular cancer in adults. In the present study, we aimed to characterize the immunological features of primary UM cancer and to provide an association with prognostic markers and outcome. Also, we assessed the influence of the microenvironment on the expression of inhibitory immune checkpoints in UM. Genes of interest included MHC Class I and Class II molecules, as well as inhibitory immune-checkpoints, i.e. PDL1, PDL2, B7-H3, B7-H4, TBFRSF6B, CD47, CD155, GAL9, HVEM and CD200. We observed significant lower levels of MHC genes in UM cells as compared to normal uveal melanocytes. Unexpectedly however, the expression levels of most of the analyzed inhibitory immune-checkpoint genes were not different in cancer cells as compared to normal melanocytes, with the exception of CD200 and HVEM, that resulted significantly reduced. On the other hand, PDL1 inversely correlated with OS, PFS and thickness of the tumor. Also, PDL1, along with PDL2, expression significantly increased under inflammatory conditions. Finally, for the first time, we propose a possible role for CD47 in the immune evasive properties of UM. We show here that CD47 is significantly upregulated by UM cells following inflammatory stimuli and that it represents a good independent predictor of disease progression. The results from this study may propel advances in the development of immune-based therapies for UM patients.

We evaluated the in silico expression and circulating levels of interleukin (IL)37 in patients with different forms of multiple sclerosis (MS) and also upon treatment with different disease-modifying drugs. The combined interpretation of the resulting data strengthens and extends the current emerging concept that endogenous IL37 plays an important role in determining onset and progression of MS. The in silico analysis revealed that production of IL37 from cluster of differentiation (CD)4+ T cells from MS patients was reduced in vitro as compared to healthy controls. The analysis of the datasets also demonstrated that &ldquo, higher&rdquo, levels of IL37 production from PBMC entailed significant protection from MS relapses. In addition, the in vivo part of the study showed that IL37 was selectively augmented in the sera of MS patients during a relapse and that treatment with the high potency disease-modifying drug fingolimod significantly increased the frequency of patients with circulating blood levels of IL37 (6/9, 66%) as compared to patients receiving no treatment (n = 48) or platform therapy (n = 59) who had levels of IL37 below the limit of the sensitivity of the assay. This finding therefore anticipates that fingolimod may at least partially exert its beneficial effects in MS by upregulating the production of IL37.

Accurate staging of early non-small cell lung cancer is fundamental for selecting the best treatment. The aim of this study was to identify risk factors for nodal upstaging after video-assisted thoracoscopic lobectomy for clinical T1-3N0 tumors.From 2014 to 2017, 3276 thoracoscopic lobectomies were recorded in the prospective database "Italian VATS Group". Linear and multiple logistic regression models were adapted to identify independent predictors of nodal upstaging and factors associated with progression in postoperative N status.Nodal upstaging was found in 417 cases (12.7%), including 206 cases (6.2%) of N1-positive nodes, 81 cases of N2 nodes (2.4%), and 130 cases (4%) of involvement of both N1 + N2 nodes. A total of 241 (7.3%) patients had single-station nodal involvement, whereas 176 (5.3%) had multiple-station involvement. In the final regression model, the tumor grade, histology, pathologic T status, and 12 resected nodes were independent predictors of nodal upstaging.The number of resected lymph nodes seems to predict nodal upstaging better than the type of intraoperative lymph node management. Other preoperative risk factors correspond to those for which the current guidelines of the European Society of Thoracic Surgery recommend more extensive preoperative mediastinal staging.

Background: Sternum may be involved by different diseases such as trauma, infection after cardiac surgery, tumors (primary and secondary) or chest wall deformities. Surgical excision with a safety margin is the primary goal after sternal resection for tumors, prevention of respiratory impairment due to flail chest and deformity and protection of surrounding organs are other important aims. Various techniques and materials have been used for this operation. We describe the use of cadaveric sternal allograft to reconstruct the chest wall in fourteen patients. Methods: Between October 2008 and February 2017, five males and nine females underwent surgical procedure because of primary sternal neoplasm, single-site metastatic disease, neuroendocrine thymic carcinoma and sternal dehiscence after cardiac surgery. Results: Fourteen sternectomy were undertaken. A muscle flap of pectoralis major was prepared to cover the graft in 9 patients. Adjuvant chemotherapy and radiotherapy were performed after surgery in three patients. No postoperative complications happened in 11 cases (84.6%). One (7.1%) patient died 9 days after surgery because of pulmonary embolism. Two patients (15.4%) had complications: one presented fever caused by systemic candidiasis and one had a muscle flap bleeding. Hospitalization median time was 11 days (range, 6–31 days). At follow up, 7 patients were alive in absence of disease, 1 patient is alive with recurrence, 6 patients died but nor infection neither rejection of the graft happened. No respiratory impairment or flail chest were registered in any patients. Conclusions: This technique for sternal replacement in our experience can be considered safe with long term results, providing optimal chest wall stability. The allograft resulted well-tolerated permitting an optimal graft integration in the host.

Background Total lung-sparing tracheobronchial sleeve resections are a step forward in the treatment of low-grade bronchial tumors in which minimal resection margins are required to achieve complete control of the disease. Methods This study retrospectively collected data on patients who underwent total lung-sparing procedures for low-grade tracheobronchial tumors at 2 thoracic surgical centers from January 1984 to October 2019. Results The study included 98 patients, 46 –female (47%) and 52 –male (53%), with a median age of 39 years (range, 7 to 70 years). Thirty-four patients underwent operative endoscopy before surgery (32 had laser treatment, and 2 had endobronchial stenting). The surgical resections were as follows: 9 (9%), tracheal carina; 18 (18%), second carina; 31 (32%), left main bronchi; 25 (26%), right main bronchi; and 15 (15%), intermediate bronchus. The median length of the resected bronchus was 2.2 cm. The median postoperative in-hospital stay was 8 days, and no perioperative mortality was observed. Postoperative complications were recorded in 26-patients (27%). The final histologic classification was as follows: 37 typical carcinoids (38%); 10 atypical carcinoids (10%); 29 adenoid cystic carcinomas (30%); 15 mucoepidermoid carcinomas (15%); 6 inflammatory myofibroblastic tumors (6%); and 1 glomic tumor (1%). Twenty-two patients had positive resection margins and underwent adjuvant radiotherapy. Three patients with adenoid cystic carcinoma had recurrences (1 local and 2 systemic). After a median follow-up time of 54.5 months (range, 4 to 360 months), the overall actuarial 5-year survival was 97%. Conclusions Total lung-sparing tracheobronchial sleeve resection for low-grade malignant disease requires advanced surgical skills, but the hospital morbidity and mortality are very low. This technique is adequate and safe for highly selected patients with low-grade endobronchial malignant diseases, and its use should be encouraged in experienced centers.

Background The outbreak of the pandemic Coronavirus disease 2019 (COVID-19), caused by a novel coronavirus named Severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2), affecting a high number of patients in Italy, forced a great number of doctors, even dermatologists, to work in the first lines in the dedicated departments. We analyzed the features and the incidence of dermatological issues emerged during the hospitalization due to COVID-19 and absent before. Methods All the SARS-CoV-2 positive patients hospitalized in Celio Military Hospital - COVID hub no-intensive care wards from March 16, 2020 until May 4, 2020 were evaluated by dermatologists several times during the hospital stay. Results Ninety-six patients (15 civilians and 81 Italian servicepeople) were enrolled: 34 (35.4%) patients developed cutaneous manifestations; 15 (16.0%) suffered from skin dryness; 5 (5.2%) irritant contact dermatitis; 4 (4.2%) seborrheic dermatitis; 4 (4.2%) morbilliform rashes; 3 (3.1%) petechial rashes and 3 (3.1%) widespread hives. Conclusions A deeper knowledge of cutaneous manifestations in military and civilian hospitalized COVID-19 patients could suggest more effective treatments to win the battle against SARS-CoV-2.

// Katia Mangano 1 , Emanuela Mazzon 2 , Maria Sofia Basile 1 , Roberto Di Marco 3 , Placido Bramanti 2 , Santa Mammana 2 , Maria Cristina Petralia 1, 4 , Paolo Fagone 1 and Ferdinando Nicoletti 1 1 Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy 2 IRCCS Centro Neurolesi “Bonino-Pulejo”, Messina, Italy 3 Department of Medicine and Health Sciences, University of Molise, Campobasso, Italy 4 Department of Formative Processes, University of Catania, Catania, Italy Correspondence to: Ferdinando Nicoletti, email: ferdinic@unict.it Keywords: macrophage migration Inhibitory factor; glioblastoma; brain tumors; neuro-oncology; D-DT Received: November 30, 2017 Accepted: March 08, 2018 Published: April 03, 2018 ABSTRACT Macrophage Migration Inhibitory Factor (MIF) is a pro-inflammatory cytokine expressed by a variety of cell types. Although MIF has been primarily studied for its role in the pathogenesis of autoimmune diseases, it has also been shown to promote tumorigenesis and it is over expressed in various malignant tumors. MIF is able to induce angiogenesis, cell cycle progression, and to block apoptosis. As tailored therapeutic approaches for the inhibition of endogenous MIF are being developed, it is important to evaluate the role of MIF in individual neoplastic conditions that may benefit from specific MIF inhibitors. Along with this line, in this paper, we have reviewed the evidence of the involvement of MIF in the etiopathogenesis and progression of glioblastoma and the preclinical data suggesting the possible use of specific MIF inhibition as a potential novel therapeutic strategy for brain tumors.

Concanavalin A (ConA)-induced hepatitis is an experimental model of human autoimmune hepatitis induced in rodents by i.v. injection of Con A. The disease is characterized by increase in serum levels of transaminases and massive immune infiltration of the livers. Type 1, type 2, and type 17 cytokines play a pathogenic role in the development of ConA-induced hepatitis. To understand further the immunoregulatory mechanisms operating in the development and regulation of ConA-induced hepatitis, we have evaluated the role of the anti-inflammatory pathway Nrf2/HO-1/CO (Nuclear Factor E2-related Factor 2/Heme Oxygenase-1/Carbon Monoxide) in this condition and determined whether the in vivo administration of CO via the CO-releasing molecule (CORM) CORM-A1, influences serological and histological development of Con-A-induced hepatitis. We have firstly evaluated in silico the genes belonging to the Nrf2/HO-1/CO pathway that are involved in the pathogenesis of autoimmune hepatitis (AIH). The data obtained from the in silico study demonstrate that a significant number of genes modulated in the liver of ConA-challenged mice belong to the Nrf2 pathway; on the other hand, the administration of CORM-A1 determines an improvement in several sero-immunological and histological parameters, and it is able to modulate genes identified by the in silico analysis. Collectively, our data indicate that the Nrf2/HO-1/CO pathway is fundamental for the regulation of the immune responses, and that therapeutic intervention aimed at its modulation by CORM-A1 may represent a valuable strategy to be considered for the treatment of autoimmune hepatitis in humans.

OBJECTIVES: Minimally invasive techniques seem to be promising alternatives to open approaches in the surgical treatment of early-stage thymoma, although there are controversies because of lack of data on long-term results. The aim of the study was to evaluate the surgical and oncological results after robotic thymectomy for early-stage thymoma compared to median sternotomy. METHODS: Between 1982 and 2017, 164 patients with early-stage thymoma (Masaoka I and II) were operated on by median sternotomy (108 patients) or the robotic approach (56 patients). Duration of surgery, amount of blood loss, complications, duration of chest drainage, postoperative hospital stay, oncological results and total costs were retrospectively evaluated. Data were analysed also after propensity score matching. RESULTS: Compared to the trans-sternal group, robotic thymectomy had significantly longer average operative times (P < 0.001) but less intraoperative blood loss (P = 0.01), less perioperative complications (P = 0.03), shorter time to chest drainage removal and hospital discharge (P < 0.001). The median expense for the trans-sternal approach was significantly higher than the cost of the robotic procedure (P < 0.001), mainly due to longer hospitalization. From an oncological point of view, there were no differences in thymoma recurrence, although follow-up of the trans-sternal group was significantly longer (P < 0.001). Data were confirmed after propensity score matching. CONCLUSIONS: Robotic thymectomy for early-stage thymoma is a technically safe and feasible procedure with low complication rate and shorter hospital stay compared to the trans-sternal approach. Cost analysis revealed lower expenses for the robotic procedure due to the reduced hospital stay. The oncological outcomes seemed comparable, but longer follow-up is needed.

Sarcomas are a heterogeneous group of malignancies with a marked propensity to metastasize to the lungs. Chemotherapy offers only a limited benefit in metastatic disease, whereas lung metastasectomy, in selected cases, can lead to long-term survival. Other local ablative techniques and hybrid therapies have been proposed. A multidisciplinary setting is of paramount importance for choosing the most appropriate treatment for each case. There is no randomized controlled trial providing formal evidence of the effectiveness of lung metastasectomy. Main areas of controversy concern the selection of surgical candidates, the operative approach and the role of chemotherapy. Five-year survival rates range from 15% to 50.9%, as reported mainly in retrospective case-series in which several prognostic factors were identified. In this article, the authors review the surgical management of sarcoma metastases to the lung, with a particular focus on the outcomes and prognostic factors associated with long-term survival after resection. The role of chemotherapy and other adjunctive therapies is also discussed.

Background and Objectives: Neuroinflammation is associated with many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). In this study, we investigate the anti-inflammatory, anti-oxidant, and anti-apoptotic properties of two non-psychoactive phytocannabinoids, cannabigerol (CBG) and cannabidiol (CBD). Materials and Methods: The motoneuron-like cell line NSC-34 differentiated by serum deprivation and with the additional treatment of all-trans retinoic acid (RA) is a valid model to investigate molecular events linked to neurodegeneration in ALS. Results: Pre-treatment with CBG (at 2.5 and 5 &micro, M doses) alone and in combination with CBD (at 2.5 and 5 &micro, M doses) was able to reduce neuroinflammation induced by a culture medium of LPS-stimulated macrophages. In particular, the pre-treatment with CBD at a 5 &micro, M dose decreased TNF-&alpha, levels and increased IL10 and IL-37 expression. CBG&ndash, CBD association at a 5 &micro, M dose also reduced NF-kB nuclear factor activation with low degradation of the inhibitor of kappaB alpha (IkB&alpha, ). CBG and CBD co-administered at a 5 &micro, M dose decreased iNOS expression and increased Nrf2 levels. Furthermore, the pre-treatment with the association of two non-psychoactive cannabinoids downregulated Bax protein expression and upregulated Bcl-2 expression. Our data show the anti-inflammatory, anti-oxidant, and anti-apoptotic effects PPAR&gamma, mediated. Conclusions: Our results provide preliminary support on the potential therapeutic application of a CBG&ndash, CBD combination for further preclinical studies.

Neuroblastoma (NB) represents one of the most frequent pediatric solid tumors. Macrophage migration inhibitory factor (MIF) is a cytokine exerting multiple biological functions. More recently, a second member of the MIF family of cytokine has been identified, the D-dopachrome tautomerase (DDT), that exerts several overlapping functions with MIF. Growing evidence suggests a key role for MIF and DDT in the development of cancer. The aim of this study is to characterize the prognostic value of MIF and DDT in NB. We show that higher expression levels of MIF and DDT in Stage 4 NB samples are associated with a poorer prognosis, independently of the presence of MYCN amplification. Moreover, higher levels of MIF are mostly enriched by Th1 cells, while lower levels of MIF are associated with an increased proportion of B cells, Cytotoxic T cells, Dendritic cells and Natural Killer T cells. We also show that treatment with the histone deacetylase (HDAC) inhibitor, vorinostat, of the NB cell line, SH-SY5Y, determines a significant reduction in the expression of both MIF and DDT. Finally, MIF and DDT inhibition by short interfering RNA is able to revert vincristine sensitivity in vitro. Overall, our data suggest that MIF exert pro-tumorigenic properties in NB, likely by dampening antigen presentation and cytotoxic immune responses, and we propose the HDAC inhibitors as a potential therapeutic strategy for NB patients.

Epidermal growth factor (EGF) represents the prototype of the group I EGF family. The pleiotropic effects of the EGF have attracted attention to the possibility that it could be implicated in autoimmune diseases, such as Multiple Sclerosis (MS). We show here that treatment with EGF, as a late prophylactic regime, improved the clinical and histological features of EAE, a preclinical model of MS. In silico analysis further corroborated these findings by demonstrating that EGF receptors are less expressed in CNS from patients with MS as compared to controls. Taken together these data provide clear-cut in vivo proof of concept for a beneficial role of exogenously administered EGF in MS, that may, therefore, represent a novel therapeutic approach.

The main focus of this study is exploring the effect and mechanism of two HIVprotease inhibitors: Ritonavir and Ritonavir‐nitric oxide (Ritonavir‐NO) on in vitro growth of melanoma cell lines. NO modification significantly improved the antitumor potential of Ritonavir, as the IC50 values of Ritonavir‐NO were approximately two times lower than IC50 values of the parental compound. Our results showed for the first time, that both compounds induced senescence in primary and metastatic melanoma cell lines. This transformation was manifested as a change in cell morphology, enlargement of nuclei, increased cellular granulation, upregulation of β‐galactosidase activity, lipofuscin granules appearance, higher production of reactive oxygen species and persistent inhibition of proliferation. The expression of p53, as one of the key regulators of senescence, was upregulated after 48 hours of Ritonavir‐ NO treatment only in metastatic B16F10 cells, ranking it as a late‐response event. The development of senescent phenotype was consistent with the alteration of the cytoskeleton—as we observed diminished expression of vinculin, α‐actin, and β‐tubulin. Permanent inhibition of S6 protein by Ritonavir‐NO, but not Ritonavir, could be responsible for a stronger antiproliferative potential of the NO‐modified compound. Taken together, induction of senescent phenotype may provide an excellent platform for developing therapeutic approaches based on selective killing of senescent cells. This is the peer reviewed version of the following article: Paskaš, S, Krajnović, T, Basile, MS, et al. Senescence as a main mechanism of Ritonavir and Ritonavir‐NO action against melanoma. Molecular Carcinogenesis. 2019; 58: 1362‐ 1375., which has been published in final form at [https://doi.org/10.1002/mc.23020]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions

KCNMA1 is a gene located at 10q22 that encodes the pore-forming &alpha, subunit of the large-conductance Ca2+-activated K+ channel. KCNMA1 is down-regulated in gastric carcinoma tumors, through hypermethylation of its promoter. In the present study, we have evaluated the expression levels of KCNMA1 both in a mouse model of Colorectal Cancer (CRC) and in human CRC samples. Additionally, epigenetic mechanisms of KCNMA1 gene regulation were investigated. We observed a significant down-regulation of KCNMA1 both in a human and mouse model of CRC. No differences in KCNMA1 levels were, however, observed at different TNM stages. We also wanted to determine whether the modulation in KCNMA1 was dependent on epigenetic mechanisms. A statistically significant inverse correlation between KCNMA1 expression and mir-17-5p levels was observed in patients with CRC. Furthermore, in the tumor samples, we found a significant hypermethylation of the promoter, in the loci cg24113782 and cg25655799, compared to healthy tissue. Overall, our data suggest the possible use of KCNMA1 as a therapeutic target in the early stages of CRC.

Bronchopleural fistula (BPF) is a potentially fatal complication of pneumonectomy. We analyze its occurrence rate, risk factors, and the methods used for its prevention. We reviewed the medical records of patients who underwent pneumonectomy at our Institution between January, 1990 and March, 2016. The risk factors for postoperative BPF were analyzed by univariate analysis and multiple logistic regression. Over the study period, 511 patients underwent pneumonectomy for non-small cell lung cancer (NSCLC) and had the bronchus closed by manual suturing. BPF developed in 23 patients (4.5%). Multiple logistic regression identified no coverage of the bronchial stump, right-sided pneumonectomy, residual tumor in the bronchial stump, postoperative ventilatory support, and completion pneumonectomy, as independent risk factors for BPF. The cumulative rate of BPF decreased significantly over time from 18% between 1990 and 1995 to 1% between 2011 and 2016 (p

Pulmonary artery sling is a rare congenital anomaly of the origin and course of the left pulmonary artery. Patients with this condition typically present with respiratory failure in young infancy, and asymptomatic cases are uncommon. We describe the case of an adult patient with a lung adenocarcinoma of the right upper lobe, extending into the hilum and superior mediastinum, and with a previously unknown pulmonary artery sling anomaly. The local invasiveness of the tumor and the peculiar vascular anatomy contributed to a unique surgical scenario, wherein multiple reconstructive procedures were required.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system of autoimmune etiopathogenesis, and is characterized by various neurological symptoms. Glatiramer acetate and interferon‑β are administered as first‑line treatments for this disease. In non‑responsive patients, several second‑line therapies are available, including natalizumab; however, a percentage of MS patients does not respond, or respond partially. Therefore, it is of the utmost importance to develop a diagnostic test for the prediction of drug response in patients suffering from complex diseases, such as MS, where several therapeutic options are already available. By a machine learning approach, the UnCorrelated Shrunken Centroid algorithm was applied to identify a subset of genes of CD4+ T cells that may predict the pharmacological response of relapsing‑remitting MS patients to natalizumab, before the initiation of therapy. The results from the present study may provide a basis for the design of personalized therapeutic strategies for patients with MS.

Introduction: Malignant pleural mesothelioma (MPM) is a fatal malignancy for which there is no definitive cure. The most effective multimodality treatment in prolonging survival is still matter of debate. Surgery remains one of the cornerstones in the multimodality therapy for MPM. Extra-pleural pneumonectomy and pleurectomy/decortication are the two main curative-intent procedures; however, the superiority of one technique over the other is still debated. This review aims to assess short- and long-term results of extrapleural pneumonectomy for MPM.Areas covered: This article focuses on the role of extrapleural pneumonectomy in MPM. A systematic review was performed by using electronic databases to identify studies that included patients treated by this procedure for MPM. Endpoints included overall survival, disease-free survival, recurrence rate, perioperative mortality, and morbidity.Expert commentary: This paper offers an overview of the results that are currently obtained in patients undergoing extrapleural pneumonectomy for MPM. The benefit of surgical treatments in MPM is still debated and its primary goal should be the achievement of a macroscopic complete resection. Several alternative multimodality protocols exist, with specific advantages and drawbacks; therefore, individualization of care for each patient is fundamental. The complexity of the surgical treatment mandates that patients be referred to specialized centers.

Background: Sternal resection is indicated for different pathological conditions. Sternectomy leaves a large anterior chest-wall defect, and so a correct reconstruction is mandatory to guarantee an optimal respiratory dynamic and to protect the mediastinal organs. This study is aimed to evaluate the results of anterior chest-wall reconstruction using a sternal allograft and to summarize the use of this technique in clinical experience worldwide. Methods: In the last ten years at our institution, 14 patients have undergone sternectomy followed by anterior chest wall reconstruction using cadaveric cryopreserved sternal allograft mainly for neoplastic disease except one patient whose surgery was performed for complex sternal dehiscence after cardiac operation. Results: One patient died in the perioperative period. No patients experienced postoperative respiratory failure, surgical site infections, or mechanical failure of the reconstruction. After a median follow-up time of 54 months, there no was occurrence of infection or graft rejection. No respiratory impairment or flail chest occurred in any patients. Eight patients are still alive at the present follow-up time. Conclusions: Thus far, complications related to graft necrosis or rejection have not been reported on in the literature. In our clinical experience, sternal allograft transplantation has been a safe and reproducible technique providing excellent results. At our institution, allografts have been well-tolerated biologically, even after long term follow-up. We hope that the good results obtained in our experience and in other published series may contribute to the further diffusion of this technique as the first choice in cases of anterior chest wall reconstruction. Further studies are necessary to consolidate the early and long term results.

Introduction Myocarditis is an inflammatory process that is caused by several factors including infection, systemic disease and/or exposure to drugs and toxins. Its clinical course is extremely variable, ranging from lack of symptoms to sudden cardiac death. Here we report a case of viral myocarditis in a cystic fibrosis (CF) patient subjected to retransplantation for chronic lung allograft dysfunction (CLAD). Case Report The patient was a 42-year-old male who had undergone his first lung transplant 18 years earlier for cystic fibrosis. He was referred for retransplantation for CLAD. The cardiac tests performed at the time of re-listing, as well as those repeated during waiting list time were unremarkable. Intraoperatively, during the first pneumonectomy, the patient developed an episode of ventricular fibrillation (VF), without recurrence after a single intrathoracic defibrillation. Due to the risk of hemodynamic instability, he was put on veno-arterial extracorporeal membrane oxygenation (ECMO). The remainder of the procedure was uneventful, and, after careful monitoring, ECMO cannulae were removed. Soon after skin closure, however, the patient first experienced multiple episodes of VF that required cardioversion, after which he quickly became asystolic. After one hour of advanced cardiac arrest treatments - including norepinephrine, cardiac massage, reopening of the chest and epicardial pacing - the patient was pronounced dead. At autopsy, coronary artery disease was excluded; the only pathological finding was the presence of multifocal acute myocarditis with fibrosis. Tissue molecular analysis detected high viral copies of Epstein Barr virus and Parvovirus B19. Summary In the present case, most probably, a surgery-induced systemic inflammatory response syndrome, with massive cytokine release, was responsible for precipitating an unsuspected preexisting condition of myocarditis. Recipients who undergo retransplantation for CLAD are severely immunocompromised and at risk of getting different forms of infections. Based on this experience, we suggest that cardiac magnetic resonance imaging be added to the preoperative workup of patient candidates for retransplantation for CLAD, so as to be able to detect potentially life-threatening pathologies of the myocardium with higher sensitivity.

Neurological complications of varicella-zoster virus (VZV) are infrequent and include various clinical pictures. The reactivation of VZV in patients with AIDS is generally associated with an acute and severe meningoencephalitis. We report the epidemiological, clinical and virological data from 11 consecutive patients with diagnosis of HIV/AIDS and central nervous system (CNS) involvement due to VZV. All patients were male and seropositive for HIV. The primary risk factor for HIV infection was unprotected sexual contact. The median of CD4 T cell count was 142 cells/µL. All of them presented signs and symptoms of meningoencephalitis. Six patients (54.5%) presented pleocytosis; they all showed high CSF protein concentrations with a median of 2.1 g/dL. Polymerase chain reaction of cerebrospinal fluid specimen was positive for VZV in all of them and they were treated with intravenous acyclovir at doses of 30/mg/kg/day for 21 days. Overall survival was 63% (7 of 11 patients). The four dead patients had low cellular counts in CSF, below the median of this parameter. VZV should be included among the opportunistic pathogens that can involve CNS with a diffuse and severe meningoencephalitis in patients with advanced HIV/AIDS disease. As complicações neurológicas do vírus varicela-zoster (VVZ) são pouco frequentes e incluem vários quadros clínicos. A reativação do VVZ em pacientes com AIDS é geralmente associada com meningoencefalite aguda e grave. Nós relatamos os dados epidemiológicos, clínicos e virológicos de onze pacientes consecutivos com diagnóstico de HIV/AIDS e comprometimento do sistema nervoso central (SNC) devido ao VVZ. Todos os pacientes eram do sexo masculino e soropositivos para HIV. O principal fator de risco para a infecção pelo HIV foi o contato sexual sem proteção. A mediana da contagem de células CD4 T foi de 142 cel/µL. Todos apresentavam sinais e sintomas devido à meningoencefalite. Seis pacientes (54,5%) apresentaram pleiocitose; todos apresentaram hiperproteinorraquia com mediana de 2,1 g/dL. A reação em cadeia da polimerase de amostra do líquido cefalorraquidiano foi positiva para VVZ em todos eles. Todos os pacientes foram tratados com aciclovir por via intravenosa em doses de 30 mg/kg/dia durante 21 dias. A sobrevida global foi de 63% (sete de 11 pacientes). Os quatro pacientes mortos tiveram uma escassa resposta celular no LCR abaixo da mediana para este parâmetro. O VVZ deve ser incluído entre os patógenos oportunistas que podem comprometer o SNC com meningoencefalite difusa e grave em pacientes com doença avançada por HIV/SIDA.

he article Ultrasensitive RT‑QuIC assay with high sensitivity and specificity for Lewy body‑

Purpose Chronic lung allograft dysfunction (CLAD) remains the major obstacle to long-term survival after lung transplantation. Two different phenotypes have recently been described. About 80% of patients have primarily obstructive lung disease associated with obliterative bronchiolitis, airway fibrosis with intraluminal narrowing (OB-CLAD) while a smaller subset has lung restriction with hypoxemia and parenchymal fibrosis (R-CLAD). Preclinical modeling is essential to better analyze the pathophysiological processes leading to CLAD development. Lung allografts from a large cohort of two different rat strain combinations orthotopically transplanted in the last decade were re-evaluated. Methods From 2007 to 2017 127 rats were transplanted in our centre: 55 Lewis (Lew; RT-1l) into Fisher 344 (F344; RT-1v) (Group 1, G1) and 72 Brown-Norway (BN; RT1n) into Lew (Group 2, G2). Chronic rejection was detected in 39 cases, 18 G1 and 21 G2 rats, respectively, at a mean time of 61 and 17 days, respectively. Several pathological lesions (airway, pleural and vascular fibrosis, airway obliteration, endothelialitis, lymphoid aggregates, epithelial hyperplasia and flattening) were graded following a recent proposed grading system for animal model CLAD (Martinu et al, 2019, AJT). Results An end stage lung remodelling was detected in 33% of G1 and 48% of G2 models. A vanishing obliterative bronchiolitis (end stage OB-CLAD) was observed in 33% and 20% of G1 and G2 rats, respectively, while signs of fibrosis/fibroelastosis (end stage R-CLAD) were detected in 67% and 80% of G1 and G2 rats, respectively. Acute fibrinous and organizing pneumonia (AFOP) was present in 37.5% of G2 strains and never observed in G1 animals. Interestingly, G2 rats showed higher endothelialitis, vascular fibrosis and lower lymphoid aggregates than G1 strain (p=0.005, p=0.01, p=0.03, respectively). A combination score of highly suggestive R-CLAD lesions (parenchymal, pleural, vascular fibrosis and endothelialitis) was more frequently detected in G2 rats (p=0.03). Conclusion CLAD associated lesions in lung rat allografts mimic those observed in humans. The earlier R-CLAD developed in G2 may be related to a higher degree of mismatch in this strain combination. These animal models could allow future mechanistic studies to better understand CLAD pathogenesis.

N-Acetylcysteine, one of the most prescribed antioxidant drugs, enhances pain threshold in rodents and humans by activating mGlu2 metabotropic glutamate receptors. Here, we assessed the analgesic activity of N-acetylcysteine in the streptozotocin model of painful diabetic neuropathy and examined the effect of N-acetylcysteine on proteins that are involved in mechanisms of nociceptive sensitization. Mice with blood glucose levels ≥250 mg/dl in response to a single intraperitoneal (i.p.) injection of streptozotocin (200 mg/kg) were used for the assessment of mechanical pain thresholds. Systemic treatment with N-acetylcysteine (100 mg/kg, i.p., either single injection or daily injections for seven days) caused analgesia in diabetic mice. N-acetylcysteine-induced analgesia was abrogated by the Sxc− inhibitors, sulfasalazine (8 mg/kg, i.p.), erastin (30 mg/kg, i.p.), and sorafenib (10 mg/kg, i.p.), or by the mGlu2/3 receptor antagonist, LY341495 (1 mg/kg, i.p.). Repeated administrations of N-acetylcysteine in diabetic mice reduced ERK1/2 phosphorylation in the dorsal region of the lumbar spinal cord. The analgesic activity of N-acetylcysteine was occluded by the MEK inhibitor, PD0325901 (25 mg/kg, i.p.), the TRPV1 channel blocker, capsazepine (40 mg/kg, i.p.), or by a cocktail of NMDA and mGlu5 metabotropic glutamate receptor antagonists (memantine, 25 mg/kg, plus MTEP, 5 mg/kg, both i.p.). These findings offer the first demonstration that N-acetylcysteine relieves pain associated with diabetic neuropathy and holds promise for the use of N-acetylcysteine as an add-on drug in diabetic patients.

Background: Tracheal sleeve pneumonectomy (TSP) is a rare and challenging procedure. In this paper, indications, techniques and outcomes of patients operated in a single centre over a time span of 36 years are presented. Methods: Hospital records of patients undergoing TSP were retrospectively reviewed. Survival was estimated with the Kaplan-Meier method. Univariable analysis of risk factors for survival was performed with the log-rank test. Results: Over the study period, we performed 59 right and 4 left tracheal sleeve pneumonectomies. Main indications were squamous cell carcinoma in 44 patients, adenocarcinoma in 10, adenoid cystic carcinoma (ACC) in 7, and other histology in 2. Twenty-three patients received induction chemotherapy. High-frequency jet ventilation (HFJV) was used in 53 cases (84%). Final pathology examination revealed N2 disease in 22 patients and N3 in 1. Resection margins were microscopically infiltrated in 11 patients. Twenty-six patients (41.3%) experienced postoperative complications, while postoperative mortality was 9.5% (6 patients). The 2-, 5- and 10-year overall survival (OS) rates were 52%, 31.6% and 20.9%, respectively. Survival was significantly worse for patients with N2 disease (P Conclusions: Morbidity and mortality rates following TSP remain elevated. Long-term follow-up is determined primarily by N status, and, therefore, accurate preoperative mediastinal staging is fundamental. Meticulous operative technique and attentive postoperative management are the foundation for good surgical results.

Thoracic outlet syndrome (TOS) is a condition arising from compression of the subclavian vessels and/or brachial plexus. Many factors or diseases may cause compression of the neurovascular bundle at the thoracic outlet. We describe the case of a 41-year-old woman with TOS who presented with vascular venous symptoms. Chest computed tomography (CT) scan showed a cystic mass at the level of cervico-thoracic junction, located between the left subclavian artery and vein, which appeared compressed. The cystic mass was removed through a cervical approach and it was found to be a cyst arising from the thoracic duct compressing and anteriorly dislocating the left subclavian vein. After surgery symptoms promptly disappeared.