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In patients with advanced triple-negative breast cancer (TNBC), translational research efforts are needed to improve the clinical efficacy of immunotherapy with checkpoint inhibitors. Here, we report on the immunological characterization of an exceptional, long-lasting, tumor complete response in a patient with metastatic TNBC treated with dual PD-1 and LAG-3 blockade within the phase I/II study CLAG525X2101C (NCT02460224) The pre-treatment tumor biopsy revealed the presence of a CD3+ and CD8+ cell infiltrate, with few PD1+ cells, rare CD4+ cells, and an absence of both NK cells and LAG3 expression. Conversely, tumor cells exhibited positive staining for the three primary LAG-3 ligands (HLA-DR, FGL-1, and galectin-3), while being negative for PD-L1. In peripheral blood, baseline expression of LAG-3 and PD-1 was observed in circulating immune cells. Following treatment initiation, there was a rapid increase in proliferating granzyme-B+ NK and T cells, including CD4+ T cells, alongside a reduction in myeloid-derived suppressor cells. The role of LAG-3 expression on circulating NK cells, as well as the expression of LAG-3 ligands on tumor cells and the early modulation of circulating cytotoxic CD4+ T cells warrant further investigation as exploitable predictive biomarkers for dual PD-1 and LAG-3 blockade. Trial registration: NCT02460224. Registered 02/06/2015.

Il volume illustra i percorsi di formazione predisposti per la Protezione Civile, con particolare attenzione alla strategie espresse in Lombardia.

Background: From 10 March up until 3 May 2020 in Northern Italy, the SARS-CoV-2 spread was not contained; disaster triage was adopted. The aim of the present study is to assess the impact of the COVID-19-pandemic on the Orthopedic and Trauma departments, focusing on: hospital reorganization (flexibility, workload, prevalence of COVID-19/SARS-CoV-2, standards of care); effects on staff; subjective orthopedic perception of the pandemic. Material and Methods: Data regarding 1390 patients and 323 surgeons were retrieved from a retrospective multicentric database, involving 14 major hospitals. The subjective directors’ viewpoints regarding the economic consequences, communication with the government, hospital administration and other departments were collected. Results: Surgical procedures dropped by 73%, compared to 2019, elective surgery was interrupted. Forty percent of patients were screened for SARS-CoV-2: 7% with positive results. Seven percent of the patients received medical therapy for COVID-19, and only 48% of these treated patients had positive swab tests. Eleven percent of surgeons developed COVID19 and 6% were contaminated. Fourteen percent of the staff were redirected daily to COVID units. Communication with the Government was perceived as adequate, whilst communication with medical Authorities was considered barely sufficient. Conclusions: Activity reduction was mandatory; the screening of carriers did not seem to be reliable and urgent activities were performed with a shortage of workers and a slower workflow. A trauma network and dedicated in hospital paths for COVID-19-patients were created. This experience provided evidence for coordinated responses in order to avoid the propagation of errors.

Background: Treatment of hip fractures during the coronavirus disease 2019 (COVID-19) pandemic has posed unique challenges for the management of COVID-19-infected patients and the maintenance of standards of care. The primary endpoint of this study is to compare the mortality rate at 1 month after surgery in symptomatic COVID-positive patients with that of asymptomatic patients. A secondary endpoint of the study is to evaluate, in the two groups of patients, mortality at 1 month on the basis of type of fracture and type of surgical treatment. Materials and methods: For this retrospective multicentre study, we reviewed the medical records of patients hospitalised for proximal femur fracture at 14 hospitals in Northern Italy. Two groups were formed: COVID-19-positive patients (C+ group) presented symptoms, had a positive swab for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and received treatment for COVID-19; COVID-19-negative patients (C− group) were asymptomatic and tested negative for SARS-CoV-2. The two groups were compared for differences in time to surgery, survival rate and complications rate. The follow-up period was 1 month. Results: Of the 1390 patients admitted for acute care for any reason, 477 had a proximal femur fracture; 53 were C+ but only 12/53 were diagnosed as such at admission. The mean age was > 80 years, and the mean American Society of Anesthesiologists (ASA) score was 3 in both groups. There was no substantial difference in time to surgery (on average, 2.3 days for the C+ group and 2.8 for the C− group). As expected, a higher mortality rate was recorded for the C+ group but not associated with the type of hip fracture or treatment. No correlation was found between early treatment (< 48 h to surgery) and better outcome in the C+ group. Conclusions: Hip fracture in COVID-19-positive patients accounted for 11% of the total. On average, the time to surgery was > 48 h, which reflects the

BACKGROUND: Patient-related and lesion-related factors may influence instantaneous wave-free ratio (iFR)/fractional flow reserve (FFR) concordance, potentially affecting the safety of revascularization deferral. METHODS: Consecutive patients with at least an intermediate coronary stenosis evaluated by both iFR and FFR were retrospectively enrolled. The agreement between iFR and FFR at their diagnostic cut-offs (FFR 0.80, iFR 0.89) was assessed. Predictors of discordance were assessed using multivariate analyses. Tailored iFR cut-offs according to predictors of discordance best matching an FFR of 0.80 were identified. The impact of reclassification according to tailored iFR cut-offs on major cardiovascular events (MACE: cardiovascular death, myocardial infarction or target-lesion revascularization) among deferred lesions was investigated. RESULTS: Two hundred and ninety-nine intermediate coronary stenosis [FFR 0.84 (0.78-0.89), iFR 0.91 (0.87-0.95), 202 left main/left anterior descending (LM/LAD) vessels, 67.6%] of 260 patients were studied. Discordance rate was 23.4% (n = 70, 10.7% iFR-negative discordant, 12.7% iFR-positive discordant). Predictors of discordance were LM/LAD disease, multivessel disease, non-ST-elevation myocardial infarction, smoking, reduced eGFR and hypertension. Lesion reclassification with tailored iFR cut-offs based on patient-level predictors carried no prognostic value among deferred lesions. Reclassification according to lesion location, which was entirely driven by LM/LAD lesions (iFR cut-offs: 0.93 for LM/LAD, 0.89 for non-LM/LAD), identified increased MACE among lesions deferred based on a negative FFR, between patients with a positive as compared with a negative iFR (19.4 vs. 6.1%, P = 0.044), whereas the same association was not observed with the conventional 0.89 iFR cut-off (15 vs. 8.6%, P = 0.303). CONCLUSION: Tailored vessel-based iFR cut-offs carry prognostic value among FFR-negative lesions, suggesting that a one-size-fit-all iFR

Background: Periprosthetic fractures (PPFs) are a growing matter for orthopaedic surgeons, and patients with PPFs may represent a frail target in the case of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The purpose of this study is to investigate whether hospital reorganisations during the most severe phase of the SARS-CoV-2 pandemic affected standards of care and early outcomes of patients treated for PPFs in Northern Italy. Materials and methods: Data were retrieved from a multicentre retrospective orthopaedics and traumatology database, including 14 hospitals. The following parameters were studied: demographics, results of nasopharyngeal swabs, prevalence of coronavirus disease 2019 (COVID-19), comorbidities, general health status (EQ-5D-5L Score), frailty (Clinical Frailty Scale, CFS), pain (visual analogue scale, VAS), anaesthesiologic risk (American Society of Anaesthesiology Score, ASA Score), classification (unified classification system, UCS), type of operation and anaesthesia, in-hospital and early complications (Clavien–Dindo Classification, CDC), and length of stay (LOS). Data were analysed by means of descriptive statistics. Out of 1390 patients treated for any reason, 38 PPFs were included. Results: Median age was 81 years (range 70–96 years). Twenty-three patients (60.5%) were swabbed on admission, and two of them (5.3%) tested positive; in three patients (7.9%), the diagnosis of COVID-19 was established on a clinical and radiological basis. Two more patients tested positive post-operatively, and one of them died due to COVID-19. Thirty-three patients (86.8%) presented a proximal femoral PPF. Median ASA Score was 3 (range, 1–4), median VAS score on admission was 3 (range, 0–6), median CFS was 4 (range, 1–8), median EQ-5D-5L Score was 3 in each one of the categories (range, 1–5). Twenty-three patients (60.5%) developed post-operative complications, and median CDC grade was 3 (range, 1–5). The median LOS was 12.8&nbs

Pulmonary immunological tolerance to inhaled particulates might create a permissive milieu for lung metastasis. Lung microbiota contribute to pulmonary tolerance; here, we explored whether its manipulation via antibiotic or probiotic aerosolization favors immune response against melanoma metastasis. In lungs of vancomycin/neomycin-aerosolized mice, a decrease in bacterial load was associated with reduced regulatory T cells and enhanced T cell and NK cell activation that paralleled a significant reduction of melanoma B16 lung metastases. Reduction of metastases also occurred in lungs transplanted with bacterial isolates from antibiotic-treated lungs. Aerosolized Lactobacillus rhamnosus strongly promoted immunity against B16 lung metastases as well. Furthermore, probiotics or antibiotics improved chemotherapy activity against advanced B16 metastases. Thus, we identify a role for lung microbiota in metastasis and show that its targeting via aerosolization is a therapy that can prevent metastases and enhance responses to chemotherapy. Le Noci et al. reveal that modulation of pulmonary microbiota by antibiotic or probiotic aerosolization decreases tumor growth in the lung. Antibiotic treatment induces a reduction of immunosuppressive cells in the lung, while probiotic administration promotes maturation of resident antigen-presenting cells.

Background: We present our experience after the introduction of Advanced Trauma Life Support (ATLS)©, Trauma Team (TT) and Preperitoneal Pelvic Packing (PPP) protocols for the treatment of hemodynamically unstable pelvic blunt trauma. Methods: This is a retrospective study with historical controls: before (Control Group, CG) and after (Study Group SG) the introduction of the protocol. A single physician managed the CG and angiography was the emergency manoeuvre. A team with ATLS guidelines and PPP as an emergency manoeuvre managed the SG. Data were collected retrospectively. Patients were divided into two groups: before and after the introduction of protocols. Results: From January 2007 to October 2014, 36 patients were treated at our Centre. We consider patients from January 2007 to August 2011 (19 patients, CG) and from September 2011 to October 2014 (17 patients, SG). Median age was 54 years (43–69) in the CG vs. 47 (40–63) in the SG (p = 0.43), median initial SBP 90 mmHg (85–103) in the CG 94 (69–103) in the SG, (p = 0.60), heart rate was 90 (80–110) in the CG and 110 (95–130) in the SG, (p = 0.09). Median Injury Severity Score was 33 (21–41) in the CG and 34 (26–41) in the SG (p = 0.29). Time from arrival in the Emergency Department to first therapeutic manoeuvre was 132 minutes (109–180) in the CG and 87 minutes (51–204) in the SG (p = 0.4). The difference in mortality was statistically significant: 64.7% (11/17) in the CG and 23.5% (4/17) in the SG (p = 0.02). Conclusions: The introduction of protocols changed our approach in hemodynamically unstable pelvic trauma, achieving a remarkable improvement in early mortality.