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Abstract Aims A set of indicators to assess the quality of care for patients hospitalized for heart failure was developed by an expert working group of the Italian Health Ministry. Because a better performance profile measured using these indicators does not necessarily translate to better outcomes, a study to validate these indicators through their relationship with measurable clinical outcomes and healthcare costs supported by the Italian National Health System was carried out. Methods and results Residents of four Italian regions (Lombardy, Marche, Lazio, and Sicily) who were newly hospitalized for heart failure (irrespective of stage and New York Heart Association class) during 2014–2015 entered in the cohort and followed up until 2019. Adherence to evidence‐based recommendations [i.e. renin–angiotensin–aldosterone system (RAS) inhibitors, beta‐blockers, mineralocorticoid receptor antagonists (MRAs), and echocardiograms (ECCs)] experienced during the first year after index discharge was assessed. Composite clinical outcomes (cardiovascular hospital admissions and all‐cause mortality) and healthcare costs (hospitalizations, drugs, and outpatient services) were assessed during the follow‐up. The restricted mean survival time at 5 years (denoted as the number of months free from clinical outcomes), the hazard of clinical outcomes (according to the Cox model), and average annual healthcare cost (expressed in euros per person‐year) were compared between adherent and non‐adherent patients. A non‐parametric bootstrap method based on 1000 resamples was used to account for uncertainty in cost‐effectiveness estimates. A total of 41 406 patients were included in this study (46.3% males, mean age 76.9 ± 9.4 years). Adherence to RAS inhibitors, beta‐blockers, MRAs, and ECCs were 64%, 57%, 62%, and 20% among the cohort members, respectively. Compared with non‐adherent patients, those who adhered to ECCs, RAS inhibitors, beta‐blockers, and MRAs experienced (i) a delay in the composite outcome of 1.6, 1.9, 1.6, and 0.6 months and reduced risks of 9% (95% confidence interval, 2–14%), 11% (7–14%), 8% (5–11%), and 4% (−1–8%), respectively; and (ii) lower (€262, €92, and €571 per year for RAS inhibitors, beta‐blockers, and MRAs, respectively) and higher costs (€511 per year for ECC). Adherence to RAS inhibitors, beta‐blockers, and MRAs showed a delay in the composite outcome and a saving of costs in 98%, 84%, and 93% of the 1000 bootstrap replications, respectively. Conclusions Strict monitoring of patients with heart failure through regular clinical examinations and drug therapies should be considered the cornerstone of national guidelines and audits.

Fibrolamellar hepatocellular carcinoma (FL-HCC) is a malignant primary hepatic cancer that affects mainly adolescents and young adults without underlying liver disease. Its biology remains unknown, but it is pathologically distinct from traditional HCC. Therapeutic strategies are not well defined and, as chemotherapies seem to have limited efficacy, surgical resection remains the only effective treatment. Here we report on a case of a metastatic FL-HCC in an 18-year-old man successfully treated with aggressive intra-thoracic bilateral lung metastasectomy following primary tumour resection and adjuvant chemotherapy. Survival time after initial hepatectomy is 39 months, with no recurrence of disease to date. Aggressive surgical resection and redo surgery should be considered until more effective multimodality therapies are identified. Multidisciplinary team discussion and involvement of medical and surgical specialties are essential in managing these rare entities.

Abstract Background Single-pill combination (SPC) of three antihypertensive drugs has been shown to improve adherence to therapy compared with free combinations, but little is known about its long-term costs and health consequences. This study aimed to evaluate the lifetime cost-effectiveness profile of a three-drug SPC of an angiotensin-converting enzyme inhibitor, a calcium-channel blocker, and a diuretic vs the corresponding two-pill administration (a two-drug SPC plus a third drug separately) from the Italian payer perspective. Methods A cost-effectiveness analysis was conducted using multi-state semi-Markov modeling and microsimulation. Using the healthcare utilization database of the Lombardy Region (Italy), 30,172 and 65,817 patients aged ≥ 40 years who initiated SPC and two-pill combination, respectively, between 2015 and 2018 were identified. The observation period extended from the date of the first drug dispensation until death, emigration, or December 31, 2019. Disease and cost models were parametrized using the study cohort, and a lifetime microsimulation was applied to project costs and life expectancy for the compared strategies, assigning each of them to each cohort member. Costs and life-years gained were discounted by 3%. Probabilistic sensitivity analysis with 1,000 samples was performed to address parameter uncertainty. Results Compared with the two-pill combination, the SPC increased life expectancy by 0.86 years (95% confidence interval [CI] 0.61–1.14), with a mean cost differential of -€12 (95% CI -9,719–8,131), making it the dominant strategy (ICER = -14, 95% CI -€15,871–€7,113). The cost reduction associated with the SPC was primarily driven by savings in hospitalization costs, amounting to €1,850 (95% CI 17–7,813) and €2,027 (95% CI 19–8,603) for patients treated with the SPC and two-pill combination, respectively. Conversely, drug costs were higher for the SPC (€3,848, 95% CI 574–10,640 vs. €3,710, 95% CI 263–11,955). The cost-effectiveness profile did not significantly change according to age, sex, and clinical status. Conclusions The SPC was projected to be cost-effective compared with the two-pill combination at almost all reasonable willingness-to-pay thresholds. As it is currently prescribed to only a few patients, the widespread use of this strategy could result in benefits for both patients and the healthcare system.

BackgroundERAS is an evidence-based multimodal perioperative protocol focused on stress reduction and promoting a return to function. The aim of this work is to perform a cost-consequence analysis for the implementation of ERAS in major lung resection by means of minimally invasive surgery (VATS) from the public health service perspective, evaluating resource consumption and clinical outcomes with respect to a control group of past patients, which did not adopt an ERAS protocol.MethodsOutcome differences (re-intervention rates, major and minor intraoperative and postoperative complications, readmissions, and mortality) as well as the costs of preoperative, operative, and postoperative care were estimated. The sample consisted of 64 consecutive patients enrolled in the ERAS programme between April 2021 and August 2022, compared to a control group (historical cohort) comprising 31 patients treated from April 2020 to December 2020, prior to the implementation of the ERAS programme. The study sample comprises patients who fulfil the established ERAS protocol inclusion criteria, including general criteria (acceptance of the protocol, proximity of residence, absence of contraindications to physiotherapy and early mobilisation), surgical criteria (anatomical lung resection up to lobectomy, absence of extensive resection, good possibility of conducting the operation in VATS) and anaesthesiologic criteria (ASA ≤2). Costs were quantified using the national health system perspective.ResultsThe average length-of-stay was at least one day shorter in the ERAS group [

BackgroundRecent literature has shown the presence of B cells and autoantibodies in idiopathic pulmonary fibrosis (IPF) which would imply the presence of tertiary lymphoid structures (TLS, sites where the immune response is triggered), yet TLS are not considered features of the histological characteristics of IPF.AimThis study aims to quantify the presence, size, and degree of activation of TLS in biopsied and explanted lungs from patients with early- and late-IPF, never treated with antifibrotics, and relate their presence and activity to the clinical course, disease progression, and lung inflammation.MethodsImmunohistochestry for B cells and CD4, CD8, and CD45 cells was performed in lung tissue from IPF patients: 18 at diagnosis (early), 39 explanted (end-stage), and 12 smoking controls. TLS activation was assessed by CD40 expression. Spirometry along 31 (12–72) months of follow-up was used to characterize end-stage IPF as slow progressors or rapid progressors.ResultsB cells, along with other inflammatory cells, were higher in early- and end-stage IPF than in controls (p < 0.001). In rapid progressors, all inflammatory cells were higher than in slow progressors (p < 0.05). TLS were present in 100% of early- and end-stage IPF and in 50% of controls. In end-stage IPF, the TLS area and activation score were higher than in early IPF (p < 0.0001; p = 0.005) and controls (p < 0.04; p < 0.002). TLS activation score correlated with FVC decline during follow-up in rapid progressors (r = 0.73; p = 0.007) but not in slow progressors.ConclusionsA prominent B-cell infiltration, along with the presence of TLS, the activity of which correlates with FVC decline, is an important component of IPF from the beginning of the disease, likely playing an important role on its mechanism and progression.

Abstract Background Infections are one of the most common causes of death after lung transplant (LT). However, the benefit of ‘targeted’ prophylaxis in LT recipients pre-colonized by Gram-negative (GN) bacteria is still unclear. Methods All consecutive bilateral LT recipients admitted to the Intensive Care Unit of the University Hospital of Padua (February 2016–2023) were retrospectively screened. Only patients with pre-existing GN bacterial isolations were enrolled and analyzed according to the antimicrobial surgical prophylaxis (‘standard’ vs. ‘targeted’ on the preoperative bacterial isolation). Results One hundred eighty-one LT recipients were screened, 46 enrolled. Twenty-two (48%) recipients were exposed to ‘targeted’ prophylaxis, while 24 (52%) to ‘standard’ prophylaxis. Overall prevalence of postoperative multi-drug resistant (MDR) GN bacteria isolation was 65%, with no differences between the two surgical prophylaxis (p = 0.364). Eleven (79%) patients treated with ‘standard’ prophylaxis and twelve (75%) with ‘targeted’ therapy reconfirmed the preoperative GN pathogen (p = 0.999). The prevalence of postoperative infections due to MDR GN bacteria was 50%. Of these recipients, 4 belonged to the ‘standard’ and 11 to the ‘targeted’ prophylaxis (p = 0.027). Conclusions The administration of a ‘targeted’ prophylaxis in LT pre-colonized recipients seemed not to prevent the occurrence of postoperative MDR GN infections.

Molecular profiles of thymomas and recurrent thymomas are far from being defined. Herein, we report an analysis of a comprehensive genetic profile (CGP) in a highly selected cohort of recurrent thymomas. Among a cohort of 426 thymomas, the tissue was available in 23 recurrent tumors for matching the biomolecular results obtained from primary and relapse samples. A control group composed of non-recurrent thymoma patients was selected through a propensity score match analysis. CGP was performed using the NGS Tru-SightOncology assay to evaluate TMB, MSI, and molecular alterations in 523 genes. CGP does not differ when comparing initial tumor with tumor relapse. A significantly higher frequency of cell cycle control genes alterations (100.0% vs. 57.1%, p = 0.022) is detected in patients with early recurrence (50% of cases (oncogenic Tier-IIC variants). In conclusion, CGPs do not substantially differ between initial tumor vs. tumor recurrence and recurrent thymomas vs. non-recurrent thymomas. Cell cycle control gene alterations are associated with an early recurrence after thymectomy. Multiple target therapies are potentially available by performing a comprehensive CGP, suggesting that a precision medicine approach on these patients could be further explored.

The role of immunotherapy in the multimodal treatment for pleural mesothelioma (PM) is still under investigation, particularly in the preoperative setting. Pathological complete response (pCR) has been previously described after chemotherapy and immunotherapy; however, there is no prior experience reported with immunotherapy alone before surgery. We report the case of a 58-year-old male with biphasic PM treated with immunotherapy, resulting in a major clinical partial response. Following a multidisciplinary evaluation between thoracic surgeons, medical oncologists, pathologists, radiologists and radiation oncologists, the patient underwent surgery with radical intent through a right extended pleurectomy/decortication (eP/D). Histopathological examination of the specimen confirmed a pathological Complete Response (pCR). This case supports the feasibility and potential efficacy of combining preoperative immunotherapy with surgery in the management of advanced PM.

Background: Scant data are available on nutritional status in bilateral lung transplant (BLT) candidates. Methods: All consecutive recipients admitted to the intensive care unit (ICU) of the University Hospital of Padua (February 2016–2020) after bilateral-lung transplant (BLT) were retrospectively screened. Data collected: (i) nutritional indices (body mass index (BMI), albumin level, prognostic nutritional index (PNI), mini nutritional assessment short-form (MNA-SF)); and (ii) muscular indices (creatinine height index (CHI)), skeletal muscle index (SMI), densitometry of paravertebral muscles on chest CT). Results: 108 BLT recipients were enrolled: 55% had a normal BMI, 83% had serum albumin levels > 35 g/L; high PNI and MNA-SF scores were recorded in most of patients. A total of 74% had a “normal or slightly reduced protein state“ according to the CHI score; 17% were identified as “sarcopenic” according to muscle densitometry (Hu < 30). Lower serum albumin was associated with longer invasive mechanical ventilation days (IMV) and ICU length of stay (p-value for non-linearity < 0.01). PNI and BMI were also associated with an increased ICU length of stay (p-value for non-linearity < 0.01). Conclusions: Most of the BLT recipients had normal nutritional and sarcopenia status. Pre-transplant albumin values correlated with the duration of IMV; serum albumin, PNI and BMI were associated with ICU stay. No nutritional or muscle parameters predicted re-intubation, 30-days rejection and overall length of hospital stay.

The understanding of mediastinal anatomy represents a real challenge because of the vital structures inside it and due to its complex relationships with surrounding anatomical regions. Human anatomical specimens are always used both for the teaching of anatomy and the training of young surgeons, thus providing a deep understanding of the most complex anatomical regions and allowing less experienced surgeons to become familiar with surgical instruments and their use on actual human tissues. Despite the spread of these learning practices, there are no principles of dissection to follow for a young physician interested in the anatomy of the mediastinum. Therefore, the main objective of this study is to define a reliable and reproducible protocol for the dissection of the mediastinum. A stratigraphic anatomical dissection on three embalmed human specimens was performed. All steps were documented by high-quality photographs, taken with a professional digital reflex camera, and subsequently edited. A step-by-step anatomical dissection guide was created, detailing every phase, guiding the dissection of the mediastinal anatomy, and leading to the correct identification of its main anatomical structures. We present a step-by-step dissection guide to the mediastinal anatomy with point-by-point explanations and dedicated images, providing an additional tool for the comprehension of this complex anatomical area.

Abstract COVID-19-related acute respiratory distress syndrome (CARDS) is associated with high mortality rates. We still have limited knowledge of the complex alterations developing in the lung microenvironment. The goal of the present study was to comprehensively analyze the cellular components, inflammatory signature, and respiratory pathogens in bronchoalveolar lavage (BAL) of CARDS patients (16) in comparison to those of other invasively mechanically ventilated patients (24). In CARDS patients, BAL analysis revealed: SARS-CoV-2 infection frequently associated with other respiratory pathogens, significantly higher neutrophil granulocyte percentage, remarkably low interferon-gamma expression, and high levels of interleukins (IL)-1β and IL-9. The most important predictive variables for worse outcomes were age, IL-18 expression, and BAL neutrophilia. To the best of our knowledge, this is the first study that was able to identify, through a comprehensive analysis of BAL, several aspects relevant to the complex pathophysiology of CARDS.

Abstract Background To evaluate the protective effect of oral antidiabetic drugs in a large cohort of elderly patients with type 2 diabetes differing for age, clinical status, and life expectancy, including patients with multiple comorbidities and short survival. Methods A nested case–control study was carried out by including the cohort of 188,983 patients from Lombardy (Italy), aged ≥ 65 years, who received ≥ 3 consecutive prescriptions of antidiabetic agents (mostly metformin and other older conventional agents) during 2012. Cases were the 49,201 patients who died for any cause during follow-up (up to 2018). A control was randomly selected for each case. Adherence to drug therapy was measured by considering the proportion of days of the follow-up covered by the drug prescriptions. Conditional logistic regression was used to model the risk of outcome associated with adherence to antidiabetic drugs. The analysis was stratified according to four categories of the clinical status (good, intermediate, poor, and very poor) differing for life expectancy. Results There was a steep increase in comorbidities and a marked reduction of the 6-year survival from the very good to the very poor (or frail) clinical category. Progressive increase in adherence to treatment was associated with a progressive decrease in the risk of all-cause mortality in all clinical categories and at all ages (65–74, 75–84 and ≥ 85 years) except for the frail patient subgroup aged ≥ 85 years. The mortality reduction from lowest to highest adherence level showed a tendency to be lower in frail patients compared to the other categories. Similar although less consistent results were obtained for cardiovascular mortality. Conclusions In elderly diabetic patients, increased adherence to antidiabetic drugs is associated with a reduction in the risk of mortality regardless of the patients’ clinical status and age, with the exception of very old patients (age ≥ 85 years) in the very poor or frail clinical category. However, in the frail patient category the benefit of treatment appears to be less than in patients in good clinical conditions.

Selection of patients who may benefit from extracorporeal life support (ECLS) as a bridge to lung transplant (LTx) is crucial. The aim was to assess if validated prognostic scores could help in selecting patients who may benefit from ECLS-bridging predicting their outcomes. Clinical data of patients successfully ECLS-bridged to LTx from 2009 to 2021 were collected from two European centers. For each patient, we calculated Sequential Organ Failure Assessment (SOFA), Simplified Acute Physiology Score III (SAPS III), Acute Physiology and Chronic Health Evaluation II (APACHE II), before placing ECLS support, and then correlated with outcome. Median values of SOFA, SAPS III, and APACHE II were 5 (IQR 3–9), 57 (IQR 47.5–65), and 21 (IQR 15–26). In-hospital, 30 and 90 days mortality were 21%, 14%, and 22%. SOFA, SAPS III, and APACHE II were analyzed as predictors of in-hospital, 30 and 90 days mortality (SOFA C-Index: 0.67, 0.78, 0.72; SAPS III C-index: 0.48, 0.45, 0.51; APACHE II C-Index: 0.49, 0.45, 0.52). For SOFA, the score with the best performance, a value ≥9 was identified to be the optimal cut-off for the prediction of the outcomes of interest. SOFA may be considered an adequate predictor in these patients, helping clinical decision-making. More specific and simplified scores for this population are necessary.

Abstract Background Even though hyperglycemia is a well-known cardiovascular risk factor, the absolute risk of cardiovascular events varies to a great extent within each glycemic category. The aim of this study is to evaluate whether N-terminal pro-B natriuretic peptide (NT-ProBNP) could help identify subjects at higher cardiovascular risk, independently of blood glucose levels. Methods Serum NT-ProBNP levels were measured in 5502 people aged 45–79 years without heart failure from the general population (3380 with normoglycemia, 1125 with pre-diabetes and 997 with diabetes) that participated in the 1999–2004 cycles of the National Health and Nutrition Examination Survey. We applied Cox and Fine Gray models adjusted for cardiovascular risk factors to evaluate the association between NT-ProBNP levels and all-cause and cardiovascular mortality through December 2015. Results After a median follow-up of 13 years, 1509 participants died, 330 of cardiovascular causes. In the multivariable-adjusted models, compared with participants with NT-ProBNP

Patients affected by long-segment tracheal defects or stenoses represent an unsolved surgical issue, since they cannot be treated with the conventional surgery of tracheal resection and consequent anastomosis. Hence, different strategies for tracheal replacement have been proposed (synthetic materials, aortic allografts, transplantation, autologous tissue composites, and tissue engineering), each with advantages and drawbacks. Tracheal tissue engineering, on the other hand, aims at recreating a fully functional tracheal substitute, without the need for the patient to receive lifelong immunosuppression or endotracheal stents. Tissue engineering approaches involve the use of a scaffold, stem cells, and humoral signals. This paper reviews the main aspects of tracheal TE, starting from the choice of the scaffold to the type of stem cells that can be used to seed the scaffold, the methods for their culture and expansion, the issue of graft revascularization at the moment of in vivo implantation, and experimental models of tracheal research. Moreover, a critical insight on the state of the art of tracheal tissue engineering is also presented.

Fungal infections (FIs) are one of the leading causes of morbidity and mortality within the first year of lung transplant (LT) in LT recipients (LTRs). Their prompt identification and treatment are crucial for a favorable LTR outcome. The objectives of our study were to assess (i) the FI incidence and colonization during the first year after a bilateral LT, (ii) the risk factors associated with FI and colonization, and (iii) the differences in fungal incidence according to the different prophylactic strategies. All bilateral LTRs admitted to the intensive care unit of Padua University Hospital were retrospectively screened, excluding patients Aspergillus spp. We did not identify independent risk factors for FI. Groups of patients receiving different prophylactic strategies reported a similar incidence of both FI and colonization. The incidence of FI and fungal colonization was 8% and 23%, respectively, with no differences between different antifungal prophylaxes or identified predisposing factors. Further studies with larger numbers are needed to confirm our results.

BackgroundThe stratification of the general population according to health needs allows to provide better-tailored services. A simple score called Multisource Comorbidity Score (MCS) has been developed and validated for predicting several outcomes. The aim of this study was to evaluate whether the ability of MCS in predicting 1-year mortality improves by incorporating socioeconomic data (as measured by a deprivation index).MethodsBeneficiaries of the Italian National Health Service who in the index year (2018) were aged 50–85 years and were resident in the Sicily region for at least 2 years were identified. For each individual, the MCS was calculated according to his/her clinical profile, and the deprivation index of the census unit level of the individual’s residence was collected. Frailty models were fitted to assess the relationship between the indexes (MCS and deprivation index) and 1-year mortality. Akaike information criterion and Bayesian information criterion statistics were used to compare the goodness of fit of the model that included only MCS and the model that also contained the deprivation index. The models were further compared by means of the area under the receiver operating characteristic curve (AUC).ResultsThe final cohort included 1,062,221 individuals, with a mortality rate of 15.6 deaths per 1,000 person-years. Both MCS and deprivation index were positively associated with mortality.The goodness of fit statistics of the two models were very similar. For MCS only and MCS plus deprivation index models, Akaike information criterion were 17,013 and 17,038, respectively, whereas Bayesian information criterion were 16,997 and 17,000, respectively. The AUC values were 0.78 for both models.ConclusionThe present study shows that socioeconomic features as measured by the deprivation index did not improve the capability of MCS in predicting 1-year risk of death. Future studies are needed to investigate other sources of data to enhance the risk stratification of populations.

BackgroundThe local, extravascular, activation of the coagulation system in response to injury is a key factor mediating the resulting inflammatory response. Coagulation Factor XIIIA (FXIIIA) found in alveolar macrophages (AM) and dendritic cells (DC), by influencing fibrin stability, might be an inflammatory modifier in COPD.AimsTo study the expression of FXIIIA in AM and Langerin+DC (DC-1) and their relation to the inflammatory response and disease progression in COPD.MethodsIn 47 surgical lungs, 36 from smokers (22 COPD and 14 no-COPD) and 11 from non-smokers we quantified by immunohistochemistry FXIIIA expression in AM and DC-1 along with numbers of CD8+Tcells and CXCR3 expression in lung parenchyma and airways. Lung function was measured prior to surgery.ResultsThe percentage of AM expressing FXIII (%FXIII+AM) was higher in COPD than no-COPD and non-smokers. DC-1 expressed FXIIIA and their numbers were higher in COPD than no-COPD and non-smokers. DC-1 positively correlated with %FXIII+AM (r=0.43; p

Background and objectives: VATS segmentectomy has been proven to be effective in the treatment of stage I NSCLC, but its technical complexity remains one of the most challenging aspects for thoracic surgeons. Furthermore, 3D-CT reconstruction images can help in planning and performing surgical procedures. In this paper, we present our personal experience of 11 VATS anatomical resections performed after accurate pre-operative planning with 3D reconstructions. Materials and methods: A 3D virtual model of the lungs, airways, and vasculature was obtained, starting from a 1.25 mm 3-phase contrast CT scan, and the original images were used for the semi-automatic segmentation of the lung parenchyma, airways, and tumor. Results: Six males and five females were included in this study. The median diameter of the pulmonary lesion at the pre-operative chest CT scan was 20 mm. The surgical indication was confirmed in seven patients: in three cases, a lobectomy, instead of a segmentectomy, was needed due to intraoperative findings of nodal metastasis. Meanwhile, only in one case, we performed a lobectomy because of inadequate surgical resection margins. Skin-to-skin operative average time was 142 (IQR 1-3 105–182.5) min. The median post-operative stay was 6 (IQR 1-3 3.5–7) days. The mean value of the closest surgical margin was 13.7 mm. Conclusion: Image-guided reconstructions are a useful tool for surgeons to perform complex resections in order to spare healthy parenchyma and to ensure disease-free margins. Nevertheless, human skill and surgeon experience still remain fundamental for the final decisions regarding the proper resection to perform.

Abstract Background The evolution of SARS-CoV-2 has led to the emergence of several new variants, and few data are available on the impact of vaccination on SARS-CoV-2 variants. We aimed to assess the association between natural (previous infection) and induced (partial or complete vaccination) exposure to SARS-CoV-2 and the onset of new infection supported by the delta variant, and of comparing it with that supported by alpha. Methods We performed a test-negative case-control study, by linking population-based registries of confirmed diagnoses of infection with SARS-CoV-2, vaccinations against Covid-19 and healthcare utilization databases of the Italian Lombardy Region. Four hundred ninety-six persons who between 27 December 2020 and 16 July 2021 had an infection by the delta variant were 1:1 matched with citizens affected by alphavariant and 1:10 matched with persons who had a negative molecular test, according to gender, age and date of molecular ascertainment. We used a conditional logistic regression for estimating relative risk reduction of either variants associated with natural and/or induced immunization and corresponding 95% confidence interval (CI). Results Previous infection was associated with 91% (95% CI 85% to 95%) reduced relative risk of reinfection, without evidence of significant differences between delta and alpha cases (p=0.547). Significant lower vaccinal protection against delta than alpha variant infection was observed with reduced relative risk associated with partial vaccination respectively of 29% (7% to 45%), and 62% (48% to 71%) (p=0.001), and with complete vaccination respectively of 75% (66% to 82%) and 90% (85% to 94%) (p=0.003). Conclusions Lower protection towards infections caused by the delta variant with respect to alpha variant was noticed, even after the completion of the vaccination cycle. This finding would support efforts to maximize both vaccine uptake with two doses and fulfilment with individual protection measures, especially as the delta variant is rampant worldwide presently.

Severe tracheal injuries that cannot be managed by mobilization and end-to-end anastomosis represent an unmet clinical need and an urgent challenge to face in surgical practice; within this scenario, decellularized scaffolds (eventually bioengineered) are currently a tempting option among tissue engineered substitutes. The success of a decellularized trachea is expression of a balanced approach in cells removal while preserving the extracellular matrix (ECM) architecture/mechanical properties. Revising the literature, many Authors report about different methods for acellular tracheal ECMs development; however, only few of them verified the devices effectiveness by an orthotopic implant in animal models of disease. To support translational medicine in this field, here we provide a systematic review on studies recurring to decellularized/bioengineered tracheas implantation. After describing the specific methodological aspects, orthotopic implant results are verified. Furtherly, the only three clinical cases of compassionate use of tissue engineered tracheas are reported with a focus on outcomes.

IntroductionPsychiatric rehabilitation can be considered a bidirectional technique, designed to allow patients to achieve their personal target, focusing on the individuals’ strengths and challenges related to these targets and also on the community organizations in which they will live them out. Unfortunately, psychiatric rehabilitation is too often not considered a first line treatment. Moreover, rehabilitation has been confused with a generic and rough practice, consisting of extemporary actions and aimless entertainments designed to fill “the time passing”.MethodsThe aim of this study was to increase the knowledge and awareness about the state of the art of different systems of management and funding of psychosocial rehabilitation in the Italian “real-world” rehabilitative settings, using a specifically developed questionnaire.ResultsThe data obtained are positive for some aspects of the rehabilitation interventions, in particular for the use of validated tools for the evaluation and revision of projects and for the trend to work on a team, even though the scarcity of evidence-based rehabilitation interventions applied in Italian psychiatric services is less encouraging.ConclusionThis survey presents, at least partially, the “real-world” of rehabilitation in Italy so that we can lay the foundations for the definition of an updated, validated and shared network of what is implemented in the context of psychiatric rehabilitation.

Introduction: Organ shortage represents one of the main issues associated with lung transplantation (LTx). Over the years, in an attempt to increase the donor pool, the use of donors after cardiac death (DCDs) has gradually increased, with good results that bode well for their wider use in the future. Methods: In this work, our experience with DCDs is presented. In addition, a brief literature review on controlled (c) and uncontrolled (u) DCDs was performed on the studies published in the last four years. Results: From 2018 to 2022 our center performed three LTx with DCDs. All the donors were uDCDs (Maastricht class II). The median warm ischemic time of the graft was 160 min. In all the three LTx, lungs were reconditioned using portable Ex-Vivo-Lung-Perfusion (EVLP) system (Organ Care System, OCS, TransMedics) for a median time of 535 min. All the three LTx were performed with an intraoperative veno-arterial extra-corporeal membrane oxygenation (V-A ECMO), which was prolonged postoperatively in one patient.Grade 3 primary graft disfunction (PGD) at 72 h was observed in one patient. No signs of acute rejection were observed in any patient at the surveillance transbronchial biopsies. One patient died 317 after LTx for consequences of a lung adenocarcinoma diagnosed in the native lung, while the other two are still alive with a preserved graft function. Summary: The most recent studies confirm similar results between DCDs and DBDs in terms of survival and graft function. Good results can also be achieved in uDCDs if standardized protocols are followed and graft function is monitored by EVLP.Hence, the use of DCDs represents a valid solution to expand the donor pool.

Abstract Aims To develop and to validate a Cancer Multimorbidity Score (CMS) predictive of mortality in elderly patients affected by solid tumor, by using population‐based administrative Italian databases. Methods Through administrative databases of Lombardy Region (Northern Italy), a cohort of patients aged ≥65 years with a new diagnosis of solid tumor during the period 2009–2014 was identified. Sixty‐one conditions and diseases, measured from hospital inpatient diagnosis and outpatient drug prescription within 2 years before cancer diagnosis in a training set randomly including 70% of the cohort patients were tested to predict 5‐year mortality using a Cox regression model. Regression coefficients were used for assigning a weight to the predictive conditions, selected by the LASSO method. Weights were summed up in order to produce an aggregate score (the CMS). CMS performance was evaluated on a validation set, including the remaining 30% of the cohort patients, in terms of discrimination and calibration. Results The study cohort included 148,242 cancer patients. Thirty conditions were selected as independent predictors of 5‐year mortality and were included in the computation of the CMS. The area under the receiving operating characteristics curve was 0.68, becoming 0.71 when considering 1‐year mortality as outcome and reaching values of 0.74 and 0.81 when focusing on patients with breast and prostate cancer, respectively. A strong increasing trend in mortality was observed with increasing CMS value. Conclusions CMS represents a new useful tool for identifying high‐risk elderly cancer patients in everyday clinical practice, as well as for risk adjustment in clinical and epidemiological studies.

Intrathymic localizations of melanoma represent a very rare entity, with fewer than ten cases of intrathymic melanoma described in the literature. Herein, we describe two cases of patients who underwent surgical removal of a thymic mass at our thoracic surgery department between 2015 and 2022. The final pathological examination revealed a malignant melanoma in both cases; we therefore carried out a literature review to identify such rare and similar cases. In the first case, the intrathymic localization of melanoma was the first manifestation of the disease, posing a dilemma regarding the metastatic and primitive nature of the neoplasm. The second case described a thymic metastasis from a known previous cutaneous melanoma, for which the patient had successfully been treated six years earlier. After carefully reviewing the literature, we identified only six cases of verified primary intrathymic melanomas and one case of intrathymic metastasis resulting from melanoma previously described. Pathologists should be aware of the occurrence of this rare entity and mindful of the differential diagnoses. Several tools, including immunostaining of melanocytic markers and molecular investigations, are mandatory for final pathological diagnosis.

Abstract Background The usefulness of digital chest drain is still debated. We are carrying out a study to determine if the use of a digital system compared with a traditional system reduces the duration of chest drainage. To evaluate safety, benefit, or futility of this trial we planned the current interim analysis. Methods An interim analysis on preliminary data from ongoing investigator-initiated, multicenter, interventional, prospective randomized trial. Original protocol number: (NCT03536130). The interim main endpoint was overall complications; secondary endpoints were the concordance between the two primary endpoints of the RCT (chest tube duration and length of hospital stay). We planned the interim analysis when half of the patients have been randomised and completed the study. Data were described using mean and standard deviation or absolute frequencies and percentage. T-test for unpaired samples, Chi-square test, Poisson regression and absolute standardized mean difference (ASMD) were used. P-value

BackgroundOsimertinib is considered the standard-of-care for previously-untreated EGFR mutant advanced non-small cell lung cancer (NSCLC). Oncogene driver screening in early NSCLC is not standard practice. A real-world study has been designed in order to investigate the optimal testing frequency and timing for EGFR mutations in early NSCLC in clinical practice.Patients and MethodsThe present observational, retrospective study evaluated the real-world diagnostic-therapeutic pathway and clinical outcomes of 225 patients with stage I-III NSCLC, with particular reference to the EGFR-mutant subgroup.ResultsPrior to surgery, 101 patients had undergone a diagnostic biopsy; EGFR mutational analysis was available in 56 (55%) patients and 12 patients (21%) had a cancer harboring an EGFR mutation. Among surgical specimens, reflex EGFR test was performed in 181 (80%) of 225 and 35 cases (19%) were EGFR mutant. The majority of patients had not received adjuvant chemotherapy (N=174, 77%) or adjuvant radiotherapy (N=201, 89%). Of 49 (22%) patients experiencing disease relapse, 26 (53%) received first-line systemic treatment. All EGFR-mutant relapsed patients (N=6, 12.2%) received an EGFR-TKI. Median overall survival (OS) and relapse-free survival for the entire population were not reached. Multivariate analysis for OS confirmed a significant correlation with age, female gender, EGFR status, necrosis score, perineural invasion, and relapsed disease. EGFR test costs represented 1.6-2.4% of the total costs of management per patient (€34,340).ConclusionsOur results suggest that the frequency of EGFR mutations in early stage (I-III) NSCLC is similar to that of advanced stages. Reflex EGFR testing in all early-stage NSCLC at diagnosis or after surgery appears to be a valid tool to give patients the chance to benefit from targeted adjuvant treatment.

Pleuroparenchymal fibroelastosis (PPFE) is a rare condition characterized by fibrosis involving the pleura and the upper lobes which can be idiopathic or secondary to chemotherapy, transplantations and occupational exposure. For the end-stage form, lung transplantation (LT) is the treatment of choice. The aim of this study was to report our single-center experience for patients subjected to LT for PPFE and comparing it with the already published evidence on this topic. At our center, we have performed 6 bilateral LTs for patients with PPFE (3 males and 3 females) with a median age of 52 years. Median ICU and in-hospital length of stay were 8 and 30 days, respectively. To date, two patients are alive and four are dead, with a median overall survival of 10 months. In addition, after a formal search using the terms “pleuroparenchymal fibroelastosis AND lung transplantation”, we collected 14 studies focused on outcomes after LT. LT for PPFE is technically challenging and its post-operative course could also be complicated. Current available data on LT outcomes are extremely poor and mostly limited to case reports. Further studies need to be published to improve knowledge of this disease and to achieve best outcomes for LT.

Tracheal reconstruction represents a challenge when primary anastomosis is not feasible. Within this scenario, the study aim was to develop a new pig-derived decellularized trachea (DecellT) to be compared with the cryopreserved counterpart (CryoT) for a close predictive analysis. Tracheal segments underwent decellularization by a physical + enzymatic + chemical method (12 cycles); in parallel, cryopreserved samples were also prepared. Once decellularized (histology/DNA quantification), the two groups were characterized for Alpha-Gal epitopes/structural proteins (immunohistochemistry/histology/biochemical assays/second harmonic generation microscopy)/ultrastructure (Scanning Electron Microscopy (SEM))/mechanical behaviour. Cytotoxicity absence was assessed in vitro (extract-test assay/direct seeding, HM1SV40 cell line) while biocompatibility was verified in BALB/c mice, followed by histological/immunohistochemical analyses and SEM (14 days). Decellularization effectively removed Alpha-Gal epitopes; cartilage histoarchitecture was retained in both groups, showing chondrocytes only in the CryoT. Cryopreservation maintained few respiratory epithelium sparse cilia, not detectable in DecellT. Focusing on ECM, preserved structural/ultrastructural organization and collagen content were observed in the cartilage of both; conversely, the GAGs were significantly reduced in DecellT, as confirmed by mechanical study results. No cytotoxicity was highlighted by CryoT/DecellT in vitro, as they were also corroborated by a biocompatibility assay. Despite some limitations (cells presence/GAGs reduction), CryoT/DecellT are both appealing options, which warrant further investigation in comparative in vivo studies.

The Thoracic Outlet Syndrome is a clinical potentially disabling condition characterized by a group of upper extremity signs and symptoms due to the compression of the neurovascular bundle passing through the thoracic outlet region. Because of the non-specific nature of signs and symptoms, to the lack of a consensus for the objective diagnosis, and to the wide range of etiologies, the actual figure is still a matter of debate among experts. We aimed to summarize the current evidence about the pathophysiology, the diagnosis and the treatment of the thoracic outlet syndrome, and to report a retrospective analysis on 324 patients followed for 5 years at the Padua University Hospital and at the Naples Fatebenefratelli Hospital in Italy, to verify the effectiveness of a specific rehabilitation program for the syndrome and to evaluate if physical therapy could relieve symptoms in these patients.

Abstract Background Despite improvement in lung function, most lung transplant (LTx) recipients show an unexpectedly reduced exercise capacity that could be explained by persisting peripheral muscle dysfunction of multifactorial origin. We analyzed the course of symptoms, including dyspnea, muscle effort and muscle pain and its relation with cardiac and pulmonary function parameters during an incremental exercise testing. Methods Twenty-four bilateral LTx recipients were evaluated in an observational cross-sectional study. Recruited patients underwent incremental cardio-pulmonary exercise testing (CPET). Arterial blood gases at rest and peak exercise were measured. Dyspnea, muscle effort and muscle pain were scored according to the Borg modified scale. Potential associations between the severity of symptoms and exercise testing parameters were analyzed using a Forest-Tree Machine Learning approach, which accomplishes for a ratio between number of observations and number of screened variables less than unit. Results Dyspnea score was significantly associated with maximum power output (WR, watts), and minute ventilation (VE, L/min) at peak exercise. In a controlled subgroup analysis, dyspnea score was a limiting symptom only in LTx recipients who reached the higher levels of WR (≥ 101 watts) and VE (≥ 53 L/min). Muscle effort score was significantly associated with breathing reserve as percent of maximal voluntary ventilation (BR%MVV). The lower the BR%MVV at peak exercise (

Background: A set of indicators to assess the quality of care for women operated for breast cancer was developed by an expert working group of the Italian Health Ministry in order to compare the Italian regions. A study to validate these indicators through their relationship with survival was carried out. Methods: The 16,753 women who were residents in three Italian regions (Lombardy, Emilia-Romagna and Lazio) and hospitalized for breast cancer surgery during 2011 entered the cohort and were followed until 2016. Adherence to selected recommendations (i.e., surgery timeliness, medical therapy timeliness, appropriateness of complementary radiotherapy and mammographic follow-up) was assessed. Multivariable proportional hazards models were fitted to estimate hazard ratios for the association between adherence with recommendations and the risk of all-cause mortality. Results: Adherence to recommendations was 53% for medical therapy timeliness, 73% for appropriateness of mammographic follow-up, 74% for surgery timeliness and 82% for appropriateness of complementary radiotherapy. Risk reductions of 26%, 62% and 56% were observed for adherence to recommendations on medical therapy timeliness, appropriateness of complementary radiotherapy and mammographic follow-up, respectively. There was no evidence that mortality was affected by surgery timeliness. Conclusions: Clinical benefits are expected from improvements in adherence to the considered recommendations. Close control of women operated for breast cancer through medical care timeliness and appropriateness of radiotherapy and mammographic monitoring must be considered the cornerstone of national guidance, national audits, and quality improvement incentive schemes.

Introduction and aim: Ectopic ACTH secretion (EAS) is mostly secondary to thoracic/ abdominal neuroendocrine tumours (NETs) or small cell-lung carcinoma (SCLC). We studied the diagnostic accuracy of CT with 68Ga-Dota derivatives (68Ga-SSTR) PET in localizing ACTH-secreting tumor in patients with EAS. Materials and methods: 68Ga-SSTR-PET/CT was performed and compared with the nearest enhanced CT in 18 cases (16 primary and 2 recurrent neo plasms). Unspecific, indeterminate and false-positive uptakes were assessed using conventional imaging, follow-up or histology. Results: We diagnosed 13 thoracic (9 primary and 2 recurrent bronchial carcinoids, 2 SCLCs) and 1 abdominal (pancreatic NET) tumors. Eight ACTH-secreting tumors were promptly identified at EAS diagnosis (’overt’, four pulmona ry carcinoids with two recurrences and two SCLC); six EAS have been discovered during the subsequent follow-up (’covert’, five bronchial carcinoids and one pancreati c NET). At the time of EAS diagnosis, imaging was able to correctly detect the ACTH-secreting tumour in 8/18 cases (6 new diagnosis and 2 recurrences). During the follow-up, six out of initially ten ‘occult’ cases became ‘covert’. At last available follow-up, CT and 68Ga-SSTR-PET/CT were able to diagnose 11/18 and 12/18 ACTH-secreting tumours, respectively (11/14 and 12/14 considering only overt and covert cases, respectively). Four cases have never been localized by conventional or nuclear imaging (’occult EAS’), despite an average follow-up of 5 years. Conclusion: The 68Ga-SSTR-PET/CT is useful in localizing EAS, especially to enhance positive prediction of the suggestive CT lesions and to detect occult neoplasms.

Chronic rejection (CR) is the main culprit for reduced survival and quality of life in patients undergoing lung transplantation (Ltx). High-throughput approaches have been used to unveil the molecular pathways of CR, mainly in the blood and/or in bronchoalveolar lavage. We hypothesized that a distinct molecular signature characterizes the biopsies of recipients with clinically confirmed histological signs of CR. Eighteen cystic fibrosis patients were included in the study and RNA sequencing was performed in 35 scheduled transbronchial biopsies (TBBs): 5 with acute cellular rejection, 9 with CR, and 13 without any sign of post-LTx complication at the time of biopsy; 8 donor lung samples were used as controls. Three networks with 33, 26, and 36 differentially expressed genes (DEGs) were found in TBBs with CR. Among these, seven genes were common to the identified pathways and possibly linked to CR and five of them (LCN2, CCL11, CX3CL1, CXCL12, MUC4) were confirmed by real-time PCR. Immunohistochemistry was significant for LCN2 and MUC4. This study identified a typical gene expression pattern in TBBs with histological signs of CR and the LCN2 gene appeared to play a central role. Thus, it could be crucial in CR pathophysiology.

Abstract Background In patients submitted to major pulmonary resection, the postoperative length of stay is mainly influenced by the duration of air leaks and chest tube removal. The measurement of air leaks largely relies on traditional chest drainage systems which are prone to subjective interpretation. Difficulty in differentiating between active air leaks and bubbles due to a pleural space effect may also lead to tentative drain clamping and prolonged time for chest drain removal. New digital systems allow continuous monitoring of air leaks, identifying subtle leakage that may be not visible during daily patient evaluation. Moreover, an objective assessment of air leaks may lead to a reduced interobserver variability and to an optimized timing for chest tube removal. Methods This study is a prospective randomized, interventional, multicenter trial designed to compare an electronic chest drainage system (Drentech™ Palm Evo) with a traditional system (Drentech™ Compact) in a cohort of patients undergoing pulmonary lobectomy through a standard three-port video-assisted thoracic surgery approach for both benign and malignant disease. The study will enroll 382 patients in three Italian centers. The duration of chest drainage and the length of hospital stay will be evaluated in the two groups. Moreover, the study will evaluate whether the use of a digital chest system compared with a traditional system reduces the interobserver variability. Finally, it will evaluate whether the digital drain system may help in distinguishing an active air leak from a pleural space effect, by the digital assessment of intrapleural differential pressure, and in identifying potential predictors of prolonged air leaks. Discussion To date, few studies have been performed to evaluate the clinical impact of digital drainage systems. The proposed prospective randomized trial will provide new knowledge to this research area by investigating and comparing the difference between digital and traditional chest drain systems. In particular, the objectives of this project are to evaluate the feasibility and usefulness of digital chest drainages and to provide new tools to identify patients at higher risk of developing prolonged air leaks. Trial registration ClinicalTrials.gov, NCT03536130. Retrospectively registered on 24 May 2018.

Objectives To develop a population-based risk stratification model (COVID-19 Vulnerability Score) for predicting severe/fatal clinical manifestations of SARS-CoV-2 infection, using the multiple source information provided by the healthcare utilisation databases of the Italian National Health Service.Design Retrospective observational cohort study.Setting Population-based study using the healthcare utilisation database from five Italian regions.Participants Beneficiaries of the National Health Service, aged 18–79 years, who had the residentship in the five participating regions. Residents in a nursing home were not included. The model was built from the 7 655 502 residents of Lombardy region.Main outcome measure The score included gender, age and 29 conditions/diseases selected from a list of 61 conditions which independently predicted the primary outcome, that is, severe (intensive care unit admission) or fatal manifestation of COVID-19 experienced during the first epidemic wave (until June 2020). The score performance was validated by applying the model to several validation sets, that is, Lombardy population (second epidemic wave), and the other four Italian regions (entire 2020) for a total of about 15.4 million individuals and 7031 outcomes. Predictive performance was assessed by discrimination (areas under the receiver operating characteristic curve) and calibration (plot of observed vs predicted outcomes).Results We observed a clear positive trend towards increasing outcome incidence as the score increased. The areas under the receiver operating characteristic curve of the COVID-19 Vulnerability Score ranged from 0.85 to 0.88, which compared favourably with the areas of generic scores such as the Charlson Comorbidity Score (0.60). A remarkable performance of the score on the calibration of observed and predicted outcome probability was also observed.Conclusions A score based on data used for public health management accurately predicted the occurrence of severe/fatal manifestations of COVID-19. Use of this score may help health decision-makers to more accurately identify high-risk citizens who need early preventive or treatment interventions.

Intraoperative veno-arterial (VA) extracorporeal membrane oxygenation (ECMO) as intraoperative hemodynamic support during lung transplantation is becoming a standard practice due to promising clinical results. Nevertheless, studies on tissue/molecular pathways investigating ischemia/reperfusion injury are still lacking. Patients receiving a bilateral lung transplantation between January 2012 and December 2018 at the University Hospital of Padova were included in this retrospective single-center observational study. The present study aimed to investigate ischemia/reperfusion injury in 51 tissue specimens obtained from 13 recipients supported by intraoperative VA-ECMO and 38 who were not. Several tissue analyses, including apoptosis evaluation and inducible nitric oxide synthase expression, were performed on the biopsies at the time of transplantation. Lung samples from the ECMO group (both pre- and post-reperfusion) were comparable, or for some parameters better, than samples from the non-ECMO group. Leukocyte margination was significantly lower in the ECMO group than in the non-ECMO group. Primary graft dysfunction, mainly at 24 and 48 h, was correlated with the tissue injury score of the post-reperfusion biopsy. The interquartile ranges for all morphological parameters showed high grade variability between pre- and post-reperfusion in the non-ECMO group. These preliminary data support the use of intraoperative ECMO based on lower lung tissue ischemia/reperfusion injury. Larger case series are mandatory to confirm our findings.

IntroductionThe COVID-19 pandemic has proved to be a historic challenge for healthcare systems, particularly with regard to cancer patients. So far, very limited data have been presented on the impact on integrated care pathways (ICPs).MethodsWe reviewed the ICPs of lung cancer patients who accessed the Veneto Institute of Oncology (IOV)/University Hospital of Padua (Center 1) and the University Hospital of Verona (Center 2) before and after the COVID-19 pandemic, through sixteen indicators chosen by the members of a multidisciplinary team (MDT).ResultsTwo window periods (March and April 2019 and 2020) were chosen for comparison. Endoscopic diagnostic procedures and major resections for early stage NSCLC patients increased at Center 1, where a priority pathway with dedicated personnel was established for cancer patients. A slight decrease was observed at Center 2 which became part of the COVID unit. Personnel shortage and different processing methods of tumor samples determined a slightly longer time for diagnostic pathway completion at both Centers. Personnel protection strategies led to a MDT reshape on a web basis and to a significant selection of cases to be discussed in both Centers. The optimization of patient access to healthcare units reduced first outpatient oncological visits, patient enrollment in clinical trials, and end-of-life cancer systemic treatments; finally, a higher proportion of hypofractionation was delivered as a radiotherapy approach for early stage and locally advanced NSCLC.ConclusionsBased on the experience of the two Centers, we identified the key steps in ICP that were impacted by the COVID-19 pandemic so as to proactively put in place a robust service provision of thoracic oncology.

Broncho-pulmonary neuroendocrine neoplasms (BP-NENs) are neoplasms orphan of an efficient therapy. Available medical treatments derived from clinical trials are not specific for the management of this malignancy. Sunitinib is a multi-receptor tyrosine-kinases (RTKs) inhibitor that has already shown its efficacy in NENs, but there are no available data about its action in BP-NENs. Therefore, our aim was to understand the effects of RTKs inhibition promoted by sunitinib in order to evaluate new putative targets useful in malignancy treatment. Since our results underlined a role for EGFR and IGF1R in modulating sunitinib antiproliferative action, we investigated the effects of erlotinib, an EGFR inhibitor, and linsitinib, an IGF1R inhibitor, in order to understand their function in regulating cells behaviour. Cell viability and caspase activation were evaluated on two immortalised human BP-NEN cell lines and primary cultures. Our results showed that after treatment with sunitinib and/or IGF1, EGF and VEGF, the antiproliferative effect of sunitinib was counteracted by EGF and IGF1 but not by VEGF. Therefore, we evaluated with AlphaScreen technology the phosphorylated EGFR and IGF1R levels in primary cultures treated with sunitinib and/or EGF and IGF1. Results showed a de crease of p-IGF1R after treatment with sunitinib and an increase after co-treatment with IGF1. Then, we assessed cell viability and caspase activation on BP-NEN cell lines after treatment with linsitinib and/or erlotinib. Results demonstrate that these two agents have a stronger antiproliferative effect compared to sunitinib. In conclusion, our results suggest that IGF1R and EGF1R could represent putative molecular targets in B P-NENs treatment.

Pulmonary hypertension (PH) in patients with Systemic Sclerosis (SSc) may stem from a variety of underlying causes, thus making a correct diagnosis and management difficult. The main challenges lie in the distinction between pulmonary arterial hypertension (PAH, group 1) and PH due to interstitial lung disease (PH-ILD, group 3) in patients with concomitant lung fibrosis — a very common occurrence in SSc. A consensus among experts remains elusive. Some studies have suggested that among SSc patients with PH, those with an ILD extension > 20% at high-resolution computed tomography (HRCT) should be considered as affected by PH-ILD, whereas other Authors have found that a wide proportion of these patients exhibit features of both PAH and group 3 PH-ILD. We report the case of a 46-year-old male SSc patient with a stable and extensive ILD (>20%) who developed a histologically documented pulmonary vasculopathy typical of PAH and received PAH-specific treatment as bridge to transplant. Moreover, we documented PH disease course by right heart catheterization (RHC), with and without specific vasodilator therapies, which are essential in PAH but not indicated and/or harmful in PH-ILD.

Background: Preterm birth is a major worldwide public health concern, being the leading cause of infant mortality. Understanding of risk factors remains limited, and early identification of women at high risk of preterm birth is an open challenge. Objective: The aim of the study was to develop and validate a novel pre-pregnancy score for preterm delivery in nulliparous women using information from Italian healthcare utilization databases. Study Design: Twenty-six variables independently able to predict preterm delivery were selected, using a LASSO logistic regression, from a large number of features collected in the 4 years prior to conception, related to clinical history and socio-demographic characteristics of 126,839 nulliparous women from Lombardy region who gave birth between 2012 and 2017. A weight proportional to the coefficient estimated by the model was assigned to each of the selected variables, which contributed to the Preterm Birth Score. Discrimination and calibration of the Preterm Birth Score were assessed using an internal validation set (i.e., other 54,359 deliveries from Lombardy) and two external validation sets (i.e., 14,703 and 62,131 deliveries from Marche and Sicily, respectively). Results: The occurrence of preterm delivery increased with increasing the Preterm Birth Score value in all regions in the study. Almost ideal calibration plots were obtained for the internal validation set and Marche, while expected and observed probabilities differed slightly in Sicily for high Preterm Birth Score values. The area under the receiver operating characteristic curve was 60%, 61% and 56% for the internal validation set, Marche and Sicily, respectively. Conclusions: Despite the limited discriminatory power, the Preterm Birth Score is able to stratify women according to their risk of preterm birth, allowing the early identification of mothers who are more likely to have a preterm delivery.

IntroductionThe CDKN2A gene plays a central role in the pathogenesis of malignant pleural mesothelioma (MPM). The gene encodes for two tumor suppressor proteins, p16/INK4A and p14/ARF, frequently lost in MPM tumors. The exact role of p14/ARF in MPM and overall its correlation with the immune microenvironment is unknown. We aimed to determine whether there is a relationship between p14/ARF expression, tumor morphological features, and the inflammatory tumor microenvironment.MethodsDiagnostic biopsies from 76 chemo-naive MPMs were evaluated. Pathological assessments of histotype, necrosis, inflammation, grading, and mitosis were performed. We evaluated p14/ARF, PD-L1 (tumor proportion score, TPS), and Ki-67 (percentage) by immunohistochemistry. Inflammatory cell components (CD3+, CD4+, CD8+ T lymphocytes; CD20+ B-lymphocytes; CD68+ and CD163+ macrophages) were quantified as percentages of positive cells, distinguishing between intratumoral and peritumoral areas. The expression of p14/ARF was associated with several clinical and pathological characteristics. A random forest-based machine-learning algorithm (Boruta) was implemented to identify which variables were associated with p14/ARF expression.Resultsp14/ARF was evaluated in 68 patients who had a sufficient number of tumor cells. Strong positivity was detected in 14 patients (21%) (11 epithelioid and 3 biphasic MPMs). At univariate analysis, p14/ARF-positive epithelioid mesotheliomas showed higher nuclear grade (G3) (p = 0.023) and higher PD-L1 expression (≥50%) (p = 0.042). The percentages of CD4 and CD163 in peritumoral areas were respectively higher and lower in p14/ARF positive tumors but did not reach statistical significance with our sample size (both p = 0.066). The Boruta algorithm confirmed the predictive value of PD-L1 percentage for p14/ARF expression in all histotypes.Conclusionsp14/ARF-positive epithelioid mesotheliomas may mark a more aggressive pathological phenotype (higher nuclear grade and PD-L1 expression). Considering the results regarding the tumor immune microenvironment, p14/ARF-negative tumors seem to have an immune microenvironment less sensitive to immune checkpoint inhibitors, being associated with low PD-L1 and CD4 expression, and high CD163 percentage. The association between p14/ARF-positive MPMs and PD-L1 expression suggests a possible interaction of the two pathways. Confirmation of our preliminary results could be important for patient selection and recruitment in future clinical trials with anticancer immunotherapy.

BackgroundThe novel coronavirus (SARS-CoV-2) pandemic spread rapidly worldwide increasing exponentially in Italy. To date, there is lack of studies describing clinical characteristics of the people at high risk of infection. Hence, we aimed (i) to identify clinical predictors of SARS-CoV-2 infection risk, (ii) to develop and validate a score predicting SARS-CoV-2 infection risk, and (iii) to compare it with unspecific scores.MethodsRetrospective case-control study using administrative health-related database was carried out in Southern Italy (Campania region) among beneficiaries of Regional Health Service aged over than 30 years. For each person with SARS-CoV-2 confirmed infection (case), up to five controls were randomly matched for gender, age and municipality of residence. Odds ratios and 90% confidence intervals for associations between candidate predictors and risk of infection were estimated by means of conditional logistic regression. SARS-CoV-2 Infection Score (SIS) was developed by generating a total aggregate score obtained from assignment of a weight at each selected covariate using coefficients estimated from the model. Finally, the score was categorized by assigning increasing values from 1 to 4. Discriminant power was used to compare SIS performance with that of other comorbidity scores.ResultsSubjects suffering from diabetes, anaemias, Parkinson's disease, mental disorders, cardiovascular and inflammatory bowel and kidney diseases showed increased risk of SARS-CoV-2 infection. Similar estimates were recorded for men and women and younger and older than 65 years. Fifteen conditions significantly contributed to the SIS. As SIS value increases, risk progressively increases, being odds of SARS-CoV-2 infection among people with the highest SIS value (SIS = 4) 1.74 times higher than those unaffected by any SIS contributing conditions (SIS = 1).ConclusionConditions and diseases making people more vulnerable to SARS-CoV-2 infection were identified by the current study. Our results support decision-makers in identifying high-risk people and adopting of preventive measures to minimize the spread of further epidemic waves.

PurposeTo evaluate if reduced muscle mass, assessed with Computed Tomography (CT), is a predictor of intensive care unit (ICU) hospitalization in COVID-19 patients.MethodsIn this Institution Review Board approved study, we retrospectively evaluated COVID-19 patients treated in our tertiary center from March to November 2020 who underwent an unenhanced chest CT scan within three weeks from hospitalization.We recorded the mean Hounsfield Unit (Hu) value of the right paravertebral muscle at the level of the 12th thoracic vertebra, the hospitalization unit (ICU and COVID-19 wards), clinical symptoms, Barthel Index, and laboratory findings.Logistic regression analysis was applied to assess if muscle loss (HuResultsOne-hundred-fifty patients matched the inclusion criteria (46 females; mean age±SD 61.3±15 years-old), 36 treated in ICU. Patients in ICU showed significantly lower Hu values (29±24 vs 39.4±12, p = 0.001). Muscle loss was a predictor of ICU admission (p = 0.004).Patients with muscle loss were significantly older (73.4±10 vs 56.4±14 years), had lower Barthel Index scores (54.4±33 vs 85.1±26), red blood-cell count (3.9±1 vs 4.6±1×1012L-1), and Hb levels (11.5±2 vs 13.2±2g/l) as well as higher white blood-cell count (9.4±7 vs 7.2±4×109L-1), C-reactive protein (71.5±71 vs 44±48U/L), and lactate dehydrogenase levels (335±163 vs 265.8±116U/L) (pConclusionsMuscle loss seems to be a predictor of ICU hospitalization in COVID-19 patients and radiologists reporting chest CT at admission should note this finding in their reports.

Background. Limited evidence exists on the balance between the benefits and harms of the COVID-19 vaccines. The aim of this study is to compare the benefits and safety of mRNA-based (Pfizer-BioNTech and Moderna) and adenovirus-vectored (Oxford-AstraZeneca) vaccines in subpopulations defined by age and sex. Methods. All citizens who are newly vaccinated from 27 December 2020 to 3 May 2021 are matched to unvaccinated controls according to age, sex, and vaccination date. Study outcomes include the events that are expected to be avoided by vaccination (i.e., hospitalization and death from COVID-19) and those that might be increased after vaccine inoculation (i.e., venous thromboembolism). The incidence rate ratios (IRR) of vaccinated and unvaccinated citizens are separately estimated within strata of sex, age category and vaccine type. When suitable, number needed to treat (NNT) and number needed to harm (NNH) are calculated to evaluate the balance between the benefits and harm of vaccines within each sex and age category. Results. In total, 2,351,883 citizens are included because they received at least one dose of vaccine (755,557 Oxford-AstraZeneca and 1,596,326 Pfizer/Moderna). A reduced incidence of COVID-19-related outcomes is observed with a lowered incidence rate ranging from 55% to 89% and NNT values ranging from 296 to 3977. Evidence of an augmented incidence of harm-related outcomes is observed only for women aged Conclusions. A favourable balance between benefits and harms is observed in the current study, even among younger women who received Oxford-AstraZeneca.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease characterized by irreversible scarring of the distal lung. IPF is best described by its histopathological pattern of usual interstitial pneumonia (UIP), characterized by spatial heterogeneity with alternating interstitial fibrosis and areas of normal lung, and temporal heterogeneity of fibrosis characterized by scattered fibroblastic foci (FF), dense acellular collagen and honeycomb changes. FF, comprising aggregated fibroblasts/myofibroblasts surrounded by metaplastic epithelial cells (EC), are the cardinal pathological lesion and their presence strongly correlates with disease progression and mortality. We hypothesized that the EC/FF sandwich from patients with UIP/IPF has a distinct molecular signature which could offer new insights into the crosstalk of these two crucial actors in the disease. Laser capture microdissection with RNAseq was used to investigate the transcriptome of the EC/FF sandwich from IPF patients versus controls (primary spontaneous pneumothorax). Differentially expressed gene analysis identified 23 up-regulated genes mainly related to epithelial dysfunction. Gene ontology analysis highlighted the activation of different pathways, mainly related to EC, immune response and programmed cell death. This study provides novel insights into the IPF pathogenetic pathways and suggests that targeting some of these up-regulated pathways (particularly those related to secreto-protein/mucin dysfunction) may be beneficial in IPF. Further studies in a larger number of lung samples, ideally from patients with early and advanced disease, are needed to validate these findings.

Objectives The aim of this study was to validate a composed coronavirus disease 2019 (COVID-19) chest radiography score (CARE) based on the extension of ground-glass opacity (GG) and consolidations (Co), separately assessed, and to investigate its prognostic performance. Methods COVID-19-positive patients referring to our tertiary centre during the first month of the outbreak in our area and with a known outcome were retrospectively evaluated. Each lung was subdivided into three areas and a three-grade score assessing the extension of GG and Co was used. The CARE was derived from the sum of the subscores. A mixed-model ANOVA with post hoc Bonferroni correction was used to evaluate whether differences related to the referring unit (emergency room, COVID-19 wards and intensive care unit (ICU)) occurred. Logistic regression analyses were used to investigate the impact of CARE, patients’ age and sex on the outcome. To evaluate the prognostic performance of CARE, receiver operating characteristic curves were computed for the entire stay and at admission only. Results A total of 1203 chest radiographs of 175 patients (120 males; mean age 67.81±15.5 years old) were examined. On average, each patient underwent 6.8±10.3 radiographs. Patients in ICU as well as deceased patients showed higher CARE scores (p