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Abstract Thousands of disease cases and hundreds of deaths occur globally each year due to invasive meningococcal disease. Neisseria meningitidis serogroup B (MenB) is the leading cause of such disease in developed countries. Two vaccines, 4CMenB and MenB‐fHbp, that protect against MenB are available and include one or two forms respectively of factor H binding protein (fHbp), a key protective antigen. Studies of circulating meningococci have identified over 1380 different fHbp amino acid sequences, which form three immunologically distinct clusters, termed variants 1, 2, and 3. Neither of the current vaccines contains a variant 2 antigen, which is less well characterized than fHbp variants 1 and 3. We characterized the interaction of fHbp variant 2 with humAb 1B1 using biochemical methods and live meningococcal assays. Further, we determined the crystal structure of the complex at 2.4 Å resolution, clearly revealing the epitope and providing the first detailed report of an antibody with distinct specificity for fHbp variant 2. Extensive mutagenesis and binding studies elucidated key hotspots in the interface. This combination of structural and functional studies provides a molecular explanation for the bactericidal potency and specificity of humAb 1B1 for fHbp variant 2. Our studies, focused on fHbp variant 2, expand the understanding of this previously under characterized group of the vast family of variants of fHbp, a virulence factor present on all meningococci. Moreover, the definition of a protective conformational epitope on fHbp variant 2 may support the design and development of novel variant 2‐containing MenB vaccines affording greater breadth of protection.

ABSTRACT Manganese (Mn) is crucial as a trace element for plant metabolism, but high concentrations in soil can induce symptoms of toxicity. This study aimed to evaluate the metabolism of nitrogen compounds and biomass production in Canavalia ensiformis and Cajanus cajan, clarifying the effects of this metal on nitrogen metabolism. The soil was treated with Mn concentrations of 80, 100, 120, 140, and 160 mg kg−1. Differential responses were observed in the metabolism of nitrogenous compounds between species. C. cajan affected nitrogen metabolism in shoots, roots, and nodules, with significant variations in amino acids, total soluble proteins, ureides, and root biomass concentration. In contrast, C. ensiformis showed stability in the concentrations of compounds, mainly ureides, and proteins, even with increasing doses of Mn in the soil. These findings highlight the importance of nitrogen metabolism in legumes studied as a key aspect for understanding their Mn tolerance mechanisms in soil.

Abstract Relevance of germline (GL) predisposition in myelodysplastic syndromes (MDSs) was stressed in both 2022 WHO and International Consensus classifications, but its incidence is probably underestimated, especially in young adult patients. We selected a cohort of 31 consecutive de novo MDS patients with unusual young age (

Abstract Background Pancreatic cancer (PC) first‐line therapy often consists of polychemotherapy regimens, but choosing a second‐line therapy after disease progression, especially following first‐line FOLFIRINOX, remains a clinical challenge. This study presents results from a large, multicenter, retrospective analysis of Italian patients with metastatic PC (mPC) treated with Nab‐paclitaxel/Gemcitabine (AG) as second or later line of treatment. Main objective of the study is to identify prognostic factors that could inform treatment decisions. Methods The study included 160 mPC patients treated with AG in 17 Italian institutions. AG was administered according to labelling dose, until disease progression, unacceptable toxicity or patient refusal. Variations in schedules, dose modifications, supportive measures, and response evaluation were determined by individual clinicians' practice. Results AG was well‐tolerated and exhibited promising clinical activity. The overall response rate (ORR) and the disease control rate (DCR) were 22.5% and 45.6%, respectively. Median progression‐free survival (PFS) and overall survival (OS) were 3.9 and 6.8 months, respectively. Among the patients who received AG as a second‐line therapy (n = 111, 66.9%), median PFS and OS were 4.2 and 7.4 months, respectively. Notably, in the 76 patients (68%) receiving AG after first‐line FOLFIRINOX, an ORR of 19.7% and a DCR of 46.0% were observed, resulting in a median PFS of 3.5 and median OS of 5.7 months. The study identified specific clinical or laboratory parameters (LDH, NLR, fasting serum glucose, liver metastases, ECOG PS, and first‐line PFS) as independent prognostic factors at multivariate level. These factors were used to create a prognostic nomogram that divided patients into three risk classes, helping to predict second‐line OS and PFS. Conclusions This study represents the largest real‐world population of mPC patients treated with AG as a second or later line of therapy. It supports the feasibility of this regimen following first‐line FOLFIRINOX, particularly in patients with specific clinical and laboratory characteristics who derived prolonged benefit from first‐line therapy.

Abstract Advancements in comprehending myelodysplastic neoplasms (MDS) have unfolded significantly in recent years, elucidating a myriad of cellular and molecular underpinnings integral to disease progression. While molecular inclusions into prognostic models have substantively advanced risk stratification, recent revelations have emphasized the pivotal role of immune dysregulation within the bone marrow milieu during MDS evolution. Nonetheless, immunotherapy for MDS has not experienced breakthroughs seen in other malignancies, partly attributable to the absence of an immune classification that could stratify patients toward optimally targeted immunotherapeutic approaches. A pivotal obstacle to establishing “immune classes” among MDS patients is the absence of validated accepted immune panels suitable for routine application in clinical laboratories. In response, we formed International Integrative Innovative Immunology for MDS (i4MDS), a consortium of multidisciplinary experts, and created the following recommendations for standardized methodologies to monitor immune responses in MDS. A central goal of i4MDS is the development of an immune score that could be incorporated into current clinical risk stratification models. This position paper first consolidates current knowledge on MDS immunology. Subsequently, in collaboration with clinical and laboratory specialists, we introduce flow cytometry panels and cytokine assays, meticulously devised for clinical laboratories, aiming to monitor the immune status of MDS patients, evaluating both immune fitness and identifying potential immune “risk factors.” By amalgamating this immunological characterization data and molecular data, we aim to enhance patient stratification, identify predictive markers for treatment responsiveness, and accelerate the development of systems immunology tools and innovative immunotherapies.

Abstract Notable treatment advances have been made in recent years for patients with myelodysplastic syndromes/neoplasms (MDS), and several new drugs are under development. For example, the emerging availability of oral MDS therapies holds the promise of improving patients' health‐related quality of life (HRQoL). Within this rapidly evolving landscape, the inclusion of HRQoL and other patient‐reported outcomes (PROs) is critical to inform the benefit/risk assessment of new therapies or to assess whether patients live longer and better, for what will likely remain a largely incurable disease. We provide practical considerations to support investigators in generating high‐quality PRO data in future MDS trials. We first describe several challenges that are to be thoughtfully considered when designing an MDS‐focused clinical trial with a PRO endpoint. We then discuss aspects related to the design of the study, including PRO assessment strategies. We also discuss statistical approaches illustrating the potential value of time‐to‐event analyses and their implications within the estimand framework. Finally, based on a literature review of MDS randomized controlled trials with a PRO endpoint, we note the PRO items that deserve special attention when reporting future MDS trial results. We hope these practical considerations will facilitate the generation of rigorous PRO data that can robustly inform MDS patient care and support treatment decision‐making for this patient population.

Abstract Background Transoral robotic surgery (TORS) opens new perspectives. We evaluated the outcomes for patients having undergone TORS after previous radiotherapy. Methods A retrospective multicenter study (n = 138) in a previously irradiated area between 2009 and 2020. Survival was assessed with the Kaplan–Meier method. Prognostic factors were evaluated using a chi‐squared test, Fisher's test, or Wilcoxon's test. Results The median length of hospital stay was 12.5 days. Bleeding was the most frequent postoperative complication (15.2%, n = 22). Prophylactic vessel ligation did not significantly decrease bleeding. Complications were significantly lower for Tis, T1, and N0 tumors. 91.6% (n = 120) of the patients with a perioperative tracheotomy could be decannulated. Larynx was functional for 65.94% of the patients. The median length of follow‐up was 26 months. The 5‐year overall and relapse‐free survival rates were respectively 59.9% and 43.4%. Conclusion Oncological and functional results confirmed the value of TORS as a treatment in previously irradiated area.

Abstract Conservation funding is currently limited; cost‐effective conservation solutions are essential. We suggest that the thousands of field stations worldwide can play key roles at the frontline of biodiversity conservation and have high intrinsic value. We assessed field stations’ conservation return on investment and explored the impact of COVID‐19. We surveyed leaders of field stations across tropical regions that host primate research; 157 field stations in 56 countries responded. Respondents reported improved habitat quality and reduced hunting rates at over 80% of field stations and lower operational costs per km2 than protected areas, yet half of those surveyed have less funding now than in 2019. Spatial analyses support field station presence as reducing deforestation. These “earth observatories” provide a high return on investment; we advocate for increased support of field station programs and for governments to support their vital conservation efforts by investing accordingly.

Abstract The Italian territory is located at the heart of one of the global hot spots of climate change, where the implementation of climate‐smart land management practices is imperative to guarantee the present and future maintenance of ecosystem functions as well as the sustainability of human socioeconomic activities. The project HIGHLANDER (HIGH performance computing to support smart LAND sERvices) led by Cineca aims at building a comprehensive and multi‐sector framework for land‐management decision‐making in Italy. The project relies on high quality information on different components of the landscape, with a focus on climate‐driven processes, and state‐of‐the‐art computing infrastructures. The HIGHLANDER Data Portal maximizes the impact of HIGHLANDER results by providing access to data products and services. In this article, we describe the architectural features of the platform, as well as the available HIGHLANDER datasets and downstream applications.

Abstract Aims The HeartLogic algorithm combines multiple implantable defibrillator (ICD) sensor data and has proved to be a sensitive and timely predictor of impending heart failure (HF) decompensation in cardiac resynchronization therapy (CRT‐D) patients. We evaluated the performance of this algorithm in non‐CRT ICD patients and in the presence of co‐morbidities. Methods and results The HeartLogic feature was activated in 568 ICD patients (410 with CRT‐D) from 26 centres. The median follow‐up was 26 months [25th–75th percentile: 16–37]. During follow‐up, 97 hospitalizations were reported (53 cardiovascular) and 55 patients died. We recorded 1200 HeartLogic alerts in 370 patients. Overall, the time IN the alert state was 13% of the total observation period. The rate of cardiovascular hospitalizations or death was 0.48/patient‐year (95% CI: 0.37–0.60) with the HeartLogic IN the alert state and 0.04/patient‐year (95% CI: 0.03–0.05) OUT of the alert state, with an incidence rate ratio of 13.35 (95% CI: 8.83–20.51, P

Abstract The rechallenge strategy is based on the concept that a subset of patients with RAS wild‐type (WT) metastatic colorectal cancer (mCRC) could still benefit of epidermal growth factor receptor (EGFR) inhibition, after progression to an anti‐EGFR based‐therapy. We performed a pooled analysis of two‐phase II prospective trials to determine the role of rechallenge in third‐line mCRC patients with RAS/BRAF WT baseline circulating tumor DNA (ctDNA). Individual data of 33 and 13 patients from CAVE and CRICKET trials that received as third‐line therapy cetuximab rechallenge were collected. Overall survival (OS), Progression‐free survival (PFS), Overall response rate (ORR), Stable disease (SD) >6 months were calculated. Adverse events were reported. For the whole 46 patient population, median PFS (mPFS) was 3.9 months (95% Confidence Interval, CI 3.0–4.9) with median OS (mOS) of 16.9 months (95% CI 11.7–22.1). For CRICKET patients, mPFS was 3.9 months (95% CI 1.7–6.2); mOS was 13.1 months (95% CI 7.3–18.9) with OS rates at 12, 18, and 24 months of 62%, 23%, and 0%, respectively. For CAVE patients, mPFS was 4.1 months (95% CI 3.0–5.2); mOS was 18.6 months (95% CI 11.7–25.4) with OS rates at 12, 18, 24 months of 61%, 52%, 21%, respectively. Skin rash was more frequently reported in CAVE trial (87.9% vs. 30.8%; p = 0.001), whereas a increased incidence of hematological toxicities was observed in CRICKET trial (53.8%% vs. 12.1%; p = 0.003). Third‐line cetuximab rechallenge in combination with either irinotecan or avelumab in RAS/BRAF WT ctDNA mCRC patients represents a promising therapy.

Abstract Background Malignant pleural mesothelioma (MPM) is an invasive, aggressive pleural tumor with a predominantly local spread. The objective of this study was to assess thoracic ultrasound (TUS) as an imaging modality with high sensitivity for the identification of malignant pleural involvement and in order to guide pleural biopsies. Methods In this retrospective single‐center study between January 2018 and June 2022, 51 consecutive patients with impassable circumferential pleural thickening underwent TUS at the Thoracic Surgery Unit of the Vanvitelli University of Naples. Pleural biopsies were performed, and then large and multiple samples were sent to the pathological anatomy for histological examination. Results In all patients who underwent ultrasound examination, we chose the optimal point of entry to perform pleural biopsies and selected the areas of greater thickening without pleural effusion. No patient had any complications. No drainage tubes were placed after the pleural biopsies and no pneumothorax was present during the following days of hospitalization. The patients were discharged on the second postoperative day. Conclusion With TUS the precise pleural thickening localization, local infiltration, mass extent, its nature (solid, cystic or complex) and ultrasound features can be easily defined. Furthermore, ultrasound is more economical than computed tomography and avoids the risks associated with radiation. Thoracic ultrasound is an important component of the diagnostic procedure in detecting a safe entry site for biopsies of MPMs.

Abstract Introduction Central airway tumors involving the trachea and main‐stem bronchi are a common cause of airway obstruction and a significant cause of mortality among the patients of thoracic diseases with respiratory failure. Debulking in rigid bronchoscopy is quick, safe, and effective. It can be complex and hard in patients with severe bronchial or tracheal obstruction and/or with intraluminal bleeding tumors because of inadequate distal airway control. We have used laser tube as a new technique of ventilation for severe central airway obstruction. Materials and Methods Forty‐six patients with severe airway obstruction undergoing rigid bronchoscopy from September 2020 to June 2022 at the Thoracic Surgery Department of the University L. Vanvitelli of Naples underwent placement of laser tube. Results In all patients who underwent rigid bronchoscopy with the use of the laser tube, a reduction of obstruction of more than 50% was obtained and in all patients no hypoxia (saturation

Abstract Introduction Staging of the mediastinum lymph nodes involvement in patients with non–small cell lung cancer (NSCLC) is an important prognostic factor determining the most appropriate multimodality treatment plan. The objective of this study is to assess ultrasound characteristics of mediastinal lymph nodes metastasis and effectiveness of intraoperative ultrasound‐guided mediastinal nodal dissection in patients with resected NSCLC. Materials and Methods All patients undergoing video‐assisted thoracoscopic surgery lobectomy and pulmonary lymphadenectomy from November 2020 to March 2022 at the thoracic surgery department of the Vanvitelli University of Naples underwent intraoperative ultrasound‐guided mediastinal lymph nodal dissection. Results This study evaluates whether individual B‐mode features and a compounding thereof can be used to accurately and reproducibly predict lymph node malignancy. Discussion Intraoperative ultrasound, during systematic mediastinal lymph node dissection, is helpful in preventing lesion to mediastinal structures. Pathological nodal sonographic characteristics are round shape, short‐axis diameter, echogenicity, margin, the absence or presence of coagulation necrosis sign, and the absence or presence of central hilar structure, increased color Doppler flow, the absence or presence of calcification, and nodal conglomeration. Operating time was not substantially prolonged. The procedure is simple, safe and highly accurate. Conclusions Ultrasonic techniques allow surgeons to detect the relationship between lymph nodes and surrounding large blood vessels during biopsy, improving the safety and simplicity of the operation, increasing the number of harvested lymph nodes, and reducing the risk of intraoperative injury; it is a fast, easily reproducible, and inexpensive method.

Abstract The potential complications related to unplanned conversion to thoracotomy remains a major concern in thoracoscopic lobectomy and may limit the wide adoption of this strategy. We reviewed the literature from 1990 until February 2022, analyzing all papers comparing successful thoracoscopic lobectomy versus converted thoracoscopic lobectomy and/or upfront thoracotomy lobectomy to establish whether unplanned conversion negatively affected outcomes. Thirteen studies provided the most applicable evidence to evaluate this issue. Conversion to thoracotomy was reported to occur in up to 23% of cases (range, 5%–16%). Vascular injury, calcified lymph nodes, and dense adhesions were the most common reasons for conversion. Converted thoracoscopic lobectomy compared to successful thoracoscopic lobectomy was associated with longer operative time and hospital stay in all studies, with higher postoperative complication rates in seven studies, and with higher perioperative mortality rates in four studies. No significant differences were found between converted thoracoscopic lobectomy and upfront thoracotomy lobectomy. Five studies evaluated long‐term survival, and in all papers conversion did not prejudice survival. Surgeons should not fear unplanned conversion during thoracoscopic lobectomy, but to avoid unexpected conversion that may negatively impact surgical outcome, a careful selection of patients is recommended–especially for frail patients.

Abstract Background Nivolumab and cabozantinib are currently approved agents in metastatic renal cell carcinoma (mRCC) but there are no data available for patients progressing to both treatments. The aim of this study was to compare active therapeutic options and best supportive care (BSC) after progression to nivolumab and cabozantinib in mRCC. Methods In this retrospective study, we selected 50 patients from eight Italian centers. The primary endpoint of the study was the overall survival (OS) of patients on active treatment versus BSC. Secondary endpoints were the progression‐free survival (PFS) and objective response rate (ORR). The efficacy of active therapy was also investigated. Results After progression to both nivolumab and cabozantinib, 57.1% of patients were given active treatment (mainly everolimus and sorafenib) while 42.9% received BSC. The median OS was 13 months (95% CI: 4‐NR) in actively treated patients and 3 months (95% CI: 2–4) in BSC patients (p = 0.001). Patients treated with sorafenib had better disease control than those treated with everolimus (stable disease: 71.4% vs. 16.7%, progression disease: 14.3% vs. 58.3%; p = 0.03), with no significant differences in PFS (5 and 3 months, 95% CI: 1–6 vs. 2–5; p = 0.6) and OS (12 and 4 months, 95% CI: 3‐NR vs. 2‐NR; p = 0.2). Conclusion After treatment with both nivolumab and cabozantinib, the choice of a safe active systemic therapy offered better outcomes than BSC.

We call for journals to commit to requiring open data be archived in a format that will be simple and clear for readers to understand and use. If applied consistently, these requirements will allow contributors to be acknowledged for their work through citation of open data, and facilitate scientific progress.

Abstract Background We investigated whether adjuvant chemotherapy, extent of resection, and immunoistochemical neuroendocrine markers affected survival of patients with the early stage of large‐cell neuroendocrine cancer. Methods This was a retrospective multicenter study including consecutive patients undergoing resection of node negative large‐cell neuroendocrine carcinoma. Five‐year survival and disease‐free survival rate were evaluated by the Kaplan–Meier method and the log‐rank test in relation to adjuvant chemotherapy, extent of resection, and immunoistochemical neuroendocrine markers (synaptophysin, chromogranin A, and neuron‐specific enolase). Results Our study population included 117 patients; 47 (40%) of these received adjuvant chemotherapy. Patients treated with adjuvant chemotherapy had better survival (74% vs. 45%, p = 0.002) and disease‐free survival (79% vs. 40%, p = 0.001) in all cases except patients with tumor 20 mm.

Abstract This paper addresses the time‐varying output formation‐containment control problem for homogeneous high‐order linear Multi‐Agent Systems (MASs). In this context, a PID‐like output‐feedback control strategy is proposed capable to guarantee that all followers reach and maintain a time‐varying formation reference behaviour, as imposed by the multiple leaders, while keeping a prescribed offset with respect to it. Moreover, the proposed approach allows dealing with both communication impairments and external disturbances acting on agents dynamics. The asymptotic stability of the closed‐loop MAS is analytically proved by means of a Lyapunov–Krasovskii approach. Stability conditions are expressed as a feasibility problem with Linear Matrix Inequalities constraints, whose solution provides the proper tuning of the robust PID control gains. Extensive numerical analysis confirms the theoretical framework and discloses the effectiveness of the proposed approach in ensuring the output time‐varying formation‐containment.

Abstract Background Here, we report our initial experience with subxifoid video‐assisted thoracoscopic surgery (SVATS) lobectomy for the management of primary lung cancer, and compared the outcomes of SVATS with those of conventional transthoracic VATS (CVATS) lobectomies to validate its feasibility and usefulness. Methods The clinical data of consecutive patients undergoing VATS lobectomy via SVATS or CVATS for lung cancer were retrospectively compared. The endpoints were to evaluate the statistical differences in surgical results, postoperative pain (measured with visual analog scale [VAS] scores at 8 hours, Day 1, Day 2, Day 3, at discharge, one month and three months after surgery) and paresthesia (measured at one‐ month, and three months after surgery). The two groups were compared before and after matching analysis. Results Our study population included 223 patients: 84 in the SVATS and 139 in the CVATS group. The two groups were not comparable for sex (P = 0.001), preoperative comorbidity as cardiopathy (P = 0.007), BMI value (P = 0.003), left‐sided procedure (P = 0.04), tumor stage (P = 0.04), and tumor size (P = 0.002). These differences were overcome by propensity score matching (PSM) analysis that yielded two well‐matched groups which included 61 patients in each group. Surgical outcomes including blood loss, hospital stay and complications were similar before and after matching analysis, but SVATS compared to CVATS was associated with longer operative time before (159 ± 13 vs. 126 ± 6.3, P

Abstract The presence of calcified or inflammatory lymph nodes between the target bronchus and pulmonary artery is a huge challenge when performing thoracoscopic lobectomy as it may frequently result in tearing of the vessel, and massive bleeding. Herein, we describe a simple strategy in which thoracoscopic lobectomy was safely completed in similar cases. After fissure dissection, the target pulmonary artery was exposed by more than two‐thirds of its circumference. A needle was passed across the nodes and the target vessel was closed with a proximal and distal suture. After dissection of lymphadenopathies, the target bronchus was exposed, and stapled. This strategy was applied with success to complete right lower lobectomies for cancer in three patients. No complications occurred during the operation. Only one patient had persistent air leaks that spontaneously ceased 11 days later. Final pathology showed pN0 disease in all cases.

Thoracoscopic lobectomy has become the preferred approach for surgical management of early stage lung cancer, but the potential higher operative costs limit its widespread use. Theoretically, higher direct costs may be significantly counterbalanced by lower indirect costs, resulting in lower overall costs for thoracoscopic than for open lobectomy. To support this hypothesis, we reviewed the literature until May 2020, analyzing all papers comparing the cost of thoracoscopic versus open lobectomy.A total of 20 studies provided the most applicable evidence to evaluate this issue. In all the studies apart from one, thoracoscopic lobectomy was associated with higher operative costs due to the increased use of disposable instruments, and prolonged operative time. By contrast, in 17 studies the increased operative costs were significantly offset by indirect costs which were lower in thoracoscopic than in open lobectomy due to fewer postoperative complications, faster recovery, and lower readmission rates. It translated into lower overall costs for thoracoscopic than for open lobectomy in 10 studies, similar costs in seven, and higher in three, despite the lower hospitalization costs. The low bed fees and high prices of disposable instruments in these three studies may explain the discordance. The careful use of disposable instruments, and the minimizing hospitalization costs can reduce the total costs of thoracoscopic lobectomy to levels similar or to below those of open lobectomy. The worry that video‐assisted thoracoscopic surgery lobectomy (VATSL) might be associated with an increased overal cost is thus not warranted, and should not be used as an excuse against the use of VATS in surgery for early stage lung cancers.