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Background: Patients with gastro-oesophageal adenocarcinoma with tumour-positive lymph nodes (ypN+) or positive surgical margins (R1) following neoadjuvant chemotherapy and resection are at high risk of recurrence. Adjuvant nivolumab is effective in oesophageal/oesophagogastric junction cancer and residual pathological disease following chemoradiation and surgery. Immune checkpoint inhibition has shown efficacy in advanced gastro-oesophageal cancer. We hypothesised that nivolumab/ipilimumab would be more effective than adjuvant chemotherapy in high-risk (ypN+ and/or R1) patients with gastro-oesophageal adenocarcinoma following neoadjuvant chemotherapy and resection., Patients and Methods: VESTIGE was an academic international, multicentre, open-label, randomised phase II trial evaluating the efficacy of adjuvant nivolumab/ipilimumab versus chemotherapy in gastro-oesophageal adenocarcinoma at high risk of recurrence. Patients were randomised 1 : 1 to receive standard adjuvant chemotherapy (same regimen as neoadjuvant) or nivolumab 3 mg/kg intravenously (i.v.) every 2 weeks plus ipilimumab 1 mg/kg i.v. every 6 weeks for 1 year. Key inclusion criteria included ypN+ and/or R1 status after neoadjuvant chemotherapy plus surgery. The primary endpoint was disease-free survival in the intent-to-treat population. Secondary endpoints included overall survival, locoregional and distant failure rates, and safety according to National Cancer Institute Common Terminology Criteria for Adverse Events v5.0., Results: The independent Data Monitoring Committee reviewed data from 189 of the planned 240 patients in June 2022 and recommended stopping recruitment due to futility. At the time of final analysis, median follow-up was 25.3 months for 195 patients (98 nivolumab/ipilimumab and 97 chemotherapy). Median disease-free survival for the nivolumab/ipilimumab group was 11.4 months [95% confidence interval (CI) 8.4-16.8 months] versus 20.8 months (95% CI 15.0-29.9 months) for the chemotherapy group, hazard ratio 1.55 (95% CI 1.07-2.25, one-sided P = 0.99). The 12-month disease-free survival rates were 47.1% and 64.0%, respectively. There were no toxicity concerns or excess early discontinuations., Conclusion: Nivolumab/ipilimumab did not improve disease-free survival compared with chemotherapy in patients with ypN+ and/or R1 gastro-oesophageal adenocarcinoma following neoadjuvant chemotherapy and surgery., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

When performing effect studies to investigate the impact of microplastic (MP) on cell lines, algae, or daphnia, it is advantageous if such experiments can be performed without the use of surfactants. The need for surfactants arises from the fact that finely milled pristine MP particles generally are hydrophobic. Methods for the preparation of larger amounts of hydrophilic and hence artificially aged MP particles and approaches for their characterization are of high importance. Here we present methods to artificially age polyethylene terephthalate (PET) and low-density polyethylene (PE) using alkaline and acidic treatments that reproducibly result in large quantities of particles below 5 µm with considerably increased hydrophilicity. The artificially aged MP particles were characterized using particle counting by single-particle extinction and scattering (SPES), particle size by laser diffraction measurements, zeta potential using electrophoretic light scattering, hydrophobicity index (Hy) through dark-field (DF) microscopy, chemical composition by inductively coupled plasma-mass spectrometry (ICP-MS), Fourier transform infrared (FTIR) microscopy, and Raman microscopy. The hydrophobicity index values obtained should allow the aged MP particles to be characterized as qualitative reference materials (RMs) with an ordinal property. Evidence for the maintained integrity and hydrophilicity of the artificially aged MP particles (in powder form) over time was obtained by measurements of zeta potential with a 33-month interval. Uniformity of subsampling with respect to particle number concentration in suspensions within a 10-day period was also investigated. It provided evidence for the possibility of reproducible spiking of a specific number of hydrophilic MP particles with relative standard deviations (RSDs) from 6.2 to 13.6%. For the development of future reference materials of artificially aged microplastics, they should be characterized for an ordinal property (artificial age as Hy-index) and nominal property (identity of PET or PE based on spectral matching)., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests. Håkan Emteborg is guest editor of ABC for the topical collection Reference Materials in Analytical Chemistry but was not involved in the peer review of this paper., (© 2025. European Union and University of Ghent.)

Background: Up to 50% of patients with advanced small-intestinal neuroendocrine tumors (SI-NETs) and carcinoid syndrome (CS) develop carcinoid heart disease (CHD). However, the true frequency and prognostic markers for CHD in CS are lacking. We described the real-world management of patients in two NET referral centers in this clinical context and relationships between clinical features, including CHD and overall survival (OS)., Patients and Methods: This is a retrospective analysis of patients with stage IV SI-NET and CS, treated at the European Institute of Oncology in Milan and Uppsala University in Sweden between 2015 and 2021. CHD was defined as at least one moderate right-sided heart valve defect. Median OS and cumulative incidence of CHD were estimated from the diagnosis of metastatic disease, and the association between clinical parameters with both OS and occurrence of CHD was evaluated., Results: We included 165 patients, with 97% having low-intermediate-grade SI-NETs and 86% having synchronous liver metastases. Ninety-eight patients (59%) became refractory to full label dose of somatostatin analogues and 25% developed a CHD. At CHD diagnosis, baseline urine 5-hydroxyindoleacetic acid (24-h u5-HIAA) value and plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) value were known in 76% of patients. Moderate-to-severe tricuspid insufficiency was the most common alteration of CHD. Prognosis was significantly impaired by CHD (multivariable hazard ratio for OS = 2.85, P < 0.001). The median OS from the CHD diagnosis was 4.5 years [95% confidence interval (CI) 2.1-7.2 years], and the 5-year survival rate was 34% (95% CI 13% to 57%)., Conclusions: In our study population of SI-NET patients with CS, more than half had a refractory carcinoid syndrome (RCS) and one-quarter developed a CHD, with a negative impact on OS. Therefore, it is recommended to screen and monitor patients with CS for CHD, ideally with a combination of u5-HIAA, NT-proBNP values, and echocardiography at CS baseline, preferably in NET referral centers., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Carcinoma of unknown primary (CUP) with a gastrointestinal profile is categorized by the European Society of Medical Oncology (ESMO) guidelines into favorable and unfavorable subsets. Favorable CUPs benefit from site-specific chemotherapy (CT), while the optimal treatment for unfavorable CUPs is still undefined., Materials and Methods: We conducted a single-center retrospective study to describe outcomes of patients with CUP with a gastrointestinal profile referred to our center from January 2000 to August 2023. Favorable CUPs were defined as CK7-/CK20+/CDX2+ by immunohistochemistry, according to the ESMO definition; all other cases were considered unfavorable. The main endpoint was the progression-free survival (PFS) of first-line CT for advanced disease in all patients and in the unfavorable group., Results: A total of 56 patients were included, of whom 46 (82%) had unfavorable CUPs. After a median follow-up of 43.9 months, the median overall survival (mOS) was 11.8 months [95% confidence interval (CI) 8.3-15.3 months]. At univariate analysis, the presence of peritoneal metastases and residual tumor after primary surgery were associated with a shorter OS. The median PFS (mPFS) was 6.1 months (95% CI 3.6-8.7 months). In the unfavorable CUP subgroup, the mOS was 12.6 months (95% CI 8.7-16.5 months), the mPFS was 6.1 months (95% CI 3.5-8.9 months) and none of the CT regimens used showed to portend better PFS. The most relevant altered genes included: KRAS (9/29; 31%), BRAF (1/26; 4%), NRAS (1/25; 4%), TP53 (9/23; 39%)., Conclusions: CUPs with a gastrointestinal profile are characterized by poor prognosis and the absence of biomarker for treatment personalization. No CT regimen was superior in terms of PFS in patients with unfavorable CUPs., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Hepatitis B, a vaccine-preventable liver infection, remains a global public health problem. Dedicated groups of experts and funding are focusing on achieving a functional cure to eradicate this disease by 2030., Areas of Uncertainty: With more than 40 molecules available or under investigation as new treatments for hepatitis B virus (HBV) infection, none of them is curative so far. Available treatments are effective in suppressing HBV replication and in decreasing the risk of developing cirrhosis, liver failure, hepatocellular carcinoma, and death, but do not eliminate the virus, and the risk of hepatocellular carcinoma remains. Nucleoside/nucleotide analogs are recommended as first-line therapy for patients with chronic hepatitis B infection to inhibit viral replication and lower the HBV DNA values, but long-term therapy is usually needed to maintain suppression. Cessation of the therapy in accordance with clinical guidelines can result in virological and clinical relapse., Data Sources: PubMed, Web of Science, clinicaltrials.gov , and gray literature sources were searched for articles discussing HBV management and new therapies., Results: With current nucleoside/nucleotide analog therapies, fewer than 5% of patients lose hepatitis B surface antigen after 12 months, which underscores the need for new drugs that can achieve a functional cure. New therapies are being developed, including small interfering RNAs. Bepirovirsen, a modified antisense oligonucleotide, shows promising results and a good safety profile, but requires further exploration in larger number of patients to determine whether a functional cure is possible., Conclusions: Eradication of HBV infection with currently available therapies is not yet possible. Experts are developing innovative treatments, such as bepirovirsen, to achieve functional cure for this disease and to reduce morbidity and mortality associated with hepatic cirrhosis and hepatocellular carcinoma., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: The primary objective was to determine the proportion of hospitals that administered norepinephrine peripheral vasopressor infusions (PVIs) in critically ill adult patients. Secondary objectives were to describe how norepinephrine is used such as the maximum duration, infusion rate and concentration, and to determine the most common first-line PVI used by country., Materials and Methods: An international multi-centre cross-sectional survey study was conducted in adult intensive care units in Australia, US, UK, Canada, and Saudi Arabia., Results: Critical care pharmacists from 132 institutions responded to the survey. Norepinephrine PVIs were utilised in 86% of institutions (n = 113/132). The median maximum duration of norepinephrine PVIs was 24 h (IQR 24-24) (n = 57/113). The most common maximum norepinephrine PVI rate was between 11 and 20 μg/min (n = 16/113). The most common maximum norepinephrine PVI concentration was 16 μg/mL (n = 60/113). Half of the institutions had a preference to administer another PVI over norepinephrine as a first-line agent (n = 66/132). The most common alternative PVI used by country was: US (phenylephrine 41%, n = 37/90), Canada (dopamine 31%, n = 5/16), UK (metaraminol 82%, n = 9/11), and Australia (metaraminol 89%, n = 8/9)., Conclusions: There is variability in clinical practice regarding PVI administration in critically ill adult patients dependent on drug availability and local institutional recommendations., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

This study aims to highlight the impact of physicochemical properties on the behaviour of nanopharmaceuticals and how much carrier structure and physiochemical characteristics weigh on the effects of a formulation. For this purpose, two commercially available nanosimilar formulations of Doxil and their respective carriers were compared as a case study. Although the two formulations were "similar", we detected different toxicological effects (profiles) in terms of in vitro toxicity and immunological responses at the level of cytokines release and complement activation (iC3b fragment), that could be correlated with the differences in the physicochemical properties of the formulations. Shedding light on nanosimilar key quality attributes of liposome-based materials and the need for an accurate characterization, including investigation of the immunological effects, is of fundamental importance considering their great potential as delivery system for drugs, genes, or vaccines and the growing market demand.

Introduction: In the treatment scenario of PanNETs-targeted therapies are desired but limited, as rarity and heterogeneity on PanNETs pose limitations to their development., Areas Covered: We performed a literature review searching for promising druggable biomarkers and potential treatments to be implemented in the next future. We focused on treatments which have already reached clinical experimentation, although in early phases. Six targets were identified, namely Hsp90, HIFa, HDACs, CDKs, uPAR, and DDR. Even though biological rational is strong, so far reported efficacy outcomes are quite disappointing. The reason of that should be searched in the patients' heterogeneity, lack of biomarker selection, poor knowledge of interfering mechanisms as well as difficulties in patients accrual. Moreover, different ways to assess treatment efficacy should be considered, other than response rate, in light of the more indolent nature of NETs., Expert Opinion: Development of targeted treatments in PanNETs is still an uncovered area, far behind other more frequent cancers. Rarity of NETs led to accrual of unselected populations, possibly jeopardizing the drug efficacy. Better patients' selection, both in terms of topography, grading and biomarkers is crucial and will help understanding which role targeted therapies can really play in these tumors.

Background: Non-invasive ventilation (NIV) is an evidence-based treatment for acute respiratory failure in chronic obstructive pulmonary disease (COPD). However, suboptimal application of NIV in clinical practice, possibly due to poor guideline adherence, can impact patient outcomes. This study aims to evaluate guideline adherence to NIV for acute COPD exacerbations and explore its impact on mortality., Methods: This retrospective study was performed in two Dutch medical centers from 2019 to 2021. All patients admitted to the pulmonary ward or intensive care unit with a COPD exacerbation were included. An indication for NIV was considered in the event of a respiratory acidosis., Results: A total of 1162 admissions (668 unique patients) were included. NIV was started in 154 of the 204 admissions (76%) where NIV was indicated upon admission. Among 78 admissions where patients deteriorated later on, NIV was started in 51 admissions (65%). Considering patients not receiving NIV due to contra-indications or patient refusal, the overall guideline adherence rate was 82%. Common reasons for not starting NIV when indicated included no perceived signs of respiratory distress, opting for comfort care only, and choosing a watchful waiting approach. Better survival was observed in patients who received NIV when indicated compared to those who did not., Conclusions: The adherence to guidelines regarding NIV initiation is good. Nevertheless, further improving NIV treatment in clinical practice could be achieved through training healthcare professionals to increase awareness and reduce reluctance in utilizing NIV. By addressing these factors, patient outcomes may be further enhanced., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Microplastics (MPs) represent a worldwide emerging relevant concern toward human and environmental health due to their intentional or unintentional release. Human exposure to MPs by inhalation is predicted to be among the most hazardous. MPs include both engineered, or primary MPs, and secondary MPs, materials obtained by fragmentation from any plastic good. The major part of the environmental MPs is constituted by the second ones that are irregular in size, shape and composition. These features make the study of the biological impact of heterogenous MPs of extremely high relevance to better estimate the real toxicological hazards of these materials on human and environmental organisms. The smallest fractions of plastic granules, relying on the micron-sized scale, can be considered as the most abundant component of the environmental MPs, and for this reason, they are typically used to perform toxicity tests using in vitro systems representative of an inhalation exposure scenario. In the present work, MPs obtained from industrial treatment of waste plastics (wMPs < 50 μm) were investigated, and after the physico-chemical characterization, the cytotoxic, inflammatory and genotoxic responses, as well as the modality of wMPs interactions with alveolar lung cells, were determined. Obtained results indicated that, at high concentrations (100 μg/ml) and prolonged exposure time (48 h), wMPs affect biological responses by inducing inflammation and genotoxicity, as a result of the cell-wMP interactions, also including the uptake of the smaller particles., (© 2022 The Authors. Journal of Applied Toxicology published by John Wiley & Sons Ltd.)

Since nanoplastics are currently considered potentially hazardous to the environment and human health, reliability of studies on nanoplastic exposure becomes crucial. However, analytical challenges limit our understanding of their formation and detection, thus hampering their biological interactions assessment. Here we provide a combined approach to quantitatively and qualitatively detect the release of nanoplastics in water matrix and, in particular, to measure direct exposure of consumers by simulated use of drinking water plastic bottles. We measured that the polyethylene sealing of the bottles released particles with a size distribution ranging from few hundreds nanometers up to about one micron and estimated a mass release in the order of few tenths of nanograms per opening/closing cycle. We observe that mechanical stress alters the physical-chemical characteristics of the generated secondary nanoplastics and degrades the material properties compared to the original bulk source, thus complicating their spectroscopic chemical identification. Our findings demonstrate that understanding material degradation processes is therefore crucial for identifying and quantifying nanoplastics in real samples. Moreover, methods allowing quantitative studies on the release of nanoplastic as a source of exposure are considered essential for proper assessment of their potential health hazards and to promote improvements in consumer products plastic packaging design., (Copyright © 2022. Published by Elsevier Ltd.)

Several cellular pathways contribute to neurodegenerative tauopathy-related disorders. Microglial activation, a major component of neuroinflammation, is an early pathologic hallmark that correlates with cognitive decline, while the unfolded protein response (UPR) contributes to synaptic pathology. Sleep disturbances are prevalent in tauopathies and may also contribute to disease progression. Few studies have investigated whether manipulations of sleep influence cellular pathologic and behavioral features of tauopathy. We investigated whether trazodone, a licensed antidepressant with hypnotic efficacy in dementia, can reduce disease-related cellular pathways and improve memory and sleep in male rTg4510 mice with a tauopathy-like phenotype. In a 9 week dosing regimen, trazodone decreased microglial NLRP3 inflammasome expression and phosphorylated p38 mitogen-activated protein kinase levels, which correlated with the NLRP3 inflammasome, the UPR effector ATF4, and total tau levels. Trazodone reduced theta oscillations during rapid eye movement (REM) sleep and enhanced REM sleep duration. Olfactory memory transiently improved, and memory performance correlated with REM sleep duration and theta oscillations. These findings on the effects of trazodone on the NLRP3 inflammasome, the unfolded protein response and behavioral hallmarks of dementia warrant further studies on the therapeutic value of sleep-modulating compounds for tauopathies. SIGNIFICANCE STATEMENT Dementia and associated behavioral symptoms such as memory loss and sleep disturbance are debilitating. Identifying treatments that alleviate symptoms and concurrently target cellular pathways contributing to disease progression is paramount for the patients and their caregivers. Here we show that a chronic treatment with trazodone, an antidepressant with positive effects on sleep, has beneficial effects on several cellular pathways contributing to neuroinflammation and tau pathology, in tauopathy-like rTg4510 mice. Trazodone also improved rapid eye movement (REM) sleep, the slowing of brain oscillations, and olfactory memory disturbances, which are all early symptoms observed in Alzheimer's disease. Thus, trazodone and compounds with REM sleep-promoting properties may represent a promising treatment approach to reduce the early symptoms of tauopathy and slow down disease progression., (Copyright © 2022 de Oliveira et al.)

Micro- and nanoplastic (pMP and pNP, respectively) release is an emerging issue since these particles constitute a ubiquitous and growing pollutant, which not only threatens the environment but may have potential consequences for human health. In particular, there is concern about the release of secondary pMP and pNP from the degradation of plastic consumer products. The phenomenon is well-documented in relation to plastic waste in the environment but, more recently, reports of pMP generated even during the normal use of plastic food contact materials, such as water bottles, tea bags, and containers, have been published. So far, a validated and harmonized strategy to tackle the issue is not available. In this study, we demonstrate that plastic breakdown to pMP and pNP can occur during the normal use of polyethylene (PE) rice cooking bags and ice-cube bags as well as of nylon teabags. A multi-instrumental approach based on Raman microscopy, X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), and particular attention on the importance of sample preparation were applied to evaluate the chemical nature of the released material and their morphology. In addition, a simple method based on Fourier transform infrared (FT-IR) spectroscopy is proposed for pNP mass quantification, resulting in the release of 1.13 ± 0.07 mg of nylon 6 from each teabag. However, temperature was shown to have a strong impact on the morphology and aggregation status of the released materials, posing to scientists and legislators a challenging question: are they micro- or nanoplastics or something else altogether?