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Current systemic therapies for metastatic pancreatic ductal adenocarcinoma are associated with poor outcomes with a 5-year overall survival rate under 5%. We aimed to assess the safety and antitumour activity of mitazalimab, a human CD40 agonistic IgG1 antibody, with modified FOLFIRINOX (mFOLFIRINOX; fluorouracil, leucovorin, oxaliplatin, and irinotecan), in chemotherapy-naive patients with metastatic pancreatic ductal adenocarcinoma. OPTIMIZE-1 was a single-arm, multicentre, phase 1b/2 study which enrolled adults with histologically-confirmed metastatic pancreatic ductal adenocarcinoma and European Cooperative Oncology Group performance status 0 or 1 in 14 university hospitals in Belgium, France, and Spain. The primary endpoint of phase 1b was to determine the recommended phase 2 dose of intravenous mitazalimab (450 μg/kg or 900 μg/kg) when combined with intravenous mFOLFIRINOX (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, irinotecan 150 mg/m2, fluorouracil 2400 mg/m2). In the first 21-day treatment cycle, mitazalimab was administered on days 1 and 10, and mFOLFIRINOX on day 8. In subsequent 14-day cycles mitazalimab was administered 2 days after mFOLFIRINOX. The phase 2 primary endpoint was objective response rate. Activity and safety analyses were conducted on the full analysis set (all patients who received the combination of mitazalimab at the recommended phase 2 dose and mFOLFIRINOX for at least two treatment cycles) and safety set (all patients who received any study treatment), respectively. Enrolment is complete, and data represents a primary analysis of the ongoing trial. The trial is registered at Clinicaltrials.gov (NCT04888312). Between Sept 29, 2021, and March 28, 2023, 88 patients were screened and 70 patients were enrolled (40 [57%] were female and 30 [43%] were male). In phase 1b, 900 μg/kg mitazalimab was determined as the recommended phase 2 dose. Overall, five patients received 450 μg/kg mitazalimab; 65 received 900 μg/kg mitazalimab. No dose-limiting toxicities were observed at 450 μg/kg, and one dose-limiting toxicity was observed at 900 μg/kg. 57 patients were evaluated for activity, and all 70 patients were included in the safety set. At data cutoff on Nov 14, 2023, median follow-up was 12·7 months (95% CI 11·1–15·7). Of the 57 patients, 29 (51%) remained on study and 18 (32%) remained on treatment. The primary endpoint (objective response rate >30%) was met (objective response rates in 23 [40%]; one-sided 90% CI ≥32 of 57 patients). The most common grade 3 or worse adverse events were neutropenia (18 [26%] of 70 patients), hypokalaemia (11 patients [16%]), and anaemia and thrombocytopenia (eight patients [11%]). Serious adverse events were reported in 29 (41%) of 70 patients, the most common being vomiting (five [7%] of 70 patients), decreased appetite (four [6%]), and diarrhoea and cholangitis (three [4%] of 70 patients for each), none considered related to mitazalimab. No treatment-related deaths were reported. Mitazalimab with mFOLFIRINOX demonstrated manageable safety and encouraging activity, warranting continued development in a phase 3, randomised, controlled trial. The results from OPTIMIZE-1 pave the way for further exploration and confirmation of a novel immunotherapy treatment regimen for metastatic pancreatic ductal adenocarcinoma, which is a complex and aggressive cancer with very low survival rates and restricted treatment options. Alligator Bioscience. [ABSTRACT FROM AUTHOR]

The histological growth pattern (HGP) of colorectal liver metastases (CRLMs) reflects tumor biology and local infiltrating behavior. In patients undergoing surgery for CRLMs, we investigated whether HGP and surgical margin status interact when influencing prognosis. Clinicopathological data, margin status, and HGP were reviewed in patients who underwent resection of CRLMs. R1 margin was defined when cancer cells were present at any point along the margin. HGPs were scored according to international guidelines, identifying patients with desmoplastic (DHGP) or non-desmoplastic (non-DHGP) CRLMs. Among 299 patients, 16% had R1 resection and 81% had non-DHGP CRLMs. Non-DHGP was the only predictive factor for R1 resection (18.7% versus 7.4% in DHGP, p = 0.04). Poorer 5-year overall survival was observed in both R1 and non-DHGP groups in univariate analysis (27.6% in R1 versus 45.6% in R0, p = 0.026, and 37.2% in non-DHGP versus 59.2% in DHGP, p = 0.013), whereas non-DHGP but not R1 remained associated with worse prognosis in multivariate analysis. In patients with non-DHGP, R1 margin has no prognostic impact. In patients undergoing resection of CRLMs, the prognostic value of poor tumor biology, such as in patients with non-DHGP, exceeds that of surgical radicality. [ABSTRACT FROM AUTHOR]

Severe coronavirus 2019 disease (CoViD-19) may lead to respiratory failure and mechanical ventilation. Therefore, ventilator associated pneumonia (VAP) may complicate the course of the disease. The aim of the current article was to investigate possible predictive factors for bacterial VAP on a retrospective manner, in a cohort of mechanically ventilated CoViD-19 patients. Additionally, determinant factors of lethality were analyzed. Medical records of patients hospitalized in the intensive care units (ICU) at the university hospital UZ Brussel during the epidemic were reviewed. VAP was defined following the National Healthcare Safety Network 2017 criteria. Univariate and multivariate logistic regressions analyses were performed. Among the 39 patients included in the study, 54% were diagnosed with bacterial VAP. Case fatality rate was 44%, but 59% of the deceased patients had a do-not-resuscitate status. Multivariate logistic regression for prediction of VAP showed significant differences in duration of ICU hospitalization and in minimal lung compliance. Additional analyses were performed on CoViD-19 patients who were affected by bacterial respiratory superinfection. The responsible pathogens correspond to the commonly found bacteria in VAP. However, 71% of the isolated germs were multi-drug resistant and bacteraemia was reported in 38%. Multivariate analyses for prediction of lethality found significant difference in SOFA score. Mechanically ventilated CoViD-19 patients might frequently develop VAP. Longer ICU hospitalization was associated with pulmonary superinfection in the current cohort. Moreover, decreased minimal lung compliance was correlated to VAP and higher SOFA score at VAP diagnosis was associated with lethality. [ABSTRACT FROM AUTHOR]

The ionic conductivity of acceptor doped ceria is strongly influenced by grain boundaries and interfaces, with most experiments showing a conductivity decrease in these regions. Classical models explain this observation by the formation of space charge layers, that are depleted of mobile ionic charge carriers. However, some experiments demonstrate an increase in ionic conductivity and recent models show that the space charge layers can also be enriched in mobile ionic species. Because of these discrepancies, it is still not certain whether nanocrystalline or thin film ceria can offer superior ionic conductivity or not. Recently, we have demonstrated by means of Monte Carlo simulations that the ionic conductivity in space charge layers can indeed exceed the bulk value. In this work, we combine these Monte Carlo simulations with a continuum model to predict charge carrier concentration profiles. This multiscale approach allows for a realistic prediction of the grain boundary ionic conductivity. [ABSTRACT FROM AUTHOR]

Abstract The ionic conductivity of acceptor doped ceria is strongly influenced by grain boundaries and interfaces. Most experiments show a decrease in ionic conductivity and an increase in electronic conductivity in these regions. Classical models explain this observation by the formation of space charge layers that are depleted of mobile ionic charge carriers and enriched in small polarons. However, some experiments demonstrate an increase in ionic conductivity and recent models show that the space charge layers can also be enriched in mobile ionic species. Because of these contradictions, it is still not clear whether nanocrystalline or thin film ceria can offer superior ionic conductivity or not. To aid this debate, we calculate the ionic conductivity of yttrium doped ceria in regions of net charge density using kinetic Monte Carlo simulations. Through an appropriate choice of the charge densities, these calculations allow to demarcate the possible conductivity gains from space charge layers. [ABSTRACT FROM AUTHOR]

Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) is emerging as a safe and effective treatment for pancreatic neuroendocrine tumors. We aimed to compare EUS-RFA and surgical resection for the treatment of pancreatic insulinoma (PI). Patients with sporadic PI who underwent EUS-RFA at 23 centers or surgical resection at 8 high-volume pancreatic surgery institutions between 2014 and 2022 were retrospectively identified and outcomes compared using a propensity-matching analysis. Primary outcome was safety. Secondary outcomes were clinical efficacy, hospital stay, and recurrence rate after EUS-RFA. Using propensity score matching, 89 patients were allocated in each group (1:1), and were evenly distributed in terms of age, sex, Charlson comorbidity index, American Society of Anesthesiologists score, body mass index, distance between lesion and main pancreatic duct, lesion site, size, and grade. Adverse event (AE) rate was 18.0% and 61.8% after EUS-RFA and surgery, respectively (P <.001). No severe AEs were observed in the EUS-RFA group compared with 15.7% after surgery (P <.0001). Clinical efficacy was 100% after surgery and 95.5% after EUS-RFA (P =.160). However, the mean duration of follow-up time was shorter in the EUS-RFA group (median, 23 months; interquartile range, 14-31 months vs 37 months; interquartile range, 17.5-67 months in the surgical group; P <.0001). Hospital stay was significantly longer in the surgical group (11.1 ± 9.7 vs 3.0 ± 2.5 days in the EUS-RFA group; P <.0001). Fifteen lesions (16.9%) recurred after EUS-RFA and underwent a successful repeat EUS-RFA (11 patients) or surgical resection (4 patients). EUS-RFA is safer than surgery and highly effective for the treatment of PI. If confirmed in a randomized study, EUS-RFA treatment can become first-line therapy for sporadic PI. [Display omitted] [ABSTRACT FROM AUTHOR]

Background and scope In the epoch of precision medicine and personalised oncology, which aims to deliver the right treatment to the right patient, molecular genetic biomarkers are a topic of growing interest. The aim of this expert discussion and position paper is to review the current status of various molecular tests for gastrointestinal (GI) cancers and especially considering their significance for the clinical routine use. Methodology Opinion leaders and experts from diverse nationalities selected on scientific merit were asked to answer to a prepared set of questions about the current status of molecular diagnostics in different GI cancers. All answers were then discussed during a plenary session and reported here in providing a well-balanced reflection of both clinical expertise and updated evidence-based medicine. Results Preselected molecular genetic biomarkers that are described and disputed in the current medical literature in different GI cancers were debated, and recommendations for clinical routine practice were made whenever possible. Furthermore, the preanalytical variations were commented and proposals for quality controls of biospecimens were made. Conclusion The current article summarises the recommendations of the expert committee regarding prognostic and predictive molecular genetic biomarkers in different entities of GI cancers. The briefly and comprehensively formulated guidelines should assist clinicians in the process of decision making in daily clinical practice. [ABSTRACT FROM AUTHOR]

Background and scope The management of GOJ cancers remains controversial and may vary between countries. Evidence-based attitudes and guidelines are not easy to elaborate since most of the trials and studies reported mixed cases of oesophageal (both adenocarcinoma and squamous cell tumours), GOJ and gastric cancers. The aim of this expert discussion and position paper is to elaborate practical recommendations that integrate evidence-reported literature and experience-based attitude covering all clinical aspects of GOJ cancer across different specialities and countries in Europe. Methodology Opinion leaders, selected on scientific merit were asked to answer to a prepared set of questions covering the approach of GOJ tumours from definition to therapeutic strategies. All answers were then discussed during a plenary session and reported here in providing a well-balanced reflection of both clinical expertise and updated evidence-based medicine. Results Definition, classification, diagnosis and staging of GOJ tumours were updated and debated. Therapeutic aspects including endoscopic therapy, surgical management, both multimodal curative and palliative management were also reviewed for proposing practical and consensual positions and recommendations whenever possible. Conclusion GOJ tumours deserve specific attention,not only for uniformising clinical management across countries but also for performing specific clinical and translational research,mainly in the curative perioperative setting. [ABSTRACT FROM AUTHOR]

No standards for staging, systemic therapy or the timing of an operation are defined for patients newly diagnosed with synchronous metastases and a primary in the colon. An expert group of radiologists, medical, radiation and surgical oncologists therefore came together to discuss staging and treatment sequence for these patients and came up with a recommendation based on current evidence of potential therapeutic options. The discussion was organized to debate recommendations centred on 5 topics and therefore the position paper is built upon these titles and their subtitles. [ABSTRACT FROM AUTHOR]

The ionic conductivity of doped ceria is strongly influenced by temperature, oxygen partial pressure, dopant concentration and microstructure of the material. While theory and experiments generally agree on the influence of the first two parameters, the other influences are still not fully understood. A reliable simulation model of the material’s electrical conductivity is thus necessary to interpret the existing measurements. Until now, prediction of the electrical conductivity of these materials relies mainly on analytical models. This approach yields useful insights but it also has drawbacks. We implement the partial differential equations that govern charge carrier transport and electrical potential in a finite element model. This numerical approach enables us to treat grains of arbitrarily small size and to predict electrical conductivities at any applied current density. The results predicted by our model are compared to the available measurements in literature. [ABSTRACT FROM AUTHOR]

Objective: In this longitudinal two-wave study, bidirectional relations between work-related stress and sleep quality were examined. Moreover, it was investigated whether perseverative cognition is a potential underlying mechanism in this association, related to both work-related stress and sleep quality.Methods: A randomly selected sample of Dutch employees received an online survey in 2012 and 2013. Of all invited employees, 877 participated in both waves. Structural equation modeling was performed to analyze the data.Results: We found evidence for reversed relations between work-related stress and sleep quality. Specifically, when controlling for perseverative cognition, work-related stress was not directly related to subsequent sleep quality, but low sleep quality was associated with an increase in work-related stress over time. Moreover, negative bidirectional associations over time were found between perseverative cognition and sleep quality, and positive bidirectional associations were found between work-related stress and perseverative cognition. Lastly, a mediation analysis showed that perseverative cognition fully mediated the relationship between work-related stress and sleep quality.Conclusion: The study findings suggest that perseverative cognition could be an important underlying mechanism in the association between work-related stress and sleep quality. The bidirectionality of the studied relationships could be an indication of a vicious cycle, in which work-related stress, perseverative cognition, and sleep quality mutually influence each other over time. [ABSTRACT FROM AUTHOR]

For many years, population-based Sanger sequencing has been the golden standard for drug resistance testing within the routine follow-up of HIV-1 infected patients in resource-rich settings. Often, the data generated within this framework were subsequently used for research and surveillance purposes: to understand therapy response and to gain insights into epidemiological processes. Sanger sequencing was however ill suited for diagnostic and prognostic use in resource-limited settings (RLS) and therefore not broadly implemented. Next-generation sequencing (NGS) technologies provide high-throughput approaches by the rapid acquisition of thousands to millions of short nucleotide sequences. Depending on the experimental design, the roll-out of NGS drug resistance testing at a larger scale is feasible, providing better characterization and understanding of the evolving population of viral variants within a patient and potentially improving the prognostic value of drug resistance testing. Whether the same will become true for RLS will largely depend on affordability and sample logistics, and this may affect other mutation-specific approaches. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Although many studies describe benefits from the comprehensive assessment of older patients, the lack of geriatricians combined with the increased number of elderly patients revealed the need for screening tools in order to detect cancer patients presenting with geriatric conditions. Objectives: (i) To assess the validity of screening tools to detect patients presenting with geriatric conditions. (ii) To analyze the relative contribution of those tools to detect some characteristics of the geriatric profile and the stage of the tumors. Materials and Methods: Two hundred eleven consecutive elderly patients were screened for the presence of geriatric conditions using the Identification of Senior At Risk score (ISAR) and the G8 score. Comprehensive geriatric assessment for functional, cognitive, mood, and nutritional status, self-perceived fatigue and comorbidities was performed. Oncological assessment included the Karnofsky performance status (KPS) and tumor staging. Results: Both scores detected an average of 80% of frail patients. The PPV and NPV of the scores to detect at least one geriatric condition were respectively 47% and 22% for an ISAR score ≥2 and 76% and 10% for a G8 <15. Area under the ROC curves between ISAR and G8 was not statistically different. In logistic models an ISAR score ≥2 was associated with comorbidity and falls whereas a G8 score <15 was associated with low KPS (<80) and the presence of generalized cancer. Conclusions: High prevalence of geriatric syndromes and comorbidities is associated with positive ISAR and G8 scores but not with the tumor stage. [Copyright &y& Elsevier]

Mature αβ T cells recognize foreign antigenic peptides presented by MHC molecules but do not recognize native antigenic proteins; features known as MHC restriction. How MHC restriction is imposed on αβ T cells has intrigued immunologists for several decades. One model proposes that germline-encoded elements in the T cell receptor (TCR) variable regions are evolutionarily conserved to only recognize MHC. However, we propose an alternative model that posits that MHC restriction is imposed by CD4 and CD8 co-receptors during thymic selection. Thus, we think that TCRs are structurally able to recognize a huge diversity of ligands but only TCRs with MHC specificity survive thymic selection. [ABSTRACT FROM AUTHOR]

Although the treatment of pancreatic ductal adenocarcinoma (PDAC) remains a huge challenge, it is entering a new era with the development of new strategies and trial designs. Because there is an increasing number of novel therapeutic agents and potential combinations available to test in patients with PDAC, the identification of robust prognostic and predictive markers and of new targets and relevant pathways is a top priority as well as the design of adequate trials incorporating molecular-driven hypothesis. We presently report a consensus strategy for research in pancreatic cancer that was developed by a multidisciplinary panel of experts from different European institutions and collaborative groups involved in pancreatic cancer. The expert panel embraces the concept of exploratory early proof of concept studies, based on the prediction of response to novel agents and combinations, and randomised phase II studies permitting the selection of the best therapeutic approach to go forward into phase III, where the recommended primary end point remains overall survival. Trials should contain as many translational components as possible, relying on standardised tissue and blood processing and robust biobanking, and including dynamic imaging. Attention should not only be paid to the pancreatic cancer cells but also to microenvironmental factors and stem/stellate cells. [ABSTRACT FROM PUBLISHER]

Abstract: During the last decades, the evolution of treatment - including radiotherapy, chemotherapy and targeted agents - has improved the cure and survival of patients with gastrointestinal (GI) cancer. Within the past 50 years of the EORTC''s existence, significant progress has been made in the fight against cancer. During this time several cancer clinical trials were completed, and through these we are able to identify the most notable advances in GI cancer research done by the EORTC Gastrointestinal Tract Cancer Group (GI Group). Several EORTC clinical trials results have changed practice (e.g. standard of care of liver metastases of colorectal cancer has been changed by the EPOC trial) or have helped to support new treatment strategies in either early- or advanced-stage GI cancers. In addition to its clinical activities the group has started an extensive program of translational research. This changed strategy towards a translational, multidisciplinary program regarded as the basis for future developments. This review of the major achievements of the GI Group shows that it has played an important role in the scientific development of the understanding and treatment of GI cancer over the last 50 years. [Copyright &y& Elsevier]