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Background: Immune dysregulation is a hallmark of autoimmune diseases of the central nervous system (CNS), characterized by an excessive immune response, and primary CNS tumors (pCNS-tumors) showing a highly immunosuppressive parenchymal microenvironment. Methods: Aiming to provide novel insights into the pathogenesis of CNS autoimmunity and cerebral tumor immunity, we analyzed the peripheral blood (PB) and cerebrospinal fluid (CSF) of 81 autoimmune limbic encephalitis (ALE), 148 relapsing–remitting multiple sclerosis (RRMS), 33 IDH-wildtype glioma, 9 primary diffuse large B cell lymphoma of the CNS (CNS-DLBCL), and 110 controls by flow cytometry (FC). Additionally, an in-depth immunophenotyping of the PB from an independent cohort of 20 RRMS and 18 IDH-wildtype glioblastoma patients compared to 19 controls was performed by FC combined with unsupervised computational approaches. Results: We identified alterations in peripheral and intrathecal adaptive immunity, mainly affecting the T cell (Tc) but also the B cell (Bc) compartment in ALE, RRMS, and pCNS-tumors compared to controls. ALE, RRMS, and pCNS-tumors featured higher expression of the T cell activation marker HLA-DR, which was even more pronounced in pCNS-tumors than in ALE or RRMS. Glioblastoma patients showed signs of T cell exhaustion that were not visible in RRMS patients. In-depth characterization of the PB revealed differences mainly in the T effector and memory compartment between RRMS and glioblastoma patients and similar alterations in the Bc compartment, including atypical Bc, CD19+CD20− double negative Bc, and plasma cells. PB and CSF mFC together with CSF routine parameters could reliably differentiate ALE and RRMS from pCNS-tumors facilitating early diagnosis and treatment. Conclusions: ALE, RRMS, and pCNS-tumors show distinct but partially overlapping changes mainly in HLA-DR+ Tc, memory Tc, exhausted Tc, and Bc subsets providing insights into disease pathogenesis. Moreover, mFC shows diagnostic potential facilitating early diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Background: Malignant mesothelioma is an aggressive cancer with poor prognosis. Programmed cell death protein-1 (PD-1) and its ligand 1 (PD-L1) immune checkpoint inhibitors (ICIs) have recently presented as a viable option in some first line but primarily as a second-line treatment of advanced-stage malignant mesothelioma (asMM). Therefore, this systematic review and meta-analysis aims to assess the safety and efficacy of PD-1/L-1 ICIs in advanced-stage malignant mesothelioma. Methods: PubMed, Scopus, and Cochrane databases were searched for all studies assessing the safety and efficacy of anti PD-1/PD-L1 agents. Primary outcomes were objective response rate (ORR) and disease control rate (DCR). Secondary outcomes were median progression free (mPFS) and overall survival (mOS). Safety outcomes were treatment- (TRAEs) and immune-related adverse events (IRAEs). A random-effects meta-analysis was performed to pool medians and to derive event rates. Results: A total of 15 studies were included with total of 1064 asMM patients. ORR and DCR were 16% and 57%, respectively. A pooled mPFS was 4.53 (CI: 3.40–5.65) and mOS was 10.51 (CI: 9.03-12.00). Overall TRAEs had an event rate of 0.69 (0.50–0.83) whereas IRAEs had an event rate of 0.28 (0.15–0.46). There were no significant differences between pembrolizumab, nivolumab primarily, and avelumab subgroups for all the outcomes. Additionally, meta-regression found no covariate to be a significant factor in ORR and DCR. Conclusion: In this meta-analysis we found that anti-PD1/PD-L1 treatment could be useful in pretreated asMM as they had at least comparable or greater mPFS, mOS, ORR, and DCR than other second-line agents currently being used. Registration number: This systematic review was registered at PROSPERO prior to the literature search, CRD42023442350. [ABSTRACT FROM AUTHOR]

Background: Understanding the risk relationship between statin use and immunerelated adverse events (irAEs) in patients undergoing immune checkpoint inhibitors (ICIs) therapy is crucial for optimizing oncological management. Objective: This study aimed to investigate whether the use of statins increases the risk of irAEs in patients receiving ICI therapy. Methods: This study primarily utilized data from FAERS database. Multivariable logistic regression was the principal method of analysis, and the Benjamini-Hochberg procedure was employed to adjust for multiple hypothesis testing. Results: In a group of 145,214 patients undergoing ICI therapy, 9,339 reported using statin medications. Multivariable analysis indicated an increased risk of irAEs among statin users (OR 1.199, 95% CI: 1.141-1.261; FDR p < 0.001) in comparison to those not using statins. Notably, increased risks were observed particularly in patients diagnosed with lung, pancreatic, and renal cancers. The link between statin usage and increased irAEs risk remained consistent across various ICIs treatments. Conclusions: Statin medication usage is linked to an elevated probability of experiencing irAEs in patients enrolled in ICI therapy. In cancer patients receiving immune checkpoint inhibitors, careful consideration of statin use is essential to avoid potentially increased irAEs risk. These findings provide critical guidance for clinicians in developing treatment strategies that balance therapeutic efficacy and safety in oncological management. [ABSTRACT FROM AUTHOR]

Background: T cells, the "superstar" of the immune system, play a crucial role in antitumor immunity. T‐cell receptors (TCR) are crucial molecules that enable T cells to identify antigens and start immunological responses. The body has evolved a unique method for rearrangement, resulting in a vast diversity of TCR repertoires. A healthy TCR repertoire is essential for the particular identification of antigens by T cells. Methods: In this article, we systematically summarized the TCR creation mechanisms and analysis methodologies, particularly focusing on the application of next‐generation sequencing (NGS) technology. We explore the TCR repertoire in health and cancer, and discuss the implications of TCR repertoire analysis in understanding carcinogenesis, cancer progression, and treatment. Results: The TCR repertoire analysis has enormous potential for monitoring the emergence and progression of malignancies, as well as assessing therapy response and prognosis. The application of NGS has dramatically accelerated our comprehension of TCR diversity and its role in cancer immunity. Conclusions: To substantiate the significance of TCR repertoires as biomarkers, more thorough and exhaustive research should be conducted. The TCR repertoire analysis, enabled by advanced sequencing technologies, is poised to become a crucial tool in the future of cancer diagnosis, monitoring, and therapy evaluation. [ABSTRACT FROM AUTHOR]

The tumor microenvironment demonstrates great immunophenotypic heterogeneity, which has been leveraged in traditional immune-hot/cold tumor categorization based on the abundance of intra-tumoral immune cells. By incorporating the spatial immune contexture, the tumor immunophenotype was further elaborated into immune-inflamed, immune-excluded, and immune-desert. However, the mechanisms underlying these different immune phenotypes are yet to be comprehensively elucidated. In this review, we discuss how tumor cells and the tumor microenvironment interact collectively to shape the immune landscape from the perspectives of tumor cells, immune cells, the extracellular matrix, and cancer metabolism, and we summarize potential therapeutic options according to distinct immunophenotypes for personalized precision medicine. [ABSTRACT FROM AUTHOR]

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Malignant pleural mesothelioma (MPM) is an aggressive cancer with a very poor prognosis. Recently, immune checkpoint inhibition (ICI) has taken center stage in the currently ongoing revolution that is changing standard-of-care treatment for several malignancies, including MPM. As multiple arguments and accumulating lines of evidence are in support of the existence of a therapeutic synergism between chemotherapy and immunotherapy, as well as between different classes of immunotherapeutics, we designed a multicenter, single-arm, phase I/II trial in which both programmed-death-ligand 1 (PD-L1) inhibition and dendritic cell (DC) vaccination are integrated in the first-line conventional platinum/pemetrexed-based treatment scheme for epithelioid MPM patients (Immuno-MESODEC, ClinicalTrials.gov identifier NCT05765084). Fifteen treatment-naïve patients with unresectable epithelioid subtype MPM will be treated with four 3-weekly (±3 days) chemo-immunotherapy cycles. Standard-of-care chemotherapy consisting of cisplatinum (75mg/m2) and pemetrexed (500mg/m2) will be supplemented with the anti-PD-L1 antibody atezolizumab (1200 mg) and autologous Wilms' tumor 1 mRNA-electroporated dendritic cell (WT1/DC) vaccination (8–10 x 106 cells/vaccination). Additional atezolizumab (1680 mg) doses and/or WT1/DC vaccinations (8–10 x 106 cells/vaccination) can be administered optionally following completion of the chemo-immunotherapy scheme. Follow-up of patients will last for up to 90 days after final atezolizumab administration and/or WT1/DC vaccination or 24 months after diagnosis, whichever occurs later. The trial's primary endpoints are safety and feasibility, secondary endpoints are clinical efficacy and immunogenicity. This phase I/II trial will evaluate whether addition of atezolizumab and WT1/DC vaccination to frontline standard-of-care chemotherapy for the treatment of epithelioid MPM is feasible and safe. If so, this novel combination strategy should be further investigated as a promising advanced treatment option for this hard-to-treat cancer. [ABSTRACT FROM AUTHOR]

Dendritic cell (DC)-based vaccines have emerged as a promising strategy in cancer immunotherapy due to low toxicity. However, the therapeutic efficacy of DC as a monotherapy is insufficient due to highly immunosuppressive tumor environment. To address these limitations of DC as immunotherapeutic agent, we have developed a polymeric nanocomplex incorporating (1) oncolytic adenovirus (oAd) co-expressing interleukin (IL)-12 and granulocyte-macrophage colonystimulating factor (GM-CSF) and (2) arginine-grafted bioreducible polymer with PEGylated paclitaxel (APP) to restore antitumor immune surveillance function in tumor milieu and potentiate immunostimulatory attributes of DC vaccine. Nanohybrid complex (oAd/APP) in combination with DC (oAd/APP+DC) induced superior expression level of antitumor cytokines (IL-12, GM-CSF, and interferon gamma) than either oAd/APP or DC monotherapy in tumor tissues, thus resulting in superior intratumoral infiltration of both endogenous and exogenous DCs. Furthermore, oAd/APP+DC treatment led superior migration of DC to secondary lymphoid organs, such as draining lymph nodes and spleen, in comparison with either monotherapy. Superior migration profile of DCs in oAd/APP+DC treatment group resulted in more prolific activation of tumor-specific T cells in these lymphoid organs and greater intratumoral infiltration of T cells. Additionally, oAd/ APP+DC treatment led to lower subset of tumor infiltrating lymphocytes and splenocytes being immunosuppressive regulatory T cells than any other treatment groups. Collectively, oAd/APP+DC led to superior induction of antitumor immune response and amelioration of immunosuppressive tumor microenvironment to elicit potent tumor growth inhibition than either monotherapy. [ABSTRACT FROM AUTHOR]

Copyright of Urban Studies (Sage Publications, Ltd.) is the property of Sage Publications, Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Malignant mesothelioma is a rare form of cancer that mostly affects the pleura and has a strong link to asbestos exposure. Greece banned the use of asbestos in 2005, however, the public was already aware of this substance in the 1980s. This research aims to present an overview of Greece's mesothelioma age-standardized mortality rates (ASMR) from 1983 to 2019 by age, gender, and geographic region and to determine whether the actions to ban asbestos impacted these rates. Methods: Data were retrieved by the Hellenic Statistical Authority (HSA) from death certificates that mentioned mesothelioma as the cause of death from 1983 to 2019 with details on the residence, gender, and age. Statistical analysis was performed using PRISM 6.0 software, a two-way ANOVA test, Trend analysis was conducted using Joinpoint Regression Program 5.0 software. The linear and non-linear model was used to calculate the age-standardized rates of annual percentage change (APC) and its 95% confidential interval (95% CI). Results: From 1983 to 2019, 850 total mesothelioma deaths were recorded, the majority of whom were males (634). A rate of 74.6% accounts for males and 25.4% for females, and the ratio of Males: Females was 3:1. Males' ASMR and the whole population's ASMR reached their highest levels in 2011 (0.93/100000person-years and 0.53/100000person-years, respectively). To look for potential changes between the first two decades of the 21st century, we compared the mean ASMR of each geographic region in Greece between two different 10-year subperiods (2000–2009 and 2010–2019). Except for Epirus, all regions of Greece had elevated regional ASMRs, particularly in those with the highest asbestos deposits. Notably, the ASMR in Epirus decreased from 0.54/100000person-years (2000–2009) to 0.31/100000person-years (2010–2019). After 2011, the ASMR for men and the general population stabilized. This stability is important since mesothelioma in men is associated with occupational asbestos exposure. The intriguing discovery of a lower ASMR in Epirus emphasizes the need to raise awareness of the condition and implement effective public health measures. Conclusions: In Greece, the annual ASMR for males and the whole population reached its highest level in 2011, which is positive and encouraging and may be a sign that the rate will stabilize during the following years. Moreover, this study showed that the actions made in the 1980s regarding public awareness and surveillance directly impacted the decrease in Epirus rates. Future research, continual awareness, information, and recording are needed to monitor the mesothelioma epidemic. The possible benefit of a mesothelioma registry and the epidemiological surveillance of asbestos-related diseases, particularly mesothelioma mortality, need to be addressed. Trial registration: Not applicable. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) are specialized monoclonal antibodies (mAbs) that target immune checkpoints and their ligands, counteracting cancer cell-induced T-cell suppression. Approved ICIs like cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1), its ligand PD-L1, and lymphocyte activation gene-3 (LAG-3) have improved cancer patient outcomes by enhancing anti-tumor responses. However, some patients are unresponsive, and others experience immune-related adverse events (irAEs), affecting organs like the lung, liver, intestine, skin and now the cardiovascular system. These cardiac irAEs include conditions like myocarditis, atherosclerosis, pericarditis, arrhythmias, and cardiomyopathy. Ongoing clinical trials investigate promising alternative co-inhibitory receptor targets, including T cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) and T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT). This review delves into the mechanisms of approved ICIs (CTLA-4, PD-1, PD-L1, and LAG-3) and upcoming options like Tim-3 and TIGIT. It explores the use of ICIs in cancer treatment, supported by both preclinical and clinical data. Additionally, it examines the mechanisms behind cardiac toxic irAEs, focusing on ICI-associated myocarditis and atherosclerosis. These insights are vital as ICIs continue to revolutionize cancer therapy, offering hope to patients, while also necessitating careful monitoring and management of potential side effects, including emerging cardiac complications. [ABSTRACT FROM AUTHOR]

Due to the scarcity of large‐sized prospective databases, the Japanese Joint Committee for Lung Cancer Registry conducted a nationwide prospective registry for newly diagnosed and untreated pleural mesothelioma. All new cases diagnosed pathologically as any subtype of pleural mesothelioma in Japan during the period between April 1, 2017, to March 31, 2019, were included before treatment. Data on survival were collected in April 2021. The eligible 346 patients (285 men [82.3%]; 61 women [17.7%]; median age, 71.0 years [range, 44–88]) were included for analysis. Among these patients, 138 (39.9%) underwent surgery, 164 (47.4%) underwent non‐surgical therapy, and the remaining 44 (12.7%) underwent best supportive care. The median overall survival for all 346 patients was 19.0 months. Survival rates at 1, 2, and 3 years for all patients were, 62.8%, 42.3%, and 26.5%, respectively. Median overall survival was significantly different among patients undergoing surgery, non‐surgical treatment, and best supportive care (32.2 months vs. 14.0 months vs. 3.8 months, p < 0.001). The median overall survival of patients undergoing pleurectomy/decortication and extrapleural pneumonectomy was 41.8 months and 25.0 months, respectively. Macroscopic complete resection resulted in longer overall survival than R2 resection and partial pleurectomy/exploratory thoracotomy (41.8 months vs. 32.2 months vs. 16.8 months, p < 0.001). Tumor shape, maximum tumor thickness, and sum of three level thickness were significant prognostic factors. The data in the prospective database would serve as a valuable reference for clinical practice and further studies for pleural mesothelioma. [ABSTRACT FROM AUTHOR]

Pleural mesothelioma (PM) is an aggressive and rare disease, characterized by a very poor prognosis. For almost two decades, the world standard treatment regimen for unresectable PM has consisted of a platinum-based drug plus pemetrexed, leading to an overall survival of approximately 12 months. The dramatic therapeutic scenario of PM has recently changed with the entry into the clinic of immune checkpoint inhibition, which has proven to be an effective approach to improve the survival of PMpatients. The aimof the present review is to provide a comprehensive overview of the most promising immunotherapeuticbased strategies currently under investigation for advanced PM. [ABSTRACT FROM AUTHOR]

Objectives: To characterize the T cell receptor (TCRβ) repertoire in peripheral blood and muscle tissues of treatment naïve patients with newly diagnosed idiopathic inflammatory myopathies (IIMs). Methods: High throughput RNA sequencing of the TCRβ chain was performed in peripheral blood and muscle tissue in twenty newly-diagnosed treatment-naïve IIM patients (9 DM, 5 NM/OM, 5 IMNM and 1 ASyS) and healthy controls. Results thereof were correlated with markers of disease activity. Results: Muscle tissue of IIM patients shows more expansion of TCRb clones and decreased diversity when compared to peripheral blood of IIM as well as healthy controls (both p=0.0001). Several expanded TCRb clones in muscle are tissue restricted and cannot be retrieved in peripheral blood. These clones have significantly longer CDR3 regions when compared to clones (also) found in circulation (p=0.0002), while their CDR3 region is more hydrophobic (p<0.01). Network analysis shows that clonal TCRβ signatures are shared between patients. Increased clonal expansion in muscle tissue is significantly correlated with increased CK levels (p=0.03), while it tends to correlate with decreased muscle strength (p=0.08). Conclusion: Network analysis of clones in muscle of IIM patients shows shared clusters of sequences across patients. Muscle-restricted CDR3 TCRβ clones show specific structural features in their T cell receptor. Our results indicate that clonal TCRβ expansion in muscle tissue might be associated with disease activity. Collectively, these findings support a role for specific clonal T cell responses in muscle tissue in the pathogenesis of the IIM subtypes studied. [ABSTRACT FROM AUTHOR]

Cuproptosis is a newly discovered cell death form with a unique mechanism. Seven genes have been identified to facilitate the process. To explore the roles of cuproptosis in different cancers, we first used Gene Expression Profiling, Interactive Analysis, version 2, and cBioPortal to analyze expression, prognosis and mutation conditions in different cancers from The Cancer Genome Atlas (TCGA). Then, we conducted single sample gene set enrichment analysis to combine the signature of the cuproptosis-promoting genes for all TCGA cancers. Moreover, we performed a survival analysis to explore if cuproptosis-score could independently influence clinical outcomes. Next, we compared pathway enrichment, immune infiltration, gene set activity and gene mutation between different cuproptosis-score groups. Finally, based on the intersected genes from difference analysis and weighted gene co-expression network analysis, consensus clustering and Least Absolute Shrinkage and Selection Operator Cox regression were performed and nomograms were constructed. Cuproptosis-score was associated with a favorable prognosis in eight TCGA cancers. Cancer-associated fibroblasts, B cells, neutrophils and mast cells were generally less abundant, and ferroptosis activity was higher in high cuproptosis-score groups. The novel classifications could differentiate patients' overall survival, and the risk models could effectively predict patients' outcomes in kidney, renal clear cell carcinoma, liver hepatocellular carcinoma, mesothelioma and stomach adenocarcinoma. Cuproptosis activity was closely related to the prognosis of several cancers. Its effects on the immune microenvironment and its relationship with other cell death modes, especially ferroptosis, may become the focus of further research. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to explore the safety and efficacy of multiple peptide-pulsed autologous dendritic cells (DCs) combined with cytotoxic T lymphocytes (CTLs) in patients with cancer. Methods: Five patients diagnosed with cancer between November 2020 and June 2021 were enrolled and received DC-CTLs therapy. Peripheral blood was collected and antigenic peptides were analyzed. The phenotype and function of DC-CTLs and the immune status of patients were detected using flow cytometry or IFN-g ELISPOT analysis. Results: DCs acquired a mature phenotype and expressed high levels of CD80, CD86, CD83, and HLA-DR after co-culture with peptides, and the DC-CTLs also exhibited high levels of IFN-g. Peripheral blood mononuclear cells from posttreatment patients showed a stronger immune response to peptides than those prior to treatment. Importantly, four of five patients maintained a favorable immune status, of which one patient's disease-free survival lasted up to 28.2 months. No severe treatment-related adverse events were observed. Conclusion: Our results show that multiple peptide-pulsed DCs combined with CTLs therapy has manageable safety and promising efficacy for cancer patients, which might provide a precise immunotherapeutic strategy for cancer. [ABSTRACT FROM AUTHOR]

Background: Concomitant medications may potentially affect the outcome of cancer patients. In this sub-analysis of the ARON-2 real-world study (NCT05290038), we aimed to assess the impact of concomitant use of proton pump inhibitors (PPI), statins, or metformin on outcome of patients with metastatic urothelial cancer (mUC) receiving second-line pembrolizumab. Methods: We collected data from the hospital medical records of patients with mUC treated with pembrolizumab as second-line therapy at 87 institutions from 22 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall response rate. We carried out a survival analysis by a Cox regression model. Results: A total of 802 patients were eligible for this retrospective study; the median follow-up time was 15.3 months. PPI users compared to non-users showed inferior PFS (4.5 vs. 7.2 months, p = 0.002) and OS (8.7 vs. 14.1 months, p < 0.001). Concomitant PPI use remained a significant predictor of PFS and OS after multivariate Cox analysis. The use of statins or metformin was not associated with response or survival. Conclusions: Our study results suggest a significant prognostic impact of concomitant PPI use in mUC patients receiving pembrolizumab in the real-world context. The mechanism of this interaction warrants further elucidation. [ABSTRACT FROM AUTHOR]

Introduction: Cancer is a major global health concern, and immune checkpoint inhibitors (ICIs) offer a promising treatment option for cancer patients. However, the efficacy of ICIs can be influenced by various factors, including the use of concomitant medications. Methods: We searched databases (PubMed, Embase, Cochrane Library, Web of Science) for systematic reviews and meta-analyses for systematic reviews and meta-analyses on the impact of concomitant medications on ICIs efficacy, published from inception to January 1, 2023. We evaluated the methodological quality of the included meta-analyses, and re-synthesized data using a random-effects model and evidence stratification. Results: We included 23 publications, comprising 11 concomitant medications and 112 associations. Class II-IV evidence suggested that antibiotics have a negative impact on ICIs efficacy. However, ICIs efficacy against melanoma, hepatocellular carcinoma, and esophageal squamous cell carcinoma was not affected, this effect was related to the exposure window (class IV). Class III evidence suggested that proton pump inhibitors have a negative impact on ICIs efficacy; nevertheless, the efficacy against melanoma and renal cell carcinoma was not affected, and the effect was related to exposure before the initiation of ICIs therapy (class II). Although class II/III evidence suggested that steroids have a negative impact, this effect was not observed when used for non-cancer indications and immune-related adverse events (class IV). Class IV evidence suggested that opioids reduce ICIs efficacy, whereas statins and probiotics may improve ICIs efficacy. ICIs efficacy was not affected by histamine 2 receptor antagonists, aspirin, metformin, b-blockers, and nonsteroidal anti-inflammatory agents. Conclusion: Current evidence suggests that the use of antibiotics, PPIs, steroids, and opioids has a negative impact on the efficacy of ICIs. However, this effect may vary depending on the type of tumor, the timing of exposure, and the intended application. Weak evidence suggests that statins and probiotics may enhance the efficacy of ICIs. Aspirin, metformin, b-blockers, and NSAIDs do not appear to affect the efficacy of ICIs. However, caution is advised in interpreting these results due to methodological limitations. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO, identifier, CRD42022328681. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Treg), as members of CD4+ T cells, have garnered extensive attention in the research of tumor progression. Treg cells have the function of inhibiting the immune effector cells, preventing tissue damage, and suppressing inflammation. Under the stimulat ion of the tumor inflammatory microenvironment (IM), the reprogramming of Treg cells enhances their suppression of immune responses, ultimately promoting tumor immune escape or tumor progression. Reducing the number of Treg cells in the IM or lowering the activity of Treg cells while preventing their reprogramming, can help promote the body's anti-tumor immune responses. This review introduces a reprogramming mechanism of Treg cells in the IM; and discusses the regulation of Treg cells on tumor progression. The control of Treg cells and the response to Treg inflammatory reprogramming in tumor immunotherapy are analyzed and countermeasures are proposed. This work will provide a foundation for downregulating the immunosuppressive role of Treg in the inflammatory environment in future tumor immunotherapy. [ABSTRACT FROM AUTHOR]

Lipid metabolic reprogramming is an emerging hallmark of cancer. In order to sustain uncontrolled proliferation and survive in unfavorable environments that lack oxygen and nutrients, tumor cells undergo metabolic transformations to exploit various ways of acquiring lipid and increasing lipid oxidation. In addition, stromal cells and immune cells in the tumor microenvironment also undergo lipid metabolic reprogramming, which further affects tumor functional phenotypes and immune responses. Given that lipid metabolism plays a critical role in supporting cancer progression and remodeling the tumor microenvironment, targeting the lipid metabolism pathway could provide a novel approach to cancer treatment. This review seeks to: (1) clarify the overall landscape and mechanisms of lipid metabolic reprogramming in cancer, (2) summarize the lipid metabolic landscapes within stromal cells and immune cells in the tumor microenvironment, and clarify their roles in tumor progression, and (3) summarize potential therapeutic targets for lipid metabolism, and highlight the potential for combining such approaches with other anti-tumor therapies to provide new therapeutic opportunities for cancer patients. [ABSTRACT FROM AUTHOR]

This study investigates the effects of top management staffing on foreign subsidiary performance, moderated by the occurrence of uncertainty shock in the home market. Building on a refined model of agency theory, this study introduces the context of a parent country to the existing theoretical framework and addresses the importance of appointing top managers with an intermediary status between host and home countries. The empirical evidence from foreign subsidiaries of South Korean firms in 102 countries (1992–2007) shows that assignment of immigrant top managers originating from the parent country is positively associated with subsidiary performance in the wake of home-country uncertainty. These findings highlight the benefits of appointing managers with dual knowledge structure and adaptive flexibility in the top management position in foreign locations. [ABSTRACT FROM AUTHOR]

Background: Statins are associated with improved survival outcomes in patients receiving immune checkpoint inhibitors (ICIs), but the impact of lipophilic and hydrophilic statin properties on patient outcomes is unknown. Objectives: We aim to investigate if statins with lipophilic properties are associated with clinical outcomes in patients receiving ICIs. Method: We conducted a retrospective cohort study at two tertiary referral centers in Taiwan comprising patients receiving ICIs between January 2015 and December 2021. We compared the comparative effect of lipophilic and hydrophilic statins on patient outcomes. The primary outcome was overall survival (OS) and the secondary outcome was progression-free survival (PFS). Results: Among 734 patients receiving ICIs, there were 51 lipophilic statin users, 25 hydrophilic statin users, and 658 nonusers. Lipophilic statin users had a longer median OS (38.0 [IQR, 16.7–not reached] vs. 15.2 [IQR, 8.2–not reached] months vs. 18.9 [IQR, 5.4 51.6] months) and PFS (13.0 [IQR, 4.7–41.5] vs. 8.2 [IQR, 2.2–14.7] months vs. 5.6 [2.3–18.7] months) than hydrophilic statin users and non-statin users. In Cox proportional hazard analyses, the use of lipophilic statins was associated with a 40–50% lower risk of mortality and disease progression compared with hydrophilic statin or non-statin users. Conclusions: The use of lipophilic statins seems to be associated with survival benefits in patients undergoing immunotherapy. [ABSTRACT FROM AUTHOR]

Combinational immunotherapy of dendritic cell (DC) vaccines and anti‐programmed cell death protein 1 antibodies (aPD1) has been regarded as a promising strategy for cancer treatment because it not only induces tumor‐specific T cell immune responses, but also prevents failure of T cell functions by the immune suppressive milieu of tumors. Microneedles have emerged as an innovative platform for efficient transdermal immunotherapies. However, co‐delivery of DC vaccines and aPD1 via microneedles has not been studied since conventional microneedle platforms are unsuitable for fragile therapeutics like living cells and antibodies. This study employs our newly invented cryomicroneedles (cryoMNs) to co‐deliver DC vaccines and aPD1 for the combinational immunotherapy. CryoMNs are fabricated by stepwise cryogenic micromoulding of cryogenic medium with pre‐suspended DCs and aPD1, which are further integrated with a homemade handle for convenient application. The viability of DCs in cryoMNs remains above 85%. CryoMNs are mechanically strong enough to insert into porcine and mouse skin, successfully releasing DCs and aPD1 inside skin tissue after melting. Co‐delivery of ovalbumin (OVA)‐pulsed DCs (OVA‐DCs) and aPD1 via cryoMNs induced higher antigen‐specific cellular immune responses compared with the mono‐delivery of OVA‐DCs or aPD1. Finally, administration with cryoMNs co‐encapsulated with OVA‐DCs and aPD1 increases the infiltration of effector T cells in the tumor, resulting in stronger anti‐tumor therapeutic efficacy in both prophylactic and therapeutic melanoma models compared with administration with cryoMNs loaded with OVA‐DCs or aPD1. This study demonstrates the great potential of cryoMNs as a co‐delivery system of therapeutic cells and biomacromolecules for combinational therapies. [ABSTRACT FROM AUTHOR]

The pathetic malignant mesothelioma (MM) is a extremely uncommon and confrontational tumor that evolves in the mesothelium layer of the pleural cavities (inner lining-visceral pleura and outer lining-parietal pleura), peritoneum, pericardium, and tunica vaginalis and is highly resistant to standard treatments. In mesothelioma, the predominant pattern of lesions is a loss of genes that limit tumour growth. Despite the worldwide ban on the manufacture and supply of asbestos, the prevalence of mesothelioma continues to increase. Mesothelioma presents and behaves in a variety of ways, making diagnosis challenging. Most treatments available today for MM are ineffective, and the median life expectancy is between 10 and 12 months. However, in recent years, considerable progress has already been made in understanding the genetics and molecular pathophysiology of mesothelioma by addressing hippo signaling pathway. The development and progression of MM are related to many important genetic alterations. This is related to NF2 and/or LATS2 mutations that activate the transcriptional coactivator YAP. The X-rays, CT scans, MRIs, and PET scans are used to diagnose the MM. The MM are treated with surgery, chemotherapy, first-line combination chemotherapy, second-line treatment, radiation therapy, adoptive T-cell treatment, targeted therapy, and cancer vaccines. Recent clinical trials investigating the function of surgery have led to the development of innovative approaches to the treatment of associated pleural effusions as well as the introduction of targeted medications. An interdisciplinary collaborative approach is needed for the effective care of persons who have mesothelioma because of the rising intricacy of mesothelioma treatment. This article highlights the key findings in the molecular pathogenesis of mesothelioma, diagnosis with special emphasis on the management of mesothelioma. [ABSTRACT FROM AUTHOR]

Background: The efficacy of immune checkpoint inhibitors (ICIs) in pleural mesothelioma has recently been established. The response to ICIs can be predicted by quantitative analysis of cells and their spatial distribution in the tumor microenvironment (TME). However, the detailed composition of the TME in pleural mesothelioma has not been reported. We evaluated the association between the TME and response to ICIs in this cancer. Methods: A retrospective analysis of 22 pleural mesothelioma patients treated with nivolumab in different centers was performed using surgical specimens. Four patients had a partial response to nivolumab (response group) and 18 patients had stable or progressive disease (nonresponse group). The number of CD4, CD8, FoxP3, CK, and PD‐L1 positive cells, cell density, and cell‐to‐cell distance were analyzed by multiplex immunofluorescence. Results: PD‐L1 expression did not differ significantly between the response and nonresponse groups. The density of total T cells and of CD8+ T cells was significantly higher in the response than in the nonresponse group. CD8+ T cells were more clustered and located closer to tumor cells, whereas regulatory T cells were located further from tumor cells in the response than in the nonresponse group. Conclusions: High density and spatial proximity of CD8+ T cells to tumor cells were associated with better response to nivolumab, whereas the proximity of regulatory T cells to tumor cells was associated with worse response, suggesting that the distinct landscape of the TME could be a potential predictor of ICI efficacy in pleural mesothelioma. [ABSTRACT FROM AUTHOR]

The tumor necrosis factor superfamily (TNFSF) and their receptors (TNFRSF) are important regulators of the immune system, mediating proliferation, survival, differentiation, and function of immune cells. As a result, their targeting for immunotherapy is attractive, although to date, under-exploited. In this review we discuss the importance of co-stimulatory members of the TNFRSF in optimal immune response generation, the rationale behind targeting these receptors for immunotherapy, the success of targeting them in pre-clinical studies and the challenges in translating this success into the clinic. The efficacy and limitations of the currently available agents are discussed alongside the development of next generation immunostimulatory agents designed to overcome current issues, and capitalize on this receptor class to deliver potent, durable and safe drugs for patients. [ABSTRACT FROM AUTHOR]

Objectives: Malignant pleural mesothelioma (MPM) is an aggressive disease with grim prognosis due to lack of effective treatment options. Disease prediction in association with early diagnosis may both contribute to improved MPM survival. Inflammation and autophagy are two processes associated with asbestos-induced transformation. We evaluated the level of two autophagic factors ATG5 and HMGB1, microRNAs (miRNAs) such as miR-126 and miR-222, and the specific biomarker of MPM, soluble mesothelin related proteins (Mesothelin) in asbestos-exposed individuals, MPM patients, and healthy subjects. The performance of these markers in detecting MPM was investigated in pre-diagnostic samples of asbestos-subjects who developed MPM during the follow-up and compared for the three groups. Results: The ATG5 best distinguished the asbestos-exposed subjects with and without MPM, while miR-126 and Mesothelin were found as a significant prognostic biomarker for MPM. ATG5 has been identified as an asbestos-related biomarker that can help to detect MPM with high sensitivity and specificity in pre-diagnostic samples for up to two years before diagnosis. To utilize this approach practically, higher number of cases has to be tested in order to give the combination of the two markers sufficient statistical power. Performance of the biomarkers should be confirmed by testing their combination in an independent cohort with pre-diagnostic samples. [ABSTRACT FROM AUTHOR]

This work explores the relationship between multinational R&D and innovation productivity among top corporate knowledge and R&D producers by adopting a twofold concept of internationalisation: (1) the firm's degree of R&D internationalisation, and (2) the firm's geographic diversification. We model the patent production process with an appropriate and robust conditional Data Envelopment Analysis (DEA) estimator, using a unique database of firms that matches financial indicators and patent information. Our results reinforce the fundamental role of internationalisation in the knowledge production process when the internationalisation process is properly and strategically managed. We interpret our empirical evidence through the theoretical lens of the learning theory of internationalisation, and we postulate that a high R&D intensity is a key driver to overcoming the challenges of internationalisation. [ABSTRACT FROM AUTHOR]

Immunotherapy with anti‐PD1/PD‐L1 is effective in only a subgroup of patients with malignant pleural mesothelioma (MPM). We investigated the efficacy of a combination of anti‐PD1/PD‐L1 and dendritic cell (DC) therapy to optimally induce effective anti‐tumor immunity in MPM in both humans and mice. Data of nine MPM patients treated with DC therapy and sequential anti‐PD1 treatment were collected and analyzed for progression‐free survival (PFS) and overall survival (OS). Survival and T‐cell responses were monitored in AC29 mesothelioma‐bearing mice treated concurrently with the combination therapy; additionally, the role of the tumor‐draining lymph node (TDLN) was investigated. The combination therapy resulted in a median OS and PFS of 17.7 and 8.0 months, respectively. Grade 3 to 4 treatment‐related adverse events had not been reported. Survival of the mesothelioma‐bearing mice treated with the combination therapy was longer than that of untreated mice, and coincided with improved T‐cell activation in peripheral blood and less T‐cell exhaustion in end stage tumors. Comparable results were obtained when solely the TDLN was targeted. We concluded that this combination therapy is safe and shows promising OS and PFS. The murine data support that PD‐L1 treatment may reinvigorate the T‐cell responses induced by DC therapy, which may primarily be the result of TDLN targeting. [ABSTRACT FROM AUTHOR]

Introduction: Malignant pleural mesothelioma (MPM) is a rare and highly aggressive thoracic tumor with poor prognosis and limited therapeutic options. Although immune checkpoint inhibitors exhibit a promising effect in some patients with unresectable MPM in clinical trials, the majority of MPM patients show only modest response rates to the currently available treatments. It is thus imperative to develop novel and innovative therapeutic modalities for MPM, including immune effector cell-based therapies. Methods: gd T cells were expanded using tetrakis-pivaloyloxymethyl 2-(thiazole-2-ylamino) ethylidene-1,1-bisphosphonate (PTA) and interleukin-2, and the therapeutic potential of gd T cells was examined through analyzing cell surface markers and cellular cytotoxicity against MPM in vitro using a europium chelatebased time-resolved fluorescence assay system and a luciferase-based luminescence assay system. Results and discussion: We successfully expanded gd T cells from peripheral blood mononuclear cells of healthy donors and MPM patients.γd T cells expressed natural killer receptors such as NKG2D and DNAM-1 and exhibited a moderate level of cytotoxicity to MPM cells in the absence of antigens. The inclusion of PTA, (E)-4-hydroxy-3-methylbut-2-enyl diphosphate (HMBPP) or zoledronic acid (ZOL) induced a TCR-dependent cytotoxicity in γd T cells and secreted interferon-γ (IFN-γ). In addition, γd T cells expressing CD16 exhibited a significant level of cytotoxicity against MPM cells in the presence of an antiepidermal growth factor receptor (EGFR) mAb, at lower concentrations than in clinical settings, whereas a detectable level of IFN-g was not produced. Taken together, γd T cells showed cytotoxic activity against MPM in three distinct mechanisms through NK receptors, TCRs and CD16. Since major histocompatibility complex (MHC) molecules are not involved in the recognition, both autologous and allogeneic γd T cells could be used for the development of γd T cell-based adoptive immunotherapy for MPM. [ABSTRACT FROM AUTHOR]

Despite the progress in outcomes seen with immunotherapy in various malignancies, including nonsmall cell lung cancer, the benefits are less in small cell lung cancer, malignant pleural mesothelioma and thymic epithelial tumours. New effective treatment options are needed, guided via more in-depth insights into the pathophysiology of these rare malignancies. This review comprehensively presents an overview of the clinical presentation, diagnostic tools, staging systems, pathophysiology and treatment options for these rare thoracic cancers. In addition, opportunities for further improvement of therapies are discussed. [ABSTRACT FROM AUTHOR]

The immunopathophysiological mechanisms underlying chronic inflammatory demyelinating polyneuropathy (CIDP) in an individual patient are largely unknown. Better understanding of these mechanisms may aid development of biomarkers and targeted therapies. Both B‐ and T‐cell dominant mechanisms have been implicated. We therefore investigated whether B‐cell and T‐cell receptor (BCR/TCR) repertoires might function as immunological biomarkers in CIDP. In this prospective cohort study, we longitudinally sampled peripheral blood of CIDP patients in three different phases of CIDP: starting induction treatment (IT), starting withdrawal from IVIg maintenance treatment (MT), and patients in remission (R). BCR and TCR repertoires were analyzed using RNA based high throughput sequencing. In baseline samples, the number of total clones, the number of dominant BCR and TCR clones and their impact on the repertoire was similar for patients in the IT, MT, and remission groups compared with healthy controls. Baseline samples in the IT or MT did not predict treatment response or potential relapse at follow‐up. Treatment responders in the IT group showed a potential IVIg‐induced increase in the number of dominant BCR clones and their impact at follow‐up (baseline1.0 [IQR 1.0‐2.8] vs. 6 m 3.5 [0.3‐6.8]; P <.05, Wilcoxon test). Although the BCR repertoire changed over time, the TCR repertoire remained robustly stable. We conclude that TCR and BCR repertoire distributions do not predict disease activity, treatment response or response to treatment withdrawal. [ABSTRACT FROM AUTHOR]

Purpose: Programmed cell death protein 1 (PD-1) and ligand programmed death ligand 1 (PD-L1) are important immune-suppressive regulators in the tumor microenvironment. A vaccine-induced immune effect on tumor cells is blunted by the immunosuppressive tumor microenvironment. Therefore, we hypothesized that a dendritic cell (DC) vaccine combined with anti-PD-1 (αPD-1) antibodies could elicit a synergistic anti-tumor immunity in bladder cancer. Materials and Methods: We produced a model of subcutaneous transplantation in C3H/HeJ mice by transplanting murine MBT-2 bladder cancer cells. DCs were isolated from normal C3H/HeJ mice, followed by stimulation against MBT-2 lysate before injection. Two weeks later of MBT-2 inoculation, αPD-1 and stimulated DCs were injected two times at one-week interval intraperitoneally and intravenously, respectively. Tumor-infiltrating immune cells and splenocytes were analyzed using flow cytometry. T-cell-mediated anti-tumor responses were measured by interferon (IFN)-γ ELISPOT and lactate dehydrogenase assays. Results: The mice treated with DC+α PD-1 showed a significant decrease in tumor volume compared to the DC-treated mice and IgG-treated group. Survival of the DC+α PD-1–treated group was improved compared with that of the IgG-treated mice. IFN-γ secretion from splenocytes against tumor cells was significantly increased in the DC+α PD-1 group compared with that of αPD-1– treated mice. The frequency of CD8+ and CD4+ T-cells in spleens was statistically increased in the DC+αPD-1–treated mice compared to those receiving monotherapy (DC- or αPD-1–treated group). Conclusions: Our results support the hypothesis that the combination therapy of a DC vaccine and αPD-1 antibodies could enhance the anti-tumor immune response against bladder cancer. [ABSTRACT FROM AUTHOR]

Background: Many studies have recently reported the association of concomitant medications with the response and survival in patients with non-small-cell lung cancer (NSCLC) treated with cancer immunotherapy. However, the clinical impact of statin therapy on the outcome of cancer immunotherapy in patients with NSCLC is poorly understood.Methods: In our database, we retrospectively identified and enrolled 390 patients with advanced or recurrent NSCLC who were treated with anti-programmed cell death-1 (PD-1) monotherapy in clinical practice between January 2016 and December 2019 at 3 medical centers in Japan to examine the clinical impact of statin therapy on the survival of patients with NSCLC receiving anti-PD-1 monotherapy. A propensity score-matched analysis was conducted to minimize the bias arising from the patients' backgrounds.Results: The Kaplan-Meier curves of the propensity score-matched cohort showed that the overall survival (OS), but not the progression-free survival (PFS), was significantly longer in patients receiving statin therapy. However, a Cox regression analysis in the propensity score-matched cohort revealed that statin therapy was not an independent favorable prognostic factor, although it tended to be correlated with a favorable outcome.Conclusions: Statin therapy may be a combination tool for cancer immunotherapy in patients with NSCLC. These findings should be validated in further prospective studies with larger sample sizes. [ABSTRACT FROM AUTHOR]

Background: Malignant mesothelioma (MMe) is a rare and fatal cancer with a poor prognosis. Our study aimed to compare the overall survival (OS) of MMe patients across various sites and develop a prognostic model to provide a foundation for individualized management of MMe patients. Methods: From the Surveillance, Epidemiology, and End Results (SEER) database, 1,772 individuals with malignant mesothelioma (MMe) were identified. The X-tile software was used to identify the optimal cut-off point for continuous variables. The Kaplan-Meier method was employed to compare the survival of MMe across different sites. The Cox proportional hazards model was applied to identify the independent risk factors of overall survival (OS) and a nomogram was constructed. Results: In the survival analysis, MMe originating from the reproductive organs and hollow organs showed a relatively better prognosis than those originating from soft tissue, solid organs, and pleura. Age, gender, location, histological type, grade of differentiation, extent of disease, lymph node status, lymph node ratio (LNR), and chemotherapy were all found to be independent risk variables for the prognosis of MMe patients (P<0.05) in a multivariate Cox analysis and were included in the construction of nomogram. In the training and testing sets, the C-index of the nomogram was 0.701 and 0.665, respectively, and the area under the ROC curve (AUROC) of the 1-, 3-, and 5-year overall survival rate was 0.749, 0.797, 0.833 and 0.730, 0.800, 0.832, respectively. The calibration curve shows that the nomogram is well-calibrated. Conclusions: This is the first research to examine the prognosis of MMe patients based on the location. However, previous studies often focused on malignant pleural mesothelioma or malignant peritoneal mesothelioma with high incidence. Furthermore, a nomograph with good prediction efficiency was established according to the variables that influence patient survival outcomes, which provides us with a reference for clinical decision-making. [ABSTRACT FROM AUTHOR]

Background: Tumour immune microenvironment heterogeneity is prevalent in numerous cancers and can negatively impact immunotherapy response. Immune heterogeneity and evolution in gastroesophageal adenocarcinoma (GEA) have not been studied in the past. Methods: Together with a multi-region sampling of normal, primary and metastatic tissues, we performed whole exome sequencing, TCR sequencing as well as immune cell infiltration estimation through deconvolution of gene expression signals. Results: We discovered high TCR repertoire and immune cell infiltration heterogeneity among metastatic sites, while they were homogeneous among primary and normal samples. Metastatic sites shared high levels of abundant TCR clonotypes with blood, indicating immune surveillance via blood. Metastatic sites also had low levels of tumour-eliminating immune cells and were undergoing heavy immunomodulation compared to normal and primary tumour tissues. There was co-evolution of neo-antigen and TCR repertoire, but only in patients with late diverging mutational evolution. Co-evolution of TCR repertoire and immune cell infiltration was seen in all except one patient. Conclusions: Our findings revealed immune heterogeneity and co-evolution in GEA, which may inform immunotherapy decision-making. [ABSTRACT FROM AUTHOR]

Purpose of Review: For patients with malignant pleural mesothelioma, prognosis is poor with extremely low 5-year survival rates and limited therapeutic options. Here, we review the current treatment landscape for mesothelioma and highlight promising future therapeutic directions. Recent Findings: Evolving frontline therapeutic options for mesothelioma include VEGF inhibition in combination with chemotherapy and dual immune checkpoint inhibition, with synergisms between the therapies and response prediction via biomarkers also being explored. Evolving experimental treatments for mesothelioma include PARP and ALK inhibitors, dendritic and CAR T-cell therapies, anti-mesothelin vaccines, and oncolytic viral therapies, representing timely advances in the field. Summary: The therapeutic landscape for malignant pleural mesothelioma is evolving and preferred treatment in the frontline and later settings will likely evolve with it. However, this does not preclude the evidence for including multi-modal therapies spanning angiogenesis and immune checkpoint inhibitors, and biomarker utilization, in current clinical trials and management. [ABSTRACT FROM AUTHOR]

This article reviews the existing literature on the internationalization of Asian business groups (BGs) by identifying the published papers on this subject in leading management and international business journals. We classify the literature based on the five most researched themes that describe the relationships among key constructs. These themes are (1) the effects of BG attributes on internationalization; (2) the effects of internationalization on firm performance; (3) the effects of BG attributes on firm performance; (4) the effects of resources and capabilities on internationalization; and (5) the effects of corporate governance on internationalization. Finally, based on what is missing in the literature, we propose an agenda for future research on the internationalization of Asian BGs. [ABSTRACT FROM AUTHOR]

Immunotherapy has gained great interest in thoracic malignancies in the last decade, first in non-small cell lung cancer (NSCLC), but also more recently in small-cell lung cancer (SCLC) and malignant pleural mesothelioma (MPM). However, while 15–20% of patients will greatly benefit from immune checkpoint blockers (ICBs), a vast majority will rapidly exhibit resistance. Reasons for this are multiple: non-immunogenic tumors, immunosuppressive tumor microenvironment or defects in immune cells trafficking to the tumor sites being some of the most frequent. Current progress in adoptive cell therapies could offer a way to overcome these hurdles and bring effective immune cells to the tumor site. In this review, we discuss advantages, limits and future perspectives of adoptive cell therapy (ACT) in thoracic malignancies from lymphokine-activated killer cells (LAK), cytokine-induced killer cells (CIK), natural killer cells (NK), dendritic cells (DC) vaccines and tumor-infiltrating lymphocytes (TILs) to TCR engineering and CARs. Trials are still in their early phases, and while there may still be many limitations to overcome, a combination of these different approaches with ICBs, chemotherapy and/or radiotherapy could vastly improve the way we treat thoracic cancers. [ABSTRACT FROM AUTHOR]

The article discusses clinical trials on treatments for patients with malignant pleural mesotheliomas. One study compared the efficacy of cytotoxic chemotherapy with cisplatin and pemetrexed versus cisplatin alone. Another clinical trial evaluated the use of cediranib, a tyrosine kinase inhibitor (TKI) which inhibit vascular endothelial growth factor (VEGF), with cisplatin and pemetrexed. An overview of randomized trials on immune checkpoint inhibitors incorporated in chemotherapy is presented.

Unresectable pleural mesothelioma is a poor prognosis disease. Improvement in overall survival (OS) has been shown with PEMETREXED combined with CISPLATIN. BEVACIZUMAB combined with chemotherapy is associated with an improvement in OS, compared to chemotherapy alone, but is not supported by health insurance everywhere. Immune Checkpoint Inhibition (ICI) monotherapy seemed to be promising but is controversial. ICI combination showed significant results. NIVOLUMAB, an anti-Programmed-Death-receptor 1, associated with IPILIMUMAB, an anti-Cytotoxic-T-Lymphocyte-Associated-protein 4, was evaluated in two phase II trials and a phase III trial, recently published. This combination led to a significant benefit in survival in first line compared to chemotherapy (OS 18.1 months (95%CI (16.8–21.4)) vs 14.1 (95%CI (12.4–16.2) HR 0.74 (95%CI 0.6–0.91) p = 0.002). These results represent a big step in unresectable pleural mesothelioma. The benefit in non-epithelioid subtype is impressive (OS 18.1 months (95%CI 12.2–22.8) vs 8.8 months 95%CI (7.4–10.2) HR 0.46 (95%CI (0.31–0.68))). Benefit in epithelioid subtype (OS 18.7 months 95%CI (16.9–22) vs 16.5 95%CI (14.9–20.5) HR 0.86 95%CI (0.69–1.08)) is similar to the benefit of the combination of BEVACIZUMAB and chemotherapy. Identification of predictive biomarkers is needed to identify patients who are most likely to benefit from each therapeutic strategy. [ABSTRACT FROM AUTHOR]

Malignant mesothelioma is a rare and aggressive cancer that develops in the thin layer surrounding the mesothelium and is mainly caused by asbestos exposure. Despite improvements in patient prognosis with conventional cancer treatments, such as surgery, chemotherapy, and radiotherapy, there are still no curative treatment modalities for advanced disease. In recent years, new therapeutic avenues have been explored. Improved understanding of the mechanisms underlying the dynamic tumor interaction with the immune system has led to the development of immunotherapeutic approaches. Numerous recent clinical trials have shown a desire to develop more effective treatments that can be used to fight against the disease. Immune checkpoint inhibitors, oncolytic adenoviruses, and their combination represent a promising strategy that can be used to synergistically overcome immunosuppression in the mesothelioma tumor microenvironment. This review provides a synthesized overview of the current state of knowledge on new therapeutic options for mesothelioma with a focus on the results of clinical trials conducted in the field. [ABSTRACT FROM AUTHOR]

This article is rooted in the endless debate of the relationship between FDI and multinational companies, which in turn connects with the controversy about economic growth and globalization. It deals with a global FDI's fraction towards the end of the twentieth century—the Japanese FDI in Spain—and the reasons for the entry of the Japanese ICT multinationals into that southern European country. It addresses the company Fujitsu España creation and evolution and is based essentially on qualitative and quantitative sources of diverse provenance and nature. The research is structured in four main sections, which outline the general framework of Japanese foreign investment in Europe, and successively addresses the circumstances in the creation of Fujitsu Spain (1983), as well as the restructuring of this company in its organisational, labour and corporate issues. [ABSTRACT FROM AUTHOR]

Background: Drug–drug interactions (DDIs) pose new challenges beyond traditional pharmacodynamics in the context of optimizing the treatment options with immune checkpoint inhibitors (ICIs). To alleviate cancer-related pain, analgesics are of absolute vital importance as chronic medications used by cancer patients. However, the possible outcome of ICI treatment concomitant with analgesics remains unclear. Methods: Original articles describing the possible influence of analgesics use on ICI treatment published before December 1, 2021 were retrieved from PubMed, Embase, and the Cochrane Library. Odds ratio (OR) with 95% confidence interval (CI) for objective response rate (ORR), hazard ratio (HR) with 95% CI for progression-free survival (PFS), and overall survival (OS) were calculated using the random-effects or fixed-effects model, and heterogeneity was assessed using the χ 2-based Q -test. Publication bias was examined by funnel plot analysis. Results: A total of 11 studies involving 4,404 patients were included. The pooled OR showed that opioid use decreased the response of opioid users to ICIs compared to non-opioid users (OR = 0.49, 95% CI = 0.37–0.65, p < 0.001). Compared to patients who did not receive opioids, opioid users had an increased risk of progression and mortality (HR = 1.61, 95% CI = 1.37–1.89, p < 0.001; HR = 1.67, 95% CI =1.30–2.14, p < 0.001, respectively). Furthermore, the concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs) was not significantly associated with differences in ORR, PFS, and OS in patients treated with ICIs (OR = 1.40, 95% CI = 0.84–2.32, p = 0.190; HR = 0.90, 95% CI = 0.77–1.06, p = 0.186; HR = 0.90, 95% CI = 0.71–1.14, p = 0.384, respectively). Conclusion: The concomitant use of opioids during ICI treatment has an adverse effect on patient prognosis, while the use of NSAIDs is not significantly associated with the prognosis in patients treated with ICIs. [ABSTRACT FROM AUTHOR]

In this paper, we examine how the international management strategy (centralized, local, and global) of an MNC affects its expatriate practices, and whether there is a contingent framework between international management strategy and expatriate practices. Drawing on a sample of 126 large Taiwanese multinational corporations, we examine the effects of international management strategies on six expatriate practices—staffing policies, selection criteria, selection methods, training, performance evaluations, and spouse/family support. We find some support for our expectation that, at the headquarters level, the specific international management strategy that an MNC employs affects the choice of expatriate practices. Implications for theory and practice are discussed. [ABSTRACT FROM AUTHOR]