-
Frontiers in Immunology 2021Immune checkpoint inhibitors (ICIs) have been widely used in hepatocellular carcinoma (HCC), while only a subset of patients experience clinical benefit. We aimed to... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND AIM
Immune checkpoint inhibitors (ICIs) have been widely used in hepatocellular carcinoma (HCC), while only a subset of patients experience clinical benefit. We aimed to investigate the effects of viral etiology on response to ICIs in HCC and depict the tumor immune microenvironment (TIME) of virally infected and uninfected HCC.
METHODS
A systematic search was conducted in PubMed, Web of Science, Embase, and the Cochrane central register of controlled trials up to August 2021. Clinical trials reporting the efficacy of ICIs in HCC were eligible. Baseline characteristics including first author, year of publication, National Clinical Trials (NCT) registry number, study region, sample sizes, interventions, line of treatment, and viral status were extracted. Meta-analysis was conducted to generate combined odds ratios (ORs) with 95% confidence intervals (CI) based on random or fixed effect model, depending on heterogeneity. Tumor immune microenvironment was depicted using ESTIMATE and CIBERSORT algorithm.
RESULTS
Eight studies involving 1,520 patients were included. Combined data suggested that there was no significant difference of objective response rate (ORR) between virally infected HCC and non-viral HCC patients [OR = 1.03 (95% CI, 0.77-1.37; I = 30.9%, p = 0.152)]. Similarly, difference was not observed on ORR between HBV-HCC and HCV-HCC patients [OR = 0.74 (95% CI, 0.52-1.06; I = 7.4%, p = 0.374)]. The infiltration of immune cells in the tumor microenvironment did not differ by etiology except for M0 macrophages, M2 macrophages, regulatory T cells, naive B cells, follicular helper T cells, activated dendritic cells, activated mast cells, and plasma cells. Despite differences in infiltration observed in specific cell types, the immune score and stromal score were generally comparable among etiology groups.
CONCLUSION
Viral etiology may not be considered as the selection criteria for patients receiving ICIs in HCC, and viral status has little impact on TIME remodeling during HCC tumorigenesis.
Topics: Animals; Carcinoma, Hepatocellular; Hepacivirus; Hepatitis C; Humans; Immune Checkpoint Inhibitors; Immunotherapy; Liver Neoplasms; Tumor Microenvironment
PubMed: 34659220
DOI: 10.3389/fimmu.2021.733530 -
Life Sciences Jan 2021Although anti-inflammatory properties are attributed to sesquiterpene lactones (SL), cutaneous hypersensitivity reactions are proposed as limitations for SL-based...
Although anti-inflammatory properties are attributed to sesquiterpene lactones (SL), cutaneous hypersensitivity reactions are proposed as limitations for SL-based therapies. Thus, the impact of SL on the skin and skin-related cells was systematically reviewed. Studies indexed in electronic databases were screened from the PRISMA strategy. The risk of bias in all studies was verified from the SYRCLE's tool. Thirty original studies were recovered and analyzed. Mice and guinea pig, keratinocytes and fibroblasts were predominantly investigated from in vivo and in vitro studies, respectively. In vivo studies indicated that most SL induced contact dermatitis associated with edema, erythema, and inflammatory infiltrate. Conversely, in vitro evidence was consistent with a dose-dependent anti-inflammatory effect of SL in response to reduced cytokines, 5-LOX, and COX-2 levels or activity in keratinocytes, fibroblasts, macrophages and dendritic cells; which are events potentially triggered by downregulation of gene expression and/or inhibition of the NF-κB signaling pathway. In vivo studies presented uncertain to high-risk of bias mainly associated with underreporting of randomization and experimental blinding. The current evidence supports potent cutaneous immunomodulatory properties of SL. Although in vitro and in vivo studies indicate opposite anti- or proinflammatory effects, this contradiction exhibits a dose-dependent component. In addition, the anti-inflammatory pathways activated by SL are better understood from in vitro evidence. However, additional studies are required to elucidating specific anti-inflammatory and proinflammatory mechanisms triggered by SL in vivo. Thus, controlling the sources of bias described in this review can contribute to improving the quality of the evidence in further investigations.
Topics: Animals; Anti-Inflammatory Agents; Dermatitis, Contact; Dose-Response Relationship, Drug; Guinea Pigs; Humans; Lactones; Mice; NF-kappa B; Sesquiterpenes; Skin
PubMed: 33278385
DOI: 10.1016/j.lfs.2020.118815 -
International Journal of Laboratory... Aug 2022An indolent T-lymphoblastic proliferation (iT-LBP) is a rare benign disorder characterized by an abnormal expansion of immature T-cells, which morphologically can mimic... (Review)
Review
An indolent T-lymphoblastic proliferation (iT-LBP) is a rare benign disorder characterized by an abnormal expansion of immature T-cells, which morphologically can mimic malignancy. Since the first case was described in 1999, dozens more have been reported in the literature. However, the epidemiologic, clinical, pathologic, and biologic features of this disease have not been well described. Here, we retrospectively reviewed all known cases reported in the literature to better understand this entity. A PubMed search up to January 2022 highlighted 25 papers describing cases/case series of iT-LBP, one of which was a case presentation in a slide workshop. Except for 9 of the cases in one of the papers, where it was evident that the number of CD3+/TdT+ cells were too few to conform with a diagnosis of iT-LBP, all papers and all the cases reported were included in the study amounting to a total of 45 cases. Clinicopathologic characteristics were analyzed using descriptive statistics and frequencies. Our analysis highlighted the previously known association with Castleman disease and Castleman-like features and underlined its association with dendritic cell proliferations in general, as well as uncovering high frequency of concurrence with hepatocellular carcinoma and autoimmune diseases, most notably myasthenia gravis, paraneoplastic pemphigus and paraneoplastic autoimmune multiorgan syndrome. Furthermore, the co-expression of CD4 and CD8 and high prevalence of extranodal disease and recurrences were other less well described features that were revealed.
Topics: Carcinoma, Hepatocellular; Cell Proliferation; Humans; Liver Neoplasms; Lymphoproliferative Disorders; Retrospective Studies
PubMed: 35577551
DOI: 10.1111/ijlh.13873 -
The European Journal of Neuroscience Aug 2023Environmental factors interact with biological and genetic factors influencing the development and well-being of an organism. The interest in better understanding the...
Τhe neuroprotective role of environmental enrichment against behavioral, morphological, neuroendocrine and molecular changes following chronic unpredictable mild stress: A systematic review.
Environmental factors interact with biological and genetic factors influencing the development and well-being of an organism. The interest in better understanding the role of environment on behavior and physiology led to the development of animal models of environmental manipulations. Environmental enrichment (EE), an environmental condition that allows cognitive and sensory stimulation as well as social interaction, improves cognitive function, reduces anxiety and depressive-like behavior and promotes neuroplasticity. In addition, it exerts protection against neurodegenerative disorders, cognitive aging and deficits aggravated by stressful experiences. Given the beneficial effects of EE on the brain and behavior, preclinical studies have focused on its protective role as an alternative, non-invasive manipulation, to help an organism to cope better with stress. A valid, reliable and effective animal model of chronic stress that enhances anxiety and depression-like behavior is the chronic unpredictable mild stress (CUMS). The variety of stressors and the unpredictability in the time and sequence of exposure to prevent habituation, render CUMS an ethologically relevant model. CUMS has been associated with dysregulation of the hypothalamic-pituitary-adrenal axis, elevation in the basal levels of stress hormones, reduction in brain volume, dendritic atrophy and alterations in markers of synaptic plasticity. Although numerous studies have underlined the compensatory role of EE against the negative effects of various chronic stress regimens (e.g. restraint and social isolation), research concerning the interaction between EE and CUMS is sparse. The purpose of the current systematic review is to present up-to-date research findings regarding the protective role of EE against the negative effects of CUMS.
Topics: Animals; Hypothalamo-Hypophyseal System; Pituitary-Adrenal System; Depression; Anxiety; Anxiety Disorders; Stress, Psychological; Disease Models, Animal; Hippocampus
PubMed: 37461295
DOI: 10.1111/ejn.16089 -
International Immunopharmacology Mar 2024Immune checkpoint inhibitors (ICIs) have effectively improved the clinical outcome of advanced non-small cell lung cancer (NSCLC). Opioids are commonly used for pain... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Immune checkpoint inhibitors (ICIs) have effectively improved the clinical outcome of advanced non-small cell lung cancer (NSCLC). Opioids are commonly used for pain relief in cancer patients. This study aims to clarify the prognostic impact of opioid use in advanced NSCLC patients receiving ICI therapy.
METHODS
A systematic literature review was carried out using online databases before July 2023. The meta-analysis was used to clarify the correlation of opioid use with the overall survival (OS) or progression-free survival (PFS) of ICI-treated NSCLC patients, both of which were determined using hazard ratios (HRs) coupled with 95 % confidence intervals (CIs). Then, an independent cohort enrolling 181 NSCLC patients was utilized for validation. Finally, a comprehensive bioinformatics analysis based on TCGA cohort was performed to investigate the prognostic significance of opioid target genes (OTGs) and their correlation with immune infiltration in NSCLC patients.
RESULTS
A total of 8 studies enrolling 1174 patients were included in the meta-analysis. Opioid use was negatively associated with worse PFS (HR = 2.16, 95 %CI: 1.26-3.71) and OS (HR = 2.02, 95 %CI: 1.54-2.63) in ICI-treated NSCLC patients. The retrospective validation confirmed the above result and identified opioid use as an independent unfavorable predictor for PFS and OS in both the entire cohort and ICI subgroup. The bioinformatic analysis identified 14 prognostic OTGs (CYP17A1, PDYN, PYCARD, FGA, NTSR1, FABP1, HPCA, PENK, PDGFB, LIN7A, FKBP5, TYMS, CACNA1H and LDHA), most of which were correlated with immune infiltration in NSCLC. A risk model was constructed based on 14 OTGs and found to effectively stratify the clinical outcome in both the training and validation set, independent of age, gender and TNM staging system. The model was also significantly correlated with infiltration of activated dendritic cells, neutrophils and tumor infiltrating lymphocytes. Finally, a nomogram was constructed based on the model, age, gender and TNM stage, which could predict well the 1-, 3- and 5-year survival of NSCLC patients.
CONCLUSION
Opioid use is correlated with the poor clinical outcome in ICI-treated NSCLC patients. Precise pain management is highly advocated and opioids are recommended to be cautiously used in these patients. OTGs have the potential to be prognostic biomarkers for NSCLC patients and their role in tumor immunity needs to be further investigated.
Topics: Humans; Analgesics, Opioid; Carcinoma, Non-Small-Cell Lung; Immune Checkpoint Inhibitors; Lung Neoplasms; Membrane Proteins; Opioid-Related Disorders; Retrospective Studies; Vesicular Transport Proteins
PubMed: 38325047
DOI: 10.1016/j.intimp.2024.111611 -
Frontiers in Molecular Biosciences 2022Immunoglobulin E (IgE)-mediated allergies are increasing in prevalence, with IgE-mediated food allergies currently affecting up to 10% of children and 6% of adults...
Immunoglobulin E (IgE)-mediated allergies are increasing in prevalence, with IgE-mediated food allergies currently affecting up to 10% of children and 6% of adults worldwide. The mechanisms underpinning the first phase of IgE-mediated allergy, allergic sensitization, are still not clear. Recently, the potential involvement of lipids in allergic sensitization has been proposed, with reports that they can bind allergenic proteins and act on immune cells to skew to a T helper type 2 (Th2) response. The objective of this systematic review is to determine if there is strong evidence for the role of lipids in allergic sensitization. Nineteen studies were reviewed, ten of which were relevant to lipids in allergic sensitization to food allergens, nine relevant to lipids in aeroallergen sensitization. The results provide strong evidence for the role of lipids in allergies. Intrinsic lipids from allergen sources can interact with allergenic proteins to predominantly enhance but also inhibit allergic sensitization through various mechanisms. Proposed mechanisms included reducing the gastrointestinal degradation of allergenic proteins by altering protein structure, reducing dendritic cell (DC) uptake of allergenic proteins to reduce immune tolerance, regulating Th2 cytokines, activating invariant natural killer T (iNKT) cells through CD1d presentation, and directly acting upon toll-like receptors (TLRs), epithelial cells, keratinocytes, and DCs. The current literature suggests intrinsic lipids are key influencers of allergic sensitization. Further research utilising human relevant models and clinical studies are needed to give a reliable account of the role of lipids in allergic sensitization.
PubMed: 35495627
DOI: 10.3389/fmolb.2022.832330 -
Oral Oncology May 2024Recurrent/Metastatic Nasopharyngeal Carcinoma (RM-NPC) remains difficult to treat and contributes to considerable mortality. The first-line treatment for RM-NPC is... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Recurrent/Metastatic Nasopharyngeal Carcinoma (RM-NPC) remains difficult to treat and contributes to considerable mortality. The first-line treatment for RM-NPC is Gemcitabine and Cisplatin and second-line treatment options differ. The endemic variant of NPC is associated with Epstein-Barr Virus (EBV). Therefore, Cell-based Immunotherapy (CBI) targeting EBV-specific RM-NPC may be effective.
METHODS
We systematically searched PubMed, Embase and the Cochrane Library for randomised or observational studies investigating the efficacy and safety of CBI in the treatment of RM-NPC. We performed all meta-analyses using the random-effects model. Studies were further stratified by endemicity, nature of disease and drug type to investigate for potential between-study heterogeneity and additional pre-specified tests were employed to assess for publication bias.
RESULTS
We screened 1,671 studies and included 13 studies with 403 participants in the systematic review, of which nine studies were eligible for meta-analysis. The use of CBI monotherapy as second or subsequent line treatment for EBV-positive RM-NPC revealed an ORR of 10 % (95 %CI = 3 %-29 %), median PFS of 2.37 months (95 %CI = 1.23-3.51) and median OS of 10.16 months (95 %CI = 0.67-19.65). For EBV-specific Cytotoxic T-Lymphocyte monotherapy, the pooled PD rate was 54 % (95 %CI = 9 %-93 %), SD rate was 22 % (95 %CI = 2 %-75 %) and incidence rate of any grade adverse events was 45 %. For Dendritic Cell monotherapy, a PD rate of 80 % (95 % CI = 29 %-98 %), SD rate of 11 % (95 % CI = 0 %-82 %) and incidence rate of any grade adverse events of 29 % was achieved.
CONCLUSION
CBI monotherapy demonstrates some activity in pre-treated RM-NPC. More trials are needed to better understand how to integrate CBI into RM-NPC care.
Topics: Humans; Cell- and Tissue-Based Therapy; Herpesvirus 4, Human; Immunotherapy; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Neoplasm Metastasis; Neoplasm Recurrence, Local; Treatment Outcome
PubMed: 38615584
DOI: 10.1016/j.oraloncology.2024.106786 -
Current Topics in Medicinal Chemistry 2021MicroRNAs (miRNAs) are short ~18-22 nucleotide, single-stranded, non-coding RNA molecules playing a crucial role in regulating diverse biological processes and are...
MicroRNAs (miRNAs) are short ~18-22 nucleotide, single-stranded, non-coding RNA molecules playing a crucial role in regulating diverse biological processes and are frequently dysregulated during disease pathogenesis. Thus, targeting miRNA could be a potential candidate for therapeutic invention. This systemic review aims to summarize our current understanding regarding the role of miRNAs associated with Th2-mediated immune disorders and strategies for therapeutic drug development and current clinical trials.
Topics: Humans; Immune System Diseases; MicroRNAs; Th2 Cells
PubMed: 33655864
DOI: 10.2174/1568026621666210303150235 -
Journal of Personalized Medicine Dec 2021Liquid biopsy is an accessible, non-invasive diagnostic tool for advanced prostate cancer (PC) patients, potentially representing a real-time monitoring test for tumor... (Review)
Review
Liquid biopsy is an accessible, non-invasive diagnostic tool for advanced prostate cancer (PC) patients, potentially representing a real-time monitoring test for tumor evolution and response to treatment through the analysis of circulating tumor cells (CTCs) and exosomes. We performed a systematic literature review (PRISMA guidelines) to describe the current knowledge about PD-L1 expression in liquid biopsies of PC patients: 101/159 (64%) cases revealed a variable number of PD-L1+ CTCs. Outcome correlations should be investigated in larger series. Nuclear PD-L1 expression by CTCs was occasionally associated with worse prognosis. Treatment (abiraterone, enzalutamide, radiotherapy, checkpoint-inhibitors) influenced PD-L1+ CTC levels. Discordance in PD-L1 status was detected between primary vs. metastatic PC tissue biopsies and CTCs vs. corresponding tumor tissues. PD-L1 is also released by PC cells through soluble exosomes, which could inhibit the T cell function, causing immune evasion. PD-L1+ PC-CTC monitoring and genomic profiling may better characterize the ongoing aggressive PC forms compared to PD-L1 evaluation on primary tumor biopsies/prostatectomy specimens (sometimes sampled a long time before recurrence/progression). Myeloid-derived suppressor cells and dendritic cells (DCs), which may have immune-suppressive effects in tumor microenvironment, have been found in PC patients circulation, sometimes expressing PD-L1. Occasionally, their levels correlated to clinical outcome. Enzalutamide-progressing castration-resistant PC patients revealed increased PD-1+ T cells and circulating PD-L1/2+ DCs.
PubMed: 34945784
DOI: 10.3390/jpm11121312 -
The Cochrane Database of Systematic... Dec 2021Non-small cell lung cancer (NSCLC) is the most common lung cancer, accounting for approximately 80% to 85% of all cases. For people with localised NSCLC (stages I to... (Review)
Review
BACKGROUND
Non-small cell lung cancer (NSCLC) is the most common lung cancer, accounting for approximately 80% to 85% of all cases. For people with localised NSCLC (stages I to III), it has been speculated that immunotherapy may be helpful for reducing postoperative recurrence rates, or improving the clinical outcomes of current treatment for unresectable tumours. This is an update of a Cochrane Review first published in 2017 and it includes two new randomised controlled trials (RCTs).
OBJECTIVES
To assess the effectiveness and safety of immunotherapy (excluding checkpoint inhibitors) among people with localised NSCLC of stages I to III who received curative intent of radiotherapy or surgery.
SEARCH METHODS
We searched the following databases (from inception to 19 May 2021): CENTRAL, MEDLINE, Embase, CINAHL, and five trial registers. We also searched conference proceedings and reference lists of included trials.
SELECTION CRITERIA
We included RCTs conducted in adults (≥ 18 years) diagnosed with NSCLC stage I to III after surgical resection, and those with unresectable locally advanced stage III NSCLC receiving radiotherapy with curative intent. We included participants who underwent primary surgical treatment, postoperative radiotherapy or chemoradiotherapy if the same strategy was provided for both intervention and control groups.
DATA COLLECTION AND ANALYSIS
Two review authors independently selected eligible trials, assessed risk of bias, and extracted data. We used survival analysis to pool time-to-event data, using hazard ratios (HRs). We used risk ratios (RRs) for dichotomous data, and mean differences (MDs) for continuous data, with 95% confidence intervals (CIs). Due to clinical heterogeneity (immunotherapeutic agents with different underlying mechanisms), we combined data by applying random-effects models.
MAIN RESULTS
We included 11 RCTs involving 5128 participants (this included 2 new trials with 188 participants since the last search dated 20 January 2017). Participants who underwent surgical resection or received curative radiotherapy were randomised to either an immunotherapy group or a control group. The immunological interventions were active immunotherapy Bacillus Calmette-Guérin (BCG) adoptive cell transfer (i.e. transfer factor (TF), tumour-infiltrating lymphocytes (TIL), dendritic cell/cytokine-induced killer (DC/CIK), antigen-specific cancer vaccines (melanoma-associated antigen 3 (MAGE-A3) and L-BLP25), and targeted natural killer (NK) cells. Seven trials were at high risk of bias for at least one of the risk of bias domains. Three trials were at low risk of bias across all domains and one small trial was at unclear risk of bias as it provided insufficient information. We included data from nine of the 11 trials in the meta-analyses involving 4863 participants. There was no evidence of a difference between the immunotherapy agents and the controls on any of the following outcomes: overall survival (HR 0.94, 95% CI 0.84 to 1.05; P = 0.27; 4 trials, 3848 participants; high-quality evidence), progression-free survival (HR 0.94, 95% CI 0.86 to 1.03; P = 0.19; moderate-quality evidence), adverse events (RR 1.12, 95% CI 0.97 to 1.28; P = 0.11; 4 trials, 4126 evaluated participants; low-quality evidence), and severe adverse events (RR 1.14, 95% CI 0.92 to 1.40; 6 trials, 4546 evaluated participants; low-quality evidence). Survival rates at different time points showed no evidence of a difference between immunotherapy agents and the controls. Survival rate at 1-year follow-up (RR 1.02, 95% CI 0.96 to 1.08; I = 57%; 7 trials, 4420 participants; low-quality evidence), 2-year follow-up (RR 1.02, 95% CI 0.93 to 1.12; 7 trials, 4420 participants; moderate-quality evidence), 3-year follow-up (RR 0.99, 95% CI 0.90 to 1.09; 7 trials, 4420 participants; I = 22%; moderate-quality evidence) and at 5-year follow-up (RR 0.98, 95% CI 0.86 to 1.12; I = 0%; 7 trials, 4389 participants; moderate-quality evidence). Only one trial reported overall response rates. Two trials provided health-related quality of life results with contradicting results. AUTHORS' CONCLUSIONS: Based on this updated review, the current literature does not provide evidence that suggests a survival benefit from adding immunotherapy (excluding checkpoint inhibitors) to conventional curative surgery or radiotherapy, for people with localised NSCLC (stages I to III). Several ongoing trials with immune checkpoints inhibitors (PD-1/PD-L1) might bring new insights into the role of immunotherapy for people with stages I to III NSCLC.
Topics: Carcinoma, Non-Small-Cell Lung; Chemoradiotherapy; Humans; Immunotherapy; Lung Neoplasms; Progression-Free Survival; Randomized Controlled Trials as Topic
PubMed: 34870327
DOI: 10.1002/14651858.CD011300.pub3