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Transfusion Medicine Reviews Apr 2023Allogeneic peripheral blood stem cells mobilization is now the basis of most stem cell transplants. In a very limited number of cases, mobilization is suboptimal leading...
Allogeneic peripheral blood stem cells mobilization is now the basis of most stem cell transplants. In a very limited number of cases, mobilization is suboptimal leading to further collection procedures, to suboptimal cell doses infusion with delayed engraftment time, increased risks of transplant procedure and of related costs. To date we have no recognized and shared criteria for early estimating the probability of poor mobilization in healthy donors. We then analyzed allogeneic peripheral blood stem cell donations performed at the Fondazione Policlinico Universitario A.Gemelli IRCCS Hospital from January 2013 to December 2021 in order to identify premobilization factors associated with successful mobilization. The following data were collected: age, gender, weight, complete blood cell count at baseline, G-CSF dose, number of collection procedures, CD34+ cell count in peripheral blood on the first day of collection, CD34+ cell dose per kg body weight of recipient. Mobilization efficacy was defined according to the number of CD34+ cells in peripheral blood on day +5 of G-CSF administration. We classified donors as sub-optimal mobilizers or good mobilizers according to the achievement of the 50 CD34+ cell/μL threshold. We observed 30 suboptimal mobilizations in 158 allogeneic peripheral blood stem cell donations. Age and baseline white blood cell count were factors significantly associated with negative or positive impact on mobilization, respectively. We did not find significant differences in mobilization based on gender or G-CSF dose. Using cut-off values of 43 years and 5.5×10/L WBC count, we built a suboptimal mobilization score: donors who reach 2, 1 or 0 points have a 46%, 16% or 4% probability of suboptimal mobilization, respectively. Our model explains 26% of the variability of mobilization confirming that most of the mobilization magnitude depends on genetically determined factors; however, suboptimal mobilization score is a simple tool providing an early assessment of mobilization efficacy before G-CSF administration begins in order to support allogeneic stem cells selection, mobilization and collection. Through a systematic review, we looked for confirmation of our findings. According to the published articles, all the variables we included in our model are confirmed to be strongly related to the success of mobilization. We believe that score system approach could be applied in clinical practice to assess the risk of mobilization failure at baseline allowing for a priori intervention.
Topics: Humans; Hematopoietic Stem Cell Mobilization; Peripheral Blood Stem Cells; Antigens, CD34; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation
PubMed: 37315997
DOI: 10.1016/j.tmrv.2023.150725 -
International Journal of Molecular... Jun 2023Acute myeloid leukaemia (AML) is characterized by impaired myeloid differentiation resulting in an accumulation of immature blasts in the bone marrow and peripheral... (Meta-Analysis)
Meta-Analysis Review
A Direct Comparison, and Prioritisation, of the Immunotherapeutic Targets Expressed by Adult and Paediatric Acute Myeloid Leukaemia Cells: A Systematic Review and Meta-Analysis.
Acute myeloid leukaemia (AML) is characterized by impaired myeloid differentiation resulting in an accumulation of immature blasts in the bone marrow and peripheral blood. Although AML can occur at any age, the incidence peaks at age 65. The pathobiology of AML also varies with age with associated differences in incidence, as well as the frequency of cytogenetic change and somatic mutations. In addition, 5-year survival rates in paediatrics are 60-75% but fall to 5-15% in older AML patients. This systematic review aimed to determine whether the altered genes in AML affect the same molecular pathways, indifferent of patient age, and, therefore, whether patients could benefit from the repurposing drugs or the use of the same immunotherapeutic strategies across age boundaries to prevent relapse. Using a PICO framework and PRISMA-P checklist, relevant publications were identified using five literature databases and assessed against an inclusion criteria, leaving 36 articles, and 71 targets for therapy, for further analysis. QUADAS-2 was used to determine the risk of bias and perform a quality control step. We then priority-ranked the list of cancer antigens based on predefined and pre-weighted objective criteria as part of an analytical hierarchy process used for dealing with complex decisions. This organized the antigens according to their potential to act as targets for the immunotherapy of AML, a treatment that offers an opportunity to remove residual leukaemia cells at first remission and improve survival rates. It was found that 80% of the top 20 antigens identified in paediatric AML were also within the 20 highest scoring immunotherapy targets in adult AML. To analyse the relationships between the targets and their link to different molecular pathways, PANTHER and STRING analyses were performed on the 20 highest scoring immunotherapy targets for both adult and paediatric AML. There were many similarities in the PANTHER and STRING results, including the most prominent pathways being angiogenesis and inflammation mediated by chemokine and cytokine signalling pathways. The coincidence of targets suggests that the repurposing of immunotherapy drugs across age boundaries could benefit AML patients, especially when used in combination with conventional therapies. However, due to cost implications, we would recommend that efforts are focused on ways to target the highest scoring antigens, such as WT1, NRAS, IDH1 and TP53, although in the future other candidates may prove successful.
Topics: Adult; Aged; Child; Humans; Immunotherapy; Leukemia, Myeloid, Acute; Meta-Analysis as Topic; Neoplasm Recurrence, Local
PubMed: 37298623
DOI: 10.3390/ijms24119667 -
Viruses May 2023Patients with chronic hepatitis B (CHB) gradually develop T cell exhaustion, and the inhibitory receptor molecule, cytotoxic T-lymphocyte antigen-4 (CTLA-4), may play a... (Review)
Review
Patients with chronic hepatitis B (CHB) gradually develop T cell exhaustion, and the inhibitory receptor molecule, cytotoxic T-lymphocyte antigen-4 (CTLA-4), may play a role in this phenomenon. This systematic review investigates the role of CTLA-4 in the development of T cell exhaustion in CHB. A systematic literature search was conducted on PubMed and Embase on 31 March 2023 to identify relevant studies. Fifteen studies were included in this review. A majority of the studies investigating CD8 T cells demonstrated increased expression of CTLA-4 in CHB patients, though one study found this only in HBeAg-positive patients. Three out of four studies investigating the expression of CTLA-4 on CD4 T cells found upregulation of CTLA-4. Several studies showed constitutive expression of CLTA-4 on CD4 regulatory T cells. CTLA-4 blockade resulted in heterogeneous responses for all T cell types, as it resulted in increased T cell proliferation and/or cytokine production in some studies, while other studies found this only when combining blockade of CTLA-4 with other inhibitory receptors. Although mounting evidence supports a role of CTLA-4 in T cell exhaustion, there is still insufficient documentation to describe the expression and exact role of CTLA-4 in T cell exhaustion in CHB.
Topics: Humans; CTLA-4 Antigen; Hepatitis B, Chronic; CD8-Positive T-Lymphocytes; T-Cell Exhaustion; T-Lymphocytes, Regulatory; Hepatitis B virus
PubMed: 37243227
DOI: 10.3390/v15051141 -
BMC Cancer May 2023Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death, worldwide. The predominant causative factor for HCC is hepatitis B virus (HBV)... (Meta-Analysis)
Meta-Analysis
Efficacy and safety of PD-1/PD-L1 inhibitors combined with anti-angiogenic therapy for the unresectable hepatocellular carcinoma and the benefit for hepatitis B virus etiology subgroup: a systematic review and meta-analysis of randomized controlled trials.
BACKGROUND
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death, worldwide. The predominant causative factor for HCC is hepatitis B virus (HBV) infection. We conducted a meta-analysis to estimate the efficacy and safety of PD-1/PD-L1 inhibitors combined with anti-angiogenic therapy for the first-line treatment of the unresectable HCC and to evaluate the benefits of different geographic regions and etiology stratifications.
METHODS
Randomized clinical trials published up to 12th November 2022 were searched by online databases. Moreover, effects of hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS) were extracted from included studies. Pooled odds ratio (OR) and 95% CI for objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events (TRAEs) were calculated.
RESULTS
A total of 3057 patients from five phase III randomized clinical trials were collected and reviewed for this meta-analysis. The pooled HR of OS (HR = 0.71; 95% CI: 0.60-0.85) and PFS (HR = 0.64; 95% CI: 0.53-0.77) demonstrated significantly better benefit in PD-1/PD-L1 inhibitors combination group than targeted monotherapy to treat unresectable HCC. In addition, combination therapy showed better ORR and DCR, with ORs of 3.29 (95% CI: 1.92-5.62) and 1.88 (95% CI: 1.35-2.61), respectively. The subgroup analysis indicated that PD-1/PD-L1 inhibitors combination therapy was significantly superior to anti-angiogenic monotherapy for HBV-related HCC in terms of OS (HR = 0.64; 95% CI: 0.55-0.74) and PFS (HR = 0.53; 95% CI:0.47-0.59), while there was no significant difference in patients with HCV (OS, HR = 0.81, p = 0.1) or non-viral (OS, HR = 0.91, p = 0.37; PFS, HR = 0.77, p = 0.05).
CONCLUSIONS
Meta-analysis revealed for the first-time that PD-1/PD-L1 inhibitors combination therapy for unresectable HCC was associated with better clinical outcomes than anti-angiogenic monotherapy, especially for HBV infection and Asian population.
Topics: Humans; Carcinoma, Hepatocellular; Hepatitis B; Hepatitis B virus; Immune Checkpoint Inhibitors; Liver Neoplasms; Programmed Cell Death 1 Receptor; Randomized Controlled Trials as Topic
PubMed: 37226111
DOI: 10.1186/s12885-023-10960-w -
International Journal of Environmental... Apr 2023The rate of new human immunodeficiency virus (HIV) infections globally is alarming. Although antiretroviral therapy (ART) improves the quality of life among this group... (Meta-Analysis)
Meta-Analysis Review
The rate of new human immunodeficiency virus (HIV) infections globally is alarming. Although antiretroviral therapy (ART) improves the quality of life among this group of patients, ARTs are associated with risk of cardiovascular diseases (CVD). Moreover, virally suppressed patients still experience immune activation associated with HIV migration from reservoir sites. Statins are widely recommended as therapeutic agents to control ART-related CVD; however, their impacts on the cluster of differentiation (CD)4 count and viral load are inconsistent. To assess the effect of statins on markers of HIV infections, immune activation and cholesterol, we thoroughly reviewed evidence from randomised controlled trials. We found 20 relevant trials from three databases with 1802 people living with HIV (PLHIV) on statin-placebo treatment. Our evidence showed no significant effect on CD4 T-cell count standardised mean difference (SMD): (-0.59, 95% confidence intervals (CI): (-1.38, 0.19), = 0.14) following statin intervention in PLHIV on ART. We also found no significant difference in baseline CD4 T-cell count (SD: (-0.01, 95%CI: (-0.25, 0.23), = 0.95). Our findings revealed no significant association between statins and risk of viral rebound in PLHIV with undetectable viral load risk ratio (RR): (1.01, 95% CI: (0.98, 1.04), = 0.65). Additionally, we found a significant increase in CD8CD38HLA-DR T-cells (SMD (1.10, 95% CI: (0.93, 1.28), < 0.00001) and CD4CD38HLA-DR T-cells (SMD (0.92, 95% CI: (0.32, 1.52), = 0.003). Finally, compared to placebo, statins significantly reduced total cholesterol (SMD: (-2.87, 95% CI: (-4.08, -1.65), < 0.0001)). Our results suggest that the statin lipid-lowering effect in PLHIV on ART may elevate immune activation without influencing the viral load and CD4 count. However, due to the limited evidence synthesised in this meta-analysis, we recommend that future powered trials with sufficient sample sizes evaluate statins' effect on CD4 count and viral load, especially in virally suppressed patients.
Topics: Humans; HIV Infections; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Quality of Life; HIV-1; HLA-DR Antigens; CD4 Lymphocyte Count; Cardiovascular Diseases; Cholesterol; Viral Load
PubMed: 37174188
DOI: 10.3390/ijerph20095668 -
Frontiers in Immunology 2023We conducted a systematic review and meta-analysis to evaluate outcomes following chimeric antigen receptor T cell (CAR-T) therapy in relapsed/refractory acute myeloid... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
We conducted a systematic review and meta-analysis to evaluate outcomes following chimeric antigen receptor T cell (CAR-T) therapy in relapsed/refractory acute myeloid leukemia (RR-AML).
METHODS
We performed a literature search on PubMed, Cochrane Library, and Clinicaltrials.gov. After screening 677 manuscripts, 13 studies were included. Data was extracted following PRISMA guidelines. Pooled analysis was done using the meta-package by Schwarzer et al. Proportions with 95% confidence intervals (CI) were computed.
RESULTS
We analyzed 57 patients from 10 clinical trials and 3 case reports. The pooled complete and overall response rates were 49.5% (95% CI 0.18-0.81, I=65%) and 65.2% (95% CI 0.36-0.91, I=57%). The pooled incidence of cytokine release syndrome, immune-effector cell associated neurotoxicity syndrome, and graft-versus-host disease was estimated as 54.4% (95% CI 0.17-0.90, I=77%), 3.9% (95% CI 0.00-0.19, I=22%), and 1.6% (95%CI 0.00-0.21, I=33%), respectively.
CONCLUSION
CAR-T therapy has demonstrated modest efficacy in RR-AML. Major challenges include heterogeneous disease biology, lack of a unique targetable antigen, and immune exhaustion.
Topics: Humans; Receptors, Chimeric Antigen; Antigens, CD19; Immunotherapy, Adoptive; Leukemia, Myeloid, Acute; Cell- and Tissue-Based Therapy
PubMed: 37168849
DOI: 10.3389/fimmu.2023.1152457 -
BMC Infectious Diseases May 2023The early diagnosis of sepsis is hampered by the lack of reliable laboratory measures. There is growing evidence that presepsin and Mid-regional pro-adrenomedullin... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The early diagnosis of sepsis is hampered by the lack of reliable laboratory measures. There is growing evidence that presepsin and Mid-regional pro-adrenomedullin (MR-proADM) are promising biomarkers in the diagnosis of sepsis. This study was conducted to evaluate and compare the diagnostic value of MR-proADM and presepsin in sepsis patients.
METHODS
We searched Web of Science, PubMed, Embase, China national knowledge infrastructure, and Wanfang up to 22th July, 2022, for studies evaluating the diagnosis performance of presepsin and MR-proADM in adult sepsis patients. Risk of bias was assessed using quadas-2. Pooled sensitivity and specificity were calculated using bivariate meta-analysis. Meta-regression and subgroup analysis were used to find source of heterogeneity.
RESULTS
A total of 40 studies were eventually selected for inclusion in this meta-analysis, including 33 for presepsin and seven for MR-proADM. Presepsin had a sensitivity of 0.86 (0.82-0.90), a specificity of 0.79 (0.71-0.85), and an AUC of 0.90 (0.87-0.92). The sensitivity of MR-proADM was 0.84 (0.78-0.88), specificity was 0.86 (0.79-0.91), and AUC was 0.91 (0.88-0.93). The profile of control group, population, and standard reference may be potential sources of heterogeneity.
CONCLUSIONS
This meta-analysis demonstrated that presepsin and MR-proADM exhibited high accuracy (AUC ≥ 0.90) in the diagnosis of sepsis in adults, with MR-proADM showing significantly higher accuracy than presepsin.
Topics: Adult; Humans; Shock, Septic; Adrenomedullin; Prognosis; Protein Precursors; Sepsis; Biomarkers; Peptide Fragments; Lipopolysaccharide Receptors
PubMed: 37147598
DOI: 10.1186/s12879-023-08262-4 -
International Journal of Surgery... Jun 2023Available evidence shows that the incidence of toxicities associated with cancer immunotherapy, such as programmed cell death 1 (PD-1) and programmed cell death 1 ligand... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Available evidence shows that the incidence of toxicities associated with cancer immunotherapy, such as programmed cell death 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1)-related toxicities, is estimated to be between 0.3 and 1.3%.
OBJECTIVE
This systematic review aimed to investigate cancer patients' susceptibility to toxicities associated with PD-1/PD-L1 inhibitors and establish a clinically relevant landscape of side effects of PD-1/PD-L1 inhibitors.
DATA SOURCES
Relevant publications from PubMed, Embase, Cochrane Library, Web of Science, and China National Knowledge Infrastructure (CNKI) between 2014 and 2019.
STUDY ELIGIBILITY CRITERIA, PARTICIPANTS, AND INTERVENTIONS
We searched randomized controlled trials (RCTs) reporting treatment-related toxicities associated with PD-1 and PD-L1 inhibitors in the treatment of cancers. The primary endpoint was to assess the difference in the incidences of toxicities between cancer patients who did and did not receive PD-1/PD-L1 inhibitors. A total of 29 RCTs, incorporating 8576 patients, met the eligibility criteria.
STUDY APPRAISAL AND SYNTHESIS METHODS
We calculated the pooled relative risks and corresponding 95% CIs using a random-effects model and assessed the heterogeneity between different groups. The subgroup analyses were conducted based on cancer type, toxicity grade (severity), system and organ, treatment regimens in the intervention arm and the control arm, PD-1/PD-L1 inhibitor drug type, and cancer type.
RESULTS
A total of 11 categories (e.g. endocrine toxicity), and 39 toxicity types (e.g. hyperthyroidism) were identified. For toxicities at any grade, those treated with PD-1/PD-L1 inhibitors were at lower risks for gastrointestinal toxicity, hematologic toxicity, and treatment event leading to discontinuation; and were at higher risks for respiratory toxicity (all P <0.05). Those treated with PD-1/PD-L1 inhibitors were at lower risks for fatigue, asthenia, and peripheral edema and were at higher risks for pyrexia, cough, dyspnea, pneumonitis, and pruritus.
LIMITATIONS
The present research is a meta-analysis at the study level rather than at the patient level; insights on risk factors associated with the development of toxicities cannot be found in our study. There was a possible overlap in Common Terminology Criteria for Adverse Events (CTCAE) definitions which prevents understanding the true rates of specific toxicities.
CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS
For most toxicity types based on system and organ, the incidence proportions for patients in the intervention arm were lower than those in the control arm, which suggested the general safety of PD-1/PD-L1 inhibitors against conventional chemotherapy and cytotoxic t-lymphocyte-associated protein 4 (CTLA-4) inhibitors. Future research should focus on taking effective targeted measures to decrease the risks of different toxicities for different patient populations.
SYSTEMATIC REVIEW REGISTRATION NUMBER
We registered the research protocol with PROSPERO (registration number CRD42019135113).
Topics: Humans; Immune Checkpoint Inhibitors; Programmed Cell Death 1 Receptor; Neoplasms; Risk; Incidence
PubMed: 37132038
DOI: 10.1097/JS9.0000000000000368 -
International Journal of Molecular... Mar 2023This systematic review aimed to assess the prognostic significance of programmed cell death-ligand 1 (PDL-1) and programmed cell death protein 1 (PD-1) in hepatocellular... (Meta-Analysis)
Meta-Analysis Review
Navigating through the PD-1/PDL-1 Landscape: A Systematic Review and Meta-Analysis of Clinical Outcomes in Hepatocellular Carcinoma and Their Influence on Immunotherapy and Tumor Microenvironment.
This systematic review aimed to assess the prognostic significance of programmed cell death-ligand 1 (PDL-1) and programmed cell death protein 1 (PD-1) in hepatocellular carcinoma (HCC). Medline, EMBASE, and Cochrane Library database searches were conducted, revealing nine relevant cohort studies (seven PDL-1 and three PD-1). Our meta-analysis showed that PD-1/PDL-1 was a marker of poor survival, regardless of the assessment method (PD-1 overall survival (OS): hazard ratio (HR) 2.40; 95% confidence interval (CI), 1.30-4.42; disease-free survival (DFS): HR 2.12; 95% CI, 1.45-3.10; PDL-1: OS: HR 3.61; 95% CI, 2.75-4.75; and DFS: HR 2.74; 95% CI, 2.09-3.59). Additionally, high level of PD-1/PDL-1 expression was associated with aging, multiple tumors, high alpha-fetoprotein levels, and advanced Barcelona Clinic Liver Cancer stage. This high level significantly predicted a poor prognosis for HCC, suggesting that anti-PD-1 therapy is plausible for patients with HCC. Furthermore, HIF-1 induces PD-1 expression, and PD1SOCS3 is associated with a better prognosis. Taken together, combination therapy may be the key to effective immunotherapy. Thus, exploring other markers, such as HIF-1 and SOCS3, along with PD-1/PDL-1 immunotherapy, may lead to improved outcomes.
Topics: Humans; B7-H1 Antigen; Biomarkers, Tumor; Carcinoma, Hepatocellular; Immunotherapy; Ligands; Liver Neoplasms; Tumor Microenvironment; Programmed Cell Death 1 Receptor
PubMed: 37047482
DOI: 10.3390/ijms24076495 -
Cancer Immunology, Immunotherapy : CII Jul 2023Immune checkpoint inhibitors (ICIs) have dramatically changed the landscape of cancer treatment. However, only a few patients respond to ICI treatment. Thus, uncovering...
BACKGROUND
Immune checkpoint inhibitors (ICIs) have dramatically changed the landscape of cancer treatment. However, only a few patients respond to ICI treatment. Thus, uncovering clinically accessible ICI biomarkers would help identify which patients will respond well to ICI treatment. A comprehensive objective response rate (ORR) data of anti-PD-1/PD-L1 monotherapy in pan-cancer would offer the original data to explore the new biomarkers for ICIs.
METHODS
We systematically searched PubMed, Cochrane, and Embase for clinical trials on July 1, 2021, limited to the years 2017-2021, from which we obtained studies centering around anti-PD-1/PD-L1 monotherapy. Finally, 121 out of 3099 publications and 143 ORR data were included. All of the 31 tumor types/subtypes can be found in the TCGA database. The gene expression profiles and mutation data were downloaded from TCGA. A comprehensive genome-wide screening of ORR highly correlated mutations among 31 cancers was conducted by Pearson correlation analysis based on the TCGA database.
RESULTS
According to the ORR, we classified 31 types of cancer into high, medium, and low response types. Further analysis uncovered that "high response" cancers had more T cell infiltration, more neoantigens, and less M2 macrophage infiltration. A panel of 28 biomarkers reviewed from recent articles were investigated with ORR. We also found the TMB as a traditional biomarker had a high correlation coefficient with ORR in pan-cancer, however, the correlation between ITH and ORR was low across pan-cancer. Moreover, we primarily identified 1044 ORR highly correlated mutations through a comprehensive screening of TCGA data, among which USH2A, ZFHX4 and PLCO mutations were found to be highly correlated to strengthened tumor immunogenicity and inflamed antitumor immunity, as well as improved outcomes for ICIs treatment among multiple immunotherapy cohorts.
CONCLUSION
Our study provides comprehensive data on ORR of anti-PD-1/PD-L1 monotherapy across 31 tumor types/subtypes and an essential reference of ORR to explore new biomarkers. We also screened out a list of 1044 immune response related genes and we showed that USH2A, ZFHX4 and PLCO mutations may act as good biomarkers for predicting patient response to anti-PD-1/PD-L1 ICIs.
Topics: Humans; B7-H1 Antigen; Biomarkers, Tumor; Neoplasms; Antigens, Neoplasm; Programmed Cell Death 1 Receptor
PubMed: 37022474
DOI: 10.1007/s00262-023-03441-3