Peripheral blood CD45RO+T cells is a predictor of the effectiveness of neoadjuvant chemoradiotherapy in locally advanced rectal cancer

To investigate the relationship between the changes in circulating CD45RO⁺T lymphocyte subsets following neoadjuvant therapy for rectal cancer in patients with locally advanced rectal cancer.The clinicopathological data of 185 patients with rectal cancer who received neoadjuvant therapy in the General Surgery Department of Beijing Chaoyang Hospital affiliated to Capital Medical University from June 2015 to June 2017 were analyzed. Venous blood samples were collected 1 week before neoadjuvant therapy and 1 week before surgery, and the expression of CD45RO⁺T was detected by flow cytometry. The receiver operating characteristic curve analysis was used to determine the optimal cut-off point of CD45RO⁺ratio. Log-rank test and multivariate Cox regression were used to analyze the overall survival rate (OS) and disease-free survival rate (DFS) associated with CD45RO⁺ratio.Circulating CD45RO⁺ratio of 1.07 was determined as the optimal cut-off point and CD45RO⁺ratio-high was associated with lower tumor regression grade grading (P = .031), T stage (P = .001), and tumor node metastasis (TNM) stage (P = .012). The 3-year DFS and OS rate in the CD45RO⁺ratio-high group was significantly higher than that in the CD45RO⁺ratio-low group (89.2% vs 60.1%, P<.001; 94.4% vs 73.2%, P<.001). The multivariate Cox analysis revealed that elevated CD45RO⁺ratio was an independent factor for better DFS (OR, 0.339; 95% CI, 0.153–0.752; P = .008) and OS (OR, 0.244; 95% CI,0.082–0.726; P = .011).Circulating CD45RO⁺ratio could predict the tumor regression grade of neoadjuvant therapy for rectal cancer, as well as long-term prognosis. These findings could be used to stratify patients and develop alternative strategies for adjuvant therapy.     

Usefulness of 123I-BMIPP and 201TlCl nuclide scintigraphy in evaluation of myocarditis in patients with polymyositis or dermatomyositis

To investigate the usefulness of ¹²³I-BMIPP/²⁰¹TlCl scintigraphy for evaluating the presence of myocarditis in patients with polymyositis (PM) or dermatomyositis (DM).We performed a retrospective study of 26 patients diagnosed with new-onset active PM/DM who underwent ¹²³I-BMIPP/²⁰¹TlCl scintigraphy between 01 April 2010 and 20 March 2015. We determined the ¹²³I-BMIPP/²⁰¹TlCl ratio and grouped the patients according to presence or absence of a mismatch. We evaluated the relationship between mismatch and the laboratory and echocardiographic findings.Mismatch was found in 13 (50%) patients. There was no statistically significant difference in age, cardiac troponin T, myoglobin, myosin light chain, aldolase levels, E wave/A wave ratio, right ventricular systolic pressure between the mismatch and non-mismatch groups. Left ventricular end-diastolic and end-systolic dimensions were significantly greater in the mismatch group (45.0 vs 42.5 mm, P =  < .01 and 29.5 mm vs 25.0 mm, P < .01). Left ventricular ejection fraction was significantly lower in the mismatch group (63.5% vs 71.5%, P = .04). Significant inverse correlation (r = −0.44, P = .03) was observed between left ventricular ejection fraction and mismatch ratio.The use of ¹²³I-BMIPP/ ²⁰¹TlCl scintigraphy may be considered for evaluating myocarditis in patients with PM/DM.     

Increased density of tolerogenic dendritic cells in the small bowel mucosa of celiac patients

AIM: To investigate the densities of dendritic cells(DCs) and FOXP3+ regulatory T cells(Tregs) and their interrelations in the small bowel mucosa in untreated celiac disease(CD) patients with and without type 1 diabetes(T1D).METHODS: Seventy-four patients(45 female, 29 male, mean age 11.1 ± 6.8 years) who underwent small bowel biopsy were studied. CD without T1 D was diagnosed in 18 patients, and CD with T1 D was diagnosed in 15 patients. Normal small bowel mucosa was found in two T1 D patients. Thirty-nine patients(mean age 12.8 ± 4.9 years) with other diagnoses(functional dyspepsia, duodenal ulcer, erosive gastritis, etc.) formed the control group. All CD patients had partial or subtotal villous atrophy according to the Marsh classification: Marsh grade Ⅲa in 9, grade Ⅲb in 21 and grade Ⅲc in 3 cases. Thirty-nine patients without CD and 2 with T1 D had normal small bowel mucosa(Marsh grade 0). The densities of CD11c+, IDO+, CD103+, Langerin(CD207+) DCs and FOXP3+ Tregs were investigated by immunohistochemistry(on paraffin-embedded specimens) and immunofluorescence(on cryostat sections) methods using a combination of mono- and double-staining. Sixtysixserum samples were tested for Ig A-tissue transglutaminase(t TG) using a fully automated Eli ATM Celikey Ig A assay(Pharmacia Diagnostics, Freiburg, Germany). RESULTS: The density of CD11c+ DCs was significantly increased in CD patients compared with patients with normal mucosa(21.67 ± 2.49 vs 13.58 ± 1.51, P = 0.007). The numbers of FOXP3+ cells were significantly higher in CD patients(10.66 ± 1.50 vs 1.92 ± 0.37, P = 0.0002) and in patients with CD and coexisting T1D(8.11 ± 1.64 vs 1.92 ± 0.37, P = 0.002) compared with patients with normal mucosa. The density of FOXP3+ cells significantly correlated with the histologicalgrade of atrophic changes in the small bowel mucosa according to the March classification(r = 0.62; P 0.0001) and with levels of Ig A antibody(r = 0.55; P 0.0001). The densities of IDO+ DCs were significantly higher in CD patients(21.6 ± 2.67 vs 6.26 ± 0.84, P = 0.00003) and in patients with CD and coexisting T1D(19.08 ± 3.61 vs 6.26 ± 0.84, P = 0.004) compared with patients with normal mucosa. A significant correlation was identified between the densities of IDO+ DCs and FOXP3+ T cells(r = 0.76; P = 0.0001). The mean values of CD103+ DCs were significantly higher in CD patients(10.66 ± 1.53 vs 6.34 ± 0.61, P = 0.01) and in patients with CD and associated T1D(11.13 ± 0.72 vs 6.34 ± 0.61, P = 0.00002) compared with subjects with normal small bowel mucosa. The mean value of Langerin+ DCs was higher in CD patients compared with persons with normal mucosa(7.4 ± 0.92 vs 5.64 ± 0.46, P = 0.04).CONCLUSION: The participation of diverse DC subsets in the pathological processes of CD and the possible involvement of tolerogenic DCs in Tregs development to maintain intestinal immunological tolerance in CD patients are revealed.     

Changes in bone marrow and peripheral blood lymphocyte subset findings with onset of hepatitis-associated aplastic anemia

Rationale:Hepatitis-associated aplastic anemia (HAAA) is a rare illness that results in bone marrow failure following hepatitis development. The etiological agent remains unknown in most HAAA cases. However, clinical features of the disease and immunotherapy response indicate that immune-mediated factors play a central role in the pathogenesis of HAAA. Activation of cytotoxic T cells and increase in CD8 cells could exert cytotoxic effects on the myelopoietic cells in the bone marrow.Patient concerns:A 15-month-old boy was brought to our hospital with complaints of generalized petechiae and purpura observed a week prior to hospitalization. His liver was palpated 3 cm below the costal margin, platelet count was 0 × 10⁴/μL, and alanine aminotransferase level was 1346 IU/L. A blood test indicated cytomegalovirus infection, and 3 bone marrow examinations revealed progressive HAAA. As the disease progressed to the 3^rd, 6^th, and 9^th week after onset, CD4⁺ T cells were markedly decreased, CD8⁺ T cells were markedly increased, and the CD4/CD8 ratio was significantly decreased. The number of B cells and natural killer cells decreased with time, eventually reaching 0.0%.Diagnosis:HAAA.Interventions:Rabbit antithymocyte globulin and eltrombopag olamine (a thrombopoietin receptor agonist) were administered.Outcomes:The patient''s platelet count returned to normal, and bone marrow transplantation was avoided. The peripheral blood lymphocytes (PBLs) improved as the patient''s general condition recovered.Lessons:This case demonstrates that HAAA induced by cytomegalovirus infection features decreasing CD4⁺ and increasing CD8⁺ PBLs as the bone marrow hypoplasia progresses. The PBLs return to their normal levels with the recovery from the disease. Our case findings thus support the involvement of immunological abnormality in HAAA.     

A retrospective study of enteral nutrition on immune and inflammatory factors after liver cancer surgery

This retrospective study aimed to explore the effect of enteral nutrition (EN) on immune and inflammatory factors after liver cancer surgery (LCS).It was retrospectively conducted on enrolled LCS patients between January 2017 and May 2020. The medical records of 528 patient case records were collected and reviewed. After selection, a total of 80 eligible patient case records were finally included. All those patients received routine diet, and they were allocated to a treatment group (n = 40) and a control group (n = 40). In addition, patients in the treatment group also received EN. The primary outcomes were immune factors (CD4⁺, CD8⁺, CD4⁺/CD8⁺) and inflammatory factors (interleukin-1, interleukin-6, and tumor necrosis factor-α). The secondary outcomes were postoperative hospital stay (day), time to first bowel sounds (hour), time to first flatus (day), time to first defecation (day), and complications.There were not significant differences in CD4⁺/CD8⁺ (P = .34), postoperative hospital stay (P = .39), and time to first bowel sounds (P = .17) between 2 groups. However, there were significant differences in CD4⁺ (P < .01), CD8⁺ (P < .01), interleukin-1 (P < .01), interleukin-6 (P < .01), tumor necrosis factor-α (P < .01), time to first flatus (P < .01), and time to first defecation (P < .01) between 2 groups. As for complications, there were not significant differences between 2 groups (P > .05).The results of this study found that EN may benefit for patients after LCS during the recovery period. Future high quality prospective studies are needed to warrant the present conclusion.     

A retrospective study of ulinastatin for the treatment of severe sepsis

This retrospective study aimed to investigate the efficacy and safety of existing approach of ulinastatin for the treatment of severe sepsis (SS).A total of 130 eligible patients with SS were included in this study. We divided them into an intervention group (n = 65) and a control group (n = 65). Patients in both groups received conventional therapy. In addition, patients in the intervention group received ulinastatin for 7 days. Outcomes were measured by Acute Physiology and Chronic Health Evaluation II (APACHE II), Multiple Organ Failure (MOF), Glasgow Coma Scale (GCS), CD3⁺, CD4⁺, CD8⁺, CD4⁺/CD8⁺, and adverse events. We assessed all outcomes before and after treatment.After treatment, patients in the intervention group showed better improvement in APACHE II (P < .01), MOF (P < .01), GCS (P < .01), CD3⁺ (P = .03), CD4⁺ (P = .03), and CD4⁺/CD8⁺ (P < .01), than those of patients in the control group. There are similar safety profiles between both groups.This study suggests that ulinastatin may be beneficial for SS. Future studies are still needed to warrant the results of this study.     

Early plasmacytoid dendritic cell leukemia/lymphoma coexpressing myeloid antigenes

Early plasmacytoid dendritic cell (pDC) leukemia/lymphoma has recently been described as a CD4⁺CD56⁺ lineage negative malignancy with characteristic clinical, morphologic, immunophenotypic, and biological features. We present a case of a 72-year-old man who was diagnosed with isolated skin involvement 30 months ago and received numerous chemotherapy cycles that did not prevent three relapses of the disease, the last two involving the bone marrow. The bone marrow was nearly completely infiltrated with small- to medium-sized blasts displaying a high nuclear to cytoplasmic ratio, a cytoplasm with faint basophilia lacking granulations or Auer rods. Small vacuoles surrounding the nucleus were frequently observed. Flow cytometry showed CD4⁺, CD56⁺, CD45⁺, CD38⁺, HLA-DR⁺, CD33⁺, CD123⁺, CD2^–, cyCD3^–, CD7^–, CD10^–, CD11b^–, CD13^–, CD14^–, CD16^–, CD19^–, cyCD22^–, CD24^–, CD34^–, CD57^–, CD61^–, CD64^–, CD65^–, cyCD79a^–, CD117^–, MPO^–, and TdT^– population. At the second bone marrow relapse, CD117 was also positive. Our patient was initially treated with acute myeloid leukemia-type chemotherapy, later he was given acute lymphoblastic leukemia-type treatment, and at the last relapse he received CHOP chemotherapy. Each treatment led to rapid response of tumor manifestations with disease-free intervals of 7 months, 9 months, and 8 months, respectively. Although patients usually have an ominous prognosis, with only 25% living more than 24 months, our patient is alive after 30+ months and has again achieved complete remission after the last chemotherapy.     

High-dimensional mass cytometry analysis of NK cell alterations in AML identifies a subgroup with adverse clinical outcome

Natural killer (NK) cells are major antileukemic immune effectors. Leukemic blasts have a negative impact on NK cell function and promote the emergence of phenotypically and functionally impaired NK cells. In the current work, we highlight an accumulation of CD56⁻CD16⁺ unconventional NK cells in acute myeloid leukemia (AML), an aberrant subset initially described as being elevated in patients chronically infected with HIV-1. Deep phenotyping of NK cells was performed using peripheral blood from patients with newly diagnosed AML (n = 48, HEMATOBIO cohort, {"type":"clinical-trial","attrs":{"text":"NCT02320656","term_id":"NCT02320656"}}NCT02320656) and healthy subjects (n = 18) by mass cytometry. We showed evidence of a moderate to drastic accumulation of CD56⁻CD16⁺ unconventional NK cells in 27% of patients. These NK cells displayed decreased expression of NKG2A as well as the triggering receptors NKp30 and NKp46, in line with previous observations in HIV-infected patients. High-dimensional characterization of these NK cells highlighted a decreased expression of three additional major triggering receptors required for NK cell activation, NKG2D, DNAM-1, and CD96. A high proportion of CD56⁻CD16⁺ NK cells at diagnosis was associated with an adverse clinical outcome and decreased overall survival (HR = 0.13; P = 0.0002) and event-free survival (HR = 0.33; P = 0.018) and retained statistical significance in multivariate analysis. Pseudotime analysis of the NK cell compartment highlighted a disruption of the maturation process, with a bifurcation from conventional NK cells toward CD56⁻CD16⁺ NK cells. Overall, our data suggest that the accumulation of CD56⁻CD16⁺ NK cells may be the consequence of immune escape from innate immunity during AML progression.

Natural killer (NK) cells are critical cytotoxic effectors involved in leukemic blast recognition, tumor cell clearance, and maintenance of long-term remission (1). NK cells directly kill target cells without prior sensitization, enabling lysis of cells stressed by viral infections or tumor transformation. NK cells are divided into different functional subsets according to CD56 and CD16 expression (2–4). CD56^bright NK cells are the most immature NK cells found in peripheral blood. This subset is less cytotoxic than mature NK cells and secretes high amounts of chemokines and cytokines such as IFNγ and TNFα. These cytokines have a major effect on the infected or tumor target cells and play a critical role in orchestration of the adaptive immune response through dendritic cell activation. CD56^dimCD16⁺ NK cells, which account for the majority of circulating human NK cells, are the most cytotoxic NK cells. NK cell activation is finely tuned by integration of signals from inhibitory and triggering receptors, in particular, those of NKp30, NKp46 and NKp44, DNAM-1, and NKG2D (5). Upon target recognition, CD56^dimCD16⁺ NK cells release perforin and granzyme granules and mediate antibody-dependent cellular cytotoxicity through CD16 (FcɣRIII) to clear transformed cells.NK cells are a major component of the antileukemic immune response, and NK cell alterations have been associated with adverse clinical outcomes in acute myeloid leukemia (AML) (6–9). Therefore, it is crucial to better characterize AML-induced NK cell alterations in order to optimize NK cell–targeted therapies. During AML progression, NK cell functions are deeply altered, with decreased expression of NK cell–triggering receptors and reduced cytotoxic functions as well as impaired NK cell maturation (6, 9–13). Cancer-induced NK cell impairment occurs through various mechanisms of immune escape, including shedding and release of ligands for NK cell–triggering receptors; release of immunosuppressive soluble factors such as TGFβ, adenosine, PGE2, or L-kynurenine; and interference with NK cell development, among others (14).Interestingly, these mechanisms of immune evasion are also seen to some extent in chronic viral infections, notably HIV (2). In patients with HIV, NK cell functional anergy is mediated by the release of inflammatory cytokines and TGFβ, the presence of MHC^low target cells, and the shedding of ligands for NK cell–triggering receptors (2). As a consequence, some phenotypical alterations described in cancer patients are also induced by chronic HIV infections, with decreased expression of major triggering receptors such as NKp30, NKp46, and NKp44 (15, 16); decreased expression of CD16 (17); and increased expression of inhibitory receptors such as T cell immunoreceptor with Ig and ITIM domains (TIGIT) (18) all observed. In addition, patients with HIV display an accumulation of CD56⁻CD16⁺ unconventional NK cells, a highly dysfunctional NK cell subset (19, 20). Mechanisms leading to the loss of CD56 are still poorly described, and the origin of this subset of CD56⁻ NK cells is still unknown. To date, two hypotheses have been considered: CD56⁻ NK cells could be terminally differentiated cells arising from a mixed population of mature NK cells with altered characteristics or could expand from a pool of immature precursor NK cells (21). Expansion of CD56⁻CD16⁺ NK cells is mainly observed in viral noncontrollers (19, 20). Indeed, CD56 is an important adhesion molecule involved in NK cell development, motility, and pathogen recognition (22–27). CD56 is also required for the formation of the immunological synapse between NK cells and target cells, lytic functions, and cytokine production (26, 28). As a consequence, CD56⁻CD16⁺ NK cells display lower degranulation capacities and decreased expression of triggering receptors, perforin, and granzyme B, dramatically reducing their cytotoxic potential, notably against tumor target cells (2, 19, 20, 29, 30). In line with this loss of the cytotoxic functions against tumor cells, patients with concomitant Burkitt lymphoma and Epstein-Barr virus infection display a dramatic increase of CD56⁻CD16⁺ NK cells (30), which could represent an important hallmark of escape to NK cell immunosurveillance in virus-driven hematological malignancies.To our knowledge, this population has not been characterized in the context of nonvirally induced hematological malignancies. In the present work, we investigated the presence of this population of unconventional NK cells in patients with AML, its phenotypical characteristics, and the consequences of its accumulation on disease control. Finally, we explored NK cell developmental trajectories leading to the emergence of this phenotype.     

Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features

Some breast cancers have been shown to contain a small fraction of cells characterized by CD44⁺/CD24^−/low cell-surface antigen profile that have high tumor-initiating potential. In addition, breast cancer cells propagated in vitro as mammospheres (MSs) have also been shown to be enriched for cells capable of self-renewal. In this study, we have defined a gene expression signature common to both CD44⁺/CD24^−/low and MS-forming cells. To examine its clinical significance, we determined whether tumor cells surviving after conventional treatments were enriched for cells bearing this CD44⁺/CD24^−/low-MS signature. The CD44⁺/CD24^−/low-MS signature was found mainly in human breast tumors of the recently identified “claudin-low” molecular subtype, which is characterized by expression of many epithelial-mesenchymal-transition (EMT)-associated genes. Both CD44⁺/CD24^−/low-MS and claudin-low signatures were more pronounced in tumor tissue remaining after either endocrine therapy (letrozole) or chemotherapy (docetaxel), consistent with the selective survival of tumor-initiating cells posttreatment. We confirmed an increased expression of mesenchymal markers, including vimentin (VIM) in cytokeratin-positive epithelial cells metalloproteinase 2 (MMP2), in two separate sets of postletrozole vs. pretreatment specimens. Taken together, these data provide supporting evidence that the residual breast tumor cell populations surviving after conventional treatment may be enriched for subpopulations of cells with both tumor-initiating and mesenchymal features. Targeting proteins involved in EMT may provide a therapeutic strategy for eliminating surviving cells to prevent recurrence and improve long-term survival in breast cancer patients.     

Platelet to Lymphocyte Percentage Ratio Is Associated With Brachial–Ankle Pulse Wave Velocity in Hemodialysis

Increased arterial stiffness in patients receiving hemodialysis (HD) is highly prevalent and is associated with cardiovascular morbidity and mortality. In HD, inflammation is one of the major causes of increased arterial stiffness. Activation of platelets and decreased lymphocyte percentage (LYMPH%) may exhibit inflammation. The aim of this study is to examine the relationship between platelet to LYMPH% ratio and arterial stiffness in HD patients.A total of 220 patients receiving HD were enrolled in this study. The brachial–ankle pulse wave velocity (baPWV) was measured using an ankle–brachial index form device. Multivariate linear regression analysis was performed to investigate the relations of the platelet to LYMPH% ratio and baPWV.The value of the platelet to LYMPH% ratio was 59.2 ± 33.3 (10⁹ cells/L/%). After multivariate stepwise analysis, diabetes (β: 163.973, P = 0.02), high systolic blood pressure (per 1 mm Hg, β: 9.010, P < 0.001), high platelet to LYMPH% ratio (per 10⁹ cells/L/%, β: 3.334, P < 0.01), and low albumin (per 0.1 mg/dL, β: −55.912, P < 0.001) were independently associated with an increased baPWV. Furthermore, high white blood cells (per 10⁹ cells/L, β: 3.941, P < 0.001), high neutrophil percentage (per 1%, β: 1.144, P < 0.001), and high CRP (per 1 mg/L, β: 9.161, P = 0.03) were independently associated with an increased platelet to LYMPH% ratio.An increased platelet to LYMPH% ratio is associated with an increased baPWV in HD patients. An easy and inexpensive laboratory measure of platelet to LYMPH% ratio may provide an important information regarding arterial stiffness in patients with HD.     

Immediate Postoperative Low Platelet Counts After Living Donor Liver Transplantation Predict Early Allograft Dysfunction

To investigate whether the platelets can improve liver function by mediating liver regeneration. Using a retrospective cohort with 234 consecutive adult-to-adult living donor liver transplantation recipients, we have discussed the relationship between immediate postoperative platelet count and outcome. Patients have been stratified into Low Platelet Group (106 patients) with platelet ≤68 × 10⁹/L and High Platelet Group (128 patients) with platelet >68 × 10⁹/L.Low Platelet Group has a higher rate of preoperative thrombocytopenia (90.6% vs. 32.8%, P < 0.001), higher model for end-stage liver disease score (15 vs. 11, P < 0.001), cirrhosis (86.8% vs. 76.6%, P = 0.046), hepatorenal syndrome (18.2% vs. 4.0%, P = 0.005) and fulminant hepatic failure (26.4% vs. 7.8%, P < 0.001). The packed red blood cells transfusion (7.5 vs. 5, P = 0.023) and plasma transfusion (1275 mL vs. 800 mL, P = 0.001) are more in patients with low platelet count. Low Platelet Group has a higher early allograft dysfunction (EAD) (22.6% vs. 7.0%, P = 0.001) and severe complications (22.6% vs. 10.9%, P = 0.016). The 90-day mortality between the 2 groups is similar. The multivariate analysis has found that postoperative platelet ≤68 × 10⁹/L is an independent risk factor for EAD.Platelet maybe influences the functional status of the liver by promoting graft regeneration after liver transplantation.     

Cholinergic drugs inhibit in vitro megakaryopoiesis via the alpha7-nicotinic acetylcholine receptor

Besides thrombopoietin several additional factors (i.e neurotransmitters and receptors) are known to be involved in the regulation of megakaryopoiesis at different stages. Recently, we identified functional α7 nicotinic acetylcholine receptors (nAChRα7) on platelets and megakaryocytic precursors. In platelets nAChRα7 form functional Ca²⁺ channels and are involved in fibrinogen receptor activation and aggregation. Here, we investigated the impact of nAChRα7 on the differentiation of the human megakaryoblastic cell line MEG-01. In vitro differentiation of MEG-01 cells was induced by the phorbol ester TPA for 5 days in the absence or presence of nicotine or the nAChRα7-selective antagonist methyllycaconitine (MLA), and this was monitored by the expression of the megakaryocytic antigens CD41 and CD61. In the presence of the cholinergic drugs (nicotine or MLA) CD41 and CD61 expression was significantly reduced, both at RNA and protein level. We postulate that the nAChRα7 receptor is involved in megakaryopoietic signal transduction and gene regulation. This could affect the generation of platelets in vivo and contribute to the development of novel therapeutic drugs that regulate platelet formation.     

High levels of CD34+CD38low/-CD123+ blasts are predictive of an adverse outcome in acute myeloid leukemia: a Groupe Ouest-Est des Leucemies Aigues et Maladies du Sang (GOELAMS) study

Background

Acute myeloid leukemias arise from a rare population of leukemic cells, known as leukemic stem cells, which initiate the disease and contribute to frequent relapses. Although the phenotype of these cells remains unclear in most patients, these cells are enriched within the CD34⁺CD38^low/− compartment expressing the interleukin-3 alpha chain receptor, CD123. The aim of this study was to determine the prognostic value of the percentage of blasts with the CD34⁺CD38^low/−CD123⁺ phenotype.

Design and Methods

The percentage of CD34⁺CD38^low/−CD123⁺ cells in the blast population was determined at diagnosis using flow cytometry. One hundred and eleven patients under 65 years of age with de novo acute myeloid leukemia and treated with intensive chemotherapy were retrospectively included in the study. Correlations with complete response, disease-free survival and overall survival were evaluated with univariate and multivariate analyses.

Results

A proportion of CD34⁺CD38^low/−CD123⁺ cells greater than 15% at diagnosis and an unfavorable karyotype were significantly correlated with a lack of complete response. By logistic regression analysis, a percentage of CD34⁺CD38^low/−CD123⁺ higher than 15% retained significance with an odds ratio of 0.33 (0.1–0.97; P=0.044). A greater than 1% population of CD34⁺CD38^low/−CD123⁺ cells negatively affected disease-free survival (0.9 versus 4.7 years; P<0.0001) and overall survival (1.25 years versus median not reached; P<0.0001). A greater than 1% population of CD34⁺CD38^low/−CD123⁺ cells retained prognostic significance for both parameters after multivariate analysis.

Conclusions

The percentage of CD34⁺CD38^low/−CD123⁺ leukemic cells at diagnosis was significantly correlated with response to treatment and survival. This prognostic marker might be easily adopted in clinical practice to rapidly identify patients at risk of treatment failure.     

The incidence and prognostic effect of Fms-like tyrosine kinase 3 gene internal tandem and nucleolar phosphoprotein 1 genes in acute myeloid leukaemia: A PRISMA-compliant systematic review and meta-analysis

Background:Molecular genotyping is an important prognostic role in acute myeloid leukemia (AML) patients. We aimed to design this meta-analysis to discuss the incidence and prognostic effect of nucleolar phosphoprotein 1 (NPM1) and Fms-like tyrosine kinase 3 gene internal tandem (FLT3-ITD) gene in AML patients.Methods:PubMed, Embase, Medline, and Cochrane library were systematically searched due to May 15, 2020. Four combinations of genotypes (FLT3-ITD^neg/NPM1^mut, FLT3-ITD^pos/NPM1^mut, FLT3-ITD^neg/NPM1^wt, FLT3-ITD^pos/NPM1^wt) were compared in association with the overall survival (OS) and leukemia-free survival (LFS) outcome, which expressed as pooled hazard ratio (HR) and 95% confidence intervals (CIs).Results:Twenty-eight studies were included in our study. The incidence of FLT3-ITD^neg/NPM1^mut, FLT3-ITD^pos/NPM1^mut, FLT3-ITD^neg/NPM1^wt, and FLT3-ITD^pos/NPM1^wt was 16%, 13%, 50%, and 10%, respectively. The patients with FLT3-ITD^neg/NPM1^mut gene may have the best OS and LFS when comparing with FLT3-ITD^pos/NPM1^mut (HR = 1.94 and 1.70, P < .01), FLT3-ITD^neg/NPM1^wt (HR = 1.57 and 2.09, P < .01), and FLT3-ITD^pos/NPM1^wt (HR = 2.25 and 2.84, P < .001).Conclusion:AML patients with FLT3-ITD^neg/NPM1^mut gene type have the best survival outcome than the other 3 gene types, which should be an independent genotyping in AML classification.     

Impact of constitutional polymorphisms in VCAM1 and CD44 on CD34+ cell collection yield after administration of granulocyte colony-stimulating factor to healthy donors

Background

The number of CD34⁺ cells mobilized from bone marrow to peripheral blood after administration of granulocyte colony-stimulating factor varies greatly among healthy donors. This fact might be explained, at least in part, by constitutional differences in genes involved in the interactions tethering CD34⁺ cells to the bone marrow.

Design and Methods

We analyzed genetic characteristics associated with CD34⁺ cell mobilization in 112 healthy individuals receiving granulocyte colony-stimulating factor (filgrastim; 10 μg/kg; 5 days).

Results

Genetic variants in VCAM1 and in CD44 were associated with the number of CD34⁺ cells in peripheral blood after granulocyte colony-stimulating factor administration (P=0.02 and P=0.04, respectively), with the quantity of CD34⁺ cells ×10⁶/kg of donor (4.6 versus 6.3; P<0.001 and 7 versus 5.6; P=0.025, respectively), and with total CD34⁺ cells ×10⁶ (355 versus 495; P=0.002 and 522 versus 422; P=0.012, respectively) in the first apheresis. Of note, granulocyte colony-stimulating factor administration was associated with complete disappearance of VCAM1 mRNA expression in peripheral blood. Moreover, genetic variants in granulocyte colony-stimulating factor receptor (CSF3R) and in CXCL12 were associated with a lower and higher number of granulocyte colony-stimulating factor-mobilized CD34⁺ cells/μL in peripheral blood (81 versus 106; P=0.002 and 165 versus 98; P=0.02, respectively) and a genetic variant in CXCR4 was associated with a lower quantity of CD34⁺ cells ×10⁶/kg of donor and total CD34⁺ cells ×10⁶ (5.3 versus 6.7; P=0.02 and 399 versus 533; P=0.01, respectively).

Conclusions

In conclusion, genetic variability in molecules involved in migration and homing of CD34⁺ cells influences the degree of mobilization of these cells.     

Rudimentary signs of immunosenescence in Cytomegalovirus-seropositive healthy young adults

Ageing is associated with a decline in immune competence termed immunosenescence. In the elderly, this process results in an accumulation of differentiated ‘effector’ phenotype memory T cells, predominantly driven by Cytomegalovirus (CMV) infection. Here, we asked whether CMV also drives immunity towards a senescent profile in healthy young adults. One hundred and fifty-eight individuals (mean ± SD; age 21 ± 3 years, body mass index 22.7 ± 2.7 kg m²) were assessed for CMV serostatus, the numbers/proportions of CD4⁺ and CD8⁺ late differentiated/effector memory cells (i.e. CD27⁻CD28⁻/CD45RA⁺), plasma interleukin-6 (IL-6) and antibody responses to an in vivo antigen challenge (half-dose influenza vaccine). Thirty percent (48/158) of participants were CMV⁺. A higher lymphocyte and CD8⁺ count (both p < 0.01) and a lower CD4/CD8 ratio (p < 0.03) were observed in CMV⁺ people. Eight percent (4/58) of CMV⁺ individuals exhibited a CD4/CD8 ratio <1.0, whereas no CMV⁻ donor showed an inverted ratio (p < 0.001). The numbers of CD4⁺ and CD8⁺CD27⁻CD28⁻/CD45RA⁺ cells were ~ fourfold higher in CMV⁺ people (p < 0.001). Plasma IL-6 was higher in CMV⁺ donors (p < 0.05) and showed a positive association with the numbers of CD8⁺CD28⁻ cells (p < 0.03). Finally, there was a significant negative correlation between vaccine-induced antibody responses to the A/Brisbane influenza strain and CMV-specific immunoglobulin G titres (p < 0.05). This reduced vaccination response was associated with greater numbers of total CD8⁺ and CD4⁺ and CD8⁺CD27⁻CD28⁻/CD45RA⁺ cells (p < 0.05). This study observed marked changes in the immune profile of young adults infected with CMV, suggesting that this virus may underlie rudimentary aspects of immunosenescence even in a chronologically young population.     

Enhanced SARS-CoV-2-Specific CD4+ T Cell Activation and Multifunctionality in Late Convalescent COVID-19 Individuals

Background: Examination of CD4⁺ T cell responses during the natural course of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection offers useful information for the improvement of vaccination strategies against this virus and the protective effect of these T cells. Methods: We characterized the SARS-CoV-2-specific CD4⁺ T cell activation marker, multifunctional cytokine and cytotoxic marker expression in recovered coronavirus disease 2019 (COVID-19) individuals. Results: CD4⁺ T-cell responses in late convalescent (>6 months of diagnosis) individuals are characterized by elevated frequencies of activated as well as mono, dual- and multi-functional Th1 and Th17 CD4⁺ T cells in comparison to early convalescent (<1 month of diagnosis) individuals following stimulation with SARS-CoV-2-specific antigens. Similarly, the frequencies of cytotoxic marker expressing CD4⁺ T cells were also enhanced in late convalescent compared to early convalescent individuals. Conclusion: Our findings from a low-to middle-income country suggest protective adaptive immune responses following natural infection of SARS-CoV-2 are elevated even at six months following initial symptoms, indicating the CD4⁺ T cell mediated immune protection lasts for six months or more in natural infection.     

Effects of hemodialysis and reduced estimated glomerular filtration rate in nonhemodialysis on clinical outcomes after fractional flow reserve-guided deferral of revascularization

The effect of renal dysfunction on clinical outcomes following fractional flow reserve (FFR)-guided deferral of revascularization remains unelucidated.We retrospectively analyzed 224 patients with atherosclerotic coronary lesions who underwent deferred revascularization based on an FFR of >0.80. The median follow-up interval was 28.1 months. Patients were divided into 2 groups: the hemodialysis (HD) and the non-HD group. The non-HD group was further classified into 2 subgroups according to their estimated glomerular filtration rate (eGFR) level: eGFR <45, equivalent to chronic kidney disease stage 3b-5 and eGFR ≥45. We evaluated major adverse cardiac events (MACE), defined as a composite of cardiac death, myocardial infarction, and any revascularization.MACE occurred in 36 patients (16.1%). The rate of HD was significantly higher in the MACE group (19% vs 6%, P < .01). In non-HD patients, the eGFR was significantly lower in the MACE group (51.2 vs 63.2 mL/min/1.73 m², P < .01). Overall, univariate Cox regression analysis revealed a significant relationship between HD and MACE (HR 2.91, P = .01), as did the multivariate model (HR 2.90, P = .01). Of the MACE, more deaths occurred in HD patients (15.8% vs 2.9%, P = .03). Among non-HD patients, eGFR <45 (HR 2.70, P = .02), FFR (per 0.01, HR 0.87, P < .01), and low-density lipoprotein cholesterol (per 10 mg/dL, HR 1.17, P = .02) were independent predictors of MACE. Any revascularization was more common in patients with eGFR<45 than in those with eGFR ≥45 (21.4% vs 7.3%, P = .02). Kaplan–Meier estimates revealed that the HD group showed a significantly lower MACE-free survival rate than the nonHD group (log-rank P < .01). In non-HD patients, the eGFR<45 group showed a lower MACE-free survival rate than the eGFR ≥45 group (log-rank P = .01).HD and reduced eGFR in non-HD patients were associated with adverse cardiac events after FFR-guided deferral of revascularization.