Pharmacoeconomic impact of up-front use of plerixafor for autologous stem cell mobilization in patients with multiple myeloma

Background aimsStem cell collection can be a major component of overall cost of autologous stem cell transplantation (ASCT). Plerixafor is an effective agent for mobilization; however, it is often reserved for salvage therapy because of its high cost. We present data on the pharmacoeconomic impact of the use of plerixafor as an up-front mobilization in patients with multiple myeloma (MM).MethodsPatients with MM who underwent ASCT between January 2008 and April 2011 at the Mount Sinai Medical Center were reviewed retrospectively. In April 2010, practice changes were instituted for patients with MM to delay initiation of granulocyte-colony-stimulating factor (G-CSF) support from day 0 to day +5 and to add plerixafor to G-CSF as an up-front autologous mobilization. Targets of collection were 5–10 × 10⁶ CD34⁺ cells/kg.ResultsOf 50 adults with MM who underwent ASCT, 25 received plerixafor/filgrastim and 25 received G-CSF alone as an up-front mobilization. Compared with the control, plerixafor mobilization yielded higher CD34⁺ cell content (16.1 versus 8.4 × 10⁶ CD34⁺ cells/kg; P = 0.0007) and required fewer sessions of apheresis (1.9 versus 3.1; P = 0.0001). In the plerixafor group, the mean number of plerixafor doses required per patient was 1.8. Although the overall cost of medications was higher in the plerixafor group, the cost for blood products and overall cost of hospitalization were similar between the two groups.ConclusionsUp-front use of plerixafor is an effective mobilization strategy in patients with MM and does not have a substantial pharmacoeconomic impact in overall cost of hospitalization combined with the apheresis procedure.     

Efficacy of cascade-primed cell infusion as an adjuvant immunotherapy with concurrent chemotherapy for patients with non–small-cell lung cancer: A retrospective observational study with a 5-year follow-up

BackgroundClinical studies have shown the efficacy of combination therapy for various malignancies. In this study, the characteristics, safety and feasibility of use of cascade-primed (CAPRI) cells for the combination treatment of non–small-cell lung cancer (NSCLC) were evaluated both in vitro and in vivo.MethodsSixty-five patients with stage II–IV NSCLC were recruited. Of these patients, 31 patients received CAPRI cell therapy combined with chemotherapy (CAPRI group), and the other 34 patients constituted the control group and received chemotherapy alone. This study primarily aimed to evaluate the overall survival (OS), progression-free survival (PFS), short-term responses and treatment efficacy.ResultsCD83, CD1a, CD80 and CD86 marker levels were significantly upregulated in CAPRI cells. Interferon-γ expression levels were highest in CD3⁺CD8⁺ cells (33.77% ± 4.40%). Furthermore, interleukin-2 levels were highest in CD3⁺CD56⁺ cells (26.73% ± 6.63%), whereas perforin expression levels were similar in CD3⁺CD8⁺ and CD3⁺CD56⁺ cells. Furthermore, CAPRI cells had a better anti-tumor potential in CD3⁺CD56⁺ cells and displayed the highest expression levels of CD107a to H460 and A549 cell lines. The 5-year OS was significantly greater in the CAPRI group than in the control group (P = 0.008), and the PFS of two groups exhibited a significant difference (P = 0.007). Median OS (48 versus 31.6 months; P = 0.004) and PFS (48 versus 36.4 months; P = 0.016) differed between these two groups. Moreover, treatment-associated toxicities were mild and well-tolerated by patients with NSCLC.ConclusionCAPRI cell therapy potentially prolongs the survival of patients with NSCLC when combined with chemotherapy.     

Increased Incidence and Severity of New Graves Disease Diagnoses in Youth During the COVID-19 Pandemic

ObjectiveGraves disease (GD), an autoimmune disease of the thyroid, is likely caused by a combination of genetic predisposition and environmental triggers. Recent data suggest that COVID-19 may be associated with the development of autoimmune disease. The aim of this study was to assess the incidence and characteristics of new GD diagnoses in youth prior to and during the COVID-19 pandemic.MethodsWe performed a retrospective chart review of all new GD diagnoses in patients aged 0 to 18 years diagnosed at a tertiary care pediatric hospital between January 1, 2018, and December 31, 2021.ResultsOver a 4-year period, 51 patients had been diagnosed with new-onset GD. We observed an increased incidence in new-onset GD during the pandemic compared with that in the 2 prior years (P = .01). During the pandemic period, heart rates (P = .03) as well as systolic (P = .005) and diastolic (P = .01) blood pressures were higher at initial evaluation, patients more frequently reported palpitations (P = .03) and tremors (P = .04), and an increased proportion of patients required beta-blockade treatment at diagnosis (P = .002). The percentage of patients requiring thionamide treatment and thionamide doses had been similar over time.ConclusionWe identified an increase in new-onset pediatric GD diagnoses during the COVID-19 pandemic. In addition, youths had increased severity of symptoms and more frequently required beta-blockade treatment at diagnosis. Further study of the relationship between COVID-19 and autoimmune thyroid disease is needed.     

Advantages of peripheral blood stem cells from unrelated donors versus bone marrow transplants in outcomes of adult acute myeloid leukemia patients

Background aimsIn allogeneic stem cell transplantation, unrelated donors are chosen in cases where appropriate related donors are not available. Peripheral blood stem cells (PBSCs) are more often selected as a graft source than bone marrow (BM). However, the prognostic benefits of PBSCs versus BM transplants from unrelated donors have not been carefully examined in patients with acute myeloid leukemia (AML). This study compared outcomes of adult AML patients who underwent unrelated PBSC and BM transplantation, evaluating post-transplant complications, including engraftment, graft-versus-host disease (GVHD) and infections, and determined subgroups of patients who are most likely to benefit from unrelated PBSCs compared with BM transplants.MethodsThe authors analyzed 2962 adult AML patients who underwent unrelated PBSC or BM transplants between 2011 and 2018 (221 PBSC and 2741 BM) using the Japanese nationwide registry database, in which graft source selection is not skewed toward PBSCs.ResultsIn 49.7% of patients, disease status at transplantation was first complete remission (CR1). In 57.1% of cases, HLA-matched donors were selected. Myeloablative conditioning was performed in 75.1% of cases, and anti-thymocyte globulin (ATG) was added to conditioning in 10.5%. Multivariate analyses showed a trend toward favorable non-relapse mortality (NRM) in PBSC recipients compared with BM recipients (hazard ratio [HR], 0.731, P = 0.096), whereas overall survival (OS) (HR, 0.959, P = 0.230) and disease-free survival (DFS) (HR, 0.868, P = 0.221) were comparable between PBSC and BM recipients. Although the rate of chronic GVHD (cGVHD) was significantly higher in PBSC patients (HR, 1.367, P = 0.016), NRM was not increased, mainly as a result of significantly reduced risk of bacterial infections (HR, 0.618, P = 0.010), reflecting more prompt engraftments in PBSC recipients. Subgroup analyses revealed that PBSC transplantation was advantageous in patients transplanted at CR1 and in those without ATG use. PBSC recipients experienced significantly better OS and/or DFS compared with BM recipients in this patient group.ConclusionsThe authors' results confirmed the overall safety of unrelated PBSC transplantation for adult AML patients and suggested an advantage of PBSCs, especially for those in CR1. Further optimization of the prophylactic strategy for cGVHD is required to improve the overall outcome in transplantation from unrelated PBSC donors.     

Preoperative neutrophil-to-lymphocyte ratio (preNLR) for the assessment of tumor characteristics in lung adenocarcinoma patients with brain metastasis

ObjectivesBrain metastases from lung adenocarcinoma cause significant patient mortality. This study aims to evaluate the role of preoperative Neutrophil-to-Lymphocyte ratio (preNLR) in predicting the survival and prognosis of Lung adenocarcinoma (LUAD) patients with brain metastasis (BM) and provide more references for predicting peritumoral edema.MethodsWe retrospectively reviewed 125 LUAD-BM patients who had undergone surgical resection from December 2015 to December 2020. The clinical characteristic, demographic, MRI data, and preNLR within 24–48 h before craniotomy were collected. Patients were divided into two groups based on preNLR (high NLR and low NLR), with cutoff values determined by receiver operating characteristic (ROC) analysis. Association between preoperative NLR and clinical features was determined by using Pearson chi-squared tests. Uni- and multivariate analyzes were performed to compare the overall survival (OS) of clinical features.ResultsThe patients were divided into NLR-low (64 patients) and NLR-high (61 patients) groups based on receiver operating characteristic analysis of NLR area. According to correlation analysis, a high preNLR (NLR≥2.8) is associated with the both supra- and infratentorial location involved (P = 0.017) and a greater incidence of severe peritumoral edema (P = 0.038). By multivariable analysis, age ≥ 65 years (P = 0.011), KPS < 70 (P = 0.043), elevated preNLR (P = 0.013), extracerebral metastases (P = 0.003), EGFR/ALK+ (P = 0.037), postoperative radiotherapy (P = 0.017) and targeted therapy (P = 0.007) were independent prognostic factors. OS nomogram was constructed based on cox model and model performance was examined (AUC = 0.935).ConclusionsPreNLR may serve as a prognosis indicator in LUAD patients with brain metastasis, and high preNLR tends to be positively associate with multiple locations and severe peritumoral edema.     

ARID1A deficiency associated with MMR deficiency and a high abundance of tumor-infiltrating lymphocytes predicts a good prognosis of endometrial carcinoma

BackgroundARID1A alterations have been detected in 40% of endometrial carcinomas (ECs) and are associated with loss of its expression. The role of ARID1A in tumorigenesis and development is complex, and the prognostic role in EC remains controversial. Hence, it is of great significance to confirm the role of ARID1A in EC.MethodsA total of 549 EC patients (cohort A) from TCGA were evaluated to explore the prognostic role of ARID1A. NGS was performed for 13 EC patients (cohort B), and expression of ARID1A, CD3, CD8 and mismatch repair (MMR) proteins in 52 patients (cohort C) from our center was determined by immunohistochemistry (IHC). The Kaplan–Meier method was used to perform survival analyses.ResultsARID1A alterations were detected in 32% of EC patients and correlated with good disease-free survival (DFS, P = 0.004) and overall survival (OS, P = 0.0353). ARID1A alterations were found to co-occur with MMR-related gene mutations and correlated with higher PD-L1 expression. Patients concomitantly harboring ARID1A alterations and MMR-related gene mutations had the best prognosis (DFS: P = 0.0488; OS: P = 0.0024). A cohort from our center showed that ARID1A deficiency was an independent prognostic factor and predicted longer recurrence-free survival (P = 0.0476). ARID1A loss was associated with a tendency toward MSI-H (P = 0.0060). ARID1A alterations and expression loss were associated with a higher abundance of CD3+ (P = 0.0406) and CD8+ (P = 0.0387) T cells.ConclusionARID1A alterations and expression loss are tightly associated with MMR deficiency and a high abundance of tumor-infiltrating lymphocytes, which might contribute to the good prognosis of EC.     

Bone marrow angiogenesis and angiogenic factors in multiple myeloma treated with novel agents

Introduction. An increased bone marrow (BM) angiogenesis is associated with poor outcome in multiple myeloma (MM). Objective. Angiogenesis study in MM treated with novel antimyeloma agents: thalidomide, lenalidomide, bortezomib, and with dexamethasone. Patients and methods. Forty-four patients with MM (14 newly diagnosed, 30 refractory/relapsed) were treated with novel agents at our institution. A BM biopsy was obtained before the initiation of therapy in 19. Angiogenesis was assessed by microvessel density (MVD) estimation in BM biopsies stained with the monoclonal anti-CD34 antibody, and by serum levels of angiogenic factors (VEGF, bFGF, and HGF) and cytokines (IL-6 and TNF-α). Results. A positive correlation was found between BM plasma cell involvement and MVD estimation (p = 0.01). However, MVD was not significantly correlated with either disease phase (p = 0.065) or response to therapy (p = 0.79). Neither baseline serum levels of angiogenic cytokines correlated to response to treatment. No significant correlation was found between BM MVD and serum levels of angiogenic cytokines. Serum levels of angiogenic cytokines before and after therapy showed a significant increase of bFGF (p = 0.008). Conclusion. There is no relationship between MVD estimation and baseline serum levels of angiogenic cytokines, neither between each of them and response to therapy.     

Systematic review and meta-analysis of the association between bridging therapy and outcomes of chimeric antigen receptor T cell therapy in patients with large B cell lymphoma

BackgroundThe existing evidence about the impact of bridging therapy (BT) on chimeric antigen receptor (CAR)-T cell therapy in patients with large B cell lymphoma (LBCL) is conflicting. Therefore, we reviewed all available evidence to examine the association between BT and CAR-T therapy outcomes by systematic review and meta-analysis approach.MethodsTwo reviewers independently searched Embase, PubMed, Web of Science, and Cochrane library to identify all records that described BT for LBCL treated with CAR-T. We then applied a fixed- or random-effects meta-analysis to estimate the pooled hazard ratios (HRs) and rate ratio (RRs) for efficacy and safety endpoints and assessed differences across various BT modalities. The Newcastle-Ottawa Scale was used to evaluate study quality.ResultsTwenty-six reports from 24 studies involving 2014 patients were included in the analysis. Pooled results showed that patients requiring BT had significantly worse 1-year overall survival rate (RR = 0.76, 95% confidence interval [CI] 0.68–0.85, P < 0.001), 1-year progression-free survival rate (RR = 0.71, 95% CI 0.60–0.85, P < 0.001), progression-free survival (HR = 1.35, 95% CI 1.07–1.69, P = 0.01), overall response rate (RR = 0.88, 95% CI 0.81–0.95, P = 0.001), complete response rate (RR = 0.78, 95% CI 0.65–0.93, P = 0.005), and grade ≥3 immune effector cell-associated neurotoxicity syndrome (RR = 1.43, 95% CI 1.10–1.87, P = 0.007), and tended to have poorer overall survival (HR = 1.42, 95% CI 0.99–2.02, P = 0.056) and grade ≥3 cytokine release syndrome (RR = 1.59, 95% CI 0.92–2.75, P = 0.096). Prolonged cytopenias were the common toxicity event associated with BT. Radiotherapy may serve as a promising BT option that can provide safe and effective disease control for patients with LBCL before CAR-T infusion. The inconsistency of patient baselines in the current study hindered further comparisons between different BT modalities. Most of the available evidence was rated as low quality because of concerns over low comparability.ConclusionBT appears to be associated with comparatively poor efficacy and safety outcomes after CAR-T infusion. However, due to the considerable heterogeneity between the BT and non-BT cohorts at disease baseline, no definitive conclusions can be made for the true impact of BT on CAR-T until further randomized studies are conducted.     

Etiology-, Sex-, and Tumor Size-Based Differences in Adrenocorticotropin-Dependent Cushing Syndrome

ObjectiveTo examine demographic, clinical, and biochemical differences in patients with adrenocorticotropin (ACTH)-dependent Cushing syndrome (CS) based on etiology, sex, and tumor size.MethodsThis was a single-center study of 211 patients with ACTH-dependent CS followed for 35 years. Patients were stratified into 3 groups based on etiology: Cushing disease (CD)/transsphenoidal surgery, Cushing disease/total bilateral adrenalectomy (CD/TBA), and ectopic ACTH secretion (EAS). Patients were also stratified based on sex and tumor size (nonvisualized, microadenoma, and macroadenoma).ResultsCD was the commonest cause of ACTH-dependent CS (190; 90%). Most patients presented in the third decade (median age, 29 years). Clinical features, cortisol, and ACTH were significantly greater in the EAS group. The CD/TBA group had more nonvisualized tumors (22% vs 8%; P = .000) and smaller tumor size (4 vs 6 mm; P = .001) compared with the CD/transsphenoidal surgery group. There was female predominance in CD (2.06:1) and male predominance in EAS (2:1). Men had shorter duration of symptoms (2 years; P = .014), were younger (23 years; P = .001), had lower body mass index (25.1 kg/m²; P = .000), and had more severe disease (low bone mineral density, hypokalemia). Macroadenomas were frequent (46; 24.2%), and ACTH correlated with tumor size in CD (r = 0.226; P = .005).ConclusionOur cohort presented at an earlier age than the Western population with a distinct, but slightly lower, female predilection. Patients with CD undergoing TBA had frequent negative imaging. Men had a clinical profile suggesting aggressive disease. Microadenoma and macroadenoma were difficult to distinguish on a clinicobiochemical basis.     

Differential diagnosis between progression and radionecrosis in brain metastases after stereotactic radiosurgery using hybrid FDG-PET and MRI coregistered images

IntroductionDual phase 18 FDG brain PET is helpful to assess brain metastases (BM) as tracer will build up in metastases or tumor recurrences while its retention remains stable within normal tissue or inflammatory processes. This is useful when MRI can’t discriminate brain tumor recurrence (TR) rom radionecrosis (RN) after stereotaxic radiosurgery (SRS) for BM. Many studies have sought to improve diagnostic performance by associating FDG-PET and MRI with interesting results but many biases, mostly within image post-processing. Coregistered MRI and dual phase FDG-PET images could alleviate these biases and be used to extract prognostic biomarkers.Materials and methodsWe retrospectively evaluated patients treated with SRS for BM which developed a contrast-enhanced MRI lesion with non-conclusive diagnosis for TR or RN. All patients underwent MRI and FDG-PET at least 3 months after their last SRS session. Dual FDG-PET consisted in an “early” and “delayed” acquisition, respectively 30 minutes and 4 h after injection. MRI included permeability and perfusion sequences. PET and MRI data were all coregistered on the contrast enhanced T1 MRI images. Semi-automated Volumes of Interest (VOI) of the tumor were drawn on the BM and a reference contralateral white-matter ROI (WM) was drawn for standardization; every metric was calculated inside these ROIs, in particular the tumor SUVmax and its variation in time. A 20% increase in the tumor SUVmax was in favor of TR while a modification of less than 100% was in favor of RN. Imaging metrics were then evaluated for their association with TR or RN based on histological, radiological and clinical criteria after at least 6 months follow-up.ResultsNine patients were ruled out as TR and 6 as RN. After standardization, there was a significant difference between groups for VP (P = 0.042), Washin (P = 0.035), Peak Enhancement (P = 0.037), standardized delayed SUVmax (P = 0.008) and RI (P = 0.016). Semi-quantitative analysis found respectively for PET and MRI a Sensitivity of 100% and 87.5% and a Specificity of 100% and 85.71%.ConclusionCoregistered PET-MRI images accurately discriminate between TR and RN. With FDG being the most commonly used PET radiotracer, this protocol remains easily transposable and should be encouraged to obtain non-invasive prognostic and clinically relevant biomarkers.     

Incomplete chimerism following myeloablative and anti-thymocyte globulin-conditioned hematopoietic cell transplantation is a risk factor for relapse and chronic graft-versus-host disease

Background aimsThe value of routine chimerism determination after myeloablative hematopoietic cell transplantation (HCT) is unclear, particularly in the setting of anti-thymocyte globulin (ATG)-based graft-versus-host disease (GVHD) prophylaxis.MethodsBlood samples were collected at 3 months post-HCT from 558 patients who received myeloablative conditioning and ATG-based GVHD prophylaxis. Chimerism was assessed using multiplex polymerase chain reaction of short tandem repeats in sorted T cells (CD3+) and leukemia lineage cells (CD13+CD33+ for myeloid malignancies and CD19+ for B-lymphoid malignancies). ATG exposure was determined using a flow cytometry-based assay. The primary outcomes of interest were relapse and chronic GVHD (cGVHD).ResultsIncomplete (<95%) T-cell chimerism and leukemia lineage chimerism were present in 17% and 4% of patients, respectively. Patients with incomplete T-cell chimerism had a significantly greater incidence of relapse (36% versus 22%, subhazard ratio [SHR] = 2.03, P = 0.001) and lower incidence of cGVHD (8% versus 25%, SHR = 0.29, P < 0.001) compared with patients with complete chimerism. In multivariate modeling, patients with high post-transplant ATG area under the curve and any cytomegalovirus (CMV) serostatus other than donor/recipient seropositivity (non-D+R+) had an increased likelihood of incomplete T-cell chimerism. Patients with incomplete leukemia lineage chimerism had a significantly greater incidence of relapse (50% versus 23%, SHR = 2.70, P = 0.011) and, surprisingly, a greater incidence of cGVHD (45% versus 20%, SHR = 2.64, P = 0.003).ConclusionsHigh post-transplant ATG exposure and non-D+R+ CMV serostatus predispose patients to incomplete T-cell chimerism, which is associated with an increased risk of relapse. The increased risk of cGVHD with incomplete B-cell/myeloid chimerism is a novel finding that suggests an important role for recipient antigen-presenting cells in cGVHD pathogenesis.     

Effects of stem cells on non-ischemic cardiomyopathy: a systematic review and meta-analysis of randomized controlled trials

Background aimsTo assess the impacts of stem cell therapy on clinical outcomes in patients with non-ischemic cardiomyopathy (NICM). The effect of stem cell therapy on prognosis is unclear and controversial.MethodsThe authors performed a systematic review and meta-analysis of the effects of autologous stem cell transplantation in patients with NICM on a composite outcome of all-cause mortality and heart transplantation, left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), New York Heart Association (NYHA) classification, 6-minute walk test (6-MWT) distance and serum brain natriuretic peptide (BNP) level, considering studies published before March 19, 2020.ResultsTwelve trials with 623 subjects met inclusion criteria. Compared with the control group, stem cell therapy improved LVEF (weighted mean difference [WMD], 4.08%, 95% confidence interval [CI], 1.93–6.23, P = 0.0002) and 6-MWT distance (WMD, 101.49 m, 95% CI, 45.62–157.35, P = 0.0004) and reduced BNP level (–294.94 pg/mL, 95% CI, –383.97 to –205.90, P < 0.00001) and NYHA classification (–0.70, 95% CI, –0.98 to –0.43, P < 0.00001). However, LVEDD showed no significant difference between the two groups (WMD, –0.09 cm, 95% CI, –0.23 to 0.06, P = 0.25). In 10 studies (535 subjects) employing the intracoronary route for cell delivery, mortality and heart transplantation were decreased (risk ratio [RR], 0.73, 95% CI, 0.52–1.00, P = 0.05). Furthermore, in four studies (248 subjects) with peripheral CD34+ cells, either all-cause mortality (RR, 0.44, 95% CI, 0.23–0.86, P = 0.02) or mortality and heart transplantation (RR, 0.45, 95% CI, 0.27–0.77, P = 0.003) improved in the treatment group compared with the control. The trial sequential analysis suggested the information size of LVEF, 6-WMT and BNP has been adequate for evidencing the benefits of stem cells on NICM. However, to determine the potential survival benefit, more clinical data are required to make the statistical significance in meta-analysis more conclusive.ConclusionsThis meta-analysis demonstrates that stem cell therapy may improve survival, exercise capacity and cardiac ejection fraction in NICM, which suggests that stem cells are a promising option for NICM treatment.     

Unraveling stem cell and progenitor subsets in autologous grafts according to methods of mobilization: implications for prediction of hematopoietic recovery

Background aimsIn the autologous setting, granulocyte colony-stimulating factor (G-CSF) (G), or, when failing, G plus plerixafor (G+P), are common regimens for mobilization of stem cells into peripheral blood. To delineate mobilization effects on graft composition and hematopoietic recovery, we compared contents of stem cells and progenitor cells in products of G+P- and G patients. Paired samples of G+P patients and prior insufficient G mobilization were available for analyses.MethodsSubset analyses of grafts were performed by flow cytometry and myeloid colony-forming assay. In search of new markers to ascertain graft quality, we determined the fractions of aldehyde dehydrogenase bright (ALDH^br) cells.ResultsG grafts contained higher percentages of CD34+ cells, CD34+CD38- cells, and committed progenitors (CD34+CD38+) compared with G+P grafts. A detailed characterization of the mobilized CD34+ cell subset showed higher percentages of CD38– among the CD34+ cells of the G+P group (P = 0.032). In contrast, the CD34+ cell subset in G grafts was characterized by a higher percentage of ALDH^br cells (P < 0.0001). Studying engraftment and day +100 graft function the G and G+P transplanted patients were comparable with respect to neutrophils, whereas in platelets they differed. In the prediction of engraftment and hematopoietic recovery, the dose of infused ALDH^br cells correlated best to both platelet (r = 0.565, P = 0.002) and neutrophil reconstitution (r = 0.366, P = 0.06).ConclusionsBesides showing dissimilar distributions of CD34+CD38– cells and progenitors in G and G+P grafts, this study further designated ALDH^br as a promising marker in determination and prediction of graft quality and hematopoietic recovery.     

Adoptive cellular immunotherapy for the treatment of patients with breast cancer: A meta-analysis

BackgroundTo evaluate the therapeutic efficacy of dendritic cells (DC) alone, cytokine-induced killer (CIK) cells alone and the combination of DC and CIK cells in the treatment of breast cancer, we performed a systemic review of the relevant published clinical studies, collectively referred to as DC-CIK cell therapy.MethodsSix hundred thirty-three patients with breast cancer were assigned to cohorts, and a meta-analysis was conducted.ResultsThe treatment of breast cancer with DC-CIK cells was associated with a significantly improved 1-year survival (P = 0.0001). The Karnofsky performance status scale of the patients treated with DC-CIK cells was significantly improved compared with that of the non-DC-CIK group (P < 0.0001). The percentage of T cells (CD3⁺, CD4⁺ and CD4⁺CD8⁺), CD16⁺ monocytes, and CD3⁺CD56⁺ natural killer T cells in the peripheral blood of cancer patients was significantly increased (P ≤ 0.05), whereas the percentage of CD4⁺CD25⁺ regulatory T cells was not significantly decreased (P = 0.32) in the DC-CIK treatment group compared with the non-DC-CIK group. The levels of interleukin-2, interleukin-12, tumor necrosis factor-α, interferon-γ, and nucleolar organizer region protein in the peripheral blood of cancer patients, which reflect immune function, were significantly increased (P < 0.001) after DC-CIK cell treatment. Furthermore, after DC-CIK treatment, the average levels of the alpha-fetoprotein, cancer antigen embryonic antigen and carbohydrate antigen tumor markers were decreased (P < 0.00001).ConclusionsDC-CIK cell therapy markedly prolongs survival time, enhances immune function, and improves the efficacy of the treatment of breast cancer patients.     

The clonogenic potential of hematopoietic stem cells and mesenchymal stromal cells in various hematologic diseases: a pilot study

Background aimsMesenchymal stromal cells (MSC) are the most popular cells used in regenerative medicine and biotechnology. The clonogenic potential of these cells is defined by colony-forming unit-fibroblasts (CFU-F). It is well known that there is an interaction between hematopoietic cells and stromal cells in disease formation pathogenesis. Therefore we hypothesized that there should be a quantitative and qualitative relationship between MSC colonies (CFU-F) and hematopoietic stem cell colonies (colony-forming unit-granulocyte-macrophages; CFU-GM) among patients with and without hematologic diseases.MethodsForty-two patients were included in this study. Patients were divided into three groups: group A, patients with hematologic malignancies (n = 20); group B, patients with bone marrow (BM) failure (n = 11); group C, patients without hematologic diseases (n = 11). BM aspirates were plated in different densities for CFU-F culture. The plating density was the same for CFU-GM culture.ResultsCFU-GM colonies grew in 90% of group A cells and all of group B and C cells (P = 0.0001). CFU-F colonies became visible on the ninth day of plating in group A and on the eight day in groups B and C. There was no statistically significant difference between the groups for the duration of CFU-F colony formation (P = 0.12). There were differences in the morphology of the colonies among the groups.ConclusionsThis is the first study that has compared the clonogenic potential of stromal cells and hematopoietic stem cells in the same subjects with and without hematologic diseases. No correlation was shown between the clonogenic potential of stromal cells and hematopoietic cells.     

The clinical and financial burden of pre-emptive management of cytomegalovirus disease after allogeneic stem cell transplantation—implications for preventative treatment approaches

Background aimsAlthough cytomegalovirus (CMV) infection after allogeneic stem cell transplantation (SCT) is rarely fatal, the management of CMV by pre-emptive medication for viral reactivation has toxicity and carries a financial burden. New strategies to prevent CMV reactivation with vaccines and antiviral T cells may represent an advance over pre-emptive strategies but have yet to be justified in terms of transplantation outcome and cost.MethodsWe compared outcomes and post-transplantation treatment cost in 44 patients who never required pre-emptive CMV treatment with 90 treated patients undergoing SCT at our institute between 2006 and 2012. Eighty-one subjects received CD34+ selected myeloablative SCT, 12 umbilical cord blood transplants, and 41 T-replete non-myeloablative SCT. One hundred nineteen patients (89%) were at risk for CMV because either the donor or recipient was seropositive. Of these, 90 patients (75.6%) reactivated CMV at a median of 30 (range 8–105) days after transplantation and received antivirals.ResultsThere was no difference in standard transplantation risk factors between the two groups. In multivariate modeling, CMV reactivation >250 copies/mL (odds ratio = 3, P < 0.048), total duration of inpatient IV antiviral therapy (odds ratio = 1.04, P < 0.001), type of transplantation (T-deplete vs. T-replete; odds ratio = 4.65, P < 0.017) were found to be significantly associated with increased non-relapse mortality. The treated group incurred an additional cost of antiviral medication and longer hospitalization within the first 6 months after SCT of $58,000 to $74,000 per patient.ConclusionsOur findings suggest that to prevent CMV reactivation, treatment should be given within 1 week of SCT. Preventative treatment may improve outcome and have significant cost savings.     

Viability and engraftment of hematopoietic progenitor cells after long-term cryopreservation: effect of diagnosis and percentage dimethyl sulfoxide concentration

Background aimsWe carried out a retrospective analysis of viability by diagnosis and dimethyl sulfoxide (DMSO) concentration in patients who had undergone autologous transplants using hematopoietic progenitor cells (HPC) after long-term storage (up to 17.8 years).MethodsViability was tested using flow cytometry for HPC that were harvested and preserved using a controlled rate freezer and 5% or 10% DMSO with human serum albumin, then stored in liquid nitrogen. Data from 262 samples were analyzed (249 myeloma patients and 13 other diagnoses): 100 consecutively thawed samples with a storage time of <1 year (all 10% DMSO), 50 consecutive samples stored for 1–4.9 years (10% DMSO), 50 samples stored for 5–9 years (5% DMSO) and all samples stored and used for transplant after >9 years (60 samples, 5% DMSO; two samples, 10% DMSO).ResultsNo statistically significant difference in viability between the 5% DMSO and 10% DMSO groups was observed (P = 0.08), so the 1–4.9 years and 5–9 years were combined and the three groups (<1 year, 1–9 years and >9 years) were compared using an anova test. There was no difference in viability based on cryostorage period (P = 0.23) or between myeloma and other diagnoses (P = 0.45). No difference was seen in time to White blood cell (WBC) engraftment (P = 0.10) or to platelet engraftment between groups (P = 0.52).ConclusionsThese data suggest that long-term storage in 5% DMSO and human serum albumin is safe.     

Immune mobilization of autologous blood progenitor cells: direct influence on the cellular subsets collected

Background aimsA phase I trial examined the ability of immunotherapy to mobilize progenitor and activated T cells.MethodsInterleukin (IL)-2 was administered subcutaneously for 11 days, with granulocyte (G)-colony-stimulating factor (CSF) (5 mcg/kg/day) and granulocyte–macrophage (GM)-CSF (7.5 mcg/kg/day) added for the last 5 days. Leukapheresis was initiated on day 11. Thirteen patients were treated (myeloma n = 11, non-Hodgkin's lymphoma n = 2).ResultsToxicities were minimal. IL-2 was stopped in two patients because of capillary leak (n = 1) and diarrhea (n = 1). Each patient required 2.5 leukaphereses (median; range 1–3) to collect 3.2 × 10⁶ CD34⁺ cells/kg (median; range 1.9–6.6 × 10⁶/kg). Immune mobilization increased the number of CD3⁺ CD8⁺ T cells (P = 0.002), CD56⁺ natural killer (NK) cells (P = 0.0001), CD8⁺ CD56⁺ T cells (P = 0.002) and CD4⁺ CD25⁺ cells (P = 0.0001) compared with cancer patients mobilized with G-CSF alone. There was increased lysis of myeloma cells after 7 days (P = 0.03) or 11 days (P = 0.02). The maximum tolerated dose of IL-2 was 1 × 10⁶ IU/m²/day.ConclusionsImmune mobilization is well tolerated with normal subsequent marrow engraftment. As cells within the graft influence lymphocyte recovery, an increased number of functional lymphocytes may result in more rapid immune reconstitution.     

Allogeneic cord blood regulatory T cells can resolve lung inflammation

Background aimsCD4⁺CD25⁺CD127^lo regulatory T cells (Tregs) are responsible for maintaining immune homeostasis. Tregs can be rendered defective and deficient as a result of the immune imbalance seen in lung injury, and such dysfunction can play a major role in continued tissue inflammation. The authors hypothesized that adoptive therapy with healthy allogeneic umbilical cord blood (UCB)-derived Tregs may be able to resolve inflammation.ResultsEx vivo-expanded UCB Tregs exhibited a unique phenotype with co-expression of CD45RA⁺CD45RO⁺ >80% and lung homing markers, including CD49d. UCB Tregs did not turn pathogenic when exposed to IL-6. Co-culture with increasing doses of dexamethasone led to a synergistic increase in UCB Treg-induced apoptosis of conventional T cells (Tcons), which translated into significantly higher suppression of proliferating Tcons, especially at a lower Treg:Tcon ratio. Multiple injections of UCB Tregs led to their preferential accumulation in lung tissue in an immune injury xenogenic model. A significant decrease in lung resident cytotoxic CD8⁺ T cells (P = 0.0218) correlated with a sustained decrease in their systemic distribution compared with controls (P < 0.0001) (n = 7 per arm) as well as a decrease in circulating human soluble CD40 ligand level (P = 0.031). Tissue architecture was preserved in the treatment arm, and a significant decrease in CD3⁺ and CD8⁺ burden was evident in immunohistochemistry analysis.ConclusionsUCB Treg adoptive therapy is a promising therapeutic strategy for treatment of lung injury.