Xuechun Lu

Low Dose Decitabine Treatment Induces CD80 Expression in Cancer Cells and Stimulates Tumor Specific Cytotoxic T Lymphocyte Responses

Lack of immunogenicity of cancer cells has been considered a major reason for their failure in induction of a tumor specific T cell response. In this paper, we present evidence that decitabine (DAC), a DNA methylation inhibitor that is currently used for the treatment of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and other malignant neoplasms, is capable of eliciting an anti-tumor cytotoxic T lymphocyte (CTL) response in mouse EL4 tumor model. C57BL/6 mice with established EL4 tumors were treated with DAC (1.0 mg/kg body weight) once daily for 5 days. We found that DAC treatment resulted in infiltration of IFN-γ producing T lymphocytes into tumors and caused tumor rejection. Depletion of CD8+, but not CD4+ T cells resumed tumor growth. DAC-induced CTL response appeared to be elicited by the induction of CD80 expression on tumor cells. Epigenetic evidence suggests that DAC induces CD80 expression in EL4 cells via demethylation of CpG dinucleotide sites in the promoter of CD80 gene. In addition, we also showed that a transient, low-dose DAC treatment can induce CD80 gene expression in a variety of human cancer cells. This study provides the first evidence that epigenetic modulation can induce the expression of a major T cell co-stimulatory molecule on cancer cells, which can overcome immune tolerance, and induce an efficient anti-tumor CTL response. The results have important implications in designing DAC-based cancer immunotherapy.

Lenalidomide Treatment for Multiple Myeloma: Systematic Review and Meta-Analysis of Randomized Controlled Trials

Background In recent years, a number of randomized controlled trials (RCTs) have reported on lenalidomide as a treatment for multiple myeloma (MM). Herein, we report results of a meta-analysis of RCTs examining the efficacy and safety of lenalidomide for MM. Patients and Methods Databases were searched using the terms “lenalidomide or revlimid AND multiple myeloma.”RCTs evaluating initial or maintenance therapeutic outcomes were included. Main outcome measures were response rates, progression-free survival (PFS), overall survival, and adverse events. Results Seven trials were included (N = 192–614 participants). Lenalidomide doses and treatment regimens differed between trials. Complete response (CR) and very good partial response (VGPR) risk ratios (RR) favored lenalidomide over placebo (CR = 2.54, 95% confidence interval [CI] = 1.29–5.02; VGPR = 2.82, 95% CI = 1.30–6.09). The PFS hazard ratio favored lenalidomide over placebo (0.37, 95% CI = 0.33–0.41). For adverse events, neutropenia, deep vein thrombosis (DVT), infection, and hematologic cancer RR favored placebo over lenalidomide (neutropenia: 4.74, 95% CI = 2.96–7.57; DVT: 2.52; 95% CI: 1.60–3.98; infection: 1.98; 95% CI: 1.50–2.62; hematologic cancer: 3.20; 95% CI: 1.28–7.98). Conclusions Lenalidomide is an effective treatment for MM; however, treatment-related adverse events must be considered and appropriate adjustments and/or prophylactic treatment should be initiated where possible.

Low-dose decitabine-based chemoimmunotherapy for patients with refractory advanced solid tumors: a phase I/II report.

Aberrant DNA methylation is one of the main drivers of tumor initiation and progression. The reversibility of methylation modulation makes it an attractive target for novel anticancer therapies. Clinical studies have demonstrated that high-dose decitabine, a hypomethylating agent, results in some clinical benefits in patients with refractory advanced tumors; however, they are extremely toxic. Low doses of decitabine minimize toxicity while potentially improving the targeted effects of DNA hypomethylation. Based on these mechanisms, low-dose decitabine combined with chemoimmunotherapy may be a new treatment option for patients with refractory advanced tumors. We proposed the regimen of low-dose decitabine-based chemoimmunotherapy for patients with refractory advanced solid tumors. A favorable adverse event profile was observed in our trial that was highlighted by the finding that most of these adverse events were grades 1-2. Besides, the activity of our cohort was optimistic and the clinical benefit rate was up to 60%, and the median PFS was prolonged compared with PFS to previous treatment. We also identified a significant correlation between the PFS to previous treatment and clinical response. The low-dose DAC decitabine-based chemoimmunotherapy might be a promising protocol for improving the specificity and efficiency of patients with refractory advanced solid tumors. This trial is registered in the ClinicalTrials.gov database (identifier NCT01799083).

Autologous CIK Cell Immunotherapy in Patients with Renal Cell Carcinoma after Radical Nephrectomy

Objective. To evaluate the efficacy of autologous cytokine-induced killer (CIK) cells in patients with renal cell carcinoma (RCC). Methods. 20 patients diagnosed with TNM stage I or II RCC were randomly divided into two groups, a CIK cell treatment group and a control group. The endpoint was progression-free survival (PFS) evaluated by Kaplan-Meier analyses. Results. CD3+, CD3+/CD8+, CD3+/CD4+, and CD3+/CD56+ levels increased after CIK cell culture (P < 0.01). The median PFS in CIK cell treatment group was significantly longer than that in control group (PFS, 32.2 months versus 21.6 months; log-rank, P = 0.032), all patients were alive during the course of followup, and there are no statistically significant differences between two groups in OS (log-rank, P = 0.214). Grade III or greater adverse events were not observed. Conclusions. CIK cells treatment could prolong survival in patients with RCC after radical nephrectomy and showed acceptable curative effect with potential enhancement of cellular immune function. This trial is registered with Clinicaltrials.gov NCT01799083.

Relationships between HDL-C, hs-CRP, with Central Arterial Stiffness in Apparently Healthy People Undergoing a General Health Examination

Background Some cardiovascular risk factors have been confirmed to be positively correlated with arterial stiffness. However, it is unclear whether HDL-C, a well-established anti-risk factor, has an independent association with arterial stiffness. The aim of this study was to evaluate the relationship between HDL-C levels and arterial stiffness and the possible role of high-sensitivity C-reactive protein (hs-CRP) in this potential correlation in apparently healthy adults undergoing a general health examination in China. Materials and Methods This was a cross-sectional survey. In total, 15,302 participants (age range, 18–82 years; mean, 43.88±8.44 years) were recruited during routine health status examinations. A questionnaire was used and we measured the body mass index, systolic and diastolic blood pressure, and fasting glucose, and serum lipid, uric acid, hs-CRP, and serum creatinine levels of each participant. Central arterial stiffness was assessed by carotid–femoral pulse wave velocity (cf-PWV). Results HDL-C levels decreased as cf-PWV increased. Pearson’s correlation analysis revealed that HDL-C levels were associated with cf-PWV (r=−0.18, P<0.001). hs-CRP levels were positively associated with cf-PWV (r=0.13). After adjustment for all confounders, HDL-C was inversely independently associated with all quartiles of cf-PWV. Furthermore, HDL-C was associated with cf-PWV in different quartiles of hs-CRP, and the correlation coefficients (r) gradually decreased with increasing hs-CRP levels (quartiles 1–4). Conclusions HDL-C is inversely independently associated with central arterial stiffness. The anti-inflammatory activity of HDL-C may mediate its relationship with cf-PWV. Further, long-term follow-up studies are needed to evaluate whether high HDL-C levels are protective against central artery stiffening through the anti-inflammatory activity of HDL-C.

Diagnosis and Treatment of Rituximab-Induced Acute Tumor Lysis Syndrome in Patients With Diffuse Large B-Cell Lymphoma

Acute tumor lysis syndrome (ATLS) is a recognized complication of the treatment of malignant lymphomas and is associated with significant morbidity and mortality. However, there have been few reports of the occurrence of ATLS in patients treated with rituximab. This study reports 2 patients with high-grade diffuse large B-cell non-Hodgkins lymphoma who presented high tumor load, were sensitive to treatment and had multiple risk factors for ATLS. Both patients developed ATLS after treatment with rituximab and, despite aggressive supportive therapy, died of multiple organ failure. These cases illustrate that ATLS can occur after treatment with rituximab and that a high index of suspicion is necessary for the prompt diagnosis of ATLS.

Analysis of adverse events following the treatment of autologous cytokine-induced killer cells for adoptive immunotherapy in malignant tumour sufferers

Background: Adoptive immune cell transfer such as cytokine-induced killer (CIK) cells has become an important adjuvant approach in patients with tumours. Objectives: The aim of this study was to analyse the adverse events (AEs) that occur during the transfusion of autologous CIK cells and to identify the risk factors associated with these AEs. Methods: Cell infusion-associated AEs were evaluated according to National Cancer Institute Common Terminology Criteria. Analysis was performed from a single-centre data on 893 malignant tumour patients who received a total of 4088 transfusions from March 2008 to October 2013. Results: A total of 215/4088 (5.26%) transfusion cases from 893 patients presented with AEs (Grade 1 – 4); 204/215 (94.88%) were Grade 1 – 2, and 156/215 (72.56%) occurred within 24 h. The most common AEs were fever (0.88%), chills (0.56%) and fatigue (0.49%). The rare but severe AEs included anaphylactoid purpura, tumour lysis syndrome, anaphylactic shock, arthralgia. No transfusion-associated death was noticed. The mainly relative risk factors for AEs included transfer cycles and clinical stages. Conclusion: This study is a large-sample AEs research, to our knowledge, relative to immune cell transfusion from a single centre data analysis, revealing that autologous CIK cell therapy represents a fairly safe and well-tolerated treatment modality for malignant tumour patients, even rare severe, but not lethal AEs were observed in few patients.

Imatinib-induced decompensated heart failure in an elderly patient with chronic myeloid leukemia: case report and literature review.

Because it is safe and well tolerated, imatinib is a standard first-line therapy for chronic myeloid leukemia (CML). Although there have been sporadic reports of imatinib-induced cardiotoxicity, including left ventricle (LV) dysfunction and heart failure, the evidence for it is contradictory. Here, we reported a case of an 88-year-old male patient with CML developed decompensated heart failure following imatinib therapy. Four days after the initiation of imatinib, the patient developed orthopnea, edema and a pleural effusion accompanied by abdominal distension, nausea and vomiting. The chest X-ray film showed an enlarged cardiac profile. The echocardiogram demonstrated a decreased LV ejection fraction and enlarged left-side cardiac chambers. B-type natriuretic peptide concentrations were markedly increased. The patient recovered soon after the withdrawal of imatinib and introduction of comprehensive therapy for heart failure. Imatinib-induced cardiotoxicity in elderly patients is a potentially serious complication that merits further evaluation.

Individualized liposomal doxorubicin-based treatment in elderly patients with non-Hodgkin's lymphoma.

Background: We retrospectively evaluated the efficacy and safety of individualized liposomal doxorubicin-based treatment in elderly patients with non-Hodgkin’s lymphoma and poor general health. Patients and Methods: 22 patients (median age 83.5 years) were treated with liposomal doxorubicin combined with CHOP-based chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone) or other individualized doxorubicin-based treatments including liposomal doxorubicin combined with rituximab. Efficacy and adverse reactions were measured. Results: Patients received a total of 80 courses of chemotherapy (mean dose 143.6 mg/patient liposomal doxorubicin). The numbers of patients achieving complete remission, uncertain complete remission, partial remission, stable disease, or progressive disease were 10 (45.5%), 4 (18.2%), 4 (18.2%), 1 (4.5%), and 3 (13.6%), respectively. The most frequently reported adverse reaction was bone marrow suppression. No serious infections were reported. 3 (13.6%) patients showed skin changes. None experienced congestive heart failure or acute myocardial infarction. There were no chemotherapyrelated deaths. Overall survival rates at 1, 3, and 5 years were 81.8, 59.1, and 40.9%, and progression-free survival rates were 83.3, 66.7, and 54.5%. Conclusions: Individualized liposomal doxorubicin-based chemotherapy is effective and safe for elderly patients with non-Hodgkin’s lymphoma.

Efficacy of cytokine-induced killer cell infusion as an adjuvant immunotherapy for hepatocellular carcinoma: a systematic review and meta-analysis

This study was designed to evaluate the efficacy and safety of cytokine-induced killer (CIK) cell-based immunotherapy as an adjuvant therapy for hepatocellular carcinoma (HCC). Published studies were identified by searching Medline, Cochrane, EMBASE, and Google Scholar databases with the keywords: cytokine-induced killer cell, hepatocellular carcinoma, and immunotherapy. The outcomes of interest were overall survival, progression-free survival, and disease-free survival. Eight randomized controlled trials (RCTs), six prospective studies, and three retrospective studies were included. The overall analysis revealed that patients in the CIK cell-treatment group had a higher survival rate (pooled hazard ratio (HR) =0.594, 95% confidence interval [CI] =0.501–0.703, P<0.001). Patients treated with CIK cells in non-RCTs had a higher progression-free survival rate (pooled HR =0.613, 95% CI =0.510–0.738, P<0.001). However, CIK cell-treated patients in RCTs had progression-free survival rates similar to those of the control group (pooled HR =0.700, 95% CI =0.452–1.084, P=0.110). The comparison between pooled results of RCTs and non-RCTs regarding the progression-free survival rate did not reach statistical significance. Patients in the CIK cell-treatment group had lower rates of relapse in RCTs (pooled HR =0.635, 95% CI =0.514–0.784, P<0.001). Similar results were found when non-RCT and RCTs were pooled (pooled HR =0.623, 95% CI =0.516–0.752, P<0.001). Adjuvant CIK cell-based immunotherapy is a promising therapeutic approach that can improve overall survival and reduce recurrence in patients with HCC.