To observe the clinical efficacy of Huajian-Badu membrane in the treatment of moderate and severe cancer pain / 国际中医中药杂志

Objective To observe the clinical efficacy of Huajian-Badu membrane in the treatment of moderate and severe cancer pain. Methods The 80 malignant tumor patients with moderate to severe cancer pain from January 2016 to June 2017 in Tianjin University of Traditional Chinese Medicine First Teaching Hospital were recruited and randomly divided into the observation group and the control group, each of 40 cases. The control group were treated with Oxycodone Hydrochloride Prolonged-release Tablets, while the treatment group were treated with Huajian-Badu membrane on the basis of the treatment in control group. The pain relief, pain frequency, morphine consumption and quality of life (Karnofsky score), adverse reaction were evaluated between two groups before and after treatment. Results Compared with the control group, the total efficiency in the observation group was significantly higher (95.0％ vs. 80.0％, χ2=4.114, P=0.043). The frequency of breakthrough pain of two groups increased on the seventh and fourteenth treatment days(0.3 ± 0.6 times vs. 0.8 ± 0.7 times, t=-3.430 and 0.4 ± 0.6 times vs. 0.9 ± 0.8 times, t=-3.162), but the number of outbreaks of pain in the observation group significantly less than the control group (P<0.05 or P<0.01). The morphine injection dosage increased on the seventh and fourteenth treatment days (3.01 ± 4.28 g vs. 5.62 ± 6.37 g, t=-2.151 and 3.21 ± 4.32 g vs. 7.84 ± 7.76 g, t=-3.297), but the amount of the observtation group was significantly lower than that of control group (P<0.05 or P<0.01). The KPS score in the observation group increased significantly, and significantly higher than the control group on the seventh and fourteenth treatment days (73.0 ± 15.0 vs. 66.0 ± 12.0, t=2.305 and 77.0 ± 13.0 vs. 70.0 ± 15.0, t=2.230, P<0.05). The adverse reaction rate of the control group was 25％, while the the observation group was 20％. The difference between two groups was significant (χ2=0.287, P=0.592). Conclusions The Huajian-Badu membrane combined Oxycodone Hydrochloride Prolonged-release Tablets can improve the total effective rate of pain relief, reduce the number of outbreaks, reduce morphine consumption, improve patient KPS score of the patients with cancer pain.

Expressions and prognostic significance of PTEN and PD-1 protein in patients with classical Hodgkin’s lymphoma / 中华血液学杂志

Objective@#To elucidate the expression levels of key immune biomarkers, phosphate and tension homology deleted on chromosome ten (PTEN) and programmed cell death protein1(PD-1),of different immune tolerance pathway in classic Hodgkin’s lymphoma (CHL) to further determine their clinical role and prognostic significance.@*Methods@#The clinical features and prognostic factors of 56 CHL patients, who were admitted to the TianJin Medical University Cancer Institute from February 2003 to August 2013, were retrospectively analyzed. PTEN and PD-1 protein expression levels were analyzed by immunohistochemistry, Epstein-Barr virus encoded RNA (EBER) was performed by in situ hybridization assay. Correlations between the expression of biomarkers and clinicopathologic parameters were examined and survival analyses were performed.@*Results@#This cohort of 56 CHL patients included 34 males and 22 females with a median age of 25 years (ranged from 7 to 71 years). In a univariate analysis, age≥45, IPS score >2, EBER positive, high expression of PTEN protein conferred inferior 5-year OS and 5-year PFS; In a multivariate model, age≥45, IPS score >2, EBER positive, high expression of PTEN protein were identified as the independent adverse prognostic factors for CHL.@*Conclusions@#This study suggested for the first time that PTEN was independent prognostic immune biomarkers in CHL, which provided the novel therapeutic strategy of immune therapy for CHL.

Clinical research on apatinib combined with Xiaoyan decoction for the treatment of non-squamous non-small cell lung cancer / 中国肿瘤临床

Objective:To determine the effect of apatinib combined with Xiaoyan decoction for the treatment of non-squamous non-small cell lung cancer. Methods:Thirty-eight patients with non-squamous non-small cell lung cancer were randomly categorized into apatinib group (group A, 18 cases) and apatinib combined with Xiaoyan decoction group (group B, 20 cases). All patients did not under-go surgical treatment, radiotherapy, or chemotherapy during the study. Results:The median progression free survival (mPFS) of ad-vanced non-squamous non-small cell lung cancer patients reached up to 3 months. The mPFS, objective response rate, and disease control rate of the apatinib combined with Xiaoyan decoction group showed no significant difference and statistical significance (P>0.05). The apatinib combined with Xiaoyan decoction group was superior to the apatinib group with regard to alleviating clinical symp-toms and adverse reactions (P<0.05). Conclusion:Xiaoyan decoction combined with apatinib can improve the clinical symptoms of pa-tients and reduce the incidence of adverse reactions in the treatment of advanced non-squamous non-small cell lung cancer.

Role of CXCR4/STAT3 in mesenchymal stromal cell-mediated drug resistance of acute leukemia cells / 中华血液学杂志

<p><b>OBJECTIVE</b>To explore the role of CXCR4/STAT3 in mesenchymal stromal cell (MSC)-mediated drug resistance of AML cells.</p><p><b>METHODS</b>AML cell lines U937 and KG1a and primary AML cells were co-cultured with MSC from bone marrow of healthy donors. The AML cell lines cultured alone were used as control. Apoptosis induced by mitoxantrone was measured by flow cytometry. Expression of CXCR4 and STAT3 protein were detected by Western blot. After incubated with STAT3 inhibitor Cucurbitacin I or CXCR4 antagonist AMD3100, the apoptosis of AML cells induced by mitoxantrone was evaluated.</p><p><b>RESULTS</b>Apoptosis of AML cells (U937 and KG1a) and primary AML cells induced by mitoxantrone significantly decreased in cocultured group than that of control group [U937 cells: (20.08±1.53)% vs (45.33 ± 1.03)% , P=0.004; KG1a cells: (25.60 ± 1.82)% vs (40.33 ± 3.29)% , P=0.020]. Expression of phosphorylated STAT3 and CXCR4 protein in AML cells were upregulated in cocultured group. After addition of Cucurbitacin I into the co-culture system, the apoptosis rate of primary AML cells significantly increased. Similar results of the apoptosis rates were also detected when the inhibitor of CXCR4 AMD3100 was added to overcome the stromal cell-mediated drug resistance. Besides, the expression of p-STAT3 in AML cells after incubated with AMD3100 decreased significantly.</p><p><b>CONCLUSIONS</b>AML cells cocultured with MSC leads to the up-regulation of phosphorylated STAT3 and CXCR4 proteins, which resulted in AML cells resistance to chemotherapeutic drugs. Therefore targeting STAT3 or CXCR4 could be a new therapeutic strategy of AML.</p>

Inhibitory effects of the phosphoinostitide-3'-kinase delta inhibitor CAL-101 on Raji and SUDHL-10 lymphoma cells and its relative mechanism / 中国肿瘤临床

Objective:To detect the inhibitory effects of CAL-101, a selective inhibitor of phosphoinostitide-3'-kinase delta (PI3Kδ), on Burkitt's lymphoma cell line Raji and diffused large B-cell lymphoma cell line SUDHL-10 and elucidate its relative mechanism. Methods:Raji and SUDHL-10 cells were treated with various concentrations of CAL-101. Methyl thiazolyl tetrazolium (MTT) assay was performed to determine the inhibitory effect of CAL-101 on lymphoma cells, and cell apoptosis was measured by Annexin V/PI and DAPI staining. Migration assays were performed with transwell to detect the migration of lymphoma cells derived from the stromal cell line HK. Western blot was used to detect the phosphorylation status of the ERK pathway. MTT and CalcuSyn software analyses were preformed to detect whether or not combining CAL-101 with bortezomib induces synergistic cytoxicity. Results:CAL-101 at con-centrations of 5, 10, 15, and 20μmol/L inhibited cell proliferation in a dose-dependent manner. The proliferation rates of the Raji cells treated with 5, 10, 15, and 20μmol/L for 48 h were 29.17%± 1.23%, 38.15%± 1.51%, 46.46%± 1.78%, and 55.8%± 2.01%, respec-tively, which were significantly higher (P<0.05) than that of the control group (1.15% ± 0.02%). Similar results were found in the SUDHL-10 cells after treatment with CAL-101 (P<0.05). CAL-101 also exerted an apoptotic effect on the lymphoma cells. The apop-totic rates of the Raji cells treated with CAL-101 for 21 h were 22.69%± 3.83%and 49.96%± 7.36%, respectively, which were signifi-cantly higher (P<0.05) than that of the control group (5.23%± 2.04%). Similar results were found in the SUDHL-10 cells (P<0.05). Treatment with 5 and 10 μmol/L CAL-101 dose-dependently inhibited the migration activity of lymphoma cells to stromal cells (P<0.05). Western blot analysis showed that the expression level of ERK phosphorylation protein was significantly downregulated in the cells treated with CAL-101. A synergistic effect between CAL-101 and bortezomib was verified. That is, these two drugs can signifi-cantly inhibit the proliferation of lymphoma cells with CI values less than 1. Conclusion:The PI3Kδ-specific inhibitor CAL-101 sup-pressed the proliferation of Raji and SUDHL-10 cells, induced apoptosis, and inhibited stromal cell-derived migration. This inhibitory effect may be induced by blocking the ERK pathway. Overall, our study indicated that CAL-101 is a novel and potential agent in the therapeutic strategy against aggressive B-cell lymphoma.

Prognostic factors in solitary plasmacytoma / 中国肿瘤临床

Objective:To investigate the clinical features, treatment strategies, and relative prognostic factors in 66 patients with solitary plasmacytoma (SP). Methods:The data of 644 patients, who were diagnosed with pathologically proven plasmacytoma in Tianjin Medical University Cancer Institute and Hospital between June 2000 and October 2012, were collected. Sixty-six of these patients (10.25%) were evaluated as SP, including 45 solitary bone plasmacytoma (SBP) and 21 extramedullary plasmacytoma (EMP). Results:SBP and EMP were the two clinical subsets of SP revealing the location of the lesion. SBP mostly occurred in the axial skeleton, whereas EMP was most frequently observed in the upper respiratory tract. The differences among tumor size, serum M-protein, and serumβ2-microglobulin exhibited statistical significance. Conclusion:Large tumor size (≥5 cm), positive serum M-protein, and serumβ2-microglobulin were the factors that affected the prognosis of SBP patients. Radiotherapy and serumβ2-microglobulin>3.5 mg/L were the favorable prognostic factors for EMP patients.

Effects of the phosphoinostitide-3'-kinase delta inhibitor, CAL-101, in combination with Bortezomib on mantle lymophma cells and exploration of its related mechanism / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To investigate the effect of CAL-101, a selective inhibitor of PI3Kδ, in combination with bortezomib on the proliferation and apoptosis in human mantle cell lymphoma cell lines Z138, HBL-2 and Jeko-1 in vitro, to explore its mechanisms and provide the foundation for effective treatment strategies against mantle cell lymphoma.</p><p><b>METHODS</b>MTT assay was applied to detect the inhibitory effects of CAL-101 and bortezomib either alone or combined on Z138, HBL-2 and Jeko-1 cells. Calcusyn software was used to analyze the synergistic cytotoxicity. Western blot was used to detect the expression of PI3K-p110σ and p-Akt, Akt, p-ERK and ERK proteins after the cells were exposed to different concentrations of CAL-101. Flow cytometry was employed to assess the apoptosis rate. NF-κB kit was used to determine the changes of location of NF-κB P65, and Western blot was applied to detect the level of caswpase-3 and the phosphorylation of Akt in different groups.</p><p><b>RESULTS</b>CAL-101 and BTZ inhibited the proliferation of Z138, HBL-2 and Jeko-1 cells in a dose- and time-dependent manner. CAL-101/BTZ combination induced significantly synergistic cytotoxicity in the MCL cells. The results of Western blot assay showed that CAL-101 significantly blocked the phosphorylation of Akt and ERK in the MCL cell lines. In addition, CAL-101 combined with BTZ induced pronounced apoptosis (P < 0.01). For example, after the Z138 cells exposed to the drugs for 48 h, the apoptosis rates of the control, CAL-101, BTZ and CAL-101 + BTZ groups were: (2.6 ± 1.8)%, (40.0 ± 3.0)%, (34.0 ± 1.0)%, and (67.4 ± 1.0)%, respectively; and when drug treatment was given to HBL-2 cells over 96 h, the apoptosis rates of these four cell groups were (7.4 ± 0.6)%, (30.7 ± 5.7)%, (12.0 ± 1.0)%, and (85.0 ± 4.0)%, respectively. The combination therapy contributed to the enhanced inactivity of nuclear factor-κB (NF-κB) and Akt inactivation in the MCL cell lines (P < 0.05), however, the casepase-3 activity was up-regulated.</p><p><b>CONCLUSIONS</b>The combination of CAL-101 and bortezomib is muchmore effective in inhibiting proliferation and promoting apoptosis of mantle cell lymphoma cell lines (Z138, HBL-2 and Jeko-1), which may be mediated through inhibiting PI3K/Akt signaling pathway and the transcription of NF-κB.</p>

In vitro synergistic effect of arsenic trioxide with conventional or new drugs on the proliferation of cutaneous T cell lymphoma cells Hut-78 and Hut-102 / 中国肿瘤临床

Objective:To investigate the in vitro effect of arsenic trioxide (As2O3) alone and in combination with dexamethasone (DXM), etoposide (VP-16), methotrexate (MTX), bortezomib (BTZ), and suberoylanilide hydroxamic acid (SAHA) on the growth of human cutaneous T cell lymphoma (CTCL) cells Hut-78 and Hut-102. Methods:Hut-78 and Hut-102 cells were cultured with different concentrations of As2O3, DXM, VP-16, MTX, BTZ, and SAHA alone and As2O3 in combination with DXM, VP-16, MTX, BTZ, or SAHA for 48 h. The effects of the different samples on Hut-78 and Hut-102 cell proliferation were determined by MTT assay. Analyses using CalcuSyn software were performed to determine whether the combination of As2O3 with DXM, VP-16, MTX, BTZ, or SAHA in-duced synergistic cytoxicity. Results:As2O3, DXM, VP-16, MTX, BTZ, and SAHA alone significantly inhibited the growth of Hut-78 and Hut-102 cells in a dose-dependent manner, with a 50%inhibiting concentration of 5μmol/L, 500μg/mL, 2.5μg/mL, 1μg/mL, 10μmol/L, and 2.5μmol/L individually after 48 h of culture. As2O3 with DXM, VP-16, MTX, BTZ, or SAHA showed remarkable antitu-mor efficacy compared with that of individual applications. Conclusion:As2O3 alone or combined with DXM, VP-16, MTX, BTZ, or SAHA significantly inhibited Hut-78 and Hut-102 cell growth in vitro. This study demonstrated that As2O3 with DXM, VP-16, MTX, BTZ, or SAHA presents synergistic antitumor effects on CTCL cells and may be an optimal regimen in clinical trials of CTCL.

"Transformation of follicular lymphoma to""double-hit""or""triple-hit""lymphoma with c-MYC gene rearrangement:A report of three cases" / 中国肿瘤临床

Objective: To analyze the diagnosis and therapy for double-hit lymphoma (DHL) and triple-hit lymphoma (THL). Methods:This study involves three patients with follicular lymphoma (FL) that transformed into DHL or THL. These patients were ad-mitted to our hospital between January 2011 and December 2012. All patients were diagnosed by immunohistochemistry and fluores-cence in situ hybridization (FISH). Results:One FL patient transformed into THL and died after 3 months. The other two FL patients who transformed into DHL and who received R-CHOP and R-ESHAP regimens still failed to achieve complete remission. Conclusion:DHL is a rare type of lymphoma that usually involves the bone marrow and central nervous system. This condition is highly resistant to intensive chemotherapy. Part of the DHL cases result from FL. FISH is important for diagnosis. However, a standard treatment for this type of lymphoma remains lacking.

Effect of PI3Kδ inhibitor CAL-101 on myeloma cell lines and preliminary study of synergistic effects with other new drugs / 中华血液学杂志

<p><b>OBJECTIVE</b>To investigate the proliferation inhibitory role and mechanism of PI3Kδ inhibitor CAL-101 on multiple myeloma (MM) cells, and to provide new therapeutic options for MM treatment.</p><p><b>METHODS</b>MM cell lines U266 and RPMI8226 cells were treated with various concentrations of CAL-101. MTT assay and CalcuSyn software were performed to determine the inhibitory effect of CAL-101 and the synergistic effect with PCI- 32765, SAHA (suberoylanilide hydroxamic acid), BTZ (Bortezomib) on MM cells. The protein expression level of p-AKT, p-ERK, AKT, ERK and PI3Kδ processed by CAL-101 were analyzed by Western blot.</p><p><b>RESULTS</b>CAL-101 at concentration of 15, 20, 25, 30 and 40 μmol/L could induce significant dose-dependent proliferation inhibition on U266 cells after treatment for 48 hours. The cell proliferation inhibition rates were (33.54 ± 1.23)%, (41.72 ± 1.78)%, (53.67 ± 2.01)%, (68.97 ± 2.11)% and (79.25 ± 1.92)%, respectively. Similar results were found in RPMI8226 cell line. Western blots showed high expression level of p-AKT, p-ERK, AKT, ERK and PI3Kδ in cell lines and MM primary cells. p-AKT and p-ERK protein expression levels were down-regulated significantly by CAL-101 treatment. Synergistic effect has been verified between CAL-101 and PCI-32765, SAHA and Bortezomib in U266 cell line, and PCI-32765, Bortezomib in RPMI8226 cell line with CI values less than 1.</p><p><b>CONCLUSION</b>CAL-101 could inhibit proliferation of MM cell lines. High levels of p-AKT, p-ERK, AKT, ERK and PI3Kδ protein expression were observed in both cell lines and primary cells. Down-regulation of p-AKT and p-ERK probably related with the mechanism of CAL-101 in MM cell proliferation inhibition. CAL-101 has significant synergistic effect with PCI-32765, SAHA and BTZ.</p>

Efficacy comparision of thalidomide for 132 cases of newly diagnosed multiple myeloma with or without extramedullary disease / 白血病·淋巴瘤

Objective To investigate the clinical efficiency and effects on prognosis of thalidomide for newly diagnosed multiple myeloma (MM) with or without extramedullary disease.Methods The clinical features and prognostic factors were retrospectively analyzed in 132 patients.Analyze the efficiency of thalidomide and its effects on prognosis of MM patients with or without extramedullary disease.Results The median age of 132 patients was 59 years (28-83 years),52 patients (39.4 ％) had extramellulary multiple myeloma (EM),other 80 patients (60.6 ％) were without EM at diagnosis.The estimate overall survival (OS) of patients with EM was 42.5 months,compared with 54.3 months in those without EM,the difference was statistically significant (P =0.004).Patients accepting thalidomide therapy had a longer estimate OS than those without thalidomide therapy (50.7 months vs 41.2 months,P =0.01).For patients with EM,whether take thalidomide or not have no effect on the prognosis,the difference was not statistically significant (39.7 months vs 38.5 months,P =0.491).While for those without EM,the prognosis for patients who take thalidomide was better than that did not take thalidomide (54.6 months vs 41.2 months,P =0.027).Log-rank univariate analysis showed that accompanied with EM (P =0.004),the proportion of plasma cells≥20 ％ (P =0.02),Hb≤110 g/L (P =0.041),β2-MG ≥ 5.5 mg/L (P =0.018) and without thalidomide therapy (P =0.01) were poor prognostic factors.Multivariate analysis with COX model showed extramedullary disease,β2-MG and the proportion of plasma cells were statistically significant (P ＜ 0.05).Conclusion Patients with EM showed aggressive and complicated prognosis.Thalidomide does not improve the prognosis of patients with EM and they may need combination therapy such as bortezomib or autologous hemopoietic stem cell transplantation.