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Long-term Outcomes of Patients with Newly Diagnosed NK/T-cell Lymphoma Treated by EPOCH Regimen

Zexiao LIN ; Yan GAO ; Huiqiang HUANG ; Xubin LIN ; Qingqing CAI ; Zhongjun XIA ; Xiaoxiao WANG ; Wenqi JIANG

Journal of Sun Yat-sen University(Medical Sciences).2010;31(2):274-277.

[Objective]This study was aimed to evaluate treatment outcomes and toxicity of continuous-infusion EPOCH regimen for NK/T-cell lymphoma(NK/TCL).[Methods]From June 2003 to June 2008,34 patients including 30 nasal NK/TCL (88.2%)and 4 nasal type NK/TCL(11.8%)received doxorubicin,vincfistine,etoposide over 96 hours infusion with bolus eyelophosphamide and oral predinisone(EPOCH)chemotherapy as first-line treatment.Median cycles of EPOCH administered were 2.5(1-6 cycles).Additional involved field radiation therapy(IFRT)was administered to patients with localized nasal focus after chemotherapy.[Results]Among 34 patients,33 were eligible for response evaluation.The response rate(RR)was 60.6% (20/33)with complete remission(CR)rate of 45.5%(15/33).The RR of patients with nasal NK/TCL was 66.7%(20/30)with CR rate of 50%(15/30).Only one of the 3 nasal type NK/TCL patients achieved stable disease(SD),the other 2 had progressive disease(PD)during chemotherapy.After a median follow-up of 22(2-68)months,the estimated 3-year overall survival rate(OS)was 52.2%.For patients with nasal NK/TCL,the estimated median survival time was not reached,the 3-year OS was 59.4%.For patients with nasal type NK/TCL,the estimated median survival time was only 7 months.The CR rate was 75.0% for localized nasal NK/TCL who received initial EPOCH chemotherapy followed IFRT with the 3-year OS of 75.0%.Major adverse effect was myelosuppression.The incidence of grade Ⅲ～Ⅳ neutropenia was 30.9%.No treatment-related mortality occurred.[Conclusions]EPOCH regiment was effective and well tolerant for nasal NK/TCL.Combined EPOCH chemotherapy followed by IFRT produced promising outcome for patients with localized disease.However,patients with nasal type NK/TCL responded poorly and more efficacious treatment strategies are urgently needed.

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Clinical Outcomes of Patients with Relapse and Refractory Non-Hodgkin's Lymphoma Treated by DHAOx Regimen

Qingqing CAI ; Yan GAO ; Ying ZHOU ; Qing BU ; Xubin LIN ; Xiaoxiao WANG ; Zexiao LIN ; Huiqiang HUANG

Journal of Sun Yat-sen University(Medical Sciences).2010;31(2):269-273.

[Objective]To evaluate the clinical efficacy and side effects of DHAOx±R regimen in the patients with relapsed and refractory non-Hodgkin's lymphoma(NHL).[Methods]Twenty patients with relapsed or refractory NHL were enrolled into this study in Cancer Center of Sun Yat-sen University.These patients were treated with DHAOx±R regimen(Dexamethasone 20 mg/day intravenous(Ⅳ)on day 1 to day 4,cytarabine 2 000 mg/m~2 3 h Ⅳ,every 12 hours on day 2;oxaliplatin 130 mg/m~2 2 h Ⅳ on day 1;with or without rituximab 375 ms/m~2 on day 0).Six patients were followed by high dose chemotherapy with autologous peripheral blood stem cell transplantation.Response to treatment wag assessed according to The International Working Group Criteria,including CR,PR,SD and PD.Side effects were graded according to WHO criteria,including 0-Ⅳ grades.[Results]Twenty patients received 47 cycles chemotherapy,13 patients(65%)received DHAOx chemotherapy and 7(35%)received DHAOx+R.The response rate(RR)for the whole group was 55%(11/20)with comeplete response(CR)rate 35%(7/20).The response can also be obtained in the patients who were already treated by platinum-based regimen before.The major toxicity Wag myelosuppression.The incidence of grade Ⅲ～Ⅳ neutropenia Wag 35%(16/47),and febrile neutropenia was 17%(8/47).The incidence of grade Ⅲ～Ⅳ thrombocytopenia was 20%(9/47).Eight cycles(17%)occurred mild neumtoxicity.With median follow-up of 12 months,1 and 2-year overall survival rate were 70.6%.[Conclusion]DHAOx was an effective regimen for recurrent and relapsed NHL patients with mild side effects and further investigation is needed.

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Prognostic Analysis of Skull-base Invasion of Nasopharyngeal Carcinoma Based on Magnetic Resonance Imaging

Lei CHEN ; Wenfei LI ; Lizhi LIU ; Yanping MAO ; Linglong TANG ; Ying SUN ; Aihua LIN ; Li LI ; Jun MA

Journal of Sun Yat-sen University(Medical Sciences).2010;31(2):258-264.

[Objective]To evaluate the prognostic value of skull-base invasion of nasopharyngeal carcinoma(NPC)based on magnetic resonance imaging(MRI).[Methods]A total of 924 patients who were diagnosed with NPC between 2003 and 2004,had undergone MRI scan and received mdiothempy as their primary treatment,and had no distant metastasis were included in this study.MRI images and medical records were analyzed retrospectively.All the 924 eases.patients who developed skull-base invasions based on MRI,315 patients with T3 disease and 227 patients with T2 disease were selected for analysis.The staging was according to the sixth edition of the American Joint Commission on Cancer(AJCC)staging system.[Results]Incidence of skullbase invasion according to MRI was 55.4%.Of 924 cases.skull-base invasion on MRI was not an independent prognostic factor for overall survival(OS)and distant metastasis-free survival(DMFS),but was a marginally significant independent prognostic factor for local relapse-free survival(LRFS),P=0.068.Grading of MRI-detected skull-base erosion according to the site of invasion was an independent prognostic factor for OS(P=0.002 and P=0.005)and DMFS(P=0.001 for both)in the 512 patients with skull-base invasions and 315 patients with T3 disease.Severe-grade of skull-base invasion on MRI was an independent prognostic factor for OS and DMFS in the 924 patients(P ＜ 0.001 for both).No significant differences were observed on OS,LRFS,and DMFS between T2a patients and T3 patients with low-grade of MRI-deteeted skull-base involvement.[Conclusions]Skull-base invasion based on MRI is not an independent prognostic factor for NPC.However,severe-grade of invasion according to the site of involvement has positive prognostic value.

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Roles of Tumor Infiltrating Dendritic Cells and T Lymphocytes in Tumor Immunity of EBV-associated Gastric Carcinoma

Lin XIAO ; Dan HE ; Yungang DING ; Zhiying FENG ; Chunkui SHAO

Journal of Sun Yat-sen University(Medical Sciences).2010;31(2):253-257.

[Objective]To explore the roles of TIDC(tumor infiltrating dendritic cell)and TIL-T(tumor infiltrating T lymphocyte)in tumor immunity of EBV-associated gastric carcinoma(EBVaGC)and their clinical significance.[Methods]TIDC and TIL-T in EBVaGC(n=49)and EBVnGC(EBV-negative gastric carcinoma)(n=20)were detected by immunohistochemistry method and then their subtypes and their relationships with clinical and pathological factors were analyzed.[Results]Mild infiltration was detected in 29 of 49(59.2%)EBVaGCs and 18 of 20(90%)EBVnGCs,while marked infiltration of TIDC was detected in 20 of 49(40.8%)EBVaGCs and 2 of 20(10%)EBVnGCs.And the difference between the two groups was significant (P=0.013).The number of TIL-T in EBVaGC was hisher than that in EBVnGC(P=0.017),and most of them were CTLs.The number of TIL-T was positively correlated with that of TIDC(r=0.386,n=49,P=0.006).The degree of TIL-T infiltration in EBVaGC had negative relationship with the lymph node metastasis(P＜0.001),while TIDC had no relationship with the clinical features.[Conclusion]TIDC and TIL-T may play important roles in the tumor immunity of EBVaGC;TIDC may contribute to the TIL-T recruitment in EBVaGC.

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Effects of Endotoxin on Growth Activity and Gap Junction of NRK52E Cells

Jing WEI ; Xiaoliang GAN ; Chenfang LUO ; Xiaoyun LI ; Jinghui CHEN ; Ziqing HEI

Journal of Sun Yat-sen University(Medical Sciences).2010;31(2):249-252.

[Objective]This study was designed to observe the effects of endotoxin(LPS)on the growth activity and gap junction(GJ)of NRK52E cells.[Methods]The NRK52E cells were divided into control group and LPS groups,and the NRK52E cells in LPS groups were treated with LPS 10 ng/mL,50 ng/mL,100 ng/mL,500 ng/mL,and 1 000 ng/mL for 24 h respectively.The NRK52E cells growth activity was measured through MTT method,and the function of gap junction of NRK52E cells was measured through the method of fluoroimmunoassay.The protein expression of connexin 43(Cx43)in control group,LPS 10 ng/mL group,and LPS 100 ng/mL group were also determined by Western blotting.[Results]①Compared with control group and LPS 10 ng/mL group,The NRK52E cells growth activity decreased significantly in LPS 50 ng/mL,100 ng/mL,500 ng/mL,and 1 000 ng/mL groups(P＜0.01).②Compared with control group,the function of GJ decreased significantly in LPS 100 ng/mL,500 ng/mL,and 1 000 ng/mL groups(P＜0.01).③There were negative correlations among the concentration of LPS and NRK52E cells growth activity and GJ function respectively(r=-0.941,-0.872,P＜0.01).④Compared with control group,the protein expression of Cx43 were decreased significantly in LPS 10 ng/mL and 100 ng/mL groups(P＜0.01).[Conclusions]LPS can inhibit the NRK52E cells growth activity in a dose-depend manner.GJ function is one of the mechanisms.

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Effect of Converted Regulatory T Cells with Renca Conditioned Media on Suppressive Profile of Allo-immunity in Mice

Lichen TENG ; Longshan LIU ; Yajuan SU ; Xiaopeng YUAN ; Jun LI ; Qian FU ; Siyang CHEN ; Changxi WANG

Journal of Sun Yat-sen University(Medical Sciences).2010;31(2):242-248.

[Objective]This study was designed to investigate capability of the conditioned media that originated from Renca cells to convert CIM~+ CD25~- T cells into CD4~+ CD25~+ T cells,which can exert immunosuppressive effect on effector T cells in vitro and in vivo.[Methods]The common media were mixed with the conditioned media at different ratios,and fresh enriched CD4~+ CD25~- T cells with MACS were cultured in mixed media for 7 days.At end-point of culture,the cells were collected and detected phenotypes in flow cytometer.Moreover,we detected immunosuppressive effect of converted CD4~+ CD25~+ T cells on effeetor T cells proliferation in one-way mixed lymphocytes reaction by using CCK-8,and we observed survival time and histology of grafts.The delayed type hypersensitivity was determined 14 days after transplantation.[Results]The mixed media could increase ratio of CD4~+ CD25~+ Foxp3~+ T cells in conditioned media ratio-dependent(P＜0.05),compared with control groups,when the mixed media contained no mote than 75% of conditioned media.The converted CD4~+ CD25~+ T cells significantly suppress proliferation of effector T cells in vitro,and prolong survival time of grafts,which were(29.6±1.4)d in converted CD4~+ CD25~+ T cells treated groups(P＜0.05),compared with that in untreated groups(9.8±0.6 d)or PBS treated groups(10.9±0.6 d).Moreover,delayed-type hypersensitivity reaction were conducted at day 14 after transplantation in the recipients,and the results showed that less pad swelling in the group treated with converted CD4~+ CD25~+ T cells than other control groups was found,according to measurement of pad swelling.In addition,progressed to complete necrosis of grafts were exhibited in the mice treated with PBS and untreated mice,whereas better healing of grafts and less lymphocytes infiltration were displayed in the mice treated with converted CD4~+ CD25~+ T cells,which were similar to the mice treated with natural regulatory T cells.[Conclusion]The converted CD4~+ CD25~+ T cells with Renca conditioned media play suppressive role in vitro and in vivo.

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Investigation and Significance of Cytokines in Local Tissues of Radiation-induced Oral Mucositis in a Rat Model

Chunyang LI ; Xiaohua CHEN ; Xiaoan TAO ; Juan XIA ; Bin CHENG

Journal of Sun Yat-sen University(Medical Sciences).2010;31(2):231-237.

[Objective]This study was designed to explore the dynamic changes of cytokines in the local tissues of radiationinduced oral mucositis in a rat model.[methods]The rat oral mucosal tissues were obtained at 5 d,8 d,and 14 d after irradiation.which were received single X-ray irradiation of 30 Gy locally.RayBio~((R)) Rat Cytokine Array was applied to analyze the 19 cytokines.The mRNA levels of the 8 inflammatory-related cytokines were analyzed by real time-PCR.ELISA was employed to detect IL-1α,IFN-γ,and TIMP-1 protein levels.[Results]Cytokine array detection showed that cytokines such as Frac,IL-4,IL-6,IL-10,and TNF-α were down-regulated after irradiation.IL-1β,LIX,VEGF,and β-NGF were no obviously changed at the same time corse.The elevate range less than 2 fold of the CINC-2,GM-CGF,Leptin,MCP-1,and MIP-3α after irradiation were detected.The increasing range more than 2 fold of CINC-3,INF-γ,IL-1α,and TIMP-1 post irradiation were detected.The mRNA levels of anti-apoptosis,such as Bcl-2,and TNF-α,IL-6,VEGF,and IL-1β were low down,while the levels of promoting apoptosis cytokine such as Bax,and neutrophil recruitment associated cytokines,CINC,and TLR-9 were up-regulated after irradiation.The ELISA results of IL-1α,IFN-γ,and TIMP-1 were identical with the results of the two previom analyses.[Conclusion]The results of the three methods in the study should present evidences to prove each other.Some cytokines in the local lesion of oral mucositis during the initiate,development,and progression stages were blocked,while others were positively up-regulated to involving the control of the pathogensis of oral mucositis.

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Mechanism of Tubular Epithelial Hypertrophy Induced by High Glucose

Xun TANG ; Li ZENG ; Dehong CAI ; Jun ZHANG

Journal of Sun Yat-sen University(Medical Sciences).2010;31(2):225-230.

[Objective]To study the mechanism of tubular epithelial hypertrophy induced by high glucose.[Methods]Human tubular epithelium line HK-2 cells were cultured in DMEM/F12 medium containing 1 g/L glucose(normal control group),4.5 g/L glacose(high slucose group),and 1 g/L glucose+3.5 g/L mannitol(iso-osmia control group),respectively.The cells of every group after cultured for 24 h,48 h.and 96 h were collected.The mRNA levels of CTGF and p27~(kip) were detected by real-time PCR.The protein levels of CTGF and p27~(kip) were detected by Western blot.The cellular proliferative activities were observed by MTT.The total cellular protein contents were detected by Bradford method.The cell cycle process was analyzed by flow cytometry.The cells of every group after being cultured for 30 win,1 h,24 h,and 48 h were collected.The levels of phospho-ERK1/2 were detected by Western blot.Every step was repeated for 3 times.[Results]High slucose could significantly up-regulate the mRNA and protein levels of CTGF and p27~(kip),activate ERK1/2 signal conductive pathway in HK-2 cells,make more cells arrest in G1 phase,decrease cellular proliferative activities,increase total cellular protein content reflecting cellular hypertrophy.[Conclusion]CTGF is an important mediator of tubular epithelial hypertrophy induced by high slucose.The mechanism is that CTGF up-regulates the p27~(kip) expression through activating ERK1/2 pathway.Up-regulated p27~(kip) lead proliferative cell to be arrested in G1 phase and cause cellular hypertrophy.

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Effects of N-methyl-N-cis-styryl-cinnamamide on Penicillin-induced Epileptiform Discharges in Rats

Jidong WU ; Sichun HE ; Xuesong HUANG ; Weizai SHEN

Journal of Sun Yat-sen University(Medical Sciences).2010;31(2):213-220.

[Objective]To investigate the effects of the seed extract of Clausena lansium,N-methyl-N-cis-styryl-cinnamamide,on the penicillin-induced epilepsy in rats.[Methods]Thirty-two Sprague-Dawely rata were randomly divided into four groups with 8 rats in each group:normal control(20 mL/L Tween 80+Normal Saline),model control(20 mL/L Tween 80+Penicillin),low dose treatment(Cinnamamide 75 mg/kg+Penicillin),hish dose treatment(Cinnamamide 150 mg/kg+Penicillin).The epilepsy rat model was established by localized intracortical injections of penicillin.The effects of pretreatments of the rats with N-methyl-N-cis-styryl-cinnamamide(intraperitoneal injection,ip)on the penicillin-induced seizure activities and the epileptiform discharges recorded by electrocorticogram(ECoG)were observed.[Results]The penicillin-induced seizure was significantly lightened in both the pretreatment groups(75 and 150 mg/kg N-methyl-N-cis-styryl-cinnamamide),compared with the model group.N-methyl-N-cis-styryl-cinnamamide(75 and 150 mg/kg)could significantly prolonged the latency of epileptiform activities,shorten the duration of epileptiform discharges and decreased the mean spike frequency in the late stage(P＜0.05 or P＜0.01).However,there was no significant difference in the highest value or the lowest value of the epileptiform waves between the model and cinnamamide treatment groups.[Conclusion]The seed extract of Clansena lansium,N-methyl-N-cis-styryl-cinnamamide,can significantly inhibit the seizure and epileptiform discharges caused by penicillin-localized injections in the cortex of rats,suggesting that the natural substance has an anticonvulsive function.

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Research Progress of Solid Tumor Stem Cells

Erwei SONG

Journal of Sun Yat-sen University(Medical Sciences).2010;31(2):172-178.

The investigation and study of cancer stem cells(CSC)have received enormous attention since the theory has been proposed,but remain topics of considerable controversy.A correct understanding of the biological characteristics of cancer stem cells and relevant mechanisms,to find new ways and methods to cure cancer are currently the most important direction.In the following text,we discuss the origin,the identification,regulatory pathway,micro-environment,the role of miRNA in the CSC and the new potential therapeutic targets elucidated by considering cancer as a problem in stem cell biology.

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