2010年 · 第123卷第22期

BackgroundRecent studies have identified signal transducer and activator of transcription 4 (STAT4) as a susceptibility gene for systemic lupus erythematosus (SLE) in different populations. In order to examine whether the allele distribution of the single nucleotide polymorphism (SNP) in geneSTAT4rs7574865 in patients with SLE is different from those of healthy controls in Chinese Northern Han population, we investigated whether the variants ofSTAT4rs7574865 were associated with any specific clinical features of SLE.MethodsWe genotyped SNPs inSTAT4rs7574865 in 252 patients with SLE and 497 healthy controls. All subjects were from the Northern part of Chinese Han population. The genotypes in rs7574865 were determined by polymerase chain reaction (PCR) and consequence direct sequencing of PCR products in the DNA samples.ResultsThere was a significant difference in distribution of the SNPs in rs7574865 between the SLE patients and healthy controls. Compared with healthy controls, there was a significant correlation between TT genotypes in rs7574865 and the risk of SLE when GG genotype was used as a reference genotype after adjusting for gender and age. The frequency of T allele in the SLE patients was strongly significantly higher than that of healthy controls. Furthermore, there was a significant difference in the distribution of SNP in rs7574865 between male and female SLE patients, when compared with healthy controls. The frequency of T allele in rs7574865 in male patients was significantly higher than that of male healthy controls or female patients. There was no significant correlation between the frequencies of T allele inSTAT4rs7574865 and the clinical features of SLE.ConclusionsThe SNP rs7574865 inSTAT4is strongly associated with risk of SLE in the Chinese Northern Han population. The TT genotype and T allele inSTAT4rs7574869 are susceptibility factors for SLE, especially for male SLE patients.

BackgroundDuloxetine, a selective serotonin and noradrenaline reuptake inhibitor, has been shown to be effective in treatment of diabetic peripheral neuropathic pain and approved for the management of patients with diabetic peripheral neuropathic pain (DPNP) in the United States, European Union, and many other countries. This study assessed the efficacy and safety of duloxetine in Chinese patients with diabetic peripheral neuropathic pain.MethodsThis double-blind, randomized, placebo-controlled, flexible-dose study treated adult patients with diabetic peripheral neuropathic pain and baseline Brief Pain Inventory (BPI) 24-hour average pain severity ratings ≥4 with duloxetine 60 mg to 120 mg once daily or placebo for 12 weeks. Dose adjustments of duloxetine or matching placebo were based upon investigator’s judgment of clinical response. Change from baseline to endpoint in BPI average pain was the primary efficacy outcome. Secondary outcome measures included BPI-severity and -Interference, Patient Global Impression of Improvement, Clinical Global Impressions of Severity, EuroQol: 5 Dimensions, Athens Insomnia Scale, and safety measures.ResultsOf 215 patients randomized, 88.4% and 82.1% of patients in placebo and duloxetine groups, respectively, completed the study. Mean change from baseline to endpoint in BPI average pain was not statistically different between the treatment groups (P=0.124). Duloxetine- treated patients showed significantly greater pain reduction compared with those in placebo group at weeks 1, 2, and 4 (P=0.004,P=0.009, andP=0.006, respectively), but not at weeks 8 (P=0.125) and 12 (P=0.107). Duloxetine-treated patients experienced statistically significant improvement in Patient Global Impression of Improvement, Clinical Global Impression of Severity, area under the curve for pain relief, BPI-severity pain right now, and BPI-interference walking ability. Patients treated with duloxetine 120 mg once daily showed significantly greater pain reduction on the Brief Pain Inventory average pain score relative to placebo. Duloxetine-treated patients reported nausea, somnolence, anorexia, and dysuria significantly more than placebo.ConclusionsAlthough the primary study endpoint was not achieved, the overall observed response pattern suggests the efficacy of duloxetine in the treatment of Chinese patients with diabetic peripheral neuropathic pain. The safety profile for duloxetine is similar to that reported in other global trials.

BackgroundGenetic modification of dendritic cells (DCs) has been used as an effective approach to enhance anti-tumor immunity. RNA interference (RNAi), which can cause the degradation of any RNA in a sequence-specific manner, is a post-transcriptional gene silencing mechanism. In this study, small-interfering RNA (siRNA) specific for the Ii gene was transfected into DCs, and the anti-tumor immunity of Ii-silenced DCs was assessed.MethodsThe silencing effect of siRNA was evaluated by Western blotting and real-time PCR analyses.In vitrocytotoxic activity of T cells was evaluated using a Cytotox 96®non-radioactive cytotoxicity assay kit. The time to tumor onset and the tumor volumes were used as reliable indices to assess the anti-tumor immunityin vivo. To further examine the mechanisms underlying the anti-tumor immunity, flow cytometry analysis was used.ResultsThe Ii expression of DCs was significantly reduced after Ii siRNA transfection. Significantin vitroanti-tumor ability was exhibited when DCs were co-transfected with Ii siRNA plus endogenous tumor antigen (P<0.05). Furthermore, tumor growth was greatly inhibited when mice were immunized with DCs transfected with Ii siRNA plus tumor antigen prior to or subsequent to tumor implantation. Flow cytometry analysisin vitroandin vivoindicated that both CD4+and CD8+T cells were significantly activated in the Ii siRNA group (P<0.05).ConclusionSilencing of the Ii gene of DCs may offer a potential approach to enhance DC-based anti-tumor immunity.

Background A retrospective analysis of clinical data were conducted reviewing patients who were given erlotinib at Peking Union Medical College (PUMC) Hospital from May 2005 to December 2009. Relationships between clinical factors, epidermal growth factor receptor (EGFR) mRNA expression, EGFRgene mutations, KRASgene mutations and clinical outcomes were investigated in Chinese patients with advanced non-small cell lung cancer (NSCLC). Methods Patients with stage IIIB/IV NSCLC who had not previously participated in erlotinib related clinical trials were enrolled into this study. All patients were given oral erlotinib 150 mg per day. Tumor samples of some patients were accessed with mutant-enriched polymerase chain reaction assay ( EGFR, KRASgene mutations) and multiplex branched DNA assay (EGFR mRNA expression). Results Seventy-nine patients were enrolled in this study, 23 patients had a partial response (PR), 36 patients had a stable disease (SD), 20 patients had a PD, with an objective response rate of 29.1%, and a disease control rate of 74.7%. Females ( P=0.023), non-smokers ( P=0.013), patients with a skin rash ( P=0.047), and with highly differentiated tumors ( P=0.037) were significantly correlated with the objective response rate. Patients with a lower ECOG PS ( P=0.002), highly differentiated tumors ( P=0.014), non-smokers ( P=0.002), and patients with a skin rash ( P<0.001) were significantly correlated with the disease control rate. The median progression-free survival was 35 weeks (95% CI: 13–57 weeks) and 1-year survival was 72.3%. Highly-differentiated tumors ( P=0.027) and patients with a skin rash ( P<0.001) were significantly correlated with PFS. Seventeen patients were tested for EGFR/KRAS gene mutations and EGFR mRNA expression. Progression-free survival (PFS) of patients with EGFR exon 19/21 mutations was 66 weeks, longer than patients with wild type EGFR exon 19/21 ( P=0.018). No significant relationships were found between EGFR mRNA expression, EGFR exon 19/21 mutations, and KRAS mutations and Objective response rate or disease control rate. The most common adverse events were skin rash (60.9%) and diarrhea (26.6%). Conclusions Erlotinib was safe and effective in treating Chinese patients with advanced NSCLC. The PFS of patients who had a skin rash, highly differentiated tumors, or EGFR exon 19/21 mutations was significantly longer.

BackgroundThe prognosis is poor for patients with relapsed or refractory non-Hodgkin’s lymphoma (NHL). The main reason for poor prognosis is multidrug resistance (MDR), for which the main phenotype is overexpression of P-glycoprotein (P-gp). This study explored the efficacy of ligustrazine as a salvage agent in patients with relapsed or refractory NHL, and the relationship to P-gp expression.MethodsSixty patients were randomized to a reversal agent group, receiving ligustrazine plus chemotherapy, and a control group, receiving chemotherapy alone. Flow cytometry was performed to evaluate P-gp expression.ResultsIn the 56 patients we were able to evaluate, there was no statistically significant difference in progression-free survival (PFS) in the two groups (P=0.0651), but the reversal agent group had a higher overall response rate (ORR) than did the control group (P=0.048). Forty-one of 56 patients had P-gp(+) tumor cells. Among these patients, six of eighteen patients in the reversal agent group and in the control group had complete remission or complete remission/unconfirmed (CR+CRu) reflecting a significant advantage in the reversal agent group (P=0.048). Patients with P-gp(+) tumor cells in the reversal agent group had a higher overall response rate (ORR) than did the control group (11/18 vs. 6/23,P=0.024). Kaplan-Meier Survival curve and log-rank test demonstrated that patients with P-gp(+) tumor cells in the reversal agent group had longer progression-free survival than did the control group (P=0.0464). A small number of patients who received ligustrazine had a decrease in blood pressure.ConclusionLigustrazine as a salvage agent in combination with chemotherapy can elevate response rate, prolong PFS with manageable toxicity, and correlate with P-gp expression in relapsed or refractory NHL.

BackgroundThere are no data on more tolerable capecitabine doses in elderly patients in Chinese population. The aim of this study was to evaluate the activity and safety of capecitabine combined with weekly docetaxel for the treatment of anthracycline-resistant metastatic breast cancer (MBC) in older Chinese patients.MethodsMBC patients aged>65 years pretreated with 1–5 prior chemotherapy regimens, including an anthracycline, received oral capecitabine 825 mg/m2twice daily, days 1–14, plus docetaxel 30 mg/m2on days 1 and 8 every 21 days. All 41 enrolled patients received at least 1 dose of treatment and were evaluable for safety; 38 received at least 2 cycles (median 4, range 2–8) and were evaluable for efficacy.ResultsThe overall objective response rate was 47%, including complete responses in 8% of patients. Median time to progression was 8.9 months. Median overall survival was 17.6 months. The most common side effects were haematological and gastrointestinal toxicities and hand-foot syndrome. The only grade 3/4 adverse events were neutropenia (12%), alopecia (7%), grade 3 nausea and vomiting (2%) and grade 3 nail toxicity (2%).ConclusionsCapecitabine 825 mg/m2twice daily plus weekly docetaxel is active with an acceptable safety profile in Chinese women>65 years with anthracycline-resistant MBC. Efficacy and tolerability compare favourably with previously reported trials evaluating higher capecitabine doses in combination with 3-weekly or weekly docetaxel.

BackgroundThe resection and reconstruction of the hepatic artery is often required in radical surgery for hilar cholangiocarcinoma. In this study, we report our experience in performing arterioportal shunting as an alternative for the arterial reconstruction.MethodsFour patients with hilar cholangiocarcinoma underwent extended left hepatectomy and caudate lobectomy combined withen blocresection of the hepatic artery and arterioportal shunting with restriction of the arterial caliber. The efficacy of arterioportal shunting was assessed by computed tomography angiography (CTA).ResultsAll the four patients recovered uneventfully without any complications. CTA showed a patent shunt and normal liver regeneration. No signs of portal hypertension were found at one year of follow-up.ConclusionsArterioportal shunting with restriction of the arterial caliber appears to be a feasible and safe alternative for the microvascular reconstruction after hepatic artery resection in radical surgery for hilar cholangiocarcinoma.

BackgroundThe consumption of carbohydrate-electrolyte beverages (CEs) has been known to be more effective than plain water for recovery from dehydration. This phenomenon suggests that the ingestion of CEs after dehydration is better than water for maintaining body fluid and plasma volume, and for the recovery from hemoconcentration and high blood viscosity as well. High blood viscosity causes infarction and other cardiovascular events. In this study, CE was compared with water and tea for the ability to reduce increased blood viscosity after dehydration.MethodsA crossover random control study was conducted to assess the effectiveness of three beverages for rehydration and decreasing of blood viscosity. Following exercise-induced dehydration of 2.2% of body weight in a permanent warm environment, 10 male subjects rested in a thermoneutral environment for 3 hours (rehydration period, REP). The subjects ingested test beverages equal to their body weight loss during the first 20 minutes in REP. Blood and urine samples were obtained throughout the experiments to assess the rehydration effect.ResultsThe change in blood viscosity at a shear rate of 5/s was significantly lower in CE ((–1.66±0.21) mPa∙s) in comparison to water ((–0.95±0.26) mPa∙s) or tea ((–0.92±0.14) mPa∙s) at 60th minute during the REP. The fluid retention rate was significantly greater for CE ((77.0±3.9)%) than water ((61.2±3.4)%) and tea ((60.5±3.7)%) for 3 hours of rest in REP.ConclusionsThe recovery from high blood viscosity induced by dehydration was higher with CE consumption than with water or tea. TheseResultssuggest that CE is useful for normalizing increased blood viscosity due to exercise-induced dehydration.

BackgroundVariations in position and relationship between the internal jugular vein (IJV) and the common carotid artery (CCA) may lead to inadvertent artery puncture which could be disastrous during central venous access. We demonstrated the anatomic relationship of the IJV with CCA in order to find the optimal site and avoid damage of CCA.MethodsTwo hundred and twenty surgical patients were enrolled. We analyzed the distance and relationship between the IJV and CCA at three cross sections (upper border of the thyroid cartilage, cricoid cartilage and second tracheal ring) by ultrasonography and then measured the diameters of the IJV and CCA and the distances from the IJV and CCA to the skin.ResultsTwenty patients were excluded on the basis of exclusion criteria. From up to down at bilateral neck, the IJV became gradually more superficial while the CCA became deeper. The diameter of the IJV became gradually larger while that of the CCA gradually smaller. The IJV from lateral to the CCA gradually moved to the front of the CCA, so the percent overlap of the IJV and CCA was gradually increased. Compared with the left side at the same transverse scan level, the distance between the CCA and IJV was wider at the right side and the right IJV was wider. The IJV location in 11 patients was medial to the CCA at one or more transverse scan levels. The angle between the IJV and CCA was significantly small in elderly patients. The CCA had already furcated at the level of the upper border of the thyroid cartilage in seven patients at the right side and in 12 patients at the left side.ConclusionsThere are variations in the position and relationship between the IJV and CCA. It is relatively more difficult to puncture at the left side of the neck, at a lower position or in elderly patients. On the contrary, it is relatively easier to puncture at the right side, at the level of the cricoid cartilage or in younger patients.

BackgroundA generally accepted guideline ("41 rules") published by the International Consensus Group for Hematology Review (ICGHR) can not be suitable for all the laboratories because the facility type, laboratory requirements, sample volume, review rate, turn around time, instrument model and characters etc. are quite different from each other, which may cause a higher workload for microscopy review or lead to false or misleading Results. Therefore, we decided to develop the personalized review criteria for 4 series of hematology analyzers in the same hospital, and describe all the implement procedures in detail.MethodsThe total 1770 blood samples were collected from Peking Union Medical College Hospital. Referring to the suggested criteria by international consensus group for hematology review ("41 rules"), the personalized review criteria for 4 series of hematology analyzers including Siemens Advia 2120, Sysmex XE-2100, Sysmex XT-1800i and Sysmex XS-800i were established and validated by adjusting the rules in order to reduce the false positive rate and keep the false negative acceptable by clinical.ResultsUsing the “41 rules”, high review rates of 37.94%, 35.56%, 33.44% and 37.94% were got respectively in Siemens Advia 2120, Sysmex XE-2100, Sysmex XT-1800i and Sysmex XS-800i. Three false positive rules mainly were observed in all of 4 analyzers: white blood cell<3×109/L or>30×109/L, platelet<100×109/L or>1000×109/L and immature granulocyte. Specialized rules were observed in different series of analyzers, atypical/variant lymphs flag were found mainly in Sysmex XE-2100, Aniso-RBC were found mainly in Sysmex XT-1800i, flag of "immature granulocyte" mainly in Sysmex XS-800i, Micro-RBC, Macro-RBC and Aniso-RBC mainly in Siemens Advia 2120. Rules of immature granulocyte, blast, and NRBC flag would be mainly triggered by hematology malignant tumor. We could not delete these rules due to the risk of false negative of serious disease, other rules were deleted or revised. After continually optimizing to the rules, we finalized the criteria suitable for Siemens Advia 2120, Sysmex XE-2100, Sysmex XT-1800i and Sysmex XS-800i in our laboratory. The false negative rates were 2.94%, 2.86%, 3.10% and 2.78%, the review rates were 31.07%, 30.00%, 30.01% and 30.09%, and there was no hematology malignant tumor missed. Validated by 547 samples, the false negative rates of our optimized rules were 0.37%, 0.55%, 0.55%, and 0.91% respectively.ConclusionThe criteria can be based on the criteria established by International Consensus Group for Hematology Review but must be optimized according to the different requirements.

BackgroundTo compare clinical efficacy and toxicity of irinotecan combined with 5-fluorouracil and leucovorin with those of oxaliplatin combined with 5-fluorouracil and leucovorin as first-line therapy for advanced colorectal cancer.MethodsLiterature search was performed by keywords "irinotecan", "oxaliplatin" and "colorectal cancer" on all randomized controlled trails reported on irinotecan versus oxaliplatin combined with 5-fluorouracil and leucovorin as first-line therapy for advanced colorectal cancer in MEDLINE, OVID, Springer, Cochrane Controlled Trials Register (CCTR) and CBMdisc (Chinese Biology and Medicine disc) before January 2010. Two authors drew the details of trial design, characteristics of patients, outcomes, and toxicity from the studies included. Data analysis was performed by RevMan 4.2.ResultsAccording to the screening criteria, 7 clinical studies with 2095 participants of advanced colorectal cancer were included in this meta analysis. The baseline characteristics of irinotecan group were similar to those of oxaliplatin group. The response rate of oxaliplatin group was higher than that of irinotecan group (relative risk (RR)=0.82, 95% confidence interval (95%CI) (0.70, 0.96),P=0.01), and the median overall survival of oxaliplatin group was longer by 2.04 months than that of irinotecan group (95%CI(–3.54, –0.54),P=0.008). In the comparison of grade 3–4 toxicity between the two groups, the incidences of nausea, emesis, diarrhoea and alopecia in irinotecan group were higher than those in oxaliplatin group (RR=1.94, 95%CI(1.22, 3.09),P=0.005; 1.71, 95%CI(1.34, 2.18),P<0.001; 14.56, 95%CI(4.11, 51.66),P<0.0001), respectively. However, the incidence of neurotoxicity, neutropenia and thrombocytopenia in irinotecan group were lower than those in oxaliplatin group (RR=0.06, 95%CI(0.03, 0.14),P<0.00001; 0.70, 95%CI(0.55, 0.91),P=0.006; 0.18, 95%CI(0.05, 0.61),P=0.006), respectively.ConclusionsBoth irinotecan and oxaliplatin combined with 5-fluorouracil and leucovorin were effective in the first-line therapy of advanced colorectal cancer. However, the combined regimen of oxaliplatin plus 5-fluorouracil and leucovorin is more excellent. Irinotecan trended to result in more gastrointestinal tract reactions than oxaliplatin did, but the myelosuppression and neurotoxicity were more frequent in oxaliplatin regimen than irinotecan regimen.

Background Dual anti-platelet treatment with aspirin and clopidogrel is established foundation for patients undergoing percutaneous coronary intervention (PCI) to prevent thrombotic events. The present study was conducted to examine whether the CYP2C19 681G>A polymorphism and cigarette smoking had independent or interactive effect on response to clopidogrel. Methods Among 722 Chinese Han patients undergoing elective coronary stent placement due to stable angina pectoris, a loading dose of 300 mg clopidogrel was given to all patients and a daily maintenance dose of 75 mg for a minimum of 12 months. CYP2C19 681G>A polymorphism was genotyped. The platelet reactivity was measured by light transmittance aggregometry (LTA) with 5 μmol/L adenosine diphosphate (ADP) induced. The poor response was defined as 10% or less absolute difference between aggregation at baseline and 24 hours after loading dose of clopidogrel. Results The results showed that the poor-response to clopidogrel was presented in 105 patients (14.5%). Overall, the genotype GA/AA carriers were likely to be poor-responsive cases (19.6% vs. 11.0%, P=0.001) with odds ratio (OR) of 1.971 (95% CI: 1.296–2.998, P=0.002), compared with the GG homozygotes. Meanwhile, compared with nonsmokers, the smokers showed lower rate of poor-response (10.9% vs. 17.3%, P=0.015) with OR of 0.582 (95% CI: 0.374–0.904, P=0.016). The smokers with GG genotype had the lowest risk with OR of 0.487 (95% CI: 0.246–0.961, P=0.038) while nonsmokers with GA/AA genotype had the highest risk of poor-response with OR of 1.823 (95% CI: 1.083–3.068, P=0.024), compared with nonsmokers with GG genotype. However, there was no significant interaction between genotype and smoking. Conclusion Our study indicated that both CYP2C19 polymorphism and smoking independently affected response to clopidogrel.

ObjectiveThere is a paucity of published works that systematically evaluate gene anomalies or clinical features of patients with renal cysts and diabetes syndrome (RCAD)/maturity onset diabetes of the young type 5 (MODY5). The purpose of this review was to systematically assess the detection rate, genetic and phenotypic implications of heterozygous autosomal dominant TCF2 anomalies.Data sourcesMEDLINE database was searched to select articles recorded in English from 1997 to 2008. The focus was monoallelic germline TCF2 gene mutations/deletions. Biallelic inactivation, polymorphisms, DNA modification (hypomethylation and hypermethylation), loci associated with cancer risk, and somatic TCF2 anomalies were all excluded. Study selection After searching the literature, 50 articles were selected.ResultsThe detection rate of TCF2 anomalies was 9.7% and varied considerably among MODY (1.4%), renal structure anomalies (RSA) (21.4%) and RSA with MODY (41.2%) subgroups. Mutations were strikingly located within the DNA binding domain and varied among exons of the DNA binding domain: exons 2 and 4 were the hottest spots, while mutations were sporadically distributed in exon 3. The consistent phenotypes were RSA (89.6%) and diabetes mellitus (DM) (45.0%). However, the concurrence of RSA and DM was relatively low (27.5%), which hinders the optimal performance of genetic testing and obtainment of timely diagnosis. Other organ involvements were complementary and necessary for the early identification of patients with TCF2 anomalies. Analysis of phenotypes of TCF2 point mutations showed significant differences in the detection rates of RSA, impaired renal function (IRF) and DM according to mutation type but not mutation location.ConclusionThese valuable features of TCF2 anomalies that previously did not receive sufficient attention should not be neglected.

ObjectiveTo review the current research into Foxp3+ regulatory T cells (Treg) cell surface molecules, plasticity of Treg cells and mechanisms of Treg cell suppression and to explore the possibilities to interfere in Treg cell suppression of anti-tumor immunity.Data sourcesA literature search of all English articles was performed on the online electronic PubMed database dated 1995 to 2010. The keywords searched included: CD4+CD25+Foxp3+ regulatory T lymphocytes, cancer, and immunotherapy. After finding relevant articles within these search limits, a manual search was conducted through the references from these articles.Study selectionArticles regarding the role of Treg cells in tumor immunity and the utility of Treg cells in tumor immunotherapy.ResultsThe results show that significant numbers of Treg cells are found in many tumors and it has been shown that the number of tumor infiltrating Treg cells correlates with adverse clinic outcomes. Treg cells are emerging as a key component of acquired tolerance to tumors.ConclusionsSeveral mechanisms of immunosuppression can be mediated by Treg cell function. Distinct immunosuppressive molecules expressed by Treg cells or diverse molecules related to Treg induction or migration represent potential drug targets for caner immunotherapy.