Population pharmacokinetics and individualized dosing of tigecycline for critically ill patients: a prospective study with intensive sampling.

Background: Due to the heterogeneity of critically ill patients, the pharmacokinetics of tigecycline are unclear, and the optimal dosing strategy is controversial. Methods: A single-center prospective clinical study that included critically ill patients who received tigecycline was performed. Blood samples were intensively sampled (eight samples each), and plasma drug concentrations were determined. A population pharmacokinetic (PPK) model was developed and evaluated by goodness-of-fit plots, bootstrap analysis and visual predictive checks. Monte Carlo simulation was conducted to optimize the dosage regimen. Results: Overall, 751 observations from 98 patients were included. The final PPK model was a two-compartment model incorporating covariates of creatinine clearance on clearance (CL), body weight on both central and peripheral volumes of distribution (V1 and V2), γ-glutamyl transferase and total bilirubin on intercompartment clearance (Q), and albumin on V2. The typical values of CL, Q, V1 and V2 were 3.09 L/h, 39.7 L/h, 32.1 L and 113 L, respectively. A dosage regimen of 50 mg/12 h was suitable for complicated intra-abdominal infections, but 100 mg/12 h was needed for community-acquired pneumonia, skin and skin structure infections and infections caused by less-susceptive bacteria. Conclusion: The Tigecycline PPK model was successfully developed and validated. Individualized dosing of tigecycline could be beneficial for critically ill patients.

Timely Reduction of Triglyceride Levels Is Associated With Decreased Persistent Organ Failure in Hypertriglyceridemic Pancreatitis.

OBJECTIVES: The aim of the study was to examine the relationship between the reduction of serum triglycerides (TGs) and the severity of disease in patients with hypertriglyceridemic pancreatitis (HTGP). METHODS: A retrospective study was conducted among patients with HTGP. Serum TGs measured on admission (TG0), 24 hours after admission (TG24), and 48 hours after admission (TG48) were compared between patients with and without persistent organ failure (POF). Multivariable analysis determined whether elevated TG levels were independently associated with POF. RESULTS: A total of 242 patients were included, of which 62 patients (25.6%) developed POF. Patients who developed POF had higher TG levels of TG0, TG24, and TG48 than those without POF (all P < 0.05). Patients with earlier TG levels of less than 5.65 mmol/L were proportionally less likely to develop POF (Ptrend = 0.002). On multivariate analysis, TG48 of 5.65 mmol/L or more was independently associated with POF (odds ratio, 3.316; 95% confidence interval, 1.256-8.755; P = 0.016). CONCLUSIONS: Timely reduction of serum TGs during the early phase of HTGP is proportionally associated with decreased development of POF. Serum TG levels by 48 hours of admission correlate independently with POF.

Characterization of Monoclonal Antibodies against σA Protein and Cross-Reactive Epitope Identification and Application for Detection of Duck and Chicken Reovirus Infections.

Although σA is an important major core protein of duck reovirus (DRV), the B-cell epitopes of this protein remain unknown to reseacrhers. Six monoclonal antibodies (MAbs) (1A7, 3F4, 5D2, 4E2, 3C7, and 2B7) were developed by using prokaryotic-expressed recombinant His-σA protein. Five of six MAbs (1A7, 3F4, 4E2, 3C7, and 2B7) reacted with His-σA protein in a conformation-independent manner, while 5D2 reacted with σA in a conformation-dependent manner. Immunofluorescence assays showed that the MAbs could specifically bind to DRV infected BHK-21 cells. The MAbs were delineated as three groups by a competitive binding assay. By using 12-mer peptide phage display and mutagenesis, MAb 4E2 was identified to recognize minimal epitope 56EAPYPG61 and MAb 1A7 recognize 341WVV/MAGLI/V347, residues 341V/M and 347I/V are replaceable. Dot blotting and sequence analysis confirmed that EAPYPG and WVV/MAGLI/V are cross-reactive epitopes in both DRV and avian reovirus (ARV). An enzyme-linked immunosorbent assay (ELISA) based on two expressed EAPYPG and WVVAGLI as antigen demonstrated its diagnostic potential by specific reacting with serum samples from DRV- or ARV-infected birds. Based on these observations, an epitope-based ELISA could be potentially used for DRV or ARV surveillance. These findings provide insights into the organization of epitopes on σA protein that might be valuable for the development of epitope-based serological diagnostic tests for DRV and ARV infection.

Expression patterns and prognostic value of miR-210, miR-494, and miR-205 in middle-aged and old patients with sepsis-induced acute kidney injury.

Septic patients suffer a 'cytokine storm' from proinflammatory cytokines, chemokines and other inflammatory mediators, resulting in acute kidney injury (AKI) and death. The purpose of the present study was to determine the expression patterns of microRNA-210 (miR-210), miR-494, and miR-205 in middle-aged and old patients with sepsis-induced AKI and to evaluate their association with patient prognosis. Serum blood urea nitrogen (BUN), creatinine (Cr) and cystatin C levels were determined in peripheral venous blood collected from 110 patients with sepsis-induced AKI and 110 healthy controls. The expression profile of 30 miRNAs was analyzed by TaqMan low-density array (TLDA) in plasma samples from patients and controls. Association of miRNAs with prognosis and survival of patients was analyzed by Spearman's rank correlation coefficient, Cox multivariate analysis, and ROC curve analysis. TILDA analysis showed 11 upregulated and 11 downregulated miRNAs in patients with sepsis-induced AKI. MiR-210 and miR-494 were the most upregulated and miR-205 was the most downregulated miRNA. High expression of miR-210 and miR-494 was positively correlated with BUN, Cr and cystatin C levels of patients, while low expression of miR-205 was negatively correlated. MiR-210 and miR-494 expression was significantly decreased and miR-205 expression was increased in survivors with sepsis-induced AKI (28-day survival, n = 68) vs. non-survivors (n = 42). BUN, Cr, and miR-205 were independent risk factors for prognosis in sepsis-induced AKI. Our study showed the predictive value of miR-210, miR-494, and miR-205 in prognosis and survival of patients with sepsis-induced AKI. MiR-205 is an independent risk factor for sepsis-induced AKI and its decreased expression is associated with shorter patient survival.

Relationship between ß-defensin-1 gene polymorphism and susceptibility and prognosis of acute respiratory distress syndrome.

OBJECTIVE: The 1st exon 5' noncoding region rs1799946 (-52A/G), rs1800972 (-44C/G), rs11362 (-20A/G) 3 single-nucleotide polymorphisms (SNPs) on human ß-defensin-1 (HBD-1) gene affect its transcription and posttranscriptional mRNA stability then affect the activity of HBD-1. This study was to investigate the effects of HBD-1 gene rs1799946, rs1800972, and rs11362 locus SNPs on genetic susceptibility and prognosis of acute respiratory distress syndrome (ARDS). METHODS: A total of 300 patients with ARDS (ARDS group) and 240 patients who were admitted to the intensive care unit and had a high risk of ARDS but did not progress to ARDS (control group) were included in this study. The genotypes of HBD-1 gene rs1799946, rs1800972, and rs11362 locus and serum HBD-1 were detected. Patients were followed for 60 days with development of ARDS as a primary outcome, ARDS-related mortality and organ dysfunction were secondary outcomes. RESULTS: HBD-1 gene rs1799946 and rs11362 gene mutations were not risk factors for ARDS (P > .05). Mutation allele G of rs1800972 locus in HBD-1 gene was a risk factor for ARDS. There was no significant difference in serum HBD-1 levels between patients with different genotypes of rs1799946 and rs11362 locus in the HBD-1 gene (P > .05). HBD-1 gene rs1800972 locus wild type, heterozygous, and mutant homozygous serum levels of HBD-1 gradually decreased, the difference was statistically significant (P < .001). The 60-day survival rate of subjects with wild type, heterozygous, and mutant homozygote at the rs1800972 locus of HBD-1 gene decreased sequentially (81.7%, 48.9%, and 39.7%), and the difference was statistically significant (P < .05). CONCLUSION: The SNP of rs1800972 (-44C/G) in HBD-1 gene is associated with the risk of ARDS. The rs1800972 locus G allele carriers are more likely to develop ARDS and have a poor prognosis.

ß-Arrestin 1/2 Aggravates Podocyte Apoptosis of Diabetic Nephropathy via Wnt/ß-Catenin Pathway.

BACKGROUND ß-arrestins have been shown to play a critical role in the progression of diabetic nephropathy. Nevertheless, the potential mechanism of ß-arrestins on the regulation of podocyte apoptosis has rarely been discussed. This study aimed to elucidate the regulation of ß-arrestin 1/2 on podocyte apoptosis through the Wnt/b-catenin pathway. MATERIAL AND METHODS This study structured ß-arrestin 1/2 down-regulated and up-regulated expression by plasmid transfection. The protein levels were detected with Western blotting, and mRNA expression was detected with RT-qPCR. The apoptotic cells were measured by flow cytometry. RESULTS ß-arrestin 1/2 expression levels of podocytes were up-regulated in high-glucose-induced podocytes. ß-arrestin 1/2 overexpression inhibited the expression of nephrin and podocin protein. Up-regulated ß-arrestin 1/2 promoted podocyte apoptosis and p53 pathway by increasing Bax, cleaved caspase-3, and p-p53 levels in high-glucose-induced podocytes. Flow cytometry showed that the apoptotic cells were markedly higher in the b-arrestin 1/2 up-regulated group compared with the scramble group. Expression of ß-catenin was increased in the ß-arrestin 1/2 up-regulated group, which indicated that the Wnt/b-catenin pathway was activated. Wnt/b-catenin pathway inhibitor (Dkk1) distinctly suppressed the apoptosis induced by ß-arrestin 1/2 overexpression and high glucose. CONCLUSIONS These results provide a molecular pathomechanism of ß-arrestin 1/2 and Wnt/ß-catenin pathway on podocyte apoptosis and provide new ideas for the treatment of diabetic nephropathy, which paves the way for the future study of diabetic nephropathy and podocytes.

Regulation of podocyte lesions in diabetic nephropathy via miR-34a in the Notch signaling pathway.

BACKGROUND: The activation of the Notch signaling pathway has been shown to play an important role in diabetic nephropathy (DN) development. Besides, Notch-1 is a target gene in miR-34a. However, the regulation of the podocyte lesions involved in DN by miR-34a has not been identified. METHODS: This study utilized miR-34a mimics and small interfering RNA transfection to construct miR-34a overexpression and lower-expression model to investigate the effect of miR-34a on the regulation of the Notch signaling pathway and podocyte lesions in DN. Western blotting and real-time quantitative polymerase chain reaction were applied for the quantitative testing of mRNA and protein expression. Apoptosis of podocyte was detected by TUNEL staining. RESULTS: In high-glucose (HG) conditions, miR-34a overexpression inhibited the expression of Notch 1, Jagged 1, NICD, Hes 1, and Hey 1 proteins. Further, cleaved caspase-3, Bax, and phosphorylation of p53 (p-p53) were reduced significantly. Therefore, miR-34a overexpression inhibited the Notch signaling pathway and podocyte lesions induced by HG. ß-arrestin was slightly reduced in HG conditions. Meanwhile, miR-34a overexpression could remit the inhibition. CONCLUSION: Results from this study provide evidence that miR-34a may offer a new approach for the treatment of diabetes.

[Reversal Effect of curcuma wenyujin extract on SGC-7901/VCR induced subcutaneous transplanted tumor in nude mice and its effect on the expression of P-glycoprotein].

OBJECTIVE: To explore the reversal effect of multidrug resistance of Curcuma Wenyujin (CW) and its possible mechanism by establishing Vincristine-resistant gastric cancer SGC-7901 cells (SGC-7901/VCR) induced subcutaneous transplanted tumor in nude mice. METHODS: First we identified the resistance of SGC-7901/VCR by using methyl thiazolyl tetrazolium (MTT). The SGC-7901/VCR induced subcutaneous transplanted tumor model was established in 50 BALB/c nude mice by tissue block method. After 2 -3 weeks 36 mice with similar tumor size were selected and divided into 6 groups by random digit table, i.e., the model group, the Vincristine (VCR) group, the low dose CW group, the high dose CW group, the low dose CW combined VCR group, and the high dose CW combined VCR group, 6 in each group. Normal saline was intraperitoneally injected to mice in the model group at 10 mL/kg, once per 2 days. VCR was intraperitoneally injected to mice in the VCR group at 0.28 mg/kg once per 2 days. CW at 1.4 and 2.8 g/kg was administered to mice in the low and high dose CW groups by gastrogavage, 0.2 mL each time, once daily. CW at 1.4 and 2.8 g/kg was administered by gastrogavage and VCR was intraperitoneally injected at 0.28 mg/kg, once per 2 days to mice in the low dose CW combined VCR group and the high dose CW combined VCR group. All medication lasted for 14 days. The tumor growth was observed. The inhibition rate was calculated. Meanwhile, the positioning and expression of P-glycoprotein (P-gp) were detected by immunohistochemistry and Western blot. RESULTS: SGC-7901/VCR had strong resistance to VCR, Adramycin (ADM), fluorouracil (5-FU), and Cisplatin (DDP), especially to VCR. Proliferation activities of SGC-7901/VCR were significantly enhanced after drug elution. The tumor volume gradually increased as time went by. The tumor volume was the minimum in the high dose CW combined VCR group. The tumor volume was obviously reduced in the high dose CW combined VCR group with obviously reduced with increased inhibition rate of 51.56%, when compared with that of the model group and the VCR group (P < 0.05). Western blot test showed that, when compared with the model group, the gray level of P-gp in the VCR group increased (P < 0.05), and the relative expression of P-gp in the high dose CW group, the low dose CW combined VCR group, and the high dose CW combined VCR group significantly decreased (P < 0.05). Compared with the VCR group, the gray level of the P-gp decreased in the low dose CW group, the high dose CW group, the low dose CW combined VCR group, and the high dose CW combined VCR group (P < 0.05). Results of immunohistochemistry showed that, when compared with the model group, expression scores of P-gp in the high dose CW group, the low dose CW combined VCR group, and the high dose CW combined VCR group decreased with statistical difference (P < 0.05). Compared with the VCR group, expression scores of P-gp were obviously lowered in the low dose CW group, the high dose CW group, the low dose CW combined VCR group, and the high dose CW combined VCR group (P < 0.05). CONCLUSIONS: CW could reverse the drug resistance of SGC-7901/VCR subcutaneous transplanted tumor. And its mechanism might be related to down-regulating the expression of P-gp, suggesting that CW could be used as a kind of multidrug resistance reversal agent based on P-gp.

Ras palmitoylation is necessary for N-Ras activation and signal propagation in growth factor signalling.

Ras GTPases undergo post-translational modifications that govern their subcellular trafficking and localization. In particular, palmitoylation of the Golgi tags N-Ras and H-Ras for exocytotic transport and residency at the PM (plasma membrane). Following depalmitoylation, PM-Ras redistributes to all subcellular membranes causing an accumulation of palmitate-free Ras at endomembranes, including the Golgi and endoplasmic reticulum. Palmitoylation is unanimously regarded as a critical modification at the crossroads of Ras activity and trafficking control, but its precise relevance to native wild-type Ras function in growth factor signalling is unknown. We show in the present study by use of palmitoylation-deficient N-Ras mutants and via the analysis of palmitate content of agonist-activated GTP-loaded N-Ras that only palmitoylated N-Ras becomes activated by agonists. In line with an essential role of palmitoylation in Ras activation, dominant-negative RasS17N loses its blocking potency if rendered devoid of palmitoylation. Live-cell Ras-GTP imaging shows that N-Ras activation proceeds only at the PM, consistent with activated N-Ras-GTP being palmitoylated. Finally, palmitoylation-deficient N-Ras does not sustain EGF (epidermal growth factor) or serum-elicited mitogenic signalling, confirming that palmitoylation is essential for signal transduction by N-Ras. These findings document that N-Ras activation proceeds at the PM and suggest that depalmitoylation, by removing Ras from the PM, may contribute to the shutdown of Ras signalling.

SAP-mediated inhibition of diacylglycerol kinase α regulates TCR-induced diacylglycerol signaling.

Diacylglycerol kinases (DGKs) metabolize diacylglycerol to phosphatidic acid. In T lymphocytes, DGKα acts as a negative regulator of TCR signaling by decreasing diacylglycerol levels and inducing anergy. In this study, we show that upon costimulation of the TCR with CD28 or signaling lymphocyte activation molecule (SLAM), DGKα, but not DGKζ, exits from the nucleus and undergoes rapid negative regulation of its enzymatic activity. Inhibition of DGKα is dependent on the expression of SAP, an adaptor protein mutated in X-linked lymphoproliferative disease, which is essential for SLAM-mediated signaling and contributes to TCR/CD28-induced signaling and T cell activation. Accordingly, overexpression of SAP is sufficient to inhibit DGKα, whereas SAP mutants unable to bind either phospho-tyrosine residues or SH3 domain are ineffective. Moreover, phospholipase C activity and calcium, but not Src-family tyrosine kinases, are also required for negative regulation of DGKα. Finally, inhibition of DGKα in SAP-deficient cells partially rescues defective TCR/CD28 signaling, including Ras and ERK1/2 activation, protein kinase C membrane recruitment, induction of NF-AT transcriptional activity, and IL-2 production. Thus SAP-mediated inhibition of DGKα sustains diacylglycerol signaling, thereby regulating T cell activation, and it may represent a novel pharmacological strategy for X-linked lymphoproliferative disease treatment.

[Preparation and properties of wood/modified UF prepolymer composite materials].

In the present research, the urea-formaldehyde prepolymer and multilayer hot-press drying were used to modify poplar plantation. The prepolymer was impregnated into cell lumen space by pulse-dipping machine. Then the timbers were compressed and dried by the multilayer hot-press drying kiln. The results showed that the physical and chemical properties of poplar were changed in this investigation. The basic density of modified wood increased 1.06 times compared with the natural wood, and the bending strength increased 33% for modified wood, compressive strength parallel to grain increased 74%, the water absorption decreased to 97% from 104%. The crystallinity decreased slightly from 39.65 to 36.89 because of the modifier impregnated. TGA analysis showed that the heat resistance of modified wood increased, the three exothermic peaks in DTA curve of modified wood were 280, 360 and 485 degrees C which were higher than natural wood in the corresponding position FTIR analysis showed that the hydroxyl modified material has a good association phenomenon, and carbonyl content decreased. The SEM spectrum showed the distribution of the prepolymer in the modified timber.

Fulvestrant 250 mg versus anastrozole for Chinese patients with advanced breast cancer: results of a multicentre, double-blind, randomised phase III trial.

BACKGROUND AND PURPOSE: Fulvestrant, an oestrogen receptor (ER) antagonist with no known agonist effects, has shown activity in postmenopausal patients with ER-positive advanced breast cancer recurring or progressing following prior endocrine therapy. This double-blind, double-dummy, randomised phase III study (NCT00327769) was designed to compare the efficacy and safety of fulvestrant versus anastrozole in advanced breast cancer of Chinese postmenopausal women whose disease has progressed following prior endocrine treatment. MATERIALS AND METHODS: A total of 234 patients were randomised to fulvestrant 250 mg/month (n = 121) or 1 mg/day anastrozole (n = 113), together with matching placebo. The primary endpoint was time to progression (TTP). Secondary endpoints included objective response rate (ORR), duration of response (DoR), clinical benefit rate (CBR) and time to treatment failure (TTF). RESULTS: Baseline characteristics were similar, with the possible exception that a higher number of fulvestrant patients had received two prior chemotherapy regimens. Median TTP was 110 days in the fulvestrant group versus 159 days in the anastrozole group (hazard ratio [HR], 1.314; 95% confidence intervals [CI], 0.948, 1.822; P = 0.101). ORR was 10% in the fulvestrant group and 14% in the anastrozole group. Median DoR from randomisation to progression was 436 days versus 432 days for the fulvestrant and anastrozole groups, respectively. CBR for fulvestrant (36.1%) versus anastrozole (48.2%) was not statistically different between the groups. TTF (110 days versus 147 days for the fulvestrant and anastrozole groups, respectively) was not statistically different between the treatments (HR, 1.307; 95% CI, 0.961, 1.778; P = 0.088). Both treatments were well tolerated, with only two patients treated with fulvestrant and four patients treated with anastrozole withdrawn from study treatment due to adverse events. CONCLUSIONS: These data demonstrate that fulvestrant 250 mg and anastrozole were similarly effective and well tolerated in the treatment of postmenopausal Chinese women with advanced breast cancer whose disease had progressed or recurred on prior endocrine treatment.

TCR-induced activation of Ras proceeds at the plasma membrane and requires palmitoylation of N-Ras.

Ras transmits manifold signals from the TCR at various crossroads in the life of a T cell. For example, selection programs in the thymus or the acquisition of a state of hypo-responsiveness known as anergy are just some of the T cell features known to be controlled by TCR-sparked signals that are intracellularly propagated by Ras. These findings raise the question of how Ras can transmit such a variety of signals leading to the shaping of equally many T cell traits. Because Ras proteins transit through endomembrane compartments on their way to the plasma membrane (PM), compartmentalized Ras activation at distinct subcellular sites represents a potential mechanism for signal diversification in TCR signaling. This hypothesis has been nurtured by studies in T cells engineered to overexpress Ras that reported distinct activation of Ras at the PM and Golgi. Contrary to this scenario, we report in this study that activation of endogenous Ras, imaged in live Jurkat T cells using novel affinity probes for Ras-GTP, proceeds only at the PM even upon enforced signal flux through the diacylglycerol/RasGRP1 pathway. Physiological engagement of the TCR at the immunological synapse in primary T cells caused focalized Ras-GTP accumulation also only at the PM. Analysis of palmitoylation-deficient Ras mutants, which are confined to endomembranes, confirmed that the TCR does not activate Ras in that compartment and revealed a critical function for palmitoylation in N-Ras/H-Ras activation. These findings identify the PM as the only site of TCR-driven Ras activation and document that endomembranes are not a signaling platform for Ras in T cells.

[A randomized phase II trial of docetaxel and doxorubicin in treatment for patients with non-small-cell lung cancer who have failed previous platinum-based chemotherapy].

OBJECTIVE: The aim of this study was to evaluate the efficacy, toxicity and safety of doxorubicin combined with domestically produced docetaxel versus with taxotere, and to investigate whether these two regimens result in similar outcomes in the treatment for non-small-cell lung cancer (NSCLC) patients who failed previous platinum-based chemotherapy. METHODS: Eighty-eight NSCLC patients were enrolled into this clinical phase II trial. The patients randomly received either domestic docetaxel (study arm) or taxotere (control arm) at a dose of 70 mg/m2 on D2, while doxorubicin at a dose of 40 mg/m2 on D1 was administered in both groups. It was repeated every 3 weeks, totally for three cycles. No granulocyte colony-stimulating factor was used to prevent granulocytopenia. The response rate and toxicity were evaluated using World Health Organization toxicity scale and Karnofsky performance status scale. RESULTS: Of the 88 patients, 81 were evaluable in terms of efficacy. There was no complete responder in this series. The response rate (RR) was 17.1% in the study arm versus 7.5% in the control arm, and the clinical benefit rate (CBR) was 80.5% in the study group versus 72.5% in the control group. The most frequent grade 3 or 4 toxicities were neutropenia, leucopenia and gastrointestinal symptoms. Other toxicities such as alopecia and vomiting were mild and generally well tolerated. No fluid retention was noticed. CONCLUSION: The administration of doxorubicin 40 mg/m2 on D1 combined with domestic docetaxel 70 mg/m2 on D2 is proved to be as effective and tolerable as with taxotere. The domestic drug docetaxel may be considered as an alternative for patients with non-small-cell lung cancer who failed previous platinum-based chemotherapy.

[Curative effects of FTQ combined with cisplatin in treatment of advanced gastric cancer: a multicenter study].

OBJECTIVE: To determine the clinical toxicities and antitumor effects of a chemotherapy regimen of FTQ, a compound preparation of tegafur, the drug prototype of 5-furacil (5-FU), gimeracil (CDHP), a decomposition inhibitor of 5-FU, oteracil potassium, phosphorylation inhibitor of 5-FU, and combined with cisplatin in patients with inoperable locally or metastatic advanced gastric cancer. METHODS: 119 patients with inoperable locally or metastatic advanced gastric cancer admitted in 10 hospitals in China were divided into 2 groups: FTQ group (n = 59), undergoing a 3-week regime, i.e. oral use of 80 mg x m(-2) x d(-1) for 14 d and then discontinuance for 1 week and intravenous drip cisplatin 75 mg/m2 on days 1-3; and control group (n = 60) undergoing a 3-week regimen including oral use of tegafur 800 mg x m(-2) x d(-1) tid for 14 d and then discontinuance for 1 week and intravenous drip of cisplatin 75 mg/m2 on days 1-3. The curative was evaluated after at least after 2 regimens. RESULTS: There were 102 patients in the per-protocol population. The overall response rate of the FTQ group was 28. 3% (15/53), significantly higher than that of the control group (4.1%, 2/49, P = 0.004). The clinical improvement of the FTQ group was 50.9%, significantly higher than that of the control group (24.5%, P = 0.006). The main toxicities occurred in bone marrow and the digestive tract. The leucopenia and thrombocytopenia rates of the FTQ group were 47.45% and 32.22% respectively, both similar to those of the control group. There were no differences in the incidence rate of digestive canal side reaction between these 2 groups . CONCLUSION: The regimen of FTQ combined with cisplatin is generally well-tolerated and has substantial antitumor activity.

[Low dose-intensity docetaxel monotherapy for patients with anthracycline-resistant metastatic breast cancer in poor physical status].

OBJECTIVE: To evaluate the efficacy and safety of a weekly schedule of low dose-intensity docetaxel monochemotherapy for patients with anthracycline-resistant metastatic breast cancer (MBC) in poor physical status. METHODS: Thirty MBC patients who were previously exposed to anthracycline treatment received docetaxel alone at a dose of 30 mg/m2 on D1, D8 and D15, repeated every 4 weeks for a maximum of 6 cycles. RESULTS: Of the 30 evaluable patients, 2 (6.7%) achieved a complete response, and 9 (30.0%) a partial response, with an overall objective response rate of 36.7% (95% CI: 20.5%-53.9%). The most common adverse event was hematologic toxicity. After an average follow-up of 15.0 months, the median time to progression (TTP) was 8. 5 months and the median overall survival (OS) had not reached yet at the end of follow-up. CONCLUSION: The weekly low dose-intensity docetaxel monochemotherapy is effective and well-tolerated in patients with anthracycline-resistant metastatic breast cancer in poor physical status.

[A randomized trial of irinotecan plus fuorouracil and leucovorin with thalidomide versus without thalidomide in the treatment for advanced colorectal cancer].

OBJECTIVE: To evaluate the efficacy, side-effects and quality of life in the advanced colorectal cancer patients treated by irinotecan plus fuorouracil and leucovorin with thalidomide or without thalidomide. METHODS: Eligible patients were randomly assigned to the treatment group and control group in a 1:1 ratio. In the treatment group, 32 evaluable patients were treated with irinotecan 180 mg/m2 i. v. on day 2, fuorouracil 400 mg/m2 bolus on day 1, 2 at a dose of 1200 mg/m2 civ. for 43 hours; leucovorin 200 mg/m2 i. v. on day 1, 2; thalidomide 300 mg, orally on day 1 - 14, two weeks as a cycle. In the control group, the regimen was the same as in the treatment group except oral intake of thalidomide. RESULTS: The response rate was 28.1% in the treatment group vs. 15.2% in the control group (P = 0.2034) with a median TTP of 3.8 months vs. 2. 5 months (P = 0.1312). Furthermore, there was no statistically difference either between two groups regarding to adverse effects. CONCLUSION: Irinotecan plus fuorouracil and leucovorin without oral intake of thalidomide is as effective and tolerable as irinotecan plus fuorouracil and leucovorin combined with oral thalidomide for advanced colorectal cancer.

[Docetaxel in the treatment of advanced breast cancer ].

OBJECTIVE: To evaluate the efficacy, toxicity and safety of an new domestic docetaxel in the treatment of pretreated advanced breast cancer. METHODS: Fourty-four breast cancer patients who had failed in first-line chemotherapy were included in this trial. They received docetaxel as the second-line chemotherapy. Docetaxel was administered alone at a dose of 70 mg/m2 every 3 weeks. The use of granulocyte colony-stimulating factor to prevent granulocytopenia was not permitted. The response rate and toxicity were evaluated by World Health Organization toxicity scale and performance status by Karnofsky scale. RESULTS: Of the 41 evaluable patients, 4 achieved complete response and 14 partial remission, with a response rate and clinical benefit rate of 43.9% and 85.4%, respectively. Grade 3 or grade 4 neutropenia developed in 42.9%, alopecia in 7.1% and vomiting in 4.8% of these patients. Fluid retention was not observed in this series. CONCLUSION: Three-week administration of docetaxel alone at a dose of 70 mg/m2 is effective and tolerable. It provides an alternative for the pretreated advanced breast cancer patients.

[Phase I/II clinical trial of weekly administration of docetaxel plus cisplatin for advanced non-small cell lung cancer].

OBJECTIVE: The purpose of this phase I/II study is to investigate the safety/toxicity profile of weekly administration of docetaxel in combination with cisplatin for the chemo-naive patients with advanced non-small cell lung cancer (NSCLC), and to evaluate the efficacy of this regime. METHODS: In phase I trial, 15 patients were included. IV infusion of escalating doses of docetaxel consisting of four levels from 25 to 40 mg/m2 (25, 30, 35, 40 mg/m2) on D1, 8, 15 and cisplatin of 75 mg/m2 on D1 was administered. The regime was repeated every 4 weeks. Blood samples were obtained on D1, 15 in the first cycle to measure the PK. Dose limiting toxicity (DLT) was determined in cycle 1 and defined as any grade 3 non-hematologic toxicity which could not be reverted into grade less than grade 2 within 4 days or any grade 4 hematologic toxicity. Eighty-three patients completed their phase II study with administration of docetaxel at a dose of 35 mg/m2 based on the data of phase I trial. RESULTS: In the phase I trial, grade 3/4 neutropenia was mainly observed in patients who received docetaxel of 40 mg/m2 (level 4) with one patient suffering from an infection signifying dose limiting toxicity (DLT). Non-hematological toxicities including nausea/vomiting, alopecia, fluid retension and asthenia were tolerable. Based on these data, the maximum tolerence dose (MTD) did not reach the level of weekly giving docetaxel at a dose of 40 mg/m2 in combination with cisplatin 75 mg/m2 every 4 weeks. The pharmacokinetic/dynamics results There was no statistically significant difference between clearance value among the 4 dose levels of docetaxel from 25 to 40 mg/m2 when measured by Cmax and AUC. The pharmacokinetics of docetaxel was not influenced by the presence of co-administration of cisplatin when compared D1 with D15 as based on CmaxN, AUCN and CL. In the phase II trial, totally 83 patients received 216 cycles of chemotherapy. One CR (complete response) and 22 PR (partial response) were achieved with an objective response rate of 27.7% in this series and 30.7% in the evaluable patients. The 1-year survival was 48.6% with a median survival of 10.7 months (range: 3-34 months). Hematologic toxicities were the major side effects, though most were mild; grade III/IV neutropenia developed in 15%. The common non-hematologic toxicities were nausea, vomiting and asthenia. CONCLUSION: Weekly consecutive administration of docetaxel on D1, 8, 15 for 3 weeks plus cisplatin on D1 is tolerable and effective with minimal myelosuppression in chemo-naive patients with advanced NSCLC.

[Randomized phase II trial on escalated doses of Rh-endostatin (YH-16) for advanced non-small cell lung cancer].

OBJECTIVE: To investigate the response rate (RR), time to tumor progression (TTP), quality of life (QOL) and adverse reaction in the treatment of pretreated advanced non-small cell lung cancer (NSCLC) using escalated doses of rh-endostatin (YH-16), and to determine the optimal dose for clinical application. METHODS: In this phase II randomized, controlled, multicenter trial, the patients were randomly divided into two groups to receive daily 3 hours intravenous infusion of either 7.5 mg x m(-2) or 15 mg/m(2) YH-16 for 28 days. RESULTS: Totally, 68 patients were entered and 60 patients were evaluable. There were no differences in RR (3.0% in both groups, P > 0.05), median TTP (ITT: 60 days versus 71 days, P > 0.05), QOL and incidence rate of adverse reactions (48.6% versus 38.7%, P > 0.05). No significant unexpected adverse events were observed. CONCLUSION: Rh-endostatin may have anti-tumor activity with high clinical benefit rate and is well tolerated in pretreated advanced NSCLC patients. The dose of 7.5 mg x (m(2))(-1) x d(-1) is clinically recommended.