Ablative Hypofractionated Radiation Therapy Enhances Non-Small Cell Lung Cancer Cell Killing via Preferential Stimulation of Necroptosis In Vitro and In Vivo.

PURPOSE: To investigate how necroptosis (ie, programmed necrosis) is involved in killing of non-small cell lung cancer (NSCLC) after ablative hypofractionated radiation therapy (HFRT). METHODS AND MATERIALS: Deoxyribonucleic acid damage, DNA repair, and the death form of NSCLC cells were assessed after radiation therapy. The overexpression and silencing of receptor-interacting protein kinases 3 (RIP3, a key protein involved activation of necroptosis)-stable NSCLC cell lines were successfully constructed. The form of cell death, the number and area of colonies, and the regulatory proteins of necroptosis were characterized after radiation therapy in vitro. Finally, NSCLC xenografts and patient specimens were used to examine involvement of necroptosis after ablative HFRT in vivo. RESULTS: Radiation therapy induced expected DNA damage and repair of NSCLC cell lines, but ablative HFRT at ≥10 Gy per fraction preferentially stimulated necroptosis in NSCLC cells and xenografts with high RIP3 expression, as characterized by induction and activation of RIP3 and mixed-lineage kinase domain-like protein and release of immune-activating chemokine high-mobility group box 1. In contrast, RNA interference of RIP3 attenuated ablative HFRT-induced necroptosis and activation of its regulatory proteins. Among central early-stage NSCLC patients receiving stereotactic body radiation therapy, high expression of RIP3 was associated with improved local control and progression-free survival (all P < .05). CONCLUSIONS: Ablative HFRT at ≥10 Gy per fraction enhances killing of NSCLC with high RIP3 expression via preferential stimulation of necroptosis. RIP3 may serve as a useful biomarker to predict favorable response to stereotactic body radiation therapy.

Stereotactic radiation therapy for oligometastases or oligorecurrence within mediastinal lymph nodes.

AIMS: This study evaluated the safety and efficacy of stereotactic radiation therapy (SRT) for the treatment of patients with oligometastases or oligorecurrence within mediastinal lymph nodes (MLNs) originating from different tumors. METHODS: Between October 2006 and May 2015, patients with MLN oligometastases or oligorecurrence were enrolled and treated with SRT at our hospital. The primary endpoint was MLN local control (LC). Secondary endpoints were time to symptom alleviation, overall survival (OS) after SRT, and toxicity using the Common Terminology Criteria for Adverse Events (CTCAE v4.0). RESULTS: Eighty-five patients with 98 MLN oligometastases or oligorecurrences were treated with SRT. For the entire cohort, the 1-year and 5-year actuarial LC rates were 97% and 77%, respectively. Of 53 symptomatic patients, symptom alleviation was observed in 47 (89%) after a median of 5 days (range, 3-30 days). The median OS was 27.2 months for all patients. For patients with non-small cell lung cancer, univariate and multivariate analyses revealed that a shorter interval between diagnosis of primary tumors and SRT and larger MLN SRT volume were associated with worse OS. CTCAE v4.0 ≥ Grade 3 toxicities occurred in six patients (7%), with Grade 5 in three patients (all with RT history to MLN station 7). CONCLUSIONS: SRT is a safe and efficacious treatment modality for patients with oligometastases or oligorecurrence to MLNs originating from different tumors, except for patients who received radiotherapy to MLN station 7. Further investigation is warranted to identify the patients who benefit most from this treatment modality.

Evaluating the clinical feasibility: The direct bisulfite genomic sequencing for examination of methylated status of protocadherin10 (PCDH10) promoter to predict the prognosis of gastric cancer.

OBJECTIVE: To elucidate the clinical significance of the methylated status of CpG site count of PCDH10 promoter in the survival prediction in gastric cancer (GC). METHODS: In the previous study, we demonstrated that the methylated CpG site count was significantly associated with the overall survival (OS) of GC patients by using the bisulfite genomic sequencing (BGS) with no less than five clones per sample. It was so complex and expensive for patients to undergo the BGS clones. In this study, we detected the different CpG site counts (hypermethylated and hypomethylated) of PCDH10 DNA promoter in GC samples of 471 patients by directly bisulfite genomic sequencing (D-BGS) without any clone. Furthermore, we evaluated the relationships between the methylated status of PCDH10 promoter and OS. RESULTS: Two hundred and fifty-seven of 471 (54.6%) GC patients were identified to present with PCDH10 promoter methylation by D-BGS. Patients who presented with 5 or more methylated CpG site counts of PCDH10 promoter had significantly poorer prognosis than patients who with less than 5 methylated CpG site counts of PCDH10 promoter (p= 0.039). With the multivariate survival analysis, we demonstrated that T stage, N stage and the hypermethylated CpG site counts of PCDH10 DNA promoter were the independent predictors of OS of GC patients. In addition, the hypermethylated CpG site counts of PCDH10 DNA promoter had smaller Akaike information criterion (AIC) and Bayesian information criterion (BIC) values than the other two independent predictors of the OS, indicating the hypermethylated CpG site counts of PCDH10 DNA promoter as the best prognostic predictor of GC. CONCLUSIONS: Our present findings suggested that the hypermethylated CpG site counts of PCDH10 DNA promoter for evaluating the prognosis of GC was reasonable by using the D-BGS.

Evaluating the clinical feasibility: The direct bisulfite genomic sequencing for examination of methylated status of E3 ubiquitin ligase RNF180 DNA promoter to predict the survival of gastric cancer.

BACKGROUND: E3 ubiquitin ligase Ring finger protein 180 (RNF180) has been identified as a novel tumor suppressor in gastric cancer and the methylated CpG site count of RNF180 DNA promoter can predict the prognosis for gastric cancer patients. OBJECTIVE: In the previous study, we demonstrated that methylated CpG site count of RNF180 DNA promoter was significantly associated with the survival of patients with gastric cancer using the bisulfite genomic sequencing (BGS) in the gastric cancer tissue with five clones per sample. It was so complicate for each patient underwent the BGS detection with clones. It is important to explore a simple, rapid and accurate method to detect methylated CpG site count to predicting the prognosis for gastric cancer patients. METHODS: At present study, we detected hypermethylated and hypomethylated CpG site count of RNF180 DNA promoter in samples of 480 gastric cancer patients by direct bisulfite sequencing. RESULTS: We found that patients who possessed seven or less hypermethylated CpG sites of RNF180 DNA promoter had much better survival (p= 0.008), which was similar to our previous research results by using the BGS with clones. With the multivariate survival analysis, we found that T stage, N stage and hypermethylated CpG site count of RNF180 DNA promoter were the independent predictors of prognosis for gastric cancer patients. CONCLUSIONS: hypermethylated CpG site count of RNF180 DNA promoter for evaluating the prognosis of gastric cancer was reasonable by using the direct bisulfite sequencing.

Pouch size influences clinical outcome of pouch construction after total gastrectomy: a meta-analysis.

AIM: To assess the clinical significance of pouch size in total gastrectomy for gastric malignancies. METHODS: We manually searched the English-language literature in PubMed, Cochrane Library, Web of Science and BIOSIS Previews up to October 31, 2013. Only randomized control trials comparing small pouch with large pouch in gastric reconstruction after total gastrectomy were eligible for inclusion. Two reviewers independently carried out the literature search, study selection, data extraction and quality assessment of included publications. Standard mean difference (SMD) or relative risk (RR) and corresponding 95%CI were calculated as summary measures of effects. RESULTS: Five RCTs published between 1996 and 2011 comparing small pouch formation with large pouch formation after total gastrectomy were included. Eating capacity per meal in patients with a small pouch was significantly higher than that in patients with a large pouch (SMD = 0.85, 95%CI: 0.25-1.44, I(2) = 0, P = 0.792), and the operative time spent in the small pouch group was significantly longer than that in the large pouch group [SMD = -3.87, 95%CI: -7.68-(-0.09), I (2) = 95.6%, P = 0]. There were no significant differences in body weight at 3 mo (SMD = 1.45, 95%CI: -4.24-7.15, I(2) = 97.7%, P = 0) or 12 mo (SMD = -1.34, 95%CI: -3.67-0.99, I(2) = 94.2%, P = 0) after gastrectomy, and no significant improvement of post-gastrectomy symptoms (heartburn, RR = 0.39, 95%CI: 0.12-1.29, I(2) = 0, P = 0.386; dysphagia, RR = 0.86, 95%CI: 0.58-1.27, I(2) = 0, P = 0.435; and vomiting, RR = 0.5, 95%CI: 0.15-1.62, I(2) = 0, P = 0.981) between the two groups. CONCLUSION: Small pouch can significantly improve the eating capacity per meal after surgery, and may improve the post-gastrectomy symptoms, including heartburn, dysphagia and vomiting.

Analysis of mammographic breast density in a group of screening chinese women and breast cancer patients.

BACKGROUND: A dense breast not only reduces the sensitivity of mammography but also is a moderate independent risk factor for breast cancer. The percentage of Western women with fat breast tissue is higher aged 40 years or older. To a certain extent, mammography as a first choice of screening imaging method for Western women of this group is reasonable. Hitherto, the frequency and age distribution of mammographic breast density patterns among Chinese women had not been characterized. The purpose of this study was to investigate the frequency and age distribution of mammographic breast density patterns among a group of Chinese screening women and breast cancer patients in order to provide useful information for age-specific guidelines for breast cancer screening in Chinese women. METHODS: A retrospective review of a total of 3,394 screening women between August and December 2009 and 2,527 breast cancer patients between July 2011 and June 2012 was conducted. Descriptive analyses were used to examine the association between age and breast density. The significance of differences of breast density between the screening women and the breast cancer patients was examined using nonparametric tests. RESULTS: There was a significant inverse relationship between age and breast density overall (r=-0.37, p<0.01). Breast density of the breast cancer patients in the subgroups of 40-49 years old was greater compared with that of the screening women, the same in those aged 50-54 years and in those 55 years old or older, less than in the screening group. CONCLUSIONS: With regard to the Chinese women younger than 55 years old, the diagnostic efficiency of breast cancer screening imaging examinations may be potentially improved by combining screening mammography with ultrasound.

Prognostic value of number of examined lymph nodes in patients with node-negative gastric cancer.

AIM: To elucidate the potential impact of examined lymph nodes (eLNs) on long-term survival of node-negative gastric cancer patients after curative surgery. METHODS: A total of 497 node-negative gastric cancer patients who underwent curative gastrectomy between January 2000 and December 2008 in our center were enrolled in this study. Patients were divided into 4 groups according to eLNs through cut-point analysis. Clinicopathological features were compared between ≤ 15 eLNs group and > 15 eLNs group and potential prognostic factors were analyzed. The Log-rank test was used to assess statistical differences between the groups. Independent prognostic factors were identified using the Cox proportional hazards regression model. Stratified analysis was performed to investigate the impact of eLNs on patient survival in each stage. Overall survival was also compared among the four groups. Finally, we explored the recurrent sites associated with eLNs. RESULTS: Patients with eLNs > 15 had a better survival compared with those with eLNs ≤ 15 for the entire cohort. By the multivariate survival analysis, we found that the depth of invasion and the number of eLNs were the independent predictors of overall survival (OS) of patients with node-negative gastric cancer. According to the cut-point analysis, T2-T4 patients with 11-15 eLNs had a significantly longer mean OS than those with 4-10 eLNs or 1-3 eLNs. Patients with ≤ 15 eLNs were more likely to experience locoregional and peritoneal recurrence than those with > 15 eLNs. CONCLUSION: Number of eLNs could predict the prognosis of node-negative gastric cancer, and dissection of > 15 eLNs is recommended during lymphadenectomy so as to improve the long-term survival.

[Interim report of prospective clinical study of two different digestive tract reconstruction after total gastrectomy].

OBJECTIVE: To compare post-operative long-term complications and quality of life of two digestive reconstruction procedures after total gastrectomy. METHODS: A total of 109 gastric cancer patients in Tianjin Medical University Cancer Hospital from March 2012 to February 2013 were prospectively enrolled and randomly divided into functional jejunal interposition (FJI) group (52 cases) and Roux-en-Y (R-Y) group (57 cases). The post-operative complications, nutritional status, and the quality of life were compared between two groups. RESULTS: One, 3 and 6 months after operation, the incidence of R-S syndrome in FJI group was lower as compared to R-Y group[13% (6/45) vs. 37% (18/49), 3% (1/30) vs. 42% (14/33), 5% (1/21) vs. 48% (11/23), all P<0.01], while 3 months after operation, the incidence of reflux and heartburn in FJI group was higher[53% (16/30) vs. 21% (7/33), P<0.01; 37% (11/30) vs. 12% (4/33), P<0.05]. There were no significant differences in quality of life questionnaire QLQ-C30 between R-Y and FJI groups. QLQ-STO22 stomach module revealed in FJI group, the eating score was better, but reflux score was worse as compared to R-Y group 3 months after operation (all P<0.01). CONCLUSIONS: Functional jejunal interposition keeps intestinal continuity preserving and food duodenal passing, which is a reasonable digestive reconstruction procedure.

Aquaporin3 is required for FGF-2-induced migration of human breast cancers.

PURPOSE: The aquaporin (AQP) family consists of a number of small integral membrane proteins that transport water and glycerol. AQPs are critical for trans-epithelial fluid transport. Recent reports demonstrated that AQPs, particularly AQP1 and AQP5, are expressed in high grade tumor cells of a variety of tissue origins, and that AQPs are involved in cell migration and metastasis. Based on this background, we examined whether AQP3, another important member of the AQP family, could facilitate cell migration in human breast cancers. METHODS: Potential role of AQP3 was examined using two representative breast cancer cell lines (MDA-MB-231 and Bcap-37). Briefly, AQP3 expression was inhibited with a lentivirus construct that stably expressed shRNA against the AQP3 mRNA. AQP3 expression inhibition was verified with Western blot. Cell migration was examined using a wound scratch assay in the presence of fibroblast growth factor-2 (FGF-2). In additional experiments, AQP3 was inhibited by CuSO4. Fibroblast growth factor receptor (FGFR) kinase inhibitor PD173074, PI3K inhibitor LY294002, and MEK1/2 inhibitor PD98059 were used to dissect the molecular mechanism of FGF-2 induced AQP3 expression. RESULTS: FGF-2 treatment increased AQP3 expression and induced cell migration in a dose dependent manner. Silencing AQP3 expression by a lentiviral shRNA inhibited FGF-2 induced cell migration. CuSO4, a water transport inhibitor selective for AQP3, also suppressed FGF-2-induced cell migration. The FGFR kinase inhibitor PD173074, significantly inhibited FGF-2-induced AQP3 expression and cell migration. The PI3K inhibitor LY294002 and MEK1/2 inhibitor PD98059 inhibited, but not fully blocked, FGF-2-induced AQP3 expression and cell migration. CONCLUSIONS: AQP3 is required for FGF-2-induced cell migration in cultured human breast cancer cells. Our findings also suggest the importance of FGFR-PI3K and FGFR-ERK signaling in FGF-2-induced AQP3 expression. In summary, our findings suggest a novel function of AQP3 in cell migration and metastasis of breast cancers.

[Mechanism study on intestinal motility of reconstruction procedures after total gastrectomy].

OBJECTIVE: To investigate the mechanism of reconstruction procedures affecting intestinal motility after total gastrectomy. METHODS: Beagle dogs were divided into 3 groups:3 dogs in sham operation group, 7 in functional jejunal interposition (FJI) group, and 3 in Roux-en Y(RY) group. These dogs were sacrificed 48 hours postoperatively. Dogs were gavaged with active carbon 1 h before sacrifice and the intestinal transit rate was evaluated. Intestinal tissues 5 cm away from the duodenojejunal anastomosis were collected for detecting inflammation, interstitial cells of Cajal (ICC), and apoptosis using HE staining, immunohistochemistry, and interference microscope respectively. RESULTS: The intestinal transit rate in sham and FJI group (0.14 ± 0.03 and 0.32 ± 0.11) was lower than that in RY group (0.52 ± 0.21, P<0.05), which indicated FJI procedure had better food storage. More ICCs were found in submucosa of FJI group than those of RY group. Inflammation in serosal side of the intestine, including hemorrhage, fibrin deposition, and ulceration, neutrophil and macrophage infiltration, and intestinal epithelial cell apoptosis were significantly reduced in FJI group as compared to RY group, which indicated that amelioration of intestinal inflammation and damage might contribute to reducing ICC loss in FJI group. CONCLUSIONS: As a reconstruction procedure with less traumatic and intestinal continuity preserving, FJI has better reservoir function and quicker recovery of intestinal motility.

Evaluation of toxicity and single-dose pharmacokinetics of intravenous ursolic acid liposomes in healthy adult volunteers and patients with advanced solid tumors.

OBJECTIVE: The purpose of this study was to investigate the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics of ursolic acid liposomes (UAL), as a new drug, in healthy adult volunteers and patients with advanced solid tumors. METHODS: All subjects received a single-dose of UAL (11, 22, 37, 56, 74, 98, and 130 mg/m(2)) administered as a 4-h intravenous infusion. Toxicity was assessed and plasma samples were analyzed using validated ultra-performance liquid chromatograph/tandem mass spectroscopy method. RESULTS: A total of 63 subjects including 4 patients and 35 healthy adult volunteers for toxicity study and 24 healthy adult volunteers for pharmacokinetic study were enrolled in this trial. The DLT was encountered at 74, 98, and 130 mg/m(2), and consisted of hepatotoxicity and diarrhea. Other adverse events included grade 1 nausea, grade 2 abdominal distention, grade 1 microscopic hematuria, grade 2 elevated serum sodium, grade 1 vascular stimulation, and grade 1 skin rash. The MTD was 98 mg/m(2). The single-dose pharmacokinetic parameters revealed a linear relationship between C(max), AUC(0→24 h), or AUC(0→∞) and escalated doses. CONCLUSIONS: The clinical data reported for the first time that UAL had manageable toxicities with MTD of 98 mg/m(2). The DLT were hepatotoxicity and diarrhea. Meanwhile, UAL had a linear pharmacokinetic profile. The registration number of this trial is ChiCTR-ONC-12002385.

[Efficacy and survival status of retuximab-NCE regimen treatment in patients with relapsed or refractory B cell non-Hodgkin's lymphoma].

OBJECTIVE: The aim of this study was to analyze the efficacy and toxicity of RNCE regimen in the treatment of relapsed or refractory B cell non-Hodgkin's lymphoma (NHL). METHODS: From January 2000 to December 2005, 46 patients with relapsed or refractory B cell NHL were treated by RNCE regimen with or without radiotherapy for the involved field. The clinical characteristics, response, toxicity and long-term survival results were analyzed retrospectively. RESULTS: A total of 46 patients were eligible. The complete response rate of second-line therapy was 52.17% (24/46), and the overall response rate was 82.61% (38/46). The median follow-up duration in this series was 69 months (range:6 to 102 months). The overall 1, 3, 5-year survival rate was 74.8%, 48.3%, 40.1%, respectively, with a median survival time of 30.2 months (5 to 65 months), and median progression free survival time of 10.9 months (2 to 31 months). The major toxicities were myelosuppression, GI toxicity, fatigue, fever and alopecia. CONCLUSION: Our data show that RNCE regimen treatment is effective and well tolerated in patients with relapsed or refractory B cell non-Hodgkin's lymphoma.

Nimotuzumab combined with gemcitabine and cisplatin as second-line chemotherapy for advanced non-small-cell lung cancer.

OBJECTIVE: To evaluate the efficacy and safety of nimotuzumab combined with gemcitabine and cisplatin as second-line chemotherapy for advanced non-small-cell lung cancer (NSCLC) and to investigate the association of the status of KRAS gene mutation and epidermal growth factor receptor (EGFR) genotype with clinical outcome. METHODS: Twenty-eight patients with advanced NSCLC were enrolled in this single center, uncontrolled pilot clinical study. All the patients developed drug resistance or disease progression after first-line chemotherapy of either a docetaxel + cisplatin regimen or a vinorelbine + cisplatin regimen and then received nimotuzumab combined with gemcitabine and cisplatin as second-line chemotherapy. Eight cases were stage IIIB and 20 were stage IV. An i.v. dosage regimen of 200 mg of nimotuzumab was given as a single dose, injected into the patient at days 1, 8 and 15; i.v. gemcitabine was injected at a dose of 1000 mg/m2 at days 1 and 8 and cisplatin (25 mg/m2 i.v.) at days 1, 2 and 3. Each patient received four or more therapeutic cycles. The efficacy and toxic reactions were evaluated, as well as time to progression and overall survival. RESULTS: In total, 28 patients with advanced NSCLC received 101 therapeutic cycles. The mean cycle number was 3.6. Median time to progression was 4.9 (2.5-6.5) months; median overall survival and 1-year survival rate were 9.8 months and 48.5%, respectively. There was one case of complete response, six cases of partial response, 11 cases of stable disease and 10 cases of progressive disease. Response rate was 25%, and clinical benefit rate was 64.3%. Major toxic reactions were bone marrow suppression and gastrointestinal reaction. Only one patient developed grade I acneiform eruption. CONCLUSION: Nimotuzumab combined with gemcitabine and cisplatin as second-line chemotherapy for advanced NSCLC was active and well-tolerated in this setting. Patients with EGFR amplification and KRAS gene wild type had a better prognosis. Prospective, randomized, controlled, large-scale clinical studies are needed to confirm the results.

Surgical outcomes of gastrointestinal stromal tumors of the stomach: a single unit experience in the era of targeted drug therapy.

The stomach is the most common site of gastrointestinal stromal tumors (GISTs), but the surgical outcomes of gastric GISTs in the era of targeted drug therapy are unclear. This study aimed to assess factors associated with adverse outcomes and to analyze the effects of targeted drug therapy on gastric GISTs. The surgical outcomes and follow-up records of consecutive patients with gastric GISTs treated at Tianjin Medical University Cancer Institute & Hospital between June 2002 and December 2008 were reviewed. Eighty-five patients were included. Surgery was undertaken in all patients with curative intent. Imatinib mesylate was administered preoperatively to 6 (7%) patients (neoadjuvant therapy), and the median durations of therapy were 6 months (range 3-17 months). Imatinib mesylate was administered postoperatively to 18 (21%) patients with high-risk lesions (adjuvant therapy) and 19 (22%) patients with recurrent disease, and the median durations of therapy were 22 months (range 6-24 months) and 25 months (range 1-64 months), respectively. Tumor size greater than 10 cm (P = 0.015), high mitotic index (P = 0.021), and no adjuvant imatinib therapy (P = 0.046) were the only significant factors associated with higher recurrence-free survival in multivariate analysis. Large tumors, high mitotic index, and the absence of imatinib treatment are associated with high recurrence-free survival. Adjuvant imatinib therapy of 2 years appears to decrease the recurrence of gastric GISTs.

[In vitro synergistic effect of bortezomib and pirarubicin on proliferation and apoptosis of T cell lymphoma cell line Hut-78 cells].

OBJECTIVE: To investigate the in vitro effect of bortezomib (BTZ) alone and in combination with pirarubicin (THP) on the growth inhibition of human cutaneous T-cell lymphoma cell line Hut-78. METHODS: Hut-78 cells were cultured with different concentrations of BTZ or THP alone and the two drugs combination for 48 h. Cell proliferation, cell cycle and apoptosis were evaluated. The cell cycle inhibitor P21 was determined by Western blot. RESULTS: BTZ or THP alone significantly inhibited the growth of Hut-78 cells in a time- and dose-dependent manner. In the combination groups, the inhibitory effect of BTZ followed by THP was the highest (P < 0.01). When the inhibition rate was more than 50%, the combination index analysis showed significant synergistic if treated with BTZ followed by THP or the two at the same time, but antagonistic if treated with THP followed by BTZ. With the inhibition rate increasing, only the synergistic effect of BTZ followed by THP was further increased. The apoptosis rate of BTZ followed by THP was higher than that of single agent each (P < 0.01). BTZ alone significantly increased the proportion of cells in G(2)/M phase (P < 0.01) in a dose-dependent manner and up-regulated the expression level of P21. Sequential THP notably enhanced BTZ-induced cell cycle arrest and apoptosis. CONCLUSIONS: BTZ alone effectively induces growth inhibition and apoptosis of Hut-78 cells in vitro. BTZ followed by THP can synergistically enhance this cytotoxic effect. The mechanism may be that THP enhances BTZ-induced G(2)/M arrest and P21 up-regulation.

[Expression of Cdc7 and mcm2 as a marker for proliferation and prognosis in diffuse large B cell lymphoma].

OBJECTIVE: The aim of this study was to assess the expression of cell division cycle 7 (Cdc7) kinase and minichromosome maintenance protein 2 (MCM2) in diffuse large B cell lymphoma (DLBCL) and explore their relationship with prognosis of DLBCL patients. METHODS: Clinical data of 60 DLBCL patients treated in our hospital from 2008.1 to 2010.1 were collected. The expression levels of Cdc7 and MCM2 in peripheral blood and bone marrow were determined by real-time PCR. A statistical analysis was carried out to evaluate their association with prognosis in DLBCL patients. RESULTS: The 2-year survival rate of patients with high expression of peripheral blood Cdc7 was 38.3% and those with low expression 65.4% (P = 0.001). The 2-year survival rate of patients with high expression of bone marrow Cdc7 was 37.2% and those with low expression was 75.5% (P = 0.032). The 2-year survival rate of patients with high expression of MCM2 in peripheral blood was 44.0% and those with low expression was 68.2% (P = 0.025). The 2-year survival rate of patients with high expression of MCM2 in bone marrow was 39.0% and those with low expression was 63.4% (P = 0.007). A poor disease specific survival was observed in DLBCL patients with high level expression of Cdc7 and MCM2. CONCLUSIONS: Cdc7 and MCM2 expression can be used to assess tumor proliferation and may be useful as an additional marker in combination with conventional markers in prediction of the outcome of DLBCL patients. Moreover, the Cdc7 and MCM2 signal pathway might be useful as a new approach in the treatment of refractory DLBCL lymphoma patients.

Capecitabine combined with weekly docetaxel in Chinese patients > 65 years with anthracycline-resistant metastatic breast cancer.

BACKGROUND: There 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. METHODS: MBC patients aged > 65 years pretreated with 1 - 5 prior chemotherapy regimens, including an anthracycline, received oral capecitabine 825 mg/m(2) twice daily, days 1 - 14, plus docetaxel 30 mg/m(2) on 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. RESULTS: The 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%). CONCLUSIONS: Capecitabine 825 mg/m(2) twice 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.

[Killing effect of interleukin-18-enhanced FasL-expressing colon cancer cells on human hepatocytes in vitro].

OBJECTIVE: To investigate the influence of mutual interactions between FasL expressed by colon carcinoma cells and endogenous cytokines interleukin-18 on liver metastasis and invasion of human colon cancer cells. METHODS: Using immunohistochemical streptavidin-biotin complex (SABC) method, the expressions of Fas receptor and Fas ligand in SW620 colon carcinoma cells and Chang liver cells were observed so as to provide morphological evidence for the functions of Fas receptor and Fas ligand. In an effort to examine the cytotoxicity of effector cells, CytoTox(96) Non-Radioactive Cytotoxicity Assay was adopted to measure the LDH releasing value after the SW620 cells were co-cultured with Chang liver cells. RESULTS: It was shown that the Fas ligand of colon carcinoma SW620 cells was positive and the positive substances were distributed in the cell membrane and cytoplasm, and the Fas receptor of colon carcinoma SW620 cells was negative. The Fas receptor of Chang liver cells turned out to be positive and the positive substances were distributed in the cell membrane, and the Fas ligand of Chang liver cells was negative. At 6 hours after co-culture of IFN-γ-stimulated Chang liver cells with interleukin-18-stimulated (for 36 h) SW620 cells or unstimulated SW620 cells, the cytotoxicity of SW620 cells to IFN-stimulated Chang liver cells at effector-to-target ratios of 10:1, 5:1, 2.5:1 and 1.25:1 was 68.3%, 49.8%, 21.1%, 9.7% (F = 76.87, P < 0.05) and 32.7%, 21.8%, 11.1%, 6.7% (F = 7.27, P < 0.05), respectively. The non-radioactive cytotoxicity assay showed that the apoptotic rate of Chang liver cells was remarkably increased with the increase of planting concentration of SW620 after the SW620 cells were co-cultured with Chang liver cells. The cytotoxicity was significantly enhanced by interleukin-18. CONCLUSION: The FasL expression of human colon cancer cells may be regulated by endogenous interleukin-18 in the host microenvironment and enhance the liver colonization competence of colon cancer cells through induction of apoptosis in the Fas-expressing hepatocytes.

What should we do to raise awareness on the issue of cancer in the global health agenda?

Developing and emerging countries, including China and India, account for a large proportion of the global population, and as measures to address infectious diseases in these countries bear results, we are seeing a transformation in the nature of diseases that affect these countries. It is against this backdrop that cancer is presenting an increasingly serious threat in developing countries (WHO. The World Health Report 2008--primary health care: now more than ever.) 'Global health' has become an often-heard term in discussions on international health, and backed by a number of well-funded global initiatives, it is now positioned as one of the major agenda items for the international community (Reich MR, Takemi K, Roberts MJ, Hsiao WC. Global Action on Health Systems: A Proposal for the Toyako G8 Summit. Lancet 2008;371:865-9). However, cancer has not yet attained its rightful position on this global health agenda. This paper gives an overview of the discussions that took place at the 5(th) Asia Cancer Forum. Based on the challenges and outlook for placing cancer on the global health agenda, we conduct analysis that focuses on top-down mechanisms and bottom-up mechanisms.

[Clinical characteristics and treatment analysis of primary breast lymphoma: 49 cases report].

OBJECTIVE: To explore the morbidity, clinical characteristics, diagnosis, metastasis, treatment and prognosis of primary breast lymphoma (PBL). METHODS: From January 1960 to August 2007, 49 cases with PBL were treated among 22811 cases of breast malignancy and 7337 cases of malignant lymphoma. The clinical data of these 49 patients, included gender, age, pathologic type, breast X ray and B ultrasound examination results, involved lymph nodes and organs, treatment, survival time, were retrospectively analyzed. RESULTS: From 1960 to 2007, the incidence rate of PBL in Tianjin Municipality was 59/10 millions; in details, the incidence rate of PBL for every 10 years was 2/10 millions, 3/10 millions, 0, 13/10 millions and 32/10 millions, respectively. According to circle graph of age, PBL occurred frequently in female aged 30 to 59 years. Most of this group of PBL was non-Hodgkin lymphoma (48 cases). No typical characteristics was found with the examination of breast X ray, B ultrasound and frozen section pathology. Bone marrow (9 cases), lung (7 cases), meninges (4 cases) and ovary (4 cases) were frequently involved organs. The overall 5-year survival rate was 6.1% for the group. The prognosis in patients with radical mastectomy combined chemotherapy was much better than that in patient received super to local mastectomy plus chemotherapy or simple tumor resection plus chemotherapy (5-year survival rates were 21.4%, 0, 0, respectively). CONCLUSIONS: PBL is a kind of rare lymphoma with incidence increasing sharply in the past few decades. The clinical manifestation is atypical. Diagnosis of PBL should adopt histological examination. Radical mastectomy combined chemotherapy could bring better prognosis, but the prognosis is still poor.