Phase Ⅰ study of postoperative radiotherapy combined with capecitabine for gastric cancer

AIM:To determine the maximum tolerated dose(MTD)and dose-limiting toxicity(DLT)of capecitabine combined with postoperative radiotherapy for gastric cancer.METHODS:We enrolled patients with any T stage and node-positive gastroesophageal or gastric adenocarcinoma after complete resection with negative margins(R0)or microscopic(R1)or macroscopic(R2)resection.Intensity modulated radiotherapy(IMRT)using a fiveto-seven-field,coplanar,sliding window technique was delivered to the tumor bed(T4b),anastomosis site,duodenal stump and regional lymph nodes(LNs)to a total dose of 45 Gy(1.8 Gy/fraction,5 d/wk).Patients with R1 or R2 resection received 10.8 Gy as a boost.Capecitabine was administered twice daily on every radiotherapy treatment day in a dose-escalation schedule (mg/m2)of 625(levelⅠ,n=6),700(levelⅡ,n=6),800(levelⅢ,n=6),900(levelⅣ,n=0)and 1000(levelⅤ,n=0).DLT was defined as grade 4 leukopenia or neutropenia,grade 3-4 thrombocytopenia or anemia and grade 3-4 non-hematological toxicity.RESULTS:Between October 2007 and August 2009,18 patients(12 men,6 women;median age,54 years)were enrolled in the study.The median number of positive LNs was 6,and total number of resected LNs was19.Twelve patients underwent R0 resection(66.7%).Fifteen patients received adjuvant chemotherapy under the leucovorin,fluorouracil and oxaliplatin(FOLFOX4)regimen.Six patients each were enrolled at dose levelsⅠ,ⅡandⅢ.Grade 1-3 leukopenia(16 patients,88.9%),anorexia(15,83.3%)and nausea(15,83.3%)were the most common toxicities.Grade 3 anorexia/nausea and grade 4 vomiting occurred in one level-Ⅰpatient.Grade 3 anorexia and nausea occurred in one level-Ⅱpatient.One level-Ⅲpatient developed grade 4neutropenia,while another developed grade 3 radiation esophagitis.No abnormal liver or renal function examinations were observed.Three patients did not finish chemoradiotherapy because of DLTs and two without DLTs received sequential boosts(total dose,55.8 Gy).CONCLUSION:The MTD of capecitabine was 800 mg/m2twice daily concurrent with IMRT for gastric cancer after surgery.The DLTs were anorexia/nausea,vomiting,neutropenia and radiation esophagitis.     

Modified docetaxel,cisplatin and capecitabine for stage Ⅳ gastric cancer in Japanese patients: A feasibility study

AIM To evaluate the feasibility of chemotherapy including fluoropyrimidine, platinum and taxane with modified dosages for unresectable gastric cancer in Japanese patients.METHODS We performed a feasibility study of a modified docetaxel, cisplatin and capecitabine (DCX) regimen for stage Ⅳ gastric cancer. In particular, 30 or 40 mg/m~2 of docetaxel on day 1, 60 mg/m~2 of cisplatin on day 1, and 2000 mg/m~2 of capecitabine for 2 wk were administered every three weeks.RESULTS Three patients were treated with modified DCX(m DCX) with 30 mg/m~2 docetaxel, and five patients were treated with this regimen with 40 mg/m~2 docetaxel. Grade 3 or 4 neutropenia was observed in six of the eight patients; no patients exhibited febrile neutropenia. Partial response was achieved in four of the eight patients. Three patients underwent gastrectomy, which achieved R0 resection without residual tumors in dissected lymph nodes. In one of these three patients, resected specimens revealed pathological complete response in the primary lesion and in lymph nodes.CONCLUSION m DCX was well tolerated by Japanese patients with stage Ⅳ gastric cancer. This regimen might be useful for allowing gastric cancer patients with distant lymph node metastasis to undergo conversion surgery.     

Improvement of prognosis for unresectable biliary tract cancer

AIM:To evaluate the chemotherapeutic outcomes and confirm the recent improvement of prognosis for unresectable biliary tract cancer.METHODS:A total of 186 consecutive patients with unresectable biliary tract cancer,who had been treated with chemotherapy between 2000 and 2009 at five institutions in Japan,were retrospectively analyzed.These patients were divided into three groups based on the year beginning chemotherapy:Group A(2000-2003),Group B(2004-2006),and Group C(2007-2009).The data were fixed at the end of December 2011.Overall survival and time-to-progression were analyzed and compared chronologically.RESULTS:No patient characteristics were significantly different among the three groups.The gallbladder was involved in about half of the patients in each group,and metastatic biliary tract cancer was present in three quarters of the enrollees.In Group A,5-fluorouracilbased chemotherapies were primarily selected as firstline chemotherapy,and only 24% were treated with second-line chemotherapy.In Group B,gemcitabine or S-1 monotherapy was mainly introduced as firstline chemotherapy,and 51% of the patients who were refractory to first-line chemotherapy were treated with second-line chemotherapy mainly with monotherapy.In Group C,the combination therapy with gemcitabine and S-1 was mainly chosen as first-line chemotherapy,and 53% of the patients refractory to first-line chemotherapy were treated with second-line chemotherapy mainly with combination therapy.The median timeto-progressions were 4.4 mo,3.5 mo and 5.9 mo in Groups A,B and C,respectively(4.4 mo vs 3.5 mo vs 5.9 mo,P < 0.01).The median overall survivals were 7.1,7.3,and 11.7 mo in Groups A,B and C(7.1 mo vs 7.3 mo vs 11.7 mo,P = 0.03).Induction rates of all three drugs(gemcitabine,platinum analogs,and fluoropyrimidine) in Groups A,B and C were 4%,2% and 27%(4% vs 2% vs 27%,P < 0.01).CONCLUSION:The prognosis of unresectable biliary tract cancer has improved recently.Using three effective drugs(gemcitabine,platinum analogs,and fluoropyrimidine) may     

Experience with gemcitabine and cisplatin in the therapy of inoperable and metastatic cholangiocarcinoma

AIM: To study the activity of gemcitabine and cisplatin in a cohort of patients with inoperable or metastatic cholangiocarcinoma. METHODS: Chemotherapy-naive patients with pathologically proven cholangiocarcinoma,receiving treatment that consisted of gemcitabine at 1250 mg/m2 in a 30-min infusion on d 1 and 8,and cisplatin at 75 mg/m2 at every 21-d cycle,were retrospectively analyzed. RESULTS: From June 2003 to December 2005,42 patients were evaluated. Twelve patients (28%) had unresectable disease and 30 (72%) had metastatic disease. There were 28 males and 14 females with a median age of 51 years (range 33-67) and median ECOG PS of 1 (range 0-2). A total of 171 cycles were given with a median number of cycles of 4 (range 1-6). There were 0 CR,9 PR,11 SD and 13 PD (response rate 21%). Grade 3-4 hematologic toxicities were: anemia in 33%,neutropenia in 22% and thrombocytopenia in 5%. Non-hematologic toxicity was generally mild. No cases of febrile neutropenia or treatment-related death were noted. The median survival was 10.8 mo (range 8.4-13 mo) and progression free survival was 8.5 mo. One-year survival rate was 40%. CONCLUSION: Our results indicate that the combination of gemcitabine and cisplatin had consistent efficacy in patients with unresectable or metastatic cholangiocarcinoma.     

A predictive factor for the response to S-1 plus cisplatin in gastric cancer

AIM:To prove that the protein expression level of thymidylate synthase is a predictive factor for the response to S-1/cisplatin(CDDP)chemotherapy in gastric cancer.METHODS:We measured the protein expression levels of thymidylate synthase(TS),dihydropyrimidine dehydrogenase(DPD),and orotate phosphoribosyltrans-ferase(OPRT)in advanced gastric cancer.Before S-1/CDDP chemotherapy,tumor specimens from primary sites were obtained by endoscopic biopsy and analyzed by enzyme-linked immunosorbent assay.The chemo-therapeutic effects on the primary sites were evaluated by endoscopic biopsy performed more than once after S-1/CDDP chemotherapy.The effects are a predictive factor for the response to S-1/CDDP chemotherapy inpatients with advanced gastric cancer,as evaluated by endoscopic biopsy over time.RESULTS:The protein expression level of TS was significantly higher(P<0.05)in the tumor than in the normal tissue,and significantly lower(P<0.05)in the responders than in the non-responders.We were able to evaluate the correlation between changes in the protein expression levels of TS,DPD and OPRT and chemotherapeutic responses in 7 patients by assessing tumor tissues more than twice.In the responders,the protein expression level of TS was<40 ng/mg protein.However,there were significant increases in the protein expression levels of TS(P<0.01)and DPD(P<0.05)after chemotherapy in 3 patients.In these cases,the patient assessment changed from"responder"to"non-responder".In the non-responders,the protein expression level of TS was>40 ng/mg protein.CONCLUSION:We have confirmed that the protein expression level of TS is a predictive factor for the response to S-1/CDDP chemotherapy in patients with advanced gastric cancer.     

A phase Ⅱ study of gemcitabine and carboplatin combination chemotherapy in gallbladder carcinoma

BACKGROUND: Patients with carcinoma of the gallbladder have advanced, unresectable tumor at the time of presentation and face a dismal prognosis in the absence of a standard palliative chemotherapy regimen. This study was undertaken to evaluate the efficacy and safety of combined chemotherapy of gemcitabine and carboplatin in 20 patients with advanced gallbladder carcinoma. METHODS: The criteria of eligibility included chemonaive patients with unresectable gallbladder cancer, bidimensionaIly measurable disease, Zubrod's performance status≤2, and adequate major organ function. The patients received gemcitabine (1000 mg/m~2) on days 1 and 8, and carboplatin (target AUC of 5.0 mg/ml) on day 1, in a 21-day cycle. CT was used for response assessment. RESULTS: In this group of 20 patients with advanced gallbladder carcinoma 6 were men and 14 women, with a median age of 55 years. The stage of the tumor at presentation was IVB in 14 patients (70%), IVA in 3 (15%) and Ⅲ in 3 (15%). Four patients (21%) achieved a complete response, and 3 (15.7%), a partial response; an overall response rate was 36.7%. The median time to progression of the tumor was 33.8 weeks, and 1-year survival rate of the patients was 43.3%. Anemia of WHO grade Ⅲ or Ⅳ was seen in 2 patients (10%) and 1 patient (5%), respectively. Grade Ⅲ neutropenia and thrombocytopenia were observed in 2 patients (10%) and 1 patient (5%), respectively. CONCLUSION: With mild toxicity, combined chemotherapy of gemcitabine and carhoplatin is effective in the treatment of advanced gallbladder carcinoma.     

Weekly docetaxel and gemcitabine in previously treated metastatic esophageal squamous cell carcinoma

AIM: To assess the efficacy and safety of weekly docetaxel plus a fixed-dose rate(FDR) of gemcitabine in metastatic esophageal squamous cell carcinoma(SCC).METHODS: A multi-center, open-label, prospective phase Ⅱ study was designed.Thirty-three esophageal SCC patients with documented progression after fluoropyrimidine/platinum-based first-line chemotherapy were enrolled and treated with docetaxel 35 mg/m2 and gemcitabine 1000 mg/m2 iv at a FDR(10 mg/m2 per minute) on days 1 and 8.Treatment was repeatedevery twenty-one days until disease progression, unacceptable toxicity, or consent withdrawal.The primary endpoint was response rate(RR), and secondary endpoints were safety, progression-free survival(PFS) and overall survival(OS).RESULTS: Combination of weekly docetaxel and FDR gemcitabine was well tolerated: the most common treatment-related adverse events were anemia(97%), fatigue(64%) and neutropenia(55%).One patient with multiple lung and lymph node metastases died of respiratory failure after receiving four cycles of chemotherapy, and the possibility of drug-induced pneumonitis could not be completely excluded.Disease control(objective response plus stable disease) in the ITT population was achieved in 88% of patients, and the overall RR was 30%(95%CI: 15%-46%).The median PFS and OS were 4.0(95%CI: 3.4-4.6) and 8.8 mo(95%CI: 7.8-9.8 mo), respectively.CONCLUSION: A combination of weekly docetaxel and FDR gemcitabine showed promising antitumor activity and tolerability in previously treated, metastatic esophageal SCC.     

Systemic gemcitabine combined with intra-arterial low-dose cisplatin and 5-fluorouracil for advanced hepatocellular carcinoma： Seven cases

The combination of intra-arterial low-dose cisplatin and 5-fluorouracil （5-FU） is effective against advanced hepatocellular carcinoma （HCC）. Systemic gemcitabine chemotherapy seems effective in many cancers. We report the results of combination therapy with systemic gemcitabine, intra-arterial low-dose cisplatin and 5-FU （GEMFP）. Seven patients with non-resectable advanced HCC were treated with GEMFP. One course of chemotherapy consisted of daily intra-arterial cisplatin （20 mg/body weight/hour on d 1, 10 mg/body weight per 0.5 h on d 2-5 and 8-12）, followed by 5-FU （250 mg/body weight per 5 h on d 1-5 and 8-12） via an injection port. Gemcitabine at 1000 mg/m2 was administered intravenously at 0.5 h on d 1 and 8. The objective response was 57%. The response to GEMFP was as follows： complete response （no patients）, partial response （four patients）, stable disease （three patients）, and progressive disease （no patients）. The median survival period was 8 mo （range, 5-55）. With regard to the National Cancer Institute Common Toxicity Criteria （NCI-CTC） grade 3 or 4 adverse reactions, seven （100%）, seven, six （86%） and one （14%） patients developed leukopenia, neutropenia, thrombocytopenia and anemia, respectively. GEMFP may potentially be effective for non- resectable advanced HCC, but it has severe hematologic toxicity.     

Chemoradiotherapy with twice-weekly administration of low-dose gemcitabine for locally advanced pancreatic cancer

AIM：To evaluate the chemoradiotherapy for locally advanced pancreatic cancer utilizing low dose gemcitabine as a radiation sensitizer administered twice weekly. METHODS： We performed a retrospective analysis of chemoradiotherapy utilizing gemcitabine administered twice weekly at a dose of 40 mg/m2. After that, maintenance systemic chemotherapy with gemcitabine, at a dose of 1000 mg/m2, was administered weekly for 3 wk with 1-wk rest until disease progression or unacceptable toxicity developed. RESULTS： Eighteen patients with locally advanced unresectable pancreatic cancer were enrolled. Three of those patients could not continue with the therapy; one patient had interstitial pneumonia during radiation therapy and two other patients showed liver metastasis or peritoneal metastasis during an early stage of the therapy. The median survival was 15.0 mo and the overall 1-year survival rate was 60%, while the median progression-free survival was 8.0 mo. The subgroup which showed the reduction of tumor development, more than 50% showed a tendency for a better prognosis; however, other parameters including age, gender and performance status did not correlate with survival. The median survival of the groups that died of liver metastasis and peritoneal metastasis were 13.0 mo and 27.7 mo, respectively.CONCLUSION： Chemoradiotherapy with low-dose gemcitabine administered twice weekly could be effective to patients with locally advanced pancreatic cancer; however, patients developing liver metastases had a worse prognosis. Another chemoradiotherapy strategy might be needed for those patients, such as administrating one or two cycles of chemotherapy initially, followed by chemoradiotherapy for the cases with no distant metastases.     

Expression of c-kit receptor in human cholangiocarcinoma and in vivo treatment with imatinib mesilate in chimeric mice

AIM: To investigate the c-kit expression in biliary tract cancer cell lines and histological sections from patients with extrahepatic cholangiocarcinoma (CC) and to evaluate the efficacy of in vitro and in vitro treatment with imatinib mesilate. METHODS: The protein expression of c-kit in the human biliary tract cancer cell lines Mz-ChA-2 and EGI-1 and histological sections from 19 patients with extrahepatic CC was assessed by immunoblotting, immunocytochemistry, and immunohistochemistry. The anti-proliferative effect of imatinib mesilate on biliary tract cancer cell lines Mz-ChA-2 and EGI-1 was studied in vitro by automated cell counting. In addition, immunodeficient NMRI mice (TaconicTM) were subcutaneously injected with 5×106 cells of cell lines MzChA-2 and EGI-1. After having reached a tumour volume of 200 mm3, daily treatment was started intra peritonea I ly with imatinib mesilate at a dose of 50 mg/kg or normal saline (NS). Tumor volume was calculated with a Vernier caliper. After 14 d, mice were sacrificed with tumors excised and tumor mass determined. RESULTS: Immunoblotting revealed presence of c-kit in Mz-ChA-2 and absence in EGI-1 cells. Immunocytochemistry with c-kit antibodies displayed a cytoplasmatic and membraneous localization of receptor protein in Mz-ChA-2 cells and absence of c-kit in EGI-1 cells, c-kit was expressed in 7 of 19 (37%) extrahepatic human CC tissue samples, 2 showed a moderate and 5 a rather weak immunostaining. Imatinib mesilate at a low concentration of 5μmol/L caused a significant growth inhibition in the c-kit positive cell line Mz-ChA-2 (31%), but not in the c-kit negative cell line EGI-1 (0%) (P<0.05). Imatinib mesilate at an intermediate concentration of 10μmol/L inhibited cellular growth of both cell lines (51% vs 57%). Imatinib mesilate at a higher concentration of 20μmol/L seemed to have a general toxic effect on both cell lines. The IC50 values were 9.7μmol/L and 11μmol/L, respectively. After 14 d of in vitro treatment with imatinib mesilate, using the chimeric mouse model, c-kit positive Mz-ChA-2 tumors had a significantly reduced volume and mass as compared to NS treatment (P< 0.05). In contrast to that, treatment of mice bearing c-kit negative EGI-1 tumors did not result in any change of tumor volume and mass as compared to NS treatment. CONCLUSION: c-kit expression is detectable at a moderate to low protein level in biliary tract cancer. Imatinib mesilate exerts marked effects on tumor growth in vitro and in vitro dependent on the level of c-kit expression.     

Elucidation of the relationship of BNIP3 expression to gemcitabine chemosensitivity and prognosis

AIM: To evaluate the significance of BNIP3 in the pathogenesis of pancreatic cancer, we analyzed the relationship between the expression of BNIP3 and survival rate of the patients with pancreatic cancer, or chemosensitivities in pancreatic cancer cell lines, particularly for gemcitabine, the first-line anti-tumor drug for pancreatic cancer. METHODS: To compare the expression level of BNIP3 with the resistance to gemcitabine, eight pancreatic cancer cell lines were subjected to gemcitabine treatment and the quantitative real-time RT-PCR method was used to evaluate BNIP3 expression. Immunohistochemical analysis was also performed using 22 pancreatic cancer specimens to study relationship between BNIP3 expression and survival rate. RESULTS: Although no significantly positive association between BNIP3 mRNA level and gemcitabine chemosensitivity was observed, pancreatic cancer cell lines that were sensitive to gemcitabine treatment tended to show high levels of BNIP3 expression. The converse, an absence of BNIP3 expression, was not correlated with gemcitabine resistance. We further compared the BNIP3 expression profiles of resected primary pancreaticcancer specimens with the prognosis of the patients, and found a tendency of favorable prognosis and low BNIP3 expression. CONCLUSION: High levels of BNIP3 expression cannot be used as one of the predicting factors for gemcitabine chemosensitivity, and some yet to be known factors will have to fill the gap for the accurate prediction of pancreatic cancer chemosensitivity to gemcitabine. However, BNIP3 expression may have an impact on prediction of prognosis of patients with pancreatic cancer.     

Esophagectomy for locally advanced esophageal cancer, followed by chemoradiotherapy and adjuvant chemotherapy

AIM: To compare the efficacy and toxicity of a three-step combination therapy with post-operative radiation alone for locally advanced esophageal cancer. METHODS: Patients with T3-4 and NO-1 esophageal carcinoma from a number of institutions were non-randomly, prospectively enrolled in the study. All patients underwent single-stage curative en bloc esophagectomy. The patients were then assigned into one of two treatment groups based on treatment consisting of either post-operative concurrent chemoradiotherapy (CCRT) with weekly cisplatin 30 mg/m~2 followed by systemic adjuvant chemotherapy (four monthly cycles of cisplatin 20 mg/m~2 and 5-fluorouracil 1000 mg/m~2 for five consecutive days), or, post-operative radiation alone. The radiotherapy dose was 55-60 Gy for all patients. Primary end-point of this study was to assess the per-protocol patients' improvement of overall survival benefit. Secondary end-point was designed to evaluate both the per-protocol and intent-totreat patients' outcome of survival. RESULTS: A total of 60 patients (n=30 per group) were enrolled in this study. The two groups were generally comparable for demographic characteristics and hematologicai and non-hematological toxicities. The CCRT with weekly cisplatin was well tolerated, with significantly better overall survival (30.9 mo vs 20.7 mo; 95% CI, 27.5-36.4 vs 15.2-26.1) and 3-year survival (70.0% vs 33.7%; P=0.003). Low histological grade of tumor (P<0.001) was associated with favorable survival in these locally advanced patients. CONCLUSION: For locally advanced esophageal cancer, the combination of esophagectomy, post-operative CCRT with weekly cisplatin and systemic adjuvant chemotherapy is well tolerated and effective. A large-scale, prospective randomized trial of this regimen is in progress.     

Inhibition of histone deacetylase for the treatment of biliary tract cancer： A new effective pharmacological approach

AIM:TO investigate in vitro and in vivo therapeutic effects of histone deacetylase inhibitors NVP-LAQ824 and NVP-LBH589 on biliary tract cancer. METHODS:Cell growth inhibition by NVP-LAQ824 and NVP-LBH589 was studied in vitro in 7 human biliary tract cancer cell lines by MTT assay.In addition,the anti- tumoral effect of NVP-LBH589 was studied in a chimeric mouse model.Anti-tumoral drug mechanism was assessed by immunoblotting for acH4 and p21~(WAF-1/CIP-1), PARP assay,cell cycle analysis,TUNEL assay,and immunhistochemistry for MIB-1. RESULTS:In vitro treatment with both compounds significantly suppressed the growth of all cancer cell lines[mean IC_(50)(3 d)0.11 and 0.05μmol/L, respectively],and was associated with hyperacetylation of nucleosomal histone H4,increased expression of p21~(WAF-1/CIP-1),induction of apoptosis(PARP cleavage),and cell cycle arrest at G2/M checkpoint.After 28 d,NVP- LBH589 significantly reduced tumor mass by 66%(bile duct cancer)and 87%(gallbladder cancer)in vivo in comparison to placebo,and potentiated the efficacy of gemcitabine.Further analysis of the tumor specimens revealed increased apoptosis by TUNEL assay and reduced cell proliferation(MIB-1). CONCLUSION:Our findings suggest that NVP-LBH589 and NVP-LAQ824 are active against human biliary tract cancer in vitro.In addition,NVP-LBH589 demonstrated significant in vivo activity and potentiated the efficacy of gemcitabine.Therefore,further clinical evaluation of this new drug for the treatment of biliary tract cancer is recommended.     

Multicenter study of endoscopic preoperative biliary drainage for malignant distal biliary obstruction

AIM: To determine the optimal method of endoscopic preoperative biliary drainage for malignant distal biliary obstruction.METHODS: Multicenter retrospective study was conducted in patients who underwent plastic stent(PS) or nasobiliary catheter(NBC) placement for resectable malignant distal biliary obstruction followed by surgery between January 2010 and March 2012. Procedurerelated adverse events, stent/catheter dysfunction(occlusion or migration of PS/NBC, developmentof cholangitis, or other conditions that required repeat endoscopic biliary intervention), and jaundice resolution(bilirubin level 3.0 mg/d L) were evaluated. Cumulative incidence of jaundice resolution and dysfunction of PS/NBC were estimated using competing risk analysis. Patient characteristics and preoperative biliary drainage were also evaluated for association with the time to jaundice resolution and PS/NBC dysfunction using competing risk regression analysis.RESULTS: In total, 419 patients were included in the study(PS, 253 and NBC, 166). Primary cancers included pancreatic cancer in 194 patients(46%), bile duct cancer in 172(41%), gallbladder cancer in three(1%), and ampullary cancer in 50(12%). The median serum total bilirubin was 7.8 mg/d L and 324 patients(77%) had ≥ 3.0 mg/d L. During the median time to surgery of 29 d [interquartile range(IQR), 30-39 d]. PS/NBC dysfunction rate was 35% for PS and 18% for NBC [Subdistribution hazard ratio(SHR) = 4.76; 95%CI: 2.44-10.0, P 0.001]; the pig-tailed tip was a risk factor for PS dysfunction. Jaundice resolution was achieved in 85% of patients and did not depend on the drainage method(PS or NBC).CONCLUSION: PS has insufficient patency for preoperative biliary drainage. Given the drawbacks of external drainage via NBC, an alternative method of internal drainage should be explored.     

Expression of annexin A5 in serum and tumor tissue of patients with colon cancer and its clinical significance

AIM To investigate the expression of annexin A5 in serum and tumor tissue of patients with colon cancer and to analyze its clinical significance.METHODS Ninety-three patients with colon cancer treated at our hospital between February 2013 and March 2016 were included in an observation group, and 40 healthy individuals were included in a control group. Enzyme-linked immunosorbent assay was performed to determine the serum level of annexin A5, while immunohistochemistry was performed to determine the expression of annexin A5 in cancer tissues.RESULTS The serum level of annexin A5 was 0.184 ± 0.043 ng/m L in the observation group, which was significantly higher than that in the control group(P 0.05). Annexin A5 expression was detected in 79.31% of the patients with lymph node metastasis, which was significantly higher than that in patients without lymph node metastasis(P 0.05). Moreover, annexin A5 expression was detected in 86.96% of the patients with stage Ⅲ to Ⅳ disease, which was significantly higher than that in patients with stage Ⅰ to Ⅱ disease(P 0.05). The serum level of annexin A5 was 0.215 ± 0.044 ng/m L in patients whose tumors were positive for annexin A5 expression, which was significantly higher than that in patients whose tumors were negative for annexin A5 expression(P 0.05). The serum level of annexin A5 was correlated with annexin A5 expression in colon cancer tissues(r= 0.312, P 0.05). When a cutoff value of 0.148 ng/m L for serum level of annexin A5 was used in the diagnosis of colon cancer, the sensitivity was 83.90%, and the specificity was 57.50%.CONCLUSION For patients with colon cancer, annexin A5 expression in cancer tissues is related to lymph node metastasis and tumor grade. Serum level of annexin A5 is related to annexin A5 expression in cancer tissues and is of diagnostic relevance.     

Elevated level of spindle checkprotein MAD2 correlates with cellular mitotic arrest,but not with aneuploidy and clinicopathological characteristics in gastric cancer

AIM:To study the relevance of spindle assembly checkprotein MAD2 to cellular mitotic status,aneuploidy and other clinicopathological characteristics in gastric cancer. METHODS:Western blot analyses were performed to analyze the protein levels of MAD2 and cyclin B1 in the tumorous and adjacent nontumorous tissues of 34 gastric cancer patients.Cell cycle distribution and DNA ploidy of cancer tissues were also determined by flow cytometry. Conventional statistical methods were adopted to determine the relevance of abnormal MAD2 level to mitotic status, aneuploidy and clinicopathological parameters. RESULTS:Out of 34 gastric cancer patients 25(74%) exhibited elevated MAD2 levels in their tumorous tissues compared with the corresponding nontumorous tissues. Elevation of MAD2 levels significantly correlated with the increased levels of cyclin B1 expression and G_2/M-phase distribution(P=0.038 and P=0.033,respectively),but was not relevant to aneuploidy.The gastric cancer patients with elevated MAD2 levels showed a tendency toward better disease-free and overall survival(P>0.05).However,no association was found between elevated MAD2 levels and patients' clinicopathological characteristics. CONCLUSION:Elevation of MAD2 level is present in 74% of gastric cancer patients,and correlates with increased mitotic checkpoint activity.However,elevation of MAD2 level is not associated with patients' aneuploidy and any of the clinicopathological characteristics.     

Efficacy and safety of gemcitabine-oxaliplatin combined with huachansu in patients with advanced gallbladder carcinoma

AIM： To evaluate the efficacy and safety of gemcitabine-oxaliplatin （GEMOX） combined with huachansu （cinobufagin） injection treatment in patients with locally advanced or metastatic gallbladder carcinoma （GBC）, and to assess the quality of life （QOL） of such patients. METHODS： Twenty-fi ve patients with locally advanced or metastatic GBC were treated with intravenous gemcitabine （1000 mg/m^2） over 30 min on days 1 and 8, 2 h infusion of oxaliplatin （120 mg/m^2） on day 1, and 2-3 h infusion of huachansu （20 mL/m^2） on days -3-11, every 3-4 wk. Treatment was continued until occurrence of unacceptable toxicity or disease progression. QOL of patients was assessed by the EORTC QLQ-C30 at baseline, at the end of the fi rst, third and sixth chemotherapy cycles, and 1 mo after the treatment. RESULTS： Among the 25 patients with a median age of 64 years （range 42-78 years）, 23 were evaluable in the study. A total of 137 cycles of therapy were performed and the median cycle was 5 （range 1-8） per patient. Out of the 23 patients whose response couldbe evaluated, 8 partial responses （PR） were observed （34.8%）, while 7 patients （30.4%） demonstrated a stable disease （SD）. The disease control rate was 65.2%. Progression of cancer was observed in 8 （34.8%） patients. The median progression-free and overall survival time was 5.8 mo （95% CI： 4.5-7.1 mo） and 10.5 mo, respectively. The therapy was well tolerated, with moderate myelosuppression as the main toxicity. Anemia grade 2 was seen in 16.0%, neutropenia grade 3 in 8.0% and thrombocytopenia grade 3 in 24.0% of patients, respectively. Non-hematologic toxicity ranged from mild to moderate. No death occurred due to toxicity. The QOL of patients was improved after chemotherapy, and the scores of QOL were increased by 10 to 20 points. CONCLUSION： GEMOX combined with huachansu （cinobufagin） injection is well tolerated, effective, thus improving the QOL of patients with advanced GBC.     

Prospective study of MMP7 serum levels in the diagnosis of cholangiocarcinoma

AIM: To determine whether the serum level of matrix metalloproteinase-7 (MMP7) has the potential to diagnosis cholangiocarcinoma from benign biliary tract diseases. METHODS: This study was performed according to the PRoBE (a prospective-specimen-collection, retrospectiveblinded-evaluation) design. A total of 187 patients with obstructive jaundice were consecutively enrolled. After the diagnostic status of these patients was ascertained, their levels of serum MMP7 were assayed and compared with serum carbohy...     

Initial experience from a combination of systemic and regional chemotherapy in the treatment of patients with nonresectable cholangiocellular carcinoma in the liver

AIM: In nonresectable cholangiocellular carcinoma (CCC) therapeutic options are limited. Recently, systemic chemotherapy has shown response rates of up to 30%. Additional regional therapy of the arterially hyper vascularized hepatic tumors might represent a rational approach in an attempt to further improve response and palliation. Hence, a protocol combining transarterial chemoembolization and systemic chemotherapy was applied in patients with CCC limited to the liver. METHODS: Eight patients (6 women, 2 men, mean age 62 years) with nonresectable CCC received systemic chemotherapy (gemcitabine 1 000 mg/m2) and additional transarterial chemoembolization procedures (50 mg/m2 cisplatin, 50 mg/m2 doxorubicin, up to 600 mg degradable starch microspheres). Clinical follow-up of patients, tumor markers, CT and ultrasound were performed to evaluate maximum response and toxicity. RESULTS: Both systemic and regional therapies were tolerated well; no severe toxicity (WHO Ⅲ/Ⅳ) was encountered. Nausea and fever were the most commonly observed side effects. A progressive rarefication of the intrahepatic arteries limited the maximum number of chemoembolization procedures in 4 patients. A median of 2 chemoembolization cycles (range, 1-3) and a median of 6.5 gemcitabine cycles (range, 4-11) were administered. Complete responses were not achieved. As maximum response, partial responses were achieved in 3 cases, stable diseases in 5 cases. Two patients died from progressive disease after 9 and 10 mo. Six patients are still alive. The current median survival is 12 mo (range, 9-18); the median time to tumor progression is 7 mo (range, 3-18). Seven patients suffered from tumor-related symptoms prior to therapy, 3 of these experienced a treatment-related clinical relief. In one patient the tumor became resectable under therapy and was successfully removed after 10 mo. CONCLUSION: The present results indicate that a combination of systemic gemcitabine therapy and repeated regional chemoembolizations is well tolerated and may enhance the effect of palliation in a selected group of patients with intrahepatic nonresectable CCC.     

Epirubicin,Cisplatin,5-FU combination chemotherapy in sorafenib-refractory metastatic hepatocellular carcinoma

AIM:To evaluate the clinical efficacy and safety of epirubicin,cisplatin,and 5-FU combination chemotherapy for the sorafenib-refractory metastatic hepatocellular carcinoma(HCC).METHODS:From April 2009 to June 2012,31 patients who were diagnosed with metastatic and progressive HCC after sorafenib treatment were retrospectively reviewed.Patients were treated with the combination of epirubicin(50 mg/m2Ⅳ;day 1),cisplatin(60 mg/m2Ⅳ;day 1),and 5-FU(1000 mg/m2Ⅳ;day 1-3)[Epirubicin,cisplatin,5-FU combination(ECF)],repeated every 4 wk.RESULTS:The overall response rate was 12.9%.Patients who responded to ECF chemotherapy showed a longer overall survival(OS)and time to progression(TTP)relative to those in the non-responder group(OS:20.4 mo vs 4.9 mo,P<0.001,TTP:9.4 mo vs 2.2 mo,P<0.001).Patients with a stable primary liver mass also exhibited a longer OS and TTP relative to those with progressive disease(OS:13.4 mo vs 5.3 mo,P=0.003;TTP:9.4 mo vs 2.3 mo,P=0.003).The most common hematologic toxicity was thrombocytopenia(87.2%),and the incidence of grade 3-4 neutropenia was 53.9%.Age older than 60,a stable primary mass,and a good response to chemotherapy were prognostic factors for OS and TTP.CONCLUSION:This combination cytotoxic chemotherapy can serve as another treatment option after sorafenib failure for the subset of patients with advanced metastatic HCC.