UGT1A1 predicts outcome in colorectal cancer treated with irinotecan and fluorouracil

AIM:To evaluate effects of UDP-glucuronosyltransferase1A1(UGT1A1) and thymidylate synthetase(TS) gene polymorphisms on irinotecan in metastatic colorectal cancer(mCRC).METHODS:Two irinotecan-and fluorouracil-based regimens,FOLFIRI and IFL,were selected as second-line therapy for 138 Chinese mCRC patients.Genomic DNA was extracted from peripheral blood samples before treatment.UGT1A1 and TS gene polymorphisms were determined by direct sequencing and restriction fragment length polymorphism,respectively.Gene polymorphisms of UGT1A1*28,UGT1A1*6 and promoter enhancer region of TS were analyzed.The relationship between genetic polymorphisms and clinical outcome,that is,response,toxicity and survival were assessed.Pharmacokinetic analyses were performed in a subgroup patients based on different UGT1A1 genotypes.Plasma concentration of irinotecan and its active metabolite SN-38 and inactive metabolite SN-38G were determined by high performance liquid chromatography.Differences in irinotecan and its metabolites between UGT1A1 gene variants were compared.RESULTS:One hundred and eight patients received the FOLFIRI regimen,29 the IFL regimen,and one irinotecan monotherapy.One hundred and thirty patients were eligible for toxicity and 111 for efficacy evaluation.One hundred and thirty-six patients were tested for UGT1A1*28 and *6 genotypes and 125 for promoter enhancer region of TS.Patients showed a higher frequency of wild-type UGT1A1*28(TA6/6) compared with a Caucasian population(69.9% vs 45.2%).No significant difference was found between response rates and UGT1A1 genotype,although wild-type showed lower response rates compared with other variants(17.9% vs 24.2% for UGT1A1*28,15.7% vs 26.8% for UGT1A1*6).When TS was considered,the subgroup with homozygous UGT1A1*28(TA7/7) and non-3RG genotypes showed the highest response rate(33.3%),while wild-type UGT1A1*28(TA6/6) with non-3RG only had a 13.6% response rate,but no significant difference was found.Logistic regression showed treatment duration was closely linked to clinical response.In toxicity comparison,UGT1A1*28 TA6/6 was associated with lower incidence of grade 2-4 diarrhea(27.8% vs 100%),and significantly reduced the risk of grade 4 neutropenia compared with TA7/7(7.8% vs 37.5%).Wild-type UGT1A1*6(G/G) tended to have a lower incidence of grade 3/4 diarrhea vs homozygous mutant(A/A) genotype(13.0% vs 40.0%).Taking UGT1A1 and TS genotypes together,lower incidence of grade 2-4 diarrhea was found in patients with non-3RG TS genotypes,when TA6/6 was compared with TA7/7(35.3% vs 100.0%).No significant association with time to progression(TTP) and overall survival(OS) was observed with either UGT1A1 or TS gene polymorphisms,although slightly longer TTP and OS were found with UGT1A1*28(TA6/6).Irinotecan PK was investigated in 34 patients,which showed high area under concentration curve(AUC) of irinotecan and SN-38,but low AUC ratio(SN-38G /SN-38) in those patients with UGT1A1*28 TA7/7.CONCLUSION:A distinct distribution pattern of UGT1A1 genotypes in Chinese patients might contribute to relatively low toxicity associated with irinotecan and 5-fluorouracil in mCRC patients.

Prognosis of HER2 over-expressing gastric cancer patients with liver metastasis

AIM:To study the risk factors for liver metastasis and the prognosis in patients with human epidermal growth factor receptor 2(HER2) over-expressing gastric cancer(GC).METHODS:A total of 84 GC patients recruited from the General Hospital of the People's Liberation Army(PLA) between 2003 and 2010 were randomly enrolled in this study.HER2 expression was detected by immunohistochemistry in 84 GC patients with liver metastases.The study group consisted of 66 men and 18 women,with an average age of 54 years(range:19-74 years).Liver metastasis was diagnosed by magnetic resonance imaging or computed tomography.Patients were followed-up and predictive factors of liver metastasis were evaluated.RESULTS:The median follow-up period was 47 mo(range:6-85 mo).The characteristics of 35(25.7%) patients with HER2 over-expression of liver metastatic GC are presented.HER2 over-expression was detected in 23 out of 49(46.9%) patients with intestinal GC,and 9 out of 35(25.7%) patients with diffuse GC.29 out of 59(49.2%) patients aged < 60 years were HER2positive,while 8 out of 25(32%) patients aged ≥ 60 were HER2-positive;a significant difference(P < 0.05).Univariate analysis(log-rank test) showed that HER2 over-expression,sex,Lauren classification,differentiation and disease-free interval were correlated with poor survival(P < 0.05).Survival analysis with a survival curve showed that HER2 over-expression was significantly relevant,with a reduced survival time in GC patients with liver metastases(P < 0.01).2-year survival was not associated with the patient's age.A diseasefree survival longer than 12 mo has a significant association with extended overall survival(OS) in GC patients with liver metastases.The median survival time after the diagnosis of liver metastases was 18 mo [95% confidence interval(CI):9.07-26.94] among HER2 positive GC patients with liver metastases.In comparison,for 49(69.4%) out of 84 HER2 negative patients with liver metastatic GC,the median survival time was 47 mo(95% CI:19.37-74.63).In patients with HER2 positive liver metastatic GC,the median OS was significantly shorter than in HER2 negative patients(median,20.32 mo;95% CI:16.51-24.13 vs median,50.14 mo;95% CI:37.83-62.45;P < 0.01).CONCLUSION:HER2 over-expressing GC patients with liver metastases have a poor prognosis.Overall survival was significantly lower in HER2 positive patients.HER2overexpression is correlated with a lower survival rate.

Prolonged overall survival in gastric cancer patients after adoptive immunotherapy

AIM:To assess the efficacy of immunotherapy with expanded activated autologous lymphocytes(EAALs) in gastric cancer.METHODS:An observational study was designed to retrospectively analyze the clinical data of 84 gastric cancer patients,of whom 42 were treated by EAAL immunotherapy plus conventional treatment and another 42 only received conventional treatment(control group).EAALs were obtained by proliferation of peripheral blood mononuclear cells from patients followed by phenotype determination.Clinical data including age,gender,clinical stage,chemotherapeutic regimens,hospitalization,surgical,radiotherapy,and survival data were collected along with EAAL therapy details and side effects.Patients were followed and the relationship between treatment and overall survival(OS) data obtained for the immunotherapy and control groups were compared retrospectively.The safety of EAAL immunotherapy was also evaluated.RESULTS:After in vitro culture and proliferation,the percentages of CD3+,CD3+CD8+,CD8+CD27+,CD8+CD28+,and CD3+CD16+/CD56+cells increased remarkably(P < 0.05),while the percentages of CD3+CD4+,CD4+CD25+,and CD3-CD16+/CD56+(natural killer cells) were overtly decreased(P < 0.05); no significant change was observed in CD4+CD25+CD127- cells(P =0.448).Interestingly,OS in the immunotherapy group was significantly higher than that in the control group,with 27.0 and 13.9 mo obtained for the two groups,respectively(P =0.028,HR =0.573,95%CI:0.347-0.945).These findings indicated a 42.7% decrease in the risk of death.In addition,we found that clinical stage and application of EAAL immunotherapy wereindependent prognostic factors for gastric cancer patients.Indeed,the OS in stage Ⅲc and Ⅳ patients that had received surgery was prolonged after EAAL immunotherapy(P < 0.05).Importantly,in vitro induction and proliferation of EAAL were easy and biologically safe.CONCLUSION:Overall,EAAL adoptive immunotherapy might prolong the OS in gastric cancer patients.

Endoscopic trans-esophageal submucosal tunneling surgery:A new therapeutic approach for diseases located around the aorta ventralis

AIM To assess the efficiency of endoscopic trans-esophageal submucosal tunneling surgery(EESTS) technique for diseases located around the aorta ventralis.METHODS Nine pigs were assigned to EESTs. The procedures were as follows: First, a long esophageal submucosal tunnel was established. Second, full-thickness myotomy was created. Third, an endoscope was entered into the abdominal cavity through a muscle incision and the endoscope was around the aorta ventralis. Eventually,celiac trunk ganglion neurolysis, partial hepatectomy and splenectomy, partial tissue resection in the area of the posterior peritoneum, and endoscopic submucosal dissection(ESD) combined with lymph node dissection were performed. The animals were given antibiotics for 5 d and necropsied 7 d after surgery.RESULTS In all surgeries, one pig died from intraperitoneal hemorrhage after doing partial splenectomy, while the other pigs were alive after successfully operating other surgeries. For surgery of celiac trunk ganglion damage, at necropsy, there was no exudation in the abdominal cavity. Regarding surgery of partial hepatectomy, the wound with part healing was observed in the left hepatic lobe, and no bleeding or obvious exudation was seen. In surgery of partial splenectomy, massive hemorrhage was observed on the splenic wound surface, and the metal clips could not stop bleeding. After surgery of retroperitoneal tissue resection, mild tissue adhesion was observed in the abdominal cavity of one animal, and another one suffered from severe infection. For surgery of ESD and lymph node dissection, a moderate tissue adhesion was observed.CONCLUSION EESTS is a feasible and safe technique for diseases located around the aorta ventralis.

Expression of hENT1 and ERCC1 genes in tumor tissues non-small cell lung cancer

Objective:To investigate the expression of hENT1 and ERCCl genes in tumor tissues non-small cell lung cancer(NSCLC).Methods:Fresh non-small lung cancer specimens were transplanted into nude mice.Twenty mice were randomized into two groups:experimental group receiving gemeitabine plus cisplatin and control group receiving 0.9%physiological saline.The expressions of hENTi and ERCC1 mRNA in tumor tissue were detccted by real-time fluorescent quantitative PCR.The volume of tumor,the weight of nude mice and tumor volume were respectively measured and calculated 2-3 times per week.Tissue samples were collected from NSCLC mice treated with gemeitabine plus carboplatin.Results:The histological examination showed that many tumor cells were well preserved in nude mice.The rate of transplanted tumor cells was 86.7%.The concomitant treatment study showed that the rate of TV,RTV,T/C in GEM + DDP group was the lowest.LBP + DOC,DDP + DOC obviously influenced the body weight.Compared with NS group,DDP group,GEM group,the survival period and the level of hENTl of DDP+GEM group increased obviously,the level of ERCC1 decreased significantly(P【0.05).Conclusions:The expression of hENT1 and ERCC1 genes in tumor tissues were closely correlated with the response to chemotherapy and prognosis of patients with NSCLC treated with gemeitabine plus cisplatin.

Sequential chemotherapy and icotinib as first-line treatment for advanced epidermal growth factor receptor-mutated non-small cell lung cancer

BACKGROUND Icotinib could have potential effect and tolerability when used sequentially with chemotherapy for advanced epidermal growth factor receptor(EGFR)-mutated non-small cell lung cancer(NSCLC).AIM To evaluate the efficacy and safety of chemotherapy followed by icotinib maintenance therapy as first-line treatment for advanced EGFR-mutated NSCLC.METHODS This multicenter,open-label,pilot randomized controlled trial enrolled 68 EGFRmutated stage IIIB/IV NSCLC patients randomized 2:3 to the icotinib alone and chemotherapy+icotinib groups.RESULTS The median progression-free survival in the icotinib alone and chemotherapy+icotinib groups was 8.0 mo(95%CI:3.84-11.63)and 13.4 mo(95%CI:10.18-16.33),respectively(P=0.0249).No significant differences were found in the curative effect when considering different cycles of chemotherapy or chemotherapy regimen(all P>0.05).CONCLUSION A sequential combination of chemotherapy and EGFR-tyrosine kinase inhibitor is feasible for stage IV EGFR-mutated NSCLC patients.

Treatment progress of brain metastases from lung cancer

Objective:Lung cancer is one of malignant tumors with the highest incidence in the world, and 30%-65% of the patients develop brain metastases in the progression of the disease. Brain metastases seriously affect the patient's cognitive function, survival time and quality of life, the prognosis is extremely poor and the natural course of disease is about 1-3 months. The main therapies for brain metastases from NSCLC include surgical resection, radiotherapy, chemotherapy, and so on. In recent years, with the improvement of surgical methods, the improvement of radiotherapy technology, the emergence of targeted drugs and the combined use of various treatments, the survival time of patients has been greatly extended, and the quality of life has also been significantly improved. In this paper, the current main treatment strategies for brain metastases are reviewed.