Breakthrough cancer medicine and its impact on novel drug development in China: report of the US Chinese Anti-Cancer Association (USCACA) and Chinese Society of Clinical Oncology (CSCO) Joint Session at the 17th CSCO Annual Meeting

The US Chinese Anti-Cancer Association(USCACA)teamed up with Chinese Society of Clinical Oncology(CSCO)to host a joint session at the17th CSCO Annual Meeting on September 20th,2014in Xiamen,China.With a focus on breakthrough cancer medicines,the session featured innovative approaches to evaluate breakthrough agents and established a platform to interactively share successful experiences from case studies of 6 novel agents from both the United States and China.The goal of the session is to inspire scientific and practical considerations for clinical trial design and strategy to expedite cancer drug development in China.A panel discussion further provided in-depth advice on advancing both early and full development of novel cancer medicines in China.

The role of LIN28B in tumor progression and metastasis in solid tumor entities

LIN28B is an RNA-binding protein that targets a broad range of microRNAs and modulates their maturation and activity.Under normal conditions,LIN28B is exclusively expressed in embryogenic stem cells,blocking differentiation and promoting proliferation.In addition,it can play a role in epithelial-to-mesenchymal transition by repressing the biogenesis of let-7 microRNAs.In malignancies,LIN28B is frequently overexpressed,which is associated with increased tumor aggressiveness and metastatic properties.In this review,we discuss the molecular mechanisms of LIN28B in promoting tumor progression and metastasis in solid tumor entities and its potential use as a clinical therapeutic target and biomarker.

Opportunities and challenges of immunotherapy for dMMR/MSI-H colorectal cancer

Colorectal cancer(CRC)with mismatch-repair deficiency(dMMR)is a distinct molecular subgroup of tumors that is characterized by a diminished capacity to correct base-pair mismatches in DNA,which leads to changes in microsatellite sequences and results in high microsatellite instability(MSI-H)accompanied by hypermutation1.

Changing patterns of colorectal cancer in China over a period of 20 years

AIM: To determine whether any changes have occurred on the patterns of colorectal cancer in China.METHODS: Data from 21 Chinese articles published from 1980 to 1999, were used to analyze the time trend of colorectal cancer according to the patients' age at diagnosis,sex, the site of the tumor, stage, and the pathology.RESULTS: From 1980s to 1990s, the mean age of the colorectal cancer patients has increased. The percentage of the female patients rose. The distribution of colorectal carcinoma shows a predominance of rectal cancer. However,the proportion of proximal colon cancer (including transverse and ascending colon) increased significantly accompanied by a decline in the percentage of rectal cancer. Similarity in the percentage of distal colon cancer between two decades was revealed. In the 1990s, statistically more Stage B patients were found than those in 1980s. In addition, databases show a significant decrease in the Stage D cases. The proportion of adenocarcinoma increased, but the mucinous adenocarcinoma decreased during two decades.CONCLUSION: These findings indicate that the patternof colorectal cancer in China has been changing. Especially,a proximal shift due to the increasing proportion of ascending and transverse colon cancer has occurred in China.

Effect of multidisciplinary team treatment on outcomes of patients with gastrointestinal malignancy

AIM: To evaluate the effect of multidisciplinary team (MDT) treatment modality on outcomes of patients with gastrointestinal malignancy in China. METHODS: Data about patients with gastric and colorectal cancer treated in our center during the past 10 years were collected and divided into two parts. Part 1 consisted of the data collected from 516 consecutive complicated cases discussed at MDT meetings in Peking University School of Oncology (PKUSO) from December 2005 to July 2009. Part 2 consisted of the data collected from 263 consecutive cases of resect-able locally advanced rectal cancer from January 2001 to January 2005. These 263 patients were divided into neoadjuvant therapy (NT) group and control group. Patients in NT group received MDT treatment, namely neoadjuvant therapy + surgery + postoperative adjuvant therapy. Patients in control group underwent direct surgery + postoperative adjuvant therapy. The outcomes in two groups were compared. RESULTS: The treatment strategy was altered after discussed at MDT meeting in 76.81% of gastric cancer patients and in 58.33% of colorectal cancer patients before operation. The sphincter-preservation and local control of tumor were better in NT group than in control group. The 5-year overall survival rate was also higher in NT group than in control group (77.23% vs 69.75%, P = 0.049). CONCLUSION: MDT treatment modality can significantly improve the outcomes of patients with gastrointestinal malignancy in China.

Clinical outcomes of EGFR-TKI treatment and genetic heterogeneity in lung adenocarcinoma patients with EGFR mutations on exons 19 and 21

Background:Epidermal growth factor receptor(EGFR) mutations,including a known exon 19 deletion(19 del) and exon 21 L858 R point mutation(L858R mutation),are strong predictors of the response to EGFR tyrosine kinase inhibitor(EGFR-TKI) treatment in lung adenocarcinoma.However,whether patients carrying EGFR 19 del and L858 R mutations exhibit different responsiveness to EGFR-TKls and what are the potential mechanism for this difference remain controversial.This study aimed to investigate the clinical outcomes of EGFR-TKI treatment in patients with EGFR 19 del and L858 R mutations and explore the genetic heterogeneity of tumors with the two mutation subtypes.Methods:Of 1127 patients with advanced lung adenocarcinoma harboring EGFR 19 del or L858 R mutations,532 received EGFR-TKI treatment and were included in this study.EGFR 19 del and L858 R mutations were detected by using denaturing high-performance liquid chromatography(DHPLC).T790 M mutation,which is a common resistant mutation on exon 20 of EGFR,was detected by amplification refractory mutation system(ARMS).Next-generation sequencing(NGS) was used to explore the genetic heterogeneity of tumors with EGFR 19 del and L858 R mutations.Results:Of the 532 patients,319(60.0%) had EGFR 19 del,and 213(40.0%) had L858 R mutations.The patients with EGFR 19 del presented a significantly higher overall response rate(ORR) for EGFR-TKI treatment(55.2%vs.43.7%,P = 0.017) and had a longer progression-free survival(PFS) after first-line EGFR-TKI treatment(14.4 vs.11.4 months,P = 0.034) compared with those with L858 R mutations.However,no statistically significant difference in overall survival(OS) was observed between the two groups of patients.T790 M mutation status was analyzed in 88 patients before EGFR-TKI treatment and 134 after EGFR-TKI treatment,and there was no significant difference in the co-existence of T790 M mutation with EGFR 19 del and L858 R mutations before EGFR-TKI treatment(5.6%vs.8.8%,P = 0.554)or after treatment(24.4%vs.35.4%,P = 0.176).In addition,24 patients with EGFR 19 del and 19 with L858 R mutations were analyzed by NGS,and no significant difference in the presence of multiple somatic mutations was observed between the two genotypes.Conclusions:Patients with EGFR 19 del exhibit longer PFS and higher ORR compared with those with L858 R mutations.Whether the heterogeneity of tumors with EGFR 19 del and L858 R mutations contribute to a therapeutic response difference needs further investigation.

Efficacy of imatinib dose escalation in Chinese gastrointestinal stromal tumor patients

AIM:To investigate the efficacy and safety of imatinib dose escalation in Chinese patients with advanced gastrointestinal stromal tumor (GIST).METHODS:Advanced GIST patients previously failing 400 mg imatinib treatment were enrolled in this study.Patients received imatinib with dose escalation to 600 mg/d,and further dose escalation to 800 mg/d if imatinib 600 mg/d failed.Progression-free survival,overall survival,clinical efficacy,c-kit/PDGFRA genotype and safety were evaluated.RESULTS:52 patients were enrolled in this study.For the 47 evaluable patients receiving imatinib (600 mg/d),the disease control rate was 40.4%,and the median progression-free survival for all patients was 17 wk (95% CI:3.9-30.1).The median overall survival after dose escalation was 81 wk (95% CI:36.2-125.8).Adverse events,mainly edema,fatigue,granulocytopenia and skin rash were tolerable.However,further dose escalation (800 mg/d) in 14 cases was ineffective,with disease progression and severe adverse events.Among 30 cases examined for gene mutations,patients with exon 9 mutations experienced a better progression-free survival of 47 wk.CONCLUSION:Imatinib dose escalation to 600 mg/d is more appropriate for Chinese patients and may achieve further survival benefit.

Validation And Reliability of Distress Thermometer in Chinese Cancer Patients

Objective：To examine the validation and reliability of the distress thermometer（DT） recommended by National Comprehensive Cancer Network（NCCN） in Chinese cancer patients.Methods：A total of 574 Chinese cancer patients from Beijing Cancer Hospital completed the detection of DT,the Hospital Anxiety and Depression Scale（HADS） and Symptom Checklist 90（SCL-90）,Receiver Operating Characteristic（ROC） curve and Area Under the Curve（AUC） were used to analyze the validation relative to HADS and SCL-90.The patients with DT≥4 and whose distress caused by emotional problems were interviewed with the MiNi International Neuro-psychiatric Interview（MINI）（Chinese Version 5.0）.This version was used to analyze cancer patients＇ psychological and Psychiatric symptoms during the cancer process;3.Another 106 cancer patients in rehabilitation stage and stable condition were asked to fill in DT two times,at the base time and after 7-10 days.Results：Data of ROC indicates that a DT cutoff score of 4 yielded AUC of 0.80 with a optimal sensitivity（0.80） and specificity（0.70） relative to HADS,and AUC of 0.83 with the greatest sensitivity（0.87） and specificity（0.72） against SCL-90.The DT also has acceptable test-retest reliability（r=0.800,P=0.000）;According to the interview results,the most common psychiatric problems cancer patients have adjustment disorder,depression,and anxiety.Conclusion：The data suggest that DT has acceptable overall accuracy and reliability as a screening tool for testing distress severity and specific problems causing distress in Chinese cancer patients.It is worth being used in oncology clinic,the rapid screening and interview could help caregivers to identify psychological and psychiatric problems of cancer patients and provide useful information for further treatment.

Evaluation of the 7^(th) edition of the TNM classification in patients with resected esophageal squamous cell carcinoma

AIM:To evaluate the prognostic factors and tumor stages of the 7th edition TNM classification for esophageal cancer.METHODS:In total,1033 patients with esophageal squamous cell carcinoma(ESCC)who underwent surgical resection with or without(neo)adjuvant therapy between January 2003 and June 2012 at the Thoracic Surgery DepartmentⅡof the Beijing Cancer Hospital,Beijing,China were included in this study.The following eligibility criteria were applied:(1)squamous cell carcinoma of the esophagus or gastroesophageal junction identified by histopathological examination;(2)treatment with esophagectomy plus lymphadenectomy with curative intent;and(3)complete pathologic reports and follow-up data.Patients who underwent non-curative(R1)resection and patients who died in hospital were excluded.Patients who received(neo)adjuvant therapy were also included in thisanalysis.All patients were restaged using the 7th edition of the Union for International Cancer Control and the American Joint Committee on Cancer TNM staging systems.Univariate and multivariate analyses were performed to identify the prognostic factors for survival.Survival curves were plotted using the Kaplan-Meier method,and the log-rank test was used to evaluate differences between the subgroups.RESULTS:Of the 1033 patients,273 patients received(neo)adjuvant therapy,and 760 patients were treated with surgery alone.The median follow-up time was 51.6mo(range:5-112 mo)and the overall 5-year survival rate was 36.4%.Gender,"p T"and"p N"descriptors,(neo)adjuvant therapy,and the 7th edition TNM stage grouping were independent prognostic factors in the univariate and multivariate analyses.However,neither histologic grade nor cancer location were independent prognostic factors in the univariate and multivariate analyses.The 5-year stage-based survival rates were as follows:ⅠA,84.9%;ⅠB,70.9%;ⅡA,56.2%;ⅡB,43.3%;ⅢA,37.9%;ⅢB,23.3%;ⅢC,12.9%andⅣ,3.4%.There were significant differences between each adjacent staging classification.Moreover,there were significant differences between each adjacent p N and p M subgroup.According to the p T descriptor,there were significant differences between each adjacent subgroup except between p T3 and p T4(P=0.405).However,there was no significant difference between each adjacent histologic grade subgroup and between each adjacent cancer location subgroup.CONCLUSION:The 7th edition is considered to be valid for patients with resected ESCC.However,the histologic grade and cancer location were not prognostic factors for ESCC.

Treatment efficacy of radiof requency ablation of 338 patients with hepatic malignant tumor and the relevant complications

AIM: To investigate the treatment efficacy of radiofrequency ablation (RFA) of hepatic malignant tumor and the relevant complications.METHODS: A total of 338 patients with 763 hepatic tumors underwent ultrasound-guided RFA (565 procedures).There were 204 cases of hepatic cellular carcinoma (HCC)with 430 tumors, the mean largest diameter was 4.0 cm.Of them, 48 patients (23.5％) were in stages Ⅰ-Ⅱ (UICC Systems) and 156 (76.5％) in stages Ⅲ-Ⅳ There were 134 cases of metastatic liver carcinoma (MLC), with 333metastases in the liver, the mean diameter was 4.1 cm,the liver metastases of 96 patients (71.6％) came from gastrointestinal tract. Ninety-three percent of the 338patients were treated using the relatively standard protocol. Crucial attention must be paid to monitor the abnormal changes in ultrasound images as well as the vital signs of the patients to find the possible hemorrhage and peripheral structures injury in time. The tumors were considered as ablated completely, if no viability was found on enhanced CT within 24 h or at 1 mo after RFA. These patients were followed up for 3-57 mo.RESULTS: The ablation success rate was 93.3％ (401/430tumors) for HCC and was 96.7％ (322/333 tumors) for MLC. The local recurrence rate for HCC and MLC was 7.9％ (34/430 tumors) and 10.5％ (35/333 tumors),respectively. A total of 137 patients (40.5％) underwent 2-11times of repeated ablations because of tumor recurrence or metastasis. The 1st, 2nd, and 3rd year survival rate was84.6％, 66.6％, and 63.1％, respectively;the survival rate from 48 patients of Ⅰ-Ⅱ stage HCC was 93.7％, 80.4％,and 80.4％, respectively. The major complication rate in this study was 2.5％ (14 of 565 procedures), which consisted of 5 hemorrhages, 1 colon perforation, 5 injuries of adjacent structures, 2 bile leakages, and 1 skin burn.CONCLUSION: RFA, as a minimally invasive local treatment,has become an effective and relatively safe alternative for the patients of hepatic malignant tumor, even of advanced liver tumor, tumor recurrence, and liver metastases. Knowledge about possible complications and their control may increase the treatment efficacy and help to promote the use of RFA technique.

Expressions of Thymidylate Synthase, Thymidine Phosphorylase, Class Ⅲ β-tubulin, and Excision Repair Cross-complementing Group 1 Predict Response in Advanced Gastric Cancer Patients Receiving Capecitabine Plus Paclitaxel or Cisplatin

Objective: To evaluate the role of class III β-tubulin (TUBB3), thymidylate synthase (TS), thymidine phosphorylase (TP), and excision repair cross-complementing group 1 (ERCC1) in clinical outcome of advanced gastric cancer patients receiving capecitabine plus paclitaxel or cisplatin. Methods: The clinical data and tumor specimens from 57 advanced gastric cancer patients receiving first-line capecitabine plus paclitaxel (cohort 1, n=36) and capecitabine plus cisplatin (cohort 2, n=21) were retrospectively collected, and TUBB3, TS, TP, and ERCC1 expressions were detected by real-time quantitative PCR. The associations between expressions of biomarkers and response or survival were analyzed statistically. Results: The median age of 57 patients was 57 years (range: 27–75 years) with 38 males and 19 females. Of all patients, the response rates of patients with high TP, low TP and high TS, low TS expressions were 57.1%, 27.6% (P=0.024), and 55.2%, 28.6% (P=0.042), respectively. Among cohort 1, the response rates and median overall survivals of patients with low and high TUBB3 expressions were 61.1% vs. 33.3% (P=0.095) and 13.8 months vs. 6.6 months (P=0.019), respectively; the response rate (87.5%) of patients with low TUBB3 and high TP expressions was higher than that (14.3%) of patients with high TUBB3 and low TP expressions (P=0.01). Among cohort 2, the response rates of patients with low ERCC1 and high ERCC1 expressions were 45.5% and 20.0% respectively (P=0.361). Conclusion: TUBB3, TS and TP expressions could predict the response of advanced gastric cancer patients receiving capecitabine-based and paclitaxel-based chemotherapy. These results will be further confirmed in future large samples.

Prognostic significance of PTEN,Ki-67 and CD44s expression patterns in gastrointestinal stromal tumors

AIM:To develop a prognostic approach for gastrointestinal stromal tumors(GISTs) using a cluster of indicators and follow-up information.METHODS:One hundred and four GISTs that had not been subjected to targeted therapies were collected and classified by NIH risk assessment and anatomic location.By immunohistochemistry,the expressions of PTEN,Ki-67,CD44s matrix metalloproteinase(MMP)-9 and TIMP-1 were detected on tissue microarray.Univariate and multimarker survival analyses were performed and then a COX hazard proportion model was constructed to evaluate a cluster of predictors of GIST.RESULTS:Our data showed small intestinal GIST are more aggressive than gastric GIST.The NIH risk assessment correlated with disease-free survival foreither gastric GIST or small intestinal GIST.Immunohistochemical analysis revealed that Ki-67 labeling indexes(LIs) < 5% predicted higher disease-specific survival(DSS) in gastric and small intestinal GIST.CD44s positivity and PTEN LIs ≥ 50% correlated with higher DSS in gastric GIST.MMP-9 and TIMP-1 had no correlation with survival.Multimarker analysis revealed that the expression pattern of PTEN LIs ≥ 50% combined with Ki-67 LIs < 5% and CD44s positivity reliably predicted favorable outcomes for gastric GIST(P = 0.009),as did the combination of PTEN LIs ≥ 50% and Ki-67 LIs < 5% for small intestinal GIST(P = 0.011).Authors also found that high NIH risk grade was correlated with DSS in patients with gastric GIST and disease-free survival in patients with small intestinal GIST.CONCLUSION:PTEN LIs ≥ 50%,Ki-67 LIs < 5% and CD44s positivity provides an accurate,favorable prognosis for gastric GIST.PTEN LIs ≥ 50% and Ki-67 LIs < 5% does the same for small intestinal GIST.Ki-67 LIs enhances the NIH assessment.

Impact of Serum Vascular Endothelial Growth Factor on Prognosis in Patients with Unresectable Hepatocellular Carcinoma after Transarterial Chemoembolization

Objective： To investigate the expression level with unresectable hepatocellular carcinoma （HCC） and to assess the impact of serum VEGF as chemoembolization （TACE） treatments. of serum vascular endothelial growth factor （VEGF） in patients and its relationship with the c a predictive factor for HCC nicopathological characteristics, prognosis during transarterial Methods： Serum VEGF levels were measured using enzyme-linked immunosorbent assay （ELISA） in 60 random patients who underwent TACE or transarterial infusion （TAI） for unresectable HCC between May and September 2008 and 12 healthy volunteers were also involved in this study to serve as control. All patients＇ clinicopathological features were retrospectively analyzed. Serum VEGF levels were correlated with clinicopathological features of the HCC patients. The patients＇ survival rates were analyzed with Kaplan-Meier survival curves and compared by the log-rank test. The prognostic significance of serum VEGF levels and factors related to survival rate were evaluated by univariate and multivariate analysis. Results： The median serum VEGF level in the HCC patients was 285 pg/ml （range 14-1,207 pg/ml）, significantly higher than that of healthy controls （P=0.021）. The serum VEGF levels were significantly correlated with platelet counts （r=0.396, P=0.002） but not other clinicopathological features. Patients with serum VEGF level 〉285 pg/ml had worse overall survival compared with those with serum VEGF level 〈285 pg/ml （P=0.002）. By multivariate analysis, the serum VEGF level was a significant prognostic factor. Conclusion： High serum VEGF levels may predict poor prognosis of HCC after TACE. This study highlights the importance of tumor biomarker as a prognostic predictor in TACE therapy for HCC, which has an intrinsic problem of unavailability of histopathological prognostic features.

Adjuvant percutaneous radiofrequency ablation of feeding artery of hepatocellular carcinoma before treatment

AIM:To evaluate the feasibility and efficacy of percutaneous radiofrequency ablation(RFA) of the feeding artery of hepatocellular carcinoma(HCC) in reducing the blood-flow-induced heat-sink effect of RFA.METHODS:A total of 154 HCC patients with 177 pathologically confirmed hypervascular lesions participated in the study and were randomly assigned into two groups.Seventy-one patients with 75 HCCs(average tumor size,4.3 ± 1.1 cm) were included in group A,in which the feeding artery of HCC was identified by color Doppler flow imaging,and were ablated with multiple small overlapping RFA foci [percutaneous ablation of feeding artery(PAA)] before routine RFA treatment of the tumor.Eighty-three patients with 102 HCC(average tumor size,4.1 ± 1.0 cm) were included in group B,in which the tumors were treated routinely with RFA.Contrast-enhanced computed tomography was used as post-RFA imaging,when patients were followed-up for 1,3 and 6 mo.RESULTS:In group A,feeding arteries were blocked in 66(88%) HCC lesions,and the size of arteries decreased in nine(12%).The average number of punctures per HCC was 2.76 ± 1.12 in group A,and 3.36 ± 1.60 in group B(P = 0.01).The tumor necrosis rate at 1 mo post-RFA was 90.67%(68/75 lesions) in group A and 90.20%(92/102 lesions) in group B.HCC recur-rence rate at 6 mo post-RFA was 17.33%(13/75) in group A and 31.37%(32/102) in group B(P = 0.04).CONCLUSION:PAA blocked effectively the feeding artery of HCC.Combination of PAA and RFA significantly decreased post-RFA recurrence and provided an alternative treatment for hypervascular HCC.

Expression of phosphatase regenerating liver 3 is an independent prognostic indicator for gastric cancer

AIM:To investigate the prognostic significance of phosphatase regenerating liver 3(PRL-3)protein expression in gastric cancer.METHODS:PRL-3 expression in paraffin-embedded tumor specimens from 293 patients with gastric cancer was studied retrospectively by immunohistochemistry.Monoclonal antibody specifically against PRL-3,3B6,was obtained with hybridoma technique.RESULTS:Positive PRL-3 expression was detected in 43.3%(127 of 293)of gastric cancer cases.High expression of PRL-3 was positively correlated with tumor size,depth of invasion,vascular/lymphatic invasion,lymph node metastasis,high TNM stage and tumor recurrence.Patients with positive PRL-3 expression had a significantly lower 5-year survival rate than those with negative expression(28.3%vs 51.9%,P<0.0001).Patients who received curative surgery,and with positive PRL-3 expression had a significant shorter overall survival and disease-free disadvantage over patients with negative expression(hazard ratio of 16.7 and 16.6,respectively;P<0.0001 for both).Multivariate analysis revealed that PRL-3 expression was an independent prognostic indicator for overall and disease-free survival of gastric cancer patients,particularly for survival in TNM stageⅢpatients.CONCLUSION:PRL-3 expression is a new independent prognostic indicator to predict the potential of recurrence and survival in patients with gastric cancer at the time of tumor resection.

Mutations in components of the Wnt signaling pathway in gastric cancer

AIM: To explore the contribution of AXIN1, AXIN2 and beta-catenin, components of Wnt signaling pathway, to the carcinogenesis of gastric cancer (GC), we examined AXIN1, AXIN2 exon7 and CTNNB1 (encoding beta- catenin) exon3 mutations in 70 GCs. METHODS: The presence of mutations was identified by polymerase chain reaction (PCR)-based denaturing high-performance liquid chromatography and direct DNA sequencing. Beta-catenin expression was detected by immunohistochemical analysis. RESULTS: Among the 70 GCs, 5 (7.1%) had mutations in one or two of these three components. A frameshift mutation (1 bp deletion) in exon7 of AXIN2 was found in one case. Four cases, including the case with a mutation in AXIN2, had frameshift mutations and missense mutations in AXIN1. Five single nucleotide polymorphisms (SNPs), 334 C>T, 874 C>T, 1396 G>A, 1690 C>T and 1942 T>G, were identified in AXIN1. A frameshift mutation (27 bp deletion) spanning exon3 of CTNNB1 was observed in one case. All four cases with mutations in AXIN1 and AXIN2 showed nuclear beta- catenin expression. CONCLUSION: These data indicate that the mutationsin AXIN1 and AXIN2 may contribute to gastric carcino- genesis.

Phenotypic classification of gastric signet ring cell carcinoma and its relationship with clinicopathologic parameters and prognosis

AIM: To distinguish subtypes of gastric signet ring cell (SRC) carcinoma by investigating the expression of gastric and intestinal phenotypic markers, and to study the significance of phenotypic classification in predicting tumor progression and outcome. METHODS: Immunohistochemistry was performed in 66 cases of SRC carcinoma with MUC2, VILLIN, CDX2, Li-cadherin antibodies as intestinal phenotype markers and MUC5AC, HGM, MUC6 antibodies as gastric phenotype markers, and the relationship was analyzed between the phenotypic expression pattern and clinicopathologic parameters, as well as the 3-year survival rate. RESULTS: Expression of intestinal phenotypic markers was positively associated with tumor size, wall invasion, vascular invasion, lymph node metastasis and tumor-node-metastasis (TNM) stage. Cases expressing one or more intestinal markers had a significant lower survival rate than cases expressing none of the intestinal markers. CONCLUSION: The SRC carcinomas expressing intestinal phenotype markers exhibited a high pro-liferative potential, bad biological behaviors and poor prognosis. Examination of phenotype expression may be useful in distinguishing histological type and in predicting the prognosis of gastric SRC carcinoma.

MUC1-positive circulating tumor cells and MUC1 protein predict chemotherapeutic efficacy in the treatment of metastatic breast cancer

Chemotherapy plays an important role in the treatment of metastatic breast cancer. It is important to monitor chemotherapeutic efficacy, to find a simple and efficient tool to guide treatment, and to predict the efficacy of treatment in a timely and accurate manner. This study aimed to detect mucin-1 (MUC1) - positive circulating tumor cells and MUC1 protein in the peripheral blood of patients with metastatic breast cancer and to investigate their relationship to chemotherapeutic efficacy. MUC1 mRNA was detected in the peripheral blood of 34 patients with newly diagnosed metastatic breast cancer by reverse transcription- polymerase chain reaction. The positive rates of MUC1 mRNA were 88.2% before chemotherapy and 70.6% after chemotherapy, without a significant difference (P = 0.564); MUC1 mRNA expression before chemotherapy had no correlation with treatment effectiveness (P = 0.281). The response rate of MUC1 mRNA -negative patients after first-cycle chemotherapy was significantly higher (P = 0.009) and the progression-free survival (PFS) was clearly longer than those of MUC1 mRNA-positive patients (P = 0.095). MUC1 protein in peripheral blood plasma was detected by an ELISA competitive inhibition assay. The patients with decreased MUC1 protein after chemotherapy had a significantly longer PFS than those with elevated MUC1 protein (P = 0.044). These results indicate that the outcomes of MUC1 mRNA - negative patients after chemotherapy are better than those of MUC1 mRNA-positive patients. In addition, patients with decreased expression of MUC1 protein have a better PFS.

Comparative analysis of dideoxy sequencing,the KRAS StripAssay and pyrosequencing for detection of KRAS mutation

AIM:To compare the differences between dideoxy sequencing/KRAS StripAssay/pyrosequencing for detection of KRAS mutation in Chinese colorectal cancer (CRC) patients.METHODS:Formalin-f ixed, paraff in-embedded (FFPE) samples with tumor cells ≥ 50% were collected from 100 Chinese CRC patients at Beijing Cancer Hospital. After the extraction of genome DNA from FFPE samples, fragments contained codons 12 and 13 of KRAS exon 2 were amplified by polymerase chain reaction and analyzed by dideoxy sequencing, the KRAS Strip Assay and pyrosequencing. In addition, the sensitivities of the 3 methods were compared on serial dilutions (contents of mutant DNA: 100%,50%,20%, 5%,10%, 5%,1%,0%) of A549 cell line DNA (carrying the codon 12 Gly>Ser mutation) into wild-type DNA (human normal intestinal mucosa). The results of dideoxy sequencing,the KRAS StripAssay and pyrosequencing were analyzed by Chromas Software, Collector forKRAS Strip Assay and the pyrosequencing PyroMarkTM Q24 system, respectively.RESULTS: Among 100 patients, KRAS mutations were identif ied in 34%, 37% and 37% of patients by dideoxy sequencing, the KRAS StripAssay and pyrosequencing, respectively. The sensitivity was highest with the KRAS Strip Assay (1%), followed by pyrosequencing (5%), and dideoxy sequencing was lowest (15%). Six different mutation types were found in this study with 3 main mutations Gly12 Asp (GGT>GAT), Gly12 Val (GGT>GTT) and Gly13 Asp (GGC>GAC). Thirty-three patients were identifi ed to have KRAS mutations by the 3 methods, and a total of 8 patients had conflicting results between 3 methods: 4 mutations not detected by dideoxy sequencing and the KRAS StripAssay were identified by pyrosequencing; 3 mutations not detected by dideoxy sequencing and pyrosequencing were identif ied by the KRAS StripAssay; and 1 mutation not detected by pyrosequencing was conf irmed by dideoxy sequencing and the KRAS StripAssay. Among these discordant results, the results identif ied by dideoxy sequencing were consistent either with the KRAS StripAssay or with pyrosequencing, which indicated that the accuracy of dideoxy sequencing was high. CONCLUSION: Taking a worldwide view of reports and our results,dideoxy sequencing remains the most popular method because of its low cost and high accuracy.

Over-expression of Metastasis-associated in Colon Cancer-1 (MACC1) Associates with Better Prognosis of Gastric Cancer Patients

Objective： The aim of this study was to detect metastasis-associated in colon cancer-1 （MACC1） expression in Chinese gastric cancer and analyze the relationship between MACC1 expression and postoperative survival. Methods： The expression of MACC1 and c-MET protein in a sample of 128 gastric cancer tissues was detected by immunohistochemistry. A retrospective cohort study on the prognosis was carried out and data were collected from medical records. Results： The positive rate of MACC1 protein expression in gastric cancer was 47.66%, higher than that in adjacent noncancerous mucosa （P0.001）. MACC1 protein expression was not related to the clinicopathological variables involved. Kaplan-Meier analysis revealed that the survival of MACC1 positive group tended to be better than that of MACC1 negative group, particularly in patients with stage III carcinoma （P=0.032）. Cox regression analysis revealed that MACC1 protein over-expression in gastric cancer tended to be a protective factor with hazard ratio of 0.621 （P=0.057）. Immunohistochemical analysis showed that the positive rate of c-MET protein expression was much higher in cases with positive MACC1 expression in gastric cancer （P=0.002）, but P53 expression was not associated with MACC1 expression. Conclusion： MACC1 over-expression implies better survival and may be an independent prognostic factor for gastric cancer in Chinese patients.