Claudin 18.2 is a potential therapeutic target for zolbetuximab in pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is frequently diagnosed and treated in advanced tumor stages with poor prognosis. More effective screening programs and novel therapeutic means are urgently needed. Recent studies have regarded tight junction protein claudin 18.2 (CLDN18.2) as a candidate target for cancer treatment, and zolbetuximab (formerly known as IMAB362) has been developed against CLDN18.2. However, there are few data reported thus far related to the clinicopathological characteristics of CLDN18.2 expression for PDAC. AIM: To investigate the expression of CLDN18.2 in PDAC patients and subsequently propose a new target for the treatment of PDAC. METHODS: The Cancer Genome Atlas, Genotype-Tissue Expression, Gene Expression Omnibus, and European Genome-phenome Archive databases were first employed to analyze the CLDN18 gene expression in normal pancreatic tissue compared to that in pancreatic cancer tissue. Second, we analyzed the expression of CLDN18.2 in 93 primary PDACs, 86 para-cancer tissues, and 13 normal pancreatic tissues by immunohistochemistry. Immunostained tissues were assessed applying the histoscore. subsequently, they fell into two groups according to the expression state of CLDN18.2. Furthermore, the correlations between CLDN18.2 expression and diverse clinicopathological characteristics, including survival, were investigated. RESULTS: The gene expression of CLDN18 was statistically higher (P < 0.01) in pancreatic tumors than in normal tissues. However, there was no significant correlation between CLDN18 expression and survival in pancreatic cancer patients. CLDN18.2 was expressed in 88 (94.6%) of the reported PDACs. Among these tumors, 50 (56.8%) cases showed strong immunostaining. The para-cancer tissues were positive in 81 (94.2%) cases, among which 32 (39.5%) of cases were characterized for strong staining intensities. Normal pancreatic tissue was identified solely via weak immunostaining. Finally, CLDN18.2 expression significantly correlated with lymph node metastasis, distant metastasis, nerve invasion, stage, and survival of PDAC patients, while there was no correlation between CLDN18.2 expression and localization, tumor size, patient age and sex, nor any other clinicopathological characteristic. CONCLUSION: CLDN18.2 expression is frequently increased in PDAC patients. Thus, it may act as a potential therapeutic target for zolbetuximab in PDAC.

Prognostic Significance of PTTG1 and Its Methylation in Lung Adenocarcinoma.

Pituitary tumor-transforming gene-1 (PTTG1), one type of DNA repair-related gene, has been reported to be dysregulated in several tumors and serve as a tumor promotor. Previously, the oncogenic roles of PTTG1 were also reported in lung adenocarcinoma (LUAD). However, the prognostic values of PTTG1 in LUAD and the possible mechanism of its dysregulation have not been clarified. We analyzed TCGA datasets and reported that PTTG1 expression showed a distinct increase within LUAD specimens in comparison with nontumor specimens. Further survival study revealed that patients containing a great PTTG1 level had noticeably less overall survival and progression-free survival as compared with patients containing a low PTTG1 level. Multivariate analyses confirmed that PTTG1 expression was a factor of prognosis that is independent in terms of LUAD patients. Besides, PTTG1 methylation had a negative regulation on PTTG1, so PTTG1 had a high expressing level in LUAD tissues. However, the relation between hypermethylation and overall survival was not demonstrated using TCGA datasets. In addition, we observed that LUAD specimens with advanced stages exhibited a higher level of PTTG1. Finally, the dysregulated genes related to PTTG1 expression were screened, and KEGG assays revealed that the above genes were involved in the p53 signaling pathway, indicating the possible regulatory function of PTTG1 in the p53 signaling pathway. Overall, our findings suggest that PTTG1 may serve as an efficient clinical biomarker and a therapeutic target for patients suffering from LUAD.

Characteristics of Differently Located Colorectal Cancers Support Proximal and Distal Classification: A Population-Based Study of 57,847 Patients.

BACKGROUND: It has been suggested that colorectal cancer be regarded as several subgroups defined according to tumor location rather than as a single entity. The current study aimed to identify the most useful method for grouping colorectal cancer by tumor location according to both baseline and survival characteristics. METHODS: Cases of pathologically confirmed colorectal adenocarcinoma diagnosed from 2000 to 2012 were identified from the Surveillance, Epidemiology, and End Results database and categorized into three groups: right colon cancer (RCC), left colon cancer (LCC), and rectal cancer (ReC). Adjusted hazard ratios for known predictors of disease-specific survival (DSS) in colorectal cancer were obtained using a Cox proportional hazards regression model. RESULTS: The study included 57847 patients: 43.5% with RCC, 37.7% with LCC, and 18.8% with ReC. Compared with LCC and ReC, RCC was more likely to affect old patients and women, and to be at advanced stage, poorly differentiated or un-differentiated, and mucinous. Patients with LCC or ReC had better DSS than those with RCC in subgroups including stage III or IV disease, age ≤70 years and non-mucinous adenocarcinoma. Conversely, patients with LCC or ReC had worse DSS than those with RCC in subgroups including age ˃70 years and mucinous adenocarcinoma. CONCLUSIONS: RCC differed from both LCC and ReC in several clinicopathologic characteristics and in DSS. It seems reasonable to group colorectal cancer into right-sided (i.e., proximal) and left-sided (i.e., distal) ones.

[Expression and clinical significance of vascular endothelial growth factor-C and nm23-H1 in stage II and III colorectal carcinomas].

OBJECTIVE: To discuss the expression and clinical significance of VEGF-C and nm23-H1 in stage II and III colorectal carcinomas. METHODS: SP immunohistochemical staining was employed to determine the expression of vascular endothelial growth factor-C (VEGF-C) and nm23-H1 in the tumor tissues of 110 cases of stage II and III colorectal carcinomas and in the adjacent mucosal tissues of 53 cases as control, and analyze their correlation with cliniopathological features and prognosis. RESULTS: The positive expression of VEGF-C in the carcinoma tissues was 71.8%, significantly higher than that in the adjacent mucosal tissues (22.6%, P < 0.001). The positive expression of nm23-H1 in the carcinoma tissues was 57.3%, significantly lower than that in the adjacent mucosal tissues (90.6%, P < 0.001). The expression of VEGF-C was significantly correlated with lymph node metastasis (P < 0.05), and the nm23-H1 expression was significantly correlated with lymph node metastasis and pathological type (P < 0.05). The expression of VEGF-C and nm23-H1 did not show a significant correlation with age, gender, primary tumor site, tumor size and depth of invasion (P > 0.05). The VEGF-C expression was negatively related with nm23-H1 expression in colorectal carcinoma (r = -0.361, P < 0.001). The median overall survival (MOS) and median disease free survival (MDFS) of 110 patients with colorectal carcinoma were 55 and 48 months, respectively. The colorectal patients with different VEGF-C and nm23-H1 expression showed significant differences in the 5-year OS rate and 5-year DFS rate (P < 0.001). The patients with negative VEGF-C expression and positive nm23-H1 expression had a better prognosis. CONCLUSIONS: The joint detection of VEGF-C and nm23-H1 expression is very promising in prediction of the prognosis of patients with stage II and III colorectal carcinoma. However, whether it can be used as a marker in prognosis judgment needs further investigation.

Induction of p53 expression and apoptosis by a recombinant dual-target MDM2/MDMX inhibitory protein in wild-type p53 breast cancer cells.

The tumor suppressor gene p53 is often inactivated in breast cancer cells due to gene mutation or overexpression of its repressors (such as murine double minute 2 and murine double minute X). Inhibitors of murine double minute 2 (MDM2) and murine double minute X (MDMX) could lead to tumor suppression by restoration of p53 activity and such an approach is a promising strategy for future control of breast cancer. This study aimed to investigate the feasibility of the recombinant MDM2 and MDMX inhibitory protein in control of breast cancer in vitro. A cell-permeable dual-target MDM2/MDMX inhibitory protein was expressed in E. coli and incubated with p53 wild-type breast cancer cells. The data showed that this recombinant MDM2/MDMX inhibitory protein reduced the viability of MCF-7 and ZR-75-30 breast cancer cell lines and promoted cell cycle arrest and apoptosis by activation and stabilization of the p53 protein. Mechanistically, this MDM2/MDMX inhibitory protein increased the expression of p21, Bax and puma proteins, and inhibitory expression of MDM2 and MDMX proteins. This recombinant protein showed a better in vitro effect than that of nutlin-3α, a small molecule MDM2 inhibitor. The data further support the hypothesis that targeting of the p53 gene pathway could effectively control breast cancer.

Advances and prospects of anginex as a promising anti-angiogenesis and anti-tumor agent.

Anginex, a novel artificial cytokine-like peptide (ßpep-25), is designed by using basic folding principles and incorporating short sequences from the ß-sheet domains of anti-angiogenic agents, including platelet factor-4 (PF4), interleukin-8 (IL-8), and bactericidal-permeability increasing protein 1 (BP1). Anginex can specially block the adhesion and migration of the angiogenically activated endothelial cells (ECs), leading to apoptosis and ultimately to the inhibition of angiogenesis and tumor growth. In vitro and in vivo studies have proved its inhibitory effects on the formation of new blood vessels and tumor growth even though the mechanism is not clear. The inhibitory effects of anginex can be enhanced when it is applied in combination with other therapies, such as chemotherapy, radiotherapy and other anti-angiogenic agents. The limitations of anginex, including poor stability, short half life, complicated synthesis and low purity, have been conquered by modifying its structure or designing novel compound anginex and recombinant anginex, which makes possible the clinical application of anginex. Here, we summarize the basic and preclinical trials of anginex and discuss the prospects of anginex in clinical application. We come to the conclusion that anginex and compound or recombinant anginex can be used as effective anti-angiogenic agents.

Anti-angiogenesis and anti-tumor effects of AdNT4-anginex.

Anginex is a novel artificial peptide that can inhibit angiogenesis. AdNT4-anginex was constructed by inserting the artificial anginex gene into a recombinant adenoviral vector. We demonstrated that AdNT4-anginex inhibited migration of human endothelial cells, angiogenesis and tumor growth in in vitro and in vivo studies. Tumor growth of human H22 hepatoma in mice was inhibited after AdNT4-anginex treatment for 4 weeks, and a significant decrease in tumor size was observed as compared with the control group. Overall, these studies indicate that AdNT4-anginex is an effective anti-tumor agent, and deserves more attention and research.

[Clinical characteristics and survival of peripheral T-cell lymphoma-not otherwise specified: a report of 57 cases].

OBJECTIVE: To analyze the clinical characteristics and survival data of 57 patients with peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS). METHODS: The medical records of 57 patients with PTCL-NOS classified according to the revised REAL-WHO criteria, treated from Jan 1993 to Dec 2007 at the First and the Third affiliated Hospitals of Medical School of Xi'an Jiaotong University, were retrospectively evaluated by K-M univariate and COX multivariate analysis. RESULTS: 39 of the patients (68.4%) were males and 18 (31.6%) were females, aged 44 (3 - 88). Nine of the 57 patients (15.8%) were treated with chemo-radiotherapy, 43 (75.4%) with chemotherapy, 3 (5.3%) with radiotherapy, and 2 with supported treatment alone (2.5%). The overall response rate was 87.3%, with a complete remission (CR) rate of 60.0% in 55 evaluable cases. The 1-, 3-, and 5-year overall survival (OS) rates were 67.0%, 48.0% and 24.3%, respectively, with a median follow-up of 30.4 months (ranged 1-100 months). The median survival time (MST) was 36.0 months. Multivariate analysis showed that the prognostic index for T cell lymphoma (PIT) score was an independent prognostic factor for PTCL-NOS (P < 0.05), but bone marrow involvement, performance status, extranodal involvement, stage, B symptom were not independent prognostic factors. CONCLUSION: Although conventional chemotherapy yields a high response rate for PTCL-NOS, the long-term survival is still low and further investigation for optional treatment is needed.

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

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

[The relationship between lymphatic metastasis and serum vascular endothelial growth factor C and cyclooxygenase 2 expression in breast cancer].

OBJECTIVE: To investigate the relationship among the serum vascular endothelial growth factor C (sVEGF-C), expression of cyclooxygenase 2 (COX-2), and lymph vessel density (LMVD), and to discuss their role in tumor progression and lymphatic metastasis. METHODS: sVEGF-C level was detected by ELISA in 68 pre-operation breast cancer patients, 35 breast benign disease patients, and 12 healthy women. Immunohistochemical method was used to detect the expression of COX-2 and lymphatic vessel endothelial hyaluronidase receptor (LYVE)-1 in the breast cancer tissues and benign disease tissues obtained during operation. RESULTS: (1) The sVEGF-C level of the pre-operation breast cancer group was (49 +/- 8) pg/ml, significantly higher than those of the begin tumor group [(8 +/- 4) pg/ml, P = 0.045] and the healthy women [(5 +/- 3) pg/ml, P = 0.003]. (2) The COX-2 overexpression positive rate in the breast cancer tissues was 44.1%, significantly higher than that in the begin disease tissues (11.4%, P = 0.002). Higher than that in the begin disease tissue; the LMVD overexpression in the breast cancer tissues was mainly located in the para-carcinoma tissue (8.7 +/- 4.7), significantly higher than that in the begin disease tissues (1.8 +/- 1.7, P = 0.002). (3) The COX-2 overexpression rate of the patients with a high sVEGF-C level was significantly higher than that of the patients with a low sVEGF-C level (P = 0.024). The LMVD level in the breast cancer of the sVEGF-C high level group was (8.7 +/- 3.9), significantly higher than that of the sVEGF-C normal group (5.6 +/- 3.3, P = 0.039). (4) The LMVD in the COX-2 overexpression breast cancer group was 9.5 +/- 3.7, significantly higher than that in the COX-2 negative group (6.0 +/- 3.8, P = 0.012). (5) The sVEGF-C level, COX-2, and LMVD expression in the breast cancer patients with lymphatic metastasis were significantly higher than those in the patients without lymphatic metastasis (P = 0.025, 0.022, and 0.002 respectively). CONCLUSION: VEGF-C, COX-2, and LMVD play important roles in the lymphatic metastasis of breast cancer. They may be important prognostic factors in evaluating breast cancer lymphatic metastasis.

[Relationship between serum VEGF level and VEGF, COX-2 and MVD expression in breast cancer tissues].

OBJECTIVE: To investigate the relationship between serum VEGF (sVEGF) level and VEGF, COX-2 and MVD expression in breast cancer, and to discuss their role in angiogensis of breast cancer. METHODS: sVEGF level was detected by ELISA in 68 preoperative breast cancer, 35 benign breast disease and 20 healthy women. The expression of VEGF, COX-2 and MVD was detected by immunohistochemical method in tissues of breast cancer and breast benign diseases, and to analyze the relationship of sVEGF, VEGF, COX-2 and MVD. RESULTS: (1) sVEGF level in preoperative breast cancers was 306.51 pg/ml (interquartile range from 190.44 to 442.04 pg/ml), in benign diseases was 150.82 pg/ml (interquartile range from 82.36 to 212.34 pg/ml), and in healthy control was 105.93 pg/ml (interquartile range from 78.54 to 157.77 pg/ml). The sVEGF level of preoperative breast cancer group was significantly higher than that of breast benign disease group and healthy women (P = 0.001). (2) The VEGF expression positive rate in breast cancer (67.65%) was significantly higher than that in breast benign disease (44.12%) (P = 0.015). The COX-2 expression positive rate in breast cancer (42.86%) was significantly higher than that in breast benign disease (11.43%) (P = 0.002). (3) the COX-2 expression positive rate in sVEGF high level patients (56.00%) was significantly higher than that in sVEGF normal level patients (11.11%) (P = 0.024), and MVD in sVEGF high level patients (27.32 +/- 3.40) was also higher than that in sVEGF normal level patients (15.31 +/- 6.16) (P = 0.011). (4) The sVEGF level (322.09 +/- 79.31) of 68 breast cancer patients whose VEGF was positive in breast cancer tissues was significantly higher than that in VEGF negative group (222.47 +/- 73.53) (P = 0.017). (5) The COX-2 expression positive rate in VEGF positive expression group (65.21%) was significantly higher than that in VEGF negative expression group (18.18%) (P = 0.017). The MVD expression in COX-2 positive expression group (22.94 +/- 5.51) was significantly higher than that in COX-2 negative expression group (10.30 +/- 4.42) (P = 0.027). CONCLUSION: sVEGF level in breast cancer is significantly higher than that in breast benign disease and healthy women, and is correlated with the expression of COX-2 and MVD in breast cancer tissues.

[Docetaxel in the treatment of advanced breast cancer ].

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

[Effect of modified MAID regimen for patients with advanced soft tissue sarcoma].

BACKGROUND & OBJECTIVES: Clinical study suggests that 72-hour continuous infusion (CIV) of MAID regimen is more effective and achieves longer time of no progression than ADR-based two-drug regimen in advanced soft tissue sarcoma (ASTS) treatment, but has no improvement on the long-term survival. Because of the severe grade 3/4 toxicities as well as treatment-related deaths, the regimen has not been widely applied in ASTS. This study was to investigate the efficacy and toxicity of the modified MAID regimen in ASTS treatment. METHODS: In the modified regimen, adriamycin (ADR) was substituted with tetrahydropyranyl adriamycin (THP-ADR) and the application of ifosfamide (IFO) was modified. All enrolled patients received chemotherapy (IFO 2,000 mg . m(-2), 4h, day 1-3; mesna 1,200 mg . m(-2) at 0, 4 and 8 hours of IFO infusion, day 1-3; THP-ADR 20 mg . m-2 and dacarbazine (DTIC) 333.3 mg . m(-2) were mixed in the same bag or pump, CIV for 3 days). The therapy was repeated every 3 weeks for at least 2 cycles before evaluating the effects and toxicities. The patients received follow-up every 2 months after completing 2 cycles until the study was finished. Life table was used to calculate long-term survival rates and time to progression. RESULTS: Fifty-four cases of evaluable patients had completed at least 2 cycles of modified MAID chemotherapy. The overall response rate was 42.59%. The toxicities were mild. Grade 3/4 neutropenia and thrombocytopenia were 25.93% and 16.17%, respectively. Neutropenia fever was 11.11%. There were no other toxicities, such as hepatic and renal toxicities; no central nervous system toxicity and treatment-related deaths. During 2 year follow-up, time to progression was 7 months, 1- and 2- year survival rates were 61.11% and 36.36%, respectively. CONCLUSIONS: Modified MAID regimen simplifies the application of treatment procedure compared with original regimen, which three drugs have to be CIV simultaneously. Moreover the modified MAID regimen has better survival rates in ASTS, with milder toxicity and better tolerance.

[Construction and identification of the recombinant prokaryotic expression plasmid containingbetapep-25 peptide].

AIM: To synthesize antiangiogenic peptide fragment of betapep-25, to construct and identify the recombinant prokaryotic expression plasmid containing betapep-25 peptide. METHODS: The fragment encoding betapep-25 peptide was designed and synthesized artificially and was cloned into vector pGEM-T easy after being identified by sequencing. After being digested by Nae I and BamH I, T-betapep-25 peptide fragment was cloned into recombinant vector pBV220-NT4, which was digested by Nae I and BamH I. The constructed recombinant prokaryotic expression plasmid pBV220-NT4-betapep-25 was digested using BamH I, EcoR I and BamH I, respectively. RESULTS: The sequcence of betapep-25 synthesized artificially and analyzed by digestion was consistent with the published results. Fragments of 4,030 bp, 364 bp and 3,666 bp were obtained after digestion of recombinant prokaryotic expression plasmid pBV220-NT4-betapep-25 using BamH I, EcoR I and BamH I, respectively, which demonstrated the successful cloning and construction of recombinant prokaryotic expression plasmid. CONCLUSION: The successful construction recombinant prokaryotic expression plasmid expressing betapep-25 provides a foundation for further research on its mechanism of anti-tumor activity in vivo and in vitro.

[Influence of P-glycoprotein expression on chemotherapeutic response of metastatic breast carcinoma].

BACKGROUND & OBJECTIVES: The clinical study showed that the P-glycoprotein(P-gp) expression was closely associated with the chemotherapeutic effect, response rate, prognosis, and survival time. Until now, few clinical papers have reported about metastatic sites and its response to chemotherapy with P-gp expression in metastatic breast carcinoma. The current study was designed to investigate the role of P-gp expression and its clinical value of chemotherapy for the patients with different metastatic sites of this carcinoma. METHODS: P-gp expression in 46 postoperative patients with metastatic breast carcinoma was detected by SABC immunohistochemical method. 43 cases treated with combination regimen: Cyclophosphamide 600 mg/m2 i.v. on day 1, Pirarubicin 60 mg/m2 i.v. on day 1, 5-Fluorouracil 600 mg/m2 i.v. on days 1 and 8. Repeat the cycle every 3 weeks for at least 2 cycles. The correlation between P-gp expression and chemotherapeutic response was analyzed. RESULTS: 1) P-gp expression positive rate was 56.5%, the P-gp expression in the patients with lung or liver viscera metastasis was higher than that in skin or lymph node metastasis (P = 0.049). 2) The overall response rate was 58.1% in 43 patients. The response rate of the P-gp negative group was higher than the P-gp positive group(P < 0.01). 3) The response rate in the patients with skin and lymph node metastasis was higher than the patients with lung and liver metastasis (P < 0.05). 4) The postoperative patients who had received CAF(cyclophosphamide + adriamycin + 5-fluorouracil) or CMF(cyclophosphamide + methotrexate + 5-fluorouracil) regimen adjuvant chemotherapy previously, the response rate of metastatic diseases to chemotherapy had no significant difference (P > 0.05). CONCLUSIONS: P-gp expression may be considered as an index for evaluating multidrug resistance, guiding drug use, and judging prognosis of the patients with metastatic breast carcinoma.