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Sample records for cancer combined analysis

  1. Saliva analysis combining membrane protein purification with surface-enhanced Raman spectroscopy for nasopharyngeal cancer detection

    NASA Astrophysics Data System (ADS)

    Feng, Shangyuan; Lin, Duo; Lin, Juqiang; Huang, Zufang; Chen, Guannan; Li, Yongzeng; Huang, Shaohua; Zhao, Jianhua; Chen, Rong; Zeng, Haishan

    2014-02-01

    A method for saliva analysis combining membrane protein purification with silver nanoparticle-based surface-enhanced Raman spectroscopy (SERS) for non-invasive nasopharyngeal cancer detection was present in this paper. In this method, cellulose acetate membrane was used to obtain purified whole proteins from human saliva while removing other native saliva constituents and exogenous substances. The purified proteins were mixed with silver nanoparticle for SERS analysis. A diagnostic accuracy of 90.2% can be achieved by principal components analysis combined with linear discriminate analysis, for saliva samples obtained from patients with nasopharyngeal cancer (n = 62) and healthy volunteers (n = 30). This exploratory study demonstrated the potential for developing non-invasive, rapid saliva SERS analysis for nasopharyngeal cancer detection.

  2. The benefit of adjuvant chemotherapy combined with postoperative radiotherapy for endometrial cancer: a meta-analysis.

    PubMed

    Park, Hyun Jong; Nam, Eun Ji; Kim, Sunghoon; Kim, Yong Bae; Kim, Young Tae

    2013-09-01

    The objective of our study was to determine whether adjuvant chemotherapy combined with postoperative radiotherapy would have benefits for the disease-free survival and overall survival in patients with high-risk endometrial cancer. Electronic searches for studies of adjuvant chemotherapy combined with postoperative radiotherapy in endometrial cancer patients between March 1971 and March 2012 were made on MEDLINE, SCOPUS, and the Cochrane library. Articles with more than 4 stars on the Newcastle-Ottawa scale or a score of more than 4 on the modified Jadad scale were included. A meta-analysis was performed, and pooled hazard ratios (HR) of progression-free survival (PFS) and overall survival (OS) between patients whose adjuvant chemotherapy was combined with radiotherapy (the CTx+RTx group) and patients with adjuvant radiotherapy only (the RTx group) were derived from the fixed effect model or random effect model. Three observational studies and 3 randomized clinical trials (RCTs) were included in the final analysis. Subgroup analysis for FIGO stage showed that the CTx+RTx group had a more significant survival benefit compared to that of the RTx group in advanced stage endometrial cancer (OS HR 0.53, 95% CI 0.36-0.80; PFS HR 0.54, 95% CI 0.37-0.77), but no significant benefit in early stage endometrial cancer (OS HR 0.96, 95% CI 0.70-1.32; PFS HR 1.00, 95% CI 0.39-2.58). This meta-analysis suggests that adjuvant chemotherapy combined with postoperative radiotherapy could probably reduce disease progression and overall death in patients with advanced-stage disease. In order to examine whether the multimodal treatment has benefit in high-risk endometrial cancer, we need further large-scale RCTs. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  3. Combined Analysis of ChIP Sequencing and Gene Expression Dataset in Breast Cancer.

    PubMed

    Liu, Pengfei; Jiang, Wenhua; Zhou, Shiyong; Gao, Jun; Zhang, Huilai

    2017-04-01

    Breast cancer is a common malignancy in women and contribute largely to the cancer related death. The purpose of this study is to confirm the roles of GATA3 and identify potential biomarkers of breast cancer. Chromatin Immunoprecipitation combined with high-throughput sequencing (ChIP-Seq) (GSM1642515) and gene expression profiles (GSE24249) were downloaded from the Gene Expression Omnibus (GEO) database. Bowtie2 and MACS2 were used for the mapping and peak calling of the ChIP-Seq data respectively. ChIPseeker, a R bioconductor package was adopted for the annotation of the enriched peaks. For the gene expression profiles, we used affy and limma package to do normalization and differential expression analysis. The genes with fold change >2 and adjusted P-Value <0.05 were screened out. Besides, BETA (Binding and Expression Target Analysis) was used to do the combined analysis of ChIP-Seq and gene expression profiles. The Database for Annotation, Visualization and Integrated Discovery (DAVID) was used for the functional enrichment analysis of overlapping genes between the target genes and differential expression genes (DEGs). What's more, the protein-protein interaction (PPI) network of the overlapping genes was obtained through the Human Protein Reference Database (HPRD). A total of 46,487 peaks were identified for GATA3 and out of which, 3256 ones were found to located at -3000 ~ 0 bp from the transcription start sites (TSS) of their nearby gene. A total of 236 down- and 343 up-regulated genes were screened out in GATA3 overexpression breast cancer samples compared with those in control. The combined analysis of ChIP-Seq and gene expression dataset showed GATA3 act as a repressor in breast cancer. Besides, 68 overlaps were obtained between the DEGs and genes included in peaks located at -3000 ~ 0 bp from TSS. Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways related to cancer progression and gene regulation were found to be

  4. Combination analysis of Bub1 and Mad2 expression in endometrial cancer: act as a prognostic factor in endometrial cancer.

    PubMed

    Li, Lin; Xu, De-Bin; Zhao, Xiao-Li; Hao, Tian-Yu

    2013-07-01

    This study aimed to evaluate the diagnostic value of Bub1 and Mad2 together in endometrial cancer. Sixty-three patients with endometrial cancer, including EECs and NEECs, were examined statistically. Bub1 and Mad2 in patient tissues were detected by indirect streptavidin-biotin-peroxidase complex method. 39 cases (61.9 %) were in clinical stage I, 17 cases (27 %) in stage II, 5 (7.9 %) in stage III and 2 cases (3.2 %) in stage IV. Bub1 positive and Mad2 positive rate were identified in 18 and 54 patients. The lower positive of Bub1 and higher positive rate of Mad2 were related to clinical stage and histological grade of endometrial cancer (P = 0.009, 0.002, respectively), especially in NEECs. The expression of Bub1 was negatively correlated with Mad2 and Mtp53 (both P < 0.05). The expression of Mad2 with Mtp53 was positively correlated (P < 0.05). Statistically significant difference between Bub1/Mad2 expression and survival was discovered in endometrial cancer. Specificity and sensitivity of combination between Bub1 negative and Mad2 positive cases were higher than those alone in NEEC subtype. Bub1 and Mad2 are associated with histological differentiation, clinical stage and decreased postoperative survival in endometrial cancer. The combination analysis of Bub1 and Mad2 might be the valuable prognostic, even diagnostic clinicopathologic factor which can be applicable in routine examination.

  5. Grade-Dependent Metabolic Reprogramming in Kidney Cancer Revealed by Combined Proteomics and Metabolomics Analysis.

    PubMed

    Wettersten, Hiromi I; Hakimi, A Ari; Morin, Dexter; Bianchi, Cristina; Johnstone, Megan E; Donohoe, Dallas R; Trott, Josephine F; Aboud, Omran Abu; Stirdivant, Steven; Neri, Bruce; Wolfert, Robert; Stewart, Benjamin; Perego, Roberto; Hsieh, James J; Weiss, Robert H

    2015-06-15

    Kidney cancer [or renal cell carcinoma (RCC)] is known as "the internist's tumor" because it has protean systemic manifestations, suggesting that it utilizes complex, nonphysiologic metabolic pathways. Given the increasing incidence of this cancer and its lack of effective therapeutic targets, we undertook an extensive analysis of human RCC tissue employing combined grade-dependent proteomics and metabolomics analysis to determine how metabolic reprogramming occurring in this disease allows it to escape available therapeutic approaches. After validation experiments in RCC cell lines that were wild-type or mutant for the Von Hippel-Lindau tumor suppressor, in characterizing higher-grade tumors, we found that the Warburg effect is relatively more prominent at the expense of the tricarboxylic acid cycle and oxidative metabolism in general. Further, we found that the glutamine metabolism pathway acts to inhibit reactive oxygen species, as evidenced by an upregulated glutathione pathway, whereas the β-oxidation pathway is inhibited, leading to increased fatty acylcarnitines. In support of findings from previous urine metabolomics analyses, we also documented tryptophan catabolism associated with immune suppression, which was highly represented in RCC compared with other metabolic pathways. Together, our results offer a rationale to evaluate novel antimetabolic treatment strategies being developed in other disease settings as therapeutic strategies in RCC.

  6. Near-infrared confocal micro-Raman spectroscopy combined with PCA-LDA multivariate analysis for detection of esophageal cancer

    NASA Astrophysics Data System (ADS)

    Chen, Long; Wang, Yue; Liu, Nenrong; Lin, Duo; Weng, Cuncheng; Zhang, Jixue; Zhu, Lihuan; Chen, Weisheng; Chen, Rong; Feng, Shangyuan

    2013-06-01

    The diagnostic capability of using tissue intrinsic micro-Raman signals to obtain biochemical information from human esophageal tissue is presented in this paper. Near-infrared micro-Raman spectroscopy combined with multivariate analysis was applied for discrimination of esophageal cancer tissue from normal tissue samples. Micro-Raman spectroscopy measurements were performed on 54 esophageal cancer tissues and 55 normal tissues in the 400-1750 cm-1 range. The mean Raman spectra showed significant differences between the two groups. Tentative assignments of the Raman bands in the measured tissue spectra suggested some changes in protein structure, a decrease in the relative amount of lactose, and increases in the percentages of tryptophan, collagen and phenylalanine content in esophageal cancer tissue as compared to those of a normal subject. The diagnostic algorithms based on principal component analysis (PCA) and linear discriminate analysis (LDA) achieved a diagnostic sensitivity of 87.0% and specificity of 70.9% for separating cancer from normal esophageal tissue samples. The result demonstrated that near-infrared micro-Raman spectroscopy combined with PCA-LDA analysis could be an effective and sensitive tool for identification of esophageal cancer.

  7. Statin as a Combined Therapy for Advanced-Stage Ovarian Cancer: A Propensity Score Matched Analysis

    PubMed Central

    Chen, Hong-Yu; Wang, Qian; Xu, Qiu-Hong; Yan, Li; Gao, Xue-Feng; Lu, Yan-Hong

    2016-01-01

    Background. Despite the great achievements in the treatment of advanced-stage ovarian cancer, it is still a severe condition with an unfavorable 5-year survival rate. Statins have been suggested to reduce the risk of several cancers beyond their cholesterol-lowing effects. However, the prognostic significance of statins in patients with advanced-stage ovarian cancer remains controversial. Methods. A retrospective study was performed to evaluate the association between statin intake and overall survival (OS) among patients with advanced-stage ovarian cancer. Patients who underwent cytoreductive surgery followed by courses of intravenous chemotherapy were matched through a propensity score analysis. Results. A total of 60 propensity-matched patients were included. Women in statin group showed a similar OS than the nonstatin counterparts (P = 0.966), whereas residual tumor was significantly associated with better OS (P = 0.013) and was an independent factor that associated with OS (P = 0.002, hazard ratio = 5.460, and 95% confidence interval: 1.894 to 15.742) in multivariable analysis. Conclusions. Our results suggested that statin usage was not associated with improved OS in patients with advanced-stage ovarian cancer undergoing surgery and chemotherapy. Considering the retrospective nature and the relative small sample size of the study, further prospective studies and random control trials are needed. PMID:27975064

  8. Identification of endometrial cancer methylation features using combined methylation analysis methods

    PubMed Central

    Trimarchi, Michael P.; Yan, Pearlly; Groden, Joanna; Bundschuh, Ralf; Goodfellow, Paul J.

    2017-01-01

    Background DNA methylation is a stable epigenetic mark that is frequently altered in tumors. DNA methylation features are attractive biomarkers for disease states given the stability of DNA methylation in living cells and in biologic specimens typically available for analysis. Widespread accumulation of methylation in regulatory elements in some cancers (specifically the CpG island methylator phenotype, CIMP) can play an important role in tumorigenesis. High resolution assessment of CIMP for the entire genome, however, remains cost prohibitive and requires quantities of DNA not available for many tissue samples of interest. Genome-wide scans of methylation have been undertaken for large numbers of tumors, and higher resolution analyses for a limited number of cancer specimens. Methods for analyzing such large datasets and integrating findings from different studies continue to evolve. An approach for comparison of findings from a genome-wide assessment of the methylated component of tumor DNA and more widely applied methylation scans was developed. Methods Methylomes for 76 primary endometrial cancer and 12 normal endometrial samples were generated using methylated fragment capture and second generation sequencing, MethylCap-seq. Publically available Infinium HumanMethylation 450 data from The Cancer Genome Atlas (TCGA) were compared to MethylCap-seq data. Results Analysis of methylation in promoter CpG islands (CGIs) identified a subset of tumors with a methylator phenotype. We used a two-stage approach to develop a 13-region methylation signature associated with a “hypermethylator state.” High level methylation for the 13-region methylation signatures was associated with mismatch repair deficiency, high mutation rate, and low somatic copy number alteration in the TCGA test set. In addition, the signature devised showed good agreement with previously described methylation clusters devised by TCGA. Conclusion We identified a methylation signature for a

  9. Early prediction of lung cancer based on the combination of trace element analysis in urine and an Adaboost algorithm.

    PubMed

    Tan, Chao; Chen, Hui; Xia, Chengyun

    2009-04-05

    Early detection of cancer is the key to effective treatment and long-term survival. Lung cancer is one of the most frequently occurring cancers and its early detection is particularly of interest. This work investigates the feasibility of a combination of Adaboost (ensemble from machining learning) using decision stumps as weak classifier and trace element analysis for predicting early lung cancer. A dataset involving the determination of 9 trace elements of 122 urine samples is used for illustration. Kennard and Stone (KS) algorithm coupled with an alternate re-sampling was used to realize sample set partitioning. The whole dataset was split into equally sized training and test set, which were then reversed to yield a second operating case, we called them case A and case B, respectively. The prediction results based on the Adaboost were compared with those from Fisher discriminant analysis (FDA). On the test set, the final Adaboost classifiers achieved a sensitivity of 100% for both cases, a specificity of 93.8%, 95.7%, and an overall accuracy of 95.1%, 96.7%, for case A and case B, respectively. In either case, Adaboost always achieves better performance than FDA; also, it is less sensitive to the composition of the training set compared to FDA and easy to control over-fitting. It seems that Adaboost is superior to FDA in the present task, indicating that integrating Adaboost and trace element analysis of urine can serve as a useful tool for diagnosing early lung cancer in clinical practice.

  10. Efficacy and safety of target combined chemotherapy in advanced gastric cancer: a meta-analysis and system review.

    PubMed

    Zou, Kun; Yang, Shuailong; Zheng, Liang; Yang, Chaogang; Xiong, Bin

    2016-09-15

    The aim of our meta-analysis is to assess the efficacy and safety of the target combined chemotherapy for the patients with unresectable advanced or recurrent gastric cancer. In accordance with the standard meta-analysis procedures, the patients included in our study were with unresectable advanced or recurrent gastric cancer and allocated randomly to receive target combined chemotherapy or the traditional chemotherapy. The search was applied to PubMed, EMBASE, Science Citation Index Expanded, Cocran's library (from inception to February 2016). All analyses were performed by STATA 12.0, with the odds ratio, hazard ratio, and 95 % confidence interval as the effect measures. Fourteen studies were included in this meta-analysis. A total of 5067 patients with advanced gastric cancer were divided into two arms: traditional chemotherapy arm and target combined chemotherapy arm. A significant improvement for overall survival (hazard ratio was 0.89, 95 % confidence interval: 0.83-0.95) and overall response rate (odds ratio was 1.44, 95 % confidence interval: 1.15-1.81) was observed, but no significant difference was found for progression-free survival (hazard ratio was 0.89, 95 % confidence interval: 0.77-1.00) in the target combined chemotherapy arm. In subgroup analysis, increasing benefits regarding overall survival and progression-free survival were found in anti epidermal growth factor receptor target drugs for selected patients subgroup and anti vascular endothelial growth factor receptor target drugs for unselected patients subgroup, but not in anti epidermal growth factor receptor target drugs for unselected patients subgroup. Besides, some adverse events were increased in the target combined chemotherapy arm. The target combined chemotherapy represented a better overall survival benefit and treatment efficiency and higher incidence of some grade 3-4 adverse events than the traditional chemotherapy for patients with unresectable advanced or recurrence gastric

  11. Comparative analysis of combined spectral and optical tomography methods for detection of skin and lung cancers.

    PubMed

    Zakharov, Valery P; Bratchenko, Ivan A; Artemyev, Dmitry N; Myakinin, Oleg O; Kornilin, Dmitry V; Kozlov, Sergey V; Moryatov, Alexander A

    2015-02-01

    Malignant skin tumors of different types were studied in vivo using optical coherence tomography (OCT), backscattering (BS), and Raman spectroscopy (RS). A multimodal method is proposed for early cancer detection based on complex analysis of OCT images by their relative alteration of scattered-radiation spectral intensities between malignant and healthy tissues. An increase in average accuracy of diagnosis was observed for a variety of cancer types (9% sensitivity, 8% specificity) by a multimodal RS-BS-OCT system in comparison with any of the three methods used separately. The proposed approach equalizes the processing rates for all methods and allows for simultaneous imaging and classification of tumors. © 2015 Society of Photo-Optical Instrumentation Engineers (SPIE)

  12. Combination of microdissection and microarray analysis to identify gene expression changes between differentially located tumour cells in breast cancer.

    PubMed

    Zhu, Gang; Reynolds, Louise; Crnogorac-Jurcevic, Tatjana; Gillett, Cheryl E; Dublin, Edwin A; Marshall, John F; Barnes, Diana; D'Arrigo, Corrado; Van Trappen, Philippe O; Lemoine, Nicholas R; Hart, Ian R

    2003-06-12

    Comparison of gene expression changes between cancer cells at the periphery and in the centre of breast cancers was performed using a combination of microdissection and microarray analysis. Cancer cells from the two areas were pooled separately from five patients with ductal carcinoma in situ and separately from five patients with frankly invasive cancer. Limited total RNA, 100-200 ng, from this microdissected tissue required use of the Atlas SMART trade mark Probe Amplification Kit to synthesize and amplify cDNA and make (33)P-labelled probes. Probes were then hybridized to Atlas Human Cancer 1.2 Arrays containing 1176 known genes. Triplicate analysis revealed that 22 genes changed their expression levels in the periphery relative to the central region: 15 upregulated and seven downregulated (arbitrary threshold of 1.5-fold or greater). Differences in RNA levels were confirmed by quantitative real-time PCR for two of the genes and by changes in protein levels, detected by immunohistochemistry, for a couple of representative gene products. Thus, changes in gene expression associated with variation in microanatomical location of neoplastic cells can be detected within even small developing tumour masses.

  13. Combined analysis of chromosomal instabilities and gene expression for colon cancer progression inference.

    PubMed

    Cava, Claudia; Zoppis, Italo; Gariboldi, Manuela; Castiglioni, Isabella; Mauri, Giancarlo; Antoniotti, Marco

    2014-01-24

    Copy number alterations (CNAs) represent an important component of genetic variations. Such alterations are related with certain type of cancer including those of the pancreas, colon, and breast, among others. CNAs have been used as biomarkers for cancer prognosis in multiple studies, but few works report on the relation of CNAs with the disease progression. Moreover, most studies do not consider the following two important issues. (I) The identification of CNAs in genes which are responsible for expression regulation is fundamental in order to define genetic events leading to malignant transformation and progression. (II) Most real domains are best described by structured data where instances of multiple types are related to each other in complex ways. Our main interest is to check whether the colorectal cancer (CRC) progression inference benefits when considering both (I) the expression levels of genes with CNAs, and (II) relationships (i.e. dissimilarities) between patients due to expression level differences of the altered genes. We first evaluate the accuracy performance of a state-of-the-art inference method (support vector machine) when subjects are represented only through sets of available attribute values (i.e. gene expression level). Then we check whether the inference accuracy improves, when explicitly exploiting the information mentioned above. Our results suggest that the CRC progression inference improves when the combined data (i.e. CNA and expression level) and the considered dissimilarity measures are applied. Through our approach, classification is intuitively appealing and can be conveniently obtained in the resulting dissimilarity spaces. Different public datasets from Gene Expression Omnibus (GEO) were used to validate the results.

  14. Combined analysis of chromosomal instabilities and gene expression for colon cancer progression inference

    PubMed Central

    2014-01-01

    Background Copy number alterations (CNAs) represent an important component of genetic variations. Such alterations are related with certain type of cancer including those of the pancreas, colon, and breast, among others. CNAs have been used as biomarkers for cancer prognosis in multiple studies, but few works report on the relation of CNAs with the disease progression. Moreover, most studies do not consider the following two important issues. (I) The identification of CNAs in genes which are responsible for expression regulation is fundamental in order to define genetic events leading to malignant transformation and progression. (II) Most real domains are best described by structured data where instances of multiple types are related to each other in complex ways. Results Our main interest is to check whether the colorectal cancer (CRC) progression inference benefits when considering both (I) the expression levels of genes with CNAs, and (II) relationships (i.e. dissimilarities) between patients due to expression level differences of the altered genes. We first evaluate the accuracy performance of a state-of-the-art inference method (support vector machine) when subjects are represented only through sets of available attribute values (i.e. gene expression level). Then we check whether the inference accuracy improves, when explicitly exploiting the information mentioned above. Our results suggest that the CRC progression inference improves when the combined data (i.e. CNA and expression level) and the considered dissimilarity measures are applied. Conclusions Through our approach, classification is intuitively appealing and can be conveniently obtained in the resulting dissimilarity spaces. Different public datasets from Gene Expression Omnibus (GEO) were used to validate the results. PMID:24456927

  15. Isobolographic analysis demonstrates additive effect of cisplatin and HDIs combined treatment augmenting their anti-cancer activity in lung cancer cell lines

    PubMed Central

    Gumbarewicz, Ewelina; Luszczki, Jarogniew J; Wawruszak, Anna; Dmoszynska-Graniczka, Magdalena; Grabarska, Aneta J; Jarząb, Agata M; Polberg, Krzysztof; Stepulak, Andrzej

    2016-01-01

    Histone deacetylase inhibitors (HDIs) are a new class of drugs which affect the activity of HDACs resulting in changed of acetylation in many proteins. HDIs can induce differentiation, cell growth arrest, apoptosis, inhibit proliferation and angiogenesis in cancer, whereas normal cells are comparatively resistant to the action of HDIs. The aim of this study was to investigate the combined effect of a well-known cytostatic agent-cisplatin (CDDP) and a histone deacetylase inhibitors-either suberoylanilide hydroxamic acid (SAHA, vorinostat) or valproic acid (VPA), on the proliferation of lung cancer cells, as well as induction of apoptosis and inhibition of the cell cycle progression. The anti-proliferative activity of VPA or SAHA used alone, or in combination with CDDP were determined by means of MTT test. The type of pharmacologic interactions between HDAC inhibitors and CDDP was assessed using isobolographic analysis. We observed additive interactions for the CCDP with SAHA, as well as for the CDDP with VPA combinations with respect to their anti-proliferative effects on three different lung cancer cell lines (A549, NCI-H1563 and NCI-H2170). Such additive effects were observed regardless of the histologic type (adenocarcinoma or squamous cell carcinoma) and sensitivity for the drugs applied. Combination treatment also augmented the induction of apoptosis and cell cycle perturbation mediated by CDDP alone, thereby enhancing anti-cancer effect of tested drugs. In conclusion, the combined therapy of HDIs and CDDP may be a promising therapeutic tool in the treatment of lung cancer. PMID:28042503

  16. Petri net siphon analysis and graph theoretic measures for identifying combination therapies in cancer.

    PubMed

    Behinaein, Behnam; Rudie, Karen; Sangrar, Waheed

    2016-10-03

    Epidermal Growth Factor Receptor (EGFR) signaling to the Ras-MAPK pathway is implicated in the development and progression of cancer and is a major focus of targeted combination therapies. Physiochemical models have been used for identifying and testing the signal-inhibiting potential of targeted therapies, however, their application to larger multi-pathway networks is limited by the availability of experimentally-determined rate and concentration parameters. An alternate strategy for identifying and evaluating drug-targetable nodes is proposed. A physiochemical model of EGFR-Ras-MAPK signaling is implemented and calibrated to experimental data. Essential topological features of the model are converted into a Petri net and nodes that behave as siphons-a structural property of Petri nets-are identified. Siphons represent potential drug-targets since they are unrecoverable if their values fall below a threshold. Centrality measures are then used to prioritize siphons identified as candidate drug-targets. Single and multiple drug-target combinations are identified which correspond to clinically relevant drug targets and exhibit inhibition synergy in physiochemical simulations of EGF-induced EGFR-Ras-MAPK signaling. Taken together, these studies suggest that siphons and centrality analyses are a promising computational strategy to identify and rank drug-targetable nodes in larger networks as they do not require knowledge of the dynamics of the system, but rely solely on topology.

  17. Gene expression patterns combined with network analysis identify hub genes associated with bladder cancer.

    PubMed

    Bi, Dongbin; Ning, Hao; Liu, Shuai; Que, Xinxiang; Ding, Kejia

    2015-06-01

    To explore molecular mechanisms of bladder cancer (BC), network strategy was used to find biomarkers for early detection and diagnosis. The differentially expressed genes (DEGs) between bladder carcinoma patients and normal subjects were screened using empirical Bayes method of the linear models for microarray data package. Co-expression networks were constructed by differentially co-expressed genes and links. Regulatory impact factors (RIF) metric was used to identify critical transcription factors (TFs). The protein-protein interaction (PPI) networks were constructed by the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) and clusters were obtained through molecular complex detection (MCODE) algorithm. Centralities analyses for complex networks were performed based on degree, stress and betweenness. Enrichment analyses were performed based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Co-expression networks and TFs (based on expression data of global DEGs and DEGs in different stages and grades) were identified. Hub genes of complex networks, such as UBE2C, ACTA2, FABP4, CKS2, FN1 and TOP2A, were also obtained according to analysis of degree. In gene enrichment analyses of global DEGs, cell adhesion, proteinaceous extracellular matrix and extracellular matrix structural constituent were top three GO terms. ECM-receptor interaction, focal adhesion, and cell cycle were significant pathways. Our results provide some potential underlying biomarkers of BC. However, further validation is required and deep studies are needed to elucidate the pathogenesis of BC. Copyright © 2015 Elsevier Ltd. All rights reserved.

  18. Combined analysis of DNA methylation and cell cycle in cancer cells.

    PubMed

    Desjobert, Cécile; El Maï, Mounir; Gérard-Hirne, Tom; Guianvarc'h, Dominique; Carrier, Arnaud; Pottier, Cyrielle; Arimondo, Paola B; Riond, Joëlle

    2015-01-01

    DNA methylation is a chemical modification of DNA involved in the regulation of gene expression by controlling the access to the DNA sequence. It is the most stable epigenetic mark and is widely studied for its role in major biological processes. Aberrant DNA methylation is observed in various pathologies, such as cancer. Therefore, there is a great interest in analyzing subtle changes in DNA methylation induced by biological processes or upon drug treatments. Here, we developed an improved methodology based on flow cytometry to measure variations of DNA methylation level in melanoma and leukemia cells. The accuracy of DNA methylation quantification was validated with LC-ESI mass spectrometry analysis. The new protocol was used to detect small variations of cytosine methylation occurring in individual cells during their cell cycle and those induced by the demethylating agent 5-aza-2'-deoxycytidine (5AzadC). Kinetic experiments confirmed that inheritance of DNA methylation occurs efficiently in S phase and revealed a short delay between DNA replication and completion of cytosine methylation. In addition, this study suggests that the uncoupling of 5AzadC effects on DNA demethylation and cell proliferation might be related to the duration of the DNA replication phase.

  19. Raman spectroscopy combined with principal component analysis and k nearest neighbour analysis for non-invasive detection of colon cancer

    NASA Astrophysics Data System (ADS)

    Li, Xiaozhou; Yang, Tianyue; Li, Siqi; Wang, Deli; Song, Youtao; Zhang, Su

    2016-03-01

    This paper attempts to investigate the feasibility of using Raman spectroscopy for the diagnosis of colon cancer. Serum taken from 75 healthy volunteers, 65 colon cancer patients and 60 post-operation colon cancer patients was measured in this experiment. In the Raman spectra of all three groups, the Raman peaks at 750, 1083, 1165, 1321, 1629 and 1779 cm-1 assigned to nucleic acids, amino acids and chromophores were consistently observed. All of these six Raman peaks were observed to have statistically significant differences between groups. For quantitative analysis, the multivariate statistical techniques of principal component analysis (PCA) and k nearest neighbour analysis (KNN) were utilized to develop diagnostic algorithms for classification. In PCA, several peaks in the principal component (PC) loadings spectra were identified as the major contributors to the PC scores. Some of the peaks in the PC loadings spectra were also reported as characteristic peaks for colon tissues, which implies correlation between peaks in PC loadings spectra and those in the original Raman spectra. KNN was also performed on the obtained PCs, and a diagnostic accuracy of 91.0% and a specificity of 92.6% were achieved.

  20. Efficacy of Neoadjuvant Carboplatin plus Docetaxel in Triple-Negative Breast Cancer: Combined Analysis of Two Cohorts.

    PubMed

    Sharma, Priyanka; López-Tarruella, Sara; García-Saenz, Jose Angel; Ward, Claire; Connor, Carol S; Gómez, Henry L; Prat, Aleix; Moreno, Fernando; Jerez-Gilarranz, Yolanda; Barnadas, Augusti; Picornell, Antoni C; Del Monte-Millán, Maria; Gonzalez-Rivera, Milagros; Massarrah, Tatiana; Pelaez-Lorenzo, Beatriz; Palomero, María Isabel; González Del Val, Ricardo; Cortes, Javier; Fuentes Rivera, Hugo; Bretel Morales, Denisse; Márquez-Rodas, Iván; Perou, Charles M; Wagner, Jamie L; Mammen, Joshua M V; McGinness, Marilee K; Klemp, Jennifer R; Amin, Amanda L; Fabian, Carol J; Heldstab, Jaimie; Godwin, Andrew K; Jensen, Roy A; Kimler, Bruce F; Khan, Qamar J; Martin, Miguel

    2017-02-01

    Recent studies demonstrate that addition of neoadjuvant (NA) carboplatin to anthracycline/taxane chemotherapy improves pathologic complete response (pCR) in triple-negative breast cancer (TNBC). Effectiveness of anthracycline-free platinum combinations in TNBC is not well known. Here, we report efficacy of NA carboplatin + docetaxel (CbD) in TNBC. The study population includes 190 patients with stage I-III TNBC treated uniformly on two independent prospective cohorts. All patients were prescribed NA chemotherapy regimen of carboplatin (AUC 6) + docetaxel (75 mg/m(2)) given every 21 days × 6 cycles. pCR (no evidence of invasive tumor in the breast and axilla) and residual cancer burden (RCB) were evaluated. Among 190 patients, median tumor size was 35 mm, 52% were lymph node positive, and 16% had germline BRCA1/2 mutation. The overall pCR and RCB 0 + 1 rates were 55% and 68%, respectively. pCRs in patients with BRCA-associated and wild-type TNBC were 59% and 56%, respectively (P = 0.83). On multivariable analysis, stage III disease was the only factor associated with a lower likelihood of achieving a pCR. Twenty-one percent and 7% of patients, respectively, experienced at least one grade 3 or 4 adverse event. The CbD regimen was well tolerated and yielded high pCR rates in both BRCA-associated and wild-type TNBC. These results are comparable with pCR achieved with the addition of carboplatin to anthracycline-taxane chemotherapy. Our study adds to the existing data on the efficacy of platinum agents in TNBC and supports further exploration of the CbD regimen in randomized studies. Clin Cancer Res; 23(3); 649-57. ©2016 AACR. ©2016 American Association for Cancer Research.

  1. Q-TWiST analysis of lapatinib combined with capecitabine for the treatment of metastatic breast cancer.

    PubMed

    Sherrill, B; Amonkar, M M; Stein, S; Walker, M; Geyer, C; Cameron, D

    2008-09-02

    The addition of lapatinib (Tykerb/Tyverb) to capecitabine (Xeloda) delays disease progression more effectively than capecitabine monotherapy in women with previously treated HER2+ metastatic breast cancer (MBC). The quality-adjusted time without symptoms of disease or toxicity of treatment (Q-TWiST) method was used to compare treatments. The area under survival curves was partitioned into health states: toxicity (TOX), time without symptoms of disease progression or toxicity (TWiST), and relapse period until death or end of follow-up (REL). Average times spent in each state, weighted by utility, were derived and comparisons of Q-TWiST between groups performed with varying combinations of the utility weights. Utility weights of 0.5 for both TOX and REL, that is, counting 2 days of TOX or REL as 1 day of TWiST, resulted in a 7-week difference in quality-adjusted survival favouring combination therapy (P=0.0013). The Q-TWiST difference is clinically meaningful and was statistically significant across an entire matrix of possible utility weights. Results were robust in sensitivity analyses. An analysis with utilities based on EQ-5D scores was consistent with the above findings. Combination therapy of lapatinib with capecitabine resulted in greater quality-adjusted survival than capecitabine monotherapy in trastuzumab-refractory MBC patients.

  2. Systems-Level Analysis of EGFR Inhibition-DNA Damage Combination Treatment in Breast Cancer

    DTIC Science & Technology

    2011-09-01

    portion of our screen we focused on classic chemotherapeutic compounds, as these are widely used to treat all forms of breast cancer clinically...drive the production of better treatment options for this disease . In this report, we present data for our systematic screen of drugs in the ErbB...Ph.D. 5e. TASK NUMBER E-Mail: mikejlee@mit.edu 5f. WORK UNIT NUMBER 7. PERFORMING ORGANIZATION NAME (S) AND ADDRESS(ES) 8. PERFORMING

  3. Efficacy of methotrexate/vinblastine/doxorubicin cisplatin combination in gemcitabine-pretreated patients with advanced urothelial cancer: a retrospective analysis

    PubMed Central

    Karadimou, Alexandra; Lianos, Evangelos; Pectasides, Dimitrios; Dimopoulos, Meletios A; Bamias, Aristotle

    2010-01-01

    Objective Second-line treatment options in advanced urothelial cancer are limited. We investigated the efficacy of a methotrexate/vinblastine/doxorubicin/cisplatin (MVAC) combination after failure of gemcitabine/platinum chemotherapy. Patients and methods Twenty-five patients with advanced urothelial cancer, who received second-line MVAC after first-line gemcitabine/cisplatin (n = 9) or gemcitabine/carboplatin (n = 16), were included in this retrospective analysis. Results Twenty-two patients (88%) relapsed within 6 months after first-line treatment. Following MVAC, there were 5 (20%) objective responses. Median follow-up was 20.2 months. Median progression-free survival (PFS) was 3.8 months (95% CI: 2.3–5.2), and median overall survival (OS) was 9 months (95% CI: 6.6–11.4). Eastern Cooperative Oncology Group performance status 0.1 versus 2 was associated with longer PFS (5 months versus 3.3 months, P = 0.049). Response or stabilization of disease during second-line chemotherapy predicted for a significantly longer PFS and OS (7.4 versus 3.5, P = 0.005; 15.5 versus 7, P = 0.046). Conclusions Second-line MVAC chemotherapy may result in prolonged survival in some patients with refractory disease. Further research in this field is necessary. PMID:24198628

  4. [Cost-effectiveness analysis of aflibercept in combination with FOLFIRI in the treatment of patients with metastatic colorectal cancer].

    PubMed

    Pericay, C; Frías, C; Abad, A; Lamas, M J; Echave, M; Oyagüez, I; Rubio, M; Giménez, E; Naoshy, S; Joulain, F

    2014-07-01

    To estimate the incremental cost per life-year gained (LYG) of aflibercept in combination with FOLFIRI as second-line treatment in metastatic colorectal cancer (mCRC) patients previously treated with oxaliplatin. Based on clinical trial VELOUR results, a three-state Markov model (stable disease, progression and death) with 2-week cycle duration was designed. Transition to health state «progression» implied the interruption of second-line treatment and administration of a third-line treatment (post-second line chemotherapy). Cost estimation included disease management cost (pharmaceutical, adverse event management, administration costs, etc.). Both cost and outcomes were discounted (3% annually). Sensitivity analyses (SA) were performed to test model robustness. Administration of aflibercept + FOLFIRI as second-line treatment provided 1.78 LYG (21 life-months gained). With FOLFIRI 1.43 LYG (17 months) were obtained. The cost of the clinical management of aflibercept + FOLFIRI implied an additional investment of Euros 13,564 compared with FOLFIRI for a lifetime horizon, being total costs for aflibercept + FOLFIRI of Euros 38,346, compared to Euros 24,782 with FOLFIRI. In the cost-effectiveness analysis Euros 38,931/LYG was obtained with aflibercept in combination with FOLFIRI versus FOLFIRI. Aflibercept in combination with FOLFIRI increased overall survival versus FOLFIRI, so it is an effective strategy in the treatment of patients with mCRC. Aflibercept in combination with FOLFIRI is an efficient strategy for second-line mCRC treatment from the National Health System perspective. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

  5. Therapeutic potential and critical analysis of trastuzumab and bevacizumab in combination with different chemotherapeutic agents against metastatic breast/colorectal cancer affecting various endpoints.

    PubMed

    Wahid, Mohd; Mandal, Raju K; Dar, Sajad A; Jawed, Arshad; Lohani, Mohtashim; Areeshi, Mohammad Y; Akhter, Naseem; Haque, Shafiul

    2016-08-01

    Researchers are working day and night across the globe to eradicate or at least lessen the menace of cancer faced by the mankind. The two very frequently occurring cancers faced by the human beings are metastatic breast cancer and metastatic colorectal cancer. The various chemotherapeutic agents like anthracycline, cyclophosphamide, paclitaxel, irinotecan, fluorouracil and leucovorin etc., have been used impressively for long. But the obstinate character of metastatic breast cancer and metastatic colorectal cancer needs more to tackle the threat. So, the scientists found the use of monoclonal antibodies trastuzumab (Herceptin(®)) and bevacizumab (Avastin(®)) for the same. The current study critically investigates the therapeutic potential of trastuzumab and bevacizumab in combination with various chemotherapeutic agents against metastatic breast cancer and metastatic colorectal cancer. To the best of our knowledge, this is the very first critical analysis showing percent wise increase in various positive endpoints like median time to disease progression, median survival, and progression free survival etc. for the treatment of metastatic breast/colorectal cancer using trastuzumab and bevacizumab in combination with different chemotherapeutic agents and provides the rational for the success and failure of the selected monoclonal antibodies.

  6. Assessing Combinational Drug Efficacy in Cancer Cells by Using Image-based Dynamic Response Analysis.

    PubMed

    Sima, Chao; Hua, Jianping; Cypert, Milana; Miller, Tasha; Wilson-Robles, Heather M; Trent, Jeffrey M; Dougherty, Edward R; Bittner, Michael L

    2015-01-01

    The landscape of translational research has been shifting toward drug combination therapies. Pairing of drugs allows for more types of drug interaction with cells. In order to accurately and comprehensively assess combinational drug efficacy, analytical methods capable of recognizing these alternative reactions will be required to prioritize those drug candidates having better chances of delivering appreciable therapeutic benefits. Traditional efficacy measures are primarily based on the "extent" of drug inhibition, which is the percentage of cells being killed after drug exposure. Here, we introduce a second dimension of evaluation criterion, speed of killing, based on a live cell imaging assay. This dynamic response trajectory approach takes advantage of both "extent" and "speed" information and uncovers synergisms that would otherwise be missed, while also generating hypotheses regarding important mechanistic modes of drug action.

  7. Segmentation and detection of breast cancer in mammograms combining wavelet analysis and genetic algorithm.

    PubMed

    Pereira, Danilo Cesar; Ramos, Rodrigo Pereira; do Nascimento, Marcelo Zanchetta

    2014-04-01

    In Brazil, the National Cancer Institute (INCA) reports more than 50,000 new cases of the disease, with risk of 51 cases per 100,000 women. Radiographic images obtained from mammography equipments are one of the most frequently used techniques for helping in early diagnosis. Due to factors related to cost and professional experience, in the last two decades computer systems to support detection (Computer-Aided Detection - CADe) and diagnosis (Computer-Aided Diagnosis - CADx) have been developed in order to assist experts in detection of abnormalities in their initial stages. Despite the large number of researches on CADe and CADx systems, there is still a need for improved computerized methods. Nowadays, there is a growing concern with the sensitivity and reliability of abnormalities diagnosis in both views of breast mammographic images, namely cranio-caudal (CC) and medio-lateral oblique (MLO). This paper presents a set of computational tools to aid segmentation and detection of mammograms that contained mass or masses in CC and MLO views. An artifact removal algorithm is first implemented followed by an image denoising and gray-level enhancement method based on wavelet transform and Wiener filter. Finally, a method for detection and segmentation of masses using multiple thresholding, wavelet transform and genetic algorithm is employed in mammograms which were randomly selected from the Digital Database for Screening Mammography (DDSM). The developed computer method was quantitatively evaluated using the area overlap metric (AOM). The mean ± standard deviation value of AOM for the proposed method was 79.2 ± 8%. The experiments demonstrate that the proposed method has a strong potential to be used as the basis for mammogram mass segmentation in CC and MLO views. Another important aspect is that the method overcomes the limitation of analyzing only CC and MLO views. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  8. Monitoring cancer treatment response using photoacoustic and ultrasound spectral analysis in combination with oxygenation measurements (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Hysi, Eno; May, Jonathan P.; Wirtzfeld, Lauren; Undzys, Elijus; Li, Shyh-Dar; Kolios, Michael C.

    2016-03-01

    At clinically-relevant depths, the frequency content of photoacoustic signals encodes information about the size, concentration and spatial distribution of non-resolvable blood vessels. This study evaluates whether photoacoustics can detect cancer therapy-induced vascular perturbations. Photoacoustic/ultrasound (PA/US) spectral analysis was combined with functional, PA-based oxygenation and power Doppler (PD) perfusion estimates to assess treatment response. Co-registered, in-vivo US/PA/PD imaging of mice bearing breast cancer tumors was performed pre-treatment and 30m/2h/5h/24h/7d post-treatment (VevoLAZR, Fujifilm VisualSonics). Hyperthermia treatment (1h, 43C) was performed after systemic injections of doxorubicin-loaded thermosensitive liposomes (TSL, n=13) or free doxorubicin (DOX, n=11). Response was classified according to 2h, PA-based oxygenation drop and endpoint (>9d), caliper-based volume reduction. At all time-points/wavelengths (750/850nm), the spectral-slope (SS) was computed from the normalized US/PA power spectra using depth-matched reference phantoms. The percent-vascularity (PV) was estimated for the animal with the largest oxygenation-drop at 2h. TLS-treated responders decreased their PA-SS by 1.9x @750nm and 5.8x @850nm 30m post-treatment and remained constant for 24h; tumor oxygenation followed the same trend. Non-responding SS remained unchanged for 24h. The 750nm SS was 18.7x lower than 850nm suggesting the TSL is sensitive vessel oxygenation. Responder PV decreased 100% when the 30m oxygenation dropped 15% and increased 7x when the 7d oxygenation increased 20%. DOX-responders exhibited similar trends to TSL-responders although the 750nm PA-SS was 1.6x smaller and post-treatment PV was 50% higher. The US-SS remained unchanged until 7d post-treatment suggesting its sensitivity to tumor cell-death. These findings suggest that PA spectral analysis has potential in monitoring cancer treatment response.

  9. ShenQi FuZheng Injection combined with chemotherapy in the treatment of colorectal cancer: A meta-analysis.

    PubMed

    Xu, Rongzhong; Lin, Liubing; Li, Yong; Li, Yan

    2017-01-01

    This study aims to investigate cellular immunity and clinical efficacy of ShenQi FuZheng Injection (SFI) in the associated chemotherapy of colorectal cancer (CRC). PubMed, Cochrane Library, EMBASE, China National Knowledge Infrastructure (CNKI), Chinese Scientific Journals Full-text Database (VIP), WanFang Database and Chinese Biomedical Literature Database (CBM) searches were undertaken to identify randomized controlled trials of SFI plus chemotherapy versus chemotherapy alone in CRC patients. The quality of each trial was assessed according to the Jadad's scale, and Review Manager 5 was used to statisitically analyze the outcomes. Eight studies involving 722 patients were included in this review. The meta-analyses suggested there was a significantly higher overall response rate (OR 1.89; CI: 1.10-3.24; p = 0.02), grades of KPS (OR 2.35; CI: 1.55-3.56; p<0.01), CD3+cells (MD 10.29; CI: 8.46-12.12; p<0.01), CD4+cells (MD 7.06; CI: 5.33-8.794; p<0.01), CD4/CD8+cells (MD 0.32; CI: 0.25-0.40; p<0.01), NK+ (MD 7.20; CI: 2.02-12.37, p = 0.006), WBC (MD 1.24; CI: 0.59-1.89; p<0.01), HB (MD 14.55; CI: 7.47-21.63; p<0.01), and PLT (MD 19.05; CI: 4.29-33.81; p = 0.01), but lower severe toxicity for leukocytopenia (OR 0.37; CI: 0.17-0.80; p = 0.01), thrombocytopenia (OR 0.32; CI: 0.14-0.74; p = 0.008), gastrointestinal toxicity (OR 0.48; CI: 0.24-0.96; p = 0.04), when chemotherapy combined with SFI was compared with chemotherapy alone. There were similarities between two groups in liver dysfunction (OR 0.44; CI: 0.18-1.08; p = 0.07) and CD8+ (MD 0.54; CI: -1.89-2.96; p = 0.66). Also, there was presence of heterogeneity in the CD8 results; after the sensitivity analysis, the result of CD8+ was reversed (MD 1.57; CI: 0.32-2.81; p = 0.01). There was no significant publication bias across studies according to the Egger's (P = 0.19) and Begg's test (P = 0.23). SFI enhances chemotherapy efficiency as they are combined and used in the treatment of colorectal cancer patients. At the

  10. Thyroid hormone receptor alpha (TRa) tissue expression in ductal invasive breast cancer: A study combining quantitative immunohistochemistry with digital slide image analysis.

    PubMed

    Charalampoudis, P; Agrogiannis, G; Kontzoglou, K; Kouraklis, G; Sotiropoulos, G C

    2017-08-01

    In breast cancer, hormonal receptors hold promise for developing novel targeted therapies. The thyroid exerts its actions via the thyroid hormone receptors alpha and beta. The clinical significance of the expression of thyroid hormone receptors in breast cancer is unclear. We studied thyroid hormone receptor alpha (TRa) expression in 82 samples from 41 women with ductal invasive breast cancer and no thyroid disease. We performed quantitative immunohistochemistry with digital image analysis and correlated TRa expression with clinicopathological parameters. TRa was expressed in both normal breast epithelium and breast cancer, but expression in breast cancer was significantly lower. TRa was expressed significantly less in larger and grade III tumors. Conversely, breast cancers with lymphovascular invasion showed increased TRa expression compared to cancers without lymphovascular invasion. TRa expression was not significantly different between node-positive and node-negative breast cancers, or among different hormonal profiles and intrinsic subtypes. This is the first-in-human study to combine quantitative immunohistochemistry with image analysis to study TRa expression in women with ductal invasive breast cancer and no clinical or biochemical evidence of thyroid dysfunction. We confirm that TRa is expressed in both normal and malignant breast epithelium and suggest that TRa expression is downregulated during breast carcinogenesis. Larger and higher grade breast cancers demonstrate partial loss in TRa expression. Alterations in TRa expression take place even in the absence of clinical or biochemical thyroid disease. The underlying mechanism of these findings and their potential significance in survival and relapse mandate further research. Copyright © 2017 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

  11. Gemcitabine Compared With Gemcitabine and S-1 Combination Therapy in Advanced Pancreatic Cancer: A Systematic Review and Meta-Analysis.

    PubMed

    Li, Doudou; Chen, Changhao; Zhou, Yu; Chen, Rufu; Fan, Xinxiang; Bi, Zhuofei; Li, Zhihua; Liu, Yimin

    2015-09-01

    Several reports suggest that gemcitabine (GEM) plus S-1 combination (GS) is associated to prolong the survival in patients with unresectable pancreatic cancer (PC). We conducted a systemic review and meta-analysis of studies comparing the safety and efficacy of GS versus GEM.Summary data from randomized trials and retrospective studies were searched in PubMed, EMBASE, Web of Science, and the Cochrane Library. Statistical analyses were conducted to calculate the hazard ratios (HRs) and relative risk (RR) with 95% confidence intervals (CIs) using random-effects models. Subgroup analyses based on the chemotherapy cycles were performed to explore the efficacy and toxicity for therapy. Sensitivity analyses were conducted by removing specific studies to assess the effects of study quality.Between January 2004 and August 2012, 4 RCTs and 2 retrospective studies including a total of 1025 cases were identified. The overall survival (OS) (HR: 0.82; 95% CI, 0.70-0.96; P = 0.01) and progression-free survival (PFS) (HR: 0.65; 95% CI, 0.55-0.77; P < 0.001) for the GS arm were significantly longer than the GEM arm. The differences in objective response rate (ORR) (RR: 1.24; 95% CI, 1.17-1.33; P < 0.001) and disease control rate (DCR) were also better in the GS arm (RR: 1.37; 95% CI, 1.19-1.59; P < 0.001). Grades 3 to 4 toxicities in both the groups were similar except neutropenia and diarrhea, which were more frequent in the GS arm (P < 0.001). In the subgroup analysis, the cycle for chemotherapy every 4 weeks has equivalent efficacy and less toxicity than regimens every 3 weeks in the GS arm.The current meta-analysis suggested that GEM significantly prolonged OS and PFS when added to S-1 combination in patients with unresectable PC. GS therapy also offers better ORR and DCR than GEM monotherapy and no unexpected toxicity was evident.

  12. Immunoregulation of Shenqi Fuzheng Injection Combined with Chemotherapy in Cancer Patients: A Systematic Review and Meta-Analysis

    PubMed Central

    Ting, Wang; Xiumei, Gao

    2017-01-01

    Background. Immunosuppression is a well-recognised complication of chemotherapy in cancer patients. We assemble the clinical evidence that SQI, an adjuvant drug for lung cancer and gastric cancer which was widely prescribed in China, interventions could increase objective tumour response and regulate immunity in cancer patients undergoing chemotherapy. Methods. We undertook a systemic review of the clinical data from randomised controlled trials up to September 2015 in which a SQI intervention was compared with a control arm in patients undergoing conventional chemotherapy. Revman 5.0 Software was used for the data analysis. Results. 49 randomised controlled trials were included in the systematic review. The meta-analysis results demonstrated that the SQI intervention with conventional chemotherapy exhibited better therapeutic efficacy than the conventional chemotherapy group with a statistically significant higher objective tumour response. Cotreatment with SQI could enhance NK, CD3+, CD4+ level, and CD4+/CD8+ ratio comparing with the conventional chemotherapy group. Conclusions. The conclusions of this review might suggest a high risk of bias due to the low quality and the limitation of cancer types in the included trials. A more reliable conclusion regarding the immunoregulation of SQI could be reached based on more trials of higher quality. PMID:28154607

  13. Application of HPLC combined with laser induced fluorescence for protein profile analysis of tissue homogenates in cervical cancer.

    PubMed

    Bhat, Sujatha; Patil, Ajeetkumar; Rai, Lavanya; Kartha, V B; Chidangil, Santhosh

    2012-01-01

    A highly objective method, High Performance Liquid Chromatography with Laser Induced Fluorescence (HPLC-LIF) technique was used to study the protein profiles of normal and cervical cancer tissue homogenates. A total of 44 samples including normal cervical biopsy samples from the hysterectomy patients and the patients suffering from different stages of the cervical cancer were recorded by HPLC-LIF and analysed by Principle Component Analysis (PCA) to get statistical information on different tissue components. Discrimination of different stages of the samples was carried out by considering three parameters--scores of factor, spectral residual, and Mahalanobis Distance. Diagnostic accuracy of the method was evaluated using Receiver Operating Characteristic (ROC) analysis, and Youden's index (J) plots. The PCA results showed high sensitivity and specificity (~100) for cervical cancer diagnosis. ROC and Youden's index curves for both normal and malignant standard sets show good diagnostic accuracy with high AUC values. The statistical analysis has shown that the differences in protein profiles can be used to diagnose biochemical changes in the tissue, and thus can be readily applied for the detection of cervical cancer, even in situations where a histopathology examination is not easy because of nonavailability of experienced pathologists.

  14. Combined analysis of Rac1, IQGAP1, Tiam1 and E-cadherin expression in gastric cancer.

    PubMed

    Walch, Axel; Seidl, Stefan; Hermannstädter, Christine; Rauser, Sandra; Deplazes, Joëlle; Langer, Rupert; von Weyhern, Claus Hann; Sarbia, Mario; Busch, Raymonde; Feith, Marcus; Gillen, Sonja; Höfler, Heinz; Luber, Birgit

    2008-05-01

    Rho GTPases are a family of major regulators of E-cadherin-mediated cell adhesion that are implicated in the carcinogenic process by deregulated expression of the family members itself or of upstream modulators or downstream effectors. Combined investigation of the Rho GTPase Rac1, the effector protein IQGAP1 and the activator Tiam1 in relation to expression or mutation of E-cadherin in gastric adenocarcinomas has not been reported. The aim of the study was to determine the expression and prognostic significance of Rac1, IQGAP1, Tiam1 and E-cadherin in gastric adenocarcinomas. Gastric carcinomas of 76 patients were investigated immunohistochemically in a tissue microarray study for expression of Rac1, IQGAP1, Tiam1 and E-cadherin. Correlations with clinical and follow-up data were examined. Moderate or strong reactivity for Rac1 was observed in 46% and for Tiam1 in 56% of tumors. Expression of IQGAP1 was present in 59% and of E-cadherin in 87% of tumors. While Rac1 and E-cadherin expression were not related to prognosis, a trend was observed between a lack of IQGAP1 expression (log-rank 0.088) as well as presence of Tiam1 (log-rank 0.097) and favorable prognosis in Kaplan-Meier survival analysis. Expression of Rac1 was positively linked to IQGAP1 expression (P=0.007, r=0.343) and tended to be inversely associated with expression of E-cadherin (P=0.055, r=-0.245). In conclusion, we observed deregulated expression of Rac1, IQGAP1, Tiam1 and E-cadherin in gastric cancer. We present evidence that either upregulation (for Rac1 and IQGAP1) or downregulation (for Tiam1 and E-cadherin) occurs. Rac1 and E-cadherin expression were not related to prognosis, while trends pointing to favorable prognosis of patients with Tiam1 expression and a lack of IQGAP1 expression were observed. These results indicate that the investigated regulators of E-cadherin-mediated cell adhesion play a role in gastric carcinogenesis.

  15. Combined analysis of eIF4E and 4E-binding protein expression predicts breast cancer survival and estimates eIF4E activity.

    PubMed

    Coleman, L J; Peter, M B; Teall, T J; Brannan, R A; Hanby, A M; Honarpisheh, H; Shaaban, A M; Smith, L; Speirs, V; Verghese, E T; McElwaine, J N; Hughes, T A

    2009-05-05

    Increased eukaryotic translation initiation factor 4E (eIF4E) expression occurs in many cancers, and makes fundamental contributions to carcinogenesis by stimulating the expression of cancer-related genes at post-transcriptional levels. This key role is highlighted by the facts that eIF4E levels can predict prognosis, and that eIF4E is an established therapeutic target. However, eIF4E activity is a complex function of expression levels and phosphorylation statuses of eIF4E and eIF4E-binding proteins (4E-BPs). Our hypothesis was that the combined analyses of these pathway components would allow insights into eIF4E activity and its influence on cancer. We have determined expression levels of eIF4E, 4E-BP1, 4E-BP2 and phosphorylated 4E-BP1 within 424 breast tumours, and have carried out analyses to combine these and relate the product to patient survival, in order to estimate eIF4E activity. We show that this analysis gives greater prognostic insights than that of eIF4E alone. We show that eIF4E and 4E-BP expression are positively associated, and that 4E-BP2 has a stronger influence on cancer behaviour than 4E-BP1. Finally, we examine eIF4E, estimated eIF4E activity, and phosphorylated 4E-BP1 as potential predictive biomarkers for eIF4E-targeted therapies, and show that each determines selection of different patient groups. We conclude that eIF4E's influence on cancer survival is modulated substantially by 4E-BPs, and that combined pathway analyses can estimate functional eIF4E.

  16. Fighting liver cancer with combination immunotherapies | Center for Cancer Research

    Cancer.gov

    A new clinical trial testing the effectiveness of immunotherapy treatment combinations against liver cancer is enrolling patients at the NIH Clinical Center in Bethesda, Maryland. Individually, immunotherapy drugs harness the power of the human immune system to better identify and kill cancer cells. Now, researchers at the NIH’s Center for Cancer Research have begun to find evidence that the drugs may work far more effectively when taken in combination with other therapies and with each other than when taken alone.

  17. Therapeutic efficacy and safety of S-1-based combination therapy compare with S-1 monotherapy following gemcitabine failure in pancreatic cancer: a meta-analysis

    PubMed Central

    Lu, Sinan; Zhang, Yuan; Zhou, Xiaohu; Zhou, Dongkai; Yang, Qifan; Ju, Bingjie; Zhao, Xinyi; Hu, Zhenhua; Xie, Haiyang; Zhou, Lin; Zheng, Shusen; Wang, Weilin

    2016-01-01

    S-1 monotherapy is widely used following gemcitabine failure in pancreatic cancer, especially in East Asia. We performed a meta-analysis to determine whether S-1-based combination therapy had better efficacy and safety compared with S-1 monotherapy. We searched Pubmed, Web of Science, ClinicalTrials.gov, and Cochrane CENTRAL and subsequently included five trials with a total of 690 patients. The combined hazard ratio (HR) or risk ratio; the corresponding 95% confidence intervals of progression-free survival, overall survival, and overall response rate; and grade 3–4 adverse events were examined. Five randomized controlled trials were included. Meta-analysis demonstrated S-1-based combination therapy significantly increased progression-free survival (HR = 0.78, 95% confidence interval [CI]: 0.67–0.90, p = 0.0009) and overall response rate (HR = 1.74, 95% CI: 1.20–2.52, p = 0.003). Evidence was insufficient to confirm that S-1-based combined regimens improved overall survival (HR = 0.87, 95% CI: 0.75–1.00, p = 0.05). There was no significant difference in adverse events between the two treatment arms. In conclusion, S-1-based combination therapy improved progression-free survival and overall response rate compared to S-1 monotherapy with acceptable toxicity. PMID:27833144

  18. Therapeutic efficacy and safety of S-1-based combination therapy compare with S-1 monotherapy following gemcitabine failure in pancreatic cancer: a meta-analysis.

    PubMed

    Lu, Sinan; Zhang, Yuan; Zhou, Xiaohu; Zhou, Dongkai; Yang, Qifan; Ju, Bingjie; Zhao, Xinyi; Hu, Zhenhua; Xie, Haiyang; Zhou, Lin; Zheng, Shusen; Wang, Weilin

    2016-11-11

    S-1 monotherapy is widely used following gemcitabine failure in pancreatic cancer, especially in East Asia. We performed a meta-analysis to determine whether S-1-based combination therapy had better efficacy and safety compared with S-1 monotherapy. We searched Pubmed, Web of Science, ClinicalTrials.gov, and Cochrane CENTRAL and subsequently included five trials with a total of 690 patients. The combined hazard ratio (HR) or risk ratio; the corresponding 95% confidence intervals of progression-free survival, overall survival, and overall response rate; and grade 3-4 adverse events were examined. Five randomized controlled trials were included. Meta-analysis demonstrated S-1-based combination therapy significantly increased progression-free survival (HR = 0.78, 95% confidence interval [CI]: 0.67-0.90, p = 0.0009) and overall response rate (HR = 1.74, 95% CI: 1.20-2.52, p = 0.003). Evidence was insufficient to confirm that S-1-based combined regimens improved overall survival (HR = 0.87, 95% CI: 0.75-1.00, p = 0.05). There was no significant difference in adverse events between the two treatment arms. In conclusion, S-1-based combination therapy improved progression-free survival and overall response rate compared to S-1 monotherapy with acceptable toxicity.

  19. Identification of benign and malignant endometrial cancer with transvaginal ultrasonography combined with elastography and tissue hardness analysis.

    PubMed

    Zhang, Y; Luo, L; Luo, Q

    2015-01-01

    This study was designed to explore tissue hardness and distinguish benign and malignant endometrial cancer with the use of transvaginal ultrasonography combined with elastography. Color Doppler ultrasonic diasonograph was used to carry out transvaginal ultrasonography and elastography. Once the nidus was observed, features of the 2D image were analyzed. Then features of elasticity of the uterine cavity in different states were analyzed by elastography, and strain rate ratio was measured. Finally, elasticity scoring (0~5 points) was made. Receiver operating characteristic (ROC) curve was drawn based on elasticity score and strain rate ratio. The area under the elasticity score curve and strain rate ratio curve was 0.761 and 0.852, respectively, and there was no statistically significant difference between them (c2= 4.663, P>0.05). Then 2.98 was confirmed as the diagnostic cut-off value of benign and malignant lesions, based on strain rate ratio. Ultrasonic elastography as an effective assistance for transvaginal ultrasonography provides more valuable information for confirmation of lesions and offers more accurate evidence for diagnosis of disease in the uterine cavity.

  20. Pharmacogenomic Characterization and Isobologram Analysis of the Combination of Ascorbic Acid and Curcumin—Two Main Metabolites of Curcuma longa—in Cancer Cells

    PubMed Central

    Ooko, Edna; Kadioglu, Onat; Greten, Henry J.; Efferth, Thomas

    2017-01-01

    Curcuma longa has long been used in China and India as anti-inflammatory agent to treat a wide variety of conditions and also as a spice for varied curry preparations. The chemoprofile of the Curcuma species exhibits the presence of varied phytochemicals with curcumin being present in all three species but AA only being shown in C. longa. This study explored the effect of a curcumin/AA combination on human cancer cell lines. The curcumin/AA combination was assessed by isobologram analysis using the Loewe additivity drug interaction model. The drug combination showed additive cytotoxicity toward CCRF-CEM and CEM/ADR5000 leukemia cell lines and HCT116p53+/+ and HCT116p53−/− colon cancer cell line, while the glioblastoma cell lines U87MG and U87MG.ΔEGFR showed additive to supra-additive cytotoxicity. Gene expression profiles predicting sensitivity and resistance of tumor cells to induction by curcumin and AA were determined by microarray-based mRNA expressions, COMPARE, and hierarchical cluster analyses. Numerous genes involved in transcription (TFAM, TCERG1, RGS13, C11orf31), apoptosis-regulation (CRADD, CDK7, CDK19, CD81, TOM1) signal transduction (NR1D2, HMGN1, ABCA1, DE4ND4B, TRIM27) DNA repair (TOPBP1, RPA2), mRNA metabolism (RBBP4, HNRNPR, SRSF4, NR2F2, PDK1, TGM2), and transporter genes (ABCA1) correlated with cellular responsiveness to curcumin and ascorbic acid. In conclusion, this study shows the effect of the curcumin/AA combination and identifies several candidate genes that may regulate the response of varied cancer cells to curcumin and AA. PMID:28210221

  1. Pharmacogenomic Characterization and Isobologram Analysis of the Combination of Ascorbic Acid and Curcumin-Two Main Metabolites of Curcuma longa-in Cancer Cells.

    PubMed

    Ooko, Edna; Kadioglu, Onat; Greten, Henry J; Efferth, Thomas

    2017-01-01

    Curcuma longa has long been used in China and India as anti-inflammatory agent to treat a wide variety of conditions and also as a spice for varied curry preparations. The chemoprofile of the Curcuma species exhibits the presence of varied phytochemicals with curcumin being present in all three species but AA only being shown in C. longa. This study explored the effect of a curcumin/AA combination on human cancer cell lines. The curcumin/AA combination was assessed by isobologram analysis using the Loewe additivity drug interaction model. The drug combination showed additive cytotoxicity toward CCRF-CEM and CEM/ADR5000 leukemia cell lines and HCT116p53(+/+) and HCT116p53(-/-) colon cancer cell line, while the glioblastoma cell lines U87MG and U87MG.ΔEGFR showed additive to supra-additive cytotoxicity. Gene expression profiles predicting sensitivity and resistance of tumor cells to induction by curcumin and AA were determined by microarray-based mRNA expressions, COMPARE, and hierarchical cluster analyses. Numerous genes involved in transcription (TFAM, TCERG1, RGS13, C11orf31), apoptosis-regulation (CRADD, CDK7, CDK19, CD81, TOM1) signal transduction (NR1D2, HMGN1, ABCA1, DE4ND4B, TRIM27) DNA repair (TOPBP1, RPA2), mRNA metabolism (RBBP4, HNRNPR, SRSF4, NR2F2, PDK1, TGM2), and transporter genes (ABCA1) correlated with cellular responsiveness to curcumin and ascorbic acid. In conclusion, this study shows the effect of the curcumin/AA combination and identifies several candidate genes that may regulate the response of varied cancer cells to curcumin and AA.

  2. Accuracy of combined dynamic contrast-enhanced magnetic resonance imaging and diffusion-weighted imaging for breast cancer detection: a meta-analysis.

    PubMed

    Zhang, Li; Tang, Min; Min, Zhiqian; Lu, Jun; Lei, Xiaoyan; Zhang, Xiaoling

    2016-06-01

    Magnetic resonance imaging (MRI) is increasingly being used to examine patients with suspected breast cancer. To determine the diagnostic performance of combined dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and diffusion-weighted imaging (DWI) for breast cancer detection. A comprehensive search of the PUBMED, EMBASE, Web of Science, and Cochrane Library databases was performed up to September 2014. Statistical analysis included pooling of sensitivity and specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and diagnostic accuracy using the summary receiver operating characteristic (SROC). All analyses were conducted using STATA (version 12.0), RevMan (version 5.2), and Meta-Disc 1.4 software programs. Fourteen studies were analyzed, which included a total of 1140 patients with 1276 breast lesions. The pooled sensitivity and specificity of combined DCE-MRI and DWI were 91.6% and 85.5%, respectively. The pooled sensitivity and specificity of DWI-MRI were 86.0% and 75.6%, respectively. The pooled sensitivity and specificity of DCE-MRI were 93.2% and 71.1%. The area under the SROC curve (AUC-SROC) of combined DCE-MRI and DWI was 0.94, the DCE-MRI of 0.85. Deeks testing confirmed no significant publication bias in all studies. Combined DCE-MRI and DWI had superior diagnostic accuracy than either DCE-MRI or DWI alone for the diagnosis of breast cancer. © The Foundation Acta Radiologica 2015.

  3. S-1 monotherapy versus S-1 combination therapy in gemcitabine-refractory advanced pancreatic cancer: A meta-analysis (PRISMA) of randomized control trials.

    PubMed

    Zhong, Sheng; Qie, Shuai; Yang, Liu; Yan, Qi; Ge, Linna; Wang, Zhongfeng

    2017-07-01

    Pancreatic cancer (PC) is one of the most lethal digestive system tumors. Most new cases are diagnosed based on metastasis or local aggression and are known as "advanced PC." Recently, studies investigating S-1 have indicated that it has a better clinical curative effect on PC. We conducted a meta-analysis to evaluate the efficacy and safety of S-1 monotherapy compared with S-1 combination regimens in patients with gemcitabine (GEM)-refractory PC. Trials published between 1978 and 2016 were identified by an electronic search of public databases (Medline, Embase, and the Cochrane Library). All prospective studies were independently identified by 2 authors for inclusion. The response rate (RR), progression-free and overall survival (PFS and OS, respectively), and the primary toxicities were extracted for the meta-analysis. Four randomized controlled trials consisting of 623 patients were included in the analysis, among which 315 patients underwent S-1 monotherapy and 308 patients underwent S-1 combination therapy. The pooled data showed a significantly higher response rate and longer PFS in the S-1 combination group than in the S-1 monotherapy group (RR, 1.75; 95% confidence interval [CI], 1.19-2.57; P = .005 and hazard ration [HR], 0.75; 95% CI, 0.62-0.91; P = .005). There were no significant differences in OS or adverse events. Compared with the S-1 monotherapy group, the S-1 combination group had a higher response rate and longer PFS. Both groups had few adverse events, which were balanced between the groups. The subgroup analysis suggested that S-1 combination regimens with leucovorin or irinotecan (CPT-11) provided promising efficacy. These promising combination regimens should be considered for patients with advanced PC who choose S-1 as their second-line therapy.

  4. Radium in drinking water and risk of bone cancer in Ontario youths: a second study and combined analysis.

    PubMed Central

    Finkelstein, M M; Kreiger, N

    1996-01-01

    OBJECTIVES: Radium induces bone sarcomas at high doses, but there is controversy about risk at low doses. A previous study in Ontario found an association between the presence of radium in birthplace water supplies and an increased risk of death from bone cancer in young people. An investigation was performed to test the findings of the previous study with an independent group of subjects for whom complete information on radium exposure would be obtained. METHODS: A population based case-control study (238 cases; 432 controls) was conducted with incident cases of bone sarcoma identified from the Ontario cancer registry. Residential histories were collected by questionnaire and water samples were obtained and analysed for radium content. RESULTS: There was an association between risk of osteosarcoma and birthplace exposures (odds ratios (ORs) and 90% confidence intervals (90% CIs) 1.77 (1.03-3.00) but not with lifetime measures of exposure. When lifetime exposure was dichotomised, the OR was 1.31 (0.76-2.24) for osteosarcoma. There was no trend with increasing exposure. Bootstrap resampling was used to simulate lifetime doses in a pooled analysis of 1293 subjects from the two Ontario studies. The ORs were 1.38 (1.08-1.73) for all sarcomas, and 1.44 (1.01-1.87) for osteosarcoma. Geometric mean doses in bone were about 26 mRad. CONCLUSIONS: An association was found between the presence of radium in birthplace water supplies and increased risk of bone sarcoma in two studies. Increased risk was present for lifetime measures of exposure, but the association was not significant, and there was no dose-response trend. Our findings are compatible with the absence of risk at low doses, but they might also reflect inadequate statistical power to measure a true risk at environmental exposure levels. If the increased risk at environmental doses is causal, risk of bone sarcoma is effectively linearly related to dose over five orders of magnitude. PMID:8673177

  5. [Clinical analysis of combination of (252)Cf neutron intracavitary brachytherapy and external beam radiotherapy for 110 cervical cancer patients].

    PubMed

    Bu, Jie; Li, Ren; Song, Wei; Cao, Jing-xu; Wang, Ying-xuan

    2010-08-01

    To evaluate the curative effect and complication of (252)Cf brachytherapy on cervical cancer. From Nov 2002 to Nov 2007, 110 cervical cancer patients were treated by combination of (252)Cf neutron intracavitary brachytherapy and external beam radiotherapy. There were 2 cases of stage Ib, 5 stage IIa, 57 stage IIb, 2 stage IIIa, 41 stage IIIb, 2 stage IVa, and 1 stage IVb. The whole pelvic cavity was irradiated with 8 MV X-ray, 1.8 Gy/fraction, 4 - 5 times per week. The total dose of external beam radiotherapy was 40 - 50 Gy (the center of whole pelvic field was blocked by 4 cm in width after 20 - 30 Gy). (252)Cf neutron intracavitary brachytherapy was delivered at 6 - 8 Gy(i)/fraction, and the total dose of reference point A was 30-51 Gy(i). The median dose was 42 Gy(i). The overall 3-year survival rate of all patients was 79.2%, and the local control rate was 90.0%. In particular, the 3-year survival rate was 1/2 for stage I, 84.3% for stage II, 53.7% for stage III. The difference between stage II and stage III was statistically significant (P < 0.05). The 3-year survival in cervical lesions larger than or equal to 4 cm and those less than 4 cm was 68.1% and 71.2%, respectively (P > 0.05). The 3-year survival rate of patients with and without anemia was 42.4% and 78.2%, respectively (P < 0.05). The 3-year survival rate of patients with squamous cell carcinoma and adenocarcinoma was 78.5% and 76.9%, respectively (P > 0.05). The late radiation complications of rectum and bladder was 11.8% (13/110) and 2.7% (3/110), respectively. It is concluded that (252)Cf is a better source for intracavitary brachytherapy. According to our initial experience, (252)Cf has advantages of a high local control rate, especially to bulky tumor and adenocarcinoma.

  6. Combined Cancer Immunotherapy Against Aurora Kinase A.

    PubMed

    Kaštánková, Iva; Poláková, Ingrid; Dušková, Martina; Šmahel, Michal

    2016-05-01

    Aurora kinase A (AURKA) is a centrosomal protein that is overexpressed in a number of human malignancies and can contribute to tumor progression. As we used this protein as a target of DNA immunization, we increased its immunogenicity by the addition of the PADRE helper epitope and decreased its potential oncogenicity by mutagenesis of the kinase domain. For in vitro analysis of induced immune responses in mice, we identified the Aurka(220-228) nonapeptide representing an H-2Kb epitope. As DNA vaccination against the Aurka self-antigen by a gene gun did not show any antitumor effect, we combined DNA immunization with anti-CD25 treatment that depletes mainly regulatory T cells. Whereas 1 anti-CD25 dose injected before DNA vaccination did not enhance the activation of Aurka-specific splenocytes, 3 doses administered on days of immunizations augmented about 10-fold immunity against Aurka. However, an opposite effect was found for antitumor immunity-only 1 anti-CD25 dose combined with DNA vaccination reduced tumor growth. Moreover, the administration of 3 doses of anti-CD25 antibody alone accelerated tumor growth. Analysis of tumor-infiltrating cells showed that 3 anti-CD25 doses not only efficiently depleted regulatory T cells but also activated helper T cells and CD3(-)CD25(+) cells. Next, we found that blockade of the PD-1 receptor initiated 1 week after the first immunization was necessary for significant inhibition of tumor growth with therapeutic DNA vaccination against Aurka combined with depletion of CD25 cells. Our results suggest that combined cancer immunotherapy should be carefully evaluated to achieve the optimal antitumor effect.

  7. Combined modality therapy for esophageal cancer.

    PubMed

    Minsky, Bruce D

    2003-08-01

    Treatment approaches for esophageal cancer include primary treatment (surgical or nonsurgical) or adjuvant treatment (preoperative or postoperative). Primary treatments include surgery alone, radiation therapy alone, and radiation therapy plus chemotherapy (combined modality therapy). Adjuvant therapies include preoperative or postoperative radiation therapy, preoperative chemotherapy, and preoperative combined modality therapy. There is considerable controversy as to the ideal therapeutic approach. This review will examine the results of these approaches as well as combined modality therapy using novel regimens.

  8. Meta-Analysis of Oxaliplatin-Based Chemotherapy Combined With Traditional Medicines for Colorectal Cancer: Contributions of Specific Plants to Tumor Response.

    PubMed

    Chen, Menghua; May, Brian H; Zhou, Iris W; Xue, Charlie C L; Zhang, Anthony L

    2016-03-01

    This meta-analysis evaluates the clinical evidence for the addition of traditional medicines (TMs) to oxaliplatin-based regimens for colorectal cancer (CRC) in terms of tumor response rate (TRR). Eight electronic databases were searched for randomized controlled trials of oxaliplatin-based chemotherapy combined with TMs compared to the same oxaliplatin-based regimen. Data on TRR from 42 randomized controlled trials were analyzed using Review Manager 5.1. Studies were conducted in China or Japan. Publication bias was not evident. The meta-analyses suggest that the combination of the TMs with oxaliplatin-based regimens increased TRR in the palliative treatment of CRC (risk ratio [RR] 1.31 [1.20-1.42], I(2) = 0%). Benefits were evident for both injection products (RR 1.36 [1.18-1.57], I(2) = 0%) and orally administered TMs (RR 1.27 [1.15-1.41], I(2) = 0%). Further sensitivity analysis of specific plant-based TMs found that Paeonia, Curcuma, and Sophora produced consistently higher contributions to the RR results. Compounds in each of these TMs have shown growth-inhibitory effects in CRC cell-line studies. Specific combinations of TMs appeared to produce higher contributions to TRR than the TMs individually. Notable among these was the combination of Hedyotis, Astragalus, and Scutellaria.

  9. Combined analysis of pri-miR-34b/c rs4938723 and TP53 Arg72Pro with cervical cancer risk.

    PubMed

    Yuan, Fang; Sun, Ruifen; Chen, Peng; Liang, Yundan; Ni, Shanshan; Quan, Yi; Huang, Juan; Zhang, Lin; Gao, Linbo

    2016-05-01

    miR-34 family members can form a p53-miR-34 positive feedback loop and induce apoptosis, DNA repair, angiogenesis, and cell cycle arrest. We conducted a case-control study to examine whether two polymorphisms (i.e., rs4938723 in the promoter of pri-miR-34b/c and TP53 Arg72Pro) were linked to the carcinogenesis of cervical cancer among Chinese Han women. Genotypes of the two polymorphisms in 328 cervical cancer patients and 568 control subjects were determined by using a polymerase chain reaction-restriction fragment length polymorphism assay. We found a significantly increased cervical cancer risk in the pri-miR-34b/c rs4938723 under dominant and overdominant model (CT/CC vs. TT: adjusted OR = 1.34, 95 % CI = 1.01-1.77; CT vs. TT/CC: adjusted OR = 1.37, 95 % CI = 1.05-1.80, respectively). Increased cervical cancer risks were also found in the TP53 Arg72Pro under a heterozygous comparison and overdominant model (CG vs. GG: adjusted OR = 1.44, 95 % CI = 1.06-1.95; CG vs. GG/CC: adjusted OR = 1.47, 95 % CI = 1.12-1.94, respectively). Stratification analysis showed that patients carrying the pri-miR-34b/c rs4938723 CT genotype had a significantly increased risk for developing poorly differential status and clinical stage I. Moreover, increased cancer risks were observed for the TP53 Arg72Pro polymorphism in patients with poorly differential status, clinical stage II, and without lymph node metastasis. Combined analysis revealed that the genotypes of rs4938723 CT/CC and TP53 Arg72Pro CG/CC had an increased cervical cancer risk (OR = 2.21, 95 % CI = 1.38-3.53). These findings suggest that the pri-miR-34b/c rs4938723 and TP53 Arg72Pro polymorphisms may contribute to the genesis of cervical cancer.

  10. A meta-analysis of anastrozole in combination with fulvestrant in the first line treatment of hormone receptor positive advanced breast cancer.

    PubMed

    Tan, Pui San; Haaland, Benjamin; Montero, Alberto J; Lopes, Gilberto

    2013-04-01

    Fulvestrant is a highly active systemic therapy in patients with metastatic hormone receptor positive breast cancer. Preclinical work suggested potential synergy of fulvestrant in combination with aromatase inhibitor therapy and delayed development of endocrine resistance. The purpose of this meta-analysis is to evaluate the effectiveness of fulvestrant plus anastrozole, compared to anastrozole alone, as first line treatment of postmenopausal stage IV hormone receptor positive, HER2-negative breast cancer. The literature search was performed using PubMed, Google Scholar, Embase, ASCO, and ESMO to search for abstracts published during the last 10 years using relevant keywords. Two prospective randomized clinical trials were found to fulfill the search criteria for combination of anastrozole plus fulvestrant versus anastrozole alone. Meta-estimates were calculated by combining study estimates using the DerSimonian and Laird random effects model. The linear mixed-effects model was used to generate 95 % prediction intervals (PIs) for study-specific hazard and odds ratios. Pooled hazard ratio for progression-free survival is 0.88 (95 % CI 0.72-1.09, 95 % PI 0.65-1.21), overall survival 0.88 (95 % CI 0.72-1.08, 95 % PI 0.68-1.14) and pooled odds ratio for response rate is 1.13 (95 % CI 0.79-1.63, 95 % PI 0.78-1.65). A non-significant trend was observed with anastrozole plus fulvestrant being only marginally better than anastrozole alone in the endpoints of: progression-free survival, overall survival, and response rates. Based on these data, there is not solid evidence that the addition of fulvestrant at a dose of 250 mg monthly is better than anastrozole alone as first line therapy in women with postmenopausal hormone receptor positive breast cancer.

  11. Nationwide multi-institutional retrospective analysis of high-dose-rate brachytherapy combined with external beam radiotherapy for localized prostate cancer: An Asian Prostate HDR-BT Consortium.

    PubMed

    Ishiyama, Hiromichi; Kamitani, Nobuhiko; Kawamura, Hidemasa; Kato, Shingo; Aoki, Manabu; Kariya, Shinji; Matsumura, Taisei; Kaidu, Motoki; Yoshida, Ken; Hashimoto, Yaichiro; Noda, Yasutaka; Lim, Keith H C; Kawase, Takatsugu; Takahashi, Takeo; Inaba, Koji; Kumano, Motoyasu; Yoshikawa, Nobuhiko; Yoshioka, Yasuo; Nakamura, Katsumasa; Hiratsuka, Junichi; Itami, Jun; Hayakawa, Kazushige

    To report outcomes and risk factors of high-dose-rate (HDR) brachytherapy combined with external beam radiotherapy with or without androgen deprivation therapy (ADT) in prostate cancer patients. This multi-institutional retrospective analysis comprised 3424 patients with localized prostate cancer at 16 Asian hospitals. One-thirds (27.7%) of patients received only neoadjuvant ADT, whereas almost half (49.5%) of patients received both neoadjuvant and adjuvant ADT. Mean duration of neoadjuvant and adjuvant ADT were 8.6 months and 27.9 months, respectively. Biochemical failure was defined by Phoenix ASTRO consensus. Biochemical control rate, clinical disease-free survival (cDFS), cause-specific survival, and overall survival (OS) were calculated. Median followup was 66 months. Ten-year biochemical control, cDFS, cause-specific survival, and OS rate were 81.4%, 81.0%, 97.2%, and 85.6%, respectively. Receiving both neoadjuvant and adjuvant ADT was detected as a favorable factor for biochemical control, cDFS, and OS, but pelvic irradiation was detected as an adverse factor for cause-specific survival, and OS. Ten-year cumulative rates of late Grade ≥2 genitourinary and gastrointestinal toxicities were 26.8% and 4.1%, respectively; receiving both neoadjuvant and adjuvant ADT was detected as a favorable factor for preventing both toxicities. HDR combined with external beam radiotherapy was an effective and safe treatment for localized prostate cancer. Combination of long-term ADT was suggested to be necessary, even for HDR brachytherapy, and was useful in suppressing late toxicities. Meanwhile, pelvic irradiation was suggested to have an adverse effect on OS of our study population. Copyright © 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

  12. Combined cholecystectomy in gastric cancer surgery.

    PubMed

    Lai, Shuo-Lun; Yang, Jyh-Chin; Wu, Jin-Ming; Lai, I-Rue; Chen, Chiung-Nien; Lin, Ming-Tsan; Lai, Hong-Shiee

    2013-01-01

    Many studies have described the risk factors of gallstone formation in gastric cancer patients after gastrectomy, but few studies focus on the management of asymptomatic gallstones. Our goal is to examine the rationale of simultaneous cholecystectomy during gastric cancer surgery, and influence of surgical mortality, morbidity and overall survival after combined cholecystectomy and gastrectomy. We retrospectively reviewed 445 gastric cancer patients and the gallbladders evaluated by abdominal ultrasound or computed tomography preoperatively and postoperatively. Clinicopathologic factors, including surgical morbidity, mortality and overall survival of combined surgery, were compared between patients receiving gastrectomy with simultaneous cholecystectomy and patients receiving gastrectomy only. We also evaluated the risk factors of gallstone formation after gastrectomy and the probability of subsequent cholecystectomy after gastrectomy in gastric cancer patients with or without asymptomatic gallstones. Of 445 gastric cancer patients, 52 (11.7%) patients had asymptomatic gallstones upon diagnosis of gastric cancer. Among patients with healthy gallbladders, 15.2% developed gallstones after gastrectomy. Men and older patients (age over 60) had significantly higher risk of gallstone formation. Rate of subsequent cholecystectomy in patients with and without preoperative asymptomatic gallstones was 30.8% and 4.5%, respectively (p = 0.005). The rates of mortality and morbidity were not significantly different between combined surgery (3.4%, 24.2%) and gastrectomy only (3.1%, 22%). There was also no significant difference in 5-year survival between combined surgery (61%) and gastrectomy only (63%) groups. Combined cholecystectomy for asymptomatic gallstone in gastric cancer surgery may be considered. It was not associated with increased surgical morbidity or mortality, and had no significant effect on overall survival. Copyright © 2013 Surgical Associates Ltd. Published

  13. Combination antiretroviral therapy and cancer risk.

    PubMed

    Borges, Álvaro H

    2017-01-01

    To review the newest research about the effects of combination antiretroviral therapy (cART) on cancer risk. HIV+ persons are at increased risk of cancer. As this risk is higher for malignancies driven by viral and bacterial coinfections, classifying malignancies into infection-related and infection-unrelated has been an emerging trend. Cohorts have detected major reductions in the incidence of Kaposi sarcoma and non-Hodgkin lymphoma (NHL) following cART initiation among immunosuppressed HIV+ persons. However, recent randomized data indicate that cART reduces risk of Kaposi sarcoma and NHL also during early HIV infection before overt immunosuppression occurs. Long-term effects of cART exposure on cancer risk are not well defined; according to basic and epidemiological research, there might be specific associations of each cART class with distinct patterns of cancer risk. The relationship between cART exposure and cancer risk is complex and nuanced. It is an intriguing fact that, whether initiated during severe immunosuppression or not, cART reduces risk of Kaposi sarcoma and NHL. Further research should identify mediators of the benefit of immediate cART initiation in reducing cancer risk, understand the relationship between long-term cART exposure and cancer incidence and assess whether adjuvant anti-inflammatory therapies can reduce cancer risk during treated HIV infection.

  14. Global and Targeted Proteomics of Prostate Cancer Cell Secretome: Combination of 2-Dimensional Image-Converted Analysis of Liquid Chromatography and Mass Spectrometry and In Silico Selection Selected Reaction Monitoring Analysis.

    PubMed

    Nurdin, Armania; Hoshi, Yutaro; Yoneyama, Toshihiro; Miyauchi, Eisuke; Tachikawa, Masanori; Watanabe, Michitoshi; Terasaki, Tetsuya

    2016-11-01

    Prostate-specific antigen is currently the only protein biomarker routinely used as a diagnostic tool for early detection and treatment monitoring of prostate cancer. However, it remains questionable whether prostate-specific antigen-based screening can sensitively and selectively identify the presence and progression status of primary and metastatic prostate cancers. Hence, the purpose of this study was to identify potential biomarker candidates in the secretome of primary and metastatic prostate cancer cells by using a combination of global and targeted proteomics. Quantitative comparisons among secretome proteins derived from androgen-responsive primary cancer cells (P-22Rv1), androgen-irresponsive bone metastatic cancer cells (M-PC-3), and noncancerous prostate cells (N-PNT2) were performed using 2-dimensional image-converted analysis of liquid chromatography and mass spectrometry followed by in silico selection selected reaction monitoring analysis. Mediator of RNA polymerase II transcription subunit 13-like, insulin-like growth factor-binding protein 2, and hepatocyte growth factor were identified as highly secreted proteins from P-22Rv1 cells compared with N-PNT2 cells. Prostate-associated microseminoprotein, proactivator polypeptide, collagen-α-1 (VI) chain, and neuropilin-1 were identified as predominantly secreted proteins in M-PC-3 cells compared with N-PNT2 cells. These proteins in biological fluids are considered to be candidate biomarkers of primary and/or metastatic prostate cancer. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  15. Oxaliplatin and Infliximab Combination Synergizes in Inducing Colon Cancer Regression

    PubMed Central

    Li, Wenya; Xu, Jian; Zhao, Jian; Zhang, Rui

    2017-01-01

    Background Colon cancer is one of the most common malignant cancers and causes millions of deaths each year. There are still no effective treatments for colon cancer patients who are at advanced stage. Tumor necrosis factor-alpha (TNF-α) might be a good therapy target due to its widely-accepted roles in regulating multiple important biological processes, especially in promoting inflammation. Material/Methods We evaluated the expression of TNF-α in 108 human colon cancer tissue samples and 2 colon cancer cell lines (CT26 and HCT116), and analyzed its prognostic values. Further, we explored the roles and mechanism of anti-TNF-α treatment in combination with chemotherapy in vitro and in vivo. Results We found that TNF-α was highly expressed in colon cancer cell lines. The survival analysis and Cox regression analysis indicated that high TNF-α was an independent adverse prognosticator of colon cancer. In addition, anti-TNF-α treatment enhanced the effects of chemotherapy in the xenograft mouse model through inducing ADCC and CDC effects. Conclusions We conclude that TNF-α is an independent adverse prognosticator of colon cancer, and anti-TNF-α might benefit colon cancer patients. PMID:28190020

  16. Centralization of Penile Cancer Management in the United States: A Combined Analysis of the American Board of Urology and National Cancer Data Base.

    PubMed

    Matulewicz, Richard S; Flum, Andrew S; Helenowski, Irene; Jovanovic, Borko; Palis, Bryan; Bilimoria, Karl Y; Meeks, Joshua J

    2016-04-01

    To assess the potential benefit of centralization of care in penile cancer. Centralization of care in other disease processes standardizes treatment and improves outcomes. Because penile cancer is a rare malignancy with unchanged mortality rates over the last two decades, we hypothesize that there may be a benefit to centralization. We identified surgeon, patient, and hospital characteristics captured by the National Cancer Data Base (1998-2012) and American Board of Urology case logs (2003-2013) for all penile cancer cases and procedures. Differences in patient demographics, stage of disease, referral patterns, and surgical quality indicators were assessed between academic and community hospitals. Using case logs to evaluate the distribution of penile cancer care, we found that only 4.1% of urologists performed a penile surgery and 1.5% performed a lymph node dissection (LND). Academic centers treated higher-stage cancers and saw more cases/year than community centers, suggesting informal centralization. Two guideline-based quality indicators demonstrated no difference in use of penile-sparing surgery but a higher likelihood of having an LND performed at an academic center (48.4% vs 26.6%). The total lymph node yield was significantly greater at academic centers (18.5 vs 12.5). Regression modeling demonstrated a 2.29 increased odds of having an LND at an academic center. Our data provide the first evidence for centralization of penile cancer in the US. At the time of diagnosis, equal number of patients is treated with penile-sparing surgery but there is greater use of LND and higher lymph node yield at academic centers. Ultimately, longer follow-up is necessary to determine if this improves survival of patients with penile cancer. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Combined p16 and p53 expression in cervical cancer of unknown primary and other prognostic parameters : A single-center analysis.

    PubMed

    Yildirim, Müjdat; Müller von der Grün, Jens; Winkelmann, Ria; Fokas, Emmanouil; Rödel, Franz; Ackermann, Hanns; Rödel, Claus; Balermpas, Panagiotis

    2017-04-01

    Cervical cancer of unknown primary (CUP) represents an uncommon and heterogeneous subentity of head and neck cancer. However, both optimal diagnostics and therapy remain unclear. An improved understanding of the underlying pathology is essential to enable future tailored therapies and optimized outcomes. We retrospectively analyzed 53 patients with head and neck CUP and 48 available cervical lymph node specimens. All patients have received radiotherapy between 2007 and 2015. Preradiotherapy involved lymph node specimens were analyzed for p16 and p53 immunoreactivity. The prognostic relevance of the combined p16 and p53 status and other clinical parameters were examined by univariate and multivariate analyses. Median patient age was 61.5 years and median irradiation dose to the involved nodal levels was 66 Gy. Of the 48 evaluated specimens, 13 (27%) were p16-positive and 31 (64.6%) p53-positive. After a median follow up of 32.9 months, patients with p16-negative and simultaneously p53-positive tumors showed a significantly inferior tumor-specific survival (TSS) compared to those with either p16+/p53-, p16+/p53+, or p16-/p53- (univariate: p = 0.055, multivariate: p = 0.038). Other factors with an adverse impact on TSS in the univariate analysis were smoking history (p = 0.032) and nodal stage (p = 0.038). The combined p16- and p53-expression status in cervical metastases of CUP may represent a simple method for risk stratification. Further validation of these biomarkers in large prospective trials is essential to design rational trials for CUP treatment optimization.

  18. Aidi injection combined with radiation in the treatment of non-small cell lung cancer: A meta-analysis evaluation the efficacy and side effects.

    PubMed

    Zhang, Hongzhi; Jiang, Huijuan; Hu, Xigang; Jia, Zongling

    2015-08-01

    The purpose of this meta-analysis was to assess the clinical efficacy and side effects of Aidi injection combined with radiation in the treatment of non-small cell lung cancer (NSCLC). By searching PubMed, the Cochrane central register of controlled trials, EMBSE and CNKI databases, the efficacy and side effect data of Aidi injection combined with radiation in the treatment of NSCLC from the published clinical studies were collected. The data were pooled using Stata version 11.0 software (http://www.stata.com; Stata Corporation, College Station, TX). Ten clinical studies with 1084 subjects were included in this meta-analysis. The combined data showed the clinical efficacy in experiment group was higher than that of control group (risk ratio [RR] = 1.72, 95% confidence interval [CI]: 1.52-1.96, P = 0.00); four articles reported the life quality improvement. The pooled data showed that the use of Aidi can significantly improve the quality of life in the procedure of radiation (RR = 2.29, 95% CI: 1.76-2.98, P = 0.00); six studies reported the radiation toxicities. The pooled data showed that Aidi injection can significant decrease the radiation pneumonia (OR = 0.46, 95% CI: 0. 34-0.63), radiation esophagitis (OR = 0.53, 95% CI: 0.40-0.71), and marrow suppression (OR = 0.50, 95% CI: 0.42-0.59). Aidi injection can improve the clinical efficacy, quality of life, and decrease the radiation-related toxicities in NSCLC patients who received radiation.

  19. Combined surgery and photodynamic therapy of cancer

    NASA Astrophysics Data System (ADS)

    Douplik, Alexandre

    According to the recent guidelines, the gold standard is resecting an extra 0.5-3 cm beyond the lesion margins that are visually detected and/or biopsy confirmed depending on type of malignancy and its localisation to avoid missing the residuals of the tumour. Often, such a large resection leads to dysfunctions of the organ or tissues, which underwent the surgery. In some cases, an extra tumour-free margin cannot be achieved because of tumour proximity to vital sites such as major vascular or nerve structures. Photodynamic Therapy (PDT) is an emerging clinical modality to locally destroy cancer lesions selectively. The limitation of photodynamic therapy is the curable depth of an order of one centimetre or less. A combination of cancer surgery following by PDT can bring a benefit to reduce the resection and minimise the impact on the organ or tissue functionality. Combination of cancer surgery and photodynamic therapy provides another opportunity-fluorescence image guidance of cancer removal. Most of the photosensitizers intensively fluoresce and hence facilitate a strong fluorescence contrast versus healthy adjacent tissues.

  20. Small RNA combination therapy for lung cancer.

    PubMed

    Xue, Wen; Dahlman, James E; Tammela, Tuomas; Khan, Omar F; Sood, Sabina; Dave, Apeksha; Cai, Wenxin; Chirino, Leilani M; Yang, Gillian R; Bronson, Roderick; Crowley, Denise G; Sahay, Gaurav; Schroeder, Avi; Langer, Robert; Anderson, Daniel G; Jacks, Tyler

    2014-08-26

    MicroRNAs (miRNAs) and siRNAs have enormous potential as cancer therapeutics, but their effective delivery to most solid tumors has been difficult. Here, we show that a new lung-targeting nanoparticle is capable of delivering miRNA mimics and siRNAs to lung adenocarcinoma cells in vitro and to tumors in a genetically engineered mouse model of lung cancer based on activation of oncogenic Kirsten rat sarcoma viral oncogene homolog (Kras) and loss of p53 function. Therapeutic delivery of miR-34a, a p53-regulated tumor suppressor miRNA, restored miR-34a levels in lung tumors, specifically down-regulated miR-34a target genes, and slowed tumor growth. The delivery of siRNAs targeting Kras reduced Kras gene expression and MAPK signaling, increased apoptosis, and inhibited tumor growth. The combination of miR-34a and siRNA targeting Kras improved therapeutic responses over those observed with either small RNA alone, leading to tumor regression. Furthermore, nanoparticle-mediated small RNA delivery plus conventional, cisplatin-based chemotherapy prolonged survival in this model compared with chemotherapy alone. These findings demonstrate that RNA combination therapy is possible in an autochthonous model of lung cancer and provide preclinical support for the use of small RNA therapies in patients who have cancer.

  1. Oxaliplatin-based chemotherapy combined with traditional medicines for neutropenia in colorectal cancer: A meta-analysis of the contributions of specific plants.

    PubMed

    Chen, Menghua; May, Brian H; Zhou, Iris W; Sze, Daniel Man-Yuen; Xue, Charlie C; Zhang, Anthony L

    2016-09-01

    This review assessed the effects on chemotherapy induced neutropenia (CIN) of combining oxaliplatin regimens with traditional plant-based medicines (TMs) in the management of colorectal cancer (CRC). 32 RCTs (2224 participants) were included. Meta-analysis showed reduced incidence of grade 3/4 CIN (RR 0.45[0.31, 0.65], I(2)=0%). No studies reported serious adverse events or reduction in tumour response rates associated with concurrent use of oxaliplatin and TM. Due to small sample sizes and risk of bias, these results should be interpreted with caution. Analyses of sub-groups of studies that used similar TM interventions assessed the relative contributions of individual plant-based ingredients to the results. Astragalus, Codonopsis, Atractylodes, Poria and Coix, in various combinations were consistently associated with reduced CIN incidence when administered orally. Experimental studies of these plants have reported reduced myelosuppression and/or enhanced immune response. Further studies of these plants may lead to the development of interventions to supplement conventional CIN treatment.

  2. Genome-wide analysis of aberrant methylation in human breast cancer cells using methyl-DNA immunoprecipitation combined with high-throughput sequencing

    PubMed Central

    2010-01-01

    Background Cancer cells undergo massive alterations to their DNA methylation patterns that result in aberrant gene expression and malignant phenotypes. However, the mechanisms that underlie methylome changes are not well understood nor is the genomic distribution of DNA methylation changes well characterized. Results Here, we performed methylated DNA immunoprecipitation combined with high-throughput sequencing (MeDIP-seq) to obtain whole-genome DNA methylation profiles for eight human breast cancer cell (BCC) lines and for normal human mammary epithelial cells (HMEC). The MeDIP-seq analysis generated non-biased DNA methylation maps by covering almost the entire genome with sufficient depth and resolution. The most prominent feature of the BCC lines compared to HMEC was a massively reduced methylation level particularly in CpG-poor regions. While hypomethylation did not appear to be associated with particular genomic features, hypermethylation preferentially occurred at CpG-rich gene-related regions independently of the distance from transcription start sites. We also investigated methylome alterations during epithelial-to-mesenchymal transition (EMT) in MCF7 cells. EMT induction was associated with specific alterations to the methylation patterns of gene-related CpG-rich regions, although overall methylation levels were not significantly altered. Moreover, approximately 40% of the epithelial cell-specific methylation patterns in gene-related regions were altered to those typical of mesenchymal cells, suggesting a cell-type specific regulation of DNA methylation. Conclusions This study provides the most comprehensive analysis to date of the methylome of human mammary cell lines and has produced novel insights into the mechanisms of methylome alteration during tumorigenesis and the interdependence between DNA methylome alterations and morphological changes. PMID:20181289

  3. Cost-effectiveness of chemotherapy combined with thoracic radiotherapy versus chemotherapy alone for limited stage small cell lung cancer: A population-based propensity-score matched analysis

    PubMed Central

    Chien, Chun-Ru; Hsia, Te-Chun; Chen, Chih-Yi

    2014-01-01

    Background The addition of thoracic radiotherapy improves the outcome of limited stage small cell lung cancer (LS-SCLC), however, the cost-effectiveness of this process has never been reported. We aimed to estimate the short-term cost-effectiveness of chemotherapy combined with thoracic radiotherapy (C-TRT) versus chemotherapy alone (C/T) for LS-SCLC patients from the payer's perspective (Taiwan National Health Insurance). Methods We identified LS-SCLC patients diagnosed within 2007–2009 through a comprehensive population-based database containing cancer and death registries, and reimbursement data. The duration of interest was one year within diagnosis. We included potential confounding covariables through literature searching and our own experience, and used a propensity score to construct a 1:1 population for adjustment. We used a net benefit (NB) approach to evaluate the cost-effectiveness at various willingness-to-pay (WTP) levels. Sensitivity analysis regarding potential unmeasured confounder(s) was performed. Results Our study population constituted 74 patients. The mean cost (2013 USD) and survival (year) was higher for C-TRT (42 439 vs. 28 357; 0.94 vs. 0.88). At the common WTP level (50 000 USD/life-year), C-TRT was not cost effective (incremental NB − 11 082) and the probability for C-TRT to be cost effective (i.e. positive net benefit) was 0.005. The result was moderately sensitive to potential unmeasured confounder(s) in sensitivity analysis. Conclusions We provide evidence that when compared to C/T, C-TRT is effective in improving survival, but is not cost-effective in the short-term at a common WTP level from a payer's perspective. This information should be considered by clinicians when discussing thoracic radiotherapy with their LS-SCLC patients. PMID:26767048

  4. Effects of S-1 Combined with Radiotherapy in the Treatment of Nasopharyngeal Cancer: A Meta-analysis Based on Randomized Controlled Trials.

    PubMed

    Fengtong, Jin; Jiangtao, Fu; Yating, Wang; Lili, Wu; Jianbo, Chen; Xiaofei, Wang

    2017-01-01

    The aim of this meta-analysis was to evaluate the effects and toxicity of S-1 combined with radiotherapy in the treatment of nasopharyngeal cancer (NPC). Through a search of the databases of PubMed, Embase, the Chinese Biomedicine Database (CBM), China National Knowledge Infrastructure (CNKI), Wanfang system and Chongqing VIP Information (CQVIP), the efficacy and side effects data of S-1 combined with radiotherapy in the treatment of NPC patients from open published randomized controlled trials (RCTs) were collected. The pooled complete response (CR), partial response (PR), objective response rate (ORR), 2-year survival rate and treatment related toxicity were analyzed by Stata12.0 software. Eight RCTs with 599 cases were included and analyzed in this meta-analysis. The general quality of the 8 studies were deemed as having moderate risk of bias. Adequate sequence generation was reported in 4 studies. Incomplete outcome data address was reported in 7 publications. Five studies indicated to be free of selective reporting. Seven studies reported the treatment complete response (CR) between S-1 combined with radiotherapy and radiotherapy alone. With significant heterogeneity, the data was pooled by random effect model. The pooled results indicated that S-1 combined with radiotherapy can significant increase the CR rate compared to radiotherapy alone (RR=1.52, 95%CI:1.33-1.74, P<0.05). Eight studies reported the partial response (PR) rate between the combined treatment and radiotherapy alone. The pooled results showed that there was no statistical difference for PR between combined treatment and radiotherapy alone (RR=0.85, 95%CI:0.62-1.16, P>0.05). For the effect size of objective response rate (ORR), pooled results indicated that S-1 combined with radiotherapy can significantly increased the ORR by random effect model (RR=1.39, 95%CI:1.23-1.57, P<0.05). The pooled results showed that S-1 combined with radiotherapy significant increase the risk of developing bone

  5. Chemotherapy with cisplatin or carboplatin in combination with etoposide for small-cell esophageal cancer: a systemic analysis of case series.

    PubMed

    Gao, R; Zhang, Y; Wen, X P; Fu, J; Zhang, G J

    2014-01-01

    Chemotherapy has been the first-choice treatment for small-cell esophageal cancer (SCEC), etoposide plus cisplatin or carboplatin (EP/CP) is the most commonly recommended chemotherapeutical strategy. However, the choice of chemotherapy in treating SCEC has not been validated by studies of large cohorts of cases because of the rarity of the malignancy, and the efficacy superiority of EP/CP over other chemotherapy combinations has not been confirmed. The present case series analysis was conducted to address the above issues. Reported studies of SCEC patients were retrieved. Case series with more than five patients were enrolled. Eight patients treated in our institute were also included as another case series. Data pertaining to clinical stages, treatment regimens, and survival time were collected and analyzed. Altogether, 19 SCEC case series were enrolled, including 164 male and 61 female patients with a median age of 63.5 years. The follow-up time ranged from 0.1 to 221 months (median 12.3 months). The median survival time (MST) was 19 months for limited disease (LD) patients (124 cases) and 9 months for extensive disease (ED) patients (88 cases) (P<0.001). For LD patients, MST was obviously prolonged by chemotherapeutical regimens (20 vs. 10 months, P<0.01), whereas this superiority was not proved in ED patients (10 vs. 10 months, P>0.05). EP/CP did not result in significantly longer MST, compared with that of the cases treated by other chemotherapy combinations (P>0.05, for either LD or ED cases). Chemotherapy prolongs the survival time of the LD SCEC patients, which indicates that chemotherapeutical treatment is effective for SCEC. EP/CP, as commonly recommended multidrug chemotherapy regimen, is not superior to other chemotherapy combinations. © 2013 Wiley Periodicals, Inc. and the International Society for Diseases of the Esophagus.

  6. Combined application of information theory on laboratory results with classification and regression tree analysis: analysis of unnecessary biopsy for prostate cancer.

    PubMed

    Hwang, Sang-Hyun; Pyo, Tina; Oh, Heung-Bum; Park, Hyun Jun; Lee, Kwan-Jeh

    2013-01-16

    The probability of a prostate cancer-positive biopsy result varies with PSA concentration. Thus, we applied information theory on classification and regression tree (CART) analysis for decision making predicting the probability of a biopsy result at various PSA concentrations. From 2007 to 2009, prostate biopsies were performed in 664 referred patients in a tertiary hospital. We created 2 CART models based on the information theory: one for moderate uncertainty (PSA concentration: 2.5-10 ng/ml) and the other for high uncertainty (PSA concentration: 10-25 ng/ml). The CART model for moderate uncertainty (n=321) had 3 splits based on PSA density (PSAD), hypoechoic nodules, and age and the other CART for high uncertainty (n=160) had 2 splits based on prostate volume and percent-free PSA. In this validation set, the patients (14.3% and 14.0% for moderate and high uncertainty groups, respectively) could avoid unnecessary biopsies without false-negative results. Using these CART models based on uncertainty information of PSA, the overall reduction in unnecessary prostate biopsies was 14.0-14.3% and CART models were simplified. Using uncertainty of laboratory results from information theoretic approach can provide additional information for decision analysis such as CART. Copyright © 2012 Elsevier B.V. All rights reserved.

  7. Combined magnetic and gravity analysis

    NASA Technical Reports Server (NTRS)

    Hinze, W. J.; Braile, L. W.; Chandler, V. W.; Mazella, F. E.

    1975-01-01

    Efforts are made to identify methods of decreasing magnetic interpretation ambiguity by combined gravity and magnetic analysis, to evaluate these techniques in a preliminary manner, to consider the geologic and geophysical implications of correlation, and to recommend a course of action to evaluate methods of correlating gravity and magnetic anomalies. The major thrust of the study was a search and review of the literature. The literature of geophysics, geology, geography, and statistics was searched for articles dealing with spatial correlation of independent variables. An annotated bibliography referencing the Germane articles and books is presented. The methods of combined gravity and magnetic analysis techniques are identified and reviewed. A more comprehensive evaluation of two types of techniques is presented. Internal correspondence of anomaly amplitudes is examined and a combined analysis is done utilizing Poisson's theorem. The geologic and geophysical implications of gravity and magnetic correlation based on both theoretical and empirical relationships are discussed.

  8. Human Lung Cancer Risks from Radon – Part III - Evidence of Influence of Combined Bystander and Adaptive Response Effects on Radon Case-Control Studies - A Microdose Analysis

    PubMed Central

    Leonard, Bobby E.; Thompson, Richard E.; Beecher, Georgia C.

    2012-01-01

    Since the publication of the BEIR VI (1999) report on health risks from radon, a significant amount of new data has been published showing various mechanisms that may affect the ultimate assessment of radon as a carcinogen, in particular the potentially deleterious Bystander Effect (BE) and the potentially beneficial Adaptive Response radio-protection (AR). The case-control radon lung cancer risk data of the pooled 13 European countries radon study (Darby et al 2005, 2006) and the 8 North American pooled study (Krewski et al 2005, 2006) have been evaluated. The large variation in the odds ratios of lung cancer from radon risk is reconciled, based on the large variation in geological and ecological conditions and variation in the degree of adaptive response radio-protection against the bystander effect induced lung damage. The analysis clearly shows Bystander Effect radon lung cancer induction and Adaptive Response reduction in lung cancer in some geographical regions. It is estimated that for radon levels up to about 400 Bq m−3 there is about a 30% probability that no human lung cancer risk from radon will be experienced and a 20% probability that the risk is below the zero-radon, endogenic spontaneous or perhaps even genetically inheritable lung cancer risk rate. The BEIR VI (1999) and EPA (2003) estimates of human lung cancer deaths from radon are most likely significantly excessive. The assumption of linearity of risk, by the Linear No-Threshold Model, with increasing radon exposure is invalid. PMID:22942874

  9. Combined modality treatment of gastric cancer

    SciTech Connect

    Gunderson, L.L.; Hoskins, R.B.; Cohen, A.C.; Kaufman, S.; Wood, W.C.; Carey, R.W.

    1983-07-01

    In a series of 46 patients with localized gastric cancer treated at Massachusetts General Hospital, problems with excessive acute or chronic toxicity due to combination treatment with irradiation (XRT) and chemotherapy (CT) were not seen. Forty of the 46 received combined treatment with 2 regimens: (1) irradiation plus concomitant 3 days of 5-FU followed by maintenance 5-FU or combined drugs-26 patients; (2) in the other 14 patients, the sequence of irradiation and chemotherapy was altered. A single course of combined drug chemotherapy was given prior to irradiation and 5 to 6 additional courses were administered after completion of XRT (CT-XRT-CT). The drug combination was initially 5-FU-BGNU but this was changed to FAM (5-FU, Adriamycin, Mitomycin C). In this series, there were no cases of septicemia or any deaths related to treatment. A 3 year survival rate of about 20% was achieved for the total group of patients and 43% in the group with resection but at high risk for later failure. Our inability to improve these numbers is undoubtedly a result of dose limitations with external beam irradiation combined with a systemic failure problem. When irradiation is combined with surgical resection of all or a majority of tumor, both survival and local control appear to be better than in the unresected patient group. Only 4 of 29 patients (14%) with curative resection, or resection but residual disease, had later evidence of failure within the irradiation field as opposed to 6 of 9 or 66% in the group with unresectable disease.

  10. Combination immunotherapy and photodynamic therapy for cancer

    NASA Astrophysics Data System (ADS)

    Hamblin, Michael R.; Castano, Ana P.; Mroz, Pawel

    2006-02-01

    Cancer is a leading cause of death among modern people largely due to metastatic disease. The ideal cancer treatment should target both the primary tumor and the metastases with minimal toxicity towards normal tissue. This is best accomplished by priming the body's immune system to recognize the tumor antigens so that after the primary tumor is destroyed, distant metastases will also be eradicated. Photodynamic therapy (PDT) involves the IV administration of photosensitizers followed by illumination of the tumor with red light producing reactive oxygen species leading to vascular shutdown and tumor cell death. Anti-tumor immunity is stimulated after PDT due to the acute inflammatory response, generation of tumor-specific antigens, and induction of heat-shock proteins. Combination regimens using PDT and immunostimulating treatments are likely to even further enhance post-PDT immunity. These immunostimulants are likely to include products derived from pathogenic microorganisms that are effectively recognized by Toll-like receptors and lead to upregulation of transcription factors for cytokines and inflammatory mediators. The following cascade of events causes activation of macrophages, dendritic and natural killer cells. Exogenous cytokine administration can be another way to increase PDT-induced immunity as well as treatment with a low dose of cyclophosphamide that selectively reduces T-regulatory cells. Although so far these combination therapies have only been used in animal models, their use in clinical trials should receive careful consideration.

  11. Nano-Engineered Drug Combinations for Breast Cancer Treatment

    DTIC Science & Technology

    2012-06-01

    Breast Cancer Treatment PRINCIPAL INVESTIGATOR: Joerg Lahann, Ph.D. CONTRACTING...CONTRACT NUMBER Nano-Engineered Drug Combinations for Breast Cancer Treatment 5b. GRANT NUMBER W81XWH-11-1-0111 5c. PROGRAM ELEMENT NUMBER 6...10 19b. TELEPHONE NUMBER (include area code) 2 Nano-engineered Drug Combinations for Breast Cancer Treatment Progress Report

  12. Tyrosine kinase inhibitor combination therapy in first-line treatment of non-small-cell lung cancer: systematic review and network meta-analysis

    PubMed Central

    Batson, Sarah; Mitchell, Stephen A; Windisch, Ricarda; Damonte, Elisabetta; Munk, Veronica C; Reguart, Noemi

    2017-01-01

    Introduction The introduction of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has improved the outlook for patients with advanced non-small-cell lung cancer (NSCLC) with EGFR+ mutations. However, most patients develop resistance, with the result that median progression-free survival (PFS) iŝ12 months. Combining EGFR-TKIs with other agents, such as bevacizumab, is a promising approach to prolonging remission. This systematic review and network meta-analysis (NMA) were undertaken to assess available evidence regarding the benefits of first-line combination therapy involving EGFR-TKIs in patients with advanced NSCLC. Methods Literature searches were performed using relevant search terms. Study-level pseudo-individual patient-level data (IPD) were recreated from digitized Kaplan–Meier curve data, using a published algorithm. Study IPD were analyzed using both the proportional hazards and the acceleration failure time (AFT) survival models, and it was concluded that the AFT model was most appropriate. An NMA was performed based on acceleration factors (AFs) using a Bayesian framework to compare EGFR-TKIs and chemotherapy. Results Nine randomized controlled trials were identified that provided data for EGFR-TKI therapy in patients with EGFR+ tumors. These included studies of afatinib (n=3), erlotinib (n=3), erlotinib plus bevacizumab (n=1) and gefitinib (n=2). Erlotinib plus bevacizumab produced the greatest increase in PFS compared with chemotherapy, with 1/AF being 0.24 (95% credible interval [CrI] 0.17, 0.34). This combination also produced greater increases in PFS compared with EGFR-TKI monotherapy: 1/AF versus afatinib, 0.51 (95% CrI 0.35, 0.73); versus erlotinib, 0.53 (95% CrI 0.39, 0.72) and versus gefitinib, 0.46 (95% CrI 0.32, 0.66). All three EGFR-TKI monotherapies prolonged PFS compared with chemotherapy; estimates of treatment effect ranged from 1/AF 0.53 (95% CrI 0.48, 0.60) for gefitinib to 1/AF 0.46 (95% CrI 0.40, 0.53) for

  13. Identification of the anticancer effects of a novel proteasome inhibitor, ixazomib, on colorectal cancer using a combined method of microarray and bioinformatics analysis

    PubMed Central

    Fan, Qiaowei; Liu, Bingrong

    2017-01-01

    Purpose The study aimed to explore the anticancer effects of a novel proteasome inhibitor, ixazomib, on colorectal cancer (CRC) using a combined method of microarray and bioinformatics analysis. Materials and methods Cell proliferation was tested by Cell Counting Kit-8 (CCK-8) assay for SW620 cells treated with different concentrations of ixazomib and different treatment times. The microarray analysis was conducted for six samples, including three samples of SW620 cells untreated with ixazomib and three samples of SW620 cells treated with ixazomib. The differentially expressed genes (DEGs) between untreated and treated samples were identified by the Linear Models for Microarray data (LIMMA) package in R language. The Gene Ontology (GO) functional and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed for the DEGs using the Database for Annotation, Visualization and Integrated Discovery (DAVID) and KEGG Orthology-Based Annotation System (KOBAS) online tool. The protein–protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database, and module analysis was performed for the PPI network. Results Ixazomib could inhibit the proliferation of SW620 cells in a dose-dependent and time-dependent manner. A total of 743 DEGs, including 203 upregulated DEGs such as HSPA6 and 540 downregulated DEGs such as APCDD1, were identified. Eighty-three GO terms were enriched for DEGs, which were mainly related to protein folding, apoptotic process, transcription factor activity, and proteasome. Thirty-seven KEGG pathways were perturbed, including pathway of apoptosis and cell cycle. Forty-six hub genes, such as TP53, JUN, and ITGA2, were screened out, and three modules with important functions were mined from the PPI network. Conclusion The novel proteasome inhibitor ixazomib significantly inhibited the proliferation of human CRC SW620 cells. It exerted anticancer effects

  14. Paclitaxel-etoposide-carboplatin/cisplatin versus etoposide-carboplatin/cisplatin as first-line treatment for combined small-cell lung cancer: a retrospective analysis of 62 cases

    PubMed Central

    Li, Yue-Ya; Zhou, Chan; Yang, Deng-Xia; Wang, Jing; Liu, Zhu-Jun; Wang, Xin-Yue; Li, Kai

    2015-01-01

    Objective To compare the efficacy and adverse effects of paclitaxel-etoposide-carboplatin/cisplatin (TEP/TCE) regimen with those of etoposide-carboplatin/cisplatin (EP/CE) regimen as first-line treatment for combined small-cell lung cancer (CSCLC). Methods A retrospective study was conducted on 62 CSCLC patients who were treated at Tianjin Medical University Cancer Institute and Hospital from July 2000 to April 2013 and administered with TEP/TCE regimen (n=19) or EP/CE regimen (n=43) as first-line CSCLC treatment. All patients received more than two cycles of chemotherapy, and the response was evaluated every two cycles. The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse effects. Results ORR between the TEP/TCE and EP/CE groups showed a statistical difference (90% vs. 53%, P=0.033). Both groups failed to reach a statistical difference in DCR (100% vs. 86%, P=0.212). The median PFS and OS of the TEP/TCE group were slightly longer than those of the EP/CE group, although both groups failed to reach a statistical difference (10.5 vs. 8.9 months, P=0.484; 24.0 vs. 17.5 months, P=0.457). However, stratified analysis indicated that the PFS of patients with stages III and IV CSCLC showed marginally significant difference between the TEP/TCE and EP/CE groups (19.5 vs. 7.6 months; P=0.071). Both rates of grade IV bone marrow depression and termination of chemotherapy in the TEP/TCE group were significantly higher than those in the EP/CE group (26.3% vs. 7.0%, P=0.036; 31.6% vs. 14.7%, P=0.004). Conclusion The TEP/TCE regimen may not be preferred for CSCLC, and this three-drug regimen requires further exploration and research. To date, the EP/CE regimen remains the standard treatment for CSCLC patients. PMID:26175927

  15. Gemcitabine Single or Combination Chemotherapy in Post Anthracycline and Taxane Salvage Treatment of Metastatic Breast Cancer: Retrospective Analysis of 124 Patients

    PubMed Central

    Kim, Min Kyoung; Ahn, Jin Hee; Lee, Soon Im; Ahn, Sei-Hyun; Son, Byung Ho; Gong, Gyungyub; Kim, Hak-Hee; Lee, Jung-Shin; Kang, Yoon-Koo; Kim, Woo Kun

    2006-01-01

    Purpose To evaluate the efficacy of gemcitabine-based chemotherapy, particularly in patients with anthracycline- and taxane-pretreated 2nd-line or greater metastatic breast cancer, and to compare gemcitabine monotherapy (G) with two gemcitabine-based doublets, gemcitabine/vinorelbine (GV) and gemcitabine/capecitabine (GX). Materials and Methods Of 124 consecutive patients who progressed after anthracycline- and taxane-containing chemotherapy, 58 received G alone, 38 received GV, and 28 received GX; their outcomes were analyzed retrospectively. Results The median number of prior metastatic chemotherapy regimens was 2 (range 0~4). Visceral metastases were observed in 65 patients (51.4%). The overall response rate was 19.3% (21 partial responses). After a median follow-up period of 21.4 months, the overall survival was 7.6 months (95% CI: 5.5~9.6 months) and the median time to progression was 3.1 months (95% CI: 2.0~4.2 months). Compared with monotherapy (G), com - bination therapy with vinorelbine or capecitabine (GV/GX) was associated with a significantly higher response rate (8.2% vs. 28.3%, p=0.008) and a significantly longer median time to progression (2.8 vs. 3.5 months; p=0.028), but overall survival did not differ between the groups (7.4 vs. 8.2 months, respectively; p=0.54). Most of the adverse treatment-related events were mild to moderate in intensity. The most common adverse event was hematologic toxicity. Multivariate analysis showed that poor performance status and a short disease-free interval were independent prognostic factors for impaired overall survival. Conclusions The combination of gemcitabine with vinorelbine or capecitabine was an active and well-tolerated treatment option for taxane- and anthracycline-pretreated 2nd-line or greater metastatic breast cancer patients, and gemcitabine-based doublets were more beneficial than gemcitabine monotherapy in alleviating symptoms for these patients. PMID:19771244

  16. Randomized controlled trials of the efficacy of lung cancer screening by sputum cytology revisited: a combined mortality analysis from the Johns Hopkins Lung Project and the Memorial Sloan-Kettering Lung Study.

    PubMed

    Doria-Rose, V Paul; Marcus, Pamela M; Szabo, Eva; Tockman, Melvyn S; Melamed, Myron R; Prorok, Philip C

    2009-11-01

    : Two randomized controlled trials of lung cancer screening initiated in the 1970s, the Johns Hopkins Lung Project and the Memorial Sloan-Kettering Lung Study, compared 1 arm that received annual chest X-ray and 4-monthly sputum cytology (dual-screen) to a second arm that received annual chest X-ray only. Previous publications from these trials reported similar lung cancer mortality between the 2 groups. However, these findings were based on incomplete follow-up, and each trial on its own was underpowered to detect a modest mortality benefit. : The authors estimated the efficacy of lung cancer screening with sputum cytology in an intention-to-screen analysis of lung cancer mortality, using combined data from these trials (n = 20,426). : Over (1/2) of squamous cell lung cancers diagnosed in the dual-screen group were identified by cytology; these cancers tended to be more localized than squamous cancers diagnosed in the X-ray only arm. After 9 years of follow-up, lung cancer mortality was slightly lower in the dual-screen than in the X-ray only arm (rate ratio [RR], 0.88; 95% confidence interval [CI], 0.74-1.05). Reductions were seen for squamous cell cancer deaths (RR, 0.79; 95% CI, 0.54-1.14) and in the heaviest smokers (RR, 0.81; 95% CI, 0.67-1.00). There were also fewer deaths from large cell carcinoma in the dual-screen group, although the reason for this is unclear. : These data are suggestive of a modest benefit of sputum cytology screening, although we cannot rule out chance as an explanation for these findings. Cancer 2009. (c) 2009 American Cancer Society.

  17. Combining Drugs to Treat Ovarian Cancer - Annual Plan

    Cancer.gov

    Approximately 70 percent of women diagnosed with ovarian cancer will die from the disease. Read about the NCI-funded combination drug trial that has successfully treated Betsy Brauser's recurrent cancer.

  18. Combination of p16(INK4a) /Ki67 immunocytology and HPV polymerase chain reaction for the noninvasive analysis of HPV involvement in head and neck cancer.

    PubMed

    Linxweiler, Maximilian; Bochen, Florian; Wemmert, Silke; Lerner, Cornelia; Hasenfus, Andrea; Bohle, Rainer Maria; Al-Kadah, Basel; Takacs, Zoltan Ferenc; Smola, Sigrun; Schick, Bernhard

    2015-04-01

    High-risk human papillomavirus (HPV) infection has been identified as a relevant risk for the development of head and neck squamous cell carcinomas (HNSCCs). As HPV status has also gained a role as a prognostic and predictive biomarker for this entity, there is a growing demand for valid HPV testing in HNSCC patients Liquid-based cytological smears from 45 HNSCC and 20 control patients were collected and used for simultaneous immunocytochemical p16(INK4a) /Ki67 staining using a CINtec PLUS kit after the presence of tumor cells was verified in a Papanicolaou-stained slide. The same cytological suspension was used for the detection of HPV DNA by specific polymerase chain reaction (PCR). Tumor cells were detected in the swab material of 44 HNSCC patients corresponding to a sensitivity of 98% (44 of 45). PCR analysis revealed the presence of HPV DNA in the cytological suspension of 13 patients (13 of 65, 20%) with simultaneous p16(INK4a) /Ki67 expression by the tumor cells in 11 of these HPV DNA-positive samples (11 of 13, 85%) - a staining pattern that is strongly associated with a carcinogenic HPV infection. A simultaneous immunocytochemical detection of p16(INK4a) and Ki67 can reliably be performed on liquid-based cytological smears from HNSCC patients using a CINtec PLUS kit. In addition, the same cytological material can be used for the detection of HPV DNA by specific PCR. The combined results of both techniques enable better discrimination between latent and carcinogenic HPV infections as well as HPV-negative cases and thus can provide information on the prognosis of HNSCC patients and facilitate therapeutic decisions. © 2014 American Cancer Society.

  19. Combining Cancer Immunotherapy and Targeted Therapy

    PubMed Central

    Ribas, Antoni; Wolchok, Jedd D.

    2013-01-01

    The ability to pharmacologically modulate key signaling pathways that drive tumor growth and progression, but do not negatively impact the function of lymphocytes, provides avenues for rational combinatorial approaches to improve the antitumor activity of tumor immunotherapies. Novel targeted agents can very specifically block oncogenic events in cancer cells, leading to a pro-apoptotic milieu and a potential increase in sensitivity to recognition and attack by cytotoxic T lymphocytes. Furthermore, targeted pathway modulation in lymphocytes may change their function and have activating effects in some instances. When tested together with recently developed powerful tumor immunotherapies, such combinations may exploit the highly specific targeting of oncogenes with small molecule inhibitors to lead to high frequency of tumor regressions, and merge this benefit with the durable responses achievable with effective tumor immunotherapies. PMID:23561594

  20. Combining Gene Signatures Improves Prediction of Breast Cancer Survival

    PubMed Central

    Zhao, Xi; Naume, Bjørn; Langerød, Anita; Frigessi, Arnoldo; Kristensen, Vessela N.; Børresen-Dale, Anne-Lise; Lingjærde, Ole Christian

    2011-01-01

    Background Several gene sets for prediction of breast cancer survival have been derived from whole-genome mRNA expression profiles. Here, we develop a statistical framework to explore whether combination of the information from such sets may improve prediction of recurrence and breast cancer specific death in early-stage breast cancers. Microarray data from two clinically similar cohorts of breast cancer patients are used as training (n = 123) and test set (n = 81), respectively. Gene sets from eleven previously published gene signatures are included in the study. Principal Findings To investigate the relationship between breast cancer survival and gene expression on a particular gene set, a Cox proportional hazards model is applied using partial likelihood regression with an L2 penalty to avoid overfitting and using cross-validation to determine the penalty weight. The fitted models are applied to an independent test set to obtain a predicted risk for each individual and each gene set. Hierarchical clustering of the test individuals on the basis of the vector of predicted risks results in two clusters with distinct clinical characteristics in terms of the distribution of molecular subtypes, ER, PR status, TP53 mutation status and histological grade category, and associated with significantly different survival probabilities (recurrence: p = 0.005; breast cancer death: p = 0.014). Finally, principal components analysis of the gene signatures is used to derive combined predictors used to fit a new Cox model. This model classifies test individuals into two risk groups with distinct survival characteristics (recurrence: p = 0.003; breast cancer death: p = 0.001). The latter classifier outperforms all the individual gene signatures, as well as Cox models based on traditional clinical parameters and the Adjuvant! Online for survival prediction. Conclusion Combining the predictive strength of multiple gene signatures improves prediction of breast

  1. Combined high-intensity local treatment and systemic therapy in metastatic head and neck squamous cell carcinoma: An analysis of the National Cancer Data Base.

    PubMed

    Zumsteg, Zachary S; Luu, Michael; Yoshida, Emi J; Kim, Sungjin; Tighiouart, Mourad; David, John M; Shiao, Stephen L; Mita, Alain C; Scher, Kevin S; Sherman, Eric J; Lee, Nancy Y; Ho, Allen S

    2017-08-17

    There is increasing evidence that primary tumor ablation can improve survival for some cancer patients with distant metastases. This may be particularly applicable to head and neck squamous cell carcinoma (HNSCC) because of its tropism for locoregional progression. This study included patients with metastatic HNSCC undergoing systemic therapy identified in the National Cancer Data Base. High-intensity local treatment was defined as radiation doses ≥ 60 Gy or oncologic resection of the primary tumor. Multivariate Cox regression, propensity score matching, landmark analysis, and subgroup analysis were performed to account for imbalances in covariates, including adjustments for the number and location of metastatic sites in the subset of patients with this information available. In all, 3269 patients were included (median follow-up, 51.5 months). Patients undergoing systemic therapy with local treatment had improved survival in comparison with patients receiving systemic therapy alone in propensity score-matched cohorts (2-year overall survival, 34.2% vs 20.6%; P < .001). Improved survival was associated only with patients receiving high-intensity local treatment, whereas those receiving lower-intensity local treatment had survival similar to that of patients receiving systemic therapy without local treatment. The impact of high-intensity local therapy was time-dependent, with a stronger impact within the first 6 months after the diagnosis (adjusted hazard ratio [AHR], 0.255; 95% confidence interval [CI], 0.210-0.309; P < .001) in comparison with more than 6 months after the diagnosis (AHR, 0.622; 95% CI, 0.561-0.689; P < .001) in the multivariate analysis. A benefit was seen in all subgroups, in landmark analyses of 1-, 2-, and 3-year survivors, and when adjusting for the number and location of metastatic sites. Aggressive local treatment warrants prospective evaluation for select patients with metastatic HNSCC. Cancer 2017. © 2017 American Cancer Society. © 2017

  2. Combination cancer immunotherapy and new immunomodulatory targets.

    PubMed

    Mahoney, Kathleen M; Rennert, Paul D; Freeman, Gordon J

    2015-08-01

    Targeting immune checkpoints such as programmed cell death protein 1 (PD1), programmed cell death 1 ligand 1 (PDL1) and cytotoxic T lymphocyte antigen 4 (CTLA4) has achieved noteworthy benefit in multiple cancers by blocking immunoinhibitory signals and enabling patients to produce an effective antitumour response. Inhibitors of CTLA4, PD1 or PDL1 administered as single agents have resulted in durable tumour regression in some patients, and combinations of PD1 and CTLA4 inhibitors may enhance antitumour benefit. Numerous additional immunomodulatory pathways as well as inhibitory factors expressed or secreted by myeloid and stromal cells in the tumour microenvironment are potential targets for synergizing with immune checkpoint blockade. Given the breadth of potential targets in the immune system, critical questions to address include which combinations should move forward in development and which patients will benefit from these treatments. This Review discusses the leading drug targets that are expressed on tumour cells and in the tumour microenvironment that allow enhancement of the antitumour immune response.

  3. Analysis of local chronic inflammatory cell infiltrate combined with systemic inflammation improves prognostication in stage II colon cancer independent of standard clinicopathologic criteria.

    PubMed

    Turner, Natalie; Wong, Hui-Li; Templeton, Arnoud; Tripathy, Sagarika; Whiti Rogers, Te; Croxford, Matthew; Jones, Ian; Sinnathamby, Mathuranthakan; Desai, Jayesh; Tie, Jeanne; Bae, Susie; Christie, Michael; Gibbs, Peter; Tran, Ben

    2016-02-01

    In Stage II colon cancer, multiple independent studies have shown that a dense intratumoural immune infiltrate (local inflammation) is associated with improved outcomes, while systemic inflammation, measured by various markers, has been associated with poorer outcomes. However, previous studies have not considered the interaction between local and systemic inflammation, nor have they assessed the type of inflammatory response compared with standard clinicopathologic criteria. In order to evaluate the potential clinical utility of inflammatory markers in Stage II colon cancer, we examined local and systemic inflammation in a consecutive series of patients with resected Stage II colon cancer between 2000 and 2010 who were identified from a prospective clinical database. Increased intratumoural chronic inflammatory cell (CIC) density, as assessed by pathologist review of hematoxylin and eosin stained slides, was used to represent local inflammation. Neutrophil-to-lymphocyte ratio (NLR) >5, as calculated from pre-operative full blood counts, was used to represent systemic inflammation. In 396 eligible patients identified, there was a non-significant inverse relationship between local and systemic inflammation. Increased CIC density was significantly associated with improved overall (HR 0.45, p = 0.001) and recurrence-free survival (HR 0.37, p = 0.003). High NLR was significantly associated with poorer overall survival (HR 2.56, p < 0.001). The combination of these markers further stratified prognosis independent of standard high-risk criteria, with a dominant systemic inflammatory response (low CIC/high NLR) associated with the worst outcome (5-year overall survival 55.8%). With further validation this simple, inexpensive combined inflammatory biomarker might assist in patient selection for adjuvant chemotherapy in Stage II colon cancer.

  4. Randomized controlled trials of the efficacy of lung cancer screening by sputum cytology revisited: a combined mortality analysis from the Johns Hopkins Lung Project and the Memorial Sloan-Kettering Lung Study

    PubMed Central

    Doria-Rose, V. Paul; Marcus, Pamela M.; Szabo, Eva; Tockman, Melvyn S.; Melamed, Myron R.; Prorok, Philip C.

    2009-01-01

    Background Two randomized controlled trials of lung cancer screening initiated in the 1970's, the Johns Hopkins Lung Project and the Memorial Sloan-Kettering Lung Study, compared one arm which received annual chest x-ray and four-monthly sputum cytology (dual-screen) to a second arm which received annual chest x-ray only. Previous publications from these trials reported similar lung cancer mortality between the two groups. However, these findings were based on incomplete follow-up, and each trial on its own was underpowered to detect a modest mortality benefit. Methods We estimated the efficacy of lung cancer screening with sputum cytology in an intention-to-screen analysis of lung cancer mortality, using combined data from these trials (n=20,426). Results Over one-half of squamous cell lung cancers diagnosed in the dual-screen group were identified by cytology; these cancers tended to be more localized than squamous cancers diagnosed in the x-ray only arm. After nine years of follow-up, lung cancer mortality was slightly lower in the dual-screen than in the x-ray only arm (rate ratio (RR) 0.88, 95% confidence interval (CI) 0.74-1.05). Reductions were seen for squamous cell cancer deaths (RR 0.79, 95% CI 0.54-1.14) and in the heaviest smokers (RR 0.81, 95% CI 0.67-1.00). There were also fewer deaths from large cell carcinoma in the dual-screen group, though the reason for this is unclear. Conclusions These data are suggestive of a modest benefit of sputum cytology screening, though we cannot rule out chance as an explanation for these findings. PMID:19637354

  5. Predicting the Toxicity of Adjuvant Breast Cancer Drug Combination Therapy

    DTIC Science & Technology

    2012-09-01

    TITLE: Predicting the Toxicity of Adjuvant Breast Cancer Drug Combination Therapy PRINCIPAL INVESTIGATOR: Susan F Hudachek, MS, PhD...toxicity of adjuvant breast cancer drug combination therapy 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-09-1-0457 5c. PROGRAM ELEMENT NUMBER 6...breast cancer. However, co-administration of drugs , particularly agents that are substrates for or inhibitors of p-glycoprotein, can result in

  6. Proteomic analysis of changes in the protein composition of MCF-7 human breast cancer cells induced by all-trans retinoic acid, 9-cis retinoic acid, and their combination.

    PubMed

    Flodrova, D; Benkovska, D; Macejova, D; Bialesova, L; Hunakova, L; Brtko, J; Bobalova, J

    2015-01-05

    Retinoic acid (all-trans and 9-cis) isomers represent important therapeutic agents for many types of cancers, including human breast cancer. Changes in protein composition of the MCF-7 human breast cancer cells were induced by all-trans retinoic acid, 9-cis retinoic acid, and their combination and subsequently proteomic strategies based on bottom-up method were applied. Proposed approach was used for the analysis of proteins extracted from MCF-7 human breast cancer cell line utilizing a commercially manufactured kit RIPA and separated on two dimensional (2D) sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) after treatment with both retinoic acid isomers. We found significant differences in occurrence of proteins probably affecting the cell migration process in tumour cells. Heat shock protein 27, ribonucleoprotein SmD3, and cofilin-1 were significantly upregulated after treatment with combination of individual retinoic acid isomers. On the other hand, AP-5 complex subunit beta-1 shows the different response. Thus, the results might help to find the answer to important medical questions on (i) the identification of signaling pathways affected by retinoic acid isomers or (ii) how the observed proteomic pattern might reflect the effectiveness of retinoic acids treatment. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  7. Biodistribution and Pharmacokinetic Analysis of Combination Lonidamine and Paclitaxel Delivery in an Orthotopic Animal Model of Multi-drug Resistant Breast Cancer Using EGFR-Targeted Polymeric Nanoparticles

    PubMed Central

    Milane, Lara; Duan, Zhen-feng; Amiji, Mansoor

    2011-01-01

    The aim of this study was to assess the biodistribution and pharmacokinetics of epidermal growth factor receptor (EGFR)-targeted polymer blend nanoparticles loaded with the anticancer drugs lonidamine and paclitaxel. Plasma, tumor, and tissue distribution profiles were quantified in an orthotopic animal model of multi-drug resistant (MDR) breast cancer and were compared to treatment with non-targeted nanoparticles and to treatment with drug solution. Poly(D,L-lactide-co-glycolide)/poly(ethylene glycol)/EGFR targeting peptide (PLGA/PEG/EFGR peptide) construct was synthesized for incorporation in poly(ε-caprolactone) (PCL) particles to achieve active EGFR targeting. An isocratic HPLC method was developed to quantify lonidamine and paclitaxel in mice plasma, tumors, and vital organs. The targeted nanoparticles demonstrated superior pharmacokinetic profile relative to drug solution and non-targeted nanoparticles, particularly for lonidamine delivery. The first target site of accumulation is the liver, followed by the kidneys, and then the tumor mass; maximal tumor accumulation occurs at 3 hours post-administration. Lonidamine/paclitaxel combination therapy administered via EGFR-targeted polymer blend nanocarriers may become a viable platform for the future treatment of MDR cancer. PMID:21220050

  8. Human Lung Cancer Risks from Radon – Part II – Influence from Combined Adaptive Response and Bystander Effects – A Microdose Analysis

    PubMed Central

    Leonard, Bobby E.; Thompson, Richard E.; Beecher, Georgia C.

    2010-01-01

    In the prior Part I, the potential influence of the low level alpha radiation induced bystander effect (BE) on human lung cancer risks was examined. Recent analysis of adaptive response (AR) research results with a Microdose Model has shown that single low LET radiation induced charged particles traversals through the cell nucleus activates AR. We have here conducted an analysis based on what is presently known about adaptive response and the bystander effect (BE) and what new research is needed that can assist in the further evaluation human cancer risks from radon. We find that, at the UNSCEAR (2000) worldwide average human exposures from natural background and man-made radiations, the human lung receives about a 25% adaptive response protection against the radon alpha bystander damage. At the UNSCEAR (2000) minimum range of background exposure levels, the lung receives minimal AR protection but at higher background levels, in the high UNSCEAR (2000) range, the lung receives essentially 100% protection from both the radon alpha damage and also the endogenic, spontaneously occurring, potentially carcinogenic, lung cellular damage. PMID:22461760

  9. Survival benefit and safety of the combinations of FOLFOXIRI ± bevacizumab versus the combinations of FOLFIRI ± bevacizumab as first-line treatment for unresectable metastatic colorectal cancer: a meta-analysis

    PubMed Central

    Xu, Wei; Kuang, Meng; Gong, Yang; Cao, Chunxiang; Chen, Jinfei; Tang, Cuiju

    2016-01-01

    Background The survival of patients with metastatic colorectal cancer (mCRC) could be improved with exposure to three active drugs, irinotecan, fluorouracil/leucovorin, and oxaliplatin, irrespective of their sequence. However, only 50%–80% of patients can be exposed to all the three drugs in a sequential strategy with two-drug combinations. We carried out this systematic assessment to compare the survival benefit and safety of FOLFOXIRI (irinotecan, fluorouracil/leucovorin, and oxaliplatin) ± bevacizumab (with or without bevacizumab) versus FOLFIRI (irinotecan and fluorouracil/leucovorin) ± bevacizumab (with or without bevacizumab) as first-line treatment for unresectable mCRC. Methods PubMed and EMBASE were searched for original articles written in English and published before December 2015. A total of 1,035 patients from three randomized controlled trials were included. Results Our results demonstrated that overall survival (hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.73–0.97), progression-free survival (HR, 0.69; 95% CI, 0.59–0.81), and overall response rate (odds ratio, 1.96; 95% CI, 1.28–2.98) were significantly improved in the FOLFOXIRI ± bevacizumab arm compared to the FOLFIRI ± bevacizumab arm. Significantly higher incidences of neutropenia, anemia, diarrhea, stomatitis, and neuropathy were observed in the FOLFOXIRI ± bevacizumab arm. Conclusion Current evidence shows that the combination of FOLFOXIRI ± bevacizumab significantly improves the overall survival, progression-free survival, and overall response rate of patients with mCRC, with an increased but manageable toxicity, compared with the combinations of FOLFIRI ± bevacizumab. The combination of FOLFOXIRI ± bevacizumab should be considered as a treatment option for these patients under the premise of reasonable selection of target population. PMID:27536147

  10. Accuracy of Combined Visual Inspection with Acetic Acid and Cervical Cytology Testing as a Primary Screening Tool for Cervical Cancer: a Systematic Review and Meta-Analysis.

    PubMed

    Chanthavilay, Phetsavanh; Mayxay, Mayfong; Phongsavan, Keokedthong; Marsden, Donald E; White, Lisa J; Moore, Lynne; Reinharz, Daniel

    2015-01-01

    The performance of combined testing visual inspection with acetic acid (VIA) and cervical cytology tests might differ from one setting to another. The average estimate of the testing accuracy across studies is informative, but no meta-analysis has been carried out to assess this combined method. The objective of this study was to estimate the average sensitivity and specificity of the combined VIA and cervical cytology tests for the detection of cervical precancerous lesions. We conducted a systematic review and a meta-analysis, according to the Cochrane Handbook for Systematic Review of Diagnostic Test Accuracy. We considered two cases. In the either-positive result case, a positive result implies positivity in at least one of the tests. A negative result implies negativity in both tests. In the both-positive case, a positive result implies having both tests positive. Eligible studies were identified using Pubmed, Embase, Website of Science, CINHAL and COCRANE databases. True positive, false positive, false negative and true negative values were extracted. Estimates of sensitivity and specificity, positive and negative likelihood (LR) and diagnostic odds ratios (DOR) were pooled using a hierarchical random effect model. Hierarchical summary receiver operating characteristics (HSROC) were generated and heterogeneity was verified through covariates potentially influencing the diagnostic odds ratio. Nine studies fulfilled inclusion criteria and were included in the analysis. Pooled estimates of the sensitivities of the combined tests in either-positive and both-positive cases were 0.87 (95% CI: 0.83-0.90) and 0.38 (95% CI: 0.29-0.48), respectively. Corresponding specificities were 0.79 (95% CI: 0.63-0.89) and 0.98 (95% CI: 0.96-0.99) respectively. The DORs of the combined tests in either-positive or both-positive result cases were 27.7 (95% CI: 12.5-61.5) and 52 (95% CI: 22.1-122.2), respectively. When including only articles without partial verification bias and

  11. Combining Radiotherapy and Immunotherapy to Target Survivin in Prostate Cancer

    DTIC Science & Technology

    2009-01-01

    1-0114 TITLE: Combining radiotherapy and immunotherapy to target survivin in prostate cancer PRINCIPAL INVESTIGATOR: Dorthe Schaue...radiotherapy and immunotherapy to target survivin in prostate cancer . 5b. GRANT NUMBER PC060403 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER DORTHE...cells to examine the vaccination responses to human survivin epitopes and to other clinically relevant human prostate cancer associated antigens

  12. The microarray gene profiling analysis of glioblastoma cancer cells reveals genes affected by FAK inhibitor Y15 and combination of Y15 and temozolomide.

    PubMed

    Huang, Grace; Ho, Baotran; Conroy, Jeffrey; Liu, Song; Qiang, Hu; Golubovskaya, Vita

    2014-01-01

    Focal adhesion is known to be highly expressed and activated in glioma cells. Recently, we demonstrated that FAK autophosphorylation inhibitor, Y15 significantly decreased tumor growth of DBTRG and U87 cells, especially in combination with temozolomide. In the present report, we performed gene expression analysis in these cells to reveal genes affected by Y15, temozolomide and combination of Y15 and temozolomide. We tested the effect of Y15 on gene expression by Illumina Human HT12v4 microarray assay and detected 8087 and 6555 genes, which were significantly either up- or down-regulated by Y15-treatment in DBTRG and U87 cells, respectively (p<0.05). Moreover, DBTRG and U87 cells treated with Y15 changed expression of 1332 and 462 genes more than 1.5 fold, p<0.05, respectively and had 237 common genes affected by Y15. The common genes up-regulated by Y15 included GADD45A, HSPA6 (heat-shock 70); DUSP1, DUSP 5 (dual-phosphatase 5); CDKN1A (p21) and common down-regulated genes included kinesins, such as KIF11, 14, 20A, 20B; topoisomerase II, TOP2A; cyclin F; cell cycle protein: BUB1; PARP1, POLA1. In addition, we detected genes affected by temozolomide and by combination of Y15 and temozolomide treatment in U87 cells. Among genes up-regulated by Y15 and temozolomide more significantly than by each agent alone were: COX7B; interferon, gamma-inducible transcript: IFI16; DDIT4; GADD45G and down-regulated: KIF3A, AKT1; ABL; JAK1, GLI3 and ALDH1A3. Thus, microarray gene expression analysis can be effective in establishing genes affected in response to FAK inhibitor alone and in response to combination of Y15 with temozolomide that is important for glioblastoma therapy.

  13. A cost-benefit analysis of bevacizumab in combination with paclitaxel in the first-line treatment of patients with metastatic breast cancer.

    PubMed

    Montero, Alberto J; Avancha, Kiran; Glück, Stefan; Lopes, Gilberto

    2012-04-01

    Bevacizumab in combination with chemotherapy increases progression-free survival (PFS), but not overall survival when compared to chemotherapy alone in the treatment of metastatic breast cancer (MBC). Recently in November, 2011 the Food and drug administration revoked approval of bevacizumab in combination with paclitaxel for the treatment of MBC. The European Medicines Agency, in contrast, maintained its approval of bevacizumab in MBC. While neither agency considers health economics in their decision-making process, one of the greatest challenges in oncology practice today is to reconcile hard-won small incremental clinical benefits with exponentially rising costs. To inform policy-makers in the US, this study aimed to assess the cost-effectiveness of bevacizumab/paclitaxel in MBC, from a payer perspective. We created a decision analytical model using efficacy and adverse events data from the ECOG 2100 trial. Health utilities were derived from available literature. Costs were obtained from the Center for Medicare Services Drug Payment Table and Physician Fee Schedule and are represented in 2010 US dollars. Quality-adjusted life-years (QALY) and incremental cost-effectiveness ratio (ICER) were calculated. Sensitivity analyses were performed. Bevacizumab added 0.49 years of PFS and 0.135 QALY with an incremental cost of $100,300, and therefore a cost of $204,000 per year of PFS gained and an ICER of $745,000 per QALY. The main drivers of the model were drug acquisition cost, PFS, and health utility values. Using a threshold of $150,000/QALY, drug price would have to be reduced by nearly 80% or alternatively PFS increased by 10 months to make bevacizumab cost-effective. The results of the model were robust in sensitivity analyses. Bevacizumab plus paclitaxel is not cost-effective in treating MBC. Value-based pricing and the development of biomarkers to improve patient selection are needed to better define the role of the drug in this population.

  14. Adverse Event Profile by Folate Receptor Status for Vintafolide and Pegylated Liposomal Doxorubicin in Combination, Versus Pegylated Liposomal Doxorubicin Alone, in Platinum-Resistant Ovarian Cancer: Exploratory Analysis of the Phase II PRECEDENT Trial.

    PubMed

    Herzog, Thomas J; Kutarska, Elżbieta; Bidzińsk, Mariusz; Symanowski, Jim; Nguyen, Binh; Rangwala, Reshma A; Naumann, R Wendel

    2016-11-01

    This exploratory analysis evaluated the incidence of adverse events (AEs) by folate receptor (FR) status in the randomized, multicenter, open-label PRECEDENT study in women with platinum-resistant ovarian cancer receiving pegylated liposomal doxorubicin (PLD) ± the small-molecule drug conjugate vintafolide. Women 18 years or older with platinum-resistant ovarian cancer were randomized 2:1 to vintafolide (2.5 mg intravenously, 3 times per week, weeks 1 and 3, every 28 days) + PLD (50 mg/m intravenously, day 1, every 28 days) or PLD alone (same dose/schedule). The expression of functionally active FR was evaluated by single-photon emission computed tomography with etarfolatide. Patients were categorized according to FR positivity: patients with all target lesions positive for FR expression (FR 100%), patients with 1 or more but not all target lesions positive for FR expression (FR 10%-90%), and patients with all lesions negative for FR expression (FR 0%). Data on FR status were available for 94 patients: 38 were FR 100%, 36 were FR 10% to 90%, and 20 were FR 0%. Across all FR subgroups, the duration of treatment was longer, and the number of cycles was higher in combination-therapy arms than PLD-alone arms. Although the frequency of AEs was relatively consistent across subgroups, the FR 100% subgroup had a higher incidence of patients with at least 1 AE for combination therapy versus PLD alone. No surprising safety signals were shown according to FR status. The incidence of grade 3 or 4 treatment-emergent drug-related AEs was generally low across all FR subgroups and treatment arms. This exploratory analysis suggests that FR status does not influence the AE profile of vintafolide + PLD combination therapy or PLD alone in patients with platinum-resistant ovarian cancer. Future a priori analyses in larger populations are needed to confirm these findings.

  15. Combinations in multimodality treatments and clinical outcomes during cancer

    PubMed Central

    Zhang, Xiao-Ying; Zhang, Pei-Ying

    2016-01-01

    Combination approach could be easily considered as the future of therapeutics in all pathological states including cancer. Scientists are trying different combinations in order to determine synergism among different therapeutics which ultimately helps in the improved and more efficient management of the affected patients. Combination of multi-chemotherapeutic agents, or multi-drug therapy, may be the most commonly used strategy for cancer treatment. Monotherapy causes drug resistance and loses its response in patients after several cycles of treatment. While combining different anticancer drugs together for cancer treatment, as in the case of the cocktail therapy for HIV, not only overcomes the drug resistance but also leads to a synergistic effect, therefore showing prolonged survival for patients. The present review article is focused on different combinations in use for better efficiency of therapeutics against cancer. We searched the electronic database PubMed for pre-clinical as well as clinical controlled trials reporting diagnostic as well as therapeutic advances of various combinations in cancer. It was observed clearly that combination approach is better in various aspects including increase in efficacy, specificity and decline in the unwanted side effects. PMID:28101195

  16. Capecitabine and docetaxel combination for the treatment of breast cancer.

    PubMed

    Morishita, Mariko; Leonard, Robert C

    2008-01-01

    The management of breast cancer depends on the tumor and patient's characteristics. Anthracycline-based regimens have been proven to decrease the risk of relapse and prolong survival time in breast cancer. Taxanes have been incorporated not only into metastatic breast cancer but also into adjuvant regimens. Capecitabine, an oral fluoropyrimidine carbamate, has good single-agent activity and, together with docetaxel, demonstrated preclinical synergy and a survival benefit in metastatic breast cancer. Recent analyses show that capecitabine/docetaxel dosing flexibility for managing side effects does not compromise efficacy, and define this combination regimen as an important treatment option for its efficacy, tolerability and cost-effectiveness.

  17. Safety profile of combined therapy inhibiting EFGR and VEGF pathways in patients with advanced non-small-cell lung cancer: A meta-analysis of 15 phase II/III randomized trials.

    PubMed

    Ma, Wang; Xu, Mingxin; Liu, Yiqian; Liu, Hao; Huang, Jiale; Zhu, Yanjie; Ji, Li-Juan; Qi, Xiaolong

    2015-07-15

    The efficacy of combined vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) inhibition in patients with advanced non-small-cell lung cancer (NSCLC) was well studied. However, few studies focused on the risk and adverse events (AEs) of combined targeted therapy. The aim of this meta-analysis was to evaluate the safety profile of combined targeted therapy against EFGR and VEGF in patients with advanced NSCLC. A comprehensive literature search in MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), ASCO Abstracts and ESMO Abstracts was conducted. Eligible studies were randomized clinical trials (RCTs) that compared safety profile of combined therapy inhibiting EFGR and VEGF pathways with control groups (placebo, single EGFR or VEGF inhibition therapy, chemotherapy or a combination of them) in patients with advanced NSCLC. The endpoints included treatment discontinuation, treatment-related deaths and AEs. The search identified 15 RCTs involving 6,919 patients. The outcomes showed that three of four pairwise comparisons detected more discontinuation due to AEs in combined targeted therapy, with odds ratio (OR) compared with the control groups ranged from 1.97 to 2.29. Treatment with combined inhibition therapy was associated with several all-grade and grade 3 or 4 AEs (e.g. rash, diarrhea and hypertension). Also, there was a significantly higher incidence of treatment-related deaths in combined inhibition using vandetanib versus single EGFR inhibition therapy (OR = 1.97, 95% CI 1.19-3.28). In conclusion, combined inhibition therapy against EGFR and VEGF in patients with advanced NSCLC was associated with increased toxicity. Increased AEs hinder patient compliance and reduce their quality of life, leading to dose reduction or discontinuation. © 2014 UICC.

  18. Opportunities and challenges in combination gene cancer therapy.

    PubMed

    Nastiuk, Kent L; Krolewski, John J

    2016-03-01

    Treatment for solid tumor malignancies, which constitute the majority of human cancers, is still dominated by surgery and radiotherapies. This is especially true for many localized solid tumors, which are often curable with these treatments. However, metastatic cancers are beyond the reach of these therapies, and many localized cancers that are initially treated with surgery and radiation will recur and metastasize. Thus, for over 60years there has been a concerted effort to develop effective drug treatments for metastatic cancers. Combination therapies are an increasingly important part of the anti-cancer drug armamentarium. In the case of cytotoxic chemotherapy, multi-drug regimens rapidly became the norm, as the earliest single agents were relatively ineffective. In contrast to chemotherapy, where combination therapies were required in order to achieve treatment efficacy, for both hormonal and targeted therapies the impetus to move toward the use of combination therapies is to prevent or reverse the development of treatment resistance. In addition, emerging evidence suggests that combination therapy may also improve cancer treatment by neutralizing an emerging treatment side effect termed therapy-induced metastasis, which accompanies some effective single agent therapies. Finally, although gene therapy is still far from use in the clinic, we propose that combination therapies may enhance its effectiveness. Copyright © 2015 Elsevier B.V. All rights reserved.

  19. Nanoparticle Based Combination Treatments for Targeting Multiple Hallmarks of Cancer.

    PubMed

    VanDyke, D; Kyriacopulos, P; Yassini, B; Wright, A; Burkhart, E; Jacek, S; Pratt, M; Peterson, C R; Rai, P

    Treatment of cancer remains one of the most challenging tasks facing the healthcare system. Cancer affects the lives of millions of people and is often fatal. Current treatment methods include surgery, chemotherapy, radiation therapies or some combinations of these. However, recurrence is a major problem. These treatments can be invasive with severe side effects. Inefficacies in treatments are a result of the complex and variable biology of cancerous cells. Malignant tumor cells and normal functioning cells share many of the same biological characteristics but the main difference is that in cancer cells there is in an overuse and over expression of these biological characteristics. These pertinent characteristics can be grouped into eight hallmarks, as illustrated by Hanahan and Weinberg. These characteristics include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, reprogramming energy metabolism, and evading immune destruction. In order to provide a noninvasive, effective treatment, delivery methods must be explored in order to transport cytotoxic agents used for targeting the hallmarks of cancer in a safer and more effective fashion. The use of nanoparticles as drug delivery carriers provides an effective method in which multiple cytotoxic agents can be safely delivered to cancer tissue to simultaneously target multiple hallmarks. By targeting multiple hallmarks of cancer at once, the efficacy of cancer treatments could be improved drastically. This review explores the uses and efficacy of combination therapies using nanoparticles that can simultaneously target multiple hallmarks of cancer.

  20. Nanoparticle Based Combination Treatments for Targeting Multiple Hallmarks of Cancer

    PubMed Central

    VanDyke, D; Kyriacopulos, P; Yassini, B; Wright, A; Burkhart, E; Jacek, S; Pratt, M; Peterson, CR; Rai, P

    2016-01-01

    Treatment of cancer remains one of the most challenging tasks facing the healthcare system. Cancer affects the lives of millions of people and is often fatal. Current treatment methods include surgery, chemotherapy, radiation therapies or some combinations of these. However, recurrence is a major problem. These treatments can be invasive with severe side effects. Inefficacies in treatments are a result of the complex and variable biology of cancerous cells. Malignant tumor cells and normal functioning cells share many of the same biological characteristics but the main difference is that in cancer cells there is in an overuse and over expression of these biological characteristics. These pertinent characteristics can be grouped into eight hallmarks, as illustrated by Hanahan and Weinberg. These characteristics include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, reprogramming energy metabolism, and evading immune destruction. In order to provide a noninvasive, effective treatment, delivery methods must be explored in order to transport cytotoxic agents used for targeting the hallmarks of cancer in a safer and more effective fashion. The use of nanoparticles as drug delivery carriers provides an effective method in which multiple cytotoxic agents can be safely delivered to cancer tissue to simultaneously target multiple hallmarks. By targeting multiple hallmarks of cancer at once, the efficacy of cancer treatments could be improved drastically. This review explores the uses and efficacy of combination therapies using nanoparticles that can simultaneously target multiple hallmarks of cancer. PMID:27547592

  1. Three-dimensional ovarian cancer models: imaging and therapeutic combinations

    NASA Astrophysics Data System (ADS)

    Celli, Jonathan P.; Rizvi, Imran; Evans, Conor L.; Abu-Yousif, Adnan; Hasan, Tayyaba

    2010-02-01

    We introduce a new platform to study treatment response in adherent micrometastatic ovarian cancer, combining an in vitro 3D model, with custom quantitative analysis routines to report growth and cytotoxic response in large sets of image data. OVCAR-5 human ovarian cancer cells were grown on a bed of Growth Factor Reduced MatrigelTM (GFR MatrigelTM). Using batch analysis routines to analyze longitudinal image data we show that in vitro tumor growth leads to a reproducible log-normal size distribution with two well-defined peaks. These distinct growth modes correspond to a population with approximately constant diameter of 20μm over the time probed, while the other peak corresponds to a more rapidly assembling sub-distribution of micronodules which shifts towards larger peak center positions with mean equivalent diameters of 92μm, 120μm and 150μm at days 7, 10 and 17 following plating. At day 10, 3D and monolayer cultures were treated with a regimen of either carboplatin or photodynamic therapy. Using a quantitative fluorescence imaging approach we report dose response curves and demonstrate that 3D nodules are significantly less sensitive to treatment than the same cells grown in monolayer. 3D cultures subject to 5J/cm2 PDT (250nM BPD-MA) exhibited a mean viability of 80% (95% CI = 73% to 82%) relative to no treatment control. 3D cultures subject to carboplatin treatment at 100μM concentration exhibited a mean viability of 92% (95% CI =86% to 97%). A combination treatment of 5J/cm2 PDT followed by 100μM carboplatin yielded an enhanced cytotoxic effect with mean viability of 46%, 95% confidence interval (CI) = (35 % to 46%).

  2. Drug combination may be highly effective in recurrent ovarian cancer

    Cancer.gov

    Significant improvement with the use of a combination drug therapy for recurrent ovarian cancer was reported at the annual meeting of the American Society of Clinical Oncology meeting in Chicago. The trial compared the activity of a combination of the dru

  3. Combining HDAC inhibitors with oncolytic virotherapy for cancer therapy.

    PubMed

    Nakashima, Hiroshi; Nguyen, Tran; Chiocca, Ennio Antonio

    2015-01-01

    Histone deacetylase (HDAC) enzymes play a critical role in the epigenetic regulation of cellular functions and signaling pathways in many cancers. HDAC inhibitors (HDACi) have been validated for single use or in combination with other drugs in oncologic therapeutics. An even more novel combination therapy with HDACi is to use them with an oncolytic virus. HDACi may lead to an amplification of tumor-specific lytic effects by facilitating increased cycles of viral replication, but there may also be direct anticancer effects of the drug by itself. Here, we review the molecular mechanisms of anti-cancer effects of the combination of oncolytic viruses with HDACi.

  4. Breast cancer screening using tomosynthesis in combination with digital mammography.

    PubMed

    Friedewald, Sarah M; Rafferty, Elizabeth A; Rose, Stephen L; Durand, Melissa A; Plecha, Donna M; Greenberg, Julianne S; Hayes, Mary K; Copit, Debra S; Carlson, Kara L; Cink, Thomas M; Barke, Lora D; Greer, Linda N; Miller, Dave P; Conant, Emily F

    2014-06-25

    Mammography plays a key role in early breast cancer detection. Single-institution studies have shown that adding tomosynthesis to mammography increases cancer detection and reduces false-positive results. To determine if mammography combined with tomosynthesis is associated with better performance of breast screening programs in the United States. Retrospective analysis of screening performance metrics from 13 academic and nonacademic breast centers using mixed models adjusting for site as a random effect. Period 1: digital mammography screening examinations 1 year before tomosynthesis implementation (start dates ranged from March 2010 to October 2011 through the date of tomosynthesis implementation); period 2: digital mammography plus tomosynthesis examinations from initiation of tomosynthesis screening (March 2011 to October 2012) through December 31, 2012. Recall rate for additional imaging, cancer detection rate, and positive predictive values for recall and for biopsy. A total of 454,850 examinations (n=281,187 digital mammography; n=173,663 digital mammography + tomosynthesis) were evaluated. With digital mammography, 29,726 patients were recalled and 5056 biopsies resulted in cancer diagnosis in 1207 patients (n=815 invasive; n=392 in situ). With digital mammography + tomosynthesis, 15,541 patients were recalled and 3285 biopsies resulted in cancer diagnosis in 950 patients (n=707 invasive; n=243 in situ). Model-adjusted rates per 1000 screens were as follows: for recall rate, 107 (95% CI, 89-124) with digital mammography vs 91 (95% CI, 73-108) with digital mammography + tomosynthesis; difference, -16 (95% CI, -18 to -14; P < .001); for biopsies, 18.1 (95% CI, 15.4-20.8) with digital mammography vs 19.3 (95% CI, 16.6-22.1) with digital mammography + tomosynthesis; difference, 1.3 (95% CI, 0.4-2.1; P = .004); for cancer detection, 4.2 (95% CI, 3.8-4.7) with digital mammography vs 5.4 (95% CI, 4.9-6.0) with digital mammography + tomosynthesis

  5. Combined modality therapy for rectal cancer.

    PubMed

    Minsky, Bruce D; Röedel, Claus; Valentini, Vincenzo

    2010-01-01

    The standard adjuvant treatment for cT3 and/or N+ rectal cancer is preoperative chemoradiation. However, there are many controversies regarding this approach. These include the role of short course radiation, whether postoperative adjuvant chemotherapy necessary for all patients and whether the type of surgery after chemoradiation should be based on the response rate. More accurate imaging techniques and/or molecular markers may help identify patients with positive pelvic nodes to reduce the chance of overtreatment with preoperative therapy. Will more effective systemic agents both improve the results of radiation as well as modify the need for pelvic radiation? These questions and others remain active areas of clinical investigation.

  6. Cost-effectiveness analysis of anastrozole versus tamoxifen as primary adjuvant therapy for postmenopausal women with early breast cancer: a US healthcare system perspective. The 5-year completed treatment analysis of the ATAC ('Arimidex', Tamoxifen Alone or in Combination) trial.

    PubMed

    Locker, Gershon Y; Mansel, Robert; Cella, David; Dobrez, Deborah; Sorensen, Sonja; Gandhi, Sanjay K

    2007-12-01

    This study evaluated the cost-effectiveness of anastrozole versus generic tamoxifen for primary adjuvant treatment of postmenopausal women with hormone receptor-positive (HR+) early breast cancer (EBC), from a US healthcare perspective. A probabilistic Markov model was developed using the 5-year completed treatment analysis of the ATAC ('Arimidex', Tamoxifen Alone or in Combination) trial (ISRCTN 18233230) to project outcomes for anastrozole and tamoxifen to 25 years. Resource utilization data were obtained primarily from published literature and a physician survey (including expert opinion from ATAC Steering Committee members). Drug costs were taken from published wholesale acquisition costs (anastrozole $6.56/day, generic tamoxifen $1.33/day). Other unit costs ($US 2003-4) were from standard sources. Utility estimates of relevant health states, used to compute quality-adjusted life-years (QALYs), were collected using the standard gamble technique in a cross-sectional sample of 44 patients. Costs and benefits were discounted 3% annually. In a cohort of 1000 postmenopausal women with HR+ EBC, the model showed anastrozole treatment (versus tamoxifen) would lead to 257 QALYs gained (0.26 QALYs gained per patient), at an additional cost of $5.21 million over 25 years ($5,212 per patient). The estimated incremental cost-effectiveness ratio (ICER) of anastrozole compared with tamoxifen was $20,246 per QALY gained ($23,541 per life-year gained). Cost-effectiveness acceptability curves indicated a >90% probability that the cost per QALY gained with anastrozole would be <$50,000. Results were robust in a sensitivity analysis. Anastrozole is a cost-effective alternative to tamoxifen for the primary adjuvant treatment of postmenopausal women with HR+ EBC.

  7. Efficacy and Safety of Combined Androgen Deprivation Therapy (ADT) and Docetaxel Compared with ADT Alone for Metastatic Hormone-Naive Prostate Cancer: A Systematic Review and Meta-Analysis

    PubMed Central

    Botrel, Tobias Engel Ayer; Clark, Otávio; Lima Pompeo, Antônio Carlos; Horta Bretas, Francisco Flávio; Sadi, Marcus Vinicius; Ferreira, Ubirajara; Borges dos Reis, Rodolfo

    2016-01-01

    Objective Prostate cancer is the most common nonskin cancer and second most common cause of cancer mortality in older men in the United States (USA) and Western Europe. Androgen-deprivation therapy alone (ADT) remains the first line of treatment in most cases, for metastatic disease. We performed a systematic review and meta-analysis of all randomized controlled trials (RCT) that compared the efficacy and adverse events profile of a chemohormonal therapy (ADT ± docetaxel) for metastatic hormone-naive prostate cancer (mHNPC). Methods Several databases were searched, including MEDLINE, EMBASE, LILACS, and CENTRAL. The primary endpoint was overall survival. Data extracted from the studies were combined by using the hazard ratio (HR) or risk ratio (RR) with their corresponding 95% confidence intervals (95% CI). Results The final analysis included 3 trials comprising 2,264 patients (mHNPC). Patients who received the chemohormonal therapy had a longer clinical progression-free survival interval (HR = 0.64; 95% CI: 0.55 to 0.75; p<0.00001), and no heterogeneity (Chi2 = 0.64; df = 1 [p = 0.42]; I2 = 0%). The biochemical progression-free survival (bPFS) also was higher in patients treated with ADT plus docetaxel (HR = 0.63; 95% CI: 0.57 to 0.69; p<0.00001), also with no heterogeneity noted (Chi2 = 0.48; df = 2 [p = 0.79]; I2 = 0%). Finally, the combination of ADT with docetaxel showed a superior overall survival (OS) compared with ADT alone (HR = 0.73; 95% CI: 0.64 to 0.84; p<0.0001), with moderate heterogeneity (Chi2 = 3.84; df = 2 [p = 0.15]; I2 = 48%). A random-effects model analysis was performed, and the results remained favorable to the use of ADT plus docetaxel (HR = 0.73; 95% CI: 0.60 to 0.89; p = 0.002). In the final combined analysis of the high-volume disease patients, the use of the combination therapy also favored an increased overall survival (HR = 0.67; 95% CI: 0.54 to 0.83; p = 0.0003). Regarding adverse events and severe toxicity (grade ≥3), the group

  8. Combination of Rapamycin and Resveratrol for Treatment of Bladder Cancer.

    PubMed

    Alayev, Anya; Salamon, Rachel S; Schwartz, Naomi S; Berman, Adi Y; Wiener, Sara L; Holz, Marina K

    2017-02-01

    Loss of TSC1 function, a crucial negative regulator of mTOR signaling, is a common alteration in bladder cancer. Mutations in other members of the PI3K pathway, leading to mTOR activation, are also found in bladder cancer. This provides rationale for targeting mTOR for treatment of bladder cancer characterized by TSC1 mutations and/or mTOR activation. In this study, we asked whether combination treatment with rapamycin and resveratrol could be effective in concurrently inhibiting mTOR and PI3K signaling and inducing cell death in bladder cancer cells. In combination with rapamycin, resveratrol was able to block rapamycin-induced Akt activation, while maintaining mTOR pathway inhibition. In addition, combination treatment with rapamycin and resveratrol induced cell death specifically in TSC1(-/-) MEF cells, and not in wild-type MEFs. Similarly, resveratrol alone or in combination with rapamycin induced cell death in human bladder cancer cell lines. These data indicate that administration of resveratrol together with rapamycin may be a promising therapeutic option for treatment of bladder cancer. J. Cell. Physiol. 232: 436-446, 2017. © 2016 Wiley Periodicals, Inc.

  9. Hyperthermia in combined treatment of cancer.

    PubMed

    Wust, P; Hildebrandt, B; Sreenivasa, G; Rau, B; Gellermann, J; Riess, H; Felix, R; Schlag, P M

    2002-08-01

    Hyperthermia, the procedure of raising the temperature of tumour-loaded tissue to 40-43 degrees C, is applied as an adjunctive therapy with various established cancer treatments such as radiotherapy and chemotherapy. The potential to control power distributions in vivo has been significantly improved lately by the development of planning systems and other modelling tools. This increased understanding has led to the design of multiantenna applicators (including their transforming networks) and implementation of systems for monitoring of E-fields (eg, electro-optical sensors) and temperature (particularly, on-line magnetic resonance tomography). Several phase III trials comparing radiotherapy alone or with hyperthermia have shown a beneficial effect of hyperthermia (with existing standard equipment) in terms of local control (eg, recurrent breast cancer and malignant melanoma) and survival (eg, head and neck lymph-node metastases, glioblastoma, cervical carcinoma). Therefore, further development of existing technology and elucidation of molecular mechanisms are justified. In recent molecular and biological investigations there have been novel applications such as gene therapy or immunotherapy (vaccination) with temperature acting as an enhancer, to trigger or to switch mechanisms on and off. However, for every particular temperature-dependent interaction exploited for clinical purposes, sophisticated control of temperature, spatially as well as temporally, in deep body regions will further improve the potential.

  10. Vitamin D in combination cancer treatment

    PubMed Central

    Ma, Yingyu; Trump, Donald L.; Johnson, Candace S.

    2010-01-01

    As a steroid hormone that regulates mineral homeostasis and bone metabolism, 1α, 25-dihydroxycholecalciferol (calcitriol) also has broad spectrum anti-tumor activities as supported by numerous epidemiological and experimental studies. Calcitriol potentiates the anti-tumor activities of multiple chemotherapeutics agents including DNA-damaging agents cisplatin, carboplatin and doxorubicin; antimetabolites 5-fluorouracil, cytarabine, hydroxyurea, cytarabine and gemcitabine; and microtubule-disturbing agents paclitaxel and docetaxel. Calcitriol elicits anti-tumor effects mainly through the induction of cancer cell apoptosis, cell cycle arrest, differentiation, angiogenesis and the inhibition of cell invasiveness by a number of mechanisms. Calcitriol enhances the cytotoxic effects of gamma irradiation and certain antioxidants and naturally derived compounds. Inhibition of calcitriol metabolism by 24-hydroxylase promotes growth inhibition effect of calcitriol. Calcitriol has been used in a number of clinical trials and it is important to note that sufficient dose and exposure to calcitriol is critical to achieve anti-tumor effect. Several trials have demonstrated that safe and feasible to administer high doses of calcitriol through intermittent regimen. Further well designed clinical trials should be conducted to better understand the role of calcitriol in cancer therapy. PMID:20842231

  11. Nanoparticle-Based Combination Therapy for Cancer Treatment.

    PubMed

    Yhee, Ji Young; Son, Sejin; Lee, Hyukjin; Kim, Kwangmeyung

    2015-01-01

    In recent years, combination of different types of therapies using nanoparticles has emerged as an advanced strategy for cancer treatment. Most of all, combination of chemotherapeutic drug and siRNA in nanoformulation has shown a great potential, because siRNA-mediated specific gene silencing can compensate for the incomplete anti-cancer actions of chemotherapy. In this article, nanoparticle-based combination therapy for cancer treatment is introduced to be focused on the therapeutic chemical and siRNA combination. It is classified into 3 groups: 1) general chemotherapy combined with siRNA carrying nanoparticle, 2) co-delivery of chemical and siRNA therapeutics within a single nanoparticle, and 3) Use of multiple nanoparticles for chemical and siRNA therapeutics. The purpose of the combination and the mechanisms of anti-cancer action was described according to the categories. Examples of some recent developments of nanotechnology-based chemo- and siRNA- therapeutics combination therapy are summarized for better understanding of its practical application.

  12. 'Smart' gold nanoshells for combined cancer chemotherapy and hyperthermia.

    PubMed

    Liang, Zhongshi; Li, Xingui; Xie, Yegui; Liu, Shunying

    2014-04-01

    Nanomaterials that circulate in the body have great potential in the diagnosis and treatment of diseases. Here we report that 'smart' gold nanoshells can carry a drug payload, and that their intrinsic near-infrared (NIR) plasmon resonance enables the combination of chemotherapeutic and hyperthermia therapies. The 'smart' gold nanoshells (named DOX/A54@GNs) consist of (a) gold nanoshells (GNs) with NIR plasmon resonance, which not only act as nanoblocks but also produce local heat to allow hyperthermia; (b) an anticancer drug, doxorubicin (DOX), which was conjugated onto the nanoblocks by pH-dependent biodegradable copolymer thiol poly(ethylene glycol) derivatives via carbamate linkage; and (c) the targeting peptide A54 (AGKGTPSLETTP) to facilitate its orientation to liver cancer cells and enhance cellular uptake. The conjugated DOX was released from the DOX/A54@GNs much more rapidly in an acidic environment (pH 5.3) than in a neutral environment (pH 7.4), which is a desirable characteristic for intracellular tumor drug release. DOX-modified GNs showed pH-dependent release behavior, and the in vitro cell uptake experiment using ICP-AES and microscopy showed greater internalization of A54-modified GNs in the human liver cancer cell line BEL-7402 than of those without A54. Flow cytometry and fluoroscopy analysis were conducted to reveal the enhanced cell apoptosis caused by the A54-modified GNs under combined chemotherapeutic and hyperthermia therapies. These results imply that DOX/A54@GNs could be used as a multifunctional nanomaterial system with pH-triggered drug-releasing properties for tumor-targeted chemotherapy and hyperthermia.

  13. Combined-modality therapy for rectal cancer using irinotecan.

    PubMed

    Minsky, Bruce D

    2002-05-01

    Preoperative or postoperative pelvic radiation plus concurrent fluorouracil-based chemotherapy is standard adjuvant treatment for patients with T3 and/or N1/2 rectal cancer. Newer chemotherapeutic regimens have been developed for the treatment of patients with metastatic disease. Irinotecan (CPT-11, Camptosar)-based regimens have improved survival in patients with metastatic disease and are being actively investigated in combination with pelvic radiation therapy for patients with rectal cancer.

  14. A combination of gefitinib and FOLFOX-4 as first-line treatment in advanced colorectal cancer patients. A GISCAD multicentre phase II study including a biological analysis of EGFR overexpression, amplification and NF-kB activation

    PubMed Central

    Cascinu, S; Berardi, R; Salvagni, S; Beretta, G D; Catalano, V; Pucci, F; Sobrero, A; Tagliaferri, P; Labianca, R; Scartozzi, M; Crocicchio, F; Mari, E; Ardizzoni, A

    2007-01-01

    Interesting activity has been reported by combining chemotherapy with cetuximab. An alternative approach for blocking EGFR function has been the development of small-molecule inhibitors of tyrosine kinase domain such as gefitinib. We designed a multicentre phase II study in advanced colorectal cancer combining gefitinib+FOLFOX in order to determine the activity and to relate EGFR expression and gene amplification and NF-kB activation to therapeutic results. Patients received FOLFOX-4 regimen plus gefitinib as first-line treatment. Tumour samples were analysed for EGFR protein expression by immunohistochemical analysis and for EGFR gene amplification by fluorescence in situ hybridisation (FISH), chromogenic in situ hybridisation (CISH) and NF-kB activation. Forty-three patients were enrolled into this study; 15 patients experienced a partial response (response rate=34.9%), whereas other 12 (27.9%) had a stable disease. Median progression-free survival (PFS) was 7.8 months and median overall survival (OS) was 13.9 months. We did not find any relationship with EGFR overexpression, gene amplification, while NF-kB activation was associated with a resistance to therapy. Gefitinib does not seem to increase the activity of FOLFOX in advanced colorectal cancer even in patients overexpressing EGFR or with EGFR amplification. Furthermore, while NF-kB activation seems to predict resistance to chemotherapy as demonstrated ‘in vitro' models, gefitinib does not overcome this mechanism of resistance, as reported for cetuximab. PMID:18059397

  15. Pancreatic cancer: systemic combination therapies for a heterogeneous disease.

    PubMed

    Melisi, Davide; Calvetti, Lorenzo; Frizziero, Melissa; Tortora, Giampaolo

    2014-01-01

    Pancreatic cancer is the only human malignancy for which patients' survival has not improved substantially during the past 30 years. Despite advances in the comprehension of the molecular mechanisms underlying pancreatic carcinogenesis, current systemic treatments offer only a modest benefit in tumor-related symptoms and survival. Over the past decades, gemcitabine and its combination with other standard cytotoxic agents have been the reference treatments for advanced pancreatic cancer patients. The recent introduction of the three-drug combination regimen FOLFIRINOX or the new taxane nab-paclitaxel represent key advances for a better control of the disease. Novel agents targeting molecular mechanisms involved in cancer development and maintenance are currently under clinical investigation. This review describes the most important findings in the field of systemic combination therapies for the treatment of pancreatic cancer. We discuss the emerging evidences for the clinical activity of combination treatments with standard chemotherapy plus novel agents targeting tumor cell-autonomous and tumor microenvironment signaling pathways. We present some of the most important advances in the comprehension of the molecular mechanisms responsible for the chemoresistance of pancreatic cancer and the emerging therapeutic targets to overcome this resistance.

  16. Comparative effectiveness of combined therapy inhibiting EGFR and VEGF pathways in patients with advanced non-small-cell lung cancer: a meta-analysis of 16 phase II/III randomized trials

    PubMed Central

    Cai, Shangli; Wu, Tongwei; Yan, Guangyue; Cheng, Sijin; Cui, Kang; Xi, Ying; Qi, Xiaolong; Zhang, Jie; Ma, Wang

    2017-01-01

    Background & Aims Combined therapy inhibiting EGFR and VEGF pathways is becoming a promising therapy in the treatment of advanced non-small-cell lung cancer (NSCLC), however, with controversy. The study aims to compare the efficacy of combined inhibition therapy versus control therapy (including placebo, single EGFR inhibition and single VEGF inhibition) in patients with advanced NSCLC. Materials and Methods An adequate literature search in EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), American Society of Clinical Oncology (ASCO) and European Society of Medical Oncology (ESMO) was conducted. Phase II or III randomized controlled trials (RCTs) that compared effectiveness between combined inhibition therapy and control therapy in patients with advanced NSCLC were eligible. The endpoint was overall response rate (ORR), progression free survival (PFS) and overall survival (OS). Results Sixteen phase II or III RCTs involving a total of 7,109 patients were included. The results indicated that the combined inhibition therapy significantly increased the ORR (OR = 1.59, 95% CI = 1.36-1.87, p<0.00001; I2 = 36%) when compared to control therapy. In the subgroup analysis, the combined inhibition therapy clearly increased the ORR (OR = 2.04, 95% CI = 1.60-2.60, p<0.00001; I2 = 0%) and improved the PFS (HR = 0.78, 95% CI = 0.71-0.85, p<0.00001;I2 = 0%) when compared with the placebo, and similar results was detected when compared with the single EGFR inhibition in terms of ORR (OR = 1.39, 95% CI = 1.12-1.74, p = 0.003; I2 = 30%) and PFS (HR = 0.73, 95% CI = 0.67-0.81, p<0.0001; I2 = 50%). No obvious difference was found between the combined inhibition therapy and single VEGF inhibition in term of ORR, however, combined inhibition therapy significantly decreased the PFS when compared to the single VEGF inhibition therapy (HR = 1.70, 95% CI = 1.34-2.17, p<0.0001; I2 = 50%). Besides, no significant difference was observed between the combined inhibition therapy

  17. Hybrid nanoparticles for combination therapy of cancer

    PubMed Central

    He, Chunbai; Lu, Jianqin; Lin, Wenbin

    2015-01-01

    Nanoparticle anticancer drug delivery enhances therapeutic efficacies and reduces side effects by improving pharmacokinetics and biodistributions of the drug payloads in animal models. Despite promising preclinical efficacy results, monotherapy nanomedicines have failed to produce enhanced response rates over conventional chemotherapy in human clinical trials. The discrepancy between preclinical data and clinical outcomes is believed to result from the less pronounced enhanced permeability and retention (EPR) effect in and the heterogeneity of human tumors as well as the intrinsic/acquired drug resistance to monotherapy over the treatment course. To address these issues, recent efforts have been devoted to developing nanocarriers that can efficiently deliver multiple therapeutics with controlled release properties and increased tumor deposition. In ideal scenarios, the drug or therapeutic modality combinations have different mechanisms of action to afford synergistic effects. In this review, we summarize recent progress in designing hybrid nanoparticles for the co-delivery of combination therapies, including multiple chemotherapeutics, chemotherapeutics and biologics, chemotherapeutics and photodynamic therapy, and chemotherapeutics and radiotherapy. The in vitro and in vivo anticancer effects are also discussed. PMID:26387745

  18. Hybrid nanoparticles for combination therapy of cancer.

    PubMed

    He, Chunbai; Lu, Jianqin; Lin, Wenbin

    2015-12-10

    Nanoparticle anticancer drug delivery enhances therapeutic efficacies and reduces side effects by improving pharmacokinetics and biodistributions of the drug payloads in animal models. Despite promising preclinical efficacy results, monotherapy nanomedicines have failed to produce enhanced response rates over conventional chemotherapy in human clinical trials. The discrepancy between preclinical data and clinical outcomes is believed to result from the less pronounced enhanced permeability and retention (EPR) effect in and the heterogeneity of human tumors as well as the intrinsic/acquired drug resistance to monotherapy over the treatment course. To address these issues, recent efforts have been devoted to developing nanocarriers that can efficiently deliver multiple therapeutics with controlled release properties and increased tumor deposition. In ideal scenarios, the drug or therapeutic modality combinations have different mechanisms of action to afford synergistic effects. In this review, we summarize recent progress in designing hybrid nanoparticles for the co-delivery of combination therapies, including multiple chemotherapeutics, chemotherapeutics and biologics, chemotherapeutics and photodynamic therapy, and chemotherapeutics and radiotherapy. The in vitro and in vivo anticancer effects are also discussed. Copyright © 2015 Elsevier B.V. All rights reserved.

  19. Erlotinib therapy after initial platinum doublet therapy in patients with EGFR wild type non-small cell lung cancer: results of a combined patient-level analysis of the NCIC CTG BR.21 and SATURN trials

    PubMed Central

    Cappuzzo, Federico; Ciuleanu, Tudor; Leon, Larry; Klughammer, Barbara

    2015-01-01

    Background The clinical benefit of erlotinib in treating epidermal growth factor receptor (EGFR) wildtype non-small cell lung cancer (NSCLC) has been questioned. We examined the impact of erlotinib in confirmed EGFR wildtype patients in two placebo-controlled phase III trials: the National Cancer Institute of Canada Clinical Trials Group BR.21 (BR.21) and Sequential Tarceva in Unresectable Non-Small Cell Lung Cancer (SATURN) trials. Methods Combined re-analysis of progression-free survival (PFS) and overall survival (OS) in patients with known wildtype EGFR, estimated by Kaplan-Meier curves and compared by two-sided log-rank test. Cox proportional hazards model was used to estimate hazard ratios (HR) adjusted for potential confounders. Additional analyses assessed comparability of patients with known and unknown EGFR mutation status to determine generalizability of the two study populations. Results Mutation status was known in 25% (n=184 of 731) of the BR.21, and 49% (n=437 of 889) of the SATURN populations, of which 82% (n=150) and 89% (n=388) respectively had wildtype EGFR. HR for PFS was 0.71 (95% CI, 0.59-0.85; P<0.01) and for OS was 0.72 (95% CI, 0.59-0.88; P<0.01). Baseline characteristics and outcome (PFS and OS) distributions were similar for patients with known and unknown EGFR status, suggesting generalizability of the EGFR wildtype data. Erlotinib benefit was sustained in all clinical subsets. Conclusions Erlotinib provided a consistent and significant improvement in survival for patients with EGFR wildtype NSCLC in both studies, individually and in combination. The benefit of erlotinib does not appear to be limited to patients with activating mutations of EGFR. PMID:26380188

  20. Erlotinib therapy after initial platinum doublet therapy in patients with EGFR wild type non-small cell lung cancer: results of a combined patient-level analysis of the NCIC CTG BR.21 and SATURN trials.

    PubMed

    Osarogiagbon, Raymond U; Cappuzzo, Federico; Ciuleanu, Tudor; Leon, Larry; Klughammer, Barbara

    2015-08-01

    The clinical benefit of erlotinib in treating epidermal growth factor receptor (EGFR) wildtype non-small cell lung cancer (NSCLC) has been questioned. We examined the impact of erlotinib in confirmed EGFR wildtype patients in two placebo-controlled phase III trials: the National Cancer Institute of Canada Clinical Trials Group BR.21 (BR.21) and Sequential Tarceva in Unresectable Non-Small Cell Lung Cancer (SATURN) trials. Combined re-analysis of progression-free survival (PFS) and overall survival (OS) in patients with known wildtype EGFR, estimated by Kaplan-Meier curves and compared by two-sided log-rank test. Cox proportional hazards model was used to estimate hazard ratios (HR) adjusted for potential confounders. Additional analyses assessed comparability of patients with known and unknown EGFR mutation status to determine generalizability of the two study populations. Mutation status was known in 25% (n=184 of 731) of the BR.21, and 49% (n=437 of 889) of the SATURN populations, of which 82% (n=150) and 89% (n=388) respectively had wildtype EGFR. HR for PFS was 0.71 (95% CI, 0.59-0.85; P<0.01) and for OS was 0.72 (95% CI, 0.59-0.88; P<0.01). Baseline characteristics and outcome (PFS and OS) distributions were similar for patients with known and unknown EGFR status, suggesting generalizability of the EGFR wildtype data. Erlotinib benefit was sustained in all clinical subsets. Erlotinib provided a consistent and significant improvement in survival for patients with EGFR wildtype NSCLC in both studies, individually and in combination. The benefit of erlotinib does not appear to be limited to patients with activating mutations of EGFR.

  1. Astragalus-containing Chinese herbal combinations for advanced non-small-cell lung cancer: a meta-analysis of 65 clinical trials enrolling 4751 patients

    PubMed Central

    Dugoua, Jean Jacques; Wu, Ping; Seely, Dugald; Eyawo, Oghenowede; Mills, Edward

    2010-01-01

    Background Non-small-cell lung cancer (NSCLC) is a leading cause of death. Interventions to reduce mortality in patients with NSCLC represent a patient-important field of research. Little is known about interventions used outside the Western world for NSCLC. One intervention widely used in Asia is astragalus-based herbal preparations. Methods We conducted a comprehensive systematic review of all published randomized clinical trials (RCTs) evaluating astragalus-based herbal preparations in NSCLC patients. We searched independently, in duplicate, 6 English language electronic databases and 2 Chinese-language databases. We abstracted data independently, in duplicate on studies reporting of methods, survival outcomes, tumor responses, and performance score responses. We applied a random-effects meta-analysis and report outcomes as relative risks (RR) with 95% confidence intervals (CIs). Results We included 65 RCTs enrolling 4751 patients. All trials included the herbal preparations plus platinum-based chemotherapy versus chemotherapy alone. We pooled 7 studies (n = 529) reporting on survival at 6 months and found a pooled RR of 0.54 (95% CI, 0.45 to 0.65, P ≤ 0.0001). We included 20 trials (n = 1520) on survival at 12 months and found a pooled RR of 0.65 (95% CI, 0.54 to 0.79, P ≤ 0.0001). This effect was consistent at 24 and 36 months. When we applied a composite endpoint of any tumor treatment response, we pooled data from 57 trials and found a pooled RR of 1.35 in favor of herbal treatment (95% CI, 1.26 to 1.44, P ≤ 0.0001). Statistical heterogeneity was low across trials. Limitations The quality of reporting the RCTs was generally poor. There is also reason to believe that studies reported as randomized may not be. Conclusions We found a large treatment effect of adding astragalus-based herbal treatment to standard chemotherapy regimens. There is a pressing need for validation of these findings in well-conducted RCTs in a Western setting. PMID:28210109

  2. Thermal dosimetry analysis combined with patient-specific thermal modeling of clinical interstitial ultrasound hyperthermia integrated within HDR brachytherapy for treatment of locally advanced prostate cancer

    NASA Astrophysics Data System (ADS)

    Salgaonkar, Vasant A.; Wootton, Jeff; Prakash, Punit; Scott, Serena; Hsu, I. C.; Diederich, Chris J.

    2017-03-01

    This study presents thermal dosimetry analysis from clinical treatments where ultrasound hyperthermia (HT) was administered following high-dose rate (HDR) brachytherapy treatment for locally advanced prostate cancer as part of a clinical pilot study. HT was administered using ultrasound applicators from within multiple 13-g brachytherapy catheters implanted along the posterior periphery of the prostate. The heating applicators were linear arrays of sectored tubular transducers (˜7 MHz), with independently powered array elements enabling energy deposition with 3D spatial control. Typical heat treatments employed time-averaged peak acoustic intensities of 1 - 3 W/cm2 and lasted for 60 - 70 minutes. Throughout the treatments, temperatures at multiple points were monitored using multi-junction thermocouples, placed within available brachytherapy catheters throughout mid-gland prostate and identified as the hyperthermia target volume (HTV). Clinical constraints allowed placement of 8 - 12 thermocouple sensors in the HTV and patient-specific 3D thermal modeling based on finite element methods (FEM) was used to supplement limited thermometry. Patient anatomy, heating device positions, orientations, and thermometry junction locations were obtained from patient CT scans and HDR and hyperthermia planning software. The numerical models utilized the applied power levels recorded during the treatments. Tissue properties such as perfusion and acoustic absorption were varied within physiological ranges such that squared-errors between measured and simulated temperatures were minimized. This data-fitting was utilized for 6 HT treatments to estimate volumetric temperature distributions achieved in the HTV and surrounding anatomy devoid of thermocouples. For these treatments, the measured and simulated T50 values in the hyperthermia target volume (HTV) were between 40.1 - 43.9 °C and 40.3 - 44.9 °C, respectively. Maximum temperatures between 46.8 - 49.8 °C were measured during

  3. Epigenetic therapy in gastrointestinal cancer: the right combination

    PubMed Central

    Abdelfatah, Eihab; Kerner, Zachary; Nanda, Nainika; Ahuja, Nita

    2016-01-01

    Epigenetics is a relatively recent field of molecular biology that has arisen over the past 25 years. Cancer is now understood to be a disease of widespread epigenetic dysregulation that interacts extensively with underlying genetic mutations. The development of drugs targeting these processes has rapidly progressed; with several drugs already FDA approved as first-line therapy in hematological malignancies. Gastrointestinal (GI) cancers possess high degrees of epigenetic dysregulation, exemplified by subtypes such as CpG island methylator phenotype (CIMP), and the potential benefit of epigenetic therapy in these cancers is evident. The application of epigenetic drugs in solid tumors, including GI cancers, is just emerging, with increased understanding of the cancer epigenome. In this review, we provide a brief overview of cancer epigenetics and the epigenetic targets of therapy including deoxyribonucleic acid (DNA) methylation, histone modifications, and chromatin remodeling. We discuss the epigenetic drugs currently in use, with a focus on DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors, and explain the pharmacokinetic and mechanistic challenges in their application. We present the strategies employed in incorporating these drugs into the treatment of GI cancers, and explain the concept of the cancer stem cell in epigenetic reprogramming and reversal of chemo resistance. We discuss the most promising combination strategies in GI cancers including: (1) epigenetic sensitization to radiotherapy, (2) epigenetic sensitization to cytotoxic chemotherapy, and (3) epigenetic immune modulation and priming for immune therapy. Finally, we present preclinical and clinical trial data employing these strategies thus far in various GI cancers including colorectal, esophageal, gastric, and pancreatic cancer. PMID:27366224

  4. Combined Label-Free Quantitative Proteomics and microRNA Expression Analysis of Breast Cancer Unravel Molecular Differences with Clinical Implications.

    PubMed

    Gámez-Pozo, Angelo; Berges-Soria, Julia; Arevalillo, Jorge M; Nanni, Paolo; López-Vacas, Rocío; Navarro, Hilario; Grossmann, Jonas; Castaneda, Carlos A; Main, Paloma; Díaz-Almirón, Mariana; Espinosa, Enrique; Ciruelos, Eva; Fresno Vara, Juan Ángel

    2015-06-01

    Better knowledge of the biology of breast cancer has allowed the use of new targeted therapies, leading to improved outcome. High-throughput technologies allow deepening into the molecular architecture of breast cancer, integrating different levels of information, which is important if it helps in making clinical decisions. microRNA (miRNA) and protein expression profiles were obtained from 71 estrogen receptor-positive (ER(+)) and 25 triple-negative breast cancer (TNBC) samples. RNA and proteins obtained from formalin-fixed, paraffin-embedded tumors were analyzed by RT-qPCR and LC/MS-MS, respectively. We applied probabilistic graphical models representing complex biologic systems as networks, confirming that ER(+) and TNBC subtypes are distinct biologic entities. The integration of miRNA and protein expression data unravels molecular processes that can be related to differences in the genesis and clinical evolution of these types of breast cancer. Our results confirm that TNBC has a unique metabolic profile that may be exploited for therapeutic intervention.

  5. Optimization of combined electron and photon beams for breast cancer

    NASA Astrophysics Data System (ADS)

    Xiong, W.; Li, J.; Chen, L.; Price, R. A.; Freedman, G.; Ding, M.; Qin, L.; Yang, J.; Ma, C.-M.

    2004-05-01

    Recently, intensity-modulated radiation therapy and modulated electron radiotherapy have gathered a growing interest for the treatment of breast and head and neck tumours. In this work, we carried out a study to combine electron and photon beams to achieve differential dose distributions for multiple target volumes simultaneously. A Monte Carlo based treatment planning system was investigated, which consists of a set of software tools to perform accurate dose calculation, treatment optimization, leaf sequencing and plan analysis. We compared breast treatment plans generated using this home-grown optimization and dose calculation software for different treatment techniques. Five different planning techniques have been developed for this study based on a standard photon beam whole breast treatment and an electron beam tumour bed cone down. Technique 1 includes two 6 MV tangential wedged photon beams followed by an anterior boost electron field. Technique 2 includes two 6 MV tangential intensity-modulated photon beams and the same boost electron field. Technique 3 optimizes two intensity-modulated photon beams based on a boost electron field. Technique 4 optimizes two intensity-modulated photon beams and the weight of the boost electron field. Technique 5 combines two intensity-modulated photon beams with an intensity-modulated electron field. Our results show that technique 2 can reduce hot spots both in the breast and the tumour bed compared to technique 1 (dose inhomogeneity is reduced from 34% to 28% for the target). Techniques 3, 4 and 5 can deliver a more homogeneous dose distribution to the target (with dose inhomogeneities for the target of 22%, 20% and 9%, respectively). In many cases techniques 3, 4 and 5 can reduce the dose to the lung and heart. It is concluded that combined photon and electron beam therapy may be advantageous for treating breast cancer compared to conventional treatment techniques using tangential wedged photon beams followed by a boost

  6. Combined Impact of Lifestyle Factors on Cancer Mortality in Men

    PubMed Central

    Lee, Chong-Do; Sui, EdD Xuemei; Hooker, Steven P.; Hébert, James R.; Blair, Steven N.

    2011-01-01

    PURPOSE The impact of lifestyle factors on cancer mortality in the U.S. population has not been thoroughly explored. We examined the combined effects of cardiorespiratory fitness, never smoking, and normal waist girth on total cancer mortality in men. METHODS We followed a total of 24,731 men ages 20–82 years who participated in the Aerobics Center Longitudinal Study. A low-risk profile was defined as never smoking, moderate or high fitness, and normal waist girth, and they were further categorized as having 0, 1, 2, or 3 combined low-risk factors. RESULTS During an average of 14.5 years of follow-up, there were a total of 384 cancer deaths. After adjustment for age, examination year, and multiple risk factors, men who were physically fit, never smoked, and had a normal waist girth had a 62% lower risk of total cancer mortality (95% confidence interval [CI], 45%-73%) compared with men with zero low-risk factors. Men with all 3 low-risk factors had a 12-year (95% CI: 8.6–14.6) longer life expectancy compared with men with 0 low-risk factors. Approximately 37% (95% CI, 17%-52%) of total cancer deaths might have been avoided if the men had maintained all three low-risk factors. CONCLUSIONS Being physically fit, never smoking, and maintaining a normal waist girth is associated with lower risk of total cancer mortality in men. PMID:21683616

  7. Combined therapeutic potential of nuclear receptors with receptor tyrosine kinase inhibitors in lung cancer

    SciTech Connect

    Wairagu, Peninah M.; Park, Kwang Hwa; Kim, Jihye; Choi, Jong-Whan; Kim, Hyun-Won; Yeh, Byung-Il; Jung, Soon-Hee; Yong, Suk-Joong; Jeong, Yangsik

    2014-05-09

    Highlights: • The 48 NR genes and 48 biological anti-cancer targets are profiled in paired-cells. • Growth inhibition by NR ligands or TKIs is target receptor level-dependent. • T0901317 with gefitinib/PHA665752 shows additive growth inhibition in lung cells. - Abstract: Cancer heterogeneity is a big hurdle in achieving complete cancer treatment, which has led to the emergence of combinational therapy. In this study, we investigated the potential use of nuclear receptor (NR) ligands for combinational therapy with other anti-cancer drugs. We first profiled all 48 NRs and 48 biological anti-cancer targets in four pairs of lung cell lines, where each pair was obtained from the same patient. Two sets of cell lines were normal and the corresponding tumor cell lines while the other two sets consisted of primary versus metastatic tumor cell lines. Analysis of the expression profile revealed 11 NRs and 15 cancer targets from the two pairs of normal versus tumor cell lines, and 9 NRs and 9 cancer targets from the primary versus metastatic tumor cell lines had distinct expression patterns in each category. Finally, the evaluation of nuclear receptor ligand T0901317 for liver X receptor (LXR) demonstrated its combined therapeutic potential with tyrosine kinase inhibitors. The combined treatment of cMET inhibitor PHA665752 or EGFR inhibitor gefitinib with T0901317 showed additive growth inhibition in both H2073 and H1993 cells. Mechanistically, the combined treatment suppressed cell cycle progression by inhibiting cyclinD1 and cyclinB expression. Taken together, this study provides insight into the potential use of NR ligands in combined therapeutics with other biological anti-cancer drugs.

  8. Combining chemotherapy and targeted therapies in metastatic colorectal cancer

    PubMed Central

    Rodriguez, J; Zarate, R; Bandres, E; Viudez, A; Chopitea, A; García-Foncillas, J; Gil-Bazo, I

    2007-01-01

    Colorectal cancer remains one of the major causes of cancer death worldwide. During the past years, the development of new effective treatment options has led to a considerable improvement in the outcome of this disease. The advent of agents such as capecitabine, irinotecan, oxaliplatin, cetuximab and bevacizumab has translated into median survival times in the range of 2 years. Intense efforts have focused on identifying novel agents targeting specific growth factor receptors, critical signal transduction pathways or mediators of angiogenesis. In addition, several clinical trials have suggested that some of these molecularly targeted drugs can be safely and effectively used in combination with conventional chemotherapy. In this article we review various treatment options combining cytotoxic and targeted therapies currently available for patients with metastatic colorectal cancer. PMID:17990352

  9. Polydopamine Nanoparticles for Combined Chemo- and Photothermal Cancer Therapy.

    PubMed

    Zhu, Zhijun; Su, Ming

    2017-06-29

    Cancer therapy with two different modalities can enhance treatment efficacy and reduce side effects. This paper describes a new method for combined chemo- and photothermal therapy of cancer using poly dopamine nanoparticles (PDA-NPs), where PDA-NPs serve not only as a photothermal agent with strong near infrared absorbance and high energy conversion efficiency, but also as a carrier to deliver cisplatin via interaction between cisplatin and catechol groups on PDA-NPs. Polyethylene glycol (PEG) was introduced through Michael addition reaction to improve the stability of PDA-NPs in physiological condition. A remarkable synergistic therapeutic effect has been achieved compared with respective single treatments. This work suggests that the PDA-based nanoplatform can be a universal scaffold for combined chemo- and photothermal therapy of cancer.

  10. Polydopamine Nanoparticles for Combined Chemo- and Photothermal Cancer Therapy

    PubMed Central

    Zhu, Zhijun; Su, Ming

    2017-01-01

    Cancer therapy with two different modalities can enhance treatment efficacy and reduce side effects. This paper describes a new method for combined chemo- and photothermal therapy of cancer using poly dopamine nanoparticles (PDA-NPs), where PDA-NPs serve not only as a photothermal agent with strong near infrared absorbance and high energy conversion efficiency, but also as a carrier to deliver cisplatin via interaction between cisplatin and catechol groups on PDA-NPs. Polyethylene glycol (PEG) was introduced through Michael addition reaction to improve the stability of PDA-NPs in physiological condition. A remarkable synergistic therapeutic effect has been achieved compared with respective single treatments. This work suggests that the PDA-based nanoplatform can be a universal scaffold for combined chemo- and photothermal therapy of cancer. PMID:28661423

  11. Combining oncolytic virotherapy and cytotoxic therapies to fight cancer.

    PubMed

    Fillat, Cristina; Maliandi, Maria Victoria; Mato-Berciano, Ana; Alemany, Ramon

    2014-01-01

    Oncolytic viruses (OV) are promising anti-cancer agents, capable of selectively replicating in tumour cells and killing them. Chemotherapy, on the other hand, remains the backbone of current cancer treatment, although it is limited by a narrow therapeutic index, significant toxicity, and frequent acquired resistance. There is an increasing body of evidence on a variety of chemotherapeutic agents that have been shown to be synergic with OV and result in increased response rates in preclinical studies. Several possible mechanisms have been proposed to mediate the enhanced anti-tumour activity of such combination treatment. Moreover, it has been shown how prodrug- activating enzymes armed oncolytic viruses promote synergy with prodrugs. In the present review we summarise the current knowledge concerning the benefits of the combination of OV and cytotoxic drug treatment and discuss the translational opportunities such therapeutic synergies have in the fight against cancer.

  12. Partnership to Explore New Drug Combination for Pancreatic Cancer | Poster

    Cancer.gov

    By Frank Blanchard, Staff Writer Scientists at NCI and Frederick National Laboratory for Cancer Research (FNLCR) are partnering with the Lustgarten Foundation to test whether a vitamin D derivative will make a difference when combined with a conventional anticancer drug in treating tumors of the pancreas.

  13. Partnership to Explore New Drug Combination for Pancreatic Cancer | Poster

    Cancer.gov

    By Frank Blanchard, Staff Writer Scientists at NCI and Frederick National Laboratory for Cancer Research (FNLCR) are partnering with the Lustgarten Foundation to test whether a vitamin D derivative will make a difference when combined with a conventional anticancer drug in treating tumors of the pancreas.

  14. Combining Immunotherapy and Targeted Therapies in Cancer Treatment

    PubMed Central

    Vanneman, Matthew; Dranoff, Glenn

    2014-01-01

    Preface During the past two decades, the paradigm for cancer treatment has evolved from relatively non-specific cytotoxic agents to selective, mechanism-based therapeutics. Cancer chemotherapies were initially identified through screens for compounds that killed rapidly dividing cells. These drugs remain a backbone of current treatment, but are limited by a narrow therapeutic index, significant toxicities, and frequently acquired resistance. More recently, an improved understanding of cancer pathogenesis has given rise to new treatment options, including targeted agents and cancer immunotherapy. Targeted approaches aim to inhibit molecular pathways that are critical to tumor growth and maintenance, whereas immunotherapy endeavors to stimulate a host response that effectuates long-lived tumor destruction. Targeted therapies and cytotoxic agents also modulate immune responses, which raises the possibility that these treatment strategies might be effectively combined with immunotherapy to improve clinical outcomes. PMID:22437869

  15. Clinically Meaningful Differences in Patient-Reported Outcomes With Amifostine in Combination With Chemoradiation for Locally Advanced Non-Small-Cell Lung Cancer: An Analysis of RTOG 9801

    SciTech Connect

    Sarna, Linda Swann, Suzanne; Langer, Corey; Werner-Wasik, Maria; Nicolaou, Nicos; Komaki, Ritsuko; Machtay, Mitchell; Byhardt, Roger; Wasserman, Todd; Movsas, Benjamin

    2008-12-01

    Purpose: The purpose of this study is to analyze changes in quality of life (QOL) and symptoms from pretreatment to 6 weeks posttreatment in a Phase III randomized study (Radiation Therapy Oncology Group 9801) of amifostine (AM) vs. no AM in patients with Stages II-III non-small-cell lung cancer receiving paclitaxel and carboplatin as induction and then concurrently with hyperfractionated radiation therapy (RT). Methods and Materials: One hundred thirty-eight patients with baseline and 6-week posttreatment QOL data were analyzed. There were no significant differences in baseline demographics between those who did and did not have QOL data. The QOL and symptoms were assessed by using the European Organization for Research and Treatment of Cancer (EORTC) Global QOL and Pain subscales and the EORTC-Lung Cancer-13 symptom tool. Clinically relevant changes in QOL were characterized by 10-point differences in individual scores pre/post treatment. A daily diary of patient-rated difficulty swallowing and a weekly physician-rated dysphagia log (using National Cancer Institute Common Toxicity Criteria) were completed during treatment. Weight loss was monitored. Differences in outcomes were examined according to smoking status, alcohol use, and sex. Results: Patients receiving AM reported significantly greater pain reduction after chemoradiation (34% vs. no AM, 21%), less difficulty swallowing during chemoradiation, and less weight loss than patients not receiving AM. However, physician-rated assessments of dysphagia were not significantly different by treatment arm. There were no other significant changes in QOL or symptoms according to treatment arm, smoking status, alcohol use, or sex. Conclusions: Patient evaluations of difficulty swallowing and pain suggest benefits from AM use that are distinct from clinician-rated assessments.

  16. Patient-reported outcomes with adjuvant exemestane versus tamoxifen in premenopausal women with early breast cancer undergoing ovarian suppression (TEXT and SOFT): a combined analysis of two phase 3 randomised trials.

    PubMed

    Bernhard, Jürg; Luo, Weixiu; Ribi, Karin; Colleoni, Marco; Burstein, Harold J; Tondini, Carlo; Pinotti, Graziella; Spazzapan, Simon; Ruhstaller, Thomas; Puglisi, Fabio; Pavesi, Lorenzo; Parmar, Vani; Regan, Meredith M; Pagani, Olivia; Fleming, Gini F; Francis, Prudence A; Price, Karen N; Coates, Alan S; Gelber, Richard D; Goldhirsch, Aron; Walley, Barbara A

    2015-07-01

    The combined efficacy analysis of the TEXT and SOFT trials showed a significant disease-free survival benefit with exemestane plus ovarian function suppression (OFS) compared with tamoxifen plus OFS. We present patient-reported outcomes from these trials. Between Nov 7, 2003, and April 7, 2011, 4717 premenopausal women with hormone-receptor positive breast cancer were enrolled in TEXT or SOFT to receive unmasked adjuvant treatment with 5 years of exemestane plus OFS or tamoxifen plus OFS. Gonadotropin-releasing hormone analogue triptorelin, bilateral oophorectomy, or bilateral ovarian irradiation were used to achieve OFS. Chemotherapy use was optional. Randomisation with permuted blocks was done with the International Breast Cancer Study Group's internet-based system and was stratified by chemotherapy use and status of lymph nodes. Patients completed a quality of life (QoL) form comprising several global and symptom indicators at baseline, every 6 months for 24 months, and then every year during years 3 to 6. Differences in the change of QoL from baseline between the two treatments were tested at 6 months, 24 months, and 60 months with mixed-models for repeated measures for each trial with and without chemotherapy and overall. The analysis was by intention to treat. At the time of analysis, the median follow-up was 5·7 years (IQR 3·7-6·9); treatment and follow-up of patients continue. The trials are registered with ClinicalTrials.gov, as NCT00066703 (TEXT) and NCT00066690 (SOFT). Patients on tamoxifen plus OFS were more affected by hot flushes and sweats over 5 years than were those on exemestane plus OFS, although these symptoms improved. Patients on exemestane plus OFS reported more vaginal dryness, greater loss of sexual interest, and difficulties becoming aroused than did patients on tamoxifen plus OFS; these differences persisted over time. An increase in bone or joint pain was more pronounced, particularly in the short term, in patients on exemestane plus

  17. Convergence analysis of combinations of different methods

    SciTech Connect

    Kang, Y.

    1994-12-31

    This paper provides a convergence analysis for combinations of different numerical methods for solving systems of differential equations. The author proves that combinations of two convergent linear multistep methods or Runge-Kutta methods produce a new convergent method of which the order is equal to the smaller order of the two original methods.

  18. Oxaliplatin-based combined-modality therapy for rectal cancer.

    PubMed

    Minsky, Bruce D

    2003-08-01

    There are two conventional treatments for clinically resectable rectal cancer. The first is surgery, and, if the tumor is T3 and/or N1-2, this is followed by postoperative combined-modality therapy. The second, for patients with ultrasound T3 or clinical T4 disease, is preoperative combined-modality therapy followed by surgery and postoperative chemotherapy. In this review, the results of these approaches as well as novel combined-modality approaches using oxaliplatin-based regimens will be presented.

  19. RAD51 135G→C Modifies Breast Cancer Risk among BRCA2 Mutation Carriers: Results from a Combined Analysis of 19 Studies

    PubMed Central

    Antoniou, Antonis C. ; Sinilnikova, Olga M. ; Simard, Jacques ; Léoné, Mélanie ; Dumont, Martine ; Neuhausen, Susan L. ; Struewing, Jeffery P. ; Stoppa-Lyonnet, Dominique ; Barjhoux, Laure ; Hughes, David J. ; Coupier, Isabelle ; Belotti, Muriel ; Lasset, Christine ; Bonadona, Valérie ; Bignon, Yves-Jean ; Rebbeck, Timothy R. ; Wagner, Theresa ; Lynch, Henry T. ; Domchek, Susan M. ; Nathanson, Katherine L. ; Garber, Judy E. ; Weitzel, Jeffrey ; Narod, Steven A. ; Tomlinson, Gail ; Olopade, Olufunmilayo I. ; Godwin, Andrew ; Isaacs, Claudine ; Jakubowska, Anna ; Lubinski, Jan ; Gronwald, Jacek ; Górski, Bohdan ; Byrski, Tomasz ; Huzarski, Tomasz ; Peock, Susan ; Cook, Margaret ; Baynes, Caroline ; Murray, Alexandra ; Rogers, Mark ; Daly, Peter A. ; Dorkins, Huw ; Schmutzler, Rita K. ; Versmold, Beatrix ; Engel, Christoph ; Meindl, Alfons ; Arnold, Norbert ; Niederacher, Dieter ; Deissler, Helmut ; Spurdle, Amanda B. ; Chen, Xiaoqing ; Waddell, Nicola ; Cloonan, Nicole ; Kirchhoff, Tomas ; Offit, Kenneth ; Friedman, Eitan ; Kaufmann, Bella ; Laitman, Yael ; Galore, Gilli ; Rennert, Gad ; Lejbkowicz, Flavio ; Raskin, Leon ; Andrulis, Irene L. ; Ilyushik, Eduard ; Ozcelik, Hilmi ; Devilee, Peter ; Vreeswijk, Maaike P. G. ; Greene, Mark H. ; Prindiville, Sheila A. ; Osorio, Ana ; Benítez, Javier ; Zikan, Michal ; Szabo, Csilla I. ; Kilpivaara, Outi ; Nevanlinna, Heli ; Hamann, Ute ; Durocher, Francine ; Arason, Adalgeir ; Couch, Fergus J. ; Easton, Douglas F. ; Chenevix-Trench, Georgia 

    2007-01-01

    RAD51 is an important component of double-stranded DNA–repair mechanisms that interacts with both BRCA1 and BRCA2. A single-nucleotide polymorphism (SNP) in the 5′ untranslated region (UTR) of RAD51, 135G→C, has been suggested as a possible modifier of breast cancer risk in BRCA1 and BRCA2 mutation carriers. We pooled genotype data for 8,512 female mutation carriers from 19 studies for the RAD51 135G→C SNP. We found evidence of an increased breast cancer risk in CC homozygotes (hazard ratio [HR] 1.92 [95% confidence interval {CI} 1.25–2.94) but not in heterozygotes (HR 0.95 [95% CI 0.83–1.07]; P=.002, by heterogeneity test with 2 degrees of freedom [df]). When BRCA1 and BRCA2 mutation carriers were analyzed separately, the increased risk was statistically significant only among BRCA2 mutation carriers, in whom we observed HRs of 1.17 (95% CI 0.91–1.51) among heterozygotes and 3.18 (95% CI 1.39–7.27) among rare homozygotes (P=.0007, by heterogeneity test with 2 df). In addition, we determined that the 135G→C variant affects RAD51 splicing within the 5′ UTR. Thus, 135G→C may modify the risk of breast cancer in BRCA2 mutation carriers by altering the expression of RAD51. RAD51 is the first gene to be reliably identified as a modifier of risk among BRCA1/2 mutation carriers. PMID:17999359

  20. Lapatinib and trastuzumab in combination with an aromatase inhibitor for the first-line treatment of metastatic hormone receptor-positive breast cancer which over-expresses human epidermal growth factor 2 (HER2): a systematic review and economic analysis.

    PubMed

    Fleeman, N; Bagust, A; Boland, A; Dickson, R; Dundar, Y; Moonan, M; Oyee, J; Blundell, M; Davis, H; Armstrong, A; Thorp, N

    2011-01-01

    Breast cancer is the uncontrolled, abnormal growth of malignant breast tissue affecting predominantly women. Metastatic breast cancer (mBC) is an advanced stage of the disease when the disease has spread beyond the original organ. Hormone receptor status and human epidermal growth factor 2 (HER2) status are two predictive factors that are taken into consideration when estimating the prognosis of patients with breast cancer. To review the clinical effectiveness and cost-effectiveness evidence base for lapatinib (LAP) in combination with an aromatase inhibitor (AI) and trastuzumab (TRA) in combination with an AI for the first-line treatment of patients who have hormone receptor-positive (HR+)/human epidermal growth factor 2-positive (HER2+) mBC. Relevant electronic databases and websites, including MEDLINE, EMBASE and the Cochrane Library, were searched until May 2010. Further data were derived from the manufacturers' submissions for LAP + AI and TRA + AI. A systematic review of the clinical effectiveness and cost-effectiveness of LAP + AI and TRA + AI was undertaken. As it was deemed inappropriate to compare LAP + AI with TRA + AI, two separate assessments of cost-effectiveness versus AIs alone were undertaken. Three trials were included in the systematic review [the patient populations of the efficacy and safety of lapatinib combined with letrozole (EGF30008) trial, the efficacy and safety of trastuzumab combined with anastrozole (TAnDEM) trial and the efficacy and safety of letrozole combined with trastuzumab (eLEcTRA) trial]. As a result of differences in the exclusion criteria and because one trial was halted prematurely, comparisons across trials were believed to be inappropriate and meta-analysis was not possible. Individually, however, the findings from the trials all suggest that LAP + AI or TRA + AI results in improved progression-free survival and/or time to progression when compared with AIs alone. The trials do not show a statistically significant

  1. Risk analysis of colorectal cancer incidence by gene expression analysis

    PubMed Central

    Shangkuan, Wei-Chuan; Lin, Hung-Che; Chang, Yu-Tien; Jian, Chen-En; Fan, Hueng-Chuen; Chen, Kang-Hua; Liu, Ya-Fang; Hsu, Huan-Ming; Chou, Hsiu-Ling; Yao, Chung-Tay

    2017-01-01

    Background Colorectal cancer (CRC) is one of the leading cancers worldwide. Several studies have performed microarray data analyses for cancer classification and prognostic analyses. Microarray assays also enable the identification of gene signatures for molecular characterization and treatment prediction. Objective Microarray gene expression data from the online Gene Expression Omnibus (GEO) database were used to to distinguish colorectal cancer from normal colon tissue samples. Methods We collected microarray data from the GEO database to establish colorectal cancer microarray gene expression datasets for a combined analysis. Using the Prediction Analysis for Microarrays (PAM) method and the GSEA MSigDB resource, we analyzed the 14,698 genes that were identified through an examination of their expression values between normal and tumor tissues. Results Ten genes (ABCG2, AQP8, SPIB, CA7, CLDN8, SCNN1B, SLC30A10, CD177, PADI2, and TGFBI) were found to be good indicators of the candidate genes that correlate with CRC. From these selected genes, an average of six significant genes were obtained using the PAM method, with an accuracy rate of 95%. The results demonstrate the potential of utilizing a model with the PAM method for data mining. After a detailed review of the published reports, the results confirmed that the screened candidate genes are good indicators for cancer risk analysis using the PAM method. Conclusions Six genes were selected with 95% accuracy to effectively classify normal and colorectal cancer tissues. We hope that these results will provide the basis for new research projects in clinical practice that aim to rapidly assess colorectal cancer risk using microarray gene expression analysis. PMID:28229027

  2. Combined Use of Tissue Morphology, Neural Network Analysis of Chromatin Texture & Clinical Variables to Predict Prostate Cancer Agressiveness from Biopsy Material

    DTIC Science & Technology

    1999-10-01

    THE PURPOSE OF THIS REPORT IS TO COMBINE CLINICAL, SERUM, PATHOLOGICAL AND COMPUTER DERIVED INFORMATION INTO AN ARTIFICIAL NEURAL NETWORK TO DEVELOP...01). Development of a artificial neural network model (year 02). Prospective validation of this model (projected year 03). All models will be tested

  3. Combined Use of Tissue Morphology, Neural Network Analysis of Chromatin Texture and Clinical Variables to Predict Prostate Cancer Agressiveness from Biopsy Water

    DTIC Science & Technology

    2000-10-01

    Purpose: To combine clinical, serum, pathologic and computer derived information into an artificial neural network to develop/validate a model to...Development of an artificial neural network (year 02). Prospective validation of this model (projected year 03). All models will be tested and

  4. Cancer immunotherapy via combining oncolytic virotherapy with chemotherapy: recent advances.

    PubMed

    Simpson, Guy R; Relph, Kate; Harrington, Kevin; Melcher, Alan; Pandha, Hardev

    2016-01-01

    Oncolytic viruses are multifunctional anticancer agents with huge clinical potential, and have recently passed the randomized Phase III clinical trial hurdle. Both wild-type and engineered viruses have been selected for targeting of specific cancers, to elicit cytotoxicity, and also to generate antitumor immunity. Single-agent oncolytic virotherapy treatments have resulted in modest effects in the clinic. There is increasing interest in their combination with cytotoxic agents, radiotherapy and immune-checkpoint inhibitors. Similarly to oncolytic viruses, the benefits of chemotherapeutic agents may be that they induce systemic antitumor immunity through the induction of immunogenic cell death of cancer cells. Combining these two treatment modalities has to date resulted in significant potential in vitro and in vivo synergies through various mechanisms without any apparent additional toxicities. Chemotherapy has been and will continue to be integral to the management of advanced cancers. This review therefore focuses on the potential for a number of common cytotoxic agents to be combined with clinically relevant oncolytic viruses. In many cases, this combined approach has already advanced to the clinical trial arena.

  5. The future of cancer treatment: immunomodulation, CARs and combination immunotherapy.

    PubMed

    Khalil, Danny N; Smith, Eric L; Brentjens, Renier J; Wolchok, Jedd D

    2016-05-01

    In the past decade, advances in the use of monoclonal antibodies (mAbs) and adoptive cellular therapy to treat cancer by modulating the immune response have led to unprecedented responses in patients with advanced-stage tumours that would otherwise have been fatal. To date, three immune-checkpoint-blocking mAbs have been approved in the USA for the treatment of patients with several types of cancer, and more patients will benefit from immunomodulatory mAb therapy in the months and years ahead. Concurrently, the adoptive transfer of genetically modified lymphocytes to treat patients with haematological malignancies has yielded dramatic results, and we anticipate that this approach will rapidly become the standard of care for an increasing number of patients. In this Review, we highlight the latest advances in immunotherapy and discuss the role that it will have in the future of cancer treatment, including settings for which testing combination strategies and 'armoured' CAR T cells are recommended.

  6. Cancer Nanomedicine: From Targeted Delivery to Combination Therapy

    PubMed Central

    Xu, Xiaoyang; Ho, William; Zhang, Xueqing; Bertrand, Nicolas; Farokhzad, Omid

    2015-01-01

    The advent of nanomedicine marks an unparalleled opportunity to advance the treatment of a variety of diseases, including cancer. The unique properties of nanoparticles, such as large surface-to volume ratio, small size, the ability to encapsulate a variety of drugs, and tunable surface chemistry, gives them many advantages over their bulk counterparts. This includes multivalent surface modification with targeting ligands, efficient navigation of the complex in vivo environment, increased intracellular trafficking, and sustained release of drug payload. These advantages make nanoparticles a mode of treatment potentially superior to conventional cancer therapies. This article highlights the most recent developments in cancer treatment using nanoparticles as drug-delivery vehicles, including promising opportunities in targeted and combination therapy. PMID:25656384

  7. Cancer nanomedicine: from targeted delivery to combination therapy.

    PubMed

    Xu, Xiaoyang; Ho, William; Zhang, Xueqing; Bertrand, Nicolas; Farokhzad, Omid

    2015-04-01

    The advent of nanomedicine marks an unparalleled opportunity to advance the treatment of various diseases, including cancer. The unique properties of nanoparticles (NPs), such as large surface-to-volume ratio, small size, the ability to encapsulate various drugs, and tunable surface chemistry, give them many advantages over their bulk counterparts. This includes multivalent surface modification with targeting ligands, efficient navigation of the complex in vivo environment, increased intracellular trafficking, and sustained release of drug payload. These advantages make NPs a mode of treatment potentially superior to conventional cancer therapies. This review highlights the most recent developments in cancer treatment using NPs as drug delivery vehicles, including promising opportunities in targeted and combination therapy. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. The Effect of ShenQi FuZheng Injection in Combination with Chemotherapy versus Chemotherapy Alone on the Improvement of Efficacy and Immune Function in Patients with Advanced Non-Small Cell Lung Cancer: A Meta-Analysis

    PubMed Central

    dedong, Cao; huilin, Xu; Anbing, He; Ximing, Xu; wei, Ge

    2016-01-01

    Objective To evaluate the effect of ShenQi FuZheng Injection (SFI) on cellular immunity and clinical efficacy in patients with advanced non small cell lung cancer(NSCLC) when combined with chemotherapy. Methods Electronic databases including EMBASE, PUBMED, the conference proceedings of the American Society of Clinical Oncology (ASCO), Cochrane, Chinese National Knowledge Infrastructure (CNKI), and Chinese Biological Medical disc(CBM) were searched, until July, 2015. The randomized controlled clinical studies reporting results of efficacy and immune function were collected according to the inclusion criteria. Cochrane handbook 5.1.0 was applied to assess the quality of included trials and Revman 5 software was used for data analysis. Results Fifteen studies including 1006 cases of advanced NSCLC were included based on the inclusion criteria. The results of meta-analysis showed that there were significant differences in percentages of CD3+ cells (SMD = 13.48; 95%CI: 8.11–18.85; p<0.01), CD4+ cells (SMD = 10.78; 95%CI, 6.38–15.18; p<0.01), NK [WMD = 8.59, 95% CI(3.97, 13.21), p = 0.003], and ratio of CD4+/ CD8+ (SMD = 0.32; 95%: 0.28–0.36; p<0.01) between SFI combination group and control group, whereas the difference was not significant in CD8+ (SMD = -1.44; 95%CI, -4.53–1.65; p = 0.36). Funnel plot, Begg's rank correlation test and Egger's linear regression analysis indicated that there was significant publication bias across studies. Conclusion SFI is effective to improve the efficacy of chemotherpay and function of cellular immunity in NSCLC patients, however, high quality RCTs are needed to further confirm the findings. PMID:27015629

  9. A clinical analysis of brain metastasis in gynecologic cancer: a retrospective multi-institute analysis.

    PubMed

    Kim, Young Zoon; Kwon, Jae Hyun; Lim, Soyi

    2015-01-01

    This study analyzes the clinical characteristics of the brain metastasis (BM) of gynecologic cancer based on the type of cancer. In addition, the study examines the factors influencing the survival. Total 61 BM patients of gynecologic cancer were analyzed retrospectively from January 2000 to December 2012 in terms of clinical and radiological characteristics by using medical and radiological records from three university hospitals. There were 19 (31.1%) uterine cancers, 32 (52.5%) ovarian cancers, and 10 (16.4%) cervical cancers. The mean interval to BM was 25.4 months (21.6 months in ovarian cancer, 27.8 months in uterine cancer, and 33.1 months in cervical cancer). The mean survival from BM was 16.7 months (14.1 months in ovarian cancer, 23.3 months in uterine cancer, and 8.8 months in cervical cancer). According to a multivariate analysis of factors influencing survival, type of primary cancer, Karnofsky performance score, status of primary cancer, recursive partitioning analysis class, and treatment modality, particularly combined therapies, were significantly related to the overall survival. These results suggest that, in addition to traditional prognostic factors in BM, multiple treatment methods such as neurosurgery and combined chemoradiotherapy may play an important role in prolonging the survival for BM patients of gynecologic cancer.

  10. Combination Approaches with Immune-Checkpoint Blockade in Cancer Therapy.

    PubMed

    Swart, Maarten; Verbrugge, Inge; Beltman, Joost B

    2016-01-01

    In healthy individuals, immune-checkpoint molecules prevent autoimmune responses and limit immune cell-mediated tissue damage. Tumors frequently exploit these molecules to evade eradication by the immune system. Over the past years, immune-checkpoint blockade of cytotoxic T lymphocyte antigen-4 and programed death-1 emerged as promising strategies to activate antitumor cytotoxic T cell responses. Although complete regression and long-term survival is achieved in some patients, not all patients respond. This review describes promising, novel combination approaches involving immune-checkpoint blockade in the context of the cancer-immunity cycle, aimed at increasing response rates to the single treatments. Specifically, we discuss combinations that promote antigen release and presentation, that further amplify T cell activation, that inhibit trafficking of regulatory T cells or MSDCs, that stimulate intratumoral T cell infiltration, that increase cancer recognition by T cells, and that stimulate tumor killing.

  11. Combination Approaches with Immune-Checkpoint Blockade in Cancer Therapy

    PubMed Central

    Swart, Maarten; Verbrugge, Inge; Beltman, Joost B.

    2016-01-01

    In healthy individuals, immune-checkpoint molecules prevent autoimmune responses and limit immune cell-mediated tissue damage. Tumors frequently exploit these molecules to evade eradication by the immune system. Over the past years, immune-checkpoint blockade of cytotoxic T lymphocyte antigen-4 and programed death-1 emerged as promising strategies to activate antitumor cytotoxic T cell responses. Although complete regression and long-term survival is achieved in some patients, not all patients respond. This review describes promising, novel combination approaches involving immune-checkpoint blockade in the context of the cancer-immunity cycle, aimed at increasing response rates to the single treatments. Specifically, we discuss combinations that promote antigen release and presentation, that further amplify T cell activation, that inhibit trafficking of regulatory T cells or MSDCs, that stimulate intratumoral T cell infiltration, that increase cancer recognition by T cells, and that stimulate tumor killing. PMID:27847783

  12. Combination cancer immunotherapies tailored to the tumour microenvironment.

    PubMed

    Smyth, Mark J; Ngiow, Shin Foong; Ribas, Antoni; Teng, Michele W L

    2016-03-01

    Evidence suggests that cancer immunotherapy will be a major part of the combination treatment plan for many patients with many cancer types in the near future. There are many types of immune processes involving different antitumour and tumour-promoting leucocytes, and tumour cells use many strategies to evade the immune response. The tumour microenvironment can help determine which immune suppressive pathways become activated to restrain antitumour immunity. This includes immune checkpoint receptors on effector T-cells and myeloid cells, and release of inhibitory cytokines and metabolites. Therapeutic approaches that target these pathways, particularly immune-checkpoint receptors, can induce durable antitumour responses in patients with advanced-stage cancers, including melanoma. Nevertheless, many patients do not have a good response to monotherapy approaches and alternative strategies are required to achieve optimal therapeutic benefit. These strategies include eliminating the bulk of tumour cells to provoke tumour-antigen release and antigen-presenting cell (APC) function, using adjuvants to enhance APC function, and using agents that enhance effector-cell activity. In this Review, we discuss the stratification of the tumour microenvironment according to tumour-infiltrating lymphocytes and PD-L1 expression in the tumour, and how this stratification enables the design of optimal combination cancer therapies tailored to target different tumour microenvironments.

  13. Prediction of late distant recurrence after 5 years of endocrine treatment: a combined analysis of patients from the Austrian breast and colorectal cancer study group 8 and arimidex, tamoxifen alone or in combination randomized trials using the PAM50 risk of recurrence score.

    PubMed

    Sestak, Ivana; Cuzick, Jack; Dowsett, Mitch; Lopez-Knowles, Elena; Filipits, Martin; Dubsky, Peter; Cowens, John Wayne; Ferree, Sean; Schaper, Carl; Fesl, Christian; Gnant, Michael

    2015-03-10

    We have previously shown that the PAM50-based risk of recurrence (ROR) score is significantly correlated with distant recurrence in both the translational research cohort within the Arimidex, Tamoxifen Alone or in Combination (ATAC) trial (TransATAC) and Austrian Breast and Colorectal Cancer Study Group 8 (ABCSG 8) randomized trials. Here, we focus on the ROR score for predicting distant recurrence after 5 years of follow-up in a combined analysis of these two randomized trials. Long-term follow-up data and tissue samples were obtained from 2,137 postmenopausal women with hormone receptor-positive early-stage breast cancer from the ABCSG 8 and TransATAC trials. We used Cox proportional hazard regression models to determine the prognostic value of ROR for distant recurrence beyond 5 years in the combined data set. A total of 2,137 women who did not have a recurrence 5 years after diagnosis were included in the combined analyses. The Clinical Treatment Score (CTS) was the strongest prognostic factor 5 years after diagnosis (univariable: likelihood ratio [LR] χ(2) = 94.12, bivariable: LR χ(2) = 61.43). The ROR score was significantly prognostic by itself in years 5 to 10. In the node-negative/human epidermal growth factor receptor 2-negative subgroup, more prognostic value for late distant recurrence was added by the ROR score compared with the CTS. The ROR score added clinically meaningful prognostic information to the CTS in all patients and all subgroups in the late follow-up period. These results suggest that the ROR score may be helpful for separating patients into risk groups who could be spared or potentially benefit from extended hormonal therapy beyond 5 years of treatment. © 2014 by American Society of Clinical Oncology.

  14. Combined clinical and genetic testing algorithm for cervical cancer diagnosis.

    PubMed

    Liou, Yu-Ligh; Zhang, Tao-Lan; Yan, Tian; Yeh, Ching-Tung; Kang, Ya-Nan; Cao, Lanqin; Wu, Nayiyuan; Chang, Chi-Feng; Wang, Huei-Jen; Yen, Carolyn; Chu, Tang-Yuan; Zhang, Yi; Zhang, Yu; Zhou, Honghao

    2016-01-01

    Opportunistic screening in hospitals is widely used to effectively reduce the incidence rate of cervical cancer in China and other developing countries. This study aimed to identify clinical risk factor algorithms that combine gynecologic examination and molecular testing (paired box gene 1 (PAX1) or zinc finger protein 582 (ZNF582) methylation or HPV16/18) results to improve diagnostic accuracy. The delta Cp of methylated PAX1 and ZNF582 was obtained via quantitative methylation-specific PCR in a training set (57 CIN2- and 43 cervical intraepithelial neoplasia ≥grade 3 (CIN3+) women), and the individual and combination gene sensitivities and specificities were determined. The detection accuracy of three algorithms combining gynecologic findings and genetic test results was then compared in a randomized case-control study comprising 449 women referred for colposcopic examination by gynecologists in the outpatient department of Xiangya Hospital between November 2011 and March 2013. Significant association was observed between CIN3+ and methylated PAX1 or ZNF582 in combination with HPV16/18 (OR:15.52, 95 % CI:7.73-31.18). The sensitivities and specificities of methylated PAX1 or ZNF582 combined with HPV16/18 for CIN3+ women were 89.2 and 76.0 %, or 85.4 and 80.1 %, respectively. Of the three algorithms applied to cohort data and validated in the study, two indicated 100 % sensitivity in detecting cervical cancer and a low rate of referrals for colposcopy. These algorithms might contribute to precise and objective cervical cancer diagnostics in the outpatient departments of hospitals in countries with high mortality and low screening rates or areas with uneven resource distribution.

  15. Response of Breast Cancer Cells and Cancer Stem Cells to Metformin and Hyperthermia Alone or Combined

    PubMed Central

    Lee, Hyemi; Park, Heon Joo; Park, Chang-Shin; Oh, Eun-Taex; Choi, Bo-Hwa; Williams, Brent; Lee, Chung K.; Song, Chang W.

    2014-01-01

    Metformin, the most widely prescribed drug for treatment of type 2 diabetes, has been shown to exert significant anticancer effects. Hyperthermia has been known to kill cancer cells and enhance the efficacy of various anti-cancer drugs and radiotherapy. We investigated the combined effects of metformin and hyperthermia against MCF-7 and MDA-MB-231 human breast cancer cell, and MIA PaCa-2 human pancreatic cancer cells. Incubation of breast cancer cells with 0.5–10 mM metformin for 48 h caused significant clonogenic cell death. Culturing breast cancer cells with 30 µM metformin, clinically relevant plasma concentration of metformin, significantly reduced the survival of cancer cells. Importantly, metformin was preferentially cytotoxic to CD44high/CD24low cells of MCF-7 cells and, CD44high/CD24high cells of MIA PaCa-2 cells, which are known to be cancer stem cells (CSCs) of MCF-7 cells and MIA PaCa-2 cells, respectively. Heating at 42°C for 1 h was slightly toxic to both cancer cells and CSCs, and it markedly enhanced the efficacy of metformin to kill cancer cells and CSCs. Metformin has been reported to activate AMPK, thereby suppressing mTOR, which plays an important role for protein synthesis, cell cycle progression, and cell survival. For the first time, we show that hyperthermia activates AMPK and inactivates mTOR and its downstream effector S6K. Furthermore, hyperthermia potentiated the effect of metformin to activate AMPK and inactivate mTOR and S6K. Cell proliferation was markedly suppressed by metformin or combination of metformin and hyperthermia, which could be attributed to activation of AMPK leading to inactivation of mTOR. It is conclude that the effects of metformin against cancer cells including CSCs can be markedly enhanced by hyperthermia. PMID:24505341

  16. Response of breast cancer cells and cancer stem cells to metformin and hyperthermia alone or combined.

    PubMed

    Lee, Hyemi; Park, Heon Joo; Park, Chang-Shin; Oh, Eun-Taex; Choi, Bo-Hwa; Williams, Brent; Lee, Chung K; Song, Chang W

    2014-01-01

    Metformin, the most widely prescribed drug for treatment of type 2 diabetes, has been shown to exert significant anticancer effects. Hyperthermia has been known to kill cancer cells and enhance the efficacy of various anti-cancer drugs and radiotherapy. We investigated the combined effects of metformin and hyperthermia against MCF-7 and MDA-MB-231 human breast cancer cell, and MIA PaCa-2 human pancreatic cancer cells. Incubation of breast cancer cells with 0.5-10 mM metformin for 48 h caused significant clonogenic cell death. Culturing breast cancer cells with 30 µM metformin, clinically relevant plasma concentration of metformin, significantly reduced the survival of cancer cells. Importantly, metformin was preferentially cytotoxic to CD44(high)/CD24(low) cells of MCF-7 cells and, CD44(high)/CD24(high) cells of MIA PaCa-2 cells, which are known to be cancer stem cells (CSCs) of MCF-7 cells and MIA PaCa-2 cells, respectively. Heating at 42°C for 1 h was slightly toxic to both cancer cells and CSCs, and it markedly enhanced the efficacy of metformin to kill cancer cells and CSCs. Metformin has been reported to activate AMPK, thereby suppressing mTOR, which plays an important role for protein synthesis, cell cycle progression, and cell survival. For the first time, we show that hyperthermia activates AMPK and inactivates mTOR and its downstream effector S6K. Furthermore, hyperthermia potentiated the effect of metformin to activate AMPK and inactivate mTOR and S6K. Cell proliferation was markedly suppressed by metformin or combination of metformin and hyperthermia, which could be attributed to activation of AMPK leading to inactivation of mTOR. It is conclude that the effects of metformin against cancer cells including CSCs can be markedly enhanced by hyperthermia.

  17. Capillary electrophoresis with online stacking in combination with AgNPs@MCM-41 reinforced hollow fiber solid-liquid phase microextraction for quantitative analysis of Capecitabine and its main metabolite 5-Fluorouracil in plasma samples isolated from cancer patients.

    PubMed

    Forough, Mehrdad; Farhadi, Khalil; Molaei, Rahim; Khalili, Hedayat; Shakeri, Ramin; Zamani, Asghar; Matin, Amir Abbas

    2017-01-01

    The purpose of this study is the development and validation of a simple, novel, selective and fast off-line microextraction technique combining capillary electrophoresis with in-column field-amplified sample injection (FASI) for the simultaneous determination of capecitabine (CAP) and its active metabolite, 5-Fluorouracil (5-FU), in human plasma. At the moment, there is a lack of using cost-effective CE tool combined with novel miniaturized sample clean-up techniques for analysis of these important anti-cancer agents in plasma samples. This paper intends to fill this gap and describe a simple off-line sample pretreatment by means of AgNPs@MCM-41 reinforced hollow fiber Solid/Liquid phase microextraction (AgNPs@MCM41-HF-SLPME) with subsequent quantitation by FASI-CE. The separation of analytes was performed using a BGE containing 60mM phosphate-Tris buffer (pH 7) with 10% methanol as an organic modifier. Before sample loading, a short water plug (50mbar, 3s) was injected to permit FASI for stacking. Various parameters affecting the off-line microextraction efficiency as well as FASI were optimized. Migration time was found to be 6.6 (±0.1)min for 5-FU and 7.4 (±0.2)min for CAP. The linearity, precision, accuracy, recovery, selectivity, specificity, stability as well as the robustness of the method was evaluated from spiked plasma samples during the course of validation. The results revealed that the presented technique demonstrates acceptable accuracy and precision, miniaturized sample preparation and a reduced need for complicated equipment along with an acceptable analysis time. The validated method was successfully applied to determine CAP and 5-FU in patient's plasma samples.

  18. Efficacy and Safety of Gemcitabine-Fluorouracil Combination Therapy in the Management of Advanced Pancreatic Cancer: A Meta-Analysis of Randomized Controlled Trials

    PubMed Central

    Li, Qin; Yan, Han; Liu, Wenting; Zhen, Hongchao; Yang, Yifan; Cao, Bangwei

    2014-01-01

    Background Gemcitabine (GEM) is the standard first-line chemotherapy that provides limited clinical benefits for patients with locally advanced/metastatic pancreatic adenocarcinoma (LA/MPC). However, the fluorouracil derivatives (CAP and S-1) show promising efficacy in these patients. This study compared the efficacy and safety of GEM with GEM plus fluorouracil drugs in the treatment of LA/MPC. Methods Pubmed, EMBASE and Cochrane Library databases were searched for relevant randomized controlled trials published on or before January 2014. The Cochrane Collaboration's tool was used to assess the risk of bias in randomized trials. The primary end point was overall survival (OS); the secondary end points were one-year survival rate, objective response rate (ORR) and toxicity rates (TRs). Results A total of 8 randomized controlled trials involving 2,126 patients were included in the systematic evaluation. The results showed that OS was significantly improved (HR 0.83, P<0.01; HR 0.87, P = 0.03; HR 0.80, P = 0.01; respectively) and ORR was significantly increased (OR 0.51, P<0.01; OR 0.66, P = 0.03; OR 0.35, P<0.01; respectively) in the GEM+5-FU/CAP/S-1, GEM+CAP and GEM+S-1 groups compared to the GEM alone group. In addition, the one-year survival rate was significantly increased (OR 0.78 P = 0.01; OR 0.47, P = 0.04; respectively) in the GEM+5-FU/CAP/S-1 and GEM+S-1 groups compared to the GEM alone group. The frequency of grade 3/4 TRs were higher in GEM+5-FU/CAP/S-1 group, the significant increase of grade 3/4 neutropenia, thrombocytopenia and diarrhea were observed. Conclusions GEM combined with fluorouracil drugs significantly improved OS and increased one-year survival rate and ORR compared to GEM alone in LA/MPC patients. GEM combined with fluorouracil drugs may be considered as an acceptable alternative treatment for LA/MPC patients. PMID:25093849

  19. Protocol for Combined Analysis of FOXFIRE, SIRFLOX, and FOXFIRE-Global Randomized Phase III Trials of Chemotherapy +/- Selective Internal Radiation Therapy as First-Line Treatment for Patients With Metastatic Colorectal Cancer.

    PubMed

    Virdee, Pradeep S; Moschandreas, Joanna; Gebski, Val; Love, Sharon B; Francis, E Anne; Wasan, Harpreet S; van Hazel, Guy; Gibbs, Peter; Sharma, Ricky A

    2017-03-28

    In colorectal cancer (CRC), unresectable liver metastases are associated with a poor prognosis. The FOXFIRE (an open-label randomized phase III trial of 5-fluorouracil, oxaliplatin, and folinic acid +/- interventional radioembolization as first-line treatment for patients with unresectable liver-only or liver-predominant metastatic colorectal cancer), SIRFLOX (randomized comparative study of FOLFOX6m plus SIR-Spheres microspheres versus FOLFOX6m alone as first-line treatment in patients with nonresectable liver metastases from primary colorectal carcinoma), and FOXFIRE-Global (assessment of overall survival of FOLFOX6m plus SIR-Spheres microspheres versus FOLFOX6m alone as first-line treatment in patients with nonresectable liver metastases from primary colorectal carcinoma in a randomized clinical study) clinical trials were designed to evaluate the efficacy and safety of combining first-line chemotherapy with selective internal radiation therapy (SIRT) using yttrium-90 resin microspheres, also called transarterial radioembolization. The aim of this analysis is to prospectively combine clinical data from 3 trials to allow adequate power to evaluate the impact of chemotherapy with SIRT on overall survival. Eligible patients are adults with histologically confirmed CRC and unequivocal evidence of liver metastases which are not treatable by surgical resection or local ablation with curative intent at the time of study entry. Patients may also have limited extrahepatic metastases. Final analysis will take place when all participants have been followed up for a minimum of 2 years. Efficacy and safety estimates derived using individual participant data (IPD) from SIRFLOX, FOXFIRE, and FOXFIRE-Global will be pooled using 2-stage prospective meta-analysis. Secondary outcome measures include progression-free survival (PFS), liver-specific PFS, health-related quality of life, response rate, resection rate, and adverse event profile. The large study population will

  20. Protocol for Combined Analysis of FOXFIRE, SIRFLOX, and FOXFIRE-Global Randomized Phase III Trials of Chemotherapy +/- Selective Internal Radiation Therapy as First-Line Treatment for Patients With Metastatic Colorectal Cancer

    PubMed Central

    Virdee, Pradeep S; Moschandreas, Joanna; Gebski, Val; Love, Sharon B; Francis, E Anne; Wasan, Harpreet S; van Hazel, Guy; Gibbs, Peter

    2017-01-01

    Background In colorectal cancer (CRC), unresectable liver metastases are associated with a poor prognosis. The FOXFIRE (an open-label randomized phase III trial of 5-fluorouracil, oxaliplatin, and folinic acid +/- interventional radioembolization as first-line treatment for patients with unresectable liver-only or liver-predominant metastatic colorectal cancer), SIRFLOX (randomized comparative study of FOLFOX6m plus SIR-Spheres microspheres versus FOLFOX6m alone as first-line treatment in patients with nonresectable liver metastases from primary colorectal carcinoma), and FOXFIRE-Global (assessment of overall survival of FOLFOX6m plus SIR-Spheres microspheres versus FOLFOX6m alone as first-line treatment in patients with nonresectable liver metastases from primary colorectal carcinoma in a randomized clinical study) clinical trials were designed to evaluate the efficacy and safety of combining first-line chemotherapy with selective internal radiation therapy (SIRT) using yttrium-90 resin microspheres, also called transarterial radioembolization. Objective The aim of this analysis is to prospectively combine clinical data from 3 trials to allow adequate power to evaluate the impact of chemotherapy with SIRT on overall survival. Methods Eligible patients are adults with histologically confirmed CRC and unequivocal evidence of liver metastases which are not treatable by surgical resection or local ablation with curative intent at the time of study entry. Patients may also have limited extrahepatic metastases. Final analysis will take place when all participants have been followed up for a minimum of 2 years. Results Efficacy and safety estimates derived using individual participant data (IPD) from SIRFLOX, FOXFIRE, and FOXFIRE-Global will be pooled using 2-stage prospective meta-analysis. Secondary outcome measures include progression-free survival (PFS), liver-specific PFS, health-related quality of life, response rate, resection rate, and adverse event profile. The

  1. Analysis of surgery for incurable gastric cancer.

    PubMed

    Zhao, Honguang; Chen, Wenhu; Lin, Yehua; Qin, Jiangfeng; Wang, Lifang

    2015-12-18

    It is important to evaluate the curability of and avoid unnecessary exploratory surgery for gastric cancer preoperatively. However, no related research has been reported until now. The aim of this study was to evaluate the factors influencing surgery for incurable gastric cancer. 310 cases of T3-4 gastric cancer patients were analyzed retrospectively, including 141 cases with radical surgery and 169 with surgery for incurable gastric cancer. The incurable factors were categorized as T status (unresectable T4 tumor), N status (unresectable lymph node), peritoneal metastasis, and distant metastasis. χ (2) test and logistic regression were performed to analyze the associations between curability, T status, N status, peritoneal metastasis, or distant metastasis and clinicopathological data. Esophageal involvement and T grade were associated with curability. Cardia involvement and Borrmann type were associated with T status. Esophageal involvement and T grade were associated with N status. Gastric body involvement, esophageal involvement, and T grade were associated with peritoneal metastasis. Gastric antrum involvement was associated with distant metastasis. The influencing factors of surgery for incurable gastric cancer should be analyzed preoperatively. Resectability should be evaluated according to these influencing factors combined with imaging analysis.

  2. First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX, and FOXFIRE-Global): a combined analysis of three multicentre, randomised, phase 3 trials.

    PubMed

    Wasan, Harpreet S; Gibbs, Peter; Sharma, Navesh K; Taieb, Julien; Heinemann, Volker; Ricke, Jens; Peeters, Marc; Findlay, Michael; Weaver, Andrew; Mills, Jamie; Wilson, Charles; Adams, Richard; Francis, Anne; Moschandreas, Joanna; Virdee, Pradeep S; Dutton, Peter; Love, Sharon; Gebski, Val; Gray, Alastair; van Hazel, Guy; Sharma, Ricky A

    2017-09-01

    Data suggest selective internal radiotherapy (SIRT) in third-line or subsequent therapy for metastatic colorectal cancer has clinical benefit in patients with colorectal liver metastases with liver-dominant disease after chemotherapy. The FOXFIRE, SIRFLOX, and FOXFIRE-Global randomised studies evaluated the efficacy of combining first-line chemotherapy with SIRT using yttrium-90 resin microspheres in patients with metastatic colorectal cancer with liver metastases. The studies were designed for combined analysis of overall survival. FOXFIRE, SIRFLOX, and FOXFIRE-Global were randomised, phase 3 trials done in hospitals and specialist liver centres in 14 countries worldwide (Australia, Belgium, France, Germany, Israel, Italy, New Zealand, Portugal, South Korea, Singapore, Spain, Taiwan, the UK, and the USA). Chemotherapy-naive patients with metastatic colorectal cancer (WHO performance status 0 or 1) with liver metastases not suitable for curative resection or ablation were randomly assigned (1:1) to either oxaliplatin-based chemotherapy (FOLFOX: leucovorin, fluorouracil, and oxaliplatin) or FOLFOX plus single treatment SIRT concurrent with cycle 1 or 2 of chemotherapy. In FOXFIRE, FOLFOX chemotherapy was OxMdG (oxaliplatin modified de Gramont chemotherapy; 85 mg/m(2) oxaliplatin infusion over 2 h, L-leucovorin 175 mg or D,L-leucovorin 350 mg infusion over 2 h, and 400 mg/m(2) bolus fluorouracil followed by a 2400 mg/m(2) continuous fluorouracil infusion over 46 h). In SIRFLOX and FOXFIRE-Global, FOLFOX chemotherapy was modified FOLFOX6 (85 mg/m(2) oxaliplatin infusion over 2 h, 200 mg leucovorin, and 400 mg/m(2) bolus fluorouracil followed by a 2400 mg/m(2) continuous fluorouracil infusion over 46 h). Randomisation was done by central minimisation with four factors: presence of extrahepatic metastases, tumour involvement of the liver, planned use of a biological agent, and investigational centre. Participants and investigators were not masked to treatment. The

  3. Combination Treatment of Tamoxifen with Risperidone in Breast Cancer

    PubMed Central

    Yeh, Wei-Lan; Lin, Hui-Yi; Wu, Hung-Ming; Chen, Dar-Ren

    2014-01-01

    Tamoxifen has long been used and still is the most commonly used endocrine therapy for treatment of both early and advanced estrogen receptor-positive breast cancer in pre- and post-menopause women. Tamoxifen exerts its cytotoxic effect primarily through cytostasis which is associated with the accumulation of cells in the G0/G1 phase of the cell cycle. Apoptotic activity can also be exerted by tamoxifen which involves cleavage of caspase 9, caspase 7, caspase 3, and poly-ADP-ribose polymerase (PARP). Down-regulation of anti-apoptotic proteins Bcl-2 and Bcl-xL and up-regulation of pro-apoptotic proteins Bax and Bak have also been observed. In addition, stress response protein of GRP 94 and GRP 78 have also been induced by tamoxifen in our study. However, side effects occur during tamoxifen treatment in breast cancer patients. Researching into combination regimen of tamoxifen and drug(s) that relieves tamoxifen-induced hot flushes is important, because drug interactions may decrease tamoxifen efficacy. Risperidone has been shown to be effective in reducing or eliminating hot flushes on women with hormonal variations. In this present study, we demonstrated that combination of tamoxifen with risperidone did not interfered tamoxifen-induced cytotoxic effects in both in vitro and in vivo models, while fluoxetine abrogated the effects of tamoxifen. This is the first paper suggesting the possibility of combination treatment of tamoxifen with risperidone in breast cancer patients, providing a conceivable resolution of tamoxifen-induced side effects without interfering the efficacy of tamoxifen against breast cancer. PMID:24886861

  4. Dose-Escalation Study of Thoracic Radiotherapy in Combination With Pemetrexed Plus Cisplatin in Japanese Patients With Locally Advanced Nonsquamous Non-Small Cell Lung Cancer: A Post Hoc Analysis of Survival and Recurrent Sites.

    PubMed

    Niho, Seiji; Nokihara, Hiroshi; Nihei, Keiji; Akimoto, Tetsuo; Sumi, Minako; Ito, Yoshinori; Yoh, Kiyotaka; Goto, Koichi; Ohmatsu, Hironobu; Horinouchi, Hidehito; Yamamoto, Noboru; Sekine, Ikuo; Kubota, Kaoru; Ohe, Yuichiro; Tamura, Tomohide

    2016-04-01

    We performed a post hoc analysis of progression-free survival (PFS), overall survival (OS), and recurrent sites in patients with locally advanced nonsquamous non-small cell lung cancer who were enrolled in a phase I trial of combination chemotherapy consisting of pemetrexed plus cisplatin with concurrent thoracic radiotherapy. Patients received pemetrexed (500 mg/m²) plus cisplatin (75 mg/m²) on day 1 every 3 weeks for 3 cycles plus concurrent thoracic radiotherapy consisting of 60 Gy (n=6) or 66 Gy (n=12); 4 to 6 weeks thereafter, patients received consolidation treatment with pemetrexed (500 mg/m) every 3 weeks for up to 3 cycles. We reviewed the medial records to collect data on progression, recurrent sites, late toxicity, and survival. No late radiation morbidity was observed. Thirteen patients (72%) exhibited disease progression: 8 patients had distant metastases, 8 patients had local recurrence (within the radiation field [n=6], outside the radiation field [n=2], and both [n=1]), and 3 patients had local recurrence plus distant metastases. The median PFS was 10.5 months (95% confidence interval [CI], 8.8-12.3), and the 3-year PFS rate was 28% (95% CI, 7.0-48.6). Ten of the 18 patients died of lung cancer. The median follow-up time for the censored cases was 42.8 months (range, 38.1 to 52.9 mo). The median OS was 27.3 months (95% CI, 13.1-41.6), and the 3-year OS rate was 50% (95% CI, 26.9-73.1). The median PFS and OS in our study were comparable to those of historical chemoradiotherapy controls.

  5. Targeting breast cancer stem cells in triple-negative breast cancer using a combination of LBH589 and salinomycin.

    PubMed

    Kai, Masaya; Kanaya, Noriko; Wu, Shang V; Mendez, Carlos; Nguyen, Duc; Luu, Thehang; Chen, Shiuan

    2015-06-01

    The aim of this study is to investigate the efficacy of combining a histone deacetylase inhibitor (LBH589) and a breast cancer stem cells (BCSC)-targeting agent (salinomycin) as a novel combination therapy for triple-negative breast cancer (TNBC). We performed in vitro studies using the TNBC cell lines to examine the combined effect. We used the mammosphere and ALDEFLUOR assays to estimate BCSC self-renewal capacity and distribution of BCSCs, respectively. Synergistic analysis was performed using CalcuSyn software. For in vivo studies, aldehyde dehydrogenase 1 ALDH1-positive cells were injected into non-obese diabetic/severe combined immunodeficiency gamma (NSG) mice. After tumor formation, mice were treated with LBH589, salinomycin, or in combination. In a second mouse model, HCC1937 cells were first treated with each treatment and then injected into NSG mice. For mechanistic analysis, immunohistochemistry and Western blot analysis were performed using cell and tumor samples. HCC1937 cells displayed BCSC properties including self-renewal capacity, an ALDH1-positive cell population, and the ability to form tumors. Treatment of HCC1937 cells with LBH589 and salinomycin had a potent synergistic effect inhibiting TNBC cell proliferation, ALDH1-positive cells, and mammosphere growth. In xenograft mouse models treated with LBH589 and salinomycin, the drug combination effectively and synergistically inhibited tumor growth of ALDH1-positive cells. The drug combination exerted its effects by inducing apoptosis, arresting the cell cycle, and regulating epithelial-mesenchymal transition (EMT). Combination of LBH589 and salinomycin has a synergistic inhibitory effect on TNBC BCSCs by inducing apoptosis, arresting the cell cycle, and regulating EMT; with no apparent associated severe toxicity. This drug combination could therefore offer a new targeted therapeutic strategy for TNBC and warrants further clinical study in patients with TNBC.

  6. Combined anticancer activity of osthole and cisplatin in NCI-H460 lung cancer cells in vitro.

    PubMed

    Xu, Xiao-Man; Zhang, Yi; Qu, Dan; Liu, Hong-Bo; Gu, Xiu; Jiao, Guang-Yu; Zhao, Li

    2013-03-01

    Drug combination therapies are common practice in the treatment of cancer. Cisplatin is the most active chemotherapeutic agent for lung cancer treatment. Osthole is a natural compound extracted from a number of medicinal plants. To determine whether osthole enhances the anticancer effect of cisplatin in human lung cancer, we treated NCI-H460 cells with osthole alone or in combination with cisplatin and evaluated cell growth and apoptosis using 3-(4,5-dimethyl thiazol-2yl)-2,5-diphenyltetrazolium bromide (MTT) assay, flow cytometry and fluorescence microscopy. The results showed that, in comparison with single agent treatment, the combination of osthole and cisplatin resulted in greater efficacy in growth inhibition and apoptosis induction. Western blot analysis revealed that the combination effect of osthole and cisplatin was due to regulation of the Bcl-2 family proteins. Findings of this investigation suggested that osthole combined with cisplatin is a potential clinical chemotherapeutic approach in human lung cancer.

  7. Average Risks of Breast and Ovarian Cancer Associated with BRCA1 or BRCA2 Mutations Detected in Case Series Unselected for Family History: A Combined Analysis of 22 Studies

    PubMed Central

    Antoniou, A.; Pharoah, P. D. P.; Narod, S.; Risch, H. A.; Eyfjord, J. E.; Hopper, J. L.; Loman, N.; Olsson, H.; Johannsson, O.; Borg, Å.; Pasini, B.; Radice, P.; Manoukian, S.; Eccles, D. M.; Tang, N.; Olah, E.; Anton-Culver, H.; Warner, E.; Lubinski, J.; Gronwald, J.; Gorski, B.; Tulinius, H.; Thorlacius, S.; Eerola, H.; Nevanlinna, H.; Syrjäkoski, K.; Kallioniemi, O.-P.; Thompson, D.; Evans, C.; Peto, J.; Lalloo, F.; Evans, D. G.; Easton, D. F.

    2003-01-01

    Germline mutations in BRCA1 and BRCA2 confer high risks of breast and ovarian cancer, but the average magnitude of these risks is uncertain and may depend on the context. Estimates based on multiple-case families may be enriched for mutations of higher risk and/or other familial risk factors, whereas risk estimates from studies based on cases unselected for family history have been imprecise. We pooled pedigree data from 22 studies involving 8,139 index case patients unselected for family history with female (86%) or male (2%) breast cancer or epithelial ovarian cancer (12%), 500 of whom had been found to carry a germline mutation in BRCA1 or BRCA2. Breast and ovarian cancer incidence rates for mutation carriers were estimated using a modified segregation analysis, based on the occurrence of these cancers in the relatives of mutation-carrying index case patients. The average cumulative risks in BRCA1-mutation carriers by age 70 years were 65% (95% confidence interval 44%–78%) for breast cancer and 39% (18%–54%) for ovarian cancer. The corresponding estimates for BRCA2 were 45% (31%–56%) and 11% (2.4%–19%). Relative risks of breast cancer declined significantly with age for BRCA1-mutation carriers (P trend .0012) but not for BRCA2-mutation carriers. Risks in carriers were higher when based on index breast cancer cases diagnosed at <35 years of age. We found some evidence for a reduction in risk in women from earlier birth cohorts and for variation in risk by mutation position for both genes. The pattern of cancer risks was similar to those found in multiple-case families, but their absolute magnitudes were lower, particularly for BRCA2. The variation in risk by age at diagnosis of index case is consistent with the effects of other genes modifying cancer risk in carriers. PMID:12677558

  8. Unique molecular landscapes in cancer: implications for individualized, curated drug combinations.

    PubMed

    Wheler, Jennifer; Lee, J Jack; Kurzrock, Razelle

    2014-12-15

    With increasingly sophisticated technologies in molecular biology and "omic" platforms to analyze patients' tumors, more molecular diversity and complexity in cancer are being observed. Recently, we noted unique genomic profiles in a group of patients with metastatic breast cancer based on an analysis with next-generation sequencing. Among 57 consecutive patients, no two had the same molecular portfolio. Applied genomics therefore appears to represent a disruptive innovation in that it unveils a heterogeneity to metastatic cancer that may be ill-suited to canonical clinical trials and practice paradigms. Upon recognizing that patients have unique tumor landscapes, it is possible that there may be a "mismatch" between our traditional clinical trials system that selects patients based on common characteristics to evaluate a drug (drug-centric approach) and optimal treatment based on curated, individualized drug combinations for each patient (patient-centric approach). ©2014 American Association for Cancer Research.

  9. Evolutionary dynamics of cancer in response to targeted combination therapy

    PubMed Central

    Bozic, Ivana; Reiter, Johannes G; Allen, Benjamin; Antal, Tibor; Chatterjee, Krishnendu; Shah, Preya; Moon, Yo Sup; Yaqubie, Amin; Kelly, Nicole; Le, Dung T; Lipson, Evan J; Chapman, Paul B; Diaz, Luis A; Vogelstein, Bert; Nowak, Martin A

    2013-01-01

    In solid tumors, targeted treatments can lead to dramatic regressions, but responses are often short-lived because resistant cancer cells arise. The major strategy proposed for overcoming resistance is combination therapy. We present a mathematical model describing the evolutionary dynamics of lesions in response to treatment. We first studied 20 melanoma patients receiving vemurafenib. We then applied our model to an independent set of pancreatic, colorectal, and melanoma cancer patients with metastatic disease. We find that dual therapy results in long-term disease control for most patients, if there are no single mutations that cause cross-resistance to both drugs; in patients with large disease burden, triple therapy is needed. We also find that simultaneous therapy with two drugs is much more effective than sequential therapy. Our results provide realistic expectations for the efficacy of new drug combinations and inform the design of trials for new cancer therapeutics. DOI: http://dx.doi.org/10.7554/eLife.00747.001 PMID:23805382

  10. Combined effects of atorvastatin and aspirin on growth and apoptosis in human prostate cancer cells.

    PubMed

    He, Yan; Huang, Huarong; Farischon, Chelsea; Li, Dongli; Du, Zhiyun; Zhang, Kun; Zheng, Xi; Goodin, Susan

    2017-02-01

    Epidemiologic studies indicate the use of either statins or aspirin have beneficial effects in prostate cancer patients. The present study was undertaken to evaluate the effects and mechanisms of atorvastatin and aspirin alone or in combination in human prostate cancer cells cultured in vitro and grown as xenograft tumors in severe combined immune-deficient (SCID) mice. The growth and apoptosis in prostate cancer cells were determined by the trypan blue exclusion and propidium iodide staining assays. Activation of the nuclear factor κB (NF-κB) was measured by luciferase reporter assay, and the levels of phospho-signal transducer and activator of transcription (Stat)3 and phospho-extracellular signal-regulated kinase (Erk)1/2 were determined by western blot analysis. Mice were injected subcutaneously with PC-3 cells in Matrigel. After 4-6 weeks, mice with PC-3 tumors received i.p. injections of vehicle, atorvastatin (5 mg/kg), aspirin (80 mg/kg), or atorvastatin (5 mg/kg) + aspirin (80 mg/kg) three times a week for 30 days. Our results demonstrated the combination of atorvastatin and aspirin had more potent effects on growth inhibition and apoptosis stimulation in prostate cancer cells than either drug alone. Mechanistic studies indicated the induction of apoptosis in PC-3 cells was associated with strong inhibition of NF-κB and decreases in the levels of phospho-Stat3 and phospho-Erk1/2. Results of the present study demonstrated a strong combined effect of atorvastatin and aspirin on inhibiting the growth of prostate cancer cells in vitro and in vivo. The findings provide a strong rationale for clinical evaluation of the combination of atorvastatin and aspirin in patients with prostate cancer.

  11. Paraneoplastic tumefactive demyelination with underlying combined germ cell cancer.

    PubMed

    Broadfoot, Jack R; Archer, Hilary A; Coulthard, Elizabeth; Appelman, Auke P A; Sutak, Judit; Braybrooke, Jeremy P; Love, Seth

    2015-12-01

    Paraneoplastic demyelination is a rare disorder of the central nervous system. We describe a 60-year-old man with tumefactive demyelination who had an underlying retroperitoneal germ cell cancer. He presented with visuospatial problems and memory loss and had a visual field defect. His MRI was interpreted as a glioma but stereotactic biopsy showed active demyelination. Investigation for multiple sclerosis was negative but CT imaging showed retroperitoneal lymphadenopathy, and nodal biopsy confirmed a combined germ cell cancer. He responded poorly to corticosteroid treatment, and his visual field defect progressed. However, 6 months after plasma exchange and successful chemotherapy, he has partially improved clinically and radiographically. Tumefactive demyelination is typically associated with multiple sclerosis but may be paraneoplastic. It is important to recognise paraneoplastic tumefactive demyelination early, as the neurological outcome relies on treating the associated malignancy.

  12. Long non-coding RNAs may serve as biomarkers in breast cancer combined with primary lung cancer

    PubMed Central

    Mao, Weimin; Chen, Bo; Yang, Shifeng; Ding, Xiaowen; Zou, Dehong; Mo, Wenju; He, Xiangming; Zhang, Xiping

    2017-01-01

    Long non-coding RNAs (lncRNAs) have been shown to play important regulatory role in certain type of cancers biology, including breast and lung cancers. However, the lncRNA expression in breast cancer combined with primary lung cancer remains unknown. In this study, databases of the Cancer Genome Atlas (TCGA) and the lncRNA profiler of contained candidate 192 lncRNAs were utilized. 11 lncRNAs were differentially expressed in breast cancer, 9 candidate lncRNAs were differentially expressed in lung cancer. In order to find the aberrant expression of lncRNAs in breast cancer combined with primary lung cancer, seven samples of primary breast cancer and lung cancer were studied for the expression of selected lncRNAs. The results showed that SNHG6 and NEAT1 were reversely expressed in breast cancer combined with primary lung cancer compared with primary breast or lung cancer. In addition, a significant correlation of lncRNAs was found in the patients whose age was above 56 in breast cancer. What's more, PVT1 expression was negatively correlated with the pathological stage, and the level of ER, PR, HER2, p53 in breast cancer. Furthermore, lncRNA expression did not have significant relationship with the 5-year survival of patients with breast cancer combined with primary lung cancer. The findings revealed that PVT1, SNHG6, NEAT1 may serve as a prognostic marker for breast cancer combined with primary lung cancer. Therefore, these lncRNAs are potential molecular indicators in the diagnosis and prognosis of cancer in the future. PMID:28938549

  13. Pemetrexed monotherapy for chemo-naïve elderly (aged ≥80) patients with non-squamous non-small cell lung cancer: results from combined analysis of two single arm phase II studies (HANSHIN002 and 003).

    PubMed

    Hata, Akito; Katakami, Nobuyuki; Hattori, Yoshihiro; Tanaka, Kosuke; Fujita, Shiro; Kotani, Yoshikazu; Nishimura, Takashi; Imamura, Fumio; Yokota, Soichiro; Satouchi, Miyako; Monden, Kazuya; Otsuka, Kojiro; Nishiyama, Akihiro; Tsubouchi, Kazuya; Kaneda, Toshihiko; Yoshioka, Hiroshige; Morita, Satoshi; Negoro, Shunichi

    2017-04-01

    The aim of this retrospective study was to evaluate via combined analysis the efficacy and safety of pemetrexed monotherapy for chemo-naïve elderly patients aged ≥80 with non-squamous non-small cell lung cancer (NSCLC). We conducted a combined analysis from two phase II studies of pemetrexed for chemo-naïve elderly (aged ≥75) (n = 47) and performance status 2 (n = 28) patients with advanced non-squamous NSCLC. Population aged ≥80 (80+ Group) was compared to those aged 70-79 (70's Group). We analyzed a total of 66 patients (37 70s and 29 80+ Groups) after exclusion of 4 ineligible and 5 aged ≤69 patients. Overall response rate, disease control rate, median progression-free survival, and median overall survival of 70s vs. 80+ Groups were 13.5 vs. 13.8% [p = not significant (NS)], 67.6 vs. 58.6% (p = 0.608), 3.7 months vs. 4.2 months (p = 0.5588) and 18.5 vs. 13.5 months (p = 0.2621), respectively. Non-hematological and hematological toxicities ≥grade 3 of 70s vs. 80+ Groups were 24 vs. 35% (p = 0.4192) and 49 vs. 52% (p = NS), respectively. Dose reduction and/or delay due to toxicities of 70s vs. 80+ Groups was 19 vs. 28% (p = 0.7784). Febrile neutropenia and interstitial lung disease were not observed. Treatment-related death (bacterial pneumonia) was confirmed in one (3%) of 29 80+ Group patients. Pemetrexed monotherapy demonstrated similar efficacy and safety between aged ≥80 and aged 70-79 populations. It could be a therapeutic option in clinical practice for elderly non-squamous NSCLC patients aged ≥80 without indications of carboplatin-based combination regimens or docetaxel monotherapy.

  14. A Combined Negative and Positive Enrichment Assay for Cancer Cells Isolation and Purification.

    PubMed

    Cheng, Boran; Wang, Shuyi; Chen, Yuanyuan; Fang, Yuan; Chen, Fangfang; Wang, Zhenmeng; Xiong, Bin

    2016-02-01

    Cancer cells that detach from solid tumor and circulate in the peripheral blood (CTCs) have been considered as a new "biomarker" for the detection and characterization of cancers. However, isolating and detecting cancer cells from the cancer patient peripheral blood have been technically challenging, owing to the small sub-population of CTCs (a few to hundreds per milliliter). Here we demonstrate a simple and efficient cancer cells isolation and purification method. A biocompatible and surface roughness controllable TiO2 nanofilm was deposited onto a glass slide to achieve enhanced topographic interactions with nanoscale cellular surface components, again, anti-CD45 (a leukocyte common antigen) and anti-EpCAM (epithelial cell adhesion molecule) were then coated onto the surface of the nanofilm for advance depletion of white blood cells (WBCs) and specific isolation of CTCs, respectively. Comparing to the conventional positive enrichment technology, this method exhibited excellent biocompatibility and equally high capture efficiency. Moreover, the maximum number of background cells (WBCs) was removed, and viable and functional cancer cells were isolated with high purity. Utilizing the horizontally packed TiO2 nanofilm improved pure CTC-capture through combining cell-capture-agent and cancer cell-preferred nanoscale topography, which represented a new method capable of obtaining biologically functional CTCs for subsequent molecular analysis.

  15. [Combination of Targeted Therapy and Immunotherapy for Cancer].

    PubMed

    Kadowaki, Norimitsu

    2015-09-01

    Targeted therapies and immunotherapies attack tumor cells through different mechanisms. In addition, these therapies exhibit quick and delayed effects, respectively, and therefore, these therapies are complementary. Furthermore, targeted therapies may enhance the function of immune cells, and therefore, both the therapies are expected to have a synergistic effect. Antitumor immune responses comprise several steps including dendritic cell activation, T cell activation, and dampening tumor-induced immunosuppression; targeted drugs that work at each step have been reported. Clinical trials of rational combinations of both therapies, while avoiding severe adverse events, will greatly advance cancer treatments in the near future.

  16. Metabolomic Profiling of the Synergistic Effects of Melittin in Combination with Cisplatin on Ovarian Cancer Cells

    PubMed Central

    Alonezi, Sanad; Tusiimire, Jonans; Wallace, Jennifer; Dufton, Mark J.; Parkinson, John A.; Young, Louise C.; Clements, Carol J.; Park, Jin-Kyu; Jeon, Jong-Woon; Ferro, Valerie A.; Watson, David G.

    2017-01-01

    Melittin, the main peptide present in bee venom, has been proposed as having potential for anticancer therapy; the addition of melittin to cisplatin, a first line treatment for ovarian cancer, may increase the therapeutic response in cancer treatment via synergy, resulting in improved tolerability, reduced relapse, and decreased drug resistance. Thus, this study was designed to compare the metabolomic effects of melittin in combination with cisplatin in cisplatin-sensitive (A2780) and resistant (A2780CR) ovarian cancer cells. Liquid chromatography (LC) coupled with mass spectrometry (MS) was applied to identify metabolic changes in A2780 (combination treatment 5 μg/mL melittin + 2 μg/mL cisplatin) and A2780CR (combination treatment 2 μg/mL melittin + 10 μg/mL cisplatin) cells. Principal components analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) multivariate data analysis models were produced using SIMCA-P software. All models displayed good separation between experimental groups and high-quality goodness of fit (R2) and goodness of prediction (Q2), respectively. The combination treatment induced significant changes in both cell lines involving reduction in the levels of metabolites in the tricarboxylic acid (TCA) cycle, oxidative phosphorylation, purine and pyrimidine metabolism, and the arginine/proline pathway. The combination of melittin with cisplatin that targets these pathways had a synergistic effect. The melittin-cisplatin combination had a stronger effect on the A2780 cell line in comparison with the A2780CR cell line. The metabolic effects of melittin and cisplatin in combination were very different from those of each agent alone. PMID:28420117

  17. Additively enhanced antiproliferative effect of interferon combined with proanthocyanidin on bladder cancer cells.

    PubMed

    Fishman, Andrew I; Johnson, Blake; Alexander, Bobby; Won, John; Choudhury, Muhammad; Konno, Sensuke

    2012-01-01

    Although interferon (IFN) has been often used as immunotherapy for bladder cancer, its efficacy is rather unsatisfactory, demanding further improvement. Combination therapy is one of viable options, and grape seed proanthocyanidin (GSP) could be such an agent to be used with IFN because it has been shown to have anticancer activity. We thus investigated whether combination of IFN and GSP might enhance the overall antiproliferative effect on bladder cancer cells in vitro. Human bladder cancer T24 cells were employed and treated with the varying concentrations of recombinant IFN-α(2b) (0-100,000 IU/ml), GSP (0-100 μg/ml), or their combinations. IFN-α(2b) alone led to a ~50% growth reduction at 20,000 (20K) IU/ml, which further declined to ~67% at ≥50K IU/ml. Similarly, GSP alone induced a ~35% and ~100% growth reduction at 25 and ≥50 μg/ml, respectively. When IFN-α(2b) and GSP were then combined, combination of 50K IU/ml IFN-α(2b) and 25 μg/ml GSP resulted in a drastic >95% growth reduction. Cell cycle analysis indicated that such an enhanced growth inhibition was accompanied by a G(1) cell cycle arrest. This was further confirmed by Western blot analysis revealing that expressions of G(1)-specific cell cycle regulators (CDK2, CDK4, cyclin E and p27/Kip1) were distinctly modulated with such IFN-α(2b)/GSP treatment. Therefore, these findings support the notion that combination of IFN-α(2b) and GSP is capable of additively enhancing antiproliferative effect on T24 cells with a G(1) cell cycle arrest, implying an adjuvant therapeutic modality for superficial bladder cancer.

  18. Repositioning FDA-Approved Drugs in Combination with Epigenetic Drugs to Reprogram Colon Cancer Epigenome.

    PubMed

    Raynal, Noël J-M; Da Costa, Elodie M; Lee, Justin T; Gharibyan, Vazganush; Ahmed, Saira; Zhang, Hanghang; Sato, Takahiro; Malouf, Gabriel G; Issa, Jean-Pierre J

    2017-02-01

    Epigenetic drugs, such as DNA methylation inhibitors (DNMTi) or histone deacetylase inhibitors (HDACi), are approved in monotherapy for cancer treatment. These drugs reprogram gene expression profiles, reactivate tumor suppressor genes (TSG) producing cancer cell differentiation and apoptosis. Epigenetic drugs have been shown to synergize with other epigenetic drugs or various anticancer drugs. To discover new molecular entities that enhance epigenetic therapy, we performed a high-throughput screening using FDA-approved libraries in combination with DNMTi or HDACi. As a screening model, we used YB5 system, a human colon cancer cell line, which contains an epigenetically silenced CMV-GFP locus, mimicking TSG silencing in cancer. CMV-GFP reactivation is triggered by DNMTi or HDACi and responds synergistically to DNMTi/HDACi combination, which phenocopies TSG reactivation upon epigenetic therapy. GFP fluorescence was used as a quantitative readout for epigenetic activity. We discovered that 45 FDA-approved drugs (4% of all drugs tested) in our FDA-approved libraries enhanced DNMTi and HDACi activity, mainly belonging to anticancer and antiarrhythmic drug classes. Transcriptome analysis revealed that combination of decitabine (DNMTi) with the antiarrhythmic proscillaridin A produced profound gene expression reprogramming, which was associated with downregulation of 153 epigenetic regulators, including two known oncogenes in colon cancer (SYMD3 and KDM8). Also, we identified about 85 FDA-approved drugs that antagonized DNMTi and HDACi activity through cytotoxic mechanisms, suggesting detrimental drug interactions for patients undergoing epigenetic therapy. Overall, our drug screening identified new combinations of epigenetic and FDA-approved drugs, which can be rapidly implemented into clinical trials. Mol Cancer Ther; 16(2); 397-407. ©2016 AACR.

  19. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233

    PubMed Central

    Mak, Raymond H.; Hunt, Daniel; Shipley, William U.; Efstathiou, Jason A.; Tester, William J.; Hagan, Michael P.; Kaufman, Donald S.; Heney, Niall M.; Zietman, Anthony L.

    2014-01-01

    Purpose Multiple prospective Radiation Therapy Oncology Group (RTOG) protocols have evaluated bladder-preserving combined-modality therapy (CMT) for muscle-invasive bladder cancer (MIBC), reserving cystectomy for salvage treatment. We performed a pooled analysis of long-term outcomes in patients with MIBC enrolled across multiple studies. Patients and Methods Four hundred sixty-eight patients with MIBC were enrolled onto six RTOG bladder-preservation studies, including five phase II studies (RTOG 8802, 9506, 9706, 9906, and 0233) and one phase III study (RTOG 8903). Overall survival (OS) was estimated using the Kaplan-Meier method, and disease-specific survival (DSS), muscle-invasive and non–muscle-invasive local failure (LF), and distant metastasis (DM) were estimated by the cumulative incidence method. Results The median age of patients was 66 years (range, 34 to 93 years), and clinical T stage was T2 in 61%, T3 in 35%, and T4a in 4% of patients. Complete response to CMT was documented in 69% of patients. With a median follow-up of 4.3 years among all patients and 7.8 years among survivors (n = 205), the 5- and 10-year OS rates were 57% and 36%, respectively, and the 5- and 10-year DSS rates were 71% and 65%, respectively. The 5- and 10-year estimates of muscle-invasive LF, non–muscle-invasive LF, and DM were 13% and 14%, 31% and 36%, and 31% and 35%, respectively. Conclusion This pooled analysis of multicenter, prospective RTOG bladder-preserving CMT protocols demonstrates long-term DSS comparable to modern immediate cystectomy studies, for patients with similarly staged MIBC. Given the low incidence of late recurrences with long-term follow-up, CMT can be considered as an alternative to radical cystectomy, especially in elderly patients not well suited for surgery. PMID:25366678

  20. Analysis of fractals with combined partition

    NASA Astrophysics Data System (ADS)

    Dedovich, T. G.; Tokarev, M. V.

    2016-03-01

    The space—time properties in the general theory of relativity, as well as the discreteness and non-Archimedean property of space in the quantum theory of gravitation, are discussed. It is emphasized that the properties of bodies in non-Archimedean spaces coincide with the properties of the field of P-adic numbers and fractals. It is suggested that parton showers, used for describing interactions between particles and nuclei at high energies, have a fractal structure. A mechanism of fractal formation with combined partition is considered. The modified SePaC method is offered for the analysis of such fractals. The BC, PaC, and SePaC methods for determining a fractal dimension and other fractal characteristics (numbers of levels and values of a base of forming a fractal) are considered. It is found that the SePaC method has advantages for the analysis of fractals with combined partition.

  1. Combined effect of tobacco smoking and alcohol drinking in the risk of head and neck cancers: a re-analysis of case-control studies using bi-dimensional spline models.

    PubMed

    Dal Maso, Luigino; Torelli, Nicola; Biancotto, Elisa; Di Maso, Matteo; Gini, Andrea; Franchin, Gianni; Levi, Fabio; La Vecchia, Carlo; Serraino, Diego; Polesel, Jerry

    2016-04-01

    The synergistic effect of tobacco smoking and alcohol consumption on the risk of head and neck cancers has been mainly investigated as a cross-product of categorical exposure, thus leading to loss of information. We propose a bi-dimensional logistic spline model to investigate the interacting dose-response relationship of two continuous exposures (i.e., ethanol intake and tobacco smoking) on the risk of head and neck cancers, representing results through three-dimensional graphs. This model was applied to a pool of hospital-based case-control studies on head and neck cancers conducted in Italy and in the Vaud Swiss Canton between 1982 and 2000, including 1569 cases and 3147 controls. Among never drinkers and for all levels of ethanol intake, the risk of head and neck cancers steeply increased with increasing smoking intensity, starting from 1 cigarette/day. The risk associated to ethanol intake increased with incrementing exposure among smokers, and a threshold effect at approximately 50 g/day emerged among never smokers. Compared to abstainers from both tobacco and alcohol consumption, the combined exposure to ethanol and/or cigarettes led to a steep increase of cancer risk up to a 35-fold higher risk (95 % confidence interval 27.30-43.61) among people consuming 84 g/day of ethanol and 10 cigarettes/day. The highest risk was observed at the highest levels of alcohol and tobacco consumption. Our findings confirmed a combined effect of tobacco smoking and alcohol drinking on head and neck cancers risk, providing evidence that bi-dimensional spline models could be a feasible and flexible method to explore the pattern of risks associated to two interacting continuous-exposure variables.

  2. In silico identification of breast cancer genes by combined multiple high throughput analyses.

    PubMed

    Shen, Dejun; He, Jianbo; Chang, Helena R

    2005-02-01

    that the combined multiple high throughput analyses is an effective data mining strategy in cancer gene identification. This approach may improve the usage of public available genomic data through strategic data mining of high throughput analysis.

  3. Arctigenin in combination with quercetin synergistically enhances the anti-proliferative effect in prostate cancer cells

    PubMed Central

    Wang, Piwen; Phan, Tien; Gordon, David; Chung, Seyung; Henning, Susanne M.; Vadgama, Jaydutt V.

    2014-01-01

    Scope We investigated whether a combination of two promising chemopreventive agents arctigenin and quercetin increases the anti-carcinogenic potency at lower concentrations than necessary when used individually in prostate cancer. Methods and results Androgen-dependent LAPC-4 and LNCaP prostate cancer cells were treated with low doses of arctigenin and quercetin alone or in combination for 48h. The anti-proliferative activity of arctigenin was 10-20 fold stronger than quercetin in both cell lines. Their combination synergistically enhanced the anti-proliferative effect, with a stronger effect in androgen receptor (AR) wild-type LAPC-4 cells than in AR mutated LNCaP cells. Arctigenin demonstrated a strong ability to inhibit AR protein expression in LAPC-4 cells. The combination treatment significantly inhibited both AR and PI3K/Akt pathways compared to control. A protein array analysis revealed that the mixture targets multiple pathways particularly in LAPC-4 cells including Stat3 pathway. The mixture significantly inhibited the expression of several oncogenic microRNAs including miR-21, miR-19b, and miR-148a compared to control. The mixture also enhanced the inhibition of cell migration in both cell lines compared to individual compounds tested. Conclusion The combination of arctigenin and quercetin, that target similar pathways, at low physiological doses, provides a novel regimen with enhanced chemoprevention in prostate cancer. PMID:25380086

  4. Arctigenin in combination with quercetin synergistically enhances the antiproliferative effect in prostate cancer cells.

    PubMed

    Wang, Piwen; Phan, Tien; Gordon, David; Chung, Seyung; Henning, Susanne M; Vadgama, Jaydutt V

    2015-02-01

    We investigated whether a combination of two promising chemopreventive agents arctigenin (Arc) and quercetin (Q) increases the anticarcinogenic potency at lower concentrations than necessary when used individually in prostate cancer. Androgen-dependent LAPC-4 and LNCaP prostate cancer cells were treated with low doses of Arc and Q alone or in combination for 48 h. The antiproliferative activity of Arc was 10- to 20-fold stronger than Q in both cell lines. Their combination synergistically enhanced the antiproliferative effect, with a stronger effect in androgen receptor (AR) wild-type LAPC-4 cells than in AR mutated LNCaP cells. Arc demonstrated a strong ability to inhibit AR protein expression in LAPC-4 cells. The combination treatment significantly inhibited both AR and PI3K/Akt pathways compared to control. A protein array analysis revealed that the mixture targets multiple pathways particularly in LAPC-4 cells including Stat3 pathway. The mixture significantly inhibited the expression of several oncogenic microRNAs including miR-21, miR-19b, and miR-148a compared to control. The mixture also enhanced the inhibition of cell migration in both cell lines compared to individual compounds tested. The combination of Arc and Q that target similar pathways, at low physiological doses, provides a novel regimen with enhanced chemoprevention in prostate cancer. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  5. Sorafenib and Radiation: A Promising Combination in Colorectal Cancer

    SciTech Connect

    Suen, Andrew W.; Galoforo, Sandra; Marples, Brian; McGonagle, Michele; Downing, Laura; Martinez, Alvaro A.; Robertson, John M.; Wilson, George D.

    2010-09-01

    Purpose: To examine the combination of radiation and the multikinase inhibitor sorafenib in human colorectal cancer cell lines and xenografts. Methods and Materials: HT29 and SW48 colorectal cancer cells were studied in vitro using MTT assays to establish the optimal timing of radiation and sorafenib. This optimal timing was then investigated in clonogenic survival assays. Xenografts were established, and the effect of a 3-week schedule of daily radiation and sorafenib was studied by growth delay. Results: Sorafenib predominantly had minimal effects on cell growth or radiation response in MTT growth assays, though growth inhibition was significantly enhanced in HT29 cells when sorafenib was administered after radiation. The highest dose of sorafenib altered the {alpha} component of the cell survival curve in clonogenic assays. The combination of radiation and sorafenib was synergistic in SW48 xenografts, with a mean time to threshold tumor size of 11.4 {+-} 1.0 days, 37.0 {+-} 9.5 days, 15.5 {+-} 3.2 days, and 98.0 {+-} 11.7 days in the control, radiation, sorafenib, and combined treatment group, respectively. The effect on HT29 tumors was additive, with mean time to threshold volume of 12.6 {+-} 1.1 days, 61.0 {+-} 4.3 days, 42.6 {+-} 11.7 days, and 100.2 {+-} 12.4 days. Conclusions: Sorafenib had little effect on radiation response in vitro but was highly effective when combined with radiation in vivo, suggesting that inhibition of proliferation and interference with angiogenesis may be the basis for the interaction.

  6. The future of cancer treatment: immunomodulation, CARs and combination immunotherapy

    PubMed Central

    Khalil, Danny N.; Smith, Eric L.; Brentjens, Renier J.; Wolchok, Jedd D.

    2017-01-01

    In the past decade, advances in the use of monoclonal antibodies (mAbs) and adoptive cellular therapy to treat cancer by modulating the immune response have led to unprecedented responses in patients with advanced-stage tumours that would otherwise have been fatal. To date, three immune-checkpoint-blocking mAbs have been approved in the USA for the treatment of patients with several types of cancer, and more patients will benefit from immunomodulatory mAb therapy in the months and years ahead. Concurrently, the adoptive transfer of genetically modified lymphocytes to treat patients with haematological malignancies has yielded dramatic results, and we anticipate that this approach will rapidly become the standard of care for an increasing number of patients. In this Review, we highlight the latest advances in immunotherapy and discuss the role that it will have in the future of cancer treatment, including settings for which testing combination strategies and ‘armoured’ CAR T cells are recommended. PMID:26977780

  7. Application of artificial neural network model combined with four biomarkers in auxiliary diagnosis of lung cancer.

    PubMed

    Duan, Xiaoran; Yang, Yongli; Tan, Shanjuan; Wang, Sihua; Feng, Xiaolei; Cui, Liuxin; Feng, Feifei; Yu, Songcheng; Wang, Wei; Wu, Yongjun

    2016-10-20

    The purpose of the study was to explore the application of artificial neural network model in the auxiliary diagnosis of lung cancer and compare the effects of back-propagation (BP) neural network with Fisher discrimination model for lung cancer screening by the combined detections of four biomarkers of p16, RASSF1A and FHIT gene promoter methylation levels and the relative telomere length. Real-time quantitative methylation-specific PCR was used to detect the levels of three-gene promoter methylation, and real-time PCR method was applied to determine the relative telomere length. BP neural network and Fisher discrimination analysis were used to establish the discrimination diagnosis model. The levels of three-gene promoter methylation in patients with lung cancer were significantly higher than those of the normal controls. The values of Z(P) in two groups were 2.641 (0.008), 2.075 (0.038) and 3.044 (0.002), respectively. The relative telomere lengths of patients with lung cancer (0.93 ± 0.32) were significantly lower than those of the normal controls (1.16 ± 0.57), t = 4.072, P < 0.001. The areas under the ROC curve (AUC) and 95 % CI of prediction set from Fisher discrimination analysis and BP neural network were 0.670 (0.569-0.761) and 0.760 (0.664-0.840). The AUC of BP neural network was higher than that of Fisher discrimination analysis, and Z(P) was 0.76. Four biomarkers are associated with lung cancer. BP neural network model for the prediction of lung cancer is better than Fisher discrimination analysis, and it can provide an excellent and intelligent diagnosis tool for lung cancer.

  8. Docetaxel combined with targeted therapies in metastatic breast cancer.

    PubMed

    Cortes, Javier; Roché, Henri

    2012-08-01

    The treatment of metastatic breast cancer (MBC) is essentially palliative and should be based on hormone therapy or optimized chemotherapy designed to delay disease progression and maximize survival with good quality of life. Novel chemotherapeutic agents introduced in the 1990 s include the taxanes (notably docetaxel), which are among the most potent of current anticancer drugs. Current research is also focusing on molecular targeted agents including those against the HER family of transmembrane receptors and vascular endothelial growth factor. Optimal effects are obtained when these compounds are used in combination with chemotherapy, as shown in preclinical models and more recently in clinical trials. Results of a large randomized trial have demonstrated a significant survival advantage for trastuzumab plus docetaxel compared with docetaxel monotherapy. Docetaxel plus bevacizumab combinations have recently been shown to significantly improve progression-free survival and objective response rate compared with docetaxel monotherapy. Overall, docetaxel in combination with novel targeted agents in MBC appears to be highly active in patients with MBC, and such combinations represent promising treatment regimens for clinical investigation. Copyright © 2011 Elsevier Ltd. All rights reserved.

  9. Reirradiation combined with hyperthermia in recurrent breast cancer results in a worthwhile local palliation

    PubMed Central

    Zee, J van der; Holt, B van der; Rietveld, P J M; Helle, P A; Wijnmaalen, A J; Putten, W L J van; Rhoon, G C van

    1999-01-01

    Both experimental and clinical research have shown that hyperthermia (HT) gives valuable additional effects when applied in combination with radiotherapy (RT). The purpose of this study was evaluation of results in patients with recurrent breast cancer, treated at the Daniel den Hoed Cancer Center (DHCC) with reirradiation (re-RT; eight fractions of 4 Gy twice weekly) combined with HT. All 134 patients for whom such treatment was planned were included in the analysis. The complete response rate in 119 patients with macroscopic tumour was 71%. Including the 15 patients with microscopic disease, the local control rate was 73%. The median duration of local control was 32 months, and toxicity was acceptable. The complete response (CR) rate was higher, and the toxicity was less with the later developed 433-MHz HT technique compared with the 2450-MHz technique used initially. With this relatively well-tolerated treatment, palliation by local tumour control of a worthwhile duration is achieved in the majority of patients. The technique used for hyperthermia appeared to influence the achieved results. The value of HT in addition to this re-RT schedule has been confirmed by a prospective randomized trial in a similar patient group. In The Netherlands, this combined treatment is offered as standard to patients with breast cancer recurring in previously irradiated areas. © 1999 Cancer Research Campaign PMID:10027317

  10. Combined Therapy of Oncolytic Adenovirus and Temozolomide Enhances Lung Cancer Virotherapy In Vitro and In Vivo

    PubMed Central

    Gomez-Gutierrez, Jorge G.; Nitz, Jonathan; Sharma, Rajesh; Wechman, Stephen L.; Riedinger, Eric; Martinez-Jaramillo, Elvis; Zhou, Heshan Sam; McMasters, Kelly M.

    2015-01-01

    Oncolytic adenoviruses (OAds) are very promising for the treatment of lung cancer. However, OAd-based monotherapeutics have not been effective during clinical trials. Therefore, the effectiveness of virotherapy must be enhanced by combining OAds with other therapies. In this study, the therapeutic potential of OAd in combination with temozolomide (TMZ) was evaluated in lung cancer cells in vitro and in vivo. The combination of OAd and TMZ therapy synergistically enhanced cancer cell death; this enhanced cancer cell death may be explained via three related mechanisms: apoptosis, virus replication, and autophagy. Autophagy inhibition partially protected cancer cells from this combined therapy. This combination significantly suppressed the growth of subcutaneous H441 lung cancer xenograft tumors in athymic nude mice. In this study, we have provided an experimental rationale to test OAds in combination with TMZ in a lung cancer clinical trial. PMID:26561948

  11. Targeting Cancer using Polymeric Nanoparticle mediated Combination Chemotherapy

    PubMed Central

    Gad, Aniket; Kydd, Janel; Piel, Brandon; Rai, Prakash

    2016-01-01

    Cancer forms exhibiting poor prognosis have been extensively researched for therapeutic solutions. One of the conventional modes of treatment, chemotherapy shows inadequacy in its methodology due to imminent side-effects and acquired drug-resistance by cancer cells. However, advancements in nanotechnology have opened new frontiers to significantly alleviate collateral damage caused by current treatments via innovative delivery techniques, eliminating pitfalls encountered in conventional treatments. Properties like reduced drug-clearance and increased dose efficacy by the enhanced permeability and retention effect deem nanoparticles suitable for this application. Optimization of size, surface charge and surface modifications have provided nanoparticles with stealth properties capable of evading immune responses, thus deeming them as excellent carriers of chemotherapeutic agents. Biocompatible and biodegradable forms of polymers enhance the bioavailability of chemotherapeutic agents, and permit a sustained and time-dependent release of drugs which is a characteristic of their composition, thereby providing a controlled therapeutic approach. Studies conducted in vitro and animal models have also demonstrated a synergism in cytotoxicity given the mechanism of action of anticancer drugs when administered in combination providing promising results. Combination therapy has also shown implications in overcoming multiple-drug resistance, which can however be subdued by the adaptable nature of tumor microenvironment. Surface modifications with targeting moieties can therefore feasibly increase nanoparticle uptake by specific receptor-ligand interactions, increasing dose efficacy which can seemingly overcome drug-resistance. This article reviews recent trends and investigations in employing polymeric nanoparticles for effectively delivering combination chemotherapy, and modifications in delivery parameters enhancing dose efficacy, thus validating the potential in this

  12. A combination of the telomerase inhibitor, BIBR1532, and paclitaxel synergistically inhibit cell proliferation in breast cancer cell lines.

    PubMed

    Shi, Yi; Sun, Lin; Chen, Ge; Zheng, Dongyan; Li, Li; Wei, Wanguo

    2015-12-01

    Breast cancer is one of the most significant causes of female cancer death worldwide. Paclitaxel, an extensively used breast cancer chemotherapeutic has limited success due to drug resistance. 2-[(E)-3-naphtalen-2-yl-but-2-enoylamino]-benzoic acid (BIBR1532), a small molecule pharmacological inhibitor of telomerase activity, can inhibit human cancer cell proliferation as well. Thus, to enhance breast cancer treatment efficacy, we studied the combination of BIBR1532 and paclitaxel in breast cancer cell lines. Cell viability assays revealed that BIBR1532 or paclitaxel alone inhibited proliferation in a dose-dependent manner, and combining the drugs synergistically induced growth inhibition in all breast cell lines tested independent of their p53, ER, and HER2 status. The drug combination also synergistically inhibited colony formation of MCF-7 cells in a dose-dependent manner. Annexin V-PI staining and Western blot assays on PARP cleavage and caspase-8 and caspase-3 revealed that BIBR1532 in combination with paclitaxel was more potent than either agent alone in promoting MCF-7 cell apoptosis. Cell cycle analysis indicated that BIBR1532 induced a G1 phase arrest and paclitaxel arrested cells at the G2/M phase. The drug combination dramatically blocked S cells from entering the G2/M phase. Our results suggest the potential of telomerase inhibition as an effective breast cancer treatment and that used in conjunction with paclitaxel; it may potentiate tumor cytotoxicity.

  13. Drug Combinations: Tests and Analysis with Isoboles

    PubMed Central

    Tallarida, Ronald J.

    2016-01-01

    Described in this unit are experimental and computational methods to detect and classify drug interactions. In most cases this relates to two drugs or compounds with overtly similar effects, e.g., two analgesics or two anti-hypertensives. From the dose-response data of the individual drugs it is possible to generate a curve, the isobole, that defines all dose combinations that are expected to yield a specified effect. The theory underlying the isobole involves the calculation of doses of drug A that are effectively equivalent to doses of drug B with that equivalence determining whether the isobole is linear or nonlinear. In either case the isobole allows for a comparison with actual combination effects making it possible to determine whether the interaction is synergistic, additive or sub-additive. Actual as well as illustrative data are employed to illustrate experimental design and data analysis. PMID:26995550

  14. A comparative analysis of EGFR mutation status in association with the efficacy of TKI in combination with WBRT/SRS/surgery plus chemotherapy in brain metastasis from non-small cell lung cancer.

    PubMed

    Cai, Ling; Zhu, Jian-fei; Zhang, Xue-wen; Lin, Su-xia; Su, Xiao-dong; Lin, Peng; Chen, Kai; Zhang, Lan-jun

    2014-11-01

    We proposed to identify the efficacy of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) using whole brain radiotherapy (WBRT)/stereotactic radiosurgery (SRS)/surgery in brain metastases from patients with non-small cell lung cancer (NSCLC) and clarify the association between treatment outcome and EGFR gene mutation status. A total of 282 patients with NSCLC brain metastases who underwent WBRT/SRS/surgery alone or in combination with TKI were enrolled in our study from 2003-2013. Amplification mutation refractory system technology was used to determine the EGFR mutation status in 109 tissue samples. EGFR mutation detection was performed in 109 patients with tumor tissues. The EGFR positive rate was 50 % (55/109), including 26 exon 19 deletions and 24 L858R mutations. The median follow-up time was 28 months. The median overall survival, median progression-free survival of intracranial disease, and median progression-free survival of extracranial disease was significantly longer for patients with TKI treatment (31.9 vs 17.0 months, P < 0.0001; 19.8 vs 12.0 months, P < 0.0001; and 19.6 vs 12.3 months, P < 0.0001; respectively). In subgroup analysis within the TKI group, patients harboring EGFR mutations had better extracranial disease control (20.4 vs 14.1 months, P = 0.032). Administration of TKI agents with conventional therapy compared with conventional therapy alone might be beneficial for overall survival, progression-free survival of intracranial disease and progression-free survival of extracranial disease in patients with brain metastases from NSCLC independent of EGFR mutations.

  15. Elevation of Plasma TGF-{beta}1 During Radiation Therapy Predicts Radiation-Induced Lung Toxicity in Patients With Non-Small-Cell Lung Cancer: A Combined Analysis From Beijing and Michigan

    SciTech Connect

    Zhao Lujun; Wang Luhua Ji Wei; Wang Xiaozhen; Zhu Xiangzhi; Hayman, James A.; Kalemkerian, Gregory P.; Yang Weizhi; Brenner, Dean; Lawrence, Theodore S.; Kong, F.-M.

    2009-08-01

    Purpose: To test whether radiation-induced elevations of transforming growth factor-{beta}1 (TGF-{beta}1) during radiation therapy (RT) correlate with radiation-induced lung toxicity (RILT) in patients with non-small-cell lung cancer (NSCLC) and to evaluate the ability of mean lung dose (MLD) to improve the predictive power. Methods and Materials: Eligible patients included those with Stage I-III NSCLC treated with RT with or without chemotherapy. Platelet-poor plasma was obtained pre-RT and at 4-5 weeks (40-50 Gy) during RT. TGF-{beta}1 was measured using an enzyme-linked immunosorbent assay. The primary endpoint was {>=} Grade 2 RILT. Mann-Whitney U test, logistic regression, and chi-square were used for statistical analysis. Results: A total of 165 patients were enrolled in this study. The median radiation dose was 60 Gy, and the median MLD was 15.3 Gy. Twenty-nine patients (17.6%) experienced RILT. The incidence of RILT was 46.2% in patients with a TGF-{beta}1 ratio > 1 vs. 7.9% in patients with a TGF-{beta}1 ratio {<=} 1 (p < 0.001), and it was 42.9% if MLD > 20 Gy vs. 17.4% if MLD {<=} 20 Gy (p = 0.024). The incidence was 4.3% in patients with a TGF-{beta}1 ratio {<=} 1 and MLD {<=} 20 Gy, 47.4% in those with a TGF-{beta}1 ratio >1 or MLD > 20 Gy, and 66.7% in those with a TGF-{beta}1 ratio >1 and MLD > 20 Gy (p < 0.001). Conclusions: Radiation-induced elevation of plasma TGF-{beta}1 level during RT is predictive of RILT. The combination of TGF- {beta}1 and MLD may help stratify the patients for their risk of RILT.

  16. Evaluation of growth inhibitory response of Resveratrol and Salinomycin combinations against triple negative breast cancer cells.

    PubMed

    Rai, Girish; Suman, Shankar; Mishra, Sanjay; Shukla, Yogeshwer

    2017-03-11

    Resveratrol (RSVL) a dietary phytochemical showed to enhance the efficacy of chemotherapeutic drugs. Recently, Salinomycin (SAL) has gained importance as cancer therapeutic value for breast cancer (BC), however, its superfluxious toxicity delimits the utility. Taking the advantage of RSVL, the therapeutic efficacy of RSVL and SAL combination was studied in vitro and in vivo system. Firstly, the synergistic combination dose of RSVL and SAL was calculated and further, the efficacy was examined by wound healing, and Western blots analysis. Further, in vivo study was performed to confirm the effect of colony formation and apoptosis detection by flow cytometry based assays. Further, the molecular mode of action was determined at both transcript and translational level by quantitative Real Time PCR combination in Ehrlich ascitic carcinoma model.The combination of IC20 (R20) of RSVL and IC10 (S10) dose of SAL showed best synergism (CI<1) with ∼5 fold dose advantage of SAL. Gene expression results at mRNA and protein level revealed that the unique combination of RSVL and SAL significantly inhibited epithelial mesenchymal transition (Fibronectin, Vimentin, N-Cadherin, and Slug); chronic inflammation (Cox2, NF-kB, p53), autophagy (Beclin and LC3) and apoptotic (Bax, Bcl-2) markers. Further, i n vivo study showed that low dose of SAL in combination with RSVL increased life span of Ehrlich ascitic mice. Overall, our study revealed that RSVL synergistically potentiated the anticancer potential of SAL against triple negative BC.

  17. [Cancer Genome Atlas Pan-cancer Analysis Project].

    PubMed

    Zhang, Kun; Wang, Hong

    2015-04-01

    Cancer can exhibit different forms depending on the site of origin, cell types, the different forms of genetic mutations which also affect cancer therapeutic effect. Although many genes have been demonstrated to change a direct result of the change in phenotype, however, many cancers lineage complex molecular mechanisms are still not fully elucidated. Therefore, The Cancer Genome Atlas (TCGA) Research Network analyzed a large human tumors, in order to find the molecular changes in DNA, RNA, protein and epigenetic level, The results contain a wealth of data provides us with an opportunity for common, personality and new ideas throughout the cancer lineages form a whole description. Pan-cancer genome program first compares the 12 kinds of cancer types. Analysis of different tumor molecular changes and their functions, will tell us how effective treatment method is applied to a similar phenotype of the tumor.

  18. Genetic analysis of cancer in families.

    PubMed

    King, M C

    1990-01-01

    Cancer is genetic, in the sense that it is caused by DNA alterations at the cellular level. On the other hand, the most important risk factors for the common cancers are environmental: cigarette smoking, environmental pollution, occupational exposures, poor diet, and so on. These two observations are not in conflict: the DNA alterations that lead to cancer are very likely to be caused by environmental mutagens. It would be valuable to know exactly what genes are altered to cause a specific cancer, because the effects of these alterations might then be reversible before cancer has a chance to develop. A key to identifying these cancer genes may lie with rare families at extremely high risk of a specific cancer. Unlike most cancer patients, members of these families may inherit an alteration that confers increased susceptibility to cancer. In these rare instances, cancer is a genetic disease at the level of the family, as well as at the level of the cell. Therefore, in these families, genes predisposing to cancer can be mapped in the same way as genes for purely genetic diseases like sickle cell anaemia, cystic fibrosis, and Huntington's disease. The hypothesis that underlies the mapping of cancer genes in families is that the genes inherited in altered form in these rare families are the same genes that are altered in somatic cells of individuals without a remarkable family history of cancer. This hypothesis has proved correct for retinoblastoma. Genes responsible for other rare cancers have been mapped in families as well: neurofibromatosis, multiple endocrine neoplasia, Wilms' tumour, and colon cancer following familial adenomatous polyps, among others. Genes responsible for common cancers are also being defined by genetic analysis, most notably breast cancer and colon cancer. This review summarizes why, how, and what genetic analysis of families can reveal about human cancers.

  19. Sleep Apnea and Cancer: Analysis of a Nationwide Population Sample

    PubMed Central

    Gozal, David; Ham, Sandra A.; Mokhlesi, Babak

    2016-01-01

    Study Objectives: Epidemiological evidence from relatively small cohorts suggests that obstructive sleep apnea (OSA) is associated with higher cancer incidence and mortality. Here we aimed to determine whether cancer incidence for major cancer types and risk of metastases or mortality from cancer are increased in the presence of OSA. Methods: All OSA diagnoses included in an employee-sponsored health insurance database spanning the years 2003–2012 were identified and 1:1 matched demographically based on age, gender, and state of residence, or alternatively matched by comorbidities. The incidence of 12 types of cancer was assessed. In addition, another cohort of patients with a primary diagnosis of cancer was retrieved, and the risk of metastatic disease or cancer mortality was determined as a function of the presence or absence of OSA. Multivariate Cox proportional hazards regression models were fitted to assess the independent associations between OSA and outcomes of interest. Results: Based on a cohort of ∼5.6 million individuals, the incidence of all cancer diagnoses combined was similar in OSA and retrospectively matched cases. However, the adjusted risk of pancreatic and kidney cancer and melanoma were significantly higher in patients with OSA, while the risk of colorectal, breast, and prostate cancers appeared to be lower. Among individuals with a diagnosis of cancer, the presence of OSA was not associated with an increased risk for metastasis or death. Conclusions: In a large nationally representative health insurance database, OSA appears to increase the risk for only a very selective number of cancer types, and does not appear to be associated with an increased risk of metastatic cancer or cancer-related deaths. Citation: Gozal D, Ham SA, Mokhlesi B. Sleep apnea and cancer: analysis of a nationwide population sample. SLEEP 2016;39(8):1493–1500. PMID:27166241

  20. Comparative genomic analysis of esophageal cancers.

    PubMed

    Caygill, Christine P J; Gatenby, Piers A C; Herceg, Zdenko; Lima, Sheila C S; Pinto, Luis F R; Watson, Anthony; Wu, Ming-Shiang

    2014-09-01

    The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on comparative genomic analysis of esophageal cancers: genomic polymorphisms, the genetic and epigenetic drivers in esophageal cancers, and the collection of data in the UK Barrett's Oesophagus Registry.

  1. Combination of Paclitaxel and MG1 oncolytic virus as a successful strategy for breast cancer treatment.

    PubMed

    Bourgeois-Daigneault, Marie-Claude; St-Germain, Lauren Elizabeth; Roy, Dominic Guy; Pelin, Adrian; Aitken, Amelia Sadie; Arulanandam, Rozanne; Falls, Theresa; Garcia, Vanessa; Diallo, Jean-Simon; Bell, John Cameron

    2016-08-08

    Breast cancer is the most common malignant disease amongst Western women. The lack of treatment options for patients with chemotherapy-resistant or recurrent cancers is pushing the field toward the rapid development of novel therapies. The use of oncolytic viruses is a promising approach for the treatment of disseminated diseases like breast cancer, with the first candidate recently approved by the Food and Drug Administration for use in patients. In this report, we demonstrate the compatibility of oncolytic virotherapy and chemotherapy using various murine breast cancer models. This one-two punch has been explored in the past by several groups with different viruses and drugs and was shown to be a successful approach. Our strategy is to combine Paclitaxel, one of the most common drugs used to treat patients with breast cancer, and the oncolytic Rhabdovirus Maraba-MG1, a clinical trial candidate in a study currently recruiting patients with late-stage metastatic cancer. We used the EMT6, 4 T1 and E0771 murine breast cancer models to evaluate in vitro and in vivo the effects of co-treatment with MG1 and Paclitaxel. Treatment-induced cytotoxicity was assessed and plaque assays, flow cytometry, microscopy and immunocytochemistry analysis were performed to quantify virus production and transgene expression. Orthotopically implanted tumors were measured during and after treatment to evaluate efficacy and Kaplan-Meier survival curves were generated. Our data demonstrate not only the compatibility of the treatments, but also their synergistic cytopathic activity. With Paclitaxel, EMT6 and 4 T1 tumors demonstrated increased virus production both in vitro and in vivo. Our results also show that Paclitaxel does not impair the safety profile of the virus treatment. Importantly, when combined, MG1 and the drug controlled tumor growth and prolonged survival. The combination of MG1 and Paclitaxel improved efficacy in all of the breast cancer models we tested and thus is a

  2. Combining synthetic carbohydrate vaccines with cancer cell glycoengineering for effective cancer immunotherapy.

    PubMed

    Qiu, Lei; Gong, Xi; Wang, Qianli; Li, Jie; Hu, Honggang; Wu, Qiuye; Zhang, Junping; Guo, Zhongwu

    2012-11-01

    Tumor-associated carbohydrate antigens (TACAs) are useful targets for the development of cancer vaccines or immunotherapies. However, a major obstacle in this application of TACAs is their poor immunogenicity. To overcome the problem, a new immunotherapeutic strategy combining synthetic vaccines made of artificial TACA derivatives and metabolic glycoengineering of cancer cells to express the artificial TACA derivatives was explored. Using a murine leukemia model FBL3 with GM3 antigen as the target, it was shown that artificial GM3 N-phenylacetyl derivative (GM3NPhAc) elicited robust antigen-specific T cell-dependent immunity and that N-phenylacetyl-D-mannosamine (ManNPhAc) as the biosynthetic precursor of GM3NPhAc selectively glycoengineered cancer cells to express GM3NPhAc both in vitro and in vivo. It was also demonstrated that GM3NPhAc-specific antisera and antibodies mediated strong cytotoxicity to ManNPhAc-treated FBL3 cell. Furthermore, vaccination with a conjugate vaccine made of GM3NPhAc followed by ManNPhAc treatment could significantly suppress tumor growth and prolong the survival of tumor-bearing mouse. These results have proved the feasibility of the new cancer immunotherapeutic strategy, as well as its efficacy to cure cancer, which is of general significance.

  3. Genitourinary Toxicity After High-Dose-Rate (HDR) Brachytherapy Combined With Hypofractionated External Beam Radiotherapy for Localized Prostate Cancer: An Analysis to Determine the Correlation Between Dose-Volume Histogram Parameters in HDR Brachytherapy and Severity of Toxicity

    SciTech Connect

    Ishiyama, Hiromichi Kitano, Masashi; Satoh, Takefumi; Kotani, Shouko; Uemae, Mineko; Matsumoto, Kazumasa; Okusa, Hiroshi; Tabata, Ken-ichi; Baba, Shiro; Hayakawa, Kazushige

    2009-09-01

    Purpose: To evaluate the severity of genitourinary (GU) toxicity in high-dose-rate (HDR) brachytherapy combined with hypofractionated external beam radiotherapy (EBRT) for prostate cancer and to explore factors that might affect the severity of GU toxicity. Methods and Materials: A total of 100 Japanese men with prostate cancer underwent {sup 192}Ir HDR brachytherapy combined with hypofractionated EBRT. Mean (SD) dose to 90% of the planning target volume was 6.3 (0.7) Gy per fraction of HDR. After 5 fractions of HDR treatment, EBRT with 10 fractions of 3 Gy was administrated. The urethral volume receiving 1-15 Gy per fraction in HDR brachytherapy (V1-V15) and the dose to at least 5-100% of urethral volume in HDR brachytherapy (D5-D100) were compared between patients with Grade 3 toxicity and those with Grade 0-2 toxicity. Prostate volume, patient age, and International Prostate Symptom Score were also compared between the two groups. Results: Of the 100 patients, 6 displayed Grade 3 acute GU toxicity, and 12 displayed Grade 3 late GU toxicity. Regarding acute GU toxicity, values of V1, V2, V3, and V4 were significantly higher in patients with Grade 3 toxicity than in those with Grade 0-2 toxicity. Regarding late GU toxicity, values of D70, D80, V12, and V13 were significantly higher in patients with Grade 3 toxicity than in those with Grade 0-2 toxicity. Conclusions: The severity of GU toxicity in HDR brachytherapy combined with hypofractionated EBRT for prostate cancer was relatively high. The volume of prostatic urethra was associated with grade of acute GU toxicity, and urethral dose was associated with grade of late GU toxicity.

  4. Genitourinary toxicity after high-dose-rate (HDR) brachytherapy combined with Hypofractionated External beam radiotherapy for localized prostate cancer: an analysis to determine the correlation between dose-volume histogram parameters in HDR brachytherapy and severity of toxicity.

    PubMed

    Ishiyama, Hiromichi; Kitano, Masashi; Satoh, Takefumi; Kotani, Shouko; Uemae, Mineko; Matsumoto, Kazumasa; Okusa, Hiroshi; Tabata, Ken-ichi; Baba, Shiro; Hayakawa, Kazushige

    2009-09-01

    To evaluate the severity of genitourinary (GU) toxicity in high-dose-rate (HDR) brachytherapy combined with hypofractionated external beam radiotherapy (EBRT) for prostate cancer and to explore factors that might affect the severity of GU toxicity. A total of 100 Japanese men with prostate cancer underwent (192)Ir HDR brachytherapy combined with hypofractionated EBRT. Mean (SD) dose to 90% of the planning target volume was 6.3 (0.7) Gy per fraction of HDR. After 5 fractions of HDR treatment, EBRT with 10 fractions of 3 Gy was administrated. The urethral volume receiving 1-15 Gy per fraction in HDR brachytherapy (V1-V15) and the dose to at least 5-100% of urethral volume in HDR brachytherapy (D5-D100) were compared between patients with Grade 3 toxicity and those with Grade 0-2 toxicity. Prostate volume, patient age, and International Prostate Symptom Score were also compared between the two groups. Of the 100 patients, 6 displayed Grade 3 acute GU toxicity, and 12 displayed Grade 3 late GU toxicity. Regarding acute GU toxicity, values of V1, V2, V3, and V4 were significantly higher in patients with Grade 3 toxicity than in those with Grade 0-2 toxicity. Regarding late GU toxicity, values of D70, D80, V12, and V13 were significantly higher in patients with Grade 3 toxicity than in those with Grade 0-2 toxicity. The severity of GU toxicity in HDR brachytherapy combined with hypofractionated EBRT for prostate cancer was relatively high. The volume of prostatic urethra was associated with grade of acute GU toxicity, and urethral dose was associated with grade of late GU toxicity.

  5. Combination of cold atmospheric plasma and iron nanoparticles in breast cancer: gene expression and apoptosis study

    PubMed Central

    Jalili, Azam; Irani, Shiva; Mirfakhraie, Reza

    2016-01-01

    Background Current cancer treatments have unexpected side effects of which the death of normal cells is one. In some cancers, iron nanoparticles (NPs) can be subjected to diagnosis and passive targeting treatment. Cold atmospheric plasma (CAP) has a proven induction of selective cell death ability. In this study, we have attempted to analyze the synergy between CAP and iron NPs in human breast adenocarcinoma cells (MCF-7). Materials and methods In vitro cytotoxicity of CAP treatment and NPs in cells measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and cell death was shown by 4′,6-diamidino-2-phenylindole and annexin V staining. Fluctuations in BAX and BCL-2 gene expression were investigated by means of real-time polymerase chain reaction. Results MTT assay results showed that combination of plasma and iron NPs decreased the viability of cancer cells significantly (P<0.05). Real-time analysis showed that the combination therapy induced shifting the BAX/BCL-2 ratio in favor of apoptosis. Conclusion Our data indicate that synergy between CAP and iron NPs can be applied in breast cancer treatment selectively. PMID:27729800

  6. Retrospective analysis of 119 Chinese noninflammatory locally advanced breast cancer cases treated with intravenous combination of vinorelbine and epirubicin as a neoadjuvant chemotherapy: a median follow-up of 63.4 months

    PubMed Central

    2009-01-01

    Background This study is a retrospective evaluation of the efficacy of neoadjuvant chemotherapy (NC) with a vinorelbine (V) and epirubicin (E) intravenous combination regimen and is aimed at identification of predictive markers for the long-term outcome in noninflammatory locally advanced breast cancer (NLABC). Methods One-hundred-and-nineteen patients with NLABC were identified from September 2001 to May 2006. Analysis was performed in March 2008, with a median follow-up of 63.4 months (range, 9-76 months). All patients were diagnosed with invasive breast cancer using 14 G core needle biopsy and treated with three cycles of VE before surgery. Local-regional radiotherapy was offered to all patients after the completion of chemotherapy followed by hormonal therapy according to hormone receptor status. Tissue sections cut from formalin-fixed paraffin-embedded blocks from biopsy specimens and postoperative tumor tissues were stained for the presence of estrogen receptor (ER), progesterone receptor (PgR), HER-2 (human epidermal growth factor receptor-2), and MIB-1(Ki-67). Results Patients characteristics were median age 52 years (range: 25-70 years); clinical TNM stage, stage IIB (n = 32), stage IIIA (n = 56), stage IIIB (n = 22) and stage IIIC (n = 9). All patients were evaluable for response: clinically complete response was documented in 27 patients (22.7%); 78 (65.6%) obtained partial response; stable disease was observed in 13 (10.9%); 1 patient (0.8%) had progressive disease. Pathological complete response was found in 22 cases (18.5%). Seventy-five patients were alive with no recurrence after a median follow-up of 63.4 months, the 5-year rates for disease-free survival and overall survival were 58.7% and 71.3%, respectively, after the start of NC. On multivariate analysis, the independent variables associated with increased risk of relapse and death were high pre-Ki-67(p = 0.012, p = 0.017, respectively), high post-Ki-67 expression (p = 0.045, p = 0

  7. Targeted Chemo-Photodynamic Combination Platform Based on the DOX Prodrug Nanoparticles for Enhanced Cancer Therapy.

    PubMed

    Zhang, Yumin; Huang, Fan; Ren, Chunhua; Yang, Lijun; Liu, Jianfeng; Cheng, Zhen; Chu, Liping; Liu, Jinjian

    2017-04-19

    Chemo-photodynamic combination therapy has been received widespread attention in cancer treatment due to its excellent characteristics, such as reducing the adverse side effects of chemo-drugs and improving the therapeutic effects for various cancers. In this study, RGD and DOX was conjugated to PEG by thiol-ene addition and Schiff's base reaction, respectively, to prepare the targeted and pH-sensitive antitumor prodrug nanoparticles (RGD-PEG-DOX NPs, RGD-NPs). Subsequently, the photosensitizer chlorin e6 (Ce6) was encapsulated into RGD-NPs, thus obtaining a simple and efficient chemo-photodynamic combination platform (RGD-PEG-DOX/Ce6 NPs, RGD-NPs/Ce6). This nanoparticle possessed high drug loading property of both the chemo-drug and photosensitizer and could simultaneously release them under the mild acidic microenvironment of cancer cells, which was expected to realize the synchronization therapy of chemotherapy and photodynamic therapy (PDT). Compared with free DOX and Ce6, RGD-NPs/Ce6 could significantly improve the cellular uptake capacities of DOX and Ce6, resulting in the increased contents of ROS in cancer cells and effective cytotoxicity for tumor cells (MDA-MB-231 cells and MCF-7 cells) upon a laser radiation. The in vivo experiment showed that RGD-NPs/Ce6 displayed superior tumor targeting, accumulation, and retention ability than the other groups (free DOX, free Ce6 and NPs/Ce6), and thus significantly enhancing the antitumor effect in vivo with a laser radiation. In addition, the cardiotoxicity induced by DOX was thoroughly wiped out after being loaded and delivered by the nanoparticles according to the pathological analysis. Therefore, the targeted chemo-photodynamic combination therapeutic platform may be a promising candidate for enhanced cancer therapy.

  8. Reirradiation combined with hyperthermia in recurrent breast cancer results in a worthwhile local palliation.

    PubMed

    van der Zee, J; van der Holt, B; Rietveld, P J; Helle, P A; Wijnmaalen, A J; van Putten, W L; van Rhoon, G C

    1999-02-01

    Both experimental and clinical research have shown that hyperthermia (HT) gives valuable additional effects when applied in combination with radiotherapy (RT). The purpose of this study was evaluation of results in patients with recurrent breast cancer, treated at the Daniel den Hoed Cancer Center (DHCC) with reirradiation (re-RT; eight fractions of 4 Gy twice weekly) combined with HT. All 134 patients for whom such treatment was planned were included in the analysis. The complete response rate in 119 patients with macroscopic tumour was 71%. Including the 15 patients with microscopic disease, the local control rate was 73%. The median duration of local control was 32 months, and toxicity was acceptable. The complete response (CR) rate was higher, and the toxicity was less with the later developed 433-MHz HT technique compared with the 2450-MHz technique used initially. With this relatively well-tolerated treatment, palliation by local tumour control of a worthwhile duration is achieved in the majority of patients. The technique used for hyperthermia appeared to influence the achieved results. The value of HT in addition to this re-RT schedule has been confirmed by a prospective randomized trial in a similar patient group. In The Netherlands, this combined treatment is offered as standard to patients with breast cancer recurring in previously irradiated areas.

  9. Cellular therapy in combination with cytokines improves survival in a xenograft mouse model of ovarian cancer.

    PubMed

    Ingersoll, Susan B; Ahmad, Sarfraz; McGann, Hasina C; Banks, Robert K; Stavitzski, Nicole M; Srivastava, Milan; Ali, Ghazanfar; Finkler, Neil J; Edwards, John R; Holloway, Robert W

    2015-09-01

    Studies have shown enhanced survival of ovarian cancer patients in which the tumors are infiltrated with tumor infiltrating lymphocytes and natural killer cells showing the importance of immune surveillance and recognition in ovarian cancer. Therefore, in this study, we tested cellular immunotherapy and varying combinations of cytokines (IL-2 and/or pegylated-IFNα-2b) in a xenograft mouse model of ovarian cancer. SKOV3-AF2 ovarian cancer cells were injected intra-peritoneally (IP) into athymic nude mice. On day 7 post-tumor cell injection, mice were injected IP with peripheral blood mononuclear cells (PBMC; 5 × 10(6) PBMC) and cytokine combinations [IL-2 ± pegylated-IFNα-2b (IFN)]. Cytokine injections were continued weekly for IFN (12,000 U/injection) and thrice weekly for IL-2 (4000 U/injection). Mice were euthanized when they became moribund due to tumor burden at which time tumor and ascitic fluid were measured and collected. Treatment efficacy was measured by improved survival at 8 weeks and overall survival by Kaplan-Meier analysis. We observed that the mice tolerated all treatment combinations without significant weight loss or other apparent illness. Mice receiving PBMC plus IL-2 showed improved median survival (7.3 weeks) compared to mice with no treatment (4.2 weeks), IL-2 (3.5 weeks), PBMC (4.0 weeks), or PBMC plus IL-2 and IFN (4.3 weeks), although PBMC plus IL-2 was not statistically different than PBMC plus IFN (5.5 weeks, p > 0.05). We demonstrate that cytokine-stimulated cellular immune therapy with PBMC and IL-2 was well tolerated and resulted in survival advantage compared to untreated controls and other cytokine combinations in the nude-mouse model.

  10. An Experimental Analysis of the Molecular Effects of Trastuzumab (Herceptin) and Fulvestrant (Falsodex), as Single Agents or in Combination, on Human HR+/HER2+ Breast Cancer Cell Lines and Mouse Tumor Xenografts

    PubMed Central

    Lu, Yunshu; Jia, Yijun; Ding, Longlong; Bai, Fang; Ge, Meixin; Lin, Qing; Wu, Kejin

    2017-01-01

    Purpose To investigate the effects of trastuzumab (herceptin) and fulvestrant (falsodex) either in combination or alone, on downstream cell signaling pathways in lab-cultured human HR+/HER2+ breast cancer cell lines ZR-75-1 and BT-474, as well as on protein expression levels in mouse xenograft tissue. Methods Cells were cultivated in the presence of trastuzumab or fulvestrant or both. Molecular events that resulted in an inhibition of cell proliferation and cell cycle progression or in an increased rate of apoptosis were studied. The distribution and abundance of the proteins p-Akt and p-Erk expressed in these cells in response to single agents or combinatorial treatment were also investigated. In addition, the effects of trastuzumab and fulvestrant, either as single agents or in combination on tumor growth as well as on expression of the protein p-MED1 expressed in in vivo mouse xenograft models was also examined. Results Cell proliferation was increasingly inhibited by trastuzumab or fulvestrant or both, with a CI<1 and DRI>1 in both human cell lines. The rate of apoptosis increased only in the BT-474 cell line and not in the ZR-75-1 cell line upon treatment with fulvestrant and not trastuzumab as a single agent (P<0.05). Interestingly, fulvestrant, in combination with trastuzumab, did not significantly alter the rate of apoptosis (in comparison with fulvestrant alone), in the BT-474 cell line (P>0.05). Cell accumulation in the G1 phase of cell cycle was investigated in all treatment groups (P<0.05), and the combination of trastuzumab and fulvestrant reversed the effects of fulvestrant alone on p-Akt and p-Erk protein expression levels. Using ZR-75-1 or BT-474 to generate in vivo tumor xenografts in BALB/c athymic mouse models, we showed that a combination of both drugs resulted in a stronger inhibition of tumor growth (P<0.05) and a greater decrease in the levels of activated MED1 (p-MED1) expressed in tumor issues compared with the use of either drug as a

  11. Inherited variation in circadian rhythm genes and risks of prostate cancer and three other cancer sites in combined cancer consortia.

    PubMed

    Gu, Fangyi; Zhang, Han; Hyland, Paula L; Berndt, Sonja; Gapstur, Susan M; Wheeler, William; Ellipse Consortium, The; Amos, Christopher I; Bezieau, Stephane; Bickeböller, Heike; Brenner, Hermann; Brennan, Paul; Chang-Claude, Jenny; Conti, David V; Doherty, Jennifer Anne; Gruber, Stephen B; Harrison, Tabitha A; Hayes, Richard B; Hoffmeister, Michael; Houlston, Richard S; Hung, Rayjean J; Jenkins, Mark A; Kraft, Peter; Lawrenson, Kate; McKay, James; Markt, Sarah; Mucci, Lorelei; Phelan, Catherine M; Qu, Conghui; Risch, Angela; Rossing, Mary Anne; Wichmann, H-Erich; Shi, Jianxin; Schernhammer, Eva; Yu, Kai; Landi, Maria Teresa; Caporaso, Neil E

    2017-11-01

    Circadian disruption has been linked to carcinogenesis in animal models, but the evidence in humans is inconclusive. Genetic variation in circadian rhythm genes provides a tool to investigate such associations. We examined associations of genetic variation in nine core circadian rhythm genes and six melatonin pathway genes with risk of colorectal, lung, ovarian and prostate cancers using data from the Genetic Associations and Mechanisms in Oncology (GAME-ON) network. The major results for prostate cancer were replicated in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial, and for colorectal cancer in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). The total number of cancer cases and controls was 15,838/18,159 for colorectal, 14,818/14,227 for prostate, 12,537/17,285 for lung and 4,369/9,123 for ovary. For each cancer site, we conducted gene-based and pathway-based analyses by applying the summary-based Adaptive Rank Truncated Product method (sARTP) on the summary association statistics for each SNP within the candidate gene regions. Aggregate genetic variation in circadian rhythm and melatonin pathways were significantly associated with the risk of prostate cancer in data combining GAME-ON and PLCO, after Bonferroni correction (ppathway  < 0.00625). The two most significant genes were NPAS2 (pgene  = 0.0062) and AANAT (pgene  = 0.00078); the latter being significant after Bonferroni correction. For colorectal cancer, we observed a suggestive association with the circadian rhythm pathway in GAME-ON (ppathway  = 0.021); this association was not confirmed in GECCO (ppathway  = 0.76) or the combined data (ppathway  = 0.17). No significant association was observed for ovarian and lung cancer. These findings support a potential role for circadian rhythm and melatonin pathways in prostate carcinogenesis. Further functional studies are needed to better understand the underlying biologic mechanisms.

  12. Proteomic Analysis of Genistein Mammary Cancer Chemoprevention

    DTIC Science & Technology

    2007-07-01

    to collect a higher yield of proteins and hopefully allow success. 15. SUBJECT TERMS Genistein , Breast Cancer Chemoprevention, Proteomics, Rats ...AD_________________ Award Number: DAMD17-03-1-0433 TITLE: Proteomic Analysis of Genistein ...SUBTITLE 5a. CONTRACT NUMBER Proteomic Analysis of Genistein Mammary Cancer Chemoprevention 5b. GRANT NUMBER DAMD17-03-1-0433 5c. PROGRAM

  13. NCI ALMANAC Tool for Research on Cancer Drug Combinations

    Cancer.gov

    A Cancer Currents blog post on the NCI ALMANAC, a new resource that provides data showing how well pairs of FDA-approved cancer drugs performed in killing tumor cells from NCI-60 Human Tumor Cell Lines.

  14. Combination therapy targeting both cancer stem-like cells and bulk tumor cells for improved efficacy of breast cancer treatment.

    PubMed

    Wang, Tao; Narayanaswamy, Radhika; Ren, Huilan; Torchilin, Vladimir P

    2016-06-02

    Many types of tumors are organized in a hierarchy of heterogeneous cell populations. The cancer stem-like cells (CSCs) hypothesis suggests that tumor development and metastasis are driven by a minority population of cells, which are responsible for tumor initiation, growth and recurrences. The inability to efficiently eliminate CSCs during chemotherapy, together with CSCs being highly tumorigenic and invasive, may result in treatment failure due to cancer relapse and metastases. CSCs are emerging as a promising target for the development of translational cancer therapies. Ideal panacea for cancer would kill all malignant cells, including CSCs and bulk tumor cells. Since both chemotherapy and CSCs-specific therapy are insufficient to cure cancer, we propose combination therapy with CSCs-targeted agents and chemotherapeutics for improved breast cancer treatment. We generated in vitro mammosphere of 2 breast cancer cell lines, and demonstrated ability of mammospheres to grow and enrich cancer cells with stem-like properties, including self-renewal, multilineage differentiation and enrichment of cells expressing breast cancer stem-like cell biomarkers CD44(+)/CD24(-/low). The formation of mammospheres was significantly inhibited by salinomycin, validating its pharmacological role against the cancer stem-like cells. In contrast, paclitaxel showed a minimal effect on the proliferation and growth of breast cancer stem-like cells. While combination therapies of salinomycin with conventional chemotherapy (paclitaxel or lipodox) showed a potential to improve tumor cell killing, different subtypes of breast cancer cells showed different patterns in response to the combination therapies. While optimization of combination therapy is warranted, the design of combination therapy should consider phenotypic attributes of breast cancer types.

  15. Combining Static Analysis and Model Checking for Software Analysis

    NASA Technical Reports Server (NTRS)

    Brat, Guillaume; Visser, Willem; Clancy, Daniel (Technical Monitor)

    2003-01-01

    We present an iterative technique in which model checking and static analysis are combined to verify large software systems. The role of the static analysis is to compute partial order information which the model checker uses to reduce the state space. During exploration, the model checker also computes aliasing information that it gives to the static analyzer which can then refine its analysis. The result of this refined analysis is then fed back to the model checker which updates its partial order reduction. At each step of this iterative process, the static analysis computes optimistic information which results in an unsafe reduction of the state space. However we show that the process converges to a fired point at which time the partial order information is safe and the whole state space is explored.

  16. Combination therapy with anti-DR5 antibody and tamoxifen for triple negative breast cancer

    PubMed Central

    Kim, Hyunki; Samuel, Sharon L; Zhai, Guihua; Rana, Samir; Taylor, Marie; Umphrey, Heidi R; Oelschlager, Denise K; Buchsbaum, Donald J; Zinn, Kurt R

    2014-01-01

    TRA-8, a monoclonal antibody targeting death receptor, has demonstrated high therapeutic effect for triple negative breast cancer (TNBC) in preclinical models. Tamoxifen, the standard of care for ERα-positive breast cancer, induces apoptosis via ERβ, which commonly presents in TNBC cells. The current study investigates the combination effects of TRA-8 and tamoxifen for TNBC. In vitro assays were implemented with two ERβ-positive TNBC cell lines, SUM159 and 2LMP, and in vivo therapy studies were followed using orthotopic breast tumor mouse models. IC50 of tamoxifen for SUM159 and 2LMP were 29 μM and 38 μM, respectively. Synergy between TRA-8 (0–1000 ng/mL) and tamoxifen (20 μM) was observed for both the cell lines. Tamoxifen (400 mg/kg diet) markedly suppressed the growth of SUM159 tumors for 6 weeks after therapy initiation, but it did not induce antitumor effect for 2LMP tumors. TRA-8 (0.1 mg, weekly, i.p.) successfully arrested the growth of both SUM159 and 2LMP tumors during therapy, but an antagonistic effect was observed when tamoxifen was combined. TRA-8 uptake into tumors was not changed by tamoxifen treatment. Histological analysis confirmed that caspase-3 activation induced by TRA-8 was significantly decreased when tamoxifen was used in combination. In conclusion, our findings suggest that the combined use of TRA-8 and tamoxifen may cause antagonistic effects for TNBC patients. PMID:25084100

  17. Synergistic antitumor effects of liposomal honokiol combined with adriamycin in breast cancer models.

    PubMed

    Hou, Wenli; Chen, Lijuan; Yang, Guangli; Zhou, Hang; Jiang, Qiqi; Zhong, Zhenhua; Hu, Jia; Chen, Xiang; Wang, Xianhuo; Yuan, Yuan; Tang, Minghai; Wen, Jing; Wei, Yuquan

    2008-08-01

    Honokiol, a novel antitumor agent, could induce apoptosis and inhibit the growth of vascular endothelium in several tumor cell lines and xenograft models. It has been suggested that the antitumor effect of chemotherapy could be increased by combining it with an antiangiogenesis agent in anticancer strategy. The present study explored the potential to increase the antitumor effect of adriamycin by combining it with honokiol in mouse 4T1 breast cancer models, and the underlining mechanism was investigated. Honokiol was encapsulated in liposomes to improve the water insolubility. In vitro, liposomal honokiol inhibited the proliferation of 4T1 cells via apoptosis and significantly enhanced the apoptosis of 4T1 cells induced by adriamycin. In vivo, the systemic administration of liposomal honokiol and adriamycin significantly decreased tumor growth through increased tumor cell apoptosis compared with either treatment alone. Collectively, these findings suggest that liposomal honokiol may augment the induction of apoptosis in 4T1 cells in vitro and in vivo, and this combined treatment has shown synergistic suppression in tumor progression according to the analysis of isobologram. The present study may be important in future exploration of the potential application of the combined approach in the treatment of breast cancer.

  18. AB063. Potential synergistic effect by combination of PED-4 and PED-5 inhibitors plus theophylline in lung cancer?

    PubMed Central

    Domvri, Kalliopi; Hohenforst-Schmidt, Wolfgang; Zogas, Nikolaos; Petanidis, Savvas; Zarogoulidis, Paul; Porpodis, Konstantinos; Kioseoglou, Efi; Zarogoulidis, Konstantinos

    2016-01-01

    Background Lung cancer remains the leading cause of cancer-related deaths worldwide and novel therapeutic approaches targeting crucial pathways are urgently needed to improve its treatment. Differentiation-based therapeutics (Methylxanthines) and phosphodiesterase inhibitors (type 4 and 5), have been implicated in cancer treatment. Our objectives were to capture any potential anti-tumor effect of these drug combinations with chemotherapeutic agents in vitro. Methods Theophylline as Methylxanthines, Roflumilast as phosphodiesterase type 4 (PED-4) inhibitor and Sildenafil as phosphodiesterase type 5 (PED-5) inhibitor are the drugs that we combined with the chemotherapeutic agents (Docetaxel, Cisplatin and Carboplatin) in vitro. Lung cancer cell lines (NCI-H1048-small cell lung cancer, A549-non-small cell lung cancer) were purchased from ATCC LGC Standards. At indicated time-point, following 24 and 48 h incubation, cell viability and apoptosis were measured with Annexin V staining by flow cytometry. Statistical analysis was performed by GraphPad Prism. Results In Small cell lung cancer cells, following 48 h incubation, combinations of carboplatin and roflumilast (P<0.05), carboplatin with roflumilast and sildenafil (P<0.0001), carboplatin with theophylline and sildenafil (P<0.001), showed increased apoptosis when compared to carboplatin alone. The only combination that showed increased apoptosis following 24 h incubation was carboplatin with theophylline (P<0.0001). Moreover, cisplatin combined with roflumilast, theophylline and sildenafil resulted in increased apoptosis after 48 h incubation when compared with cisplatin alone (P<0.05). In non-small cell lung cancer cells, the 24 h incubation was not enough to induce satisfactory apoptosis, except for the combination of cisplatin with roflumilast and theophylline. However, following 48 h incubation, carboplatin plus sildenafil, carboplatin plus sildenafil, theophylline and roflumilast showed more cytotoxicity when

  19. Combined Arms Training Program Cost Analysis.

    DTIC Science & Technology

    1980-12-01

    Air Ground Combat Center is tasked with the mission of developing , administering, and evaluating the Marine Corps Combined Arms Training Program. The...Marine Corps Air Ground Combat Center is tasked with the mission of developing , administering, and evaluating the Marine Corps Combined Arms Training...Combined Arms Exercises (CAX). It has the mission of developing , administering, and evaluating the Combined Arms Training Program (CATP) [13:1]. A CAX is

  20. Combination chemoprevention for colon cancer targeting polyamine synthesis and inflammation

    PubMed Central

    Gerner, Eugene W.; Meyskens, Frank L.

    2009-01-01

    Increased polyamine synthesis and inflammation have long been associated with colon carcinogenesis in both preclinical models and in humans. Recent experimental studies suggest that polyamines may be mechanistically involved in colonic inflammatory processes. Genetic epidemiology results indicate that a single nucleotide polymorphism influencing the expression of a polyamine biosynthetic gene is associated with both risk of colon polyp occurrence and recurrence, and the response to aspirin as a polyp preventive agent. A prospective, randomized, placebo-controlled clinical trial of combination difluoromethylornithine (DFMO), a selective inhibitor of polyamine synthesis, and sulindac, a non-steroidal anti-inflammatory drug (NSAID), found that the three year treatment was associated with a 70% reduction recurrence of all adenomas, and over a 90% reduction in recurrence of advanced and/or multiple adenomas, without evidence of serious toxicities. This proof-of-principle trial indicates that targeting polyamine synthesis and inflammation can be an effective strategy for preventing the occurrence of the advanced and/or multiple adenomas that are most closely associated with the development of colon cancers in humans. PMID:19188144

  1. UFT/leucovorin plus vinorelbine combination for advanced breast cancer.

    PubMed

    Fumoleau, P; Déporte, R; Kerbrat, P; Bonneterre, J; Fargeot, P

    2000-10-01

    This phase I study was undertaken to define the maximum tolerated dose, the dose-limiting toxicity, and the recommended dose of UFT plus leucovorin and vinorelbine in combination treatment of patients with metastatic breast cancer previously treated with one chemotherapy regimen. The pharmacokinetics of UFT and vinorelbine were also evaluated. Patients were treated with escalating doses of UFT and vinorelbine, given every 4 weeks. At least three patients were treated at each dose level before escalating to the next level. As of September 1, 1999, 22 patients have been treated. Eighteen patients were evaluable for antitumor response. One patient had a complete response (which was obtained after three cycles); four patients had a partial response. The area under the concentration-time curve (AUC0-6 h) of 5-fluorouracil increase was more than dose-proportional. The AUC0-6 h values of fluorouracil were significantly higher than those noted for the four patients who developed dose-limiting toxicity at day 15. The removal of one administration of vinorelbine at dose levels 3 and 4 has allowed for increased UFT dosage and AUC0-6 h of fluorouracil, with no dose-limiting toxicity reported for these patients. No pharmacokinetic interaction between UFT and vinorelbine was observed.

  2. [Treatment outcomes of colon cancer surgery combined with radical lymphadenectomy].

    PubMed

    Lipská, L; Visokai, V; Mrácek, M; Levý, M

    2008-05-01

    The authors analyzed a group of 1281 subjects with colorectal cancer operated and followed up in a single institution from I/1992 to VIII/2007. Colon carcinoma patients were assessed separately (C18). Patients with rectal and rectosigmoid tumors are not included in the presentation. A total of 846 patients were operated for colon carcinomas. In 546 subjects, radical R0 resections were achieved. In the R0 group, the male/female ratio is 315/231, age 29-94 years, the mean age of 69 years. The R0 group stratification by TNM classification was: I 17.8%, II 49.6%, III 24.0%, IV 8.1%, TNMx 0.5%. Irrespective of the TNM staging, three-year, five-year and ten-year survival rates were 80%, 71%, and 51%, resp. The median survival time was 9.85 years. Postoperative morality was 5.5%, morbidity 29.8%, anastomic leak occured in 5.7%. Systematic lymph node dissection up to the apical level, had been gradually introduced as an integral part of the R0 surgery. The aim of the study is to analyze outcomes of the colon carcinoma surgical management, combined with radical lymphadenectomy. Furthermore, effects of the extensive procedure on the postoperative morbidity and moratility rates are analyzed as well.

  3. EMP combination chemotherapy and low-dose monotherapy in advanced prostate cancer.

    PubMed

    Kitamura, Tadaichi; Nishimatsu, Hiroaki; Hamamoto, Toshiaki; Tomita, Kyoichi; Takeuchi, Takumi; Ohta, Nobutaka

    2002-02-01

    Many chemotherapeutic regimens combined with estramustine phosphate (EMP) have been elaborated for the treatment of hormone-refractory prostate cancer over 30 years. However, older EMP-based combination chemotherapies with vinblastine, vinorelbine, doxorubicin or cyclophosphamide showed relatively low PSA response rate (25-58%) accompanied with high toxicities. On the other hand, newly developed EMP-based combination regimens with etoposide, pacitaxel, carboplatin or docetaxel demonstrated promising PSA response rate (43-77%) with moderate to severe toxicity in the rate of thromboembolic event (5-18%) and of neutropenia (9-41%). Treatment-related death was less in the latter combination group (5/615, 0.8%) than that in the former group (3/234, 1.3%). Of note, in the docetaxel combination with EMP, PSA response rate is as high as 77% with high rate (41%) of neutropenia but no treatment-related death was observed. Docetaxel combination with EMP seems to be the best regimen, though not completely justified by randomized trials, to be selected in the modern era, which will be followed by paclitaxel, carboplatin and EMP combination with PSA response rate of 71%. In addition, an interim report in 83 patients was presented. They were not consecutively enrolled but were treated on low-dose EMP monotherapy for previously untreated advanced prostate cancer in Department of Urology of Tokyo University and our 21 affiliated hospitals. Overall PSA response rate was as high as 93.4% out of 76 assessable patients. However, overall toxicity rate was abnormally high (39.5%) with drug discontinuation rate of 32.1%. The reason of low drug compliance may be attributed to gastrointestinal symptoms. To overcome the low drug compliance, appropriate patients for EMP administration should be selected by using gene analysis on the basis of sophisticated tailor-made medicine.

  4. Cancer risk in waterpipe smokers: a meta-analysis.

    PubMed

    Mamtani, Ravinder; Cheema, Sohaila; Sheikh, Javaid; Al Mulla, Ahmad; Lowenfels, Albert; Maisonneuve, Patrick

    2017-01-01

    To quantify by meta-analysis the relationship between waterpipe smoking and cancer, including cancer of the head and neck, esophagus, stomach, lung and bladder. We performed a systematic literature search to identify relevant studies, scored their quality, used fixed and random-effect models to estimate summary relative risks (SRR), evaluated heterogeneity and publication bias. We retrieved information from 28 published reports. Considering only highquality studies, waterpipe smoking was associated with increased risk of head and neck cancer (SRR 2.97; 95 % CI 2.26-3.90), esophageal cancer (1.84; 1.42-2.38) and lung cancer (2.22; 1.24-3.97), with no evidence of heterogeneity or publication bias. Increased risk was also observed for stomach and bladder cancer but based mainly on poor-quality studies. For colorectum, liver and for all sites combined risk estimates were elevated, but there were insufficient reports to perform a meta-analysis. Contrary to the perception of the relative safety of waterpipe smoking, this meta-analysis provides quantitative estimates of its association with cancers of the head and neck, esophagus and lung. The scarcity and limited quality of available reports point out the need for larger carefully designed studies in well-defined populations.

  5. Combined conjugated esterified estrogen plus methyltestosterone supplementation and risk of breast cancer in postmenopausal women.

    PubMed

    Kabat, Geoffrey C; Kamensky, Victor; Heo, Moonseong; Bea, Jennifer W; Hou, Lifang; Lane, Dorothy S; Liu, Simin; Qi, LiHong; Simon, Michael S; Wactawski-Wende, Jean; Rohan, Thomas E

    2014-09-01

    Testosterone supplementation is being prescribed increasingly to treat symptoms of hormone deficiency in pre- and postmenopausal women; however, studies of the association of testosterone therapy, alone or in combination with estrogen, with risk of breast cancer are limited. The current study assessed the association of combination conjugated esterified estrogen and methyltestosterone (CEE+MT) use and breast cancer risk in postmenopausal women in the Women's Health Initiative (WHI). At Year 3 of follow-up, women in the WHI observational study (N=71,964) provided information on CEE+MT use in the past two years, duration of use, and the brand name of the product. In addition, in each of years 4-8, women were asked whether they had used CEE+MT in the previous year. After 10 years of follow-up, 2832 incident breast cancer cases were identified. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for the association of CEE+MT use (irrespective of use of other hormones) and of exclusive CEE+MT use in relation to breast cancer risk. Neither CEE+MT use nor exclusive use of CEE+MT was associated with risk: multivariable-adjusted HR 1.06, 95% CI 0.82-1.36 and HR 1.22, 95% CI 0.78-1.92, respectively. Among women with a natural menopause, the HR for exclusive use was 1.32 (95% CI 0.68-2.55). There was no indication of an association when repeated measures of CEE+MT use were included in a time-dependent covariates analysis. The present study, the largest prospective study to date, did not show a significant association of CEE+MT supplementation and risk of breast cancer. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  6. [Epidemiological analysis of childhood cancer in China].

    PubMed

    Zhou, Yan-Ling; An, Jia-Lu; Tian, Ling

    2015-07-01

    To analyze the epidemiological features of childhood cancer in China, and to provide some clues and basis for related academic research, the formulation of prevention and control strategy, and the construction of prevention and control system of childhood cancer. The data of childhood cancer in children aged 0-14 years which were published in Chinese Cancer Registry Annual Report in 2009-2012 and from GLOBOCAN2012 database were collected. A descriptive statistical analysis was done to determine the distributions of incidence and mortality by time, area, age, and sex. In China, the incidence of childhood cancer showed a slight fluctuation with time, while the mortality rate remained stable. The incidence of childhood cancer in China was lower than the world average, and it was much lower than in the United States and Japan. However, the mortality of childhood cancer in China was higher than that in the United States and Japan. The incidence of childhood cancer in Chinese urban areas was about 2 times that in Chinese rural areas, while the mortality in the urban and rural areas was similar. The incidence and the mortality of childhood cancer both declined with increasing age. The incidence and the mortality of childhood cancer in boys were higher than those in girls. The incidence and mortality of childhood cancer in China show distribution characteristics by time, area, age, and sex, which can help to make clear the future direction of childhood cancer research and provide some ideas for the comprehensive prevention and control.

  7. Propranolol and survival from breast cancer: a pooled analysis of European breast cancer cohorts.

    PubMed

    Cardwell, Chris R; Pottegård, Anton; Vaes, Evelien; Garmo, Hans; Murray, Liam J; Brown, Chris; Vissers, Pauline A J; O'Rorke, Michael; Visvanathan, Kala; Cronin-Fenton, Deirdre; De Schutter, Harlinde; Lambe, Mats; Powe, Des G; van Herk-Sukel, Myrthe P P; Gavin, Anna; Friis, Søren; Sharp, Linda; Bennett, Kathleen

    2016-12-01

    Preclinical studies have demonstrated that propranolol inhibits several pathways involved in breast cancer progression and metastasis. We investigated whether breast cancer patients who used propranolol, or other non-selective beta-blockers, had reduced breast cancer-specific or all-cause mortality in eight European cohorts. Incident breast cancer patients were identified from eight cancer registries and compiled through the European Cancer Pharmacoepidemiology Network. Propranolol and non-selective beta-blocker use was ascertained for each patient. Breast cancer-specific and all-cause mortality were available for five and eight cohorts, respectively. Cox regression models were used to calculate hazard ratios (HR) and 95% confidence intervals (CIs) for cancer-specific and all-cause mortality by propranolol and non-selective beta-blocker use. HRs were pooled across cohorts using meta-analysis techniques. Dose-response analyses by number of prescriptions were also performed. Analyses were repeated investigating propranolol use before cancer diagnosis. The combined study population included 55,252 and 133,251 breast cancer patients in the analysis of breast cancer-specific and all-cause mortality respectively. Overall, there was no association between propranolol use after diagnosis of breast cancer and breast cancer-specific or all-cause mortality (fully adjusted HR = 0.94, 95% CI, 0.77, 1.16 and HR = 1.09, 95% CI, 0.93, 1.28, respectively). There was little evidence of a dose-response relationship. There was also no association between propranolol use before breast cancer diagnosis and breast cancer-specific or all-cause mortality (fully adjusted HR = 1.03, 95% CI, 0.86, 1.22 and HR = 1.02, 95% CI, 0.94, 1.10, respectively). Similar null associations were observed for non-selective beta-blockers. In this large pooled analysis of breast cancer patients, use of propranolol or non-selective beta-blockers was not associated with improved survival.

  8. Combination of chemotherapy and cancer stem cell targeting agents: Preclinical and clinical studies.

    PubMed

    Li, Yanyan; Atkinson, Katharine; Zhang, Tao

    2017-03-12

    The cancer stem cell model claims that the initiation, maintenance, and growth of a tumor are driven by a small population of cancer cells termed cancer stem cells. Cancer stem cells possess a variety of phenotypes associated with therapeutic resistance and often cause recurrence of the diseases. Several strategies have been investigated to target cancer stem cells in a variety of cancers, such as blocking one or more self-renewal signaling pathways, reducing the expression of drug efflux and ATP-binding cassette efflux transporters, modulating epigenetic aberrations, and promoting cancer stem cell differentiation. A number of cell and animal studies strongly support the potential benefits of combining chemotherapeutic drugs with cancer stem cell targeting agents. Clinical trials are still underway to address the pharmacokinetics, safety, and efficacy of combination treatment. This mini-review provides an updated discussion of these preclinical and clinical studies.

  9. Analysis of multiwavelength coherent beam combining effect.

    PubMed

    Kai, Han; Xiaojun, Xu; Zejin, Liu

    2012-12-01

    The combination effect of multiwavelength active coherent beam combination (CBC) is investigated theoretically. The dependence of the combination effect on the optical path control precision, spectral width, wavelength number, and channel number is revealed. In the case of small optical path variance, the combination effect approximately decreases in quadratic form with wavelength number N, spectral width Δν, and optical path variance σ increasing. In the case of large optical path variance, the combination effect is independent of the optical path variance and the spectral width. The larger the wavelength number is, the smaller the Strehl ratio expectation is, and it finally degenerates to the incoherent combination. The necessity of optical path control is discussed. This study is helpful for multiwavelength CBC system design and the combination effect estimation.

  10. Combination of integrin siRNA and irradiation for breast cancer therapy

    SciTech Connect

    Cao Qizhen; Cai Weibo; Li Tianfang; Yang Yong; Chen Kai; Xing Lei; Chen Xiaoyuan . E-mail: shawchen@stanford.edu

    2006-12-22

    Up-regulation of integrin {alpha}{sub v}{beta}{sub 3} has been shown to play a key role in tumor angiogenesis and metastasis. In this study, we evaluated the role of integrin {alpha}{sub v}{beta}{sub 3} in breast cancer cell resistance to ionizing irradiation (IR) and tested the anti-tumor efficacy of combining integrin {alpha}{sub v} siRNA and IR. Colonogenic survival assay, cell proliferation, apoptosis, and cell cycle analysis were carried out to determine the treatment effect of siRNA, IR, or combination of both on MDA-MB-435 cells (integrin {alpha}{sub v}{beta}{sub 3}-positive). Integrin {alpha}{sub v}{beta}{sub 3}-negative MCF-7 cells exert more radiosensitivity than MDA-MB-435 cells. IR up-regulates integrin {alpha}{sub v}{beta}{sub 3} expression in MDA-MB-435 cells and integrin {alpha}{sub v} siRNA can effectively reduce both {alpha}{sub v} and {alpha}{sub v}{beta}{sub 3} integrin expression, leading to increased radiosensitivity. Integrin {alpha}{sub v} siRNA also promotes IR-induced apoptosis and enhances IR-induced G2/M arrest in cell cycle progression. This study, with further optimization, may provide a simple and highly efficient treatment strategy for breast cancer as well as other integrin {alpha}{sub v}{beta}{sub 3}-positive cancer types.

  11. Mechanistic Support for Combined MET and AR Blockade in Castration-Resistant Prostate Cancer.

    PubMed

    Qiao, Yuanyuan; Feng, Felix Y; Wang, Yugang; Cao, Xuhong; Han, Sumin; Wilder-Romans, Kari; Navone, Nora M; Logothetis, Christopher; Taichman, Russell S; Keller, Evan T; Palapattu, Ganesh S; Alva, Ajjai S; Smith, David C; Tomlins, Scott A; Chinnaiyan, Arul M; Morgan, Todd M

    2016-01-01

    A recent phase III trial of the MET kinase inhibitor cabozantinib in men with castration-resistant prostate cancer (CRPC) failed to meet its primary survival end point; however, most men with CRPC have intact androgen receptor (AR) signaling. As previous work supports negative regulation of MET by AR signaling, we hypothesized that intact AR signaling may have limited the efficacy of cabozantinib in some of these patients. To assess the role of AR signaling on MET inhibition, we first performed an in silico analysis of human CRPC tissue samples stratified by AR signaling status ((+) or (-)), which identified MET expression as markedly increased in AR(-) samples. In vitro, AR signaling inhibition in AR(+) CRPC models increased MET expression and resulted in susceptibility to ligand (HGF) activation. Likewise, MET inhibition was only effective in blocking cancer phenotypes in cells with MET overexpression. Using multiple AR(+) CRPC in vitro and in vivo models, we showed that combined cabozantinib and enzalutamide (AR antagonist) treatment was more efficacious than either inhibitor alone. These data provide a compelling rationale to combine AR and MET inhibition in CRPC and may explain the negative results of the phase III cabozantinib study in CRPC. Similarly, the expression of MET in AR(-) disease, whether due to AR inhibition or loss of AR signaling, suggests potential utility for MET inhibition in select patients with AR therapy resistance and in AR(-) prostate cancer.

  12. Use of a combination of biomarkers in serum and urine to improve detection of prostate cancer.

    PubMed

    Prior, Celia; Guillen-Grima, Francisco; Robles, Jose E; Rosell, David; Fernandez-Montero, Jose M; Agirre, Xabier; Catena, Raúl; Calvo, Alfonso

    2010-12-01

    To measure a combination of novel molecular biomarkers in urine/blood samples of consecutive patients referring lower urinary tract symptoms (LUTS) not previously diagnosed, to improve prostate cancer diagnosis. Serum and urine samples from 113 men who went consecutively to the Department of Urology of our Institution. Biomarkers analyzed were AMACR and MMP-2 levels, and GSTP1/RASSF1A methylation status, in addition to PSA levels. Sensitivity, specificity, area under the ROC (AUROC) curves, and discriminant function analysis were assessed to determine the diagnostic potential of each variable alone or in combination. Of the patients, 30.08% had PCa and the remaining ones were tumor free. Areas under the ROC (AUROC) curves were as follows: 0.476 for PSA, 0.532 for AMACR, and 0.706 for MMP-2. Sensitivity and specificity for methylation status were 53.3 and 45.9%, respectively. The combination of these biomarkers resulted in an AUROC curve of 0.788, which significantly outperformed AUROC curves for PSA (P = 0.0033) and AMACR (P = 0.0375). Sensitivity, specificity, positive and negative predictive values for the combination of biomarkers were 57.1, 96.6, 88.9, and 82.4%, respectively. We conclude that analysis of this biomarker combination in body fluids improves very significantly the diagnosis of PCa compared to the PSA test.

  13. Clinical efficacy of metallic biliary stents combined with different anti-cancer treatments in the management of bile duct cancer.

    PubMed

    Li, Teng-Fei; Chen, Chen; Han, Xin-Wei; Zhen, Li; Jiao, De-Chao; Ma, Ji

    2014-01-01

    The appropriate selection of an anti-cancer treatment after biliary stenting for bile duct cancer and the effects of new anti-cancer treatments are unclear. To determine the clinical efficacy of metallic biliary stents combined with different anticancer treatments in the management of bile duct cancer. We compared 49 patients with bile duct cancer who underwent biliary stenting plus anticancer treatment with 60 patients who underwent stenting alone (controls) in our hospital, between December 1998 and December 2012. In the combined-treatment group, 23 patients underwent three-dimensional radiation therapy, 21 underwent chemotherapy, and 5 underwent both three-dimensional radiation therapy and chemotherapy. The survival rate (chi2 = 41.563, P = 0.000) and duration of stent patency (chi2 = 50.268, P = 0.000) were significantly greater in the combined-treatment group than the control group. Adverse reactions were observed .The patients in the combined-treatment group developed nausea, vomiting and leukopenia, which were cured with symptomatic treatment. No biliary stent-related complications occurred in either group. Metallic biliary stent insertion combined with different anti-cancer treatments can increase survival and stent patency rates in bile duct cancer patients. This combination treatment was safe and effective.

  14. Effects of combination of melatonin and laser irradiation on ovarian cancer cells and endothelial lineage viability.

    PubMed

    Akbarzadeh, Maryam; Nouri, Mohammad; Banekohal, Maryam Vahidi; Cheraghi, Omid; Tajalli, Habib; Movassaghpour, Aliakbar; Soltani, Sina; Cheraghi, Hadi; Feizy, Navid; Montazersaheb, Soheila; Rahbarghazi, Reza; Samadi, Nasser

    2016-11-01

    The main goal of anti-cancer therapeutic approaches is to induce apoptosis in tumor masses but not in the normal tissues. Nevertheless, the combination of photodynamic irradiation with complementary oncostatic agents contributes to better therapeutic performance. Here, we applied two different cell lines; SKOV3 ovarian carcinoma cells and HUVECs umbilical cord cells as in vitro models to pinpoint whether pharmacological concentration of melatonin in combination with photodynamic therapy induces cell cytotoxicity. The cells were separately treated with various concentrations of melatonin (0 to 10 mM) and photodynamic irradiation alone or in combination. Cells were preliminary exposed to increasing concentrations of melatonin for 24 h and subsequently underwent laser irradiation for 60 s with an output power of 80 mW in continuous mode at 675 nm wavelength and a total light dose of 13.22 J/cm(2). Cell viability, apoptosis/necrosis rates, and reactive oxygen species levels as well as heat shock protein 70 expression were monitored after single and combined treatments. A statistical analysis was performed by applying one-way analysis of variance (ANOVA) and post hoc Tukey's test. Combination treatment of both cell lines caused a marked increase in apoptosis/necrosis rate, reactive oxygen species generation, and heat shock protein 70 expression compared to incubation of the cells with each agent alone (p < 0.05). SKOV3 cancer cells expressed higher level of heat shock protein 70 under experimental procedure as compared to HUVECs (p < 0.05). Our results introduce melatonin as a potent stimulus for enhancing the efficacy of laser on induction of apoptosis in tumor cells.

  15. The Cancer Genome Atlas Pan-Cancer analysis project.

    PubMed

    Weinstein, John N; Collisson, Eric A; Mills, Gordon B; Shaw, Kenna R Mills; Ozenberger, Brad A; Ellrott, Kyle; Shmulevich, Ilya; Sander, Chris; Stuart, Joshua M

    2013-10-01

    The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile.

  16. Individual and combined soy isoflavones exert differential effects on metastatic cancer progression

    PubMed Central

    Martínez-Montemayor, Michelle M.; Otero-Franqui, Elisa; Martinez, Joel; De La Mota-Peynado, Alina; Cubano, Luis A.

    2010-01-01

    To investigate the effects soy isoflavones in established cancers, the role of genistein, daidzein, and combined soy isoflavones was studied on progression of subcutaneous tumors in nude mice created from green fluorescent protein (GFP) tagged-MDA-MB-435 cells. Following tumor establishment, mice were gavaged with vehicle or genistein or daidzein at 10 mg/kg body weight (BW) or a combination of genistein (10 mg/kg BW), daidzein (9 mg/kg BW), and glycitein (1 mg/kg BW) three times per week. Tumor progression was quantified by whole body fluorescence image analysis followed by microscopic image analysis of excised organs for metastases. Results show that daidzein increased while genistein decreased mammary tumor growth by 38 and 33% respectively, compared to vehicle. Daidzein increased lung and heart metastases while genistein decreased bone and liver metastases. Combined soy isoflavones did not affect primary tumor growth but increased metastasis to all organs tested, which include lung, liver, heart, kidney, and bones. Phosphoinositide-3-kinase (PI3-K) pathway real time PCR array analysis and western blotting of excised tumors demonstrate that genistein significantly downregulated 10/84 genes, including the Rho GTPases RHOA, RAC1, and CDC42 and their effector PAK1. Daidzein significantly upregulated 9/84 genes that regulate proliferation and protein synthesis including EIF4G1, eIF4E, and survivin protein levels. Combined soy treatment significantly increased gene and protein levels of EIF4E and decreased TIRAP gene expression. Differential regulation of Rho GTPases, initiation factors, and survivin may account for the disparate responses of breast cancers to genistein and daidzein diets. This study indicates that consumption of soy foods may increase metastasis. Electronic supplementary material The online version of this article (doi:10.1007/s10585-010-9336-x) contains supplementary material, which is available to authorized users. PMID:20517637

  17. Clinical outcomes of surgically resected combined small cell lung cancer: a two-institutional experience

    PubMed Central

    Zhang, Chao; Yang, Haitang; Zhao, Heng; Lang, Baoping; Yu, Xiangdong; Xiao, Peng

    2017-01-01

    Background The combined small cell lung cancer (c-SCLC) was rare and its clinicopathological characteristics had not been thoroughly described. The aim of this study was to determine prognostic factors and survival in c-SCLC patients. Methods Clinical records of patients with c-SCLC who underwent surgery between January 2009 and December 2013 in two institutions were retrospectively reviewed. Results Ninety-seven patients were identified. The most common pathology was combined SCLC and large cell neuroendocrine carcinoma (LCNEC, N=46), followed by combined SCLC and squamous cell carcinoma (SCC) (N=32), combined SCLC and adenocarcinoma (AC) (N=12), and combined SCLC and adenosquamous carcinoma (ASC) (N=7). The overall survival (OS) rates of the entire cohort were 42.4% and 35.2% at 3 and 5 years, respectively. Multivariate analysis identified sex [female vs. male, hazards ratio (HR) =0.38; 95% confidence interval (CI): 0.19–0.79; P=0.010], age (<53 vs. >53 years, HR =0.28; 95% CI: 0.09–0.81; P=0.019), performance status (<2 vs. >2, HR =0.08; 95% CI: 0.02–0.32; P<0.001), combined non-small cell lung cancer (NSCLC) components (LCNEC vs. non-LCNEC, HR =3.00; 95% CI: 1.03–8.76; P=0.045), adjuvant therapy (yes vs. no, HR =0.33; 95% CI: 0.17–0.67; P=0.002) as significantly prognostic factors of OS in patients with complete resection and lymphadenectomy. Conclusions The mixed NSCLC components within c-SCLCs had a significant influence on the survival. Compared with surgery alone, adjuvant therapy was associated with significantly improved survival in patients with complete resection and lymphadenectomy. PMID:28203418

  18. An application of a Hill-based response surface model for a drug combination experiment on lung cancer.

    PubMed

    Ning, Shaoyang; Xu, Hongquan; Al-Shyoukh, Ibrahim; Feng, Jiaying; Sun, Ren

    2014-10-30

    Combination chemotherapy with multiple drugs has been widely applied to cancer treatment owing to enhanced efficacy and reduced drug resistance. For drug combination experiment analysis, response surface modeling has been commonly adopted. In this paper, we introduce a Hill-based global response surface model and provide an application of the model to a 512-run drug combination experiment with three chemicals, namely AG490, U0126, and indirubin-3  ' -monoxime (I-3-M), on lung cancer cells. The results demonstrate generally improved goodness of fit of our model from the traditional polynomial model, as well as the original Hill model on the basis of fixed-ratio drug combinations. We identify different dose-effect patterns between normal and cancer cells on the basis of our model, which indicates the potential effectiveness of the drug combination in cancer treatment. Meanwhile, drug interactions are analyzed both qualitatively and quantitatively. The distinct interaction patterns between U0126 and I-3-M on two types of cells uncovered by the model could be a further indicator of the efficacy of the drug combination.

  19. Antitumor effects and the underlying mechanism of licochalcone A combined with 5-fluorouracil in gastric cancer cells

    PubMed Central

    Lin, Xiaolin; Tian, Lei; Wang, Lisha; Li, Wenyan; Xu, Qi; Xiao, Xiuying

    2017-01-01

    Licochalcone A (LCA) is a flavonoid extracted from licorice root that has antiparasitic, antibacterial and antitumor properties. Previous studies have revealed that LCA may be a novel treatment for gastric cancer. The present study further assessed the potential antitumor effects of LCA alone or in combination with 5-fluorouracil (5-FU), and the underlying mechanisms responsible for those effects in gastric cancer cells. The effects of LCA alone or in combination with 5-FU on SGC7901 and MKN-45 gastric cancer cell lines were studied using Cell Counting Kit-8, cell cycle, apoptosis and western blot analyses of cell check points and apoptosis-associated proteins. The results revealed that LCA inhibited cell proliferation, blocked cell cycle progression at the G2/M transition and induced apoptosis. Western blot analysis demonstrated that LCA treatment increased the levels of tumor proteins 21 and 27, as well as mouse double minute 2 homolog in gastric cancer cells. In addition, LCA treatment increased the expression levels of Bax, cleaved-poly ADP ribose polymerase, tumor protein 53 and caspase 3, and decreased the expression levels of Bcl-2. Therefore, the present study demonstrated that LCA alone or in combination with 5-FU may have significant anticancer effects on gastric cancer cells, and may be a novel therapeutic for the treatment of gastric cancer in the future. PMID:28454311

  20. Identification of PSME3 as a novel serum tumor marker for colorectal cancer by combining two-dimensional polyacrylamide gel electrophoresis with a strictly mass spectrometry-based approach for data analysis.

    PubMed

    Roessler, Markus; Rollinger, Wolfgang; Mantovani-Endl, Liliana; Hagmann, Marie-Luise; Palme, Stefan; Berndt, Peter; Engel, Alfred M; Pfeffer, Michael; Karl, Johann; Bodenmüller, Heinz; Rüschoff, Josef; Henkel, Thomas; Rohr, Gerhard; Rossol, Siegbert; Rösch, Wolfgang; Langen, Hanno; Zolg, Werner; Tacke, Michael

    2006-11-01

    The purpose of this study was to identify and validate novel serological protein biomarkers of human colorectal cancer (CRC). Proteins from matched CRC and adjacent normal tissue samples were resolved by two-dimensional gel electrophoresis. From each gel all spots were excised, and enveloped proteins were identified by MS. By comparison of the resulting protein profiles, dysregulated proteins can be identified. A list of all identified proteins and validation of five exemplarily selected proteins, elevated in CRC was reported previously (Roessler, M., Rollinger, W., Palme, S., Hagmann, M. L., Berndt, P., Engel, A. M., Schneidinger, B., Pfeffer, M., Andres, H., Karl, J., Bodenmuller, H., Ruschoff, J., Henkel, T., Rohr, G., Rossol, S., Rosch, W., Langen, H., Zolg, W., and Tacke, M. (2005) Identification of nicotinamide N-methyltransferase as a novel serum tumor marker for colorectal cancer. Clin. Cancer Res. 11, 6550-6557). Here we describe identification and initial validation of another potential marker protein for CRC. Comparison of tissue protein profiles revealed strong elevation of proteasome activator complex subunit 3 (PSME3) expression in CRC tissue. This dysregulation was not detectable based on the spot pattern. The PSME3-containing spot on tumor gels showed no visible difference to the corresponding spot on matched control gels. MS analysis revealed the presence of two proteins, PSME3 and annexin 4 (ANXA4) in one and the same spot on tumor gels, whereas the matched spot contained only one protein, ANXA4, on control gels. Therefore, dysregulation of PSME3 was masked by ANXA4 and could only be recognized by MS-based analysis but not by image analysis. To validate this finding, antibody to PSME3 was developed, and up-regulation in CRC was confirmed by Western blot analysis and immunohistochemistry. Finally by developing a highly sensitive immunoassay, PSME3 could be detected in human sera and was significantly elevated in CRC patients compared with healthy

  1. Reliability analysis of RC containment structures under combined loads

    SciTech Connect

    Hwang, H.; Reich, M.; Kagami, S.

    1984-01-01

    This paper discusses a reliability analysis method and load combination design criteria for reinforced concrete containment structures under combined loads. The probability based reliability analysis method is briefly described. For load combination design criteria, derivations of the load factors for accidental pressure due to a design basis accident and safe shutdown earthquake (SSE) for three target limit state probabilities are presented.

  2. Combining near-infrared-excited autofluorescence and Raman spectroscopy improves in vivo diagnosis of gastric cancer.

    PubMed

    Bergholt, Mads Sylvest; Zheng, Wei; Lin, Kan; Ho, Khek Yu; Teh, Ming; Yeoh, Khay Guan; So, Jimmy Bok Yan; Huang, Zhiwei

    2011-06-15

    This study aims to evaluate the diagnostic utility of the combined near-infrared (NIR) autofluorescence (AF) and Raman spectroscopy for improving in vivo detection of gastric cancer at clinical gastroscopy. A rapid Raman endoscopic technique was employed for in vivo spectroscopic measurements of normal (n=1098) and cancer (n=140) gastric tissues from 81 gastric patients. The composite NIR AF and Raman spectra in the range of 800-1800 cm(-1) were analyzed using principal component analysis (PCA) and linear discriminant (LDA) to extract diagnostic information associated with distinctive spectroscopic processes of gastric malignancies. High quality in vivo composite NIR AF and Raman spectra can routinely be acquired from the gastric within 0.5s. The integrated intensity over the range of 800-1800 cm(-1) established the diagnostic implications (p=1.6E-14) of the change of NIR AF intensity associated with neoplastic transformation. PCA-LDA diagnostic modeling on the in vivo tissue NIR AF and Raman spectra acquired yielded a diagnostic accuracy of 92.2% (sensitivity of 97.9% and specificity of 91.5%) for identifying gastric cancer from normal tissue. The integration area under the receiver operating characteristic (ROC) curve using the combined NIR AF and Raman spectroscopy was 0.985, which is superior to either the Raman spectroscopy or NIR AF spectroscopy alone. This work demonstrates that the complementary Raman and NIR AF spectroscopy techniques can be integrated together for improving the in vivo diagnosis and detection of gastric cancer at endoscopy.

  3. Detection of colorectal neoplasia: Combination of eight blood-based, cancer-associated protein biomarkers.

    PubMed

    Wilhelmsen, Michael; Christensen, Ib J; Rasmussen, Louise; Jørgensen, Lars N; Madsen, Mogens R; Vilandt, Jesper; Hillig, Thore; Klaerke, Michael; Nielsen, Knud T; Laurberg, Søren; Brünner, Nils; Gawel, Susan; Yang, Xiaoqing; Davis, Gerard; Heijboer, Annemieke; Martens, Frans; Nielsen, Hans J

    2017-03-15

    Serological biomarkers may be an option for early detection of colorectal cancer (CRC). The present study assessed eight cancer-associated protein biomarkers in plasma from subjects undergoing first time ever colonoscopy due to symptoms attributable to colorectal neoplasia. Plasma AFP, CA19-9, CEA, hs-CRP, CyFra21-1, Ferritin, Galectin-3 and TIMP-1 were determined in EDTA-plasma using the Abbott ARCHITECT® automated immunoassay platform. Primary endpoints were detection of (i) CRC and high-risk adenoma and (ii) CRC. Logistic regression was performed. Final reduced models were constructed selecting the four biomarkers with the highest likelihood scores. Subjects (N = 4,698) were consecutively included during 2010-2012. Colonoscopy detected 512 CRC patients, 319 colonic cancer and 193 rectal cancer. Extra colonic malignancies were detected in 177 patients, 689 had adenomas of which 399 were high-risk, 1,342 had nonneoplastic bowell disease and 1,978 subjects had 'clean' colorectum. Univariable analysis demonstrated that all biomarkers were statistically significant. Multivariate logistic regression demonstrated that the blood-based biomarkers in combination significantly predicted the endpoints. The reduced model resulted in the selection of CEA, hs-CRP, CyFra21-1 and Ferritin for the two endpoints; AUCs were 0.76 and 0.84, respectively. The postive predictive value at 90% sensitivity was 25% for endpoint 1 and the negative predictive value was 93%. For endpoint 2, the postive predictive value was 18% and the negative predictive value was 97%. Combinations of serological protein biomarkers provided a significant identification of subjects with high risk of the presence of colorectal neoplasia. The present set of biomarkers could become important adjunct in early detection of CRC. © 2016 UICC.

  4. Fueling the engine and releasing the break: combinational therapy of cancer vaccines and immune checkpoint inhibitors

    PubMed Central

    Kleponis, Jennifer; Skelton, Richard; Zheng, Lei

    2015-01-01

    Immune checkpoint inhibitors are increasingly drawing much attention in the therapeutic development for cancer treatment. However, many cancer patients do not respond to treatments with immune checkpoint inhibitors, partly because of the lack of tumor-infiltrating effector T cells. Cancer vaccines may prime patients for treatments with immune checkpoint inhibitors by inducing effector T-cell infiltration into the tumors and immune checkpoint signals. The combination of cancer vaccine and an immune checkpoint inhibitor may function synergistically to induce more effective antitumor immune responses, and clinical trials to test the combination are currently ongoing. PMID:26487965

  5. Molecular target based combinational therapeutic approaches in thyroid cancer

    PubMed Central

    2012-01-01

    Background Thyroid cancer, as with other types of cancer, is dependent on angiogenesis for its continued growth and development. Interestingly, estrogen has been shown to contribute to thyroid cancer aggressiveness in vitro, which is in full support of the observed increased incidence of thyroid cancer in women over men. Provided that estrogen has been observed to contribute to increased angiogenesis of estrogen responsive breast cancer, it is conceivable to speculate that estrogen also contributes to angiogenesis of estrogen responsive thyroid cancer. Methods In this study, three human thyroid cancer cells (B-CPAP, CGTH-W-1, ML-1) were treated with estrogen alone or estrogen and anti-estrogens (fulvestrant and 3,3′-diindolylmethane, a natural dietary compound) for 24 hours. The cell culture media was then added to human umbilical vein endothelial cell (HUVECs) and assayed for angiogenesis associated events. Vascular endothelial growth factor (VEGF) levels were also quantified in the conditioned media so as to evaluate if it is a key player involved in these observations. Results Conditioned medium from estrogen treated thyroid cancer cells enhanced phenotypical changes (proliferation, migration and tubulogenesis) of endothelial cells typically observed during angiogenesis. These phenotypic changes observed in HUVECs were determined to be modulated by estrogen induced secretion of VEGF by the cancer cells. Lastly, we show that VEGF secretion was inhibited by the anti-estrogens, fulvestrant and 3,3′-diindolylmethane, which resulted in diminished angiogenesis associated events in HUVECs. Conclusion Our data establishes estrogen as being a key regulator of VEGF secretion/expression in thyroid cells which enhances the process of angiogenesis in thyroid cancer. These findings also suggest the clinical utility of anti-estrogens as anti-angiogenic compounds to be used as a therapeutic means to treat thyroid cancer. We also observed that 3,3′-diindolylmethane is a

  6. Combinational treatment of gap junctional activator and tamoxifen in breast cancer cells.

    PubMed

    Gakhar, Gunjan; Hua, Duy H; Nguyen, Thu Annelise

    2010-01-01

    Tamoxifen is a drug of choice for endocrine-responsive breast tumor patients. However, tamoxifen resistance has become a major concern for the treatment of breast cancer. Combinational therapies of tamoxifen and different drugs are being frequently studied. In this study, we tested the efficacy of substituted quinolines (code name=PQ1; a gap junctional activator) in combination with tamoxifen in T47D cells. Colony growth assay was performed using soft agar to measure the colony growth, whereas cell proliferation was measured by the MTT assay in T47D cells. The level of Ki67, survivin, and BAX was measured using confocal microscopy along with western blot analysis. Apoptosis-bromodeoxyuridine triphosphate labeling was also examined in the induced treatment of T47D cells. We observed a 55% decrease in the colony growth in the presence of combination of PQ1 and tamoxifen, whereas tamoxifen alone had little effect. A combination of 10 micromol/l tamoxifen and 200 or 500 nmol/l PQ1 resulted in only 16% cell viability compared with controls at 48 h in T47D cells by the MTT assay. We found a significant increase in BAX protein at 1 h in the presence of 500 nmol/l PQ1 alone, 10 micromol/l tamoxifen alone, and the combination of PQ1 and tamoxifen. A two-fold increase was observed in active caspase 3 in the presence of combinational treatment of 10 micromol/l tamoxifen and 200 or 500 nmol/l PQ1. In addition, flow cytometric analysis showed a 50% increase in the number of apoptotic cells in the presence of the combination of tamoxifen and PQ1 compared with the control. Furthermore, the results show that combinational treatment of tamoxifen and PQ1 significantly reduces the expression of survivin in T47D cells. Gap junction inhibitor studies with carbenexolone were also performed confirming the role of gap junctions in cell proliferation and cell death. The combinational treatment of PQ1 and tamoxifen has a significant increase in BAX expression, caspase 3 activation, and DNA

  7. A combined DNA-affinic molecule and N-mustard alkylating agent has an anti-cancer effect and induces autophagy in oral cancer cells.

    PubMed

    Lo, Wen-Liang; Chu, Pen-Yuan; Lee, Tsung-Heng; Su, Tsann-Long; Chien, Yueh; Chen, Yi-Wei; Huang, Pin-I; Tseng, Ling-Ming; Tu, Pang-Hsien; Kao, Shou-Yen; Lo, Jeng-Fan

    2012-01-01

    Although surgery or the combination of chemotherapy and radiation are reported to improve the quality of life and reduce symptoms in patients with oral cancer, the prognosis of oral cancer remains generally poor. DNA alkylating agents, such as N-mustard, play an important role in cancer drug development. BO-1051 is a new 9-anilinoacridine N-mustard-derivative anti-cancer drug that can effectively target a variety of cancer cell lines and inhibit tumorigenesis in vivo. However, the underlying mechanism of BO-1051-mediated tumor suppression remains undetermined. In the present study, BO-1051 suppressed cell viability with a low IC(50) in oral cancer cells, but not in normal gingival fibroblasts. Cell cycle analysis revealed that the tumor suppression by BO-1051 was accompanied by cell cycle arrest and downregulation of stemness genes. The enhanced conversion of LC3-I to LC3-II and the formation of acidic vesicular organelles indicated that BO-1501 induced autophagy. The expression of checkpoint kinases was upregulated as demonstrated with Western blot analysis, showing that BO-1051 could induce DNA damage and participate in DNA repair mechanisms. Furthermore, BO-1051 treatment alone exhibited a moderate tumor suppressive effect against xenograft tumor growth in immunocompromised mice. Importantly, the combination of BO-1051 and radiation led to a potent inhibition on xenograft tumorigenesis. Collectively, our findings demonstrated that BO-1051 exhibited a cytotoxic effect via cell cycle arrest and the induction of autophagy. Thus, the combination of BO-1051 and radiotherapy may be a feasible therapeutic strategy against oral cancer in the future.

  8. Combination Therapy Shows Promise for Treating Advanced Breast Cancer

    Cancer.gov

    Adding the drug everolimus (Afinitor®) to exemestane helped postmenopausal women whose advanced breast cancer had stopped responding to hormonal therapy live about 4 months longer without the disease progressing than women who received exemestane alone.

  9. A CASE STUDY OF CANCER DATA SET COMBINATIONS FOR PCBs

    EPA Science Inventory

    Results of several animal bioassays have demonstrated the carcinogenic potential of polychlorinated biphenyl (PCB) mixtures. Although PCBs are no longer manufactured, cancer risk assessment for PCBs remains an important issue because of continued potential human exposure from man...

  10. Combining Chemotherapy with Bevacizumab Improves Outcomes for Ovarian Cancer Patients

    Cancer.gov

    Results from two phase III randomized clinical trials suggest that, at least for some patients with ovarian cancer, adding the antiangiogenesis agent bevacizumab to chemotherapy increases the time to disease progression and may improve survival.

  11. A CASE STUDY OF CANCER DATA SET COMBINATIONS FOR PCBs

    EPA Science Inventory

    Results of several animal bioassays have demonstrated the carcinogenic potential of polychlorinated biphenyl (PCB) mixtures. Although PCBs are no longer manufactured, cancer risk assessment for PCBs remains an important issue because of continued potential human exposure from man...

  12. Effect of lipoic acid combined with paclitaxel on breast cancer cells.

    PubMed

    Li, B J; Hao, X Y; Ren, G H; Gong, Y

    2015-12-22

    Breast cancer is the most common gynecologic tumor globally that threatens women's health. Lipoic acid is a type of antioxidant that can alleviate oxidative stress damage. Studies showed that lipoic acid could inhibit the proliferation of tumor cells in cervical cancer and colon cancer. This paper intends to explore the combined effect of lipoic acid and paclitaxel on breast cancer cells. Breast cancer MCF-7 cells were divided into four groups: control group, lipoic acid group, paclitaxel group, and a combination group. MTT was applied to detect the drugs' influence on breast cancer cell proliferation. A colony formation test was used to determine the effects on breast cancer cell clone formation rate. Western blot was performed to detect the effects on nuclear factor (NF)-κB. Lipoic acid alone can inhibit tumor cell proliferation and clone formation with time dependence. Compared with the control, paclitaxel alone can significantly suppress tumor cell proliferation and clone formation (P < 0.05). Lipoic acid and paclitaxel in combination obviously strengthened their individual inhibitory effects on tumor cells (P < 0.05). Compared with the paclitaxel alone group, the combination group exhibited more remarkable inhibitory effect (P < 0.05). Lipoic acid alone or combined with paclitaxel can inhibit NF-κB expression and inhibit breast cancer cell proliferation.

  13. Targeting Metabolic Survival Pathways in Lung Cancer via Combination Therapy

    DTIC Science & Technology

    2014-06-01

    critical metabolic pathways necessary for survival of liver kinase B1 (LKB1)-deficient non -small cell lung cancer (NSCLC) cell lines. We have conducted...removal/washout of phenformin. Given the dependence of LKB1-deficient tumor cells on glutamine metabolism, we are targeting a critical enzyme responsible...B1, non -small cell lung cancer, glutamine metabolism, biguanides 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF

  14. Combined Radiation Therapy and Immune Checkpoint Blockade Therapy for Breast Cancer.

    PubMed

    Hu, Zishuo I; Ho, Alice Y; McArthur, Heather L

    2017-09-01

    Treatment with checkpoint inhibitors has shown durable responses in a number of solid tumors, including melanoma, lung, and renal cell carcinoma. However, most breast cancers are resistant to monotherapy with checkpoint inhibitors. Radiation therapy (RT) has been shown to have a number of immunostimulatory effects, including priming the immune system, recruiting immune cells to the tumor environment, and altering the immunosuppressive effects of the tumor microenvironment. RT therefore represents a promising adjuvant therapy to checkpoint blockade in breast cancer. We review the data from the checkpoint blockade studies on breast cancer reported to date, the mechanisms by which RT potentiates immune responses, the preclinical and clinical data of checkpoint blockade and RT combinations, and the landscape of current clinical trials of RT and immune checkpoint inhibitor combinations in breast cancer. Clinical trials with checkpoint blockade therapy have demonstrated response rates of up to 19% in breast cancer, and many of the responses are durable. Preclinical data indicate that RT combined with checkpoint inhibition synergizes not only to enhance antitumor efficacy but also to induce responses outside of the radiation field. Thus multiple clinical trials are currently investigating the combination of checkpoint inhibition with RT. The use of combination strategies that incorporate chemotherapy and/or local strategies such as RT may be needed to augment responses to immune therapy in breast cancer. Preclinical and clinical results show that RT in combination with checkpoint blockade may be a promising therapeutic option in breast cancer. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Silver nanoparticles enhance the apoptotic potential of gemcitabine in human ovarian cancer cells: combination therapy for effective cancer treatment

    PubMed Central

    Yuan, Yu-Guo; Peng, Qiu-Ling; Gurunathan, Sangiliyandi

    2017-01-01

    Background Gemcitabine (GEM) is widely used as an anticancer agent in several types of solid tumors. Silver nanoparticles (AgNPs) possess unique cytotoxic features and can induce apoptosis in a variety of cancer cells. In this study, we investigated whether the combination of GEM and AgNPs can exert synergistic cytotoxic effects in the human ovarian cancer cell line A2780. Methods We synthesized AgNPs using resveratrol as a reducing and stabilizing agent. The synthesized nanomaterials were characterized using various analytical techniques. The anticancer effects of a combined treatment with GEM and AgNPs were evaluated using a series of cellular assays. The expression of pro- and antiapoptotic genes was measured using real-time reverse transcription polymerase chain reaction. Apoptosis was confirmed by TUNEL assay. Results In this study, combined treatment with GEM and AgNPs significantly inhibited viability and proliferation in A2780 cells. Moreover, the levels of apoptosis in cells treated with a combination of GEM and AgNPs were significantly higher compared with those in cells treated with GEM or AgNPs alone. Our data suggest that GEM and AgNPs exhibit potent apoptotic activity in human ovarian cancer cells. Combined treatment with GEM and AgNPs showed a significantly higher cytotoxic effect in ovarian cancer cells compared with that induced by either of these agents alone. Conclusion Our study demonstrated that the interaction between GEM and AgNPs was cytotoxic in ovarian cancer cells. Combined treatment with GEM and AgNPs caused increased cytotoxicity and apoptosis in A2780 cells. This treatment may have therapeutic potential as targeted therapy for the treatment of ovarian cancer. To our knowledge, this study could provide evidence that AgNPs can enhance responsiveness to GEM in ovarian cancer cells and that AgNPs can potentially be used as chemosensitizing agents in ovarian cancer therapy. PMID:28919750

  16. Microfluidic platform combining droplets and magnetic tweezers: application to HER2 expression in cancer diagnosis

    PubMed Central

    Ferraro, Davide; Champ, Jérôme; Teste, Bruno; Serra, Marco; Malaquin, Laurent; Viovy, Jean-Louis; de Cremoux, Patricia; Descroix, Stephanie

    2016-01-01

    The development of precision medicine, together with the multiplication of targeted therapies and associated molecular biomarkers, call for major progress in genetic analysis methods, allowing increased multiplexing and the implementation of more complex decision trees, without cost increase or loss of robustness. We present a platform combining droplet microfluidics and magnetic tweezers, performing RNA purification, reverse transcription and amplification in a fully automated and programmable way, in droplets of 250nL directly sampled from a microtiter-plate. This platform decreases sample consumption about 100 fold as compared to current robotized platforms and it reduces human manipulations and contamination risk. The platform’s performance was first evaluated on cell lines, showing robust operation on RNA quantities corresponding to less than one cell, and then clinically validated with a cohort of 21 breast cancer samples, for the determination of their HER2 expression status, in a blind comparison with an established routine clinical analysis. PMID:27157697

  17. Microfluidic platform combining droplets and magnetic tweezers: application to HER2 expression in cancer diagnosis

    NASA Astrophysics Data System (ADS)

    Ferraro, Davide; Champ, Jérôme; Teste, Bruno; Serra, Marco; Malaquin, Laurent; Viovy, Jean-Louis; de Cremoux, Patricia; Descroix, Stephanie

    2016-05-01

    The development of precision medicine, together with the multiplication of targeted therapies and associated molecular biomarkers, call for major progress in genetic analysis methods, allowing increased multiplexing and the implementation of more complex decision trees, without cost increase or loss of robustness. We present a platform combining droplet microfluidics and magnetic tweezers, performing RNA purification, reverse transcription and amplification in a fully automated and programmable way, in droplets of 250nL directly sampled from a microtiter-plate. This platform decreases sample consumption about 100 fold as compared to current robotized platforms and it reduces human manipulations and contamination risk. The platform’s performance was first evaluated on cell lines, showing robust operation on RNA quantities corresponding to less than one cell, and then clinically validated with a cohort of 21 breast cancer samples, for the determination of their HER2 expression status, in a blind comparison with an established routine clinical analysis.

  18. Biologics in combination with chemotherapy for gastric cancer: is this the answer?

    PubMed

    Charalampakis, Nikolaos; Elimova, Elena; Shimodaira, Yusuke; Shiozaki, Hironori; Wadhwa, Roopma; Ajani, Jaffer A

    2015-05-01

    Gastric cancer (GC) continues to be a significant problem worldwide and is the third leading cause of cancer death. Armamentarium to treat GC whether it is potentially curable or metastatic (incurable) has changed little over the last decades with only two new agents being approved (trastuzumab and ramucirumab). Many relatively healthy patients after second-line therapy have limited and generally ineffective options. The recent The Cancer Genome Atlas analysis has uncovered four genotypes of GC; however, it is not sufficient to change our treatment strategies and more work needs to be done. The popular front-line regimen containing a platinum compound and a fluoropyrimidine is widely used for drug development and has worked well globally. Thus, this combination appears suitable for adding a biologic agent. The search for new classes of cytotoxics has almost stopped, but it is clear that cytotoxic therapy continues to contribute and it is here to stay. Biologic agents that modulate the immune system of the host appear promising along with many other biologics that can potentially inhibit signaling pathways that are often employed by GC cells. We will briefly describe the efforts that have targeted EGFR, mTOR, angiogenesis and MET pathways.

  19. Changes in body composition of cancer patients following combined nutritional support

    SciTech Connect

    Cohn, S.H.; Vartsky, D.; Vaswani, A.N.; Sawitsky, A.; Rai, K.; Gartenhaus, W.; Yasumura, S.; Ellis, K.J.

    1982-01-01

    The effects of combined nutritional support (parenteral, enteral, and oral) were measured in cancer patients unable to maintain normal alimentation.Changes in body composition were quantified by measurement of total body levels of nitrogen, potassium, water, and fat. The protein-calorie intake of the patients was also evaluated by dietary survey (4-day recall). Standard anthropometric and biochemical measurements for nutritional assessment were obtained for comparison. The dietary evaluation indicated that the dietary supplementation for all patients was more than adequate to meet their energy requirements. Determination of body composition indicated that change in body weight was equal to the sum of the changes in body protein, total body water, and total body fat. Information on the nature of the tissue gained was obtained by comparison of body composition data with the ratio of protein:water:lean body mass for normal tissue. The mean gain of protein in the cancer patients was quite small (0.3-0.6 kg). The main change in body weight appeared to be the result of gains in body water and body fat. The total body nitrogen to potassium ratio served to define the extent of tissue anabolism following hyperalimentation. The ratio dropped in the cancer patients following hyperalimentation toward the value of the control subjects on ad libitum diets. Total body nitrogen was determined by prompt gamma neutron activation analysis, total body potassium by whole-body counting. (JMT)

  20. Combination of Fenretinide and Selenite Inhibits Proliferation and Induces Apoptosis in Ovarian Cancer Cells

    PubMed Central

    Liu, Jie; Li, Jia; Zhang, Jian-Fang; Xin, Xiao-Yan

    2013-01-01

    The combination of fenretinide and selenite on ovarian cancer cells was investigated to assess its effects on proliferation and ability to induce apoptosis. Our results showed that fenretinide and selenite in combination significantly suppress the proliferation of ovarian cancer cells and induced apoptosis (including reactive oxygen species generation, and the loss of mitochondrial membrane potential) compared with either drug used alone. The caspase3/9-dependent pathway was triggered significantly in combination treatment, and moreover, the AMPK pathway also mediated the apoptosis induction in fenretinide and selenite combination. Fenretinide and selenite combination treatment was demonstrated to suppress tumor growth in vivo, this drug combination has been thus found to have an enhanced anti-tumor effect on ovarian cancers cells. PMID:24192821

  1. Combination of fenretinide and selenite inhibits proliferation and induces apoptosis in ovarian cancer cells.

    PubMed

    Liu, Jie; Li, Jia; Zhang, Jian-Fang; Xin, Xiao-Yan

    2013-11-04

    The combination of fenretinide and selenite on ovarian cancer cells was investigated to assess its effects on proliferation and ability to induce apoptosis. Our results showed that fenretinide and selenite in combination significantly suppress the proliferation of ovarian cancer cells and induced apoptosis (including reactive oxygen species generation, and the loss of mitochondrial membrane potential) compared with either drug used alone. The caspase3/9-dependent pathway was triggered significantly in combination treatment, and moreover, the AMPK pathway also mediated the apoptosis induction in fenretinide and selenite combination. Fenretinide and selenite combination treatment was demonstrated to suppress tumor growth in vivo, this drug combination has been thus found to have an enhanced anti-tumor effect on ovarian cancers cells.

  2. Comparison of the safety and efficacy of paclitaxel plus gemcitabine combination in young and elderly patients with locally advanced or metastatic non-small cell lung cancer. A retrospective analysis of the Southern Italy Cooperative Oncology Group trials.

    PubMed

    Comella, Pasquale; Gambardella, Antonio; Frasci, Giuseppe; Avallone, Antonio; Costanzo, Raffaele

    2008-02-01

    We retrospectively assessed tolerability and efficacy of paclitaxel plus gemcitabine combination in 259 patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) enrolled in three randomized SICOG trials according to their age (70 years) at study entry. Apart from age, demographic and clinical characteristics were similar in the two groups. Response rate of paclitaxel plus gemcitabine was similar in younger and in elderly (36% versus 30%). Chemotherapy was well tolerated, but severe neutropenia (12% versus 7%), anaemia (6.6% versus 1.8%), and vomiting (5% versus 0) were more frequent in elderly patients. Both median progression-free survival (PFS, 5.5 months versus 4.2 months), and overall survival (OS, 11.1 months versus 9.1 months) resulted slightly prolonged for younger patients. However, only stage and performance status resulted independently affecting PFS and OS. In conclusion, paclitaxel plus gemcitabine were similarly tolerated and active in younger and elderly patients. This regimen should be considered an option for the management of fit elderly patients.

  3. Evaluation of the efficacy of paclitaxel with curcumin combination in ovarian cancer cells

    PubMed Central

    Liu, Zeng; Zhu, Yuan-Yuan; Li, Zhao-Yuan; Ning, Si-Qing

    2016-01-01

    The aim of the present study was to evaluate the efficacy of paclitaxel combined with curcumin (CUR) against drug resistance in ovarian cancer cells. PLGA-phospholipid-PEG nanoparticles were prepared using the nano precipitation method. The size and morphology of the nanoparticles were determined using a transmission electron microscope and particle size analyzer. The encapsulation efficiency of nanoparticles was determined using the ultrafiltration centrifugation method. The dialysis method was used to study the release of PLGA-phospholipid-PEG nanoparticles. ADM was used to induce the A2780 cell line (human ovarian cancer cell line) to establish the model of the multidrug-resistant (MDR) cell line, and the protein activity of P-glycoprotein (P-gp) in the A2780 cell line and A2780/ADM resistant cell line was determined using western blot analysis. The results showed that, the prepared nanoparticles were uniform in size, with a size of approximately 100 nm, and round in shape. Additionally, the nanoparticles had a more gentle and slow release than the free drug release. The results of the protein trace printing experiment showed that the P-gp content of the drug-resistant cell line was significantly reduced by the CUR nanoparticles. In conclusion, PLGA-phospholipid nanoparticles containing taxol and CUR have improved solubility and stability together with a slow release effect. In addition, CUR was able to overcome the MDR of tumor cells by elevating the paclitaxel concentration in the tumor cells to improve the antitumor activity of this combination. PMID:27895754

  4. Coenzyme complex decreased cardiotoxicity when combined with chemotherapy in treating elderly patients with gastrointestinal cancer.

    PubMed

    Zhang, Hai-Yan; Lu, Xiang

    2015-01-01

    To investigate the effect of coenzyme complex on decreasing cardiotoxicity in elderly patients with gastrointestinal cancer who were treated by chemotherapy. From September 2011 to February 2015, we recruited 54 elderly (with more than 70 years of age) patients with gastrointestinal cancer, with advanced disease. Then treated with chemotherapy combined with or without coenzyme complex. After two cycles of treatment, the effect of coenzyme complex on decreasing cardiotoxicity were evaluated. Chemotherapy was combined with coenzyme complex in 32 patients (22man, 10 woman; median age: 74 years, range: 70-87 years) without coenzyme complex in 22 patients (15man, 7 woman; median age: 73 years, range: 70-80 years) with gastrointestinal cancer. Cardiac event was significantly lower in patients treated with chemotherapy combined with coenzyme complex (p<0.01). Coenzyme Complex decreased cardiotoxicity when combined with chemotherapy in treating elderly patients with gastrointestinal cancer.

  5. Synergistic Combination Agent for Cancer Therapy | NCI Technology Transfer Center | TTC

    Cancer.gov

    The Nanotechnology Characterization Laboratory of the Frederick National Laboratory for Biomedical Research seeks parties interested in collaborative research to co-develop a ceramide and vinca alkaloid combination therapy for treatment of cancer.

  6. A matched couple: Combining kinase inhibitors with immunotherapy for cancer treatment.

    PubMed

    Jiang, Qun; Weiss, Jonathan M; Wiltrout, Robert H

    2012-01-01

    Small-molecule kinase inhibitors targeting oncogenic signaling pathways have been explored as cancer therapeutic agents due to their strong anti-tumor activity and manageable toxicity. Accumulating evidence shows that many kinase inhibitors also profoundly modulate immune cell functions, suggesting they may be promising candidates for combination with immunotherapeutic agents for the improved treatment of cancer.

  7. Radiotherapy combined with surgery as treatment for advanced cervical cancer.

    PubMed

    Perches, R D; Lobaton, A T; Garcia, M C

    1983-12-01

    Experience obtained in a group of 44 patients with advanced cervical cancer is reported here. In this study, patients with residual cancer underwent laparotomy eight weeks after one or two different radiotherapy protocols. Sixty-eight percent of patients underwent radical surgery, 85% of patients pelvic exenterations, and 15% radical hysterectomies. In 27% of patients, no evidence of residual cancer was found in surgical specimens. Radical surgery was well tolerated, and one-third of patients were free of disease for one year or more. Control of disease was obtained in 50% of pelvic exenterations and in 60% of radical hysterectomies, regardless of prognosis, clinical stage or radiotherapy scheme. Although results show an improvement of up to 22% when comparing this to other more conventional treatments, we have concluded that we must obtain a wider experience in order to support our findings.

  8. Pharmacodynamic Modeling of Cell Cycle Effects for Gemcitabine and Trabectedin Combinations in Pancreatic Cancer Cells

    PubMed Central

    Miao, Xin; Koch, Gilbert; Ait-Oudhia, Sihem; Straubinger, Robert M.; Jusko, William J.

    2016-01-01

    Combinations of gemcitabine and trabectedin exert modest synergistic cytotoxic effects on two pancreatic cancer cell lines. Here, systems pharmacodynamic (PD) models that integrate cellular response data and extend a prototype model framework were developed to characterize dynamic changes in cell cycle phases of cancer cell subpopulations in response to gemcitabine and trabectedin as single agents and in combination. Extensive experimental data were obtained for two pancreatic cancer cell lines (MiaPaCa-2 and BxPC-3), including cell proliferation rates over 0–120 h of drug exposure, and the fraction of cells in different cell cycle phases or apoptosis. Cell cycle analysis demonstrated that gemcitabine induced cell cycle arrest in S phase, and trabectedin induced transient cell cycle arrest in S phase that progressed to G2/M phase. Over time, cells in the control group accumulated in G0/G1 phase. Systems cell cycle models were developed based on observed mechanisms and were used to characterize both cell proliferation and cell numbers in the sub G1, G0/G1, S, and G2/M phases in the control and drug-treated groups. The proposed mathematical models captured well both single and joint effects of gemcitabine and trabectedin. Interaction parameters were applied to quantify unexplainable drug-drug interaction effects on cell cycle arrest in S phase and in inducing apoptosis. The developed models were able to identify and quantify the different underlying interactions between gemcitabine and trabectedin, and captured well our large datasets in the dimensions of time, drug concentrations, and cellular subpopulations. PMID:27895579

  9. Topography, nanomechanics, and cell surface components of cancer cells examined by combined atomic force microscopy and Raman microspectroscopy

    NASA Astrophysics Data System (ADS)

    Wu, Yangzhe; McEwen, Gerald D.; Baker, Sherry M.; Yu, Tian; Gilbertson, Timothy A.; DeWald, Daryll B.; Zhou, Anhong

    2010-02-01

    The investigation of the nanostructures and hydrophobic properties of cancer cell membranes is of importance for elucidating the plasma membrane roles in protein folding, membrane fusion, and cell adhesion that are directly related to cancer cell biophysical properties, such as aggressive growth and migration. On the other hand, the chemical component analysis of the cancer cell membrane could be potentially applied in the clinical diagnosis of cancer by the identification of specific biomarker receptors expressed on cancer cell surfaces. In the present work, a combined atomic force microscopy (AFM) and Raman microspectroscopy technique was applied to detect the difference in nanomechanics and membrane chemical components between two cancer cell lines, human lung adenocarcinoma epithelial cells (A549) and human breast cancer cells (MDA-MB-435 with and without expression of BRMS1 metastasis suppressor). The membrane surface adhesion forces for these cancer cells acquired in culture medium were measured using AFM at 0.478+/-0.091 nN for A549 cells, 0.253+/-0.070 nN for 435 cells, and 1.114+/-0.281 nN for 435/BRMS1 cells, and the cell spring constant was measured at 2.62+/-0.682 mN/m for A549 cells, 2.105+/-0.691 mN/m for 435 cells, and 5.448+/-1.081 mN/m for 435/BRMS1 cells. Raman spectral analysis indicated similar peaks between the A549 cells and the breast cancer cell lines 435 and 435/BRMS1 including ~720 cm-1 (guanine band of DNA), 940 cm-1 (skeletal mode polysaccharide), 1006 cm-1 (symmetric ring breathing phenylalanine), and 1451 cm-1 (CH deformation). Slight variations were observed between ~780 - 985 cm-1 (DNA/RNA and proteins) and 1035 - 1210 cm-1 (lipid and proteins).

  10. SHIELDING ANALYSIS FOR PORTABLE GAUGING COMBINATION SOURCES

    SciTech Connect

    J. TOMPKINS; L. LEONARD; ET AL

    2000-08-01

    Radioisotopic decay has been used as a source of photons and neutrons for industrial gauging operations since the late 1950s. Early portable moisture/density gauging equipment used Americium (Am)-241/Beryllium (Be)/Cesium (Cs)-137 combination sources to supply the required nuclear energy for gauging. Combination sources typically contained 0.040 Ci of Am-241 and 0.010 Ci of CS-137 in the same source capsule. Most of these sources were manufactured approximately 30 years ago. Collection, transportation, and storage of these sources once removed from their original device represent a shielding problem with distinct gamma and neutron components. The Off-Site Source Recovery (OSR) Project is planning to use a multi-function drum (MFD) for the collection, shipping, and storage of AmBe sources, as well as the eventual waste package for disposal. The MFD is an approved TRU waste container design for DOE TRU waste known as the 12 inch Pipe Component Overpack. As the name indicates, this drum is based on a 12 inch ID stainless steel weldment approximately 25 inch in internal length. The existing drum design allows for addition of shielding within the pipe component up to the 110 kg maximum pay load weight. The 12 inch pipe component is packaged inside a 55-gallon drum, with the balance of the interior space filled with fiberboard dunnage. This packaging geometry is similar to the design of a DOT 6M, Type B shipping container.

  11. Neoadjuvant chemotherapy of breast cancer with pirarubicin versus epirubicin in combination with cyclophosphamide and docetaxel.

    PubMed

    Gu, Xi; Jia, Shi; Wei, Wei; Zhang, Wen-Hai

    2015-07-01

    Breast cancers (BC) are treated with surgery, radiotherapy, and chemotherapy. Neoadjuvant chemotherapy (NACT) is an emerging treatment option in many cancers and is given before primary therapy to shrink tumor size. The efficacy of NACT in varied settings of BC, such as inoperable tumors, borderline resectable tumors, and breast-conserving surgery, has been debated extensively in literature, and the results remain unclear and depended on a wide variety of factors such as cancer type, disease extent, and the specific combination of chemotherapy drugs. This study was performed to examine the efficacy, toxicity, and tolerability of pirarubicin (THP) and epirubicin (EPI) in combination with docetaxel and cyclophosphamide in a NACT setting for BC. A total of 48 patients with stage II or III breast cancers were randomly divided into two groups: THP group and EPI group. The patients in THP group received 2-4 cycles of neoadjuvant chemotherapy with DTC regimen (docetaxel, THP, cyclophosphamide), while patients in the EPI group received 2-4 cycles of DEC regimen (docetaxel, EPI, cyclophosphamide) before surgery. The incidence of adverse reactions and the efficacy of the treatment regimen were compared between the two groups. Prognostic evaluation indexes were estimated by Kaplan-Meier survival analysis, including the 5-year disease-free survival (DFS) and overall survival (OS). The overall response rate in THP group was 83.3 %, and the EPI group showed a response rate of 79.2 %, with no statistically significant difference in response rate between the two groups. The incidence of cardiac toxicity, myelosuppression, nausea, and vomiting in the THP group was significantly lower than the EPI group (all P < 0.05). The incidence of hepatic toxicity, alopecia, and diarrhea in the THP group was also lower than the EPI group, but these differences were not statistically significant. The 5-year DFS and OS in THP versus EPI groups were 80 versus 76 % (DFS) and 86 versus 81 % (OS

  12. Combination of the FGFR4 inhibitor PD173074 and 5-fluorouracil reduces proliferation and promotes apoptosis in gastric cancer.

    PubMed

    Ye, Yan-Wei; Hu, Shuang; Shi, Ying-Qiang; Zhang, Xie-Fu; Zhou, Ye; Zhao, Chun-Lin; Wang, Guo-Jun; Wen, Jian-Guo; Zong, Hong

    2013-12-01

    Our previous findings revealed that FGFR4 may be a novel therapeutic target for gastric cancer. The aim of the present study was to explore the effects of a combination of PD173074 (PD) and 5-fluorouracil (5-Fu) on the biological behavior of gastric cancer cell lines and the relevant mechanisms involved. MKN45, a gastric cancer cell line, was treated with each single agent alone or a combination of FGF19, PD and 5-Fu. Then, a series of functional assays were performed using CCK-8 assay and flow cytometry. Western blot analysis was used to determine the expression of signaling pathway and downstream-related molecules in the MKN45 cells following the different treatments. As the concentration of PD and 5-Fu increased, the cell viability gradually decreased; the viability of the combination group was less than the viability following single administration. Western blot analysis showed that FGFR4 expression was weak in the 5-Fu-treated groups when compared with the control. PD markedly increased the apoptosis rate of MKN45 cells when compared to the control; the apoptosis rate in the cells treated with the combination of PD and 5-Fu was higher than that in the cells following single treatment. Furthermore, PD reduced the expression of p-ERK and Bcl-xl and increased caspase-3 expression. Inhibition of the activity of FGFR4 may be the main mechanisms of PD effect while 5-Fu reduced FGFR4 expression. Furthermore, the effects of the combination of 5-Fu and PD in inhibiting proliferation, increasing apoptosis and arresting cell cycle were superior to these effects following the single agent treatments, suggesting that the two drugs applied in combination may contribute to the effective treatment of gastric cancer.

  13. Combination Immunotherapy for the Treatment of High-Risk HER2-Positive Breast Cancer

    DTIC Science & Technology

    2015-10-01

    1 AWARD NUMBER: W81XWH-14-1-0109 TITLE: Combination Immunotherapy for the Treatment of High-Risk HER2-Positive Breast Cancer PRINCIPAL...Report 3. DATES COVERED 4. TITLE AND SUBTITLE Combination Immunotherapy for the Treatment of High-Risk HER2Positive Breast Cancer 5a. CONTRACT NUMBER...Positive Breast Cancer 5b. GRANT NUMBER W81XWH-14-1-0109 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Elizabeth A. Mittendorf, MD, PhD 5d. PROJECT

  14. Withaferin A Alone and in Combination with Cisplatin Suppresses Growth and Metastasis of Ovarian Cancer by Targeting Putative Cancer Stem Cells

    PubMed Central

    Kakar, Sham S.; Ratajczak, Mariusz Z.; Powell, Karen S.; Moghadamfalahi, Mana; Miller, Donald M.; Batra, Surinder K.; Singh, Sanjay K.

    2014-01-01

    Currently, the treatment for ovarian cancer entails cytoreductive surgery followed by chemotherapy, mainly, carboplatin combined with paclitaxel. Although this regimen is initially effective in a high percentage of cases, unfortunately within few months of initial treatment, tumor relapse occurs because of platinum-resistance. This is attributed to chemo-resistance of cancer stem cells (CSCs). Herein we show for the first time that withaferin A (WFA), a bioactive compound isolated from the plant Withania somnifera, when used alone or in combination with cisplatin (CIS) targets putative CSCs. Treatment of nude mice bearing orthotopic ovarian tumors generated by injecting human ovarian epithelial cancer cell line (A2780) with WFA and cisplatin (WFA) alone or in combination resulted in a 70 to 80% reduction in tumor growth and complete inhibition of metastasis to other organs compared to untreated controls. Histochemical and Western blot analysis of the tumors revealed that inclusion of WFA (2 mg/kg) resulted in a highly significant elimination of cells expressing CSC markers - CD44, CD24, CD34, CD117 and Oct4 and downregulation of Notch1, Hes1 and Hey1 genes. In contrast treatment of mice with CIS alone (6 mg/kg) had opposite effect on those cells. Increase in cells expressing CSC markers and Notch1 signaling pathway in tumors exposed to CIS may explain recurrence of cancer in patients treated with carboplatin and paclitaxel. Since, WFA alone or in combination with CIS eliminates putative CSCs, we conclude that WFA in combination with CIS may present more efficacious therapy for ovarian cancer. PMID:25264898

  15. Paclitaxel combined with harmine inhibits the migration and invasion of gastric cancer cells through downregulation of cyclooxygenase-2 expression

    PubMed Central

    SUN, KUN; TANG, XIAO-HE; XIE, YI-KUI

    2015-01-01

    Cyclooxygenase-2 (COX-2) has a critical role in the invasiveness and metastasis of gastric cancer. In addition, paclitaxel (PTX) and harmine (HM) were reported to be potential therapeutic drug candidates for cancer therapy; however, the synergistic antitumor effect of PTX and HM combined treatment on the human gastric cancer cells remains to be elucidated. The aim of the present study was to evaluate the effects of PTX and/or HM on the cell migration and invasion in two human gastric cancer cell lines, SGC-7901 and MKN-45. MTT assay was used to detect the growth inhibition induced by PTX and HM. The Transwell assay was employed to assess the effects of PTX and HM on the cell migration and invasion. The expression levels of COX-2 and matrix metalloproteinase-9 (MMP-9) were analyzed by western blot analysis. The results demonstrated that PTX and HM inhibited cell proliferation in a dose-dependent manner. Individually PTX and HM were able to inhibit the migration and invasion of two human gastric cancer cells; however, the combination of PTX and HM exerted synergistic effects on migration and invasion inhibition, with downregulation of COX-2 and matrix metalloproteinase (MMP)-9. In conclusion, the results of the present study indicated that combination chemotherapy using PTX with HM exerted an antitumor effect, which may be implicated for the treatment of gastric cancer. Of note, the combination of the two drugs inhibited migration and invasion more effectively compared with each drug alone, the mechanism of which proceeded via the downregulation of COX-2 expression. PMID:26622726

  16. Atomic-Based-Combined-Cycle Analysis

    NASA Technical Reports Server (NTRS)

    Han, Samuel S.

    1999-01-01

    Atomic-based-combined-cycle (ABCC) engine combines an air-breathing ramjet engine with an atomic reactor to increase the mission-averaged specific impulse and thereby increasing the dry-mass ratio. ABCC engine is similar to RBCC engine except that energy needed for the propulsive power is derived from nuclear reaction rather than chemical combustion used in the RBCC engine. The potential performance improvement of an ABCC engine over a RBCC engine comes from two factors. Firstly, the energy density of nuclear reaction is several order of magnitudes higher than the chemical combustion. Secondly, hydrogen can produce much higher nozzle exit velocity because of its small molecular weight. A one-dimensional, transient numerical model was used to analyze a generic RBCC engine and it is used as a baseline to evaluate an imaginary ABCC engine performance. A nuclear reactor is treated as a black box energy source that replaces the role of the primary rocket and the chemical combustion chamber in a RBCC engine. The performance of a generic ABCC engine along a flight path (q0 =10 (exp 3) lbf per square ft) shows that the mission averaged-specific impulse is about twice larger than RBCC engine and the dry mass-ratio is about 50% larger. Results of the present ABCC engine performance are based on the assumptions that the flow passage of working fluids is identical to that of RBCC engine and that a nuclear reactor is treated as an energy black box. Preliminary heat transfer calculation shows that the rate of heat transfer to the working fluids is within the limit of turbulent convective heat transfer regimes. The flow passage of realistic ABCC engine must be known for a better prediction of ABCC engine performance. Also, critical heat transfer calculations must be performed for the ejector mode and ramjet mode operations. This is possible only when the details of a reactor configuration are available.

  17. Atomic-Based-Combined-Cycle Analysis

    NASA Technical Reports Server (NTRS)

    Han, Sam; Bai, Don; Schmidt, George

    2000-01-01

    Atomic-based-combined-cycle (ABCC) engine combines an air-breathing ramjet engine with an atomic reactor to increase the mission-averaged specific impulse and thereby increasing the dry-mass ratio. ABCC engine is similar to RBCC engine except that energy needed for the propulsive power is derived from nuclear reaction rather than chemical combustion used in the RBCC engine. The potential performance improvement of an ABCC engine over a RBCC engine comes from two factors. Firstly, the energy density of nuclear reaction is several order of magnitudes higher than the chemical combustion. Secondly, hydrogen can produce much higher nozzle exit velocity because of its small molecular weight. A one-dimensional, transient numerical model was used to analyze a generic scramjet engine and it is used as a baseline to evaluate an imaginary ABCC engine performance. A nuclear reactor is treated as a black box energy source that replaces the role of the primary rocket and the chemical combustion chamber in a RBCC engine. Hydrogen is heated by the reactor and accelerated to produce high-speed ejection velocity. The ejection velocity up 10,000 m/sec is theoretically possible because of high energy density from the reactor and large gas constant of the hydrogen. Oxygen contained in the entrained air reacts with hydrogen and produces propulsive power for ejector mode operation. To provide enough thrust for initial acceleration, relatively large amount of hydrogen must be pumped through the reactor. Amount of oxygen contained in the entrained air may not be sufficient to burn all hydrogen and consequently combustion could occur at the end of exit nozzle. It is assumed that this combustion process is constant-pressure combustion at 1.0 atmospheric pressure and thus not affects the nozzle exit condition.

  18. Nanotechnology-based combination therapy for overcoming multidrug-resistant cancer

    PubMed Central

    Zhang, Meng; Liu, Ergang; Cui, Yanna; Huang, Yongzhuo

    2017-01-01

    Multidrug resistance (MDR) is a major obstacle to successful cancer treatment and is crucial to cancer metastasis and relapse. Combination therapy is an effective strategy for overcoming MDR. However, the different pharmacokinetic (PK) profiles of combined drugs often undermine the combination effect in vivo, especially when greatly different physicochemical properties (e.g., those of macromolecules and small drugs) combine. To address this issue, nanotechnology-based codelivery techniques have been actively explored. They possess great advantages for tumor targeting, controlled drug release, and identical drug PK profiles. Thus, a powerful tool for combination therapy is provided, and the translation from in vitro to in vivo is facilitated. In this review, we present a summary of various combination strategies for overcoming MDR and the nanotechnology-based combination therapy. PMID:28884039

  19. Waterpipe smoking and cancer: systematic review and meta-analysis.

    PubMed

    Montazeri, Zahra; Nyiraneza, Christine; El-Katerji, Hoda; Little, Julian

    2017-01-01

    Although accumulating evidence suggests harmful effects of waterpipe smoking, there is limited information about its direct association with chronic diseases, notably cancer. We provide an up-to-date systematic review and meta-analysis of the association between waterpipe smoking and cancer. Systematic search of articles indexed in main biomedical databases: Pubmed, EmBase, Google Scholar and Web of Science, published between 1962 and September 2014. Search keywords included a combination of waterpipe or hookah, sheesha, nargile, hubble-bubble, goza or gaylan, and cancer. Focus on observational studies (cohort, case-control, cross-sectional) that evaluated the association between waterpipe smoking and cancer. Studies with mixed exposures excluded. Two investigators independently extracted data and reached consensus on all items. 13 case-control studies met the inclusion criteria and were considered for meta-analysis. The methodological quality of included studies was assessed using the Newcastle-Ottawa Scale (NOS). Meta-analysis revealed a positive association between waterpipe smoking and lung cancer (OR=4.58 (2.61 to 8.03); I(2)=44.67%), and oesophageal cancer (OR=3.63 (1.39 to 9.44); I(2) =94.49%). The majority of studies had a NOS score of 5-6 or 7, indicating 'fair' or 'good' quality, respectively. Our findings support a positive association between waterpipe smoking and cancer risk. However, high-quality studies with standardised exposure measurements are needed to clarify the contribution of waterpipe smoking to chronic diseases. More investments in initiatives for surveillance, intervention and regulatory policy for waterpipe smoking are urgently warranted. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  20. Chemoprevention of Colon Cancer in a Rat Carcinogenesis Model Using a Novel Nanotechnology-based Combined Treatment System

    PubMed Central

    Chaudhary, Abhishek; Sutaria, Dhruvitkumar; Huang, Ying; Wang, Jeffrey; Prabhu, Sunil

    2011-01-01

    Colorectal cancer (CRC) is the third most common cause of cancer death in the US, accounting for ~51,000 deaths each year. We have previously shown in vitro chemopreventive effects of mixtures of aspirin, folic acid and calcium (AFAC) on colon cancer cell lines. The objective of the present study was to evaluate the in vivo effects of orally administered, colon targeted chemopreventive combination regimens on the inhibition of aberrant crypt foci (ACF) in a rat model of colon carcinogenesis using (1) unmodified (free drug) combinations of AFAC, and (2) nanoparticle-encapsulated combinations of the same agents. A 14-week animal study was conducted in three phases to determine an optimal effective dose from AFAC combinations and evaluate the efficacy of nanotechnology-based chemopreventive regimens administered in combined (mixtures), and individual (single entity) forms. ACF inhibition when compared to azoxymethane (AOM)-treated rat control group was significant in both, the unmodified and the modified nanoparticle-mediated chemopreventive regimens, demonstrating a range of 31 – 38% (p < 0.05) and 50 – 75% (p < 0.001) reduction respectively, in the number of ACFs. In addition, the nanoparticulate combination regimens of AFAC demonstrated a 2-fold increase in suppression of ACF compared to free drug mixtures. Individual administration of nanoparticle encapsulated drugs showed no significant effect on the reduction of ACF. Histochemical analysis provided further confirmation of chemopreventive effects, demonstrating a significant reduction in cell nuclear proliferation. Overall, our results provide a strong proof-of-concept using nanoparticle-mediated combination treatment in the chemoprevention of colon cancer. PMID:21914855

  1. Preclinical evaluation of olaparib and metformin combination in BRCA1 wildtype ovarian cancer.

    PubMed

    Hijaz, M; Chhina, J; Mert, I; Taylor, M; Dar, S; Al-Wahab, Z; Ali-Fehmi, R; Buekers, T; Munkarah, A R; Rattan, R

    2016-08-01

    BRCA mutated ovarian cancers show increased responsiveness to PARP inhibitors. PARP inhibitors target DNA repair and provide a second hit to BRCA mutated tumors, resulting in "synthetic lethality". We investigated a combination of metformin and olaparib to provide "synthetic lethality" in BRCA intact ovarian cancer cells. Ovarian cancer cell lines (UWB1.289, UWB1.289.BRCA, SKOV3, OVCAR5, A2780 and C200) were treated with a combination of metformin and olaparib. Cell viability was assessed by MTT and colony formation assays. Flow cytometry was used to detect cell cycle events. In vivo studies were performed in SKOV3 or A2780 xenografts in nude mice. Animals were treated with single agent, metformin or olaparib or combination. Molecular downstream effects were examined by immunohistochemistry. Compared to single drug treatment, combination of olaparib and metformin resulted in significant reduction of cell proliferation and colony formation (p<0.001) in ovarian cancer cells. This treatment was associated with a significant S-phase cell cycle arrest (p<0.05). Combination of olaparib and metformin significantly inhibited SKOV3 and A2780 ovarian tumor xenografts which were accompanied with decreased Ki-index (p<0.001). Metformin did not affect DNA damage signaling, while olaparib induced adenosine monophosphate activated kinase activation; that was further potentiated with metformin combination in vivo. Combining PARP inhibitors with metformin enhances its anti-proliferative activity in BRCA mutant ovarian cancer cells. Furthermore, the combination showed significant activity in BRCA intact cancer cells in vitro and in vivo. This is a promising treatment regimen for women with epithelial ovarian cancer irrespective of BRCA status. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Predicting Drug Response in Human Prostate Cancer from Preclinical Analysis of In Vivo Mouse Models.

    PubMed

    Mitrofanova, Antonina; Aytes, Alvaro; Zou, Min; Shen, Michael M; Abate-Shen, Cory; Califano, Andrea

    2015-09-29

    Although genetically engineered mouse (GEM) models are often used to evaluate cancer therapies, extrapolation of such preclinical data to human cancer can be challenging. Here, we introduce an approach that uses drug perturbation data from GEM models to predict drug efficacy in human cancer. Network-based analysis of expression profiles from in vivo treatment of GEM models identified drugs and drug combinations that inhibit the activity of FOXM1 and CENPF, which are master regulators of prostate cancer malignancy. Validation of mouse and human prostate cancer models confirmed the specificity and synergy of a predicted drug combination to abrogate FOXM1/CENPF activity and inhibit tumorigenicity. Network-based analysis of treatment signatures from GEM models identified treatment-responsive genes in human prostate cancer that are potential biomarkers of patient response. More generally, this approach allows systematic identification of drugs that inhibit tumor dependencies, thereby improving the utility of GEM models for prioritizing drugs for clinical evaluation.

  3. Potentiating NK cell activity by combination of Rosuvastatin and Difluoromethylornithine for effective chemopreventive efficacy against Colon Cancer

    PubMed Central

    Janakiram, Naveena B.; Mohammed, Altaf; Bryant, Taylor; Zhang, Yuting; Brewer, Misty; Duff, Ashley; Biddick, Laura; Singh, Anil; Lightfoot, Stan; Steele, Vernon E; Rao, Chinthalapally V.

    2016-01-01

    Colorectal cancer (CRC) is the second highest cause of cancer-related deaths. A successful strategy to improve chemopreventive efficacies is by down-regulating tumor polyamines and enhancing NK cell activities. Colonic carcinogenesis was induced by azoxymethane (AOM) in male F344 rats. Eight weeks after AOM treatment, animals were fed diets containing Rosuvastatin and difluromethylornithine (DFMO) individually and in combination for 40 weeks. Both agents showed significant suppression of adenocarcinoma multiplicity and incidence with no toxicity compared to untreated rats. Low-dose Rosuvastatin plus DFMO suppressed colon adenocarcinoma multiplicity by 76% compared to low-dose Rosuvastatin (29%) and DFMO (46%), suggesting additive efficacy. Furthermore, low-dose combination caused a delay in colonic adenocarcinoma progression. DFMO, Rosuvastatin and/or combinations significantly decreased polyamine content and increased intra-tumoral NK cells expressing perforin plus IFN-γ compared to untreated colon tumors. Further ex-vivo analysis of splenic NK cells exposed to DFMO, Rosuvastatin or combination resulted in an increase of NKs with perforin expression. This is the first report on Rosuvastatin alone or combination strategy using clinically relevant statin plus DFMO doses which shows a significant suppression of colon adenocarcinomas, and their potential in increasing functional NK cells. This strategy has potential for further testing in high risk individuals for colon cancer. PMID:27841323

  4. [Efficacy and side effects of combination therapy of oxaliplatin and S-1 for colorectal cancer].

    PubMed

    Zhu, Qing-chao; Jin, Zhi-ming

    2011-05-01

    To observe the efficacy and side effects of the combination therapy of oxaliplatin and S-1 in treating postoperative colorectal cancer patients. 54 postoperative colorectal cancer patients received the combination therapy of oxaliplatin and S-1 regimen, repeated every 3 weeks, and evaluate the efficacy after 3 cycles. All of the 54 patients but 2 (changed the chemotherapy regimen after the first cycle because of economic reason) finished 6 cycles of the chemotherapy treatment. There were 6 cases (11.5%) with complete response (CR), 28 cases (53.8%) with partial response (PR), and the overall response rate was 65.4%. Major adverse effects were hematological toxicities, gastrointestinal disturbance, neurosensory toxicity. There were no chemotherapy-related deaths. Oxaliplatin combined with S-1 is an effective and better tolerated chemotherapy treatment for postoperative colorectal cancer patients, with no serious side effects for liver and kidney. Therefore, it can be used as an alternative chemotherapy regimen for postoperative colorectal cancer patients.

  5. Pooled Analysis of the Prognostic and Predictive Effects of TP53 Comutation Status Combined With KRAS or EGFR Mutation in Early-Stage Resected Non-Small-Cell Lung Cancer in Four Trials of Adjuvant Chemotherapy.

    PubMed

    Shepherd, Frances A; Lacas, Benjamin; Le Teuff, Gwénaël; Hainaut, Pierre; Jänne, Pasi A; Pignon, Jean-Pierre; Le Chevalier, Thierry; Seymour, Lesley; Douillard, Jean-Yves; Graziano, Stephen; Brambilla, Elizabeth; Pirker, Robert; Filipits, Martin; Kratzke, Robert; Soria, Jean-Charles; Tsao, Ming-Sound

    2017-06-20

    Purpose Our previous work evaluated individual prognostic and predictive roles of TP53, KRAS, and EGFR in non-small-cell lung cancer (NSCLC). In this analysis, we explore the prognostic and predictive roles of TP53/KRAS and TP53/EGFR comutations in randomized trials of adjuvant chemotherapy versus observation. Patients and Methods Mutation analyses (wild-type [WT] and mutant) for TP53, KRAS, and EGFR were determined in blinded fashion in multiple laboratories. Primary and secondary end points of pooled analysis were overall survival and disease-free survival. We evaluated the role of TP53/KRAS comutation in all patients and in the adenocarcinoma subgroup as well as the TP53/EGFR comutation in adenocarcinoma only through a multivariable Cox proportional hazards model stratified by trial. Results Of 3,533 patients with NSCLC, 1,181 (557 deaths) and 404 (170 deaths) were used for TP53/KRAS and TP53/EGFR analyses. For TP53/KRAS mutation status, no prognostic effect was observed ( P = .61), whereas a borderline predictive effect ( P = .04) was observed with a deleterious effect of chemotherapy with TP53/KRAS comutations versus WT/WT (hazard ratio, 2.49 [95% CI, 1.10 to 5.64]; P = .03). TP53/EGFR comutation in adenocarcinoma was neither prognostic ( P = .83), nor significantly predictive ( P = .86). Similar results were observed for both groups for disease-free survival. Conclusion We could identify no prognostic effect of the KRAS or EGFR driver and TP53 tumor suppressor comutation. Our observation of a potential negative predictive effect of TP53/KRAS comutation requires validation.

  6. Effect of ketamine combined with butorphanol on emergence agitation of postoperative patients with gastric cancer

    PubMed Central

    Lin, Liang; Liu, Shuncui; Chen, Zhenyi; Lin, Shaoli

    2016-01-01

    Background This study aimed to investigate the effect of ketamine combined with butorphanol on emergence agitation (EA) in postoperative gastric cancer patients. Materials and methods A total of 150 patients with gastric cancer were included and divided into group B (1 mg butorphanol before anesthesia induction, n=50), group K (1 mg/kg ketamine, n=50), and group C (1 mg butorphanol combined with 1 mg/kg ketamine, n=50). Mean arterial pressure (MAP) and heart rate (HR) at the end of operation, just before extubation (T0) and at 0 minute (T1), 5 minutes (T2), and 30 minutes (T3) after extubation were compared. Statistical analysis of recovery time, extubation time, time in postanesthesia care unit, and EA incidence and adverse reactions were performed. Results There were no differences among groups with respect to MAP and HR at T0 and T1 (P>0.05). Compared with patients in group C, significant reduction of MAP and HR were observed in groups K and B at T2 and T3 (P<0.05), while no differences were found between group K and group B (P>0.05). Recovery time, extubation time, time in postanesthesia care unit, and incidence of EA in group C were significantly less than those in groups K and B (P<0.05), but no differences were observed between group K and group B (P>0.05). Total incidence of adverse reactions were significantly increased in group K compared to those in groups C and B (P<0.05). Conclusion Injection of ketamine combined with butorphanol before anesthesia induction was more effective than injection of ketamine or butorphanol separately in the prevention of EA. PMID:27217761

  7. Dietary Factors Affecting Thyroid Cancer Risk: A Meta-Analysis.

    PubMed

    Cho, Young Ae; Kim, Jeongseon

    2015-01-01

    Some dietary factors are proposed to affect thyroid carcinogenesis, but previous studies have reported inconsistent findings. Therefore, we performed a meta-analysis, including 18 eligible studies, to clarify the role of dietary factors in the risk of thyroid cancer. The relative risks (RRs) with 95% confidence intervals (95% CIs) were estimated to assess the association and heterogeneity tests and subgroup and sensitivity analyses, and bias assessments were performed. When the results from all studies were combined, dietary iodine, fish, and cruciferous vegetable intake were not associated with thyroid cancer. However, when the data were divided by geographic location based on iodine availability, a slight increase in the risk of thyroid cancer was observed among those consuming a high total amount of fish in iodine nondeficient areas (RR: 1.18; 95% CI: 1.03-1.35; P for heterogeneity = 0.282). When excluding the studies examining a single food item and hospital-based controls, a high intake of cruciferous vegetables was associated with an increased risk of thyroid cancer in iodine-deficient areas (RR: 1.43; 95% CI: 1.18-1.74; P for heterogeneity = 0.426). This meta-analysis implies that the role of dietary factors, such as fish and cruciferous vegetables, in thyroid cancer risk can differ based on iodine availability.

  8. New clinical trial tests safety and efficacy of combination therapy in ovarian cancer and other women's malignancies | Center for Cancer Research

    Cancer.gov

    The Center for Cancer Research has opened a new clinical trial in ovarian cancer that will test the safety and efficacy a therapy combining two drugs.   The phase I trial will test a combination therapy for ovarian, fallopian tube, and peritoneal cancers and is enrolling patients at the NIH Clinical Center. Learn more...  

  9. Combined Raman and autofluorescence ex vivo diagnostics of skin cancer in near-infrared and visible regions

    NASA Astrophysics Data System (ADS)

    Bratchenko, Ivan A.; Artemyev, Dmitry N.; Myakinin, Oleg O.; Khristoforova, Yulia A.; Moryatov, Alexander A.; Kozlov, Sergey V.; Zakharov, Valery P.

    2017-02-01

    The differentiation of skin melanomas and basal cell carcinomas (BCCs) was demonstrated based on combined analysis of Raman and autofluorescence spectra stimulated by visible and NIR lasers. It was ex vivo tested on 39 melanomas and 40 BCCs. Six spectroscopic criteria utilizing information about alteration of melanin, porphyrins, flavins, lipids, and collagen content in tumor with a comparison to healthy skin were proposed. The measured correlation between the proposed criteria makes it possible to define weakly correlated criteria groups for discriminant analysis and principal components analysis application. It was shown that the accuracy of cancerous tissues classification reaches 97.3% for a combined 6-criteria multimodal algorithm, while the accuracy determined separately for each modality does not exceed 79%. The combined 6-D method is a rapid and reliable tool for malignant skin detection and classification.

  10. Breast cancer evaluation by fluorescent dot detection using combined mathematical morphology and multifractal techniques

    PubMed Central

    2011-01-01

    Background Fluorescence in situ hybridization (FISH) is very accurate method for measuring HER2 gene copies, as a sign of potential breast cancer. This method requires small tissue samples, and has a high sensitivity to detect abnormalities from a histological section. By using multiple colors, this method allows the detection of multiple targets simultaneously. The target parts in the cells become visible as colored dots. The HER-2 probes are visible as orange stained spots under a fluorescent microscope while probes for centromere 17 (CEP-17), the chromosome on which the gene HER-2/neu is located, are visible as green spots. Methods The conventional analysis involves the scoring of the ratio of HER-2/neu over CEP 17 dots within each cell nucleus and then averaging the scores for a number of 60 cells. A ratio of 2.0 of HER-2/neu to CEP 17 copy number denotes amplification. Several methods have been proposed for the detection and automated evaluation (dot counting) of FISH signals. In this paper the combined method based on the mathematical morphology (MM) and inverse multifractal (IMF) analysis is suggested. Similar method was applied recently in detection of microcalcifications in digital mammograms, and was very successful. Results The combined MM using top-hat and bottom-hat filters, and the IMF method was applied to FISH images from Molecular Biology Lab, Department of Pathology, Wielkoposka Cancer Center, Poznan. Initial results indicate that this method can be applied to FISH images for the evaluation of HER2/neu status. Conclusions Mathematical morphology and multifractal approach are used for colored dot detection and counting in FISH images. Initial results derived on clinical cases are promising. Note that the overlapping of colored dots, particularly red/orange dots, needs additional improvements in post-processing. PMID:21489192

  11. Efficacy and safety of single agent or combination adjuvant chemotherapy in elderly patients with colon cancer: a Canadian cancer institute experience.

    PubMed

    Kim, Christina A K; Spratlin, Jennifer L; Armstrong, Dawn E; Ghosh, Sunita; Mulder, Karen E

    2014-09-01

    The pattern of adjuvant chemotherapy (AC) use, toxicity profile, and survival benefit in elderly patients with colon cancer (CC) is unclear. We sought to (1) determine whether patients ≥ 65 years with stage III CC were offered single-agent or combination AC, (2) evaluate the reason for selecting single-agent versus combination AC, (3) evaluate the toxicity profile of single-agent and combination AC in the elderly, and (4) determine whether a survival benefit exists for elderly patients receiving combination AC. A retrospective analysis of records of patients ≥ 65 years diagnosed with stage III CC from 2004 to 2010 was performed to identify baseline characteristics, AC protocols, toxicity, dose intensity, and survival. Two hundred sixty-eight patients ≥ 65 years were diagnosed and treated with AC from 2004 to 2010. Of these patients, 178 were treated with single-agent AC and 90 were treated with combination AC. The most common reasons for choosing single-agent AC were patient preference, comorbidities, and lack of drug coverage. For each year over 65 years, the odds of receiving combination over single-agent AC decreased by 22%. There were more dose delays, dose reductions, and early chemotherapy discontinuation in the combination AC group because of hematologic toxicity. The 5-year overall survival (OS) was 73% in patients who received single-agent AC compared with 84% in those who received combination AC. There was no difference in cancer-related deaths between the groups. In elderly patients treated with AC for stage III CC, single-agent AC is used more frequently than combination AC, based on age, comorbidities, and patient choice. Toxicity with combination AC in elderly patients is high. No survival benefit was seen with combination AC over single-agent AC. Copyright © 2014 Elsevier Inc. All rights reserved.

  12. The combination effect of amrubicin with cisplatin or irinotecan for small-cell lung cancer cells.

    PubMed

    Takigawa, Nagio; Takeyama, Masako; Shibayama, Takuo; Tada, Atsuhiko; Kawata, Noriko; Okada, Chiharu; Aoe, Keisuke; Kozuki, Toshiyuki; Hotta, Katsuyuki; Tabata, Masahiro; Kiura, Katsuyuki; Ueoka, Hiroshi; Tanimoto, Mitsune; Takahashi, Kiyoshi

    2006-04-01

    The single agent of amrubicin is active in untreated small-cell lung cancer (SCLC). Cytotoxicity of amrubicinol, the active form of amrubicin, was evaluated in a parent SCLC cell line (SBC-3); an active metabolite of irinotecan, 7-ethyl-10-hydroxy-camptothecin (SN-38)-resistant subline (SBC-3/SN-38); and cisplatin-resistant subline (SBC-3/CDDP) using AlamarBlue assay. Interaction of the combined drugs was evaluated by median-effect plot analysis, and the fraction of apoptotic cells was determined using flow cytometry. SBC-3/SN-38 was 34-fold more resistant to SN-38 and SBC-3/CDDP was 7.2-fold more resistant to cisplatin than parental SBC-3. However, these resistant sublines retained sensitivity to amrubicinol (1.8- and 1.7-fold, respectively). Simultaneous exposure of SBC-3/SN-38 cells to amrubicinol and cisplatin showed a synergistic effect. Simultaneous exposure of SBC-3/CDDP cells to amrubicinol and SN-38 displayed synergistic or additive effects. The two-drug combination produced an increase of apoptotic cells compared to each single agent alone in both resistant cells. These findings suggest that amrubicin alone and in combination with cisplatin or irinotecan is effective against SCLC refractory to irinotecan and/or cisplatin.

  13. Use of a combination of CEA and tumor budding to identify high-risk patients with stage II colon cancer.

    PubMed

    Du, Changzheng; Xue, Weicheng; Dou, Fangyuan; Peng, Yifan; Yao, Yunfeng; Zhao, Jun; Gu, Jin

    2017-07-24

    High-risk patients with stage II colon cancer may benefit from adjuvant chemotherapy, but identifying this patient population can be difficult. We assessed the prognosis value for predicting tumor progression in patients with stage II colon cancer, of a panel of 2 biomarkers for colon cancer: tumor budding and preoperative carcinoembryonic antigen (CEA). Consecutive patients (N = 134) with stage II colon cancer who underwent curative surgery from 2000 to 2007 were included. Multivariate analysis was used to evaluate the association of CEA and tumor budding grade with 5-year disease-free survival (DFS). The prognostic accuracy of CEA, tumor budding grade and the combination of both (CEA-budding panel) was determined. The study found that both CEA and tumor budding grade were associated with 5-year DFS. The prognostic accuracy for disease progression was higher for the CEA-budding panel (82.1%) than either CEA (70.9%) or tumor budding grade (72.4%) alone. The findings indicate that the combination of CEA levels and tumor budding grade has greater prognostic value for identifying patients with stage II colon cancer who are at high-risk for disease progression, than either marker alone.

  14. Gene Expression Analysis of Breast Cancer Progression

    DTIC Science & Technology

    2005-07-01

    representation of the retroviral vectors SFG-tdRFP-cmvFLuc, constitutively expressing tdRFP and firefly luciferase; and Cis-TGFD1-Smads- HSV1 - tk/GFP...AD Award Number: DAMD 17-02-1-0484 TITLE: Gene Expression Analysis of Breast Cancer Progression PRINCIPAL INVESTIGATOR: William L. Gerald, M.D., Ph.D...CONTRACT NUMBER Gene Expression Analysis of Breast Cancer Progression 5b. GRANT NUMBER DAMD17-02-1-0484 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 6d

  15. Effect of a combination of S-1 and gemcitabine on cell cycle regulation in pancreatic cancer cell lines.

    PubMed

    Morimoto, Yoshihito; Takeuchi, Osamu; Takizawa, Asako; Yoneyama, Hiroshi; Asanuma, Fumiki; Suzuki, Yukio; Atsuda, Koichiro; Yamada, Yoshinori

    2012-06-01

    In a previous study, we showed that a combination of an oral fluoropyrimidine anticancer agent (S-1) and gemcitabine (GEM) had synergistic effects on cell growth and cell cycle arrest in the pancreatic cancer cell line MIA PaCa-2. Therefore, we conducted further mechanistic studies using the pancreatic cancer cell lines MIA PaCa-2 and SUIT-2. The combined effect of S-1 and GEM in SUIT-2 cells was evaluated using an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and the effects of S-1, GEM and S-1 plus GEM on cell cycle regulation were assessed using flow cytometry. We also examined the expression of several cell cycle regulatory proteins in both MIA PaCa-2 and SUIT-2 cells by western blotting. Classical isobolographic analysis of the MTT assay results showed that the combination of S-1 and GEM had a synergistic effect in SUIT-2 cells, and flow cytometric analysis of the cell cycle showed that the combination of S-1 plus GEM induced S-phase arrest to a greater degree than did either S-1 or GEM alone. Also, the combination of S-1 and GEM resulted in the downregulation of cyclin D1 expression and upregulation of cyclin A, p21 and p27 expression levels. Treatment of MIA PaCa-2 and SUIT-2 cells with a combination of both drugs also led to the increased phosphorylation of checkpoint kinase 1. Combined treatment with S-1 and GEM resulted in more prolonged S-phase arrest than with either treatment alone. This difference is shown to be potentially due to the higher levels of phosphorylated checkpoint kinase 1 in pancreatic cancer cell lines treated with the two agents.

  16. Recent advances in delivery of drug-nucleic acid combinations for cancer treatment.

    PubMed

    Li, Jing; Wang, Yan; Zhu, Yu; Oupický, David

    2013-12-10

    Cancer treatment that uses a combination of approaches with the ability to affect multiple disease pathways has been proven highly effective in the treatment of many cancers. Combination therapy can include multiple chemotherapeutics or combinations of chemotherapeutics with other treatment modalities like surgery or radiation. However, despite the widespread clinical use of combination therapies, relatively little attention has been given to the potential of modern nanocarrier delivery methods, like liposomes, micelles, and nanoparticles, to enhance the efficacy of combination treatments. This lack of knowledge is particularly notable in the limited success of vectors for the delivery of combinations of nucleic acids with traditional small molecule drugs. The delivery of drug-nucleic acid combinations is particularly challenging due to differences in the physicochemical properties of the two types of agents. This review discusses recent advances in the development of delivery methods using combinations of small molecule drugs and nucleic acid therapeutics to treat cancer. This review primarily focuses on the rationale used for selecting appropriate drug-nucleic acid combinations as well as progress in the development of nanocarriers suitable for simultaneous delivery of drug-nucleic acid combinations.

  17. Calcitriol in Combination Therapy for Prostate Cancer: Pharmacokinetic and Pharmacodynamic Interactions

    PubMed Central

    Ben-Eltriki, Mohamed; Deb, Subrata; Guns, Emma S. Tomlinson

    2016-01-01

    Epidemiological studies indicate that vitamin D insufficiency could have an etiological role in prostate cancer. In addition, calcitriol, used in combination with currently available drugs, has the potential to potentiate their anticancer effects or act synergistically by inhibiting distinct mechanisms involved in prostate cancer growth. Clinical data have not yet provided sufficient evidence to demonstrate benefit of vitamin D due to the limited and underpowered studies that have been published to date. Here, we review the preclinical and clinical studies that describe the activity of calcitriol, applied either alone or in combination and assessed the mechanistic basis of pharmacodynamic and pharmacokinetic interactions with calcitriol. Important considerations for calcitriol use in combination therapy with respect to safety and clinical outcomes have been discussed. Many of these combinations have therapeutic potential for the treatment of several cancer types and it is anticipated that future clinical research will put emphasis on well‑designed clinical trials to establish efficacy. PMID:26918053

  18. The combination of rapamycin and resveratrol blocks autophagy and induces apoptosis in breast cancer cells.

    PubMed

    Alayev, Anya; Berger, Sara Malka; Kramer, Melissa Y; Schwartz, Naomi S; Holz, Marina K

    2015-03-01

    Hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1) is a frequent event in breast cancer and current efforts are aimed at targeting the mTORC1 signaling pathway in combination with other targeted therapies. However, patients often develop drug resistance in part due to activation of the oncogenic Akt signaling and upregulation of autophagy, which protects cancer cells from apoptosis. In the present study we investigated the effects of combination therapy of rapamycin (an allosteric mTORC1 inhibitor) together with resveratrol (a phytoestrogen that inhibits autophagy). Our results show that combination of these drugs maintains inhibition of mTORC1 signaling, while preventing upregulation of Akt activation and autophagy, causing apoptosis. Additionally, this combination was effective in estrogen receptor positive and negative breast cancer cells, underscoring its versatility.

  19. Traditional Chinese patent medicines for cancer treatment in China: a nationwide medical insurance data analysis.

    PubMed

    Wu, Min; Lu, Peng; Shi, Luwen; Li, Shao

    2015-11-10

    Based on the nationwide survey into inpatients' utilization of the health service covered by China's urban basic medical insurance from 2008 to 2010, we analyzed the use rate, cancer profile and combined use of anticancer Chinese patent medicines (CPMs) on 51,382 insured cancer patients by using statistical, bi-clustering and network methods. We found that 42.4% of 51,382 cancer patients used 33 anticancer CPMs, and 51.7% used 71 anticancer Western medicines (WMs). The CPMs were most often used in lung (52%) and nasopharynx (52%) cancer patients, and least in bladder cancer (21%) and leukemia of unspecified cell type (21%) patients. The cost per patient for all 33 anticancer CPMs was 2069RMB, lower than that of the WMs (3458RMB). The cancer profile of commonly used CPMs and WMs for the top 17 cancers (>500 sampled patients) were provided, indicating anticancer CPMs had a broad spectrum of cancers and lacked selectivity in cancer treatment (CPM mean CV = 49%; WM mean CV = 152%). Moreover, 24.8% of the cancer patients used both CPMs and WMs, and CPM-WM combined use networks were constructed for four major cancers. This first nationwide analysis revealed the use characteristics and herb-drug combined use patterns of insurance covered anticancer CPMs in China. The study offers valuable information to guide future studies of the precision, safety and standard use of CPMs.

  20. Traditional Chinese patent medicines for cancer treatment in China: a nationwide medical insurance data analysis

    PubMed Central

    Wu, Min; Lu, Peng; Shi, Luwen; Li, Shao

    2015-01-01

    Based on the nationwide survey into inpatients' utilization of the health service covered by China's urban basic medical insurance from 2008 to 2010, we analyzed the use rate, cancer profile and combined use of anticancer Chinese patent medicines (CPMs) on 51,382 insured cancer patients by using statistical, bi-clustering and network methods. We found that 42.4% of 51,382 cancer patients used 33 anticancer CPMs, and 51.7% used 71 anticancer Western medicines (WMs). The CPMs were most often used in lung (52%) and nasopharynx (52%) cancer patients, and least in bladder cancer (21%) and leukemia of unspecified cell type (21%) patients. The cost per patient for all 33 anticancer CPMs was 2069RMB, lower than that of the WMs (3458RMB). The cancer profile of commonly used CPMs and WMs for the top 17 cancers (>500 sampled patients) were provided, indicating anticancer CPMs had a broad spectrum of cancers and lacked selectivity in cancer treatment (CPM mean CV = 49%; WM mean CV = 152%). Moreover, 24.8% of the cancer patients used both CPMs and WMs, and CPM-WM combined use networks were constructed for four major cancers. This first nationwide analysis revealed the use characteristics and herb-drug combined use patterns of insurance covered anticancer CPMs in China. The study offers valuable information to guide future studies of the precision, safety and standard use of CPMs. PMID:26513017

  1. Anti-tumor effect of honokiol alone and in combination with other anti-cancer agents in breast cancer.

    PubMed

    Liu, Hongyu; Zang, Chuanbing; Emde, Anna; Planas-Silva, Maricarmen D; Rosche, Marleen; Kühnl, Andrea; Schulz, Carsten-Oliver; Elstner, Elena; Possinger, Kurt; Eucker, Jan

    2008-09-04

    Honokiol, an active component isolated and purified from Chinese traditional herb magnolia, was demonstrated to inhibit growth and induce apoptosis of different cancer cell lines such as human leukaemia, colon, and lung cancer cell lines; to attenuate the angiogenic activities of human endothelial cells in vitro; and to efficiently suppress the growth of angiosarcoma in nude mice. In this study, we have demonstrated that treatment of different human breast cancer cell lines with honokiol resulted in a time- and concentration-dependent growth inhibition in both estrogen receptor-positive and -negative breast cancer cell lines, as well as in drug-resistant breast cancer cell lines such as adriamycin-resistant and tamoxifen-resistant cell lines. The inhibition of growth was associated with a G1-phase cell cycle arrest and induction of caspase-dependent apoptosis. The effects of honokiol might be reversely related to the expression level of human epidermal growth receptor 2, (HER-2, also known as erbB2, c-erbB2) since knockdown of her-2 expression by siRNA significantly enhanced the sensitivity of the her-2 over-expressed BT-474 cells to the honokiol-induced apoptosis. Furthermore, inhibition of HER-2 signalling by specific human epidermal growth receptor 1/HER-2 (EGFR/HER-2) kinase inhibitor lapatinib synergistically enhanced the anti-cancer effects of honokiol in her-2 over-expressed breast cancer cells. Finally, we showed that honokiol was able to attenuate the PI3K/Akt/mTOR (Phosphoinositide 3-kinases/Akt/mammalian target of rapamycin) signalling by down-regulation of Akt phosphorylation and upregulation of PTEN (Phosphatase and Tensin homolog deleted on chromosome Ten) expression. Combination of honokiol with the mTOR inhibitor rapamycin presented synergistic effects on induction of apoptosis of breast cancer cells. In conclusion, honokiol, either alone or in combination with other therapeutics, could serve as a new, promising approach for breast cancer treatment.

  2. Treatment of small cell lung cancer with TRA-8 in combination with cisplatin and radiation.

    PubMed

    Bonner, James A; Willey, Christopher D; Yang, Eddy S; Dobelbower, Michael C; Sanford, Leisa L; Bright, Sheila J; Buchsbaum, Donald J; Raisch, Kevin P

    2011-10-01

    Limited stage small cell lung cancer (SCLC) represents a minority of SCLC. Despite extensive clinical trials, standard treatment remains cisplatin-based chemotherapy and thoracic irradiation (TI). This study focused on the interaction of cisplatin/radiation with the anti-human DR5 monoclonal antibody TRA-8 in SCLC cells. TRA-8 binds specifically to DR5 and has been shown to activate apoptosis. Four human SCLC cell lines were utilized for experimentation (SCLC-41, SCLC-58, SCLC-68, and SCLC-74). Immunoblot analysis was used to determine relative protein levels of DR5, DR4 and pro-caspase 8 for each cell line. Using a tetrazolium-based assay (XTT), the IC(50) values for cisplatin with or without TRA-8 were determined for the SCLC cell lines. Four SCLC lines were assayed with a combination of TRA-8 (10 μg/ml), 2 Gy radiation and various concentrations of cisplatin. Apoptosis was evaluated using Annexin V-FITC and cleaved caspase immunoblotting. Using a SCLC-58 subcutaneous xenograft model, treatment began 21 d after tumor cell injection. Treatment included weekly cisplatin (4 mg/kg) and radiation of 1 Gy (24 h after cisplatin) and TRA-8 (200 μg) was administered i.p. twice weekly for three weeks. Immunoblot analysis showed similar levels of DR5 for all cell lines with variable levels of DR4. Various concentrations of TRA-8 antibody (≤ 10 μg/ml) induced no significant cytotoxicity in the SCLC cell lines. The in vitro combination treatment with TRA-8 (10 μg/ml), 1.25 μg/ml cisplatin and 2 Gy radiation showed increased cytotoxicity when compared to combinations without TRA-8. Furthermore, the triple combination demonstrated the greatest amount of apoptosis as measured by Annexin V staining. The in vivo studies showed the combination of 1G y, cisplatin and TRA-8 extended the tumor doubling time to 44 d as compared to any doublet treatment groups that ranged from 12 to 20 d. Analysis of survival data showed 100% of the combination group (RT+cisplatin+TRA-8) were

  3. Pleiotropic Role of Dietary Phytochemicals in Cancer: Emerging Perspectives for Combinational Therapy.

    PubMed

    Banudevi, Sivanantham; Swaminathan, Sethuraman; Maheswari, Krishnan Uma

    2015-01-01

    Cancer is considered a complicated health issue worldwide. The mean cancer survival through standard therapeutic strategies has not been significantly improved over the past few decades. Hence, alternate remedies are needed to treat or prevent this dreadful disease being explored. Currently, it has been recognized that repeated treatment with chemotherapeutic agents has been largely ineffective due to multidrug resistance and further conventional treatment possesses limited drug accessibility to cancerous tissues, which in turn necessitates a higher dose resulting in increased cytotoxicity. Drug combinations have been practiced to address the problems associated with conventional single drug treatment. Recently, natural dietary agents have attracted much attention in cancer therapy because of their synergistic effects with anticancer drugs against different types of cancer. Natural phytochemicals may execute their anticancer activity through targeting diverse cancer cell signaling pathways, promoting cell cycle arrest and apoptosis, regulating antioxidant status and detoxification. This review focuses mainly on the anticancer efficacy of dietary phytochemicals in combination with standard therapeutic drugs reported from various in vitro and in vivo experimental studies apart from clinical trials. This review adds knowledge to the field of intervention studies using combinational modalities that opens a new window for cancer treatment/chemoprevention.

  4. Combination of sulindac and dichloroacetate kills cancer cells via oxidative damage.

    PubMed

    Ayyanathan, Kasirajan; Kesaraju, Shailaja; Dawson-Scully, Ken; Weissbach, Herbert

    2012-01-01

    Sulindac is an FDA-approved non-steroidal anti-inflammatory drug with documented anticancer activities. Our recent studies showed that sulindac selectively enhanced the killing of cancer cells exposed to oxidizing agents via production of reactive oxygen species (ROS) resulting in mitochondrial dysfunction. This effect of sulindac and oxidative stress on cancer cells could be related to the defect in respiration in cancer cells, first described by Warburg 50 years ago, known as the Warburg effect. We postulated that sulindac might enhance the selective killing of cancer cells when combined with any compound that alters mitochondrial respiration. To test this hypothesis we have used dichloroacetate (DCA), which is known to shift pyruvate metabolism away from lactic acid formation to respiration. One might expect that DCA, since it stimulates aerobic metabolism, could stress mitochondrial respiration in cancer cells, which would result in enhanced killing in the presence of sulindac. In this study, we have shown that the combination of sulindac and DCA enhances the selective killing of A549 and SCC25 cancer cells under the conditions used. As predicted, the mechanism of killing involves ROS production, mitochondrial dysfunction, JNK signaling and death by apoptosis. Our results suggest that the sulindac-DCA drug combination may provide an effective cancer therapy.

  5. Combination of Sulindac and Dichloroacetate Kills Cancer Cells via Oxidative Damage

    PubMed Central

    Dawson-Scully, Ken; Weissbach, Herbert

    2012-01-01

    Sulindac is an FDA-approved non-steroidal anti-inflammatory drug with documented anticancer activities. Our recent studies showed that sulindac selectively enhanced the killing of cancer cells exposed to oxidizing agents via production of reactive oxygen species (ROS) resulting in mitochondrial dysfunction. This effect of sulindac and oxidative stress on cancer cells could be related to the defect in respiration in cancer cells, first described by Warburg 50 years ago, known as the Warburg effect. We postulated that sulindac might enhance the selective killing of cancer cells when combined with any compound that alters mitochondrial respiration. To test this hypothesis we have used dichloroacetate (DCA), which is known to shift pyruvate metabolism away from lactic acid formation to respiration. One might expect that DCA, since it stimulates aerobic metabolism, could stress mitochondrial respiration in cancer cells, which would result in enhanced killing in the presence of sulindac. In this study, we have shown that the combination of sulindac and DCA enhances the selective killing of A549 and SCC25 cancer cells under the conditions used. As predicted, the mechanism of killing involves ROS production, mitochondrial dysfunction, JNK signaling and death by apoptosis. Our results suggest that the sulindac-DCA drug combination may provide an effective cancer therapy. PMID:22866174

  6. Primary combined-modality therapy for esophageal cancer.

    PubMed

    Minsky, Bruce D

    2006-04-01

    Based on positive results from the Radiation Therapy Oncology Group (RTOG) 85-01 trial, the conventional nonsurgical treatment of esophageal carcinoma is combined-modality therapy. Dose intensification of the RTOG 85-01 regimen, examined in the Intergroup (INT)-0123/RTOG 94-05 trial, did not improve local control or survival. Areas of clinical investigation include the development of combined-modality therapy regimens with newer systemic agents, the use of 18F-fluorodeoxyglucose positron-emission tomography to assist in the development of innovative radiation treatment planning techniques, and the identification of prognostic molecular markers. The addition of surgery following primary combined-modality therapy apparently does not improve survival, but this finding is controversial.

  7. DOXIL when combined with Withaferin A (WFA) targets ALDH1 positive cancer stem cells in ovarian cancer.

    PubMed

    Kakar, Sham S; Worth, Christopher A; Wang, Zhenglong; Carter, Kelsey; Ratajczak, Mariusz; Gunjal, Pranesh

    Ovarian cancer is a highly aggressive and deadly disease. Currently, the treatment for ovarian cancer entails cytoreductive surgery followed by chemotherapy, mainly cisplatin or carboplatin combined with paclitaxel. Although this regimen is initially effective in a high percentage of cases, unfortunately, after few months of initial treatment, tumor relapse occurs due to platinum-resistance. DOXIL (liposomal preparation of doxorubicin) is a choice of drug for recurrent ovarian cancer. However, its response rate is very low and is accompanied by myocardial toxicity. Resistance to chemotherapy and recurrence of cancer is primarily attributed to the presence of cancer stem cells (CSCs), a small population of cells present in cancer. Effect of DOXIL and withaferin A (WFA), both alone and in combination, was investigated on cell proliferation of ovarian cancer cell line A2780 and tumor growth in SCID mice bearing i.p. ovarian tumors. ALDH1 cells were isolated from A2780 using cell sorter, and effect of DOXIL and WFA both alone and in combination on tumorigenic function of ALDH1 was studied using spheroids formation assays in vitro. Western blots were performed to examine the expression of ALDH1 and Notch 1 genes. In our studies, we showed, for the first time, that DOXIL when combined with withaferin A (WFA) elicits synergistic effect on inhibition of cell proliferation of ovarian cancer cells and inhibits the expression of ALDH1 protein, a marker for ALDH1 positive cancer stem cells (CSCs), and Notch1, a signaling pathway gene required for self-renewal of CSCs. Inhibition of expression of both ALDH1 and Notch1 genes by WFA was found to be dose dependent, whereas DOXIL (200 nM) was found to be ineffective. SCID mice, bearing i.p. ovarian tumors, were treated with a small dose of DOXIL (2 mg/kg) in combination with a sub-optimal dose of WFA (2 mg/kg) which resulted in a highly significant (60% to 70%) reduction in tumor growth, and complete inhibition of metastasis

  8. Esophageal cancer detection based on tissue surface-enhanced Raman spectroscopy and multivariate analysis

    NASA Astrophysics Data System (ADS)

    Feng, Shangyuan; Lin, Juqiang; Huang, Zufang; Chen, Guannan; Chen, Weisheng; Wang, Yue; Chen, Rong; Zeng, Haishan

    2013-01-01

    The capability of using silver nanoparticle based near-infrared surface enhanced Raman scattering (SERS) spectroscopy combined with principal component analysis (PCA) and linear discriminate analysis (LDA) to differentiate esophageal cancer tissue from normal tissue was presented. Significant differences in Raman intensities of prominent SERS bands were observed between normal and cancer tissues. PCA-LDA multivariate analysis of the measured tissue SERS spectra achieved diagnostic sensitivity of 90.9% and specificity of 97.8%. This exploratory study demonstrated great potential for developing label-free tissue SERS analysis into a clinical tool for esophageal cancer detection.

  9. Optical pathology of human brain metastasis of lung cancer using combined resonance Raman and spatial frequency spectroscopies

    NASA Astrophysics Data System (ADS)

    Zhou, Yan; Liu, Cheng-hui; Pu, Yang; Cheng, Gangge; Zhou, Lixin; Chen, Jun; Zhu, Ke; Alfano, Robert R.

    2016-03-01

    Raman spectroscopy has become widely used for diagnostic purpose of breast, lung and brain cancers. This report introduced a new approach based on spatial frequency spectra analysis of the underlying tissue structure at different stages of brain tumor. Combined spatial frequency spectroscopy (SFS), Resonance Raman (RR) spectroscopic method is used to discriminate human brain metastasis of lung cancer from normal tissues for the first time. A total number of thirty-one label-free micrographic images of normal and metastatic brain cancer tissues obtained from a confocal micro- Raman spectroscopic system synchronously with examined RR spectra of the corresponding samples were collected from the identical site of tissue. The difference of the randomness of tissue structures between the micrograph images of metastatic brain tumor tissues and normal tissues can be recognized by analyzing spatial frequency. By fitting the distribution of the spatial frequency spectra of human brain tissues as a Gaussian function, the standard deviation, σ, can be obtained, which was used to generate a criterion to differentiate human brain cancerous tissues from the normal ones using Support Vector Machine (SVM) classifier. This SFS-SVM analysis on micrograph images presents good results with sensitivity (85%), specificity (75%) in comparison with gold standard reports of pathology and immunology. The dual-modal advantages of SFS combined with RR spectroscopy method may open a new way in the neuropathology applications.

  10. Synergistic inhibition of cancer cell proliferation with a combination of δ-tocotrienol and ferulic acid

    SciTech Connect

    Eitsuka, Takahiro; Tatewaki, Naoto; Nishida, Hiroshi; Kurata, Tadao; Nakagawa, Kiyotaka; Miyazawa, Teruo

    2014-10-24

    Highlights: • δ-Tocotrienol (δ-T3) and ferulic acid (FA) synergistically inhibit cancer cell growth. • The combination of δ-T3 and FA induces G1 arrest by up-regulating p21. • The synergy is attributed to an increase in the cellular concentration of δ-T3 by FA. - Abstract: Rice bran consists of many functional compounds and thus much attention has been focused on the health benefits of its components. Here, we investigated the synergistic inhibitory effects of its components, particularly δ-tocotrienol (δ-T3) and ferulic acid (FA), against the proliferation of an array of cancer cells, including DU-145 (prostate cancer), MCF-7 (breast cancer), and PANC-1 (pancreatic cancer) cells. The combination of δ-T3 and FA markedly reduced cell proliferation relative to δ-T3 alone, and FA had no effect when used alone. Although δ-T3 induced G1 arrest by up-regulating p21 in PANC-1 cells, more cells accumulated in G1 phase with the combination of δ-T3 and FA. This synergistic effect was attributed to an increase in the cellular concentration of δ-T3 by FA. Our results suggest that the combination of δ-T3 and FA may present a new strategy for cancer prevention and therapy.

  11. Imaging nonmelanoma skin cancers with combined ultrasound-photoacoustic microscopy

    NASA Astrophysics Data System (ADS)

    Sunar, Ulas; Rohrbach, Daniel J.; Morgan, Janet; Zeitouni, Natalie

    2013-03-01

    PDT has become a treatment of choice especially for the cases with multiple sites and large areas. However, the efficacy of PDT is limited for thicker and deeper tumors. Depth and size information as well as vascularity can provide useful information to clinicians for planning and evaluating PDT. High-resolution ultrasound and photoacoustic imaging can provide information regarding skin structure and vascularity. We utilized combined ultrasound-photoacoustic microscopy for imaging a basal cell carcinoma (BCC) tumor pre-PDT and the results indicate that combined ultrasound-photoacoustic imaging can be useful tool for PDT planning by providing both structural and functional contrasts.

  12. Prognostic and predictive value of circulating tumor cells and CXCR4 expression as biomarkers for a CXCR4 peptide antagonist in combination with carboplatin-etoposide in small cell lung cancer: exploratory analysis of a phase II study.

    PubMed

    Salgia, Ravi; Weaver, R Waide; McCleod, Michael; Stille, John R; Yan, S Betty; Roberson, Stephanie; Polzer, John; Flynt, Amy; Raddad, Eyas; Peek, Victoria L; Wijayawardana, Sameera R; Um, Suzane L; Gross, Steve; Connelly, Mark C; Morano, Carrie; Repollet, Madeline; Sanders, Renouard; Baeten, Kurt; D'Haese, David; Spigel, David R

    2017-06-01

    Background Circulating tumor cells (CTCs) and chemokine (C-X-C motif) receptor 4 (CXCR4) expression in CTCs and tumor tissue were evaluated as prognostic or predictive markers of CXCR4 peptide antagonist LY2510924 plus carboplatin-etoposide (CE) versus CE in extensive-stage disease small cell lung cancer (ED-SCLC). Methods This exploratory analysis of a phase II study evaluated CXCR4 expression in baseline tumor tissue and peripheral blood CTCs and in post-treatment CTCs. Optimum cutoff values were determined for CTC counts and CXCR4 expression in tumors and CTCs as predictors of survival outcome. Kaplan-Meier estimates and hazard ratios were used to determine biomarker prognostic and predictive values. Results There was weak positive correlation at baseline between CXCR4 expression in tumor tissue and CTCs. Optimum cutoff values were H-score ≥ 210 for CXCR4(+) tumor, ≥7% CTCs with CXCR4 expression (CXCR4(+) CTCs), and ≥6 CTCs/7.5 mL blood. Baseline H-score for CXCR4(+) tumor was not prognostic of progression-free survival (PFS) or overall survival (OS). Baseline CXCR4(+) CTCs ≥7% was prognostic of shorter PFS. CTCs ≥6 at baseline and cycle 2, day 1 were prognostic of shorter PFS and OS. None of the biomarkers at their respective optimum cutoffs was predictive of treatment response of LY2510924 plus CE versus CE. Conclusions In patients with ED-SCLC, baseline CXCR4 expression in tumor tissue was not prognostic of survival or predictive of LY2510924 treatment response. Baseline CXCR4(+) CTCs ≥7% was prognostic of shorter PFS. CTC count ≥6 at baseline and after 1 cycle of treatment were prognostic of shorter PFS and OS.

  13. Differential action on cancer and normal tissue by adrenochrome monoaminoguanidine methanesulfonate and cytochrome C combined with radiotherapy

    SciTech Connect

    Nakatsugawa, S. ); Sugahara, T. )

    1994-06-15

    The possibility that radioprotective effects on potent natural killer (NK) cells by adrenochrome monoaminoguanidine methanesulfonate (AMM) + cytochrome C during radiotherapy (RT) for lung cancer might result in the radiosensitization of human lung cancer cells in vivo is examined. Human lung cancer xenografts in the right hind legs of KSN mice (10 weeks old) were locally irradiated with 20 Gy of X ray. AMM (10 mg/kg/day) and/or cytochrome C (CCC) (5 mg/kg/day) were given intraperitoneally immediately before or after RT, followed by daily administration for 4 days. Natural killer activities of host splenocytes were also tested with the standard [sup 51]Cr releasing assay with YAC-1 cells as target cells. In a clinical study, 65 patients with lung cancer were treated with more than 50 Gy of RT with or without combination with AMM + CCC, OK-432 or AMM + CCC + OK-432. Before and after RT, lymphocyte subsets in the peripheral blood were examined with dichromatic analysis using an Ortho Spectrum IIIFCM system and fluorescent MABs. In this study, the change in the absolute number of each subset was investigated. AMM + cytochrome C augumented NK activity in KSN nude mice, protected potent NK cells in patients with lung cancer against RT and sensitized the human lung cancer xenografts to RT. AMM + cytochrome C may have potential as a differential modulator of radiosensitivity of normal tissues and of tumors. 8 refs., 2 figs., 1 tab.

  14. Incidence and Timing of Cancer in HIV-Infected Individuals Following Initiation of Combination Antiretroviral Therapy

    PubMed Central

    Yanik, Elizabeth L.; Napravnik, Sonia; Cole, Stephen R.; Achenbach, Chad J.; Gopal, Satish; Olshan, Andrew; Dittmer, Dirk P.; Kitahata, Mari M.; Mugavero, Michael J.; Saag, Michael; Moore, Richard D.; Mayer, Kenneth; Mathews, W. Christopher; Hunt, Peter W.; Rodriguez, Benigno; Eron, Joseph J.

    2013-01-01

    Background Cancer is an important cause of morbidity and mortality in individuals infected with human immunodeficiency virus (HIV), but patterns of cancer incidence after combination antiretroviral therapy (ART) initiation remain poorly characterized. Methods We evaluated the incidence and timing of cancer diagnoses among patients initiating ART between 1996 and 2011 in a collaboration of 8 US clinical HIV cohorts. Poisson regression was used to estimate incidence rates. Cox regression was used to identify demographic and clinical characteristics associated with cancer incidence after ART initiation. Results At initiation of first combination ART among 11 485 patients, median year was 2004 (interquartile range [IQR], 2000–2007) and median CD4 count was 202 cells/mm3 (IQR, 61–338). Incidence rates for Kaposi sarcoma (KS) and lymphomas were highest in the first 6 months after ART initiation (P < .001) and plateaued thereafter, while incidence rates for all other cancers combined increased from 416 to 615 cases per 100 000 person-years from 1 to 10 years after ART initiation (average 7% increase per year; 95% confidence interval, 2%–13%). Lower CD4 count at ART initiation was associated with greater risk of KS, lymphoma, and human papillomavirus–related cancer. Calendar year of ART initiation was not associated with cancer incidence. Conclusions KS and lymphoma rates were highest immediately following ART initiation, particularly among patients with low CD4 cell counts, whereas other cancers increased with time on ART, likely reflecting increased cancer risk with aging. Our results underscore recommendations for earlier HIV diagnosis followed by prompt ART initiation along with ongoing aggressive cancer screening and prevention efforts throughout the course of HIV care. PMID:23735330

  15. Incidence and timing of cancer in HIV-infected individuals following initiation of combination antiretroviral therapy.

    PubMed

    Yanik, Elizabeth L; Napravnik, Sonia; Cole, Stephen R; Achenbach, Chad J; Gopal, Satish; Olshan, Andrew; Dittmer, Dirk P; Kitahata, Mari M; Mugavero, Michael J; Saag, Michael; Moore, Richard D; Mayer, Kenneth; Mathews, W Christopher; Hunt, Peter W; Rodriguez, Benigno; Eron, Joseph J

    2013-09-01

    Cancer is an important cause of morbidity and mortality in individuals infected with human immunodeficiency virus (HIV), but patterns of cancer incidence after combination antiretroviral therapy (ART) initiation remain poorly characterized. We evaluated the incidence and timing of cancer diagnoses among patients initiating ART between 1996 and 2011 in a collaboration of 8 US clinical HIV cohorts. Poisson regression was used to estimate incidence rates. Cox regression was used to identify demographic and clinical characteristics associated with cancer incidence after ART initiation. At initiation of first combination ART among 11 485 patients, median year was 2004 (interquartile range [IQR], 2000-2007) and median CD4 count was 202 cells/mm(3) (IQR, 61-338). Incidence rates for Kaposi sarcoma (KS) and lymphomas were highest in the first 6 months after ART initiation (P < .001) and plateaued thereafter, while incidence rates for all other cancers combined increased from 416 to 615 cases per 100 000 person-years from 1 to 10 years after ART initiation (average 7% increase per year; 95% confidence interval, 2%-13%). Lower CD4 count at ART initiation was associated with greater risk of KS, lymphoma, and human papillomavirus-related cancer. Calendar year of ART initiation was not associated with cancer incidence. KS and lymphoma rates were highest immediately following ART initiation, particularly among patients with low CD4 cell counts, whereas other cancers increased with time on ART, likely reflecting increased cancer risk with aging. Our results underscore recommendations for earlier HIV diagnosis followed by prompt ART initiation along with ongoing aggressive cancer screening and prevention efforts throughout the course of HIV care.

  16. Theragnosis-based combined cancer therapy using doxorubicin-conjugated microRNA-221 molecular beacon.

    PubMed

    Lee, Jonghwan; Choi, Kyung-Ju; Moon, Sung Ung; Kim, Soonhag

    2016-01-01

    Recently, microRNA (miRNA or miR) has emerged as a new cancer biomarker because of its high expression level in various cancer types and its role in the control of tumor suppressor genes. In cancer studies, molecular imaging and treatment based on target cancer markers have been combined to facilitate simultaneous cancer diagnosis and therapy. In this study, for combined therapy with diagnosis of cancer, we developed a doxorubicin-conjugated miR-221 molecular beacon (miR-221 DOXO MB) in a single platform composed of three different nucleotides: miR-221 binding sequence, black hole quencher 1 (BHQ1), and doxorubicin binding site. Imaging of endogenous miR-221 was achieved by specific hybridization between miR-221 and the miR-221 binding site in miR-221 DOXO MB. The presence of miR-221 triggered detachment of the quencher oligo and subsequent activation of a fluorescent signal of miR-221 DOXO MB. Simultaneous cancer therapy in C6 astrocytoma cells and nude mice was achieved by inhibition of miRNA-221 function that downregulates tumor suppressor genes. The detection of miR-221 expression and inhibition of miR-221 function by miR-221 DOXO MB provide the feasibility as a cancer theragnostic probe. Furthermore, a cytotoxic effect was induced by unloading of doxorubicin intercalated into miR-221 DOXO MB inside cells. Loss of miR-221 function and cytotoxicity induced by the miR-221 DOXO MB provides combined therapeutic efficacy against cancers. This method could be used as a new theragnostic probe with enhanced therapy to detect and inhibit many cancer-related miRNAs. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. Combination Therapy of Lactobacillus plantarum Supernatant and 5-Fluouracil Increases Chemosensitivity in Colorectal Cancer Cells.

    PubMed

    An, JaeJin; Ha, Eun-Mi

    2016-08-28

    Colorectal cancer (CRC) is the third most common cancer in the world. Although 5-fluorouracil (5-FU) is the representative chemotherapy drug for colorectal cancer, it has therapeutic limits due to its chemoresistant characteristics. Colorectal cancer cells can develop into cancer stem cells (CSCs) with self-renewal potential, thereby causing malignant tumors. The human gastrointestinal tract contains a complex gut microbiota that is essential for the host's homeostasis. Recently, many studies have reported correlations between gut flora and the onset, progression, and treatment of CRC. The present study confirms that the most representative symbiotic bacteria in humans, Lactobacillus plantarum (LP) supernatant (SN), selectively inhibit the characteristics of 5-FU-resistant colorectal cancer cells (HT-29 and HCT- 116). LP SN inhibited the expression of the specific markers CD44, 133, 166, and ALDH1 of CSCs. The combination therapy of LP SN and 5-FU inhibited the survival of CRCs and led to cell death by inducing caspase-3 activity. The combination therapy of LP SN and 5-FU induced an anticancer mechanism by inactivating the Wnt/β-catenin signaling of chemoresistant CRC cells, and reducing the formation and size of colonospheres. In conclusion, our results show that LP SN can enhance the therapeutic effect of 5-FU for colon cancer, and reduce colorectal cancer stem-like cells by reversing the development of resistance to anticancer drugs. This implies that probiotic substances may be useful therapeutic alternatives as biotherapeutics for chemoresistant CRC.

  18. Prediction of Candidate Drugs for Treating Pancreatic Cancer by Using a Combined Approach

    PubMed Central

    Dong, Xinran; Li, Ying; Yang, Bo; Tian, Weidong; Wang, Xiaoqin

    2016-01-01

    Pancreatic cancer is the leading cause of death from solid malignancies worldwide. Currently, gemcitabine is the only drug approved for treating pancreatic cancer. Developing new therapeutic drugs for this disease is, therefore, an urgent need. The C-Map project has provided a wealth of gene expression data that can be mined for repositioning drugs, a promising approach to new drug discovery. Typically, a drug is considered potentially useful for treating a disease if the drug-induced differential gene expression profile is negatively correlated with the differentially expressed genes in the target disease. However, many of the potentially useful drugs (PUDs) identified by gene expression profile correlation are likely false positives because, in C-Map, the cultured cell lines to which the drug is applied are not derived from diseased tissues. To solve this problem, we developed a combined approach for predicting candidate drugs for treating pancreatic cancer. We first identified PUDs for pancreatic cancer by using C-Map-based gene expression correlation analyses. We then applied an algorithm (Met-express) to predict key pancreatic cancer (KPC) enzymes involved in pancreatic cancer metabolism. Finally, we selected candidates from the PUDs by requiring that their targets be KPC enzymes or the substrates/products of KPC enzymes. Using this combined approach, we predicted seven candidate drugs for treating pancreatic cancer, three of which are supported by literature evidence, and three were experimentally validated to be inhibitory to pancreatic cancer celllines. PMID:26910401

  19. Multivariate survival analysis of the patients with recurrent endometrial cancer

    PubMed Central

    Odagiri, Tetsuji; Hosaka, Masayoshi; Mitamura, Takashi; Konno, Yousuke; Kato, Tatsuya; Kobayashi, Noriko; Sudo, Satoko; Takeda, Mahito; Kaneuchi, Masanori; Sakuragi, Noriaki

    2011-01-01

    Objective Few studies on the prognosticators of the patients with recurrent endometrial cancer after relapse have been reported in the literature. The aim of this study was to determine the prognosticators after relapse in patients with recurrent endometrial cancer who underwent primary complete cytoreductive surgery and adjuvant chemotherapy. Methods Thirty-five patients with recurrent endometrial cancer were included in this retrospective analysis. The prognostic significance of several clinicopathological factors including histologic type, risk for recurrence, time to relapse after primary surgery, number of relapse sites, site of relapse, treatment modality, and complete resection of recurrent tumors were evaluated. Survival analyses were performed by Kaplan-Meier curves and the log-rank test. Independent prognostic factors were determined by multivariate Cox regression analysis. Results Among the clinicopathological factors analyzed, histologic type (p=0.04), time to relapse after primary surgery (p=0.03), and the number of relapse sites (p=0.03) were significantly related to survival after relapse. Multivariate analysis revealed that time to relapse after primary surgery (hazard ratio, 6.8; p=0.004) and the number of relapse sites (hazard ratio, 11.1; p=0.002) were independent prognostic factors for survival after relapse. Survival after relapse could be stratified into three groups by the combination of two independent prognostic factors. Conclusion We conclude that time to relapse after primary surgery, and the number of relapse sites were independent prognostic factors for survival after relapse in patients with recurrent endometrial cancer. PMID:21607089

  20. [Liver Atrophy and Failure Associated with Paclitaxel and Bevacizumab Combination Therapy for Metastatic Breast Cancer].

    PubMed

    Yamamoto, Mari; Ikeda, Masahiko; Kubo, Shinichiro; Tsukioki, Takahiro; Nakamoto, Shougo

    2016-07-01

    We managed 6 cases of severe liver atrophy and failure associated with paclitaxel and bevacizumab combination therapy (PB therapy)for HER2-negative metastatic breast cancer. In this case-controlstudy, we examined the records of these 6 patients to investigate past treatment, medication history, and degree of atrophy, and compared their data with that of 67 patients without liver atrophy. The degree of the liver atrophy used SYNAPSE VINCENT®of the image analysis software. The results showed that patients with liver atrophy had a longer pretreatment period than those without liver atrophy(33.5 months vs 15.5 months), and they also experienced a longer median time to treatment failure with PB therapy than other patients(11 months vs 6 months). The ratio of individuals presenting with diffuse liver metastasis among patients with liver metastasis was 80% with liver atrophy, compared to 8% without liver atrophy. The degree of liver atrophy was an average of 67%in terms of volume ratio before/after PB therapy(57-82%). The individualwith the greatest extent of liver atrophy died of liver failure, not as a result of breast cancer progression. The direct causal link between bevacizumab and liver atrophy and failure is unclear, but the individuals in this study had a long previous history of treatment, and diffuse liver metastases may develop in patients undergoing long periods of PB therapy, which may also cause liver atrophy; therefore, the possibility of liver failure should be considered in such cases.

  1. Biologics in Combination with Chemotherapy for Gastric Cancer: Is This the Answer?

    PubMed Central

    Charalampakis, N.; Elimova, E.; Shimodaira, Y.; Shiozaki, H.; Wadhwa, R.; Ajani, J.A.

    2015-01-01

    Gastric cancer (GC) continues to be a significant problem worldwide and is the third leading cause of cancer death. Armamentarium to treat GC whether it is potentially curable or metastatic (incurable) has changed little over the last decades with only two new agents being approved (trastuzumab and ramucirumab). Many relatively healthy patients after second line therapy have limited and generally ineffective options. The recent TCGA analysis has uncovered 4 genotypes of GC, however, it is not sufficient to change our treatment strategies and more work needs to be done. The popular front line regimen containing a platinum compound and a fluoropyrimidine is widely used for drug development and has worked well globally. Thus, this combination appears suitable for adding a biologic agent. The search for new classes of cytotoxics has almost stopped but it is clear that cytotoxic therapy continues to contribute and it is here to stay. Biologic agents that modulate the immune system of the host appear promising along with many other biologics that can potentially inhibit signaling pathways that are often employed by GC cells. We will briefly describe the efforts that have targeted EGFR, mTOR, angiogenesis, and MET pathways. PMID:25850442

  2. The Efficacy of Combining Antiangiogenic Agents with Chemotherapy for Patients with Advanced Non-Small Cell Lung Cancer Who Failed First-Line Chemotherapy: A Systematic Review and Meta-Analysis

    PubMed Central

    Yang, Bijun; Zhang, Yaxiong; Kang, Shiyang; Zhou, Ting; Hong, Shaodong; Qin, Tao; Hu, Zhihuang; Fang, Wenfeng; Huang, Yan; Zhang, Li

    2015-01-01

    Background The clinical outcomes of patients with NSCLC who progressed after first-line treatments remain poor. The purpose of this study was to assess the advantage of antiangiogenic therapy plus standard treatment versus standard treatment alone for this population of patients. Methods We conducted a rigorous search using electronic databases for eligible studies reporting antiangiogenic therapy combined with standard second-line chemotherapy versus standard second-line treatment for patient who progressed after front-line treatment. Pooled risk ratio and 95% confidence intervals were calculated using proper statistical method. Predefined subgroup analyses were conducted to identify the potential proper patients. Results Thirteen phase II/III RCTs which involved a total of 8358 participants were included. Overall, there was significant improvement in OS (HR 0.94, 95%CI: 0.89-0.99, p=0.03), PFS (HR 0.80, 95%CI: 0.76-0.84, p<0.00001), ORR (RR 1.75, 95%CI: 1.55-1.98, p<0.00001) and DCR (RR 1.23, 95%CI: 1.18-1.28, p<0.00001) in the group with antiangiogenic therapy plus standard treatment versus the group with standard treatment alone. Subgroup analysis showed that OS benefit was presented only in patients treated with docetaxel plus antiangiogenic agents (HR 0.92, 95%CI: 0.86-0.99, p=0.02) and patients with non-squamous NSCLC (HR for OS 0.92, 95%CI: 0.86-0.99, p=0.02). Conclusions This study revealed that the addition of antiangiogenic agents to the standard treatments could provide clinical benefit to NSCLC patients who failed their first-line therapy. Furthermore, proper selection of the combined standard cytotoxic agent, as well as the patient population by tumor histology, is warranted for future studies and clinical application of antiangiogenic therapy. PMID:26034985

  3. [The results of combined treatment patients with olfactory neuroblastoma in material of Cancer Center in Warsaw].

    PubMed

    Jarząbski, Andrzej; Kiprian, Dorota; Szutkowski, Zbigniew; Kawecki, Andrzej; Michalski, Wojciech

    2011-09-01

    The results of combined treatment patients with olfactory neuroblastoma in material of Cancer Center in Warsaw The analysis of the results of combined treatment patients with olfactory neuroblastoma in material of Cancer Center in Warsaw. Authors present material of 27 cases olfactory neuroblastoma treated in Cancer Center of Warsaw from 1965 to 2008. The median age was 44 years (range 10-74). The median observation was 72 months (range 2-235).The tumors were seen in 15 women and 12 men. According to Kadish staging there were one A, eight B, and seventeen C stage tumor. The patients in stage A and B was treated by surgery and radiotherapy (mean dose in whole material was 57.15 Gy range 44-70). Five patients in stage C was treated by surgery, radiotherapy and adjuvant chemotherapy. Five patients were treated by neoadjuvant chemotherapy and radiotherapy. Six patients underwent surgery and radiotherapy. One patient was died during adjuvant chemotherapy. One patient in stage B had local recurrence, one local recurrence and metastases and one had only metastases. In stage C 4 patients was died because of metastases, one had local recurrence and, 3 was died because of other reasons. Patients who was failed, underwent surgery, chemotherapy or radiotherapy, it was dependent of clinical situation. A complete regression was seen in 100% patients in early stages (A and B) and 82% patients in stage C. The 5-year local progression-free survival rate was 91% in early stages and 60% in stage C. The LPFS in whole group was 66.7%. The 5-year disease-free survival rate was 91% in early stages, 46% in stage C. The DSF rate in whole group was 44.4%. The 5-year overall survival rate was 80% in stages A and B, 41.2% in stage C. The OS in whole group was 55.6%. The 5-year survival rate was 20% for patients who had recurrence and/or metastases. A combination of surgery and radiotherapy appears to be adequate treatment for early stages (A and B) olfactory neuroblastoma. There are still no

  4. Content analysis of cancer blog posts*

    PubMed Central

    Kim, Sujin

    2009-01-01

    Objectives: The efficacy of user-defined subject tagging and software-generated subject tagging for describing and organizing cancer blog contents was explored. Methods: The Technorati search engine was used to search the blogosphere for cancer blog postings generated during a two-month period. Postings were mined for relevant subject concepts, and blogger-defined tags and Text Analysis Portal for Research (TAPoR) software–defined tags were generated for each message. Descriptive data were collected, and the blogger-defined tags were compared with software-generated tags. Three standard vocabularies (Opinion Templates, Basic Resource, and Medical Subject Headings [MeSH] Resource) were used to assign subject terms to the blogs, with results compared for efficacy in information retrieval. Results: Descriptive data showed that most of the studied cancer blogs (80%) contained fewer than 500 words each. The numbers of blogger-defined tags per posting (M = 4.49 per posting) were significantly smaller than the TAPoR keywords (M = 23.55 per posting). Both blogger-defined subject tags and software-generated subject tags were often overly broad or overly narrow in focus, producing less than effective search results for those seeking to extract information from cancer blogs. Conclusions: Additional exploration into methods for systematically organizing cancer blog postings is necessary if blogs are to become stable and efficacious information resources for cancer patients, friends, families, or providers. PMID:19851489

  5. Exhaled breath analysis for lung cancer.

    PubMed

    Dent, Annette G; Sutedja, Tom G; Zimmerman, Paul V

    2013-10-01

    Early diagnosis of lung cancer results in improved survival compared to diagnosis with more advanced disease. Early disease is not reliably indicated by symptoms. Because investigations such as bronchoscopy and needle biopsy have associated risks and substantial costs, they are not suitable for population screening. Hence new easily applicable tests, which can be used to screen individuals at risk, are required. Biomarker testing in exhaled breath samples is a simple, relatively inexpensive, non-invasive approach. Exhaled breath contains volatile and non-volatile organic compounds produced as end-products of metabolic processes and the composition of such compounds varies between healthy subjects and subjects with lung cancer. Many studies have analysed the patterns of these compounds in exhaled breath. In addition studies have also reported that the exhaled breath condensate (EBC) can reveal gene mutations or DNA abnormalities in patients with lung cancer. This review has summarised the scientific evidence demonstrating that lung cancer has distinct chemical profiles in exhaled breath and characteristic genetic changes in EBC. It is not yet possible to accurately identify individuals with lung cancer in at risk populations by any of these techniques. However, analysis of both volatile organic compounds in exhaled breath and of EBC have great potential to become clinically useful diagnostic and screening tools for early stage lung cancer detection.

  6. Exhaled breath analysis for lung cancer

    PubMed Central

    Sutedja, Tom G.; Zimmerman, Paul V.

    2013-01-01

    Early diagnosis of lung cancer results in improved survival compared to diagnosis with more advanced disease. Early disease is not reliably indicated by symptoms. Because investigations such as bronchoscopy and needle biopsy have associated risks and substantial costs, they are not suitable for population screening. Hence new easily applicable tests, which can be used to screen individuals at risk, are required. Biomarker testing in exhaled breath samples is a simple, relatively inexpensive, non-invasive approach. Exhaled breath contains volatile and non-volatile organic compounds produced as end-products of metabolic processes and the composition of such compounds varies between healthy subjects and subjects with lung cancer. Many studies have analysed the patterns of these compounds in exhaled breath. In addition studies have also reported that the exhaled breath condensate (EBC) can reveal gene mutations or DNA abnormalities in patients with lung cancer. This review has summarised the scientific evidence demonstrating that lung cancer has distinct chemical profiles in exhaled breath and characteristic genetic changes in EBC. It is not yet possible to accurately identify individuals with lung cancer in at risk populations by any of these techniques. However, analysis of both volatile organic compounds in exhaled breath and of EBC have great potential to become clinically useful diagnostic and screening tools for early stage lung cancer detection. PMID:24163746

  7. Content analysis of cancer blog posts.

    PubMed

    Kim, Sujin

    2009-10-01

    The efficacy of user-defined subject tagging and software-generated subject tagging for describing and organizing cancer blog contents was explored. The Technorati search engine was used to search the blogosphere for cancer blog postings generated during a two-month period. Postings were mined for relevant subject concepts, and blogger-defined tags and Text Analysis Portal for Research (TAPoR) software-defined tags were generated for each message. Descriptive data were collected, and the blogger-defined tags were compared with software-generated tags. Three standard vocabularies (Opinion Templates, Basic Resource, and Medical Subject Headings [MeSH] Resource) were used to assign subject terms to the blogs, with results compared for efficacy in information retrieval. Descriptive data showed that most of the studied cancer blogs (80%) contained fewer than 500 words each. The numbers of blogger-defined tags per posting (M = 4.49 per posting) were significantly smaller than the TAPoR keywords (M = 23.55 per posting). Both blogger-defined subject tags and software-generated subject tags were often overly broad or overly narrow in focus, producing less than effective search results for those seeking to extract information from cancer blogs. Additional exploration into methods for systematically organizing cancer blog postings is necessary if blogs are to become stable and efficacious information resources for cancer patients, friends, families, or providers.

  8. Combined Modality Therapy Including Intraoperative Electron Irradiation for Locally Recurrent Colorectal Cancer

    SciTech Connect

    Haddock, Michael G.; Miller, Robert C.; Nelson, Heidi; Pemberton, John H.; Dozois, Eric J.; Alberts, Steven R.; Gunderson, Leonard L.

    2011-01-01

    Purpose: To evaluate survival, relapse patterns, and prognostic factors in patients with colorectal cancer relapse treated with curative-intent therapy, including intraoperative electron radiation therapy (IOERT). Methods and Materials: From April 1981 through January 2008, 607 patients with recurrent colorectal cancer received IOERT as a component of treatment. IOERT was preceded or followed by external radiation (median dose, 45.5 Gy) in 583 patients (96%). Resection was classified as R0 in 227 (37%), R1 in 224 (37%), and R2 in 156 (26%). The median IOERT dose was 15 Gy (range, 7.5-30 Gy). Results: Median overall survival was 36 months. Five- and 10-year survival rates were 30% and 16%, respectively. Survival estimates at 5 years were 46%, 27%, and 16% for R0, R1, and R2 resection, respectively. Multivariate analysis revealed that R0 resection, no prior chemotherapy, and more recent treatment (in the second half of the series) were associated with improved survival. The 3-year cumulative incidence of central, local, and distant relapse was 12%, 23%, and 49%, respectively. Central and local relapse were more common in previously irradiated patients and in those with subtotal resection. Toxicity Grade 3 or higher partially attributable to IOERT was observed in 66 patients (11%). Neuropathy was observed in 94 patients (15%) and was more common with IOERT doses exceeding 12.5 Gy. Conclusions: Long-term survival and disease control was achievable in patients with locally recurrent colorectal cancer. Continued evaluation of curative-intent, combined-modality therapy that includes IOERT is warranted in this high-risk population.

  9. Combination Chemotherapy With or Without Vismodegib in Treating Patients With Advanced Stomach Cancer or Gastroesophageal Junction Cancer

    ClinicalTrials.gov

    2015-12-16

    Adenocarcinoma of the Gastroesophageal Junction; Adenocarcinoma of the Stomach; Recurrent Gastric Cancer; Stage IIIA Gastric Cancer; Stage IIIB Gastric Cancer; Stage IIIC Gastric Cancer; Stage IV Gastric Cancer

  10. Multiplex Quantitative Histologic Analysis of Human Breast Cancer Cell Signaling and Cell Fate

    DTIC Science & Technology

    2010-05-01

    Breast cancer, cell signaling, cell proliferation, histology, image analysis 15. NUMBER OF PAGES - 51 16. PRICE CODE 17. SECURITY CLASSIFICATION...revealed by individual stains in multiplex combinations; and (3) software (FARSIGHT) for automated multispectral image analysis that (i) segments...Task 3. Develop computational algorithms for multispectral immunohistological image analysis FARSIGHT software was developed to quantify intrinsic

  11. Combination of erlotinib and EGCG induces apoptosis of head and neck cancers through posttranscriptional regulation of Bim and Bcl-2.

    PubMed

    Haque, Abedul; Rahman, Mohammad Aminur; Chen, Zhuo Georgia; Saba, Nabil F; Khuri, Fadlo R; Shin, Dong M; Ruhul Amin, A R M

    2015-07-01

    Combinatorial approaches using two or more compounds are gaining increasing attention for cancer therapy. We have previously reported that the combination of the EGFR-TKI erlotinib and epigallocatechin-3-gallate (EGCG) exhibited synergistic chemopreventive effects in head and neck cancers by inducing the expression of Bim, p21, p27, and by inhibiting the phosphorylation of ERK and AKT and expression of Bcl-2. In the current study, we further investigated the mechanism of regulation of Bim, Bcl-2, p21 and p27, and their role in apoptosis. shRNA-mediated silencing of Bim significantly inhibited apoptosis induced by the combination of erlotinib and EGCG (p = 0.005). On the other hand, overexpression of Bcl-2 markedly protected cells from apoptosis (p = 0.003), whereas overexpression of constitutively active AKT only minimally protected cells from apoptosis induced by the combination of the two compounds. Analysis of mRNA expression by RT-PCR revealed that erlotinib, EGCG and their combination had no significant effects on the mRNA expression of Bim, p21, p27 or Bcl-2 suggesting the post-transcriptional regulation of these molecules. Furthermore, we found that erlotinib or the combination of EGCG and erlotinib inhibited the phosphorylation of Bim and stabilized Bim after inhibition of protein translation by cycloheximide. Taken together, our results strongly suggest that the combination of erlotinib and EGCG induces apoptosis of SCCHN cells by regulating Bim and Bcl-2 at the posttranscriptional level.

  12. PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer

    PubMed Central

    Milella, Michele; Falcone, Italia; Conciatori, Fabiana; Matteoni, Silvia; Sacconi, Andrea; De Luca, Teresa; Bazzichetto, Chiara; Corbo, Vincenzo; Simbolo, Michele; Sperduti, Isabella; Benfante, Antonina; Del Curatolo, Anais; Cesta Incani, Ursula; Malusa, Federico; Eramo, Adriana; Sette, Giovanni; Scarpa, Aldo; Konopleva, Marina; Andreeff, Michael; McCubrey, James Andrew; Blandino, Giovanni; Todaro, Matilde; Stassi, Giorgio; De Maria, Ruggero; Cognetti, Francesco; Del Bufalo, Donatella; Ciuffreda, Ludovica

    2017-01-01

    Combined MAPK/PI3K pathway inhibition represents an attractive, albeit toxic, therapeutic strategy in oncology. Since PTEN lies at the intersection of these two pathways, we investigated whether PTEN status determines the functional response to combined pathway inhibition. PTEN (gene, mRNA, and protein) status was extensively characterized in a panel of cancer cell lines and combined MEK/mTOR inhibition displayed highly synergistic pharmacologic interactions almost exclusively in PTEN-loss models. Genetic manipulation of PTEN status confirmed a mechanistic role for PTEN in determining the functional outcome of combined pathway blockade. Proteomic analysis showed greater phosphoproteomic profile modification(s) in response to combined MEK/mTOR inhibition in PTEN-loss contexts and identified JAK1/STAT3 activation as a potential mediator of synergistic interactions. Overall, our results show that PTEN-loss is a crucial determinant of synergistic interactions between MAPK and PI3K pathway inhibitors, potentially exploitable for the selection of cancer patients at the highest chance of benefit from combined therapeutic strategies. PMID:28220839

  13. [Combination of external irradiation and androgen suppression for prostate cancer: facts and questions].

    PubMed

    Bolla, M; Fourneret, P; Beneyton, V; Tessier, A; Jover, F; Verry, C

    2010-10-01

    The combination of radiotherapy and androgen suppression with luteinizing hormone releasing hormone agonist is mainly devoted to locally advanced prostate cancer and intermediate or poor risk localized prostate cancer. They are based on phase III randomized trials which have shown that for locally advanced prostate cancer, a four-month complete androgen blockade initiated two months prior radiotherapy and stopped at the completion of radiotherapy increased overall survival in patients with Gleason scores 2-6, meanwhile, an adjuvant long-term androgen suppression (2.5 to three years) improved significantly the overall survival. Complete androgen blockade with a four to six months duration, combined with external irradiation, enhanced the overall survival in patients with intermediate or poor risk localized prostate cancer. Copyright © 2010 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.

  14. Recent Developments in Active Tumor Targeted Multifunctional Nanoparticles for Combination Chemotherapy in Cancer Treatment and Imaging

    PubMed Central

    Glasgow, Micah D. K.; Chougule, Mahavir B.

    2016-01-01

    Nanotechnology and combination therapy are two major fields that show great promise in the treatment of cancer. The delivery of drugs via nanoparticles helps to improve drug’s therapeutic effectiveness while reducing adverse side effects associated with high dosage by improving their pharmacokinetics. Taking advantage of molecular markers over-expressing on tumor tissues compared to normal cells, an “active” molecular marker targeted approach would be beneficial for cancer therapy. These actively targeted nanoparticles would increase drug concentration at the tumor site, improving efficacy while further reducing chemo-resistance. The multidisciplinary approach may help to improve the overall efficacy in cancer therapy. This review article summarizes recent developments of targeted multifunctional nanoparticles in the delivery of various drugs for a combinational chemotherapy approach to cancer treatment and imaging. PMID:26554150

  15. Immunotherapy for the treatment of breast cancer: checkpoint blockade, cancer vaccines, and future directions in combination immunotherapy.

    PubMed

    McArthur, Heather L; Page, David B

    2016-11-01

    Immunotherapy encompasses both vaccines that direct immune responses to tumor-associated antigens, and checkpoint blocking antibodies that inhibit immune system suppression by targeting key pathways mediated by cytotoxic T-lymphocyte-associated antigen 4, programmed death 1 (PD-1), and programmed death ligand 1 (PD-L1). Both of these approaches currently are being explored as potential strategies for the treatment of breast cancer. Recent studies suggest that immunotherapy is poised to change the therapeutic landscape for some breast cancers. Specifically, overall response rates of 19% with PD-1/PD-L1-directed antibodies have been reported in 2 small studies of women with PD-L1-positive, heavily pretreated advanced triple-negative breast cancer. In combination with nab-paclitaxel, confirmed response rates were 46% in a PD-L1-unselected population in the first-line metastatic triple-negative breast cancer setting. Checkpoint-blocking antibodies also have been evaluated in small studies of women with hormone receptor-positive metastatic breast cancer, and in women whose breast cancers lack PD-L1 expression, with more modest response rates. It has been hypothesized that some breast cancers are not inherently recognized by the immune system; however, preclinical and preliminary clinical data suggest that inherently modest immunogenicity may be overcome with novel vaccination strategies, as well as strategies that combine immune checkpoint blockade with methods of optimizing antigen presentation, such as tumor ablation, radiation, chemotherapy, or other approaches. If ongoing registrational trials support the use of immunotherapy, it could revolutionize the care of early-stage and metastatic breast cancer, and ideally improve cure rates.

  16. Combined Biology and Bioinformatics Approaches to Breast Cancer

    DTIC Science & Technology

    2006-04-01

    AD_________________ Award Number: W81XWH-04- 1 -0483 TITLE: Combined Biology and Bioinformatics...reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching...ABOVE ADDRESS. 1 . REPORT DATE 01-04-2006 2. REPORT TYPE Annual 3. DATES COVERED 1 Apr 2005 – 31 Mar 2006 4. TITLE AND SUBTITLE 5a. CONTRACT

  17. A Combined PD-1/C5a Blockade Synergistically Protects against Lung Cancer Growth and Metastasis.

    PubMed

    Ajona, Daniel; Ortiz-Espinosa, Sergio; Moreno, Haritz; Lozano, Teresa; Pajares, María J; Agorreta, Jackeline; Bértolo, Cristina; Lasarte, Juan J; Vicent, Silvestre; Hoehlig, Kai; Vater, Axel; Lecanda, Fernando; Montuenga, Luis M; Pio, Ruben

    2017-07-01

    Disruption of the programmed cell death protein 1 (PD-1) pathway with immune checkpoint inhibitors represents a major breakthrough in the treatment of non-small cell lung cancer. We hypothesized that combined inhibition of C5a/C5aR1 and PD-1 signaling may have a synergistic antitumor effect. The RMP1-14 antibody was used to block PD-1, and an L-aptamer was used to inhibit signaling of complement C5a with its receptors. Using syngeneic models of lung cancer, we demonstrate that the combination of C5a and PD-1 blockade markedly reduces tumor growth and metastasis and leads to prolonged survival. This effect is accompanied by a negative association between the frequency of CD8 T cells and myeloid-derived suppressor cells within tumors, which may result in a more complete reversal of CD8 T-cell exhaustion. Our study provides support for the clinical evaluation of anti-PD-1 and anti-C5a drugs as a novel combination therapeutic strategy for lung cancer.Significance: Using a variety of preclinical models of lung cancer, we demonstrate that the blockade of C5a results in a substantial improvement in the efficacy of anti-PD-1 antibodies against lung cancer growth and metastasis. This study provides the preclinical rationale for the combined blockade of PD-1/PD-L1 and C5a to restore antitumor immune responses, inhibit tumor cell growth, and improve outcomes of patients with lung cancer. Cancer Discov; 7(7); 694-703. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 653. ©2017 American Association for Cancer Research.

  18. Combining polarimetry and spectropolarimetry techniques in diagnostics of cancer changes in biological tissues

    NASA Astrophysics Data System (ADS)

    Yermolenko, Sergey; Ivashko, Pavlo; Gruia, Ion; Gruia, Maria; Peresunko, Olexander; Zelinska, Natalia; Voloshynskyi, Dmytro; Fedoruk, Olexander; Zimnyakov, Dmitry; Alonova, Marina

    2015-02-01

    The aim of the study is combining polarimetry and spectropolarimetry techniques for identifying the changes of opticalgeometrical structure in different kinds of biotissues with solid tumours. It is researched that a linear dichroism appears in biotissues (human esophagus, muscle tissue of rats, human prostate tissue, cervical smear) with cancer diseases, magnitude of which depends on the type of the tissue and on the time of cancer process development.

  19. Combination of surgery and radiation in the treatment of cancer. A review

    SciTech Connect

    McLeod, D.A.; Thrall, D.E.

    1989-01-01

    Although radiation and surgery have been combined for the treatment of cancer in humans and animals since the 1920s, little has been written about the methods of combining radiation and surgery and the efficacy of this combination for the treatment of animal tumors. This article reviews the rationale for combining radiation and surgery for the treatment of cancer and the ways in which these two modalities can be combined with emphasis placed on the advantages and disadvantages of preoperative and postoperative radiotherapy. The role of preoperative and postoperative irradiation for the treatment of various animal tumors is discussed. Directions for future clinical trials are pointed out. Finally, the importance of surgeons and radiation oncologists communicating with each other and participating in cooperative treatment methods is stressed. 36 references.

  20. Filtration and Analysis of Circulating Cancer Associated Cells from the Blood of Cancer Patients.

    PubMed

    Tang, Cha-Mei; Zhu, Peixuan; Li, Shuhong; Makarova, Olga V; Amstutz, Platte T; Adams, Daniel L

    2017-01-01

    Filtration is one of the most efficient methods to remove red and white blood cells from whole blood, while retaining larger cells on the surface of the filter. Precision pore microfilters, such as the CellSieve™ microfilters, are ideally suited for this purpose, as they are strong, with uniform pore size and distribution, and have low fluorescent background required for microscopic image analysis. We present a system to implement the filtration of whole blood in combination with CellSieve™ microfilters that is simple and straightforward to use. Being that the blood of cancer patients often contains both tumor cells and stromal cells associated with cancer that are larger than normal blood cells, microfiltration shows great promise in better understanding these cell types. Accurate identification and characterization of cancer associated cells has led to increased specificity as it relates to CTCs and epithelial-mesenchymal transition cells (EMTs) and enabled the identification of previously unknown cell types, such as cancer associated macrophage-like cells (CAMLs). Using a system that isolates both CTCs and circulating stromal cells, clinicians can better diagnose cancer patients to determine therapy, monitor treatment, and watch for recurrence.

  1. Smac therapeutic Peptide nanoparticles inducing apoptosis of cancer cells for combination chemotherapy with Doxorubicin.

    PubMed

    Li, Mingxing; Liu, Peng; Gao, Guanhui; Deng, Jizhe; Pan, Zhengyin; Wu, Xu; Xie, Gaofeng; Yue, Caixia; Cho, Chi Hin; Ma, Yifan; Cai, Lintao

    2015-04-22

    Smac-conjugated nanoparticle (Smac-NP) was designed to induce the apoptosis of cancer cells and as a drug carrier for combination therapy. It contained three parts, a SmacN7 peptide which could induce apoptosis of cancer cells by interacting with XIAPs, the cell penetrating domain rich in arginine, and four hydrophobic tails for self-assembled Smac-NP. We demonstrated that Smac-NPs exerted an antitumor effect in breast cancer cell MDA-MB-231 and nonsmall lung cancer (NSCLC) cell H460, which efficiently inhibited cancer cells proliferation without influencing normal liver cell lines LO2. Smac-NPs also significantly induced apoptosis of MDA-MB-231 and H460 cells through activating pro-caspase-3, down-regulating the expression of antiapoptotic protein Bcl-2 and up-regulating the pro-apoptotic protein Bax. Furthermore, Smac-NPs could be explored as a drug delivery system to load hydrophobic drug such as DOX for combination therapy. The DOX-loaded nanoparticles (DOX-Smac-NPs) exhibited higher cellular uptake efficiency and antitumor effect. Our work provided a new insight into therapeutic peptides integrated with drug simultaneously in one system for cancer combination treatment.

  2. Combined chemotherapy or biotherapy with jasmonates: targeting energy metabolism for cancer treatment.

    PubMed

    Elia, Uri; Flescher, Eliezer

    2013-01-01

    Mitochondria are known to play a key role in various cellular processes essential to both the life and death of cells, including calcium homeostasis, programmed cell death, and energy metabolism. Over 80 years ago, Otto Warburg discovered that in contrast to normal cells which produce most of their ATP via mitochondrial oxidative phosphorylation, cancer cells preferentially utilize glycolysis for production of ATP, a phenomenon known today as the "Warburg effect", and one which has been of great importance in the emergence of novel drugs and chemotherapeutic agents specifically targeting cancer cells. Several groups have reported in recent years that members of the plant stress hormones family of jasmonates, and some of their synthetic derivatives, exhibit anti-cancer activity in vitro and in vivo. Jasmonates have been shown to act directly on mitochondria of cancer cells, leading to mitochondrial swelling, membrane depolarization and cytochrome c release. Throughout the last few years, different groups have demonstrated that combination of jasmonates and various cytotoxic and chemotherapeutic agents yielded a synergistic cytotoxic effect. These results have been demonstrated in a variety of different cancer cell lines and may provide a strong basis for future clinical treatments which involve combination of MJ and different anti-cancerous agents. The potential synergistic effect may allow reduction of the administered dose, decrease of unwanted side effects, and reduction of the likelihood that the tumor will display resistance to the combined therapy.

  3. Rationale and evidence to combine radiation therapy and immunotherapy for cancer treatment.

    PubMed

    Ishihara, Dan; Pop, Laurentiu; Takeshima, Tsuguhide; Iyengar, Puneeth; Hannan, Raquibul

    2017-03-01

    Cancer immunotherapy exploits the immune system's ability to differentiate between tumor target cells and host cells. Except for limited success against a few tumor types, most immunotherapies have not achieved the desired clinical efficacy until recently. The field of cancer immunotherapy has flourished with a variety of new agents for clinical use, and remarkable progress has been made in the design of effective immunotherapeutic regimens. Furthermore, the therapeutic outcome of these novel agents is enhanced when combined with conventional cancer treatment modalities including radiotherapy (RT). An increasing number of studies have demonstrated the abscopal effect, an immunologic response occurring in cancer sites distant from irradiated areas. The present work reviews studies on the combination between RT and immunotherapy to induce synergistic and abscopal effects involved in cancer immunomodulation. Further insight into the complex interactions between the immune system and cancer cells in the tumor microenvironment, and their modulation by RT, may reveal the abscopal effect as a clinically relevant and reproducible event leading to improved cancer outcome.

  4. Carnosic acid and fisetin combination therapy enhances inhibition of lung cancer through apoptosis induction.

    PubMed

    Shi, Bin; Wang, Li-Fang; Meng, Wen-Shu; Chen, Liang; Meng, Zi-Li

    2017-06-01

    Carnosic acid is a phenolic diterpene with anti-inflammation, anticancer, anti-bacterial, anti-diabetic, as well as neuroprotective properties, which is generated by many species from Lamiaceae family. Fisetin (3,3',4',7-tetrahydroxyflavone), a naturally flavonoid is abundantly produced in different vegetables and fruits. Fisetin has been reported to have various positive biological effects, including anti-proliferative, anticancer, anti-oxidative and neuroprotective effects. Lung cancer is reported as the most common neoplasm in human world-wide. In the present study, the possible benefits of carnosic acid combined with fisetin on lung cancer in vitro and in vivo was explored. Carnosic acid and fisetin combination led to apoptosis in lung cancer cells. Caspase-3 signaling pathway was promoted in carnosic acid and fisetin co-treatment, which was accompanied by anti-apoptotic proteins of Bcl-2 and Bcl-xl decreasing and pro-apoptotic signals of Bax and Bad increasing. The death receptor (DR) of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) was enhanced in carnosic acid and fisetin combined treatment. Furthermore, the mouse xenograft model in vivo suggested that carnosic acid and fisetin combined treatment inhibited lung cancer growth in comparison to the carnosic acid or fisetin monotherapy. This study supplies a novel therapy to induce apoptosis to inhibit lung cancer through caspase-3 activation.

  5. Targeted near infrared hyperthermia combined with immune stimulation for optimized therapeutic efficacy in thyroid cancer treatment

    PubMed Central

    Zhou, Le; Zhang, Mengchao; Fu, Qingfeng; Li, Jingting; Sun, Hui

    2016-01-01

    Treatment of thyroid cancer has incurred much focus because of its high prevalency. As a new strategy treating thyroid cancer, hyperthermia takes several advantages compared with surgery or chemotherapy, including minimal invasion, low systematic toxicity and the ability to enhance the immunogenicity of cancer cells with the expression Hsp70 which serves as Toll-like receptors-4 (TLR-4 agonist). However, Hsp70 as a molecular chaperone can protect cells from heat induced apoptosis and therefore compromise the tumor killing effect of hyperthermia. In this study, to solve this problem, a combined hyperthermia therapy was employed to treat thyroid cancer. We prepared a probe with the tumor targeting agent AG to monitor thyroid tumor issue and generate heat to kill tumor cells in vivo. At the same time Quercetin (inhibitor of HSP70) and lipopolysaccharide (LPS) (agonist of TLR-4) were used for the combined hyperthermia therapy. The results showed that compared with free IR820, AG modification facilitated much enhanced cellular uptake and greatly pronounced tumor targeting ability. The combined therapy exhibited the most remarkable tumor inhibition compared with the single treatments both in vitro and in vivo. These findings verified that the new therapeutic combination could significantly improve the effect of hyperthermia and shed light on a novel clinical strategy in thyroid cancer treatment. PMID:26769848

  6. Quantitative DNA Methylation Analysis of Candidate Genes in Cervical Cancer

    PubMed Central

    Siegel, Erin M.; Riggs, Bridget M.; Delmas, Amber L.; Koch, Abby; Hakam, Ardeshir; Brown, Kevin D.

    2015-01-01

    Aberrant DNA methylation has been observed in cervical cancer; however, most studies have used non-quantitative approaches to measure DNA methylation. The objective of this study was to quantify methylation within a select panel of genes previously identified as targets for epigenetic silencing in cervical cancer and to identify genes with elevated methylation that can distinguish cancer from normal cervical tissues. We identified 49 women with invasive squamous cell cancer of the cervix and 22 women with normal cytology specimens. Bisulfite-modified genomic DNA was amplified and quantitative pyrosequencing completed for 10 genes (APC, CCNA, CDH1, CDH13, WIF1, TIMP3, DAPK1, RARB, FHIT, and SLIT2). A Methylation Index was calculated as the mean percent methylation across all CpG sites analyzed per gene (~4-9 CpG site) per sequence. A binary cut-point was defined at >15% methylation. Sensitivity, specificity and area under ROC curve (AUC) of methylation in individual genes or a panel was examined. The median methylation index was significantly higher in cases compared to controls in 8 genes, whereas there was no difference in median methylation for 2 genes. Compared to HPV and age, the combination of DNA methylation level of DAPK1, SLIT2, WIF1 and RARB with HPV and age significantly improved the AUC from 0.79 to 0.99 (95% CI: 0.97–1.00, p-value = 0.003). Pyrosequencing analysis confirmed that several genes are common targets for aberrant methylation in cervical cancer and DNA methylation level of four genes appears to increase specificity to identify cancer compared to HPV detection alone. Alterations in DNA methylation of specific genes in cervical cancers, such as DAPK1, RARB, WIF1, and SLIT2, may also occur early in cervical carcinogenesis and should be evaluated. PMID:25826459

  7. Combination Regimens of Radiation Therapy and Therapeutic Cancer Vaccines: Mechanisms and Opportunities

    PubMed Central

    Garnett-Benson, Charlie; Hodge, James W.; Gameiro, Sofia R.

    2014-01-01

    Radiation therapy is widely used with curative or palliative intent in the clinical management of multiple cancers. Although mainly aimed at direct tumor cell killing, mounting evidence suggests that radiation can alter the tumor to become an immunostimulatory milieu. Data suggest that the immunogenic effects of radiation can be exploited to promote synergistic antitumor effects in combination with immunotherapeutic agents. Here we review concepts associated with the immunogenic consequences of radiation therapy, and highlight how preclinical findings are translating into clinical benefit for patients receiving combination regimens of radiation therapy and therapeutic cancer vaccines. PMID:25481266

  8. Safety Study of Enoblituzumab (MGA271) in Combination With Pembrolizumab in Refractory Cancer

    ClinicalTrials.gov

    2016-09-26

    Melanoma; Head and Neck Cancer; Non Small Cell Lung Cancer; Mesothelioma; Urethelial Carcinoma; Clear Cell Renal Cell Carcinoma; Ovarian Cancer; Thyroid Cancer; Triple Negative Breast Cancer; Pancreatic Cancer; Colon Cancer; Soft Tissue Sarcoma; Prostate Cancer

  9. Safety Study of Enoblituzumab (MGA271) in Combination With Ipilimumab in Refractory Cancer

    ClinicalTrials.gov

    2016-08-10

    Melanoma; Head and Neck Cancer; Non Small Cell Lung Cancer; Mesothelioma; Urothelial Carcinoma; Clear Cell Renal Cell Carcinoma; Ovarian Cancer; Thyroid Cancer; Triple Negative Breast Cancer; Pancreatic Cancer; Colon Cancer; Soft Tissue Sarcoma; Prostate Cancer

  10. A novel cancer vaccine strategy with combined IL-18 and HSV-TK gene therapy driven by the hTERT promoter in a murine colorectal cancer model.

    PubMed

    Higashi, Kosuke; Hazama, Shoichi; Araki, Atsuhiro; Yoshimura, Kiyoshi; Iizuka, Norio; Yoshino, Shigefumi; Noma, Takafumi; Oka, Masaaki

    2014-10-01

    A therapeutic vaccine against minimal residual cancer cells is needed for the treatment of patients with colorectal cancer. Several gene therapy studies have revealed that the combination of a suicide gene and cytokine gene might induce effective antitumor immunity. In this study, we constructed an interleukin (IL)-18 and herpes simplex virus-thymidine kinase (HSV-TK) expression vector driven by the human telomerase reverse transcriptase (hTERT) promoter to study the efficacy of combination gene therapy with IL-18 and the HSV-TK suicide gene. Low immunogenic colon 26 cells were used for transfection and inoculation into syngeneic BALB/c mice. Large established tumors of colon 26 transfectants expressing IL-18 and HSV-TK driven by the hTERT promoter were completely eradicated after GCV administration in syngeneic BALB/c mice. Immunohistochemical analysis at the tumor rejection sites revealed enormous infiltrations of CD8+ T lymphocytes as well as CD4+ T lymphocytes and CD11b+ monocytes. Moreover, established distant tumors were completely eradicated by vaccination with the IL-18 and HSV-TK transfectants in combination with GCV. These data suggest that the IL-18 and suicide gene therapy can elicit antitumor specific immunity. In conclusion, gene therapy with IL-18 and HSV-TK plasmid vector driven by the hTERT promoter may be useful for cancer vaccination.

  11. Combined effect of tumor necrosis factor-related apoptosis-inducing ligand and ionizing radiation in breast cancer therapy

    PubMed Central

    Chinnaiyan, Arul M.; Prasad, Uttara; Shankar, Sunita; Hamstra, Daniel A.; Shanaiah, Murthy; Chenevert, Thomas L.; Ross, Brian D.; Rehemtulla, Alnawaz

    2000-01-01

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent endogenous activator of the cell death pathway and functions by activating the cell surface death receptors 4 and 5 (DR4 and DR5). TRAIL is nontoxic in vivo and preferentially kills neoplastically transformed cells over normal cells by an undefined mechanism. Radiotherapy is a common treatment for breast cancer as well as many other cancers. Here we demonstrate that ionizing radiation can sensitize breast carcinoma cells to TRAIL-induced apoptosis. This synergistic effect is p53-dependent and may be the result of radiation-induced up-regulation of the TRAIL-receptor DR5. Importantly, TRAIL and ionizing radiation have a synergistic effect in the regression of established breast cancer xenografts. Changes in tumor cellularity and extracellular space were monitored in vivo by diffusion-weighted magnetic resonance imaging (diffusion MRI), a noninvasive technique to produce quantitative images of the apparent mobility of water within a tissue. Increased water mobility was observed in combined TRAIL- and radiation-treated tumors but not in tumors treated with TRAIL or radiation alone. Histological analysis confirmed the loss of cellularity and increased numbers of apoptotic cells in TRAIL- and radiation-treated tumors. Taken together, our results provide support for combining radiation with TRAIL to improve tumor eradication and suggest that efficacy of apoptosis-inducing cancer therapies may be monitored noninvasively, using diffusion MRI. PMID:10677530

  12. An in Vivo shRNA-Drug Screen to Identify Novel Targeted Therapy Combinations for KRAS Mutant Cancers

    DTIC Science & Technology

    2014-12-01

    AWARD NUMBER: W81XWH-12-1-0420 TITLE: An in Vivo shRNA-Drug Screen to Identify Novel Targeted Therapy Combinations for KRAS Mutant Cancers...2012 - 31 Aug 2014 4. TITLE AND SUBTITLE An in Vivo shRNA-Drug Screen to Identify Novel Targeted Therapy Combinations for KRAS Mutant Cancers...through the MAPK pathway, a key KRAS effector) to kill KRAS mutant pancreatic cancer cells in order to develop novel therapeutic combinations for these

  13. Combination of drug-conjugated SWCNT nanocarriers for efficient therapy of cancer stem cells in a breast cancer animal model.

    PubMed

    Al Faraj, Achraf; Shaik, Asma Sultana; Ratemi, Elaref; Halwani, Rabih

    2016-03-10

    Targeting breast cancer and more specifically cancer stem cell (CSC) subpopulation, responsible for tumor growth, resistance and self-renewal, using combination of therapeutic drugs selectively delivered via biocompatible nanocarriers, provides a novel approach for effective therapy. Here, we propose to evaluate the potential therapeutic efficacy of combining Paclitaxel and Salinomycin drugs actively targeted to both breast cancer and CSCs in xenograft murine model after conjugation with biocompatible CD44 antibody conjugated SWCNTs via hydrazone linker allowing pH-responsive release mechanism near the acidic tumor microenvironment. Both in vitro investigations on MDA-MB-231, sorted CSC negative or CSC positive fractions and in vivo evaluations on tumor-bearing mice using noninvasive bioluminescence and magnetic resonance imaging confirmed the enhanced therapeutic effect of the combined therapy compared to treatment with individual drug-conjugated nanocarriers or free drug suspensions. Thus, confirmed the great promise of the developed SWCNTs drug delivery system for effective breast cancer treatment by targeting and eradicating both whole tumor cells and CSCs populations.

  14. Prostate cancer immunotherapy, particularly in combination with androgen deprivation or radiation treatment. Customized pharmacogenomic approaches to overcome immunotherapy cancer resistance

    PubMed Central

    ALBERTI, C.

    2016-01-01

    Conventional therapeutic approaches for advanced prostate cancer - such as androgen deprivation, chemotherapy, radiation - come up often against lack of effectiveness because of possible arising of correlative cancer cell resistance and/or inadequate anti-tumor immune conditions. Whence the timeliness of resorting to immune-based treatment strategies including either therapeutic vaccination-based active immunotherapy or anti-tumor monoclonal antibody-mediated passive immunotherapy. Particularly attractive, as for research studies and clinical applications, results to be the cytotoxic T-lymphocyte check point blockade by the use of anti-CTLA-4 and PD-1 monoclonal antibodies, particularly when combined with androgen deprivation therapy or radiation. Unlike afore said immune check point inhibitors, both cell-based (by the use of prostate specific antigen carriers autologous dendritic cells or even whole cancer cells) and recombinant viral vector vaccines are able to induce immune-mediated focused killing of specific antigen-presenting prostate cancer cells. Such vaccines, either used alone or concurrently/sequentially combined with above-mentioned conventional therapies, led to generally reach, in the field of various clinical trials, reasonable results particularly as regards the patient’s overall survival. Adoptive trasferred T-cells, as adoptive T-cell passive immunotherapy, and monoclonal antibodies against specific antigen-endowed prostate cancer cells can improve immune micro-environmental conditions. On the basis of a preliminary survey about various immunotherapy strategies, are here also outlined their effects when combined with androgen deprivation therapy or radiation. What’s more, as regard the immune-based treatment effectiveness, it has to be pointed out that suitable personalized epigenetic/gene profile-achieved pharmacogenomic approaches to target identified gene aberrations, may lead to overcome – as well as for conventional therapies

  15. Analysis of registered cancer clinical trials in Latin America and the Caribbean, 2007-2013.

    PubMed

    Lee, Bridget; Cuervo, Luis G; Rodríguez-Feria, Pablo; Luciani, Silvana

    2016-02-01

    Objective To characterize cancer clinical trials in Latin America and the Caribbean (LAC), with a focus on registration and enrollment trends. Methods Data were collected from 1 285 active cancer clinical trials registered up until 31 May 2014 in the World Health Organization's International Clinical Trial Registry Platform (ICTRP). The trials were categorized by six characteristics of the continuum of cancer control and care: 1) control and planning, 2) prevention, 3) detection and screening, 4) diagnosis, 5) treatment, and 6) survivorship and palliative care. The search strategy protocol included the use of optimized keywords combined with the names of the 43 countries selected for a descriptive analysis. Results A total of 973 registered and 972 enrolled cancer clinical trials between January 2007 and December 2013 were identified. Trends of growth were observed for both registration and enrollment of cancer treatment clinical trials; for other types of cancer clinical trials, trends for registration and enrollment varied in direction. Conclusions Growth trends in the registration of cancer treatment clinical trials indicate incremental adherence to cancer research reporting and improvements in cancer research transparency. The higher proportion of cancer treatment trials versus other types of cancer clinical trials indicates an imbalance in cancer research in the LAC region and suggests the need for more funding and incentives for other areas of research in order to achieve a more comprehensive approach to gaining knowledge on cancer issues.

  16. Combined surgical treatment of lung cancer and heart diseases.

    PubMed

    Kovacicova, K; Omran, N; Mandak, J

    2014-01-01

    The co-incidence of lung cancer and heart disease is increasing. This can be caused by population ageing, which has more co-morbidities and most likely due to the common etiological causes of both entities, i.e. smoking, hypertension and obesity. The aim of this study was to analyze the outcomes of simultaneously performed heart surgery and pulmonary resection in a selected group of patients. From January 2002 to December 2011 we performed in our department 1115 pulmonary resections for lung tumor. Significant heart disease requiring surgical treatment was diagnosed in 21 patients from the whole group. In 12 patients, group A; simultaneous heart surgery and lung resection procedure were performed. Group A consisted of 8 men and 4 women with the median age of 67.8 ± 5.9 years. In this group, 10 lobectomy procedures and 2 wedge resections for pulmonary metastasis were done. Nine patients underwent coronary artery revascularization, 2 patients underwent mitral valve replacement and one patient underwent tumor removal from the left atrium. In 5 patients, extracorporeal circulation (ECC) was needed, the remaining 7 patients underwent myocardial revascularization using an off-pump technique. Group B consisted of 7 men and 5 women with the age of 68.5 ± 7.4 years. Ten lobectomy procedures and 2 wedge resections were performed. The risk of simultaneously performed lung resection and cardiac surgery is not high. Despite the certain differences in clinical indicators between group A and B, the safety of simultaneous procedure, in group A, was evident. Furthermore, earlier lung resection was enabled and the eventual complications from further surgical procedure were avoided (Tab. 5, Ref. 33).

  17. Primary cancer prevention by green tea, and tertiary cancer prevention by the combination of green tea catechins and anticancer compounds.

    PubMed

    Fujiki, Hirota; Sueoka, Eisaburo; Watanabe, Tatsuro; Suganuma, Masami

    2015-03-01

    Green tea is a daily beverage, a non-oxidized non-fermented product containing at least four green tea catechins. Considering our first results when repeated applications of (-)-epigallocatechin gallate (EGCG) prevented tumor promotion in mouse skin, we have continued to look at green tea as a possible cancer preventive agent. 1) The 10-year prospective cohort study by Drs. K. Nakachi and K. Imai revealed that drinking 10 Japanese-size cups (120 mL/cup) of green tea per day delayed cancer onset in humans by 7.3 years among females and by 3.2 years among males. The delay of cancer onset is of course significant evidence of primary cancer prevention in humans. 2) In collaboration with Dr. H. Moriwaki's group we successfully presented a prototype of tertiary cancer prevention showing that 10 Japanese-size cups of green tea daily, supplemented with tablets of green tea extract (G.T.E), reduced recurrence of colorectal adenomas in polypectomy patients by 51.6% (from 31% to 15%). 3) In 1999, we first reported that the combination of green tea catechins and non-steroidal anti-inflammatory drugs showed synergistic anticancer effects in both in vitro and in vivo experiments, along with elucidation of the mechanism. 4) Further studies by other investigators have revealed that various combinations of EGCG or green tea extract and anticancer compounds inhibit tumor volume in xenograft mouse models implanted with various human cancer cell lines. Green tea is a cancer preventive, and green tea catechins act as synergists with anticancer compounds.

  18. [Nimotuzumab in combination with chemotherapy in patients with advanced non-small cell lung cancer].

    PubMed

    Li, Lan-Fang; Wang, Hua-Qing; Liu, Xian-Ming; Zhang, Hui-Lai; Qiu, Li-Hua; Qian, Zheng-Zi; Li, Wei

    2011-08-01

    To evaluate the role of nimotuzumab in combination with chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). The clinical data of 37 NSCLC patients who received nimotuzumab in combination with chemotherapy in Tianjin Medical University Cancer Hospital from January 2009 to October 2010 were retrospectively reviewed. Of the thirty-seven patients, 12 patients were in stage III B, 25 patients in stage IV. Twenty-four patients recived platinum-based chemotherapy in combination with nimotuzumab, 13 patients recived nonplatinum-based chemotherapy in combination with nimotuzumab. Ten patients received nimotuzumab in combination with chemotherapy as first-line regimen, 23 patients as second-line regimen, 4 patients as third-line regimen. Of the 37 advanced NSCLC patients who received nimotuzumab in combination with chemotherapy, the total number of chemotherapy were 137 cycles, the mean number was 3.7 cycles. One patient had complete remission (CR), 9 patients had partial remission (PR), 16 cases had stable disease (SD), and 11 patients had progressive disease (PD). The response rate (RR) was 27% and clinical benefit rate (CBR) was 70.3%. The main side effects were bone marrow suppression and gastrointestinal reactions. Grade I acneiform rash was found in one patient. The regimen of nimotuzumab in combination with chemotherapy can improve the response rate and was well tolerated in patients with advanced non-small cell lung cancer.

  19. A computational study on convolutional feature combination strategies for grade classification in colon cancer using fluorescence microscopy data

    NASA Astrophysics Data System (ADS)

    Chowdhury, Aritra; Sevinsky, Christopher J.; Santamaria-Pang, Alberto; Yener, Bülent

    2017-03-01

    The cancer diagnostic workflow is typically performed by highly specialized and trained pathologists, for which analysis is expensive both in terms of time and money. This work focuses on grade classification in colon cancer. The analysis is performed over 3 protein markers; namely E-cadherin, beta actin and colagenIV. In addition, we also use a virtual Hematoxylin and Eosin (HE) stain. This study involves a comparison of various ways in which we can manipulate the information over the 4 different images of the tissue samples and come up with a coherent and unified response based on the data at our disposal. Pre- trained convolutional neural networks (CNNs) is the method of choice for feature extraction. The AlexNet architecture trained on the ImageNet database is used for this purpose. We extract a 4096 dimensional feature vector corresponding to the 6th layer in the network. Linear SVM is used to classify the data. The information from the 4 different images pertaining to a particular tissue sample; are combined using the following techniques: soft voting, hard voting, multiplication, addition, linear combination, concatenation and multi-channel feature extraction. We observe that we obtain better results in general than when we use a linear combination of the feature representations. We use 5-fold cross validation to perform the experiments. The best results are obtained when the various features are linearly combined together resulting in a mean accuracy of 91.27%.

  20. PDT combined with Intravesical BCG instillation would form an autovaccine for bladder cancer?

    PubMed

    Pan, HuiXuan; Ma, Xiaopeng; Chen, JunZhang; Jiang, Hong

    2009-10-01

    Bladder cancer is the second most common urologic malignancy after prostate cancer. Intravesical BCG as a treatment of superficial bladder cancer (SBC) has been used by urologists for over 30 years. Recently, photodynamic therapy (PDT), which uses a red laser and a photosensitive drug to destroy cancer cells, has been showed encouraging results in SBC treatment. However, BCG and PDT are applied to treatment of SBC alone. Currently, cancer vaccines are made in vitro. Several studies confirmed that tumour cells treated in vitro by PDT can be used for generating potent cancer vaccines, which were more effective than other modes of creating whole tumor vaccines, i.e., UV or ionizing irradiation [Gollnick SO, Vaughan L, Henderson BW. Generation of effective antitumor vaccines using photodynamic therapy. Cancer Res 2002;62:1604-8]. Moreover, BCG is a pleiotropic immune stimulator oriented to cellular immunity. We thought that: after PDT destroyed targeted tumor cells on a large scale, Intravesical BCG could elicit and amplify the immune responses, which would directly form an in situ autovaccine in vivo against the primary tumor and metastases at distant sites. In this paper, we propose that the combination of Intravesical BCG and PDT would be a promising new modality for bladder cancer.

  1. Caspase-8 activation by TRAIL monotherapy predicts responses to IAPi and TRAIL combination treatment in breast cancer cell lines

    PubMed Central

    Polanski, R; Vincent, J; Polanska, U M; Petreus, T; Tang, E K Y

    2015-01-01

    The discovery of cancer cell-selective tumour necrosis factor-related apoptosis inducing ligand (TRAIL)-induced apoptosis generated broad excitement and development of TRAIL receptor agonists (TRA) as potential cancer therapy. Studies demonstrating the synergistic combination effect of SMAC mimetics and TRA further suggested potentially effective treatment in multiple tumour settings. However, predictive biomarkers allowing identification of patients that could respond to treatment are lacking. Here, we described a high throughput combination screen conducted across a panel of 31 breast cancer cell lines in which we observed highly synergistic activity between TRAIL and the inhibitors of apoptosis proteins (IAP) inhibitor (IAPi) AZD5582 in ~30% of cell lines. We detected no difference in the expression levels of the IAPi or TRAIL-targeted proteins or common modulators of the apoptotic pathway between the sensitive and resistant cell lines. Synergistic combination effect of AZD5582 and TRAIL correlated with sensitivity to TRAIL, but not to AZD5582 as a single agent. TRAIL treatment led to significantly greater activity of Caspase-8 in sensitive than in resistant cell lines (P=0.002). The majority (12/14) of AZD5582+TRAIL-resistant cell lines retained a functional cell death pathway, as they were sensitive to AZD5582+TNFα combination treatment. This suggested that failure of the TRAIL receptor complex to transduce the death signal to Caspase-8 underlies AZD5582+TRAIL resistance. We developed a 3D spheroid assay and demonstrated its suitability for the ex vivo analysis of the Caspase-8 activity as a predictive biomarker. Altogether, our study demonstrated a link between the functionality of the TRAIL receptor pathway and the synergistic activity of the IAPi+TRA combination treatment. It also provided a rationale for development of the Caspase-8 activity assay as a functional predictive biomarker that could allow better prediction of the response to IAPi

  2. Synergistic Effect of Trabectedin and Olaparib Combination Regimen in Breast Cancer Cell Lines

    PubMed Central

    Ávila-Arroyo, Sonia; Nuñez, Gema Santamaría; García-Fernández, Luis Francisco

    2015-01-01

    Purpose Trabectedin induces synthetic lethality in tumor cells carrying defects in homologous recombinant DNA repair. We evaluated the effect of concomitant inhibition of nucleotide-excision repair and poly (ADP-ribose) polymerase (PARP) activity with trabectedin and PARP inhibitors, respectively, and whether the synthetic lethality effect had the potential for a synergistic effect in breast cancer cell lines. Additionally, we investigated if this approach remained effective in BRCA1-positive breast tumor cells. Methods We have evaluated the in vitro synergistic effect of combinations of trabectedin and three different PARP inhibitors (veliparib, olaparib, and iniparib) in four breast cancer cell lines, each presenting a different BRCA1 genetic background. Antiproliferative activity, DNA damage, cell cycle perturbations and poly(ADP-ribosyl)ation were assessed by MTT assay, comet assay, flow cytometry and western blot, respectively. Results The combination of trabectedin and olaparib was synergistic in all the breast cancer cell lines tested. Our data indicated that the synergy persisted regardless of the BRCA1 status of the tumor cells. Combination treatment was associated with a strong accumulation of double-stranded DNA breaks, G2/M arrest, and apoptotic cell death. Synergistic effects were not observed when trabectedin was combined with veliparib or iniparib. Conclusion Collectively, our results indicate that the combination of trabectedin and olaparib induces an artificial synthetic lethality effect that can be used to kill breast cancer cells, independent of BRCA1 status. PMID:26770239

  3. New potential chemotherapy for ovarian cancer - Combined therapy with WP 631 and epothilone B.

    PubMed

    Bukowska, Barbara; Rogalska, Aneta; Marczak, Agnieszka

    2016-04-15

    Despite more modern therapeutics approaches and the use of new drugs for chemotherapy, patients with ovarian cancer still have poor prognosis and therefore, new strategies for its cure are highly needed. One of the promising ways is combined therapy, which has many advantages as minimizing drug resistance, enhancing efficacy of treatment, and reducing toxicity. Combined therapy has rich and successful history in the field of ovarian cancer treatment. Currently use therapy is usually based on platinum-containing agent (carboplatin or cisplatin) and a member of taxanes (paclitaxel or docetaxel). In the mid-2000s this standard regimen has been expanded with bevacizumab, monoclonal antibody directed to Vascular Endothelial Growth Factor (VEGF). Another drug combination with promising perspectives is WP 631 given together with epothilone B (Epo B). WP 631 is a bisanthracycline composed of two molecules of daunorubicin linked with a p-xylenyl linker. Epo B is a 16-membered macrolide manifesting similar mechanism of action to taxanes. Their effectiveness against ovarian cancer as single agents is well established. However, the combination of WP 631 and Epo B appeared to act synergistically, meaning that it is much more potent than the single drugs. The mechanism lying under its efficacy includes disturbing essential cell cycle-regulating proteins leading to mitotic slippage and following apoptosis, as well as affecting EpCAM and HMGB1 expression. In this article, we summarized the current state of knowledge regarding combined therapy based on WP 631 and Epo B as a potential way of ovarian cancer treatment.

  4. Combinational Treatment of Curcumin and Quercetin against Gastric Cancer MGC-803 Cells in Vitro.

    PubMed

    Zhang, Jian-Ye; Lin, Min-Ting; Zhou, Meng-Jia; Yi, Tao; Tang, Yi-Na; Tang, Si-Li; Yang, Zhi-Jun; Zhao, Zhong-Zhen; Chen, Hu-Biao

    2015-06-22

    Gastric cancer remains a major health problem worldwide. Natural products, with stronger antitumor activity and fewer side effects, are potential candidates for pharmaceutical development as anticancer agents. In this study, quercetin and curcumin were chosen for testing and were applied separately and in combination to human gastric cancer MGC-803 cells. The MTT assay was used to evaluate cell growth inhibition. Annexin V-FITC/PI was carried out to measure apoptosis rate. Flow cytometry was performed to analyze mitochondrial membrane potential levels. Western blots were applied to detect expression of cytochrome c, total and phosphorylated ERK and AKT. Combined treatment with curcumin and quercetin resulted in significant inhibition of cell proliferation, accompanied by loss of mitochondrial membrane potential (ΔΨm), release of cytochrome c and decreased phosphorylation of AKT and ERK. These results indicate that the combination of curcumin and quercetin induces apoptosis through the mitochondrial pathway. Notably, effect of combined treatment with curcumin and quercetin on gastric cancer MGC-803 cells is stronger than that of individual treatment, indicating that curcumin and quercetin combinations have potential as anti-gastric cancer drugs for further development.

  5. Synergistic Effect of Trabectedin and Olaparib Combination Regimen in Breast Cancer Cell Lines.

    PubMed

    Ávila-Arroyo, Sonia; Nuñez, Gema Santamaría; García-Fernández, Luis Francisco; Galmarini, Carlos M

    2015-12-01

    Trabectedin induces synthetic lethality in tumor cells carrying defects in homologous recombinant DNA repair. We evaluated the effect of concomitant inhibition of nucleotide-excision repair and poly (ADP-ribose) polymerase (PARP) activity with trabectedin and PARP inhibitors, respectively, and whether the synthetic lethality effect had the potential for a synergistic effect in breast cancer cell lines. Additionally, we investigated if this approach remained effective in BRCA1-positive breast tumor cells. We have evaluated the in vitro synergistic effect of combinations of trabectedin and three different PARP inhibitors (veliparib, olaparib, and iniparib) in four breast cancer cell lines, each presenting a different BRCA1 genetic background. Antiproliferative activity, DNA damage, cell cycle perturbations and poly(ADP-ribosyl)ation were assessed by MTT assay, comet assay, flow cytometry and western blot, respectively. The combination of trabectedin and olaparib was synergistic in all the breast cancer cell lines tested. Our data indicated that the synergy persisted regardless of the BRCA1 status of the tumor cells. Combination treatment was associated with a strong accumulation of double-stranded DNA breaks, G2/M arrest, and apoptotic cell death. Synergistic effects were not observed when trabectedin was combined with veliparib or iniparib. Collectively, our results indicate that the combination of trabectedin and olaparib induces an artificial synthetic lethality effect that can be used to kill breast cancer cells, independent of BRCA1 status.

  6. Iodine and doxorubicin, a good combination for mammary cancer treatment: antineoplastic adjuvancy, chemoresistance inhibition, and cardioprotection

    PubMed Central

    2013-01-01

    Background Although mammary cancer (MC) is the most common malignant neoplasia in women, the mortality for this cancer has decreased principally because of early detection and the use of neoadjuvant chemotherapy. Of several preparations that cause MC regression, doxorubicin (DOX) is the most active, first-line monotherapeutic. Nevertheless, its use is limited due to the rapid development of chemoresistance and to the cardiotoxicity caused by free radicals. In previous studies we have shown that supplementation with molecular iodine (I2) has a powerful antineoplastic effect in methylnitrosourea (MNU)-induced experimental models of MC. These studies also showed a consistent antioxidant effect of I2 in normal and tumoral tissues. Methods Here, we analyzed the effect of I2 in combination with DOX treatment in female Sprague Dawley rats with MNU-induced MC. In the first experiment (short) animals were treated with the therapeutic DOX dose (16 mg/kg) or with lower doses (8 and 4 mg/Kg), in each case with and without 0.05% I2 in drinking water. Iodine treatment began on day 0, a single dose of DOX was injected (ip) on day 2, and the analysis was carried out on day 7. In the second experiment (long) animals with and without iodine supplement were treated with one or two injections of 4 mg/kg DOX (on days 0 and 14) and were analyzed on day 56. Results At all DOX doses, the short I2 treatment induced adjuvant antineoplastic effects (decreased tumor size and proliferating cell nuclear antigen level) with significant protection against body weight loss and cardiotoxicity (creatine kinase MB, cardiac lipoperoxidation, and heart damage). With long-term I2, mammary tumor tissue became more sensitive to DOX, since a single injection of the lowest dose of DOX (4 mg/Kg) was enough to stop tumor progression and a second DOX4 injection on day 14 caused a significant and rapid decrease in tumor size, decreased the expression of chemoresistance markers (Bcl2 and survivin), and increased

  7. A genetic strategy for combined screening and localized imaging of breast cancer

    PubMed Central

    Warram, Jason M.; Borovjagin, Anton V.; Zinn, Kurt R.

    2015-01-01

    PURPOSE Improvements are needed for the early detection of breast cancer, as current imaging methods lack sensitivity to detect small tumors and assess their disease phenotype. PROCEDURES To address this issue the dual reporter adenoviral vector (Ad5/3-Id1-SEAP-Id1-mCherry) was produced with a cancer specific Id1 promoter driving expression of a blood-based screening reporter (secreted embryonic alkaline phosphatase, SEAP) and a fluorescent imaging reporter (mCherry). This diagnostic system was assessed for its screening potential on breast cancer cell lines of various aggressive phenotypes. Reporter expression was measured and correlated with promoter level expression using western blot. Adenovirus receptor expression was normalized against reporter expression with luciferase infectivity assays. Ad5/3-Id1-SEAP-Id1-mCherry infected MDA-MB-231 cells combined with uninfected cells were implanted into the mammary fat pad of athymic nude mice to recapitulate low dose tumor delivery. Id1 driven SEAP expression and mCherry imaging were monitored to validate diagnostic sensitivity and efficacy. RESULTS Infected breast cancer cell lines displayed SEAP levels in the media that were 10-fold above background by 2 days after infection. Ad5/3-Id1-SEAP-Id1-mCherry infected cells (MOI=10) implanted in athymic nude mice demonstrated a 14-fold increase in serum SEAP levels over baseline when as little as 2.5% of the tumor contained infected cells. This robust response was also found for the mCherry reporter which was clearly visible in tumor xenografts on day 2 post implantation. CONCLUSIONS This diagnostic system that combines screening with imaging for early detection and monitoring of breast cancer can be easily extended to other reporters/modalities and cancer-targeting methods. Combining screening with imaging in a genetic, cancer-specific mechanism allows sensitive multi-modal detection and localization of breast cancer. PMID:20658194

  8. A genetic strategy for combined screening and localized imaging of breast cancer.

    PubMed

    Warram, Jason M; Borovjagin, Anton V; Zinn, Kurt R

    2011-06-01

    Improvements are needed for the early detection of breast cancer, as current imaging methods lack sensitivity to detect small tumors and assess their disease phenotype. To address this issue, the dual reporter adenoviral vector (Ad5/3-Id1-SEAP-Id1-mCherry) was produced with a cancer-specific Id1 promoter driving expression of a blood-based screening reporter (secreted embryonic alkaline phosphatase, SEAP) and a fluorescent imaging reporter (mCherry). This diagnostic system was assessed for its screening potential on breast cancer cell lines of various aggressive phenotypes. Reporter expression was measured and correlated with promoter level expression using Western blot. Adenovirus receptor expression was normalized against reporter expression with luciferase infectivity assays. Ad5/3-Id1-SEAP-Id1-mCherry infected MDA-MB-231 cells combined with uninfected cells were implanted into the mammary fat pad of athymic nude mice to recapitulate low-dose tumor delivery. Id1 driven SEAP expression and mCherry imaging were monitored to validate diagnostic sensitivity and efficacy. Infected breast cancer cell lines displayed SEAP levels in the media that were 10-fold above background by 2 days after infection. Ad5/3-Id1-SEAP-Id1-mCherry infected cells (multiplicity of infection = 10) implanted in athymic nude mice demonstrated a 14-fold increase in serum SEAP levels over baseline when as little as 2.5% of the tumor contained infected cells. This robust response was also found for the mCherry reporter, which was clearly visible in tumor xenografts on day 2 post implantation. This diagnostic system that combines screening with imaging for early detection and monitoring of breast cancer can be easily extended to other reporters/modalities and cancer-targeting methods. Combining screening with imaging in a genetic, cancer-specific mechanism allows sensitive multi-modal detection and localization of breast cancer.

  9. Treatment effects of oxaliplatin combined with gemcitabine on colorectal cancer and its influence on HMGB1 expression

    PubMed Central

    Wen, Shuangshuang; Du, Xiaopeng; Gou, Yanyan; Jiang, Lin

    2016-01-01

    In the present study, we analyzed the supra-additive effect of oxaliplatin in combination with gemcitabine on terminal colorectal cancer and its influence on high-mobility group box 1 (HMGB1) expression. A total of 86 patients with terminal colorectal cancer were enrolled in this study. Patients received oxaliplatin in combination with gemcitabine. Immunohistochemistry was used to determined the subcellular localization of HMGB1 in cancer tissues as well as in para-carcinoma tissues, and RT-PCR and western blot analysis were used to assess the mRNA and protein expression level, respectively. The total effective rate was analyzed based on WHO tumor chemotherapy reference where complete remission (CR) implies the complete disappearance of the tumor; partial remission (PR) implies that the tumor size was reduced at least by 50%; stable disease (SD) implies that the tumor size remained unchanged and progressive disease (PD) implies an increase in the size of the tumor by ≥25%. We identified 20 cases of CR, 37 cases of PR, 12 cases of SD and 17 cases of PD. The total effective rate (CR+PR) was 66.3%. HMGB1 expression rate in the cancer tissues in the effective group was significantly lower than that in the ineffective group. Positive expression of HMGB1 protein was mainly localized in the karyon. Survival time in the patients with positive HMGB1 expression was significantly shorter than that in the patients with negative HMGB1 expression. In the effective group, HMGB1 mRNA and protein expression levels were obviously lower than those in the ineffective group. We conclude that the reduced expression rate of HMGB1 in terminal colorectal cancer cases was probably related to the effects of oxaliplatin combined with gemcitabine. PMID:27899980

  10. Combination of Anti-IGF-1R Antibody A12 and Ionizing Radiation in Upper Respiratory Tract Cancers

    SciTech Connect

    Riesterer, Oliver; Yang Qiuan; Raju, Uma; Torres, Mylin; Molkentine, David; Patel, Nalini; Valdecanas, David; Milas, Luka; Ang, K. Kian

    2011-03-15

    Purpose: The IGF1/IGF-1R signaling pathway has emerged as a potential determinant of radiation resistance in human cancer cell lines. Therefore we investigated the potency of monoclonal anti-IGF-1R antibody, A12, to enhance radiation response in upper respiratory tract cancers. Methods and Materials: Cell lines were assessed for IGF-1R expression and IGF1-dependent response to A12 or radiation using viability and clonogenic cancer cell survival assays. In vivo response of tumor xenografts to 10 or 20 Gy and A12 (0.25-2 mg x 3) was assessed using growth delay assays. Combined treatment effects were also analyzed by immunohistochemical assays for tumor cell proliferation, apoptosis, necrosis, and vascular endothelial growth factor expression at Days 1 and 6 after start of treatment. Results: A12 enhanced the radiosensitivity of HN5 and FaDu head-and-neck carcinomas in vitro (p < 0.05) and amplified the radioresponse of FaDu xenografts in a dose-dependent manner, with enhancement factors ranging from 1.2 to 1.8 (p < 0.01). Immunohistochemical analysis of FaDu xenografts demonstrated that A12 inhibited tumor cell proliferation (p < 0.05) and vascular endothelial growth factor expression. When A12 was combined with radiation, this resulted in apoptosis induction that persisted until 6 days from the start of treatment and in increased necrosis at Day 1 (p < 0.01, respectively). Combined treatment with A12 and radiation resulted in additive or subadditive growth delay in H460 or A549 xenografts, respectively. Conclusions: The results of this study strengthen the evidence for investigating how anti-IGF-1R strategies can be integrated into radiation and radiation-cetuximab regimen in the treatment of cancer of the upper aerodigestive tract cancers.

  11. Combination of cisplatin and bromelain exerts synergistic cytotoxic effects against breast cancer cell line MDA-MB-231 in vitro.

    PubMed

    Pauzi, Ahmad Zaim Mat; Yeap, Swee Keong; Abu, Nadiah; Lim, Kian Lam; Omar, Abdul Rahman; Aziz, Suraini Abdul; Chow, Adam Leow Thean; Subramani, Tamilselvan; Tan, Soon Guan; Alitheen, Noorjahan Banu

    2016-01-01

    Bromelain, which is a cysteine endopeptidase commonly found in pineapple stems, has been investigated as a potential anti-cancer agent for the treatment of breast cancer. However, information pertaining to the effects of combining bromelain with existing chemotherapeutic drugs remains scarce. This study aimed to investigate the possible synergistic cytotoxic effects of using bromelain in combination with cisplatin on MDA-MB-231 human breast cancer cells. MDA-MB-231 cells were treated with different concentrations (0.24-9.5 µM) of bromelain or cisplatin alone, as well as four different combinations of these two agents to assess their individual and combination effects after 24 and 48 h. Cell viability was analyzed using an MTT assay. The induction of apoptosis was assessed using cell cycle analysis and an Annexin V-FITC assay. The role of the mitochondrial membrane potential in the apoptotic process was assessed using a JC-1 staining assay. Apoptotic protein levels were assessed by western blot analysis and proteome profiling using an antibody array kit. Single-agent treatment with cisplatin or bromelain led to dose- and time-dependent decreases in the viability of the MDA-MB-231 cells at 24 and 48 h. Furthermore, most of the combinations evaluated in this study displayed synergistic effects against MDA-MB-231 cells at 48 h, with combination 1 (bromelain 2 µM + cisplatin 1.5 µM) exhibiting the greatest synergistic effect (P = 0.000). The results of subsequent assays indicated that combination 1 treatment induced apoptosis via mitochondria-mediated pathway. Combination 1 also resulted in significant decreases in the levels of several apoptotic proteins such as Bcl-x and HSP70, compared with bromelain (P = 0.002 and 0.000, respectively) or cisplatin (P = 0.000 and 0.001, respectively) single treatment. Notably, MDA-MB-231 cells treated with combination 1 showed increased levels of the pro-apoptotic proteins Bax compared with those treated with

  12. Tobacco and alcohol in relation to male breast cancer: an analysis of the male breast cancer pooling project consortium.

    PubMed

    Cook, Michael B; Guénel, Pascal; Gapstur, Susan M; van den Brandt, Piet A; Michels, Karin B; Casagrande, John T; Cooke, Rosie; Van Den Eeden, Stephen K; Ewertz, Marianne; Falk, Roni T; Gaudet, Mia M; Gkiokas, George; Habel, Laurel A; Hsing, Ann W; Johnson, Kenneth; Kolonel, Laurence N; La Vecchia, Carlo; Lynge, Elsebeth; Lubin, Jay H; McCormack, Valerie A; Negri, Eva; Olsson, Håkan; Parisi, Dominick; Petridou, Eleni Th; Riboli, Elio; Sesso, Howard D; Swerdlow, Anthony; Thomas, David B; Willett, Walter C; Brinton, Louise A

    2015-03-01

    The etiology of male breast cancer is poorly understood, partly due to its relative rarity. Although tobacco and alcohol exposures are known carcinogens, their association with male breast cancer risk remains ill-defined. The Male Breast Cancer Pooling Project consortium provided 2,378 cases and 51,959 controls for analysis from 10 case-control and 10 cohort studies. Individual participant data were harmonized and pooled. Unconditional logistic regression was used to estimate study design-specific (case-control/cohort) ORs and 95% confidence intervals (CI), which were then combined using fixed-effects meta-analysis. Cigarette smoking status, smoking pack-years, duration, intensity, and age at initiation were not associated with male breast cancer risk. Relations with cigar and pipe smoking, tobacco chewing, and snuff use were also null. Recent alcohol consumption and average grams of alcohol consumed per day were also not associated with risk; only one subanalysis of very high recent alcohol consumption (>60 g/day) was tentatively associated with male breast cancer (ORunexposed referent = 1.29; 95% CI, 0.97-1.71; OR>0-<7 g/day referent = 1.36; 95% CI, 1.04-1.77). Specific alcoholic beverage types were not associated with male breast cancer. Relations were not altered when stratified by age or body mass index. In this analysis of the Male Breast Cancer Pooling Project, we found little evidence that tobacco and alcohol exposures were associated with risk of male breast cancer. Tobacco and alcohol do not appear to be carcinogenic for male breast cancer. Future studies should aim to assess these exposures in relation to subtypes of male breast cancer. ©2014 American Association for Cancer Research.

  13. Combination Therapy Improves Survival in Prostate Cancer Model | Center for Cancer Research

    Cancer.gov

    Surgery and radiotherapy are the recommended treatments for localized prostate cancer. Recurrent prostate cancer, however, is often treated with androgen-deprivation therapy. Most patients who undergo this type of therapy eventually develop castration-resistant prostate cancer (CRPC). Though initially androgen-related therapies for CRPC had been thought to be ineffective, further studies have demonstrated that the disease remains dependent on the signaling of androgens, such as testosterone, for its continued progression. This development suggests that alternative strategies for manipulating androgen signaling may prove useful for treating CRPC.

  14. Meta-Analysis of Tumor Stem-Like Breast Cancer Cells Using Gene Set and Network Analysis.

    PubMed

    Lee, Won Jun; Kim, Sang Cheol; Yoon, Jung-Ho; Yoon, Sang Jun; Lim, Johan; Kim, You-Sun; Kwon, Sung Won; Park, Jeong Hill

    2016-01-01

    Generally, cancer stem cells have epithelial-to-mesenchymal-transition characteristics and other aggressive properties that cause metastasis. However, there have been no confident markers for the identification of cancer stem cells and comparative methods examining adherent and sphere cells are widely used to investigate mechanism underlying cancer stem cells, because sphere cells have been known to maintain cancer stem cell characteristics. In this study, we conducted a meta-analysis that combined gene expression profiles from several studies that utilized tumorsphere technology to investigate tumor stem-like breast cancer cells. We used our own gene expression profiles along with the three different gene expression profiles from the Gene Expression Omnibus, which we combined using the ComBat method, and obtained significant gene sets using the gene set analysis of our datasets and the combined dataset. This experiment focused on four gene sets such as cytokine-cytokine receptor interaction that demonstrated significance in both datasets. Our observations demonstrated that among the genes of four significant gene sets, six genes were consistently up-regulated and satisfied the p-value of < 0.05, and our network analysis showed high connectivity in five genes. From these results, we established CXCR4, CXCL1 and HMGCS1, the intersecting genes of the datasets with high connectivity and p-value of < 0.05, as significant genes in the identification of cancer stem cells. Additional experiment using quantitative reverse transcription-polymerase chain reaction showed significant up-regulation in MCF-7 derived sphere cells and confirmed the importance of these three genes. Taken together, using meta-analysis that combines gene set and network analysis, we suggested CXCR4, CXCL1 and HMGCS1 as candidates involved in tumor stem-like breast cancer cells. Distinct from other meta-analysis, by using gene set analysis, we selected possible markers which can explain the biological

  15. [Application of serum proteomic mass spectrum analysis in breast cancer].

    PubMed

    Ying, Min-gang; Chen, Qiang; Ye, Yun-bin; Chen, Hui-jing; Chen, Xia; Zheng, Hong-yu; Wu, Fan

    2010-09-01

    To analyze the characteristics of serum proteins mass spectra in healthy controls, benign breast tumors, and CA15-3 negative or CA15-3 positive breast cancer patients by surface enhanced laser desorption ionization time of flight mass spectrometry (SELDI-TOF-MS). Tissue samples of 113 cases of breast cancer (93 case of CA15-3 negative, 20 case of CA15-3 positive), 103 cases of benign breast tumor and 92 cases of healthy controls were examined and analyzed by SELDI and protein chip (CM10) techniques. Biomarker Pattern Software (BPS) was used to detect the protein peaks significantly different between them and establish a diagnostic pattern which was further evaluated by a blind test. Twelve significantly different protein peaks were found in serum samples between breast cancer patients and healthy controls. Eleven significantly different peaks were found between benign breast tumor patients and healthy controls. By combined analysis of those three different protein mass spectra, the peak 15 952 was found to be significantly different between breast cancer group and healthy controls, and the peak 7985 was significantly different among breast cancer group, benign breast tumor group and health controls. The blind test with the differential proteins for the serum samples of 93 cases of CA15-3 negative breast cancer and 36 cases of benign breast tumors showed that the sensitivity was 80.6% and specificity was 91.7%. The blind test in 20 cases of CA15-3 positive breast cancer and 36 cases of benign breast tumors showed that the sensitivity was 75.0% and specificity was 91.7%. Four significantly different protein peaks were found between the benign breast tumor patients and CA15-3 negative breast cancer patients. No significantly different protein were found between CA15-3 negative and CA15-3 positive patients. Significantly different protein peaks can be screened out in breast cancer, benign breast tumor patients and healthy controls by SELDI-TOF-MS analysis.

  16. Honokiol in combination with radiation targets notch signaling to inhibit colon cancer stem cells.

    PubMed

    Ponnurangam, Sivapriya; Mammen, Joshua M V; Ramalingam, Satish; He, Zhiyun; Zhang, Youcheng; Umar, Shahid; Subramaniam, Dharmalingam; Anant, Shrikant

    2012-04-01

    Cancer stem cells are implicated in resistance to ionizing radiation (IR) and chemotherapy. Honokiol, a biphenolic compound has been used in traditional Chinese medicine for treating various ailments. In this study, we determined the ability of honokiol to enhance the sensitivity of colon cancer stem cells to IR. The combination of honokiol and IR suppressed proliferation and colony formation while inducing apoptosis of colon cancer cells in culture. There were also reduced numbers and size of spheroids, which was coupled with reduced expression of cancer stem cell marker protein DCLK1. Flow cytometry studies confirmed that the honokiol-IR combination reduced the number of DCLK1+ cells. In addition, there were reduced levels of activated Notch-1, its ligand Jagged-1, and the downstream target gene Hes-1. Furthermore, expression of components of the Notch-1 activating γ-secretase complex, presenilin 1, nicastrin, Pen2, and APH-1 was also suppressed. On the other hand, the honokiol effects were mitigated when the Notch intracellular domain was expressed. To determine the effect of honokiol-IR combination on tumor growth in vivo, nude mice tumor xenografts were administered honokiol intraperitoneally and exposed to IR. The honokiol-IR combination significantly inhibited tumor xenograft growth. In addition, there were reduced levels of DCLK1 and the Notch signaling-related proteins in the xenograft tissues. Together, these data suggest that honokiol is a potent inhibitor of colon cancer growth that targets the stem cells by inhibiting the γ-secretase complex and the Notch signaling pathway. These studies warrant further clinical evaluation for the combination of honokiol and IR for treating colon cancers.

  17. Optimal combinations of systematic sextant and laterally directed biopsies for the detection of prostate cancer.

    PubMed

    Gore, J L; Shariat, S F; Miles, B J; Kadmon, D; Jiang, N; Wheeler, T M; Slawin, K M

    2001-05-01

    The standard sextant protocol for obtaining transrectal ultrasound guided biopsy of the prostate has been shown to underestimate the presence of prostate cancer. Studies have demonstrated an increased cancer detection rate with additional laterally directed biopsies. We compared the sensitivity of individual biopsy cores and evaluated combinations of these cores to identify an optimal biopsy strategy. A total of 396 consecutive patients underwent biopsy of the lateral peripheral zone in addition to standard sextant biopsy. The cancer detection rate for each biopsy core was calculated. The sensitivity of different combinations of biopsy cores was compared with those of standard sextant biopsies and with a 12 core biopsy protocol that combined the standard sextant biopsy with a complete set of laterally directed cores. Cancer was detected in 160 of 396 (40.3%) patients. Of the possible combinations of biopsy cores a strategy that included laterally directed cores at the base, mid gland and apex of the prostate with mid lobar base and apical cores detected 98.5% of cancers. The detection rate of this 10 core biopsy regimen was significantly better than that of the standard sextant protocol (p < or =0.001), and was equivalent to that of the 12 core regional biopsy (p > or =0.302). The standard sextant protocol failed to detect a large proportion of cancers located laterally in the peripheral zone. A 10 core biopsy regimen that combined laterally directed cores at the base, mid gland and apex of the prostate with mid lobar biopsy cores at the base and apex maximizes the sensitivity of transrectal ultrasound guided systematic biopsy.

  18. Combined Lifestyle Factors and Risk of Incident Colorectal Cancer in a Chinese Population

    PubMed Central

    Odegaard, Andrew O.; Koh, Woon-Puay; Yuan, Jian-Min

    2013-01-01

    A body of research links dietary intake, alcohol consumption, smoking, physical activity, body mass index (BMI), and possibly sleep patterns with colorectal cancer risk. However, little research has examined the association of the combination of these lifestyle factors with incidence of colorectal cancer, especially in non-western populations. A protective lifestyle factor index of these 6 aforementioned factors was created and examined in relation to risk of developing colorectal cancer. This study is a prospective observational study of 50,466 Chinese men and women in Singapore aged 45–74 during enrollment in the Singapore Chinese Health Study in 1993–1998 and followed up through 2007. The main outcome measures were standardized rates and hazard ratios of incident colorectal cancer. The protective levels of each lifestyle factor were independently associated with reduced age- and sex-standardized incidence rates of colon cancer. When all the factors were combined into a single protective lifestyle factor index, there was a strong, monotonic decrease in incidence rate of colon cancer with an increasing score. Relative to participants with an index score of 0–3, the hazard ratios (95% confidence intervals) of colon cancer for an index score of 4, 5, 6, 7, 8, 9/10 were 0.58 (0.35–0.95), 0.56 (0.36–0.86), 0.50 (0.33–0.76), 0.43 (0.28–0.66), 0.39 (0.25–0.63), and 0.25 (0.12–0.54) (P for trend <0.0001). The results were consistent by sex. Conversely, there was no association with rectal cancer risk. An increasing protective lifestyle factor index score is associated with a marked decreased risk of developing colon cancer in Chinese men and women. PMID:23275007

  19. Combining lymphovascular invasion with reactive stromal grade predicts prostate cancer mortality.

    PubMed

    Saeter, Thorstein; Vlatkovic, Ljiljana; Waaler, Gudmund; Servoll, Einar; Nesland, Jahn M; Axcrona, Karol; Axcrona, Ulrika

    2016-09-01

    Previous studies suggest that lymphovascular invasion (LVI) has a weak and variable effect on prognosis. It is uncertain whether LVI, determined by diagnostic prostate biopsy, predicts prostate cancer death. Data from experimental studies have indicated that carcinoma-associated fibroblasts in the reactive stroma could promote LVI and progression to metastasis. Thus, combining LVI with reactive stromal grade may identify prostate cancer patients at high risk of an unfavorable outcome. The purpose of the present study was to examine if LVI, determined by diagnostic biopsy, alone and in combination with reactive stromal grade could predict prostate cancer death. This population-based study included 283 patients with prostate cancer diagnosed by needle biopsy in Aust-Agder County (Norway) from 1991 to 1999. Clinical data were obtained by medical charts review. Two uropathologists evaluated LVI and reactive stromal grade. The endpoint was prostate cancer death. Patients with LVI had marginally higher risk of prostate cancer death compared to patients without LVI (hazard ratio: 1.8, P-value = 0.04). LVI had a stronger effect on prostate cancer death risk when a high reactive stromal grade was present (hazard ratio: 16.0, P-value <0.001). Therefore, patients with concomitant LVI and high reactive stromal grade were at particularly high risk for prostate cancer death. Evaluating LVI together with reactive stromal grade on diagnostic biopsies could be used to identify patients at high risk of death from prostate cancer. Prostate 76:1088-1094, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  20. Bevacizumab in combination with chemotherapy for the treatment of advanced ovarian cancer: a systematic review

    PubMed Central

    2014-01-01

    As increased angiogenesis has been linked with the progression of ovarian cancer, a number of anti-angiogenic agents have been investigated, or are currently in development, as potential treatment options for patients with advanced disease. Bevacizumab, a recombinant monoclonal antibody against vascular endothelial growth factor, has gained European Medicines Agency approval for the front-line treatment of advanced epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer in combination with carboplatin and paclitaxel, and for the treatment of first recurrence of platinum-sensitive ovarian cancer in combination with carboplatin and gemcitabine. We conducted a systematic literature review to identify available efficacy and safety data for bevacizumab in ovarian cancer as well as for newer anti-angiogenic agents in development. We analyzed published data from randomized, controlled phase II/III clinical trials enrolling women with ovarian cancer to receive treatment with bevacizumab. We also reviewed available data for emerging anti-angiogenic agents currently in phase II/III development, including trebananib, aflibercept, nintedanib, cediranib, imatinib, pazopanib, sorafenib and sunitinib. Significant efficacy gains were achieved with the addition of bevacizumab to standard chemotherapy in four randomized, double-blind, phase III trials, both as front-line treatment (GOG-0218 and ICON7) and in patients with recurrent disease (OCEANS and AURELIA). The type and frequency of bevacizumab-related adverse events was as expected in these studies based on published data. Promising efficacy data have been published for a number of emerging anti-angiogenic agents in phase III development for advanced ovarian cancer. Further research is needed to identify predictive or prognostic markers of response to bevacizumab in order to optimize patient selection and treatment benefit. Data from phase III trials of newer anti-angiogenic agents in ovarian cancer are

  1. Prospective study of percutaneous cryoablation combined with allogenic NK cell immunotherapy for advanced renal cell cancer.

    PubMed

    Lin, Mao; Xu, Kecheng; Liang, Shuzhen; Wang, Xiaohua; Liang, Yinqing; Zhang, Mingjie; Chen, Jibing; Niu, LiZhi

    2017-03-05

    In this study, the clinical efficacy of cryosurgery combined with allogenic NK cell immunotherapy for advanced renal cell cancer was evaluated. From July to December 2016, we enrolled 60 patients who met the enrollment criteria and divided them into two groups: (1) the simple cryoablation group (n=30); and (2) the cryoablation combined with allogenic NK cells group (n=30). The clinical efficacy, quality of life, immune function, and other related indicators were evaluated. Combining allogeneic NK cells with cryoablation had a synergistic effect, not only enhancing the immune function and improving the quality of life of the patients, but also significantly exhibiting good clinical efficacy of the patients. This study is the first clinical trial that has evaluated the safety and efficacy of allogenic NK cells combined with cryosurgery for the treatment of renal cell cancer.

  2. Californium-252 neutron brachytherapy combined with external pelvic radiotherapy plus concurrent chemotherapy for cervical cancer: a retrospective clinical study.

    PubMed

    Qian, Shen; Ye, Ling; Tian, Yun-Hong; Wang, Li-Gen; Huang, Zuo-Ping; Li, Feng; Hou, Bing; Song, Ni; Chen, Juan; Liu, Ying; Liu, Xiao; Zhou, Tao

    2017-02-28

    Cervical cancer is the sixth most common cancer in Chinese women. A standard treatment modality for cervical cancer is the combination of surgery, chemotherapy, external-beam radiotherapy and intracavitary brachytherapy. The aim of this study was to retrospectively assess the long-term treatment outcomes of patients with cervical cancer who were treated with californium-252 neutron brachytherapy combined with external-beam radiotherapy plus concurrent chemotherapy. We retrospectively analyzed the medical records of 150 patients with primary stages IB-IVB cervical cancer who received neutron brachytherapy combined with external-beam radiotherapy concurrently with cisplatin chemotherapy. All patients were followed up. Using an actuarial analysis, patient outcomes and treatment-related adverse effects were evaluated and compared. The median overall survival (OS) was 33.2 months. The 3-year progression-free survival rates for patients with stages I-II, III, and IV diseases were 81.0% (68/84), 65.0% (39/60), and 0% (0/6), respectively; the 3-year OS rates were 90.5% (76/84), 85.0% (51/60), and 16.7% (1/6), respectively. Vaginal bleeding was controlled within the median time of 4.0 days. One month after treatment, 97.3% of patients achieved short-term local control. The local recurrence rates for patients with stages I-II, III, and IV disease were 4.8% (4/84), 11.7% (7/60), and 33.3% (2/6), respectively, and the occurrence rates of distant metastasis were 16.7% (14/84), 25.0% (15/60), and 100.0% (6/6), respectively. Cancer stage, tumor size, and lymph node metastasis were identified as prognostic risk factors, but only lymph node metastasis was found to be an independent prognostic factor. The most common adverse effects during treatment were grades 1 and 2 irradiation-related proctitis and radiocystitis. For patients with cervical cancer, neutron brachytherapy combined with external-beam radiotherapy plus concurrent chemotherapy produces a rapid response and greatly

  3. Tobacco and Alcohol in Relation to Male Breast Cancer: An Analysis of the Male Breast Cancer Pooling Project Consortium

    PubMed Central

    Cook, Michael B.; Guénel, Pascal; Gapstur, Susan M.; van den Brandt, Piet A.; Michels, Karin B.; Casagrande, John T.; Cooke, Rosie; Van Den Eeden, Stephen K.; Ewertz, Marianne; Falk, Roni T.; Gaudet, Mia M.; Gkiokas, George; Habel, Laurel A.; Hsing, Ann W.; Johnson, Kenneth; Kolonel, Laurence N.; La Vecchia, Carlo; Lynge, Elsebeth; Lubin, Jay H.; McCormack, Valerie A.; Negri, Eva; Olsson, Håkan; Parisi, Dominick; Petridou, Eleni Th.; Riboli, Elio; Sesso, Howard D.; Swerdlow, Anthony; Thomas, David B.; Willett, Walter C.; Brinton, Louise A.

    2015-01-01

    Background The etiology of male breast cancer is poorly understood, partly due to its relative rarity. Although tobacco and alcohol exposures are known carcinogens, their association with male breast cancer risk remains ill-defined. Methods The Male Breast Cancer Pooling Project consortium provided 2,378 cases and 51,959 controls for analysis from 10 case-control and 10 cohort studies. Individual participant data were harmonized and pooled. Unconditional logistic regression was used to estimate study design-specific (case-control/cohort) odds ratios (OR) and 95% confidence intervals (CI), which were then combined using fixed effects meta-analysis. Results Cigarette smoking status, smoking pack-years, duration, intensity, and age at initiation were not associated with male breast cancer risk. Relations with cigar and pipe smoking, tobacco chewing, and snuff use were also null. Recent alcohol consumption and average grams of alcohol consumed per day were also not associated with risk; only one sub-analysis of very high recent alcohol consumption (>60 grams/day) was tentatively associated with male breast cancer (ORunexposed referent=1.29, 95%CI:0.97–1.71; OR>0–<7 g/day referent=1.36, 95%CI:1.04–1.77). Specific alcoholic beverage types were not associated with male breast cancer. Relations were not altered when stratified by age or body mass index. Conclusions In this analysis of the Male Breast Cancer Pooling Project we found little evidence that tobacco and alcohol exposures were associated with risk of male breast cancer. Impact Tobacco and alcohol do not appear to be carcinogenic for male breast cancer. Future studies should aim to assess these exposures in relation to subtypes of male breast cancer. PMID:25515550

  4. Clinical trial combines enzalutamide with immunotherapy for advanced prostate cancer | Center for Cancer Research

    Cancer.gov

    Dr. Ravi Madan, Clinical Director of the Genitourinary Malignancies Branch, is conducting a clinical trial for men who have metastatic prostate cancer but have not yet been treated with chemotherapy, abiraterone or enzalutamide.

  5. The incidence rate of cancer in patients with schizophrenia: A meta-analysis of cohort studies.

    PubMed

    Li, Hailong; Li, Jiasi; Yu, Xiya; Zheng, Huiwen; Sun, Xu; Lu, Yue; Zhang, Yanbo; Li, Chunbo; Bi, Xiaoying

    2017-09-21

    Numerous studies report that cancer prevalence in patients with schizophrenia might be different from the general population, but findings remain controversial. Our updated meta-analysis of cohort studies aims to analyze the data from cohort studies concerning the incidence risk of overall cancer and some site-specific cancers in patients with schizophrenia. We performed a systemic search through electronic databases. Cohort studies evaluating and describing the cancer incidence among patients with schizophrenia were included. Pooled risk ratios (RRs) were calculated for assessing the incidence risk of cancer. There were 16 cohort studies included in this meta-analysis, which combined a total of 480,356 participants with schizophrenia and 41,999 cases of cancer. Results showed that there was a slight significant decreased overall risk ratio of cancer incidence among patients with schizophrenia (RR=0.90, 95% CI 0.81-0.99). When stratified by cancer site and gender, there were significant decreased incidence risk rates of colorectal cancer (RR=0.82, 95% CI 0.69-0.98) and prostate cancer (RR=0.55, 95% CI 0.42-0.71) in those patients, moreover, the incidence rate of colorectal cancer decreased significantly in male patients (RR=0.89, 95% CI 0.81-0.98), and the incidence rate of lung cancer increased significantly in female patients (RR=1.12, 95% CI 1.01-1.25). The incidence risk of some cancers was reduced in patients with schizophrenia. Gender and type of cancer were two important confounding factors contributed to the heterogeneity that required adjustment in our cancer incidence meta-analysis. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Feasibility of using lower doses of chemopreventive agents in a combination regimen for cancer protection.

    PubMed

    Ip, C

    1988-04-01

    In experimental cancer chemoprevention studies, the doses of the agent used to produce an inhibitory response are generally very high, sometimes bordering on levels that will result in toxicity to the test animals. The present study was designed to test the hypothesis that low doses of two or more agents may be just as effective as high doses of a single agent. An earlier report from our laboratory showed that vitamin E, although ineffective by itself, potentiates the anti-carcinogenic potency of selenite. Our objective was to complete a comprehensive set of dose titration experiments in the quantitative analysis of the synergism between selenium (Se) and vitamin E. Results indicated that the minimal amount of vitamin E required was around 500 ppm, which when combined with as little as 1 ppm Se, produced a significant protective effect in the 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat mammary tumor model. This level of Se is 5 times below the marginal toxicity level of 5 ppm observed in our previous experience. With a 3-agent combination protocol involving Se (1 ppm), vitamin E (500 ppm) and vitamin A (66 ppm), it was found that vitamin A at this particular dose did not contribute any further chemoprevention than that provided by the Se/vitamin E duo. Both Se and vitamin E were present at a concentration 10 times, while vitamin A was present at 30 times their respective nutritional requirement. Our findings thus suggest that the minimum effective dose has to be systematically established for each micronutrient, and that it is feasible to use lower doses of a combination of agents if the threshold level of each agent can be determined under a prescribed set of conditions.

  7. A combination of trastuzumab and BAG-1 inhibition synergistically targets HER2 positive breast cancer cells.

    PubMed

    Papadakis, Emmanouil; Robson, Natalia; Yeomans, Alison; Bailey, Sarah; Laversin, Stephanie; Beers, Stephen; Sayan, A Emre; Ashton-Key, Margaret; Schwaiger, Stefan; Stuppner, Hermann; Troppmair, Jakob; Packham, Graham; Cutress, Ramsey

    2016-04-05

    Treatment of HER2+ breast cancer with trastuzumab is effective and combination anti-HER2 therapies have demonstrated benefit over monotherapy in the neoadjuvant and metastatic settings. This study investigated the therapeutic potential of targeting the BAG-1 protein co-chaperone in trastuzumab-responsive or -resistant cells. In the METABRIC dataset, BAG-1 mRNA was significantly elevated in HER2+ breast tumors and predicted overall survival in a multivariate analysis (HR = 0.81; p = 0.022). In a breast cell line panel, BAG-1 protein was increased in HER2+ cells and was required for optimal growth as shown by siRNA knockdown. Overexpression of BAG-1S in HER2+ SKBR3 cells blocked growth inhibition by trastuzumab, whereas overexpression of a mutant BAG-1S protein (BAG-1S H3AB), defective in binding HSC70, potentiated the effect of trastuzumab. Injection of a Tet-On SKBR3 clone, induced to overexpress myc-BAG-1S into the mammary fat pads of immunocompromised mice, resulted in 2-fold larger tumors compared to uninduced controls. Induction of myc-BAG-1S expression in two Tet-On SKBR3 clones attenuated growth inhibition by trastuzumab in vitro. Targeting endogenous BAG-1 by siRNA enhanced growth inhibition of SKBR3 and BT474 cells by trastuzumab, while BAG-1 protein-protein interaction inhibitor (Thio-S or Thio-2) plus trastuzumab combination treatment synergistically attenuated growth. In BT474 cells this reduced protein synthesis, caused G1/S cell cycle arrest and targeted the ERK and AKT signaling pathways. In a SKBR3 subpopulation with acquired resistance to trastuzumab BAG-1 targeting remained effective and either Thio-2 or BAG-1 siRNA reduced growth more compared to trastuzumab-responsive parental cells. In summary, targeting BAG-1 function in combination with anti-HER2 therapy might prove beneficial.

  8. A combination of trastuzumab and BAG-1 inhibition synergistically targets HER2 positive breast cancer cells

    PubMed Central

    Papadakis, Emmanouil; Robson, Natalia; Yeomans, Alison; Bailey, Sarah; Laversin, Stephanie; Beers, Stephen; Sayan, A. Emre; Ashton-Key, Margaret; Schwaiger, Stefan; Stuppner, Hermann; Troppmair, Jakob; Packham, Graham; Cutress, Ramsey

    2016-01-01

    Treatment of HER2+ breast cancer with trastuzumab is effective and combination anti-HER2 therapies have demonstrated benefit over monotherapy in the neoadjuvant and metastatic settings. This study investigated the therapeutic potential of targeting the BAG-1 protein co-chaperone in trastuzumab-responsive or -resistant cells. In the METABRIC dataset, BAG-1 mRNA was significantly elevated in HER2+ breast tumors and predicted overall survival in a multivariate analysis (HR = 0.81; p = 0.022). In a breast cell line panel, BAG-1 protein was increased in HER2+ cells and was required for optimal growth as shown by siRNA knockdown. Overexpression of BAG-1S in HER2+ SKBR3 cells blocked growth inhibition by trastuzumab, whereas overexpression of a mutant BAG-1S protein (BAG-1S H3AB), defective in binding HSC70, potentiated the effect of trastuzumab. Injection of a Tet-On SKBR3 clone, induced to overexpress myc-BAG-1S into the mammary fat pads of immunocompromised mice, resulted in 2-fold larger tumors compared to uninduced controls. Induction of myc-BAG-1S expression in two Tet-On SKBR3 clones attenuated growth inhibition by trastuzumab in vitro. Targeting endogenous BAG-1 by siRNA enhanced growth inhibition of SKBR3 and BT474 cells by trastuzumab, while BAG-1 protein-protein interaction inhibitor (Thio-S or Thio-2) plus trastuzumab combination treatment synergistically attenuated growth. In BT474 cells this reduced protein synthesis, caused G1/S cell cycle arrest and targeted the ERK and AKT signaling pathways. In a SKBR3 subpopulation with acquired resistance to trastuzumab BAG-1 targeting remained effective and either Thio-2 or BAG-1 siRNA reduced growth more compared to trastuzumab-responsive parental cells. In summary, targeting BAG-1 function in combination with anti-HER2 therapy might prove beneficial. PMID:26958811

  9. The Combination of DNA Ploidy Status and PTEN/6q15 Deletions Provides Strong and Independent Prognostic Information in Prostate Cancer.

    PubMed

    Lennartz, Maximilian; Minner, Sarah; Brasch, Sophie; Wittmann, Hilko; Paterna, Leonard; Angermeier, Katja; Öztürk, Eray; Shihada, Rami; Ruge, Mingu; Kluth, Martina; Koop, Christina; Wilczak, Waldemar; Krech, Till; Lebok, Patrick; Wittmer, Corinna; Heinzer, Hans; Steuber, Thomas; Adam, Meike; Huland, Hartwig; Graefen, Markus; Haese, Alexander; Simon, Ronald; Sauter, Guido; Schlomm, Thorsten

    2016-06-01

    Aberrant DNA content has been discussed as a potential prognostic feature in prostate cancer. We analyzed the clinical significance of DNA ploidy in combination with prognostic relevant deletions of PTEN and 6q15 in 3,845 prostate cancers. The DNA status was diploid in 67.8%, tetraploid in 25.6%, and aneuploid in 6.8% of tumors, and deletions of PTEN and 6q15 occurred in 17.8% and 20.3% of tumors. Abnormal DNA content and deletions were linked to high Gleason score, advanced tumor stage, and positive nodal stage (P < 0.0001 each). The risk of PSA recurrence increased from diploid to tetraploid and from tetraploid to aneuploid DNA status (P < 0.0001 each). However, 40% of patients with Gleason score ≥4+4 and 55% of patients with PSA recurrence had diploid cancers. This fraction decreased to 21% (Gleason ≥4+4) and 29% (PSA recurrence) if PTEN and/or 6q deletion data were added to ploidy data to identify cancers with an aberrant DNA status. The significance of combining both deletions and ploidy was further demonstrated in a combined recurrence analysis. Presence of deletions increased the risk of PSA recurrence in diploid (P < 0.0001), tetraploid (P < 0.0001), and aneuploid cancers (P = 0.0049), and the combination of ploidy data and deletions provided clinically relevant information beyond the CAPRA-S nomogram. Multivariate modeling including preoperatively and postoperatively available parameters identified the "combined DNA status" as a strong independent predictor of poor patient outcome. The combinatorial DNA content analysis involving general (ploidy) and specific events (deletions) has the potential for clinical utility in prostate cancer. Clin Cancer Res; 22(11); 2802-11. ©2016 AACR. ©2016 American Association for Cancer Research.

  10. Optimal combinations for detection of prostate cancer: systematic sextant and laterally directed biopsies versus systematic sextant and color Doppler-targeted biopsies.

    PubMed

    Kravchick, Sergey; Cytron, Shmuel; Peled, Ronit; London, Daniel; Sibi, Yosef; Ben-Dor, David

    2004-02-01

    To determine the accuracy of different combinations of biopsies in detecting prostate cancer. The standard sextant protocol for obtaining prostate biopsy underestimates the presence of prostate cancer. Conversely, an increased cancer detection rate has been obtained with additional laterally directed biopsies. The results of the studies dedicated to transrectal color Doppler (CD) sonography have shown that it might detect neoplastic lesions with no corresponding gray-scale abnormality. A total of 120 consecutive patients underwent sextant biopsy with additional biopsy cores taken from the lateral peripheral zone (four to six cores, depending on the prostate volume) and CD-guided biopsy. The sensitivity of laterally directed, CD-guided, and different combinations of biopsies was compared. Various patient, clinical, and pathologic factors were compared, and multivariate analysis was performed to assess the strongest predictor of cancer detection. Cancer was detected in 43 (35.8%) of 120 patients. The combination of sextant biopsy with laterally directed cores gained sensitivity to 56.6% compared with 67.4% obtained in the regimen that combined sextant and CD-guided biopsy. The CD regimen detected cancer in 11 additional patients. However, the differences in the detection rates of these combinations were not statistically significant (P = 0.797). The results of multivariate analysis showed that sextant biopsy and laterally directed cores were the strongest predictors of cancer detection (odds ratio 8.356 versus 49.282; 95% confidence interval 1.698 to 41.114 versus 10.508 to 231.130). The regimen that included sextant and CD-guided biopsy was the most sensitive. However, only standard sextant and laterally directed biopsies were statistically significant predictors of cancer detection on biopsy.

  11. Combining hedgehog signaling inhibition with focal irradiation on reduction of pancreatic cancer metastasis

    PubMed Central

    Gu, Dongsheng; Liu, Hailan; Su, Gloria H.; Zhang, Xiaoli; Chin-Sinex, Helen; Hanenberg, Helmut; Mendonca, Marc S.; Shannon, Harlan E.; Chiorean, E. Gabriela; Xie, Jingwu

    2013-01-01

    Pancreatic cancer often presents in advanced stages and is unresponsive to conventional treatments. Thus, the need to develop novel treatment strategies for pancreatic cancer has never been greater. Here we report that combination of focal irradiation with hedgehog (Hh) signaling inhibition exerts better than additive effects on reducing metastases. In an orthotopic model, we found that focal irradiation alone effectively reduced primary tumor growth but did not significantly affect metastasis. We hypothesized that cancer stem cells (CSC) of pancreatic cancer are responsible for the residual tumors following irradiation, which may be regulated by Hh signaling. To test our hypothesis, we showed that tumor metastasis in our model was accompanied by increased expression of CSC cell surface markers as well as Hh target genes. We generated tumor spheres from orthotopic pancreatic and metastatic tumors, which have elevated levels of CSC markers relative to the parental cells and elevated expression of Hh target genes. Irradiation of tumor spheres further elevated CSC cell surface markers and increased Hh target gene expression. Combination of Hh signaling inhibition with radiation had more than additive effects on tumor sphere regeneration in vitro. This phenotype was observed in two independent cell lines. In our orthotopic animal model, focal radiation plus Hh inhibition had more than additive effects on reducing lymph node metastasis. We identified several potential molecules in mediating Hh signaling effects. Taken together, our data provide a rationale for combined use of Hh inhibition with irradiation for clinical treatment of pancreatic cancer patients. PMID:23468532

  12. Ameliorative potential of fluoxetine/raloxifene combination on experimentally induced breast cancer.

    PubMed

    Kabel, Ahmed M; Elkhoely, Abeer A

    2016-04-01

    Breast cancer is one of the most common types of malignancies in females worldwide. Targeting the estrogen receptors alone with raloxifene (RAL) reduces the incidence of estrogen receptor positive tumors. Fluoxetine (FLX) is one of selective serotonin reuptake inhibitors that was proven to have anticancer properties. Our aim was to detect the effects of RAL/FLX combination on experimentally induced breast cancer. Eighty female Wistar rats were divided into four equal groups: 7,12-Dimethyl Benzanthracene (DMBA) induced breast cancer group, DMBA+RAL, DMBA+FLX and DMBA+RAL+FLX. Tumor volume, tissue malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD), tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6) and transforming growth factor beta1 (TGF-β1) were determined in the tumor tissues. Parts of the tumor were subjected to histopathological examination. RAL or FLX alone or in combination induced significant increase in tumor CAT and SOD with significant decrease in tumor volume, tissue MDA, TNF-α, IL-6 and TGF-β1 and alleviated the histopathological and immunohistochemical changes compared to DMBA group. In conclusion, RAL/FLX combination had a better effect than each of RAL or FLX alone against DMBA-induced breast cancer in rats which may represent a new therapeutic modality for management of breast cancer.

  13. Combined modality treatment of aromatherapy, footsoak, and reflexology relieves fatigue in patients with cancer.

    PubMed

    Kohara, Hiroyuki; Miyauchi, Takako; Suehiro, Yoko; Ueoka, Hiroshi; Takeyama, Hiroyasu; Morita, Tatsuya

    2004-12-01

    Fatigue is one of the most distressful symptoms experienced by patients with advanced cancer. Aromatherapy, footsoak, and reflexology are popular health care modality treatments in Japan, however, the effectiveness of each treatment for cancer-related fatigue has not been fully established. To investigate the effectiveness of combined modality treatment consisting of aromatherapy, footsoak, and reflexology against fatigue, an open study was performed in 20 terminally ill patients with cancer. After a patch test was performed, patients received aromatherapy that was accompanied with footsoak in warm water containing lavender essential oil for 3 minutes, followed by reflexology treatment with jojoba oil containing lavender for 10 min. Fatigue was evaluated using the Cancer Fatigue Scale (CFS) before, 1 hour after, and 4 hours after treatment. Total CFS scores improved significantly after this treatment (from 25.6 +/- 11.0 to 18.1 +/- 10.0, p < 0.001). Among three CFS subscales, physical and cognitive subscale scores were reduced significantly (11.3 +/- 6.1 to 6.7 +/- 6.1, p < 0.001; 4.5 +/- 3.2 to 2.4 +/- 2.4, p < 0.001). No adverse effects were experienced. Because all patients desired to continue this treatment, they received treatment eight times on average. Combined modality treatment consisting of aromatherapy, footsoak, and reflexology appears to be effective for alleviating fatigue in terminally ill cancer patients. To confirm safety and effectiveness of this combined modality treatment, further investigation including randomized treatment assignment is warranted.

  14. Combining hedgehog signaling inhibition with focal irradiation on reduction of pancreatic cancer metastasis.

    PubMed

    Gu, Dongsheng; Liu, Hailan; Su, Gloria H; Zhang, Xiaoli; Chin-Sinex, Helen; Hanenberg, Helmut; Mendonca, Marc S; Shannon, Harlan E; Chiorean, E Gabriela; Xie, Jingwu

    2013-06-01

    Pancreatic cancer often presents in advanced stages and is unresponsive to conventional treatments. Thus, the need to develop novel treatment strategies for pancreatic cancer has never been greater. Here, we report that combination of focal irradiation with hedgehog (Hh) signaling inhibition exerts better than additive effects on reducing metastases. In an orthotopic model, we found that focal irradiation alone effectively reduced primary tumor growth but did not significantly affect metastasis. We hypothesized that cancer stem cells (CSC) of pancreatic cancer are responsible for the residual tumors following irradiation, which may be regulated by Hh signaling. To test our hypothesis, we showed that tumor metastasis in our model was accompanied by increased expression of CSC cell surface markers as well as Hh target genes. We generated tumor spheres from orthotopic pancreatic and metastatic tumors, which have elevated levels of CSC markers relative to the parental cells and elevated expression of Hh target genes. Irradiation of tumor spheres further elevated CSC cell surface markers and increased Hh target gene expression. Combination of Hh signaling inhibition with radiation had more than additive effects on tumor sphere regeneration in vitro. This phenotype was observed in two independent cell lines. In our orthotopic animal model, focal radiation plus Hh inhibition had more than additive effects on reducing lymph node metastasis. We identified several potential molecules in mediating Hh signaling effects. Taken together, our data provide a rationale for combined use of Hh inhibition with irradiation for clinical treatment of patients with pancreatic cancer.

  15. Combination of quercetin and hyperoside inhibits prostate cancer cell growth and metastasis via regulation of microRNA‑21.

    PubMed

    Yang, Feng-Qiang; Liu, Min; Li, Wei; Che, Jian-Ping; Wang, Guang-Chun; Zheng, Jun-Hua

    2015-02-01

    Previous studies have reported that hyperoside and quercetin in combination (QH; 1:1) inhibited the growth of human leukemia cells. The aim of the present study was to investigate the anti‑cancer effect of QH on prostate cancer cells. The results demonstrated that QH decreased the production of reactive oxygen species (ROS) and increased antioxidant capacity in PC3 cells at various concentrations (2.5‑60 µg/ml) with peak inhibition and augmentation changes of 3.22‑ and 3.00‑fold, respectively. Following treatment with QH for 48 and 72 h, the IC50-values on PC3 cells were 19.7 and 12.4 µg/ml, respectively. Western blot analysis revealed that QH induced apoptosis in human prostate cancer cells via activation of caspase‑3 and cleavage of poly(adenosine diphosphate ribose) polymerase. In addition, QH significantly inhibited the invasion and migration of PC3 cells as well as reduced the expression of numerous prostate tumor‑associated microRNAs (miRs), including miR‑21, compared to that of untreated human prostate cancer cells. QH was also found to enhance the expression of tumor suppressor programmed cell death protein 4, which was negatively regulated by miR‑21. Furthermore, induced overexpression of miR‑21 using pre‑miR‑21 oligonucleotides attenuated the beneficial effect of QH on prostate cancer cells. In conclusion, the results of the present study indicated that QH exerted an anti‑cancer effect on human prostate cancer cells, the mechanism of which proceeded, at least in part, via the inhibition of the miR‑21 signaling pathway.

  16. Combined-modality therapy of rectal cancer with oxaliplatin-based regimens.

    PubMed

    Minsky, Bruce D

    2004-06-01

    There are 2 conventional treatments for clinically resectable rectal cancer. First is surgery and, if the tumor is stage T3 and/or N1/2, this is followed by postoperative combined modality therapy. The second is preoperative combined modality therapy followed by surgery and postoperative combined modality therapy if the tumor is stage uT3/4 and/or node-positive. There are a number of new chemotherapeutic agents that have been developed for the treatment of patients with colorectal cancer. Phase I/II trials examining the use of these new chemotherapeutic agents in combination with pelvic radiation therapy, most commonly in the preoperative setting are in progress and suggest higher complete response rates. There is considerable interest in integrating oxaliplatin into preoperative combined modality therapy regimens for rectal cancer. Based on results from phase I/II trials, the recommended regimen for patients who receive oxaliplatin-based combined modality therapy is continuous infusion 5-fluorouracil or capecitabine with pelvic radiation.

  17. Combined-modality therapy of rectal cancer with irinotecan-based regimens.

    PubMed

    Minsky, Bruce D

    2004-12-01

    There are two conventional treatments for clinically resectable rectal cancer. The first is surgery followed by postoperative combined-modality therapy if the tumor is T3 and/or N1/2. The second, if the tumor is ultrasound T3 or clinical T4, is preoperative combined-modality therapy followed by surgery and postoperative chemotherapy. There are a number of new chemotherapeutic agents that have been developed for the treatment of colorectal cancer. Phase I/II trials are examining the use of new chemotherapeutic agents in combination with pelvic radiation therapy, most commonly in the preoperative setting. There is considerable interest in integrating irinotecan (Camptosar) into preoperative combined-modality therapy regimens for rectal cancer. Based on these trials, the recommended regimen for patients who receive irinotecan-based combined-modality therapy is continuous infusion fluorouracil (5-FU), irinotecan, and pelvic radiation. New trials examining preoperative combined-modality therapy regimens substituting capecitabine (Xeloda) for continuous infusion 5-FU are in progress.

  18. Identification and exploration of herb-drug combinations used by cancer patients.

    PubMed

    Engdal, Silje; Klepp, Olbjørn; Nilsen, Odd Georg

    2009-03-01

    This survey aims to identify herb-chemotherapeutic drug combinations in a defined group of cancer patients and to explore possible clinical consequences of these combinations. Herb-chemotherapeutic drug combinations were identified among adult cancer patients, and clinical consequences of the combinations were explored by literature searches in medical databases on possible mutual effects on similar cytochrome P-450 metabolising enzymes (CYPs) and/or the P-glycoprotein (P-gp) transporter. Among 42 cancer patients using herbal remedies concurrently with chemotherapy, 136 two-agent herb-drug combinations were registered and 47 different potential herb-drug interactions were identified on the level of CYP metabolism and P-gp transport in vitro. Garlic, ginger, green tea and noni juice were the herbal remedies most frequently used in such combinations. For 48 % of the herbal remedies identified no literature data exist on their interaction potentials. Clinical studies were available for four herbal remedies only. Minor clinical potential for CYP interactions in humans was indicated for green tea and Echinacea. P-gp interactions were only investigated for garlic, which showed a significant interaction potential both in vivo and in vitro. The large number of in vitro potential herb-drug interactions identified urge for more clinical pharmacokinetic interaction studies in humans.

  19. Lung cancer risk among patients with combined pulmonary fibrosis and emphysema.

    PubMed

    Kwak, Nakwon; Park, Chang-Min; Lee, Jinwoo; Park, Young Sik; Lee, Sang-Min; Yim, Jae-Joon; Yoo, Chul-Gyu; Kim, Young Whan; Han, Sung Koo; Lee, Chang-Hoon

    2014-03-01

    Although combined pulmonary fibrosis and emphysema (CPFE) might be relevant to lung cancer, no comparison studies have been done. We evaluated the risk of lung cancer among CPFE patients compared to IPF and emphysema patients. We retrospectively reviewed the medical records of patients who were diagnosed as CPFE, IPF and emphysema using chest CT scans at Seoul National University Hospital from Jan 2000 to Dec 2011. Patients with CPFE were enrolled and matched (1:1:2) with IPF and emphysema patients based on the radiological criteria. The main outcome was time to diagnosis of lung cancer and evaluated with Cox-proportional hazard regression. Forty-eight CPFE, 48 IPF, and 96 emphysema patients were included in this study. Twenty-five cases of lung cancer occurred. The CPFE group had a higher risk of lung cancer (adjusted HR 4.62, 95% CI 1.58-13.55) than that of the emphysema group. Also, IPF group had a higher risk of lung cancer (adjusted HR 4.15, 95% CI 1.03-16.78) than that of emphysema group. However, there was no statistically significant difference in lung cancer risk between the CPFE and IPF group. Additionally, the CPFE group had a higher risk of lung cancer or death (adjusted HR 4.62, 95% CI 2.25-9.47) than that of the emphysema group. In conclusion, patients with CPFE and IPF had a higher risk of lung cancer than those with emphysema, although lung cancer risk was similar between CPFE and IPF.

  20. Combining immunotherapy and anticancer agents: the right path to achieve cancer cure?

    PubMed

    Apetoh, L; Ladoire, S; Coukos, G; Ghiringhelli, F

    2015-09-01

    Recent clinical trials revealed the impressive efficacy of immunological checkpoint blockade in different types of metastatic cancers. Such data underscore that immunotherapy is one of the most promising strategies for cancer treatment. In addition, preclinical studies provide evidence that some cytotoxic drugs have the ability to stimulate the immune system, resulting in anti-tumor immune responses that contribute to clinical efficacy of these agents. These observations raise the hypothesis that the next step for cancer treatment is the combination of cytotoxic agents and immunotherapies. The present review aims to summarize the immune-mediated effects of chemotherapeutic agents and their clinical relevance, the biological and clinical features of immune checkpoint blockers and finally, the preclinical and clinical rationale for novel therapeutic strategies combining anticancer agents and immune checkpoint blockers. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  1. Combining Dissimilarities in a Hyper Reproducing Kernel Hilbert Space for Complex Human Cancer Prediction

    PubMed Central

    Martín-Merino, Manuel; Blanco, Ángela; De Las Rivas, Javier

    2009-01-01

    DNA microarrays provide rich profiles that are used in cancer prediction considering the gene expression levels across a collection of related samples. Support Vector Machines (SVM) have been applied to the classification of cancer samples with encouraging results. However, they rely on Euclidean distances that fail to reflect accurately the proximities among sample profiles. Then, non-Euclidean dissimilarities provide additional information that should be considered to reduce the misclassification errors. In this paper, we incorporate in the ν-SVM algorithm a linear combination of non-Euclidean dissimilarities. The weights of the combination are learnt in a (Hyper Reproducing Kernel Hilbert Space) HRKHS using a Semidefinite Programming algorithm. This approach allows us to incorporate a smoothing term that penalizes the complexity of the family of distances and avoids overfitting. The experimental results suggest that the method proposed helps to reduce the misclassification errors in several human cancer problems. PMID:19584909

  2. [Efficacy evaluation and exploration of TACE combined with CT-guided precision microwave ablation treatment for primary liver cancer].

    PubMed

    Zhao, P; Zheng, J S; Zhang, H H; Yuan, C W; Cui, S C; Du, N; Zhao, L Y

    2016-02-01

    To analyze the clinical therapeutic efficacy of transcatheter arterial chemoembolization combined with CT-guided percutaneous precision microwave ablation for the treatment of primary liver cancer and its influencing factors. A total of 126 patients with primary liver cancer were treated by transcatheter arterial chemoembolization combined with CT-guided percutaneous precision microwave ablation from Mar 2010 to Oct 2014 in our center. The treatment effect, postoperative complications and recurrence rates were observed, and the factors related to recurrence and survival time were analyzed. All 126 primary liver cancer patients with 201 tumors were ablated for 177 times, and 113 cases with 185 tumors were completed ablated, the complete ablation rate was 92.0%. In all patients, 4 cases had serious complications, the incidence rate was 3.2%. 37 cases had recurrence, with a recurrence rate of 29.4%. All patients were followed up for 10 to 65 months, 17 patients died, and the 1-, 2-, and 3-year cumulative survival rates were 95.2%, 88.1%, and 84.1%, respectively, and the 1-, 2-, and 3-year progression-free-survival rates were 81.5%, 62.7% and 49.2%, respectively .Univariate analysis showed that preoperative AFP level, Child-Pugh score, BCLC stage and the largest tumor size were associated with the survival of patients who received TACE combined with CT-guided precision MWA, and the preoperative AFP level, internal medicine therapy, tumor number and the largest tumor size were associated with the progression-free-survival after the treatment (P<0.05). Multivariate analysis showed that Child-Pugh score and BCLC stage were independent factors affecting the survival of patients with primary liver cancer patients treated with TACE combined with CT guided percutaneous MWA, and the tumor number and the maximum tumor size were independent factors affecting the progression-free-survival of the patients (P<0.05). TACE combined with CT-guided percutaneous precision microwave

  3. [Recurrence of esophageal cancer treated by combination TS-1/CDDP therapy].

    PubMed

    Hiraki, Masatsugu; Yunotani, Seiji; Noguchi, Ryo; Shinozaki, Yukari; Tani, Hiroki; Sakai, Masashi; Ishimitsu, Toshiyuki; Tabuchi, Masanobu

    2005-02-01

    A 68-year-old man underwent subtotal esophagectomy with two fields lymphadenectomy and postoperative chemotherapy so called low dose FP therapy for advanced esophageal cancer (Stage IIIa, pT 3, pN 1, M 0) in October 1999. As he was diagnosed with a recurrence of esophageal cancer as metastatic lymph node tumors which were placed in the right anterocervical and supraclavicular region in March 2001, he underwent enucleation of metastatic lymph node tumors and postoperative chemoradiation therapy, so-called low-dose FP-R therapy. Recently, since other metastatic lymph node tumors in the neck appeared again in August 2001, he underwent radical neck lymph node dissection and postoperative chemoradiation treatment, so-called FAP-R therapy. In October 2003, a chest CT showed multiple lung tumors. He was diagnosed with multiple metastatic lung tumors originating from esophageal cancer. Then, two courses of a combined chemotherapy consisting of TS-1 and CDDP were administered at an interval of one month. We judged the effect of this chemotherapy to be a partial response (PR), because the largest metastatic lung tumor 18 mm in diameter showed a reduction rate of 81.9%, and other tumors had almost disappeared in the chest CT after the combined therapy. No severe adverse effects of more than grade 3 were observed during this combined therapy. This combined chemotherapy consisting of TS-1 and CDDP may prove effective for treating recurrent cases of esophageal cancer.

  4. The association of statins and taxanes: an efficient combination trigger of cancer cell apoptosis

    PubMed Central

    Follet, J; Corcos, L; Baffet, G; Ezan, F; Morel, F; Simon, B; Le Jossic-Corcos, C

    2012-01-01

    Background: Cancer cell killing might be achieved by the combined use of available drugs. Statins are major anti-hypercholesterolemia drugs, which also trigger apoptosis of many cancer cell types, while docetaxel is a potent microtubule-stabilising agent. Methods: Here, we looked at the combined effects of lovastatin and docetaxel in cancer cells. Results: Whole transcriptome microarrays in HGT-1 gastric cancer cells demonstrated that lovastatin strongly suppressed expression of genes involved in cell division, while docetaxel had very little transcriptional effects. Both drugs triggered apoptosis, and their combination was more than additive. A marked rise in the cell-cycle inhibitor p21, together with reduction of aurora kinases A and B, cyclins B1 and D1 proteins was induced by lovastatin alone or in combination with docetaxel. The drug treatments induced the proteolytic cleavage of procaspase-3, a drop of the anti-apoptotic Mcl-1 protein, Poly-ADP-Ribose Polymerase and Bax. Strikingly, docetaxel-resistant HGT-1 cell derivatives overexpressing the MDR-1 gene were much more sensitive to lovastatin than docetaxel-sensitive cells. Conclusion: These results suggest that the association of lovastatin and docetaxel, or lovastatin alone, shows promise as plausible anticancer strategies, either as a direct therapeutic approach or following acquired P-glycoprotein-dependent resistance. PMID:22294184

  5. Recent Advances in Upconversion Nanoparticles-Based Multifunctional Nanocomposites for Combined Cancer Therapy.

    PubMed

    Tian, Gan; Zhang, Xiao; Gu, Zhanjun; Zhao, Yuliang

    2015-12-16

    Lanthanide-doped upconversion nanoparticles (UCNPs) have the ability to generate ultraviolet or visible emissions under continuous-wave near-infrared (NIR) excitation. Utilizing this special luminescence property, UCNPs are approved as a new generation of contrast agents in optical imaging with deep tissue-penetration ability and high signal-to-noise ratio. The integration of UCNPs with other functional moieties can endow them with highly enriched functionalities for imaging-guided cancer therapy, which makes composites based on UCNPs emerge as a new class of theranostic agents in biomedicine. Here, recent progress in combined cancer therapy using functional nanocomposites based on UCNPs is reviewed. Combined therapy referring to the co-delivery of two or more therapeutic agents or a combination of different treatments is becoming more popular in clinical treatment of cancer because it generates synergistic anti-cancer effects, reduces individual drug-related toxicity and suppresses multi-drug resistance through different mechanisms of action. Here, the recent advances of combined therapy contributed by UCNPs-based nanocomposites on two main branches are reviewed: i) photodynamic therapy and ii) chemotherapy, which are the two most widely adopted therapies of UCNPs-based composites. The future prospects and challenges in this emerging field will be also discussed. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. Pancreatic Cancer Combination Therapy Using a BH3 Mimetic and a Synthetic Tetracycline.

    PubMed

    Quinn, Bridget A; Dash, Rupesh; Sarkar, Siddik; Azab, Belal; Bhoopathi, Praveen; Das, Swadesh K; Emdad, Luni; Wei, Jun; Pellecchia, Maurizio; Sarkar, Devanand; Fisher, Paul B

    2015-06-01

    Improved treatments for pancreatic cancer remain a clinical imperative. Sabutoclax, a small-molecule BH3 mimetic, inhibits the function of antiapoptotic Bcl-2 proteins. Minocycline, a synthetic tetracycline, displays antitumor activity. Here, we offer evidence of the combinatorial antitumor potency of these agents in several preclinical models of pancreatic cancer. Sabutoclax induced growth arrest and apoptosis in pancreatic cancer cells and synergized with minocycline to yield a robust mitochondria-mediated caspase-dependent cytotoxicity. This combinatorial property relied upon loss of phosphorylated Stat3 insofar as reintroduction of activated Stat3-rescued cells from toxicity. Tumor growth was inhibited potently in both immune-deficient and immune-competent models with evidence of extended survival. Overall, our results showed that the combination of sabutoclax and minocycline was highly cytotoxic to pancreatic cancer cells and safely efficacious in vivo.

  7. The effect of artificial neural network model combined with six tumor markers in auxiliary diagnosis of lung cancer.

    PubMed

    Feng, Feifei; Wu, Yiming; Wu, Yongjun; Nie, Guangjin; Ni, Ran

    2012-10-01

    To evaluate the diagnosis potential of artificial neural network (ANN) model combined with six tumor markers in auxiliary diagnosis of lung cancer, to differentiate lung cancer from lung benign disease, normal control, and gastrointestinal cancers. Serum carcino-embryonic antigen (CEA), gastrin, neurone specific enolase (NSE), sialic acid (SA), Cu/Zn, Ca were measured through different experimental procedures in 117 lung cancer patients, 93 lung benign disease patients, 111 normal control, 47 gastric cancer patients, 50 patients with colon cancer and 50 esophagus cancer patients, 19 parameters of basic information were surveyed among lung cancer, lung benign disease and normal control, then developed and evaluated ANN models to distinguish lung cancer. Using the ANN model with the six serum tumor markers and 19 parameters to distinguish lung cancer from benign lung disease and healthy people, the sensitivity was 98.3%, the specificity was 99.5% and the accuracy was 96.9%. Another three ANN models with the six serum tumor markers were employed to differentiate lung cancer from three gastrointestinal cancers, the sensitivity, specificity and accuracy of distinguishing lung cancer from gastric cancer by the ANN model of lung cancer-gastric cancer were 100%, 83.3% and 93.5%, respectively; The sensitivity, specificity and accuracy of discriminating lung cancer by lung cancer-colon cancer ANN model were 90.0%, 90.0%, and 90.0%; And which were 86.7%, 84.6%, and 86.0%, respectively, by lung cancer-esophagus cancer ANN model. ANN model built with the six serum tumor markers could distinguish lung cancer, not only from lung benign disease and normal people, but also from three common gastrointestinal cancers. And our evidence indicates the ANN model maybe is an excellent and intelligent system to discriminate lung cancer.

  8. Continuous Combined Estrogen Plus Progestin and Endometrial Cancer: The Women’s Health Initiative Randomized Trial

    PubMed Central

    Anderson, G. L.; Sarto, G. E.; Haque, R.; Runowicz, C. D.; Aragaki, A. K.; Thomson, C. A.; Howard, B. V.; Wactawski-Wende, J.; Chen, C.; Rohan, T. E.; Simon, M. S.; Reed, S. D.; Manson, J. E.

    2016-01-01

    Background: While progestin addition to estrogen mitigates endometrial cancer risk, the magnitude of the effect on incidence, specific endometrial cancer histologies, and endometrial cancer mortality remains unsettled. These issues were assessed by analyses after extended follow-up of the Women’s Health Initiative (WHI) randomized clinical trial evaluating continuous combined estrogen plus progestin use. Methods: The WHI enrolled 16 608 postmenopausal women into a randomly assigned, double-blind, placebo-controlled trial. Women age 50 to 79 years with intact uteri with normal endometrial biopsy at entry were randomly assigned to once-daily 0.625mg conjugated equine estrogen plus 2.5mg medroxyprogesterone acetate (n = 8506) as a single pill or matching placebo (n = 8102). Follow-up beyond the original trial completion date required reconsent, obtained from 12 788 (83%) of surviving participants. Analyses were by intent-to-treat. All statistical tests were two-sided. Results: After 5.6 years’ median intervention and 13 years’ median cumulative follow-up, there were fewer endometrial cancers in the combined hormone therapy compared with the placebo group (66 vs 95 case patients, yearly incidence, 0.06% vs 0.10%; hazard ratio [HR] = 0.65, 95% confidence interval [CI] = 0.48 to 0.89, P = .007). While there were somewhat fewer endometrial cancers during intervention (25 vs 30, respectively; HR = 0.77, 95% CI = 0.45 to 1.31), the difference became statistically significant postintervention (41 vs 65, respectively; HR = 0.59, 95% CI = 0.40 to 0.88, P = .008), but hazard ratios did not differ between phases (P difference = .46). There was a statistically nonsignificant reduction in deaths from endometrial cancer in the estrogen plus progestin group (5 vs 11 deaths, HR = 0.42, 95% CI = 0.15 to 1.22). Conclusion: In postmenopausal women, continuous combined estrogen plus progestin decreases endometrial cancer incidence. PMID:26668177

  9. Anti-cancer effects of oncolytic viral therapy combined with photodynamic therapy in human pancreatic cancer cell lines.

    PubMed

    Khaled, Yazan S; Wright, Kathleen; Melcher, Alan; Jayne, David

    2015-02-26

    Oncolytic viral therapy and photodynamic therapy are potential therapies for inoperable or advanced pancreatic cancer. Our aim was to investigate the anti-cancer killing effects of reovirus therapy combined with protoporphyrin IX (PpIX)-mediated photodynamic therapy on a variety of human pancreatic cancer cell lines. Pancreatic cancer cell lines (PsPC-1 and BXPC-3) and a non-cancer control cell line (HEK293) were infected with reovirus serotype 3 strain Dearing (T3D) at 0, 0·1, 1, and 10 plaque-forming units (PFU) per cell for 48 h. Cells were incubated with PpIX pro-drug 5-aminolevulinic acid (5-ALA) at 0, 1, 2, 3, and 4 mM for 4 h. Then, cells were photo-irradiated for 15 min with visible red light-emitting diodes with a light-fluence of 0·54 J/cm(2) of 653 nm (PpIX optimal excitation wavelength). The killing effects of reovirus combined with PpIX-mediated photodynamic therapy were analysed in methylthiazoltetrazolium (MTT) and trypan blue assays. The effect of adding reovirus after photodynamic therapy was also assessed. The statistical significance of the difference between groups was assessed with the two-tailed Student's t test. p<0·05 was considered statistically significant. Reovirus monotherapy induced cell death in the two pancreatic lines (mean 57% [SE 10·2] at 10 PFU per cell). PpIX-mediated PDT monotherapy induced cell death in a dose-dependent manner (mean 10% [SE 2·2], 30 [6·4], 50 [8·2], and 70 [13·2] after 1, 2, 3, and 4 mM 5-ALA, respectively). Reovirus with PpIX-mediated photodynamic therapy resulted in a significantly increased cytotoxic effect compared with reovirus monotherapy and photodynamic therapy (p=0·042) with 100% cell death observed across pancreatic cell lines with 10 PFU per cell combined with 1 and 2 mM 5-ALA. There was no difference in cytotoxicity observed between added reovirus before or after photodynamic therapy. To our knowledge, this is the first in-vitro study to combine reovirus oncolytic viral therapy with Pp

  10. Oral contraceptives and colorectal cancer risk: a meta-analysis

    PubMed Central

    Fernandez, E; Vecchia, C La; Balducci, A; Chatenoud, L; Franceschi, S; Negri, E

    2001-01-01

    Several studies have suggested an inverse association between use of combined oral contraceptives (OC) and the risk of colorectal cancer and here we present a meta-analysis of published studies. Articles considered were epidemiological studies published as full papers in English up to June 2000 that included quantitative information on OC use. The pooled relative risks (RR) of colorectal cancer for ever OC use from the 8 case-control studies was 0.81 (95% confidence interval (CI): 0.69–0.94), and the pooled estimate from the 4 cohort studies was 0.84 (95% CI: 0.72–0.97). The pooled estimate from all studies combined was 0.82 (95% CI: 0.74–0.92), without apparent heterogeneity. Duration of use was not associated with a decrease in risk, but there was some indication that the apparent protection was stronger for women who had used OCs more recently (RR = 0.46; 95% CI: 0.30–0.71). A better understanding of this potential relation may help informed choice of contraception. © 2001 Cancer Research Campaign http://www.bjcancer.com PMID:11237397

  11. Combining fisetin and ionizing radiation suppresses the growth of mammalian colorectal cancers in xenograft tumor models.

    PubMed

    Leu, Jyh-Der; Wang, Bo-Shen; Chiu, Shu-Jun; Chang, Chun-Yuan; Chen, Chien-Chih; Chen, Fu-Du; Avirmed, Shiirevnyamba; Lee, Yi-Jang

    2016-12-01

    Fisetin (3,7,3',4'-tetrahydroxyflavone), which belongs to the flavonoid group of polyphenols and is found in a wide range of plants, has been reported to exhibit a number of biological activities in human cancer cells, including antioxidant, anti-inflammatory, antiangiogenic, anti-invasive and antiproliferative effects. Although previous in vitro studies have shown that fisetin treatment increases the apoptotic rate and enhances the radiosensitivity of human colorectal cancer cells, the in vivo effects of fisetin on tumor growth remain unclear. In the present study a murine xenograft tumor model was employed to investigate the therapeutic effects of fisetin in combination with radiation on CT-26 colon cancer cells and human HCT116 colorectal cancer cells. This revealed that intratumoral injection of fisetin significantly suppressed the growth of CT-26 tumors compared with the untreated control group, but had little effect on the growth of HCT116 tumors. However, fisetin in combination with 2-Gy radiation enhanced tumor suppressor activity in murine colon and human colorectal xenograft tumors, as compared with 2-Gy fractionated radiation administered alone for 5 days and fisetin alone. Interestingly, fisetin downregulated the expression of the oncoprotein securin in a p53-independent manner. However, securin-null HCT116 tumors showed only moderate sensitivity to fisetin treatment, and the combination of fisetin and radiation did not significantly suppress securin-null HCT116 tumor growth compared with normal HCT116 tumors. Therefore, the role of securin in mediating the effect of fisetin on colorectal cancer growth warrants further investigation. In conclusion, the results of the current study provide important preclinical data for evaluating the efficacy of fisetin and radiation combination treatment as an adjuvant chemoradiotherapy for human colorectal cancers.

  12. Low-dose naltrexone suppresses ovarian cancer and exhibits enhanced inhibition in combination with cisplatin.

    PubMed

    Donahue, Renee N; McLaughlin, Patricia J; Zagon, Ian S

    2011-07-01

    Ovarian cancer is the leading cause of death from gynecological malignancies. Although initial therapeutic modalities are successful, 65% of these women relapse with only palliative treatments available thereafter. Endogenous opioids repress the proliferation of human ovarian cancer cells in vitro, and do so in a receptor-mediated manner. The present study examined whether modulation of opioid systems by the opioid antagonist naltrexone (NTX), alone or in combination with standard of care therapies (taxol/paclitaxel, cisplatin), alters human ovarian cancer cell proliferation in tissue culture and tumor progression in mice. Administration of NTX for six hours every two days, but not continuously, reduced DNA synthesis and cell replication from vehicle-treated controls in tissue culture. Moreover, brief exposure to NTX in combination with taxol or cisplatin had an enhanced anticancer action. Mice with established ovarian tumors and treated with a low dosage of NTX (LDN), which invokes a short period of opioid receptor blockade, repressed tumor progression in a non-toxic fashion by reducing DNA synthesis and angiogenesis but not altering cell survival. The combination of LDN with cisplatin, but not taxol, resulted in an additive inhibitory effect on tumorigenesis with enhanced depression of DNA synthesis and angiogenesis. LDN combined with cisplatin alleviated the toxicity (e.g. weight loss) associated with cisplatin. LDN treatment upregulated the expression of the opioid growth factor (OGF, chemical term ([Met(5)]-enkephalin) and its receptor, OGFr. Previous tissue culture studies have reported that OGF is the only opioid peptide with antiproliferative activity on ovarian cancer cells, with OGF action mediated by OGFr. Thus, the common denominator of intermittent opioid receptor blockade by short-term NTX or LDN on ovarian cancer proliferation and tumorigenesis recorded herein appears to be related to the OGF-OGFr axis. These preclinical data may offer a non

  13. Combining fisetin and ionizing radiation suppresses the growth of mammalian colorectal cancers in xenograft tumor models

    PubMed Central

    Leu, Jyh-Der; Wang, Bo-Shen; Chiu, Shu-Jun; Chang, Chun-Yuan; Chen, Chien-Chih; Chen, Fu-Du; Avirmed, Shiirevnyamba; Lee, Yi-Jang

    2016-01-01

    Fisetin (3,7,3′,4′-tetrahydroxyflavone), which belongs to the flavonoid group of polyphenols and is found in a wide range of plants, has been reported to exhibit a number of biological activities in human cancer cells, including antioxidant, anti-inflammatory, antiangiogenic, anti-invasive and antiproliferative effects. Although previous in vitro studies have shown that fisetin treatment increases the apoptotic rate and enhances the radiosensitivity of human colorectal cancer cells, the in vivo effects of fisetin on tumor growth remain unclear. In the present study a murine xenograft tumor model was employed to investigate the therapeutic effects of fisetin in combination with radiation on CT-26 colon cancer cells and human HCT116 colorectal cancer cells. This revealed that intratumoral injection of fisetin significantly suppressed the growth of CT-26 tumors compared with the untreated control group, but had little effect on the growth of HCT116 tumors. However, fisetin in combination with 2-Gy radiation enhanced tumor suppressor activity in murine colon and human colorectal xenograft tumors, as compared with 2-Gy fractionated radiation administered alone for 5 days and fisetin alone. Interestingly, fisetin downregulated the expression of the oncoprotein securin in a p53-independent manner. However, securin-null HCT116 tumors showed only moderate sensitivity to fisetin treatment, and the combination of fisetin and radiation did not significantly suppress securin-null HCT116 tumor growth compared with normal HCT116 tumors. Therefore, the role of securin in mediating the effect of fisetin on colorectal cancer growth warrants further investigation. In conclusion, the results of the current study provide important preclinical data for evaluating the efficacy of fisetin and radiation combination treatment as an adjuvant chemoradiotherapy for human colorectal cancers. PMID:28105204

  14. Fatal breast cancer risk in relation to use of unopposed estrogen and combined hormone therapy.

    PubMed

    Pocobelli, Gaia; Newcomb, Polly A; Li, Christopher I; Cook, Linda S; Barlow, William E; Weiss, Noel S

    2014-06-01

    Use of combined hormone therapy (CHT) is associated with increased breast cancer incidence, but it is unclear whether this translates into increased breast cancer mortality. To address this question, we conducted a population-based nested case-control study in Saskatchewan, Canada, where a population-based prescription drug database has existed since 1975. We evaluated fatal breast cancer risk in relation to recency and duration of use of CHT and unopposed estrogen hormone therapy (EHT). A total of 1,288 cases and 12,535 controls were included in the analyses. Exclusive use of EHT was not associated with fatal breast cancer risk, either overall or within categories of recency or duration [odds ratio (OR) for current vs. never use = 1.1; 95 % confidence interval (CI) 0.8-1.3]. Use of CHT (includes women who had also used EHT) was also not associated with fatal breast cancer risk (OR for current vs. never use = 0.9; 95 % CI 0.7-1.3), except for a suggestion of an increased risk with current long-term use. Consistent with prior studies, we observed no increased risk of fatal breast cancer associated with use of EHT. To date only a few studies have evaluated fatal breast cancer risk in relation to use of CHT, and collectively the results are inconsistent.

  15. Fatal Breast Cancer Risk in Relation to Use of Unopposed Estrogen and Combined Hormone Therapy

    PubMed Central

    Pocobelli, Gaia; Newcomb, Polly A.; Li, Christopher I.; Cook, Linda S.; Barlow, William E.; Weiss, Noel S.

    2014-01-01

    Background Use of combined hormone therapy (CHT) is associated with increased breast cancer incidence, but it is unclear whether this translates into increased breast cancer mortality. Methods We conducted a population-based nested case-control study in Saskatchewan, Canada, where a population-based prescription drug database has existed since 1975. We evaluated fatal breast cancer risk in relation to recency and duration of use of CHT and unopposed estrogen hormone therapy (EHT). Results A total of 1,288 cases and 12,535 controls were included in the analyses. Exclusive use of EHT was not associated with fatal breast cancer risk, either overall or within categories of recency or duration (odds ratio (OR) for current versus never use=1.1; 95% CI (confidence interval), 0.8–1.3). Use of CHT (includes women who had also used EHT) was also not associated with fatal breast cancer risk (OR for current versus never use=0.9; 95% CI, 0.7–1.3), except for a suggestion of an increased risk with current long-term use. Conclusion Consistent with prior studies, we observed no increased risk of fatal breast cancer associated with use of EHT. To date only a few studies have evaluated fatal breast cancer risk in relation to use of CHT, and collectively the results are inconsistent. PMID:24671356

  16. A novel resveratrol-salinomycin combination sensitizes ER-positive breast cancer cells to apoptosis.

    PubMed

    Venkatadri, Rajkumar; Iyer, Anand Krishnan V; Kaushik, Vivek; Azad, Neelam

    2017-08-01

    Resveratrol is a dietary compound that has been widely reported for its anticancer activities. However, successful extrapolation of its effects to pre-clinical studies is met with limited success due to inadequate bioavailability. We investigated the potential of combination therapy to improve the efficacy of resveratrol in a more physiologically relevant dose range. The effect of resveratrol on canonical Wnt signaling was evaluated by Western blotting. Wnt modulators HLY78 (activator) and salinomycin (inhibitor) were evaluated in combination with resveratrol for their effect on breast cancer cell viability (MTT assay), cell cycle progression and apoptosis (Western blotting). Bliss independency model was used to evaluate combinatorial effects of resveratrol-salinomycin combination. Resveratrol downregulated canonical Wnt signaling proteins in treated breast cancer cells (MCF-7, MDA-MB-231 and MDA-MB-468) in the dose range of 50-200μM, which also affected cellular viability. However, at very low doses (0-50μM), resveratrol exhibited no cellular toxicity. Co-treatment with salinomycin significantly potentiated the anti-cancer effects of resveratrol, whereas HLY78 co-treatment had minimal effect. Bliss independency model revealed that Wnt inhibition synergistically potentiates the effects of resveratrol in MCF-7 and BT474 cells. Significantly downregulated canonical Wnt signaling proteins and marker of epithelial-mesenchymal transition (EMT), vimentin were observed in cells treated with resveratrol-salinomycin combination. Cell cycle arrest, caspase activation and apoptosis induction in cells treated with resveratrol-salinomycin combination further confirmed the efficacy of the combination. We report a novel resveratrol-salinomycin combination for targeting ER-positive breast cancer cells and present evidence for successful pre-clinical implementation of resveratrol. Copyright © 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban

  17. Synergistic effect of MEK inhibitor and metformin combination in low grade serous ovarian cancer.

    PubMed

    Mert, Ismail; Chhina, Jasdeep; Allo, Ghassan; Dai, Jing; Seward, Shelly; Carey, Mark S; Llaurado, Marta; Giri, Shailendra; Rattan, Ramandeep; Munkarah, Adnan R

    2017-08-01

    Low-grade serous ovarian cancer (LGSOC) constitutes 5-8% of epithelial ovarian cancers and is refractory to chemotherapy. We and others have shown metformin to cause significant growth inhibition in high-grade ovarian cancer both in vitro and in vivo. Here, we aimed to analyze if metformin was effective in inhibiting proliferation of LGSOC alone and in combination with MEK inhibitor. Three LGSOC lines (VOA1056, VOA1312 and VOA5646) were treated with metformin, trametinib or 2-deoxyglucose (2DG) alone or in combination with metformin. Proliferation was measured by MTT assay over a period of four days. Protein expression was measured by western blotting. Seahorse Analyzer was used to measure effect of metformin on glycolysis and mitochondrial respiration. All LGSOC cell lines showed significant inhibition with metformin in a dose- and time-dependent manner. Trametinib significantly inhibited the growth of Ras mutated LGSOC lines (VOA1312 and VOA1056), while VOA5646 cells without RAS mutation did not show any response. Metformin and trametinib combination showed synergistic inhibition of RAS mutated VOA1312 and VOA1056 cells, but not for non-Ras mutated VOA5646 cells. Metformin and trametinib increased phosphorylated AMPK expression in LGSOC lines with combination showing stronger expression. Trametinib decreased 42/44 mitogen activated kinase phosphorylation in all cell lines, while metformin and combination had no significant effect. 2-DG significantly inhibited glycolysis in all LGSOC lines and combination with metformin showed synergistic inhibitory effect. Metformin alone or in combination with MEK and glycolytic inhibitors may be a potential therapy for LGSOC, a cancer that is indolent but chemo-resistant. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Preclinical rationale for combination of crizotinib with mitomycin C for the treatment of advanced colorectal cancer.

    PubMed

    Lev, Avital; Deihimi, Safoora; Shagisultanova, Elena; Xiu, Joanne; Lulla, Amriti R; Dicker, David T; El-Deiry, Wafik S

    2017-09-08

    Colorectal cancer (CRC) is a leading cause of cancer-related deaths in the United States. We analyzed 26 MSI-High and 558 non-MSI-High CRC tumors. BRCA2 mutations were highly enriched (50%) in MSI-High CRC. Immunohistochemistry showed that BRCA2-mutated MSI-High CRC had high c-MET (64%) expression compared with BRCA-WT (17%). We hypothesized a mechanistic link between BRCA2-deficiency and c-MET overexpression and synergistic interaction between drugs that treat BRCA-deficient tumors (mitomycin C (MMC) or PARP inhibitors) and c-MET inhibitors (crizotinib). We tested CRC cell lines for sensitivity to MMC plus crizotinib or other drug combinations including PARP-inhibitors. Combined treatment of tumor cells with crizotinib and MMC led to increased apoptosis as compared with each drug alone. Additionally, combination treatment with increasing concentrations of both drugs demonstrated a synergistic anti-cancer effect (CI = 0.006-0.74). However, we found no evidence for c-MET upregulation upon effective BRCA2 knockdown in tumor cells -/+DNA damage. Although we found no mechanistic link between BRCA2 deficiency and c-MET overexpression, c-MET is frequently overexpressed in CRC and BRCA2 is mutated especially in MSI-H CRC. The combination of crizotinib with MMC appeared synergistic regardless of MSI or BRCA2 status. Using an in-vivo CRC xenograft model we found reduced tumor growth with combined crizotinib and MMC therapy (p = 0.0088). Our preclinical results support clinical testing of the combination of MMC and crizotinib in advanced CRC. Targeting cell survival mediated by c-MET in combination with targeting DNA repair may be a reasonable strategy for therapy development in CRC or other cancers.

  19. Combined brachytherapy and external beam radiation: an effective approach for palliation in esophageal cancer

    PubMed Central

    Lewis, Shirley; Agarwal, Jai Prakash; Mishra, Shagun; Mehta, Shaesta; Patil, Prachi

    2015-01-01

    Purpose Palliation of dysphagia is a challenge in advanced esophageal cancer. The addition of external beam radiotherapy (EBRT) to intraluminal brachytherapy (ILBT) has shown significant improvement in dysphagia relief and symptom scores. The aim of the present study was to evaluate the efficacy of combined use of ILBT and EBRT. Material and methods The medical records of 148 patients with advanced/metastatic esophageal cancer were screened from January 2008 to April 2014, and 74 patients were found eligible for the analysis. All patients received two fractions of 8 Gy each of ILBT, followed by EBRT. Patients were assessed for the symptom scores of dysphagia, odynophagia, regurgitation, and chest pain and weight was recorded periodically. Results For a median follow-up of 6 months, the median OS was 9.5 mon