Sample records for cancer combined analysis

  1. A meta-analysis of bevacizumab combined with chemotherapy in the treatment of ovarian cancer.

    PubMed

    Wang, T S; Lei, W; Cui, W; Wen, P; Guo, H F; Ding, S G; Yang, Y P; Xu, Y Q; Lv, S W; Zhu, Y L

    2014-03-01

    Angiogenesis plays an important role in the biology of ovarian cancer. The clinical efficacy and side effects of bevacizumab, the vascular endothelial growth factor inhibitor, on survival and toxicity in women with this ovarian cancer, was not conclusive. We performed this systematic review and meta-analysis in order to clarify the efficacy of bevacizumab combined with chemotherapy in the treatment of ovarian cancer. We searched the electronic database of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and CNKI for clinical controlled trials of comparing bevacizumab combined with chemotherapy and chemotherapy alone in the treatment of ovarian cancer. The primary outcomes of eligible studies included median progression-free survival (PFS), overall survival (OS), and toxicities such as enterobrosis, hypertension, albuminuria, congestive heart failure (CHF), neutrophils, thrombosis, and bleeding. The Hazard ratio (HR) and relative risk were used for the meta-analysis and were expressed with 95% confidence intervals (CIs). All the statistical analyses were carried out by  Stata 11.0 software (http://www.stata.com; Stata Corporation, College Station, TX, USA). We included 5 studies with 1798 cases in the bevacizumab combined with the chemotherapy group and 1810 subjects in the chemotherapy alone group. The pooled results showed that bevacizumab + chemotherapy compared with chemotherapy alone can significant prolong the median PFS (HR, 0.64; 95% CI, 0.46-0.82; P < 0.05) but not the OS (HR, 0.84; 95% CI, 0.59-10.9; P > 0.05); the toxicity analysis showed that the enterobrosis, hypertension, albuminuria, neutrophils, thrombosis, and bleeding were significantly increased in the bevacizumab + chemotherapy group compared with chemotherapy alone (Pall < 0.05). But the CHF risk between the two groups was not statistical different (P > 0.05). Bevacizumab combined with chemotherapy prolonged the median PFS in patients with ovarian cancer but also increase the

  2. 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.

  3. Combining aneuploidy and dysplasia for colitis' cancer risk assessment outperforms current surveillance efficiency: a meta-analysis.

    PubMed

    Meyer, Rüdiger; Freitag-Wolf, Sandra; Blindow, Silke; Büning, Jürgen; Habermann, Jens K

    2017-02-01

    Cancer risk assessment for ulcerative colitis patients by evaluating histological changes through colonoscopy surveillance is still challenging. Thus, additional parameters of high prognostic impact for the development of colitis-associated carcinoma are necessary. This meta-analysis was conducted to clarify the value of aneuploidy as predictor for individual cancer risk compared with current surveillance parameters. A systematic web-based search identified studies published in English that addressed the relevance of the ploidy status for individual cancer risk during surveillance in comparison to neoplastic mucosal changes. The resulting data were included into a meta-analysis, and odds ratios (OR) were calculated for aneuploidy or dysplasia or aneuploidy plus dysplasia. Twelve studies addressing the relevance of aneuploidy compared to dyplasia were comprehensively evaluated and further used for meta-analysis. The meta-analysis revealed that aneuploidy (OR 5.31 [95 % CI 2.03, 13.93]) is an equally effective parameter for cancer risk assessment in ulcerative colitis patients as dysplasia (OR 4.93 [1.61, 15.11]). Strikingly, the combined assessment of dysplasia and aneuploidy is superior compared to applying each parameter alone (OR 8.99 [3.08, 26.26]). This meta-analysis reveals that aneuploidy is an equally effective parameter for individual cancer risk assessment in ulcerative colitis as the detection of dysplasia. More important, the combined assessment of dysplasia and aneuploidy outperforms the use of each parameter alone. We suggest image cytometry for ploidy assessment to become an additional feature of consensus criteria to individually assess cancer risk in UC.

  4. Cancer cell-selective killing polymer/copper combination.

    PubMed

    He, Huacheng; Altomare, Diego; Ozer, Ufuk; Xu, Hanwen; Creek, Kim; Chen, Hexin; Xu, Peisheng

    2016-01-01

    Chemotherapy has been adopted for cancer treatment for decades. However, its efficacy and safety are frequently compromised by the multidrug-resistance of cancer cells and the poor cancer cell selectivity of anticancer drugs. Hereby, we report a combination of a pyridine-2-thiol containing polymer and copper which can effectively kill a wide spectrum of cancer cells, including drug resistant cancer cells, while sparing normal cells. The polymer nanoparticle enters cells via an exofacial thiol facilitated route, and releases active pyridine-2-thiol with the help of intracellularly elevated glutathione (GSH). Due to their high GSH level, cancer cells are more vulnerable to the polymer/copper combination. In addition, RNA microarray analysis revealed that the treatment can reverse cancer cells' upregulated oncogenes (CIRBP and STMN1) and downregulated tumor suppressor genes (CDKN1C and GADD45B) to further enhance the selectivity for cancer cells.

  5. Identification of Linkages between EDCs in Personal Care Products and Breast Cancer through Data Integration Combined with Gene Network Analysis.

    PubMed

    Jeong, Hyeri; Kim, Jongwoon; Kim, Youngjun

    2017-09-30

    Approximately 1000 chemicals have been reported to possibly have endocrine disrupting effects, some of which are used in consumer products, such as personal care products (PCPs) and cosmetics. We conducted data integration combined with gene network analysis to: (i) identify causal molecular mechanisms between endocrine disrupting chemicals (EDCs) used in PCPs and breast cancer; and (ii) screen candidate EDCs associated with breast cancer. Among EDCs used in PCPs, four EDCs having correlation with breast cancer were selected, and we curated 27 common interacting genes between those EDCs and breast cancer to perform the gene network analysis. Based on the gene network analysis, ESR1, TP53, NCOA1, AKT1, and BCL6 were found to be key genes to demonstrate the molecular mechanisms of EDCs in the development of breast cancer. Using GeneMANIA, we additionally predicted 20 genes which could interact with the 27 common genes. In total, 47 genes combining the common and predicted genes were functionally grouped with the gene ontology and KEGG pathway terms. With those genes, we finally screened candidate EDCs for their potential to increase breast cancer risk. This study highlights that our approach can provide insights to understand mechanisms of breast cancer and identify potential EDCs which are in association with breast cancer.

  6. Identification of Linkages between EDCs in Personal Care Products and Breast Cancer through Data Integration Combined with Gene Network Analysis

    PubMed Central

    Kim, Jongwoon

    2017-01-01

    Approximately 1000 chemicals have been reported to possibly have endocrine disrupting effects, some of which are used in consumer products, such as personal care products (PCPs) and cosmetics. We conducted data integration combined with gene network analysis to: (i) identify causal molecular mechanisms between endocrine disrupting chemicals (EDCs) used in PCPs and breast cancer; and (ii) screen candidate EDCs associated with breast cancer. Among EDCs used in PCPs, four EDCs having correlation with breast cancer were selected, and we curated 27 common interacting genes between those EDCs and breast cancer to perform the gene network analysis. Based on the gene network analysis, ESR1, TP53, NCOA1, AKT1, and BCL6 were found to be key genes to demonstrate the molecular mechanisms of EDCs in the development of breast cancer. Using GeneMANIA, we additionally predicted 20 genes which could interact with the 27 common genes. In total, 47 genes combining the common and predicted genes were functionally grouped with the gene ontology and KEGG pathway terms. With those genes, we finally screened candidate EDCs for their potential to increase breast cancer risk. This study highlights that our approach can provide insights to understand mechanisms of breast cancer and identify potential EDCs which are in association with breast cancer. PMID:28973975

  7. Combination therapy in combating cancer

    PubMed Central

    Mokhtari, Reza Bayat; Homayouni, Tina S.; Baluch, Narges; Morgatskaya, Evgeniya; Kumar, Sushil; Das, Bikul; Yeger, Herman

    2017-01-01

    Combination therapy, a treatment modality that combines two or more therapeutic agents, is a cornerstone of cancer therapy. The amalgamation of anti-cancer drugs enhances efficacy compared to the mono-therapy approach because it targets key pathways in a characteristically synergistic or an additive manner. This approach potentially reduces drug resistance, while simultaneously providing therapeutic anti-cancer benefits, such as reducing tumour growth and metastatic potential, arresting mitotically active cells, reducing cancer stem cell populations, and inducing apoptosis. The 5-year survival rates for most metastatic cancers are still quite low, and the process of developing a new anti-cancer drug is costly and extremely time-consuming. Therefore, new strategies that target the survival pathways that provide efficient and effective results at an affordable cost are being considered. One such approach incorporates repurposing therapeutic agents initially used for the treatment of different diseases other than cancer. This approach is effective primarily when the FDA-approved agent targets similar pathways found in cancer. Because one of the drugs used in combination therapy is already FDA-approved, overall costs of combination therapy research are reduced. This increases cost efficiency of therapy, thereby benefiting the “medically underserved”. In addition, an approach that combines repurposed pharmaceutical agents with other therapeutics has shown promising results in mitigating tumour burden. In this systematic review, we discuss important pathways commonly targeted in cancer therapy. Furthermore, we also review important repurposed or primary anti-cancer agents that have gained popularity in clinical trials and research since 2012. PMID:28410237

  8. Grade-Dependent Metabolic Reprogramming in Kidney Cancer Revealed by Combined Proteomics and Metabolomics Analysis [Combined Proteomics and Metabolomics Analysis Reveals Grade-Dependent Metabolism Pathways in Kidney Cancer

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Wettersten, Hiromi I.; Hakimi, A. Ari; Morin, Dexter

    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 Warburgmore » 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. Altogether, our results offer a rationale to evaluate novel antimetabolic treatment strategies being developed in other disease settings as therapeutic strategies in RCC« less

  9. Grade-Dependent Metabolic Reprogramming in Kidney Cancer Revealed by Combined Proteomics and Metabolomics Analysis [Combined Proteomics and Metabolomics Analysis Reveals Grade-Dependent Metabolism Pathways in Kidney Cancer

    DOE PAGES

    Wettersten, Hiromi I.; Hakimi, A. Ari; Morin, Dexter; ...

    2015-05-07

    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 Warburgmore » 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. Altogether, our results offer a rationale to evaluate novel antimetabolic treatment strategies being developed in other disease settings as therapeutic strategies in RCC« less

  10. Jianpi Bushen, a Traditional Chinese Medicine Therapy, Combined with Chemotherapy for Gastric Cancer Treatment: A Meta-Analysis of Randomized Controlled Trials

    PubMed Central

    Chen, Yunbo; Zhang, Guijuan; Chen, Xiaoping; Jiang, Xuefeng; Yuan, Naijun; Wang, Yurong; Hao, Xiaoqian

    2018-01-01

    Objective. To investigate the effects of Jianpi Bushen (JPBS), a traditional Chinese medicine that is used to invigorate the spleen and tonify the kidney, combined with chemotherapy for the treatment of gastric cancer. Methods. Literature retrieval was performed in PubMed, EMBASE, Cochrane Library, MEDLINE, CNKI, Wanfang Data Information Site, and VIP from inception to October 2017. Randomized controlled trials to evaluate the effects of JPBS combined with chemotherapy were identified. The primary reported outcomes were KPS (Karnofsky Performance Status), clinical curative efficiency, immune function, blood system, and nonhematologic system. Review Manager 5.3 (RevMan 5.3) was used for data analysis, and the quality of the studies was also appraised. Results. A total of 26 studies were included with 3098 individuals. The results of the meta-analysis indicated that treatment of gastric cancer with the combination of JPBS and chemotherapy resulted in better outcomes compared to chemotherapy alone. Conclusion. Evidence from the meta-analysis suggested that JPBS combined with chemotherapy has a positive effect on gastric cancer treatment. However, additional rigorously designed and large sample randomized controlled trials are required to confirm the efficacy and safety of this treatment. PMID:29675052

  11. Meta-Analysis of Oxaliplatin-Based Chemotherapy Combined With Traditional Medicines for Colorectal Cancer

    PubMed Central

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

    2015-01-01

    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], I2 = 0%). Benefits were evident for both injection products (RR 1.36 [1.18-1.57], I2 = 0%) and orally administered TMs (RR 1.27 [1.15-1.41], I2 = 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. PMID:26254190

  12. Comparative study of CEA and CA19-9 in esophageal, gastric and colon cancers individually and in combination (ROC curve analysis).

    PubMed

    Bagaria, Bhawna; Sood, Sadhna; Sharma, Rameshwaram; Lalwani, Soniya

    2013-09-01

    To determine the clinical serum levels of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9), individually and in combination, for the diagnosis of 50 healthy subjects and 150 cases of esophageal, gastric, and colon cancers. The sensitivities of the two markers were compared individually and in combination, with specificity set at 100%. Receiver operating characteristic (ROC) curves were plotted. Serum CEA levels were significantly higher in cancer patients than in the control group. The sensitivity of CEA was determined: in esophageal cancer, sensitivity=28%, negative predictive value (NPV)=61.72%, and AUC=0.742 
(SE=0.05), with a significance level of P<0.0001; in gastric cancer, sensitivity=30%, NPV=58.82%, and AUC=0.734 (SE=0.05), with a significance level of P<0.0001; in colon cancer, sensitivity=74%, NPV=79.36%, and AUC=0.856 
(SE=0.04), with a significance level of P<0.0001. The sensitivity of CA19-9 was also evaluated: in esophageal cancer, sensitivity=18%, NPV=54.94%, and AUC=0.573 (SE =0.05), with a significance level of P=0.2054. In gastric cancer, sensitivity=42%, NPV=63.29%, and AUC=0.679 (SE =0.05), with a significance level of P<0.0011. In colon cancer, sensitivity=26%, NPV=57.47%, and AUC=0.580 (SE =0.05), with a significance level of P=0.1670. The following were the sensitivities of CEA/CA19-9 combined: in esophageal cancer, sensitivity=42%, NPV=63.29%, SE=0.078 (95% CI: 0.0159-0.322); gastric cancer, sensitivity=58%, NPV=70.42%, SE=0.072 (95% CI: -0.0866-0.198); and colon cancer, sensitivity=72%, NPV=78.12%, SE=0.070 (95% CI: 0.137-0.415). CEA exhibited the highest sensitivity for colon cancer, and CA19-9 exhibited the highest sensitivity for gastric cancer. Combined analysis indicated an increase in diagnostic sensitivity in esophageal and gastric cancer compared with that in colon cancer.

  13. A combined analysis of North American case-control studies of residential radon and lung cancer.

    PubMed

    Krewski, Daniel; Lubin, Jay H; Zielinski, Jan M; Alavanja, Michael; Catalan, Vanessa S; Field, R William; Klotz, Judith B; Létourneau, Ernest G; Lynch, Charles F; Lyon, Joseph L; Sandler, Dale P; Schoenberg, Janet B; Steck, Daniel J; Stolwijk, Jan A; Weinberg, Clarice; Wilcox, Homer B

    2006-04-01

    Cohort studies have consistently shown underground miners exposed to high levels of radon to be at excess risk of lung cancer, and extrapolations based on those results indicate that residential radon may be responsible for nearly 10-15% of all lung cancer deaths per year in the United States. However, case-control studies of residential radon and lung cancer have provided ambiguous evidence of radon lung cancer risks. Regardless, alpha-particle emissions from the short-lived radioactive radon decay products can damage cellular DNA. The possibility that a demonstrated lung carcinogen may be present in large numbers of homes raises a serious public health concern. Thus, a systematic analysis of pooled data from all North American residential radon studies was undertaken to provide a more direct characterization of the public health risk posed by prolonged radon exposure. To evaluate the risk associated with prolonged residential radon exposure, a combined analysis of the primary data from seven large scale case-control studies of residential radon and lung cancer risk was conducted. The combined data set included a total of 4081 cases and 5281 controls, representing the largest aggregation of data on residential radon and lung cancer conducted to date. Residential radon concentrations were determined primarily by a-track detectors placed in the living areas of homes of the study subjects in order to obtain an integrated 1-yr average radon concentration in indoor air. Conditional likelihood regression was used to estimate the excess risk of lung cancer due to residential radon exposure, with adjustment for attained age, sex, study, smoking factors, residential mobility, and completeness of radon measurements. Although the main analyses were based on the combined data set as a whole, we also considered subsets of the data considered to have more accurate radon dosimetry. This included a subset of the data involving 3662 cases and 4966 controls with a-track radon

  14. 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.

  15. 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

  16. Grade-dependent metabolic reprogramming in kidney cancer revealed by combined proteomics and metabolomics analysis

    PubMed Central

    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.

    2015-01-01

    Kidney cancer (or renal cell carcinoma [RCC]) is known as “the internist’s tumor” because it has protean systemic manifestations suggesting it utilizes complex, non-physiologic 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 VHL 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, while the β-oxidation pathway is inhibited leading to increased fatty acyl-carnitines. 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 to other metabolic pathways. Together, our results offer a rationale to evaluate novel anti-metabolic treatment strategies being developed in other disease settings as therapeutic strategies in RCC. PMID:25952651

  17. Combining immunotherapies for the treatment of prostate cancer.

    PubMed

    Redman, Jason M; Gulley, James L; Madan, Ravi A

    2017-12-01

    Sipuleucel-T, a therapeutic dendritic-cell vaccine, was Food and Drug Administration-approved for prostate cancer in 2010. No new immunotherapies for prostate cancer have been approved since. However, novel agents and combination approaches offer great promise for improving outcomes for prostate cancer patients. Here we review the latest developments in immunotherapy for prostate cancer. Sipuleucel-T has demonstrated a survival advantage of 4.1 months in metastatic castration-resistant prostate cancer. PSA-TRICOM (PROSTVAC), a prostate-specific antigen-targeted vaccine platform, showed evidence of clinical and immunologic efficacy in early-phase clinical trials, and results from a phase III trial in advanced disease are pending. While immune checkpoint inhibitors appear to have modest activity as monotherapy, preclinical and clinical data suggest that they may synergize with vaccines, poly [ADP-ribose] polymerase inhibitors, and other agents. Several clinical studies that combine these therapies are underway. Combining prostate cancer vaccines with immune checkpoint inhibitors has great potential for improving clinical outcomes in prostate cancer. Such combination approaches may create and then recruit tumor-specific T cells to tumor while also increasing their effector function. Other emerging agents may also enhance immune-mediated tumor destruction. Copyright © 2017. Published by Elsevier Inc.

  18. 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

  19. Sequential combination therapy of ovarian cancer with cisplatin and γ-secretase inhibitor MK-0752.

    PubMed

    Chen, XiuXiu; Gong, LiHua; Ou, RongYing; Zheng, ZhenZhen; Chen, JinYan; Xie, FengFeng; Huang, XiaoXiu; Qiu, JianGe; Zhang, WenJi; Jiang, QiWei; Yang, Yang; Zhu, Hua; Shi, Zhi; Yan, XiaoJian

    2016-03-01

    Ovarian cancer is one of the most lethal of women cancers and lack potent therapeutic options. There have many evidences demonstrate the Notch signaling has deregulation in variety of human malignancies.MK-0752 is a novel potent γ-secretase inhibitor and now assessed in clinical trial for treatment of several types of cancer, our objective was to investigate the anticancer effects and mechanisms of MK-0752 alone or combined with cisplatin in ovarian cancer. Cell lines used: A2780, OVCAR3, SKOV3, HO8910PM, the effects of MK-0752 and cisplatin on cell proliferation were measured by MTT assay. The effect of combination treatment was examined by isobologram analysis. The distribution of cell cycle and cell apoptosis were analyzed using PI and Annexin V-FITC/PI staining by flow cytometric analysis. The mechanism in biochemistry was analyzed by using Western blot. Mouse xenograft model of A2780 was established to observe the anti-ovarian cancer effects in vivo setting, nude mice were randomized into four groups (n=6 per group) and treated every 4 days with control (solvent) group, MK-0752(25mg/kg) group, cisplatin (2mg/kg)group, combination group (both of MK-0752 and cisplatin). MK-0752 alone actively induced cell growth inhibition, G2/M phase cell cycle arrest and apoptosis with down-regulation of Notch1 and its downstream effectors including Hes1, XIAP, c-Myc and MDM2 in a dose- and time-dependent manner. Moreover, sequential combination of cisplatin prior to MK-0752 significantly promoted cell apoptosis and inhibited the subcutaneous xenograft growth of ovarian cancer in nude mice. Our data supports the sequential combination of cisplatin prior to MK-0752 is a highly promising novel experimental therapeutic strategy against ovarian cancer. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. Radiation and Anti-Cancer Vaccines: A Winning Combination.

    PubMed

    Cadena, Alexandra; Cushman, Taylor R; Anderson, Clark; Barsoumian, Hampartsoum B; Welsh, James W; Cortez, Maria Angelica

    2018-01-30

    The emerging combination of radiation therapy with vaccines is a promising new treatment plan in the fight against cancer. While many cancer vaccines such as MUC1, p53 CpG oligodeoxynucleotide, and SOX2 may be great candidates for antitumor vaccination, there still remain many investigations to be done into possible vaccine combinations. One fruitful partnership that has emerged are anti-tumor vaccines in combination with radiation. Radiation therapy was previously thought to be only a tool for directly or indirectly damaging DNA and therefore causing cancer cell death. Now, with much preclinical and clinical data, radiation has taken on the role of an in situ vaccine. With both cancer vaccines and radiation at our disposal, more and more studies are looking to combining vaccine types such as toll-like receptors, viral components, dendritic-cell-based, and subunit vaccines with radiation. While the outcomes of these combinatory efforts are promising, there is still much work to be covered. This review sheds light on the current state of affairs in cancer vaccines and how radiation will bring its story into the future.

  1. Cancer nanomedicine: gold nanoparticle mediated combined cancer therapy

    NASA Astrophysics Data System (ADS)

    Yang, C.; Bromma, Kyle; Chithrani, B. D.

    2018-02-01

    Recent developments in nanotechnology has provided new tools for cancer therapy and diagnosis. Among other nanomaterial systems, gold nanoparticles are being used as radiation dose enhancers and anticancer drug carriers in cancer therapy. Fate of gold nanoparticles within biological tissues can be probed using techniques such as TEM (transmission electron microscopy) and SEM (Scanning Electron Microscopy) due to their high electron density. We have shown for the first time that cancer drug loaded gold nanoparticles can reach the nucleus (or the brain) of cancer cells enhancing the therapeutic effect dramatically. Nucleus of the cancer cells are the most desirable target in cancer therapy. In chemotherapy, smart delivery of highly toxic anticancer drugs through packaging using nanoparticles will reduce the side effects and improve the quality and care of cancer patients. In radiation therapy, use of gold nanoparticles as radiation dose enhancer is very promising due to enhanced localized dose within the cancer tissue. Recent advancement in nanomaterial characterization techniques will facilitate mapping of nanomaterial distribution within biological specimens to correlate the radiobiological effects due to treatment. Hence, gold nanoparticle mediated combined chemoradiation would provide promising tools to achieve personalized and tailored cancer treatments in the near future.

  2. 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

  3. Meta-Analysis of Tumor Stem-Like Breast Cancer Cells Using Gene Set and Network Analysis

    PubMed Central

    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

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

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Wairagu, Peninah M.; Institute of Lifestyle Medicine, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do 220-701; Nuclear Receptor Research Consortium, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do 220-701

    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 eachmore » 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.« less

  5. 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.

  6. 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.

  7. 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

  8. Curcumin in combined cancer therapy.

    PubMed

    Troselj, Koraljka Gall; Kujundzic, Renata Novak

    2014-01-01

    The mechanisms of beneficial preventive and therapeutic effects achieved by traditional and complementary medicine are currently being deciphered in molecular medicine. Curcumin, a yellow-colored polyphenol derived from the rhizome of turmeric (Curcuma longa), influences a wide variety of cellular processes through the reshaping of many molecular targets. One of them, nuclear factor kappa B (NF-κB), represents a strong mediator of inflammation and, in a majority of systems, supports the pro-proliferative features of cancer cells. The application of various anticancer drugs, cytostatics, triggers signals which lead to an increase in cellular NF-κB activity. As a consequence, cancer cells often reshape their survival signaling pathways and, over time, become resistant to applied therapy. Curcumin was shown to be a strong inhibitor of NF-κB activity and its inhibitory effect on NF-κB related pathways often leads to cellular apoptotic response. All these facts, tested and confirmed in many different biological systems, have paved the way for research aimed to elucidate the potential beneficial effects of combining curcumin and various anti-cancer drugs in order to establish more efficient and less toxic cancer treatment modalities. This review addresses certain aspects of NF-κB-related inflammatory response, its role in carcinogenesis and therapy benefits that may be gained through silencing NF-κB by selectively combining curcumin and various anticancer drugs.

  9. Two drugs are better than one. A short history of combined therapy of ovarian cancer.

    PubMed

    Bukowska, Barbara; Gajek, Arkadiusz; Marczak, Agnieszka

    2015-01-01

    Combined therapy of ovarian cancer has a long history. It has been applied for many years. The first drug which was commonly combined with other chemotherapeutics was cisplatin. It turned out to be effective given together with alkylating agents as well as with taxanes. Another drug which is often the basis of first-line therapy is doxorubicin. The use of traditional chemotherapy is often limited due to side effects. This is why new drugs, targeted specifically at cancer cells (e.g. monoclonal antibodies or epidermal growth factor receptor inhibitors), offer a welcome addition when used in combination with conventional anticancer agents. Drugs applied in combination should be synergistic or at least additive. To evaluate the type of interaction between drugs in a plausible sequence, isobolographic analysis is used. This method allows one to assess whether the two agents could make an efficient combination, which might improve the therapy of ovarian cancer.

  10. Immunotherapy Combination Approved for Advanced Kidney Cancer

    Cancer.gov

    FDA has approved the combination of the immunotherapy drugs nivolumab (Opdivo) and ipilimumab (Yervoy) as an initial treatment for some patients with advanced kidney cancer. The approval is expected to immediately affect patient care, as this Cancer Currents post explains.

  11. Patient-derived models of acquired resistance can identify effective drug combinations for cancer.

    PubMed

    Crystal, Adam S; Shaw, Alice T; Sequist, Lecia V; Friboulet, Luc; Niederst, Matthew J; Lockerman, Elizabeth L; Frias, Rosa L; Gainor, Justin F; Amzallag, Arnaud; Greninger, Patricia; Lee, Dana; Kalsy, Anuj; Gomez-Caraballo, Maria; Elamine, Leila; Howe, Emily; Hur, Wooyoung; Lifshits, Eugene; Robinson, Hayley E; Katayama, Ryohei; Faber, Anthony C; Awad, Mark M; Ramaswamy, Sridhar; Mino-Kenudson, Mari; Iafrate, A John; Benes, Cyril H; Engelman, Jeffrey A

    2014-12-19

    Targeted cancer therapies have produced substantial clinical responses, but most tumors develop resistance to these drugs. Here, we describe a pharmacogenomic platform that facilitates rapid discovery of drug combinations that can overcome resistance. We established cell culture models derived from biopsy samples of lung cancer patients whose disease had progressed while on treatment with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors and then subjected these cells to genetic analyses and a pharmacological screen. Multiple effective drug combinations were identified. For example, the combination of ALK and MAPK kinase (MEK) inhibitors was active in an ALK-positive resistant tumor that had developed a MAP2K1 activating mutation, and the combination of EGFR and fibroblast growth factor receptor (FGFR) inhibitors was active in an EGFR mutant resistant cancer with a mutation in FGFR3. Combined ALK and SRC (pp60c-src) inhibition was effective in several ALK-driven patient-derived models, a result not predicted by genetic analysis alone. With further refinements, this strategy could help direct therapeutic choices for individual patients. Copyright © 2014, American Association for the Advancement of Science.

  12. Docetaxel Alone or in Combination With a Therapeutic Cancer Vaccine (PANVAC) in Patients With Metastatic Breast Cancer: A Randomized Clinical Trial.

    PubMed

    Heery, Christopher R; Ibrahim, Nuhad K; Arlen, Philip M; Mohebtash, Mahsa; Murray, James L; Koenig, Kimberly; Madan, Ravi A; McMahon, Sheri; Marté, Jennifer L; Steinberg, Seth M; Donahue, Renee N; Grenga, Italia; Jochems, Caroline; Farsaci, Benedetto; Folio, Les R; Schlom, Jeffrey; Gulley, James L

    2015-11-01

    Previous phase 1 and 2 trials of PANVAC, a poxviral-based cancer vaccine, have suggested clinical efficacy in some patients with breast, ovarian, and colorectal cancer and have shown evidence of immunologic activity. Preclinical data have shown that docetaxel can modify tumor phenotype, making tumor cells more amenable to T cell-mediated killing. The goal of this study was to determine if the treatment combination of docetaxel and PANVAC improves clinical outcomes in patients with metastatic breast cancer compared with docetaxel treatment alone. Between May 2006 and February 2012, this open-label, phase 2 randomized clinical trial enrolled 48 patients with metastatic breast cancer of all subtypes, without limitation on other lines of previous therapy, to receive treatment with either docetaxel with PANVAC (arm A) or docetaxel alone (arm B). Final clinical data were collected on September 16, 2013. All patients were treated at either the National Cancer Institute or the Department of Breast Medical Oncology, MD Anderson Cancer Center. The primary end point was progression-free survival (PFS), using a phase 2.5 statistical design, with the intent of identifying a trend toward benefit (defined as 1-sided P≤.10) to guide a larger trial design. Secondary end points included safety and immunologic correlative studies. Forty-eight participants were enrolled: 25 were randomized to the combination treatment arm A, and 23 to arm B. No patient remained in the study at the time of the final analysis. Patient and tumor characteristics were well matched. Analysis of adverse events in both treatment arms demonstrated very little difference between the 2 groups. In the combination treatment arm (arm A), statistically significant increases were noted in the frequency of grades 1 and 2 edema (P=.02, likely related to greater median number of docetaxel cycles) and injection-site reactions (P<.001). In the final data analysis, median PFS was 7.9 months in arm A vs 3.9 months in arm

  13. Two drugs are better than one. A short history of combined therapy of ovarian cancer

    PubMed Central

    Gajek, Arkadiusz; Marczak, Agnieszka

    2014-01-01

    Combined therapy of ovarian cancer has a long history. It has been applied for many years. The first drug which was commonly combined with other chemotherapeutics was cisplatin. It turned out to be effective given together with alkylating agents as well as with taxanes. Another drug which is often the basis of first-line therapy is doxorubicin. The use of traditional chemotherapy is often limited due to side effects. This is why new drugs, targeted specifically at cancer cells (e.g. monoclonal antibodies or epidermal growth factor receptor inhibitors), offer a welcome addition when used in combination with conventional anticancer agents. Drugs applied in combination should be synergistic or at least additive. To evaluate the type of interaction between drugs in a plausible sequence, isobolographic analysis is used. This method allows one to assess whether the two agents could make an efficient combination, which might improve the therapy of ovarian cancer. PMID:26793017

  14. Combined inhibition of glycolysis and AMPK induces synergistic breast cancer cell killing

    PubMed Central

    Wu, Yong; Sarkissyan, Marianna; Mcghee, Eva; Lee, Sangkyu

    2015-01-01

    Targeting glycolysis for cancer treatment has been investigated as a therapeutic method but has not offered a feasible chemotherapeutic strategy. Our aim was to examine whether AMP-activated protein kinase (AMPK), a conditional oncogene, rescues the energetic stress and cytotoxicity induced by 2-deoxyglucose (2-DG), a glycolytic inhibitor, and the related mechanisms. Luciferin/luciferase adenosine triphosphate (ATP) determination, Western analysis, qRT-PCR analyses, MTT growth assay, clonogenic assay, and statistical analysis were performed in this study. 2-DG decreased ATP levels and subsequently activated AMPK, which contribute to intracellular ATP recovery in MCF-7 cells thus exhibiting no apparent cytotoxicity. Compound C, an AMPK inhibitor, further potentiates 2-DG-induced decrease in ATP levels and inhibits their recovery. 2-DG, via AMPK activation, stimulated cAMP response element-binding protein (CREB) phosphorylation and activity and promoted nuclear peroxisome proliferator-activated receptor gamma coactivator-1-beta (PGC-1β) and estrogen-related receptor α (ERRα) protein expression, leading to augmented mitochondrial biogenesis and expression of fatty acid oxidation (FAO) genes including PPARα, MCAD, CPT1C, and ACO. This metabolic adaptation elicited by AMPK counteracts the ATP-depleting and cancer cell-killing effect of 2-DG. However, 2-DG in combination with AMPK antagonists or small interfering RNA caused a dramatic increase in cytotoxicity in MCF-7 but not in MCF-10A cells. Similarly, when combined with inhibition of CREB/PGC-1β/ERRα pathway, 2-DG saliently suppressed mitochondrial biogenesis and the expression of FAO genes, depleted ATP production, and enhanced cytotoxicity in cancer cells. Collectively, the combination of 2-DG and AMPK inhibition synergistically enhanced the cytotoxic potential in breast cancer cells with a relative nontoxicity to normal cells and may offer a promising, safe, and effective breast cancer therapeutic strategy

  15. 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.

  16. Metformin and propranolol combination prevents cancer progression and metastasis in different breast cancer models

    PubMed Central

    Bondarenko, Maryna; Laluce, Nahuel Cesatti; Rozados, Viviana; Nicolas, André; Carré, Manon; Scharovsky, O. Graciela; Márquez, Mauricio Menacho

    2017-01-01

    Discovery of new drugs for cancer treatment is an expensive and time-consuming process and the percentage of drugs reaching the clinic remains quite low. Drug repositioning refers to the identification and development of new uses for existing drugs and represents an alternative drug development strategy. In this work, we evaluated the antitumor effect of metronomic treatment with a combination of two repositioned drugs, metformin and propranolol, in triple negative breast cancer models. By in vitro studies with five different breast cancer derived cells, we observed that combined treatment decreased proliferation (P < 0.001), mitochondrial activity (P < 0.001), migration (P < 0.001) and invasion (P < 0.001). In vivo studies in immunocompetent mice confirmed the potential of this combination in reducing tumor growth (P < 0.001) and preventing metastasis (P < 0.05). Taken together our results suggest that metformin plus propranolol combined treatment might be beneficial for triple negative breast cancer control, with no symptoms of toxicity. PMID:27926515

  17. Combined serum and EPS-urine proteomic analysis using iTRAQ technology for discovery of potential prostate cancer biomarkers.

    PubMed

    Zhang, Mo; Chen, Lizhu; Yuan, Zhengwei; Yang, Zeyu; Li, Yue; Shan, Liping; Yin, Bo; Fei, Xiang; Miao, Jianing; Song, Yongsheng

    2016-11-01

    Prostate cancer (PCa) is one of the most common malignant tumors and a major cause of cancer-related death for men worldwide. The aim of our study was to identify potential non-invasive serum and expressed prostatic secretion (EPS)-urine biomarkers for accurate diagnosis of PCa. Here, we performed a combined isobaric tags for relative and absolute quantification (iTRAQ) proteomic analysis to compare protein profiles using pooled serum and EPS-urine samples from 4 groups of patients: benign prostate hyperplasia (BPH), high grade prostatic intraepithelial neoplasia (HGPIN), localized PCa and metastatic PCa. The differentially expressed proteins were rigorously selected and further validated in a large and independent cohort using classical ELISA and Western blot assays. Finally, we established a multiplex biomarker panel consisting of 3 proteins (serum PF4V1, PSA, and urinary CRISP3) with an excellent diagnostic capacity to differentiate PCa from BPH [area under the receiver operating characteristic curve (AUC) of 0.941], which showed an evidently greater discriminatory ability than PSA alone (AUC, 0.757) (P<0.001). Importantly, even when PSA level was in the gray zone (4-10 ng/mL), a combination of PF4V1 and CRISP3 could achieve a relatively high diagnostic efficacy (AUC, 0.895). Furthermore, their combination also had the potential to distinguish PCa from HGPIN (AUC, 0.934). Our results demonstrated that the combined application of serum and EPS-urine biomarkers can improve the diagnosis of PCa and provide a new prospect for non-invasive PCa detection.

  18. 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.

  19. 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. © 2016 Wiley Periodicals, Inc.

  20. Characterization and functional analysis of a slow-cycling subpopulation in colorectal cancer enriched by cell cycle inducer combined chemotherapy.

    PubMed

    Wu, Feng-Hua; Mu, Lei; Li, Xiao-Lan; Hu, Yi-Bing; Liu, Hui; Han, Lin-Tao; Gong, Jian-Ping

    2017-10-03

    The concept of cancer stem cells has been proposed in various malignancies including colorectal cancer. Recent studies show direct evidence for quiescence slow-cycling cells playing a role in cancer stem cells. There exists an urgent need to isolate and better characterize these slow-cycling cells. In this study, we developed a new model to enrich slow-cycling tumor cells using cell-cycle inducer combined with cell cycle-dependent chemotherapy in vitro and in vivo . Our results show that Short-term exposure of colorectal cancer cells to chemotherapy combined with cell-cycle inducer enriches for a cell-cycle quiescent tumor cell population. Specifically, these slow-cycling tumor cells exhibit increased chemotherapy resistance in vitro and tumorigenicity in vivo . Notably, these cells are stem-cell like and participate in metastatic dormancy. Further exploration indicates that slow-cycling colorectal cancer cells in our model are less sensitive to cytokine-induced-killer cell mediated cytotoxic killing in vivo and in vitro . Collectively, our cell cycle inducer combined chemotherapy exposure model enriches for a slow-cycling, dormant, chemo-resistant tumor cell sub-population that are resistant to cytokine induced killer cell based immunotherapy. Studying unique signaling pathways in dormant tumor cells enriched by cell cycle inducer combined chemotherapy treatment is expected to identify novel therapeutic targets for preventing tumor recurrence.

  1. Characterization and functional analysis of a slow-cycling subpopulation in colorectal cancer enriched by cell cycle inducer combined chemotherapy

    PubMed Central

    Wu, Feng-Hua; Mu, Lei; Li, Xiao-Lan; Hu, Yi-Bing; Liu, Hui; Han, Lin-Tao; Gong, Jian-Ping

    2017-01-01

    The concept of cancer stem cells has been proposed in various malignancies including colorectal cancer. Recent studies show direct evidence for quiescence slow-cycling cells playing a role in cancer stem cells. There exists an urgent need to isolate and better characterize these slow-cycling cells. In this study, we developed a new model to enrich slow-cycling tumor cells using cell-cycle inducer combined with cell cycle-dependent chemotherapy in vitro and in vivo. Our results show that Short-term exposure of colorectal cancer cells to chemotherapy combined with cell-cycle inducer enriches for a cell-cycle quiescent tumor cell population. Specifically, these slow-cycling tumor cells exhibit increased chemotherapy resistance in vitro and tumorigenicity in vivo. Notably, these cells are stem-cell like and participate in metastatic dormancy. Further exploration indicates that slow-cycling colorectal cancer cells in our model are less sensitive to cytokine-induced-killer cell mediated cytotoxic killing in vivo and in vitro. Collectively, our cell cycle inducer combined chemotherapy exposure model enriches for a slow-cycling, dormant, chemo-resistant tumor cell sub-population that are resistant to cytokine induced killer cell based immunotherapy. Studying unique signaling pathways in dormant tumor cells enriched by cell cycle inducer combined chemotherapy treatment is expected to identify novel therapeutic targets for preventing tumor recurrence. PMID:29108242

  2. A new semi-supervised learning model combined with Cox and SP-AFT models in cancer survival analysis.

    PubMed

    Chai, Hua; Li, Zi-Na; Meng, De-Yu; Xia, Liang-Yong; Liang, Yong

    2017-10-12

    Gene selection is an attractive and important task in cancer survival analysis. Most existing supervised learning methods can only use the labeled biological data, while the censored data (weakly labeled data) far more than the labeled data are ignored in model building. Trying to utilize such information in the censored data, a semi-supervised learning framework (Cox-AFT model) combined with Cox proportional hazard (Cox) and accelerated failure time (AFT) model was used in cancer research, which has better performance than the single Cox or AFT model. This method, however, is easily affected by noise. To alleviate this problem, in this paper we combine the Cox-AFT model with self-paced learning (SPL) method to more effectively employ the information in the censored data in a self-learning way. SPL is a kind of reliable and stable learning mechanism, which is recently proposed for simulating the human learning process to help the AFT model automatically identify and include samples of high confidence into training, minimizing interference from high noise. Utilizing the SPL method produces two direct advantages: (1) The utilization of censored data is further promoted; (2) the noise delivered to the model is greatly decreased. The experimental results demonstrate the effectiveness of the proposed model compared to the traditional Cox-AFT model.

  3. Successful treatment of ovarian cancer with apatinib combined with chemotherapy

    PubMed Central

    Zhang, Mingzi; Tian, Zhongkai; Sun, Yehong

    2017-01-01

    Abstract Rationale: The standard treatment for ovarian cancer is chemotherapy with 2 drugs (taxanes and platinum drugs). However, the traditional combination of the 2 drugs has many adverse effects (AEs) and the cancer cells will quickly become resistant to the drugs. Apatinib is a small-molecule antiangiogenic agent which has shown promising therapeutic effects against diverse tumor types, but it still remains unknown whether apatinib has an antitumor effect in patients with ovarian cancer. Herein, we present a successfully treated case of ovarian cancer using chemotherapy and apatinib, in order to demonstrate the effectiveness of this new combined regimen in ovarian cancer. Patients concerns: A 51-year-old Chinese woman presented with ovarian cancer >4.5 years. The disease and the cancer antigen 125 (CA-125) had been controlled well by surgical treatment and following chemotherapy. However, the drugs could not control the disease anymore as the CA-125 level was significantly increasing. Diagnosis: Ovarian cancer. Interventions: The patient was treated with apatinib combined with epirubicin. Apatinib was administered orally, at an initial daily dose of 500 mg, and was then reduced to 250 mg qd after the appearance of intolerable hand–foot syndrome (HFS) and oral ulcer. Then, the oral ulcer disappeared and the HFS was controlled by dose adjustment, oral vitamin B6, and hand cream application. Outcomes: The CA-125 reverted to the normal value after treatment with the new regimen. Magnetic resonance imaging showed that the original tumor lesions had disappeared. Apatinib monotherapy as maintenance therapy was then used to successfully control the cancer with a complete response. Our study is the first, to our knowledge, to report the therapeutic effects of apatinib and epirubicin on ovarian cancer. Lessons: Apatinib combined with chemotherapy and apatinib monotherapy as maintenance therapy could be a new therapeutic strategy for ovarian cancer, especially

  4. Combined panel of serum human tissue kallikreins and CA-125 for the detection of epithelial ovarian cancer.

    PubMed

    Koh, Stephen Chee Liang; Huak, Chan Yiong; Lutan, Delfi; Marpuang, Johny; Ketut, Suwiyoga; Budiana, Nyoma Gede; Saleh, Agustria Zainu; Aziz, Mohamad Farid; Winarto, Hariyono; Pradjatmo, Heru; Hoan, Nguyen Khac Han; Thanh, Pham Viet; Choolani, Mahesh

    2012-07-01

    To determine the predictive accuracy of the combined panels of serum human tissue kallikreins (hKs) and CA-125 for the detection of epithelial ovarian cancer. Serum specimens collected from 5 Indonesian centers and 1 Vietnamese center were analyzed for CA-125, hK6, and hK10 levels. A total of 375 specimens from patients presenting with ovarian tumors, which include 156 benign cysts, 172 epithelial ovarian cancers (stage I/II, n=72; stage III/IV, n=100), 36 germ cell tumors and 11 borderline tumors, were included in the study analysis. Receiver operating characteristic analysis were performed to determine the cutoffs for age, CA-125, hK6, and hK10. Sensitivity, specificity, negative, and positive predictive values were determined for various combinations of the biomarkers. The levels of hK6 and hK10 were significantly elevated in ovarian cancer cases compared to benign cysts. Combination of 3 markers, age/CA-125/hk6 or CA-125/hk6/hk10, showed improved specificity (100%) and positive predictive value (100%) for prediction of ovarian cancer, when compared to the performance of single markers having 80-92% specificity and 74-87% positive predictive value. Four-marker combination, age/CA-125/hK6/hK10 also showed 100% specificity and 100% positive predictive value, although it demonstrated low sensitivity (11.9%) and negative predictive value (52.8%). The combination of human tissue kallikreins and CA-125 showed potential for improving prediction of epithelial ovarian cancer in patients presenting with ovarian tumors.

  5. Combination cancer chemotherapy with one compound: pluripotent bradykinin antagonists.

    PubMed

    Stewart, John M; Gera, Lajos; Chan, Daniel C; York, Eunice J; Simkeviciene, Vitalija; Bunn, Paul A; Taraseviciene-Stewart, Laimute

    2005-08-01

    Lung and prostate cancers are major health problems worldwide. Treatments with standard chemotherapy agents are relatively ineffective. Combination chemotherapy gives better treatment than a single agent because the drugs can inhibit the cancer in different pathways, but new therapeutic agents are needed for the treatment of both tumor types. Bradykinin (BK) antagonists offer advantages of combination therapy in one compound. These promising multitargeted anti-cancer compounds selectively stimulate apoptosis in cancers and also inhibit both angiogenesis and matrix metalloprotease (MMP) action in treated lung and prostate tumors in nude mice. The highly potent, metabolism-resistant bradykinin antagonist peptide dimer, B-9870 [SUIM-(DArg-Arg-Pro-Hyp-Gly-Igl-Ser-DIgl-Oic-Arg)2] (SUIM=suberimidyl; Hyp=4-hydroxyproline; Igl=alpha-(2-indanyl)glycine; Oic=octahydroindole-2-carboxylic acid) and its non-peptide mimetic, BKM-570 [2,3,4,5,6-pentafluorocinnamoyl-(o-2,6-dichlorobenzyl)-L-tyrosine-N-(4-amino-2,2,6,6-tetramethylpiperidyl)amide] are superior to the widely used but toxic chemotherapeutic drugs cisplatin and taxotere. In certain combinations, they act synergistically with standard anti-cancer drugs. Due to its structure and biological activity, BKM-570 is an attractive lead compound for derivatization and evaluation for lung and prostate cancer drugs.

  6. 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

  7. 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.

  8. 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. Copyright © 2014 John Wiley & Sons, Ltd.

  9. Informatics Approaches for Predicting, Understanding, and Testing Cancer Drug Combinations.

    PubMed

    Tang, Jing

    2017-01-01

    Making cancer treatment more effective is one of the grand challenges in our health care system. However, many drugs have entered clinical trials but so far showed limited efficacy or induced rapid development of resistance. We urgently need multi-targeted drug combinations, which shall selectively inhibit the cancer cells and block the emergence of drug resistance. The book chapter focuses on mathematical and computational tools to facilitate the discovery of the most promising drug combinations to improve efficacy and prevent resistance. Data integration approaches that leverage drug-target interactions, cancer molecular features, and signaling pathways for predicting, understanding, and testing drug combinations are critically reviewed.

  10. Understanding intratumor heterogeneity by combining genome analysis and mathematical modeling.

    PubMed

    Niida, Atsushi; Nagayama, Satoshi; Miyano, Satoru; Mimori, Koshi

    2018-04-01

    Cancer is composed of multiple cell populations with different genomes. This phenomenon called intratumor heterogeneity (ITH) is supposed to be a fundamental cause of therapeutic failure. Therefore, its principle-level understanding is a clinically important issue. To achieve this goal, an interdisciplinary approach combining genome analysis and mathematical modeling is essential. For example, we have recently performed multiregion sequencing to unveil extensive ITH in colorectal cancer. Moreover, by employing mathematical modeling of cancer evolution, we demonstrated that it is possible that this ITH is generated by neutral evolution. In this review, we introduce recent advances in a research field related to ITH and also discuss strategies for exploiting novel findings on ITH in a clinical setting. © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  11. Principal component directed partial least squares analysis for combining nuclear magnetic resonance and mass spectrometry data in metabolomics: application to the detection of breast cancer.

    PubMed

    Gu, Haiwei; Pan, Zhengzheng; Xi, Bowei; Asiago, Vincent; Musselman, Brian; Raftery, Daniel

    2011-02-07

    Nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) are the two most commonly used analytical tools in metabolomics, and their complementary nature makes the combination particularly attractive. A combined analytical approach can improve the potential for providing reliable methods to detect metabolic profile alterations in biofluids or tissues caused by disease, toxicity, etc. In this paper, (1)H NMR spectroscopy and direct analysis in real time (DART)-MS were used for the metabolomics analysis of serum samples from breast cancer patients and healthy controls. Principal component analysis (PCA) of the NMR data showed that the first principal component (PC1) scores could be used to separate cancer from normal samples. However, no such obvious clustering could be observed in the PCA score plot of DART-MS data, even though DART-MS can provide a rich and informative metabolic profile. Using a modified multivariate statistical approach, the DART-MS data were then reevaluated by orthogonal signal correction (OSC) pretreated partial least squares (PLS), in which the Y matrix in the regression was set to the PC1 score values from the NMR data analysis. This approach, and a similar one using the first latent variable from PLS-DA of the NMR data resulted in a significant improvement of the separation between the disease samples and normals, and a metabolic profile related to breast cancer could be extracted from DART-MS. The new approach allows the disease classification to be expressed on a continuum as opposed to a binary scale and thus better represents the disease and healthy classifications. An improved metabolic profile obtained by combining MS and NMR by this approach may be useful to achieve more accurate disease detection and gain more insight regarding disease mechanisms and biology. Copyright © 2010 Elsevier B.V. All rights reserved.

  12. Laparoscopic sentinel node procedure using a combination of patent blue and radiocolloid in women with endometrial cancer.

    PubMed

    Barranger, Emmanuel; Cortez, Annie; Grahek, Dany; Callard, Patrice; Uzan, Serge; Darai, Emile

    2004-03-01

    We assessed the feasibility of a laparoscopic sentinel node (SN) procedure based on the combined use of radiocolloid and patent blue labeling in patients with endometrial cancer. Seventeen patients (median age, 69 years) with endometrial cancer of stage I (16 patients) or stage II (1 patient) underwent a laparoscopic SN procedure based on combined radiocolloid and patent blue injected pericervically. After the SN procedure, all patients underwent complete laparoscopic pelvic lymphadenectomy and either laparoscopically assisted vaginal hysterectomy (16 patients) or laparoscopic radical hysterectomy (1 patient). SNs (mean number per patient, 2.6; range, 1-4) were identified in 16 (94.1%) of the 17 patients. Macrometastases were detected in three SNs from two patients by hematoxylin and eosin staining. In three other patients, immunohistochemical analysis identified six micrometastatic SNs and one SN containing isolated tumor cells. No false-negative SN results were observed. An SN procedure based on a combination of radiocolloid and patent blue is feasible in patients with early endometrial cancer. Combined use of laparoscopy and this SN procedure permits minimally invasive management of endometrial cancer.

  13. Fish oil-enriched nutrition combined with systemic chemotherapy for gastrointestinal cancer patients with cancer cachexia.

    PubMed

    Shirai, Yumiko; Okugawa, Yoshinaga; Hishida, Asahi; Ogawa, Aki; Okamoto, Kyoko; Shintani, Miki; Morimoto, Yuki; Nishikawa, Ryutaro; Yokoe, Takeshi; Tanaka, Koji; Urata, Hisashi; Toiyama, Yuji; Inoue, Yasuhiro; Tanaka, Motoyoshi; Mohri, Yasuhiko; Goel, Ajay; Kusunoki, Masato; McMillan, Donald C; Miki, Chikao

    2017-07-06

    Despite recent advances in chemotherapy for gastrointestinal cancer, a crucial factor related to poor prognosis is reduced tolerance to chemotherapy induced by cancer cachexia. Fish oil (FO)-derived eicosapentaenoic acid (EPA) modulates inflammation in patients with various malignancies; however, the impact of FO-enriched nutrition as a combined modality therapy on clinical outcomes remains controversial. We systemically analysed chronological changes in biochemical and physiological status using bioelectrical impedance analysis in 128 gastrointestinal cancer patients provided with or without FO-enriched nutrition during chemotherapy. Furthermore, we evaluated the clinical significance of FO-enriched nutrition and clarified appropriate patient groups that receive prognostic benefits from FO-enriched nutrition during treatment of gastrointestinal cancer. The control group showed significant up-regulation of serum CRP) levels and no significant difference in both skeletal muscle mass and lean body mass. In contrast, the FO-enriched nutrition group showed no changes in serum CRP concentration and significantly increased skeletal muscle mass and lean body mass over time. Furthermore, high CRP levels significantly correlated with reduced tolerance to chemotherapy, and FO-enriched nutrition improved chemotherapy tolerance and prognosis, particularly in gastrointestinal cancer patients with a modified Glasgow prognostic score (mGPS) of 1 or 2. We conclude that FO-enriched nutrition may improve the prognosis of patients with cancer cachexia and systemic inflammation (i.e., those with a mGPS of 1 or 2).

  14. Comorbidity and prognosis in advanced hypopharyngeal-laryngeal cancer under combined therapy.

    PubMed

    Montero, Elena Hernández; Trufero, Javier Martínez; Romeo, Javier Azúa; Terré, Fernando Clau

    2008-01-01

    The success of combined treatment in head and neck cancer resides largely in its completion, which can be compromised when the patient's general health status is precarious. The objective of this investigation was to study the role of comorbidity as a prognostic factor in a large, homogeneous population affected by locally advanced pharyngeal-laryngeal cancer, under a combined protocol treatment. The a priori hypothesis is that comorbidity strongly conditions overall survival and specific overall survival in these patients and can aid in the selection and individualization of treatments. After a 24-month follow-up, a univariate and multivariate retrospective analysis of survival and prognostic factors was performed using 14 clinical, pathological and molecular variables including the comorbidity index calculated following the Picarillo method. The settings were the Otolaryngology, Oncology and Pathology Departments of the Miguel Servet University Hospital, Zaragoza, Spain, a referral center of the National Health System. Of the original 114 patients selected, 15 were withdrawn because the tumor spread to maxillofacial areas, or due to the lack of attendance at the clinic, incomplete clinical data or coexistent primary tumors. The group under analysis consisted of the 99 remaining patients affected by stage III and IV laryngeal and/or hypopharyngeal cancers that had not received previous treatments. The main outcomes to analyze were overall survival, specific overall survival and relative risk. Overall survival at 2.5 years was 68.1% (95% CI, 57.7-78.5). Specific overall survival at 2.5 years was 74.8% (95% CI, 64.9-84.6). In the multivariate analysis, tumor staging, neoadjuvant chemotherapy response and comorbidity (RR = 1.55 and 1.44 for overall and specific overall survival, respectively) present themselves as three prognostic factors independent of overall and specific overall survival. The role of comorbidity as an independent prognostic factor in patients

  15. 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.

  16. Soy food intake after diagnosis of breast cancer and survival: an in-depth analysis of combined evidence from cohort studies of US and Chinese women123

    PubMed Central

    Nechuta, Sarah J; Caan, Bette J; Chen, Wendy Y; Lu, Wei; Chen, Zhi; Kwan, Marilyn L; Flatt, Shirley W; Zheng, Ying; Zheng, Wei; Pierce, John P; Shu, Xiao Ou

    2012-01-01

    Background: Soy isoflavones have antiestrogenic and anticancer properties but also possess estrogen-like properties, which has raised concern about soy food consumption among breast cancer survivors. Objective: We prospectively evaluated the association between postdiagnosis soy food consumption and breast cancer outcomes among US and Chinese women by using data from the After Breast Cancer Pooling Project. Design: The analysis included 9514 breast cancer survivors with a diagnosis of invasive breast cancer between 1991 and 2006 from 2 US cohorts and 1 Chinese cohort. Soy isoflavone intake (mg/d) was measured with validated food-frequency questionnaires. HRs and 95% CIs were estimated by using delayed-entry Cox regression models, adjusted for sociodemographic, clinical, and lifestyle factors. Results: After a mean follow-up of 7.4 y, we identified 1171 total deaths (881 from breast cancer) and 1348 recurrences. Despite large differences in soy isoflavone intake by country, isoflavone consumption was inversely associated with recurrence among both US and Chinese women, regardless of whether data were analyzed separately by country or combined. No heterogeneity was observed. In the pooled analysis, consumption of ≥10 mg isoflavones/d was associated with a nonsignificant reduced risk of all-cause (HR: 0.87; 95% CI: 0.70, 1.10) and breast cancer–specific (HR: 0.83; 95% CI: 0.64, 1.07) mortality and a statistically significant reduced risk of recurrence (HR: 0.75; 95% CI: 0.61, 0.92). Conclusion: In this large study of combined data on US and Chinese women, postdiagnosis soy food consumption of ≥10 mg isoflavones/d was associated with a nonsignificant reduced risk of breast cancer–specific mortality and a statistically significant reduced risk of recurrence. One of the studies included in the After Breast Cancer Pooling Project, the Women's Healthy Eating & Living Study, was registered at clinicaltrials.gov as NCT00003787. PMID:22648714

  17. 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.

  18. Nanomedicine of synergistic drug combinations for cancer therapy – strategies and perspectives

    PubMed Central

    Xue, Hui Yi; Eoh, June Young; Wu, Xiao Yu

    2016-01-01

    Nanomedicine of synergistic drug combinations has shown increasing significance in cancer therapy due to its promise in providing superior therapeutic benefits to the current drug combination therapy used in clinical practice. In this article, we will examine the rationale, principles, and advantages of applying nanocarriers to improve anticancer drug combination therapy, review the use of nanocarriers for delivery of a variety of combinations of different classes of anticancer agents including small molecule drugs and biologics, and discuss the challenges and future perspectives of the nanocarrier-based combination therapy. The goal of this review is to provide better understanding of this increasingly important new paradigm of cancer treatment and key considerations for rational design of nanomedicine of synergistic drug combinations for cancer therapy. PMID:27287891

  19. A blood tumor marker combination assay produces high sensitivity and specificity for cancer according to the natural history.

    PubMed

    Kobayashi, Tsuneo

    2018-03-01

    Diagnosis using a specific tumor marker is difficult because the sensitivity of this detection method is under 20%. Herein, a tumor marker combination assay, combining growth-related tumor marker and associated tumor marker (Cancer, 73(7), 1994), was employed. This double-blind tumor marker combination assay (TMCA) showed 87.5% sensitivity as the results, but a low specificity, ranging from 30 to 76%. To overcome this low specificity, we exploited complex markers, a multivariate analysis and serum fractionation by biochemical biopsy. Thus, in this study, a combination of new techniques was used to re-evaluate these serum samples. Three serum panels, containing 90, 120, and 97 samples were obtained from the Mayo Clinic. The final results showed 80-90% sensitivity, 84-85% specificity, and 83-88% accuracy. We demonstrated a notable tumor marker combination assay with high accuracy. This TMCA should be applicable for primary cancer detection and recurrence prevention. © 2018 The Author. Cancer Medicine published by John Wiley & Sons Ltd.

  20. New clinical trial studies drug combination for recurring ovarian cancer | Center for Cancer Research

    Cancer.gov

    A new clinical trial is studying the effectiveness of an investigational drug combination that looks to see whether reducing the supply of oxygen to the cancer cells can make ovarian cancer shrink or slow its growth in association with an enzyme that repairs DNA damage.

  1. Splenectomy combined with gastrectomy and immunotherapy for advanced gastric cancer.

    PubMed

    Miwa, H; Orita, K

    1983-06-01

    We studied the effects of a splenectomy in combination with immunotherapy on the survival of patients who had undergone a total gastrectomy. It was found that a splenectomy was not effective against advanced gastric cancer at stage III, and that the spleen should be retained for immunotherapy. Splenectomy for gastric cancer at terminal stage IV, particularly in combination with immunotherapy, produced not only augmentation of cellular immunity, but also increased survival.

  2. 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

  3. Experimental design and statistical analysis for three-drug combination studies.

    PubMed

    Fang, Hong-Bin; Chen, Xuerong; Pei, Xin-Yan; Grant, Steven; Tan, Ming

    2017-06-01

    Drug combination is a critically important therapeutic approach for complex diseases such as cancer and HIV due to its potential for efficacy at lower, less toxic doses and the need to move new therapies rapidly into clinical trials. One of the key issues is to identify which combinations are additive, synergistic, or antagonistic. While the value of multidrug combinations has been well recognized in the cancer research community, to our best knowledge, all existing experimental studies rely on fixing the dose of one drug to reduce the dimensionality, e.g. looking at pairwise two-drug combinations, a suboptimal design. Hence, there is an urgent need to develop experimental design and analysis methods for studying multidrug combinations directly. Because the complexity of the problem increases exponentially with the number of constituent drugs, there has been little progress in the development of methods for the design and analysis of high-dimensional drug combinations. In fact, contrary to common mathematical reasoning, the case of three-drug combinations is fundamentally more difficult than two-drug combinations. Apparently, finding doses of the combination, number of combinations, and replicates needed to detect departures from additivity depends on dose-response shapes of individual constituent drugs. Thus, different classes of drugs of different dose-response shapes need to be treated as a separate case. Our application and case studies develop dose finding and sample size method for detecting departures from additivity with several common (linear and log-linear) classes of single dose-response curves. Furthermore, utilizing the geometric features of the interaction index, we propose a nonparametric model to estimate the interaction index surface by B-spine approximation and derive its asymptotic properties. Utilizing the method, we designed and analyzed a combination study of three anticancer drugs, PD184, HA14-1, and CEP3891 inhibiting myeloma H929 cell line

  4. 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

  5. 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.

  6. Structure-Functional Prediction and Analysis of Cancer Mutation Effects in Protein Kinases

    PubMed Central

    Dixit, Anshuman; Verkhivker, Gennady M.

    2014-01-01

    A central goal of cancer research is to discover and characterize the functional effects of mutated genes that contribute to tumorigenesis. In this study, we provide a detailed structural classification and analysis of functional dynamics for members of protein kinase families that are known to harbor cancer mutations. We also present a systematic computational analysis that combines sequence and structure-based prediction models to characterize the effect of cancer mutations in protein kinases. We focus on the differential effects of activating point mutations that increase protein kinase activity and kinase-inactivating mutations that decrease activity. Mapping of cancer mutations onto the conformational mobility profiles of known crystal structures demonstrated that activating mutations could reduce a steric barrier for the movement from the basal “low” activity state to the “active” state. According to our analysis, the mechanism of activating mutations reflects a combined effect of partial destabilization of the kinase in its inactive state and a concomitant stabilization of its active-like form, which is likely to drive tumorigenesis at some level. Ultimately, the analysis of the evolutionary and structural features of the major cancer-causing mutational hotspot in kinases can also aid in the correlation of kinase mutation effects with clinical outcomes. PMID:24817905

  7. Structure-functional prediction and analysis of cancer mutation effects in protein kinases.

    PubMed

    Dixit, Anshuman; Verkhivker, Gennady M

    2014-01-01

    A central goal of cancer research is to discover and characterize the functional effects of mutated genes that contribute to tumorigenesis. In this study, we provide a detailed structural classification and analysis of functional dynamics for members of protein kinase families that are known to harbor cancer mutations. We also present a systematic computational analysis that combines sequence and structure-based prediction models to characterize the effect of cancer mutations in protein kinases. We focus on the differential effects of activating point mutations that increase protein kinase activity and kinase-inactivating mutations that decrease activity. Mapping of cancer mutations onto the conformational mobility profiles of known crystal structures demonstrated that activating mutations could reduce a steric barrier for the movement from the basal "low" activity state to the "active" state. According to our analysis, the mechanism of activating mutations reflects a combined effect of partial destabilization of the kinase in its inactive state and a concomitant stabilization of its active-like form, which is likely to drive tumorigenesis at some level. Ultimately, the analysis of the evolutionary and structural features of the major cancer-causing mutational hotspot in kinases can also aid in the correlation of kinase mutation effects with clinical outcomes.

  8. Potential use of COX-2–aromatase inhibitor combinations in breast cancer

    PubMed Central

    Bundred, N J; Barnes, N L P

    2005-01-01

    Cyclooxygenase-2 (COX-2) is overexpressed in several epithelial tumours, including breast cancer. Cyclooxygenase-2-positive tumours tend to be larger, higher grade, node-positive and HER-2/neu-positive. High COX-2 expression is associated with poor prognosis. Cyclooxygenase-2 inhibition reduces the incidence of tumours in animal models, inhibits the development of invasive cancer in colorectal cancer and reduces the frequency of polyps in familial adenomatous polyposis (FAP). These effects may be as a result of increased apoptosis, reduced angiogenesis and/or proliferation. Studies of COX-2 inhibitors in breast cancer are underway both alone and in combination with other agents. There is evidence to suggest that combining COX-2 inhibitors with aromatase inhibitors, growth factor receptor blockers, or chemo- or radiotherapy may be particularly effective. Preliminary results from combination therapy with celecoxib and exemestane in postmenopausal women with advanced breast cancer showed that the combination increased the time to recurrence. Up to 80% of ductal carcinomas in situ (DCISs) express COX-2, therefore COX-2 inhibition may be of particular use in this situation. Cyclooxygenase-2 expression correlates strongly with expression of HER-2/neu. As aromatase inhibitors appear particularly effective in patients with HER-2/neu-positive tumours, the combination of aromatase inhibitors and COX-2 inhibitors may be particularly useful in both DCIS and invasive cancer. PMID:16100520

  9. 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.

  10. Cancers in Australia in 2010 attributable to and prevented by the use of combined oral contraceptives.

    PubMed

    Jordan, Susan J; Wilson, Louise F; Nagle, Christina M; Green, Adele C; Olsen, Catherine M; Bain, Christopher J; Pandeya, Nirmala; Whiteman, David C; Webb, Penelope M

    2015-10-01

    To estimate the proportion and number of cancers occurring in Australia in 2010 attributable to combined oral contraceptive pill (OCP) use. We estimated the population attributable fraction (PAF) for cancers causally associated with combined OCP use (breast, cervix), and the proportion of endometrial and ovarian cancers prevented (prevented fraction [PF]). We used standard formulae incorporating prevalence of combined OCP use in the Australian population, relative risks of cancer associated with this exposure and cancer incidence. An estimated 105 breast and 52 cervical cancers (0.7% and 6.4% of each cancer, respectively) in Australia in 2010 were attributable to current use of combined OCP. Past combined OCP use was estimated to have prevented 1,032 endometrial and 308 ovarian cancers in 2010, reducing the number of cancers that would otherwise have occurred by 31% and 19%, respectively. A small proportion of breast and cervical cancers is attributable to combined OCP use; OCP use is likely to have prevented larger numbers of endometrial and ovarian cancers. Women seeking contraceptive advice should be told of potential adverse effects, but should also be told that - along with reproductive health benefits - combined OCP use can reduce long-term risks of ovarian and endometrial cancers. © 2015 The Authors.

  11. 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

  12. Advances in combination therapy of lung cancer: Rationales, delivery technologies and dosage regimens.

    PubMed

    Wu, Lan; Leng, Donglei; Cun, Dongmei; Foged, Camilla; Yang, Mingshi

    2017-08-28

    Lung cancer is a complex disease caused by a multitude of genetic and environmental factors. The progression of lung cancer involves dynamic changes in the genome and a complex network of interactions between cancer cells with multiple, distinct cell types that form tumors. Combination therapy using different pharmaceuticals has been proven highly effective due to the ability to affect multiple cellular pathways involved in the disease progression. However, the currently used drug combination designs are primarily based on empirical clinical studies, and little attention has been given to dosage regimens, i.e. how administration routes, onsets, and durations of the combinations influence the therapeutic outcome. This is partly because combination therapy is challenged by distinct physicochemical properties and in vivo pharmacokinetics/pharmacodynamics of the individual pharmaceuticals, including small molecule drugs and biopharmaceuticals, which make the optimization of dosing and administration schedule challenging. This article reviews the recent advances in the design and development of combinations of pharmaceuticals for the treatment of lung cancer. Focus is primarily on rationales for the selection of specific combination therapies for lung cancer treatment, and state of the art of delivery technologies and dosage regimens for the combinations, tested in preclinical and clinical trials. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Liposome encapsulation of curcumin and resveratrol in combination reduces prostate cancer incidence in PTEN knockout mice.

    PubMed

    Narayanan, Narayanan K; Nargi, Dominick; Randolph, Carla; Narayanan, Bhagavathi A

    2009-07-01

    Increasing interest in the use of phytochemicals to reduce prostate cancer led us to investigate 2 potential agents, curcumin and resveratrol as preventive agents. However, there is concern about the bioavailability of these agents pertinent to the poor absorption and thereby limiting its clinical use. With the view to improve their bioavailability, we used the liposome encapsulated curcumin, and resveratrol individually and in combination in male B6C3F1/J mice. Further, we examined the chemopreventive effect of liposome encapsulated curcumin and resveratrol in combination in prostate-specific PTEN knockout mice. In vitro assays using PTEN-CaP8 cancer cells were performed to investigate the combined effects curcumin with resveratrol on (i) cell growth, apoptosis and cell cycle (ii) impact on activated p-Akt, cyclin D1, m-TOR and androgen receptor (AR) proteins involved in tumor progression. HPLC analysis of serum and prostate tissues showed a significant increase in curcumin level when liposome encapsulated curcumin coadministered with liposomal resveratrol (p < 0.001). Combination of liposomal forms of curcumin and resveratrol significantly decreased prostatic adenocarcinoma in vivo (p < 0.001). In vitro studies revealed that curcumin plus resveratrol effectively inhibit cell growth and induced apoptosis. Molecular targets activated due to the loss of phosphatase and tensin homolog (PTEN) including p-Akt, cyclin D1, mammalian target of rapamycin and AR were downregulated by these agents in combination. Findings from this study for the first time provide evidence on phytochemicals in combination to enhance chemopreventive efficacy in prostate cancer. These findings clearly suggest that phytochemicals in combination may reduce prostate cancer incidence due to the loss of the tumor suppressor gene PTEN.

  14. 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.

  15. Anticonvulsants or Antidepressants in Combination Pharmacotherapy for Treatment of Neuropathic Pain in Cancer Patients: A Systematic Review and Meta-analysis.

    PubMed

    Guan, Jia; Tanaka, Shiro; Kawakami, Koji

    2016-08-01

    To investigate the efficacy of anticonvulsants or antidepressants in combination pharmacotherapy for treatment of neuropathic pain in cancer patients. We systematically searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and the metaRegister of Controlled Trials for randomized controlled trials that compared anticonvulsants or antidepressants in combination pharmacotherapy (experimental group) with treatments without anticonvulsants or antidepressants (control group) for neuropathic pain in cancer patients. Risk of bias was evaluated in accordance with the Cochrane Handbook for Systematic Reviews of Interventions. The primary outcome was a mean difference (MD) in change in global pain analyzed by a random-effects model. Eight trials met the inclusion criteria with a total of 1359 participants of whom 698 received an experimental intervention. The MD in change in global pain suggested a favorable association with anticonvulsants or antidepressants in combination pharmacotherapy compared with control groups (MD, -0.41; 95% confidence interval, -0.70 to -0.12) with no heterogeneity across trials (I=0%). The MD in change estimated in all sensitivity analyses ranged from -0.36 to -0.47, suggesting that these effects were consistent across different study designs and statistical assumptions. Anticonvulsants or antidepressants in combination pharmacotherapy reduce neuropathic pain in cancer patients compared with treatments without anticonvulsants or antidepressants. Limited evidence precludes a recommendation on specific adjuvants in combination pharmacotherapy.

  16. Combined image and genomic analysis of high-grade serous ovarian cancer reveals PTEN loss as a common driver event and prognostic classifier.

    PubMed

    Martins, Filipe C; Santiago, Ines de; Trinh, Anne; Xian, Jian; Guo, Anne; Sayal, Karen; Jimenez-Linan, Mercedes; Deen, Suha; Driver, Kristy; Mack, Marie; Aslop, Jennifer; Pharoah, Paul D; Markowetz, Florian; Brenton, James D

    2014-12-17

    TP53 and BRCA1/2 mutations are the main drivers in high-grade serous ovarian carcinoma (HGSOC). We hypothesise that combining tissue phenotypes from image analysis of tumour sections with genomic profiles could reveal other significant driver events. Automatic estimates of stromal content combined with genomic analysis of TCGA HGSOC tumours show that stroma strongly biases estimates of PTEN expression. Tumour-specific PTEN expression was tested in two independent cohorts using tissue microarrays containing 521 cases of HGSOC. PTEN loss or downregulation occurred in 77% of the first cohort by immunofluorescence and 52% of the validation group by immunohistochemistry, and is associated with worse survival in a multivariate Cox-regression model adjusted for study site, age, stage and grade. Reanalysis of TCGA data shows that hemizygous loss of PTEN is common (36%) and expression of PTEN and expression of androgen receptor are positively associated. Low androgen receptor expression was associated with reduced survival in data from TCGA and immunohistochemical analysis of the first cohort. PTEN loss is a common event in HGSOC and defines a subgroup with significantly worse prognosis, suggesting the rational use of drugs to target PI3K and androgen receptor pathways for HGSOC. This work shows that integrative approaches combining tissue phenotypes from images with genomic analysis can resolve confounding effects of tissue heterogeneity and should be used to identify new drivers in other cancers.

  17. Recent Advances in Delivery of Drug-Nucleic Acid Combinations for Cancer Treatment

    PubMed Central

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

    2013-01-01

    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. PMID:23624358

  18. 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. Copyright © 2013 Elsevier B.V. All rights reserved.

  19. Association of choline and betaine levels with cancer incidence and survival: A meta-analysis.

    PubMed

    Youn, Jiyoung; Cho, Eunyoung; Lee, Jung Eun

    2018-03-22

    Evidences suggest possible link between betaine and choline, methyl group donors, and cancer progression. We examined the association between choline and betaine levels and cancer incidence and survival in a meta-analysis of observational studies. We identified observational studies examining the association between choline and/or betaine levels from diet or blood and cancer incidence and survival by searching the PubMed and Web of Science databases for studies published up to Jan, 2018. After applying the selection criteria, 28 observational studies (9 case-control, 1 cross-sectional, and 18 cohort studies) were included. Relative risks (RRs) and 95% confidence intervals (CIs) were extracted, and combined RRs were calculated using random-effects models. Choline levels were not associated with cancer incidence in a meta-analysis of cohort studies. Betaine levels reduced the risk of cancer incidence in a meta-analysis of cohort studies; combined relative risks (RRs) (95% CIs) comparing the top with the bottom categories were 0.93 (0.87-0.99). When we analyzed separately according to exposure assessment method, combined RRs (95% CIs) comparing the top with the bottom categories of betaine levels were 0.87 (95% CI: 0.78-0.95) for dietary betaine and 0.88 (95% CI: 0.77-0.99) for blood levels of betaine. There were no significant associations with cancer survivorship of choline or betaine levels. We concluded that high betaine levels were associated with lower risk of the cancer incidence, especially for colorectal cancer. Copyright © 2018 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

  20. Antitumor Effects of Epidrug/IFNα Combination Driven by Modulated Gene Signatures in Both Colorectal Cancer and Dendritic Cells.

    PubMed

    Fragale, Alessandra; Romagnoli, Giulia; Licursi, Valerio; Buoncervello, Maria; Del Vecchio, Giorgia; Giuliani, Caterina; Parlato, Stefania; Leone, Celeste; De Angelis, Marta; Canini, Irene; Toschi, Elena; Belardelli, Filippo; Negri, Rodolfo; Capone, Imerio; Presutti, Carlo; Gabriele, Lucia

    2017-07-01

    Colorectal cancer results from the progressive accumulation of genetic and epigenetic alterations. IFN signaling defects play an important role in the carcinogenesis process, in which the inability of IFN transcription regulatory factors (IRF) to access regulatory sequences in IFN-stimulated genes (ISG) in tumors and in immune cells may be pivotal. We reported that low-dose combination of two FDA-approved epidrugs, azacytidine (A) and romidepsin (R), with IFNα2 (ARI) hampers the aggressiveness of both colorectal cancer metastatic and stem cells in vivo and triggers immunogenic cell death signals that stimulate dendritic cell (DC) function. Here, we investigated the molecular signals induced by ARI treatment and found that this drug combination increased the accessibility to regulatory sequences of ISGs and IRFs that were epigenetically silenced in both colorectal cancer cells and DCs. Likewise, specific ARI-induced histone methylation and acetylation changes marked epigenetically affected ISG promoters in both metastatic cancer cells and DCs. Analysis by ChIP-seq confirmed such ARI-induced epigenetically regulated IFN signature. The activation of this signal endowed DCs with a marked migratory capability. Our results establish a direct correlation between reexpression of silenced ISGs by epigenetic control and ARI anticancer activity and provide new knowledge for the development of innovative combined therapeutic strategies for colorectal cancer. Cancer Immunol Res; 5(7); 604-16. ©2017 AACR . ©2017 American Association for Cancer Research.

  1. 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

  2. New Strategies Using Antibody Combinations to Increase Cancer Treatment Effectiveness

    PubMed Central

    Corraliza-Gorjón, Isabel; Somovilla-Crespo, Beatriz; Santamaria, Silvia; Garcia-Sanz, Jose A.; Kremer, Leonor

    2017-01-01

    Antibodies have proven their high value in antitumor therapy over the last two decades. They are currently being used as the first-choice to treat some of the most frequent metastatic cancers, like HER2+ breast cancers or colorectal cancers, currently treated with trastuzumab (Herceptin) and bevacizumab (Avastin), respectively. The impressive therapeutic success of antibodies inhibiting immune checkpoints has extended the use of therapeutic antibodies to previously unanticipated tumor types. These anti-immune checkpoint antibodies allowed the cure of patients devoid of other therapeutic options, through the recovery of the patient’s own immune response against the tumor. In this review, we describe how the antibody-based therapies will evolve, including the use of antibodies in combinations, their main characteristics, advantages, and how they could contribute to significantly increase the chances of success in cancer therapy. Indeed, novel combinations will consist of mixtures of antibodies against either different epitopes of the same molecule or different targets on the same tumor cell; bispecific or multispecific antibodies able of simultaneously binding tumor cells, immune cells or extracellular molecules; immunomodulatory antibodies; antibody-based molecules, including fusion proteins between a ligand or a receptor domain and the IgG Fab or Fc fragments; autologous or heterologous cells; and different formats of vaccines. Through complementary mechanisms of action, these combinations could contribute to elude the current limitations of a single antibody which recognizes only one particular epitope. These combinations may allow the simultaneous attack of the cancer cells by using the help of the own immune cells and exerting wider therapeutic effects, based on a more specific, fast, and robust response, trying to mimic the action of the immune system. PMID:29312320

  3. High-Throughput Testing of Novel-Novel Combination Therapies for Cancer: An Idea Whose Time Has Come.

    PubMed

    Scarlett, Uciane K; Chang, Dennis C; Murtagh, Thomas J; Flaherty, Keith T

    2016-09-01

    Combination therapies are essential to address the genetic complexity, plasticity, and heterogeneity of tumors and to overcome resistance mechanisms that confound single-agent approaches, and are a paradigm that became well established in the era of conventional cytotoxic chemotherapies. Today, we are well equipped to address many of the scientific, clinical, and collaboration challenges that have existed historically; however, the pace of testing rational combinations is modest. Our analysis shows that the volume of clinical trials testing multiple investigational pipeline agents ("novel-novel" combinations) is dismally low, as out of approximately 1,500 phase I to III investigational combination trials initiated in 2014-2015, only 80 were for novel-novel combinations, and only 9 of those involved more than one company. The Collaborative Novel-Novel Combination Therapies (CoNNCT) initiative aims to alleviate this bottleneck by developing a new, faster paradigm for early investigation of scientifically informed, novel-novel drug combinations. The initiative kicked off on March 7, 2016, when representatives from top academic centers, biopharma, nonprofits, the FDA, and other groups gathered to define an actionable path forward. Cancer Discov; 6(9); 956-62. ©2016 AACR. ©2016 American Association for Cancer Research.

  4. A versatile nanoplatform for synergistic combination therapy to treat human esophageal cancer.

    PubMed

    Wang, Xin-Shuai; Kong, De-Jiu; Lin, Tzu-Yin; Li, Xiao-Cen; Izumiya, Yoshihiro; Ding, Xue-Zhen; Zhang, Li; Hu, Xiao-Chen; Yang, Jun-Qiang; Gao, She-Gan; Lam, Kit S; Li, Yuan-Pei

    2017-06-01

    One of the major goals of precision oncology is to promote combination therapy to improve efficacy and reduce side effects of anti-cancer drugs based on their molecular mechanisms. In this study, we aimed to develop and validate new nanoformulations of docetaxel (DTX) and bortezomib (BTZ) for targeted combination therapy to treat human esophageal cancer. By leveraging our versatile disulfide cross-linked micelles (DCMs) platform, we developed nanoformulations of DTX and BTZ (named DTX-DCMs and BTZ-DCMs). Their physical properties were characterized; their anti-cancer efficacies and mechanisms of action were investigated in a human esophageal cancer cell line in vitro. Furthermore, the in vitro anti-tumor activities of combination therapies (concurrent drug treatment, sequential drug treatment, and treatment using different ratios of the drugs) were examined in comparison with the single drug treatment and free drug strategies. These drug-loaded nanoparticles were spherical in shape and relatively small in size of approximately 20-22 nm. The entrapment efficiencies of DTX and BTZ into nanoparticles were 82.4% and 84.1%, respectively. The drug release rates of DTX-DCMs and BTZ-DCMs were sustained, and greatly increased in the presence of GSH. These nanodrugs were effectively internalized by KYSE30 esophageal cancer cells, and dose-dependently induced cell apoptosis. We further revealed a strong synergistic effect between DTX-DCMs and BTZ-DCMs against KYSE30 esophageal cancer cells. Sequential combination therapy with DTX-DCMs followed by BTZ-DCMs exhibited the best anti-tumor efficacy in vitro. This study demonstrates that DTX and BTZ could be successfully nanoformulated into disulfide cross-linked micelles. The nanoformulations of DTX and BTZ demonstrate an immense potential for synergistic combination therapy to treat human esophageal cancer.

  5. 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%).

  6. Molecular mechanism of Poria cocos combined with oxaliplatin on the inhibition of epithelial-mesenchymal transition in gastric cancer cells.

    PubMed

    Wang, Na; Liu, Dengxiang; Guo, Jun; Sun, Yawei; Guo, Ting; Zhu, Xiaoyan

    2018-06-01

    Natural product Poria cocos possesses antitumor effect. This study will explore the molecular mechanism of Poria cocos combined with chemotherapy in the inhibition of gastric cancer cell EMT process. The experiment was divided into blank control group, Poria cocos group, oxaliplatin group and Poria cocos combined with oxaliplatin group. Scratch and Transwell assay were used to detect cell migration and invasion respectively. RT-qPCR and Western Blot analyses were used to detect mRNA and protein expression of the epithelial-mesenchymal transition (EMT) related factors including Snail, Twist, Vimentin, E-cadherin and N-cadherin respectively. Morphologic assessment was performed with HPIAS-1000 automated image analysis system. The migration and invasion abilities of gastric cancer cells in the Poria cocos combined with oxaliplatin group were significantly decreased (P < 0.01). The mRNA and protein expression of Snail, Twist, Vimentin and N-cadherin were significantly decreased while the mRNA and protein expression of E-cadherin were significantly increased (P < 0.01) compared with blank control group. Nude mice model of gastric cancer was successfully established. Poria cocos combined with oxaliplatin could significantly inhibit gastric tumor progression. The expression of EMT related factors were consistent with in vitro study. Morphologic assessment showed that the nucleus area, perimeter, mean diameter, volume, long diameter and shape factor in the Poria cocos combined with oxaliplatin group were significantly different compared with the blank control group (P < 0.01) but not significantly different compared with the normal control. Poria cocos combined with oxaliplatin could significantly inhibit the migration and invasion of gastric cancer cells. Through both in vitro and in vivo studies, it is confirmed that Poria cocos combined with oxaliplatin could significantly inhibit the EMT process of gastric cancer. Poria cocos combined with oxaliplatin could

  7. Combination chemoprevention: future direction of colorectal cancer prevention.

    PubMed

    Zhou, Ping; Cheng, Shao-Wen; Yang, Rong; Wang, Bing; Liu, Jian

    2012-05-01

    Recent research has drawn attention to protective effects of chemopreventive agents that reverse, suppress, or prevent the carcinogenic progression using pharmacological or nutritional agents. Aspirin and celecoxib are the promising preventive agents to effectively reduce the risk of colorectal cancer, but such agents are associated with severe gastrointestinal and cardiovascular side effects in long-term administration at high doses. Recently, the strategy that combinational use with several chemopreventive agents at low doses induces greater inhibition of carcinogenesis has become the focus. The nonsteroidal anti-inflammatory drugs (NSAIDs) may combine with ornithine decarboxylase inhibitors, hydroxymethylglutaryl-CoA reductase inhibitors, epidermal growth factor signaling inhibitors, peroxisome proliferator-activated receptor-γ ligands, and tumor necrosis factor-related apoptosis-inducing ligand, to magnify the chemoprophylactic effect. It is noteworthy that the phase III trial of difluoromethylornithine combination with sulidac has shown greater and effective preventive roles, which pave the way for the use of combinations of other agents. The long-term statins and low-dose NSAIDs have also been associated with risk reduction in vitro, in vivo, and in retrospective studies; however, the data are inconsistent. Epidermal growth factor signaling inhibitors, peroxisome proliferator-activated receptor-γ ligands and tumor necrosis factor-related apoptosis-inducing ligand have been demonstrated to potentiate the preventive effects of NSAIDs in vitro and in vivo, but these combinational regimens have not yet been applied to clinical research. The major goal of this study was to review combination chemoprevention for colorectal cancer by means of combining low doses of potential preventive agents to increase their chemoprophylaxis efficacy and to minimize toxicity.

  8. Lapatinib in combination with paclitaxel plays synergistic antitumor effects on esophageal squamous cancer.

    PubMed

    Guo, Xiao-Fang; Li, Sai-Sai; Zhu, Xiao-Fei; Dou, Qiao-Hua; Liu, Duan

    2018-06-16

    Paclitaxel-based chemoradiotherapy was proven to be efficacious in treating patients with advanced esophageal cancer. However, the toxicity and the development of resistance limited its anticancer efficiency. The present study was to evaluate the antitumor effects of lapatinib, a dual tyrosine inhibitor of both epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2), combined with paclitaxel on the esophageal squamous cancer. MTT assays were used to evaluate the effects of the combination of lapatinib and paclitaxel on the growth of esophageal squamous cancer cell lines (KYSE150, KYSE450, KYSE510 and TE-7). The activity of the combination of two agents on cell invasion, migration and apoptosis was measured by wound healing assay, transwell assay and Annexin V-FITC/PI stain assay. Western blot assay was used to analyze the effects of the two agents on the EGFR/HER2 signaling. The in vivo efficacy was evaluated in KYSE450 xenograft nude mouse model. The combination of lapatinib and paclitaxel was highly synergistic in inhibiting cell growth with a combination index of < 1, and suppressed significantly the invasion and migration capability of esophageal squamous cancer cells. Esophageal squamous cancer cells displayed increased rates of apoptosis after treatment with lapatinib plus paclitaxel. The phosphorylated EGFR and HER2 as well as the activation of downstream molecules MAPKs and AKT significantly decreased when exposed to lapatinib and paclitaxel. In vivo studies showed that the combination of two agents had greater antitumor efficacy than either agent alone. The combination of lapatinib with paclitaxel showed synergistic antitumor activity, suggesting their potential in treating patients with esophageal squamous cancer.

  9. 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

  10. Combined caveolin-1 and epidermal growth factor receptor expression as a prognostic marker for breast cancer.

    PubMed

    Liang, Ya-Nan; Liu, Yu; Wang, Letian; Yao, Guodong; Li, Xiaobo; Meng, Xiangning; Wang, Fan; Li, Ming; Tong, Dandan; Geng, Jingshu

    2018-06-01

    Previous studies have indicated that caveolin-1 (Cav-1) is able to bind the signal transduction factor epidermal growth factor receptor (EGFR) to regulate its tyrosine kinase activity. The aim of the present study was to evaluate the clinical significance of Cav-1 gene expression in association with the expression of EGFR in patients with breast cancer. Primary breast cancer samples from 306 patients were analyzed for Cav-1 and EGFR expression using immunohistochemistry, and clinical significance was assessed using multivariate Cox regression analysis, Kaplan-Meier estimator curves and the log-rank test. Stromal Cav-1 was downregulated in 38.56% (118/306) of tumor tissues, whereas cytoplasmic EGFR and Cav-1 were overexpressed in 53.92% (165/306) and 44.12% (135/306) of breast cancer tissues, respectively. EGFR expression was positively associated with cytoplasmic Cav-1 and not associated with stromal Cav-1 expression in breast cancer samples; however, low expression of stromal Cav-1 was negatively associated with cytoplasmic Cav-1 expression in total tumor tissues, and analogous results were identified in the chemotherapy group. Multivariate Cox's proportional hazards model analysis revealed that, for patients in the estrogen receptor (ER)(+) group, the expression of stromal Cav-1 alone was a significant prognostic marker of breast cancer. However, in the chemotherapy, human epidermal growth factor receptor 2 (HER-2)(-), HER-2(+) and ER(-) groups, the use of combined markers was more effective prognostic marker. Stromal Cav-1 has a tumor suppressor function, and the combined marker stromal Cav-1/EGFR expression was identified as an improved prognostic marker in the diagnosis of breast cancer. Parenchymal expression of Cav-1 is able to promote EGFR signaling in breast cancer, potentially being required for EGFR-mediated initiation of mitosis.

  11. 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

  12. Successful treatment of ovarian cancer with apatinib combined with chemotherapy: A case report.

    PubMed

    Zhang, Mingzi; Tian, Zhongkai; Sun, Yehong

    2017-11-01

    The standard treatment for ovarian cancer is chemotherapy with 2 drugs (taxanes and platinum drugs). However, the traditional combination of the 2 drugs has many adverse effects (AEs) and the cancer cells will quickly become resistant to the drugs. Apatinib is a small-molecule antiangiogenic agent which has shown promising therapeutic effects against diverse tumor types, but it still remains unknown whether apatinib has an antitumor effect in patients with ovarian cancer. Herein, we present a successfully treated case of ovarian cancer using chemotherapy and apatinib, in order to demonstrate the effectiveness of this new combined regimen in ovarian cancer. A 51-year-old Chinese woman presented with ovarian cancer >4.5 years. The disease and the cancer antigen 125 (CA-125) had been controlled well by surgical treatment and following chemotherapy. However, the drugs could not control the disease anymore as the CA-125 level was significantly increasing. Ovarian cancer. The patient was treated with apatinib combined with epirubicin. Apatinib was administered orally, at an initial daily dose of 500 mg, and was then reduced to 250 mg qd after the appearance of intolerable hand-foot syndrome (HFS) and oral ulcer. Then, the oral ulcer disappeared and the HFS was controlled by dose adjustment, oral vitamin B6, and hand cream application. The CA-125 reverted to the normal value after treatment with the new regimen. Magnetic resonance imaging showed that the original tumor lesions had disappeared. Apatinib monotherapy as maintenance therapy was then used to successfully control the cancer with a complete response. Our study is the first, to our knowledge, to report the therapeutic effects of apatinib and epirubicin on ovarian cancer. Apatinib combined with chemotherapy and apatinib monotherapy as maintenance therapy could be a new therapeutic strategy for ovarian cancer, especially adenocarcinomas.

  13. Californium-252 Brachytherapy Combined With External-Beam Radiotherapy for Cervical Cancer: Long-Term Treatment Results

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Lei Xin; Qian Chengyuan; Qing Yi

    Purpose: To observe, by retrospective analysis, the curative effects and complications due to californium-252 ({sup 252}Cf) neutron intracavitary brachytherapy (ICBT) combined with external-beam radiotherapy (EBRT) in the treatment of cervical cancer. Methods and Materials: From February 1999 to December 2007, 696 patients with cervical cancer (Stages IB to IIIB) were treated with {sup 252}Cf-ICBT in combination of EBRT. Of all, 31 patients were at Stage IB, 104 at IIA, 363 at IIB, 64 at IIIA, and 134 at IIIB. Californium-252 ICBT was delivered at 7-12 Gy per insertion per week, with a total dose of 29-45 Gy to reference pointmore » A in three to five insertions. The whole pelvic cavity was treated with 8-MV X-ray external irradiation at 2 Gy per fraction, four times per week. After 16-38 Gy of external irradiation, the center of the whole pelvic field was blocked with a 4-cm-wide lead shield, with a total external irradiation dose of 44-56 Gy. The total treatment course was 5 to 6 weeks. Results: Overall survival rate at 3 and 5 years for all patients was 76.0% and 64.9%, respectively. Disease-free 3- and 5-year survival rates of patients were 71.2% and 58.4%, respectively. Late complications included vaginal contracture and adhesion, radiation proctitis, radiation cystitis, and inflammatory bowel, which accounted for 5.8%, 7.1%, 6.2%, and 4.9%, respectively. Univariate analysis results showed significant correlation of stage, age, histopathologic grade, and lymph node status with overall survival. Cox multiple regression analysis showed that the independent variables were stage, histopathologic grade, tumor size, and lymphatic metastasis in all patients. Conclusion: Results of this series suggest that the combined use of {sup 252}Cf-ICBT with EBRT is an effective method for treatment of cervical cancer.« less

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

    DTIC Science & Technology

    2017-10-01

    AWARD NUMBER: W81XWH-14-1-0109 TITLE: Combination Immunotherapy for the Treatment of High-Risk HER2-Positive Breast Cancer PRINCIPAL INVESTIGATOR...Elizabeth A. Mittendorf, MD, PhD CONTRACTING ORGANIZATION: University of Texas MD Anderson Cancer Center Houston, TX 77030 REPORT DATE: October...CONTRACT NUMBER Combination Immunotherapy for the Treatment of High-Risk HER2-Positive Breast Cancer 5b. GRANT NUMBER W81XWH-14-1-0109 5c. PROGRAM

  15. 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...  

  16. 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.

  17. EGFR Gene Amplification and KRAS Mutation Predict Response to Combination Targeted Therapy in Metastatic Colorectal Cancer.

    PubMed

    Khan, Sajid A; Zeng, Zhaoshi; Shia, Jinru; Paty, Philip B

    2017-07-01

    Genetic variability in KRAS and EGFR predicts response to cetuximab in irinotecan refractory colorectal cancer. Whether these markers or others remain predictive in combination biologic therapies including bevacizumab is unknown. We identified predictive biomarkers from patients with irinotecan refractory metastatic colorectal cancer treated with cetuximab plus bevacizumab. Patients who received cetuximab plus bevacizumab for irinotecan refractory colorectal cancer in either of two Phase II trials conducted were identified. Tumor tissue was available for 33 patients. Genomic DNA was extracted and used for mutational analysis of KRAS, BRAF, and p53 genes. Fluorescence in situ hybridization was performed to assess EGFR copy number. The status of single genes and various combinations were tested for association with response. Seven of 33 patients responded to treatment. KRAS mutations were found in 14/33 cases, and 0 responded to treatment (p = 0.01). EGFR gene amplification was seen in 3/33 of tumors and in every case was associated with response to treatment (p < 0.001). TP53 and BRAF mutations were found in 18/33 and 0/33 tumors, respectively, and there were no associations with response to either gene. EGFR gene amplification and KRAS mutations are predictive markers for patients receiving combination biologic therapy of cetuximab plus bevacizumab for metastatic colorectal cancer. One marker or the other is present in the tumor of half of all patients allowing treatment response to be predicted with a high degree of certainty. The role for molecular markers in combination biologic therapy seems promising.

  18. 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.

  19. 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. © The Author(s) 2014.

  20. PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer.

    PubMed

    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

    2017-02-21

    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.

  1. Thymidine kinase 1 combined with CEA, CYFRA21-1 and NSE improved its diagnostic value for lung cancer.

    PubMed

    Jiang, Z F; Wang, M; Xu, J L

    2018-02-01

    Thymidine kinase 1 (TK1) is a tumor biomarker in human malignancies. The purpose of this study was to evaluate the diagnostic efficiency of this marker for lung cancer using the combined analysis of carcinoembryonic antigen (CEA), cytokeratin-19 fragment (CYFRA21-1), neuron specific enolase (NSE) and TK1. From 2013 to 2014, 147 patients with lung cancer and 228 patients with lung benign diseases who were admitted to our hospital were reviewed. Peripheral blood samples were collected for the detection of TK1, CEA, CYFRA21-1 and NSE. The diagnostic value of each marker was analyzed using receiver operating characteristic (ROC) curves and logistic regression equations. The serum levels of TK1, CEA, CYFRA21-1 and NSE were significantly higher than those in patients with lung benign diseases (all P<0.05). The TK1 concentration was dependent on TNM stage (P=0.005). The ROC curve analyses showed that the diagnostic value of TK1 combined with CEA, CYFRA21-1 and NSE in lung cancer was significantly higher than that of each biomarker alone (all P<0.0001). In addition, TK1 combined with CEA, CYFRA21-1, or NSE could also improve the diagnosis of the squamous cell carcinoma, adenocarcinoma and small cell lung cancer subtypes, respectively. The combined detection of TK1 and the other three markers significantly improved the diagnosis of lung cancer. Furthermore, the detection of TK1 combined with that of CYFRA21-1, CEA or NSE increased the diagnostic value of TK1 for lung squamous cell carcinoma, adenocarcinoma and SCLC, respectively. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Combination therapy of cancer with cancer vaccine and immune checkpoint inhibitors: A mathematical model

    PubMed Central

    Friedman, Avner

    2017-01-01

    In this paper we consider a combination therapy of cancer. One drug is a vaccine which activates dendritic cells so that they induce more T cells to infiltrate the tumor. The other drug is a checkpoint inhibitor, which enables the T cells to remain active against the cancer cells. The two drugs are positively correlated in the sense that an increase in the amount of each drug results in a reduction in the tumor volume. We consider the question whether a treatment with combination of the two drugs at certain levels is preferable to a treatment by one of the drugs alone at ‘roughly’ twice the dosage level; if that is the case, then we say that there is a positive ‘synergy’ for this combination of dosages. To address this question, we develop a mathematical model using a system of partial differential equations. The variables include dendritic and cancer cells, CD4+ and CD8+ T cells, IL-12 and IL-2, GM-CSF produced by the vaccine, and a T cell checkpoint inhibitor associated with PD-1. We use the model to explore the efficacy of the two drugs, separately and in combination, and compare the simulations with data from mouse experiments. We next introduce the concept of synergy between the drugs and develop a synergy map which suggests in what proportion to administer the drugs in order to achieve the maximum reduction of tumor volume under the constraint of maximum tolerated dose. PMID:28542574

  3. Clinical omics analysis of colorectal cancer incorporating copy number aberrations and gene expression data.

    PubMed

    Yoshida, Tsuyoshi; Kobayashi, Takumi; Itoda, Masaya; Muto, Taika; Miyaguchi, Ken; Mogushi, Kaoru; Shoji, Satoshi; Shimokawa, Kazuro; Iida, Satoru; Uetake, Hiroyuki; Ishikawa, Toshiaki; Sugihara, Kenichi; Mizushima, Hiroshi; Tanaka, Hiroshi

    2010-07-29

    Colorectal cancer (CRC) is one of the most frequently occurring cancers in Japan, and thus a wide range of methods have been deployed to study the molecular mechanisms of CRC. In this study, we performed a comprehensive analysis of CRC, incorporating copy number aberration (CRC) and gene expression data. For the last four years, we have been collecting data from CRC cases and organizing the information as an "omics" study by integrating many kinds of analysis into a single comprehensive investigation. In our previous studies, we had experienced difficulty in finding genes related to CRC, as we observed higher noise levels in the expression data than in the data for other cancers. Because chromosomal aberrations are often observed in CRC, here, we have performed a combination of CNA analysis and expression analysis in order to identify some new genes responsible for CRC. This study was performed as part of the Clinical Omics Database Project at Tokyo Medical and Dental University. The purpose of this study was to investigate the mechanism of genetic instability in CRC by this combination of expression analysis and CNA, and to establish a new method for the diagnosis and treatment of CRC. Comprehensive gene expression analysis was performed on 79 CRC cases using an Affymetrix Gene Chip, and comprehensive CNA analysis was performed using an Affymetrix DNA Sty array. To avoid the contamination of cancer tissue with normal cells, laser micro-dissection was performed before DNA/RNA extraction. Data analysis was performed using original software written in the R language. We observed a high percentage of CNA in colorectal cancer, including copy number gains at 7, 8q, 13 and 20q, and copy number losses at 8p, 17p and 18. Gene expression analysis provided many candidates for CRC-related genes, but their association with CRC did not reach the level of statistical significance. The combination of CNA and gene expression analysis, together with the clinical information

  4. Wilms tumor gene (WT1) peptide-based cancer vaccine combined with gemcitabine for patients with advanced pancreatic cancer.

    PubMed

    Nishida, Sumiyuki; Koido, Shigeo; Takeda, Yutaka; Homma, Sadamu; Komita, Hideo; Takahara, Akitaka; Morita, Satoshi; Ito, Toshinori; Morimoto, Soyoko; Hara, Kazuma; Tsuboi, Akihiro; Oka, Yoshihiro; Yanagisawa, Satoru; Toyama, Yoichi; Ikegami, Masahiro; Kitagawa, Toru; Eguchi, Hidetoshi; Wada, Hiroshi; Nagano, Hiroaki; Nakata, Jun; Nakae, Yoshiki; Hosen, Naoki; Oji, Yusuke; Tanaka, Toshio; Kawase, Ichiro; Kumanogoh, Atsushi; Sakamoto, Junichi; Doki, Yuichiro; Mori, Masaki; Ohkusa, Toshifumi; Tajiri, Hisao; Sugiyama, Haruo

    2014-01-01

    Wilms tumor gene (WT1) protein is an attractive target for cancer immunotherapy. We aimed to investigate the feasibility of a combination therapy consisting of gemcitabine and WT1 peptide-based vaccine for patients with advanced pancreatic cancer and to make initial assessments of its clinical efficacy and immunologic response. Thirty-two HLA-A*24:02 patients with advanced pancreatic cancer were enrolled. Patients received HLA-A*24:02-restricted, modified 9-mer WT1 peptide (3 mg/body) emulsified with Montanide ISA51 adjuvant (WT1 vaccine) intradermally biweekly and gemcitabine (1000 mg/m) on days 1, 8, and 15 of a 28-day cycle. This combination therapy was well tolerated. The frequencies of grade 3-4 adverse events for this combination therapy were similar to those for gemcitabine alone. Objective response rate was 20.0% (6/30 evaluable patients). Median survival time and 1-year survival rate were 8.1 months and 29%, respectively. The association between longer survival and positive delayed-type hypersensitivity to WT1 peptide was statistically significant, and longer survivors featured a higher frequency of memory-phenotype WT1-specific cytotoxic T lymphocytes both before and after treatment. WT1 vaccine in combination with gemcitabine was well tolerated for patients with advanced pancreatic cancer. Delayed-type hypersensitivity-positivity to WT1 peptide and a higher frequency of memory-phenotype WT1-specific cytotoxic T lymphocytes could be useful prognostic markers for survival in the combination therapy with gemcitabine and WT1 vaccine. Further clinical investigation is warranted to determine the effectiveness of this combination therapy.

  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. Hyaluronic acid-functionalized polymeric nanoparticles for colon cancer-targeted combination chemotherapy

    NASA Astrophysics Data System (ADS)

    Xiao, Bo; Han, Moon Kwon; Viennois, Emilie; Wang, Lixin; Zhang, Mingzhen; Si, Xiaoying; Merlin, Didier

    2015-10-01

    Nanoparticle (NP)-based combination chemotherapy has been proposed as an effective strategy for achieving synergistic effects and targeted drug delivery for colon cancer therapy. Here, we fabricated a series of hyaluronic acid (HA)-functionalized camptothecin (CPT)/curcumin (CUR)-loaded polymeric NPs (HA-CPT/CUR-NPs) with various weight ratios of CPT to CUR (1 : 1, 2 : 1 and 4 : 1). The resultant spherical HA-CPT/CUR-NPs had a desirable particle size (around 289 nm), relative narrow size distribution, and slightly negative zeta potential. These NPs exhibited a simultaneous sustained release profile for both drugs throughout the time frame examined. Subsequent cellular uptake experiments demonstrated that the introduction of HA to the NP surface endowed NPs with colon cancer-targeting capability and markedly increased cellular uptake efficiency compared with chitosan-coated NPs. Importantly, the combined delivery of CPT and CUR in one HA-functionalized NP exerted strong synergistic effects. HA-CPT/CUR-NP (1 : 1) showed the highest antitumor activity among the three HA-CPT/CUR-NPs, resulting in an extremely low combination index. Collectively, our findings indicate that this HA-CPT/CUR-NP can be exploited as an efficient formulation for colon cancer-targeted combination chemotherapy.Nanoparticle (NP)-based combination chemotherapy has been proposed as an effective strategy for achieving synergistic effects and targeted drug delivery for colon cancer therapy. Here, we fabricated a series of hyaluronic acid (HA)-functionalized camptothecin (CPT)/curcumin (CUR)-loaded polymeric NPs (HA-CPT/CUR-NPs) with various weight ratios of CPT to CUR (1 : 1, 2 : 1 and 4 : 1). The resultant spherical HA-CPT/CUR-NPs had a desirable particle size (around 289 nm), relative narrow size distribution, and slightly negative zeta potential. These NPs exhibited a simultaneous sustained release profile for both drugs throughout the time frame examined. Subsequent cellular uptake experiments

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

    DTIC Science & Technology

    2012-09-01

    treatment strategy for potentiating the effects of chemotherapy in these cells (Figure 1). The goal of this current work is to gain a molecular...2000 DEGs (Figure 2B-C). By comparison, in the HER2+ MDA-MB- 453 cells, which were desensitized to doxorubicin by erlotinib exposure, we observed only...identify which cancer genes were likely to be targeted. Using CGN analysis, we identified two networks as being of potential interest: ATM and Caspase

  8. Combined Magnetic Resonance Imaging and Spectroscopic Imaging Approach to Molecular Imaging of Prostate Cancer

    PubMed Central

    Kurhanewicz, John; Swanson, Mark G.; Nelson, Sarah J.; Vigneron, Daniel B.

    2005-01-01

    Magnetic resonance spectroscopic imaging (MRSI) provides a noninvasive method of detecting small molecular markers (historically the metabolites choline and citrate) within the cytosol and extracellular spaces of the prostate, and is performed in conjunction with high-resolution anatomic imaging. Recent studies in pre-prostatectomy patients have indicated that the metabolic information provided by MRSI combined with the anatomical information provided by MRI can significantly improve the assessment of cancer location and extent within the prostate, extracapsular spread, and cancer aggressiveness. Additionally, pre- and post-therapy studies have demonstrated the potential of MRI/MRSI to provide a direct measure of the presence and spatial extent of prostate cancer after therapy, a measure of the time course of response, and information concerning the mechanism of therapeutic response. In addition to detecting metabolic biomarkers of disease behavior and therapeutic response, MRI/MRSI guidance can improve tissue selection for ex vivo analysis. High-resolution magic angle spinning (1H HR-MAS) spectroscopy provides a full chemical analysis of MRI/MRSI-targeted tissues prior to pathologic and immunohistochemical analyses of the same tissue. Preliminary 1H HR-MAS spectroscopy studies have already identified unique spectral patterns for healthy glandular and stromal tissues and prostate cancer, determined the composition of the composite in vivo choline peak, and identified the polyamine spermine as a new metabolic marker of prostate cancer. The addition of imaging sequences that provide other functional information within the same exam (dynamic contrast uptake imaging and diffusion-weighted imaging) have also demonstrated the potential to further increase the accuracy of prostate cancer detection and characterization. PMID:12353259

  9. Intra-Peritoneal Hyperthermia Combining α-Galactosylceramide in the Treatment of Ovarian Cancer

    PubMed Central

    Hsu, Yun-Ting; Huang, Jung-Tang; Wu, T. -C; Hung, Chien-Fu; Yang, Yuh-Cheng; Chang, Chih-Long

    2013-01-01

    The purpose of this study was to investigate the anti-tumor effect and potential mechanisms of i.p. hyperthermia in combination with α-galactosylceramide (α-GalCer) for the treatment of ovarian cancer. In this study, immuno-competent tumor models were established using murine ovarian cancer cell lines and treated with i.p. hyperthermia combining α-GalCer. Th1/Th2 cytokine expression profiles in the serum, NK cell cytotoxicity and phagocytic activities of dendritic cells (DCs) were assayed. We also analyzed the number of CD8+/IFN-γ+ tumor specific cytotoxic T cells, as well as the tumor growth based on depletion of lymphocyte sub-population. Therapeutic effect on those ovarian tumors was monitored by a non-invasive luminescent imaging system. Intra-peritoneal hyperthermia induced significant pro-inflammatory cytokines expression, and sustained the response of NK and DCs induced by α-GalCer treatment. The combination treatment enhanced the cytotoxic T lymphocyte (CTL) immune response in two mouse ovarian cancer models. This novel treatment modality by combination of hyperthermia and glycolipid provides a pronounced anti-tumor immune response and better survival. In conclusion, intra-peritoneal hyperthermia enhanced the pro-inflammatory cytokine secretion and phagocytic activity of DCs stimulated by α-GalCer. The subsequent CTL immune response induced by α-GalCer was further strengthened by combining with i.p. hyperthermia. Both innate and adaptive immunities were involved and resulted in a superior therapeutic effect in treating the ovarian cancer. PMID:23935988

  10. 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

    2017-08-01

    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.

  11. 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.

  12. [Combined surgical intervention treatments for lung cancer and coronary heart disease patients].

    PubMed

    Ma, Xuchen; Zhang, Zhitai; Hu, Yansheng; Song, Feiqiang; Zhang, Shaoyan; Ou, Songlei

    2012-10-01

    The number of patients with both lung cancer and coronary heart disease has increased for the last ten years. The aim of this study is to analyze the outcome of the combined treatment of radical surgery and off-pump coronary artery bypass grafting (OPCABG) for patients with both lung cancer and coronary heart disease. The clinical data of 18 patients (16 males and 2 females, mean age of 66.11 years) with both lung cancer and coronary heart disease who went through combined surgical interventions between 2003 and 2012 were summarized and analyzed. The lung cancer in these patients was predominantly at stages I and II (TNM). All patients' cardio-pulmonary function was favorable. All the patients survived the operation, without any recorded death and new myocardial infarction occurrence during the perioperative period. Squamous carcinoma and adenocarcinoma were found in 10 and 8 patients, respectively. Pathological lung cancer stage was Ia in 2 cases, Ib in 8 cases, IIa in 3 cases, II b in 3 cases, and IIIa in 2 cases. The most frequently observed complications were cardiac arrhythmias, atelectasis, and pulmonary infections. The mean values of operating room time, postoperative drainage, drainage tube time, and blood transfusion were significantly different between video-assisted thoracoscopic surgery (VATS) groups and thoractomy groups. No significant differences in survival rate were found (P=0.187). The combined method of OPCABG and pulmonary resection is a safe and effective treatment for patients with both lung cancer and coronary heart disease. VATS lobectomy is beneficial for lung cancer patients because it reduces lesions.

  13. Analysis of the genomic response of human prostate cancer cells to histone deacetylase inhibitors.

    PubMed

    Kortenhorst, Madeleine S Q; Wissing, Michel D; Rodríguez, Ronald; Kachhap, Sushant K; Jans, Judith J M; Van der Groep, Petra; Verheul, Henk M W; Gupta, Anuj; Aiyetan, Paul O; van der Wall, Elsken; Carducci, Michael A; Van Diest, Paul J; Marchionni, Luigi

    2013-09-01

    Histone deacetylases (HDACs) have emerged as important targets for cancer treatment. HDAC-inhibitors (HDACis) are well tolerated in patients and have been approved for the treatment of patients with cutaneous T-cell lymphoma (CTCL). To improve the clinical benefit of HDACis in solid tumors, combination strategies with HDACis could be employed. In this study, we applied Analysis of Functional Annotation (AFA) to provide a comprehensive list of genes and pathways affected upon HDACi-treatment in prostate cancer cells. This approach provides an unbiased and objective approach to high throughput data mining. By performing AFA on gene expression data from prostate cancer cell lines DU-145 (an HDACi-sensitive cell line) and PC3 (a relatively HDACi-resistant cell line) treated with HDACis valproic acid or vorinostat, we identified biological processes that are affected by HDACis and are therefore potential treatment targets for combination therapy. Our analysis revealed that HDAC-inhibition resulted among others in upregulation of major histocompatibility complex (MHC) genes and deregulation of the mitotic spindle checkpoint by downregulation of genes involved in mitosis. These findings were confirmed by AFA on publicly available data sets from HDACi-treated prostate cancer cells. In total, we analyzed 375 microarrays with HDACi treated and non-treated (control) prostate cancer cells. All results from this extensive analysis are provided as an online research source (available at the journal's website and at http://luigimarchionni.org/HDACIs.html). By publishing this data, we aim to enhance our understanding of the cellular changes after HDAC-inhibition, and to identify novel potential combination strategies with HDACis for the treatment of prostate cancer patients.

  14. Analysis of the genomic response of human prostate cancer cells to histone deacetylase inhibitors

    PubMed Central

    Kortenhorst, Madeleine SQ; Wissing, Michel D; Rodriguez, Ronald; Kachhap, Sushant K; Jans, Judith JM; Van der Groep, Petra; Verheul, Henk MW; Gupta, Anuj; Aiyetan, Paul O; van der Wall, Elsken; Carducci, Michael A; Van Diest, Paul J; Marchionni, Luigi

    2013-01-01

    Histone deacetylases (HDACs) have emerged as important targets for cancer treatment. HDAC-inhibitors (HDACis) are well tolerated in patients and have been approved for the treatment of patients with cutaneous T-cell lymphoma (CTCL). To improve the clinical benefit of HDACis in solid tumors, combination strategies with HDACis could be employed. In this study, we applied Analysis of Functional Annotation (AFA) to provide a comprehensive list of genes and pathways affected upon HDACi-treatment in prostate cancer cells. This approach provides an unbiased and objective approach to high throughput data mining. By performing AFA on gene expression data from prostate cancer cell lines DU-145 (an HDACi-sensitive cell line) and PC3 (a relatively HDACi-resistant cell line) treated with HDACis valproic acid or vorinostat, we identified biological processes that are affected by HDACis and are therefore potential treatment targets for combination therapy. Our analysis revealed that HDAC-inhibition resulted among others in upregulation of major histocompatibility complex (MHC) genes and deregulation of the mitotic spindle checkpoint by downregulation of genes involved in mitosis. These findings were confirmed by AFA on publicly available data sets from HDACi-treated prostate cancer cells. In total, we analyzed 375 microarrays with HDACi treated and non-treated (control) prostate cancer cells. All results from this extensive analysis are provided as an online research source (available at the journal’s website and at http://luigimarchionni.org/HDACIs.html). By publishing this data, we aim to enhance our understanding of the cellular changes after HDAC-inhibition, and to identify novel potential combination strategies with HDACis for the treatment of prostate cancer patients. PMID:23880963

  15. Efficacy of Yun Zhi (Coriolus versicolor) on survival in cancer patients: systematic review and meta-analysis.

    PubMed

    Eliza, Wong L Y; Fai, Cheng K; Chung, Leung P

    2012-01-01

    Patients with cancer frequently use herbs along with the conventional medical treatment, hoping to enhance recovery. Mushrooms have an established history of use in traditional oriental therapies. In Asian cultures, mushrooms are combined with herbal mixtures to treat cancer. This systematic review and meta-analysis draw from randomized, placebo-controlled, double-blind trials to assess the efficacy of Yun Zhi (YZ) for survival in cancer patients. Systematic review and meta-analysis technique were used to aggregate and analyze the efficacy of Yun Zhi on survival in cancer patients from 13 clinical trials using computerized database and manual search. The findings show that Yun Zhi results in a significant survival advantage compared with standard conventional anti-cancer treatment alone. Of patient randomized to Yun Zhi, there was a 9% absolute reduction in 5-year mortality, resulting in one additional patient alive for every 11 patients treated. In patients with breast cancer, gastric cancer, or colorectal cancer treated with chemotherapy, the effects of the combination of Yun Zhi preparation on the overall 5-year survival rate was more evident, but not in esophageal cancer and nasophayngeal carcinoma. However, subgroup analysis could not conclude which type of anti-cancer treatment may maximize the benefit from Yun Zhi. This meta-analysis has provided strong evidence that Yun Zhi would have survival benefit in cancer patients, particularly in carcinoma of breast, gastric and colorectal. Nevertheless, the findings highlight the need for further evidence from prospective studies of outcome to guide future potential modifications of treatment regimes. Recent patents on the use of mushrooms for the treatment of cancer are also summarized in this review.

  16. A network meta-analysis on the efficacy of sixteen targeted drugs in combination with chemotherapy for treatment of advanced/metastatic colorectal cancer

    PubMed Central

    Ba-Sang, Dan-Zeng; Long, Zi-Wen; Teng, Hao; Zhao, Xu-Peng; Qiu, Jian; Li, Ming-Shan

    2016-01-01

    Objective A network meta-analysis was conducted comparing the short-term efficacies of 16 targeted drugs in combination with chemotherapy for treatment of advanced/metastatic colorectal cancer (CRC). Results Twenty-seven RCTs were ultimately incorporated into this network meta-analysis. Compared with chemotherapy alone, bevacizumab + chemotherapy, panitumumab + chemotherapy and conatumumab + chemotherapy had higher PR rate. Bevacizumab + chemotherapy, cetuximab + chemotherapy, panitumumab + chemotherapy, trebananib + chemotherapy and conatumumab + chemotherapy had higher ORR rate in comparison to chemotherapy alone. Furthermore, bevacizumab + chemotherapy had higher DCR rate than chemotherapy alone. The results of our cluster analysis showed that chemotherapy combined with bevacizumab, cetuximab, panitumumab, conatumumab, ganitumab, or brivanib + cetuximab had better efficacies for the treatment of advanced/metastatic CRC in comparison to chemotherapy alone. Materials and Methods Electronic databases were comprehensively searched for potential and related randomized controlled trials (RCTs). Direct and indirect evidence were incorporated for evaluation of stable disease (SD), progressive disease (PD), complete response (CR), partial response (PR), disease control rate (DCR) and overall response ratio (ORR) by calculating odds ratio (OR) and 95% confidence intervals (CI), and using the surface under the cumulative ranking curve (SUCRA). Conclusions These results indicated that bevacizumab + chemotherapy, panitumumab + chemotherapy, conatumumab + chemotherapy and brivanib + cetuximab + chemotherapy may have better efficacies for the treatment of advanced/metastatic CRC. PMID:27806321

  17. The Effect of Combined Aspirin and Clopidogrel Treatment on Cancer Incidence.

    PubMed

    Leader, Avi; Zelikson-Saporta, Ravit; Pereg, David; Spectre, Galia; Rozovski, Uri; Raanani, Pia; Hermoni, Doron; Lishner, Michael

    2017-07-01

    Multiple studies have shown an association between aspirin treatment and a reduction in newly diagnosed cancer. Conversely, there are conflicting clinical and laboratory data on the effect of combined clopidogrel and aspirin therapy on cancer incidence, including analyses suggesting an increased cancer risk. No large-scale cohort study has been performed to address this issue in a heterogeneous real-world scenario. We investigated the effect of clopidogrel and aspirin on cancer incidence compared with aspirin alone and no antiplatelet therapy. A population-based historical cohort study of subjects aged ≥50 years covered by Clalit Health Services, an Israeli health maintenance organization, was performed. Patients treated with the newer antiplatelet drugs, prasugrel or ticagrelor, which, like clopidogrel, inhibit adenosine diphosphate receptors, and those with prior cancer were excluded. Prescription records of antiplatelet medication were retrieved. The cohort included 183,912 subjects diagnosed with 21,974 cancer cases based upon the International Classification of Diseases, Ninth Revision. Dual aspirin and clopidogrel was prescribed in 9.6%, while 49% received aspirin alone and 41% used neither. Compared with nonusers, there was a lower risk of cancer in subjects exposed to aspirin with (hazard ratio [HR] 0.46; 95% confidence interval [CI], 0.44-0.49) or without clopidogrel (HR 0.54; 95% CI, 0.52-0.56), on long-term follow-up. Combined treatment was associated with a lower cancer risk than the aspirin-only group (HR 0.92; 95% CI, 0.86-0.97). Dual clopidogrel and aspirin treatment is safe regarding the cancer risk. This study generates the hypothesis that clopidogrel may reduce cancer incidence. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Anti-tumor effects of retinoids combined with trastuzumab or tamoxifen in breast cancer cells: induction of apoptosis by retinoid/trastuzumab combinations.

    PubMed

    Koay, Debbie C; Zerillo, Cynthia; Narayan, Murli; Harris, Lyndsay N; DiGiovanna, Michael P

    2010-01-01

    HER2 and estrogen receptor (ER) are important in breast cancer and are therapeutic targets of trastuzumab (Herceptin) and tamoxifen, respectively. Retinoids inhibit breast cancer growth, and modulate signaling by HER2 and ER. We hypothesized that treatment with retinoids and simultaneous targeting of HER2 and/or ER may have enhanced anti-tumor effects. The effects of retinoids combined with trastuzumab or tamoxifen were examined in two human breast cancer cell lines in culture, BT474 and SKBR3. Assays of proliferation, apoptosis, differentiation, cell cycle distribution, and receptor signaling were performed. In HER2-overexpressing/ER-positive BT474 cells, combining all-trans retinoic acid (atRA) with tamoxifen or trastuzumab synergistically inhibited cell growth, and altered cell differentiation and cell cycle. Only atRA/trastuzumab-containing combinations induced apoptosis. BT474 and HER2-overexpressing/ER-negative SKBR3 cells were treated with a panel of retinoids (atRA, 9-cis-retinoic acid, 13-cis-retinoic acid, or N-(4-hydroxyphenyl) retinamide (fenretinide) (4-HPR)) combined with trastuzumab. In BT474 cells, none of the single agents except 4-HPR induced apoptosis, but again combinations of each retinoid with trastuzumab did induce apoptosis. In contrast, the single retinoid agents did cause apoptosis in SKBR3 cells; this was only modestly enhanced by addition of trastuzumab. The retinoid drug combinations altered signaling by HER2 and ER. Retinoids were inactive in trastuzumab-resistant BT474 cells. Combining retinoids with trastuzumab maximally inhibits cell growth and induces apoptosis in trastuzumab-sensitive cells. Treatment with such combinations may have benefit for breast cancer patients.

  19. Novel quantitative analysis of autofluorescence images for oral cancer screening.

    PubMed

    Huang, Tze-Ta; Huang, Jehn-Shyun; Wang, Yen-Yun; Chen, Ken-Chung; Wong, Tung-Yiu; Chen, Yi-Chun; Wu, Che-Wei; Chan, Leong-Perng; Lin, Yi-Chu; Kao, Yu-Hsun; Nioka, Shoko; Yuan, Shyng-Shiou F; Chung, Pau-Choo

    2017-05-01

    VELscope® was developed to inspect oral mucosa autofluorescence. However, its accuracy is heavily dependent on the examining physician's experience. This study was aimed toward the development of a novel quantitative analysis of autofluorescence images for oral cancer screening. Patients with either oral cancer or precancerous lesions and a control group with normal oral mucosa were enrolled in this study. White light images and VELscope® autofluorescence images of the lesions were taken with a digital camera. The lesion in the image was chosen as the region of interest (ROI). The average intensity and heterogeneity of the ROI were calculated. A quadratic discriminant analysis (QDA) was utilized to compute boundaries based on sensitivity and specificity. 47 oral cancer lesions, 54 precancerous lesions, and 39 normal oral mucosae controls were analyzed. A boundary of specificity of 0.923 and a sensitivity of 0.979 between the oral cancer lesions and normal oral mucosae were validated. The oral cancer and precancerous lesions could also be differentiated from normal oral mucosae with a specificity of 0.923 and a sensitivity of 0.970. The novel quantitative analysis of the intensity and heterogeneity of VELscope® autofluorescence images used in this study in combination with a QDA classifier can be used to differentiate oral cancer and precancerous lesions from normal oral mucosae. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Synergistic suppression of human breast cancer cells by combination of plumbagin and zoledronic acid In vitro.

    PubMed

    Qiao, Han; Wang, Ting-yu; Yan, Wei; Qin, An; Fan, Qi-ming; Han, Xiu-guo; Wang, Yu-gang; Tang, Ting-ting

    2015-09-01

    Zoledronic acid (ZA), a bisphosphonate, is currently used in combination with chemotherapeutic agents to suppress breast cancer cell proliferation or breast cancer-induced osteolysis. The aim of this study was to investigate the effects of ZA combined with a natural anticancer compound plumbagin (PL) against human breast cancer cells in vitro. Human breast cancer MDA-MB-231SArfp cells were treated with ZA, PL or a combination of ZA and PL. The cell growth, apoptosis and migration were evaluated using CCK-8 assay, flow cytometry and transwell assay, respectively. The expression of apoptosis-related proteins was measured using real-time PCR and Western blotting. Synergism was evaluated using Compusyn software, and the combination index (CI) and drug reduction index (DRI) values were determined. PL or ZA alone caused mild cytotoxicity (the IC50 value at 24 h was 12.18 and above 100 μmol/L, respectively). However, the combination of ZA and PL caused a synergistic cytotoxicity (CI=0.26). The DRI values also showed a synergistic effect between PL and ZA, with actual values of 5.52 and 3.59, respectively. Furthermore, PL and ZA synergistically induced apoptosis and inhibited migration of the breast cancer cells. Moreover, the combination of ZA and PL decreased the expression of Notch-1, cleaved PARP, Bcl-2 and Bcl-xl, and increased the expression of cleaved caspase-3, CDKN1A and ID1. When the breast cancer cells were transfected with specific siRNA against Notch-1, the combination of ZA and PL markedly increased the expression of Bcl-2. Combination of ZA and PL synergistically suppresses human breast cancer MDA-MB-231SArfp cells in vitro. PL can inhibit ZA-induced activation of the Notch-1 signaling pathway and subsequently reduce the expression of Bcl-2, thus potentiating cancer cell apoptosis.

  1. Blood glucose concentration and risk of liver cancer: systematic review and meta-analysis of prospective studies.

    PubMed

    Han, Hedong; Zhang, Tianyi; Jin, Zhichao; Guo, Honglei; Wei, Xin; Liu, Yuzhou; Chen, Qi; He, Jia

    2017-07-25

    The question of whether elevated blood glucose is a risk factor for liver cancer has been intensively studied, yet with inconsistent results. To explore the relationship between blood glucose concentration and risk of liver cancer, we conduct a meta-analysis of prospective studies. Literature search was comprehensively performed using database of PubMed, EMBASE and the Cochrane Library through October 2016. Random-effect models were used to combine the effect estimations. Eight articles containing ten studies with a total of 1975 liver cancer cases were included. The pooled RRs demonstrated that elevated fasting blood glucose was associated with increased risk of liver cancer (combined RRs: 1.77; 95% CI: 1.46, 2.13) with mild heterogeneity (I2 = 30.40%, P = 0.17). In sensitivity analysis, the pooled result remained significant (combined RRs: 1.33; 95% CI: 1.12, 1.59; I2 = 33.90%, P = 0.16) when we restricted blood glucose categories in the range of nondiabetic subjects. We also detected a J-shaped non-linear dose-response relationship between blood glucose concentration and risk of liver cancer. There is evidence that elevated blood glucose increases risk of liver cancer across the range of prediabetes and diabetes. Considering the rapidly increasing prevalence of prediabetes and diabetes, controlling blood glucose may lower the risk of liver cancer.

  2. The impact of IGF-1R expression on the outcomes of patients with breast cancer: a meta-analysis

    PubMed Central

    Yan, Shunchao; Jiao, Xin; Li, Kai; Li, Wusheng; Zou, Huawei

    2015-01-01

    Purpose The value of insulin-like growth factor 1 receptor (IGF-1R) for predicting survival of patients with breast cancer remains controversial. The purpose of this study was to perform a meta-analysis of the published data to attempt to clarify the impact of IGF-1R. Methods Studies published between January 1, 1990 and October 1, 2014 were identified using an electronic search to aggregate the available survival results. Studies were included if they reported detecting IGF-1R expression in the primary breast cancer and analyzed patient survival data according to IGF-1R status. The principal outcome measures were hazard ratios (HRs) for survival of IGF-1R-positive patients. Combined HRs and 95% confidence intervals (CIs) were estimated using fixed- or random-effects models according to between-study heterogeneity. Results Ten studies, involving 5,406 patients, satisfied our inclusion criteria. Data from five studies provided the impact of IGF-1R on overall survival (OS), three studies the impact on breast cancer-specific survival (BCSS), and seven studies the impact on disease-free survival (DFS). The results of meta-analysis showed that for DFS, membranous IGF-1R positivity was not a significant predictor. The combined HR for OS/BCSS was 0.63 (95% CI: 0.42–0.95, P=0.03), indicating that membranous IGF-1R positivity was a significant predictor of better survival. IGF-1R cytoplasmic positivity was significantly associated with longer DFS and OS/BCSS (combined HR: 0.56, 95% CI: 0.35–0.89, P=0.01; combined HR: 0.55, 95% CI: 0.35–0.85, P=0.008, respectively). The results of subgroup analysis suggested that membranous IGF-1R positivity in hormone-receptor-positive breast cancer was correlated with favorable DFS (combined HR: 0.61, 95% CI: 0.41–0.92, P=0.02) and OS/BCSS (combined HR: 0.73, 95% CI: 0.57–0.93, P=0.01). Membranous IGF-1R positivity in triple-negative breast cancer predicted worse DFS (combined HR: 1.86, 95% CI: 1.03–3.34, P=0.04). Membranous

  3. Schiff base-Poloxamer P85 combination demonstrates chemotherapeutic effect on prostate cancer cells in vitro.

    PubMed

    Demirci, Selami; Doğan, Ayşegül; Türkmen, Neşe Başak; Telci, Dilek; Rizvanov, Albert A; Şahin, Fikrettin

    2017-02-01

    Prostate cancer is a multistep and complicated cancer type that is regulated by androgens at the cellular level and remains the second commonest cause of death among men. Discovery and development of novel chemotherapeutic agents enabling rapid tumor cell death with minimal toxic effects to healthy tissues might greatly improve the safety of chemotherapy. The present study evaluates the anti-cancer activity of a novel heterodinuclear copper(II)Mn(II) complex (Schiff base) in combination with poly(ethylene oxide) and poly(propylene oxide) block copolymer (Pluronic) P85. We used assays for cell proliferation, apoptosis, cell migration and invasion, DNA binding and cleavage to elucidate the molecular mechanisms of action, in addition to the anti-inflammatory potency of the new combination. The combined treatment of Schiff base and P85 lead to a remarkable anti-cancer effect on prostate cancer cell lines. Cell proliferation was inhibited in Schiff base-P85 treatment. The activity of this formulation is on DNA binding and cleavage and prevents inflammation in in vitro conditions. This is the first study presenting the anti-cancer activity of the present Schiff base derivative and its combination with P85 to treat prostate cancer in vitro. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  4. '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.

  5. 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

  6. OY-TES-1 may regulate the malignant behavior of liver cancer via NANOG, CD9, CCND2 and CDCA3: a bioinformatic analysis combine with RNAi and oligonucleotide microarray.

    PubMed

    Hu, Qiping; Fu, Jun; Luo, Bin; Huang, Miao; Guo, Wenwen; Lin, Yongda; Xie, Xiaoxun; Xiao, Shaowen

    2015-04-01

    Given its tumor-specific expression, including liver cancer, OY-TES-1 is a potential molecular marker for the diagnosis and immunotherapy of liver cancers. However, investigations of the mechanisms and the role of OY-TES-1 in liver cancer are rare. In the present study, based on a comprehensive bioinformatic analysis combined with RNA interference (RNAi) and oligonucleotide microarray, we report for the first time that downregulation of OY-TES-1 resulted in significant changes in expression of NANOG, CD9, CCND2 and CDCA3 in the liver cancer cell line BEL-7404. NANOG, CD9, CCND2 and CDCA3 may be involved in cell proliferation, migration, invasion and apoptosis, yet also may be functionally related to each other and OY-TES-1. Among these molecules, we identified that NANOG, containing a Kazal-2 binding motif and homeobox, may be the most likely candidate protein interacting with OY-TES-1 in liver cancer. Thus, the present study may provide important information for further investigation of the roles of OY-TES-1 in liver cancer.

  7. Prognostic impact of CXCL16 and CXCR6 in non-small cell lung cancer: combined high CXCL16 expression in tumor stroma and cancer cells yields improved survival.

    PubMed

    Hald, Sigurd M; Kiselev, Yury; Al-Saad, Samer; Richardsen, Elin; Johannessen, Charles; Eilertsen, Marte; Kilvaer, Thomas K; Al-Shibli, Khalid; Andersen, Sigve; Busund, Lill-Tove; Bremnes, Roy M; Donnem, Tom

    2015-05-29

    The chemokine CXCL16 and its receptor CXCR6 are expressed by a variety of immune cells and have been shown to influence angiogenesis. The expression of CXCR6 and CXCL16 has been examined in numerous human cancers; however no studies have yet investigated their influence on prognosis in non-small cell lung cancer (NSCLC). We aimed to explore their prognostic significance in NSCLC, in addition to examining associations with previously investigated markers. Resected tumor tissue from 335 consecutive unselected stage I-IIIA NSCLC patients (1990-2005) were collected. Immunohistochemistry was used to evaluate the expression of CXCR6 and CXCL16 on tissue microarrays. In vitro, NSCLC cells (NCI-H460, A549 cells) were transfected with CXCL16 siRNA to examine effects on proliferation. In univariate analysis, ↑ stromal cell CXCL16 expression was a significant positive prognostic factor (P = 0.016). CXCR6 was expressed in cancer cells, but did not show any prognostic impact. In the multivariate analysis, combinedcancer, and ↑stromal cell CXCL16 expression was an independent positive prognostic factor when compared to ↓stromal and ↓cancer cell expression (HR: 0.42; 95 % CI: 0.20-0.88; P = 0.022). Knockdown of CXCL16 by siRNA resulted in accelerated proliferation of NSCLC cell lines. We have shown that combinedcancer and ↑stromal cell CXCL16 expression is an independent positive prognostic factor in NSCLC. Further studies are warranted to elucidate the biological mechanism underlying this finding.

  8. 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

  9. 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.

  10. Trend Analysis of Betel Nut-associated Oral Cancer 
and Health Burden in China.

    PubMed

    Hu, Yan Jia; Chen, Jie; Zhong, Wai Sheng; Ling, Tian You; Jian, Xin Chun; Lu, Ruo Huang; Tang, Zhan Gui; Tao, Lin

    To forecast the future trend of betel nut-associated oral cancer and the resulting burden on health based on historical oral cancer patient data in Hunan province, China. Oral cancer patient data in five hospitals in Changsha (the capital city of Hunan province) were collected for the past 12 years. Three methods were used to analyse the data; Microsoft Excel Forecast Sheet, Excel Trendline, and the Logistic growth model. A combination of these three methods was used to forecast the future trend of betel nut-associated oral cancer and the resulting burden on health. Betel nut-associated oral cancer cases have been increasing rapidly in the past 12  years in Changsha. As of 2016, betel nuts had caused 8,222 cases of oral cancer in Changsha and close to 25,000 cases in Hunan, resulting in about ¥5 billion in accumulated financial loss. The combined trend analysis predicts that by 2030, betel nuts will cause more than 100,000 cases of oral cancer in Changsha and more than 300,000 cases in Hunan, and more than ¥64 billion in accumulated financial loss in medical expenses. The trend analysis of oral cancer patient data predicts that the growing betel nut industry in Hunan province will cause a humanitarian catastrophe with massive loss of human life and national resources. To prevent this catastrophe, China should ban betel nuts and provide early oral cancer screening for betel nut consumers as soon as possible.

  11. Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the cBioPortal

    PubMed Central

    Gao, Jianjiong; Aksoy, Bülent Arman; Dogrusoz, Ugur; Dresdner, Gideon; Gross, Benjamin; Sumer, S. Onur; Sun, Yichao; Jacobsen, Anders; Sinha, Rileen; Larsson, Erik; Cerami, Ethan; Sander, Chris; Schultz, Nikolaus

    2014-01-01

    The cBioPortal for Cancer Genomics (http://cbioportal.org) provides a Web resource for exploring, visualizing, and analyzing multidimensional cancer genomics data. The portal reduces molecular profiling data from cancer tissues and cell lines into readily understandable genetic, epigenetic, gene expression, and proteomic events. The query interface combined with customized data storage enables researchers to interactively explore genetic alterations across samples, genes, and pathways and, when available in the underlying data, to link these to clinical outcomes. The portal provides graphical summaries of gene-level data from multiple platforms, network visualization and analysis, survival analysis, patient-centric queries, and software programmatic access. The intuitive Web interface of the portal makes complex cancer genomics profiles accessible to researchers and clinicians without requiring bioinformatics expertise, thus facilitating biological discoveries. Here, we provide a practical guide to the analysis and visualization features of the cBioPortal for Cancer Genomics. PMID:23550210

  12. Analysis of Content Shared in Online Cancer Communities: Systematic Review.

    PubMed

    van Eenbergen, Mies C; van de Poll-Franse, Lonneke V; Krahmer, Emiel; Verberne, Suzan; Mols, Floortje

    2018-04-03

    The content that cancer patients and their relatives (ie, posters) share in online cancer communities has been researched in various ways. In the past decade, researchers have used automated analysis methods in addition to manual coding methods. Patients, providers, researchers, and health care professionals can learn from experienced patients, provided that their experience is findable. The aim of this study was to systematically review all relevant literature that analyzes user-generated content shared within online cancer communities. We reviewed the quality of available research and the kind of content that posters share with each other on the internet. A computerized literature search was performed via PubMed (MEDLINE), PsycINFO (5 and 4 stars), Cochrane Central Register of Controlled Trials, and ScienceDirect. The last search was conducted in July 2017. Papers were selected if they included the following terms: (cancer patient) and (support group or health communities) and (online or internet). We selected 27 papers and then subjected them to a 14-item quality checklist independently scored by 2 investigators. The methodological quality of the selected studies varied: 16 were of high quality and 11 were of adequate quality. Of those 27 studies, 15 were manually coded, 7 automated, and 5 used a combination of methods. The best results can be seen in the papers that combined both analytical methods. The number of analyzed posts ranged from 200 to 1,500,000; the number of analyzed posters ranged from 75 to 90,000. The studies analyzing large numbers of posts mainly related to breast cancer, whereas those analyzing small numbers were related to other types of cancers. A total of 12 studies involved some or entirely automatic analysis of the user-generated content. All the authors referred to two main content categories: informational support and emotional support. In all, 15 studies reported only on the content, 6 studies explicitly reported on content and social

  13. 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.

  14. 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 (p pathway  < 0.00625). The two most significant genes were NPAS2 (p gene  = 0.0062) and AANAT (p gene  = 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 (p pathway  = 0.021); this association was not confirmed in GECCO (p pathway  = 0.76) or the combined data (p pathway  = 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

  15. Retrospective analysis of an oral combination of dexamethasone, uracil plus tegafur and cyclophosphamide for hormone-refractory prostate cancer.

    PubMed

    Hatano, Koji; Nonomura, Norio; Nishimura, Kazuo; Kawashima, Atsunari; Mukai, Masatoshi; Nagahara, Akira; Nakai, Yasutomo; Nakayama, Masashi; Takayama, Hitoshi; Tsujimura, Akira; Okuyama, Akihiko

    2011-02-01

    To evaluate the clinical utility of an oral combination of dexamethasone, uracil plus tegafur and cyclophosphamide as a treatment for patients with hormone-refractory prostate cancer. Fifty-seven patients with hormone-refractory prostate cancer were treated with an oral administration of dexamethasone (1.0 mg/day), uracil plus tegafur (400 mg/day) and cyclophosphamide (100 mg/day). The median patient age was 71 years. Sixteen patients had symptomatic bone metastasis, 31 had asymptomatic bone metastasis and 8 showed lymph node metastasis. Eight patients presented with only biochemical progression as evaluated by serum prostate-specific antigen levels. Thirty-six (63%) of 57 patients demonstrated a ≥50% decline in serum prostate-specific antigen levels. The median time to prostate-specific antigen progression was 7.2 months. In patients with a prostate-specific antigen decline of ≥50%, the median time to progression was 13.3 months. With respect to pre-treatment markers, the duration of response to initial hormonal treatment was associated with the time to prostate-specific antigen progression. In 11 of 16 (69%) patients who complained of bone pain, the pain improved and became stable in 5 of those patients (31%). Most adverse events were mild and only three (5%) patients showed neutropenia of Grade 3 or higher. The combination of dexamethasone, uracil plus tegafur and cyclophosphamide is an effective and well tolerated regimen for hormone-refractory prostate cancer. To evaluate the survival benefits, further randomized studies are required.

  16. Proteomics Analysis of Bladder Cancer Exosomes*

    PubMed Central

    Welton, Joanne L.; Khanna, Sanjay; Giles, Peter J.; Brennan, Paul; Brewis, Ian A.; Staffurth, John; Mason, Malcolm D.; Clayton, Aled

    2010-01-01

    Exosomes are nanometer-sized vesicles, secreted by various cell types, present in biological fluids that are particularly rich in membrane proteins. Ex vivo analysis of exosomes may provide biomarker discovery platforms and form non-invasive tools for disease diagnosis and monitoring. These vesicles have never before been studied in the context of bladder cancer, a major malignancy of the urological tract. We present the first proteomics analysis of bladder cancer cell exosomes. Using ultracentrifugation on a sucrose cushion, exosomes were highly purified from cultured HT1376 bladder cancer cells and verified as low in contaminants by Western blotting and flow cytometry of exosome-coated beads. Solubilization in a buffer containing SDS and DTT was essential for achieving proteomics analysis using an LC-MALDI-TOF/TOF MS approach. We report 353 high quality identifications with 72 proteins not previously identified by other human exosome proteomics studies. Overrepresentation analysis to compare this data set with previous exosome proteomics studies (using the ExoCarta database) revealed that the proteome was consistent with that of various exosomes with particular overlap with exosomes of carcinoma origin. Interrogating the Gene Ontology database highlighted a strong association of this proteome with carcinoma of bladder and other sites. The data also highlighted how homology among human leukocyte antigen haplotypes may confound MASCOT designation of major histocompatability complex Class I nomenclature, requiring data from PCR-based human leukocyte antigen haplotyping to clarify anomalous identifications. Validation of 18 MS protein identifications (including basigin, galectin-3, trophoblast glycoprotein (5T4), and others) was performed by a combination of Western blotting, flotation on linear sucrose gradients, and flow cytometry, confirming their exosomal expression. Some were confirmed positive on urinary exosomes from a bladder cancer patient. In summary, the

  17. Summary of combined treatment under endoscope on 70 esophagus cancer inpatients

    NASA Astrophysics Data System (ADS)

    Wang, Cheng; Nong, Meilong; Li, Laisheng; Jia, Fang; Hao, Runchun

    1993-03-01

    We announce with satisfaction that combined treatment on 70 inpatients who suffered esophageal cancer in its middle or late course is perfectly successful. The combined methods include phototherapy, microwave therapy, and anticarcinogen local injection. The results are as follows: CR 3 cases, holds 4.3% of the total inpatients; PR 36 cases, 51.4%; MR 24 cases, 34.3%; NR 7 cases, 10%; the total effective rate 90%. Splendid results of treatment on enlarging the canal, improving dysphagia, and releasing obstruction have been obtained. The dysphagic grade increased from 66 to 148, the grade of esophagostenosis from 64 to 147, and the obstruction releasing rate is 69 out of 70 (that is 98.6%). The histological observation after treatment shows that 59/62 inpatients being reported as having cancer cells appear to have retrogression accompanied with a few or large quantities of necrotic cancer cells, and 3 inpatients were changed to negative reaction. No obvious poisoning or side effects arose. The combined treatment is more advantageous on those of old age or the physically weak and those who cannot stand for an operation, radiotherapy, or normal chemotherapy.

  18. Improved anti-tumor efficacy via combination of oxaliplatin and fibrin glue in colorectal cancer

    PubMed Central

    Hu, Yuzhu; Yu, Ting; Liu, Xiaoxiao; He, Yihong; Deng, Lihong; Guo, Jiajuan; Hua, Yuanqi; Luo, Ting; Gao, Xiang

    2018-01-01

    Colorectal cancer is very common worldwide and advanced colorectal cancer exhibited very poor clinical outcome. Oxaliplatin (OXP) is one of the principal chemotherapeutic agents in colorectal cancer treatment presenting impressive anti-tumor ability, limited by adverse effect in clinical practice. Fibrin glue (FG) is a biocompatible formulation made of fibrinogen and thrombin, extensively used in surgery for hemostasis, tissue adhesion and sealing. In this study, FG was innovatively applied as OXP delivery system and results showed enhanced anti-tumor performance in subcutaneous model and abdominal metastasis model of murine colorectal cancer compared with that of OXP used alone. It is revealed that combination of OXP and FG could increase activated CD8+ T cells, reduce regulatory T (Treg) cells and increase interferon-γ (IFN-γ). Furthermore, results showed promoted tumor apoptosis, decreased proliferation and inhibited tumor angiogenesis by OXP and FG combination. No obvious systemic toxicity was observed in this study. Finally, our findings provided basis for promising application of OXP and FG combination in colorectal cancer treatment. PMID:29416788

  19. Combined modality treatment of gastric cancer

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Gunderson, L.L.; Hoskins, R.B.; Cohen, A.C.

    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).more » 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.« less

  20. Diagnostic test pepsinogen I and combination with tumor marker CEA in gastric cancer

    NASA Astrophysics Data System (ADS)

    Sembiring, J.; Sarumpaet, K.; Ganie, R. A.

    2018-03-01

    Gastric cancer (GC) is the fifth leading cause of cancer and the third leading cause of cancer-related mortality globally. Human pepsinogens (HP) are considered promising serological biomarkers for the screening of atrophic gastritis (AG) and GC. HP are biochemically and immunochemically classified into two groups: pepsinogen I (PG I) and PG II. Carcinoembryonic antigen (CEA) is a glycoprotein, which is present in normal mucosal cells but increased amounts are associated with adenocarcinoma, especially colorectal cancer. CEA in combination with other tumour markers can be used in pre-operative staging and thereby assist in the planning of the type of surgery required and future management options. The purpose of this study was to diagnose test PG I and combination with tumor marker CEA in 32 patients suspected with GC. There was a significant difference in levels of CEA between GC group with non-GC with a value p <0.001. PGI sensitivity was 70.58% and specificity 93.3%. The sensitivity of PGI and CEA combination of 94.1% and specificity 80%. The area of AUC obtained was 92.7% at 95% confidence interval (82.7-100%). This AUC value indicated that the value of diagnostic accuracy of the PGI and CEA combinations of 92.7%.

  1. Multifunctional superparamagnetic iron oxide nanoparticles for combined chemotherapy and hyperthermia cancer treatment

    NASA Astrophysics Data System (ADS)

    Quinto, Christopher A.; Mohindra, Priya; Tong, Sheng; Bao, Gang

    2015-07-01

    Superparamagnetic iron oxide (SPIO) nanoparticles have the potential for use as a multimodal cancer therapy agent due to their ability to carry anticancer drugs and generate localized heat when exposed to an alternating magnetic field, resulting in combined chemotherapy and hyperthermia. To explore this potential, we synthesized SPIOs with a phospholipid-polyethylene glycol (PEG) coating, and loaded Doxorubicin (DOX) with a 30.8% w/w loading capacity when the PEG length is optimized. We found that DOX-loaded SPIOs exhibited a sustained DOX release over 72 hours where the release kinetics could be altered by the PEG length. In contrast, the heating efficiency of the SPIOs showed minimal change with the PEG length. With a core size of 14 nm, the SPIOs could generate sufficient heat to raise the local temperature to 43 °C, sufficient to trigger apoptosis in cancer cells. Further, we found that DOX-loaded SPIOs resulted in cell death comparable to free DOX, and that the combined effect of DOX and SPIO-induced hyperthermia enhanced cancer cell death in vitro. This study demonstrates the potential of using phospholipid-PEG coated SPIOs for chemotherapy-hyperthermia combinatorial cancer treatment with increased efficacy.Superparamagnetic iron oxide (SPIO) nanoparticles have the potential for use as a multimodal cancer therapy agent due to their ability to carry anticancer drugs and generate localized heat when exposed to an alternating magnetic field, resulting in combined chemotherapy and hyperthermia. To explore this potential, we synthesized SPIOs with a phospholipid-polyethylene glycol (PEG) coating, and loaded Doxorubicin (DOX) with a 30.8% w/w loading capacity when the PEG length is optimized. We found that DOX-loaded SPIOs exhibited a sustained DOX release over 72 hours where the release kinetics could be altered by the PEG length. In contrast, the heating efficiency of the SPIOs showed minimal change with the PEG length. With a core size of 14 nm, the SPIOs could

  2. Analysis of Content Shared in Online Cancer Communities: Systematic Review

    PubMed Central

    van de Poll-Franse, Lonneke V; Krahmer, Emiel; Verberne, Suzan; Mols, Floortje

    2018-01-01

    Background The content that cancer patients and their relatives (ie, posters) share in online cancer communities has been researched in various ways. In the past decade, researchers have used automated analysis methods in addition to manual coding methods. Patients, providers, researchers, and health care professionals can learn from experienced patients, provided that their experience is findable. Objective The aim of this study was to systematically review all relevant literature that analyzes user-generated content shared within online cancer communities. We reviewed the quality of available research and the kind of content that posters share with each other on the internet. Methods A computerized literature search was performed via PubMed (MEDLINE), PsycINFO (5 and 4 stars), Cochrane Central Register of Controlled Trials, and ScienceDirect. The last search was conducted in July 2017. Papers were selected if they included the following terms: (cancer patient) and (support group or health communities) and (online or internet). We selected 27 papers and then subjected them to a 14-item quality checklist independently scored by 2 investigators. Results The methodological quality of the selected studies varied: 16 were of high quality and 11 were of adequate quality. Of those 27 studies, 15 were manually coded, 7 automated, and 5 used a combination of methods. The best results can be seen in the papers that combined both analytical methods. The number of analyzed posts ranged from 200 to 1,500,000; the number of analyzed posters ranged from 75 to 90,000. The studies analyzing large numbers of posts mainly related to breast cancer, whereas those analyzing small numbers were related to other types of cancers. A total of 12 studies involved some or entirely automatic analysis of the user-generated content. All the authors referred to two main content categories: informational support and emotional support. In all, 15 studies reported only on the content, 6 studies

  3. Combination therapy for non-small cell lung cancer studied in new clinical trial | Center for Cancer Research

    Cancer.gov

    Non-small cell lung cancer (NSCLC), the most common type of lung cancer, is slow growing and can affect smokers and non-smokers alike. David S. Schrump, M.D., Surgical Chief of the Thoracic and Gastrointestinal Oncology Branch, is leading the NCI’s participation in a multicenter trial of a combination drug therapy in patients with NSCLC. Read more...

  4. 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

  5. A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer.

    PubMed

    Al Olama, Ali Amin; Kote-Jarai, Zsofia; Berndt, Sonja I; Conti, David V; Schumacher, Fredrick; Han, Ying; Benlloch, Sara; Hazelett, Dennis J; Wang, Zhaoming; Saunders, Ed; Leongamornlert, Daniel; Lindstrom, Sara; Jugurnauth-Little, Sara; Dadaev, Tokhir; Tymrakiewicz, Malgorzata; Stram, Daniel O; Rand, Kristin; Wan, Peggy; Stram, Alex; Sheng, Xin; Pooler, Loreall C; Park, Karen; Xia, Lucy; Tyrer, Jonathan; Kolonel, Laurence N; Le Marchand, Loic; Hoover, Robert N; Machiela, Mitchell J; Yeager, Merideth; Burdette, Laurie; Chung, Charles C; Hutchinson, Amy; Yu, Kai; Goh, Chee; Ahmed, Mahbubl; Govindasami, Koveela; Guy, Michelle; Tammela, Teuvo L J; Auvinen, Anssi; Wahlfors, Tiina; Schleutker, Johanna; Visakorpi, Tapio; Leinonen, Katri A; Xu, Jianfeng; Aly, Markus; Donovan, Jenny; Travis, Ruth C; Key, Tim J; Siddiq, Afshan; Canzian, Federico; Khaw, Kay-Tee; Takahashi, Atsushi; Kubo, Michiaki; Pharoah, Paul; Pashayan, Nora; Weischer, Maren; Nordestgaard, Borge G; Nielsen, Sune F; Klarskov, Peter; Røder, Martin Andreas; Iversen, Peter; Thibodeau, Stephen N; McDonnell, Shannon K; Schaid, Daniel J; Stanford, Janet L; Kolb, Suzanne; Holt, Sarah; Knudsen, Beatrice; Coll, Antonio Hurtado; Gapstur, Susan M; Diver, W Ryan; Stevens, Victoria L; Maier, Christiane; Luedeke, Manuel; Herkommer, Kathleen; Rinckleb, Antje E; Strom, Sara S; Pettaway, Curtis; Yeboah, Edward D; Tettey, Yao; Biritwum, Richard B; Adjei, Andrew A; Tay, Evelyn; Truelove, Ann; Niwa, Shelley; Chokkalingam, Anand P; Cannon-Albright, Lisa; Cybulski, Cezary; Wokołorczyk, Dominika; Kluźniak, Wojciech; Park, Jong; Sellers, Thomas; Lin, Hui-Yi; Isaacs, William B; Partin, Alan W; Brenner, Hermann; Dieffenbach, Aida Karina; Stegmaier, Christa; Chen, Constance; Giovannucci, Edward L; Ma, Jing; Stampfer, Meir; Penney, Kathryn L; Mucci, Lorelei; John, Esther M; Ingles, Sue A; Kittles, Rick A; Murphy, Adam B; Pandha, Hardev; Michael, Agnieszka; Kierzek, Andrzej M; Blot, William; Signorello, Lisa B; Zheng, Wei; Albanes, Demetrius; Virtamo, Jarmo; Weinstein, Stephanie; Nemesure, Barbara; Carpten, John; Leske, Cristina; Wu, Suh-Yuh; Hennis, Anselm; Kibel, Adam S; Rybicki, Benjamin A; Neslund-Dudas, Christine; Hsing, Ann W; Chu, Lisa; Goodman, Phyllis J; Klein, Eric A; Zheng, S Lilly; Batra, Jyotsna; Clements, Judith; Spurdle, Amanda; Teixeira, Manuel R; Paulo, Paula; Maia, Sofia; Slavov, Chavdar; Kaneva, Radka; Mitev, Vanio; Witte, John S; Casey, Graham; Gillanders, Elizabeth M; Seminara, Daniella; Riboli, Elio; Hamdy, Freddie C; Coetzee, Gerhard A; Li, Qiyuan; Freedman, Matthew L; Hunter, David J; Muir, Kenneth; Gronberg, Henrik; Neal, David E; Southey, Melissa; Giles, Graham G; Severi, Gianluca; Cook, Michael B; Nakagawa, Hidewaki; Wiklund, Fredrik; Kraft, Peter; Chanock, Stephen J; Henderson, Brian E; Easton, Douglas F; Eeles, Rosalind A; Haiman, Christopher A

    2014-10-01

    Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of > 10 million SNPs in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P < 5 × 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. These 23 variants, in combination with known prostate cancer risk variants, explain 33% of the familial risk for this disease in European-ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease.

  6. Inactivation of nuclear factor κB by MIP-based drug combinations augments cell death of breast cancer cells.

    PubMed

    Subramaniam, Menaga; Liew, Su Ki; In, Lionel LA; Awang, Khalijah; Ahmed, Niyaz; Nagoor, Noor Hasima

    2018-01-01

    Drug combination therapy to treat cancer is a strategic approach to increase successful treatment rate. Optimizing combination regimens is vital to increase therapeutic efficacy with minimal side effects. In the present study, we evaluated the in vitro cytotoxicity of double and triple combinations consisting of 1'S-1'-acetoxychavicol acetate (ACA), Mycobacterium indicus pranii (MIP) and cisplatin (CDDP) against 14 various human cancer cell lines to address the need for more effective therapy. Our data show synergistic effects in MCF-7 cells treated with MIP:ACA, MIP:CDDP and MIP:ACA:CDDP combinations. The type of interaction between MIP, ACA and CDDP was evaluated based on combination index being <0.8 for synergistic effect. Identifying the mechanism of cell death based on previous studies involved intrinsic apoptosis and nuclear factor kappa B (NF-κB) and tested in Western blot analysis. Inactivation of NF-κB was confirmed by p65 and IκBα, while intrinsic apoptosis pathway activation was confirmed by caspase-9 and Apaf-1 expression. All combinations confirmed intrinsic apoptosis activation and NF-κB inactivation. Double and triple combination regimens that target induction of the same death mechanism with reduced dosage of each drug could potentially be clinically beneficial in reducing dose-related toxicities.

  7. Genistein and resveratrol, alone and in combination, suppress prostate cancer in SV-40 tag rats.

    PubMed

    Harper, Curt E; Cook, Leah M; Patel, Brijesh B; Wang, Jun; Eltoum, Isam A; Arabshahi, Ali; Shirai, Tomoyuki; Lamartiniere, Coral A

    2009-11-01

    Chemoprevention utilizing dietary agents is an effective means to slow the development of prostate cancer. We evaluated the potential additive and synergistic effects of genistein and resveratrol for suppressing prostate cancer in the Simian Virus-40 T-antigen (SV-40 Tag) targeted probasin promoter rat model, a transgenic model of spontaneously developing prostate cancer. Rats were fed genistein or resveratrol (250 mg/kg AIN-76A diet) alone and in combination, and a low-dose combination (83 mg genistein + 83 mg resveratrol/kg diet). Histopathology and mechanisms of action studies were conducted at 30 and 12 weeks of age, respectively. Genistein, resveratrol, and the high-dose combination treatments suppressed prostate cancer. The low-dose combination did not elicit protection against prostate cancer and was most likely below the effective dose for causing significant histopathological changes. Total genistein and resveratrol concentrations in the blood reached 2,160 and 211 nM, respectively in rats exposed to the single treatments. Polyphenol treatments decreased cell proliferation and insulin-like growth factor-1 (IGF-1) protein expression in the prostate. In addition, genistein as a single agent induced apoptosis and decreased steroid receptor coactivator-3 (SRC-3) in the ventral prostate (VP). Genistein and resveratrol, alone and in combination, suppress prostate cancer development in the SV-40 Tag model. Regulation of SRC-3 and growth factor signaling proteins are consistent with these nutritional polyphenols reducing cell proliferation and increasing apoptosis in the prostate.

  8. Population-based pharmacoeconomic model for adopting capecitabine/docetaxel combination treatment for anthracycline-pretreated metastatic breast cancer.

    PubMed

    Verma, Shailendra; Ilersich, A Lane

    2003-01-01

    To model the cost-effectiveness of adopting capecitabine/docetaxel combination therapy in place of single-agent taxane therapy for women in the province of Ontario, Canada, receiving treatment for anthracycline-pretreated metastatic breast cancer. Clinical effectiveness and economic data were combined in a population model, from the perspective of a universal health care system. Estimates of clinical effectiveness and medical resource utilization were derived prospectively during a phase III randomized controlled trial comparing single-agent docetaxel with capecitabine/docetaxel combination therapy. Population data were obtained from the Cancer Care Ontario Registry and provincial prescription claims data. During 1999-2000, 542 patients were eligible for taxane monotherapy. As capecitabine/docetaxel treatment confers a median 3-month survival benefit compared with docetaxel monotherapy, the projected survival gain in these patients was 136 life-years. The results of the cost-effectiveness analysis demonstrate that the survival benefit provided by the addition of capecitabine to single-agent docetaxel is afforded at a small incremental cost of Canadian $3,691 per life-year gained. Hospitalization costs for treatment of adverse events were less for patients receiving capecitabine/docetaxel combination therapy than for those receiving docetaxel monotherapy. The results were robust for adjustments in treatment costs and adverse effects costs. Due to its 3-month survival gain and small incremental treatment cost, capecitabine/docetaxel is judged to be a highly cost-effective treatment in anthracycline-pretreated advanced breast cancer. From the perspective of the Ontario health care system, the addition of capecitabine to docetaxel in this patient population is a clinically appropriate and economically acceptable treatment strategy.

  9. Combination Immunotherapy in Non-small Cell Lung Cancer.

    PubMed

    Marmarelis, Melina E; Aggarwal, Charu

    2018-05-08

    Checkpoint blockade has changed the treatment landscape in non-small cell lung cancer (NSCLC), but single-agent approaches are effective for only a select subset of patients. Here, we will review the evidence for combination immunotherapies in NSCLC and the clinical data evaluating the efficacy of this approach. Clinical trials evaluating combination PD-1 and CTLA-4 blockade as well as PD-1 in combination with agents targeting IDO1, B7-H3, VEGF, and EGFR show promising results. Additional studies targeting other immune pathways like TIGIT, LAG-3, and cellular therapies are ongoing. Combination immunotherapy has the potential to improve outcomes in NSCLC. Data from early clinical trials is promising and reveals that these agents can be administered together safely without a significant increase in toxicity. Further studies are needed to evaluate their long-term safety and efficacy and to determine appropriate patient selection.

  10. Integrated analysis of germline and somatic variants in ovarian cancer.

    PubMed

    Kanchi, Krishna L; Johnson, Kimberly J; Lu, Charles; McLellan, Michael D; Leiserson, Mark D M; Wendl, Michael C; Zhang, Qunyuan; Koboldt, Daniel C; Xie, Mingchao; Kandoth, Cyriac; McMichael, Joshua F; Wyczalkowski, Matthew A; Larson, David E; Schmidt, Heather K; Miller, Christopher A; Fulton, Robert S; Spellman, Paul T; Mardis, Elaine R; Druley, Todd E; Graubert, Timothy A; Goodfellow, Paul J; Raphael, Benjamin J; Wilson, Richard K; Ding, Li

    2014-01-01

    We report the first large-scale exome-wide analysis of the combined germline-somatic landscape in ovarian cancer. Here we analyse germline and somatic alterations in 429 ovarian carcinoma cases and 557 controls. We identify 3,635 high confidence, rare truncation and 22,953 missense variants with predicted functional impact. We find germline truncation variants and large deletions across Fanconi pathway genes in 20% of cases. Enrichment of rare truncations is shown in BRCA1, BRCA2 and PALB2. In addition, we observe germline truncation variants in genes not previously associated with ovarian cancer susceptibility (NF1, MAP3K4, CDKN2B and MLL3). Evidence for loss of heterozygosity was found in 100 and 76% of cases with germline BRCA1 and BRCA2 truncations, respectively. Germline-somatic interaction analysis combined with extensive bioinformatics annotation identifies 222 candidate functional germline truncation and missense variants, including two pathogenic BRCA1 and 1 TP53 deleterious variants. Finally, integrated analyses of germline and somatic variants identify significantly altered pathways, including the Fanconi, MAPK and MLL pathways.

  11. Partnership to Explore New Drug Combination for Pancreatic Cancer | Frederick National Laboratory for Cancer Research

    Cancer.gov

    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

  12. 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

  13. 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.

  14. The application of prodrug-based nano-drug delivery strategy in cancer combination therapy.

    PubMed

    Ge, Yanxiu; Ma, Yakun; Li, Lingbing

    2016-10-01

    Single drug therapy that leads to the multidrug resistance of cancer cells and severe side-effect is a thing of the past. Combination therapies that affect multiple signaling pathways have been the focus of recent active research. Due to the successful development of prodrug-based nano-drug delivery systems (P-N-DDSs), their use has been extended to combination therapy as drug delivery platforms. In this review, we focus specifically on the P-N-DDSs in the field of combination therapy including the combinations of prodrugs with different chemotherapeutic agents, other therapeutic agents, nucleic acid or the combination of different types of therapy (e.g. chemotherapy and phototherapy). The relevant examples of prodrug-based nanoparticulate drug delivery strategy in combination cancer therapy from the recent literature are discussed to demonstrate the feasibilities of relevant technology. Copyright © 2016 Elsevier B.V. All rights reserved.

  15. 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

  16. MYC RNAi-Pt Combination Nanotherapy for Metastatic Prostate Cancer Treatment

    DTIC Science & Technology

    2017-10-01

    RNAseq data analysis and gene signatures. All trainees also have access to a number of lectures on cancer including our Fall Course on Cancer Biology ...given in the oncology department that meets twice per week and covers major topics related to cancer biology and treatment. Dr. Bieberich holds

  17. Dose-Dependent Associations between Wine Drinking and Breast Cancer Risk - Meta-Analysis Findings.

    PubMed

    Chen, Jia-Yan; Zhu, Hong-Cheng; Guo, Qing; Shu, Zheng; Bao, Xu-Hui; Sun, Feng; Qin, Qin; Yang, Xi; Zhang, Chi; Cheng, Hong-Yan; Sun, Xin-Chen

    2016-01-01

    To investigate any potential association between wine and breast cancer risk. We quantitatively assessed associations by conducting a meta-analysis based on evidence from observational studies. In May 2014, we performed electronic searches in PubMed, EmBase and the Cochrane Library to identify studies examining the effect of wine drinking on breast cancer incidence. The relative risk (RR) or odds ratio (OR) were used to measure any such association. The analysis was further stratified by confounding factors that could influence the results. A total of twenty-six studies (eight case-control and eighteen cohort studies) involving 21,149 cases were included in our meta-analysis. Our study demonstrated that wine drinking was associated with breast cancer risk. A 36% increase in breast cancer risk was observed across overall studies based on the highest versus lowest model, with a combined RR of 1.0059 (95%CI 0.97-1.05) in dose-response analysis. However, 5 g/d ethanol from wine seemed to have protective value from our non-linear model. Our findings indicate that wine drinking is associated with breast cancer risk in a dose-dependent manner. High consumption of wine contributes to breast cancer risk with protection exerted by low doses. Further investigations are needed for clarification.

  18. Combination of HDAC inhibitor TSA and silibinin induces cell cycle arrest and apoptosis by targeting survivin and cyclinB1/Cdk1 in pancreatic cancer cells.

    PubMed

    Feng, Wan; Cai, Dawei; Zhang, Bin; Lou, Guochun; Zou, Xiaoping

    2015-08-01

    Histone deacetylases (HDAC) are involved in diverse biological processes and therefore emerge as potential targets for pancreatic cancer. Silibinin, an active component of silymarin, is known to inhibit growth of pancreatic cancer in vivo and in vitro. Herein, we examined the cytotoxic effects of TSA in combination with silibinin and investigated the possible mechanism in two pancreatic cancer cell lines (Panc1 and Capan2). Our study found that combination treatment of HDAC inhibitor and silibinin exerted additive growth inhibitory effect on pancreatic cancer cell. Annexin V-FITC/PI staining and flow cytometry analysis demonstrated that combination therapy induced G2/M cell cycle arrest and apoptosis in Panc1and Capan2 cells. The induction of apoptosis was further confirmed by evaluating the activation of caspases. Moreover, treatment with TSA and silibinin resulted in a profound reduction in the expression of cyclinA2, cyclinB1/Cdk1 and survivin. Taken together, our study might indicate that the novel combination of HDAC inhibitor and silibinin could offer therapeutic potential against pancreatic cancer. Copyright © 2015. Published by Elsevier Masson SAS.

  19. 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.

  20. BET inhibitors in metastatic prostate cancer: therapeutic implications and rational drug combinations.

    PubMed

    Markowski, Mark C; De Marzo, Angelo M; Antonarakis, Emmanuel S

    2017-12-01

    The bromodomain and extra-terminal (BET) family of proteins are epigenetic readers of acetylated histones regulating a vast network of protein expression across many different cancers. Therapeutic targeting of BET is an attractive area of clinical development for metastatic castration-resistant prostate cancer (mCRPC), particularly due to its putative effect on c-MYC expression and its interaction with the androgen receptor (AR). Areas covered: We speculate that a combination approach using inhibitors of BET proteins (BETi) with other targeted therapies may be required to improve the therapeutic index of BET inhibition in the management of prostate cancer. Preclinical data has identified several molecular targets that may enhance the effect of BET inhibition in the clinic. This review will summarize the known preclinical data implicating BET as an important therapeutic target in advanced prostate cancer, highlight the ongoing clinical trials targeting this protein family, and speculate on rationale combination strategies using BETi together with other agents in prostate cancer. A literature search using Pubmed was performed for this review. Expert opinion: Use of BETi in the treatment of mCRPC patients may require the addition of a second novel agent.

  1. [Systematic review and Meta-analysis of Shenqi Fuzheng injection combined with first-line chemotherapy for non-small cell lung cancer].

    PubMed

    Hao, Teng-teng; Xie, Yan-ming; Liao, Xing; Wang, Jing

    2015-10-01

    The paper is to systematically evaluate the effect and safety of Shenqi Fuzheng injection (SFI) combined with first-line chemotherapy for non-small cell lung cancer (NSCLC). Randomized controlled trials (RCTs) on Shenqi Fuzheng injection (SFI) combined with first-line chemotherapy (experiment group) and chemotherapy alone group ( control group) were electronically retrieved from Medline, EMbase, Clinical Trials, Cochrane Library, CBM, CNKI, VIP, and Wanfang Data base. All trials were assessed for quality according to the Cochrane Reviewer's Handbook for Systematic Reviews of Intervention and then Meta-analysis was performed withRevMan5. 2 Software. A total of 43 RCTs (3433 patients) were included after screening and selecting. Results of Meta-analysis showed that: Objective remission rate (ORR): ORR of experimental group was about 20% higher than that of control group [RR = 1.23, 95% CI (1.11,1.35), P < 0.0001]. Disease control rate (DCR):DCR of SFI combined with first-line chemotherapy was 11% higher than that of first-line chemotherapy alone [RR = 1.11, 95% CI (1.07, 1.16), P < 0.000 01]. Life quality evaluated by Kosovan performance status (KPS) showed that: life quality improvement rate of experimental group was about twice of that in control group [RR = 2.02, 95% CI (1.81, 2.26), P < 0.000 01]. Toxic and side reaction analysis showed that: the incidence of side reactions in experimental group was about 50% lower than that in control group [RR = 0.59, 95% CI (0.53, 0.66), P < 0.000 01]. Immune function test showed that: the function of experimental group was 3.2 (standard deviations) times greater than that of control group [MD = 3.23, 95% CI (2.86, 3.60), P < 0.000 01]. We can see that SFI combined with first-line chemotherapy for NSCLC can increase objective efficacy, improve life quality, decrease toxic and side reactionsinduced by chemotherapy, and improve the immune functions. As most of the included studies in this systematic evaluation had poor quality

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

    DTIC Science & Technology

    2014-06-01

    B1, non-small cell lung cancer, glutamine metabolism, biguanides 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18 . NUMBER OF...combination therapy (months 15-16) Task 5. In vivo testing of biguanide and glutamine metabolism inhibitors in xenograft models of LKB1-proficient and...combination therapies in xenograft mice (months 12-15) IACUC and ACURO approval have been granted for in vivo xenograft studies, which will commence in

  3. Fruit and vegetable intake and prostate cancer risk: a meta-analysis.

    PubMed

    Meng, Hongzhou; Hu, Wenyi; Chen, Zhaodian; Shen, Yuehong

    2014-06-01

    Recent reports have examined the effect of fruit and vegetable intake on the risk of prostate cancer, but the results are inconsistent. A meta-analysis of prospective studies was conducted to arrive at quantitative conclusions about the contribution of vegetable and fruit intake to the incidence of prostate cancer. A comprehensive, systematic search of medical literature published up to June 2012 was performed to identify relevant studies. Separate meta-analyses were conducted for fruit and vegetable consumption. The presence of publication bias was assessed using Egger and Begg tests. In total, 16 cohort studies met the inclusion criteria and were included in the meta-analysis. The combined adjusted relative risk comparing highest with lowest categories showed that there was no association between vegetable and fruit consumption and prostate cancer incidence. The pooled relative risk was 0.97 (95%CI 0.93, 1.01) for vegetables and 1.02 (95%CI 0.98, 1.07) for fruit. There is no heterogeneity between the studies. No publication bias was detected. This meta-analysis suggests that total fruit or vegetable consumption may not exert a protective role in the risk of prostate cancer. © 2013 Wiley Publishing Asia Pty Ltd.

  4. Accelerating cancer therapy development: the importance of combination strategies and collaboration. Summary of an Institute of Medicine workshop.

    PubMed

    LoRusso, Patricia M; Canetta, Renzo; Wagner, John A; Balogh, Erin P; Nass, Sharyl J; Boerner, Scott A; Hohneker, John

    2012-11-15

    Cancer cells contain multiple genetic changes in cell signaling pathways that drive abnormal cell survival, proliferation, invasion, and metastasis. Unfortunately, patients treated with single agents inhibiting only one of these pathways--even if showing an initial response--often develop resistance with subsequent relapse or progression of their cancer, typically via the activation of an alternative uninhibited pathway. Combination therapies offer the potential for inhibiting multiple targets and pathways simultaneously to more effectively kill cancer cells and prevent or delay the emergence of drug resistance. However, there are many unique challenges to developing combination therapies, including devising and applying appropriate preclinical tests and clinical trial designs, prioritizing which combination therapies to test, avoiding overlapping toxicity of multiple agents, and overcoming legal, cultural, and regulatory barriers that impede collaboration among multiple companies, organizations, and/or institutions. More effective strategies to efficiently develop combination cancer therapies are urgently needed. Thus, the Institute of Medicine's National Cancer Policy Forum recently convened a workshop with the goal of identifying barriers that may be impeding the development of combination investigational cancer therapies, as well as potential solutions to overcome those barriers, improve collaboration, and ultimately accelerate the development of promising combinations of investigational cancer therapies. ©2012 AACR.

  5. The Combination of Rapamycin and Resveratrol Blocks Autophagy and Induces Apoptosis in Breast Cancer Cells

    PubMed Central

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

    2015-01-01

    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. PMID:25336146

  6. Synergistic inhibition of cancer cell proliferation with a combination of δ-tocotrienol and ferulic acid

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Eitsuka, Takahiro, E-mail: eitsuka@nupals.ac.jp; Tatewaki, Naoto; Nishida, Hiroshi

    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-1more » (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.« less

  7. Surgery combined with intraoperative hyperthermic intraperitoneal chemotherapy (IHIC) for gastric cancer: a systematic review and meta-analysis of randomised controlled trials.

    PubMed

    Mi, Deng-Hai; Li, Zheng; Yang, Ke-Hu; Cao, Nong; Lethaby, Anne; Tian, Jin-Hui; Santesso, Nancy; Ma, Bin; Chen, Yao-Long; Liu, Ya-Li

    2013-01-01

    Adjuvant intraoperative hyperthermic intraperitoneal chemotherapy (IHIC) is a therapy which combines thermotherapy and intraperitoneal chemotherapy. It is theoretically powerful for patients with advanced gastric cancer (AGC), but is there evident advantage in clinical practice? We need evidence to guide our decision-making. Meta-analysis was performed to assess the effectiveness and safety of adjuvant intraoperative hyperthermic intraperitoneal chemotherapy (IHIC) for patients with resectable locally advanced gastric cancer, and to provide the reference for clinical practice and study. We searched the Cochrane Library, PubMed, Embase, Web of Science and Chinese databases (Chinese BioMedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI) and Wanfang) electronically and also retrieved papers from other sources (tracing related references and communication with other authors). All relevant randomised controlled trials (RCTs) were collected to compare surgery combined with IHIC to surgery without IHIC for AGC. There were no language restrictions. After independent quality assessment and data extraction by two reviewers, meta-analysis was conducted by RevMan 5.1 software. 16 RCTs involving 1,906 patients were included. Compared with surgery alone, combination therapy (surgery plus IHIC) was associated with a significant improvement in survival rate at 1 year (hazard ratio (HR) = 2.99; 95% confidence interval (CI) = 2.21 to 4.05; p < 0.00001), 2 years (HR = 2.43; 95%CI = 1.81 to 3.26; p < 0.00001), 3 years (HR = 2.63; 95%CI = 2.17 to 3.20; p < 0.00001), 5 years (HR = 2.49; 95%CI = 1.97 to 3.14; p < 0.00001), and 9 years (HR = 2.14; 95%CI = 1.38 to 3.32; p = 0.0007). Compared with surgery alone, combination therapy was associated with a significant reduction in recurrence rate at 2 years (RR = 0.42; 95%CI = 0.29 to 0.61; p < 0.00001), 3 years (RR = 0.35; 95%CI = 0

  8. Diagnostic Value of Combining Tumor and Inflammatory Markers in Lung Cancer.

    PubMed

    Yoon, Ho Il; Kwon, Oh-Ran; Kang, Kyung Nam; Shin, Yong Sung; Shin, Ho Sang; Yeon, Eun Hee; Kwon, Keon Young; Hwang, Ilseon; Jeon, Yoon Kyung; Kim, Yongdai; Kim, Chul Woo

    2016-09-01

    Despite major advances in lung cancer treatment, early detection remains the most promising way of improving outcomes. To detect lung cancer in earlier stages, many serum biomarkers have been tested. Unfortunately, no single biomarker can reliably detect lung cancer. We combined a set of 2 tumor markers and 4 inflammatory or metabolic markers and tried to validate the diagnostic performance in lung cancer. We collected serum samples from 355 lung cancer patients and 590 control subjects and divided them into training and validation datasets. After measuring serum levels of 6 biomarkers (human epididymis secretory protein 4 [HE4], carcinoembryonic antigen [CEA], regulated on activation, normal T cell expressed and secreted [RANTES], apolipoprotein A2 [ApoA2], transthyretin [TTR], and secretory vascular cell adhesion molecule-1 [sVCAM-1]), we tested various sets of biomarkers for their diagnostic performance in lung cancer. In a training dataset, the area under the curve (AUC) values were 0.821 for HE4, 0.753 for CEA, 0.858 for RANTES, 0.867 for ApoA2, 0.830 for TTR, and 0.552 for sVCAM-1. A model using all 6 biomarkers and age yielded an AUC value of 0.986 and sensitivity of 93.2% (cutoff at specificity 94%). Applying this model to the validation dataset showed similar results. The AUC value of the model was 0.988, with sensitivity of 93.33% and specificity of 92.00% at the same cutoff point used in the validation dataset. Analyses by stages and histologic subtypes all yielded similar results. Combining multiple tumor and systemic inflammatory markers proved to be a valid strategy in the diagnosis of lung cancer.

  9. Reversible slurred speech related to capecitabine and lapatinib combination in patients with breast cancer.

    PubMed

    Mutlu, Hasan; Büyükçelik, Abdullah; Akça, Zeki; Erden, Abdülsamet

    2015-02-01

    Capecitabine plus lapatinib combination is an effective chemotherapy regimen in patients with advanced breast cancer. Neurological adverse effects secondary to this regimen were reported rarely in literature. A woman with breast cancer presented with complaints of slurred speech while using the capecitabine and lapatinib combination. Her major complaint was slurred speech. No other radiologic or laboratory disorders were detected in the patient. Slurred speech improved one week after the capecitabine and lapatinib combination was discontinued without any further intervention. © The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

  10. Evaluation of the cytotoxicity of the Bithionol - cisplatin combination in a panel of human ovarian cancer cell lines.

    PubMed

    Ayyagari, Vijayalakshmi N; Hsieh, Tsung-Han Jeff; Diaz-Sylvester, Paula L; Brard, Laurent

    2017-01-13

    Combination drug therapy appears a promising approach to overcome drug resistance and reduce drug-related toxicities in ovarian cancer treatments. In this in vitro study, we evaluated the antitumor efficacy of cisplatin in combination with Bithionol (BT) against a panel of ovarian cancer cell lines with special focus on cisplatin-sensitive and cisplatin-resistant cell lines. The primary objectives of this study are to determine the nature of the interactions between BT and cisplatin and to understand the mechanism(s) of action of BT-cisplatin combination. The cytotoxic effects of drugs either alone or in combination were evaluated using presto-blue assay. Cellular reactive oxygen species were measured by flow cytometry. Immunoblot analysis was carried out to investigate changes in levels of cleaved PARP, XIAP, bcl-2, bcl-xL, p21 and p27. Luminescent and colorimetric assays were used to test caspases 3/7 and ATX activity. The efficacy of the BT-cisplatin combination depends upon the cell type and concentrations of cisplatin and BT. In cisplatin-sensitive cell lines, BT and cisplatin were mostly antagonistic except when used at low concentrations, where synergy was observed. In contrast, in cisplatin-resistant cells, BT-cisplatin combination treatment displayed synergistic effects at most of the drug ratios/concentrations. Our results further revealed that the synergistic interaction was linked to increased reactive oxygen species generation and apoptosis. Enhanced apoptosis was correlated with loss of pro-survival factors (XIAP, bcl-2, bcl-xL), expression of pro-apoptotic markers (caspases 3/7, PARP cleavage) and enhanced cell cycle regulators p21 and p27. In cisplatin-resistant cell lines, BT potentiated cisplatin-induced cytotoxicity at most drug ratios via enhanced ROS generation and modulation of key regulators of apoptosis. Low doses of BT and cisplatin enhanced efficiency of cisplatin treatment in all the ovarian cancer cell lines tested. Our results suggest

  11. Highly sensitive detection and mutational analysis of lung cancer circulating tumor cells using integrated combined immunomagnetic beads with a droplet digital PCR chip.

    PubMed

    Gao, Wanlei; Huang, Ting; Yuan, Haojun; Yang, Jun; Jin, Qinghui; Jia, Chunping; Mao, Guoxin; Zhao, Jianlong

    2018-08-01

    Circulating tumor cells (CTCs) have become an important biomarker for liquid biopsy to monitor tumor progression and indicate response to therapies. Many epithelial cellular adhesion molecule (EpCAM) dependent CTC isolation methods have been developed, which have a limitation for low EpCAM expressed tumor cells. In an effort to overcome these drawbacks, we developed combined immunomagnetic beads (EpCAM, Mucin1 and epidermal growth factor receptor) to sensitively isolate CTCs for immunofluorescence analysis and genetic characterization. With this combined immunomagnetic beads, 93.35% H446 cells from spiked blood sample can be recovered. We were able to detect CTCs in 127 among 143 patients included in the study (88.8%). Some CTC clusters were captured with the combined magnetic beads system. In 17 of them, CTCs after chemotherapy significantly decreased compared to that before chemotherapy (4.42 (± 3.94) vs. 12 (± 7)/mL, P = 0.002). For subsequent genetic characterization of CTCs, 2 of 6 samples, using a droplet digital PCR (ddPCR) chip, have detectable EGFR L858R mutation in the cells enriched with the combined immunomagnetic beads. In conclusion, this method integrating the combined immunomagnetic beads and the ddPCR chip for CTCs detection can be of potential application in terms of diagnosis, therapeutic evaluation and personalized medicine in lung cancer. Copyright © 2018 Elsevier B.V. All rights reserved.

  12. Effects of neratinib and combination with irradiation and chemotherapy in head and neck cancer cells.

    PubMed

    Schneider, S; Thurnher, D; Kadletz, L; Seemann, R; Brunner, M; Kotowski, U; Schmid, R; Lill, C; Heiduschka, G

    2016-11-01

    Prognosis of patients with head and neck squamous cell carcinoma (HNSCC) is still poor. Novel therapeutic approaches are of great interest to improve the effects of radiochemotherapy. We evaluated the effects of tyrosine kinase inhibitor neratinib on HNSCC cell lines CAL27, SCC25 and FaDu as a single agent and in combination with irradiation and chemotherapy. Effects of neratinib were evaluated in HNSCC cell lines CAL27, SCC25 and FaDu. Effect on cell viability of neratinib and combination with cisplatin and irradiation was measured using CCK-8 assays and clonogenic assays. Western blot analysis was performed to distinguish the effect on epithelial growth factor receptor and HER2 expression. Apoptosis was evaluated by flow cytometry analysis. Growth inhibition was achieved in all cell lines, whereas combination of cisplatin and neratinib showed greater inhibition than each agent alone. Apoptosis was induced in all cell lines. Combination of neratinib with irradiation or cisplatin showed significantly increased apoptosis. In clonogenic assays, significant growth inhibition was observed in all investigated cell lines. Neratinib, as a single agent or in combination with chemo-irradiation, may be a promising treatment option for patients with head and neck cancer. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  13. Combination of Anti-IGF-1R Antibody A12 and Ionizing Radiation in Upper Respiratory Tract Cancers

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Riesterer, Oliver; Yang Qiuan; Raju, Uma

    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,more » 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.« less

  14. Combined immunotherapy of breast cancer with EGF and VEGF vaccines from DNA shuffling in a mouse model.

    PubMed

    Jin, Dong; Yu, Xin; Chen, Bing; Li, Zhitao; Ding, Jia; Zhao, Xiuyun; Qi, Gaofu

    2017-06-01

    Development of EGF and VEGF vaccines with high antigenicity for combined immunotherapy of EGF-EGFR signaling-dependent epithelial tumors such as breast cancer. EGF genes from mouse, human and chicken were randomly assembled to chimeric genes by DNA shuffling, then a chimeric EGF was selected out by PCR, SDS-PAGE and immunization for combined immunotherapy of breast cancer with a previously constructed chimeric VEGF vaccine from shuffling. Combined vaccination with chimeric EGF and VEGF from shuffling could induce high titer of antibodies against EGF and VEGF to inhibit tumor growth and angiogenesis, and improve the survival rate of mice with breast cancer. Combined vaccination with EGF and VEGF from shuffling showed better immunotherapy on EGF-EGFR signaling-dependent epithelial tumors such as breast cancer than the single-agent EGF vaccination.

  15. A Synthetic Lethal Screen Identifies DNA Repair Pathways that Sensitize Cancer Cells to Combined ATR Inhibition and Cisplatin Treatments

    PubMed Central

    Mohni, Kareem N.; Thompson, Petria S.; Luzwick, Jessica W.; Glick, Gloria G.; Pendleton, Christopher S.; Lehmann, Brian D.; Pietenpol, Jennifer A.; Cortez, David

    2015-01-01

    The DNA damage response kinase ATR may be a useful cancer therapeutic target. ATR inhibition synergizes with loss of ERCC1, ATM, XRCC1 and DNA damaging chemotherapy agents. Clinical trials have begun using ATR inhibitors in combination with cisplatin. Here we report the first synthetic lethality screen with a combination treatment of an ATR inhibitor (ATRi) and cisplatin. Combination treatment with ATRi/cisplatin is synthetically lethal with loss of the TLS polymerase ζ and 53BP1. Other DNA repair pathways including homologous recombination and mismatch repair do not exhibit synthetic lethal interactions with ATRi/cisplatin, even though loss of some of these repair pathways sensitizes cells to cisplatin as a single-agent. We also report that ATRi strongly synergizes with PARP inhibition, even in homologous recombination-proficient backgrounds. Lastly, ATR inhibitors were able to resensitize cisplatin-resistant cell lines to cisplatin. These data provide a comprehensive analysis of DNA repair pathways that exhibit synthetic lethality with ATR inhibitors when combined with cisplatin chemotherapy, and will help guide patient selection strategies as ATR inhibitors progress into the cancer clinic. PMID:25965342

  16. Gaining ground on a cure through synergy: combining checkpoint inhibitors with cancer vaccines.

    PubMed

    Vreeland, T J; Clifton, G T; Herbert, G S; Hale, D F; Jackson, D O; Berry, J S; Peoples, G E

    2016-12-01

    The approval of multiple checkpoint inhibitors (CPIs) for the treatment of advanced malignancies has sparked an explosion of research in the field of cancer immunotherapy. Despite the success of these medications, a large number of patients with advanced malignancy do not benefit from therapy. Early research indicates that a therapeutic combination of cancer vaccines with checkpoint inhibitors may lead to synergistic effects and higher response rates than monotherapy. Areas covered: This paper summarizes the previously completed and ongoing research on this exciting combination, including the use of the tumor lysate, particle-loaded dendritic cell (TLPLDC) vaccine combined with checkpoint inhibitors in advanced melanoma. Expert commentary: Increasing experience with CPIs has led to improved understanding of which patients may benefit and it is increasingly clear that the presence of a pre-existing immune response to the tumor, along with tumor-infiltrating lymphocytes, is key to the success of CPIs. One exciting possibility for the future is the addition of a cancer vaccine to CPI therapy, eliciting these crucial T cells, which can then be augmented and protected by the CPI. A number of current and future studies are addressing this very exciting combination therapy.

  17. Dietary fiber intake and head and neck cancer risk: A pooled analysis in the International Head and Neck Cancer Epidemiology consortium.

    PubMed

    Kawakita, Daisuke; Lee, Yuan-Chin Amy; Turati, Federica; Parpinel, Maria; Decarli, Adriano; Serraino, Diego; Matsuo, Keitaro; Olshan, Andrew F; Zevallos, Jose P; Winn, Deborah M; Moysich, Kirsten; Zhang, Zuo-Feng; Morgenstern, Hal; Levi, Fabio; Kelsey, Karl; McClean, Michael; Bosetti, Cristina; Garavello, Werner; Schantz, Stimson; Yu, Guo-Pei; Boffetta, Paolo; Chuang, Shu-Chun; Hashibe, Mia; Ferraroni, Monica; La Vecchia, Carlo; Edefonti, Valeria

    2017-11-01

    The possible role of dietary fiber in the etiology of head neck cancers (HNCs) is unclear. We used individual-level pooled data from ten case-control studies (5959 cases and 12,248 controls) participating in the International Head and Neck Cancer Epidemiology (INHANCE) consortium, to examine the association between fiber intake and cancer of the oral cavity/pharynx and larynx. Odds Ratios (ORs) and their 95% Confidence Intervals (CIs) were estimated using unconditional multiple logistic regression applied to quintile categories of non-alcohol energy-adjusted fiber intake and adjusted for tobacco and alcohol use and other known or putative confounders. Fiber intake was inversely associated with oral and pharyngeal cancer combined (OR for 5th vs. 1st quintile category = 0.49, 95% CI: 0.40-0.59; p for trend <0.001) and with laryngeal cancer (OR = 0.66, 95% CI: 0.54-0.82, p for trend <0.001). There was, however, appreciable heterogeneity of the estimated effect across studies for oral and pharyngeal cancer combined. Nonetheless, inverse associations were consistently observed for the subsites of oral and pharyngeal cancers and within most strata of the considered covariates, for both cancer sites. Our findings from a multicenter large-scale pooled analysis suggest that, although in the presence of between-study heterogeneity, a greater intake of fiber may lower HNC risk. © 2017 UICC.

  18. 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.

  19. Influencing Cancer Screening Participation Rates-Providing a Combined Cancer Screening Program (a 'One Stop' Shop) Could Be a Potential Answer.

    PubMed

    Bobridge, Amanda; Price, Kay; Gill, Tiffany K; Taylor, Anne W

    2017-01-01

    Participation in established cancer screening programs remains variable. Therefore, a renewed focus on how to increase screening uptake, including addressing structural barriers such as time, travel, and cost is needed. One approach could be the provision of combined cancer screening, where multiple screening tests are provided at the same time and location (essentially a 'One Stop' screening shop). This cohort study explored both cancer screening behavior and the acceptability of a combined screening approach. Participants of the North Western Adelaide Health Study (NWAHS), South Australia were invited to participate in a questionnaire about cancer screening behaviors and the acceptability of a proposed 'One Stop' cancer screening shop. Data were collected from 10th August 2015 to 18th January 2016, weighted for selection probability, age, and sex and analyzed using descriptive and multivariable logistic regression analysis. 1,562 people, 52% female (mean age 54.1 years ± 15.2) participated. Reported screening participation was low, the highest being for Pap Smear (34.4%). Common reasons for screening participation were preventing sickness (56.1%, CI 53.2-59.0%), maintaining health (51%, CI 48-53.9%), and free program provision (30.9%, CI 28.2-33.6%). Females were less likely to state that screening is not beneficial [OR 0.37 (CI 0.21-0.66), p  < 0.001] and to cite sickness prevention [OR 2.10 (CI 1.46-3.00), p  < 0.001] and free program [OR 1.75 (CI 1.22-2.51), p  < 0.003] as reasons for screening participation. Of those who did not participate, 34.6% (CI 30.3-39.1%) stated that there was nothing that discouraged them from participation, with 55- to 64-year olds [OR 0.24 (CI 0.07-0.74), p  < 0.04] being less likely to cite this reason. 21% (CI 17.2-24.8%) thought they did not need screening, while a smaller proportion stated not having time (6.9%, CI 4.9-9.7%) and the costs associated with screening (5.2%, CI 3.5-7.7%). The majority of

  20. Secondary Analysis and Integration of Existing Data to Elucidate the Genetic Architecture of Cancer Risk and Related Outcomes, R21 | Informatics Technology for Cancer Research (ITCR)

    Cancer.gov

    This funding opportunity announcement (FOA) encourages applications that propose to conduct secondary data analysis and integration of existing datasets and database resources, with the ultimate aim to elucidate the genetic architecture of cancer risk and related outcomes. The goal of this initiative is to address key scientific questions relevant to cancer epidemiology by supporting the analysis of existing genetic or genomic datasets, possibly in combination with environmental, outcomes, behavioral, lifestyle, and molecular profiles data.

  1. Secondary Analysis and Integration of Existing Data to Elucidate the Genetic Architecture of Cancer Risk and Related Outcomes, R01 | Informatics Technology for Cancer Research (ITCR)

    Cancer.gov

    This funding opportunity announcement (FOA) encourages applications that propose to conduct secondary data analysis and integration of existing datasets and database resources, with the ultimate aim to elucidate the genetic architecture of cancer risk and related outcomes. The goal of this initiative is to address key scientific questions relevant to cancer epidemiology by supporting the analysis of existing genetic or genomic datasets, possibly in combination with environmental, outcomes, behavioral, lifestyle, and molecular profiles data.

  2. Diagnostic Value of Combining Tumor and Inflammatory Markers in Lung Cancer

    PubMed Central

    Yoon, Ho Il; Kwon, Oh-Ran; Kang, Kyung Nam; Shin, Yong Sung; Shin, Ho Sang; Yeon, Eun Hee; Kwon, Keon Young; Hwang, Ilseon; Jeon, Yoon Kyung; Kim, Yongdai; Kim, Chul Woo

    2016-01-01

    Background Despite major advances in lung cancer treatment, early detection remains the most promising way of improving outcomes. To detect lung cancer in earlier stages, many serum biomarkers have been tested. Unfortunately, no single biomarker can reliably detect lung cancer. We combined a set of 2 tumor markers and 4 inflammatory or metabolic markers and tried to validate the diagnostic performance in lung cancer. Methods We collected serum samples from 355 lung cancer patients and 590 control subjects and divided them into training and validation datasets. After measuring serum levels of 6 biomarkers (human epididymis secretory protein 4 [HE4], carcinoembryonic antigen [CEA], regulated on activation, normal T cell expressed and secreted [RANTES], apolipoprotein A2 [ApoA2], transthyretin [TTR], and secretory vascular cell adhesion molecule-1 [sVCAM-1]), we tested various sets of biomarkers for their diagnostic performance in lung cancer. Results In a training dataset, the area under the curve (AUC) values were 0.821 for HE4, 0.753 for CEA, 0.858 for RANTES, 0.867 for ApoA2, 0.830 for TTR, and 0.552 for sVCAM-1. A model using all 6 biomarkers and age yielded an AUC value of 0.986 and sensitivity of 93.2% (cutoff at specificity 94%). Applying this model to the validation dataset showed similar results. The AUC value of the model was 0.988, with sensitivity of 93.33% and specificity of 92.00% at the same cutoff point used in the validation dataset. Analyses by stages and histologic subtypes all yielded similar results. Conclusions Combining multiple tumor and systemic inflammatory markers proved to be a valid strategy in the diagnosis of lung cancer. PMID:27722145

  3. Selective inhibition of esophageal cancer cells by combination of HDAC inhibitors and Azacytidine

    PubMed Central

    Ahrens, Theresa D; Timme, Sylvia; Hoeppner, Jens; Ostendorp, Jenny; Hembach, Sina; Follo, Marie; Hopt, Ulrich T; Werner, Martin; Busch, Hauke; Boerries, Melanie; Lassmann, Silke

    2015-01-01

    Esophageal cancers are highly aggressive tumors with poor prognosis despite some recent advances in surgical and radiochemotherapy treatment options. This study addressed the feasibility of drugs targeting epigenetic modifiers in esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) cells. We tested inhibition of histone deacetylases (HDACs) by SAHA, MS-275, and FK228, inhibition of DNA methyltransferases by Azacytidine (AZA) and Decitabine (DAC), and the effect of combination treatment using both types of drugs. The drug targets, HDAC1/2/3 and DNMT1, were expressed in normal esophageal epithelium and tumor cells of ESCC or EAC tissue specimens, as well as in non-neoplastic esophageal epithelial (Het-1A), ESCC (OE21, Kyse-270, Kyse-410), and EAC (OE33, SK-GT-4) cell lines. In vitro, HDAC activity, histone acetylation, and p21 expression were similarly affected in non-neoplastic, ESCC, and EAC cell lines post inhibitor treatment. Combined MS-275/AZA treatment, however, selectively targeted esophageal cancer cell lines by inducing DNA damage, cell viability loss, and apoptosis, and by decreasing cell migration. Non-neoplastic Het-1A cells were protected against HDACi (MS-275)/AZA treatment. RNA transcriptome analyses post MS-275 and/or AZA treatment identified novel regulated candidate genes (up: BCL6, Hes2; down: FAIM, MLKL), which were specifically associated with the treatment responses of esophageal cancer cells. In summary, combined HDACi/AZA treatment is efficient and selective for the targeting of esophageal cancer cells, despite similar target expression of normal and esophageal cancer epithelium, in vitro and in human esophageal carcinomas. The precise mechanisms of action of treatment responses involve novel candidate genes regulated by HDACi/AZA in esophageal cancer cells. Together, targeting of epigenetic modifiers in esophageal cancers may represent a potential future therapeutic approach. PMID:25923331

  4. Pharmacokinetics and Drug Interactions Determine Optimum Combination Strategies in Computational Models of Cancer Evolution.

    PubMed

    Chakrabarti, Shaon; Michor, Franziska

    2017-07-15

    The identification of optimal drug administration schedules to battle the emergence of resistance is a major challenge in cancer research. The existence of a multitude of resistance mechanisms necessitates administering drugs in combination, significantly complicating the endeavor of predicting the evolutionary dynamics of cancers and optimal intervention strategies. A thorough understanding of the important determinants of cancer evolution under combination therapies is therefore crucial for correctly predicting treatment outcomes. Here we developed the first computational strategy to explore pharmacokinetic and drug interaction effects in evolutionary models of cancer progression, a crucial step towards making clinically relevant predictions. We found that incorporating these phenomena into our multiscale stochastic modeling framework significantly changes the optimum drug administration schedules identified, often predicting nonintuitive strategies for combination therapies. We applied our approach to an ongoing phase Ib clinical trial (TATTON) administering AZD9291 and selumetinib to EGFR-mutant lung cancer patients. Our results suggest that the schedules used in the three trial arms have almost identical efficacies, but slight modifications in the dosing frequencies of the two drugs can significantly increase tumor cell eradication. Interestingly, we also predict that drug concentrations lower than the MTD are as efficacious, suggesting that lowering the total amount of drug administered could lower toxicities while not compromising on the effectiveness of the drugs. Our approach highlights the fact that quantitative knowledge of pharmacokinetic, drug interaction, and evolutionary processes is essential for identifying best intervention strategies. Our method is applicable to diverse cancer and treatment types and allows for a rational design of clinical trials. Cancer Res; 77(14); 3908-21. ©2017 AACR . ©2017 American Association for Cancer Research.

  5. 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%.

  6. Combined Treatment Effects of Radiation and Immunotherapy: Studies in an Autochthonous Prostate Cancer Model

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Wada, Satoshi; Harris, Timothy J.; Tryggestad, Erik

    2013-11-15

    Purpose: To optimize the combination of ionizing radiation and cellular immunotherapy using a preclinical autochthonous model of prostate cancer. Methods and Materials: Transgenic mice expressing a model antigen under a prostate-specific promoter were treated using a platform that integrates cone-beam CT imaging with 3-dimensional conformal therapy. Using this technology we investigated the immunologic and therapeutic effects of combining ionizing radiation with granulocyte/macrophage colony-stimulating factor-secreting cellular immunotherapy for prostate cancer in mice bearing autochthonous prostate tumors. Results: The combination of ionizing radiation and immunotherapy resulted in a significant decrease in pathologic tumor grade and gross tumor bulk that was not evidentmore » with either single-modality therapy. Furthermore, combinatorial therapy resulted in improved overall survival in a preventive metastasis model and in the setting of established micrometastases. Mechanistically, combined therapy resulted in an increase of the ratio of effector-to-regulatory T cells for both CD4 and CD8 tumor-infiltrating lymphocytes. Conclusions: Our preclinical model establishes a potential role for the use of combined radiation-immunotherapy in locally advanced prostate cancer, which warrants further exploration in a clinical setting.« less

  7. Progestin and estrogen potency of combination oral contraceptives and endometrial cancer risk.

    PubMed

    Maxwell, G L; Schildkraut, J M; Calingaert, B; Risinger, J I; Dainty, L; Marchbanks, P A; Berchuck, A; Barrett, J C; Rodriguez, G C

    2006-11-01

    Using data from a case-control study of endometrial cancer, we investigated the relationship between the progestin and estrogen potency in combination oral contraceptives (OCs) and the risk of developing endometrial cancer. Subjects included 434 endometrial cancer cases and 2,557 controls identified from the Cancer and Steroid Hormone (CASH) study. OCs were classified into four categories according to the individual potencies of each hormonal constituent (high versus low estrogen or progestin potency). Logistic regression was used to evaluate associations between endometrial cancer risk and combination OC formulations. With non-users as the referent group, use of OCs with either high potency progestin [odds ratio for endometrial cancer (OR)=0.21, 95% confidence interval (CI)=0.10 to 0.43] or with low potency progestin (OR=0.39, 95% CI=0.25 to 0.60) were both associated with a decreased risk of endometrial cancer. Overall high progestin potency OCs did not confer significantly more protection than low progestin potency OCs (OR=0.52, 95% CI=0.24 to 1.14). However, among women with a body mass index of 22.1 kg/m2 or higher, those who used high progestin potency oral contraceptives had a lower risk of endometrial cancer than those who used low progestin potency oral contraceptives (OR=0.31, 95% CI=0.11 to 0.92) while those with a BMI below 22.1 kg/m2 did not (OR=1.36, 95% CI=0.39 to 4.70). The potency of the progestin in most OCs appears adequate to provide a protective effect against endometrial cancer. Higher progestin-potency OCs may be more protective than lower progestin potency OCs among women with a larger body habitus.

  8. 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.

  9. 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.

  10. The combined effects of high-energy shock waves and ionising radiation on a human bladder cancer cell line.

    PubMed

    Fickweiler, S; Steinbach, P; Wörle, K; Hofstädter, F

    1996-01-01

    The effects of high-energy shock waves (HESW) generated by an experimental Siemens lithotripter in combination with 137Cs gamma-rays were examined in vitro. Proliferation after treatment of immobilised pellets of either single cells or multicellular spheroids of the bladder cancer cell line RT4 was determined using colony-forming assays and cell cycle analysis. Surviving and cell cycle fractions were calculated for each shock wave and radiation application mode separately, and for sequential combination in different successions for the purpose of characterizing the interaction of both treatment modalities. Combination of HESW and ionising radiation turned out to act additively or slightly supra-additively on both biologic models.

  11. Synergistic anti-tumor activity of Nimotuzumab in combination with Trastuzumab in HER2-positive breast cancer.

    PubMed

    Yang, Yun; Guo, Rui; Tian, Xiaoting; Zhang, Ziheng; Zhang, Pengfei; Li, Changzheng; Feng, Zhiwei

    2017-08-05

    Breast cancer is characterized with poor prognosis and high recurrence. HER2 is highly expressed in breast cancer and is a target for cancer therapy and prevention. Here, we investigated the anti-tumor activity of the combination of an HER2 inhibitor, trastuzumab with an EGFR-inhibitor, nimotuzumab in HER2-overexpressing breast cancer. Our data showed that a greater anti-tumor activity from the combination of trastuzumab and nimotuzumab than any alone usage of above antibody both in vitro and in vivo. Based on the combination index value, our data demonstrated that nimotuzumab synergistically enhanced trastuzumab-induced cell growth inhibition. Furthermore, we investigated the possible mechanism of this synergistic efficacy induced by trastuzumab plus nimotuzumab. Data showed that the combination was more potent in reducing the phosphorylation of HER2 and ERK1/2. We also found that the synergistic inhibition was partly attributed to the ROS generation and repression of NRF2 pathway that is known to promote cell growth. These results support the clinical development of this two-drug regimen for the treatment of HER2-amplified breast cancer. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Enhanced inhibition of urinary bladder cancer growth and muscle invasion by allyl isothiocyanate and celecoxib in combination

    PubMed Central

    Zhang, Yuesheng

    2013-01-01

    Allyl isothiocyanate (AITC) occurs in cruciferous vegetables that are commonly consumed by humans and has been shown to inhibit urinary bladder cancer growth and progression in previous preclinical studies. However, AITC does not significantly modulate cyclooxygenase-2 (Cox-2), whose oncogenic activity has been well documented in bladder cancer and other cancers. Celecoxib is a selective Cox-2 inhibitor and has been widely used for treatment of several diseases. Celecoxib has also been evaluated in bladder cancer patients, but its efficacy against bladder cancer as a single agent remains unclear. In a syngeneic rat model of orthotopic bladder cancer, treatment of the animals with the combination of AITC and celecoxib at low dose levels (AITC at 1mg/kg and celecoxib at 10mg/kg) led to increased or perhaps synergistic inhibition of bladder cancer growth and muscle invasion, compared with each agent used alone. The combination regime was also more effective than each single agent in inhibiting microvessel formation and stimulating microvessel maturation in the tumor tissues. The anticancer efficacy of the combination regime was associated with depletion of prostaglandin E2, a key downstream signaling molecule of Cox-2, caspase activation and downregulation of vascular endothelial growth factor in the tumor tissues. These data show that AITC and celecoxib complement each other for inhibition of bladder cancer and provide a novel combination approach for potential use for prevention or treatment of human bladder cancer. PMID:23946495

  13. Safety of Lienal Polypeptide Injection Combined with Chemotherapy in Treating Patients with Advanced Cancer.

    PubMed

    Huang, Xin-En; Wang, Lin; Ji, Zhu-Qing; Liu, Meng-Yan; Qian, Ting; Li, Li

    2015-01-01

    To assess the safety of Liena polypeptide injection (produced by JILIN FSENS PHARMACEUTICAL CO.,LTD) combined with chemotherapy in treating patients with advanced cancers. A consecutive cohort of patients with advanced cancers were treated with Liena polypeptide injection combined with chemotherapy. And chemotherapy for patients with advanced cancers were adopted from regimens suggested by NCCN guideline. Liena polypeptide injection was intravenously injected at a dosage of 2 ml plus 100ml normal saline for continuous 7 days during chemotherapy as one course. After at least two courses of treatment, safety and side effects were evaluated. There were 20 female and 14 male patients with advanced cancer recruited into this study, including 10 patients with breast, 8 patients with colorectal, 8 patients with lung, 4 patients with gastric, and 1 patient with esophageal cancer, as well as 1 patient with non-Hodgkin's lymphoma, 1 patient with low pharyngeal and 1 patient with urethral cancer. The median age of patients was 59 (40-82) years. Incidences of Grade 1 to 2 myelosuppression was observed in 5/34 patients, and Grade 1 to 2 elevation of hepatic enzyme was recorded in 3/34 patients. Adverse effects on the gastrointestinal tract were documented in 5/34 patients, and were Grade 1. No Grade 3-4 toxicities were diagnosed. No treatment related death was found. Liena polypeptide injection combined with chemotherapy was safe in treating several sites of tumors, that mainly included lung, colorectal and breast cancer. However, further study should be conducted to clarify the effectiveness of this treatment.

  14. 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.

  15. Synergistic enhancement of breast cancer cell death using ultrasound-microbubbles in combination with cisplatin

    NASA Astrophysics Data System (ADS)

    Jetha, Sheliza; Karshafian, Raffi

    2017-03-01

    Cisplatin (CDDP), an anti-cancer agent, can effectively treat several cancerous tumourstumors such as testicular, bladder, and ovarian cancers. CDDP binds to specific DNA bases causing 1,2-intrastrand cross-links, single strand and double strand breaks inducing apoptosis. However, the effectiveness of CDDP is limited in tumourtumors such as breast cancer due to drug resistance. In this study, the application of ultrasound-microbubble (USMB) in improving the therapeutic effect of CDDP in breast cancer cell line is investigated. Human breast cancer (MDA-MB-231) cells in suspension (2×106 cells/mL concentration and 0.6 mL volume) were treated with CDDP (3 µM, 30 µM and 300 µM) and USMB at 0.5 MHz pulse centered frequency, 60 s insonation time, 16 µs pulse duration, 1 kHz pulse repetition frequency, and 1.7% v/v (volume concentration) of Definity microbubble agent. Following USMB treatment, cells were plated in 96-well plates for 24 and 48-hour incubation, after which cell viability was measured using MTT assay (VMTT). Cell viability decreased significantly with the combined treatment of CDDP and USMB compared to CDDP alone (p<0.001) after both 24 and 48-hour incubation. After 24-hour incubation, the VMMT was 40±2%, 32±1% and 18±1% with the combined treatment compared to 96±3%, 81±3% and 63±3% with CDDP alone at 3 µM, 30 µM and 300 µM, respectively. The combined treatment was additive at both concentrations (3 µM, p=0.9957) and (30 µM, p=0.6018) and synergistic at the highest concentration (300 µM, p=0.0169), based on Bliss Independence model with a 95% confidence interval of p<0.05. Furthermore, after 48-hour incubation, the VMTT was 54±3%, 22±1% and 13±1% with the combined treatment compared to 94±9%, 68±3% and 44±2%with CDDP alone at 3 µM, 30 µM and 300 µM, respectively. The combined treatment was still additive at the lowest concentration (3 µM, p=0.6689) and synergistic at the higher concentrations (30 µM, p=0.0001) and (300 µM, p=0

  16. Fruits, vegetables and breast cancer risk: a systematic review and meta-analysis of prospective studies.

    PubMed

    Aune, D; Chan, D S M; Vieira, A R; Rosenblatt, D A Navarro; Vieira, R; Greenwood, D C; Norat, T

    2012-07-01

    Evidence for an association between fruit and vegetable intake and breast cancer risk is inconclusive. To clarify the association, we conducted a systematic review and meta-analysis of the evidence from prospective studies. We searched PubMed for prospective studies of fruit and vegetable intake and breast cancer risk until April 30, 2011. We included fifteen prospective studies that reported relative risk estimates and 95 % confidence intervals (CIs) of breast cancer associated with fruit and vegetable intake. Random effects models were used to estimate summary relative risks. The summary relative risk (RR) for the highest versus the lowest intake was 0.89 (95 % CI: 0.80-0.99, I (2) = 0 %) for fruits and vegetables combined, 0.92 (95 % CI: 0.86-0.98, I (2) = 9 %) for fruits, and 0.99 (95 % CI: 0.92-1.06, I (2) = 20 %) for vegetables. In dose-response analyses, the summary RR per 200 g/day was 0.96 (95 % CI: 0.93-1.00, I (2) = 2 %) for fruits and vegetables combined, 0.94 (95 % CI: 0.89-1.00, I (2) = 39 %) for fruits, and 1.00 (95 % CI: 0.95-1.06, I (2) = 17 %) for vegetables. In this meta-analysis of prospective studies, high intake of fruits, and fruits and vegetables combined, but not vegetables, is associated with a weak reduction in risk of breast cancer.

  17. 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

  18. A novel combination treatment for breast cancer cells involving BAPTA-AM and proteasome inhibitor bortezomib

    PubMed Central

    YERLIKAYA, AZMI; ERDOĞAN, ELIF; OKUR, EMRAH; YERLIKAYA, ŞERIFE; SAVRAN, BIRCAN

    2016-01-01

    Glucose-regulated protein 78 kDa/binding immunoglobulin protein (GRP78/BIP) is a well-known endoplasmic reticulum (ER) chaperone protein regulating ER stress by facilitating protein folding, assembly and Ca2+ binding. GRP78 is also a member of the heat shock protein 70 gene family and induces tumor cell survival and resistance to chemotherapeutics. Bortezomib is a highly specific 26S proteasome inhibitor that has been approved as treatment for patients with multiple myeloma. The present study first examined the dose- and time-dependent effects of bortezomib on GRP78 expression levels in the highly metastatic mouse breast cancer 4T1 cell line using western blot analysis. The analysis results revealed that GRP78 levels were significantly increased by bortezomib at a dose as low as 10 nM. Time-dependent experiments indicated that the accumulation of GRP78 was initiated after a 24 h incubation period following the addition of 10 nM bortezomib. Subsequently, the present study determined the half maximal inhibitory concentration of intracellular calcium chelator BAPTA-AM (13.6 µM) on 4T1 cells. The combination effect of BAPTA-AM and bortezomib on the 4T1 cells was investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and WST-1 assays and an iCELLigence system. The results revealed that the combination of 10 nM bortezomib + 5 µM BAPTA-AM is more cytotoxic compared with monotherapies, including 10 nM bortezomib, 1 µM BAPTA-AM and 5 µM BAPTA-AM. In addition, the present results revealed that bortezomib + BAPTA-AM combination causes cell death through the induction of apoptosis. The present results also revealed that bortezomib + BAPTA-AM combination-induced apoptosis is associated with a clear increase in the phosphorylation of stress-activated protein kinase/Jun amino-terminal kinase SAPK/JNK. Overall, the present results suggest that bortezomib and BAPTA-AM combination therapy may be a novel therapeutic strategy for breast cancer treatment

  19. 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.

  20. [Analysis of the factors related to the needs of patients with cancer].

    PubMed

    Lee, Jung A; Lee, Sun Hee; Park, Jong Hyock; Park, Jae Hyun; Kim, Sung Gyeong; Seo, Ju Hyun

    2010-05-01

    Limited research has investigated the specific needs of patients with cancer. This study was performed to explore patients needs and the related factors. The data were collected by 1 National Cancer Center and 9 regional cancer centers in Korea. An interview survey was performed with using a structured questionnaire for the subjects (2,661 patients who gave written informed consent to participate) survey 4 months after diagnosis and review of medical records. Data were analyzed using t-test, ANOVA and multiple regression analysis. When comparing the relating factors related with patient needs to the sociodemographic characteristics, the female group showed a higher level of recognition for physical symptoms, social support needs. The younger group showed a significantly higher level of recognition for health care staff, psychological problems, information and education, social support, hospital services needs. In addition, the higher educated group showed a higher level of recognition for health care staff, physical symptoms, social support needs. The higher income and office workers group showed a higher level of recognition for hospital services needs. When comparing the relating factors related with patient needs to the cancer, the breast cancer group showed a higher level of recognition for all needs excluding physical symptoms, accessibility and financial support needs. The combined radiotherapy with surgery and chemotherapy group showed a higher level of recognition for psychological problems, information and education, social support needs. This study showed that needs on patient with cancer was significantly influenced by female, higher education, lower income, having religion, office worker, liver cancer, breast cancer, colon cancer, chemotherapy, and combined therapy.

  1. Combination of α-Tomatine and Curcumin Inhibits Growth and Induces Apoptosis in Human Prostate Cancer Cells

    PubMed Central

    Li, Dongli; He, Yan; Li, Yu; Du, Zhiyun; Zhang, Kun; DiPaola, Robert; Goodin, Susan; Zheng, Xi

    2015-01-01

    α-Tomatine is a glycoalkaloid found in tomatoes and curcumin is a major yellow pigment of turmeric. In the present study, the combined effect of these two compounds on prostate cancer cells was studied. Treatment of different prostate cancer cells with curcumin or α-tomatine alone resulted in growth inhibition and apoptosis in a concentration-dependent manner. Combinations of α-tomatine and curcumin synergistically inhibited the growth and induced apoptosis in prostate cancer PC-3 cells. Effects of the α-tomatine and curcumin combination were associated with synergistic inhibition of NF-κB activity and a potent decrease in the expression of its downstream gene Bcl-2 in the cells. Moreover, strong decreases in the levels of phospho-Akt and phosphor-ERK1/2 were found in PC-3 cells treated with α-tomatine and curcumin in combination. In animal experiment, SCID mice with PC-3 xenograft tumors were treated with α-tomatine and curcumin. Combination of α-tomatine and curcumin more potently inhibited the growth of PC-3 tumors than either agent alone. Results from the present study indicate that α-tomatine in combination with curcumin may be an effective strategy for inhibiting the growth of prostate cancer. PMID:26630272

  2. Combined Treatments with Photodynamic Therapy for Non-Melanoma Skin Cancer

    PubMed Central

    Lucena, Silvia Rocío; Salazar, Nerea; Gracia-Cazaña, Tamara; Zamarrón, Alicia; González, Salvador; Juarranz, Ángeles; Gilaberte, Yolanda

    2015-01-01

    Non-melanoma skin cancer (NMSC) is the most common form of cancer in the Caucasian population. Among NMSC types, basal cell carcinoma (BCC) has the highest incidence and squamous cell carcinoma (SCC) is less common although it can metastasize, accounting for the majority of NMSC-related deaths. Treatment options for NMSC include both surgical and non-surgical modalities. Even though surgical approaches are most commonly used to treat these lesions, Photodynamic Therapy (PDT) has the advantage of being a non-invasive option, and capable of field treatment, providing optimum cosmetic outcomes. Numerous clinical research studies have shown the efficacy of PDT for treating pre-malignant and malignant NMSC. However, resistant or recurrent tumors appear and sometimes become more aggressive. In this sense, the enhancement of PDT effectiveness by combining it with other therapeutic modalities has become an interesting field in NMSC research. Depending on the characteristics and the type of tumor, PDT can be applied in combination with immunomodulatory (Imiquimod) and chemotherapeutic (5-fluorouracil, methotrexate, diclofenac, or ingenol mebutate) agents, inhibitors of some molecules implicated in the carcinogenic process (COX2 or MAPK), surgical techniques, or even radiotherapy. These new strategies open the way to a wider improvement of the prevention and eradication of skin cancer. PMID:26516853

  3. Combined Treatments with Photodynamic Therapy for Non-Melanoma Skin Cancer.

    PubMed

    Lucena, Silvia Rocío; Salazar, Nerea; Gracia-Cazaña, Tamara; Zamarrón, Alicia; González, Salvador; Juarranz, Ángeles; Gilaberte, Yolanda

    2015-10-28

    Non-melanoma skin cancer (NMSC) is the most common form of cancer in the Caucasian population. Among NMSC types, basal cell carcinoma (BCC) has the highest incidence and squamous cell carcinoma (SCC) is less common although it can metastasize, accounting for the majority of NMSC-related deaths. Treatment options for NMSC include both surgical and non-surgical modalities. Even though surgical approaches are most commonly used to treat these lesions, Photodynamic Therapy (PDT) has the advantage of being a non-invasive option, and capable of field treatment, providing optimum cosmetic outcomes. Numerous clinical research studies have shown the efficacy of PDT for treating pre-malignant and malignant NMSC. However, resistant or recurrent tumors appear and sometimes become more aggressive. In this sense, the enhancement of PDT effectiveness by combining it with other therapeutic modalities has become an interesting field in NMSC research. Depending on the characteristics and the type of tumor, PDT can be applied in combination with immunomodulatory (Imiquimod) and chemotherapeutic (5-fluorouracil, methotrexate, diclofenac, or ingenol mebutate) agents, inhibitors of some molecules implicated in the carcinogenic process (COX2 or MAPK), surgical techniques, or even radiotherapy. These new strategies open the way to a wider improvement of the prevention and eradication of skin cancer.

  4. Molecular evidence for increased antitumor activity of gemcitabine in combination with a cyclin-dependent kinase inhibitor, P276-00 in pancreatic cancers

    PubMed Central

    2012-01-01

    Background P276-00 is a novel cyclin-dependent kinase inhibitor currently in Phase II clinical trials. Gemcitabine is a standard of care for the treatment of pancreatic cancer. The present study investigated the effect of the combination of P276-00 and gemcitabine in five pancreatic cancer cell lines. Methods Cytotoxic activity was evaluated by Propidium Iodide assay. Cell cycle and apoptosis was analyzed by flow cytometry. Genes and proteins known to inhibit apoptosis and contribute to chemoresistance were analysed using western blot analysis and RT-PCR. In vivo efficacy was studied in PANC-1 xenograft model. Results The combination of gemcitabine followed by P276-00 was found to be highly to weakly synergistic in various pancreatic cancer cell lines as assessed by the combination index. Enhancement of apoptosis in PANC-1 cells and decrease in the antiapoptotic protein Bcl-2 and survivin was seen. P276-00 potentiated the gemcitabine-induced cytotoxicity by modulation of proteins involved in chemoresistance to gemcitabine and cell cycle viz. antiapoptotic proteins p8 and cox-2, proapoptotic protein BNIP3 and cell cycle related proteins Cdk4 and cyclin D1. The above results could explain the novel mechanisms of action of the combination therapy. We also show here that gemcitabine in combination with P276-00 is much more effective as an antitumor agent compared with either agent alone in the PANC-1 xenograft tumor model in SCID mice. Conclusions The chemosensitzation of pancreatic tumors to gemcitabine would likely be an important and novel strategy for treatment of pancreatic cancer and enable the use of lower and safer concentrations, to pave the way for a more effective treatment in this devastating disease. Phase IIb clinical trials of P276-00 in combination with gemcitabine in pancreatic cancer patients are ongoing. PMID:22873289

  5. Molecular evidence for increased antitumor activity of gemcitabine in combination with a cyclin-dependent kinase inhibitor, P276-00 in pancreatic cancers.

    PubMed

    Rathos, Maggie J; Joshi, Kavita; Khanwalkar, Harshal; Manohar, Sonal M; Joshi, Kalpana S

    2012-08-08

    P276-00 is a novel cyclin-dependent kinase inhibitor currently in Phase II clinical trials. Gemcitabine is a standard of care for the treatment of pancreatic cancer. The present study investigated the effect of the combination of P276-00 and gemcitabine in five pancreatic cancer cell lines. Cytotoxic activity was evaluated by Propidium Iodide assay. Cell cycle and apoptosis was analyzed by flow cytometry. Genes and proteins known to inhibit apoptosis and contribute to chemoresistance were analysed using western blot analysis and RT-PCR. In vivo efficacy was studied in PANC-1 xenograft model. The combination of gemcitabine followed by P276-00 was found to be highly to weakly synergistic in various pancreatic cancer cell lines as assessed by the combination index. Enhancement of apoptosis in PANC-1 cells and decrease in the antiapoptotic protein Bcl-2 and survivin was seen. P276-00 potentiated the gemcitabine-induced cytotoxicity by modulation of proteins involved in chemoresistance to gemcitabine and cell cycle viz. antiapoptotic proteins p8 and cox-2, proapoptotic protein BNIP3 and cell cycle related proteins Cdk4 and cyclin D1. The above results could explain the novel mechanisms of action of the combination therapy. We also show here that gemcitabine in combination with P276-00 is much more effective as an antitumor agent compared with either agent alone in the PANC-1 xenograft tumor model in SCID mice. The chemosensitzation of pancreatic tumors to gemcitabine would likely be an important and novel strategy for treatment of pancreatic cancer and enable the use of lower and safer concentrations, to pave the way for a more effective treatment in this devastating disease. Phase IIb clinical trials of P276-00 in combination with gemcitabine in pancreatic cancer patients are ongoing.

  6. 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

  7. A meta-analysis of interleukin-10-1082 promoter polymorphism associated with gastric cancer risk.

    PubMed

    Ni, Peihua; Xu, Hong; Xue, Huiping; Lin, Bing; Lu, Yang

    2012-04-01

    We aimed to explore the role of allele A/G single nucleotide polymorphism (SNP) of gene Interleukin 10 (IL-10) promoter-1082 in the susceptibility to gastric cancer through a systematic review and meta-analysis. Each initially included article was scored for quality appraisal. Desirable data were extracted and registered into databases. Twenty studies were ultimately eligible for the meta-analysis of IL-10-1082 A/G SNP. We adopted the most probably appropriate genetic model (dominant model), with the combined group of GG-plus-GA genotypes compared with the AA genotype. Potential sources of heterogeneity were sought out via subgroup analyses and sensitivity analyses, and publication biases were estimated. Between IL-10-1082 GG-plus-GA genotypes with the risk of developing gastric cancer, statistically significant association could be noted with overall gastric cancer, being mainly in Asian subgroup, large sample subgroup, high quality subgroup, intestinal-type subgroup, cardia-type subgroup, and some genotyping method subgroups. Our meta-analysis indicates that IL-10-1082 GG-plus-GA genotypes are associated with the overall risk of developing gastric cancer and seem to be more susceptible to overall gastric cancer in Asian populations. IL-10-1082 GG-plus-GA genotypes are more associated with the pathologically intestinal-type gastric cancer or anatomically cardia-type gastric cancer.

  8. Multifunctional superparamagnetic iron oxide nanoparticles for combined chemotherapy and hyperthermia cancer treatment.

    PubMed

    Quinto, Christopher A; Mohindra, Priya; Tong, Sheng; Bao, Gang

    2015-08-07

    Superparamagnetic iron oxide (SPIO) nanoparticles have the potential for use as a multimodal cancer therapy agent due to their ability to carry anticancer drugs and generate localized heat when exposed to an alternating magnetic field, resulting in combined chemotherapy and hyperthermia. To explore this potential, we synthesized SPIOs with a phospholipid-polyethylene glycol (PEG) coating, and loaded Doxorubicin (DOX) with a 30.8% w/w loading capacity when the PEG length is optimized. We found that DOX-loaded SPIOs exhibited a sustained DOX release over 72 hours where the release kinetics could be altered by the PEG length. In contrast, the heating efficiency of the SPIOs showed minimal change with the PEG length. With a core size of 14 nm, the SPIOs could generate sufficient heat to raise the local temperature to 43 °C, sufficient to trigger apoptosis in cancer cells. Further, we found that DOX-loaded SPIOs resulted in cell death comparable to free DOX, and that the combined effect of DOX and SPIO-induced hyperthermia enhanced cancer cell death in vitro. This study demonstrates the potential of using phospholipid-PEG coated SPIOs for chemotherapy-hyperthermia combinatorial cancer treatment with increased efficacy.

  9. Sub-Thz Vibrational Spectroscopy for Analysis of Ovarian Cancer Cells

    NASA Astrophysics Data System (ADS)

    Ferrance, Jerome P.; Sizov, Igor; Jazaeri, Amir; Moyer, Aaron; Gelmont, Boris; Globus, Tatiana

    2016-06-01

    Sub-THz vibrational spectroscopy utilizes wavelengths in the submillimeter-wave range ( 1.5-30 wn), beyond those traditionally used for chemical and biomolecular analysis. This low energy radiation excites low-frequency internal molecular motions (vibrations) involving hydrogen bonds and other weak connections within these molecules. The ability of sub-THz spectroscopy to identify and quantify biological molecules is based on detection of signature resonance absorbance at specific frequencies between 0.05 and 1 THz, for each molecule. The long wavelengths of this radiation, mean that it can even pass through entire cells, detecting the combinations of proteins and nucleic acids that exist within the cell. This research introduces a novel sub-THz resonance spectroscopy instrument with spectral resolution sufficient to identify individual resonance absorption peaks, for the analysis of ovarian cancer cells. In vitro cell cultures of SK-OV-3 and ES-2 cells, two human ovarian cancer subtypes, were characterized and compared with a normal non-transformed human fallopian tube epithelial cell line (FT131). A dramatic difference was observed between the THz absorption spectra of the cancer and normal cell sample materials with much higher absorption intensity and a very strong absorption peak at a frequency of 13 wn dominating the cancer sample spectra. Comparison of experimental spectra with molecular dynamic simulated spectroscopic signatures suggests that the high intensity spectral peak could originate from overexpressed mi-RNA molecules specific for ovarian cancer. Ovarian cancer cells are utilized as a proof of concept, but the sub-THz spectroscopy method is very general and could also be applied to other types of cancer.

  10. 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.

  11. 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

  12. Combination-oriented molecular-targeting prevention” of cancer: a model involving the combination of TRAIL and a DR5 inducer

    PubMed Central

    Yoshida, Tatsushi; Horinaka, Mano

    2010-01-01

    Malignant tumors carry a high risk of death, and the prevention of malignant tumors is a crucial issue in preventive medicine. To this end, many chemopreventive agents have been tested, but the effects of single agents have been found to be insufficient to justify clinical trials. We have therefore hypothesized that combinations of different chemopreventive agents may synergistically enhance the preventive effect of chemopreventive agents used singly. To provide the treating physician with some guideline by which to choose the most effective agents to be combined, we propose a strategy which we have termed the “combination-oriented molecular-targeting prevention” of cancer. As the molecular target of our model, we focused on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which specifically causes apoptosis in malignant tumor cells. Many of these agents were found to up-regulate the expression of death receptor 5, a TRAIL receptor. They were also found to synergistically induce apoptosis in malignant tumor cells when combined with TRAIL. Here, we strongly advocate that the strategy of “combination-oriented molecular-targeting prevention” of cancer will be a practical approach for chemoprevention against human malignant tumors. PMID:21432546

  13. [Effect of ginseng rare ginsenoside components combined with paclitaxel on A549 lung cancer].

    PubMed

    Yang, Lei; Zhang, Zhen-Hai; Jia, Xiao-Bin

    2018-04-01

    Traditional Chinese medicine combined with anticancer drugs is a new direction of clinical cancer therapy in recent years. In this study, the optimal ratio of ginseng rare ginsenoside components and paclitaxel was optimized by MTT method, and the proliferative, apoptotic and anti-tumor effects of lung cancer A549 cells were investigated. It was found that the inhibitory effect on the proliferation of lung cancer A549 cells was the same as that on paclitaxel when the ratio of rare ginseng rare ginsenoside components to paclitaxel was 4∶6. Further studies showed that the combined therapy significantly increased the inductive effect of apoptosis in A549 cells, and up-regulated the expression of caspase-3 protein and down-regulated the ratio of Bcl-2/Bax. The tumor-bearing mice model showed that the combination therapy of ginseng rare ginsenoside components and paclitaxel could significantly inhibit the growth of tumor and alleviate the toxic and side effects of paclitaxel on liver. A multi-component system of ginseng rare ginsenoside components-paclitaxel was established in this paper. The proliferation and growth of lung cancer A549 cells were inhibited by paclitaxel-induced apoptosis, the dosage of paclitaxel and the toxicity of paclitaxel were reduced, and the effect of anti-lung cancer was enhanced, which provided a theoretical basis for later studies and clinical application. Copyright© by the Chinese Pharmaceutical Association.

  14. Vitamin B6 Intake and the Risk of Colorectal Cancer: A Meta-Analysis of Prospective Cohort Studies.

    PubMed

    Jia, Kai; Wang, Rong; Tian, Jingfeng

    2017-07-01

    We performed this meta-analysis to estimate the association between vitamin B 6 intake and colorectal cancer risk. Prospective cohort studies on vitamin B 6 intake and colorectal cancer risk were identified by searching databases from the period of 1960 to 2016. Results from individual studies were synthetically combined using Stata 13.0 software. A total of 10 prospective cohort studies including 13 data sets were included in our meta-analysis, containing 7,817 cases and 784,550 subjects. The combined relative risks (RR) of colorectal cancer for the highest vitamin B 6 intake compared with the lowest vitamin B 6 intake was 0.88 [95% confidence intervals (CIs): 0.77-1.02]. Dose-response meta-analysis based on five eligible studies showed that for each additional 3 and 5 mg of vitamin B 6 intake, the risk would decrease by 11% (RR: 0.89, 95%CI: 0.81-0.98) and 17% (RR: 0.83, 95%CI: 0.71-0.97), respectively. Little evidence of publication bias was found. This meta-analysis provides evidence of a nonsignificant decrease in colorectal cancer risk associated with the high level of vitamin B 6 intake, but the risk in dose-response analysis is significant. However, the latter finding is based on a limited number of studies, which should be interpreted with caution.

  15. Increase in apoptosis by combination of metformin with silibinin in human colorectal cancer cells

    PubMed Central

    Tsai, Cheng-Chia; Chuang, Tang-Wei; Chen, Li-Jen; Niu, Ho-Shan; Chung, Kun-Ming; Cheng, Juei-Tang; Lin, Kao-Chang

    2015-01-01

    AIM: To investigate the effect of metformin on silibinin-induced apoptosis in human colorectal cancer (COLO 205) cells. METHODS: MTT assays were performed to quantify cell viability. Western blot assays were applied to identify the expression of signaling proteins. RESULTS: The combined treatment of COLO 205 cells with metformin and silibinin decreased cell survival at a dose insufficient to influence the non-malignant cells [Human colonic epithelial cells (HCoEpiC)]. Silibinin and metformin increased phosphatase and tensin homolog and 5’-adenosine monophosphate-activated protein kinase expression in COLO 205 cells and inhibited the phosphorylation of mammol/Lalian target of rapamycin. This combined treatment resulted in an increase in the expression of activated caspase 3 and apoptosis inducing factor, indicating apoptosis. CONCLUSION: The combined treatment of human colorectal cancer cells with silibinin and metformin may induce apoptosis at a dose that does not affect HCoEpiC. This finding reveals a potential therapeutic strategy for the treatment of colorectal cancer. PMID:25892866

  16. Clinical trial tests combinations of immunotherapy drugs for prostate cancer | Center for Cancer Research

    Cancer.gov

    Metastatic castration-resistant prostate cancer (mCRPC) is a disease that has spread beyond the prostate and no longer responds to hormone therapy. James Gulley, M.D., Ph.D., of the Genitourinary Malignancies Branch is leading a study of combination immunotherapy where patients will be treated with two, three or four drugs that affect the immune system in different ways to

  17. The allele combinations of three loci based on, liver, stomach cancers, hematencephalon, COPD and normal population: A preliminary study.

    PubMed

    Gai, Liping; Liu, Hui; Cui, Jing-Hui; Yu, Weijian; Ding, Xiao-Dong

    2017-03-20

    The purpose of this study was to examine the specific allele combinations of three loci connected with the liver cancers, stomach cancers, hematencephalon and patients with chronic obstructive pulmonary disease (COPD) and to explore the feasibility of the research methods. We explored different mathematical methods for statistical analyses to assess the association between the genotype and phenotype. At the same time we still analyses the statistical results of allele combinations of three loci by difference value method and ratio method. All the DNA blood samples were collected from patients with 50 liver cancers, 75 stomach cancers, 50 hematencephalon, 72 COPD and 200 normal populations. All the samples were from Chinese. Alleles from short tandem repeat (STR) loci were determined using the STR Profiler plus PCR amplification kit (15 STR loci). Previous research was based on combinations of single-locus alleles, and combinations of cross-loci (two loci) alleles. Allele combinations of three loci were obtained by computer counting and stronger genetic signal was obtained. The methods of allele combinations of three loci can help to identify the statistically significant differences of allele combinations between liver cancers, stomach cancers, patients with hematencephalon, COPD and the normal population. The probability of illness followed different rules and had apparent specificity. This method can be extended to other diseases and provide reference for early clinical diagnosis. Copyright © 2016. Published by Elsevier B.V.

  18. 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.

  19. Role of p38 MAPK in enhanced human cancer cells killing by the combination of aspirin and ABT-737

    PubMed Central

    Zhang, Chong; Shi, Jing; Mao, Shi-ying; Xu, Ya-si; Zhang, Dan; Feng, Lin-yi; Zhang, Bo; Yan, You-you; Wang, Si-cong; Pan, Jian-ping; Yang, You-ping; Lin, Neng-ming

    2015-01-01

    Regular use of aspirin after diagnosis is associated with longer survival among patients with mutated-PIK3CA colorectal cancer, but not among patients with wild-type PIK3CA cancer. In this study, we showed that clinically achievable concentrations of aspirin and ABT-737 in combination could induce a synergistic growth arrest in several human PIK3CA wild-type cancer cells. In addition, our results also demonstrated that long-term combination treatment with aspirin and ABT-737 could synergistically induce apoptosis both in A549 and H1299 cells. In the meanwhile, short-term aspirin plus ABT-737 combination treatment induced a greater autophagic response than did either drug alone and the combination-induced autophagy switched from a cytoprotective signal to a death-promoting signal. Furthermore, we showed that p38 acted as a switch between two different types of cell death (autophagy and apoptosis) induced by aspirin plus ABT-737. Moreover, the increased anti-cancer efficacy of aspirin combined with ABT-737 was further validated in a human lung cancer A549 xenograft model. We hope that this synergy may contribute to failure of aspirin cancer therapy and ultimately lead to efficacious regimens for cancer therapy. PMID:25388762

  20. Cost-effectiveness analysis of different types of human papillomavirus vaccination combined with a cervical cancer screening program in mainland China.

    PubMed

    Mo, Xiuting; Gai Tobe, Ruoyan; Wang, Lijie; Liu, Xianchen; Wu, Bin; Luo, Huiwen; Nagata, Chie; Mori, Rintaro; Nakayama, Takeo

    2017-07-18

    China has a high prevalence of human papillomavirus (HPV) and a consequently high burden of disease with respect to cervical cancer. The HPV vaccine has proved to be effective in preventing cervical cancer and is now a part of routine immunization programs worldwide. It has also proved to be cost effective. This study aimed to assess the cost-effectiveness of 2-, 4-, and 9-valent HPV vaccines (hereafter, HPV2, 4 or 9) combined with current screening strategies in China. A Markov model was developed for a cohort of 100,000 HPV-free girls to simulate the natural history to HPV infection. Three recommended screening methods (1. liquid-based cytology test + HPV DNA test; 2. pap smear cytology test + HPV DNA test; 3. visual inspection with acetic acid) and three types of HPV vaccination program (HPV2/4/9) were incorporated into 15 intervention options, and the incremental cost-effectiveness ratio (ICER) was calculated to determine the dominant strategies. Costs, transition probabilities and utilities were obtained from a review of the literature and national databases. One-way sensitivity analyses and threshold analyses were performed for key variables in different vaccination scenarios. HPV9 combined with screening showed the highest health impact in terms of reducing HPV-related diseases and increasing the number of quality-adjusted life years (QALYs). Under the current thresholds of willingness to pay (WTP, 3 times the per capita GDP or USD$ 23,880), HPV4/9 proved highly cost effective, while HPV2 combined with screening cost more and was less cost effective. Only when screening coverage increased to 60% ~ 70% did the HPV2 and screening combination strategy become economically feasible. The combination of the HPV4/9 vaccine with current screening strategies for adolescent girls was highly cost-effective and had a significant impact on reducing the HPV infection-related disease burden in Mainland China.

  1. Novel liposomal combination treatments using dual genes knockdown in oral cancer treatment

    NASA Astrophysics Data System (ADS)

    Wu, Jyun-Sian; Yeh, Chia-Hsien; Huang, Leaf; Hsu, Yih-Chih

    2018-02-01

    Small interfering RNA (siRNA) can be used to treat tumor because it can effectively knockdown target oncoprotein expression and it leads to cancer cell death and apoptosis. Hypoxia-inducible factors-1 (HIF-1) is a transcription factor gene. Its high expression of tumor hypoxia cells, activation of transcription factor HIF-1α and angiogenesis found in most cancerous tissues. HIF-1α protein in cancer cells are critical to cell survival, tumor growth and proliferation. Epidermal growth factor receptor (EGFR) gene is another common head and neck oncogene. The dual self-designed siRNA sequences were encapsulated in the lipid-calcium-phosphate (LCP) and targeted to sigma receptors on the surface of cancer cells via binding to amino ethyl anisamide (AEAA). We used human oral cancer cells to establish the xenograft animal model to study the combination therapy for therapeutic results.

  2. Cost-Effectiveness Analysis of Breast Cancer Control Interventions in Peru

    PubMed Central

    Zelle, Sten G.; Vidaurre, Tatiana; Abugattas, Julio E.; Manrique, Javier E.; Sarria, Gustavo; Jeronimo, José; Seinfeld, Janice N.; Lauer, Jeremy A.; Sepulveda, Cecilia R.; Venegas, Diego; Baltussen, Rob

    2013-01-01

    Objectives In Peru, a country with constrained health resources, breast cancer control is characterized by late stage treatment and poor survival. To support breast cancer control in Peru, this study aims to determine the cost-effectiveness of different breast cancer control interventions relevant for the Peruvian context. Methods We performed a cost-effectiveness analysis (CEA) according to WHO-CHOICE guidelines, from a healthcare perspective. Different screening, early detection, palliative, and treatment interventions were evaluated using mathematical modeling. Effectiveness estimates were based on observational studies, modeling, and on information from Instituto Nacional de Enfermedades Neoplásicas (INEN). Resource utilizations and unit costs were based on estimates from INEN and observational studies. Cost-effectiveness estimates are in 2012 United States dollars (US$) per disability adjusted life year (DALY) averted. Results The current breast cancer program in Peru ($8,426 per DALY averted) could be improved through implementing triennial or biennial screening strategies. These strategies seem the most cost-effective in Peru, particularly when mobile mammography is applied (from $4,125 per DALY averted), or when both CBE screening and mammography screening are combined (from $4,239 per DALY averted). Triennially, these interventions costs between $63 million and $72 million per year. Late stage treatment, trastuzumab therapy and annual screening strategies are the least cost-effective. Conclusions Our analysis suggests that breast cancer control in Peru should be oriented towards early detection through combining fixed and mobile mammography screening (age 45-69) triennially. However, a phased introduction of triennial CBE screening (age 40-69) with upfront FNA in non-urban settings, and both CBE (age 40-49) and fixed mammography screening (age 50-69) in urban settings, seems a more feasible option and is also cost-effective. The implementation of this

  3. Cost-effectiveness analysis of breast cancer control interventions in Peru.

    PubMed

    Zelle, Sten G; Vidaurre, Tatiana; Abugattas, Julio E; Manrique, Javier E; Sarria, Gustavo; Jeronimo, José; Seinfeld, Janice N; Lauer, Jeremy A; Sepulveda, Cecilia R; Venegas, Diego; Baltussen, Rob

    2013-01-01

    In Peru, a country with constrained health resources, breast cancer control is characterized by late stage treatment and poor survival. To support breast cancer control in Peru, this study aims to determine the cost-effectiveness of different breast cancer control interventions relevant for the Peruvian context. We performed a cost-effectiveness analysis (CEA) according to WHO-CHOICE guidelines, from a healthcare perspective. Different screening, early detection, palliative, and treatment interventions were evaluated using mathematical modeling. Effectiveness estimates were based on observational studies, modeling, and on information from Instituto Nacional de Enfermedades Neoplásicas (INEN). Resource utilizations and unit costs were based on estimates from INEN and observational studies. Cost-effectiveness estimates are in 2012 United States dollars (US$) per disability adjusted life year (DALY) averted. The current breast cancer program in Peru ($8,426 per DALY averted) could be improved through implementing triennial or biennial screening strategies. These strategies seem the most cost-effective in Peru, particularly when mobile mammography is applied (from $4,125 per DALY averted), or when both CBE screening and mammography screening are combined (from $4,239 per DALY averted). Triennially, these interventions costs between $63 million and $72 million per year. Late stage treatment, trastuzumab therapy and annual screening strategies are the least cost-effective. Our analysis suggests that breast cancer control in Peru should be oriented towards early detection through combining fixed and mobile mammography screening (age 45-69) triennially. However, a phased introduction of triennial CBE screening (age 40-69) with upfront FNA in non-urban settings, and both CBE (age 40-49) and fixed mammography screening (age 50-69) in urban settings, seems a more feasible option and is also cost-effective. The implementation of this intervention is only meaningful if

  4. Screening biomarkers of bladder cancer using combined miRNA and mRNA microarray analysis.

    PubMed

    Jin, Ning; Jin, Xuefei; Gu, Xinquan; Na, Wanli; Zhang, Muchun; Zhao, Rui

    2015-08-01

    Biomarkers, such as microRNAs (miRNAs) may be useful for the diagnosis of bladder cancer. In order to understand the molecular mechanisms underlying bladder cancer, differentially expressed miRNAs (DE-miRNAs) and their target genes in bladder cancer were analyzed. In the present study, miRNA and mRNA expression profiles (GSE40355) were obtained from the Gene Expression Omnibus. These consisted of healthy bladder samples (n=8) and urothelial carcinoma samples (low-grade, n=8 and high-grade, n=8). DE-miRNAs and differentially expressed genes (DEGs) were identified using the limma package and the Benjamin and Hochberg method from the multtest package in R. Target genes of DE-miRNAs were screened. Associations between DEGs were investigated using STRING, and an interaction network was constructed using Cytoscape. Functional and pathway enrichment analyses were performed for DEGs from the interaction network. 87 DE-miRNAs and 2058 DEGs were screened from low-grade bladder cancer samples, and 40 DE-miRNAs and 2477 DEGs were screened from high-grade bladder cancer samples. DE-target genes were significantly associated with the regulation of cell apoptosis. Bladder cancer, non-small cell lung cancer and pancreatic cancer biological pathways were found to be enriched. The results of the present study demonstrated that E2F transcription factor 1, which is targeted by miR-106b, and cyclin-dependent kinase inhibitor 2A (CDKN2A) and V-Erb-B2 avian erythroblastic leukemia viral oncogene homolog-2, which are targeted by miR-125b, participate in the bladder cancer pathway. In conclusion, DE-miRNAs in bladder cancer tissue samples and DE-targeted genes, such as miR-106b and CDKN2A, which were identified in the present study, may provide the basis for targeted therapy for breast cancer and enhance understanding of its pathogenesis.

  5. A Meta-Analysis of Interleukin-10-1082 Promoter Polymorphism Associated with Gastric Cancer Risk

    PubMed Central

    Ni, Peihua; Xu, Hong; Xue, Huiping; Lin, Bing

    2012-01-01

    We aimed to explore the role of allele A/G single nucleotide polymorphism (SNP) of gene Interleukin 10 (IL-10) promoter-1082 in the susceptibility to gastric cancer through a systematic review and meta-analysis. Each initially included article was scored for quality appraisal. Desirable data were extracted and registered into databases. Twenty studies were ultimately eligible for the meta-analysis of IL-10-1082 A/G SNP. We adopted the most probably appropriate genetic model (dominant model), with the combined group of GG-plus-GA genotypes compared with the AA genotype. Potential sources of heterogeneity were sought out via subgroup analyses and sensitivity analyses, and publication biases were estimated. Between IL-10-1082 GG-plus-GA genotypes with the risk of developing gastric cancer, statistically significant association could be noted with overall gastric cancer, being mainly in Asian subgroup, large sample subgroup, high quality subgroup, intestinal-type subgroup, cardia-type subgroup, and some genotyping method subgroups. Our meta-analysis indicates that IL-10-1082 GG-plus-GA genotypes are associated with the overall risk of developing gastric cancer and seem to be more susceptible to overall gastric cancer in Asian populations. IL-10-1082 GG-plus-GA genotypes are more associated with the pathologically intestinal-type gastric cancer or anatomically cardia-type gastric cancer. PMID:22335769

  6. Garlic consumption and colorectal cancer risk in man: a systematic review and meta-analysis.

    PubMed

    Chiavarini, Manuela; Minelli, Liliana; Fabiani, Roberto

    2016-02-01

    Colorectal cancer shows large incidence variations worldwide that have been attributed to different dietary factors. We conducted a meta-analysis on the relationship between garlic consumption and colorectal cancer risk. We systematically reviewed publications obtained by searching ISI Web of Knowledge, MEDLINE and EMBASE literature databases. We extracted the risk estimate of the highest and the lowest reported categories of intake from each study and conducted meta-analysis using a random-effects model. The pooled analysis of all fourteen studies, seven cohort and seven case-control, indicated that garlic consumption was not associated with colorectal cancer risk (OR=0·93; 95 % CI 0·82, 1·06, P=0·281; I 2=83·6 %, P≤0·001). Separate analyses on the basis of cancer sites and sex also revealed no statistically significant effects on cancer risk. However, when separately analysed on the basis of study type, we found that garlic was associated with an approximately 37 % reduction in colorectal cancer risk in the case-control studies (combined risk estimate=0·63, 95 % CI 0·48, 0·82, P=0·001; I 2=75·6 %, P≤0·001). Our results suggest that consumption of garlic is not associated with a reduced colorectal cancer risk. Further investigations are necessary to clarify the discrepancy between results obtained from different types of epidemiological studies.

  7. 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.

  8. Chemopreventive effects of combination of honokiol and magnolol with α-santalol on skin cancer developments.

    PubMed

    Chilampalli, C; Zhang, X; Kaushik, R S; Young, A; Zeman, D; Hildreth, M B; Fahmy, H; Dwivedi, C

    2013-06-01

    α-Santalol is active component of sandalwood oil and has been shown to have chemopreventive effects against chemically and UVB-induced skin cancer development in mice. α-Santalol is also shown to have skin permeation enhancing effects. Honokiol and magnolol isolated from Magnolia officinalis bark extract have also been shown to have chemopreventive effects against chemically and UVB-induced skin cancer in mice. This study was conducted to investigate the combination effects of α-santalol, honokiol and magnolol to study any additive/synergistic effects to lower the doses required for chemoprevention. Pretreatment of combinations of α-santalol with honokiol and magnolol significantly decreased tumor multiplicity upto 75% than control, α-santalol, honokiol and magnolol alone in SKH-1 mice. Combination of α-santalol with honokiol and magnolol also decreased cell viability, proliferation, and enhanced apotosis in comparison to α-santalol, honokiol and magnolol alone in Human epidrmoid carcinoma A431 cells. Overall, the results of present study indicated combinations of α-santalol with honokiol and magnolol could provide chemoprevention of skin cancer at lower doses than given alone.

  9. Potential Combinational Anti-Cancer Therapy in Non-Small Cell Lung Cancer with Traditional Chinese Medicine Sun-Bai-Pi Extract and Cisplatin

    PubMed Central

    Wang, Jhih-Syuan; Chung, Meng-Chi; Chang, Jing-Fen; Chao, Ming-Wei

    2016-01-01

    Traditional lung cancer treatments involve chemical or radiation therapies after surgical tumor removal; however, these procedures often kill normal cells as well. Recent studies indicate that chemotherapies, when combined with Traditional Chinese Medicines, may offer a new way to treat cancer. In vitro tests measuring the induction of autophagy and/or apoptosis were used to examine the cytotoxicity of SBPE, commonly used for lung inflammation on A549 cell line. The results indicated that intercellular levels of p62 and Atg12 were increased, LC3-I was cleaved into LC3-II, and autophagy was induced with SBPE only. After 24 hours, the apoptotic mechanism was induced. If the Cisplatin was added after cells reached the autophagy state, we observed synergistic effects of the two could achieve sufficient death of lung cancer cells. Therefore, the Cisplatin dosage used to induce apoptosis could be reduced by half, and the amount of time needed to achieve the inhibitory concentration of 50% was also half that of the original. In addition to inducing autophagy within a shortened period of time, the SBPE and chemotherapy drug combination therapy was able to achieve the objective of rapid low-dosage cancer cell elimination. Besides, SBPE was applied with Gemcitabine or Paclitaxel, and found that the combination treatment indeed achieve improved lung cancer cell killing effects. However, SBPE may also be less toxic to normal cells. PMID:27171432

  10. [A Meta-analysis on tea drinking and the risk of lung cancer in Chinese population].

    PubMed

    Jin, Zi-yi; Han, Ren-qiang; Liu, Ai-min; Wang, Xu-shan; Wu, Ming; Zhang, Zuo-feng; Zhao, Jin-kou

    2012-08-01

    To examine the association between tea drinking and the risk of lung cancer in Chinese population. All relevant published articles in Chinese and English literature database were identified. Meta-analysis was conducted. Combined odds ratio (OR) and 95% confidence interval (CI) were calculated to estimate the associations and dose-response relationship between tea drinking and the risk of lung cancer. Twelve studies were included. An inverse association with lung cancer was observed on tea drinkers when compared to non-tea drinkers (OR = 0.66, 95%CI: 0.49 - 0.89). Tea drinking might serve as a protective factor on lung cancer in the Chinese population.

  11. Predictive role of repair enzymes in the efficacy of Cisplatin combinations in pancreatic and lung cancer.

    PubMed

    Peters, Godefridus J; Avan, Abolfazl; Ruiz, Marielle Gallegos; Orsini, Vanessa; Avan, Amir; Giovannetti, Elisa; Smit, Egbert F

    2014-01-01

    Platinum combinations are the mainstay of treatment for non-small cell lung cancer (NSCLC), while for pancreatic cancer platinum combinations are being given to good-performance status patients. These platinum combinations consist of cis- or carboplatin with gemcitabine, while, for non-squamous NSCLC and mesothelioma, of pemetrexed. The combination of gemcitabine and cisplatin is based on gemcitabine-induced increased formation and retention of DNA-platinum adducts, which can be explained by a decrease of excision repair cross-complementing group-1 (ERCC1)-mediated DNA repair. In these patients, survival and response is prolonged when ERCC1 has a low protein or mRNA expression. A low expression of ribonucleotide reductase (RR) is related to a better treatment outcome after both gemcitabine and gemcitabine-platinum combinations. For pemetrexed combinations, ERCC1 expression was not related to survival. For both NSCLC and pancreatic cancer, polymorphisms in ERCC1 (C118T) and Xeroderma pigmentosum group D (XPD) (A751C) were related to survival. In currently ongoing and future prospective studies, patients should be selected based on their DNA repair status, but it still has to be determined whether this should be by immunohistochemistry, mRNA expression, or a polymorphism.

  12. Impact of totally laparoscopic combined management of colorectal cancer with synchronous hepatic metastases on severity of complications: a propensity-score-based analysis.

    PubMed

    Ratti, Francesca; Catena, Marco; Di Palo, Saverio; Staudacher, Carlo; Aldrighetti, Luca

    2016-11-01

    Thanks to widespread diffusion of minimally invasive approach in the setting of both colorectal and hepatic surgeries, the interest in combined resections for colorectal cancer and synchronous liver metastases (SCLM) by totally laparoscopic approach (TLA) has increased. Aim of this study was to compare outcome of combined resections for SCLM performed by TLA or by open approach, in a propensity-score-based study. All 25 patients undergoing combined TLA for SCLM at San Raffaele Hospital in Milano were compared in a case-matched analysis with 25 out of 91 patients undergoing totally open approach (TOA group). Groups were matched with 1:2 ratio using propensity scores based on covariates representing disease severity. Main endpoints were postoperative morbidity and long-term outcome. The Modified Accordion Severity Grading System was used to quantify complications. The groups resulted comparable in terms of patients and disease characteristics. The TLA group, as compared to the TOA group, had lower blood loss (350 vs 600 mL), shorter postoperative stay (9 vs 12 days), lower postoperative morbidity index (0.14 vs 0.20) and severity score for complicated patients (0.60 vs 0.85). Colonic anastomosis leakage had the highest fractional complication burden in both groups. In spite of comparable long-term overall survival, the TLA group had better recurrence-free survival. TLA for combined resections is feasible, and its indications can be widened to encompass a larger population of patients, provided its benefits in terms of reduced overall risk and severity of complications, rapid functional recovery and favorable long-term outcomes.

  13. The Role of p-STAT3 as a Prognostic and Clinicopathological Marker in Colorectal Cancer: A Systematic Review and Meta-Analysis

    PubMed Central

    Chu, Qi; Gan, Yong; Ren, Hui; Zhang, Liyan; Wang, Liwei; Li, Xiaoxiu; Wang, Wei

    2016-01-01

    Objective High expression of phosphorylated signal transducer and activator of transcription 3 (p-STAT3) has been detected in a variety of human tumors. However, the association of positive p-STAT3 expression with clinicopathological parameters and the prognosis of colorectal cancer patients remain controversial. To identify the relationship between p-STAT3 expression and clinicopathological parameters and prognosis in patients with colorectal cancer, a systematic review and meta-analysis were performed. Methods We performed a comprehensive literature search from PubMed, EMBASE, and SinoMed through 27 March, 2016. Hazard ratios (HRs) with 95% confidence intervals (CI) were combined to evaluate the association between p-STAT3 expression and overall survival of colorectal cancer patients. Odds ratios (ORs) with 95% CI were combined to evaluate the association between p-STAT3 expression and clinicopathological parameters in patients with colorectal cancer. Results Seventeen studies including a total of 2,346 colorectal cancer patients were included in this meta-analysis. The combined HR was 1.43 (95% CI: 1.23–1.67, P < 0.001), which suggested a positive relationship between p-STAT3 overexpression and poorer overall survival of colorectal cancer patients. In addition, the results indicated that positive p-STAT3 expression was significantly associated with the presence of lymph node metastasis (OR: 2.43, 95% CI: 1.18–5.01, P = 0.02) but was not associated with TNM stage, tumor differentiation or gender. Conclusion The meta-analysis results suggest that p-STAT3 overexpression is unfavorable for the prognosis of colorectal cancer patients, and p-STAT3 overexpression is associated with the presence of lymph node metastasis among colorectal cancer patients. PMID:27504822

  14. Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study.

    PubMed

    Liu, Joyce F; Barry, William T; Birrer, Michael; Lee, Jung-Min; Buckanovich, Ronald J; Fleming, Gini F; Rimel, Bj; Buss, Mary K; Nattam, Sreenivasa; Hurteau, Jean; Luo, Weixiu; Quy, Philippa; Whalen, Christin; Obermayer, Lisa; Lee, Hang; Winer, Eric P; Kohn, Elise C; Ivy, S Percy; Matulonis, Ursula A

    2014-10-01

    Olaparib is a poly(ADP-ribose) polymerase inhibitor and cediranib is an anti-angiogenic agent with activity against VEGF receptor (VEGFR) 1, VEGFR2, and VEGFR3. Both oral agents have antitumour activity in women with recurrent ovarian cancer, and their combination was active and had manageable toxicities in a phase 1 trial. We investigated whether this combination could improve progression-free survival (PFS) compared with olaparib monotherapy in women with recurrent platinum-sensitive ovarian cancer. In our randomised, open-label, phase 2 study, we recruited women (aged ≥18 years) who had measurable platinum-sensitive, relapsed, high-grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer, or those with deleterious germline BRCA1/2 mutations from nine participating US academic medical centres. We randomly allocated participants (1:1) according to permuted blocks, stratified by germline BRCA status and previous anti-angiogenic therapy, to receive olaparib capsules 400 mg twice daily or the combination at the recommended phase 2 dose of cediranib 30 mg daily and olaparib capsules 200 mg twice daily. The primary endpoint was progression-free survival analysed in the intention-to-treat population. The phase 2 trial is no longer accruing patients. An interim analysis was conducted in November, 2013, after 50% of expected events had occurred and efficacy results were unmasked. The primary analysis was performed on March 31, 2014, after 47 events (66% of those expected). The trial is registered with ClinicalTrials.gov, number NCT01116648. Between Oct 26, 2011, and June 3, 2013, we randomly allocated 46 women to receive olaparib alone and 44 to receive the combination of olaparib and cediranib. Median PFS was 17·7 months (95% CI 14·7-not reached) for the women treated with cediranib plus olaparib compared with 9·0 months (95% CI 5·7-16·5) for those treated with olaparib monotherapy (hazard ratio 0·42, 95% CI 0·23-0·76; p=0·005). Grade

  15. Second-line chemotherapy in advanced biliary cancer progressed to first-line platinum-gemcitabine combination: a multicenter survey and pooled analysis with published data.

    PubMed

    Fornaro, Lorenzo; Vivaldi, Caterina; Cereda, Stefano; Leone, Francesco; Aprile, Giuseppe; Lonardi, Sara; Silvestris, Nicola; Santini, Daniele; Milella, Michele; Caparello, Chiara; Musettini, Gianna; Pasquini, Giulia; Falcone, Alfredo; Brandi, Giovanni; Sperduti, Isabella; Vasile, Enrico

    2015-12-23

    After progression to a standard first-line platinum and gemcitabine combination (GP), there is no established second-line therapy for patients with advanced biliary tract cancers (aBTC). Indeed, literature data suggest limited activity of most second-line agents evaluated so far. We collected a large retrospective series of aBTC patients treated with second-line chemotherapy after progression to a first-line GP regimen at different Italian institutions. We then pooled the data with those reported in previous studies, which were identified with a Medline search and the on-line abstract datasets of major international oncology meetings. A total of 174 patients were included in the multicenter survey: response rate (RR) with second-line chemotherapy was low (3.4 %), with median PFS and OS of 3.0 months and 6.6 months, respectively. At multivariate analysis, preserved performance status, low CA19.9 levels and absence of distant metastases were favorable prognostic factors. Data from other five presented or published series were identified, for a total of 499 patients included in the pooled analysis. The results confirmed marginal activity of second-line chemotherapy (RR: 10.2 %), with limited efficacy in unselected patient populations (median PFS: 3.1 months; median OS: 6.3 months). The current analysis highlights the limited value of second-line chemotherapy after a first-line GP combination in aBTC. While waiting for effective biologic agents in this setting, ongoing randomized trials will identify the optimal second-line chemotherapy regimen and validate prognostic factors for individual patient management.

  16. 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.

  17. A Healthy Dietary Pattern Reduces Lung Cancer Risk: A Systematic Review and Meta-Analysis.

    PubMed

    Sun, Yanlai; Li, Zhenxiang; Li, Jianning; Li, Zengjun; Han, Jianjun

    2016-03-04

    Diet and nutrients play an important role in cancer development and progress; a healthy dietary pattern has been found to be associated with several types of cancer. However, the association between a healthy eating pattern and lung cancer risk is still unclear. Therefore, we conducted a systematic review with meta-analysis to evaluate whether a healthy eating pattern might reduce lung cancer risk. We identified relevant studies from the PubMed and Embase databases up to October 2015, and the relative risks were extracted and combined by the fixed-effects model when no substantial heterogeneity was observed; otherwise, the random-effects model was employed. Subgroup and publication bias analyses were also performed. Finally, eight observational studies were included in the meta-analysis. The pooled relative risk of lung cancer for the highest vs. lowest category of healthy dietary pattern was 0.81 (95% confidence interval, CI: 0.75-0.86), and no significant heterogeneity was detected. The relative risks (RRs) for non-smokers, former smokers and current smokers were 0.89 (95% CI: 0.63-1.27), 0.74 (95% CI: 0.62-0.89) and 0.86 (95% CI: 0.79-0.93), respectively. The results remained stable in subgroup analyses by other confounders and sensitivity analysis. The results of our meta-analysis suggest that a healthy dietary pattern is associated with a lower lung cancer risk, and they provide more beneficial evidence for changing the diet pattern in the general population.

  18. Combining quantitative and qualitative breast density measures to assess breast cancer risk.

    PubMed

    Kerlikowske, Karla; Ma, Lin; Scott, Christopher G; Mahmoudzadeh, Amir P; Jensen, Matthew R; Sprague, Brian L; Henderson, Louise M; Pankratz, V Shane; Cummings, Steven R; Miglioretti, Diana L; Vachon, Celine M; Shepherd, John A

    2017-08-22

    Accurately identifying women with dense breasts (Breast Imaging Reporting and Data System [BI-RADS] heterogeneously or extremely dense) who are at high breast cancer risk will facilitate discussions of supplemental imaging and primary prevention. We examined the independent contribution of dense breast volume and BI-RADS breast density to predict invasive breast cancer and whether dense breast volume combined with Breast Cancer Surveillance Consortium (BCSC) risk model factors (age, race/ethnicity, family history of breast cancer, history of breast biopsy, and BI-RADS breast density) improves identifying women with dense breasts at high breast cancer risk. We conducted a case-control study of 1720 women with invasive cancer and 3686 control subjects. We calculated ORs and 95% CIs for the effect of BI-RADS breast density and Volpara™ automated dense breast volume on invasive cancer risk, adjusting for other BCSC risk model factors plus body mass index (BMI), and we compared C-statistics between models. We calculated BCSC 5-year breast cancer risk, incorporating the adjusted ORs associated with dense breast volume. Compared with women with BI-RADS scattered fibroglandular densities and second-quartile dense breast volume, women with BI-RADS extremely dense breasts and third- or fourth-quartile dense breast volume (75% of women with extremely dense breasts) had high breast cancer risk (OR 2.87, 95% CI 1.84-4.47, and OR 2.56, 95% CI 1.87-3.52, respectively), whereas women with extremely dense breasts and first- or second-quartile dense breast volume were not at significantly increased breast cancer risk (OR 1.53, 95% CI 0.75-3.09, and OR 1.50, 95% CI 0.82-2.73, respectively). Adding continuous dense breast volume to a model with BCSC risk model factors and BMI increased discriminatory accuracy compared with a model with only BCSC risk model factors (C-statistic 0.639, 95% CI 0.623-0.654, vs. C-statistic 0.614, 95% CI 0.598-0.630, respectively; P < 0.001). Women

  19. Ovarian Cancer Differential Interactome and Network Entropy Analysis Reveal New Candidate Biomarkers.

    PubMed

    Ayyildiz, Dilara; Gov, Esra; Sinha, Raghu; Arga, Kazim Yalcin

    2017-05-01

    Ovarian cancer is one of the most common cancers and has a high mortality rate due to insidious symptoms and lack of robust diagnostics. A hitherto understudied concept in cancer pathogenesis may offer new avenues for innovation in ovarian cancer biomarker development. Cancer cells are characterized by an increase in network entropy, and several studies have exploited this concept to identify disease-associated gene and protein modules. We report in this study the changes in protein-protein interactions (PPIs) in ovarian cancer within a differential network (interactome) analysis framework utilizing the entropy concept and gene expression data. A compendium of six transcriptome datasets that included 140 samples from laser microdissected epithelial cells of ovarian cancer patients and 51 samples from healthy population was obtained from Gene Expression Omnibus, and the high confidence human protein interactome (31,465 interactions among 10,681 proteins) was used. The uncertainties of the up- or downregulation of PPIs in ovarian cancer were estimated through an entropy formulation utilizing combined expression levels of genes, and the interacting protein pairs with minimum uncertainty were identified. We identified 105 proteins with differential PPI patterns scattered in 11 modules, each indicating significantly affected biological pathways in ovarian cancer such as DNA repair, cell proliferation-related mechanisms, nucleoplasmic translocation of estrogen receptor, extracellular matrix degradation, and inflammation response. In conclusion, we suggest several PPIs as biomarker candidates for ovarian cancer and discuss their future biological implications as potential molecular targets for pharmaceutical development as well. In addition, network entropy analysis is a concept that deserves greater research attention for diagnostic innovation in oncology and tumor pathogenesis.

  20. The Preoperative Composite Physiologic Index May Predict Mortality in Lung Cancer Patients with Combined Pulmonary Fibrosis and Emphysema.

    PubMed

    Ueno, Fumika; Kitaguchi, Yoshiaki; Shiina, Takayuki; Asaka, Shiho; Miura, Kentaro; Yasuo, Masanori; Wada, Yosuke; Yoshizawa, Akihiko; Hanaoka, Masayuki

    2017-01-01

    It remains unclear whether the preoperative pulmonary function parameters and prognostic indices that are indicative of nutritional and immunological status are associated with prognosis in lung cancer patients with combined pulmonary fibrosis and emphysema (CPFE) who have undergone surgery. The aim of this study is to identify prognostic determinants in these patients. The medical records of all patients with lung cancer associated with CPFE who had undergone surgery at Shinshu University Hospital were retrospectively reviewed to obtain clinical data, including the results of preoperative pulmonary function tests and laboratory examinations, chest high-resolution computed tomography (HRCT), and survival. Univariate Cox proportional hazards regression analysis showed that a high pathological stage of the lung cancer, a higher preoperative serum carcinoembryonic antigen level, and a higher preoperative composite physiologic index (CPI) were associated with a high risk of death. Multivariate analysis showed that a high pathological stage of the lung cancer (HR: 1.579; p = 0.0305) and a higher preoperative CPI (HR: 1.034; p = 0.0174) were independently associated with a high risk of death. In contrast, the severity of fibrosis or emphysema on chest HRCT, the individual pulmonary function parameters, the prognostic nutritional index, the neutrophil-to-lymphocyte ratio, and the platelet-to-lymphocyte ratio were not associated with prognosis. In the Kaplan-Meier analysis, the log-rank test showed significant differences in survival between the high-CPI and the low-CPI group (p = 0.0234). The preoperative CPI may predict mortality and provide more powerful prognostic information than individual pulmonary function parameters in lung cancer patients with CPFE who have undergone surgery. © 2017 S. Karger AG, Basel.

  1. 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

  2. Coffee consumption and risk of esophageal cancer incidence: A meta-analysis of epidemiologic studies.

    PubMed

    Zhang, Juan; Zhou, Bin; Hao, Chuanzheng

    2018-04-01

    In epidemiologic studies, association between coffee consumption and esophageal cancer risk is inconsistent. The aim of tjis study was to evaluate the effect of coffee on esophageal cancer by combining several similar studies. We conducted a meta-analysis for association of coffee intake and esophageal cancer incidence. Eleven studies, including 457,010 participants and 2628 incident cases, were identified. A relative risk (RR, for cohort study) or odds ratio (OR, for case-control study) of heavy coffee drinkers was calculated, compared with light coffee drinkers or non-drinkers. The analysis was also stratified by cancer types (esophageal squamous cell carcinoma and esophageal adenocarcinoma), sex, and geographic region. The summarized OR of having esophageal cancer in heavy coffee drinkers was 0.93 (95% confidence interval [CI]: 0.73-1.12), compared with light coffee drinkers. When stratified by sex, pathologic type of esophageal cancer, and type of epidemiologic study, we did not find any association of coffee consumption and esophageal cancer incidence. However, an inverse association between coffee consumption and incidence of esophageal cancer was found in East Asia participants with OR of 0.64 (95% CI: 0.44-0.83), but not in Euro-America participants (OR = 1.05; 95% CI: 0.81-1.29). There is a protective role of coffee consumption against esophageal cancer in East Asians, but not in Euro-Americans.

  3. 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

    2017-09-02

    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.

  4. Synergistic effects of combined treatment with histone deacetylase inhibitor suberoylanilide hydroxamic acid and TRAIL on human breast cancer cells

    PubMed Central

    Zhou, Weiqiang; Feng, Xiuyan; Han Han; Guo, Shanchun; Wang, Guangdi

    2016-01-01

    Previous studies showed that either histone deacetylase (HDAC) inhibitors or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce apoptosis in tumor cells including breast cancer. However, the underling mechanisms of combining HDAC inhibitors with TRAIL in the treatment of breast cancer are poorly understood. In this study, we determined the ability of SAHA and TRAIL as single agents or in combination to inhibit the growth and survival of MCF-7 and MDA-MB-231 breast cancer cells. Our results demonstrate that the distinct effects of SAHA or TRAIL individually and in combination on the proliferation, cell viability, apoptosis, cell cycle distribution, and morphological changes of MDA-MB-231 and MCF-7 cells. We further determined the different effects of SAHA or TRAIL alone and combining SAHA with TRAIL on the expression of a number of apoptosis-related molecules, cell cycle, growth factors and their receptors in cancer cells. Our results demonstrated that the combinatorial treatment of SAHA and TRAIL may target multiple pathways and serve as an effective therapeutic strategy against breast cancer. An improved understanding of the molecular mechanisms may facilitate either SAHA or TRAIL targeted use and the selection of suitable combinations. PMID:27292433

  5. Evaluation of the Effects of Aminonaphthoquinone Derivatives in Combination with Curcumin Against ER-positive Breast Cancer and Related Tumours.

    PubMed

    Pereira, Melanie C; Mohammed, Raushaan; VAN Otterlo, Willem A L; DE Koning, Charles B; Davids, Hajierah

    2017-12-01

    Combination therapies are often explored to treat cancer. The use of curcumin as an adjuvant to current chemotherapies has been reported, whilst aminonaphthoquinones have shown potential as anticancer agents in various tumour cell lines. This study aimed at screening synthetic aminonathoquinone derivatives (Rau 008, Rau 010, Rau 015 and Rau 018) alone and in combination with curcumin for anti-breast cancer activity. Combination effects were determined in MCF-7 breast cancer cells using combination index analyses. Synergistic anti-proliferative effects were further investigated in breast (MCF-7, MDA-MB-231), osteosarcoma (MG-63) and endometrial (HEC-1A) cancer-derived cells. Rau 015 (15 μM) and curcumin (112.5 μM) significantly reduced MCF-7, MDA-MB-231 and MG-63 cell proliferation compared to individual treatment, indicating synergistic anti-proliferative effects. Rau 018 (30 μM) and curcumin (100 μM) displayed similar effects in MCF-7 and MG-63 cells. We report on the potential of Rau 015 or Rau 018 as anti-breast cancer agents when combined with curcumin. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  6. Abiraterone acetate/androgen deprivation therapy combination versus docetaxel/androgen deprivation therapy combination in advanced hormone-sensitive prostate cancer: a network meta-analysis on safety and efficacy.

    PubMed

    Kassem, Loay; Shohdy, Kyrillus S; Abdel-Rahman, Omar

    2018-05-01

    A major, yet precisely studied, shift has occurred in the treatment of advanced hormone-sensitive prostate cancer (HSPC) by the addition of docetaxel to androgen deprivation therapy (ADT) in the first line. Recently, two landmark trials showed that abiraterone acetate (AA) can be an effective alternative along with ADT in the same setting. We implemented a network meta-analysis to compare the safety and efficacy of the two combinations. PubMed database, ASCO and ESMO meeting library databases of all results published until June 2017 were searched using the keywords: "prostate cancer" AND "docetaxel" OR "abiraterone acetate". Efficacy endpoints including progression-free survival (PFS) and overall survival (OS), and safety endpoints (including treatment related deaths and selected adverse events) were assessed. Twenty relevant studies were retrieved and assessed for eligibility. Of those trials, eight were found potentially eligible. Inconsistent reporting of efficacy outcomes limited our analysis to M1 HSPC. The pooled hazard ratios (HRs) of OS and PFS of the direct comparison of abiraterone acetate plus ADT versus ADT were 0.63 (95% CI: 0.545-0.717) and 0.38 (95% CI: 0.34-0.43), respectively. Meanwhile, in the trials of docetaxel plus ADT the pooled HRs of OS and PFS were 0.75 (95% CI: 0.65-0.86) and 0.634 (95% CI: 0.57-0.70), respectively. The indirect comparison showed that the HRs of OS and PFS in DOC + ADT in comparison to AA + ADT were 1.2 (95% CI: 0.98-1.46) and 1.65 (1.40-1.94), respectively. The pooled RR of treatment-related mortality in docetaxel + ADT versus AA + ADT was 1.438 (95% CI: 0.508-4.075). Patients with metastatic HSPC (mHSPC) who received abiraterone acetate with ADT had better PFS and less toxicity compared to those receiving docetaxel with ADT. A trend towards superior OS and fewer treatment-related deaths was also observed, but was statistically non-significant. In view of lacking clear OS advantage, the choice between

  7. 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

  8. 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.

  9. Combined colonoscopy and endometrial biopsy cancer screening results in women with Lynch syndrome

    PubMed Central

    Nebgen, Denise R.; Lu, Karen H.; Rimes, Sue; Keeler, Elizabeth; Broaddus, Russell; Munsell, Mark F.; Lynch, Patrick M.

    2015-01-01

    Objective Endometrial biopsy (EMBx) and colonoscopy performed under the same sedation is termed combined screening and has been shown to be feasible and to provide a less painful and more satisfactory experience for women with Lynch syndrome (LS). However, clinical results of these screening efforts have not been reported. The purpose of this study was to evaluate the long-term clinical outcomes and patient compliance with serial screenings over the last 10.5 years. Methods We retrospectively analyzed the data for 55 women with LS who underwent combined screening every 1–2 years between 2002 and 2013. Colonoscopy and endometrial biopsy were performed by a gastroenterologist and a gynecologist, with the patient under conscious sedation. Results Out of 111 screening visits in these 55 patients, endometrial biopsies detected one simple hyperplasia, three complex hyperplasia, and one endometrioid adenocarcinoma (FIGO Stage 1A). Seventy one colorectal polyps were removed in 29 patients, of which 29 were tubular adenomas. EMBx in our study detected endometrial cancer in 0.9% (1/111) of surveillance visits, and premalignant hyperplasia in 3.6% (4/111) of screening visits. No interval endometrial or colorectal cancers were detected. Conclusions Combined screening under sedation is feasible and less painful than EMBx alone. Our endometrial pathology detection rates were comparable to yearly screening studies. Our results indicate that screening of asymptomatic LS women with EMBx every 1–2 years, rather than annually, is effective in the early detection of (pre)cancerous lesions, leading to their prompt definitive management, and potential reduction in endometrial cancer. PMID:25149916

  10. Combined colonoscopy and endometrial biopsy cancer screening results in women with Lynch syndrome.

    PubMed

    Nebgen, Denise R; Lu, Karen H; Rimes, Sue; Keeler, Elizabeth; Broaddus, Russell; Munsell, Mark F; Lynch, Patrick M

    2014-10-01

    Endometrial biopsy (EMBx) and colonoscopy performed under the same sedation is termed combined screening and has been shown to be feasible and to provide a less painful and more satisfactory experience for women with Lynch syndrome (LS). However, clinical results of these screening efforts have not been reported. The purpose of this study was to evaluate the long-term clinical outcomes and patient compliance with serial screenings over the last 10.5 years. We retrospectively analyzed the data for 55 women with LS who underwent combined screening every 1-2 years between 2002 and 2013. Colonoscopy and endometrial biopsy were performed by a gastroenterologist and a gynecologist, with the patient under conscious sedation. Out of 111 screening visits in these 55 patients, endometrial biopsies detected one simple hyperplasia, three complex hyperplasia, and one endometrioid adenocarcinoma (FIGO Stage 1A). Seventy-one colorectal polyps were removed in 29 patients, of which 29 were tubular adenomas. EMBx in our study detected endometrial cancer in 0.9% (1/111) of surveillance visits, and premalignant hyperplasia in 3.6% (4/111) of screening visits. No interval endometrial or colorectal cancers were detected. Combined screening under sedation is feasible and less painful than EMBx alone. Our endometrial pathology detection rates were comparable to yearly screening studies. Our results indicate that screening of asymptomatic LS women with EMBx every 1-2 years, rather than annually, is effective in the early detection of (pre)cancerous lesions, leading to their prompt definitive management, and potential reduction in endometrial cancer. Copyright © 2014 Elsevier Inc. All rights reserved.

  11. Early diagnostic role of PSA combined miR-155 detection in prostate cancer.

    PubMed

    Guo, T; Wang, X-X; Fu, H; Tang, Y-C; Meng, B-Q; Chen, C-H

    2018-03-01

    As a kind of malignant tumor in the male genitourinary system, prostate cancer exhibits significantly increased occurrence. Prostate-specific antigen (PSA) expression can be seen in the prostate cancer, prostatitis, and other diseases, therefore, lack of diagnostic specificity. The miR-155 expression is abnormally increased in the tumors. Therefore, this study aims to explore the clinical significance of PSA combined miR-155 detection in the early diagnosis of prostate cancer. A total of 86 patients diagnosed with prostate cancer were enrolled in this study. PSA and miR-155 gene expression in tumor tissue were detected by using Real-time PCR. The serum levels of PSA were measured by using enzyme-linked immunosorbent assay (ELISA). The correlation of PSA and miR-155 expression with age, body mass index (BMI), tumor volume, tumor-node-metastasis (TNM) stage, lymph node metastasis (LNM), and other clinicopathological features were analyzed, respectively. Serum PSA expression and PSA gene in tumor tissue were significantly higher compared to that in adjacent tissues (p<0.05). PSA gene and protein increased significantly with the clinical stage of TNM and decreased following the increase of grade (p<0.05). The miR-155 level was significantly elevated in the tumor tissue compared with para-carcinoma tissue (p<0.05). PSA and miR-155 expressions were positively correlated with TNM stage, tumor volume, and LNM, and negatively correlated with grade (p<0.05). PSA and miR-155 were closely related to the clinicopathological features of prostate cancer. Combined detection is helpful for the early diagnosis of prostate cancer.

  12. Shared decision making for prostate cancer screening: the results of a combined analysis of two practice-based randomized controlled trials.

    PubMed

    Sheridan, Stacey L; Golin, Carol; Bunton, Audrina; Lykes, John B; Schwartz, Bob; McCormack, Lauren; Driscoll, David; Bangdiwala, Shrikant I; Harris, Russell P

    2012-11-13

    Professional societies recommend shared decision making (SDM) for prostate cancer screening, however, most efforts have promoted informed rather than shared decision making. The objective of this study is to 1) examine the effects of a prostate cancer screening intervention to promote SDM and 2) determine whether framing prostate information in the context of other clearly beneficial men's health services affects decisions. We conducted two separate randomized controlled trials of the same prostate cancer intervention (with or without additional information on more clearly beneficial men's health services). For each trial, we enrolled a convenience sample of 2 internal medicine practices, and their interested physicians and male patients with no prior history of prostate cancer (for a total of 4 practices, 28 physicians, and 128 men across trials). Within each practice site, we randomized men to either 1) a video-based decision aid and researcher-led coaching session or 2) a highway safety video. Physicians at each site received a 1-hour educational session on prostate cancer and SDM. To assess intervention effects, we measured key components of SDM, intent to be screened, and actual screening. After finding that results did not vary by trial, we combined data across sites, adjusting for the random effects of both practice and physician. Compared to an attention control, our prostate cancer screening intervention increased men's perceptions that screening is a decision (absolute difference +41%; 95% CI 25 to 57%) and men's knowledge about prostate cancer screening (absolute difference +34%; 95% CI 19% to 50%), but had no effect on men's self-reported participation in shared decisions or their participation at their preferred level. Overall, the intervention decreased screening intent (absolute difference -34%; 95% CI -50% to -18%) and actual screening rates (absolute difference -22%; 95% CI -38 to -7%) with no difference in effect by frame. SDM interventions can

  13. Fecal immunochemical tests in combination with blood tests for colorectal cancer and advanced adenoma detection—systematic review

    PubMed Central

    Niedermaier, Tobias; Weigl, Korbinian; Hoffmeister, Michael; Brenner, Hermann

    2017-01-01

    Background Colorectal cancer (CRC) is a common but largely preventable cancer. Although fecal immunochemical tests (FITs) detect the majority of CRCs, they miss some of the cancers and most advanced adenomas (AAs). The potential of blood tests in complementing FITs for the detection of CRC or AA has not yet been systematically investigated. Methods We conducted a systematic review of performance of FIT combined with an additional blood test for CRC and AA detection versus FIT alone. PubMed and Web of Science were searched until June 9, 2017. Results Some markers substantially increased sensitivity for CRC when combined with FIT, albeit typically at a major loss of specificity. For AA, no relevant increase in sensitivity could be achieved. Conclusion Combining FIT and blood tests might be a promising approach to enhance sensitivity of CRC screening, but comprehensive evaluation of promising marker combinations in screening populations is needed. PMID:29435309

  14. 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.

  15. 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

  16. A novel analysis strategy for integrating methylation and expression data reveals core pathways for thyroid cancer aetiology

    PubMed Central

    2015-01-01

    Background Recently, a wide range of diseases have been associated with changes in DNA methylation levels, which play a vital role in gene expression regulation. With ongoing developments in technology, attempts to understand disease mechanism have benefited greatly from epigenetics and transcriptomics studies. In this work, we have used expression and methylation data of thyroid carcinoma as a case study and explored how to optimally incorporate expression and methylation information into the disease study when both data are available. Moreover, we have also investigated whether there are important post-translational modifiers which could drive critical insights on thyroid cancer genetics. Results In this study, we have conducted a threshold analysis for varying methylation levels to identify whether setting a methylation level threshold increases the performance of functional enrichment. Moreover, in order to decide on best-performing analysis strategy, we have performed data integration analysis including comparison of 10 different analysis strategies. As a result, combining methylation with expression and using genes with more than 15% methylation change led to optimal detection rate of thyroid-cancer associated pathways in top 20 functional enrichment results. Furthermore, pooling the data from different experiments increased analysis confidence by improving the data range. Consequently, we have identified 207 transcription factors and 245 post-translational modifiers with more than 15% methylation change which may be important in understanding underlying mechanisms of thyroid cancer. Conclusion While only expression or only methylation information would not reveal both primary and secondary mechanisms involved in disease state, combining expression and methylation led to a better detection of thyroid cancer-related genes and pathways that are found in the recent literature. Moreover, focusing on genes that have certain level of methylation change improved the

  17. Targeting the receptor tyrosine kinase RET in combination with aromatase inhibitors in ER positive breast cancer xenografts.

    PubMed

    Andreucci, Elena; Francica, Paola; Fearns, Antony; Martin, Lesley-Ann; Chiarugi, Paola; Isacke, Clare M; Morandi, Andrea

    2016-12-06

    The majority of breast cancers are estrogen receptor positive (ER+). Blockade of estrogen biosynthesis by aromatase inhibitors (AIs) is the first-line endocrine therapy for post-menopausal women with ER+ breast cancers. However, AI resistance remains a major challenge. We have demonstrated previously that increased GDNF/RET signaling in ER+ breast cancers promotes AI resistance. Here we investigated the efficacy of different small molecule RET kinase inhibitors, sunitinib, cabozantinib, NVP-BBT594 and NVP-AST487, and the potential of combining a RET inhibitor with the AI letrozole in ER+ breast cancers. The most effective inhibitor identified, NVP-AST487, suppressed GDNF-stimulated RET downstream signaling and 3D tumor spheroid growth. Ovariectomized mice were inoculated with ER+ aromatase-overexpressing MCF7-AROM1 cells and treated with letrozole, NVP-AST487 or the two drugs in combination. Surprisingly, the three treatment regimens showed similar efficacy in impairing MCF7-AROM1 tumor growth in vivo. However in vitro, NVP-AST487 was superior to letrozole in inhibiting the GDNF-induced motility and tumor spheroid growth of MCF7-AROM1 cells and required in combination with letrozole to inhibit GDNF-induced motility in BT474-AROM3 aromatase expressing cells. These data indicate that inhibiting RET is as effective as the current therapeutic regimen of AI therapy but that a combination treatment may delay cancer cell dissemination and metastasis.

  18. Opium and bladder cancer: A systematic review and meta-analysis of the odds ratios for opium use and the risk of bladder cancer

    PubMed Central

    Afshari, Mahdi; Janbabaei, Ghasem; Bahrami, Mohammad Amin

    2017-01-01

    Objective The association between opium use and bladder cancer has been investigated in many studies, with varying reporting results reported. This study aims to estimate the total odds ratio for the association between bladder cancer and opium consumption using meta-analysis. Methods The study was designed according to PRISMA guidelines. Two independent researchers searched for the relevant studies using PubMed, Web of Science, Scopus, OVID, Embase, and Google Scholar. After systematic screening of the studies identified during the first step, Cochrane risk of bias tool was determined for the selected studies. The case-control and the cohort studies were investigated to assess risk of bladder cancer due to opium use. In addition, the cross-sectional studies were analysed separately to assess frequency of opium consumption. These estimates were combined using the inverse variance method. Fixed or random effect models were applied to combine the point odds ratios. The heterogeneity between the primary results was assessed using the Cochran test and I-square index. The suspected factors for heterogeneity were investigated using meta-regression models. An Egger test was conducted to identify any probable publication bias. Forest plots illustrated the point and pooled estimates. All analyses were performed using Stata version 14 software and RevMan version 5.3. Results We included 17 primary studies (11 case-control, one cohort and five cross-sectional) in the final meta-analysis. The total odds ratios (95% confidence intervals) for developing bladder cancer by opium use alone, and concurrent use of opium and cigarettes were estimated as 3.85 (3.05–4.87) and 5.7 (1.9–16.3) respectively. The odds ratio (95% confidence interval) for opium use with or without cigarette smoking was estimated as 5.3 (3.6–7.7). Conclusion This meta-analysis showed that opium use similar to cigarette smoking and maybe with similar mechanisms can be a risk factor for bladder cancer. It

  19. Combined immunotherapy and antiangiogenic therapy of cancer with microencapsulated cells.

    PubMed

    Cirone, Pasquale; Bourgeois, Jacqueline M; Shen, Feng; Chang, Patricia L

    2004-10-01

    An alternative form of gene therapy involves immunoisolation of a nonautologous cell line engineered to secrete a therapeutic product. Encapsulation of these cells in a biocompatible polymer serves to protect these allogeneic cells from host-versus-graft rejection while recombinant products and nutrients are able to pass by diffusion. This strategy was applied to the treatment of cancer with some success by delivering either interleukin 2 or angiostatin. However, as cancer is a complex, multifactorial disease, a multipronged approach is now being developed to attack tumorigenesis via multiple pathways in order to improve treatment efficacy. A combination of immunotherapy with angiostatic therapy was investigated by treating B16-F0/neu melanoma-bearing mice with intraperitoneally implanted, microencapsulated mouse myoblasts (C2C12) genetically modified to deliver angiostatin and an interleukin 2 fusion protein (sFvIL-2). The combination treatment resulted in improved survival, delayed tumor growth, and increased histological indices of antitumor activity (apoptosis and necrosis). In addition to improved efficacy, the combination treatment also ameliorated some of the undesirable side effects from the individual treatments that have led to the previous failure of the single treatments, for example, inflammatory response to IL-2 or vascular mimicry due to angiostatin. In conclusion, the combination of immuno- and antiangiogenic therapies delivered by immunoisolated cells was superior to individual treatments for antitumorigenesis activity, not only because of their known mechanisms of action but also because of unexpected protection against the adverse side effects of the single treatments. Thus, the concept of a "cocktail" strategy, with microencapsulation delivering multiple antitumor recombinant molecules to improve efficacy, is validated.

  20. Cancer prevalence and education by cancer site: logistic regression analysis.

    PubMed

    Johnson, Stephanie; Corsten, Martin J; McDonald, James T; Gupta, Michael

    2010-10-01

    Previously, using the American National Health Interview Survey (NHIS) and a logistic regression analysis, we found that upper aerodigestive tract (UADT) cancer is correlated with low socioeconomic status (SES). The objective of this study was to determine if this correlation between low SES and cancer prevalence exists for other cancers. We again used the NHIS and employed education level as our main measure of SES. We controlled for potentially confounding factors, including smoking status and alcohol consumption. We found that only two cancer subsites shared the pattern of increased prevalence with low education level and decreased prevalence with high education level: UADT cancer and cervical cancer. UADT cancer and cervical cancer were the only two cancers identified that had a link between prevalence and lower education level. This raises the possibility that an associated risk factor for the two cancers is causing the relationship between lower education level and prevalence.

  1. Investments in cancer research awarded to UK institutions and the global burden of cancer 2000-2013: a systematic analysis.

    PubMed

    Maruthappu, Mahiben; Head, Michael G; Zhou, Charlie D; Gilbert, Barnabas J; El-Harasis, Majd A; Raine, Rosalind; Fitchett, Joseph R; Atun, Rifat

    2017-04-20

    To systematically categorise cancer research investment awarded to United Kingdom (UK) institutions in the period 2000-2013 and to estimate research investment relative to disease burden as measured by mortality, disability-adjusted life years (DALYs) and years lived with disability (YLDs). Systematic analysis of all open-access data. Public and philanthropic funding to all UK cancer research institutions, 2000-2013. Number and financial value of cancer research investments reported in 2013 UK pounds (UK£). Mortality, DALYs and YLDs data were acquired from the Global Burden of Disease Study. A compound metric was adapted to estimate research investment relative to disease burden as measured by mortality, DALYs and YLDs. We identified 4299 funded studies with a total research investment of £2.4 billion. The highest fundings by anatomical sites were haematological, breast, prostate, colorectal and ovarian cancers. Relative to disease burden as determined by a compound metric combining mortality, DALYs and YLDs, gender-specific cancers were found to be highest funded-the five sites that received the most funding were prostate, ovarian, breast, mesothelioma and testicular cancer; the least well-funded sites were liver, thyroid, lung, upper gastrointestinal (GI) and bladder. Preclinical science accounted for 66.2% of award numbers and 62.2% of all funding. The top five areas of primary research focus by funding were pathogenesis, drug therapy, diagnostic, screening and monitoring, women's health and immunology. The largest individual funder was the Medical Research Council. In combination, the five lowest funded site-specific cancers relative to disease burden account for 47.9%, 44.3% and 20.4% of worldwide cancer mortality, DALYs and YLDs. Research funding for cancer is not allocated according to relative disease burden. These findings are in line with earlier published studies. Funding agencies and industry should openly document their research investments to

  2. Gendermetrics of cancer research: results from a global analysis on lung cancer.

    PubMed

    Bendels, Michael H K; Brüggmann, Dörthe; Schöffel, Norman; Groneberg, David A

    2017-11-24

    Cancer research is critically dependent on a continuous recruitment of junior research staff that devotes its academic life not only to clinical duties but also to basic and translational research. The present study aims to elucidate the success concerning gender equality in cancer research in the last decade (from 2008 to 2016) with lung cancer as the target parameter. On the basis of the Gendermetrics Platform, a total of 19,724 articles related to lung cancer research were analyzed. The key method was the combined analysis of the proportion of female authorships and the female-to-male odds ratio for first, co- and last authorships. The distribution of prestigious authorships was measured by the Prestige Index. 31.3% of all authorships and 35.2% of the first, 32.2% of the co- and 22.1% of the last authorships were held by women. The corresponding female-to-male odds ratio is 1.22 (CI: 1.18-1.27) for first, 1.19 (CI: 1.16-1.23) for co- and 0.59 (CI: 0.57-0.61) for last authorships. Women are underrepresented at prestigious authorships compared to men (Prestige Index = -0.22). The female underrepresentation accentuates in articles with many authors that attract the highest citation rates. While the current system promotes early career promotion of women, men still outnumber women in leadership positions. However, this male-female career dichotomy has been narrowed in the last decade and will likely be further reduced in the next decade.

  3. Cost-effectiveness analysis of prognostic gene expression signature-based stratification of early breast cancer patients.

    PubMed

    Blank, Patricia R; Filipits, Martin; Dubsky, Peter; Gutzwiller, Florian; Lux, Michael P; Brase, Jan C; Weber, Karsten E; Rudas, Margaretha; Greil, Richard; Loibl, Sibylle; Szucs, Thomas D; Kronenwett, Ralf; Schwenkglenks, Matthias; Gnant, Michael

    2015-02-01

    The individual risk of recurrence in hormone receptor-positive primary breast cancer patients determines whether adjuvant endocrine therapy should be combined with chemotherapy. Clinicopathological parameters and molecular tests such as EndoPredict(®) (EPclin) can support decision making in patients with estrogen receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative cancer. Using a life-long Markov state transition model, we determined the health economic impact and incremental cost effectiveness of EPclin-based risk stratification in combination with clinical guidelines [German-S3, National Comprehensive Cancer Center Network (NCCN), and St. Gallen] to decide on chemotherapy use. Information on overall and metastasis-free survival came from Austrian Breast & Colorectal Cancer Study Group clinical trials 6/8 (n = 1,619) and published literature. Effectiveness was assessed as quality-adjusted life-years (QALYs). Costs (2010) were assessed from a German third-party payer perspective. Lifetime costs per patient ranged from 28,268 (St.Gallen and EPclin) to 33,756 (NCCN). Due to an imperfect prognostic value and differences in chemotherapy use, strategies achieved between 13.165 QALYs (NCCN) and 13.173 QALYs (EPclin alone) per patient. Using German-S3 as reference, three strategies showed dominant results (St. Gallen and EPclin, German-S3 and EPclin, EPclin alone). Compared to German-S3, the addition of EPclin saved 3,388 and gained 0.002 QALYs per patient. Combining guidelines with EPclin remained preferable in sensitivity analysis. Our study suggests that molecular markers can be sensibly combined with clinical guidelines to determine the risk profile of adjuvant breast cancer patients. Compared with the current German best practice (German-S3), combinations of EPclin with the St. Gallen, German-S3 or NCCN guideline and EPclin alone were dominant from the perspective of the German healthcare system.

  4. Cancer-Related Psychological Distress: A Concept Analysis.

    PubMed

    Gundelach, Amy; Henry, Barb

    2016-12-01

    Cancer-related psychological distress, as a concept, has limited research literature substantiation. Several studies report that patients with cancer suffer from significant psychological distress; however, the description of the concept of cancer-related psychological distress has not been clearly described. Theoretical work based on the concept is also unclear. This article is a report on the concept of cancer-related psychological distress to clarify the concept as separate from non-cancer-related psychological distress and promote the use of the term in nursing practice and research across the cancer trajectory. This article used a content analysis to examine the literature. The literature review for this article used CINAHL®, PsycINFO®, and PubMed to search publications from 1999-2016. Content analysis of the literature revealed that the term psychological distress was used often with regard to distress in patients with cancer, but the concept of cancer-related psychological distress was not clearly defined. Four attributes encompass the concept of cancer-related psychological distress.

  5. Natural compounds and combination therapy in colorectal cancer treatment.

    PubMed

    Rejhová, A; Opattová, A; Čumová, A; Slíva, D; Vodička, P

    2018-01-20

    Colorectal cancer (CRC) therapy using conventional chemotherapeutics represents a considerable burden for the patient's organism because of high toxicity while the response is relatively low. Our review summarizes the findings about natural compounds as chemoprotective agents for decreasing risk of CRC. It also identifies natural compounds which possess anti-tumor effects of various characteristics, mainly in vitro on colorectal cell lines or in vivo studies on experimental models, but also in a few clinical trials. Many of natural compounds suppress proliferation by inducing cell cycle arrest or induce apoptosis of CRC cells resulting in the inhibition of tumor growth. A novel employment of natural substances is a so-called combination therapy - administration of two or more substances - conventional chemotherapeutics and a natural compound or more natural compounds at a time. Some natural compounds may sensitize to conventional cytotoxic therapy, reinforce the drug effective concentration, intensify the combined effect of both administered therapeutics or exert cytotoxic effects specifically on tumor cells. Moreover, combined therapy by targeting multiple signaling pathways, uses various mechanisms to reduce the development of resistance to antitumor drugs. The desired effect could be to diminish burden on the patient's organism by replacing part of the dose of a conventional chemotherapeutic with a natural substance with a defined effect. Many natural compounds are well tolerated by the patients and do not cause toxic effects even at high doses. Interaction of conventional chemotherapeutics with natural compounds introduces a new aspect in the research and therapy of cancer. It could be a promising approach to potentially achieve improvements, while minimizing of adverse effects associated with conventional chemotherapy. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  6. Combining metformin and nelfinavir exhibits synergistic effects against the growth of human cervical cancer cells and xenograft in nude mice

    PubMed Central

    Xia, Chenglai; Chen, Ruihong; Chen, Jinman; Qi, Qianqian; Pan, Yanbin; Du, Lanying; Xiao, Guohong; Jiang, Shibo

    2017-01-01

    Human cervical cancer is the fourth most common carcinoma in women worldwide. However, the emergence of drug resistance calls for continuously developing new anticancer drugs and combination chemotherapy regimens. The present study aimed to investigate the anti-cervical cancer effects of metformin, a first-line therapeutic drug for type 2 diabetes mellitus, and nelfinavir, an HIV protease inhibitor, when used alone or in combination. We found that both metformin and nelfinavir, when used alone, were moderately effective in inhibiting proliferation, inducing apoptosis and suppressing migration and invasion of human cervical cell lines HeLa, SiHa and CaSki. When used in combination, these two drugs acted synergistically to inhibit the growth of human cervical cancer cells in vitro and cervical cancer cell xenograft in vivo in nude mice, and suppress cervical cancer cell migration and invasion. The protein expression of phosphoinositide 3-kinase catalytic subunit PI3K(p110α), which can promote tumor growth, was remarkably downregulated, while the tumor suppressor proteins p53 and p21 were substantially upregulated following the combinational treatment in vitro and in vivo. These results suggest that clinical use of metformin and nelfinavir in combination is expected to have synergistic antitumor efficacy and significant potential for the treatment of human cervical cancer. PMID:28252027

  7. Combining metformin and nelfinavir exhibits synergistic effects against the growth of human cervical cancer cells and xenograft in nude mice.

    PubMed

    Xia, Chenglai; Chen, Ruihong; Chen, Jinman; Qi, Qianqian; Pan, Yanbin; Du, Lanying; Xiao, Guohong; Jiang, Shibo

    2017-03-02

    Human cervical cancer is the fourth most common carcinoma in women worldwide. However, the emergence of drug resistance calls for continuously developing new anticancer drugs and combination chemotherapy regimens. The present study aimed to investigate the anti-cervical cancer effects of metformin, a first-line therapeutic drug for type 2 diabetes mellitus, and nelfinavir, an HIV protease inhibitor, when used alone or in combination. We found that both metformin and nelfinavir, when used alone, were moderately effective in inhibiting proliferation, inducing apoptosis and suppressing migration and invasion of human cervical cell lines HeLa, SiHa and CaSki. When used in combination, these two drugs acted synergistically to inhibit the growth of human cervical cancer cells in vitro and cervical cancer cell xenograft in vivo in nude mice, and suppress cervical cancer cell migration and invasion. The protein expression of phosphoinositide 3-kinase catalytic subunit PI3K(p110α), which can promote tumor growth, was remarkably downregulated, while the tumor suppressor proteins p53 and p21 were substantially upregulated following the combinational treatment in vitro and in vivo. These results suggest that clinical use of metformin and nelfinavir in combination is expected to have synergistic antitumor efficacy and significant potential for the treatment of human cervical cancer.

  8. "Textural analysis of multiparametric MRI detects transition zone prostate cancer".

    PubMed

    Sidhu, Harbir S; Benigno, Salvatore; Ganeshan, Balaji; Dikaios, Nikos; Johnston, Edward W; Allen, Clare; Kirkham, Alex; Groves, Ashley M; Ahmed, Hashim U; Emberton, Mark; Taylor, Stuart A; Halligan, Steve; Punwani, Shonit

    2017-06-01

    To evaluate multiparametric-MRI (mpMRI) derived histogram textural-analysis parameters for detection of transition zone (TZ) prostatic tumour. Sixty-seven consecutive men with suspected prostate cancer underwent 1.5T mpMRI prior to template-mapping-biopsy (TPM). Twenty-six men had 'significant' TZ tumour. Two radiologists in consensus matched TPM to the single axial slice best depicting tumour, or largest TZ diameter for those with benign histology, to define single-slice whole TZ-regions-of-interest (ROIs). Textural-parameter differences between single-slice whole TZ-ROI containing significant tumour versus benign/insignificant tumour were analysed using Mann Whitney U test. Diagnostic accuracy was assessed by receiver operating characteristic area under curve (ROC-AUC) analysis cross-validated with leave-one-out (LOO) analysis. ADC kurtosis was significantly lower (p < 0.001) in TZ containing significant tumour with ROC-AUC 0.80 (LOO-AUC 0.78); the difference became non-significant following exclusion of significant tumour from single-slice whole TZ-ROI (p = 0.23). T1-entropy was significantly lower (p = 0.004) in TZ containing significant tumour with ROC-AUC 0.70 (LOO-AUC 0.66) and was unaffected by excluding significant tumour from TZ-ROI (p = 0.004). Combining these parameters yielded ROC-AUC 0.86 (LOO-AUC 0.83). Textural features of the whole prostate TZ can discriminate significant prostatic cancer through reduced kurtosis of the ADC-histogram where significant tumour is included in TZ-ROI and reduced T1 entropy independent of tumour inclusion. • MR textural features of prostate transition zone may discriminate significant prostatic cancer. • Transition zone (TZ) containing significant tumour demonstrates a less peaked ADC histogram. • TZ containing significant tumour reveals higher post-contrast T1-weighted homogeneity. • The utility of MR texture analysis in prostate cancer merits further investigation.

  9. Clinical and multiple gene expression variables in survival analysis of breast cancer: Analysis with the hypertabastic survival model

    PubMed Central

    2012-01-01

    Background We explore the benefits of applying a new proportional hazard model to analyze survival of breast cancer patients. As a parametric model, the hypertabastic survival model offers a closer fit to experimental data than Cox regression, and furthermore provides explicit survival and hazard functions which can be used as additional tools in the survival analysis. In addition, one of our main concerns is utilization of multiple gene expression variables. Our analysis treats the important issue of interaction of different gene signatures in the survival analysis. Methods The hypertabastic proportional hazards model was applied in survival analysis of breast cancer patients. This model was compared, using statistical measures of goodness of fit, with models based on the semi-parametric Cox proportional hazards model and the parametric log-logistic and Weibull models. The explicit functions for hazard and survival were then used to analyze the dynamic behavior of hazard and survival functions. Results The hypertabastic model provided the best fit among all the models considered. Use of multiple gene expression variables also provided a considerable improvement in the goodness of fit of the model, as compared to use of only one. By utilizing the explicit survival and hazard functions provided by the model, we were able to determine the magnitude of the maximum rate of increase in hazard, and the maximum rate of decrease in survival, as well as the times when these occurred. We explore the influence of each gene expression variable on these extrema. Furthermore, in the cases of continuous gene expression variables, represented by a measure of correlation, we were able to investigate the dynamics with respect to changes in gene expression. Conclusions We observed that use of three different gene signatures in the model provided a greater combined effect and allowed us to assess the relative importance of each in determination of outcome in this data set. These

  10. Epigenetic regulation of gene expression in cancer: techniques, resources and analysis

    PubMed Central

    Kagohara, Luciane T; Stein-O’Brien, Genevieve L; Kelley, Dylan; Flam, Emily; Wick, Heather C; Danilova, Ludmila V; Easwaran, Hariharan; Favorov, Alexander V; Qian, Jiang; Gaykalova, Daria A; Fertig, Elana J

    2018-01-01

    Abstract Cancer is a complex disease, driven by aberrant activity in numerous signaling pathways in even individual malignant cells. Epigenetic changes are critical mediators of these functional changes that drive and maintain the malignant phenotype. Changes in DNA methylation, histone acetylation and methylation, noncoding RNAs, posttranslational modifications are all epigenetic drivers in cancer, independent of changes in the DNA sequence. These epigenetic alterations were once thought to be crucial only for the malignant phenotype maintenance. Now, epigenetic alterations are also recognized as critical for disrupting essential pathways that protect the cells from uncontrolled growth, longer survival and establishment in distant sites from the original tissue. In this review, we focus on DNA methylation and chromatin structure in cancer. The precise functional role of these alterations is an area of active research using emerging high-throughput approaches and bioinformatics analysis tools. Therefore, this review also describes these high-throughput measurement technologies, public domain databases for high-throughput epigenetic data in tumors and model systems and bioinformatics algorithms for their analysis. Advances in bioinformatics data that combine these epigenetic data with genomics data are essential to infer the function of specific epigenetic alterations in cancer. These integrative algorithms are also a focus of this review. Future studies using these emerging technologies will elucidate how alterations in the cancer epigenome cooperate with genetic aberrations during tumor initiation and progression. This deeper understanding is essential to future studies with epigenetics biomarkers and precision medicine using emerging epigenetic therapies. PMID:28968850

  11. Occupational mortality and cancer analysis.

    PubMed

    Lynge, E

    The 1970-census populations have been followed up for deaths and emigrations in the ten-year period 1970-80 in all the Nordic countries. The data show more than a 2-fold difference in overall mortality between the low-risk group of men with pedagogical work and the high-risk group of deck and engine crew workers. These data files have also been supplemented with cancer register records. In Denmark this combined data set has been used in four different ways. First, in order to check the validity of the register, classic associations known from in-depth epidemiological studies were tabulated. Examples are cancer of the lip in farmers and fishermen, where the standardized incidence ratio (SIR) values were 1.85 and 3.17, respectively, and cancer of the nasal cavities and sinuses in skilled furniture makers, SIR = 12.25. Second, a social cancer map was produced by tabulating the cancer incidence by 20 socioeconomic groups. The social gradient was steepest for certain rare cancers related to specific etiologic factors. The social gradient also varied across cancer sites. Third, the register was used as a library for elucidation of newly reported associations. An association confirmed in the Danish data is an excess risk of bladder cancer in hairdressers, SIR = 2.05. An unconfirmed example is an excess risk of malignant melanoma in the printing industry, where Danish data show an SIR of 0.95. Fourth, a systematic tabulation of each cancer diagnosis across detailed occupational groups may lead to identification of previously unknown associations. This procedure is illustrated using cancer of the larynx as an example. Smiths, mechanics, foremen, and shop owners of engineering works and workshops all have an excess risk of laryngeal cancer, SIR = 1.63.

  12. 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.

  13. Hypoxia-inducible factor-targeting prodrug TOP3 combined with gemcitabine or TS-1 improves pancreatic cancer survival in an orthotopic model.

    PubMed

    Hoang, Ngoc Thi Hong; Kadonosono, Tetsuya; Kuchimaru, Takahiro; Kizaka-Kondoh, Shinae

    2016-08-01

    Pancreatic cancer is one of the most lethal digestive system cancers with a 5-year survival rate of 4-7%. Despite extensive efforts, recent chemotherapeutic regimens have provided only limited benefits to pancreatic cancer patients. Gemcitabine and TS-1, the current standard-of-care chemotherapeutic drugs for treatment of this severe cancer, have a low response rate. Hypoxia is one of the factors contributing to treatment resistance. Specifically, overexpression of hypoxia-inducible factor, a master transcriptional regulator of cell adaption to hypoxia, is strongly correlated with poor prognosis in many human cancers. TAT-ODD-procaspase-3 (TOP3) is a protein prodrug that is specifically processed and activated in hypoxia-inducible factor-active cells in cancers, leading to cell death. Here, we report combination therapies in which TOP3 was combined with gemcitabine or TS-1. As monotherapy, gemcitabine and TS-1 showed a limited effect on hypoxic and starved pancreatic cancer cells, whereas co-treatment with TOP3 successfully overcame this limitation in vitro. Furthermore, combination therapies of TOP3 with these drugs resulted in a significant improvement in survival of orthotopic pancreatic cancer models involving the human pancreatic cancer cell line SUIT-2. Overall, our study indicates that the combination of TOP3 with current chemotherapeutic drugs can significantly improve treatment outcome, offering a promising new therapeutic option for patients with pancreatic cancer. © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  14. Combination therapy strategies for improving PD-1 blockade efficacy: a new era in cancer immunotherapy.

    PubMed

    Chowdhury, P S; Chamoto, K; Honjo, T

    2018-02-01

    Programmed death 1 (PD-1) is an immune checkpoint molecule that negatively regulates T-cell immune function through the interaction with its ligand PD-L1. Blockage of this interaction unleashes the immune system to fight cancer. Immunotherapy using PD-1 blockade has led to a paradigm shift in the field of cancer drug discovery, owing to its durable effect against a wide variety of cancers with limited adverse effects. A brief history and development of PD-1 blockade, from the initial discovery of PD-1 to the recent clinical output of this therapy, have been summarized here. Despite its tremendous clinical success rate over other cancer treatments, PD-1 blockade has its own pitfall; a significant fraction of patients remains unresponsive to this therapy. The key to improve the PD-1 blockade therapy is the development of combination therapies. As this approach has garnered worldwide interest, here, we have summarized the recent trends in the development of PD-1 blockade-based combination therapies and the ongoing clinical trials. These include combinations with checkpoint inhibitors, radiation therapy, chemotherapy and several other existing cancer treatments. Importantly, FDA has approved PD-1 blockade agent to be used in combination with either CTLA-4 blockade or chemotherapy. Responsiveness to the PD-1 blockade therapy is affected by tumour and immune system-related factors. The role of the immune system, especially T cells, in determining the responsiveness has been poorly studied compared with those factors related to the tumour side. Energy metabolism has emerged as one of the important regulatory mechanisms for the function and differentiation of T cells. We have documented here the recent results regarding the augmentation of PD-1 blockade efficacy by augmenting mitochondrial energy metabolism of T cell. © 2017 The Association for the Publication of the Journal of Internal Medicine.

  15. The Cancer Genome Atlas Pan-Cancer Analysis Project

    PubMed Central

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

    2014-01-01

    Cancer can take hundreds of different forms depending on the location, cell of origin and spectrum of genomic alterations that promote oncogenesis and affect therapeutic response. Although many genomic events with direct phenotypic impact have been identified, much of the complex molecular landscape remains incompletely charted for most cancer lineages. For that reason, The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumours 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 tumour lineages. The Pan-Cancer initiative compares the first twelve tumour types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumour types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile. PMID:24071849

  16. Biological effective dose for comparison and combination of external beam and low-dose rate interstitial brachytherapy prostate cancer treatment plans

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Jani, Ashesh B.; Hand, Christopher M.; Lujan, Anthony E.

    2004-03-31

    We report a methodology for comparing and combining dose information from external beam radiotherapy (EBRT) and interstitial brachytherapy (IB) components of prostate cancer treatment using the biological effective dose (BED). On a prototype early-stage prostate cancer patient treated with EBRT and low-dose rate I-125 brachytherapy, a 3-dimensional dose distribution was calculated for each of the EBRT and IB portions of treatment. For each component of treatment, the BED was calculated on a point-by-point basis to produce a BED distribution. These individual BED distributions could then be summed for combined therapies. BED dose-volume histograms (DVHs) of the prostate, urethra, rectum, andmore » bladder were produced and compared for various combinations of EBRT and IB. Transformation to BED enabled computation of the relative contribution of each modality to the prostate dose, as the relative weighting of EBRT and IB was varied. The BED-DVHs of the prostate and urethra demonstrated dramatically increased inhomogeneity with the introduction of even a small component of IB. However, increasing the IB portion relative to the EBRT component resulted in lower dose to the surrounding normal structures, as evidenced by the BED-DVHs of the bladder and rectum. Conformal EBRT and low-dose rate IB conventional dose distributions were successfully transformed to the common 'language' of BED distributions for comparison and for merging prostate cancer radiation treatment plans. The results of this analysis can assist physicians in quantitatively determining the best combination and weighting of radiation treatment modalities for individual patients.« less

  17. Combination of gemcitabine and erlotinib inhibits recurrent pancreatic cancer growth in mice via the JAK-STAT pathway

    PubMed Central

    Chen, Liwen; Zhou, Ding'An; Liu, Zhehao; Huang, Xinhao; Liu, Qianfan; Kang, Yiping; Chen, Zili; Guo, Yuntao; Zhu, Haitao; Sun, Chengyi

    2018-01-01

    Compared to single gemcitabine treatment, the combination of gemcitabine and erlotinib has shown effective response in patients with locally advanced or metastatic pancreatic cancer. However, the combination therapy has not proven effective in patients with pancreatic cancer after R0 or R1 resection. In the present study, a nude mice model of orthotopic xenotransplantation after tumor resection was established using pancreatic cancer cell lines, BxPC-3 and PANC-1. Mice were divided in four groups (each with n=12) and were treated as follows: the control group received a placebo via intraperitoneal injection (i.p.), while the other three groups were treated with gemcitabine (50 mg/kg i.p., twice a week), erlotinib (50 mg/kg oral gavage, once every three days), and combined treatment of gemcitabine and erlotinib, respectively. The treatment lasted for 21 days, after which all mice were sacrificed and tumors were examined ex vivo. We determined that the combination of gemcitabine and erlotinib inhibited recurrent tumor growth and induced apoptosis in vivo by downregulating phosphorylation levels of JAKs and STATs, which in turn downregulated the downstream proteins HIF-1α and cyclin D1, and upregulated caspase-9 and caspase-3 expression. To sum up, the combination of gemcitabine with erlotinib was effective in treating patients with pancreatic cancer after R0 or R1 resection. PMID:29328487

  18. Socioeconomic deprivation and cancer survival in Germany: an ecological analysis in 200 districts in Germany.

    PubMed

    Jansen, Lina; Eberle, Andrea; Emrich, Katharina; Gondos, Adam; Holleczek, Bernd; Kajüter, Hiltraud; Maier, Werner; Nennecke, Alice; Pritzkuleit, Ron; Brenner, Hermann

    2014-06-15

    Although socioeconomic inequalities in cancer survival have been demonstrated both within and between countries, evidence on the variation of the inequalities over time past diagnosis is sparse. Furthermore, no comprehensive analysis of socioeconomic differences in cancer survival in Germany has been conducted. Therefore, we analyzed variations in cancer survival for patients diagnosed with one of the 25 most common cancer sites in 1997-2006 in ten population-based cancer registries in Germany (covering 32 million inhabitants). Patients were assigned a socioeconomic status according to the district of residence at diagnosis. Period analysis was used to derive 3-month, 5-year and conditional 1-year and 5-year age-standardized relative survival for 2002-2006 for each deprivation quintile in Germany. Relative survival of patients living in the most deprived district was compared to survival of patients living in all other districts by model-based period analysis. For 21 of 25 cancer sites, 5-year relative survival was lower in the most deprived districts than in all other districts combined. The median relative excess risk of death over the 25 cancer sites decreased from 1.24 in the first 3 months to 1.16 in the following 9 months to 1.08 in the following 4 years. Inequalities persisted after adjustment for stage. These major regional socioeconomic inequalities indicate a potential for improving cancer care and survival in Germany. Studies on individual-level patient data with access to treatment information should be conducted to examine the reasons for these socioeconomic inequalities in cancer survival in more detail. © 2013 UICC.

  19. 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.

  20. Quantitative Analysis of Human Cancer Cell Extravasation Using Intravital Imaging.

    PubMed

    Willetts, Lian; Bond, David; Stoletov, Konstantin; Lewis, John D

    2016-01-01

    Metastasis, or the spread of cancer cells from a primary tumor to distant sites, is the leading cause of cancer-associated death. Metastasis is a complex multi-step process comprised of invasion, intravasation, survival in circulation, extravasation, and formation of metastatic colonies. Currently, in vitro assays are limited in their ability to investigate these intricate processes and do not faithfully reflect metastasis as it occurs in vivo. Traditional in vivo models of metastasis are limited by their ability to visualize the seemingly sporadic behavior of where and when cancer cells spread (Reymond et al., Nat Rev Cancer 13:858-870, 2013). The avian embryo model of metastasis is a powerful platform to study many of the critical steps in the metastatic cascade including the migration, extravasation, and invasion of human cancer cells in vivo (Sung et al., Nat Commun 6:7164, 2015; Leong et al., Cell Rep 8, 1558-1570, 2014; Kain et al., Dev Dyn 243:216-28, 2014; Leong et al., Nat Protoc 5:1406-17, 2010; Zijlstra et al., Cancer Cell 13:221-234, 2008; Palmer et al., J Vis Exp 51:2815, 2011). The chicken chorioallantoic membrane (CAM) is a readily accessible and well-vascularized tissue that surrounds the developing embryo. When the chicken embryo is grown in a shell-less, ex ovo environment, the nearly transparent CAM provides an ideal environment for high-resolution fluorescent microcopy approaches. In this model, the embryonic chicken vasculature and labeled cancer cells can be visualized simultaneously to investigate specific steps in the metastatic cascade including extravasation. When combined with the proper image analysis tools, the ex ovo chicken embryo model offers a cost-effective and high-throughput platform for the quantitative analysis of tumor cell metastasis in a physiologically relevant in vivo setting. Here we discuss detailed procedures to quantify cancer cell extravasation in the shell-less chicken embryo model with advanced fluorescence

  1. 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

  2. Synergistic Anti-Breast-Cancer Effects of Combined Treatment With Oleuropein and Doxorubicin In Vivo.

    PubMed

    Elamin, Maha H; Elmahi, Abdelsalam B; Daghestani, Maha H; Al-Olayan, Ebtesam M; Al-Ajmi, Reem A; Alkhuriji, Afrah F; Hamed, Sherifa S; Elkhadragy, Manal F

    2017-06-23

    Context • Breast cancer is a leading cause of cancer fatalities among women worldwide. Of the more than 80% of patients who receive adjuvant chemotherapy, approximately 40% relapse. The majority of these patients die of disseminated metastatic disease, which emphasizes the need for new therapeutic strategies Objective • The study intended to investigate the anticancer effects of oleuropein (OL) and doxorubicin (DOX) individually and in combination on breast tumor xenografts and also to evaluate the molecular pathways involved. Design • The research team designed in vivo (animal) and in vitro (cell culture) studies. The study was performed in the College of Science of King Saud University in the University Center for Women Students (Riyadh, Saudi Arabia). Animals • The study involved 40 female, nude mice (BALB/c OlaHsd-foxn1). Intervention • The mice were injected subcutaneously with MDA-MB-231 human breast cancer cells. After the growth of tumors, the animals were randomly divided into 4 groups to receive intraperitoneal injections: (1) group 1 (control group)-dimethyl sulfoxide, (2) group 2 (intervention group)-50 mg/kg of OL, (3) group 3 (intervention group)-2.5 mg/kg of DOX, and (4) group 4 (intervention group)-1.5 mg/kg of DOX, immediately followed by 50 mg/kg of OL. The OL was extracted from Manzanillo olive trees (Olea europaea) grown in Tabouk, Saudi Arabia. Outcome Measures • The measures included the isolation and primary culture of the tumor xenografts, apoptosis analysis by annexin V, cellular lysate preparation, and immunoblotting. The volume of the tumor increased aggressively, reaching 173 mm3 in the control animals in a time-dependent manner. On the other hand, a sharp drop, to 48.7 mm3, in the volume of the tumor was observed with the 2 drugs combined, a more than 3-fold decrease. The effect was mediated through the induction of apoptosis via the mitochondrial pathway. The combined treatment downregulated the antiapoptosis and

  3. Primary treatments for clinically localised prostate cancer: a comprehensive lifetime cost-utility analysis.

    PubMed

    Cooperberg, Matthew R; Ramakrishna, Naren R; Duff, Steven B; Hughes, Kathleen E; Sadownik, Sara; Smith, Joseph A; Tewari, Ashutosh K

    2013-03-01

    WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Multiple treatment alternatives exist for localised prostate cancer, with few high-quality studies directly comparing their comparative effectiveness and costs. The present study is the most comprehensive cost-effectiveness analysis to date for localised prostate cancer, conducted with a lifetime horizon and accounting for survival, health-related quality-of-life, and cost impact of secondary treatments and other downstream events, as well as primary treatment choices. The analysis found minor differences, generally slightly favouring surgical methods, in quality-adjusted life years across treatment options. However, radiation therapy (RT) was consistently more expensive than surgery, and some alternatives, e.g. intensity-modulated RT for low-risk disease, were dominated - that is, both more expensive and less effective than competing alternatives. To characterise the costs and outcomes associated with radical prostatectomy (open, laparoscopic, or robot-assisted) and radiation therapy (RT: dose-escalated three-dimensional conformal RT, intensity-modulated RT, brachytherapy, or combination), using a comprehensive, lifetime decision analytical model. A Markov model was constructed to follow hypothetical men with low-, intermediate-, and high-risk prostate cancer over their lifetimes after primary treatment; probabilities of outcomes were based on an exhaustive literature search yielding 232 unique publications. In each Markov cycle, patients could have remission, recurrence, salvage treatment, metastasis, death from prostate cancer, and death from other causes. Utilities for each health state were determined, and disutilities were applied for complications and toxicities of treatment. Costs were determined from the USA payer perspective, with incorporation of patient costs in a sensitivity analysis. Differences across treatments in quality-adjusted life years across methods were modest, ranging from 10.3 to

  4. Effectiveness of the combined evaluation of KLK3 genetics and free-to-total prostate specific antigen ratio for prostate cancer diagnosis.

    PubMed

    Zambon, Carlo-Federico; Prayer-Galetti, Tommaso; Basso, Daniela; Padoan, Andrea; Rossi, Elisa; Secco, Silvia; Pelloso, Michela; Fogar, Paola; Navaglia, Filippo; Moz, Stefania; Zattoni, Filiberto; Plebani, Mario

    2012-10-01

    Of serum prostate specific antigen variability 40% depends on inherited factors. We ascertained whether the knowledge of KLK3 genetics would enhance prostate specific antigen diagnostic performance in patients with clinical suspicion of prostate cancer. We studied 1,058 men who consecutively underwent prostate biopsy for clinical suspicion of prostate cancer. At histology prostate cancer was present in 401 cases and absent in 657. Serum total prostate specific antigen and the free-to-total prostate specific antigen ratio were determined. Four polymorphisms of the KLK3 gene (rs2569733, rs2739448, rs925013 and rs2735839) and 1 polymorphism of the SRD5A2 gene (rs523349) were studied. The influence of genetics on prostate specific antigen variability was evaluated by multivariate linear regression analysis. The performance of total prostate specific antigen and the free-to-total prostate specific antigen ratio alone or combined with a genetically based patient classification were defined by ROC curve analyses. For prostate cancer diagnosis the free-to-total prostate specific antigen ratio index alone (cutoff 11%) was superior to total prostate specific antigen (cutoff 4 ng/ml) and to free-to-total prostate specific antigen ratio reflex testing (positive predictive value 61%, 43% and 54%, respectively). Prostate specific antigen correlated with KLK3 genetics (rs2735839 polymorphism p = 0.001, and rs2569733, rs2739448 and rs925013 haplotype combination p = 0.003). In patients with different KLK3 genetics 2 optimal free-to-total prostate specific antigen ratio cutoffs (11% and 14.5%) were found. For free-to-total prostate specific antigen ratio values between 11% and 14.5% the prostate cancer probability ranged from 30.0% to 47.4% according to patient genetics. The free-to-total prostate specific antigen ratio is superior to total prostate specific antigen for prostate cancer diagnosis, independent of total prostate specific antigen results. Free-to-total prostate

  5. Evaluation of the combined use of metronomic zoledronic acid and Coriolus versicolor in intratibial breast cancer mouse model.

    PubMed

    Ko, Chun-Hay; Yue, Grace Gar-Lee; Gao, Si; Luo, Ke-Wang; Siu, Wing-Sum; Shum, Wai-Ting; Shiu, Hoi-Ting; Lee, Julia Kin-Ming; Li, Gang; Leung, Ping-Chung; Evdokiou, Andreas; Lau, Clara Bik-San

    2017-05-23

    Coriolus versicolor (CV) is a mushroom traditionally used for strengthening the immune system and nowadays used as immunomodulatory adjuvant in anticancer therapy. Breast cancer usually metastasizes to the skeleton, interrupts the normal bone remodeling process and causes osteolytic bone lesions. The aims of the present study were to evaluate its herb-drug interaction with metronomic zoledronate in preventing cancer propagation, metastasis and bone destruction. Mice inoculated with human breast cancer cells tagged with a luciferase (MDA-MB-231-TXSA) in tibia were treated with CV aqueous extract, mZOL, or the combination of both for 4 weeks. Alteration of the luciferase signals in tibia, liver and lung were quantified using the IVIS imaging system. The skeletal response was evaluated using micro-computed tomography (micro-CT). In vitro experiments were carried out to confirm the in vivo findings. Results showed that combination of CV and mZOL diminished tumor growth without increasing the incidence of lung and liver metastasis in intratibial breast tumor model. The combination therapy also reserved the integrity of bones. In vitro studies demonstrated that combined use of CV and mZOL inhibited cancer cell proliferation and osteoclastogenesis. These findings suggested that combination treatment of CV and mZOL attenuated breast tumor propagation, protected against osteolytic bone lesion without significant metastases. This study provides scientific evidences on the beneficial outcome of using CV together with mZOL in the management of breast cancer and metastasis, which may lead to the development of CV as adjuvant health supplement for the control of breast cancer. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

  6. CRCDA—Comprehensive resources for cancer NGS data analysis

    PubMed Central

    Thangam, Manonanthini; Gopal, Ramesh Kumar

    2015-01-01

    Next generation sequencing (NGS) innovations put a compelling landmark in life science and changed the direction of research in clinical oncology with its productivity to diagnose and treat cancer. The aim of our portal comprehensive resources for cancer NGS data analysis (CRCDA) is to provide a collection of different NGS tools and pipelines under diverse classes with cancer pathways and databases and furthermore, literature information from PubMed. The literature data was constrained to 18 most common cancer types such as breast cancer, colon cancer and other cancers that exhibit in worldwide population. NGS-cancer tools for the convenience have been categorized into cancer genomics, cancer transcriptomics, cancer epigenomics, quality control and visualization. Pipelines for variant detection, quality control and data analysis were listed to provide out-of-the box solution for NGS data analysis, which may help researchers to overcome challenges in selecting and configuring individual tools for analysing exome, whole genome and transcriptome data. An extensive search page was developed that can be queried by using (i) type of data [literature, gene data and sequence read archive (SRA) data] and (ii) type of cancer (selected based on global incidence and accessibility of data). For each category of analysis, variety of tools are available and the biggest challenge is in searching and using the right tool for the right application. The objective of the work is collecting tools in each category available at various places and arranging the tools and other data in a simple and user-friendly manner for biologists and oncologists to find information easier. To the best of our knowledge, we have collected and presented a comprehensive package of most of the resources available in cancer for NGS data analysis. Given these factors, we believe that this website will be an useful resource to the NGS research community working on cancer. Database URL: http

  7. Exercise and other non-pharmaceutical interventions for cancer-related fatigue in patients during or after cancer treatment: a systematic review incorporating an indirect-comparisons meta-analysis

    PubMed Central

    Meichtry, Andre; Nilsson Balfe, Lina; Knols, Ruud H; Verra, Martin L; Taeymans, Jan

    2018-01-01

    Aim To assess the relative effects of different types of exercise and other non-pharmaceutical interventions on cancer-related fatigue (CRF) in patients during and after cancer treatment. Design Systematic review and indirect-comparisons meta-analysis. Data sources Articles were searched in PubMed, Cochrane CENTRAL and published meta-analyses. Eligibility criteria for selecting studies Randomised studies published up to January 2017 evaluating different types of exercise or other non-pharmaceutical interventions to reduce CRF in any cancer type during or after treatment. Study appraisal and synthesis Risk of bias assessment with PEDro criteria and random effects Bayesian network meta-analysis. Results We included 245 studies. Comparing the treatments with usual care during cancer treatment, relaxation exercise was the highest ranked intervention with a standardisedmean difference (SMD) of −0.77 (95% Credible Interval (CrI) −1.22 to −0.31), while massage (−0.78; −1.55 to −0.01), cognitive–behavioural therapy combined with physical activity (combined CBT, −0.72; −1.34 to −0.09), combined aerobic and resistance training (−0.67; −1.01 to −0.34), resistance training (−0.53; −1.02 to −0.03), aerobic (−0.53; −0.80 to −0.26) and yoga (−0.51; −1.01 to 0.00) all had moderate-to-large SMDs. After cancer treatment, yoga showed the highest effect (−0.68; −0.93 to −0.43). Combined aerobic and resistance training (−0.50; −0.66 to −0.34), combined CBT (−0.45; −0.70 to −0.21), Tai-Chi (−0.45; −0.84 to −0.06), CBT (−0.42; −0.58 to −0.25), resistance training (−0.35; −0.62 to −0.08) and aerobic (−0.33; −0.51 to −0.16) showed all small-to-moderate SMDs. Conclusions Patients can choose among different effective types of exercise and non-pharmaceutical interventions to reduce CRF. PMID:28501804

  8. Exploiting cancer cell vulnerabilities to develop a combination therapy for Ras-driven tumors

    PubMed Central

    De Raedt, Thomas; Walton, Zandra; Yecies, Jessica L.; Li, Danan; Chen, Yimei; Malone, Clare F.; Maertens, Ophelia; Jeong, Seung Min; Bronson, Roderick T.; Lebleu, Valerie; Kalluri, Raghu; Normant, Emmanuel; Haigis, Marcia C.; Manning, Brendan D.; Wong, Kwok-Kin; Macleod, Kay F; Cichowski, Karen

    2011-01-01

    Summary Ras-driven tumors are often refractory to conventional therapies. Here we identify a promising targeted therapeutic strategy for two Ras-driven cancers: Nf1-deficient malignancies and KRas/p53-mutant lung cancer. We show that agents that enhance proteotoxic stress, including the HSP90 inhibitor IPI-504, induce tumor regression in aggressive mouse models, but only when combined with rapamycin. These agents synergize by promoting irresolvable ER stress, resulting in catastrophic ER and mitochondrial damage. This process is fueled by oxidative stress, which is caused by IPI-504-dependent production of reactive oxygen species, and the rapamycin-dependent suppression of glutathione, an important endogenous antioxidant. Notably, the mechanism by which these agents cooperate reveals a therapeutic paradigm that can be expanded to develop additional combinations. PMID:21907929

  9. 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.

  10. Ginseng and Anticancer Drug Combination to Improve Cancer Chemotherapy: A Critical Review

    PubMed Central

    Chen, Shihong; Huang, Ying; O'Barr, Stephen A.; Wong, Rebecca A.; Chow, Moses Sing Sum

    2014-01-01

    Ginseng, a well-known herb, is often used in combination with anticancer drugs to enhance chemotherapy. Its wide usage as well as many documentations are often cited to support its clinical benefit of such combination therapy. However the literature based on objective evidence to make such recommendation is still lacking. The present review critically evaluated relevant studies reported in English and Chinese literature on such combination. Based on our review, we found good evidence from in vitro and in vivo animal studies showing enhanced antitumor effect when ginseng is used in combination with some anticancer drugs. However, there is insufficient clinical evidence of such benefit as very few clinical studies are available. Future research should focus on clinically relevant studies of such combination to validate the utility of ginseng in cancer. PMID:24876866

  11. Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes

    PubMed Central

    McKay, James D.; Hung, Rayjean J.; Han, Younghun; Zong, Xuchen; Carreras-Torres, Robert; Christiani, David C.; Caporaso, Neil E.; Johansson, Mattias; Xiao, Xiangjun; Li, Yafang; Byun, Jinyoung; Dunning, Alison; Pooley, Karen A.; Qian, David C.; Ji, Xuemei; Liu, Geoffrey; Timofeeva, Maria N.; Bojesen, Stig E.; Wu, Xifeng; Le Marchand, Loic; Albanes, Demetrios; Bickeböller, Heike; Aldrich, Melinda C.; Bush, William S.; Tardon, Adonina; Rennert, Gad; Teare, M. Dawn; Field, John K.; Kiemeney, Lambertus A.; Lazarus, Philip; Haugen, Aage; Lam, Stephen; Schabath, Matthew B.; Andrew, Angeline S.; Shen, Hongbing; Hong, Yun-Chul; Yuan, Jian-Min; Bertazzi, Pier Alberto; Pesatori, Angela C.; Ye, Yuanqing; Diao, Nancy; Su, Li; Zhang, Ruyang; Brhane, Yonathan; Leighl, Natasha; Johansen, Jakob S.; Mellemgaard, Anders; Saliba, Walid; Haiman, Christopher A.; Wilkens, Lynne R.; Fernandez-Somoano, Ana; Fernandez-Tardon, Guillermo; van der Heijden, Henricus F.M.; Kim, Jin Hee; Dai, Juncheng; Hu, Zhibin; Davies, Michael PA; Marcus, Michael W.; Brunnström, Hans; Manjer, Jonas; Melander, Olle; Muller, David C.; Overvad, Kim; Trichopoulou, Antonia; Tumino, Rosario; Doherty, Jennifer A.; Barnett, Matt P.; Chen, Chu; Goodman, Gary E.; Cox, Angela; Taylor, Fiona; Woll, Penella; Brüske, Irene; Wichmann, H.-Erich; Manz, Judith; Muley, Thomas R.; Risch, Angela; Rosenberger, Albert; Grankvist, Kjell; Johansson, Mikael; Shepherd, Frances A.; Tsao, Ming-Sound; Arnold, Susanne M.; Haura, Eric B.; Bolca, Ciprian; Holcatova, Ivana; Janout, Vladimir; Kontic, Milica; Lissowska, Jolanta; Mukeria, Anush; Ognjanovic, Simona; Orlowski, Tadeusz M.; Scelo, Ghislaine; Swiatkowska, Beata; Zaridze, David; Bakke, Per; Skaug, Vidar; Zienolddiny, Shanbeh; Duell, Eric J.; Butler, Lesley M.; Koh, Woon-Puay; Gao, Yu-Tang; Houlston, Richard S.; McLaughlin, John; Stevens, Victoria L.; Joubert, Philippe; Lamontagne, Maxime; Nickle, David C.; Obeidat, Ma’en; Timens, Wim; Zhu, Bin; Song, Lei; Kachuri, Linda; Artigas, María Soler; Tobin, Martin D.; Wain, Louise V.; Rafnar, Thorunn; Thorgeirsson, Thorgeir E.; Reginsson, Gunnar W.; Stefansson, Kari; Hancock, Dana B.; Bierut, Laura J.; Spitz, Margaret R.; Gaddis, Nathan C.; Lutz, Sharon M.; Gu, Fangyi; Johnson, Eric O.; Kamal, Ahsan; Pikielny, Claudio; Zhu, Dakai; Lindströem, Sara; Jiang, Xia; Tyndale, Rachel F.; Chenevix-Trench, Georgia; Beesley, Jonathan; Bossé, Yohan; Chanock, Stephen; Brennan, Paul; Landi, Maria Teresa; Amos, Christopher I.

    2017-01-01

    Summary While several lung cancer susceptibility loci have been identified, much of lung cancer heritability remains unexplained. Here, 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated GWAS analysis of lung cancer on 29,266 patients and 56,450 controls. We identified 18 susceptibility loci achieving genome wide significance, including 10 novel loci. The novel loci highlighted the striking heterogeneity in genetic susceptibility across lung cancer histological subtypes, with four loci associated with lung cancer overall and six with lung adenocarcinoma. Gene expression quantitative trait analysis (eQTL) in 1,425 normal lung tissues highlighted RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes, OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer. PMID:28604730

  12. The novel sigma-2 receptor ligand SW43 stabilizes pancreas cancer progression in combination with gemcitabine

    PubMed Central

    2010-01-01

    Background Sigma-2 receptors are over-expressed in proliferating cancer cells, making an attractive target for the targeted treatment of pancreatic cancer. In this study, we investigated the role of the novel sigma-2 receptor ligand SW43 to induce apoptosis and augment standard chemotherapy. Results The binding affinity for sigma-2 ligands is high in pancreas cancer, and they induce apoptosis with a rank order of SV119 < SW43 < SRM in vitro. Combining these compounds with gemcitabine further increased apoptosis and decreased viability. Our in vivo model showed that sigma-2 ligand treatment decreased tumor volume to the same extent as gemcitabine. However, SW43 combination treatment with gemcitabine was superior to the other compounds and resulted in stabilization of tumor volume during treatment, with minimal toxicities. Conclusions This study shows that the sigma-2 ligand SW43 has the greatest capacity to augment gemcitabine in a pre-clinical model of pancreas cancer and has provided us with the rationale to move this compound forward with clinical investigations for patients with pancreatic cancer. PMID:21092190

  13. Prostate cancer detection using machine learning techniques by employing combination of features extracting strategies.

    PubMed

    Hussain, Lal; Ahmed, Adeel; Saeed, Sharjil; Rathore, Saima; Awan, Imtiaz Ahmed; Shah, Saeed Arif; Majid, Abdul; Idris, Adnan; Awan, Anees Ahmed

    2018-02-06

    Prostate is a second leading causes of cancer deaths among men. Early detection of cancer can effectively reduce the rate of mortality caused by Prostate cancer. Due to high and multiresolution of MRIs from prostate cancer require a proper diagnostic systems and tools. In the past researchers developed Computer aided diagnosis (CAD) systems that help the radiologist to detect the abnormalities. In this research paper, we have employed novel Machine learning techniques such as Bayesian approach, Support vector machine (SVM) kernels: polynomial, radial base function (RBF) and Gaussian and Decision Tree for detecting prostate cancer. Moreover, different features extracting strategies are proposed to improve the detection performance. The features extracting strategies are based on texture, morphological, scale invariant feature transform (SIFT), and elliptic Fourier descriptors (EFDs) features. The performance was evaluated based on single as well as combination of features using Machine Learning Classification techniques. The Cross validation (Jack-knife k-fold) was performed and performance was evaluated in term of receiver operating curve (ROC) and specificity, sensitivity, Positive predictive value (PPV), negative predictive value (NPV), false positive rate (FPR). Based on single features extracting strategies, SVM Gaussian Kernel gives the highest accuracy of 98.34% with AUC of 0.999. While, using combination of features extracting strategies, SVM Gaussian kernel with texture + morphological, and EFDs + morphological features give the highest accuracy of 99.71% and AUC of 1.00.

  14. GSCALite: A Web Server for Gene Set Cancer Analysis.

    PubMed

    Liu, Chun-Jie; Hu, Fei-Fei; Xia, Mengxuan; Han, Leng; Zhang, Qiong; Guo, An-Yuan

    2018-05-22

    The availability of cancer genomic data makes it possible to analyze genes related to cancer. Cancer is usually the result of a set of genes and the signal of a single gene could be covered by background noise. Here, we present a web server named Gene Set Cancer Analysis (GSCALite) to analyze a set of genes in cancers with the following functional modules. (i) Differential expression in tumor vs normal, and the survival analysis; (ii) Genomic variations and their survival analysis; (iii) Gene expression associated cancer pathway activity; (iv) miRNA regulatory network for genes; (v) Drug sensitivity for genes; (vi) Normal tissue expression and eQTL for genes. GSCALite is a user-friendly web server for dynamic analysis and visualization of gene set in cancer and drug sensitivity correlation, which will be of broad utilities to cancer researchers. GSCALite is available on http://bioinfo.life.hust.edu.cn/web/GSCALite/. guoay@hust.edu.cn or zhangqiong@hust.edu.cn. Supplementary data are available at Bioinformatics online.

  15. Integrative Analysis of Response to Tamoxifen Treatment in ER-Positive Breast Cancer Using GWAS Information and Transcription Profiling.

    PubMed

    Hicks, Chindo; Kumar, Ranjit; Pannuti, Antonio; Miele, Lucio

    2012-01-01

    Variable response and resistance to tamoxifen treatment in breast cancer patients remains a major clinical problem. To determine whether genes and biological pathways containing SNPs associated with risk for breast cancer are dysregulated in response to tamoxifen treatment, we performed analysis combining information from 43 genome-wide association studies with gene expression data from 298 ER(+) breast cancer patients treated with tamoxifen and 125 ER(+) controls. We identified 95 genes which distinguished tamoxifen treated patients from controls. Additionally, we identified 54 genes which stratified tamoxifen treated patients into two distinct groups. We identified biological pathways containing SNPs associated with risk for breast cancer, which were dysregulated in response to tamoxifen treatment. Key pathways identified included the apoptosis, P53, NFkB, DNA repair and cell cycle pathways. Combining GWAS with transcription profiling provides a unified approach for associating GWAS findings with response to drug treatment and identification of potential drug targets.

  16. In vitro investigation on the magnetic thermochemotherapy mediated by magnetic nanoparticles combined with methotrexate for breast cancer treatment.

    PubMed

    Zhao, Lingyun; Huo, Meijun; Liu, Jiayi; Yao, Zhu; Li, Danye; Zhao, Zhiwei; Tang, Jintian

    2013-02-01

    Cancer comprehensive treatment has been fully recognized as it can provide an effective multimodality approach for fighting cancers. In therapeutic oncology, hyperthermic adjuvant chemotherapy termed as thermochemotherapy plays an increasing role in multimodality cancer treatment. Currently, targeted nanothermotherapy is one of the effective hyperthermia approach based on magnetic nanoparticles (MNPs), which can be achieved by applying biocompatible nanoscaled metallic particles that convert electromagnetic energy into heat, for instance, magnetic fluid hyperthermia (MFH) mediated by superparamagnetic iron oxide nanoparticles (SPIONs). Upon exposure under alternative magnetic field (AMF), SPIONs can generate heat through oscillation of their magnetic moment. Nowadays, clinical trials at phase II are now under investigations for MFH on patients in Germany and Japan and demonstrate very inspiring for cancer therapy. In this work we explore the feasibility and effectiveness of magnetic thermochemotherapy mediated by magnetic nanoparticles combined with methotrexate, an anti-cancer drug, for breast cancer comprehensive treatment. Amino silane coated MNPs as agent of MFH were prepared by the chemical precipitation method. Physiochemical characterizations on MNPs have been systematically carried out by various instrumental analyses. Inductive heating property of the MNPs was evaluated by monitoring the temperature increase of the MNPs suspension under AMF. The in-vitro cytotoxicity results on human breast cancer cell MCF-7 by CCK-8 assay indicated the bi-modal cancer treatment approach for combined MFH and chemotherapy is more effective than mono-modal treatment, indicating a thermal enhancement effect of hyperthermia on drug cytocoxicity. The magnetic thermochemotherapy mediated by MNPs combined with methotrexate can realize cancer comprehensive treatment thus has great potential in clinical application.

  17. Investments in cancer research awarded to UK institutions and the global burden of cancer 2000–2013: a systematic analysis

    PubMed Central

    Maruthappu, Mahiben; Head, Michael G; Zhou, Charlie D; Gilbert, Barnabas J; El-Harasis, Majd A; Raine, Rosalind; Fitchett, Joseph R; Atun, Rifat

    2017-01-01

    Objectives To systematically categorise cancer research investment awarded to United Kingdom (UK) institutions in the period 2000–2013 and to estimate research investment relative to disease burden as measured by mortality, disability-adjusted life years (DALYs) and years lived with disability (YLDs). Design Systematic analysis of all open-access data. Setting and participants Public and philanthropic funding to all UK cancer research institutions, 2000–2013. Main outcome measures Number and financial value of cancer research investments reported in 2013 UK pounds (UK£). Mortality, DALYs and YLDs data were acquired from the Global Burden of Disease Study. A compound metric was adapted to estimate research investment relative to disease burden as measured by mortality, DALYs and YLDs. Results We identified 4299 funded studies with a total research investment of £2.4 billion. The highest fundings by anatomical sites were haematological, breast, prostate, colorectal and ovarian cancers. Relative to disease burden as determined by a compound metric combining mortality, DALYs and YLDs, gender-specific cancers were found to be highest funded—the five sites that received the most funding were prostate, ovarian, breast, mesothelioma and testicular cancer; the least well-funded sites were liver, thyroid, lung, upper gastrointestinal (GI) and bladder. Preclinical science accounted for 66.2% of award numbers and 62.2% of all funding. The top five areas of primary research focus by funding were pathogenesis, drug therapy, diagnostic, screening and monitoring, women's health and immunology. The largest individual funder was the Medical Research Council. In combination, the five lowest funded site-specific cancers relative to disease burden account for 47.9%, 44.3% and 20.4% of worldwide cancer mortality, DALYs and YLDs. Conclusions Research funding for cancer is not allocated according to relative disease burden. These findings are in line with earlier published studies

  18. Docetaxel in combination with epirubicin in metastatic breast cancer: pharmacokinetic interactions.

    PubMed

    Ceruti, M; Tagini, V; Recalenda, V; Arpicco, S; Cattel, L; Airoldi, M; Bumma, C

    1999-01-01

    Epirubicin (75 mg/m2) and docetaxel (75 mg/m2) were administered to 16 patients affected by metastatic breast cancer following two different schedules: (1) docetaxel as infusion administered 1 h after epirubicin administration (schedule A); and (2) docetaxel as infusion immediately (10 min) after the end of epirubicin i.v. bolus administration (schedule B). Experimental non-compartmental analyses such as AUC and Css, were affected very little by the drug combination, irrespective of whether the administration of docetaxel was immediately after the epirubicin bolus (10 min) or delayed (1 h). However, serum levels showed evidence of transient drug interaction: in schedule A, docetaxel infusion was associated with a transient increase of plasma epirubicin in correspondence with Cssmax of docetaxel. Bi-compartmental analysis showed a significant difference in epirubicin clearance between protocols A and B. It is suggested that polysorbate 80, used in minimal amounts to formulate docetaxel, may interfere with epirubicin plasma level.

  19. The association between Selenium and Prostate Cancer: a Systematic Review and Meta-Analysis

    PubMed

    Sayehmiri, Kourosh; Azami, Milad; Mohammadi, Younes; Soleymani, Ali; Tardeh, Zainab

    2018-06-25

    Background: Evidence of relationship between selenium and prostate cancer has been inconsistent. The present metaanalysis was conducted to determine relationship between selenium and prostate cancer. Methods: A systematic review and meta-analysis was carried out using preferred reporting items for systematic reviews and meta-analysis (PRISMA). We searched PubMed, Scopus, Web of Science, ScienceDirect, Embase, CINAHL, Cochrane Library, EBSCO and Google scholar search engines and the reference lists of the retrieved papers for relevant data, without any limitation regarding language or time until 2016. Heterogeneity among studies was evaluated using Q test and I2 Index. Finally, a random effects model was used for combining results using STATA software version 11.1. P<0.05 was considered significant. Results: Thirty-eight studies including 36,419 cases and 105,293 controls were included in the final analysis. The pooled relative risk (RR) of relation between selenium and prostate cancer was 0.86 (95% Confidence Interval [CI]:0.78-0.94). Sub-group analyses based on case-control, cohort, and RCT studies gave values of 0.89 (95% CI: 0.80-1.00), 0.77 (95% CI: 0.52-1.14) and 0.90 (95% CI: 0.74-1.09), respectively. RRs based on serum, plasma and nail samples were 0.69 (95% CI: 0.51-0.95), 0.85 (95% CI: 0.61-1.17), 0.66 (95% CI: 0.41-1.05), respectively. According to 10 studies, investigated the relation between advanced prostate cancer and selenium in which the RR was 0.67 (95% CI: 0.52-0.87). Conclusions: This meta-analysis indicated that selenium most probably has a protective role against development of prostate cancer and its progression to advanced stages. Therefore, selenium supplementation can be proposed for prevention of prostate cancer. Creative Commons Attribution License

  20. A Combined Pharmacokinetic and Radiologic Assessment of Dynamic Contrast-Enhanced Magnetic Resonance Imaging Predicts Response to Chemoradiation in Locally Advanced Cervical Cancer

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Semple, Scott; Harry, Vanessa N. MRCOG.; Parkin, David E.

    2009-10-01

    Purpose: To investigate the combination of pharmacokinetic and radiologic assessment of dynamic contrast-enhanced magnetic resonance imaging (MRI) as an early response indicator in women receiving chemoradiation for advanced cervical cancer. Methods and Materials: Twenty women with locally advanced cervical cancer were included in a prospective cohort study. Dynamic contrast-enhanced MRI was carried out before chemoradiation, after 2 weeks of therapy, and at the conclusion of therapy using a 1.5-T MRI scanner. Radiologic assessment of uptake parameters was obtained from resultant intensity curves. Pharmacokinetic analysis using a multicompartment model was also performed. General linear modeling was used to combine radiologic andmore » pharmacokinetic parameters and correlated with eventual response as determined by change in MRI tumor size and conventional clinical response. A subgroup of 11 women underwent repeat pretherapy MRI to test pharmacokinetic reproducibility. Results: Pretherapy radiologic parameters and pharmacokinetic K{sup trans} correlated with response (p < 0.01). General linear modeling demonstrated that a combination of radiologic and pharmacokinetic assessments before therapy was able to predict more than 88% of variance of response. Reproducibility of pharmacokinetic modeling was confirmed. Conclusions: A combination of radiologic assessment with pharmacokinetic modeling applied to dynamic MRI before the start of chemoradiation improves the predictive power of either by more than 20%. The potential improvements in therapy response prediction using this type of combined analysis of dynamic contrast-enhanced MRI may aid in the development of more individualized, effective therapy regimens for this patient group.« less

  1. Preferential Allele Expression Analysis Identifies Shared Germline and Somatic Driver Genes in Advanced Ovarian Cancer

    PubMed Central

    Halabi, Najeeb M.; Martinez, Alejandra; Al-Farsi, Halema; Mery, Eliane; Puydenus, Laurence; Pujol, Pascal; Khalak, Hanif G.; McLurcan, Cameron; Ferron, Gwenael; Querleu, Denis; Al-Azwani, Iman; Al-Dous, Eman; Mohamoud, Yasmin A.; Malek, Joel A.; Rafii, Arash

    2016-01-01

    Identifying genes where a variant allele is preferentially expressed in tumors could lead to a better understanding of cancer biology and optimization of targeted therapy. However, tumor sample heterogeneity complicates standard approaches for detecting preferential allele expression. We therefore developed a novel approach combining genome and transcriptome sequencing data from the same sample that corrects for sample heterogeneity and identifies significant preferentially expressed alleles. We applied this analysis to epithelial ovarian cancer samples consisting of matched primary ovary and peritoneum and lymph node metastasis. We find that preferentially expressed variant alleles include germline and somatic variants, are shared at a relatively high frequency between patients, and are in gene networks known to be involved in cancer processes. Analysis at a patient level identifies patient-specific preferentially expressed alleles in genes that are targets for known drugs. Analysis at a site level identifies patterns of site specific preferential allele expression with similar pathways being impacted in the primary and metastasis sites. We conclude that genes with preferentially expressed variant alleles can act as cancer drivers and that targeting those genes could lead to new therapeutic strategies. PMID:26735499

  2. Serum uric acid and cancer mortality and incidence: a systematic review and meta-analysis.

    PubMed

    Dovell, Frances; Boffetta, Paolo

    2018-07-01

    Elevated serum uric acid (SUA) is a marker of chronic inflammation and has been suggested to be associated with increased risk of cancer, but its antioxidant capacity would justify an anticancer effect. Previous meta-analyses did not include all available results. We conducted a systematic review of prospective studies on SUA level and risk of all cancers and specific cancers, a conducted a meta-analysis based on random-effects models for high versus low SUA level as well as for an increase in 1 mg/dl SUA. The relative risk of all cancers for high versus low SUA level was 1.11 (95% confidence interval: 0.94-1.27; 11 risk estimates); that for a mg/dl increase in SUA level was 1.03 (95% confidence interval: 0.99-1.07). Similar results were obtained for lung cancer (six risk estimates) and colon cancer (four risk estimates). Results for other cancers were sparse. Elevated SUA levels appear to be associated with a modest increase in overall cancer risk, although the combined risk estimate did not reach the formal level of statistical significance. Results for specific cancers were limited and mainly negative.

  3. Dual Targeting Biomimetic Liposomes for Paclitaxel/DNA Combination Cancer Treatment

    PubMed Central

    Liu, Guo-Xia; Fang, Gui-Qing; Xu, Wei

    2014-01-01

    Combinations of chemotherapeutic drugs with nucleic acid has shown great promise in cancer therapy. In the present study, paclitaxel (PTX) and DNA were co-loaded in the hyaluronic acid (HA) and folate (FA)-modified liposomes (HA/FA/PPD), to obtain the dual targeting biomimetic nanovector. The prepared HA/FA/PPD exhibited nanosized structure and narrow size distributions (247.4 ± 4.2 nm) with appropriate negative charge of −25.40 ± 2.7 mV. HA/FA/PD (PTX free HA/FA/PPD) showed almost no toxicity on murine malignant melanoma cell line (B16) and human hepatocellular carcinoma cell line (HepG2) (higher than 80% cell viability), demonstrating the safety of the blank nanovector. In comparison with the FA-modified PTX/DNA co-loaded liposomes (FA/PPD), HA/FA/PPD showed significant superiority in protecting the nanoparticles from aggregation in the presence of plasma and degradation by DNase I. Moreover, HA/FA/PPD could also significantly improve the transfection efficiency and cellular internalization rates on B16 cells comparing to that of FA/PPD (p < 0.05) and PPD (p < 0.01), demonstrating the great advantages of dual targeting properties. Furthermore, fluorescence microscope and flow cytometry results showed that PTX and DNA could be effectively co-delivered into the same tumor cell via HA/FA/PPD, contributing to PTX/DNA combination cancer treatment. In conclusion, the obtained HA/FA/PPD in the study could effectively target tumor cells, enhance transfection efficiency and subsequently achieve the co-delivery of PTX and DNA, displaying great potential for optimal combination therapy. PMID:25177862

  4. Combined effect of microRNA, nutraceuticals and drug on pancreatic cancer cell lines.

    PubMed

    Pandita, Archana; Manvati, Siddharth; Singh, Shashank K; Vaishnavi, Samantha; Bamezai, Rameshwar N K

    2015-05-25

    We proposed to investigate the combination effect of microRNA, nutraceuticals and drug (MND), in two pancreatic cancer cell lines to assess the therapeutic potential. MIA PaCa-2 and PANC-1 cells transfected with miR-101 or miR-24-2 were treated with Betulinic acid or Thymoquinone and gemcitabine independently and in combination and assessed for the extent of synergism in both experimental and control conditions, considering significance at the p value of <0.05. miR-101 or miR-24-2 over-expressing cells when treated with lower than IC50 doses of the dietary compounds and drug showed a reduced (37-50%) viability in two cell lines with differential synergistic effect and the outcome for Pro-caspase3, Poly (ADP-ribose) polymerase (PARP) cleavage and PKM2 expression. Two independent microRNA backgrounds showed promise in therapeutic intervention of gemcitabine sensitive, MIA PaCa-2 and resistant, PANC-1 pancreatic cancer cells, in combination with dietary agents and drug. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  5. The protein kinase C (PKC) inhibitors combined with chemotherapy in the treatment of advanced non-small cell lung cancer: meta-analysis of randomized controlled trials.

    PubMed

    Zhang, L L; Cao, F F; Wang, Y; Meng, F L; Zhang, Y; Zhong, D S; Zhou, Q H

    2015-05-01

    The application of newer signaling pathway-targeted agents has become an important addition to chemotherapy in the treatment of advanced non-small cell lung cancer (NSCLC). In this study, we evaluated the efficacy and toxicities of PKC inhibitors combined with chemotherapy versus chemotherapy alone for patients with advanced NSCLC systematically. Literature retrieval, trials selection and assessment, data collection, and statistic analysis were performed according to the Cochrane Handbook 5.1.0. The outcome measures were tumor response rate, disease control rate, progression-free survival (PFS), overall survival (OS), and adverse effects. Five randomized controlled trials, comprising totally 1,005 patients, were included in this study. Meta-analysis showed significantly decreased response rate (RR 0.79; 95 % CI 0.64-0.99) and disease control rate (RR 0.90; 95 % CI 0.82-0.99) in PKC inhibitors-chemotherapy groups versus chemotherapy groups. There was no significant difference between the two treatment groups regarding progression-free survival (PFS, HR 1.05; 95 % CI 0.91-1.22) and overall survival (OS, HR 1.00; 95 % CI 0.86-1.16). The risk of grade 3/4 neutropenia, leucopenia, and thrombosis/embolism increased significantly in PKC inhibitors combination groups as compared with chemotherapy alone groups. The use of PKC inhibitors in addition to chemotherapy was not a valid alternative for patients with advanced NSCLC.

  6. A combination of circulating miRNAs for the early detection of ovarian cancer

    PubMed Central

    Yokoi, Akira; Yoshioka, Yusuke; Hirakawa, Akihiro; Yamamoto, Yusuke; Ishikawa, Mitsuya; Ikeda, Shun-ichi; Kato, Tomoyasu; Niimi, Kaoru; Kajiyama, Hiroaki; Kikkawa, Fumitaka; Ochiya, Takahiro

    2017-01-01

    Ovarian cancer is the leading cause of gynecologic cancer mortality, due to the difficulty of early detection. Current screening methods lack sufficient accuracy, and it is still challenging to propose a new early detection method that improves patient outcomes with less-invasiveness. Although many studies have suggested the utility of circulating microRNAs in cancer detection, their potential for early detection remains elusive. Here, we develop novel predictive models using a combination of 8 circulating serum miRNAs. This method was able to successfully distinguish ovarian cancer patients from healthy controls (area under the curve, 0.97; sensitivity, 0.92; and specificity, 0.91) and early-stage ovarian cancer from patients with benign tumors (0.91, 0.86 and 0.83, respectively). This method also enables subtype classification in 4 types of epithelial ovarian cancer. Furthermore, it is found that most of the 8 miRNAs were packaged in extracellular vesicles, including exosomes, derived from ovarian cancer cells, and they were circulating in murine blood stream. The circulating miRNAs described in this study may serve as biomarkers for ovarian cancer patients. Early detection and subtype determination prior to surgery are crucial for clinicians to design an effective treatment strategy for each patient, as is the goal of precision medicine. PMID:29163790

  7. The effect of icotinib combined with chemotherapy in untreated non-small-cell lung cancer that harbored EGFR-sensitive mutations in a real-life setting: a retrospective analysis.

    PubMed

    Wang, Lulu; Li, Yan; Li, Luchun; Wu, Zhijuan; Yang, Dan; Ma, Huiwen; Wang, Donglin

    2018-01-01

    This study was conducted to compare the efficacy of a combination of icotinib and chemotherapy with icotinib or chemotherapy alone in untreated non-small cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR)-sensitive mutations and to analyze the curative effect of different treatments on different genetic mutations (EGFR 19 exon deletion and L858R mutation) in a real-life setting. One hundred ninety-one patients were studied in this retrospective analysis from January 2013 to December 2015. The baseline characteristics, curative effects and adverse events of patients were analyzed. The primary endpoint was progression free survival (PFS). Longer PFS and overall survival (OS), and better objective response rate (ORR) were observed in the combination group compared to icotinib or chemotherapy along. For patients with an EGFR 19 exon deletion, the PFS, OS, and ORR in the combination group were superior to those in the icotinib or chemotherapy group. For the patients with the EGFR L858R mutation, better PFS and ORR were observed in the combination group, but OS was not obviously prolonged. Grade 3 or 4 adverse events were most commonly reported with combination therapy or chemotherapy alone. No possible drug-related interstitial lung disease or of drug related deaths occurred. The combination of icotinib and chemotherapy in patients with untreated NSCLC harboring sensitive EGFR mutations resulted in improved PFS and OS, especially in those who harbored the EGFR exon 19 deletion.

  8. The effect of icotinib combined with chemotherapy in untreated non-small-cell lung cancer that harbored EGFR-sensitive mutations in a real-life setting: a retrospective analysis

    PubMed Central

    Wang, Lulu; Li, Yan; Li, Luchun; Wu, Zhijuan; Yang, Dan; Ma, Huiwen; Wang, Donglin

    2018-01-01

    Purpose This study was conducted to compare the efficacy of a combination of icotinib and chemotherapy with icotinib or chemotherapy alone in untreated non-small cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR)-sensitive mutations and to analyze the curative effect of different treatments on different genetic mutations (EGFR 19 exon deletion and L858R mutation) in a real-life setting. Patients and methods One hundred ninety-one patients were studied in this retrospective analysis from January 2013 to December 2015. The baseline characteristics, curative effects and adverse events of patients were analyzed. The primary endpoint was progression free survival (PFS). Results Longer PFS and overall survival (OS), and better objective response rate (ORR) were observed in the combination group compared to icotinib or chemotherapy along. For patients with an EGFR 19 exon deletion, the PFS, OS, and ORR in the combination group were superior to those in the icotinib or chemotherapy group. For the patients with the EGFR L858R mutation, better PFS and ORR were observed in the combination group, but OS was not obviously prolonged. Grade 3 or 4 adverse events were most commonly reported with combination therapy or chemotherapy alone. No possible drug-related interstitial lung disease or of drug related deaths occurred. Conclusion The combination of icotinib and chemotherapy in patients with untreated NSCLC harboring sensitive EGFR mutations resulted in improved PFS and OS, especially in those who harbored the EGFR exon 19 deletion. PMID:29731642

  9. Receiver operating characteristic analysis of prediction for gastric cancer development using serum pepsinogen and Helicobacter pylori antibody tests.

    PubMed

    Hamashima, Chisato; Sasazuki, Shizuka; Inoue, Manami; Tsugane, Shoichiro

    2017-03-09

    Chronic Helicobacter pylori infection plays a central role in the development of gastric cancer as shown by biological and epidemiological studies. The H. pylori antibody and serum pepsinogen (PG) tests have been anticipated to predict gastric cancer development. We determined the predictive sensitivity and specificity of gastric cancer development using these tests. Receiver operating characteristic analysis was performed, and areas under the curve were estimated. The predictive sensitivity and specificity of gastric cancer development were compared among single tests and combined methods using serum pepsinogen and H. pylori antibody tests. From a large-scale population-based cohort of over 100,000 subjects followed between 1990 and 2004, 497 gastric cancer subjects and 497 matched healthy controls were chosen. The predictive sensitivity and specificity were low in all single tests and combination methods. The highest predictive sensitivity and specificity were obtained for the serum PG I/II ratio. The optimal PG I/II cut-off values were 2.5 and 3.0. At a PG I/II cut-off value of 3.0, the sensitivity was 86.9% and the specificity was 39.8%. Even if three biomarkers were combined, the sensitivity was 97.2% and the specificity was 21.1% when the cut-off values were 3.0 for PG I/II, 70 ng/mL for PG I, and 10.0 U/mL for H. pylori antibody. The predictive accuracy of gastric cancer development was low with the serum pepsinogen and H. pylori antibody tests even if these tests were combined. To adopt these biomarkers for gastric cancer screening, a high specificity is required. When these tests are adopted for gastric cancer screening, they should be carefully interpreted with a clear understanding of their limitations.

  10. Pancreatic cancer combination therapy using a BH3 mimetic and a synthetic tetracycline

    PubMed Central

    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.

    2015-01-01

    Improved treatments for pancreatic cancer remain a clinical imperative. Sabutoclax, a small molecule BH3 mimetic, inhibits the function of anti-apoptotic 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 that the combination of Sabutoclax and Minocycline was highly cytotoxic to pancreatic cancer cells and safely efficacious in vivo. PMID:26032425

  11. Synergistic combination of fluoro chalcone and doxorubicin on HeLa cervical cancer cells by inducing apoptosis

    NASA Astrophysics Data System (ADS)

    Arianingrum, Retno; Arty, Indyah Sulistyo; Atun, Sri

    2017-03-01

    Doxorubicin (Dox), a primary chemotherapeutic agent used for cancer treatment is known to have various side effect included multidrug resistance (MDR) phenomenon. Combination chemotherapy is one of some approaches to reduce Dox side effect. Chalcones have been reported to reduce the proliferation of many cancer cells. The research were conducted to investigate the cytotoxic activity and apoptosis induction of a chalcone derivate which is containing fluoro substituent [1 - (4" - fluorophenyl) -3 - (4' - hydroxy - 3' - methoxyphenyl) - 2 - propene - 1 -on] (FHM) and its combination with Dox on HeLa cells line. The observation of the cytotoxic activity was conducted using MTT [3 - (4, 5 - dimethyl thiazol - 2 - y1) - 2.5 - diphenyltetrazolium bromide] assay. Apoptosis induction was determined by flow cytometric. The changes of cell morphology were observed using phase contrast microscopy. The combination index (CI) was used to determine the effect of the combination. The study showed that FHM inhibited the HeLa cell growth with IC50 of 34 μM, while the IC50 of Dox was 1 μM. The combination had a higher inhibitory effect on cell growth compare to the single treatment of FHM and Dox. All of the combination doses under IC50 of FHM and Dox gave synergistic (CI: - 0.7) up to strong synergistic effect (CI: 0.l - 0.3). The synergistic effects of the combination were due to their ability to induce apoptosis in the HeLa cells. According to the result, FHM was potential to be developed as a co-chemotherapeutic agent with Dox for cervical cancer.

  12. Efficiency and prognosis of whole brain irradiation combined with precise radiotherapy on triple-negative breast cancer.

    PubMed

    Wu, Xinhong; Luo, Bo; Wei, Shaozhong; Luo, Yan; Feng, Yaojun; Xu, Juan; Wei, Wei

    2013-11-01

    To investigate the treatment efficiency of whole brain irradiation combined with precise radiotherapy on triple-negative (TN) phenotype breast cancer patients with brain metastases and their survival times. A total of 112 metastatic breast cancer patients treated with whole brain irradiation and intensity modulated radiotherapy (IMRT) or 3D conformal radiotherapy (3DCRT) were analyzed. Thirty-seven patients were of TN phenotype. Objective response rates were compared. Survival times were estimated by using the Kaplan-Meier method. Log-rank test was used to compare the survival time difference between the TN and non-TN groups. Potential prognostic factors were determined by using a Cox proportional hazard regression model. The efficiency of radiotherapy treatment on TN and non-TN phenotypes was 96.2% and 97%, respectively. TN phenotype was associated with worse survival times than non-TN phenotype after radiotherapy (6.9 months vs. 17 months) (P < 0.01). On multivariate analysis, good prognosis was associated with non-TN status, lower graded prognosis assessment class, and nonexistence of active extracranial metastases. After whole brain irradiation followed by IMRT or 3DCRT treatment, TN phenotype breast cancer patients with intracranial metastasis had high objective response rates but shorter survival time. With respect to survival in breast cancer patients with intracranial metastasis, the TN phenotype represents a significant adverse prognostic factor.

  13. Cost-Effectiveness Analysis of Second-Line Chemotherapy Agents for Advanced Gastric Cancer.

    PubMed

    Lam, Simon W; Wai, Maya; Lau, Jessica E; McNamara, Michael; Earl, Marc; Udeh, Belinda

    2017-01-01

    Gastric cancer is the fifth most common malignancy and second leading cause of cancer-related mortality. Chemotherapy options for patients who fail first-line treatment are limited. Thus the objective of this study was to assess the cost-effectiveness of second-line treatment options for patients with advanced or metastatic gastric cancer. Cost-effectiveness analysis using a Markov model to compare the cost-effectiveness of six possible second-line treatment options for patients with advanced gastric cancer who have failed previous chemotherapy: irinotecan, docetaxel, paclitaxel, ramucirumab, paclitaxel plus ramucirumab, and palliative care. The model was performed from a third-party payer's perspective to compare lifetime costs and health benefits associated with studied second-line therapies. Costs included only relevant direct medical costs. The model assumed chemotherapy cycle lengths of 30 days and a maximum number of 24 cycles. Systematic review of literature was performed to identify clinical data sources and utility and cost data. Quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) were calculated. The primary outcome measure for this analysis was the ICER between different therapies, where the incremental cost was divided by the number of QALYs saved. The ICER was compared with a willingness-to-pay (WTP) threshold that was set at $50,000/QALY gained, and an exploratory analysis using $160,000/QALY gained was also used. The model's robustness was tested by using 1-way sensitivity analyses and a 10,000 Monte Carlo simulation probabilistic sensitivity analysis (PSA). Irinotecan had the lowest lifetime cost and was associated with a QALY gain of 0.35 year. Docetaxel, ramucirumab alone, and palliative care were dominated strategies. Paclitaxel and the combination of paclitaxel plus ramucirumab led to higher QALYs gained, at an incremental cost of $86,815 and $1,056,125 per QALY gained, respectively. Based on our prespecified

  14. [Proteome analysis for identification of tumor-associated biomarkers in breast cancer].

    PubMed

    Wang, Xi; Liang, Wei-Jiang; Zhu, Zhen-Yu; Yang, Ming-Tian; Zeng, Yi-Xin

    2004-11-01

    Pre-symptomatic screening of early-stage breast cancer may greatly reduce tumor-related mortality. Some tumor markers, such as CA15-3 and CA27-29, are recommended only for monitoring therapy of advanced or relapsed breast cancer. This study was to find new biomarkers that could be used individually or in combination with an existing modality for cost-effective screening of breast cancer by proteome analysis. Protein expression differences among 128 serum samples of 64 breast cancer patients (19 of stage I, 24 of stage II, and 21 of stage III), 52 patients with benign breast diseases, and 12 healthy women were analyzed with IMAC3 and WCX2 Ciphergen ProteinChip Arrays. On WCX2 chip, a panel of 5 proteins (9 116, 8 905, 8 749, 9 470, and 9 692 Da) was selected based on their collective contribution to the optimal separation between breast cancer patients and both non-cancer patients and healthy women, and expression of another 2 proteins (9 405 and 6 424 Da) was different between patients with breast cancer of stage I and stage III. On IMAC3 chip, a panel of 9 proteins (5 236, 7 823, 7 464, 5 213, 5 334, 5 064, 5 374, 7 756, and 7 623 Da) was selected based on their collective contribution to the optimal separation between breast cancer patients and both non-cancer patients and healthy women, and expression of another 3 proteins (7 922, 4 641, and 5 910 Da) was different between patients with breast cancer of stage I and stage III. Protein expression in breast cancer patients is different from that in both non-cancer patients and healthy women, and those proteins with different expression may be used as new biomarkers in breast cancer.

  15. Combination of Osthole and Cisplatin Against Rhabdomyosarcoma TE671 Cells Yielded Additive Pharmacologic Interaction by Means of Isobolographic Analysis.

    PubMed

    Jarząb, Agata; Łuszczki, Jarogniew; Guz, Małgorzata; Skalicka-Woźniak, Krystyna; Hałasa, Marta; Smok-Kalwat, Jolanta; Polberg, Krzysztof; Stepulak, Andrzej

    2018-01-01

    Osthole is a simple coumarin that has been found to have anticancer, anti-inflammatory, antiviral, anticoagulant, anticonvulsant and antiallergic activities. The aim of this study was to analyze the combined anti-proliferative effect of cisplatin (CDDP) and osthole on a rhabdomyosarcoma cell line, and assess the pharmacology of drug-drug interaction between these drugs using isobolographic analysis. The anticancer actions of osthole in combination with CDDP were evaluated using the tetrazolium dye-based MTT cell proliferation assay. Osthole and CDDP applied together augmented their anti-cancer activities and yielded an additive type of pharmacologic interaction by means of isobolographic analysis. Combined therapy using osthole and cisplatin could be suggested as a potential chemotherapy regimen against rhabdomyosarcoma. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  16. Combined Modality Therapy Including Intraoperative Electron Irradiation for Locally Recurrent Colorectal Cancer

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Haddock, Michael G., E-mail: haddock.michael@mayo.ed; Miller, Robert C.; Nelson, Heidi

    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-yearmore » 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.« less

  17. Combined ginger extract & Gelam honey modulate Ras/ERK and PI3K/AKT pathway genes in colon cancer HT29 cells.

    PubMed

    Tahir, Analhuda Abdullah; Sani, Nur Fathiah Abdul; Murad, Noor Azian; Makpol, Suzana; Ngah, Wan Zurinah Wan; Yusof, Yasmin Anum Mohd

    2015-04-01

    The interconnected Ras/ERK and PI3K/AKT pathways play a central role in colorectal tumorigenesis, and they are targets for elucidating mechanisms involved in attempts to induce colon cancer cell death. Both ginger (Zingiber officinale) and honey have been shown to exhibit anti-tumor and anti-inflammation properties against many types of cancer, including colorectal cancer. However, there are currently no reports showing the combined effect of these two dietary compounds in cancer growth inhibition. The aim of this study was to evaluate the synergistic effect of crude ginger extract and Gelam honey in combination as potential cancer chemopreventive agents against the colorectal cancer cell line HT29. The cells were divided into 4 groups: the first group represents HT29 cells without treatment, the second and third groups were cells treated singly with either ginger or Gelam honey, respectively, and the last group represents cells treated with ginger and Gelam honey combined. The results of MTS assay showed that the IC50 of ginger and Gelam honey alone were 5.2 mg/ml and 80 mg/ml, respectively, whereas the IC50 of the combination treatment was 3 mg/ml of ginger plus 27 mg/ml of Gelam honey with a combination index of < 1, suggesting synergism. Cell death in response to the combined ginger and Gelam honey treatment was associated with the stimulation of early apoptosis (upregulation of caspase 9 and IκB genes) accompanied by downregulation of the KRAS, ERK, AKT, Bcl-xL, NFkB (p65) genes in a synergistic manner. In conclusion, the combination of ginger and Gelam honey may be an effective chemopreventive and therapeutic strategy for inducing the death of colon cancer cells.

  18. Oestrogen plus progestin and lung cancer in postmenopausal women (Women's Health Initiative trial): a post-hoc analysis of a randomised controlled trial.

    PubMed

    Chlebowski, Rowan T; Schwartz, Ann G; Wakelee, Heather; Anderson, Garnet L; Stefanick, Marcia L; Manson, JoAnn E; Rodabough, Rebecca J; Chien, Jason W; Wactawski-Wende, Jean; Gass, Margery; Kotchen, Jane Morley; Johnson, Karen C; O'Sullivan, Mary Jo; Ockene, Judith K; Chen, Chu; Hubbell, F Allan

    2009-10-10

    In the post-intervention period of the Women's Health Initiative (WHI) trial, women assigned to treatment with oestrogen plus progestin had a higher risk of cancer than did those assigned to placebo. Results also suggested that the combined hormone therapy might increase mortality from lung cancer. To assess whether such an association exists, we undertook a post-hoc analysis of lung cancers diagnosed in the trial over the entire follow-up period. The WHI study was a randomised, double-blind, placebo-controlled trial undertaken in 40 centres in the USA. 16 608 postmenopausal women aged 50-79 years with an intact uterus were randomly assigned by a computerised, stratified, permuted block algorithm to receive a once-daily tablet of 0.625 mg conjugated equine oestrogen plus 2.5 mg medroxyprogesterone acetate (n=8506) or matching placebo (n=8102). We assessed incidence and mortality rates for all lung cancer, small-cell lung cancer, and non-small-cell lung cancer by use of data from treatment and post-intervention follow-up periods. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00000611. After a mean of 5.6 years (SD 1.3) of treatment and 2.4 years (0.4) of additional follow-up, 109 women in the combined hormone therapy group had been diagnosed with lung cancer compared with 85 in the placebo group (incidence per year 0.16%vs 0.13%; hazard ratio [HR] 1.23, 95% CI 0.92-1.63, p=0.16). 96 women assigned to combined therapy had non-small-cell lung cancer compared with 72 assigned to placebo (0.14%vs 0.11%; HR 1.28, 0.94-1.73, p=0.12). More women died from lung cancer in the combined hormone therapy group than in the placebo group (73 vs 40 deaths; 0.11%vs 0.06%; HR 1.71, 1.16-2.52, p=0.01), mainly as a result of a higher number of deaths from non-small-cell lung cancer in the combined therapy group (62 vs 31 deaths; 0.09%vs 0.05%; HR 1.87, 1.22-2.88, p=0.004). Incidence and mortality rates of small-cell lung cancer were

  19. Long noncoding RNA MALAT1 as a potential novel biomarker in digestive system cancers: a meta-analysis.

    PubMed

    Song, Wei; Zhang, Run J; Zou, Shu B

    2016-08-01

    Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a newly discovered long non-coding RNA (lncRNA), has been reported to be overexpressed in various cancers. However, the clinical value of MALAT1 in digestive system cancers is unclear. This study was designed to investigate the potential value of MALAT1 as a prognostic biomarker in digestive system cancers. We searched the Medline, Embase and Cochrane Library databases. All studies that explored the correlation between lncRNA MALAT1 expression and survival in digestive system tumors were selected. A quantitative meta-analysis was performed for the correlation between lncRNA MALAT1 expression and survival in digestive system tumors. Five studies were eligible for analysis, which included 547 patients. Meta-analysis showed that high expression of MALAT1 could predict poor overall survival (OS) in digestive system cancers (pooled HR: 1.85, 95% CI: 1.41-2.43, P<0.0001). For disease-free survival (DFS), elevated MALAT1 expression was also a significant predictor with a combined HR of 2.28 (95% CI: 1.42-3.67, P=0.0007). lncRNA MALAT1 may serve as a potential novel prognostic biomarker in digestive system cancers.

  20. Long noncoding RNA MALAT1 as a potential novel biomarker in digestive system cancers: a meta-analysis.

    PubMed

    Song, Wei; Zhang, Run J; Zou, Shu B

    2016-05-17

    MALAT1 (Metastasis-associated lung adenocarcinoma transcript 1), a newly discovered long non-coding RNA (lncRNA), has been reported to be overexpressed in various cancers. However, the clinical value of MALAT1 in digestive system cancers is unclear. This study was designed to investigate the potential value of MALAT1 as a prognostic biomarker in digestive system cancers. We searched the MEDLINE, EMBASE and Cochrane Library databases. All studies that explored the correlation between lncRNA MALAT1 expression and survival in digestive system tumors were selected. A quantitative meta-analysis was performed for the correlation between lncRNA MALAT1 expression and survival in digestive system tumors. Five studies were eligible for analysis, which included 547 patients. Meta-analysis showed that high expression of MALAT1 could predict poor overall survival (OS) in digestive system cancers (pooled HR: 1.85, 95% CI: 1.41-2.43, p < 0.0001). For disease-free survival (DFS), elevated MALAT1 expression was also a significant predictor with a combined HR of 2.28 (95% CI: 1.42-3.67, p = 0.0007). lncRNA MALAT1 may serve as a potential novel prognostic biomarker in digestive system cancers.

  1. Analysis of a novel protocol of combined induction chemotherapy and concurrent chemoradiation in unresected non-small-cell lung cancer: a ten-year experience with vinblastine, Cisplatin, and radiation therapy.

    PubMed

    Waters, Eugenie; Dingle, Brian; Rodrigues, George; Vincent, Mark; Ash, Robert; Dar, Rashid; Inculet, Richard; Kocha, Walter; Malthaner, Richard; Sanatani, Michael; Stitt, Larry; Yaremko, Brian; Younus, Jawaid; Yu, Edward

    2010-07-01

    The London Regional Cancer Program (LRCP) uses a unique schedule of induction plus concurrent chemoradiation, termed VCRT (vinblastine, cisplatin, and radiation therapy), for the treatment of a subset of unresectable stage IIIA and IIIB non-small-cell lung cancer (NSCLC). This analysis was conducted to better understand the outcomes in VCRT-treated patients. We report a retrospective analysis of a large cohort of patients who underwent VCRT at the LRCP over a 10-year period, from 1996 to 2006. The analysis focused on OS, toxicities, and the outcomes from completion surgery in a small subset of patients. A total of 294 patients were included and 5-year OS, determined using Kaplan-Meier methodology, was 19.8% with a MST of 18.2 months. Reported grade 3-4 toxicities included neutropenia (39%), anemia (10%), pneumonitis (1%), and esophagitis (3%). Significant differences in survival between groups of patients were demonstrated with log-rank tests for completion surgery, use of radiation therapy, and cisplatin dose. Similarly, Univariate Cox regression showed that completion surgery, use of radiation therapy, cisplatin dose, and vinblastine dose were associated with increased survival. This retrospective analysis of a large cohort of patients reveals an OS for VCRT comparable to that reported in the literature for other current combined chemoradiation protocols. The success of this protocol seems to be dose dependent and the outcomes in those who underwent completion surgery suggests that pathologic complete remission is possible for IIIA and IIIB NSCLC.

  2. Meta-analysis of residential exposure to radon gas and lung cancer.

    PubMed Central

    Pavia, Maria; Bianco, Aida; Pileggi, Claudia; Angelillo, Italo F.

    2003-01-01

    OBJECTIVES: To investigate the relation between residential exposure to radon and lung cancer. METHODS: A literature search was performed using Medline and other sources. The quality of studies was assessed. Adjusted odds ratios with 95% confidence intervals (CI) for the risk of lung cancer among categories of levels of exposure to radon were extracted. For each study, a weighted log-linear regression analysis of the adjusted odds ratios was performed according to radon concentration. The random effect model was used to combine values from single studies. Separate meta-analyses were performed on results from studies grouped with similar characteristics or with quality scores above or equal to the median. FINDINGS: Seventeen case-control studies were included in the meta-analysis. Quality scoring for individual studies ranged from 0.45 to 0.77 (median, 0.64). Meta-analysis based on exposure at 150 Bq/m3 gave a pooled odds ratio estimate of 1.24 (95% CI, 1.11-1.38), which indicated a potential effect of residential exposure to radon on the risk of lung cancer. Pooled estimates of fitted odds ratios at several levels of randon exposure were all significantly different from unity--ranging from 1.07 at 50 Bq/m3 to 1.43 at 250 Bq/m3. No remarkable differences from the baseline analysis were found for odds ratios from sensitivity analyses of studies in which > 75% of eligible cases were recruited (1.12, 1.00-1.25) and studies that included only women (1.29, 1.04-1.60). CONCLUSION: Although no definitive conclusions may be drawn, our results suggest a dose-response relation between residential exposure to radon and the risk of lung cancer. They support the need to develop strategies to reduce human exposure to radon. PMID:14758433

  3. Gemcitabine-Based Combination Chemotherapy Followed by Radiation With Capecitabine as Adjuvant Therapy for Resected Pancreas Cancer

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Desai, Sameer; Ben-Josef, Edgar; Griffith, Kent A.

    2009-12-01

    Purpose: To report outcomes for patients with resected pancreas cancer treated with an adjuvant regimen consisting of gemcitabine-based combination chemotherapy followed by capecitabine and radiation. Patients and Methods: We performed a retrospective review of a series of patients treated at a single institution with a common postoperative adjuvant program. Between January 2002 and August 2006, 43 resected pancreas cancer patients were offered treatment consisting of 4, 21-day cycles of gemcitabine 1 g/m{sup 2} intravenously over 30 min on Days 1 and 8, with either cisplatin 35 mg/m{sup 2} intravenously on Days 1 and 8 or capecitabine 1500 mg/m{sup 2} orallymore » in divided doses on Days 1-14. After completion of combination chemotherapy, patients received a course of radiotherapy (54 Gy) with concurrent capecitabine (1330 mg/m{sup 2} orally in divided doses) day 1 to treatment completion. Results: Forty-one patients were treated. Median progression-free survival for the entire group was 21.7 months (95% confidence interval 13.9-34.5 months), and median overall survival was 45.9 months. In multivariate analysis a postoperative CA 19-9 level of >=180 U/mL predicted relapse and death. Toxicity was mild, with only two hospitalizations during adjuvant therapy. Conclusions: A postoperative adjuvant program using combination chemotherapy with gemcitabine and either cisplatin or capecitabine followed by radiotherapy with capecitabine is tolerable and efficacious and should be considered for Phase III testing in this group of patients.« less

  4. 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

  5. Multiple primary cancers of breast and cervix uteri: An epidemiological approach to analysis

    PubMed Central

    Prior, P.; Waterhouse, J. A. H.

    1981-01-01

    Index sites of breast and cervix uteri were selected from populationbased data held at the West Midlands and Birmingham Regional Cancer Registry, and the expected numbers of second primary cancers in cervix and breast were computed (sequence analyses). In the breast series (17,756 patients) a small deficit of cervical tumours was observed (O = 16, E = 2·119, O/E = 0·76, P > 0·05), while in the cervix series (4817 patients) a small excess of breast tumours was found (O = 29, E = 23·38, O/E = 1·24, P > 0·05) over a period of 15 years. A theoretical statement of the combined risk of the 2 tumours occurring in the same individual of a general population was developed and was compared with the practical approach of summing the sequence analyses (complementary analysis). Complementary analysis indicated that there was no excess of women with the 2 primary tumours (O = 45, E = 44·57, O/E = 1·01) and that cancers of the breast and cervix uteri are not aetiologically related. PMID:7248147

  6. Dose Constraint for Minimizing Grade 2 Rectal Bleeding Following Brachytherapy Combined With External Beam Radiotherapy for Localized Prostate Cancer: Rectal Dose-Volume Histogram Analysis of 457 Patients

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Shiraishi, Yutaka; Yorozu, Atsunori; Ohashi, Toshio, E-mail: ohashi@rad.med.keio.ac.jp

    2011-11-01

    Purpose: To determine the rectal tolerance to Grade 2 rectal bleeding after I-125 seed brachytherapy combined with external beam radiotherapy (EBRT), based on the rectal dose-volume histogram. Methods and Materials: A total of 458 consecutive patients with stages T1 to T3 prostate cancer received combined modality treatment consisting of I-125 seed implantation followed by EBRT to the prostate and seminal vesicles. The prescribed doses of brachytherapy and EBRT were 100 Gy and 45 Gy in 25 fractions, respectively. The rectal dosimetric factors were analyzed for rectal volumes receiving >100 Gy and >150 Gy (R100 and R150) during brachytherapy and formore » rectal volumes receiving >30 Gy to 40 Gy (V30-V40) during EBRT therapy in 373 patients for whom datasets were available. The patients were followed from 21 to 72 months (median, 45 months) after the I-125 seed implantation. Results: Forty-four patients (9.7%) developed Grade 2 rectal bleeding. On multivariate analysis, age (p = 0.014), R100 (p = 0.002), and V30 (p = 0.001) were identified as risk factors for Grade 2 rectal bleeding. The rectal bleeding rate increased as the R100 increased: 5.0% (2/40 patients) for 0 ml; 7.5% (20/267 patients) for >0 to 0.5 ml; 11.0% (11/100 patients) for >0.5 to 1 ml; 17.9% (5/28 patients) for >1 to 1.5 ml; and 27.3% (6/22 patients) for >1.5 ml (p = 0.014). Grade 2 rectal bleeding developed in 6.4% (12/188) of patients with a V30 {<=}35% and in 14.1% (26/185) of patients with a V30 >35% (p = 0.02). When these dose-volume parameters were considered in combination, the Grade 2 rectal bleeding rate was 4.2% (5/120 patients) for a R100 {<=}0.5 ml and a V30 {<=}35%, whereas it was 22.4% (13/58 patients) for R100 of >0.5 ml and V30 of >35%. Conclusion: The risk of rectal bleeding was found to be significantly volume-dependent in patients with prostate cancer who received combined modality treatment. Rectal dose-volume analysis is a practical method for predicting the risk of

  7. Re-irradiation using proton beam therapy combined with weekly intra-arterial chemotherapy for recurrent oral cancer.

    PubMed

    Hayashi, Yuichiro; Nakamura, Tatsuya; Mitsudo, Kenji; Kimura, Kanako; Yamaguchi, Hisashi; Ono, Takashi; Azami, Yusuke; Takayama, Kanako; Hirose, Katsumi; Yabuuchi, Tomonori; Suzuki, Motohisa; Hatayama, Yoshiomi; Kikuchi, Yasuhiro; Wada, Hitoshi; Fuwa, Nobukazu; Hareyama, Masato; Tohnai, Iwai

    2017-10-01

    The purpose of this study was to clarify the efficacy and toxicities of re-irradiation using proton beam therapy combined with weekly intra-arterial chemotherapy for recurrent oral cancer. Between October 2009 and July 2014, 34 patients who had recurrent oral cancer were treated by proton beam therapy combined with intra-arterial infusion chemotherapy at the Southern Tohoku Proton Therapy Center, Japan. For all patients, the median follow-up was 25 months (range, 3-77 months). After treatment, 22 patients (65%) achieved a complete response, and 12 patients (35%) achieved a partial response at the primary tumor site. One-year and 2-year overall survival (OS) rates were 62% and 42%, respectively. One-year and 2-year LC rates were 77% and 60%, respectively. No treatment-related deaths were observed during the treatment and follow-up periods. Re-irradiation using proton beam therapy combined with weekly intra-arterial chemotherapy improved OS and local control rates compared with other treatment modalities and could become a new treatment modality for patients with recurrent oral cancer. © 2016 John Wiley & Sons Australia, Ltd.

  8. p-Akt as a potential poor prognostic factor for gastric cancer: a systematic review and meta-analysis.

    PubMed

    Cao, Fang; Zhang, Cong; Han, Wei; Gao, Xiao-Jiao; Ma, Jun; Hu, Yong-Wei; Gu, Xing; Ding, Hou-Zhong; Zhu, Li-Xia; Liu, Qin

    2017-08-29

    To understand the relationship between p-Akt expression and the prognosis of patients with gastric cancer, we searched six databases, Pubmed, EMBASE, Cochrane Library, CNKI, Wanfang and CBM for relevant articles in order to conduct this metaanalysis. The pooled hazard ratios and corresponding 95%CI of overall survival were calculated to evaluate the prognostic value of p-Akt expression in patients with gastric cancer. With 2261 patients combined from 13 available studies, the pooled HR showed a poor prognosis in patients with gastric cancer in the univariate analysis (HR=1.88, 95%CI:1.45-2.43, P<0.00001), and the group "univariate analysis+estimate" (HR=1.41, 95%CI: 1.01-1.97, P=0.04), but not in multivariate analysis (HR=0.66, 95%CI: 0.29-1.52, P=0.33) and estimate (HR=1.13, 95%CI: 0.65-1.95, P=0.67). In conclusion, our results indicated that p-Akt was likely to be an indicator of poor prognosis in patients with gastric cancer.

  9. Cellular Effect of Curcumin and Citral Combination on Breast Cancer Cells: Induction of Apoptosis and Cell Cycle Arrest.

    PubMed

    Patel, Pinaki B; Thakkar, Vasudev R; Patel, Jagdish S

    2015-09-01

    The unmanageable side effects caused by current chemotherapy regimens to treat cancer are an unresolved problem. Although many phytonutrients are useful as chemoprevention without side effects, their effects are slower and smaller than conventional chemotherapy. In the present work, we examined the cumulative effect of two phytonutrients, curcumin and citral, on breast cancer cell lines and compared their effect with the known chemotherapy regimen of cyclophosphamide, methotrexate, and 5-fluorouracil. Using cultured breast cancer and normal epithelial cells, the cytotoxic and apoptotic effect of curcumin and citral was evaluated in vitro. The synergistic effect of curcumin and citral was calculated by a combination index study using the method by Chou and Talalay. Cell death pathways and mechanisms were analyzed by measuring intracellular reactive oxygen species (ROS) and apoptotic protein levels. Curcumin and citral caused dose and time dependent cell death and showed a synergistic effect at effective concentration EC50 and above concentrations in breast cancer cells without disturbing normal breast epithelial cells. With combination curcumin and citral treatment, apoptosis induction and cell cycle arrest at G0/G1 phase in breast cancer cells were observed. Curcumin and citral generated ROS and activated p53 and poly (ADP-ribose) polymerase-1 mediated apoptotic pathways. The results of this study suggest that curcumin and citral in combination may be a useful therapeutic intervention for breast cancer.

  10. Effect of histone deacetylase inhibitor in combination with 5-fluorouracil on pancreas cancer and cholangiocarcinoma cell lines.

    PubMed

    Iwahashi, Shuichi; Ishibashi, Hiroki; Utsunomiya, Tohru; Morine, Yuji; Ochir, Tovuu Lkhaguva; Hanaoka, Jun; Mori, Hiroki; Ikemoto, Tetsuya; Imura, Satoru; Shimada, Mitsuo

    2011-02-01

    Histone deacetylase (HDAC) is well known to be associated with tumorigenesis through epigenetic regulation, and its inhibitors (HDACIs) induce differentiation and apoptosis of tumor cells. We examined the therapeutic effects of valproic acid (VPA, a HDACI) with a combination of 5-fluorouracil (5-FU) in vitro. A human pancreas cancer cell line (SUIT-2) and a cholangiocarcinoma cell line (HuCCT1) were used. Cell viabilities were evaluated by a cell proliferation assay. We determined the anticancer effects of VPA combined with 5-FU in these cell lines. Pancreas cancer (SUIT-2): No effect of 5-FU (1.0 µM) was observed, but 17% and 30% of proliferation-inhibitory effects were recognized in a dose of 2.5 or 5.0 µM, respectively. Cell viability was only weakly reduced by VPA (0.5 mM). However, in combination of 5-FU (1.0 µM) with VPA (0.5 mM), 19% of inhibitory effect was observed. Cholangiocarcinoma (HuCCT1): 5-FU (1.0 µM) did not suppress the cell viability, but 5-FU (2.5 µM) suppressed by 23%. VPA (0.5 mM) did not suppress the cell viability, while VPA (1.0 mM) weakly decreased it by 11%. Combination of 5-FU (1.0 µM) and VPA (0.5 mM) markedly reduced the cell viability by 30%. VPA augmented the anti-tumor effects of 5-FU in cancer cell lines. Therefore, a combination therapy of 5-FU plus VPA may be a promising therapeutic option for patients with pancreas cancer and cholangiocarcinoma.

  11. Primary treatments for clinically localized prostate cancer: a comprehensive lifetime cost-utility analysis

    PubMed Central

    Cooperberg, Matthew R.; Ramakrishna, Naren R.; Duff, Steven B.; Hughes, Kathleen E.; Sadownik, Sara; Smith, Joseph A.; Tewari, Ashutosh K.

    2012-01-01

    Objectives To characterize the costs and outcomes associated with radical prostatectomy (open, laparoscopic, or robot-assisted) and radiation therapy (dose-escalated 3-dimensional conformal radiation, intensity-modulated radiation, brachytherapy, or combination), using a comprehensive, lifetime decision analytic model. Patients and Methods A Markov model was constructed to follow hypothetical men with low-, intermediate-, and high-risk prostate cancer over their lifetimes following primary treatment; probabilities of outcomes were based on an exhaustive literature search yielding 232 unique publications. Patients could experience remission, recurrence, salvage treatment, metastasis, death from prostate cancer, and death from other causes. Utilities for each health state were determined, and disutilities were applied for complications and toxicities of treatment. Costs were determined from the U.S. payer perspective, with incorporation of patient costs in a sensitivity analysis. Results Differences in quality-adjusted life years across modalities were modest, ranging from 10.3 to 11.3 for low-risk patients, 9.6 to 10.5 for intermediate-risk patients, and 7.8 to 9.3 for high-risk patients. There were no statistically significant differences among surgical modalities, which tended to be more effective than radiation modalities, with the exception of combination external beam + brachytherapy for high-risk disease. Radiation modalities were consistently more expensive than surgical modalities; costs ranged from $19,901 (robot-assisted prostatectomy for low-risk disease) to $50,276 (combination radiation for high-risk disease). These findings were robust to an extensive set of sensitivity analyses. Conclusions Our analysis found small differences in outcomes and substantial differences in payer and patient costs across treatment alternatives. These findings may inform future policy discussions regarding strategies to improve efficiency of treatment selection for

  12. Pretreatment Endorectal Coil Magnetic Resonance Imaging Findings Predict Biochemical Tumor Control in Prostate Cancer Patients Treated With Combination Brachytherapy and External-Beam Radiotherapy

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Riaz, Nadeem; Afaq, Asim; Akin, Oguz

    Purpose: To investigate the utility of endorectal coil magenetic resonance imaging (eMRI) in predicting biochemical relapse in prostate cancer patients treated with combination brachytherapy and external-beam radiotherapy. Methods and Materials: Between 2000 and 2008, 279 men with intermediate- or high-risk prostate cancer underwent eMRI of their prostate before receiving brachytherapy and supplemental intensity-modulated radiotherapy. Endorectal coil MRI was performed before treatment and retrospectively reviewed by two radiologists experienced in genitourinary MRI. Image-based variables, including tumor diameter, location, number of sextants involved, and the presence of extracapsular extension (ECE), were incorporated with other established clinical variables to predict biochemical control outcomes.more » The median follow-up was 49 months (range, 1-13 years). Results: The 5-year biochemical relapse-free survival for the cohort was 92%. Clinical findings predicting recurrence on univariate analysis included Gleason score (hazard ratio [HR] 3.6, p = 0.001), PSA (HR 1.04, p = 0.005), and National Comprehensive Cancer Network risk group (HR 4.1, p = 0.002). Clinical T stage and the use of androgen deprivation therapy were not correlated with biochemical failure. Imaging findings on univariate analysis associated with relapse included ECE on MRI (HR 3.79, p = 0.003), tumor size (HR 2.58, p = 0.04), and T stage (HR 1.71, p = 0.004). On multivariate analysis incorporating both clinical and imaging findings, only ECE on MRI and Gleason score were independent predictors of recurrence. Conclusions: Pretreatment eMRI findings predict for biochemical recurrence in intermediate- and high-risk prostate cancer patients treated with combination brachytherapy and external-beam radiotherapy. Gleason score and the presence of ECE on MRI were the only significant predictors of biochemical relapse in this group of patients.« less

  13. The antitumor effect of GDC-0941 alone and in combination with rapamycin in breast cancer cells.

    PubMed

    Zheng, Jie; Zou, Xianjin; Yao, Jia

    2012-01-01

    The phosphatidylinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is a key potential target in breast cancer therapy. Because some cancer cell lines are resistant to mTOR inhibition, we combined the mTOR inhibitor with the PI3K inhibitor and assayed the inhibitory effect of this combination versus that of a single inhibitor. The proliferation of MCF7, SK-BR-3, T-47D, and MDA-MB-231 cells was measured by MTT assay in the presence of GDC-0941 and/or rapamycin. Afterwards, we determined the visible changes in signaling in the PI3K/AKT/mTOR pathway by Western blotting. GDC-0941 exhibited excellent inhibition on MCF7, T-47D and SK-BR-3 cells with different characteristics. In addition, GDC-0941 blocked the feedback of PI3K/Akt through S6K1, resulting in decreased Akt activity by rapamycin activation. The combination of GDC-0941 and rapamycin downregulated the key components of the cell cycle machinery, such as cyclin D1 and upregulated the apoptotic markers. Our findings suggest that GDC-0941, either alone or in combination with rapamycin, may serve as a new, promising approach for breast cancer treatment. Copyright © 2012 S. Karger AG, Basel.

  14. Alzheimer disease and cancer risk: a meta-analysis.

    PubMed

    Shi, Hai-bin; Tang, Bo; Liu, Yao-Wen; Wang, Xue-Feng; Chen, Guo-Jun

    2015-03-01

    Alzheimer disease (AD) and cancer are seemingly two opposite ends of one spectrum. Studies have suggested that patients with AD showed a reduced risk of cancer and vice versa. However, available evidences are not conclusive. So we conducted a meta-analysis using published literatures to systematically examine cancer risk in AD patients. A PubMed, EMBASE, and Web of Science search were conducted in May 2014. Pooled risk ratios (RRs) with their corresponding 95 % confidence intervals (CIs) were obtained using random-effects meta-analysis. We tested for publication bias and heterogeneity, and stratified for study characteristics, smoking-related cancers versus nonsmoking-related cancers, and site-specific cancers. Nine studies were included in this meta-analysis. Compared with controls, the pooled RR of cancer in AD patients was 0.55 (95 % CI 0.41-0.75), with significant heterogeneity among these studies (P < 0.001, I(2) = 83.5 %). The reduced cancer risk was more substantial when we restricted analyses to cohort studies, studies with adjusted estimates, studies defining AD by generally accepted criteria, and studies with longer length of follow-up. In sub-analyses for site-specific cancers, only lung cancer showed significant decreased risk (RR 0.72; 95 % CI 0.56-0.91). We did not find significant publication bias (P = 0.251 for Begg and Mazumdar's test and P = 0.143 for Egger's regression asymmetry test). These results support an association between AD and decreased cancer risk.

  15. Integrative prescreening in analysis of multiple cancer genomic studies

    PubMed Central

    2012-01-01

    Background In high throughput cancer genomic studies, results from the analysis of single datasets often suffer from a lack of reproducibility because of small sample sizes. Integrative analysis can effectively pool and analyze multiple datasets and provides a cost effective way to improve reproducibility. In integrative analysis, simultaneously analyzing all genes profiled may incur high computational cost. A computationally affordable remedy is prescreening, which fits marginal models, can be conducted in a parallel manner, and has low computational cost. Results An integrative prescreening approach is developed for the analysis of multiple cancer genomic datasets. Simulation shows that the proposed integrative prescreening has better performance than alternatives, particularly including prescreening with individual datasets, an intensity approach and meta-analysis. We also analyze multiple microarray gene profiling studies on liver and pancreatic cancers using the proposed approach. Conclusions The proposed integrative prescreening provides an effective way to reduce the dimensionality in cancer genomic studies. It can be coupled with existing analysis methods to identify cancer markers. PMID:22799431

  16. A phase Ib study of everolimus combined with metformin for patients with advanced cancer.

    PubMed

    Molenaar, Remco J; van de Venne, Tim; Weterman, Mariëtte J; Mathot, Ron A; Klümpen, Heinz-Josef; Richel, Dick J; Wilmink, Johanna W

    2018-02-01

    Background The efficacy to monotherapy with the mTOR inhibitor everolimus in advanced cancer is often limited due to therapy resistance. Combining everolimus with metformin may decrease the chance of therapy resistance. Methods Patients received everolimus and metformin in a 3 + 3 dose-escalation scheme. Objectives were to determine the dose-limiting toxicities (DLTs), maximum tolerated dose, toxic effects, pharmacokinetics and anti-tumour efficacy. Results 9 patients received study treatment for a median duration of 48 days (range: 4-78). 6 patients discontinued due to toxicity and 3 patients because of progressive disease. At the starting dose level of 10 mg everolimus qd and 500 mg metformin bid, 3 out of 5 patients experienced a DLT. After de-escalation to 5 mg everolimus qd and 500 mg metformin bid, considerable toxicity was still observed and patient enrollment was terminated. In pharmacokinetic analyses, metformin was eliminated slower when co-administered with everolimus than as single-agent. After 9 weeks of treatment, 3 patients were still on study and all had stable disease. Conclusion The combination of everolimus and metformin is poorly tolerated in patients with advanced cancer. The pharmacokinetic interaction between everolimus and metformin may have implications for diabetic cancer patients that are treated with these drugs. Our results advocate for future clinical trials with combinations of other mTOR inhibitors and biguanides.

  17. Effect of Combined Folic Acid, Vitamin B6, and Vitamin B12 on Cancer Risk: Results from a Randomized Trial

    PubMed Central

    Zhang, Shumin M.; Cook, Nancy R.; Albert, Christine M.; Gaziano, J. Michael; Buring, Julie E.; Manson, JoAnn E.

    2008-01-01

    Context Folate, vitamin B6, and vitamin B12 are thought to play an important role in cancer prevention. Objective To evaluate the effect of combined folic acid, vitamin B6, and vitamin B12 treatment on cancer risk in women at high risk for cardiovascular disease. Design, Setting, and Participants In the Women’s Antioxidant and Folic Acid Cardiovascular Study, 5442 US female health professionals aged 42 years or older with preexisting cardiovascular disease or 3 or more coronary risk factors were randomly assigned to receive either a daily combination of folic acid, vitamin B6, and vitamin B12 or placebo in April 1998, and treated through July 31, 2005 for 7.3 years. Intervention Daily supplementation of a combination of 2.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of vitamin B12 (n=2721) or placebo (n=2721). Main Outcome Measures Confirmed newly diagnosed total invasive cancer. Results A total of 379 women developed invasive cancer (187 in the active group and 192 in the placebo group). Compared with placebo, women receiving combined folic acid, vitamin B6, and vitamin B12 had similar risk of developing total invasive cancer (101.1/10000 person-years vs 104.3/10000 person-years for the active vs placebo group; hazard ratio, 0.97; 95% confidence interval, 0.79–1.18; P=.75), breast cancer (37.8/10000 person-years vs 45.6/10000 person-years; hazard ratio, 0.83; 95% confidence interval, 0.60–1.14; P=.24), and any cancer death (24.6/10000 person-years vs 30.1/10000 person-years; hazard ratio, 0.82; 95% confidence interval, 0.56–1.21; P=.32). Conclusions Combined folic acid, vitamin B6, and vitamin B12 treatment had no significant effect on overall risk of total invasive cancer or breast cancer among women during folic acid fortification era. Trial Registration clinicaltrials.gov Identifier: NCT00000541 PMID:18984888

  18. The Combination of Laser Therapy and Metal Nanoparticles in Cancer Treatment Originated From Epithelial Tissues: A Literature Review

    PubMed Central

    Fekrazad, Reza; Naghdi, Nafiseh; Nokhbatolfoghahaei, Hanieh; Bagheri, Hossein

    2016-01-01

    Several methods have been employed for cancer treatment including surgery, chemotherapy and radiation therapy. Today, recent advances in medical science and development of new technologies, have led to the introduction of new methods such as hormone therapy, Photodynamic therapy (PDT), treatments using nanoparticles and eventually combinations of lasers and nanoparticles. The unique features of LASERs such as photo-thermal properties and the particular characteristics of nanoparticles, given their extremely small size, may provide an interesting combined therapeutic effect. The purpose of this study was to review the simultaneous application of lasers and metal nanoparticles for the treatment of cancers with epithelial origin. A comprehensive search in electronic sources including PubMed, Google Scholar and Science Direct was carried out between 2000 and 2013. Among the initial 400 articles, 250 articles applied nanoparticles and lasers in combination, in which more than 50 articles covered the treatment of cancer with epithelial origin. In the future, the combination of laser and nanoparticles may be used as a new or an alternative method for cancer therapy or diagnosis. Obviously, to exclude the effect of laser’s wavelength and nanoparticle’s properties more animal studies and clinical trials are required as a lack of perfect studies PMID:27330701

  19. Anti-metastatic and pro-apoptotic effects elicited by combination photodynamic therapy with sonodynamic therapy on breast cancer both in vitro and in vivo.

    PubMed

    Wang, Pan; Li, Caifeng; Wang, Xiaobing; Xiong, Wenli; Feng, Xiaolan; Liu, Quanhong; Leung, Albert Wingnang; Xu, Chuanshan

    2015-03-01

    Sono-Photodynamic therapy (SPDT), a new modality for cancer treatment, is aimed at enhancing anticancer effects by the combination of sonodynamic therapy (SDT) and photodynamic therapy (PDT). In this study, we investigated the antitumor effect and possible mechanisms of Chlorin e6 (Ce6) mediated SPDT (Ce6-SPDT) on breast cancer both in vitro and in vivo. MTT assay revealed that the combined therapy markedly enhanced cell viability loss of breast cancer cell lines (MDA-MB-231, MCF-7 and 4T1) compared with SDT and PDT alone. Propidium iodide/hoechst33342 double staining reflected that 4T1 cells with apoptotic morphological characteristics were significantly increased in groups given combined therapy. Besides, the combined therapy caused obvious mitochondrial membrane potential (MMP) loss at early 1 h post SPDT treatment. The generation of intracellular reactive oxygen species (ROS) detected by flow cytometry was greatly increased in 4T1 cells treated with the combination therapy, and the loss of cell viability and MMP could be effectively rescued by pre-treatment with the ROS scavenger N-acetylcysteine (NAC). Further, Ce6-SPDT markedly inhibited the tumor growth (volume and weight) and lung metastasis in 4T1 tumor-bearing mice, but had no effect on the body weight. Hematoxylin and eosin staining revealed obvious tissue destruction with large spaces in the Ce6-SPDT groups, and TUNEL staining indicated tumor cell apoptosis after treatment. Immunohistochemistry analysis showed that the expression level of VEGF and MMP were significantly decreased in the combined groups. These results indicated that Ce6-mediated SPDT enhanced the antitumor efficacy on 4T1 cells compared with SDT and PDT alone, loss of MMP and generation of ROS might be involved. In addition, Ce6-mediated SPDT significantly inhibited tumor growth and metastasis in mouse breast cancer 4T1 xenograft model, in which MMP-9 and VEGF may play a crucial role.

  20. Progressive Muscle Relaxation Combined with Chinese Medicine Five-Element Music on Depression for Cancer Patients: A Randomized Controlled Trial.

    PubMed

    Liao, Juan; Wu, Yu; Zhao, Yang; Zhao, Yuan-Chen; Zhang, Xu; Zhao, Nan; Lee, Chun-Ging; Yang, Yu-Fei

    2018-05-01

    To evaluate the effects of progressive muscle relaxation training (PMRT) combined with fifive elements music therapy of Chinese medicine (CM) for improving anxiety and depression of cancer patients. From June 2015 to March 2016, 60 cancer patients were included into the study. The patients were randomly assigned to a control group and a treatment group by envelope randomization, receiving PMRT and PMRT plus CM five elements music therapy, respectively, for 8 weeks. Hospital Anxiety and Depression Scale (HADS), Benefit Finding Scales (BFS), Functional Assessment of Chronic Illness Therapy-Spiritual (FACIT-Sp), and Intervention Expectations Questionnaire (IEQU) were adopted to assess the depression of the two groups before and after the treatment. Four cases dropped out during the study, and 29 cases in the treatment group and 27 in the control group were included in the fifinal analysis. Prior to the treatments, the baselines of the 4 questionnaires in the two groups showed no difference. After the 8-week treatment, the treatment group presented better levels of HADS, BFS and FACIT-Sp scores compared with the control group (P<0.05). Among the single items of HADS, 4 items involving vexation, feeling fifidgeted, pleasure and prospecting the future in the treatment group were improved compared with the control group (P<0.05). As a simple and reliable and effective intervention, PMRT combined with fifive elements music therapy mitigated anxiety and depression of cancer patients. Cancer patients have been found to respond well to psychological intervention in areas regarding stabilisation of emotions, disease awareness, and therapeutic compliance. This brings about a great difference in improving their quality of life and psychological state, offers an effective approach to better self-management in cancer treatment.

  1. Gold Nanostructures as a Platform for Combinational Therapy in Future Cancer Therapeutics

    PubMed Central

    Jelveh, Salomeh; Chithrani, Devika B.

    2011-01-01

    The field of nanotechnology is currently undergoing explosive development on many fronts. The technology is expected to generate innovations and play a critical role in cancer therapeutics. Among other nanoparticle (NP) systems, there has been tremendous progress made in the use of spherical gold NPs (GNPs), gold nanorods (GNRs), gold nanoshells (GNSs) and gold nanocages (GNCs) in cancer therapeutics. In treating cancer, radiation therapy and chemotherapy remain the most widely used treatment options and recent developments in cancer research show that the incorporation of gold nanostructures into these protocols has enhanced tumor cell killing. These nanostructures further provide strategies for better loading, targeting, and controlling the release of drugs to minimize the side effects of highly toxic anticancer drugs used in chemotherapy and photodynamic therapy. In addition, the heat generation capability of gold nanostructures upon exposure to UV or near infrared light is being used to damage tumor cells locally in photothermal therapy. Hence, gold nanostructures provide a versatile platform to integrate many therapeutic options leading to effective combinational therapy in the fight against cancer. In this review article, the recent progress in the development of gold-based NPs towards improved therapeutics will be discussed. A multifunctional platform based on gold nanostructures with targeting ligands, therapeutic molecules, and imaging contrast agents, holds an array of promising directions for cancer research. PMID:24212654

  2. Cervical cancer and the global health agenda: Insights from multiple policy-analysis frameworks

    PubMed Central

    Parkhurst, Justin O.; Vulimiri, Madhulika

    2013-01-01

    Cervical cancer is the second leading cause of cancer deaths for women globally, with an estimated 88% of deaths occurring in the developing world. Available technologies have dramatically reduced mortality in high-income settings, yet cervical cancer receives considerably little attention on the global health policy landscape. The authors applied four policy-analysis frameworks to literature on global cervical cancer to explore the question of why cervical cancer may not be receiving the international attention it may otherwise warrant. Each framework explores the process of agenda setting and discerns factors that either facilitate or hinder policy change in cases where there is both a clear problem and a potential effective solution. In combination, these frameworks highlight a number of crucial elements that may be needed to raise the profile of cervical cancer on global health agendas, including improving local (national or sub-national) information on the condition; increasing mobilisation of affected civil society groups; framing cervical cancer debates in ways that build upon its classification as a non-communicable disease (NCD) and an issue of women's rights; linking cervical cancer screening to well-funded services such as those for HIV treatment in some countries; and identifying key global policy windows of opportunity to promote the cervical cancer agenda, including emerging NCD global health discussions and post-2015 reviews of the Millennium Development Goals. PMID:24236409

  3. Cervical cancer and the global health agenda: Insights from multiple policy-analysis frameworks.

    PubMed

    Parkhurst, Justin O; Vulimiri, Madhulika

    2013-01-01

    Cervical cancer is the second leading cause of cancer deaths for women globally, with an estimated 88% of deaths occurring in the developing world. Available technologies have dramatically reduced mortality in high-income settings, yet cervical cancer receives considerably little attention on the global health policy landscape. The authors applied four policy-analysis frameworks to literature on global cervical cancer to explore the question of why cervical cancer may not be receiving the international attention it may otherwise warrant. Each framework explores the process of agenda setting and discerns factors that either facilitate or hinder policy change in cases where there is both a clear problem and a potential effective solution. In combination, these frameworks highlight a number of crucial elements that may be needed to raise the profile of cervical cancer on global health agendas, including improving local (national or sub-national) information on the condition; increasing mobilisation of affected civil society groups; framing cervical cancer debates in ways that build upon its classification as a non-communicable disease (NCD) and an issue of women's rights; linking cervical cancer screening to well-funded services such as those for HIV treatment in some countries; and identifying key global policy windows of opportunity to promote the cervical cancer agenda, including emerging NCD global health discussions and post-2015 reviews of the Millennium Development Goals.

  4. Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.

    PubMed

    McKay, James D; Hung, Rayjean J; Han, Younghun; Zong, Xuchen; Carreras-Torres, Robert; Christiani, David C; Caporaso, Neil E; Johansson, Mattias; Xiao, Xiangjun; Li, Yafang; Byun, Jinyoung; Dunning, Alison; Pooley, Karen A; Qian, David C; Ji, Xuemei; Liu, Geoffrey; Timofeeva, Maria N; Bojesen, Stig E; Wu, Xifeng; Le Marchand, Loic; Albanes, Demetrios; Bickeböller, Heike; Aldrich, Melinda C; Bush, William S; Tardon, Adonina; Rennert, Gad; Teare, M Dawn; Field, John K; Kiemeney, Lambertus A; Lazarus, Philip; Haugen, Aage; Lam, Stephen; Schabath, Matthew B; Andrew, Angeline S; Shen, Hongbing; Hong, Yun-Chul; Yuan, Jian-Min; Bertazzi, Pier Alberto; Pesatori, Angela C; Ye, Yuanqing; Diao, Nancy; Su, Li; Zhang, Ruyang; Brhane, Yonathan; Leighl, Natasha; Johansen, Jakob S; Mellemgaard, Anders; Saliba, Walid; Haiman, Christopher A; Wilkens, Lynne R; Fernandez-Somoano, Ana; Fernandez-Tardon, Guillermo; van der Heijden, Henricus F M; Kim, Jin Hee; Dai, Juncheng; Hu, Zhibin; Davies, Michael P A; Marcus, Michael W; Brunnström, Hans; Manjer, Jonas; Melander, Olle; Muller, David C; Overvad, Kim; Trichopoulou, Antonia; Tumino, Rosario; Doherty, Jennifer A; Barnett, Matt P; Chen, Chu; Goodman, Gary E; Cox, Angela; Taylor, Fiona; Woll, Penella; Brüske, Irene; Wichmann, H-Erich; Manz, Judith; Muley, Thomas R; Risch, Angela; Rosenberger, Albert; Grankvist, Kjell; Johansson, Mikael; Shepherd, Frances A; Tsao, Ming-Sound; Arnold, Susanne M; Haura, Eric B; Bolca, Ciprian; Holcatova, Ivana; Janout, Vladimir; Kontic, Milica; Lissowska, Jolanta; Mukeria, Anush; Ognjanovic, Simona; Orlowski, Tadeusz M; Scelo, Ghislaine; Swiatkowska, Beata; Zaridze, David; Bakke, Per; Skaug, Vidar; Zienolddiny, Shanbeh; Duell, Eric J; Butler, Lesley M; Koh, Woon-Puay; Gao, Yu-Tang; Houlston, Richard S; McLaughlin, John; Stevens, Victoria L; Joubert, Philippe; Lamontagne, Maxime; Nickle, David C; Obeidat, Ma'en; Timens, Wim; Zhu, Bin; Song, Lei; Kachuri, Linda; Artigas, María Soler; Tobin, Martin D; Wain, Louise V; Rafnar, Thorunn; Thorgeirsson, Thorgeir E; Reginsson, Gunnar W; Stefansson, Kari; Hancock, Dana B; Bierut, Laura J; Spitz, Margaret R; Gaddis, Nathan C; Lutz, Sharon M; Gu, Fangyi; Johnson, Eric O; Kamal, Ahsan; Pikielny, Claudio; Zhu, Dakai; Lindströem, Sara; Jiang, Xia; Tyndale, Rachel F; Chenevix-Trench, Georgia; Beesley, Jonathan; Bossé, Yohan; Chanock, Stephen; Brennan, Paul; Landi, Maria Teresa; Amos, Christopher I

    2017-07-01

    Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genome-wide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.

  5. [A Case Report of Disappearance of Gastric Metastasis of Breast Cancer Treated with Combination Therapy Consisting of Paclitaxel and Cisplatin].

    PubMed

    Nakajima, Tooru; Taniwaka, Koichi; Goto, Hideki; Kawamura, Shunji

    2017-04-01

    A 63-year-old postmenopausal woman was treated with combination therapy consisting of paclitaxel(PTX)and cisplatin (CDDP)for gastric metastasis of breast cancer; she achieved a complete response as revealed by pathological examination. Combination therapy with PTX and CDDP seems to be an optional treatment for gastric metastasis of breast cancer.

  6. Synergistic Effect of the Combination of Novel Suberoylanilide Hydroxamic Acid Derivatives with Cisplatin on Anti-proliferation of Human Cancer Cells.

    PubMed

    Xie, Rui; Shi, Jinghua; Cheng, Chunhui; Yun, Fan; Liu, Xia; Tang, Pingwah; Wu, Xinying; Yang, Ming; Yuan, Qipeng

    2016-01-01

    A novel, green, and atom-economical boric acid catalyzed direct amidation without the use of any coupling agents for the preparation of suberoylanilide hydroxamic acid (SAHA) and SAHA-based inhibitors targeting anti-proliferation of cancer cells is provided. The new SAHA-based inhibitor B123, when used alone, exhibited higher anti-proliferative activities than SAHA or Cisplatin against a number of human cancer cells. We have examined the effect of combination of these SAHA-based inhibitors with Cisplatin. We found synergistic effects of the combination of SAHA-based inhibitors with Cisplatin over a wide range of concentrations against human liver cancer cells HepG2 and two human lung cancer cell lines H1299 and H460. This synergism leads up to 8-fold of dose reduction for Cisplatin in the combination with our synthesized inhibitor B123 against H1299.

  7. Optimal Use of Combined Modality Therapy in the Treatment of Esophageal Cancer.

    PubMed

    Shaikh, Talha; Meyer, Joshua E; Horwitz, Eric M

    2017-07-01

    Esophageal cancer is associated with a poor prognosis with 5-year survival rates of approximately 15% to 20%. Although patients with early stage disease may adequately be treated with a single modality, combined therapy typically consisting of neoadjuvant chemoradiation followed by esophagectomy is being adopted increasingly in patients with locally advanced disease. In patients who are not surgical candidates, definitive chemoradiation is the preferred treatment approach. All patients with newly diagnosed esophageal cancer should be evaluated in the multidisciplinary setting by a surgeon, radiation oncologist, and medical oncologist owing to the importance of each specialty in the management of these patients. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Antitumor Efficacy of Combination Therapy Consisting of S-1, Leucovorin, and Oxaliplatin against Human Gastric Cancer Xenografts.

    PubMed

    Nagase, Hideki; Nakagawa, Fumio; Uchida, Junji

    2018-01-01

    A phase 3 trial of S-1, leucovorin (LV), and oxaliplatin for treating gastric cancer is now underway. However, the antitumor efficacy of the combination has not yet been examined in an in vivo preclinical study. This study examined the antitumor efficacy of combination therapy consisting of S-1, LV, and oxaliplatin against 4 human gastric cancer xenografts: NUGC-4, St-40, SC-2, and SC-4. The antitumor efficacy was evaluated using human gastric cancer xenograft-bearing nude mice. S-1 and LV were administered orally once daily on days 1-7 at doses of 6.9 and 10 mg/kg, respectively. Oxaliplatin was administered intravenously at a dose of 8.3 mg/kg on day 1. The tumor volume was measured on day 15, and the relative tumor volume (RTV) was calculated. In all 4 xenograft models, S-1 alone and oxaliplatin alone, but not LV alone, had significant antitumor activities (p < 0.001). Combination therapy consisting of S-1 and LV resulted in a significantly smaller RTV than S-1 alone (p < 0.001). Combination therapy consisting of S-1 and oxaliplatin also resulted in a significantly smaller RTV than either S-1 alone (p < 0.001) or oxaliplatin alone (p < 0.001). Furthermore, combination therapy consisting of S-1, LV, and oxaliplatin resulted in the highest antitumor activity in these models (p < 0.001 vs. S-1 + LV; p < 0.001 or p = 0.003 vs. S-1 + oxaliplatin). Combination therapy consisting of S-1, LV, and oxaliplatin administered according to a 1-week-on/1-week-off schedule may be useful for the treatment of patients with gastric cancer. © 2018 S. Karger AG, Basel.

  9. Warehousing re-annotated cancer genes for biomarker meta-analysis.

    PubMed

    Orsini, M; Travaglione, A; Capobianco, E

    2013-07-01

    Translational research in cancer genomics assigns a fundamental role to bioinformatics in support of candidate gene prioritization with regard to both biomarker discovery and target identification for drug development. Efforts in both such directions rely on the existence and constant update of large repositories of gene expression data and omics records obtained from a variety of experiments. Users who interactively interrogate such repositories may have problems in retrieving sample fields that present limited associated information, due for instance to incomplete entries or sometimes unusable files. Cancer-specific data sources present similar problems. Given that source integration usually improves data quality, one of the objectives is keeping the computational complexity sufficiently low to allow an optimal assimilation and mining of all the information. In particular, the scope of integrating intraomics data can be to improve the exploration of gene co-expression landscapes, while the scope of integrating interomics sources can be that of establishing genotype-phenotype associations. Both integrations are relevant to cancer biomarker meta-analysis, as the proposed study demonstrates. Our approach is based on re-annotating cancer-specific data available at the EBI's ArrayExpress repository and building a data warehouse aimed to biomarker discovery and validation studies. Cancer genes are organized by tissue with biomedical and clinical evidences combined to increase reproducibility and consistency of results. For better comparative evaluation, multiple queries have been designed to efficiently address all types of experiments and platforms, and allow for retrieval of sample-related information, such as cell line, disease state and clinical aspects. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  10. Determination of thiol metabolites in human urine by stable isotope labeling in combination with pseudo-targeted mass spectrometry analysis

    NASA Astrophysics Data System (ADS)

    Liu, Ping; Qi, Chu-Bo; Zhu, Quan-Fei; Yuan, Bi-Feng; Feng, Yu-Qi

    2016-02-01

    Precursor ion scan and multiple reaction monitoring scan (MRM) are two typical scan modes in mass spectrometry analysis. Here, we developed a strategy by combining stable isotope labeling (IL) with liquid chromatography-mass spectrometry (LC-MS) under double precursor ion scan (DPI) and MRM for analysis of thiols in 5 types of human cancer urine. Firstly, the IL-LC-DPI-MS method was applied for non-targeted profiling of thiols from cancer samples. Compared to traditional full scan mode, the DPI method significantly improved identification selectivity and accuracy. 103 thiol candidates were discovered in all cancers and 6 thiols were identified by their standards. It is worth noting that pantetheine, for the first time, was identified in human urine. Secondly, the IL-LC-MRM-MS method was developed for relative quantification of thiols in cancers compared to healthy controls. All the MRM transitions of light and heavy labeled thiols were acquired from urines by using DPI method. Compared to DPI method, the sensitivity of MRM improved by 2.1-11.3 folds. In addition, the concentration of homocysteine, γ-glutamylcysteine and pantetheine enhanced more than two folds in cancer patients compared to healthy controls. Taken together, the method demonstrated to be a promising strategy for identification and comprehensive quantification of thiols in human urines.

  11. Soy and isoflavone consumption and risk of gastrointestinal cancer: a systematic review and meta-analysis.

    PubMed

    Tse, Genevieve; Eslick, Guy D

    2016-02-01

    Evidence suggests that soy foods have chemoprotective properties that may reduce the risk of certain cancers such as breast and prostate cancer. However, data involving gastrointestinal (GI) have been limited, and the evidence remains controversial. This study aims to determine the potential relationship between dietary soy intake and GI cancer risk with an evaluation of the effects of isoflavone as an active soy constituent. Relevant studies were identified after literature search via electronic databases through May 2014. Subgroup analysis for isoflavone intake (studies n = 10) was performed. Covariants including gender types, anatomical subsites and preparation methods were also evaluated. Pooled adjusted odds ratios (ORs) comparing highest and lowest categories of dietary pattern scores were calculated using a random effects model. Twenty-two case-control and 18 cohort studies were included for meta-analysis, which contained a total of 633,476 participants and 13,639 GI cancer cases. The combined OR was calculated as 0.93 (95% CI 0.87-0.99; p value heterogeneity = 0.01), showing only a slight decrease in risk, the association was stronger for colon cancer (OR 0.92; 95% CI 0.96-0.99; p value heterogeneity = 0.163) and colorectal cancer (CRC) (OR 0.92; 95% CI 0.87-0.97; p value heterogeneity = 0.3). Subgroup analysis for isoflavone intake showed a statistically significant risk reduction with a risk estimate of 0.73 (95% CI 0.59-0.92; p value heterogeneity = 0), and particularly for CRC (OR 0.76; 95% CI 0.59-0.98; p value heterogeneity = 0). This study provides evidence that soy intake as a food group is only associated with a small reduction in GI cancer risk. Separate analysis for dietary isoflavone intakes suggests a stronger inverse association.

  12. Quantitative diagnosis of bladder cancer by morphometric analysis of HE images

    NASA Astrophysics Data System (ADS)

    Wu, Binlin; Nebylitsa, Samantha V.; Mukherjee, Sushmita; Jain, Manu

    2015-02-01

    In clinical practice, histopathological analysis of biopsied tissue is the main method for bladder cancer diagnosis and prognosis. The diagnosis is performed by a pathologist based on the morphological features in the image of a hematoxylin and eosin (HE) stained tissue sample. This manuscript proposes algorithms to perform morphometric analysis on the HE images, quantify the features in the images, and discriminate bladder cancers with different grades, i.e. high grade and low grade. The nuclei are separated from the background and other types of cells such as red blood cells (RBCs) and immune cells using manual outlining, color deconvolution and image segmentation. A mask of nuclei is generated for each image for quantitative morphometric analysis. The features of the nuclei in the mask image including size, shape, orientation, and their spatial distributions are measured. To quantify local clustering and alignment of nuclei, we propose a 1-nearest-neighbor (1-NN) algorithm which measures nearest neighbor distance and nearest neighbor parallelism. The global distributions of the features are measured using statistics of the proposed parameters. A linear support vector machine (SVM) algorithm is used to classify the high grade and low grade bladder cancers. The results show using a particular group of nuclei such as large ones, and combining multiple parameters can achieve better discrimination. This study shows the proposed approach can potentially help expedite pathological diagnosis by triaging potentially suspicious biopsies.

  13. Nimotuzumab combined with concurrent chemoradiotherapy in Japanese patients with esophageal cancer: A phase I study.

    PubMed

    Kato, Ken; Ura, Takashi; Koizumi, Wasaburo; Iwasa, Satoru; Katada, Chikatoshi; Azuma, Mizutomo; Ishikura, Satoshi; Nakao, Yoshinori; Onuma, Hiroshi; Muro, Kei

    2018-03-01

    Nimotuzumab is a humanized anti-epidermal growth factor receptor IgG1 monoclonal antibody. This phase I study assessed the tolerability, safety, efficacy, and pharmacokinetics of nimotuzumab in combination with chemoradiotherapy in Japanese patients with esophageal cancer. Patients with stage II, III, and IV esophageal cancer were enrolled. Patients were planned to receive nimotuzumab (level 1: 200 mg/wk for 25 weeks; or level 2: 400 mg/wk in the chemoradiation period, 400 mg biweekly in an additional chemotherapy period [8 weeks after the chemoradiation period] and a maintenance therapy period [after chemotherapy to 25 weeks]) combined with cisplatin (75 mg/m 2 on day 1) and fluorouracil (1000 mg/m 2 on days 1-4) in the chemoradiation and additional chemotherapy periods. Radiotherapy was given concurrently at 50.4 Gy. A total of 10 patients were enrolled in level 1. Dose-limiting toxicities were observed in 2 patients (grade 3 infection and renal disorder). Maximum-tolerated dose was estimated to be at least 200 mg/wk and the dose was not escalated to level 2. The most common grade ≥3 toxicities were lymphopenia (90%), leukopenia (60%), neutropenia (50%), and febrile neutropenia, decreased appetite, hyponatremia, and radiation esophagitis (30% each). Neither treatment-related death nor grade ≥3 skin toxicity was observed in any patient. Complete response rate was 50%. Progression-free survival was 13.9 months. One- and 3-year survival rates were 75% and 37.5%, respectively. Immunogenicity was not reported in any patient. Nimotuzumab in combination with concurrent chemoradiotherapy was tolerable and effective for Japanese patients with esophageal cancer. © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  14. Tracer injection sites and combinations for sentinel lymph node detection in patients with endometrial cancer.

    PubMed

    Niikura, Hitoshi; Kaiho-Sakuma, Michiko; Tokunaga, Hideki; Toyoshima, Masafumi; Utsunomiya, Hiroki; Nagase, Satoru; Takano, Tadao; Watanabe, Mika; Ito, Kiyoshi; Yaegashi, Nobuo

    2013-11-01

    The aim of the present study was to clarify the most effective combination of injected tracer types and injection sites in order to detect sentinel lymph nodes (SLNs) in early endometrial cancer. The study included 100 consecutive patients with endometrial cancer treated at Tohoku University Hospital between June 2001 and December 2012. The procedure for SLN identification entailed either radioisotope (RI) injection into the endometrium during hysteroscopy (55 cases) or direct RI injection into the uterine cervix (45 cases). A combination of blue dye injected into the uterine cervix or uterine body intraoperatively in addition to preoperative RI injection occurred in 69 of 100 cases. All detected SLNs were recorded according to the individual tracer and the resultant staging from this method was compared to the final pathology of lymph node metastases including para-aortic nodes. SLN detection rate was highest (96%) by cervical RI injection; however, no SLNs were detected in para-aortic area. Para-aortic SLNs were detected only by hysteroscopic RI injection (56%). All cases with pelvic lymph node metastases were detected by pelvic SLN biopsy. Isolated positive para-aortic lymph nodes were detected in 3 patients. Bilateral SLN detection rate was high (96%; 26 of 27 cases) by cervical RI injection combined with dye. RI injection into the uterine cervix is highly sensitive in detection of SLN metastasis in early stage endometrial cancer. It is a useful and safe modality when combined with blue dye injection into the uterine body. © 2013.

  15. A combination of p53-activating APR-246 and phosphatidylserine-targeting antibody potently inhibits tumor development in hormone-dependent mutant p53-expressing breast cancer xenografts

    PubMed Central

    Liang, Yayun; Mafuvadze, Benford; Besch-Williford, Cynthia; Hyder, Salman M

    2018-01-01

    Background Between 30 and 40% of human breast cancers express a defective tumor suppressor p53 gene. Wild-type p53 tumor suppressor protein promotes cell-cycle arrest and apoptosis and inhibits vascular endothelial growth factor–dependent angiogenesis, whereas mutant p53 protein (mtp53) lacks these functions, resulting in tumor cell survival and metastasis. Restoration of p53 function is therefore a promising drug-targeted strategy for combating mtp53-expressing breast cancer. Methods In this study, we sought to determine whether administration of APR-246, a small-molecule drug that restores p53 function, in combination with 2aG4, an antibody that targets phosphatidylserine residues on tumor blood vessels and disrupts tumor vasculature, effectively inhibits advanced hormone-dependent breast cancer tumor growth. Results APR-246 reduced cell viability in mtp53-expressing BT-474 and T47-D human breast cancer cells in vitro, and significantly induced apoptosis in a dose-dependent manner. However, APR-246 did not reduce cell viability in MCF-7 breast cancer cells, which express wild-type p53. We next examined APR-246’s anti-tumor effects in vivo using BT-474 and T47-D tumor xenografts established in female nude mice. Tumor-bearing mice were treated with APR-246 and/or 2aG4 and tumor volume followed over time. Tumor growth was more effectively suppressed by combination treatment than by either agent alone, and combination therapy completely eradicated some tumors. Immunohistochemistry analysis of tumor tissue sections demonstrated that combination therapy more effectively induced apoptosis and reduced cell proliferation in tumor xenografts than either agent alone. Importantly, combination therapy dramatically reduced the density of blood vessels, which serve as the major route for tumor metastasis, in tumor xenografts compared with either agent alone. Conclusion Based on our findings, we contend that breast tumor growth might effectively be controlled by simultaneous

  16. Clinical features, anti-cancer treatments and outcomes of lung cancer patients with combined pulmonary fibrosis and emphysema.

    PubMed

    Minegishi, Yuji; Kokuho, Nariaki; Miura, Yukiko; Matsumoto, Masaru; Miyanaga, Akihiko; Noro, Rintaro; Saito, Yoshinobu; Seike, Masahiro; Kubota, Kaoru; Azuma, Arata; Kida, Kouzui; Gemma, Akihiko

    2014-08-01

    Combined pulmonary fibrosis and emphysema (CPFE) patients may be at significantly increased risk of lung cancer compared with either isolated emphysema or pulmonary fibrosis patients. Acute exacerbation (AE) of interstitial lung disease caused by anticancer treatment is the most common lethal complication in Japanese lung cancer patients. Nevertheless, the clinical significance of CPFE compared with isolated idiopathic interstitial pneumonias (IIPs) in patients with lung cancer is not well understood. A total of 1536 patients with lung cancer at Nippon Medical School Hospital between March 1998 and October 2011 were retrospectively reviewed. Patients with IIPs were categorized into two groups: (i) CPFE; IIP patients with definite emphysema and (ii) non-CPFE; isolated IIP patients without definite emphysema. The clinical features, anti-cancer treatments and outcomes of the CPFE group were compared with those of the non-CPFE group. CPFE and isolated IIPs were identified in 88 (5.7%) and 63 (4.1%) patients respectively, with lung cancer. AE associated with initial treatment occurred in 22 (25.0%) patients in the CPFE group and in 8 (12.7%) patients in the non-CPFE group, irrespective of treatment modality. Median overall survival (OS) of the CPFE group was 23.7 months and that of the non-CPFE group was 20.3 months (P=0.627). Chemotherapy was performed in a total of 83 patients. AE associated with chemotherapy for advanced lung cancer occurred in 6 (13.6%) patients in the CPFE group and 5 (12.8%) patients in the non-CPFE group. Median OS of the CPFE group was 14.9 months and that of the non-CPFE group was 21.6 months (P=0.679). CPFE was not an independent risk factor for AE and was not an independent prognosis factor in lung cancer patients with IIPs. Therefore, great care must be exercised with CPFE as well as IIP patients when performing anticancer treatment for patients with lung cancer. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  17. The Effect of Hypnosis on Anxiety in Patients With Cancer: A Meta-Analysis.

    PubMed

    Chen, Pei-Ying; Liu, Ying-Mei; Chen, Mei-Ling

    2017-06-01

    Anxiety is a common form of psychological distress in patients with cancer. One recognized nonpharmacological intervention to reduce anxiety for various populations is hypnotherapy or hypnosis. However, its effect in reducing anxiety in cancer patients has not been systematically evaluated. This meta-analysis was designed to synthesize the immediate and sustained effects of hypnosis on anxiety of cancer patients and to identify moderators for these hypnosis effects. Qualified studies including randomized controlled trials (RCT) and pre-post design studies were identified by searching seven electronic databases: Scopus, Medline Ovidsp, PubMed, PsycInfo-Ovid, Academic Search Premier, CINAHL Plus with FT-EBSCO, and SDOL. Effect size (Hedges' g) was computed for each study. Random-effect modeling was used to combine effect sizes across studies. All statistical analyses were conducted with Comprehensive Meta-Analysis, version 2 (Biostat, Inc., Englewood, NJ, USA). Our meta-analysis of 20 studies found that hypnosis had a significant immediate effect on anxiety in cancer patients (Hedges' g: 0.70-1.41, p < .01) and the effect was sustained (Hedges' g: 0.61-2.77, p < .01). The adjusted mean effect size (determined by Duvan and Tweedie's trim-and-fill method) was 0.46. RCTs had a significantly higher effect size than non-RCT studies. Higher mean effect sizes were also found with pediatric study samples, hematological malignancy, studies on procedure-related stressors, and with mixed-gender samples. Hypnosis delivered by a therapist was significantly more effective than self-hypnosis. Hypnosis can reduce anxiety of cancer patients, especially for pediatric cancer patients who experience procedure-related stress. We recommend therapist-delivered hypnosis should be preferred until more effective self-hypnosis strategies are developed. © 2017 Sigma Theta Tau International.

  18. Gastric Cancer Screening by Combined Determination of Serum Helicobacter pylori Antibody and Pepsinogen Concentrations: ABC Method for Gastric Cancer Screening.

    PubMed

    Chen, Xian-Zhe; Huang, Cheng-Zhi; Hu, Wei-Xian; Liu, Ying; Yao, Xue-Qing

    2018-05-20

    Gastroscopy combined with gastric mucosa biopsies is currently regarded as a gold standard for diagnosis of gastric cancer. However, its application is restricted in clinical practice due to its invasive property. A new noninvasive population screening process combining the assay of anti-Helicobacter pylori antibody and serum pepsinogen (PG) (ABC method) is adopted to recognize the high-risk patients for further endoscopy examination, avoiding the unnecessary gastroscopy for most population and saving the cost consumption for mass screening annually. Nevertheless, controversies exist for the grouping of ABC method and the intervals of gastroscopy surveillance for each group. In this review, we summarized these popular concerned topics for providing useful references to the healthcare practitioner in clinical practice. The PubMed databases were systematically searched from the inception dates to November 22, 2017, using the keywords "Helicobacter pylori," "Pepsinogens," and "Stomach Neoplasms." Original articles and reviews on the topics were selected. Anti-H. pylori antibody and serum PG concentration showed significant changes under the different status of H. pylori infection and the progression of atrophic gastritis, which can be used for risk stratification of gastric cancer in clinic. In addition, anti-H. pylori antibody titer can be used for further risk stratification of gastric cancer contributing to determine better endoscopy surveillance interval. The early detection and diagnosis of gastric cancer benefit from the risk stratification, but the cutoff values for H. pylori antibody and serum PG concentration require further modification.

  19. Breast cancer histopathology image analysis: a review.

    PubMed

    Veta, Mitko; Pluim, Josien P W; van Diest, Paul J; Viergever, Max A

    2014-05-01

    This paper presents an overview of methods that have been proposed for the analysis of breast cancer histopathology images. This research area has become particularly relevant with the advent of whole slide imaging (WSI) scanners, which can perform cost-effective and high-throughput histopathology slide digitization, and which aim at replacing the optical microscope as the primary tool used by pathologist. Breast cancer is the most prevalent form of cancers among women, and image analysis methods that target this disease have a huge potential to reduce the workload in a typical pathology lab and to improve the quality of the interpretation. This paper is meant as an introduction for nonexperts. It starts with an overview of the tissue preparation, staining and slide digitization processes followed by a discussion of the different image processing techniques and applications, ranging from analysis of tissue staining to computer-aided diagnosis, and prognosis of breast cancer patients.

  20. Using Antigen-Specific B Cells to Combine Antibody and T Cell-Based Cancer Immunotherapy.

    PubMed

    Wennhold, Kerstin; Thelen, Martin; Schlößer, Hans Anton; Haustein, Natalie; Reuter, Sabrina; Garcia-Marquez, Maria; Lechner, Axel; Kobold, Sebastian; Rataj, Felicitas; Utermöhlen, Olaf; Chakupurakal, Geothy; Theurich, Sebastian; Hallek, Michael; Abken, Hinrich; Shimabukuro-Vornhagen, Alexander; von Bergwelt-Baildon, Michael

    2017-09-01

    Cancer immunotherapy by therapeutic activation of T cells has demonstrated clinical potential. Approaches include checkpoint inhibitors and chimeric antigen receptor T cells. Here, we report the development of an alternative strategy for cellular immunotherapy that combines induction of a tumor-directed T-cell response and antibody secretion without the need for genetic engineering. CD40 ligand stimulation of murine tumor antigen-specific B cells, isolated by antigen-biotin tetramers, resulted in the development of an antigen-presenting phenotype and the induction of a tumor antigen-specific T-cell response. Differentiation of antigen-specific B cells into antibody-secreting plasma cells was achieved by stimulation with IL21, IL4, anti-CD40, and the specific antigen. Combined treatment of tumor-bearing mice with antigen-specific CD40-activated B cells and antigen-specific plasma cells induced a therapeutic antitumor immune response resulting in remission of established tumors. Human CEA or NY-ESO-1-specific B cells were detected in tumor-draining lymph nodes and were able to induce antigen-specific T-cell responses in vitro, indicating that this approach could be translated into clinical applications. Our results describe a technique for the exploitation of B-cell effector functions and provide the rationale for their use in combinatorial cancer immunotherapy. Cancer Immunol Res; 5(9); 730-43. ©2017 AACR . ©2017 American Association for Cancer Research.

  1. Combined circulating tumor DNA and protein biomarker-based liquid biopsy for the earlier detection of pancreatic cancers.

    PubMed

    Cohen, Joshua D; Javed, Ammar A; Thoburn, Christopher; Wong, Fay; Tie, Jeanne; Gibbs, Peter; Schmidt, C Max; Yip-Schneider, Michele T; Allen, Peter J; Schattner, Mark; Brand, Randall E; Singhi, Aatur D; Petersen, Gloria M; Hong, Seung-Mo; Kim, Song Cheol; Falconi, Massimo; Doglioni, Claudio; Weiss, Matthew J; Ahuja, Nita; He, Jin; Makary, Martin A; Maitra, Anirban; Hanash, Samir M; Dal Molin, Marco; Wang, Yuxuan; Li, Lu; Ptak, Janine; Dobbyn, Lisa; Schaefer, Joy; Silliman, Natalie; Popoli, Maria; Goggins, Michael G; Hruban, Ralph H; Wolfgang, Christopher L; Klein, Alison P; Tomasetti, Cristian; Papadopoulos, Nickolas; Kinzler, Kenneth W; Vogelstein, Bert; Lennon, Anne Marie

    2017-09-19

    The earlier diagnosis of cancer is one of the keys to reducing cancer deaths in the future. Here we describe our efforts to develop a noninvasive blood test for the detection of pancreatic ductal adenocarcinoma. We combined blood tests for KRAS gene mutations with carefully thresholded protein biomarkers to determine whether the combination of these markers was superior to any single marker. The cohort tested included 221 patients with resectable pancreatic ductal adenocarcinomas and 182 control patients without known cancer. KRAS mutations were detected in the plasma of 66 patients (30%), and every mutation found in the plasma was identical to that subsequently found in the patient's primary tumor (100% concordance). The use of KRAS in conjunction with four thresholded protein biomarkers increased the sensitivity to 64%. Only one of the 182 plasma samples from the control cohort was positive for any of the DNA or protein biomarkers (99.5% specificity). This combinatorial approach may prove useful for the earlier detection of many cancer types.

  2. Comparative proteomics analysis of oral cancer cell lines: identification of cancer associated proteins

    PubMed Central

    2014-01-01

    Background A limiting factor in performing proteomics analysis on cancerous cells is the difficulty in obtaining sufficient amounts of starting material. Cell lines can be used as a simplified model system for studying changes that accompany tumorigenesis. This study used two-dimensional gel electrophoresis (2DE) to compare the whole cell proteome of oral cancer cell lines vs normal cells in an attempt to identify cancer associated proteins. Results Three primary cell cultures of normal cells with a limited lifespan without hTERT immortalization have been successfully established. 2DE was used to compare the whole cell proteome of these cells with that of three oral cancer cell lines. Twenty four protein spots were found to have changed in abundance. MALDI TOF/TOF was then used to determine the identity of these proteins. Identified proteins were classified into seven functional categories – structural proteins, enzymes, regulatory proteins, chaperones and others. IPA core analysis predicted that 18 proteins were related to cancer with involvements in hyperplasia, metastasis, invasion, growth and tumorigenesis. The mRNA expressions of two proteins – 14-3-3 protein sigma and Stress-induced-phosphoprotein 1 – were found to correlate with the corresponding proteins’ abundance. Conclusions The outcome of this analysis demonstrated that a comparative study of whole cell proteome of cancer versus normal cell lines can be used to identify cancer associated proteins. PMID:24422745

  3. Combination effects of sorafenib with PI3K inhibitors under hypoxia in colorectal cancer.

    PubMed

    Bhatia, Dimple R; Thiagarajan, Padma

    2016-01-01

    This study reports the influence of hypoxia on response of colorectal cancer cells to anticancer effects of sorafenib in combination with PI3K inhibitors GDC-0941 and BEZ-235. All hypoxic exposures were carried out at 1% O 2 /5% CO 2 . Antiproliferation activity was evaluated by 48 hours propidium iodide and 14 days clonogenic assay. Protein levels were evaluated by fluorescence ELISA. Metabolites lactate and glucose were evaluated biochemically. In the 48-hour proliferation assay, sorafenib acted synergistically with GDC-0941 but not with BEZ-235. In long-term colony-forming assays, both GDC-0941 and BEZ-235 were shown to potentiate the antiproliferative activity of sorafenib. At the molecular level, the synergism is mediated through inhibition of pAKT, pS6, p4EBP1, pERK, cyclin D1, and Bcl-2. No change in hypoxia-inducible factor-1α (HIF-1α) levels was observed in cells treated with the combination of compounds under hypoxia. A significant reduction in glucose uptake and lactate release was observed in cells treated with the combination of compounds under normoxia and hypoxia. Combinations of sorafenib with PI3K inhibitors BEZ-235 and GDC-0941 are efficacious under hypoxia. Thus, these anticancer combinations have a potential to overcome the hypoxia-mediated resistance mechanisms to antiproliferative agents in cancer therapy.

  4. Combining doxorubicin-nanobubbles and shockwaves for anaplastic thyroid cancer treatment: preclinical study in a xenograft mouse model.

    PubMed

    Marano, Francesca; Frairia, Roberto; Rinella, Letizia; Argenziano, Monica; Bussolati, Benedetta; Grange, Cristina; Mastrocola, Raffaella; Castellano, Isabella; Berta, Laura; Cavalli, Roberta; Catalano, Maria Graziella

    2017-06-01

    Anaplastic thyroid cancer is one of the most lethal diseases, and a curative therapy does not exist. Doxorubicin, the only drug approved for anaplastic thyroid cancer treatment, has a very low response rate and causes numerous side effects among which cardiotoxicity is the most prominent. Thus, doxorubicin delivery to the tumor site could be an import goal aimed to improve the drug efficacy and to reduce its systemic side effects. We recently reported that, in human anaplastic thyroid cancer cell lines, combining doxorubicin-loaded nanobubbles with extracorporeal shock waves, acoustic waves used in lithotripsy and orthopedics without side effects, increased the intracellular drug content and in vitro cytotoxicity. In the present study, we tested the efficacy of this treatment on a human anaplastic thyroid cancer xenograft mouse model. After 21 days, the combined treatment determined the greatest drug accumulation in tumors with consequent reduction of tumor volume and weight, and an extension of the tumor doubling time. Mechanistically, the treatment induced tumor apoptosis and decreased cell proliferation. Finally, although doxorubicin caused the increase of fibrosis markers and oxidative stress in animal hearts, loading doxorubicin into nanobubbles avoided these effects preventing heart damage. The improvement of doxorubicin anti-tumor effects together with the prevention of heart damage suggests that the combination of doxorubicin-loaded nanobubbles with extracorporeal shock waves might be a promising drug delivery system for anaplastic thyroid cancer treatment. © 2017 Society for Endocrinology.

  5. Citrus fruits intake and oral cancer risk: a systematic review and meta-analysis.

    PubMed

    Cirmi, Santa; Navarra, Michele; Woodside, Jayne V; Cantwell, Marie M

    2018-05-10

    To quantify the relationship between Citrus intake and risk of cancer of the oral cavity and pharynx. Systematic review and meta-analysis. Ovid MEDLINE, EMBASE, and Web of Science were searched until September 2017. Search terms included Citrus, Citrus aurantifolia, Citrus sinensis, Citrus paradisi, Citrus fruits, Citrus fruits extract, Citrus oil, fruits, oral cancer, mouth cancer, mouth neoplasm. The selection of studies and the systematic review were carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. A pre-defined inclusion checklist resulted in the inclusion of articles which were (i) published in peer-reviewed scientific journals; (ii) English language; (iii) and included a measure of Citrus fruit intake and risk of oral and pharyngeal cancer. Studies were excluded if (i) preparations derived from other fruits were used, (ii) Citrus intake was combined with intake of other fruits; (iii) in vitro or animal models were used. We also excluded reviews, systematic reviews, meta-analyses, letters, personal opinions, conference abstracts and book chapters. Three reviewers independently performed the extraction of data from studies included. Seventeen studies met our inclusion criteria and were included in the final review. Pooled analyses showed that those with the highest Citrus fruit intake compared to the lowest intake had a 50% reduction in risk of oral cavity and pharyngeal cancer (OR 0.50; 95% CI 0.43-0.59). The studies included in this review and meta-analysis showed an inverse association between Citrus fruit intake and oral cancer. Copyright © 2018. Published by Elsevier Ltd.

  6. Advancing cancer drug discovery towards more agile development of targeted combination therapies.

    PubMed

    Carragher, Neil O; Unciti-Broceta, Asier; Cameron, David A

    2012-01-01

    Current drug-discovery strategies are typically 'target-centric' and are based upon high-throughput screening of large chemical libraries against nominated targets and a selection of lead compounds with optimized 'on-target' potency and selectivity profiles. However, high attrition of targeted agents in clinical development suggest that combinations of targeted agents will be most effective in treating solid tumors if the biological networks that permit cancer cells to subvert monotherapies are identified and retargeted. Conventional drug-discovery and development strategies are suboptimal for the rational design and development of novel drug combinations. In this article, we highlight a series of emerging technologies supporting a less reductionist, more agile, drug-discovery and development approach for the rational design, validation, prioritization and clinical development of novel drug combinations.

  7. Impact of Thin-Section Computed Tomography-Determined Combined Pulmonary Fibrosis and Emphysema on Outcomes Among Patients With Resected Lung Cancer.

    PubMed

    Hashimoto, Naozumi; Iwano, Shingo; Kawaguchi, Koji; Fukui, Takayuki; Fukumoto, Koichi; Nakamura, Shota; Mori, Shunsuke; Sakamoto, Koji; Wakai, Kenji; Yokoi, Kohei; Hasegawa, Yoshinori

    2016-08-01

    There is only limited information on the clinical impact of combined pulmonary fibrosis and emphysema (CPFE) on postoperative and survival outcomes among patients with resected lung cancer. In a retrospective analysis, data were reviewed from 685 patients with resected lung cancer between 2006 and 2011. The clinical impact of thin-section computed tomography (TSCT)-determined emphysema, fibrosis, and CPFE on postoperative and survival outcomes was evaluated. The emphysema group comprised 32.4% of the study population, the fibrosis group 2.8%, and the CPFE group 8.3%. The CPFE group had a more advanced pathologic stage and higher prevalence of squamous cell carcinoma as compared with the normal group without emphysema or fibrosis findings on TSCT. The incidence of postoperative complications was significantly higher in the CPFE group. Overall, the 30-day mortality in the CPFE group was 5.3%. Cancer recurrence at pathologic stage I and death due to either cancer or other causes were significantly higher in the CPFE group. Survival curves indicated that a finding of CPFE was associated with worse overall survival for patients with any stage disease. Multivariate analysis suggested that pathologic stage and CPFE were independent factors associated with worse overall survival. The adjusted hazard ratio of overall survival for the CPFE group versus the normal group was 2.990 (95% confidence interval: 1.801 to 4.962). Among patients with resected lung cancer, the presence of TSCT-determined CPFE might predict worse postoperative and survival outcomes. Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

  8. Comparisons of the survival time of patients with ovarian cancer adopting post-operative chemotherapy by use of paclitaxel combined with carboplatin or nedaplatin.

    PubMed

    Gao, Hongfei; Yuan, Lijun; Han, Yimin

    2016-06-24

    The current study aims to evaluate and compare the efficacy of post-operative chemotherapy using paclitaxel plus carboplatin or nedaplatin in patients with ovarian cancer, as well as the effects of different combinational therapies on the survival times of patients. Ninety-four patients were recruited for the study. These ovarian cancer patients were admitted into the Cancer Hospital Affiliated with Harbin Medical University for surgery from January 2008 to October 2009. They were divided into different groups according to their post-operative chemotherapy schemes: paclitaxel plus carboplatin (CBP group, n = 48) and paclitaxel plus nedaplatin (NDP group, n = 46). Variance analysis was used to compare the effects of different chemotherapy schemes and pathological types of ovarian cancer on the level of CA125 in serum at different treatment time points. Univariate and multivariate analyses were employed to evaluate the survival times of patients in different groups and pathological types and ages. No significant differences were observed regarding the effects of various chemotherapy schemes (P = 0.561) and pathological types (P = 0.903) on the level of CA125 in serum of patients with ovarian cancer. However, the duration of chemotherapy had a profound impact on the level of CA125 in serum (P < 0.001). The survival times of patients was not affected by age (P = 0.101) and pathological type of ovarian cancer (P = 0.94) significantly. However, it was significantly affected by the chemotherapy scheme. Combined chemotherapy using carboplatin plus paclitaxel should be considered as the preferred treatment scheme for the initial treatment of ovarian cancer.

  9. Long Noncoding RNA HOTAIR as an Independent Prognostic Marker in Cancer: A Meta-Analysis

    PubMed Central

    Yang, Guang; Gu, Fang; Li, Minrui; Zhong, Bihui; Hu, Jifan; Hoffman, Andrew; Chen, Minhu

    2014-01-01

    Background HOTAIR, a newly discovered long intergenic noncoding RNA (lincRNA), has been reported to be aberrantly expressed in many types of cancers. This meta-analysis summarizes its potential role as a biomarker in malignancy. Methods A quantitative meta-analysis was performed through a systematic search in Pubmed, Medline and Web of Science for eligible papers on the prognostic impact of HOTAIR in cancer from inception to Feb. 28, 2014. Pooled hazard ratios (HRs) with 95% confidence interval (95% CI) were calculated to summarize the effect. Results Nineteen studies were included in the study, with a total of 2033 patients. A significant association was observed between high HOTAIR expression and poor overall survival (OS) in patients with cancer (pooled HR 2.22, 95% CI: 1.68–2.93). Place of residence (Asian or Western countries), type of cancer (digestive or non-digestive disease), sample size (more or less than 100), and paper quality (score more or less than 85%) did not alter the significant predictive value of HOTAIR in OS from various kinds of cancer but preoperative status did. By combining HRs from Cox multivariate analyses, we found that HOTAIR expression was an independent prognostic factor for cancer patients (pooled HR 2.26, 95% CI: 1.62–3.15). Subgroup analysis showed that HOTAIR abundance was an independent prognostic factor for cancer metastasis (HR 3.90, 95% CI: 2.25–6.74). For esophageal carcinoma, high HOTAIR expression was significantly associated with TNM stage (III/IV vs. I/II: OR 6.90, 95% CI: 2.81–16.9) without heterogeneity. In gastric cancer, HOTAIR expression was found to be significantly associated with lymph node metastases (present vs. absent: OR 4.47, 95% CI: 1.88–10.63) and vessel invasion (positive vs. negative: OR 2.88, 95% CI: 1.38–6.04) without obvious heterogeneity. Conclusions HOTAIR abundance may serve as a novel predictive factor for poor prognosis in different types of cancers in both Asian and Western countries

  10. Combination immunotherapy with prostate GVAX and ipilimumab: safety and toxicity.

    PubMed

    Karan, Dev; Van Veldhuizen, Peter

    2012-06-01

    Evaluation of: van den Eertwegh AJ, Versluis J, van den Berg HP et al. Combined immunotherapy with granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells and ipilimumab in patients with metastatic castration-resistant prostate cancer: a Phase 1 dose-escalation trial. Lancet Oncol. 13(5), 509 – 517 (2012). A significant interest in the development of therapeutic cancer vaccines over the last decade has led to an improvement in overall survival of cancer patients in several clinical trials. As a result, two active immunotherapy agents, sipuleucel-T and ipilimumab, have been approved by the US FDA for the treatment of prostate cancer and melanoma, respectively. GVAX(®) cellular vaccine (Cell Genesysis, Inc., CA, USA) is another active immunotherapy agent targeting prostate cancer and it has been well studied in various clinical trials. The current publication, by van den Eertwegh et al., demonstrated a combination of two active immunotherapy approaches, using GVAX and ipilimumab for the treatment of metastatic castration-resistant prostate cancer. While GVAX is designed to amplify the antitumor response specific to prostate cancer cells, ipilimumab contributes to T-cell activation. Thus, the authors presented the possibility of augmenting antitumor T-cell activity in two different ways. They successfully demonstrated a tolerable dose and safety profile of ipilimumab in combination with GVAX for patients with metastatic castration-resistant prostate cancer. However, further studies of such immunotherapy combinations and detailed analysis of their immunological effects are needed to observe clinical benefit.

  11. A characteristic biosignature for discrimination of gastric cancer from healthy population by high throughput GC-MS analysis

    PubMed Central

    Guo, Lei; Liu, Lei; Wen, Jingran; Xu, Lu; Yan, Min; Li, Zuofeng; Zhang, Xiaoyan; Nan, Peng; Jiang, Jinling; Ji, Jun; Zhang, Jianian; Cai, Wei; Zhuang, Huisheng; Wang, Yan; Zhu, Zhenggang; Yu, Yingyan

    2016-01-01

    Early diagnosis of gastric cancer is crucial to improve patient′ outcome. A good biomarker will function in early diagnosis for gastric cancer. In order to find practical and cost-effective biomarkers, we used gas chromatography combined mass spectrometer (GC-MS) to profile urinary metabolites on 293 urine samples. Ninety-four samples are taken as training set, others for validating study. Orthogonal partial least squares discriminant analysis (OPLS-DA), significance analysis of microarray (SAM) and Mann-Whitney U test are used for data analysis. The diagnostic value of urinary metabolites was evaluated by ROC curve. As results, Seventeen metabolites are significantly different between patients and healthy controls in training set. Among them, 14 metabolites show diagnostic value better than classic blood biomarkers by quantitative assay on validation set. Ten of them are amino acids and four are organic metabolites. Importantly, proline, p-cresol and 4-hydroxybenzoic acid disclose outcome-prediction value by means of survival analysis. Therefore, the examination of urinary metabolites is a promising noninvasive strategy for gastric cancer screening. PMID:27589838

  12. A systems biology analysis of autophagy in cancer therapy.

    PubMed

    Shi, Zheng; Li, Chun-yang; Zhao, Si; Yu, Yang; An, Na; Liu, Yong-xi; Wu, Chuan-fang; Yue, Bi-song; Bao, Jin-ku

    2013-09-01

    Autophagy, which degrades redundant or damaged cellular constituents, is intricately relevant to a variety of human diseases, most notably cancer. Autophagy exerts distinct effects on cancer initiation and progression, due to the intrinsic overlapping of autophagic and cancer signalling pathways. However, due to the complexity of cancer as a systemic disease, the fate of cancer cells is not decided by any one signalling pathway. Numerous autophagic inter-connectivity and cross-talk pathways need to be further clarified at a systems level. In this review, we propose a systems biology perspective for the comprehensive analysis of the autophagy-cancer network, focusing on systems biology analysis in autophagy and cancer therapy. Together, these analyses may not only improve our understanding on autophagy-cancer relationships, but also facilitate cancer drug discovery. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  13. Meta-analysis of thirty-two case-control and two ecological radon studies of lung cancer.

    PubMed

    Dobrzynski, Ludwik; Fornalski, Krzysztof W; Reszczynska, Joanna

    2018-03-01

    A re-analysis has been carried out of thirty-two case-control and two ecological studies concerning the influence of radon, a radioactive gas, on the risk of lung cancer. Three mathematically simplest dose-response relationships (models) were tested: constant (zero health effect), linear, and parabolic (linear-quadratic). Health effect end-points reported in the analysed studies are odds ratios or relative risk ratios, related either to morbidity or mortality. In our preliminary analysis, we show that the results of dose-response fitting are qualitatively (within uncertainties, given as error bars) the same, whichever of these health effect end-points are applied. Therefore, we deemed it reasonable to aggregate all response data into the so-called Relative Health Factor and jointly analysed such mixed data, to obtain better statistical power. In the second part of our analysis, robust Bayesian and classical methods of analysis were applied to this combined dataset. In this part of our analysis, we selected different subranges of radon concentrations. In view of substantial differences between the methodology used by the authors of case-control and ecological studies, the mathematical relationships (models) were applied mainly to the thirty-two case-control studies. The degree to which the two ecological studies, analysed separately, affect the overall results when combined with the thirty-two case-control studies, has also been evaluated. In all, as a result of our meta-analysis of the combined cohort, we conclude that the analysed data concerning radon concentrations below ~1000 Bq/m3 (~20 mSv/year of effective dose to the whole body) do not support the thesis that radon may be a cause of any statistically significant increase in lung cancer incidence.

  14. Novel Cancer Therapeutics with Allosteric Modulation of the Mitochondrial C-Raf-DAPK Complex by Raf Inhibitor Combination Therapy.

    PubMed

    Tsai, Yi-Ta; Chuang, Mei-Jen; Tang, Shou-Hung; Wu, Sheng-Tang; Chen, Yu-Chi; Sun, Guang-Huan; Hsiao, Pei-Wen; Huang, Shih-Ming; Lee, Hwei-Jen; Yu, Cheng-Ping; Ho, Jar-Yi; Lin, Hui-Kuan; Chen, Ming-Rong; Lin, Chung-Chih; Chang, Sun-Yran; Lin, Victor C; Yu, Dah-Shyong; Cha, Tai-Lung

    2015-09-01

    Mitochondria are the powerhouses of cells. Mitochondrial C-Raf is a potential cancer therapeutic target, as it regulates mitochondrial function and is localized to the mitochondria by its N-terminal domain. However, Raf inhibitor monotherapy can induce S338 phosphorylation of C-Raf (pC-Raf(S338)) and impede therapy. This study identified the interaction of C-Raf with S308 phosphorylated DAPK (pDAPK(S308)), which together became colocalized in the mitochondria to facilitate mitochondrial remodeling. Combined use of the Raf inhibitors sorafenib and GW5074 had synergistic anticancer effects in vitro and in vivo, but targeted mitochondrial function, rather than the canonical Raf signaling pathway. C-Raf depletion in knockout MEF(C-Raf-/-) or siRNA knockdown ACHN renal cancer cells abrogated the cytotoxicity of combination therapy. Crystal structure simulation showed that GW5074 bound to C-Raf and induced a C-Raf conformational change that enhanced sorafenib-binding affinity. In the presence of pDAPK(S308), this drug-target interaction compromised the mitochondrial targeting effect of the N-terminal domain of C-Raf, which induced two-hit damages to cancer cells. First, combination therapy facilitated pC-Raf(S338) and pDAPK(S308) translocation from mitochondria to cytoplasm, leading to mitochondrial dysfunction and reactive oxygen species (ROS) generation. Second, ROS facilitated PP2A-mediated dephosphorylation of pDAPK(S308) to DAPK. PP2A then dissociated from the C-Raf-DAPK complex and induced profound cancer cell death. Increased pDAPK(S308) modification was also observed in renal cancer tissues, which correlated with poor disease-free survival and poor overall survival in renal cancer patients. Besides mediating the anticancer effect, pDAPK(S308) may serve as a predictive biomarker for Raf inhibitors combination therapy, suggesting an ideal preclinical model that is worthy of clinical translation. ©2015 American Association for Cancer Research.

  15. Meta-Analysis of Massage Therapy on Cancer Pain.

    PubMed

    Lee, Sook-Hyun; Kim, Jong-Yeop; Yeo, Sujung; Kim, Sung-Hoon; Lim, Sabina

    2015-07-01

    Cancer pain is the most common complaint among patients with cancer. Conventional treatment does not always relieve cancer pain satisfactorily. Therefore, many patients with cancer have turned to complementary therapies to help them with their physical, emotional, and spiritual well-being. Massage therapy is increasingly used for symptom relief in patients with cancer. The current study aimed to investigate by meta-analysis the effects of massage therapy for cancer patients experiencing pain. Nine electronic databases were systematically searched for studies published through August 2013 in English, Chinese, and Korean. Methodological quality was assessed using the Physiotherapy Evidence Database (PEDro) and Cochrane risk-of-bias scales. Twelve studies, including 559 participants, were used in the meta-analysis. In 9 high-quality studies based on the PEDro scale (standardized mean difference, -1.24; 95% confidence interval, -1.72 to -0.75), we observed reduction in cancer pain after massage. Massage therapy significantly reduced cancer pain compared with no massage treatment or conventional care (standardized mean difference, -1.25; 95% confidence interval, -1.63 to -0.87). Our results indicate that massage is effective for the relief of cancer pain, especially for surgery-related pain. Among the various types of massage, foot reflexology appeared to be more effective than body or aroma massage. Our meta-analysis indicated a beneficial effect of massage for relief of cancer pain. Further well-designed, large studies with longer follow-up periods are needed to be able to draw firmer conclusions regarding the effectiveness. © The Author(s) 2015.

  16. Inflammation on Prostate Needle Biopsy is Associated with Lower Prostate Cancer Risk: A Meta-Analysis.

    PubMed

    Vasavada, Shaleen R; Dobbs, Ryan W; Kajdacsy-Balla, André A; Abern, Michael R; Moreira, Daniel M

    2018-05-01

    We performed a comprehensive literature review and meta-analysis to evaluate the association of inflammation on prostate needle biopsies and prostate cancer risk. We searched Embase®, PubMed® and Web of Science™ from January 1, 1990 to October 1, 2016 for abstracts containing the key words prostate cancer, inflammation and biopsy. Study inclusion criteria were original research, adult human subjects, cohort or case-control study design, histological inflammation on prostate needle biopsy and prostate cancer on histology. Two independent teams reviewed abstracts and extracted data from the selected manuscripts. Combined ORs and 95% CIs of any, acute and chronic inflammation were calculated using the random effects method. Of the 1,030 retrieved abstracts 46 underwent full text review and 25 were included in the final analysis, comprising a total of 20,585 subjects and 6,641 patients with prostate cancer. There was significant heterogeneity among studies (I 2 = 84.4%, p <0.001). The presence of any inflammation was significantly associated with a lower prostate cancer risk in 25 studies (OR 0.455, 95% CI 0.337-0.573). There was no evidence of publication bias (p >0.05). When subanalyzed by inflammation type, acute inflammation in 4 studies and chronic inflammation in 15 were each associated with a lower prostate cancer risk (OR 0.681, 95% CI 0.450-0.913 and OR 0.499, 95% CI 0.334-0.665, respectively). In a meta-analysis of 25 studies inflammation on prostate needle biopsy was associated with a lower prostate cancer risk. Clinically the presence of inflammation on prostate needle biopsy may lower the risk of a subsequent prostate cancer diagnosis. Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  17. Sorafenib tosylate, Ribavirn and Sofosbuvir combination therapy for HCV virus infected patients with decompensated liver cancer.

    PubMed

    Munir, Bushra; Ahmed, Bilal; Kiran, Shumaila; Jalal, Fatima; Zahoor, Muhammad Kashif; Shehzadi, Saba; Oranab, Sadaf; Kamran, Sayed Kashif; Ghaffar, Abdul

    2017-11-01

    Hepatitis C is the most common health problem worldwide and is major cause of death due to proliferation of hepatocellular carcinoma. The medicines available for HCV treatment overcome up-to 95% complications of HCV. However, liver cancer needs some additional care. Normally Sorafenib tosylate 200 mg is recommended for liver cancer. There is no such trial in which this drug could effectively be used in combination of direct acting antivirals for HCV. The study was conducted for HCV patients (n=30) with liver cancer having decompensated stage. Combination of Sorafenib tosylate, Ribavirn and Sofosbuvir were used for the pharmacokinetics of these medicines. Child pugh score less then 7 (CP A) in adults during treatment phase (received 12 weeks of Sorafenib tosylate 200 mg, Ribavirn and Sofosbuvir 400 mg once daily) have no side effect while child pugh score 7-9 (CP B) have evidence of hypertension. The main efficiency end point sustained virology response with overcoming liver cancer as well in 12 weeks after end treatment (SVR-LLC 12). Mean pharmacokinetic exposure to Sorafenib tosylate 200 mg, Ribavirn and Sofosbuvir at week 8th was 2.1, 1.5,1.2 times greater in CP B than in CP A. Adverse effects (AEs) were observed in 12 out of 30 patients but not severe as lethal for life. Treatment with Sorafenib tosylate, Ribavirn and Sofosbuvir for twelve weeks was harmless and well accepted, 100 % patients achieve (SVR LLC 12) with 10-fold cure rate more than previous ones. The combination therapy of Sorafenib tosylate, Ribavirn and Sofosbuvir was found helpful for the management of decompensated liver cancer.

  18. The combination effect of sodium butyrate and 5-Aza-2'-deoxycytidine on radiosensitivity in RKO colorectal cancer and MCF-7 breast cancer cell lines.

    PubMed

    Cho, Hang Joo; Kim, Sin Young; Kim, Kee Hwan; Kang, Won Kyung; Kim, Ji Il; Oh, Seong Tack; Kim, Jeong Soo; An, Chang Hyeok

    2009-05-21

    The overall level of chromatin compaction is an important mechanism of radiosensitivity, and modification of DNA methylation and histone deacetylation may increase radiosensitivity by altering chromatin compaction. In this study, we investigated the effect of a demethylating agent, a histone deacetylase(HDAC) inhibitor, and the two agents combined on radiosensitivity in human colon and breast cancer cell lines. In this study, we used RKO colorectal cancer cell line and MCF-7 breast cancer cell lines and normal colon cell lines. On each of the cell lines, we used three different agents: the HDAC inhibitor sodium butyrate(SB), the demethylating agent 5-Aza-2'-deoxycytidine(5-aza-DC), and radiation. We then estimated the percentage of the cell survival using the XTT method and experimented to determine if there was an augmentation in the therapeutic effect by using different combinations of the two or three of the treatment methods. After treatment of each cell lines with 5-aza-DC, SB and 6 grays of radiation, we observed that the survival fraction was lower after the treatment with 5-aza-DC or SB than with radiation alone in RKO and MCF-7 cell lines(p < 0.001). The survival fraction was lowest when the two agents, 5-aza-DC and SB were combined with radiation in both RKO and MCF-cell lines. In conclusion, 5-aza-DC and SB can enhance radiosensitivity in both MCF-7 and RKO cell lines. The combination effect of a demethylating agent and an HDAC inhibitor is more effective than that of single agent treatment in both breast and colon cancer cell lines.

  19. Quantitative proteomic analysis of microdissected oral epithelium for cancer biomarker discovery.

    PubMed

    Xiao, Hua; Langerman, Alexander; Zhang, Yan; Khalid, Omar; Hu, Shen; Cao, Cheng-Xi; Lingen, Mark W; Wong, David T W

    2015-11-01

    Specific biomarkers are urgently needed for the detection and progression of oral cancer. The objective of this study was to discover cancer biomarkers from oral epithelium through utilizing high throughput quantitative proteomics approaches. Morphologically malignant, epithelial dysplasia, and adjacent normal epithelial tissues were laser capture microdissected (LCM) from 19 patients and used for proteomics analysis. Total proteins from each group were extracted, digested and then labelled with corresponding isobaric tags for relative and absolute quantitation (iTRAQ). Labelled peptides from each sample were combined and analyzed by liquid chromatography-mass spectrometry (LC-MS/MS) for protein identification and quantification. In total, 500 proteins were identified and 425 of them were quantified. When compared with adjacent normal oral epithelium, 17 and 15 proteins were consistently up-regulated or down-regulated in malignant and epithelial dysplasia, respectively. Half of these candidate biomarkers were discovered for oral cancer for the first time. Cornulin was initially confirmed in tissue protein extracts and was further validated in tissue microarray. Its presence in the saliva of oral cancer patients was also explored. Myoglobin and S100A8 were pre-validated by tissue microarray. These data demonstrated that the proteomic biomarkers discovered through this strategy are potential targets for oral cancer detection and salivary diagnostics. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. Combined anxiety and depressive symptoms before diagnosis of breast cancer.

    PubMed

    Van Esch, Lotje; Roukema, Jan A; Ernst, Miranda F; Nieuwenhuijzen, Grard A P; De Vries, Jolanda

    2012-02-01

    To determine the relationship between pre-diagnosis state anxiety, depressive symptoms, and combined state anxiety and depressive symptoms (CADS) with quality of life (QOL), fatigue, state anxiety and depressive symptoms one and two years after surgery in women with breast cancer. Women with breast problems referred to a Dutch outpatient clinic were recruited for the study. Participants (N=428) completed a set of questionnaires before diagnosis (Time0) and the women with breast cancer subsequently received questionnaires at 12 (Time1) and 24 months (Time2) after surgical treatment. The questionnaire set consisted of questionnaires on demographics, state anxiety, depressive symptoms, fatigue, QOL, neuroticism, and trait anxiety. Chi-square tests, independent samples T-tests, and multivariate linear regression analyses were used to do the analyses. Before their diagnosis of breast cancer, 111 women (28%) had CADS. Of the CADS-group, a higher percentage had elevated levels of anxiety, depressive symptoms, and CADS at all follow-up moments than of the non-CADS-group. CADS-score at before diagnosis and neuroticism were the most important predictors of outcome measures at Time1 and Time2. More than one in four women, who later received the diagnosis breast cancer, had elevated levels of both state anxiety and depressive symptoms (CADS) just before diagnosis. This factor was also a major predictor of QOL, state anxiety, depressive symptoms, and fatigue 12 and 24 months after surgery. This implies that women with a higher score on both state anxiety and depressive symptoms should be identified as soon as possible in the process of diagnosis and treatment of breast cancer using validated questionnaires or screening instruments. Only by identifying this group of patients, tailored psychological care can be accomplished. Copyright © 2011. Published by Elsevier B.V.

  1. Investigation of urinary volatile organic metabolites as potential cancer biomarkers by solid-phase microextraction in combination with gas chromatography-mass spectrometry

    PubMed Central

    Silva, C L; Passos, M; Câmara, J S

    2011-01-01

    Background: Non-invasive diagnostic strategies aimed at identifying biomarkers of cancer are of great interest for early cancer detection. Urine is potentially a rich source of volatile organic metabolites (VOMs) that can be used as potential cancer biomarkers. Our aim was to develop a generally reliable, rapid, sensitive, and robust analytical method for screening large numbers of urine samples, resulting in a broad spectrum of native VOMs, as a tool to evaluate the potential of these metabolites in the early diagnosis of cancer. Methods: To investigate urinary volatile metabolites as potential cancer biomarkers, urine samples from 33 cancer patients (oncological group: 14 leukaemia, 12 colorectal and 7 lymphoma) and 21 healthy (control group, cancer-free) individuals were qualitatively and quantitatively analysed. Dynamic solid-phase microextraction in headspace mode (dHS-SPME) using a carboxen-polydimethylsiloxane (CAR/PDMS) sorbent in combination with GC-qMS-based metabolomics was applied to isolate and identify the volatile metabolites. This method provides a potential non-invasive method for early cancer diagnosis as a first approach. To fulfil this objective, three important dHS-SPME experimental parameters that influence extraction efficiency (fibre coating, extraction time and temperature of sampling) were optimised using a univariate optimisation design. The highest extraction efficiency was obtained when sampling was performed at 50°C for 60 min using samples with high ionic strengths (17% sodium chloride, w v−1) and under agitation. Results: A total of 82 volatile metabolites belonging to distinct chemical classes were identified in the control and oncological groups. Benzene derivatives, terpenoids and phenols were the most common classes for the oncological group, whereas ketones and sulphur compounds were the main classes that were isolated from the urine headspace of healthy subjects. The results demonstrate that compound concentrations were

  2. PSMA-Specific Theranostic Nanoplex for Combination of TRAIL Gene and 5-FC Prodrug Therapy of Prostate Cancer

    PubMed Central

    Chen, Zhihang; Penet, Marie-France; Krishnamachary, Balaji; Banerjee, Sangeeta R.; Pomper, Martin G.; Bhujwalla, Zaver M.

    2015-01-01

    Metastatic prostate cancer causes significant morbidity and mortality and there is a critical unmet need for effective treatments. We have developed a theranostic nanoplex platform for combined imaging and therapy of prostate cancer. Our prostate-specific membrane antigen (PSMA) targeted nanoplex is designed to deliver plasmid DNA encoding tumor necrosis factor related apoptosis-inducing ligand (TRAIL), together with bacterial cytosine deaminase (bCD) as a prodrug enzyme. Nanoplex specificity was tested using two variants of human PC3 prostate cancer cells in culture and in tumor xenografts, one with high PSMA expression and the other with negligible expression levels. The expression of EGFP-TRAIL was demonstrated by fluorescence optical imaging and real-time PCR. Noninvasive 19F MR spectroscopy detected the conversion of the nontoxic prodrug 5-fluorocytosine (5-FC) to cytotoxic 5-fluorouracil (5-FU) by bCD. The combination strategy of TRAIL gene and 5-FC/bCD therapy showed significant inhibition of the growth of prostate cancer cells and tumors. These data demonstrate that the PSMA-specific theranostic nanoplex can deliver gene therapy and prodrug enzyme therapy concurrently for precision medicine in metastatic prostate cancer. PMID:26706476

  3. Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer.

    PubMed

    Klein, Alison P; Wolpin, Brian M; Risch, Harvey A; Stolzenberg-Solomon, Rachael Z; Mocci, Evelina; Zhang, Mingfeng; Canzian, Federico; Childs, Erica J; Hoskins, Jason W; Jermusyk, Ashley; Zhong, Jun; Chen, Fei; Albanes, Demetrius; Andreotti, Gabriella; Arslan, Alan A; Babic, Ana; Bamlet, William R; Beane-Freeman, Laura; Berndt, Sonja I; Blackford, Amanda; Borges, Michael; Borgida, Ayelet; Bracci, Paige M; Brais, Lauren; Brennan, Paul; Brenner, Hermann; Bueno-de-Mesquita, Bas; Buring, Julie; Campa, Daniele; Capurso, Gabriele; Cavestro, Giulia Martina; Chaffee, Kari G; Chung, Charles C; Cleary, Sean; Cotterchio, Michelle; Dijk, Frederike; Duell, Eric J; Foretova, Lenka; Fuchs, Charles; Funel, Niccola; Gallinger, Steven; M Gaziano, J Michael; Gazouli, Maria; Giles, Graham G; Giovannucci, Edward; Goggins, Michael; Goodman, Gary E; Goodman, Phyllis J; Hackert, Thilo; Haiman, Christopher; Hartge, Patricia; Hasan, Manal; Hegyi, Peter; Helzlsouer, Kathy J; Herman, Joseph; Holcatova, Ivana; Holly, Elizabeth A; Hoover, Robert; Hung, Rayjean J; Jacobs, Eric J; Jamroziak, Krzysztof; Janout, Vladimir; Kaaks, Rudolf; Khaw, Kay-Tee; Klein, Eric A; Kogevinas, Manolis; Kooperberg, Charles; Kulke, Matthew H; Kupcinskas, Juozas; Kurtz, Robert J; Laheru, Daniel; Landi, Stefano; Lawlor, Rita T; Lee, I-Min; LeMarchand, Loic; Lu, Lingeng; Malats, Núria; Mambrini, Andrea; Mannisto, Satu; Milne, Roger L; Mohelníková-Duchoňová, Beatrice; Neale, Rachel E; Neoptolemos, John P; Oberg, Ann L; Olson, Sara H; Orlow, Irene; Pasquali, Claudio; Patel, Alpa V; Peters, Ulrike; Pezzilli, Raffaele; Porta, Miquel; Real, Francisco X; Rothman, Nathaniel; Scelo, Ghislaine; Sesso, Howard D; Severi, Gianluca; Shu, Xiao-Ou; Silverman, Debra; Smith, Jill P; Soucek, Pavel; Sund, Malin; Talar-Wojnarowska, Renata; Tavano, Francesca; Thornquist, Mark D; Tobias, Geoffrey S; Van Den Eeden, Stephen K; Vashist, Yogesh; Visvanathan, Kala; Vodicka, Pavel; Wactawski-Wende, Jean; Wang, Zhaoming; Wentzensen, Nicolas; White, Emily; Yu, Herbert; Yu, Kai; Zeleniuch-Jacquotte, Anne; Zheng, Wei; Kraft, Peter; Li, Donghui; Chanock, Stephen; Obazee, Ofure; Petersen, Gloria M; Amundadottir, Laufey T

    2018-02-08

    In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/TNS3, P = 4.35 × 10 -8 ). Replication of 10 promising signals in up to 2737 patients and 4752 controls from the PANcreatic Disease ReseArch (PANDoRA) consortium yields new genome-wide significant loci: rs13303010 at 1p36.33 (NOC2L, P = 8.36 × 10 -14 ), rs2941471 at 8q21.11 (HNF4G, P = 6.60 × 10 -10 ), rs4795218 at 17q12 (HNF1B, P = 1.32 × 10 -8 ), and rs1517037 at 18q21.32 (GRP, P = 3.28 × 10 -8 ). rs78417682 is not statistically significantly associated with pancreatic cancer in PANDoRA. Expression quantitative trait locus analysis in three independent pancreatic data sets provides molecular support of NOC2L as a pancreatic cancer susceptibility gene.

  4. Combined 18F-Fluciclovine PET/MRI Shows Potential for Detection and Characterization of High-Risk Prostate Cancer.

    PubMed

    Elschot, Mattijs; Selnæs, Kirsten M; Sandsmark, Elise; Krüger-Stokke, Brage; Størkersen, Øystein; Giskeødegård, Guro F; Tessem, May-Britt; Moestue, Siver A; Bertilsson, Helena; Bathen, Tone F

    2018-05-01

    The objective of this study was to investigate whether quantitative imaging features derived from combined 18 F-fluciclovine PET/multiparametric MRI show potential for detection and characterization of primary prostate cancer. Methods: Twenty-eight patients diagnosed with high-risk prostate cancer underwent simultaneous 18 F-fluciclovine PET/MRI before radical prostatectomy. Volumes of interest (VOIs) for prostate tumors, benign prostatic hyperplasia (BPH) nodules, prostatitis, and healthy tissue were delineated on T2-weighted images, using histology as a reference. Tumor VOIs were marked as high-grade (≥Gleason grade group 3) or not. MRI and PET features were extracted on the voxel and VOI levels. Partial least-squared discriminant analysis (PLS-DA) with double leave-one-patient-out cross-validation was performed to distinguish tumors from benign tissue (BPH, prostatitis, or healthy tissue) and high-grade tumors from other tissue (low-grade tumors or benign tissue). The performance levels of PET, MRI, and combined PET/MRI features were compared using the area under the receiver-operating-characteristic curve (AUC). Results: Voxel and VOI features were extracted from 40 tumor VOIs (26 high-grade), 36 BPH VOIs, 6 prostatitis VOIs, and 37 healthy-tissue VOIs. PET/MRI performed better than MRI and PET alone for distinguishing tumors from benign tissue (AUCs of 87%, 81%, and 83%, respectively, at the voxel level and 96%, 93%, and 93%, respectively, at the VOI level) and high-grade tumors from other tissue (AUCs of 85%, 79%, and 81%, respectively, at the voxel level and 93%, 93%, and 91%, respectively, at the VOI level). T2-weighted MRI, diffusion-weighted MRI, and PET features were the most important for classification. Conclusion: Combined 18 F-fluciclovine PET/multiparametric MRI shows potential for improving detection and characterization of high-risk prostate cancer, in comparison to MRI and PET alone. © 2018 by the Society of Nuclear Medicine and Molecular

  5. Metformin combined with quercetin synergistically repressed prostate cancer cells via inhibition of VEGF/PI3K/Akt signaling pathway.

    PubMed

    Sun, Shuben; Gong, Fanger; Liu, Ping; Miao, Qilong

    2018-04-17

    The aim of present study was to examine whether metformin in association with quercetin has any synergistically anti-tumor effects on prostate cancer. Our findings showed that metformin in combination with quercetin synergistically inhibited the growth, migration and invasion of both PC-3 and LNCaP cells. Co-treatment of these two agents induced more apoptosis than single agent treatment. The co-treatment-induced apoptosis was caspase-dependent and accompanied by the down-regulation of Bcl-2 family members. Our data also indicated that co-treatment of metformin and quercetin strongly inhibited the VEGF/Akt/PI3K pathway. Moreover, these two agents acted synergistically to repress the growth of human prostate cancer cell xenograft in vivo in nude mice. In conclusion, our findings indicate that the combination therapy of metformin and quercetin exerted synergistic antitumor effects in prostate cancers via inhibition of VEGF/Akt/PI3K pathway. Thus, combination treatment of metformin and quercetin would be a promising therapeutic strategy for prostate cancer patients. Copyright © 2017. Published by Elsevier B.V.

  6. Cediranib, a pan-VEGFR inhibitor, and olaparib, a PARP inhibitor, in combination therapy for high grade serous ovarian cancer.

    PubMed

    Ivy, S Percy; Liu, Joyce F; Lee, Jung-Min; Matulonis, Ursula A; Kohn, Elise C

    2016-01-01

    An estimated 22,000 women are diagnosed annually with ovarian cancer in the United States. Initially chemo-sensitive, recurrent disease ultimately becomes chemoresistant and may kill ~14,000 women annually. Molecularly targeted therapy with cediranib (AZD2171), a vascular endothelial growth factor receptor (VEGFR)-1, 2, and 3 signaling blocker, and olaparib (AZD2281), a poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor, administered orally in combination has shown anti-tumor activity in the treatment of high grade serous ovarian cancer (HGSOC). This combination has the potential to change the treatment of HGSOC. Preclinical and clinical studies of single agent cediranib and olaparib or their combination are reviewed. Data are presented from peer-reviewed published manuscripts, completed and ongoing early phase clinical trials registered in ClinicalTrials.gov, National Cancer Institute-sponsored clinical trials, and related recent abstracts. Advances in the treatment of HGSOC that improve progression-free and overall survival have proven elusive despite examination of molecularly targeted therapy. HGSOC patients with deleterious germline or somatic mutations in BRCA1 or BRCA2 (BRCAm) are most responsive to PARP inhibitors (PARPi). PARPi combined with angiogenesis inhibition improved anti-cancer response and duration in both BRCAm and BRCA wild type HGSOC patients, compared to olaparib single agent treatment, demonstrating therapeutic chemical and contextual synthetic lethality.

  7. Does the prediction of breast cancer improve using a combination of mammographic density measures compared to individual measures alone?

    NASA Astrophysics Data System (ADS)

    Wong Sik Hee, Joseph Ryan; Harkness, Elaine F.; Gadde, Soujanya; Lim, Yit Y.; Maxwell, Anthony J.; Evans, D. Gareth; Howell, Anthony; Astley, Susan M.

    2017-03-01

    High mammographic density is associated with an increased risk of breast cancer, however whether the association is stronger when there is agreement across measures is unclear. This study investigates whether a combination of density measures is a better predictor of breast cancer risk than individual methods alone. Women recruited to the Predicting Risk of Cancer At Screening (PROCAS) study and with mammographic density assessed using three different methods were included (n=33,304). Density was assessed visually using Visual Analogue Scales (VAS) and by two fully automated methods, Quantra and Volpara. Percentage breast density was divided into (high, medium and low) and combinations of measures were used to further categorise individuals (e.g. `all high'). A total of 667 breast cancers were identified and logistic regression was used to determine the relationship between breast density and breast cancer risk. In total, 44% of individuals were in the same tertile for all three measures, 8.6% were in non-adjacent (high and low) or mixed categories (high, medium and low). For individual methods the strongest association with breast cancer risk was for medium and high tertiles of VAS with odds ratios (OR) adjusted for age and BMI of 1.63 (95% CI 1.31-2.03) and 2.33 (1.87-2.90) respectively. For the combination of density methods the strongest association was for `all high' (OR 2.42, 1.77-3.31) followed by "two high" (OR 1.90, 1.35-3.31) and "two medium" (OR 1.88, 1.40-2.52). Combining density measures did not affect the magnitude of risk compared to using individual methods.

  8. Effective co-delivery of doxorubicin and dasatinib using a PEG-Fmoc nanocarrier for combination cancer chemotherapy.

    PubMed

    Zhang, Peng; Li, Jiang; Ghazwani, Mohammed; Zhao, Wenchen; Huang, Yixian; Zhang, Xiaolan; Venkataramanan, Raman; Li, Song

    2015-10-01

    A simple PEGylated peptidic nanocarrier, PEG5000-lysyl-(α-Fmoc-ε-Cbz-lysine)2 (PLFCL), was developed for effective co-delivery of doxorubicin (DOX) and dasatinib (DAS) for combination chemotherapy. Significant synergy of DOX and DAS in inhibition of cancer cell proliferation was demonstrated in various types of cancer cells, including breast, prostate, and colon cancers. Co-encapsulation of the two agents was facilitated by incorporation of 9-Fluorenylmethoxycarbonyl (Fmoc) and carboxybenzyl (Cbz) groups into a nanocarrier for effective carrier-drug interactions. Spherical nanomicelles with a small size of ∼30 nm were self-assembled by PLFCL. Strong carrier/drug intermolecular π-π stacking was demonstrated in fluorescence quenching and UV absorption. Fluorescence study showed more effective accumulation of DOX in nuclei of cancer cells following treatment with DOX&DAS/PLFCL in comparison with cells treated with DOX/PLFCL. DOX&DAS/PLFCL micelles were also more effective than other treatments in inhibiting the proliferation and migration of cultured cancer cells. Finally, a superior anti-tumor activity was demonstrated with DOX&DAS/PLFCL. A tumor growth inhibition rate of 95% was achieved at a respective dose of 5 mg/kg for DOX and DAS in a murine breast cancer model. Our nanocarrier may represent a simple and effective system that could facilitate clinical translation of this promising multi-agent regimen in combination chemotherapy. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. Capturing tumor heterogeneity and clonal evolution in solid cancers using circulating tumor DNA analysis.

    PubMed

    Perdigones, Nieves; Murtaza, Muhammed

    2017-06-01

    Circulating tumor DNA analysis has emerged as a potential noninvasive alternative to tissue biopsies for tumor genotyping in patients with metastatic cancer. This is particularly attractive in cases where tissue biopsies are contraindicated or repeat genotyping after progression on treatment is required. However, tissue and plasma analysis results are not always concordant and clinical interpretation of discordant results is not completely understood. Discordant results could arise due to analytical limits of assays used for tumor and plasma DNA analysis or due to low overall contribution of tumor-specific DNA in plasma. Once these factors are ruled out, tissue-plasma concordance and quantitative levels of somatic mutations in plasma can capture tumor heterogeneity. During longitudinal follow-up of patients, this feature can be leveraged to track subclonal evolution and to guide combination or sequential adaptive treatment. Here, we summarize recent results evaluating the opportunities and limitations of circulating tumor DNA analysis in the context of tumor heterogeneity and subclonal evolution in patients with advanced cancers. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Genome-wide combination profiling of DNA copy number and methylation for deciphering biomarkers in non-small cell lung cancer patients.

    PubMed

    Son, Ji Woong; Jeong, Kang Jin; Jean, Woo-Sean; Park, Soon Young; Jheon, Sanghoon; Cho, Hyun Min; Park, Chang Gyo; Lee, Hoi Young; Kang, Jaeku

    2011-12-01

    Early detection of lung cancer provides the highest potential for saving lives. To date, no routine screening method enabling early detection is available, which is a key factor in the disease's high mortality rate. Copy number changes and DNA methylation alterations are good indicators of carcinogenesis and cancer prognosis. In this study, we attempted to combine profiles of DNA copy number and methylation patterns in 20 paired cancerous and noncancerous tissue samples from non-small cell lung cancer (NSCLC) patients, and we detected several clinically important genes with genetic and epigenetic relationships. Using array comparative genomic hybridization (aCGH), statistically significant differences were observed across the histological subtypes for gains at 1p31.1, 3q26.1, and 3q26.31-3q29 as well as for losses at 1p21.1, 2q33.3, 2q37.3, 3p12.3, 4q35.2, and 13q34 in squamous cell carcinoma (SQ) patients, and losses at 12q24.33 were measured in adenocarcinoma (AD) patients (p < 0.05). In an analysis of DNA methylation at 1505 autosomal CpG loci that are associated with 807 cancer-related genes, we identified six and nine loci with higher and lower DNA methylation levels, respectively, in tumor tissue compared to non-tumor lung tissues from AD patients. In addition, three loci with higher and seven loci with lower DNA methylation levels were identified in tumor tissue from SQ patients compared to non-tumor lung tissue. Subsequently, we searched for regions exhibiting concomitant hypermethylation and genomic loss in both ADs and SQs. One clone representing 7p15.2 (which includes candidate genes such as HOXA9 and HOXA11) and one target ID representing HOXA9_E252_R were detected. Quantitative real-time PCR identified the potential candidate gene HOXA9 as being down-regulated in the majority of NSCLC patients. Moreover, following HOXA9 over-expression, the invasion of representative cell lines, A549 and HCC95, were significantly inhibited. Taken together, our results

  11. Hedyotis diffusa Combined with Scutellaria barbata Are the Core Treatment of Chinese Herbal Medicine Used for Breast Cancer Patients: A Population-Based Study

    PubMed Central

    Yeh, Yuan-Chieh; Chen, Hsing-Yu; Yang, Sien-Hung; Lin, Yi-Hsien; Chiu, Jen-Hwey; Lin, Yi-Hsuan; Chen, Jiun-Liang

    2014-01-01

    Traditional Chinese medicine (TCM), which is the most common type of complementary and alternative medicine (CAM) used in Taiwan, is increasingly used to treat patients with breast cancer. However, large-scale studies on the patterns of TCM prescriptions for breast cancer are still lacking. The aim of this study was to determine the core treatment of TCM prescriptions used for breast cancer recorded in the Taiwan National Health Insurance Research Database. TCM visits made for breast cancer in 2008 were identified using ICD-9 codes. The prescriptions obtained at these TCM visits were evaluated using association rule mining to evaluate the combinations of Chinese herbal medicine (CHM) used to treat breast cancer patients. A total of 37,176 prescriptions were made for 4,436 outpatients with breast cancer. Association rule mining and network analysis identified Hedyotis diffusa plus Scutellaria barbata as the most common duplex medicinal (10.9%) used for the core treatment of breast cancer. Jia-Wei-Xiao-Yao-San (19.6%) and Hedyotis diffusa (41.9%) were the most commonly prescribed herbal formula (HF) and single herb (SH), respectively. Only 35% of the commonly used CHM had been studied for efficacy. More clinical trials are needed to evaluate the efficacy and safety of these CHM used to treat breast cancer. PMID:24734104

  12. Hedyotis diffusa Combined with Scutellaria barbata Are the Core Treatment of Chinese Herbal Medicine Used for Breast Cancer Patients: A Population-Based Study.

    PubMed

    Yeh, Yuan-Chieh; Chen, Hsing-Yu; Yang, Sien-Hung; Lin, Yi-Hsien; Chiu, Jen-Hwey; Lin, Yi-Hsuan; Chen, Jiun-Liang

    2014-01-01

    Traditional Chinese medicine (TCM), which is the most common type of complementary and alternative medicine (CAM) used in Taiwan, is increasingly used to treat patients with breast cancer. However, large-scale studies on the patterns of TCM prescriptions for breast cancer are still lacking. The aim of this study was to determine the core treatment of TCM prescriptions used for breast cancer recorded in the Taiwan National Health Insurance Research Database. TCM visits made for breast cancer in 2008 were identified using ICD-9 codes. The prescriptions obtained at these TCM visits were evaluated using association rule mining to evaluate the combinations of Chinese herbal medicine (CHM) used to treat breast cancer patients. A total of 37,176 prescriptions were made for 4,436 outpatients with breast cancer. Association rule mining and network analysis identified Hedyotis diffusa plus Scutellaria barbata as the most common duplex medicinal (10.9%) used for the core treatment of breast cancer. Jia-Wei-Xiao-Yao-San (19.6%) and Hedyotis diffusa (41.9%) were the most commonly prescribed herbal formula (HF) and single herb (SH), respectively. Only 35% of the commonly used CHM had been studied for efficacy. More clinical trials are needed to evaluate the efficacy and safety of these CHM used to treat breast cancer.

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

    PubMed

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

    2016-05-09

    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.

  14. 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

  15. 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.

  16. [A Case of Locally Advanced Thoracic Esophageal Cancer with Larynx Preservation and Curative Resection via Combined Modality Therapy].

    PubMed

    Iwama, Mitsuru; Kimura, Yutaka; Shiraishi, Osamu; Kato, Hiroaki; Hiraki, Yoko; Tanaka, Yumiko; Yasuda, Atsushi; Shinkai, Masayuki; Imano, Motohiro; Imamoto, Haruhiko; Yasuda, Takushi

    2017-11-01

    Prognosis of locally advanced esophageal cancer is poor. The greatest prognostic factor of locally advanced esophageal cancer is a local control. We experienced a case of T4 locally advanced thoracic esophageal cancer who was successfully resected without any combined resection after multimodality therapy. A male in 75-year-old. was diagnosed with type 3 locally advanced upper thoracic esophageal cancer whose metastatic right recurrent laryngeal lymph node invaded into the trachea. Definitive chemoradiation therapy(CRT)was performed, leading to a significant shrinkage of the main tumor, but T4 lesion remained. Next, adding DCF therapy(docetaxel, CDDP and 5-FU), a relief of T4 was finally obtained. Then, salvage surgery with subtotalesophagectomy and retrosternalesophagealreconstruction with gastric tube was performed, resulting in R0 resection without any combined resection. The postoperative course was uneventful, and the patient has been alive without recurrence for 1 year after surgery. In locally advanced cancer, focusing on T4 downstaging, it is significantly important in terms of safety, curativity and organ preservation to perform surgery after a sure sign of T4 relief by multimodality therapy.

  17. Low dose combinations of 2-methoxyestradiol and docetaxel block prostate cancer cells in mitosis and increase apoptosis.

    PubMed

    Reiner, Teresita; de las Pozas, Alicia; Gomez, Lourdes A; Perez-Stable, Carlos

    2009-04-08

    Clinical trials have shown that chemotherapy with docetaxel (Doc) combined with prednisone can improve survival of patients with androgen-independent prostate cancer (AI-PC). It is likely that the combination of Doc with other novel agents would also improve the survival of AI-PC patients. We investigated whether the combination of Doc and 2-methoxyestradiol (2ME2), an endogenous metabolite of estradiol promising for cancer therapy, can increase apoptotic cell death in prostate cancer cells. Low concentration 2ME2 (0.5-1 microM)+Doc (0.05-0.1 nM) combinations inhibit cell growth, increase G2/M cell cycle arrest, and increase apoptosis more effectively than the single concentrations in a variety of human AI-PC cells. Effects on apoptosis were associated with an increase in p53 protein and a decrease in cyclin A-dependent kinase activity. We then investigated whether the combination of 2ME2+Doc can increase apoptotic cell death and inhibit the growth of prostate tumors in the FG/Tag transgenic mouse model of AI-PC. Doses of 2ME2 and Doc that increase mitotic cell cycle arrest result in an increase in apoptosis and lower primary prostate tumor weights in FG/Tag mice. High dose 2ME2+Doc combinations did not increase G2/M cell cycle arrest or apoptosis in AI-PC cell lines and in the FG/Tag mice more than the single drugs. Overall, our data indicate that low dose 2ME2+Doc combinations may provide a treatment strategy that can improve therapeutic efficacy against AI-PC while reducing toxicity often seen in patients treated with Doc.

  18. Efficient treatment of breast cancer xenografts with multifunctionalized iron oxide nanoparticles combining magnetic hyperthermia and anti-cancer drug delivery.

    PubMed

    Kossatz, Susanne; Grandke, Julia; Couleaud, Pierre; Latorre, Alfonso; Aires, Antonio; Crosbie-Staunton, Kieran; Ludwig, Robert; Dähring, Heidi; Ettelt, Volker; Lazaro-Carrillo, Ana; Calero, Macarena; Sader, Maha; Courty, José; Volkov, Yuri; Prina-Mello, Adriele; Villanueva, Angeles; Somoza, Álvaro; Cortajarena, Aitziber L; Miranda, Rodolfo; Hilger, Ingrid

    2015-05-13

    Tumor cells can effectively be killed by heat, e.g. by using magnetic hyperthermia. The main challenge in the field, however, is the generation of therapeutic temperatures selectively in the whole tumor region. We aimed to improve magnetic hyperthermia of breast cancer by using innovative nanoparticles which display a high heating potential and are functionalized with a cell internalization and a chemotherapeutic agent to increase cell death. The superparamagnetic iron oxide nanoparticles (MF66) were electrostatically functionalized with either Nucant multivalent pseudopeptide (N6L; MF66-N6L), doxorubicin (DOX; MF66-DOX) or both (MF66-N6LDOX). Their cytotoxic potential was assessed in a breast adenocarcinoma cell line MDA-MB-231. Therapeutic efficacy was analyzed on subcutaneous MDA-MB-231 tumor bearing female athymic nude mice. All nanoparticle variants showed an excellent heating potential around 500 W/g Fe in the alternating magnetic field (AMF, conditions: H=15.4 kA/m, f=435 kHz). We could show a gradual inter- and intracellular release of the ligands, and nanoparticle uptake in cells was increased by the N6L functionalization. MF66-DOX and MF66-N6LDOX in combination with hyperthermia were more cytotoxic to breast cancer cells than the respective free ligands. We observed a substantial tumor growth inhibition (to 40% of the initial tumor volume, complete tumor regression in many cases) after intratumoral injection of the nanoparticles in vivo. The proliferative activity of the remaining tumor tissue was distinctly reduced. The therapeutic effects of breast cancer magnetic hyperthermia could be strongly enhanced by the combination of MF66 functionalized with N6L and DOX and magnetic hyperthermia. Our approach combines two ways of tumor cell killing (magnetic hyperthermia and chemotherapy) and represents a straightforward strategy for translation into the clinical practice when injecting nanoparticles intratumorally.

  19. Combined determination of circulating miR-196a and miR-196b levels produces high sensitivity and specificity for early detection of oral cancer.

    PubMed

    Lu, Ya-Ching; Chang, Joseph Tung-Chieh; Huang, Yu-Chen; Huang, Chi-Che; Chen, Wen-Ho; Lee, Li-Yu; Huang, Bing-Shen; Chen, Yin-Ju; Li, Hsiao-Fang; Cheng, Ann-Joy

    2015-02-01

    The aim of this study was to determine whether the oncogenic microRNA family members miR-196a and miR-196b can be circulating biomarkers for the early detection of oral cancer. To determine the stability of circulating miRNA, the blood sample was aliquot and stored at different temperature conditions for analysis. To assess the diagnostic efficacy, we determined the levels of miR-196s in plasma samples, including 53 from healthy individuals, 16 from pre-cancer patients, and 90 from oral cancer patients. In general, circulating miRNA was very stable when storing plasma samples at -20°C or below. In clinical study, both circulating miR-196a and miR-196b were substantially up-regulated in patients with oral pre-cancer lesions (5.9- and 14.8-fold, respectively; P < 0.01), as well as in oral cancer patients (9.3- and 17.0-fold, respectively; P < 0.01). These results show prominent discrimination between normal and pre-cancer patients (AUC = 0.764 or 0.840, miR-196a or miR-196b, respectively), and between normal and cancer patients (AUC = 0.864 or 0.960, miR-196a or miR-196b, respectively). The combined determination of miR-196a and miR-196b levels produces excellent sensitivity and specificity in the diagnosis of patients with oral pre-cancer (AUC = 0.845) or oral cancer (AUC = 0.963), as well as in the prediction of potential malignancy (AUC = 0.950, sensitivity = 91%, specificity = 85%). Combined determination of circulating miR-196a and miR-196b levels may serve as panel plasma biomarkers for the early detection of oral cancer. Copyright © 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

  20. Combined MEK and PI3K inhibition in a mouse model of pancreatic cancer.

    PubMed

    Alagesan, Brinda; Contino, Gianmarco; Guimaraes, Alex R; Corcoran, Ryan B; Deshpande, Vikram; Wojtkiewicz, Gregory R; Hezel, Aram F; Wong, Kwok-Kin; Loda, Massimo; Weissleder, Ralph; Benes, Cyril H; Engelman, Jeffrey; Bardeesy, Nabeel

    2015-01-15

    Improved therapeutic approaches are needed for the treatment of pancreatic ductal adenocarcinoma (PDAC). As dual MEK and PI3K inhibition is presently being used in clinical trials for patients with PDAC, we sought to test the efficacy of combined targeting of these pathways in PDAC using both in vitro drug screens and genetically engineered mouse models (GEMM). We performed high-throughput screening of >500 human cancer cell lines (including 46 PDAC lines), for sensitivity to 50 clinically relevant compounds, including MEK and PI3K inhibitors. We tested the top hit in the screen, the MEK1/2 inhibitor, AZD6244, for efficacy alone or in combination with the PI3K inhibitors, BKM120 or GDC-0941, in a Kras(G12D)-driven GEMM that recapitulates the histopathogenesis of human PDAC. In vitro screens revealed that PDAC cell lines are relatively resistant to single-agent therapies. The response profile to the MEK1/2 inhibitor, AZD6244, was an outlier, showing the highest selective efficacy in PDAC. Although MEK inhibition alone was mainly cytostatic, apoptosis was induced when combined with PI3K inhibitors (BKM120 or GDC-0941). When tested in a PDAC GEMM and compared with the single agents or vehicle controls, the combination delayed tumor formation in the setting of prevention and extended survival when used to treat advanced tumors, although no durable responses were observed. Our studies point to important contributions of MEK and PI3K signaling to PDAC pathogenesis and suggest that dual targeting of these pathways may provide benefit in some patients with PDAC. Clin Cancer Res; 21(2); 396-404. ©2014 AACR. ©2014 American Association for Cancer Research.

  1. Combination of imatinib and clotrimazole enhances cell growth inhibition in T47D breast cancer cells.

    PubMed

    Motawi, Tarek M K; Sadik, Nermin A H; Fahim, Sally A; Shouman, Samia A

    2015-05-25

    Imatinib mesylate (IM), a tyrosine kinase inhibitor, is used as targeted cancer therapy. However, mono-targeting by IM does not always achieve full tumor eradication and thus it is recommended to combine IM with other anticancer agents. Clotrimazole (CLT) is an antifungal azole derivative with promising anticancer effects due to inhibiting the activity of glycolytic enzymes. The present study aimed to evaluate the effect of combining CLT with IM on breast cancer cell line in an attempt to establish effective new combination. T47D human breast cancer cell line was treated with different concentrations of IM and/or CLT for 48 h. IM-CLT interaction was determined by isobologram equation and combination index. Cell viability was confirmed by measuring LDH activity. As indicators of glycolysis inhibition, the expression of hexokinase-2 (HK-2) and 6-phosphofructo-1-kinase (PFK-1) plus the activity of intracellular lactate dehydrogenase (LDH) and pyruvate kinase (PK) were determined. In addition, glucose consumption and adenosine triphosphate (ATP) production were measured. Moreover, nitric oxide (NO), vascular endothelial growth factor (VEGF) and hypoxia inducible factor-α (HIF-α) were also determined as they are modulators for glycolysis. This study demonstrated that IM or CLT synergistically inhibited cell growth in T47D as shown by combination and dose reduction indices. The combination of 15 μM IM and 20 μM CLT significantly decreased glucose consumption, activity of both PK and intracellular LDH, while increased leaked LDH, VEGF and NO in the medium compared to each drug alone. Furthermore the combination decreased gene expression of HK-2, PFK-1 and ATP content compared to the control. In conclusion, the synergistic effect of CLT on IM cytotoxicity in T47D cell line maybe mediated through inhibition of glycolysis and increasing both NO and VEGF. Further studies are required to confirm the efficiency and safety of this combination. Copyright © 2015 Elsevier

  2. Determination of thiol metabolites in human urine by stable isotope labeling in combination with pseudo-targeted mass spectrometry analysis

    PubMed Central

    Liu, Ping; Qi, Chu-Bo; Zhu, Quan-Fei; Yuan, Bi-Feng; Feng, Yu-Qi

    2016-01-01

    Precursor ion scan and multiple reaction monitoring scan (MRM) are two typical scan modes in mass spectrometry analysis. Here, we developed a strategy by combining stable isotope labeling (IL) with liquid chromatography-mass spectrometry (LC-MS) under double precursor ion scan (DPI) and MRM for analysis of thiols in 5 types of human cancer urine. Firstly, the IL-LC-DPI-MS method was applied for non-targeted profiling of thiols from cancer samples. Compared to traditional full scan mode, the DPI method significantly improved identification selectivity and accuracy. 103 thiol candidates were discovered in all cancers and 6 thiols were identified by their standards. It is worth noting that pantetheine, for the first time, was identified in human urine. Secondly, the IL-LC-MRM-MS method was developed for relative quantification of thiols in cancers compared to healthy controls. All the MRM transitions of light and heavy labeled thiols were acquired from urines by using DPI method. Compared to DPI method, the sensitivity of MRM improved by 2.1–11.3 folds. In addition, the concentration of homocysteine, γ-glutamylcysteine and pantetheine enhanced more than two folds in cancer patients compared to healthy controls. Taken together, the method demonstrated to be a promising strategy for identification and comprehensive quantification of thiols in human urines. PMID:26888486

  3. Comparative trace elemental analysis of cancerous and non-cancerous tissues of rectal cancer patients using PIXE

    NASA Astrophysics Data System (ADS)

    Naga Raju, G. J.; Sarita, P.; Murthy, K. S. R.

    2017-08-01

    Particle Induced X-ray Emission (PIXE), an accelerator based analytical technique has been employed in this work for the analysis of trace elements in the cancerous and non-cancerous tissues of rectal cancer patients. A beam of 3 MeV protons generated from 3 MV Pelletron accelerator at the Ion Beam Laboratory of Institute of Physics, Bhubaneswar, India was used as projectile to excite the atoms present in the tissues samples. PIXE technique, with its capability to detect simultaneously several elements present at very low concentrations, offers an excellent tool for trace element analysis. The characteristic X-rays emitted by the samples were recorded by a high resolution Si (Li) detector. On the basis of the PIXE spectrum obtained for each sample, the elements Cl, K, Ca, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, and Br were identified and their relative concentrations were estimated in the cancerous and non-cancerous tissues of rectum. The levels of Mn, Fe, Co, Cu, Zn, and As were higher (p < 0.005) while the levels of Ca, Cr and Ni were lower (p < 0.005) in the cancer tissues relative to the normal tissues. The alterations in the levels of the trace elements observed in the present work are discussed in this paper with respect to their potential role in the initiation, promotion and inhibition of cancer of the rectum.

  4. Continuous low-dose cyclophosphamide and methotrexate combined with celecoxib for patients with advanced cancer

    PubMed Central

    Khan, O A; Blann, A D; Payne, M J; Middleton, M R; Protheroe, A S; Talbot, D C; Taylor, M; Han, C; Patil, M; Harris, A L

    2011-01-01

    Background: Combined therapy of metronomic cyclophosphamide, methotrexate and high-dose celecoxib targeting angiogenesis was used in a phase II trial. Methods: Patients with advanced cancer received oral cyclophosphamide 50 mg o.d., celecoxib 400 mg b.d. and methotrexate 2.5 mg b.d. for two consecutive days each week. Response was determined every 8 weeks; toxicity was evaluated according to CTC version 2.0. Plasma markers of inflammation, coagulation and angiogenesis were measured. Results: Sixty-seven of 69 patients were evaluable for response. Twenty-three patients had stable disease (SD) after 8 weeks, but there were no objective responses to therapy. Median time to progression was 57 days. There was a low incidence of toxicities. Among plasma markers, levels of tissue factor were higher in the SD group of patients at baseline, and levels of both angiopoietin-1 and matrix metalloproteinase-9 increased in the progressive disease group only. There were no changes in other plasma markers. Conclusion: This metronomic approach has negligible activity in advanced cancer albeit with minimal toxicity. Analysis of plasma markers indicates minimal effects on endothelium in this trial. These data for this particular regimen do not support basic tenets of metronomic chemotherapy, such as the ability to overcome resistant tumours by targeting the endothelium. PMID:21587257

  5. Continuous low-dose cyclophosphamide and methotrexate combined with celecoxib for patients with advanced cancer.

    PubMed

    Khan, O A; Blann, A D; Payne, M J; Middleton, M R; Protheroe, A S; Talbot, D C; Taylor, M; Kirichek, O; Han, C; Patil, M; Harris, A L

    2011-06-07

    Combined therapy of metronomic cyclophosphamide, methotrexate and high-dose celecoxib targeting angiogenesis was used in a phase II trial. Patients with advanced cancer received oral cyclophosphamide 50 mg o.d., celecoxib 400 mg b.d. and methotrexate 2.5 mg b.d. for two consecutive days each week. Response was determined every 8 weeks; toxicity was evaluated according to CTC version 2.0. Plasma markers of inflammation, coagulation and angiogenesis were measured. Sixty-seven of 69 patients were evaluable for response. Twenty-three patients had stable disease (SD) after 8 weeks, but there were no objective responses to therapy. Median time to progression was 57 days. There was a low incidence of toxicities. Among plasma markers, levels of tissue factor were higher in the SD group of patients at baseline, and levels of both angiopoietin-1 and matrix metalloproteinase-9 increased in the progressive disease group only. There were no changes in other plasma markers. This metronomic approach has negligible activity in advanced cancer albeit with minimal toxicity. Analysis of plasma markers indicates minimal effects on endothelium in this trial. These data for this particular regimen do not support basic tenets of metronomic chemotherapy, such as the ability to overcome resistant tumours by targeting the endothelium.

  6. Combined circulating tumor DNA and protein biomarker-based liquid biopsy for the earlier detection of pancreatic cancers

    PubMed Central

    Cohen, Joshua D.; Javed, Ammar A.; Thoburn, Christopher; Wong, Fay; Tie, Jeanne; Gibbs, Peter; Schmidt, C. Max; Yip-Schneider, Michele T.; Allen, Peter J.; Schattner, Mark; Brand, Randall E.; Singhi, Aatur D.; Petersen, Gloria M.; Hong, Seung-Mo; Kim, Song Cheol; Falconi, Massimo; Doglioni, Claudio; Weiss, Matthew J.; Ahuja, Nita; He, Jin; Makary, Martin A.; Maitra, Anirban; Hanash, Samir M.; Dal Molin, Marco; Wang, Yuxuan; Li, Lu; Ptak, Janine; Dobbyn, Lisa; Schaefer, Joy; Silliman, Natalie; Popoli, Maria; Goggins, Michael G.; Hruban, Ralph H.; Wolfgang, Christopher L.; Klein, Alison P.; Tomasetti, Cristian; Papadopoulos, Nickolas; Kinzler, Kenneth W.; Vogelstein, Bert; Lennon, Anne Marie

    2017-01-01

    The earlier diagnosis of cancer is one of the keys to reducing cancer deaths in the future. Here we describe our efforts to develop a noninvasive blood test for the detection of pancreatic ductal adenocarcinoma. We combined blood tests for KRAS gene mutations with carefully thresholded protein biomarkers to determine whether the combination of these markers was superior to any single marker. The cohort tested included 221 patients with resectable pancreatic ductal adenocarcinomas and 182 control patients without known cancer. KRAS mutations were detected in the plasma of 66 patients (30%), and every mutation found in the plasma was identical to that subsequently found in the patient’s primary tumor (100% concordance). The use of KRAS in conjunction with four thresholded protein biomarkers increased the sensitivity to 64%. Only one of the 182 plasma samples from the control cohort was positive for any of the DNA or protein biomarkers (99.5% specificity). This combinatorial approach may prove useful for the earlier detection of many cancer types. PMID:28874546

  7. Bone Metastasis in Advanced Breast Cancer: Analysis of Gene Expression Microarray.

    PubMed

    Cosphiadi, Irawan; Atmakusumah, Tubagus D; Siregar, Nurjati C; Muthalib, Abdul; Harahap, Alida; Mansyur, Muchtarruddin

    2018-03-08

    Approximately 30% to 40% of breast cancer recurrences involve bone metastasis (BM). Certain genes have been linked to BM; however, none have been able to predict bone involvement. In this study, we analyzed gene expression profiles in advanced breast cancer patients to elucidate genes that can be used to predict BM. A total of 92 advanced breast cancer patients, including 46 patients with BM and 46 patients without BM, were identified for this study. Immunohistochemistry and gene expression analysis was performed on 81 formalin-fixed paraffin-embedded samples. Data were collected through medical records, and gene expression of 200 selected genes compiled from 6 previous studies was performed using NanoString nCounter. Genetic expression profiles showed that 22 genes were significantly differentially expressed between breast cancer patients with metastasis in bone and other organs (BM+) and non-BM, whereas subjects with only BM showed 17 significantly differentially expressed genes. The following genes were associated with an increasing incidence of BM in the BM+ group: estrogen receptor 1 (ESR1), GATA binding protein 3 (GATA3), and melanophilin with an area under the curve (AUC) of 0.804. In the BM group, the following genes were associated with an increasing incidence of BM: ESR1, progesterone receptor, B-cell lymphoma 2, Rab escort protein, N-acetyltransferase 1, GATA3, annexin A9, and chromosome 9 open reading frame 116. ESR1 and GATA3 showed an increased strength of association with an AUC of 0.928. A combination of the identified 3 genes in BM+ and 8 genes in BM showed better prediction than did each individual gene, and this combination can be used as a training set. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  8. [A paclitaxel-resistant case of recurrent breast cancer responded to combination therapy of capecitabine and trastuzumab].

    PubMed

    Marutaka, Masahito; Suguri, Takayasu; Miyake, Mikio; Yoshimura, Kouichi

    2005-12-01

    The patient was a 72-year-old female. Under the supervision of her former doctor, this patient had an operation and adjuvant chemotherapy for progressive breast cancer. During the following period, local recurrence of breast cancer and pulmonary lymphopathia developed. Although medication with paclitaxel was attempted, the focus was resistant to this treatment, and metastasis to the brain was also observed. Due to the dyscrasia above, the patient had difficulty breathing and became bedridden. Subsequently, combination treatment of capecitabine and trastuzumab was attempted. As a result,metastasis in the brain and pulmonary lymphopathia were improved. The patient recovered enough to be discharged at one time. However, his condition took a turn for the worse after the interruption of the combination treatment by a side effect. In conclusion, the combination treatment of capecitabine and trastuzumab is thought to be effective for non-responders to paclitaxel.

  9. Gene Therapy for Brain Cancer: Combination Therapies Provide Enhanced Efficacy and Safety

    PubMed Central

    Candolfi, Marianela; Kroeger, Kurt M.; Muhammad, A.K.M.G.; Yagiz, Kader; Farrokhi, Catherine; Pechnick, Robert N.; Lowenstein, Pedro R.; Castro, Maria G.

    2009-01-01

    Glioblastoma multiforme (GBM) is the most common primary brain cancer in adults. Despite significant advances in treatment and intensive research, the prognosis for patients with GBM remains poor. Therapeutic challenges for GBM include its invasive nature, the proximity of the tumor to vital brain structures often preventing total resection, and the resistance of recurrent GBM to conventional radiotherapy and chemotherapy. Gene therapy has been proposed as a useful adjuvant for GBM, to be used in conjunction with current treatment. Work from our laboratory has shown that combination of conditional cytotoxic with immunotherapeutic approaches for the treatment of GBM elicits regression of large intracranial tumor masses and anti-tumor immunological memory in syngeneic rodent models of GBM. In this review we examined the currently available animal models for GBM, including rodent transplantable models, endogenous rodent tumor models and spontaneous GBM in dogs. We discuss non-invasive surrogate end points to assess tumor progression and therapeutic efficacy, such as behavioral tests and circulating biomarkers. Growing preclinical and clinical data contradict the old dogma that cytotoxic anti-cancer therapy would lead to an immune-suppression that would impair the ability of the immune system to mount an anti-tumor response. The implications of the findings reviewed indicate that combination of cytotoxic therapy with immunotherapy will lead to synergistic antitumor efficacy with reduced neurotoxicity and supports the clinical implementation of combined cytotoxic-immunotherapeutic strategies for the treatment of patients with GBM. PMID:19860655

  10. Modeling combination therapy for breast cancer with BET and immune checkpoint inhibitors.

    PubMed

    Lai, Xiulan; Stiff, Andrew; Duggan, Megan; Wesolowski, Robert; Carson, William E; Friedman, Avner

    2018-05-07

    CTLA-4 is an immune checkpoint expressed on active anticancer T cells. When it combines with its ligand B7 on dendritic cells, it inhibits the activity of the T cells. The Bromo- and Extra-Terminal (BET) protein family includes proteins that regulate the expression of key oncogenes and antiapoptotic proteins. BET inhibitor (BETi) has been shown to reduce the expression of MYC by suppressing its transcription factors and to down-regulate the hypoxic transcriptome response to VEGF-A. This paper develops a mathematical model of the treatment of cancer by combination therapy of BETi and CTLA-4 inhibitor. The model shows that the two drugs are positively correlated in the sense that the tumor volume decreases as the dose of each of the drugs is increased. The model also considers the effect of the combined therapy on levels of myeloid-derived suppressor cells (MDSCs) and the overexpression of TNF-[Formula: see text], which may predict gastrointestinal side effects of the combination.

  11. Beneficial immune modulatory effects of a specific nutritional combination in a murine model for cancer cachexia

    PubMed Central

    Faber, J; Vos, P; Kegler, D; van Norren, K; Argilés, J M; Laviano, A; Garssen, J; van Helvoort, A

    2008-01-01

    The majority of patients with advanced cancer are recognised by impaired immune competence influenced by several factors, including the type and stage of the tumour and the presence of cachexia. Recently, a specific nutritional combination containing fish oil, specific oligosaccharide mixture, high protein content and leucine has been developed aimed to support the immune system of cancer patients in order to reduce the frequency and severity of (infectious) complications. In a recently modified animal model cachexia is induced by inoculation of C26 tumour cells in mice. In a pre-cachectic state, no effect was observed on contact hypersensitivity, a validated in vivo method to measure Th1-mediated immune function, after adding the individual nutritional ingredients to the diet of tumour-bearing mice. However, the complete mixture resulted in significantly improved Th1 immunity. Moreover, in a cachectic state, the complete mixture reduced plasma levels of pro-inflammatory cytokines and beneficially affected ex vivo immune function. Accordingly, the combination of the nutritional ingredients is required to obtain a synergistic effect, leading to a reduced inflammatory state and improved immune competence. From this, it can be concluded that the specific nutritional combination has potential as immune-supporting nutritional intervention to reduce the risk of (infectious) complications in cancer patients. PMID:19018259

  12. Prospective Study of Combined Colon and Endometrial Cancer Screening in Women With Lynch Syndrome: A Patient-Centered Approach

    PubMed Central

    Huang, Marilyn; Sun, Charlotte; Boyd-Rogers, Stephanie; Burzawa, Jennifer; Milbourne, Andrea; Keeler, Elizabeth; Yzquierdo, Rebecca; Lynch, Patrick; Peterson, Susan K.; Lu, Karen

    2011-01-01

    Background: Endometrial and colorectal cancers are the most common cancers in Lynch syndrome. Consensus guidelines recommend annual endometrial biopsy (EMB) and regular colonoscopies. We assessed the feasibility of concurrently performing EMB and colonoscopy and evaluated women's perception of pain, satisfaction, and acceptability. Methods: From July 2002 to December 2009, women who had a gene mutation for Lynch syndrome, met the Amsterdam II criteria, or had a high-risk situation that required screening were prospectively enrolled. After conscious sedation, the procedures were sequentially performed. Patients completed pre- and postprocedure questionnaires assessing pain, level of satisfaction, and acceptability. The Wilcoxon rank test and Mann-Whitney test were used to compare pain scores. Results: Forty-two women completed the study. Median age was 37 years (range, 25 to 73). Nineteen had previously had an EMB in the office setting. Women reported significantly lower median levels of pain in the combined procedure compared with previous office setting biopsies (P < .001). Regardless of parity, women reported significantly less pain for an EMB as part of the combined screen compared with an office EMB (parous, P = .003; nulliparous, P = .026). Women also reported a high level of satisfaction and more convenience in the combined procedure. All participants preferred combined to separately scheduled procedures and would recommend the combined procedure to their relatives. Conclusion: Combined colon and endometrial cancer screening is a patient-centered approach that is feasible, acceptable, and may improve adherence to Lynch syndrome screening recommendations. PMID:21532810

  13. Combination of Near Infrared Light-Activated Photodynamic Therapy Mediated by Indocyanine Green with Etoposide to Treat Non-Small-Cell Lung Cancer

    PubMed Central

    Luo, Ting; Zhang, Qinrong; Lu, Qing-Bin

    2017-01-01

    Indocyanine green (ICG) has been reported as a potential near-infrared (NIR) photosensitizer for photodynamic therapy (PDT) of cancer. However the application of ICG-mediated PDT is both intrinsically and physiologically limited. Here we report a combination of ICG-PDT with a chemotherapy drug etoposide (VP-16), aiming to enhance the anticancer efficacy, to circumvent limitations of PDT using ICG, and to reduce side effects of VP-16. We found in controlled in vitro cell-based assays that this combination is effective in killing non-small-cell lung cancer cells (NSCLC, A549 cell line). We also found that the combination of ICG-PDT and VP-16 exhibits strong synergy in killing non-small-cell lung cancer cells partially through inducing more DNA double-strand breaks (DSBs), while it has a much weaker synergy in killing human normal cells (GM05757). Furthermore, by studying the treatment sequence dependence and the cytotoxicity of laser-irradiated mixtures of ICG and VP-16, we found that the observed synergy involves direct/indirect reactions between ICG and VP-16. We further propose that there exists an electron transfer reaction between ICG and VP-16 under irradiation. This study therefore shows the anticancer efficacy of ICG-PDT combined with VP-16. These findings suggest that ICG-mediated PDT may be applied in combination with the chemotherapy drug VP-16 to treat some cancers, especially the non-small-cell lung cancer. PMID:28587258

  14. Synergistic Antiproliferative Effects of Combined γ-Tocotrienol and PPARγ Antagonist Treatment Are Mediated through PPARγ-Independent Mechanisms in Breast Cancer Cells

    PubMed Central

    Sylvester, Paul W.

    2014-01-01

    Previous findings showed that the anticancer effects of combined γ-tocotrienol and peroxisome proliferator activated receptor γ (PPARγ) antagonist treatment caused a large reduction in PPARγ expression. However, other studies suggest that the antiproliferative effects of γ-tocotrienol and/or PPARγ antagonists are mediated, at least in part, through PPARγ-independent mechanism(s). Studies were conducted to characterize the role of PPARγ in mediating the effects of combined treatment of γ-tocotrienol with PPARγ agonists or antagonists on the growth of PPARγ negative +SA mammary cells and PPARγ-positive and PPARγ-silenced MCF-7 and MDA-MB-231 breast cancer cells. Combined treatment of γ-tocotrienol with PPARγ antagonist decreased, while combined treatment of γ-tocotrienol with PPARγ agonist increased, growth of all cancer cells. However, treatment with high doses of 15d-PGJ2, an endogenous natural ligand for PPARγ, had no effect on cancer cell growth. Western blot and qRT-PCR studies showed that the growth inhibitory effects of combined γ-tocotrienol and PPARγ antagonist treatment decreased cyclooxygenase (COX-2), prostaglandin synthase (PGDS), and prostaglandin D2 (PGD2) synthesis. In conclusion, the anticancer effects of combined γ-tocotrienol and PPARγ antagonists treatment in PPARγ negative/silenced breast cancer cells are mediated through PPARγ-independent mechanisms that are associated with a downregulation in COX-2, PGDS, and PGD2 synthesis. PMID:24729783

  15. Combination cancer therapy by hapten-targeted prodrug-activating enzymes and cytokines.

    PubMed

    Chuang, Kuo-Hsiang; Cheng, Chiu-Min; Roffler, Steve R; Lu, Yu-Lin; Lin, Shiu-Ru; Wang, Jaw-Yuan; Tzou, Wen-Shyong; Su, Yu-Cheng; Chen, Bing-Mae; Cheng, Tian-Lu

    2006-01-01

    Combination therapy can help overcome limitations in the treatment of heterogeneous tumors. In the current study, we examined whether multiple therapeutic agents could be targeted to anti-dansyl single-chain antibodies (DNS scFv) that were anchored on the plasma membrane of cancer cells. Functional DNS scFv could be stably expressed on CT-26 colon cancer cells both in vitro and in vivo. Dansyl moieties were covalently attached to recombinant beta-glucuronidase (betaG) and interleukin 2 (IL-2) via a flexible poly(ethylene glycol) linker to form DNS-PEG-betaG and DNS-PEG-IL-2 conjugates. The conjugates displayed enzymatic and splenocyte-stimulatory activities, respectively, that were similar to those of the unmodified proteins. The conjugates selectively bound CT-26 cells that expressed anti-DNS scFv (CT-26/DNS cells) but not CT-26 cells that expressed control scFv (CT-26/phOx cells). DNS-PEG-betaG preferentially activated a glucuronide prodrug (BHAMG) of p-hydroxy aniline mustard at CT-26/DNS cells in culture and accumulated in subcutaneous CT-26/DNS tumors after intravenous administration. Systemic administration of DNS-PEG-IL-2 or DNS-PEG-betaG and BHAMG significantly delayed the growth of CT-26/DNS but not control CT-26/phOx tumors. Combination treatment with DNS-PEG-betaG and BHAMG followed by DNS-PEG-IL-2 therapy significantly suppressed the growth of CT-26/DNS tumors as compared to either single-agent regimen. These results show that at least two DNS-modified therapeutic agents can be selectively delivered to DNS scFv receptors in vitro and in vivo, allowing combination therapy of DNS scFv-modified tumors.

  16. Selective Targeting of CTNNB1-, KRAS- or MYC-Driven Cell Growth by Combinations of Existing Drugs

    PubMed Central

    Uitdehaag, Joost C. M.; de Roos, Jeroen A. D. M.; van Doornmalen, Antoon M.; Prinsen, Martine B. W.; Spijkers-Hagelstein, Jill A. P.; de Vetter, Judith R. F.; de Man, Jos; Buijsman, Rogier C.; Zaman, Guido J. R.

    2015-01-01

    The aim of combination drug treatment in cancer therapy is to improve response rate and to decrease the probability of the development of drug resistance. Preferably, drug combinations are synergistic rather than additive, and, ideally, drug combinations work synergistically only in cancer cells and not in non-malignant cells. We have developed a workflow to identify such targeted synergies, and applied this approach to selectively inhibit the proliferation of cell lines with mutations in genes that are difficult to modulate with small molecules. The approach is based on curve shift analysis, which we demonstrate is a more robust method of determining synergy than combination matrix screening with Bliss-scoring. We show that the MEK inhibitor trametinib is more synergistic in combination with the BRAF inhibitor dabrafenib than with vemurafenib, another BRAF inhibitor. In addition, we show that the combination of MEK and BRAF inhibitors is synergistic in BRAF-mutant melanoma cells, and additive or antagonistic in, respectively, BRAF-wild type melanoma cells and non-malignant fibroblasts. This combination exemplifies that synergistic action of drugs can depend on cancer genotype. Next, we used curve shift analysis to identify new drug combinations that specifically inhibit cancer cell proliferation driven by difficult-to-drug cancer genes. Combination studies were performed with compounds that as single agents showed preference for inhibition of cancer cells with mutations in either the CTNNB1 gene (coding for β-catenin), KRAS, or cancer cells expressing increased copy numbers of MYC. We demonstrate that the Wnt-pathway inhibitor ICG-001 and trametinib acted synergistically in Wnt-pathway-mutant cell lines. The ERBB2 inhibitor TAK-165 was synergistic with trametinib in KRAS-mutant cell lines. The EGFR/ERBB2 inhibitor neratinib acted synergistically with the spindle poison docetaxel and with the Aurora kinase inhibitor GSK-1070916 in cell lines with MYC amplification

  17. Cancer Nursing Education: Literature Review and Documentary Analysis.

    ERIC Educational Resources Information Center

    Langton, Helen; Blunden, Gillian; Hek, Gill

    The knowledge and skills needed by cancer nurses and the content and strategies of England's existing cancer nursing education programs were examined. The study included a comprehensive literature review and an analysis of course documents from selected English National Board-approved post-qualifying cancer nursing and palliative care courses…

  18. A Mass Spectrometric Analysis Method Based on PPCA and SVM for Early Detection of Ovarian Cancer.

    PubMed

    Wu, Jiang; Ji, Yanju; Zhao, Ling; Ji, Mengying; Ye, Zhuang; Li, Suyi

    2016-01-01

    Background. Surfaced-enhanced laser desorption-ionization-time of flight mass spectrometry (SELDI-TOF-MS) technology plays an important role in the early diagnosis of ovarian cancer. However, the raw MS data is highly dimensional and redundant. Therefore, it is necessary to study rapid and accurate detection methods from the massive MS data. Methods. The clinical data set used in the experiments for early cancer detection consisted of 216 SELDI-TOF-MS samples. An MS analysis method based on probabilistic principal components analysis (PPCA) and support vector machine (SVM) was proposed and applied to the ovarian cancer early classification in the data set. Additionally, by the same data set, we also established a traditional PCA-SVM model. Finally we compared the two models in detection accuracy, specificity, and sensitivity. Results. Using independent training and testing experiments 10 times to evaluate the ovarian cancer detection models, the average prediction accuracy, sensitivity, and specificity of the PCA-SVM model were 83.34%, 82.70%, and 83.88%, respectively. In contrast, those of the PPCA-SVM model were 90.80%, 92.98%, and 88.97%, respectively. Conclusions. The PPCA-SVM model had better detection performance. And the model combined with the SELDI-TOF-MS technology had a prospect in early clinical detection and diagnosis of ovarian cancer.

  19. Methylation analysis of plasma cell-free DNA for breast cancer early detection using bisulfite next-generation sequencing.

    PubMed

    Li, Zibo; Guo, Xinwu; Tang, Lili; Peng, Limin; Chen, Ming; Luo, Xipeng; Wang, Shouman; Xiao, Zhi; Deng, Zhongping; Dai, Lizhong; Xia, Kun; Wang, Jun

    2016-10-01

    Circulating cell-free DNA (cfDNA) has been considered as a potential biomarker for non-invasive cancer detection. To evaluate the methylation levels of six candidate genes (EGFR, GREM1, PDGFRB, PPM1E, SOX17, and WRN) in plasma cfDNA as biomarkers for breast cancer early detection, quantitative analysis of the promoter methylation of these genes from 86 breast cancer patients and 67 healthy controls was performed by using microfluidic-PCR-based target enrichment and next-generation bisulfite sequencing technology. The predictive performance of different logistic models based on methylation status of candidate genes was investigated by means of the area under the ROC curve (AUC) and odds ratio (OR) analysis. Results revealed that EGFR, PPM1E, and 8 gene-specific CpG sites showed significantly hypermethylation in cancer patients' plasma and significantly associated with breast cancer (OR ranging from 2.51 to 9.88). The AUC values for these biomarkers were ranging from 0.66 to 0.75. Combinations of multiple hypermethylated genes or CpG sites substantially improved the predictive performance for breast cancer detection. Our study demonstrated the feasibility of quantitative measurement of candidate gene methylation in cfDNA by using microfluidic-PCR-based target enrichment and bisulfite next-generation sequencing, which is worthy of further validation and potentially benefits a broad range of applications in clinical oncology practice. Quantitative analysis of methylation pattern of plasma cfDNA by next-generation sequencing might be a valuable non-invasive tool for early detection of breast cancer.

  20. Cost-effectiveness of Paclitaxel + Ramucirumab Combination Therapy for Advanced Gastric Cancer Progressing After First-line Chemotherapy in Japan.

    PubMed

    Saito, Shota; Muneoka, Yusuke; Ishikawa, Takashi; Akazawa, Kouhei

    2017-12-01

    The combination of paclitaxel + ramucirumab is a standard second-line treatment in patients with advanced gastric cancer. This therapy has been associated with increased median overall survival and progression-free survival compared with those with paclitaxel monotherapy. We evaluated the cost-effectiveness of paclitaxel + ramucirumab combination therapy in patients with advanced gastric cancer, from the perspective of health care payers in Japan. We constructed a Markov model to compare, over a time horizon of 3 years, the costs and effectiveness of the combination of paclitaxel + ramucirumab and paclitaxel alone as second-line therapies for advanced gastric cancer in Japan. Health outcomes were measured in life-years (LYs) and quality-adjusted (QA) LYs gained. Costs were calculated using year-2016 Japanese yen (¥1 = US $17.79) according to the social insurance reimbursement schedule and drug tariff of the fee-for-service system in Japan. Model robustness was addressed through 1-way and probabilistic sensitivity analyses. The costs and QALYs were discounted at a rate of 2% per year. The willingness-to-pay threshold was set at the World Health Organization's criterion of ¥12 million, because no consensus exists regarding the threshold for acceptable cost per QALY ratios in Japan's health policy. Paclitaxel + ramucirumab combination therapy was estimated to provide an additional 0.09 QALYs (0.10 LYs) at a cost of ¥3,870,077, resulting in an incremental cost-effectiveness ratio of ¥43,010,248/QALY. The incremental cost-effectiveness ratio for the combination therapy was >¥12 million/QALY in all of the 1-way and probabilistic sensitivity analyses. Adding ramucirumab to a regimen of paclitaxel in the second-line treatment of advanced gastric cancer is expected to provide a minimal incremental benefit at a high incremental cost per QALY. Based on our findings, adjustments in the price of ramucirumab, as well as improves in other clinical parameters such as survival

  1. Genetic Modifiers of Ovarian Cancer

    DTIC Science & Technology

    2014-08-01

    samples from many countries. To account for population stratification, the genotyping data in combination with HapMap data (CEU, Yoruban, Han Chinese...Cambridge, we evaluated associations with both breast and ovarian cancer using a retrospective likelihood model. This accounts for the age extremes of...carriers we used a competing risk analysis that accounted for the effects on breast and ovarian cancer in parallel. In this competing risk analysis

  2. Independent Pre-Transplant Recipient Cancer Risk Factors after Kidney Transplantation and the Utility of G-Chart Analysis for Clinical Process Control.

    PubMed

    Schrem, Harald; Schneider, Valentin; Kurok, Marlene; Goldis, Alon; Dreier, Maren; Kaltenborn, Alexander; Gwinner, Wilfried; Barthold, Marc; Liebeneiner, Jan; Winny, Markus; Klempnauer, Jürgen; Kleine, Moritz

    2016-01-01

    The aim of this study is to identify independent pre-transplant cancer risk factors after kidney transplantation and to assess the utility of G-chart analysis for clinical process control. This may contribute to the improvement of cancer surveillance processes in individual transplant centers. 1655 patients after kidney transplantation at our institution with a total of 9,425 person-years of follow-up were compared retrospectively to the general German population using site-specific standardized-incidence-ratios (SIRs) of observed malignancies. Risk-adjusted multivariable Cox regression was used to identify independent pre-transplant cancer risk factors. G-chart analysis was applied to determine relevant differences in the frequency of cancer occurrences. Cancer incidence rates were almost three times higher as compared to the matched general population (SIR = 2.75; 95%-CI: 2.33-3.21). Significantly increased SIRs were observed for renal cell carcinoma (SIR = 22.46), post-transplant lymphoproliferative disorder (SIR = 8.36), prostate cancer (SIR = 2.22), bladder cancer (SIR = 3.24), thyroid cancer (SIR = 10.13) and melanoma (SIR = 3.08). Independent pre-transplant risk factors for cancer-free survival were age <52.3 years (p = 0.007, Hazard ratio (HR): 0.82), age >62.6 years (p = 0.001, HR: 1.29), polycystic kidney disease other than autosomal dominant polycystic kidney disease (ADPKD) (p = 0.001, HR: 0.68), high body mass index in kg/m2 (p<0.001, HR: 1.04), ADPKD (p = 0.008, HR: 1.26) and diabetic nephropathy (p = 0.004, HR = 1.51). G-chart analysis identified relevant changes in the detection rates of cancer during aftercare with no significant relation to identified risk factors for cancer-free survival (p<0.05). Risk-adapted cancer surveillance combined with prospective G-chart analysis likely improves cancer surveillance schemes by adapting processes to identified risk factors and by using G-chart alarm signals to trigger Kaizen events and audits for root

  3. Self-advocacy and cancer: a concept analysis.

    PubMed

    Hagan, Teresa L; Donovan, Heidi S

    2013-10-01

    To report an analysis of the concept of self-advocacy among individuals with cancer to clarify its meaning, to differentiate this meaning with related concepts, and to unify understanding of the concept in cancer research and practice. Cancer survivors are increasingly required to assume an active role in their health care. A thorough analysis of how survivors advocate for themselves is a crucial aspect in supporting survivors' ability to engage and manage their care throughout all stages of cancer survivorship. Walker and Avant's eight-step process of conducting a concept analysis was used. PubMed, PsycINFO, and CINAHL databases were searched for articles, reviews, editorials, and grey literature directly addressing self-advocacy. A broad inquiry into the literature from 1960 to 2012 that produces a definition of self-advocacy. Model and contrary cases of self-advocacy demonstrate the concept's application and intricacies. Antecedents to self-advocacy include particular personal characteristics, learned skills, and attainable support. The essential element of self-advocacy and what differentiates it from related concepts, is the internalization of these antecedent resources into self-advocacy thoughts and actions while incorporating personal values and priorities in a way that upholds the survivors' goals and beliefs. A full realization of self-advocacy facilitates a cancer survivor attaining a strong self-concept, sense of control, and adaptation to a life with cancer. Self-advocacy is a process of internalizing skills and resources to act in a way that supports survivors' needs and goals. © 2013 Blackwell Publishing Ltd.

  4. Self-Advocacy and Cancer: A Concept Analysis

    PubMed Central

    Hagan, Teresa L.; Donovan, Heidi S.

    2013-01-01

    Aim This paper is a report of an analysis of the concept of self-advocacy among individuals with cancer to clarify its meaning, to differentiate this meaning with related concepts and to unify understanding of the concept in cancer research and practice. Background Cancer survivors are increasingly required to assume an active role in their healthcare. A thorough analysis of how survivors advocate for themselves is a crucial aspect in supporting survivors’ ability to engage and manage their care throughout all stages of cancer survivorship. Design Walker and Avant’s eight-step process of conducting a concept analysis was used. Data Sources PubMed, PsycINFO and CINAHL databases were searched for articles, reviews, editorials and gray literature directly addressing self-advocacy. Review Methods A broad inquiry into the literature from 1960 – 2012 that produces a definition of self-advocacy. Model and contrary cases of self-advocacy demonstrate the concept’s application and intricacies. Results Antecedents to self-advocacy include particular personal characteristics, learned skills and attainable support. The essential element of self-advocacy and what differentiates it from related concepts, is the internalization of these antecedent resources into self-advocacy thoughts and actions while incorporating personal values and priorities in a way that upholds the survivors’ goals and beliefs. A full realization of self-advocacy facilitates a cancer survivor attaining a strong self-concept, sense of control and adaptation to a life with cancer. Conclusions Self-advocacy is a process of internalizing skills and resources to act in a way that supports survivors’ needs and goals. PMID:23347224

  5. Combination chemotherapy with Regorafenib in metastatic colorectal cancer treatment: A single center, retrospective study

    PubMed Central

    Lin, Chun-Yu; Lin, Tseng-Hsi; Chen, Chou-Chen; Chen, Ming-Cheng

    2018-01-01

    Background Regorafenib has been demonstrated as effective in refractory metastatic colorectal cancer. Combination use with chemotherapy has not been reported. We examined the efficacy and safety of adding chemotherapy to Regorafenib for the treatment of metastatic colorectal cancer(mCRC) patients. Methods We recruited mCRC patients at our institute who received either regorafenib monotherapy or regorafenib in combination with other chemotherapies. All patients had received chemo and target therapies and presented with disease progression before regorafenib treatment. The primary end point was overall survival. Findings Between September1, 2015 and May 31, 2017, 100 mCRC patients at our institute received regorafenib treatment. 39 patients were excluded due to poor performance, lack of timely treatment, or inadequate clinical data. A total of 34 patients received regorafenib combined with other chemotherapies, and 27 patients received regorafenib alone. Median follow up time was 10.4 and 6.1 months, respectively. The primary end point of median OS was higher in the combination group than in the single use group (20.9m vs 10.3m, p = 0.015). The most frequent adverse events were hand-foot skin reactions(16[47.1%]vs 12[44.4%]), fatigue(6[17.6%] vs 7[25.9%]), gastrointestinal discomfort (7[20.6%] vs 6[22.2%]), neutropenia (4[11.8%] vs 1[3.7%]), diarrhea(4[11.8%] vs 1[3.7%]), and mucositis(5[14.7%] vs 1[3.7%]). Conclusion The present study showed the efficacy and side effects of regorafenib combination treatment. Superiority in median OS and median PFS was noted in the combination group. The sampling difference between the study and observation groups effects justifies the comparison. Further clinical evidence of combination therapy efficacy is pending future studies. PMID:29304109

  6. Alcohol and cigarette consumption predict mortality in patients with head and neck cancer: a pooled analysis within the International Head and Neck Cancer Epidemiology (INHANCE) Consortium

    PubMed Central

    Giraldi, L; Leoncini, E; Pastorino, R; Wünsch-Filho, V; de Carvalho, M; Lopez, R; Cadoni, G; Arzani, D; Petrelli, L; Bosetti, C; La Vecchia, C; Garavello, W; Polesel, J; Serraino, D; Simonato, L; Canova, C; Richiardi, L; Boffetta, P; Hashibe, M; Lee, Y C A; Boccia, S

    2017-01-01

    Abstract Background This study evaluated whether demographics, pre-diagnosis lifestyle habits and clinical data are associated with the overall survival (OS) and head and neck cancer (HNC)-specific survival in patients with HNC. Patients and methods We conducted a pooled analysis, including 4759 HNC patients from five studies within the International Head and Neck Cancer Epidemiology (INHANCE) Consortium. Cox proportional hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) were estimated including terms reported significantly associated with the survival in the univariate analysis. Results Five-year OS was 51.4% for all HNC sites combined: 50.3% for oral cavity, 41.1% for oropharynx, 35.0% for hypopharynx and 63.9% for larynx. When we considered HNC-specific survival, 5-year survival rates were 57.4% for all HNC combined: 54.6% for oral cavity, 45.4% for oropharynx, 37.1% for hypopharynx and 72.3% for larynx. Older ages at diagnosis and advanced tumour staging were unfavourable predictors of OS and HNC-specific survival. In laryngeal cancer, low educational level was an unfavourable prognostic factor for OS (HR = 2.54, 95% CI 1.01–6.38, for high school or lower versus college graduate), and status and intensity of alcohol drinking were prognostic factors both of the OS (current drinkers HR = 1.73, 95% CI 1.16–2.58) and HNC-specific survival (current drinkers HR = 2.11, 95% CI 1.22–3.66). In oropharyngeal cancer, smoking status was an independent prognostic factors for OS. Smoking intensity (>20 cigarettes/day HR = 1.41, 95% CI 1.03–1.92) was also an independent prognostic factor for OS in patients with cancer of the oral cavity. Conclusions OS and HNC-specific survival differ among HNC sites. Pre-diagnosis cigarette smoking is a prognostic factor of the OS for patients with cancer of the oral cavity and oropharynx, whereas pre-diagnosis alcohol drinking is a prognostic factor of OS and HNC-specific survival for

  7. Radon and cancers other than lung cancer in underground miners: a collaborative analysis of 11 studies.

    PubMed

    Darby, S C; Whitley, E; Howe, G R; Hutchings, S J; Kusiak, R A; Lubin, J H; Morrison, H I; Tirmarche, M; Tomásek, L; Radford, E P

    1995-03-01

    Exposure to the radioactive gas radon and its progeny (222Rn and its radioactive decay products) has recently been linked to a variety of cancers other than lung cancer in geographic correlation studies of domestic radon exposure and in individual cohorts of occupationally exposed miners. This study was designed to characterize further the risks for cancers other than lung cancer (i.e., non-lung cancers) from atmospheric radon. Mortality from non-lung cancer was examined in a collaborative analysis of data from 11 cohorts of underground miners in which radon-related excesses of lung cancer had been established. The study included 64,209 men who were employed in the mines for 6.4 years on average, received average cumulative exposures of 155 working-level months (WLM), and were followed for 16.9 years on average. For all non-lung cancers combined, mortality was close to that expected from mortality rates in the areas surrounding the mines (ratio of observed to expected deaths [O/E] = 1.01; 95% confidence interval [CI] = 0.95-1.07, based on 1179 deaths), and mortality did not increase with increasing cumulative exposure. Among 28 individual cancer categories, statistically significant increases in mortality for cancers of the stomach (O/E = 1.33; 95% CI = 1.16-1.52) and liver (O/E = 1.73; 95% CI = 1.29-2.28) and statistically significant decreases for cancers of the tongue and mouth (O/E = 0.52; 95% CI = 0.26-0.93), pharynx (O/E = 0.35; 95% CI = 0.16-0.66), and colon (O/E = 0.77; 95% CI = 0.63-0.95) were observed. For leukemia, mortality was increased in the period less than 10 years since starting work (O/E = 1.93; 95% CI = 1.19-2.95) but not subsequently. For none of these diseases was mortality significantly related to cumulative exposure. Among the remaining individual categories of non-lung cancer, mortality was related to cumulative exposure only for cancer of the pancreas (excess relative risk per WLM = 0.07%; 95% CI = 0.01-0.12) and, in the period less than

  8. [Mechanism and Prospect of Radiotherapy Combined with Apotatinib
in the Treatment of Non-small Cell Lung Cancer].

    PubMed

    Liu, Guohui; Wang, Chunbo; E, Mingyan

    2017-12-20

    Non-small cell lung cancer is one of the most commom malignant tumor being harmful to people's life and health. Most of the patients have developed to the last stage which not suitable for surgical indications, so radiation and chemotherapy is the main treatment strategy. In recent years, with the theory of anti-angiogenesis therapy for malignant tumors, apatinib as a promising novel medicine to treat malignant tumors, represents synergistic antitumor effects in combination with radiotherapy. The underlying mechanisms may include make blood vessel normalization, alleviating inner hypoxia, and angiogenic factors regulation. Apatinib in combination with radiotherapy may become a new and effective treatment strategy of non-small cell lung cancer.

  9. CCR 20th Anniversary commentary: in search of cetuximab's first indication-combination therapy with irinotecan in colorectal cancer.

    PubMed

    Hicklin, Daniel J

    2015-04-01

    The research article by Prewett and colleagues, published in the May 1, 2002, issue of Clinical Cancer Research, provided important translational data that extended earlier preclinical and clinical studies with the human-murine chimeric anti-EGFR monoclonal antibody C225. Subsequent clinical trials with C225 led to the demonstration of its efficacy in combination with irinotecan and regulatory approval for the treatment of metastatic colorectal cancer. ©2015 American Association for Cancer Research.

  10. Clinicopathological significance of plasminogen activator inhibitor-1 promoter 4G/5G polymorphism in breast cancer: a meta-analysis.

    PubMed

    Lee, Ju-Han; Kim, Younghye; Choi, Jung-Woo; Kim, Young-Sik

    2013-01-01

    Plasminogen activator inhibitor type 1 (PAI-1) is associated with poor prognosis in breast cancer. Transcriptional expression of the PAI-1 can be controlled by PAI-1 promoter 4G/5G polymorphism. However, the significance of PAI-1 promoter 4G/5G polymorphism in breast cancer patients is contentious. To address this controversy, we conducted a meta-analysis for the relationships between PAI-1 promoter polymorphism and clinicopathological characteristics of breast cancer. Relevant published studies were identified using a search of PubMed, Embase, and the ISI Web of Science. The effect sizes of PAI-1 promoter 4G/5G polymorphism on breast cancer risk, lymph node metastasis, histologic grade, and overall survival were calculated by odds ratio (OR) or hazard ratio. The effect sizes were combined using a random-effects model. Individuals with 4G/4G genotype had a higher risk of breast cancer than those with the combined 4G/5G and 5G/5G genotypes (OR = 1.388; p = 0.031). Breast cancer patients with the 5G/5G genotype displayed lymph node metastasis more than patients with either the combined other genotypes (OR = 1.495; p = 0.027) or with the 4G/4G genotype (OR = 1.623; p = 0.018). However, the PAI-1 promoter 4G/5G polymorphism was not associated with histological grade or overall survival. PAI-1 promoter 4G/5G polymorphism is associated with a relatively increased risk of breast cancer development and lymph node metastasis. Copyright © 2013 IMSS. Published by Elsevier Inc. All rights reserved.

  11. Adoptive transfer of ex vivo expanded Vγ9Vδ2 T cells in combination with zoledronic acid inhibits cancer growth and limits osteolysis in a murine model of osteolytic breast cancer.

    PubMed

    Zysk, Aneta; DeNichilo, Mark O; Panagopoulos, Vasilios; Zinonos, Irene; Liapis, Vasilios; Hay, Shelley; Ingman, Wendy; Ponomarev, Vladimir; Atkins, Gerald; Findlay, David; Zannettino, Andrew; Evdokiou, Andreas

    2017-02-01

    Bone metastases occur in over 75% of patients with advanced breast cancer and are responsible for high levels of morbidity and mortality. In this study, ex vivo expanded cytotoxic Vγ9Vδ2 T cells isolated from human peripheral blood were tested for their anti-cancer efficacy in combination with zoledronic acid (ZOL), using a mouse model of osteolytic breast cancer. In vitro, expanded Vγ9Vδ2 T cells were cytotoxic against a panel of human breast cancer cell lines, and ZOL pre-treatment further sensitised breast cancer cells to killing by Vγ9Vδ2 T cells. Vγ9Vδ2 T cells adoptively transferred into NOD/SCID mice localised to osteolytic breast cancer lesions in the bone, and multiple infusions of Vγ9Vδ2 T cells reduced tumour growth in the bone. ZOL pre-treatment potentiated the anti-cancer efficacy of Vγ9Vδ2 T cells, with mice showing further reductions in tumour burden. Mice treated with the combination also had reduced tumour burden of secondary pulmonary metastases, and decreased bone degradation. Our data suggests that adoptive transfer of Vγ9Vδ2 T cell in combination with ZOL may prove an effective immunotherapeutic approach for the treatment of breast cancer bone metastases. Copyright © 2016. Published by Elsevier Ireland Ltd.

  12. Combining markers with and without the limit of detection

    PubMed Central

    Dong, Ting; Liu, Catherine Chunling; Petricoin, Emanuel F.; Tang, Liansheng Larry

    2014-01-01

    In this paper, we consider the combination of markers with and without the limit of detection (LOD). LOD is often encountered when measuring proteomic markers. Because of the limited detecting ability of an equipment or instrument, it is difficult to measure markers at a relatively low level. Suppose that after some monotonic transformation, the marker values approximately follow multivariate normal distributions. We propose to estimate distribution parameters while taking the LOD into account, and then combine markers using the results from the linear discriminant analysis. Our simulation results show that the ROC curve parameter estimates generated from the proposed method are much closer to the truth than simply using the linear discriminant analysis to combine markers without considering the LOD. In addition, we propose a procedure to select and combine a subset of markers when many candidate markers are available. The procedure based on the correlation among markers is different from a common understanding that a subset of the most accurate markers should be selected for the combination. The simulation studies show that the accuracy of a combined marker can be largely impacted by the correlation of marker measurements. Our methods are applied to a protein pathway dataset to combine proteomic biomarkers to distinguish cancer patients from non-cancer patients. PMID:24132938

  13. Trend Analysis of Cancer Mortality and Incidence in Panama, Using Joinpoint Regression Analysis.

    PubMed

    Politis, Michael; Higuera, Gladys; Chang, Lissette Raquel; Gomez, Beatriz; Bares, Juan; Motta, Jorge

    2015-06-01

    Cancer is one of the leading causes of death worldwide and its incidence is expected to increase in the future. In Panama, cancer is also one of the leading causes of death. In 1964, a nationwide cancer registry was started and it was restructured and improved in 2012. The aim of this study is to utilize Joinpoint regression analysis to study the trends of the incidence and mortality of cancer in Panama in the last decade. Cancer mortality was estimated from the Panamanian National Institute of Census and Statistics Registry for the period 2001 to 2011. Cancer incidence was estimated from the Panamanian National Cancer Registry for the period 2000 to 2009. The Joinpoint Regression Analysis program, version 4.0.4, was used to calculate trends by age-adjusted incidence and mortality rates for selected cancers. Overall, the trend of age-adjusted cancer mortality in Panama has declined over the last 10 years (-1.12% per year). The cancers for which there was a significant increase in the trend of mortality were female breast cancer and ovarian cancer; while the highest increases in incidence were shown for breast cancer, liver cancer, and prostate cancer. Significant decrease in the trend of mortality was evidenced for the following: prostate cancer, lung and bronchus cancer, and cervical cancer; with respect to incidence, only oral and pharynx cancer in both sexes had a significant decrease. Some cancers showed no significant trends in incidence or mortality. This study reveals contrasting trends in cancer incidence and mortality in Panama in the last decade. Although Panama is considered an upper middle income nation, this study demonstrates that some cancer mortality trends, like the ones seen in cervical and lung cancer, behave similarly to the ones seen in high income countries. In contrast, other types, like breast cancer, follow a pattern seen in countries undergoing a transition to a developed economy with its associated lifestyle, nutrition, and body weight

  14. Bevacizumab Plus Radiosurgery for Nonsquamous Non-Small Cell Lung Cancer Patients with Brain Metastases: Safe Combination?

    PubMed

    Guinde, Julien; Carron, Romain; Tomasini, Pascale; Greillier, Laurent; Régis, Jean; Barlesi, Fabrice

    2017-11-01

    In the context of bronchial cancers, the brain is one of the most frequent sites for metastases. Local treatments of these metastases have evolved and are often combined to obtain greater efficiency, while the main objective remains to reduce the symptoms. Radiosurgery is currently used as a primary option for patients harboring few numbers of small to middle-sized brain metastases. In nonsquamous non-small cell lung cancer (NSCLC), chemotherapy is often associated with bevacizumab. Our goal was to assess the safety of this early combination. Six patients with advanced nonsquamous NSCLC were treated with radiosurgery for the management of their brain metastases (n = 40), followed within <4 weeks by a treatment with bevacizumab. No systemic or cerebral adverse event of grade 3 (intratumoral or parenchymal hemorrhage) or unexpected toxicity secondary to bevacizumab has been indexed. Radiosurgery may be safely combined with bevacizumab quite early on for patients with nonsquamous NSCLC with brain metastases. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Telomerase reverse transcriptase locus polymorphisms and cancer risk: a field synopsis and meta-analysis.

    PubMed

    Mocellin, Simone; Verdi, Daunia; Pooley, Karen A; Landi, Maria T; Egan, Kathleen M; Baird, Duncan M; Prescott, Jennifer; De Vivo, Immaculata; Nitti, Donato

    2012-06-06

    Several recent studies have provided evidence that polymorphisms in the telomerase reverse transcriptase (TERT) gene sequence are associated with cancer development, but a comprehensive synopsis is not available. We conducted a systematic review and meta-analysis of the available molecular epidemiology data regarding the association between TERT locus polymorphisms and predisposition to cancer. A systematic review of the English literature was conducted by searching PubMed, Embase, Cancerlit, Google Scholar, and ISI Web of Knowledge databases for studies on associations between TERT locus polymorphisms and cancer risk. Random-effects meta-analysis was performed to pool per-allele odds ratios for TERT locus polymorphisms and risk of cancer, and between-study heterogeneity and potential bias sources (eg, publication and chasing bias) were assessed. Because the TERT locus includes the cleft lip and palate transmembrane 1-like (CLPTM1L) gene, which is in linkage disequilibrium with TERT, CLPTM1L polymorphisms were also analyzed. Cumulative evidence for polymorphisms with statistically significant associations was graded as "strong," "moderate," and "weak" according to the Venice criteria. The joint population attributable risk was calculated for polymorphisms with strong evidence of association. Eighty-five studies enrolling 490 901 subjects and reporting on 494 allelic contrasts were retrieved. Data were available on 67 TERT locus polymorphisms and 24 tumor types, for a total of 221 unique combinations of polymorphisms and cancer types. Upon meta-analysis, a statistically significant association with the risk of any cancer type was found for 22 polymorphisms. Strong, moderate, and weak cumulative evidence for association with at least one tumor type was demonstrated for 11, 9, and 14 polymorphisms, respectively. For lung cancer, which was the most studied tumor type, the estimated joint population attributable risk for three polymorphisms (TERT rs2736100, intergenic

  16. Telomerase Reverse Transcriptase Locus Polymorphisms and Cancer Risk: A Field Synopsis and Meta-Analysis

    PubMed Central

    Verdi, Daunia; Pooley, Karen A.; Landi, Maria T.; Egan, Kathleen M.; Baird, Duncan M.; Prescott, Jennifer; De Vivo, Immaculata; Nitti, Donato

    2012-01-01

    Background Several recent studies have provided evidence that polymorphisms in the telomerase reverse transcriptase (TERT) gene sequence are associated with cancer development, but a comprehensive synopsis is not available. We conducted a systematic review and meta-analysis of the available molecular epidemiology data regarding the association between TERT locus polymorphisms and predisposition to cancer. Methods A systematic review of the English literature was conducted by searching PubMed, Embase, Cancerlit, Google Scholar, and ISI Web of Knowledge databases for studies on associations between TERT locus polymorphisms and cancer risk. Random-effects meta-analysis was performed to pool per-allele odds ratios for TERT locus polymorphisms and risk of cancer, and between-study heterogeneity and potential bias sources (eg, publication and chasing bias) were assessed. Because the TERT locus includes the cleft lip and palate transmembrane 1-like (CLPTM1L) gene, which is in linkage disequilibrium with TERT, CLPTM1L polymorphisms were also analyzed. Cumulative evidence for polymorphisms with statistically significant associations was graded as “strong,” “moderate,” and “weak” according to the Venice criteria. The joint population attributable risk was calculated for polymorphisms with strong evidence of association. Results Eighty-five studies enrolling 490 901 subjects and reporting on 494 allelic contrasts were retrieved. Data were available on 67 TERT locus polymorphisms and 24 tumor types, for a total of 221 unique combinations of polymorphisms and cancer types. Upon meta-analysis, a statistically significant association with the risk of any cancer type was found for 22 polymorphisms. Strong, moderate, and weak cumulative evidence for association with at least one tumor type was demonstrated for 11, 9, and 14 polymorphisms, respectively. For lung cancer, which was the most studied tumor type, the estimated joint population attributable risk for three

  17. Association Between Cd Exposure and Risk of Prostate Cancer: A PRISMA-Compliant Systematic Review and Meta-Analysis.

    PubMed

    Ju-Kun, Song; Yuan, Dong-Bo; Rao, Hao-Fu; Chen, Tian-Fei; Luan, Bo-Shi; Xu, Xiao-Ming; Jiang, Fu-Neng; Zhong, Wei-De; Zhu, Jian-Guo

    2016-02-01

    Several observational studies on the association between Cd exposure and risk of prostate cancer have yielded inconsistent results. To address this issue, we conducted a meta-analysis to evaluate the correlation between Cd exposure and risk of prostate cancer.Relevant studies in PubMed and Embase databases were retrieved until October 2015. We compared the highest and lowest meta-analyses to quantitatively evaluate the relationship between Cd exposure and risk of prostate cancer. Summary estimates were obtained using a random-effects model.In the general population, high Cd exposure was not associated with increased prostate cancer (OR 1.21; 95% CI 0.91-1.64), whereas the combined standardized mortality ratio of the association between Cd exposure and risk of prostate cancer was 1.66 (95% CI 1.10-2.50) in populations exposed to occupational Cd. In addition, high D-Cd intake (OR 1.07; 95% CI 0.96-1.20) and U-Cd concentration (OR 0.86; 95% CI 0.48-1.55) among the general population was not related to the increased risk of prostate cancer. In the dose analysis, the summary relative risk was 1.07 (95% CI 0.73-1.57) for each 0.5 μg/g creatinine increase in U-Cd and 1.02 (95% CI 0.99-1.06) for each 10 μg/day increase of dietary Cd intake. However, compared with nonoccupational exposure, high occupational Cd exposure may be associated with the increased risk of prostate cancer.This meta-analysis suggests high Cd exposure as a risk factor for prostate cancer in occupational rather than nonoccupational populations. However, these results should be carefully interpreted because of the significant heterogeneity among studies. Additional large-scale and high-quality prospective studies are needed to confirm the association between Cd exposure and risk of prostate cancer.

  18. Survival analysis of colorectal cancer patients with tumor recurrence using global score test methodology

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Zain, Zakiyah, E-mail: zac@uum.edu.my; Ahmad, Yuhaniz, E-mail: yuhaniz@uum.edu.my; Azwan, Zairul, E-mail: zairulazwan@gmail.com, E-mail: farhanaraduan@gmail.com, E-mail: drisagap@yahoo.com

    Colorectal cancer is the third and the second most common cancer worldwide in men and women respectively, and the second in Malaysia for both genders. Surgery, chemotherapy and radiotherapy are among the options available for treatment of patients with colorectal cancer. In clinical trials, the main purpose is often to compare efficacy between experimental and control treatments. Treatment comparisons often involve several responses or endpoints, and this situation complicates the analysis. In the case of colorectal cancer, sets of responses concerned with survival times include: times from tumor removal until the first, the second and the third tumor recurrences, andmore » time to death. For a patient, the time to recurrence is correlated to the overall survival. In this study, global score test methodology is used in combining the univariate score statistics for comparing treatments with respect to each survival endpoint into a single statistic. The data of tumor recurrence and overall survival of colorectal cancer patients are taken from a Malaysian hospital. The results are found to be similar to those computed using the established Wei, Lin and Weissfeld method. Key factors such as ethnic, gender, age and stage at diagnose are also reported.« less

  19. Survival analysis of colorectal cancer patients with tumor recurrence using global score test methodology

    NASA Astrophysics Data System (ADS)

    Zain, Zakiyah; Aziz, Nazrina; Ahmad, Yuhaniz; Azwan, Zairul; Raduan, Farhana; Sagap, Ismail

    2014-12-01

    Colorectal cancer is the third and the second most common cancer worldwide in men and women respectively, and the second in Malaysia for both genders. Surgery, chemotherapy and radiotherapy are among the options available for treatment of patients with colorectal cancer. In clinical trials, the main purpose is often to compare efficacy between experimental and control treatments. Treatment comparisons often involve several responses or endpoints, and this situation complicates the analysis. In the case of colorectal cancer, sets of responses concerned with survival times include: times from tumor removal until the first, the second and the third tumor recurrences, and time to death. For a patient, the time to recurrence is correlated to the overall survival. In this study, global score test methodology is used in combining the univariate score statistics for comparing treatments with respect to each survival endpoint into a single statistic. The data of tumor recurrence and overall survival of colorectal cancer patients are taken from a Malaysian hospital. The results are found to be similar to those computed using the established Wei, Lin and Weissfeld method. Key factors such as ethnic, gender, age and stage at diagnose are also reported.

  20. Selenium Exposure and Cancer Risk: an Updated Meta-analysis and Meta-regression

    PubMed Central

    Cai, Xianlei; Wang, Chen; Yu, Wanqi; Fan, Wenjie; Wang, Shan; Shen, Ning; Wu, Pengcheng; Li, Xiuyang; Wang, Fudi

    2016-01-01

    The objective of this study was to investigate the associations between selenium exposure and cancer risk. We identified 69 studies and applied meta-analysis, meta-regression and dose-response analysis to obtain available evidence. The results indicated that high selenium exposure had a protective effect on cancer risk (pooled OR = 0.78; 95%CI: 0.73–0.83). The results of linear and nonlinear dose-response analysis indicated that high serum/plasma selenium and toenail selenium had the efficacy on cancer prevention. However, we did not find a protective efficacy of selenium supplement. High selenium exposure may have different effects on specific types of cancer. It decreased the risk of breast cancer, lung cancer, esophageal cancer, gastric cancer, and prostate cancer, but it was not associated with colorectal cancer, bladder cancer, and skin cancer. PMID:26786590

  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

    2017-12-01

    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;123:4583-4593. © 2017 American Cancer

  2. Effect of Combined 68Ga-PSMAHBED-CC Uptake Pattern and Multiparametric MRI Derived With Simultaneous PET/MRI in the Diagnosis of Primary Prostate Cancer: Initial Experience.

    PubMed

    Taneja, Sangeeta; Jena, Amarnath; Taneja, Rajesh; Singh, Aru; Ahuja, Aashim

    2018-06-01

    The purpose of this study is to assess whether temporal changes in 68 Ga-prostate-specific membrane antigen (PSMA)-HBED-CC uptake and multiparametric MRI parameters derived using PET/MRI can aid in characterization of benign and malignant prostate lesions. Thirty-five men with 29 malignant and six benign prostate lesions undergoing complete clinical workup including histologic analysis were enrolled for this retrospective study. All had undergone simultaneous whole-body 68 Ga-PSMAHBED-CC PET/MRI. Prostate Imaging Reporting and Data System version 2 (PI-RADSv2) assessment was made using a 5-point scale showing the likelihood of cancer with the combination of multiparametric MRI findings. Gallium-68-PSMA uptake was recorded at two time points: early (7 minutes) and delayed (54 minutes), adopting a copy-and-paste function of the ROI defined on MR images. ROC curve analysis was performed to test the diagnostic accuracy of early versus delayed PSMA uptake (measured as maximum standardized uptake value [SUV]). A multiple-ROI analysis was done to obtain ROCs for combined PET SUV and multiparametric MRI datasets. Spearman analysis was performed to assess the correlations. There was a significant difference between early and delayed PSMA uptake in malignant prostatic lesions (p < 0.01), which was able to characterize prostate lesions with an AUC of 0.83 and 0.94. Combined ROC analysis of PI-RADSv2 category derived from multiparametric MRI and differential PSMA uptake in characterizing prostatic lesions improved the AUC to 0.99. Dual-phase PSMA uptake improves accuracy of classifying malignant versus benign prostate lesions and complements multiparametric MRI in the diagnosis of prostate cancer.

  3. Combined Microsatellite Instability, MLH1 Methylation Analysis, and Immunohistochemistry for Lynch Syndrome Screening in Endometrial Cancers From GOG210: An NRG Oncology and Gynecologic Oncology Group Study.

    PubMed

    Goodfellow, Paul J; Billingsley, Caroline C; Lankes, Heather A; Ali, Shamshad; Cohn, David E; Broaddus, Russell J; Ramirez, Nilsa; Pritchard, Colin C; Hampel, Heather; Chassen, Alexis S; Simmons, Luke V; Schmidt, Amy P; Gao, Feng; Brinton, Louise A; Backes, Floor; Landrum, Lisa M; Geller, Melissa A; DiSilvestro, Paul A; Pearl, Michael L; Lele, Shashikant B; Powell, Matthew A; Zaino, Richard J; Mutch, David

    2015-12-20

    The best screening practice for Lynch syndrome (LS) in endometrial cancer (EC) remains unknown. We sought to determine whether tumor microsatellite instability (MSI) typing along with immunohistochemistry (IHC) and MLH1 methylation analysis can help identify women with LS. ECs from GOG210 patients were assessed for MSI, MLH1 methylation, and mismatch repair (MMR) protein expression. Each tumor was classified as having normal MMR, defective MMR associated with MLH1 methylation, or probable MMR mutation (ie, defective MMR but no methylation). Cancer family history and demographic and clinical features were compared for the three groups. Lynch mutation testing was performed for a subset of women. Analysis of 1,002 ECs suggested possible MMR mutation in 11.8% of tumors. The number of patients with a family history suggestive of LS was highest among women whose tumors were classified as probable MMR mutation (P = .001). Lynch mutations were identified in 41% of patient cases classified as probable mutation (21 of 51 tested). One of the MSH6 Lynch mutations was identified in a patient whose tumor had intact MSH6 expression. Age at diagnosis was younger for mutation carriers than noncarriers (54.3 v 62.3 years; P < .01), with five carriers diagnosed at age > 60 years. Combined MSI, methylation, and IHC analysis may prove useful in Lynch screening in EC. Twenty-four percent of mutation carriers presented with ECs at age > 60 years, and one carrier had an MSI-positive tumor with no IHC defect. Restricting Lynch testing to women diagnosed at age < 60 years or to women with IHC defects could result in missing a substantial fraction of genetic disease. © 2015 by American Society of Clinical Oncology.

  4. Combined Microsatellite Instability, MLH1 Methylation Analysis, and Immunohistochemistry for Lynch Syndrome Screening in Endometrial Cancers From GOG210: An NRG Oncology and Gynecologic Oncology Group Study

    PubMed Central

    Goodfellow, Paul J.; Billingsley, Caroline C.; Lankes, Heather A.; Ali, Shamshad; Cohn, David E.; Broaddus, Russell J.; Ramirez, Nilsa; Pritchard, Colin C.; Hampel, Heather; Chassen, Alexis S.; Simmons, Luke V.; Schmidt, Amy P.; Gao, Feng; Brinton, Louise A.; Backes, Floor; Landrum, Lisa M.; Geller, Melissa A.; DiSilvestro, Paul A.; Pearl, Michael L.; Lele, Shashikant B.; Powell, Matthew A.; Zaino, Richard J.; Mutch, David

    2015-01-01

    Purpose The best screening practice for Lynch syndrome (LS) in endometrial cancer (EC) remains unknown. We sought to determine whether tumor microsatellite instability (MSI) typing along with immunohistochemistry (IHC) and MLH1 methylation analysis can help identify women with LS. Patients and Methods ECs from GOG210 patients were assessed for MSI, MLH1 methylation, and mismatch repair (MMR) protein expression. Each tumor was classified as having normal MMR, defective MMR associated with MLH1 methylation, or probable MMR mutation (ie, defective MMR but no methylation). Cancer family history and demographic and clinical features were compared for the three groups. Lynch mutation testing was performed for a subset of women. Results Analysis of 1,002 ECs suggested possible MMR mutation in 11.8% of tumors. The number of patients with a family history suggestive of LS was highest among women whose tumors were classified as probable MMR mutation (P = .001). Lynch mutations were identified in 41% of patient cases classified as probable mutation (21 of 51 tested). One of the MSH6 Lynch mutations was identified in a patient whose tumor had intact MSH6 expression. Age at diagnosis was younger for mutation carriers than noncarriers (54.3 v 62.3 years; P < .01), with five carriers diagnosed at age > 60 years. Conclusion Combined MSI, methylation, and IHC analysis may prove useful in Lynch screening in EC. Twenty-four percent of mutation carriers presented with ECs at age > 60 years, and one carrier had an MSI-positive tumor with no IHC defect. Restricting Lynch testing to women diagnosed at age < 60 years or to women with IHC defects could result in missing a substantial fraction of genetic disease. PMID:26552419

  5. Exposure to secondhand tobacco smoke and lung cancer by histological type: a pooled analysis of the International Lung Cancer Consortium (ILCCO)

    PubMed Central

    Kim, Claire H; Lee, Yuan-Chin Amy; Hung, Rayjean J; McNallan, Sheila R; Cote, Michele L; Lim, Wei-Yen; Chang, Shen-Chih; Kim, Jin Hee; Ugolini, Donatella; Chen, Ying; Liloglou, Triantafillos; Andrew, Angeline S; Onega, Tracy; Duell, Eric J; Field, John K; Lazarus, Philip; Le Marchand, Loic; Neri, Monica; Vineis, Paolo; Kiyohara, Chikako; Hong, Yun-Chul; Morgenstern, Hal; Matsuo, Keitaro; Tajima, Kazuo; Christiani, David C; McLaughlin, John R; Bencko, Vladimir; Holcatova, Ivana; Boffetta, Paolo; Brennan, Paul; Fabianova, Eleonora; Foretova, Lenka; Janout, Vladimir; Lissowska, Jolanta; Mates, Dana; Rudnai, Peter; Szeszenia-Dabrowska, Neonila; Mukeria, Anush; Zaridze, David; Seow, Adeline; Schwartz, Ann G; Yang, Ping; Zhang, Zuo-Feng

    2014-01-01

    While the association between exposure to secondhand smoke and lung cancer risk is well established, few studies with sufficient power have examined the association by histological type. In this study, we evaluated the secondhand smoke-lung cancer relationship by histological type based on pooled data from 18 case-control studies in the International Lung Cancer Consortium (ILCCO), including 2,504 cases and 7,276 controls who were never smokers and 10,184 cases and 7,176 controls who were ever smokers. We used multivariable logistic regression, adjusting for age, sex, race/ethnicity, smoking status, pack-years of smoking, and study. Among never smokers, the odds ratios (OR) comparing those ever exposed to secondhand smoke with those never exposed were 1.31 (95% CI: 1.17–1.45) for all histological types combined, 1.26 (95% CI: 1.10–1.44) for adenocarcinoma, 1.41 (95% CI: 0.99–1.99) for squamous cell carcinoma, 1.48 (95% CI: 0.89–2.45) for large cell lung cancer, and 3.09 (95% CI: 1.62–5.89) for small cell lung cancer. The estimated association with secondhand smoke exposure was greater for small cell lung cancer than for non-small cell lung cancers (OR=2.11, 95% CI: 1.11–4.04). This analysis is the largest to date investigating the relation between exposure to secondhand smoke and lung cancer. Our study provides more precise estimates of the impact of secondhand smoke on the major histological types of lung cancer, indicates the association with secondhand smoke is stronger for small cell lung cancer than for the other histological types, and suggests the importance of intervention against exposure to secondhand smoke in lung cancer prevention. PMID:24615328

  6. Pathway and network analysis of cancer genomes.

    PubMed

    Creixell, Pau; Reimand, Jüri; Haider, Syed; Wu, Guanming; Shibata, Tatsuhiro; Vazquez, Miguel; Mustonen, Ville; Gonzalez-Perez, Abel; Pearson, John; Sander, Chris; Raphael, Benjamin J; Marks, Debora S; Ouellette, B F Francis; Valencia, Alfonso; Bader, Gary D; Boutros, Paul C; Stuart, Joshua M; Linding, Rune; Lopez-Bigas, Nuria; Stein, Lincoln D

    2015-07-01

    Genomic information on tumors from 50 cancer types cataloged by the International Cancer Genome Consortium (ICGC) shows that only a few well-studied driver genes are frequently mutated, in contrast to many infrequently mutated genes that may also contribute to tumor biology. Hence there has been large interest in developing pathway and network analysis methods that group genes and illuminate the processes involved. We provide an overview of these analysis techniques and show where they guide mechanistic and translational investigations.

  7. Combined Analysis of COX-2 and p53 Expressions Reveals Synergistic Inverse Correlations with Microsatellite Instability and CpG Island Methylator Phenotype in Colorectal Cancer1

    PubMed Central

    Ogino, Shuji; Brahmandam, Mohan; Kawasaki, Takako; Kirkner, Gregory J; Loda, Massimo; Fuchs, Charles S

    2006-01-01

    Abstract Cyclooxygenase-2 (COX-2) overexpression and mutations of p53 (a known COX-2 regulator) are inversely associated with microsatellite instability—high (MSI-H) and CpG island methylator phenotype (CIMP), characterized by extensive promoter methylation, is associated with MSI-H. However, no studies have comprehensively examined interrelations between COX-2, p53, MSI, and CIMP. Using MethyLight, we measured DNA methylation in five CIMP-specific gene promoters [CACNA1G, CDKN2A (p16/INK4A), CRABP1, MLH1, and NEUROG1] in relatively unbiased samples of 751 colorectal cancer cases obtained from two large prospective cohorts; 115 (15%) tumors were CIMP-high (≥ 4 of 5 methylated promoters), 251 (33%) were CIMP-low (1 to 3 methylated promoters), and the remaining 385 (51%) were CIMP-0 (no methylated promoters). CIMP-high tumors were much less frequent in COX-2+/p53+ tumors (4.6%) than in COX-2+/p53- tumors (19%; P < .0001), COX-2-/p53+ tumors (17%; P= .04), and COX-2-/p53- tumors (28%; P < .0001). In addition, COX-2+/p53+ tumors were significantly less common in MSI-H CIMP-high tumors (9.7%) than in non-MSI-H CIMP-low/CIMP-0 tumors (44–47%; P< .0001). In conclusion, COX-2 and p53 alterations were synergistically inversely correlated with both MSI-H and CIMP-high. Our data suggest that a combined analysis of COX-2 and p53 may be more useful for the molecular classification of colorectal cancer than either COX-2 or p53 analysis alone. PMID:16820091

  8. Chromium VI and stomach cancer: a meta-analysis of the current epidemiological evidence.

    PubMed

    Welling, Roberta; Beaumont, James J; Petersen, Scott J; Alexeeff, George V; Steinmaus, Craig

    2015-02-01

    Chromium VI (hexavalent chromium, Cr(VI)) is an established cause of lung cancer, but its association with gastrointestinal cancer is less clear. The goal of this study was to examine whether the current human epidemiological research on occupationally inhaled Cr(VI) supports the hypothesis that Cr(VI) is associated with human stomach cancer. Following a thorough literature search and review of individual studies, we used meta-analysis to summarise the current epidemiological literature on inhaled Cr(VI) and stomach cancer, explore major sources of heterogeneity, and assess other elements of causal inference. We identified 56 cohort and case-control studies and 74 individual relative risk (RR) estimates on stomach cancer and Cr(VI) exposure or work in an occupation associated with high Cr(VI) exposure including chromium production, chrome plating, leather work and work with Portland cement. The summary RR for all studies combined was 1.27 (95% CI 1.18 to 1.38). In analyses limited to only those studies identifying increased risks of lung cancer, the summary RR for stomach cancer was higher (RR=1.41, 95% CI 1.18 to 1.69). Overall, these results suggest that Cr(VI) is a stomach carcinogen in humans, which is consistent with the tumour results reported in rodent studies. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  9. Integrative analysis identifies targetable CREB1/FoxA1 transcriptional co-regulation as a predictor of prostate cancer recurrence.

    PubMed

    Sunkel, Benjamin; Wu, Dayong; Chen, Zhong; Wang, Chiou-Miin; Liu, Xiangtao; Ye, Zhenqing; Horning, Aaron M; Liu, Joseph; Mahalingam, Devalingam; Lopez-Nicora, Horacio; Lin, Chun-Lin; Goodfellow, Paul J; Clinton, Steven K; Jin, Victor X; Chen, Chun-Liang; Huang, Tim H-M; Wang, Qianben

    2016-05-19

    Identifying prostate cancer-driving transcription factors (TFs) in addition to the androgen receptor promises to improve our ability to effectively diagnose and treat this disease. We employed an integrative genomics analysis of master TFs CREB1 and FoxA1 in androgen-dependent prostate cancer (ADPC) and castration-resistant prostate cancer (CRPC) cell lines, primary prostate cancer tissues and circulating tumor cells (CTCs) to investigate their role in defining prostate cancer gene expression profiles. Combining genome-wide binding site and gene expression profiles we define CREB1 as a critical driver of pro-survival, cell cycle and metabolic transcription programs. We show that CREB1 and FoxA1 co-localize and mutually influence each other's binding to define disease-driving transcription profiles associated with advanced prostate cancer. Gene expression analysis in human prostate cancer samples found that CREB1/FoxA1 target gene panels predict prostate cancer recurrence. Finally, we showed that this signaling pathway is sensitive to compounds that inhibit the transcription co-regulatory factor MED1. These findings not only reveal a novel, global transcriptional co-regulatory function of CREB1 and FoxA1, but also suggest CREB1/FoxA1 signaling is a targetable driver of prostate cancer progression and serves as a biomarker of poor clinical outcomes. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

  10. Pleiotropic Analysis of Lung Cancer and Blood Triglycerides.

    PubMed

    Zuber, Verena; Marconett, Crystal N; Shi, Jianxin; Hua, Xing; Wheeler, William; Yang, Chenchen; Song, Lei; Dale, Anders M; Laplana, Marina; Risch, Angela; Witoelar, Aree; Thompson, Wesley K; Schork, Andrew J; Bettella, Francesco; Wang, Yunpeng; Djurovic, Srdjan; Zhou, Beiyun; Borok, Zea; van der Heijden, Henricus F M; de Graaf, Jacqueline; Swinkels, Dorine; Aben, Katja K; McKay, James; Hung, Rayjean J; Bikeböller, Heike; Stevens, Victoria L; Albanes, Demetrius; Caporaso, Neil E; Han, Younghun; Wei, Yongyue; Panadero, Maria Angeles; Mayordomo, Jose I; Christiani, David C; Kiemeney, Lambertus; Andreassen, Ole A; Houlston, Richard; Amos, Christopher I; Chatterjee, Nilanjan; Laird-Offringa, Ite A; Mills, Ian G; Landi, Maria Teresa

    2016-12-01

    Epidemiologically related traits may share genetic risk factors, and pleiotropic analysis could identify individual loci associated with these traits. Because of their shared epidemiological associations, we conducted pleiotropic analysis of genome-wide association studies of lung cancer (12 160 lung cancer case patients and 16 838 control subjects) and cardiovascular disease risk factors (blood lipids from 188 577 subjects, type 2 diabetes from 148 821 subjects, body mass index from 123 865 subjects, and smoking phenotypes from 74 053 subjects). We found that 6p22.1 (rs6904596, ZNF184) was associated with both lung cancer (P = 5.50x10(-6)) and blood triglycerides (P = 1.39x10(-5)). We replicated the association in 6097 lung cancer case patients and 204 657 control subjects (P = 2.40 × 10(-4)) and in 71 113 subjects with triglycerides data (P = .01). rs6904596 reached genome-wide significance in lung cancer meta-analysis (odds ratio = 1.15, 95% confidence interval = 1.10 to 1.21 ,: Pcombined = 5.20x10(-9)). The large sample size provided by the lipid GWAS data and the shared genetic risk factors between the two traits contributed to the uncovering of a hitherto unidentified genetic locus for lung cancer. Published by Oxford University Press 2016. This work is written by US Government employees and is in the public domain in the United States.

  11. National Patterns of Care and Outcomes after Combined Modality Therapy for Stage IIIA Non-small Cell Lung Cancer

    PubMed Central

    Patel, Aalok P.; Crabtree, Traves D.; Bell, Jennifer M.; Guthrie, Tracey J.; Robinson, Clifford G.; Morgensztern, Daniel; Colditz, Graham A.; Kreisel, Daniel; Krupnick, A. Sasha; Bradley, Jeffrey D.; Patterson, G. Alexander; Meyers, Bryan F.; Puri, Varun

    2014-01-01

    Introduction The role of surgery in addition to chemotherapy and radiation for stage IIIA non-small cell lung cancer (NSCLC) remains controversial. Since there is limited data on the benefit from surgery in this setting, we evaluated the use of combined modality therapy nationally, and explored the outcomes with and without the addition of surgery. Methods Patient variables and treatment-related outcomes were abstracted for patients with clinical stage IIIA NSCLC from the National Cancer Database. Patients receiving chemotherapy and radiation (CR) were compared to those undergoing chemotherapy, radiation, and surgery in any sequence (CRS). Results Between 1998 and 2010, 61339 patients underwent combined modality treatment for clinical stage IIIA NSCLC. Of these, 51979 (84.7%) received CR while 9360 (15.3%) underwent CRS. Patients in the CRS group were younger, more likely females and Caucasians, had smaller tumors and lower Charlson comorbidity scores. The 30-day surgical mortality was 200/8993 (2.2%). The median overall survival favored the CRS group in both unmatched (32.4 months vs. 15.7 months, p<.001) and matched analysis based on patient characteristics (34.3 months vs. 18.4months, p<.001). Conclusion There is significant heterogeneity in the treatment of stage IIIA NSCLC in the United States. Patients selected for surgery in addition to chemoradiation therapy appear to have better long-term survival. PMID:24722151

  12. Endoscopic analysis of colorectal serrated lesions with cancer.

    PubMed

    Nagata, Shuichiro; Mitsuyama, Keiichi; Kawano, Hiroshi; Noda, Tetsuhiro; Maeyama, Yasuhiko; Mukasa, Michita; Takedatsu, Hidetoshi; Yoshioka, Shinichiro; Kuwaki, Kotaro; Akiba, Jun; Tsuruta, Osamu; Torimura, Takuji

    2018-06-01

    Serrated lesions, including hyperplastic polyps (HPs), traditional serrated adenomas (TSAs) and sessile serrated adenomas/polyps (SSA/Ps), are important contributors to colorectal carcinogenesis. The aim of the present study was to analyze the potential of conventional endoscopy and advanced endoscopic imaging techniques to delineate the characteristic features of serrated lesions with cancer. The present study was a retrospective analysis of the data of 168 patients who had undergone colonoscopy, and a total of 228 serrated lesions (77 HPs, 58 TSAs, 84 SSA/Ps, 9 SSA/P plus TSAs) have been identified in these patients. A cancer component was identified in 2.6% of HPs, 13.8% of TSAs and 10.7% of SSA/Ps, but none of SSA/P plus TSAs. Compared with the lesions without cancer, the lesions with cancer exhibited a larger size (HP, TSA and SSA/P), a reddish appearance (SSA/P), a two-tier raised appearance (HP and SSA/P), a central depression (HP, TSA and SSA/P), the type V pit pattern (HP, TSA and SSA/P), and/or the type III capillary pattern (TSA and SSA/P). Deep invasion was identified in 50.0% of HPs, 12.5% of TSAs and 55.6% of SSA/Ps with cancer. The Ki-67 proliferative zone was distributed diffusely within the area of the cancer, but partially within the non-cancer area of HPs, TSAs and SSA/Ps. The lesion types were also analyzed on the basis of mucin phenotype. The present study suggested that a detailed endoscopic analysis of serrated lesions with cancer is useful for delineating characteristic features, and the analysis aids treatment selection.

  13. Treatment with docetaxel in combination with Aneustat leads to potent inhibition of metastasis in a patient-derived xenograft model of advanced prostate cancer

    PubMed Central

    Qu, Sifeng; Ci, Xinpei; Xue, Hui; Dong, Xin; Hao, Jun; Lin, Dong; Clermont, Pier-Luc; Wu, Rebecca; Collins, Colin C; Gout, Peter W; Wang, Yuzhuo

    2018-01-01

    Background: Docetaxel used for first-line treatment of advanced prostate cancer (PCa) is only marginally effective. We previously showed, using the LTL-313H subrenal capsule patient-derived metastatic PCa xenograft model, that docetaxel combined with Aneustat (OMN54), a multivalent plant-derived therapeutic, led to marked synergistic tumour growth inhibition. Here, we investigated the effect of docetaxel+Aneustat on metastasis. Methods: C4-2 cells were incubated with docetaxel, Aneustat and docetaxel+Aneustat to assess effects on cell migration. The LTL-313H model, similarly treated, was analysed for effects on lung micro-metastasis and kidney invasion. The LTL-313H gene expression profile was compared with profiles of PCa patients (obtained from Oncomine) and subjected to IPA to determine involvement of cancer driver genes. Results: Docetaxel+Aneustat markedly inhibited C4-2 cell migration and LTL-313H lung micro-metastasis/kidney invasion. Oncomine analysis indicated that treatment with docetaxel+Aneustat was associated with improved patient outcome. The drug combination markedly downregulated expression of cancer driver genes such as FOXM1 (and FOXM1-target genes). FOXM1 overexpression reduced the anti-metastatic activity of docetaxel+Aneustat. Conclusions: Docetaxel+Aneustat can inhibit PCa tissue invasion and metastasis. This activity appears to be based on reduced expression of cancer driver genes such as FOXM1. Use of docetaxel+Aneustat may provide a new, more effective regimen for therapy of metastatic PCa. PMID:29381682

  14. Cancer treatment by photodynamic therapy combined with NK-cell-line-based adoptive immunotherapy

    NASA Astrophysics Data System (ADS)

    Korbelik, Mladen; Sun, Jinghai

    1998-05-01

    Treatment of solid cancers by photodynamic therapy (PDT) triggers a strong acute inflammatory reaction localized to the illuminated malignant tissue. This event is regulated by a massive release of various potent mediators which have a profound effect not only on local host cell populations, but also attract different types of immune cells to the treated tumor. Phagocytosis of PDT-damaged cancerous cells by antigen presenting cells, such as activated tumor associated macrophages, enables the recognition of even poorly immunogenic tumors by specific immune effector cells and the generation of immune memory populations. Because of its inflammatory/immune character, PDT is exceptionally responsive to adjuvant treatments with various types of immunotherapy. Combining PDT with immuneactivators, such as cytokines or other specific or non-specific immune agents, rendered marked improvements in tumor cures with various cancer models. Another clinically attractive strategy is adoptive immunotherapy, and the prospects of its use in conjunction with PDT are outlined.

  15. Combination Therapy Targeting BCL6 and Phospho-STAT3 Defeats Intratumor Heterogeneity in a Subset of Non-Small Cell Lung Cancers. | Office of Cancer Genomics

    Cancer.gov

    Oncogene-specific changes in cellular signaling have been widely observed in lung cancer. Here, we investigated how these alterations could affect signaling heterogeneity and suggest novel therapeutic strategies. We compared signaling changes across six human bronchial epithelial cell (HBEC) strains that were systematically transformed with various combinations of TP53, KRAS, and MYC-oncogenic alterations commonly found in non-small cell lung cancer (NSCLC).

  16. [A Case of Pancreatic Head Cancer Treated with Pancreaticoduodenectomy Combined with Hepatic Artery Resection Following Neoadjuvant Chemotherapy].

    PubMed

    Maeda, Shintaro; Takano, Shigetsugu; Shimizu, Hiroaki; Ohtsuka, Masayuki; Kato, Atsushi; Yoshitomi, Hideyuki; Furukawa, Katsunori; Takayashiki, Tsukasa; Kuboki, Satoshi; Suzuki, Daisuke; Sakai, Nozomu; Kagawa, Shingo; Miyazaki, Masaru

    2015-11-01

    A 70-year-old woman was diagnosed with pancreatic head cancer with hepatic artery invasion by multi-detector computed tomography (MD-CT). After 3 courses of gemcitabine plus S-1 neoadjuvant therapy, the tumor size was not diminished; however, the tumor marker CA19-9 level was decreased to less than 90% of its initial level. Pancreaticoduodenectomy combined with hepatic artery resection was performed, and an end-to-end anastomosis was made between the common and proper hepatic artery to reconstruct the hepatic artery. The pathological examination indicated adenosquamous carcinoma, no vascular invasion, and negative margin status, and the efficacy of chemotherapy was classified as GradeⅡb using Evans' classification. Usually, pancreatic head cancer with hepatic artery invasion is considered unresectable due to its high morbidity/mortality and poor prognosis. However, with the recently developed surgical strategy and appropriate therapeutic interventions, such as a combination of neoadjuvant chemotherapy and resection/reconstruction of the hepatic artery, a curative operation can be feasible for locally advanced pancreatic head cancer.

  17. Soy Consumption and the Risk of Prostate Cancer: An Updated Systematic Review and Meta-Analysis

    PubMed Central

    Ranard, Katherine M.; Jeon, Sookyoung; Erdman, John W.

    2018-01-01

    Prostate cancer (PCa) is the second most commonly diagnosed cancer in men, accounting for 15% of all cancers in men worldwide. Asian populations consume soy foods as part of a regular diet, which may contribute to the lower PCa incidence observed in these countries. This meta-analysis provides a comprehensive updated analysis that builds on previously published meta-analyses, demonstrating that soy foods and their isoflavones (genistein and daidzein) are associated with a lower risk of prostate carcinogenesis. Thirty articles were included for analysis of the potential impacts of soy food intake, isoflavone intake, and circulating isoflavone levels, on both primary and advanced PCa. Total soy food (p < 0.001), genistein (p = 0.008), daidzein (p = 0.018), and unfermented soy food (p < 0.001) intakes were significantly associated with a reduced risk of PCa. Fermented soy food intake, total isoflavone intake, and circulating isoflavones were not associated with PCa risk. Neither soy food intake nor circulating isoflavones were associated with advanced PCa risk, although very few studies currently exist to examine potential associations. Combined, this evidence from observational studies shows a statistically significant association between soy consumption and decreased PCa risk. Further studies are required to support soy consumption as a prophylactic dietary approach to reduce PCa carcinogenesis. PMID:29300347

  18. The effect of fruit and vegetable intake on the development of lung cancer: a meta-analysis of 32 publications and 20,414 cases.

    PubMed

    Wang, M; Qin, S; Zhang, T; Song, X; Zhang, S

    2015-11-01

    Quantification of the association between the intake of vegetables and fruits and the risk of lung cancer is controversial. Thus, we conducted a meta-analysis to assess the relationship between vegetables and fruits and lung cancer risk. Pertinent studies were identified by a search in PubMed and Web of Knowledge. Random-effects models were used to calculate summary relative risks (RR) and the corresponding 95% confidence intervals (CI). Publication bias was estimated using Begg's test. Finally, 30 articles with 37 studies comprising of 20,075 lung cancer cases for vegetables intake with lung cancer risk and 31 articles with 38 studies comprising of 20,213 lung cancer cases for fruits intake with lung cancer risk were included in this meta-analysis. The combined results showed that there were significant associations between vegetables and fruits intake and lung cancer risk. The pooled RR were 0.74 (95% CI: 0.67, 0.82) for vegetables and 0.80 (95% CI: 0.74, 0.88) for fruits. Significant association was found in females on vegetables intake and lung cancer but not in males. The association was also stronger in females than males on fruits intake and lung cancer risk. No publication bias was detected. Our analysis indicated that intake of vegetables and fruits may have a protective effect on lung cancer, and the associations were stronger in females. As the potential biases and confounders could not be ruled out completely in this meta-analysis, further studies are needed.

  19. Combination Treatment with Apricoxib and IL-27 Enhances Inhibition of Epithelial-Mesenchymal Transition in Human Lung Cancer Cells through a STAT1 Dominant Pathway

    PubMed Central

    Lee, Mi-Heon; Kachroo, Puja; Pagano, Paul C; Yanagawa, Jane; Wang, Gerald; Walser, Tonya C; Krysan, Kostyantyn; Sharma, Sherven; John, Maie St.; Dubinett, Steven M; Lee, Jay M

    2015-01-01

    Background The cyclooxygenase 2 (COX-2) pathway has been implicated in the molecular pathogenesis of many malignancies, including lung cancer. Apricoxib, a selective COX-2 inhibitor, has been described to inhibit epithelial-mesenchymal transition (EMT) in human malignancies. The mechanism by which apricoxib may alter the tumor microenvironment by affecting EMT through other important signaling pathways is poorly defined. IL-27 has been shown to have anti-tumor activity and our recent study showed that IL-27 inhibited EMT through a STAT1 dominant pathway. Objective The purpose of this study is to investigate the role of apricoxib combined with IL-27 in inhibiting lung carcinogenesis by modulation of EMT through STAT signaling. Methods and Results Western blot analysis revealed that IL-27 stimulation of human non-small cell lung cancer (NSCLC) cell lines results in STAT1 and STAT3 activation, decreased Snail protein and mesenchymal markers (N-cadherin and vimentin) and a concomitant increase in expression of epithelial markers (E-cadherin, β-and γ-catenins), and inhibition of cell migration. The combination of apricoxib and IL-27 resulted in augmentation of STAT1 activation. However, IL-27 mediated STAT3 activation was decreased by the addition of apricoxib. STAT1 siRNA was used to determine the involvement of STAT1 pathway in the enhanced inhibition of EMT and cell migration by the combined IL-27 and apricoxib treatment. Pretreatment of cells with STAT1 siRNA inhibited the effect of combined IL-27 and apricoxib in the activation of STAT1 and STAT3. In addition, the augmented expression of epithelial markers, decreased expression mesenchymal markers, and inhibited cell migration by the combination treatment were also inhibited by STAT1 siRNA, suggesting that the STAT1 pathway is important in the enhanced effect from the combination treatment. Conclusion Combined apricoxib and IL-27 has an enhanced effect in inhibition of epithelial-mesenchymal transition and cell

  20. Combination PI3K/MEK inhibition promotes tumor apoptosis and regression in PIK3CA wild-type, KRAS mutant colorectal cancer

    PubMed Central

    Roper, Jatin; Sinnamon, Mark J.; Coffee, Erin M.; Belmont, Peter; Keung, Lily; Georgeon-Richard, Larissa; Wang, Wei Vivian; Faber, Anthony C.; Yun, Jihye; Yilmaz, Omer H.; Bronson, Roderick T.; Martin, Eric S.; Tsichlis, Philip N.; Hung, Kenneth E.

    2014-01-01

    PI3K inhibition in combination with other agents has not been studied in the context of PIK3CA wild-type, KRAS mutant cancer. In a screen of phospho-kinases, PI3K inhibition of KRAS mutant colorectal cancer cells activated the MAPK pathway. Combination PI3K/MEK inhibition with NVP-BKM120 and PD-0325901 induced tumor regression in a mouse model of PIK3CA wild-type, KRAS mutant colorectal cancer, which was mediated by inhibition of mTORC1, inhibition of MCL-1, and activation of BIM. These findings implicate mitochondrial-dependent apoptotic mechanisms as determinants for the efficacy of PI3K/MEK inhibition in the treatment of PIK3CA wild-type, KRAS mutant cancer. PMID:24576621

  1. Effects of Nurse-Led Telephone-Based Supportive Interventions for Patients With Cancer: A Meta-Analysis.

    PubMed

    Suh, Soon-Rim; Lee, Myung Kyung

    2017-07-01

    To evaluate the effects of nurse-led telephone-based supportive interventions (NTSIs) for patients with cancer.
. Electronic databases, including EMBASE®, MEDLINE, Google Scholar, 
Cochrane Library CENTRAL, ProQuest Medical Library, and CINAHL®, were searched through February 2016.
. 239 studies were identified; 16 were suitable for meta-analysis. Cochrane's risk of bias tool and the Comprehensive Meta-Analysis software were used.
. The authors performed a meta-analysis of 16 trials that met eligibility criteria. Thirteen randomized, controlled trials (RCTs) and three non-RCTs examined a total of 2,912 patients with cancer. Patients who received NTSIs were compared with those who received attentional control or usual care (no intervention).
. Telephone interventions delivered by a nurse in an oncology care setting reduced cancer symptoms with a moderate effect size (ES) (-0.33) and emotional distress with a small ES (-0.12), and improved self-care with a large ES (0.64) and health-related quality of life (HRQOL) with a small ES (0.3). Subgroup analyses indicated that the significant effects of NTSIs on cancer symptoms, emotional distress, and HRQOL were larger for studies that combined an application of a theoretical framework, had a control group given usual care, and used an RTC design.
. The findings suggest that an additional tiered evaluation that has a theoretical underpinning and high-quality methodology is required to confirm the efficacy of NTSI for adoption of specific care models.

  2. Combination therapy with dendritic cells and lenalidomide is an effective approach to enhance antitumor immunity in a mouse colon cancer model.

    PubMed

    Vo, Manh-Cuong; Nguyen-Pham, Thanh-Nhan; Lee, Hyun-Ju; Jaya Lakshmi, Thangaraj; Yang, Seoyun; Jung, Sung-Hoon; Kim, Hyeoung-Joon; Lee, Je-Jung

    2017-04-18

    In this study, we investigated efficacy of lenalidomide in combination with tumor antigen-loaded dendritic cells (DCs) in murine colon cancer model. MC-38 cell lines were injected subcutaneously to establish colon cancer-bearing mice. After tumor growth, lenalidomide (50 mg/kg/day) was injected intraperitoneally on 3 consecutive days in combination with tumor antigen-loaded DC vaccination on days 8, 12, 16, and 20. The tumor antigen-loaded DCs plus lenalidomide combination treatment exhibited a significant inhibition of tumor growth compared with the other groups. These effects were associated with a reduction in immune suppressor cells, such as myeloid-derived suppressor cells and regulatory T cells, with the induction of immune effector cells, such as natural killer cells, CD4+ T cells and CD8+ T cells in spleen, and with the activation of cytotoxic T lymphocytes and NK cells. This study suggests that a combination of tumor antigen-loaded DC vaccination and lenalidomide synergistically enhanced antitumor immune response in the murine colon cancer model, by inhibiting the generation of immune suppressive cells and recovery of effector cells, and demonstrated superior polarization of Th1/Th2 balance in favor of Th1 immune response. This combination approach with DCs and lenalidomide may provide a new therapeutic option to improve the treatment of colon cancer.

  3. The classification of lung cancers and their degree of malignancy by FTIR, PCA-LDA analysis, and a physics-based computational model.

    PubMed

    Kaznowska, E; Depciuch, J; Łach, K; Kołodziej, M; Koziorowska, A; Vongsvivut, J; Zawlik, I; Cholewa, M; Cebulski, J

    2018-08-15

    Lung cancer has the highest mortality rate of all malignant tumours. The current effects of cancer treatment, as well as its diagnostics, are unsatisfactory. Therefore it is very important to introduce modern diagnostic tools, which will allow for rapid classification of lung cancers and their degree of malignancy. For this purpose, the authors propose the use of Fourier Transform InfraRed (FTIR) spectroscopy combined with Principal Component Analysis-Linear Discriminant Analysis (PCA-LDA) and a physics-based computational model. The results obtained for lung cancer tissues, adenocarcinoma and squamous cell carcinoma FTIR spectra, show a shift in wavenumbers compared to control tissue FTIR spectra. Furthermore, in the FTIR spectra of adenocarcinoma there are no peaks corresponding to glutamate or phospholipid functional groups. Moreover, in the case of G2 and G3 malignancy of adenocarcinoma lung cancer, the absence of an OH groups peak was noticed. Thus, it seems that FTIR spectroscopy is a valuable tool to classify lung cancer and to determine the degree of its malignancy. Copyright © 2018 Elsevier B.V. All rights reserved.

  4. Novel Biomarker Candidates for Colorectal Cancer Metastasis: A Meta-analysis of In Vitro Studies

    PubMed Central

    Long, Nguyen Phuoc; Lee, Wun Jun; Huy, Nguyen Truong; Lee, Seul Ji; Park, Jeong Hill; Kwon, Sung Won

    2016-01-01

    Colorectal cancer (CRC) is one of the most common and lethal cancers. Although numerous studies have evaluated potential biomarkers for early diagnosis, current biomarkers have failed to reach an acceptable level of accuracy for distant metastasis. In this paper, we performed a gene set meta-analysis of in vitro microarray studies and combined the results from this study with previously published proteomic data to validate and suggest prognostic candidates for CRC metastasis. Two microarray data sets included found 21 significant genes. Of these significant genes, ALDOA, IL8 (CXCL8), and PARP4 had strong potential as prognostic candidates. LAMB2, MCM7, CXCL23A, SERPINA3, ABCA3, ALDH3A2, and POLR2I also have potential. Other candidates were more controversial, possibly because of the biologic heterogeneity of tumor cells, which is a major obstacle to predicting metastasis. In conclusion, we demonstrated a meta-analysis approach and successfully suggested ten biomarker candidates for future investigation. PMID:27688707

  5. Novel Biomarker Candidates for Colorectal Cancer Metastasis: A Meta-analysis of In Vitro Studies.

    PubMed

    Long, Nguyen Phuoc; Lee, Wun Jun; Huy, Nguyen Truong; Lee, Seul Ji; Park, Jeong Hill; Kwon, Sung Won

    2016-01-01

    Colorectal cancer (CRC) is one of the most common and lethal cancers. Although numerous studies have evaluated potential biomarkers for early diagnosis, current biomarkers have failed to reach an acceptable level of accuracy for distant metastasis. In this paper, we performed a gene set meta-analysis of in vitro microarray studies and combined the results from this study with previously published proteomic data to validate and suggest prognostic candidates for CRC metastasis. Two microarray data sets included found 21 significant genes. Of these significant genes, ALDOA, IL8 (CXCL8), and PARP4 had strong potential as prognostic candidates. LAMB2, MCM7, CXCL23A, SERPINA3, ABCA3, ALDH3A2, and POLR2I also have potential. Other candidates were more controversial, possibly because of the biologic heterogeneity of tumor cells, which is a major obstacle to predicting metastasis. In conclusion, we demonstrated a meta-analysis approach and successfully suggested ten biomarker candidates for future investigation.

  6. Cost-Utility Analysis of Cancer Prevention, Treatment, and Control

    PubMed Central

    Winn, Aaron N.; Ekwueme, Donatus U.; Guy, Gery P.; Neumann, Peter J.

    2018-01-01

    Context Substantial innovation related to cancer prevention and treatment has occurred in recent decades. However, these innovations have often come at a significant cost. Cost-utility analysis provides a useful framework to assess if the benefits from innovation are worth the additional cost. This systematic review on published cost-utility analyses related to cancer care is from 1988 through 2013. Analyses were conducted in 2013–2015. Evidence acquisition This review analyzed data from the Tufts Medical Center Cost-Effectiveness Analysis Registry (www.cearegistry.org), a comprehensive registry with detailed information on 4,339 original cost-utility analyses published in the peer-reviewed medical and economic literature through 2013. Evidence synthesis There were 721 cancer-related cost-utility analyses published from 1998 through 2013, with roughly 12% of studies focused on primary prevention and 17% focused on secondary prevention. The most often studied cancers were breast cancer (29%); colorectal cancer (11%); and prostate cancer (8%). The median reported incremental cost-effectiveness ratios (in 2014 U.S. dollars) were $25,000 for breast cancer, $24,000 for colorectal cancer, and $34,000 for prostate cancer. Conclusions The current evidence indicates that there are many interventions that are cost effective across cancer sites and levels of prevention. However, the results highlight the relatively small number of cancer cost-utility analyses devoted to primary prevention compared with secondary or tertiary prevention. PMID:26470806

  7. Combination of somatostatin analog, dexamethasone, and standard androgen ablation therapy in stage D3 prostate cancer patients with bone metastases.

    PubMed

    Koutsilieris, Michael; Mitsiades, Constantine S; Bogdanos, John; Dimopoulos, Theodoros; Karamanolakis, Dimitrios; Milathianakis, Constantine; Tsintavis, Athanassios

    2004-07-01

    Androgen ablation-refractory prostate cancer patients (stage D3) develop painful bone metastases and limited responsiveness to conventional therapies, hence the lack of universally accepted "gold standard" treatment for this poor prognosis clinical setting. We tested the safety and efficacy in stage D3 patients of the combination hormonal therapy, which combines administration of somatostatin analog and dexamethasone with standard androgen ablation monotherapy (luteinizing-hormone releasing-hormone analog or orchiectomy). Thirty eight patients with stage D3 prostate cancer (mean age 71.8 +/- 5.9 years) continued receiving androgen ablation therapy in combination with oral dexamethasone (4 mg daily for the 1st month of treatment, tapered down to 1 mg daily by the 4th month, with 1 mg daily maintenance dose thereafter) and somatostatin analog (20 mg octreotide i.m. injections every 28 days). Twenty-three of 38 patients (60.5%) receiving this combination regimen had partial responses [PR, >/=50% prostate-specific antigen (PSA) decline], 9 (21.1%) had stable disease, and 7 (18.4%) had progressive disease. In 47.7% (18 of 38) of patients, their serum PSA levels decreased with treatment but did not return to their respective baselines until the end of follow-up (or death from non-prostate cancer-related causes). The median time-to-return to baseline PSA was 12 months (95% CI, 7-17 months), median progression-free survival was 7 months (95% CI, 4.5-9.5 months), median overall survival was 14 months (95% CI, 10.7-17.4 months), and median prostate cancer-specific overall survival (defined as time from onset of combination therapy until prostate cancer-related death) was 16.0 months (95% CI, 11.9-20.1 months). All patients reported significant and durable improvement of bone pain and performance status (for a median duration of 14 months; 95% CI, 9-19 months), without major treatment-related side effects. We observed a statistically significant (P < 0.01) reduction in serum

  8. Core–Shell Nanoparticle-Based Peptide Therapeutics and Combined Hyperthermia for Enhanced Cancer Cell Apoptosis

    PubMed Central

    2015-01-01

    Mitochondria-targeting peptides have garnered immense interest as potential chemotherapeutics in recent years. However, there is a clear need to develop strategies to overcome the critical limitations of peptides, such as poor solubility and the lack of target specificity, which impede their clinical applications. To this end, we report magnetic core–shell nanoparticle (MCNP)-mediated delivery of a mitochondria-targeting pro-apoptotic amphipathic tail-anchoring peptide (ATAP) to malignant brain and metastatic breast cancer cells. Conjugation of ATAP to the MCNPs significantly enhanced the chemotherapeutic efficacy of ATAP, while the presence of targeting ligands afforded selective delivery to cancer cells. Induction of MCNP-mediated hyperthermia further potentiated the efficacy of ATAP. In summary, a combination of MCNP-mediated ATAP delivery and subsequent hyperthermia resulted in an enhanced effect on mitochondrial dysfunction, thus resulting in increased cancer cell apoptosis. PMID:25133971

  9. Integrated analysis of gene expression and methylation profiles of 48 candidate genes in breast cancer patients.

    PubMed

    Li, Zibo; Heng, Jianfu; Yan, Jinhua; Guo, Xinwu; Tang, Lili; Chen, Ming; Peng, Limin; Wu, Yepeng; Wang, Shouman; Xiao, Zhi; Deng, Zhongping; Dai, Lizhong; Wang, Jun

    2016-11-01

    Gene-specific methylation and expression have shown biological and clinical importance for breast cancer diagnosis and prognosis. Integrated analysis of gene methylation and gene expression may identify genes associated with biology mechanism and clinical outcome of breast cancer and aid in clinical management. Using high-throughput microfluidic quantitative PCR, we analyzed the expression profiles of 48 candidate genes in 96 Chinese breast cancer patients and investigated their correlation with gene methylation and associations with breast cancer clinical parameters. Breast cancer-specific gene expression alternation was found in 25 genes with significant expression difference between paired tumor and normal tissues. A total of 9 genes (CCND2, EGFR, GSTP1, PGR, PTGS2, RECK, SOX17, TNFRSF10D, and WIF1) showed significant negative correlation between methylation and gene expression, which were validated in the TCGA database. Total 23 genes (ACADL, APC, BRCA2, CADM1, CAV1, CCND2, CST6, EGFR, ESR2, GSTP1, ICAM5, NPY, PGR, PTGS2, RECK, RUNX3, SFRP1, SOX17, SYK, TGFBR2, TNFRSF10D, WIF1, and WRN) annotated with potential TFBSs in the promoter regions showed negative correlation between methylation and expression. In logistics regression analysis, 31 of the 48 genes showed improved performance in disease prediction with combination of methylation and expression coefficient. Our results demonstrated the complex correlation and the possible regulatory mechanisms between DNA methylation and gene expression. Integration analysis of methylation and expression of candidate genes could improve performance in breast cancer prediction. These findings would contribute to molecular characterization and identification of biomarkers for potential clinical applications.

  10. Selenium Metabolism in Cancer Cells: The Combined Application of XAS and XFM Techniques to the Problem of Selenium Speciation in Biological Systems

    PubMed Central

    Weekley, Claire M.; Aitken, Jade B.; Finney, Lydia; Vogt, Stefan; Witting, Paul K.; Harris, Hugh H.

    2013-01-01

    Determining the speciation of selenium in vivo is crucial to understanding the biological activity of this essential element, which is a popular dietary supplement due to its anti-cancer properties. Hyphenated techniques that combine separation and detection methods are traditionally and effectively used in selenium speciation analysis, but require extensive sample preparation that may affect speciation. Synchrotron-based X-ray absorption and fluorescence techniques offer an alternative approach to selenium speciation analysis that requires minimal sample preparation. We present a brief summary of some key HPLC-ICP-MS and ESI-MS/MS studies of the speciation of selenium in cells and rat tissues. We review the results of a top-down approach to selenium speciation in human lung cancer cells that aims to link the speciation and distribution of selenium to its biological activity using a combination of X-ray absorption spectroscopy (XAS) and X-ray fluorescence microscopy (XFM). The results of this approach highlight the distinct fates of selenomethionine, methylselenocysteine and selenite in terms of their speciation and distribution within cells: organic selenium metabolites were widely distributed throughout the cells, whereas inorganic selenium metabolites were compartmentalized and associated with copper. New data from the XFM mapping of electrophoretically-separated cell lysates show the distribution of selenium in the proteins of selenomethionine-treated cells. Future applications of this top-down approach are discussed. PMID:23698165

  11. Synergistic Effect of Curcumin in Combination with Anticancer Agents in Human Retinoblastoma Cancer Cell Lines.

    PubMed

    Sreenivasan, Seethalakshmi; Krishnakumar, Subramanian

    2015-01-01

    Curcumin (diferuloylmethane), a phenolic compound obtained from the rhizome of the herb Curcuma longa, is known to have anti-proliferative and anti-tumor properties. In this study, we evaluated the cytotoxic effect of curcumin alone and in combination with individual drugs like carboplatin, etoposide, or vincristine in a human retinoblastoma (RB) cancer cell line. A drug-drug interaction was analyzed using the median effect/isobologram method and combination index values were used to characterize the interaction as synergistic or additive. We also performed the apoptosis and cell-cycle kinetics study with single drugs in combination with curcumin in a human RB cell lines (Y79 and Weri-Rb1). Curcumin caused concentration-dependent decrease in cell proliferation, cell kinetics, and also induced apoptosis in both the RB cell lines. When combination of curcumin with individual drugs like carboplatin or etoposide or vincristine was treated on to RB cells, both cell viability and cell cycling were reduced and increased apoptosis was noted, in comparison with single drug treatment. These effects were significant in both the cell lines, indicating the ability of curcumin to increase the sensitivity of RB cells to chemotherapy drugs. Our in vitro findings showed that the combination of curcumin with single drug treatment showed marked synergistic inhibitory effect against RB cell lines. These results suggest that curcumin can be used as a modulator which may have a potential therapeutic value for the treatment of RB cancer patients.

  12. Targeting Strategies for the Combination Treatment of Cancer Using Drug Delivery Systems

    PubMed Central

    Kydd, Janel; Jadia, Rahul; Velpurisiva, Praveena; Gad, Aniket; Paliwal, Shailee; Rai, Prakash

    2017-01-01

    Cancer cells have characteristics of acquired and intrinsic resistances to chemotherapy treatment—due to the hostile tumor microenvironment—that create a significant challenge for effective therapeutic regimens. Multidrug resistance, collateral toxicity to normal cells, and detrimental systemic side effects present significant obstacles, necessitating alternative and safer treatment strategies. Traditional administration of chemotherapeutics has demonstrated minimal success due to the non-specificity of action, uptake and rapid clearance by the immune system, and subsequent metabolic alteration and poor tumor penetration. Nanomedicine can provide a more effective approach to targeting cancer by focusing on the vascular, tissue, and cellular characteristics that are unique to solid tumors. Targeted methods of treatment using nanoparticles can decrease the likelihood of resistant clonal populations of cancerous cells. Dual encapsulation of chemotherapeutic drug allows simultaneous targeting of more than one characteristic of the tumor. Several first-generation, non-targeted nanomedicines have received clinical approval starting with Doxil® in 1995. However, more than two decades later, second-generation or targeted nanomedicines have yet to be approved for treatment despite promising results in pre-clinical studies. This review highlights recent studies using targeted nanoparticles for cancer treatment focusing on approaches that target either the tumor vasculature (referred to as ‘vascular targeting’), the tumor microenvironment (‘tissue targeting’) or the individual cancer cells (‘cellular targeting’). Recent studies combining these different targeting methods are also discussed in this review. Finally, this review summarizes some of the reasons for the lack of clinical success in the field of targeted nanomedicines. PMID:29036899

  13. Umbilical cord blood-derived natural killer cells combined with Bevacizumab for colorectal cancer treatment.

    PubMed

    Xu, Chen; Liu, Dongning; Chen, Zhixin; Zhuo, Fan; Sun, Huankui; Hu, Jiaping; Li, Taiyuan

    2018-06-19

    Colorectal cancer (CRC) is among cancers with highest incidence globally and currently ranks fourth as the leading cause of cancer-related deaths worldwide. It remains an urgent need for novel strategies in the management of patients with advanced CRC. Adoptive transfer of allogeneic natural killer (NK) cells represent an attractive option in the treatment of patients with CRC. In this study, we successfully expanded NK cells from umbilical cord blood (UCB) with membrane-bound IL-21, termed eUCB-NK cells. eUCB-NK cells efficiently lysed CRC cell lines in vitro and secreted significantly higher levels of IFN-γ, TNF-α, GM-CSF and CCL3 compared with IL-2 stimulated NK cells. Adoptive transfer of these NK cells significantly inhibited the growth of HT29 xenografts, whereas LoVo tumors were not effectively controlled with eUCB-NK cells. More NK cells inside HT29 tumors, not seen in LoVo tumors, might contribute to the differences in response to eUCB-NK cells. Combination of bevacizumab can increase extravasation of adoptively transferred NK cells into the LoVo tumors and improve the therapeutic activity of eUCB-NK cells. These results justified clinical translation of this UCB-derived NK cell-based therapeutics, either used alone or combined with bevacizumab, as a novel treatment option for patients with CRC.

  14. Perspectives on the combination of radiotherapy and targeted therapy with DNA repair inhibitors in the treatment of pancreatic cancer

    PubMed Central

    Yang, Shih-Hung; Kuo, Ting-Chun; Wu, Hsu; Guo, Jhe-Cyuan; Hsu, Chiun; Hsu, Chih-Hung; Tien, Yu-Wen; Yeh, Kun-Huei; Cheng, Ann-Lii; Kuo, Sung-Hsin

    2016-01-01

    Pancreatic cancer is highly lethal. Current research that combines radiation with targeted therapy may dramatically improve prognosis. Cancerous cells are characterized by unstable genomes and activation of DNA repair pathways, which are indicated by increased phosphorylation of numerous factors, including H2AX, ATM, ATR, Chk1, Chk2, DNA-PKcs, Rad51, and Ku70/Ku80 heterodimers. Radiotherapy causes DNA damage. Cancer cells can be made more sensitive to the effects of radiation (radiosensitization) through inhibition of DNA repair pathways. The synergistic effects, of two or more combined non-lethal treatments, led to co-administration of chemotherapy and radiosensitization in BRCA-defective cells and patients, with promising results. ATM/Chk2 and ATR/Chk1 pathways are principal regulators of cell cycle arrest, following DNA double-strand or single-strand breaks. DNA double-stranded breaks activate DNA-dependent protein kinase, catalytic subunit (DNA-PKcs). It forms a holoenzyme with Ku70/Ku80 heterodimers, called DNA-PK, which catalyzes the joining of nonhomologous ends. This is the primary repair pathway utilized in human cells after exposure to ionizing radiation. Radiosensitization, induced by inhibitors of ATM, ATR, Chk1, Chk2, Wee1, PP2A, or DNA-PK, has been demonstrated in preclinical pancreatic cancer studies. Clinical trials are underway. Development of agents that inhibit DNA repair pathways to be clinically used in combination with radiotherapy is warranted for the treatment of pancreatic cancer. PMID:27621574

  15. Clinical trial uses combination therapy for certain types of non-Hodgkin lymphoma | Center for Cancer Research

    Cancer.gov

    Researchers are testing the safety of the combination of an experimental drug with rituximab, a standard treatment, for patients with indolent or diffuse large B-cell lymphoma. The antibody is designed to target and block a protein that is present on cancer cells and is used by those cells to protect themselves from your body’s immune system. Blocking the protein may enable your body’s immune system to find and destroy the cancer cells. Read more…

  16. Cotton dust, endotoxin and cancer mortality among the Shanghai textile workers cohort: a 30-year analysis

    PubMed Central

    Fang, S C; Mehta, A J; Hang, J Q; Eisen, E A; Dai, H L; Zhang, H X; Su, L; Christiani, D C

    2013-01-01

    Background Although occupational exposure to cotton dust and endotoxin is associated with adverse respiratory health, associations with cancer are unclear. We investigated cancer mortality in relation to cotton dust and endotoxin exposure in the Shanghai textile workers cohort. Methods We followed 444 cotton textile and a reference group of 467 unexposed silk workers for 30 years (26 777 person-years). HRs for all cancers combined (with and without lung cancer) and gastrointestinal cancer were estimated in Cox regression models as functions of cotton textile work and categories of cumulative exposure (low, medium, high), after adjustment for covariates including pack-years smoked. Different lag years accounted for disease latency. Results Risks of mortality from gastrointestinal cancers and all cancers combined, with the exclusion of lung cancer, were increased in cotton workers relative to silk workers. When stratified by category of cumulative cotton exposure, in general, risks were greatest for 20-year lagged medium exposure (all cancers HR=2.7 (95% CI 1.4 to 5.2); cancer excluding lung cancer HR=3.4 (1.7–7.0); gastrointestinal cancer HR=4.1 (1.8–9.7)). With the exclusion of lung cancer, risks of cancer were more pronounced. When stratified by category of cumulative endotoxin exposure, consistent associations were not observed for all cancers combined. However, excluding lung cancer, medium endotoxin exposure was associated with all cancers and gastrointestinal cancer in almost all lag models. Conclusions Cotton dust may be associated with cancer mortality, especially gastrointestinal cancer, and endotoxin may play a causative role. Findings also indirectly support a protective effect of endotoxin on lung cancer. PMID:23828454

  17. Combination of tolfenamic acid and curcumin induces colon cancer cell growth inhibition through modulating specific transcription factors and reactive oxygen species.

    PubMed

    Sankpal, Umesh T; Nagaraju, Ganji Purnachandra; Gottipolu, Sriharika R; Hurtado, Myrna; Jordan, Christopher G; Simecka, Jerry W; Shoji, Mamoru; El-Rayes, Bassel; Basha, Riyaz

    2016-01-19

    Curcumin (Cur) has been extensively studied in several types of malignancies including colorectal cancer (CRC); however its clinical application is greatly affected by low bioavailability. Several strategies to improve the therapeutic response of Cur are being pursued, including its combination with small molecules and drugs. We investigated the therapeutic efficacy of Cur in combination with the small molecule tolfenamic acid (TA) in CRC cell lines. TA has been shown to inhibit the growth of human cancer cells in vitro and in vivo, via targeting the transcription factor specificity protein1 (Sp1) and suppressing survivin expression. CRC cell lines HCT116 and HT29 were treated with TA and/or Cur and cell viability was measured 24-72 hours post-treatment. While both agents caused a steady reduction in cell viability, following a clear dose/ time-dependent response, the combination of TA+Cur showed higher growth inhibition when compared to either single agent. Effects on apoptosis were determined using flow cytometry (JC-1 staining to measure mitochondrial membrane potential), Western blot analysis (c-PARP expression) and caspase 3/7 activity. Reactive oxygen species (ROS) levels were measured by flow cytometry and the translocation of NF-kB into the nucleus was determined using immunofluorescence. Results showed that apoptotic markers and ROS activity were significantly upregulated following combination treatment, when compared to the individual agents. This was accompanied by decreased expression of Sp1, survivin and NF-kB translocation. The combination of TA+Cur was more effective in HCT116 cells than HT29 cells. These results demonstrate that TA may enhance the anti-proliferative efficacy of Cur in CRC cells.

  18. [A case of lung metastasis from esophageal cancer resistant to fluorouracil and cisplatin combination therapy but responsive to radiation therapy].

    PubMed

    Ami, Katsunori; Seki, Ryouta; Takasaki, Jun; Amagasa, Hidetoshi; Kamikozuru, Hirotaka; Ganno, Hideaki; Kurokawa, Toshiaki; Fukuda, Akira; Nagahama, Takeshi; Ando, Masayuki; Yamada, Yosuke; Kodaka, Fumi; Arai, Kuniyoshi

    2012-11-01

    At present, fluorouracil and cisplatin combination therapy is the standard chemotherapy against esophageal cancer, but the choice of second-line chemotherapy is controversial. Furthermore, the effect of radiation therapy against lung metastasis from esophageal cancer is unclear. We report a case of lung metastasis from esophageal cancer resistant to fluorouracil and cisplatin combination therapy but responsive to radiation therapy. The patient was a 55-year-old woman who had undergone an operation for esophageal cancer at another hospital. A single right lung metastasis appeared 1 year after the operation. Combined fluorouracil and cisplatin therapy was administrated for 5 courses, but the lung metastasis increased in size. Afterwards, she was admitted to our hospital. We treated her with 14 courses of S-1 and docetaxel combination therapy administered over 13 months. The lung metastasis was decreased for a period. Furthermore, radiofrequency ablation under computed tomography was performed against the lung metastasis re-growth at another hospital. Although the lung metastasis increased in size, no further metastases were detected during the clinical course. The patient was treated with radiotherapy for the lung metastasis re-growth. The tumor had almost disappeared by 10 months after the completion of radiotherapy. Currently, she is receiving palliative care as an outpatient and the lung metastasis has not been evident for 2 years since the completion of radiotherapy.

  19. Combining Machine Learning and Nanofluidic Technology To Diagnose Pancreatic Cancer Using Exosomes.

    PubMed

    Ko, Jina; Bhagwat, Neha; Yee, Stephanie S; Ortiz, Natalia; Sahmoud, Amine; Black, Taylor; Aiello, Nicole M; McKenzie, Lydie; O'Hara, Mark; Redlinger, Colleen; Romeo, Janae; Carpenter, Erica L; Stanger, Ben Z; Issadore, David

    2017-11-28

    Circulating exosomes contain a wealth of proteomic and genetic information, presenting an enormous opportunity in cancer diagnostics. While microfluidic approaches have been used to successfully isolate cells from complex samples, scaling these approaches for exosome isolation has been limited by the low throughput and susceptibility to clogging of nanofluidics. Moreover, the analysis of exosomal biomarkers is confounded by substantial heterogeneity between patients and within a tumor itself. To address these challenges, we developed a multichannel nanofluidic system to analyze crude clinical samples. Using this platform, we isolated exosomes from healthy and diseased murine and clinical cohorts, profiled the RNA cargo inside of these exosomes, and applied a machine learning algorithm to generate predictive panels that could identify samples derived from heterogeneous cancer-bearing individuals. Using this approach, we classified cancer and precancer mice from healthy controls, as well as pancreatic cancer patients from healthy controls, in blinded studies.

  20. Nimotuzumab combined with radiotherapy for esophageal cancer: preliminary study of a Phase II clinical trial.

    PubMed

    Liang, Jun; E, Mingyan; Wu, Gang; Zhao, Lujun; Li, Xia; Xiu, Xia; Li, Ning; Chen, Bo; Hui, Zhouguang; Lv, Jima; Fang, Hui; Tang, Yu; Bi, Nan; Wang, Wenqing; Zhai, Yirui; Li, Tao; Chen, Dongfu; Zou, Shuangmei; Lu, Ning; Perez-Rodríguez, Rolando; Zheng, Junqi; Wang, Luhua

    2013-01-01

    To determine the safety and therapeutic effects of nimotuzumab (h-R3) combined with radiotherapy in esophageal cancer. This Phase II clinical trial involved 42 patients with stage II (inoperable or refused surgery) to stage IV (supraclavicular lymph node metastasis only) esophageal cancers treated between November 2008 and July 2010. All patients had squamous cell carcinomas, and all received three-dimensional conformal radiotherapy and 200 mg nimotuzumab per week during radiotherapy. There were 9, 25, and 8 patients with stage II, III and IV disease, respectively. All except two patients received 50-70 Gy radiation; 37 patients (88.1%) received more than five nimotuzumab doses. Grade III toxicities (21.4% of all adverse events) included esophagitis and gastrointestinal, dermatological and hematological toxicities. Complete response, partial response, stable disease, and progressive disease were observed in 0, 22 (52.4%), 17 (40.5%) and 3 (7.1%) patients at 1 month after the treatment. The epidermal growth factor receptor (EGFR) overexpression rate was 95.2%. After a median follow-up of 37 months, the median survival time (MST) was 14 months. The 2 year and 3 year overall survival (OS) rates were 33.3% and 26.2%, respectively. The median progression-free survival (PFS) time was 10 months. The 2 year and 3 year PFS rates were 24.5% and 22.1%, respectively. The MST in the 13 patients with (+++) EGFR expression (group A) and 7 patients with (++) EGFR expression (group B) was 15 and 11 months, respectively. The 2 year and 3 year OS rates were 46.2% and 38.5% in group A and 28.6% and 28.6% in group B, respectively (P = 0.405). Although concurrent chemoradiotherapy was the standard care for locally advanced esophageal cancer, radiotherapy was the choice for those who were refused or could not tolerate chemoradiotherapy. Our study shows that nimotuzumab combined with radiotherapy was well tolerated in patients with esophageal cancer. EGFR overexpression was more common

  1. Combination of metformin and curcumin targets breast cancer in mice by angiogenesis inhibition, immune system modulation and induction of p53 independent apoptosis

    PubMed Central

    Falah, Rabah Rashad; Talib, Wamidh H.; Shbailat, Seba Jamal

    2017-01-01

    Background: The effects of metformin (MET) and curcumin (CUR) single treatments have been tested against breast cancer; however, their combination has not been explored. Here, we evaluated the antitumor activity of MET and CUR combination against breast cancer in mice. Materials and methods: The antiproliferative activity of single and combined treatments against breast cancer cell lines was determined. Vascular endothelial growth factor (VEGF) and Trp53 expression was examined in EMT6/P cells. In vivo studies were carried out by inoculating BALB/c mice with EMT6/P cells and examining tumor growth and apoptosis induction in tumor sections. Furthermore, serum levels of different cytokines and transaminases and creatinine were measured to detect the immune response and toxicity, respectively. Results: The combination treatment exhibited the highest effects against tumor proliferation and growth. It significantly reduced VEGF expression, induced Trp53 independent apoptosis, triggered Th2 immune response and showed no toxicity. Conclusion: The combination can be a potential therapeutic option to treat breast cancer. However, further testing is needed to measure the exact serum levels of MET and CUR and to further explain the obtained results. PMID:28491145

  2. Combined Gemcitabine and Metronidazole Is a Promising Therapeutic Strategy for Cancer Stem-like Cholangiocarcinoma.

    PubMed

    Kawamoto, Makoto; Umebayashi, Masayo; Tanaka, Hiroto; Koya, Norihiro; Nakagawa, Sinichiro; Kawabe, Ken; Onishi, Hideya; Nakamura, Masafumi; Morisaki, Takashi

    2018-05-01

    Metronidazole (MNZ) is a common antibiotic that exerts disulfiram-like effects when taken together with alcohol. However, the relationship between MNZ and aldehyde dehydrogenase (ALDH) activity remains unclear. This study investigated whether MNZ reduces cancer stemness by suppressing ALDH activity and accordingly reducing the malignancy of cholangiocarcinoma (CCA). We developed gemcitabine (GEM)-resistant TFK-1 cells and originally established CCA cell line from a patient with GEM-resistant CCA. Using these cell lines, we analyzed the impacts of MNZ for cancer stem cell markers, invasiveness, and chemosensitivity. MNZ reduced ALDH activity in GEM-resistant CCA cells, leading to decreased invasiveness and enhanced chemosensitivity. MNZ diminished the invasiveness by inducing mesenchymal-epithelial transition and enhancing chemosensitivity by increasing ENT1 (equilibrative nucleoside transporter 1) and reducing RRM1 (ribonucleotide reductase M1). MNZ reduced cancer stemness in GEM-resistant CCA cells. Combined GEM and MNZ would be a promising therapeutic strategy for cancer stem-like CAA. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  3. High Spicy Food Intake and Risk of Cancer: A Meta-analysis of Case-control Studies.

    PubMed

    Chen, Yu-Heng; Zou, Xiao-Nong; Zheng, Tong-Zhang; Zhou, Qi; Qiu, Hui; Chen, Yuan-Li; He, Mei; Du, Jia; Lei, Hai-Ke; Zhao, Ping

    2017-09-20

    Studies on the association between spicy food intake and cancer risk have reported inconsistent results. We quantitatively assessed this association by conducting a meta-analysis based on evidence from case-control studies. PubMed, EMBASE, and the Cochrane Library were searched for eligible publications. Combined odds ratios (OR s) with their 95% confidence interval (CI) were calculated using a random- or fixed-effects model. The methodological quality of the included articles was assessed using the Newcastle-Ottawa scale (NOS). All data were analyzed using STATA 11.0 software (version 11.0; StataCorp., College Station, TX, USA). Subgroup analyses were also performed with stratification by region, sex, number of cases, cancer subtype, source of the control group, and NOS score. A total 39 studies from 28 articles fulfilled the inclusion criteria for the meta-analysis (7884 patients with cancer and 10,142 controls). Comparison of the highest versus lowest exposure category in each study revealed a significant OR of 1.76 (95% CI = 1.35-2.29) in spite of significant heterogeneity (P < 0.001). In the subgroup analyses, this positive correlation was still found for gastric cancer, different regions, different numbers of cases, different sources of the control group, and high-quality articles (NOS score of ≥ 7). However, no statistically significant association was observed for women, esophageal cancer, gallbladder cancer, or low-quality articles (NOS score of <7). No evidence of publication bias was found. Evidence from case-control studies suggested that a higher level of spicy food intake may be associated with an increased incidence of cancer despite significant heterogeneity. More studies are warranted to clarify our understanding of the association between high spicy food intake and the risk of cancer.

  4. Mechanisms of colitis-accelerated colon carcinogenesis and its prevention with the combination of aspirin and curcumin: Transcriptomic analysis using RNA-seq.

    PubMed

    Guo, Yue; Su, Zheng-Yuan; Zhang, Chengyue; Gaspar, John M; Wang, Rui; Hart, Ronald P; Verzi, Michael P; Kong, Ah-Ng Tony

    2017-07-01

    Colorectal cancer (CRC) remains the leading cause of cancer-related death in the world. Aspirin (ASA) and curcumin (CUR) are widely investigated chemopreventive candidates for CRC. However, the precise mechanisms of their action and their combinatorial effects have not been evaluated. The purpose of the present study was to determine the effect of ASA, CUR, and their combination in azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colitis-accelerated colorectal cancer (CAC). We also aimed to characterize the differential gene expression profiles in AOM/DSS-induced tumors as well as in tumors modulated by ASA and CUR using RNA-seq. Diets supplemented with 0.02% ASA, 2% CUR or 0.01% ASA+1% CUR were given to mice from 1week prior to the AOM injection until the experiment was terminated 22weeks after AOM initiation. Our results showed that CUR had a superior inhibitory effect in colon tumorigenesis compared to that of ASA. The combination of ASA and CUR at a lower dose exhibited similar efficacy to that of a higher dose of CUR at 2%. RNA isolated from colonic tissue from the control group and from tumor samples from the experimental groups was subjected to RNA-seq. Transcriptomic analysis suggested that the low-dose combination of ASA and CUR modulated larger gene sets than the single treatment. These differentially expressed genes were situated in several canonical pathways important in the inflammatory network and liver metastasis in CAC. We identified a small subset of genes as potential molecular targets involved in the preventive action of the combination of ASA and CUR. Taken together, the current results provide the first evidence in support of the chemopreventive effect of a low-dose combination of ASA and CUR in CAC. Moreover, the transcriptional profile obtained in our study may provide a framework for identifying the mechanisms underlying the carcinogenesis process from normal colonic tissue to tumor development as well as the cancer inhibitory effects

  5. Prostate cancer susceptibility polymorphism rs2660753 is not associated with invasive ovarian cancer

    PubMed Central

    Amankwah, Ernest K; Kelemen, Linda E; Wang, Qinggang; Song, Honglin; Chenevix-Trench, Georgia; Beesley, Jonathan; Webb, Penelope M; Pearce, Celeste L; Wu, Anna H; Pike, Malcolm C; Stram, Daniel O; Chang-Claude, Jenny; Wang-Gohrke, Shan; Ness, Roberta B; Goode, Ellen L; Cunningham, Julie M; Fridley, Brooke L; Vierkant, Robert A; Tworoger, Shelley S; Whittemore, Alice S; McGuire, Valerie; Sieh, Weiva; Gayther, Simon A; Gentry-Maharaj, Aleksandra; Menon, Usha; Ramus, Susan J; Rossing, Mary Anne; Doherty, Jennifer A; Goodman, Marc T; Carney, Michael E; Lurie, Galina; Wilkens, Lynne R; Kjær, Susanne Krüger; Høgdall, Estrid; Cramer, Daniel W; Terry, Kathryn L; Garcia-Closas, Montserrat; Yang, Hannah; Lissowska, Jolanta; Anton-Culver, Hoda; Ziogas, Argyrios; Schildkraut, Joellen M; Berchuck, Andrew; Pharoah, Paul DP

    2011-01-01

    Background We previously reported an association between rs2660753, a prostate cancer susceptibility polymorphism, and invasive epithelial ovarian cancer (EOC) [odds ratio (OR)=1.2, 95% confidence interval (CI)=1.0-1.4, Ptrend=0.01] that showed a stronger association with the serous histological subtype (OR=1.3, 95% CI=1.1-1.5, Ptrend=0.003). Methods We sought to replicate this association in 12 other studies comprising 4,482 cases and 6,894 controls of white non-Hispanic ancestry in the Ovarian Cancer Association Consortium. Results No evidence for an association with all cancers or serous cancers was observed in a combined analysis of data from the replication studies (all: OR=1.0, 95% CI=0.9-1.1, Ptrend=0.61; serous: OR=1.0, 95% CI=0.9-1.1, Ptrend=0.85) or from the combined analysis of discovery and replication studies (all: OR=1.0, 95% CI=1.0-1.1, Ptrend= 0.28; serous: OR=1.1, 95% CI=1.0-1.2, Ptrend=0.11). There was no evidence for statistical heterogeneity in ORs across the studies. Conclusions Although rs2660753 is a strong a prostate cancer susceptibility polymorphism, the association with another hormonally related cancer, invasive EOC, is not supported by this replication study. Impact Our findings, based on a larger sample size, emphasize the importance of replicating potentially promising genetic risk associations. PMID:21415361

  6. Grid-Enabled Quantitative Analysis of Breast Cancer

    DTIC Science & Technology

    2010-10-01

    large-scale, multi-modality computerized image analysis . The central hypothesis of this research is that large-scale image analysis for breast cancer...research, we designed a pilot study utilizing large scale parallel Grid computing harnessing nationwide infrastructure for medical image analysis . Also

  7. A cost-utility analysis of cervical cancer screening and human papillomavirus vaccination in the Philippines.

    PubMed

    Guerrero, Anna Melissa; Genuino, Anne Julienne; Santillan, Melanie; Praditsitthikorn, Naiyana; Chantarastapornchit, Varit; Teerawattananon, Yot; Alejandria, Marissa; Toral, Jean Anne

    2015-07-30

    Cervical cancer is the second leading cause of cancer cases and deaths among Filipino women because of inadequate access to screening and treatment services. This study aims to evaluate the health and economic benefits of HPV vaccination and its combination with different screening strategies to find the most optimal preventive strategy in the Philippines. A cost-utility analysis was conducted using an existing semi-Markov model to evaluate different screening (i.e., Pap smear, visual inspection with acetic acid) and vaccination strategies against HPV infection implemented alone or as part of a combination strategy at different coverage scenarios. The model was run using country-specific epidemiologic, cost and clinical parameters from a health system perspective. Sensitivity analysis was performed for vaccine efficacy, duration of protection and costs of vaccination, screening and treatment. Across all coverage scenarios, VIA has been shown to be a dominant and cost-saving screening strategy with incremental cost-effectiveness ratio (ICER) ranging from dominant to Php 61,059 (1443 USD) per QALY gained. VIA can reduce cervical cancer cases and deaths by 25%. Pap smear screening was found to be not cost-effective due to its high cost in the Philippines. Adding HPV vaccination at a cost of 54 USD per vaccinated girl on top of VIA screening was found to be potentially cost-effective using a threshold of 1 GDP per capita (i.e., Php 120,000 or 2835 USD/ QALY) with the most favorable assumption of providing lifelong immunity against high-risk oncogenic HPV types 16/18. The highest incremental QALY gain was achieved with 80% coverage of the combined strategy of VIA at 35 to 45 years old done every five years following vaccination at 11 years of age with an ICER of Php 33,126 (783 USD). This strategy may result in a two-thirds reduction in cervical cancer burden. HPV vaccination is not cost-effective when vaccine protection lasts for less than 20 years. High VIA coverage

  8. Association Between N-acetyltransferase 2 Polymorphism and Bladder Cancer Risk: Results From Studies of the Past Decade and a Meta-Analysis.

    PubMed

    Wu, Haoran; Wang, Xugang; Zhang, Liang; Mo, Naixin; Lv, Zhong

    2016-04-01

    Numerous studies have identified that the slow acetylation status of N-acetyltransferase 2 (NAT2) is associated with an elevated bladder cancer risk. However, the results remain inconclusive. The aim of our study was to evaluate the effect of NAT2 acetylation status in patients with bladder cancer. Electronic databases were searched to retrieve related studies published in the past decade. The pooled odds ratio (OR) with its 95% confidence interval (CI) was used to calculate the strength of this relationship. Overall, a total of 18 studies were selected for the analysis, which included 4473 bladder cancer cases and 7204 matched controls. Our result showed that the NAT2 slow acetylation phenotypes were significantly associated with an increased risk of bladder cancer compared with the rapid phenotypes (OR, 1.56; 95% CI, 1.33-1.82; P < .00001) in a random-effect model. This significant association was also found in a subgroup analysis of ethnicity (P < .05). Furthermore, the NAT2 slow phenotypes also significantly increased the risk of bladder cancer in smokers (OR, 0.75; 95% CI, 0.62-0.90; P = .002). However, no correlation was found between the combined effect of NAT2 slow phenotypes and gender with bladder cancer risk (OR, 0.89; 95% CI, 0.28-2.78; P = .84). In conclusion, our results suggest that the NAT2 slow acetylator, in particular, the NAT2 slow acetylator combined with smoking, are associated with an increased bladder cancer risk. Future well-designed studies with large populations and more ethnicities are needed to clarify this association further. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. [Effectiveness of FTA Elute® indicating cartridge in combination with hybrid capture 2 for cervical cancer screening].

    PubMed

    Chen, Feng; Zhang, Xi; Wang, Shaoming; Hu, Shangying; Chen, Wen; Zhao, Fanghui; He, Wei; Zhang, Yuqing; Qiao, Youlin

    2015-02-01

    To evaluate the effectiveness of FTA Elute® Cartridge (GE healthcare, Kent, UK) in combination with hybrid capture 2 (HC2) testing for cervical cancer screening. From May to June 2012, 412 women aged 25 to 65 years in Jiangxi Tonggu were enrolled in the study. We used pathological outcome as the gold standard, and the accuracy of the FTA card in combination with HC2 testing was investigated from both physician- and self-sampling, respectively. Physician sampling using the FTA card in combination with HC2 testing showed a comparable sensitivity (12/13) with the liquid based medium, but a higher specificity 69.5% (266/383) vs (77.8%, 298/383) (P < 0.001).When self sampling method was used, the sensitivity and specificity of using the FTA card in combination with HC2 testing with liquid based medium was 10/13 vs 8/13(P = 0.625) and (62.3%, 238/382) vs (75.7%, 289/382) (P < 0.001). The agreement of detection results for HC2 between FTA and liquid-based sampling medium was 86.1% (340/395) and 79.5% (314/395). For physician-collected samples used for HC2 testing to detect CIN2+, the accuracy of the FTA card was superior to that of the liquid-based medium (area under the receiver operating characteristic curve (AUC) = 0.898, 95%CI:0.838-0.958). FTA Elute® cartridge in combination with HC2 testing is a promising method of specimen transport for cervical cancer screening programs with a good precision.With further optimization, it could become an effective method for cervical cancer screening in various economic levels of areas.

  10. Increased chemopreventive effect by combining arctigenin, green tea polyphenol and curcumin in prostate and breast cancer cells

    PubMed Central

    Wang, Piwen; Wang, Bin; Chung, Seyung; Wu, Yanyuan; Henning, Susanne M.; Vadgama, Jaydutt V.

    2014-01-01

    The low bioavailability of most flavonoids limits their application as anti-carcinogenic agents in humans. A novel approach of treatment with a mixture of bioactive compounds that share molecular anti-carcinogenic targets may enhance the effect on these targets at low concentrations of individual compound, thereby overcoming the limitations of reduced bioavailability. We therefore investigated whether a combination of three natural products arctigenin (Arc), a novel anti-inflammatory lignan from the seeds of Arctium lappa, green tea polyphenol (−)-epigallocatechin gallate (EGCG) and curcumin (Cur) increases the chemopreventive potency of individual compounds. LNCaP prostate cancer and MCF-7 breast cancer cells were treated with 2–4 mg/L (about 5–10μM) Cur, 1μM Arc and 40μM EGCG alone or in combination for 48h. In both cell lines treatment with the mixture of Cur, Arc and EGCG synergistically increased the antiproliferative effect. In LNCaP cells both Arc and EGCG increased the pro-apoptotic effect of Cur. Whereas in MCF-7 cells Arc increased the cell apoptosis of Cur while EGCG enhanced cell cycle arrest of Cur at G0/G1 phase. The strongest effects on cell cycle arrest and apoptosis were achieved by combining all three compounds in both cell lines. The combination treatment significantly increased the ratio of Bax to Bcl-2 proteins, decreased the activation of NFκB, PI3K/Akt and Stat3 pathways and cell migration compared to individual treatment. These results warrant in vivo studies to confirm the efficacy of this novel regimen by combining Arc and EGCG with Cur to enhance chemoprevention in both prostate and breast cancer. PMID:25243063

  11. Platinum covalent shell cross-linked micelles designed to deliver doxorubicin for synergistic combination cancer therapy

    PubMed Central

    Zhu, Caiying; Xiao, Jingjing; Tang, Ming; Feng, Hua; Chen, Wulian; Du, Ming

    2017-01-01

    The preparation of polymer therapeutics capable of controlled release of multiple chemotherapeutic drugs has remained a tough problem in synergistic combination cancer therapy. Herein, a novel dual-drug co-delivery system carrying doxorubicin (DOX) and platinum(IV) (Pt[IV]) was developed. An amphiphilic diblock copolymer, PCL-b-P(OEGMA-co-AzPMA), was synthesized and used as a nanoscale drug carrier in which DOX and Pt(IV) could be packaged together. The copolymers were shell cross-linked by Pt(IV) prodrug via a click reaction. Studies on the in vitro drug release and cellular uptake of the dual-drug co-delivery system showed that the micelles were effectively taken up by the cells and simultaneously released drugs in the cells. Futhermore, the co-delivery polymer nanoparticles caused much higher cell death in HeLa and A357 tumor cells than either the free drugs or single-drug-loaded micelles at the same dosage, exhibiting a synergistic combination of DOX and Pt(IV). The results obtained with the shell cross-linked micelles based on an anticancer drug used as a cross-linking linkage suggested a promising application of the micelles for multidrug delivery in combination cancer therapy. PMID:28553108

  12. A Reactive 1O2 - Responsive Combined Treatment System of Photodynamic and Chemotherapy for Cancer

    NASA Astrophysics Data System (ADS)

    Wang, Xiaojun; Meng, Guoqing; Zhang, Song; Liu, Xinli

    2016-07-01

    The development of reactive oxygen species (ROS)-responsive drug delivery and drug release has gradually attracted much attention in recent years as a promising therapeutic strategy. Singlet oxygen (1O2) as the major ROS species is widely used in photodynamic therapy (PDT) of cancer. In the present study, we introduce a combined treatment using ROS-sensitive thioketal (TK) linkage as a linker between upconversion nanoparticles (UNs)-based PDT and doxorubicin (DOX)-based chemotherapy. UNs can not only play a role in PDT, but can also be used as a nanocarrier for drug delivery of DOX. Moreover, the products of 1O2 during PDT are able to cleave TK linker inducing the release of DOX which can further achieve the goal of chemotherapy. By using this 1O2-responsive nanocarrier delivery system, DOX can easily reach the tumor site and be accumulated in the nuclei to effectively kill the cancer cells, and therefore decreasing the side effects of chemotherapy on the body. Thus, PDT also has the function of controlling drug release in this combination treatment strategy. Compared with monotherapy, the combination of PDT with chemotherapy also possesses excellent drug loading capability and anticancer efficiency.

  13. Ticarcillin in Combination with Cephalothin or Gentamicin as Empiric Antibiotic Therapy in Granulocytopenic Cancer Patients

    PubMed Central

    Schimpff, Stephen C.; Landesman, Sheldon; Hahn, Davis M.; Standiford, Harold C.; Fortner, Clarence L.; Young, Viola Mae; Wiernik, Peter H.

    1976-01-01

    Ticarcillin was used in combination with either cephalothin or gentamicin as initial empiric antibiotic therapy for 127 patient trials of suspected infection in granulocytopenic cancer patients. Bacteremia was present in 20%, nonbacteremic microbiologically documented infections in 21%, clinically documented infections in 23%, and possible infections in 5%; infection was doubtful in 31%. Although Staphylococcus aureus was the most common single organism isolated (23%), gram-negative bacilli accounted for 54% of all pathogens. Both antibiotic regimens were highly efficacious, with complete resolution in 46% of bacteremias, 88% of nonbacteremic microbiologically documented infections, and 95% of clinically documented infections. Among bacteremias, 8 of 9 caused by S. aureus but only 4 of 15 (27%) caused by gram-negative bacilli were completely resolved with these antibiotic combinations. Reasons for nonresponse in bacteremias were persistent granulocytopenia, mixed infection and, in two patients, antibiotic-resistant organisms. Toxicities other than hypokalemia were minimal. Although the rate of further infections was high overall (18/127), only one occurred among the 39 patients with <4 days of antibiotic therapy. Ticarcillin in combination with either cephalothin or gentamicin was effective as initial empiric therapy of suspected infection in granulocytopenic cancer patients. PMID:795372

  14. Technology Insight: Combined external-beam radiation therapy and brachytherapy in the management of prostate cancer.

    PubMed

    Hurwitz, Mark D

    2008-11-01

    External-beam radiation therapy (EBRT) combined with brachytherapy is an attractive treatment option for selected patients with clinically localized prostate cancer. This therapeutic strategy offers dosimetric coverage if local-regional microscopic disease is present and provides a highly conformal boost of radiation to the prostate and immediate surrounding tissues. Either low-dose-rate (LDR) permanent brachytherapy or high-dose-rate (HDR) temporary brachytherapy can be combined with EBRT; such combined-modality therapy (CMT) is typically used to treat patients with intermediate-risk to high-risk, clinically localized disease. Controversy persists with regard to indications for CMT, choice of LDR or HDR boost, isotope selection for LDR, and integration of EBRT and brachytherapy. Initial findings from prospective, multicenter trials of CMT support the feasibility of this strategy. Updated results from these trials as well as those of ongoing and new phase III trials should help to define the role of CMT in the management of prostate cancer. In the meantime, long-term expectations for outcomes of CMT are based largely on the experience of single institutions, which demonstrate that CMT with EBRT and either LDR or HDR brachytherapy can provide freedom from disease recurrence with acceptable toxicity.

  15. Construction and analysis of lncRNA-lncRNA synergistic networks to reveal clinically relevant lncRNAs in cancer.

    PubMed

    Li, Yongsheng; Chen, Juan; Zhang, Jinwen; Wang, Zishan; Shao, Tingting; Jiang, Chunjie; Xu, Juan; Li, Xia

    2015-09-22

    Long non-coding RNAs (lncRNAs) play key roles in diverse biological processes. Moreover, the development and progression of cancer often involves the combined actions of several lncRNAs. Here we propose a multi-step method for constructing lncRNA-lncRNA functional synergistic networks (LFSNs) through co-regulation of functional modules having three features: common coexpressed genes of lncRNA pairs, enrichment in the same functional category and close proximity within protein interaction networks. Applied to three cancers, we constructed cancer-specific LFSNs and found that they exhibit a scale free and modular architecture. In addition, cancer-associated lncRNAs tend to be hubs and are enriched within modules. Although there is little synergistic pairing of lncRNAs across cancers, lncRNA pairs involved in the same cancer hallmarks by regulating same or different biological processes. Finally, we identify prognostic biomarkers within cancer lncRNA expression datasets using modules derived from LFSNs. In summary, this proof-of-principle study indicates synergistic lncRNA pairs can be identified through integrative analysis of genome-wide expression data sets and functional information.

  16. Independent Pre-Transplant Recipient Cancer Risk Factors after Kidney Transplantation and the Utility of G-Chart Analysis for Clinical Process Control

    PubMed Central

    Kurok, Marlene; Goldis, Alon; Dreier, Maren; Kaltenborn, Alexander; Gwinner, Wilfried; Barthold, Marc; Liebeneiner, Jan; Winny, Markus; Klempnauer, Jürgen; Kleine, Moritz

    2016-01-01

    Background The aim of this study is to identify independent pre-transplant cancer risk factors after kidney transplantation and to assess the utility of G-chart analysis for clinical process control. This may contribute to the improvement of cancer surveillance processes in individual transplant centers. Patients and Methods 1655 patients after kidney transplantation at our institution with a total of 9,425 person-years of follow-up were compared retrospectively to the general German population using site-specific standardized-incidence-ratios (SIRs) of observed malignancies. Risk-adjusted multivariable Cox regression was used to identify independent pre-transplant cancer risk factors. G-chart analysis was applied to determine relevant differences in the frequency of cancer occurrences. Results Cancer incidence rates were almost three times higher as compared to the matched general population (SIR = 2.75; 95%-CI: 2.33–3.21). Significantly increased SIRs were observed for renal cell carcinoma (SIR = 22.46), post-transplant lymphoproliferative disorder (SIR = 8.36), prostate cancer (SIR = 2.22), bladder cancer (SIR = 3.24), thyroid cancer (SIR = 10.13) and melanoma (SIR = 3.08). Independent pre-transplant risk factors for cancer-free survival were age <52.3 years (p = 0.007, Hazard ratio (HR): 0.82), age >62.6 years (p = 0.001, HR: 1.29), polycystic kidney disease other than autosomal dominant polycystic kidney disease (ADPKD) (p = 0.001, HR: 0.68), high body mass index in kg/m2 (p<0.001, HR: 1.04), ADPKD (p = 0.008, HR: 1.26) and diabetic nephropathy (p = 0.004, HR = 1.51). G-chart analysis identified relevant changes in the detection rates of cancer during aftercare with no significant relation to identified risk factors for cancer-free survival (p<0.05). Conclusions Risk-adapted cancer surveillance combined with prospective G-chart analysis likely improves cancer surveillance schemes by adapting processes to identified risk factors and by using G-chart alarm

  17. [Survey and analysis of awareness of lung cancer prevention and control in a LDCT lung cancer screening project in Tianjin Dagang Oilfield of China].

    PubMed

    Ren, Guanhua; Ye, Jianfei; Fan, Yaguang; Wang, Jing; Sun, Zhijuan; Jia, Hui; Du, Xinxin; Hou, Chaohua; Wang, Ying; Zhao, Yongcheng; Zhou, Qinghua

    2014-02-01

    It has been proven that increase of the awareness level of lung cancer prevention and control could enhance participation of lung cancer screening of lung cancer high risk group. The aim of this study is to investigate the awareness level of lung cancer prevention and control and the effect of individual characteristics on lung cancer awareness, and to provide evidence for comprehensive lung cancer prevention in high risk areas of lung cancer. Staffs of Tianjin Dagang Oil Field who participate low dose CT (LDCT) lung cancer screening by cluster sampling or according to voluntary principle were surveyed, data of lung cancer awareness were collected by questionnaire. A total of 1,633 valid questionnaires were collected. The average age of respondents was 60.08±6.58. Most participants were males (82.2%) while female only accounted for 17.8%. The proportions of awareness about lung cancer in China, risk factors, screening methods and the knowledge of health examination were 64.5%, 77.1%, 43.7%, 49.6% respectively. Result of multiple logistic regression analysis showed that education level, smoking (pack-year), age, prior tuberculosis were the influencing factors of lung cancer awareness with adjusted Ors for education and age level as of 0.567 (95%CI: 0.439-0.733) and 1.373 (95%CI: 1.084-1.739) respectively. 80.3% of the participants can accept health examination once a year, while the ability to pay the medical expenses was not high. The influencing factors of health examination willingness were gender, age, income, the knowledge of lung cancer. Education level and smoking affect the awareness of lung cancer prevention and control, health education for lung cancer should be conducted especially in population with low education level. Comprehensive lung cancer control in high risk areas should combined lung cancer screening, tobacco control and health education.

  18. Genetic heterogeneity in Finnish hereditary prostate cancer using ordered subset analysis

    PubMed Central

    Simpson, Claire L; Cropp, Cheryl D; Wahlfors, Tiina; George, Asha; Jones, MaryPat S; Harper, Ursula; Ponciano-Jackson, Damaris; Tammela, Teuvo; Schleutker, Johanna; Bailey-Wilson, Joan E

    2013-01-01

    Prostate cancer (PrCa) is the most common male cancer in developed countries and the second most common cause of cancer death after lung cancer. We recently reported a genome-wide linkage scan in 69 Finnish hereditary PrCa (HPC) families, which replicated the HPC9 locus on 17q21-q22 and identified a locus on 2q37. The aim of this study was to identify and to detect other loci linked to HPC. Here we used ordered subset analysis (OSA), conditioned on nonparametric linkage to these loci to detect other loci linked to HPC in subsets of families, but not the overall sample. We analyzed the families based on their evidence for linkage to chromosome 2, chromosome 17 and a maximum score using the strongest evidence of linkage from either of the two loci. Significant linkage to a 5-cM linkage interval with a peak OSA nonparametric allele-sharing LOD score of 4.876 on Xq26.3-q27 (ΔLOD=3.193, empirical P=0.009) was observed in a subset of 41 families weakly linked to 2q37, overlapping the HPCX1 locus. Two peaks that were novel to the analysis combining linkage evidence from both primary loci were identified; 18q12.1-q12.2 (OSA LOD=2.541, ΔLOD=1.651, P=0.03) and 22q11.1-q11.21 (OSA LOD=2.395, ΔLOD=2.36, P=0.006), which is close to HPC6. Using OSA allows us to find additional loci linked to HPC in subsets of families, and underlines the complex genetic heterogeneity of HPC even in highly aggregated families. PMID:22948022

  19. A robust response to combination immune checkpoint inhibitor therapy in HPV-related small cell cancer: a case report.

    PubMed

    Ho, Won Jin; Rooper, Lisa; Sagorsky, Sarah; Kang, Hyunseok

    2018-05-09

    Human papillomavirus-related small cell carcinoma of the head and neck is an extremely rare, aggressive subtype with poor outcomes. Therapeutic options are limited and are largely adopted from small cell lung cancer treatment paradigms. This report describes a 69-year old male who was diagnosed of HPV-related oropharyngeal cancer with mixed small cell and squamous cell pathology which was clinically aggressive and progressed through multimodal platinum-based therapies. Upon manifestation of worsening metastatic disease, the patient was initiated on a combination of ipilimumab and nivolumab. Within 2 months of starting immunotherapy, a robust partial response was observed. During the treatment course, the patient developed immune-related adverse effects including new diabetes mellitus, colitis, and hypothyroidism. The disease-specific survival was 26 months. Combination immunotherapy may be an attractive option for HPV-related small cell head and neck cancers resistant to other treatment modalities and thus warrants further evaluation.

  20. Vitamin C and survival among women with breast cancer: a meta-analysis.

    PubMed

    Harris, Holly R; Orsini, Nicola; Wolk, Alicja

    2014-05-01

    The association between dietary vitamin C intake and breast cancer survival is inconsistent and few studies have specifically examined vitamin C supplement use among women with breast cancer. The purpose of this study was to summarise results from prospective studies on the association between vitamin C supplement use and dietary vitamin C intake and breast cancer-specific mortality and total mortality. Studies were identified using the PubMed database through February 6, 2014 and by examining the references of retrieved articles. Prospective studies were included if they reported relative risks (RR) with 95% confidence intervals (95% CIs) for at least two categories or as a continuous exposure. Random-effects models were used to combine study-specific results. The ten identified studies examined vitamin C supplement use (n=6) and dietary vitamin C intake (n=7) and included 17,696 breast cancer cases, 2791 total deaths, and 1558 breast cancer-specific deaths. The summary RR (95% CI) for post-diagnosis vitamin C supplement use was 0.81 (95% CI 0.72-0.91) for total mortality and 0.85 (95% CI 0.74-0.99) for breast cancer-specific mortality. The summary RR for a 100mg per day increase in dietary vitamin C intake was 0.73 (95% CI 0.59-0.89) for total mortality and 0.78 (95% CI 0.64-0.94) for breast cancer-specific mortality. Results from this meta-analysis suggest that post-diagnosis vitamin C supplement use may be associated with a reduced risk of mortality. Dietary vitamin C intake was also statistically significantly associated with a reduced risk of total mortality and breast cancer-specific mortality. Copyright © 2014 Elsevier Ltd. All rights reserved.