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Sample records for initial du cancer

  1. Screening for bladder cancer at the Du Pont Chambers Works: initial findings

    SciTech Connect

    Mason, T.J.; Prorok, P.C.; Neeld, W.E. Jr.; Vogler, W.J.

    1986-10-01

    The following data have been abstracted on all persons ever screened for bladder cancer and on all persons known to have developed bladder cancer among the Chambers Works employees, regardless of whether they had been screened: complete work histories, including dates of employment by job title and location for the duration of employment by Du Pont; medical histories, including the dates and results of every urinary cytological reading and urinary blood test, and the dates and type of every physical examination; and vital status information, including data from death certificates. For each bladder cancer case, detailed clinical histories were abstracted to provide information concerning signs or symptoms of bladder cancer, procedures performed, findings, and recommendations. Pathological information includes type, grade, stage, evidence of multicentricity, metastatic sites, and second primary sites of malignancy. Data are being edited and subjected to preliminary analysis.

  2. Stochastic dynamics of cancer initiation

    NASA Astrophysics Data System (ADS)

    Foo, Jasmine; Leder, Kevin; Michor, Franziska

    2011-02-01

    Most human cancer types result from the accumulation of multiple genetic and epigenetic alterations in a single cell. Once the first change (or changes) have arisen, tumorigenesis is initiated and the subsequent emergence of additional alterations drives progression to more aggressive and ultimately invasive phenotypes. Elucidation of the dynamics of cancer initiation is of importance for an understanding of tumor evolution and cancer incidence data. In this paper, we develop a novel mathematical framework to study the processes of cancer initiation. Cells at risk of accumulating oncogenic mutations are organized into small compartments of cells and proliferate according to a stochastic process. During each cell division, an (epi)genetic alteration may arise which leads to a random fitness change, drawn from a probability distribution. Cancer is initiated when a cell gains a fitness sufficiently high to escape from the homeostatic mechanisms of the cell compartment. To investigate cancer initiation during a human lifetime, a 'race' between this fitness process and the aging process of the patient is considered; the latter is modeled as a second stochastic Markov process in an aging dimension. This model allows us to investigate the dynamics of cancer initiation and its dependence on the mutational fitness distribution. Our framework also provides a methodology to assess the effects of different life expectancy distributions on lifetime cancer incidence. We apply this methodology to colorectal tumorigenesis while considering life expectancy data of the US population to inform the dynamics of the aging process. We study how the probability of cancer initiation prior to death, the time until cancer initiation, and the mutational profile of the cancer-initiating cell depends on the shape of the mutational fitness distribution and life expectancy of the population.

  3. Translation initiation in colorectal cancer.

    PubMed

    Parsyan, Armen; Hernández, Greco; Meterissian, Sarkis

    2012-06-01

    Colorectal cancers (CRC) are one of the most common causes of morbidity and mortality in high-income countries. Targeted screening programs have resulted in early treatment and a substantial decrease in mortality. However, treatment strategies for CRC still require improvement. Understanding the etiology and pathogenesis of CRC would provide tools for improving treatment of patients with this disease. It is only recently that deregulation of the protein synthesis apparatus has begun to gain attention as a major player in cancer development and progression. Among the numerous steps of protein synthesis, deregulation of the process of translation initiation appears to play a key role in cancer growth and proliferation. This manuscript discusses a fascinating and rapidly growing field exploring translation initiation as a fundamental component in CRC development and progression and summarizing CRC treatment perspectives based on agents targeting translation initiation. PMID:22418835

  4. Oncoplastie avec conservation mammaire dans le traitement du cancer du sein: à propos de 16 cas

    PubMed Central

    Bouzoubaa, Wail; Laadioui, Meryam; Jayi, Sofia; Alaoui, Fatime Zahra Fdili; Bouguern, Hakima; Chaara, Hikmat; Melhouf, Moulay Abdelilah

    2015-01-01

    Le cancer du sein est actuellement le cancer le plus fréquent chez la femme, et pose un véritable problème diagnostique et thérapeutique. Le dépistage des lésions à un stade de plus en plus précoce, a permis une extension des indications du traitement conservateur radiochirurgical, qui était initialement limitées aux tumeurs de moins de 3 cm, unifocales, non inflammatoires. Par ailleurs, l'utilisation de traitements préopératoires permet d’étendre les indications du traitement conservateur à des tumeurs plus volumineuses. Parallèlement à cette extension des indications de conservation mammaire, on a observé le développement de nouvelles approches thérapeutiques notamment la chirurgie oncoplastique, technique du ganglion sentinelle et chirurgie stéréotaxique, dont les résultats initiaux sont très encouragent. A travers cette étude réalisée dans le service de gynécologie et obstétrique II du CHU HASSAN II de FES au MAROC, après l'analyse rétrospective de 16 patientes traitées par traitement conservateur et oncoplastie, nous avons voulus montrer notre aptitude a réalisé ses techniques chirurgicales et a bien prendre en charge ces patientes, mais aussi évaluer ces techniques en termes de résultat carcinologique et de résultat esthétique, aussi en terme de survie globale, survie sans métastase et en termes de récidive locale entre les plasties mammaires et les traitements usuels: mastectomie et traitement conservateur classique. PMID:26430477

  5. Classification moléculaire du cancer du sein au Maroc

    PubMed Central

    Fouad, Abbass; Yousra, Akasbi; Kaoutar, Znati; Omar, El Mesbahi; Afaf, Amarti; Sanae, Bennis

    2012-01-01

    Introduction La classification moléculaire des cancers du sein basée sur l'expression génique puis sur le profil protéique a permis de distinguer cinq groupes moléculaires: luminal A, luminal B, Her2/neu, basal-like et non-classées. L'objectif de cette étude réalisée au CHU Hassan II de Fès est de classer 335 cancers du sein infiltrant en groupes moléculaires, puis de les corréler avec les caractéristiques clinicopathologiques. Méthodes Etude rétrospective étalée sur 45 mois, comportant 335 patientes colligées au CHU pour le diagnostic et le suivi. Les tumeurs sont analysées histologiquement et classées après une étude immunohistochimique en groupes: luminal A, luminal B, Her2+, basal-like et non-classées. Résultats 54.3% des tumeurs sont du groupe luminal A, 16% luminal B, 11.3% Her2+, 11.3% basal-like et 7% non-classées. Le groupe luminal A renferme le plus faible taux de grade III, d'emboles vasculaires ainsi que de métastases; alors que le groupe des non-classées et basal-like représentent un taux élevé de grade III, une faible proportion d'emboles vasculaires et d'envahissement ganglionnaire. Ces facteurs sont significativement élevés dans les groupes luminal B et Her2+ avec un taux de survie globale de 78% et 76% respectivement. Dans le groupe luminal A, la survie globale des patientes est élevée (87%) alors qu'elle n'est que de 49% dans le groupe des triples négatifs (basal-like et non-classés). Conclusion Le groupe luminal B est différent du luminal A et il est de pronostic péjoratif vis à vis du groupe Her2+. Les caractéristiques clinicopathologiques concordent avec le profil moléculaire donc devraient être pris en considération comme facteurs pronostiques. PMID:23396646

  6. Restauration fonctionnelle du rachis : effet du niveau initial de douleur sur les performances des sujets lombalgiques chroniques

    PubMed Central

    Caby, Isabelle; Olivier, N; Mendelek, F; Kheir, R Bou; Vanvelcenaher, J; Pelayo, P

    2014-01-01

    HISTORIQUE : La lombalgie chronique est une douleur lombaire persistante d’origine multifactorielle. Le niveau de douleur initial reste faiblement utilisé pour analyser et comparer les réponses des patients lombalgiques au programme de reconditionnement. OBJECTIFS : Apprécier et évaluer les réponses des sujets lombalgiques chroniques très douloureux à une prise en charge dynamique et intensive. MÉTHODOLOGIE : 144 sujets atteints de lombalgie chronique ont été inclus dans un programme de restauration fonctionnelle du rachis de 5 semaines. Les sujets ont été classés en deux groupes de niveau de douleur: un groupe atteint de douleur sévère (n = 28) et un groupe atteint de douleur légère à modérée (n = 106). L’ensemble des sujets ont bénéficié d’une prise en charge identique comprenant principalement de la kinésithérapie, de l’ergothérapie, du reconditionnement musculaire et cardio-vasculaire ainsi qu’un suivi psychologique. Les paramètres physiques (flexibilité, force musculaire) et psychologiques (qualité de vie) ont été mesurés avant (T0) et après le programme (T5sem). RÉSULTATS : L’ensemble des performances physiques et fonctionnelles des sujets très douloureux sont moins bonnes et le retentissement de la lombalgie sur la qualité de vie, pour ces mêmes sujets, est majoré à T0. Toutes les différences significatives constatées à T0 entre les deux groupes s’effacent à T5sem. CONCLUSIONS : Les sujets lombalgiques chroniques très douloureux répondent favorablement au programme dynamique et intensif. L’intensité douloureuse de la lombalgie n’aurait pas d’effet sur les réponses au programme. La restauration fonctionnelle du rachis apporterait aux sujets la possibilité de mieux gérer leur douleur quel que soit son niveau. PMID:25299476

  7. Specialized Initiatives - Cancer Imaging Program

    Cancer.gov

    CIP has sponsored a number of programs for specific purposes, using set-aside funds. Among these are Phase 2 N01 ProgramIn-Vivo Cellular & Molecular Imaging Centers (ICMICs) Quantitative Imaging for Evaluation of Responses to Cancer Therapies (QIN) Network for Translational Research (NTR): Optical Imaging in Multimodal Platforms Small Animal Imaging Resource Program (SAIRP) Development of Preclinical Drugs and Enhancers (DCIDE) program.

  8. National Cancer Moonshot Initiative platform | Office of Cancer Genomics

    Cancer.gov

    As part of the Vice President’s National Cancer Moonshot Initiative, the National Cancer Institute has launched an online engagement platform to enable the research community and the public to submit cancer research ideas to a Blue Ribbon Panel of scientific experts. Any member of the public is encouraged to submit his or her ideas for reducing the incidence of cancer and developing better ways to prevent, treat, and cure all types of cancer. Research ideas may be submitted in the following areas:

  9. Diosmin induces genotoxicity and apoptosis in DU145 prostate cancer cell line.

    PubMed

    Lewinska, Anna; Siwak, Justyna; Rzeszutek, Iwona; Wnuk, Maciej

    2015-04-01

    Plant-derived dietary polyphenolic compounds, such as flavonoids, with cancer cell-specific pro-apoptotic activity and chemopreventive potential are thought to be promising anticancer agents. In the present study, we were interested in determining if flavonoid-induced genotoxicity may also provoke cancer cell death. Cyto- and genotoxicity of three selected flavonoid glycosides (naringin, diosmin and hesperidin) in DU145 prostate cancer cell line were investigated. Flavonoid glycosides decreased cancer cell number and proliferative activity in a different manner. Flavonoid glycosides induced oxidative stress: intracellular total ROS and superoxide production were augmented after flavonoid treatment. Flavonoid glycosides stimulated DNA double strand breaks (DSBs) and micronuclei production. Diosmin was found the most potent genotoxic agent in DU145 cells, which, in turn, resulted in its pro-apoptotic activity. The more robust recruitment of 53BP1 was correlated with lower DNA and chromosomal damage after naringin and hesperidin treatment compared with diosmin treatment. Flavonoid glycosides were also found to be DNA hypomethylating agents with an ability to modulate cancer cell epigenome leading to changes in the gene expression patterns. Taken together, diosmin, a dietary flavonoid glycoside, was found active against DU145 cells by promoting genotoxic events and a concomitant apoptotic cell death. Thus, a comprehensive analysis of biological activity of diosmin against cancer cells both in vitro and in vivo deserves further investigation. PMID:25499067

  10. Cancer du sein de l'homme: à propos de 6 cas

    PubMed Central

    Laabadi, Kamilia; Jayi, Sofia; Alaoui, Fatimazohra Fdili; Bouguern, Hakima; Chaara, Hikmat; Melhouf, My Abdelilah; Hassani, Karim Ibn Majdoub; Laalim, Said Ait; Anoun, Hicham; Toughrai, Imane; Mazaz, Khalid

    2013-01-01

    Le but de ce travail était d'analyser les caractéristiques cliniques, histologiques, thérapeutiques et pronostiques du cancer du sein chez l'homme. Il s'agissait d'une étude rétrospective portant sur six patients colligés au service de gynécologie obstétrique II, CHU Hassan II durant la période 2009-2012. L’âge moyen de nos patients est de 65.3 ans. Il s'agit dans 83.3% des cas, d'une tumeur rétroaréolaire dont la taille moyenne est de 44.16 mm. Nous avons retrouvé 4 (66.7%) T4, 1 (16.7%) T3 et dans un cas, une tumeur inclassable. Le type histologique le plus représenté est le carcinome canalaire infiltrant (66.7%). Le taux d'envahissement ganglionnaire axillaire est de 66.7%. L'hormonodépendance de ces tumeurs est prouvée dans 100% des cas. La survie à cinq ans est en cours d’évaluation. L'envahissement ganglionnaire, l'invasion du derme, le stade clinique TNM sont des facteurs qui influencent significativement la survenue de métastases. Aucun de ces facteurs de risque n'est apparu significatif en termes de survie globale. Le cancer du sein chez l'homme est une maladie rare (environ 1% des cancers du sein) au pronostic sombre. Le diagnostic est le plus souvent tardif et les lésions sont traitées à des stades avancés. PMID:24711870

  11. Artocarpus altilis (Parkinson) Fosberg Extracts and Geranyl Dihydrochalcone Inhibit STAT3 Activity in Prostate Cancer DU145 Cells.

    PubMed

    Jeon, Yoon Jung; Jung, Seung-Nam; Chang, Hyeyoun; Yun, Jieun; Lee, Chang Woo; Lee, Joonku; Choi, Sangho; Nash, Oyekanmi; Han, Dong Cho; Kwon, Byoung-Mog

    2015-05-01

    Artocarpus altilis (Parkinson) Fosberg has traditionally been used in Indonesia for the treatment of liver cirrhosis, hypertension, and diabetes. In many other countries, it is used for the treatment of malaria, yellow fever, and dengue fever. It has been reported that A. altilis extracts have antiatherosclerotic and cytoprotective effects, but its molecular targets in tumor cells are not yet fully understood. The A. altilis extracts and the partially purified fraction have been shown to inhibit STAT3 activity and the phosphorylation of STAT3 in a dose-dependent manner. To identify the active components, a bioassay-guided isolation of the partially purified fraction resulted in the identification of a geranyl dihydrochalcone, CG901. Its chemical structure was established on the basis of spectroscopic evidence and comparison with published data. The partially purified fraction and the isolated a geranyl dihydrochalcone, CG901, down-regulated the expression of STAT3 target genes, induced apoptosis in DU145 prostate cancer cells via caspase-3 and PARP degradation, and inhibited tumor growth in human prostate tumor (DU145) xenograft initiation model. These results suggest that A. altilis could be a good natural source and that the isolated compound will be a potential lead molecule for developing novel therapeutics against STAT3-related diseases, including cancer and inflammation. PMID:25682949

  12. Docetaxel induces Bcl-2- and pro-apoptotic caspase-independent death of human prostate cancer DU145 cells

    PubMed Central

    OGURA, TAKEHARU; TANAKA, YOSHIYUKI; TAMAKI, HIROKI; HARADA, MAMORU

    2016-01-01

    Docetaxel is a useful chemotherapeutic agent for the first-line treatment of hormone-refractory prostate cancer. Abnormal expression of Bcl-2 is commonly found in cancer cells, which increases their anti-apoptotic potency and chemo-resistance. We investigated the effects of Bcl-2 expression status on the susceptibility of DU145 cells, an androgen-independent human prostate cancer cell line, to docetaxel and other anticancer agents. A panel of Bcl-2-expressing DU145 cell lines was established. Bcl-2 expression levels were unrelated to the susceptibility of DU145 cells to docetaxel. The sensitivity of DU145 cells to cisplatin fluctuated, and the sensitivity to tumor necrosis factor (TNF)-α was decreased by Bcl-2 overexpression. In a xenograft mouse model, overexpression of Bcl-2 drastically decreased the sensitivity of DU145 cells to cisplatin and TNF-α; however, there was no change in the response to docetaxel. Fluorescent microscopy revealed that Bcl-2-overexpression had no effect on the docetaxel-induced death of DU145 cells, but significantly decreased DU145 cell death induced by cisplatin or TNF-α. Interestingly, docetaxel hardly induced caspase-3/7 activation in control or Bcl-2-overexpressing DU145 cells, but did at a low level in LNCaP cells, another prostate cancer cell line. Moreover, in contrast to LNCaP cells, the reduced viabilities of docetaxel-treated control and Bcl-2-overexpressing DU145 cells were not restored by the addition of either a Bid inhibitor or a panel of pro-apoptotic caspase inhibitors. These findings indicate that the antitumor effects of docetaxel on DU145 cells are independent of both Bcl-2 and pro-apoptotic caspases. PMID:27082738

  13. Docetaxel induces Bcl-2- and pro-apoptotic caspase-independent death of human prostate cancer DU145 cells.

    PubMed

    Ogura, Takeharu; Tanaka, Yoshiyuki; Tamaki, Hiroki; Harada, Mamoru

    2016-06-01

    Docetaxel is a useful chemotherapeutic agent for the first-line treatment of hormone-refractory prostate cancer. Abnormal expression of Bcl-2 is commonly found in cancer cells, which increases their anti-apoptotic potency and chemoresistance. We investigated the effects of Bcl-2 expression status on the susceptibility of DU145 cells, an androgen-independent human prostate cancer cell line, to docetaxel and other anticancer agents. A panel of Bcl-2-expressing DU145 cell lines was established. Bcl-2 expression levels were unrelated to the susceptibility of DU145 cells to docetaxel. The sensitivity of DU145 cells to cisplatin fluctuated, and the sensitivity to tumor necrosis factor (TNF)-α was decreased by Bcl-2 overexpression. In a xenograft mouse model, overexpression of Bcl-2 drastically decreased the sensitivity of DU145 cells to cisplatin and TNF-α; however, there was no change in the response to docetaxel. Fluorescent microscopy revealed that Bcl-2-overexpression had no effect on the docetaxel-induced death of DU145 cells, but significantly decreased DU145 cell death induced by cisplatin or TNF-α. Interestingly, docetaxel hardly induced caspase-3/7 activation in control or Bcl-2-overexpressing DU145 cells, but did at a low level in LNCaP cells, another prostate cancer cell line. Moreover, in contrast to LNCaP cells, the reduced viabilities of docetaxel-treated control and Bcl-2-overexpressing DU145 cells were not restored by the addition of either a Bid inhibitor or a panel of pro-apoptotic caspase inhibitors. These findings indicate that the antitumor effects of docetaxel on DU145 cells are independent of both Bcl-2 and pro-apoptotic caspases. PMID:27082738

  14. Restructuring dynamics of DU 145 and LNCaP prostate cancer spheroids.

    PubMed

    Song, Hong; Jain, Shamik K; Enmon, Richard M; O'Connor, Kim C

    2004-01-01

    Neoplastic cells acquire multidrug resistance as they assemble into multicellular spheroids. Image analysis and Monte Carlo simulation provided an insight into the adhesion and motility events during spheroid restructuring in liquid-overlay culture of DU 145 and LNCaP human prostate cancer cells. Irregularly shaped, two-dimensional aggregates restructured through incremental cell movements into three-dimensional spheroids. Of the two cultures examined, restructuring was more pronounced for DU 145 aggregates. Motile DU 145 cells formed spheroids with a minimum cell overlay of 30% for 25-mers as estimated by simulation versus 5% for adhesive LNCaP cells in aggregates of the same size. Over 72 h, the texture ratio increased from 0.55 +/- 0.05 for DU 145 aggregates with projected areas exceeding 2000 microm2 to a value approaching 0.75 +/- 0.02 (P < 0.05). For LNCaP aggregates of comparable size, the increase in texture ratio was more modest, less than 15% during the same time period (P < 0.05). Combined, these data suggest that motility events govern the overall rate of spheroid restructuring. This information has application to the chemosensitization of solid tumors and kinetic modeling of spheroid production. PMID:15723561

  15. Aspects cliniques des cancers bronchopulmonaires primitifs au service d'oncologie du CHUA-HUJRA Antananarivo

    PubMed Central

    Refeno, Valéry; Hasiniatsy, Nomeharisoa Rodrigue Emile; Andrianandrasana, Ny Ony Tiana Florence; Ramahandrisoa, Andriatsihoarana Voahary Nasandratriniavo; Rakotonarivo, Jean Marc; Maevazaka, Joée Larissa; Rakotovao, Hanitrala Jean Louis; Rafaramino, Florine

    2015-01-01

    Le retard de diagnostic des cancers broncho-pulmonaires est l'une des sources du retard de leur prise en charge dans les pays en développement. A notre connaissance, l'aspect clinique des cancers broncho-pulmonaires au Centre Hospitalier Universitaire d'Antananarivo-Hôpital Universitaire Joseph Ravoahangy Andrianavalona (CHUA-HUJRA) n'a jamais été étudié. L'objectif était de décrire les aspects cliniques des cancers broncho-pulmonaires primitifs dans le plus grand centre de cancérologie de Madagascar. C'est une étude rétrospective et descriptive des patients atteints de cancers broncho-pulmonaires primitifs vus au service d'oncologie du CHUA-HUJRA du 1er janvier 2008 au 31 décembre 2013. Nous avons recensé 101 patients (80 hommes et 21 femmes). Les circonstances de découverte sont principalement la toux chronique (n = 29), la dyspnée (n = 16) et l'association d'une hémoptysie à la toux chronique (n = 12). Soixante et onze patients avaient un index de performans status ≥ à 2 au moment du diagnostic. On a retrouvé des bacilles de Koch actives dans le crachat de deux patients. Le délai moyen entre l'apparition des premiers signes et la première consultation était de 11 mois. Le délai moyen entre la première consultation et le diagnostic anatomopathologique était de 3 mois. Le cancer broncho-pulmonaire peut avoir des manifestations cliniques non spécifiques parfois trompeuses qui peuvent retarder leur prise en charge. De ce fait, il doit être recherché devant tout signe respiratoire persistant. Par ailleurs, le délai de prise en charge pré-hospitalière et hospitalière de ces cancers doit être amélioré. PMID:26958134

  16. Imagerie par modulation acoustique de conductivite electrique destinee au diagnostic du cancer du sein

    NASA Astrophysics Data System (ADS)

    Gendron, Mathieu

    used to reconstruct the electrical conductivity distribution. The second model presented in the thesis uses a unipolar acoustic wave to generate AECM signals of relatively large amplitude. There are two aspects related to this type of wave. The first aspect is that the acoustic modulation is unidirectional if the applied pressure is unidirectional. As a result, a positive pressure only produces an increase in electrical conductivity and this will result in a large AECM signal even when the thickness of the object is large. The second aspect concerns the shape of the acoustic field. Since the unipolar acoustic wave is not focused, it modulates the conductivity over a large area, and thus the associated AECM signals needs to be processed through a reconstruction algorithm so as to recover local conductivity. In this model, the data required for image reconstruction are acquired by rotating the transducer around the target object. An experimental setup has been developed during our project to get values of certain parameter that are required to define the numerical models. The setup comprises a large tank which is filled with water and in which are immersed the ultrasound transducer, a hydrophone and a measurement cell. The acousto-electric interaction takes place within this cell. A computer controlled positioning system allows precise displacements of the transducer relative to the hydrophone and the measurement cell. This cell comprises a cavity in which the object to be analyzed is placed and that is then filled with an electrolytic solution. The cavity is closed on two sides by an acoustic window to allow propagation of the ultrasound wave and on another side by six Ag/AgCl electrodes that are used to apply current and to measure the resulting electrical potential. Mammography is presently the most widely used medical imaging procedure for breast cancer screening. The average sensitivity of this technique is 80 % but it is less for younger women. According to recent

  17. Imagerie par modulation acoustique de conductivite electrique destinee au diagnostic du cancer du sein

    NASA Astrophysics Data System (ADS)

    Gendron, Mathieu

    used to reconstruct the electrical conductivity distribution. The second model presented in the thesis uses a unipolar acoustic wave to generate AECM signals of relatively large amplitude. There are two aspects related to this type of wave. The first aspect is that the acoustic modulation is unidirectional if the applied pressure is unidirectional. As a result, a positive pressure only produces an increase in electrical conductivity and this will result in a large AECM signal even when the thickness of the object is large. The second aspect concerns the shape of the acoustic field. Since the unipolar acoustic wave is not focused, it modulates the conductivity over a large area, and thus the associated AECM signals needs to be processed through a reconstruction algorithm so as to recover local conductivity. In this model, the data required for image reconstruction are acquired by rotating the transducer around the target object. An experimental setup has been developed during our project to get values of certain parameter that are required to define the numerical models. The setup comprises a large tank which is filled with water and in which are immersed the ultrasound transducer, a hydrophone and a measurement cell. The acousto-electric interaction takes place within this cell. A computer controlled positioning system allows precise displacements of the transducer relative to the hydrophone and the measurement cell. This cell comprises a cavity in which the object to be analyzed is placed and that is then filled with an electrolytic solution. The cavity is closed on two sides by an acoustic window to allow propagation of the ultrasound wave and on another side by six Ag/AgCl electrodes that are used to apply current and to measure the resulting electrical potential. Mammography is presently the most widely used medical imaging procedure for breast cancer screening. The average sensitivity of this technique is 80 % but it is less for younger women. According to recent

  18. The AURORA initiative for metastatic breast cancer.

    PubMed

    Zardavas, D; Maetens, M; Irrthum, A; Goulioti, T; Engelen, K; Fumagalli, D; Salgado, R; Aftimos, P; Saini, K S; Sotiriou, C; Campbell, P; Dinh, P; von Minckwitz, G; Gelber, R D; Dowsett, M; Di Leo, A; Cameron, D; Baselga, J; Gnant, M; Goldhirsch, A; Norton, L; Piccart, M

    2014-11-11

    Metastatic breast cancer is one of the leading causes of cancer-related mortality among women in the Western world. To date most research efforts have focused on the molecular analysis of the primary tumour to dissect the genotypes of the disease. However, accumulating evidence supports a molecular evolution of breast cancer during its life cycle, with metastatic lesions acquiring new molecular aberrations. Recognising this critical gap of knowledge, the Breast International Group is launching AURORA, a large, multinational, collaborative metastatic breast cancer molecular screening programme. Approximately 1300 patients with metastatic breast cancer who have received no more than one line of systemic treatment for advanced disease will, after giving informed consent, donate archived primary tumour tissue, as well as will donate tissue collected prospectively from the biopsy of metastatic lesions and blood. Both tumour tissue types, together with a blood sample, will then be subjected to next generation sequencing for a panel of cancer-related genes. The patients will be treated at the discretion of their treating physicians per standard local practice, and they will be followed for clinical outcome for 10 years. Alternatively, depending on the molecular profiles found, patients will be directed to innovative clinical trials assessing molecularly targeted agents. Samples of outlier patients considered as 'exceptional responders' or as 'rapid progressors' based on the clinical follow-up will be subjected to deeper molecular characterisation in order to identify new prognostic and predictive biomarkers. AURORA, through its innovative design, will shed light onto some of the unknown areas of metastatic breast cancer, helping to improve the clinical outcome of breast cancer patients. PMID:25225904

  19. The AURORA initiative for metastatic breast cancer

    PubMed Central

    Zardavas, D; Maetens, M; Irrthum, A; Goulioti, T; Engelen, K; Fumagalli, D; Salgado, R; Aftimos, P; Saini, K S; Sotiriou, C; Campbell, P; Dinh, P; von Minckwitz, G; Gelber, R D; Dowsett, M; Di Leo, A; Cameron, D; Baselga, J; Gnant, M; Goldhirsch, A; Norton, L; Piccart, M

    2014-01-01

    Metastatic breast cancer is one of the leading causes of cancer-related mortality among women in the Western world. To date most research efforts have focused on the molecular analysis of the primary tumour to dissect the genotypes of the disease. However, accumulating evidence supports a molecular evolution of breast cancer during its life cycle, with metastatic lesions acquiring new molecular aberrations. Recognising this critical gap of knowledge, the Breast International Group is launching AURORA, a large, multinational, collaborative metastatic breast cancer molecular screening programme. Approximately 1300 patients with metastatic breast cancer who have received no more than one line of systemic treatment for advanced disease will, after giving informed consent, donate archived primary tumour tissue, as well as will donate tissue collected prospectively from the biopsy of metastatic lesions and blood. Both tumour tissue types, together with a blood sample, will then be subjected to next generation sequencing for a panel of cancer-related genes. The patients will be treated at the discretion of their treating physicians per standard local practice, and they will be followed for clinical outcome for 10 years. Alternatively, depending on the molecular profiles found, patients will be directed to innovative clinical trials assessing molecularly targeted agents. Samples of outlier patients considered as ‘exceptional responders' or as ‘rapid progressors' based on the clinical follow-up will be subjected to deeper molecular characterisation in order to identify new prognostic and predictive biomarkers. AURORA, through its innovative design, will shed light onto some of the unknown areas of metastatic breast cancer, helping to improve the clinical outcome of breast cancer patients. PMID:25225904

  20. Metastatic prostate cancer initially presenting as chylothorax: A case report

    PubMed Central

    YANG, YU-JIN; SEO, MINJUNG; JEON, HEE-JEONG; NOH, JIN-HEE; PARK, SEOL HOON; CHOI, YUNSUK; JO, JAE-CHEOL; BAEK, JIN HO; KOH, SU-JIN; KIM, HAWK; MIN, YOUNG JOO

    2016-01-01

    Chylothorax is caused by disruption or obstruction of the thoracic duct, which results in leakage of chyle in the pleural space. The most common etiologies are malignancy and trauma. Among the causative malignancies, lymphoma is the most common, followed by primary lung cancer, mediastinal tumors, and other metastatic malignancies. Conversely, prostate cancer has rarely been reported as the cause of chylothorax. We herein report a case of metastatic prostate cancer initially presenting as chylothorax, with disappearance of the pleural effusion after the initiation of androgen deprivation therapy. Moreover, we also discuss the various rare manifestations of metastatic prostate cancer, including chylothorax. PMID:27313861

  1. Spatial Moran models, II: cancer initiation in spatially structured tissue

    PubMed Central

    Foo, J; Leder, K

    2016-01-01

    We study the accumulation and spread of advantageous mutations in a spatial stochastic model of cancer initiation on a lattice. The parameters of this general model can be tuned to study a variety of cancer types and genetic progression pathways. This investigation contributes to an understanding of how the selective advantage of cancer cells together with the rates of mutations driving cancer, impact the process and timing of carcinogenesis. These results can be used to give insights into tumor heterogeneity and the “cancer field effect,” the observation that a malignancy is often surrounded by cells that have undergone premalignant transformation. PMID:26126947

  2. Curiethérapie dans le traitement palliatif du cancer de l’œsophage

    PubMed Central

    Toulba, Ahmedou; Bakkali, Hanae; Boutayeb, Salwa; Kebdani, Tayeb; Ahid, Samir; Benjaafar, Noureddine

    2015-01-01

    Les patients atteints du cancer de l’œsophage ont souvent une maladie localement avancée, la dysphagie est le symptôme majeur chez la plupart de ces patients, plusieurs modalités thérapeutiques ont été utilisées pour améliorer cette dysphagie. Le but de ce travail est d’étudier l'efficacité et la tolérance de la curiethérapie haut débit de dose (HDR) endo-luminale dans le traitement palliatif des cancers de l’œsophage inopérable. Sur une période de 15 ans, l’étude a inclus les patients atteints de cancer de l’œsophage inopérable et/ou métastatique avec une dysphagie, sans extension à l'hypopharynx ou a la trachée et qui ont bénéficié d'une curiethérapie HDR avec ou sans radiothérapie externe à visée palliative. Au total 46 patients ont été inclus dans l’étude, 58,7% étaient des hommes, 42,2% avaient une dysphagie grade 2 et 37,8% étaient aphagiques, 78,6% des patients étaient performance satus PS 2, l'amaigrissement à été trouvé chez 81,4%, la localisation de la tumeur était surtout au niveau du tiers moyen et inférieur dans 97,8%, la hauteur médiane de la tumeur était de 7 cm (5,5-9), le carcinome épidermoïde était le type histologique le plus fréquent chez 31 patients (70,5%). Après un médiane de suivi de 5 mois, l'amélioration de la dysphagie a été retrouvée chez 76% des malades (p1]. L′incidence la plus élevée est observée dans certains pays notamment en Asie et en Afrique, et l′incidence dans les pays développés occidentaux est en augmentation [2]. Selon le registre du cancer de Rabat 2006-2008, le cancer de l’œsophage est rare et constitue 1,5% de tous les cancers chez l'homme [3]. Le taux de survie globale à 5 ans est de 8%, avec 80% des décès liés à l’évolution locale de la maladie [4]. Pour la minorité des patients avec une maladie localisée, le traitement par radiochimiothérapie concomitante avec ou sans chirurgie permet une amélioration de la survie [5]. Plus de 50

  3. Optimizing initial chemotherapy for metastatic pancreatic cancer.

    PubMed

    Mantripragada, Kalyan C; Safran, Howard

    2016-05-01

    The two combination chemotherapy regimens FOLFIRINOX and gemcitabine plus nab-paclitaxel represent major breakthroughs in the management of metastatic pancreatic cancer. Both regimens showed unprecedented survival advantage in the setting of front-line therapy. However, their application for treatment of patients in the community is challenging because of significant toxicities, thus limiting potential benefits to a narrow population of patients. Modifications to the dose intensity or schedule of those regimens improve their tolerability, while likely retaining survival advantage over single-agent chemotherapy. Newer strategies to optimize these two active regimens in advanced pancreatic cancer are being explored that can help personalize treatment to individual patients. PMID:26939741

  4. L’effet du yoga chez les patients atteints de cancer

    PubMed Central

    Côté, Andréanne; Daneault, Serge

    2012-01-01

    Résumé Objectif Déterminer si le yoga thérapeutique améliore la qualité de vie de patients atteints de cancer. Sources des données Recherche effectuée avec la base de données MEDLINE (1950–2010) en utilisant les mots-clés yoga, cancer et quality of life. Sélection des études Priorité accordée aux études cliniques randomisées contrôlées évaluant l’effet du yoga sur différents symptômes susceptibles de se présenter chez des patients atteints de cancer en Amérique du Nord. Synthèse Quatre études cliniques randomisées contrôlées ont d’abord été analysées, puis 2 études sans groupe-contrôle. Trois études réalisées en Inde et au Proche-Orient ont également apporté des éléments intéressants au plan méthodologique. Les interventions proposées comprenaient des séances de yoga d’une durée et d’une fréquence variables. Les paramètres mesurés variaient également d’une étude à l’autre. Plusieurs symptômes ont connu des améliorations significatives avec le yoga (meilleure qualité du sommeil, diminution des symptômes anxieux ou dépressifs, amélioration du bien-être spirituel, etc.). Il a aussi semblé que la qualité de vie, dans sa globalité ou dans certaines de ses composantes spécifiques, s’améliorait. Conclusion La variété des effets bénéfiques produits, l’absence d’effet secondaire et le rapport coût-bénéfice avantageux du yoga thérapeutique en fait une intervention intéressante à suggérer par les médecins de famille aux patients atteints de cancer. Certaines lacunes méthodologiques ont pu diminuer la puissance statistique des études présentées, à commencer par la taille restreinte des échantillons et par l’assiduité variable des patients soumis à l’intervention. Il est également possible que les échelles de mesure utilisées ne convenaient pas à ce type de situation et de clientèle pour qu’en soit dégagé un effet significatif. Toutefois, les commentaires

  5. Metabolic, autophagic, and mitophagic activities in cancer initiation and progression.

    PubMed

    Hjelmeland, Anita; Zhang, Jianhua

    2016-04-01

    Cancer is a complex disease marked by uncontrolled cell growth and invasion. These processes are driven by the accumulation of genetic and epigenetic alterations that promote cancer initiation and progression. Contributing to genome changes are the regulation of oxidative stress and reactive species-induced damage to molecules and organelles. Redox regulation, metabolic plasticity, autophagy, and mitophagy play important and interactive roles in cancer hallmarks including sustained proliferation, activated invasion, and replicative immortality. However, the impact of these processes can differ depending on the signaling pathways altered in cancer, tumor type, tumor stage, and/or the differentiation state. Here, we highlight some of the representative studies on the impact of oxidative and nitrosative activities, mitochondrial bioenergetics, metabolism, and autophagy and mitophagy in the context of tumorigenesis. We discuss the implications of these processes for cellular activities in cancer for anti-cancer-based therapeutics. PMID:27372165

  6. c-Met inhibitor SU11274 enhances the response of the prostate cancer cell line DU145 to ionizing radiation

    SciTech Connect

    Yu, Hongliang; Li, Xiaoying; Sun, Shaoqian; Gao, Xianshu; Zhou, Demin

    2012-10-26

    Highlights: Black-Right-Pointing-Pointer c-Met inhibition could significantly enhance the radiosensitivity of DU145 cells. Black-Right-Pointing-Pointer The mechanisms of the radiosensitization effect of c-Met inhibition on DU145 cells were also presented in this paper. Black-Right-Pointing-Pointer This is the first study demonstrating the effectiveness of c-Met inhibition on treating HRPC cells with radiotherapy. -- Abstract: Hormone-refractory prostate cancer shows substantial resistance to most conventional therapies including radiotherapy, constitutes a key impediment to curing patients with the disease. c-Met overexpression plays a key role in prostate cancer tumorigenesis and disease progression. Here, we demonstrate that c-Met inhibition by SU11274 could significantly suppress cell survival and proliferation as well as enhance the radiosensitivity of DU145 cells. The underlying mechanisms of the effects of SU11274 on DU145 cells may include the inhibition of c-Met signaling, depolarization of the mitochondrial membrane potential, impairment of DNA repair function, abrogation of cell cycle arrest, and enhancement of cell death. Our study is the first to show the effectiveness of combining c-Met inhibition with ionizing radiation to cure hormone-refractory prostate cancer.

  7. Etude descriptive et analytique du cancer de l’œsophage au Togo

    PubMed Central

    Oumboma, Bouglouga; Mawuli, Lawson-Ananissoh Laté; Aklesso, Bagny; Laconi, Kaaga; Datouda, Redah

    2014-01-01

    Introduction Décrire les aspects épidémiologiques, cliniques, endoscopiques et histologiques du cancer de l’œsophage (CO) au Togo. Méthodes Il s'agit d'une étude rétrospective descriptive et analytique menée sur 8 ans (Janvier 2005-Décembre 2012) dans le service d'hépato-gastroentérologie (HGE) du CHU Campus de Lomé. Etaient inclus les dossiers des patients hospitalisés pour CO confirmé histologiquement. Résultats Sur 8 ans, 24 patients remplissant nos critères d'inclusion ont été retenus soit 3cas de CO par an et 0,55% des hospitalisations. L’âge moyen des patients était de 57,08 ans (extrêmes: 32 et 82 ans). La dysphagie et l’épigastralgie étaient les motifs d'hospitalisation les plus rencontrés. L'alcool (n=15), le tabac (n=13) étaient les facteurs de risque les plus présents. A la fibroscopie, les lésions étaient ulcéro-bourgeonnantes et hémorragiques (n=12), ulcéro-bourgeonnantes (n=5); ces lésions siégeaient au niveau du 1/3 inférieur (n= 11), à l'union 1/3 supérieur 1/3moyen de l’œsophage (n= 13) et aucun au niveau du 1/3 supérieur. Seize lésions étaient des carcinomes épidermoïdes et 3 des adénocarcinomes. L’évolution dans le service a été fatale dans 2cas; 16 patients avaient été transférés en chirurgie pour des soins palliatifs et 5 patients (20,8%) étaient perdus de vue. Conclusion Le CO semble en augmentation au Togo. L'alcool et le tabac sont les facteurs de risque et le pronostic sévère dans notre série est lié au retard diagnostic. Son dépistage précoce passe par une consultation rapide devant toute dysphagie chez un sujet de 50 ans et plus. PMID:25883742

  8. Depurinating estrogen-DNA adducts, generators of cancer initiation: their minimization leads to cancer prevention.

    PubMed

    Cavalieri, Ercole L; Rogan, Eleanor G

    2016-03-01

    Estrogens can initiate cancer by reacting with DNA. Specific metabolites of endogenous estrogens, the catechol estrogen-3,4-quinones, react with DNA to form depurinating estrogen-DNA adducts. Loss of these adducts leaves apurinic sites in the DNA, generating mutations that can lead to the initiation of cancer. A variety of endogenous and exogenous factors can disrupt estrogen homeostasis, which is the normal balance between estrogen activating and protective enzymes. In fact, if estrogen metabolism becomes unbalanced and generates excessive catechol estrogen 3,4-quinones, formation of depurinating estrogen-DNA adducts increases and the risk of initiating cancer is greater. The levels of depurinating estrogen-DNA adducts are high in women diagnosed with breast cancer and those at high risk for the disease. High levels of depurinating estrogen-DNA adducts before the presence of breast cancer indicates that adduct formation is a critical factor in breast cancer initiation. Women with thyroid or ovarian cancer also have high levels of estrogen-DNA adducts, as do men with prostate cancer or non-Hodgkin lymphoma. Depurinating estrogen-DNA adducts are initiators of many prevalent types of human cancer. These findings and other discoveries led to the recognition that reducing the levels of estrogen-DNA adducts could prevent the initiation of human cancer. The dietary supplements N-acetylcysteine and resveratrol inhibit formation of estrogen-DNA adducts in cultured human breast cells and in women. These results suggest that the two supplements offer an approach to reducing the risk of developing various prevalent types of human cancer. Graphical abstract Major metabolic pathway in cancer initiation by estrogens. PMID:26979321

  9. Capsaicin-induced genotoxic stress does not promote apoptosis in A549 human lung and DU145 prostate cancer cells.

    PubMed

    Lewinska, Anna; Jarosz, Paulina; Czech, Joanna; Rzeszutek, Iwona; Bielak-Zmijewska, Anna; Grabowska, Wioleta; Wnuk, Maciej

    2015-02-01

    Capsaicin is the major pungent component of the hot chili peppers of the genus Capsicum, which are consumed worldwide as a food additive. More recently, the selective action of capsaicin against cancer cells has been reported. Capsaicin was found to induce apoptosis and inhibit proliferation of a wide range of cancer cells in vitro, whereas being inactive against normal cells. As data on capsaicin-induced genotoxicity are limited and the effects of capsaicin against human lung A549 and DU145 prostate cancer cells were not explored in detail, we were interested in determining whether capsaicin-associated genotoxicity may also provoke A549 and DU145 cell death. Capsaicin-induced decrease in metabolic activity and cell proliferation, and changes in the cell cycle were limited to high concentrations used (≥ 100 μM), whereas, at lower concentrations, capsaicin stimulated both DNA double strand breaks and micronuclei production. Capsaicin was unable to provoke apoptotic cell death when used up to 250 μM concentrations. Capsaicin induced oxidative stress, but was ineffective in provoking the dissipation of the mitochondrial inner transmembrane potential. A different magnitude of p53 binding protein 1 (53BP1) recruitment contributed to diverse capsaicin-induced genotoxic effects in DU145 and A549 cells. Capsaicin was also found to be a DNA hypermethylating agent in A549 cells. In summary, we have shown that genotoxic effects of capsaicin may contribute to limited susceptibility of DU145 and A549 cancer cells to apoptosis in vitro, which may question the usefulness of capsaicin-based anticancer therapy, at least in a case of lung and prostate cancer. PMID:25813723

  10. Cancer du sein au Cameroun, profil histo-épidémiologique: à propos de 3044 cas

    PubMed Central

    Engbang, Jean Paul Ndamba; Essome, Henri; Koh, Valère Mve; Simo, Godefroy; Essam, Jean Daniel Sime; Mouelle, Albert Sone; Essame, Jean Louis Oyono

    2015-01-01

    Décrire les caractéristiques épidémiologiques et histo-pathologiques des tumeurs malignes du sein au Cameroun. Il s'agissait d'une étude rétrospective descriptive portant sur les tumeurs malignes du sein, colligées, dans les registres des différents laboratoires d'Anatomie Pathologique publiques et privés repartis dans cinq régions (centre, littoral, Ouest, Nord-ouest, Sud-ouest), pendant une période de 10 ans (2004-2013). Les paramètres étudiés étaient la fréquence, l’âge, le sexe, la localisation, le type et le grade histologique, et les récepteurs hormonaux. Un total de 3044 cas de cancers du sein a été recensé, soit une fréquence annuelle de 304,4 cas en moyenne. Le sexe féminin était le plus représenté avec 2971 cas (97,60%) et les hommes avec 73 cas (2,40%), soit un sexe ratio (H/F) de 0,02. L’âge moyen des patients était de 46±15,87 ans, avec des extrêmes de 13 et 95 ans. Selon la localisation, le sein gauche était atteint dans 1244 cas (52%) et le sein droit dans 1115 cas (47%). Au plan histologique, on retrouvait essentiellement des carcinomes avec 96,50% des cas, des sarcomes 1,39%, des lymphomes 1,07% et la maladie de Paget du mamelon, 1,03%. Les tumeurs épithéliales étaient infiltrantes dans 2049 cas (84,46%), avec une prédominance du carcinome canalaire infiltrant (1870 cas) et non infiltrantes dans 377 cas (15,54%). Le grade histo-pronostic de SBR avait révélé une prédominance du grade II dans 66% des cas. Les cancers du sein restent une pathologie fréquente au Cameroun et atteignent principalement la population féminine en âge de procréer. Ils sont caractérisés par la prédominance du carcinome canalaire infiltrant. PMID:26523182

  11. 76 FR 66932 - The National Cancer Institute (NCI) Announces the Initiation of a Public Private Industry...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-28

    ... Initiation of a Public Private Industry Partnership on Translation of Nanotechnology in Cancer (TONIC) To Promote Translational Research and Development Opportunities of Nanotechnology-Based Cancer Solutions AGENCY: National Cancer Institute (NCI), Office of Cancer Nanotechnology Research (OCNR),...

  12. Abdominal pain as initial presentation of lung cancer

    PubMed Central

    Eisa, Naseem; Alhafez, Bishr; Alraiyes, Abdul Hamid; Alraies, M Chadi

    2014-01-01

    Isolated spleen metastasis (ISM) in general is very rare with a reported incidence of 2.3–7.1% for all solid cancers. Lung cancers rarely metastasise to the spleen. It is very atypical for ISM to be the initial presentation of lung cancer as well. In our case, a 55-year-old woman presented with a 3-week history of left-sided abdominal fullness and dull pain. Workup was remarkable for splenic mass that turns out to be adenocarcinoma with unknown primary tumour. Biopsy of the mass with immunohistochemistry and whole body position emission tomography scan was able to identify lung cancer as the primary tumour. The patient underwent splenectomy, wedge resection of the lung mass along with short-course of chemotherapy. She never had any recurrences since then. PMID:24835801

  13. Targeting Cancer-initiating Cells With Oncolytic Viruses

    PubMed Central

    Cripe, Timothy P; Wang, Pin-Yi; Marcato, Paola; Mahller, Yonatan Y; Lee, Patrick WK

    2009-01-01

    Recent studies in a variety of leukemias and solid tumors indicate that there is significant heterogeneity with respect to tumor-forming ability within a given population of tumor cells, suggesting that only a subpopulation of cells is responsible for tumorigenesis. These cells have been commonly referred to as cancer stem cells (CSCs) or cancer-initiating cells (CICs). CICs have been shown to be relatively resistant to conventional anticancer therapies and are thus thought to be responsible for disease relapse. As such, they represent a potentially critical therapeutic target. Oncolytic viruses are in clinical trials for cancer and kill cells through mechanisms different from conventional therapeutics. Because these viruses are not susceptible to the same pathways of drug or radiation resistance, it is important to learn whether CICs are susceptible to oncolytic virus infection. Here we review the available data regarding the ability of several different oncolytic virus types to target CICs for destruction. PMID:19672244

  14. Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles’ heel?

    PubMed Central

    Sabharwal, Simran S.; Schumacker, Paul T.

    2015-01-01

    Mitochondria cooperate with their host cells by contributing to bioenergetics, metabolism, biosynthesis, and cell death or survival functions. Reactive oxygen species (ROS) generated by mitochondria participate in stress signalling in normal cells but also contribute to the initiation of nuclear or mitochondrial DNA mutations that promote neoplastic transformation. In cancer cells, mitochondrial ROS amplify the tumorigenic phenotype and accelerate the accumulation of additional mutations that lead to metastatic behaviour. As mitochondria carry out important functions in normal cells, disabling their function is not a feasible therapy for cancer. However, ROS signalling contributes to proliferation and survival in many cancers, so the targeted disruption of mitochondria-to-cell redox communication represents a promising avenue for future therapy. PMID:25342630

  15. In vitro Enrichment of Ovarian Cancer Tumor-initiating Cells

    PubMed Central

    House, Carrie D.; Hernandez, Lidia; Annunziata, Christina M.

    2015-01-01

    Evidence suggests that small subpopulations of tumor cells maintain a unique self-renewing and differentiation capacity and may be responsible for tumor initiation and/or relapse. Clarifying the mechanisms by which these tumor-initiating cells (TICs) support tumor formation and progression could lead to the development of clinically favorable therapies. Ovarian cancer is a heterogeneous and highly recurrent disease. Recent studies suggest TICs may play an important role in disease biology. We have identified culture conditions that enrich for TICs from ovarian cancer cell lines. Growing either adherent cells or non-adherent ‘floater’ cells in a low attachment plate with serum free media in the presence of growth factors supports the propagation of ovarian cancer TICs with stem cell markers (CD133 and ALDH activity) and increased tumorigenicity without the need to physically separate the TICs from other cell types within the culture. Although the presence of floater cells is not common for all cell lines, this population of cells with innate low adherence may have high tumorigenic potential.Compared to adherent cells grown in the presence of serum, TICs readily form spheres, are significantly more tumorigenic in mice, and express putative stem cell markers. The conditions are easy to establish in a timely manner and can be used to study signaling pathways important for maintaining stem characteristics, and to identify drugs or combinations of drugs targeting TICs. The culture conditions described herein are applicable for a variety of ovarian cancer cells of epithelial origin and will be critical in providing new information about the role of TICs in tumor initiation, progression, and relapse. PMID:25742116

  16. Differential remodeling of extracellular matrices by breast cancer initiating cells.

    PubMed

    Raja, Anju M; Xu, Shuoyu; Zhuo, Shuangmu; Tai, Dean C S; Sun, Wanxin; So, Peter T C; Welsch, Roy E; Chen, Chien-Shing; Yu, Hanry

    2015-10-01

    Cancer initiating cells (CICs) have been the focus of recent anti-cancer therapies, exhibiting strong invasion capability via potentially enhanced ability to remodel extracellular matrices (ECM). We have identified CICs in a human breast cancer cell line, MX-1, and developed a xenograft model in SCID mice. We investigated the CICs' matrix-remodeling effects using Second Harmonic Generation (SHG) microscopy to identify potential phenotypic signatures of the CIC-rich tumors. The isolated CICs exhibit higher proliferation, drug efflux and drug resistant properties in vitro; were more tumorigenic than non-CICs, resulting in more and larger tumors in the xenograft model. The CIC-rich tumors have less collagen in the tumor interior than in the CIC-poor tumors supporting the idea that the CICs can remodel the collagen more effectively. The collagen fibers were preferentially aligned perpendicular to the CIC-rich tumor boundary while parallel to the CIC-poor tumor boundary suggesting more invasive behavior of the CIC-rich tumors. These findings would provide potential translational values in quantifying and monitoring CIC-rich tumors in future anti-cancer therapies. CIC-rich tumors remodel the collagen matrix more than CIC-poor tumors. PMID:25597396

  17. A role for SIRT1 in cell growth and chemoresistance in prostate cancer PC3 and DU145 cells

    SciTech Connect

    Kojima, Keitaro; Ohhashi, Riyako; Fujita, Yasunori; Hamada, Nanako; Akao, Yukihiro; Nozawa, Yoshinori; Deguchi, Takashi; Ito, Masafumi

    2008-08-29

    SIRT1, which belongs to the family of type III histone deacetylase, is implicated in diverse cellular processes. We have determined the expression levels of SIRT1 in human prostate cancer cell lines and have examined the roles of SIRT1 in cell growth and chemoresistance. SIRT1 expression was markedly up-regulated in androgen-refractory PC3 and DU145 cells compared with androgen-sensitive LNCaP cells and its expression level was correlated with cell growth in PC3 cells. Treatment with a SIRT1 inhibitor, sirtinol, inhibited cell growth and increased sensitivity to camptothecin and cisplatin. Silencing of SIRT1 expression by siRNA also suppressed cell proliferation and reduced camptothecin resistance in PC3 cells, mimicking the chemosensitizing effect caused by sirtinol. Also in DU145 cells, sirtinol treatment enhanced sensitivity to camptothecin and cisplatin. These results suggest that up-regulation of SIRT1 expression may play an important role in promoting cell growth and chemoresistance in androgen-refractory PC3 and DU145 cells.

  18. GPNMB/OA protein increases the invasiveness of human metastatic prostate cancer cell lines DU145 and PC3 through MMP-2 and MMP-9 activity

    SciTech Connect

    Fiorentini, Chiara; Bodei, Serena; Bedussi, Francesca; Fragni, Martina; Bonini, Sara Anna; Simeone, Claudio; Zani, Danilo; Berruti, Alfredo; Missale, Cristina; Memo, Maurizio; Spano, PierFranco; Sigala, Sandra

    2014-04-15

    Non-metastatic glycoprotein melanoma protein B (GPNMB), also known as osteoactivin (OA) is expressed in a wide array of tumors and represents an emerging target for drug development. In this study, we investigated the role of GPNMB/OA in the progression of human metastatic DU145 and PC3 prostate cancer cells. GPNMB/OA contribution in PCa malignant phenotype has been analyzed by small interfering RNA-induced GPNMB/OA silencing. We found that following GPNMB/OA silencing the migration capability of both DU145 and PC3 cells, evaluated by using in vitro invasivity assay, as well as the metalloproteinases MMP-2 and MMP-9 activity were equally strongly inhibited. By contrast knocking down GPNMB/OA weakly attenuated cell proliferation rate of DU145, an effect that paralleled with an increase number of apoptotic cells. However, PC3 cell growth seems to be not affected by GPNMB/OA. Together, these data reveal that GPNMB/OA acts as a critical molecular mediator promoting the acquisition of the more aggressive, pro-metastatic phenotype distinctive of human DU145 and PC3 cell lines. - Highlights: • GPNMB/OA expression correlates with DU145 and PC3 cells malignant phenotype. • GPNMB/OA silencing affects the migration capability of both DU145 and PC3 cells. • GPNMB/OA increases invasiveness by up-regulating MMPs activity. • GPNMB/OA promotes DU145 and PC3 cells progression into a more aggressive phenotype.

  19. SOX4 is essential for prostate tumorigenesis initiated by PTEN ablation | Office of Cancer Genomics

    Cancer.gov

    Understanding remains incomplete of the mechanisms underlying initiation and progression of prostate cancer, the most commonly diagnosed cancer in American men. The transcription factor SOX4 is overexpressed in many human cancers, including prostate cancer, suggesting it may participate in prostate tumorigenesis. In this study, we investigated this possibility by genetically deleting Sox4 in a mouse model of prostate cancer initiated by loss of the tumor suppressor Pten.

  20. Activation of polyamine catabolic enzymes involved in diverse responses against epibrassinolide-induced apoptosis in LNCaP and DU145 prostate cancer cell lines.

    PubMed

    Obakan, Pinar; Arisan, Elif Damla; Calcabrini, Annarica; Agostinelli, Enzo; Bolkent, Sehnaz; Palavan-Unsal, Narçin

    2014-03-01

    Epibrassinolide (EBR) is a biologically active compound of the brassinosteroids, steroid-derived plant growth regulator family. Generally, brassinosteroids are known for their cell expansion and cell division-promoting roles. Recently, EBR was shown as a potential apoptotic inducer in various cancer cells without affecting the non-tumor cell growth. Androgen signaling controls cell proliferation through the interaction with the androgen receptor (AR) in the prostate gland. Initially, the development of prostate cancer is driven by androgens. However, in later stages, a progress to the androgen-independent stage is observed, resulting in metastatic prostate cancer. The androgen-responsive or -irresponsive cells are responsible for tumor heterogeneity, which is an obstacle to effective anti-cancer therapy. Polyamines are amine-derived organic compounds, known for their role in abnormal cell proliferation as well as during malignant transformation. Polyamine catabolism-targeting agents are being investigated against human cancers. Many chemotherapeutic agents including polyamine analogs have been demonstrated to induce polyamine catabolism that depletes polyamine levels and causes apoptosis in tumor models. In our study, we aimed to investigate the mechanism of apoptotic cell death induced by EBR, related with polyamine biosynthetic and catabolic pathways in LNCaP (AR+), DU145 (AR-) prostate cancer cell lines and PNT1a normal prostate epithelial cell line. Induction of apoptotic cell death was observed in prostate cancer cell lines after EBR treatment. In addition, EBR induced the decrease of intracellular polyamine levels, accompanied by a significant ornithine decarboxylase (ODC) down-regulation in each prostate cancer cell and also modulated ODC antizyme and antizyme inhibitor expression levels only in LNCaP cells. Catabolic enzymes SSAT and PAO expression levels were up-regulated in both cell lines; however, the specific SSAT and PAO siRNA treatments prevented the

  1. MYC Activation Is a Hallmark of Cancer Initiation and Maintenance

    PubMed Central

    Gabay, Meital; Li, Yulin; Felsher, Dean W.

    2014-01-01

    The MYC proto-oncogene has been implicated in the pathogenesis of most types of human tumors. MYC activation alone in many normal cells is restrained from causing tumorigenesis through multiple genetic and epigenetically controlled checkpoint mechanisms, including proliferative arrest, apoptosis, and cellular senescence. When pathologically activated in a permissive epigenetic and/or genetic context, MYC bypasses these mechanisms, enforcing many of the “hallmark” features of cancer, including relentless tumor growth associated with DNA replication and transcription, cellular proliferation and growth, protein synthesis, and altered cellular metabolism. MYC mandates tumor cell fate, by inducing stemness and blocking cellular senescence and differentiation. Additionally, MYC orchestrates changes in the tumor microenvironment, including the activation of angiogenesis and suppression of the host immune response. Provocatively, brief or even partial suppression of MYC back to its physiological levels of activation can result in the restoration of intrinsic checkpoint mechanisms, resulting in acute and sustained tumor regression, associated with tumor cells undergoing proliferative arrest, differentiation, senescence, and apoptosis, as well as remodeling of the tumor microenvironment, recruitment of an immune response, and shutdown of angiogenesis. Hence, tumors appear to be “addicted” to MYC because of both tumor cell–intrinsic, cell-autonomous and host-dependent, immune cell–dependent mechanisms. Both the trajectory and persistence of many human cancers require sustained MYC activation. Multiscale mathematical modeling may be useful to predict when tumors will be addicted to MYC. MYC is a hallmark molecular feature of both the initiation and maintenance of tumorigenesis. PMID:24890832

  2. Roles of signaling pathways in drug resistance, cancer initiating cells and cancer progression and metastasis.

    PubMed

    McCubrey, James A; Abrams, Stephen L; Fitzgerald, Timothy L; Cocco, Lucio; Martelli, Alberto M; Montalto, Giuseppe; Cervello, Melchiorre; Scalisi, Aurora; Candido, Saverio; Libra, Massimo; Steelman, Linda S

    2015-01-01

    The EGFR/PI3K/PTEN/Akt/mTORC pathway plays prominent roles in malignant transformation, prevention of apoptosis, drug resistance, cancer initiating cells (CICs) and metastasis. The expression of this pathway is frequently altered in breast and other cancers due to mutations at or aberrant expression of: HER2, EGFR1, PIK3CA, and PTEN as well as other oncogenes and tumor suppressor genes. miRs and epigenetic mechanisms of gene regulation are also important events which regulate this pathway. In some breast cancer cases, mutations at certain components of this pathway (e.g., PIK3CA) are associated with a better prognosis than breast cancers lacking these mutations. The expression of this pathway has been associated with CICs and in some cases resistance to therapeutics. We will review the effects of activation of the EGFR/PI3K/PTEN/Akt/mTORC pathway primarily in breast cancer and development of drug resistance. The targeting of this pathway and other interacting pathways will be discussed as well as clinical trials with novel small molecule inhibitors as well as established drugs that are used to treat other diseases. In this manuscript, we will discuss an inducible EGFR model (v-ERB-B:ER) and its effects on cell growth, cell cycle progression, activation of signal transduction pathways, prevention of apoptosis in hematopoietic, breast and prostate cancer models. PMID:25453219

  3. Tumor-initiating label-retaining cancer cells in human gastrointestinal cancers undergo asymmetric cell division.

    PubMed

    Xin, Hong-Wu; Hari, Danielle M; Mullinax, John E; Ambe, Chenwi M; Koizumi, Tomotake; Ray, Satyajit; Anderson, Andrew J; Wiegand, Gordon W; Garfield, Susan H; Thorgeirsson, Snorri S; Avital, Itzhak

    2012-04-01

    Label-retaining cells (LRCs) have been proposed to represent adult tissue stem cells. LRCs are hypothesized to result from either slow cycling or asymmetric cell division (ACD). However, the stem cell nature and whether LRC undergo ACD remain controversial. Here, we demonstrate label-retaining cancer cells (LRCCs) in several gastrointestinal (GI) cancers including fresh surgical specimens. Using a novel method for isolation of live LRCC, we demonstrate that a subpopulation of LRCC is actively dividing and exhibits stem cells and pluripotency gene expression profiles. Using real-time confocal microscopic cinematography, we show live LRCC undergoing asymmetric nonrandom chromosomal cosegregation LRC division. Importantly, LRCCs have greater tumor-initiating capacity than non-LRCCs. Based on our data and that cancers develop in tissues that harbor normal-LRC, we propose that LRCC might represent a novel population of GI stem-like cancer cells. LRCC may provide novel mechanistic insights into the biology of cancer and regenerative medicine and present novel targets for cancer treatment. PMID:22331764

  4. Sulforaphane-cysteine suppresses invasion via downregulation of galectin-1 in human prostate cancer DU145 and PC3 cells.

    PubMed

    Tian, Hua; Zhou, Yan; Yang, Gaoxiang; Geng, Yang; Wu, Sai; Hu, Yabin; Lin, Kai; Wu, Wei

    2016-09-01

    Our previous study showed that sulforaphane (SFN) inhibits invasion in human prostate cancer DU145 cells; however, the underlying mechanisms were not profoundly investigated. In the present study, we found that sulforaphane-cysteine (SFN-Cys), as a metabolite of SFN, inhibits invasion and possesses a novel mechanism in prostate cancer DU145 and PC3 cells. The scratch and Transwell assays showed that SFN-Cys (15 µM) inhibited both migration and invasion, with cell morphological changes, such as cell shrinkage and pseudopodia shortening. The cell proliferation (MTS) assay indicated that cell viability was markedly suppressed with increasing concentrations of SFN‑Cys. Furthermore, the Transwell assay showed that inhibition of SFN‑Cys‑triggered invasion was tightly linked to the sustained extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation. Western blot analysis revealed that SFN-Cys downregulated galectin-1 protein, an invasion‑related protein, and that the galectin‑1 reduction could be blocked by ERK1/2 inhibitor PD98059 (25 µM). Moreover, immunofluorescence staining showed that the expression level of galectin-1 protein was significantly reduced in the cells treated with SFN‑Cys. Hence, SFN‑Cys‑inhibited invasion resulted from the sustained ERK1/2 phosphorylation and ERK1/2‑triggered galectin-1 downregulation, suggesting that galectin-1 is a new SFN-Cys target inhibiting invasion apart from ERK1/2, in the treatment of prostate cancer. PMID:27430422

  5. The Significance of Ras Activity in Pancreatic Cancer Initiation

    PubMed Central

    Logsdon, Craig D.; Lu, Weiqin

    2016-01-01

    The genetic landscape of pancreatic cancer shows nearly ubiquitous mutations of K-RAS. However, oncogenic K-Rasmt alone is not sufficient to lead to pancreatic ductal adenocarcinoma (PDAC) in either human or in genetically modified adult mouse models. Many stimulants, such as high fat diet, CCK, LPS, PGE2 and others, have physiological effects at low concentrations that are mediated in part through modest increases in K-Ras activity. However, at high concentrations, they induce inflammation that, in the presence of oncogenic K-Ras expression, substantially accelerates PDAC formation. The mechanism involves increased activity of oncogenic K-Rasmt. Unlike what has been proposed in the standard paradigm for the role of Ras in oncogenesis, oncogenic K-Rasmt is now known to not be constitutively active. Rather, it can be activated by standard mechanisms similar to wild-type K-Ras, but its activity is sustained for a prolonged period. Furthermore, if the level of K-Ras activity exceeds a threshold at which it begins to generate its own activators, then a feed-forward loop is formed between K-Ras activity and inflammation and pathological processes including oncogenesis are initiated. Oncogenic K-Rasmt activation, a key event in PDAC initiation and development, is subject to complex regulatory mechanisms. Reagents which inhibit inflammation, such as the Cox2 inhibitor celecoxib, block the feed-forward loop and prevent induction of PDAC in models with endogenous oncogenic K-Rasmt. Increased understanding of the role of activating and inhibitory mechanisms on oncogenic K-Rasmt activity is of paramount importance for the development of preventive and therapeutic strategies to fight against this lethal disease. PMID:26929740

  6. Long Island Breast Cancer Study Project (Past Initiative)

    Cancer.gov

    The Long Island Breast Cancer Study Project is a multistudy effort to investigate whether environmental factors are responsible for breast cancer in Suffolk and Nassau counties, NY, as well as in Schoharie County, NY, and Tolland County, CT.

  7. Plumbagin elicits differential proteomic responses mainly involving cell cycle, apoptosis, autophagy, and epithelial-to-mesenchymal transition pathways in human prostate cancer PC-3 and DU145 cells

    PubMed Central

    Qiu, Jia-Xuan; Zhou, Zhi-Wei; He, Zhi-Xu; Zhao, Ruan Jin; Zhang, Xueji; Yang, Lun; Zhou, Shu-Feng; Mao, Zong-Fu

    2015-01-01

    Plumbagin (PLB) has exhibited a potent anticancer effect in preclinical studies, but the molecular interactome remains elusive. This study aimed to compare the quantitative proteomic responses to PLB treatment in human prostate cancer PC-3 and DU145 cells using the approach of stable-isotope labeling by amino acids in cell culture (SILAC). The data were finally validated using Western blot assay. First, the bioinformatic analysis predicted that PLB could interact with 78 proteins that were involved in cell proliferation and apoptosis, immunity, and signal transduction. Our quantitative proteomic study using SILAC revealed that there were at least 1,225 and 267 proteins interacting with PLB and there were 341 and 107 signaling pathways and cellular functions potentially regulated by PLB in PC-3 and DU145 cells, respectively. These proteins and pathways played a critical role in the regulation of cell cycle, apoptosis, autophagy, epithelial to mesenchymal transition (EMT), and reactive oxygen species generation. The proteomic study showed substantial differences in response to PLB treatment between PC-3 and DU145 cells. PLB treatment significantly modulated the expression of critical proteins that regulate cell cycle, apoptosis, and EMT signaling pathways in PC-3 cells but not in DU145 cells. Consistently, our Western blotting analysis validated the bioinformatic and proteomic data and confirmed the modulating effects of PLB on important proteins that regulated cell cycle, apoptosis, autophagy, and EMT in PC-3 and DU145 cells. The data from the Western blot assay could not display significant differences between PC-3 and DU145 cells. These findings indicate that PLB elicits different proteomic responses in PC-3 and DU145 cells involving proteins and pathways that regulate cell cycle, apoptosis, autophagy, reactive oxygen species production, and antioxidation/oxidation homeostasis. This is the first systematic study with integrated computational, proteomic, and

  8. YAP/TEAD Co-Activator Regulated Pluripotency and Chemoresistance in Ovarian Cancer Initiated Cells

    PubMed Central

    Yu, Chao; Chang, Ting; Fan, Heng-Yu

    2014-01-01

    Recent evidence suggests that some solid tumors, including ovarian cancer, contain distinct populations of stem cells that are responsible for tumor initiation, growth, chemo-resistance, and recurrence. The Hippo pathway has attracted considerable attention and some investigators have focused on YAP functions for maintaining stemness and cell differentiation. In this study, we successfully isolated the ovarian cancer initiating cells (OCICs) and demonstrated YAP promoted self-renewal of ovarian cancer initiated cell (OCIC) through its downstream co-activator TEAD. YAP and TEAD families were required for maintaining the expression of specific genes that may be involved in OCICs' stemness and chemoresistance. Taken together, our data first indicate that YAP/TEAD co-activator regulated ovarian cancer initiated cell pluripotency and chemo-resistance. It proposed a new mechanism on the drug resistance in cancer stem cell that Hippo-YAP signal pathway might serve as therapeutic targets for ovarian cancer treatment in clinical. PMID:25369529

  9. Les déterminants du statut “perdu de vue” chez les patients pris en charge pour cancer au Maroc: situation avant le Plan Cancer

    PubMed Central

    Najdi, Adil; Berraho, Mohamed; Bendahhou, Karima; Obtel, Majdouline; Zidouh, Ahmed; Errihani, Hassan; Nejjari, Chakib

    2014-01-01

    Introduction Le cancer au Maroc représente un problème majeur de santé publique, sa prise en charge doit être globale, active et complète pour tous les patients. L'objectif de ce travail était d'estimer la fréquence des perdus de vue « PDV » en oncologie au Maroc durant la première année de suivi et de déterminer les facteurs associés à ce problème. Méthodes Par une étude rétrospective portant sur 2854 dossiers de malades hospitalisés dans les trois principaux centres d'oncologie au Maroc depuis janvier 2003 jusqu’à juin 2007 et concernant les cinq principales localisations de cancer au Maroc, nous avons cherché la date des dernières nouvelles des patients ayant un recul de 18 mois minimum afin de déterminer le statut de ces malades après un an de suivi. Résultats La moyenne d’âge était de 52±14 ans, une proportion féminine de 63%, les sujets actifs constituaient 28%, les mariés 71%, les analphabètes 51%, 70% des patients habitaient en milieu urbain et seulement 11% des malades disposaient d'une couverture sociale. La localisation cancéreuse la plus fréquente était le poumon (23,8%) suivie du colon-rectum (23,5%) puis le col (21,9%), le sein (20,4%) et les lymphomes (10,4%). Le taux des «PDV» à un an de suivi était de 48%, ce statut était significativement lié au sexe, à l’âge, au NSE et au statut matrimonial. Sur le plan médical, le statut «PDV» était lié à la localisation du cancer, au stade de diagnostic et au type de traitement reçu. Conclusion Notre étude a mis en évidence la grande ampleur du problème des PDV en cancérologie au Maroc ainsi que ces déterminants. Ces résultats incitent tous les acteurs dans le domaine de la cancérologie à collaborer ensemble pour prendre les mesures qui s'imposent pour y pallier PMID:25400850

  10. The E1 copper binding domain of full-length amyloid precursor protein mitigates copper-induced growth inhibition in brain metastatic prostate cancer DU145 cells

    SciTech Connect

    Gough, Mallory Blanthorn-Hazell, Sophee Delury, Craig Parkin, Edward

    2014-10-31

    Highlights: • Copper levels are elevated in the tumour microenvironment. • APP mitigates copper-induced growth inhibition of DU145 prostate cancer (PCa) cells. • The APP intracellular domain is a prerequisite; soluble forms have no effect. • The E1 CuBD of APP is also a prerequisite. • APP copper binding potentially mitigates copper-induced PCa cell growth inhibition. - Abstract: Copper plays an important role in the aetiology and growth of tumours and levels of the metal are increased in the serum and tumour tissue of patients affected by a range of cancers including prostate cancer (PCa). The molecular mechanisms that enable cancer cells to proliferate in the presence of elevated copper levels are, therefore, of key importance in our understanding of tumour growth progression. In the current study, we have examined the role played by the amyloid precursor protein (APP) in mitigating copper-induced growth inhibition of the PCa cell line, DU145. A range of APP molecular constructs were stably over-expressed in DU145 cells and their effects on cell proliferation in the presence of copper were monitored. Our results show that endogenous APP expression was induced by sub-toxic copper concentrations in DU145 cells and over-expression of the wild-type protein was able to mitigate copper-induced growth inhibition via a mechanism involving the cytosolic and E1 copper binding domains of the full-length protein. APP likely represents one of a range of copper binding proteins that PCa cells employ in order to ensure efficient proliferation despite elevated concentrations of the metal within the tumour microenvironment. Targeting the expression of such proteins may contribute to therapeutic strategies for the treatment of cancers.

  11. Targeting breast cancer-initiating/stem cells with melanoma differentiation-associated gene-7/interleukin-24.

    PubMed

    Bhutia, Sujit K; Das, Swadesh K; Azab, Belal; Menezes, Mitchell E; Dent, Paul; Wang, Xiang-Yang; Sarkar, Devanand; Fisher, Paul B

    2013-12-01

    Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) displays a broad range of antitumor properties including cancer-specific induction of apoptosis, inhibition of tumor angiogenesis and modulation of antitumor immune responses. In our study, we elucidated the role of MDA-7/IL-24 in inhibiting growth of breast cancer-initiating/stem cells. Ad.mda-7 infection decreased proliferation of breast cancer-initiating/stem cells without affecting normal breast stem cells. Ad.mda-7 induced apoptosis and endoplasmic reticulum stress in breast cancer-initiating/stem cells similar to unsorted breast cancer cells and inhibited the self-renewal property of breast cancer-initiating/stem cells by suppressing Wnt/β-catenin signaling. Prevention of inhibition of Wnt signaling by LiCl increased cell survival upon Ad.mda-7 treatment, suggesting that Wnt signaling inhibition might play a key role in MDA-7/IL-24-mediated death of breast cancer-initiating/stem cells. In a nude mouse subcutaneous xenograft model, Ad.mda-7 injection profoundly inhibited growth of tumors generated from breast cancer-initiating/stem cells and also exerted a potent "bystander" activity inhibiting growth of distant uninjected tumors. Further studies revealed that tumor growth inhibition by Ad.mda-7 was associated with a decrease in proliferation and angiogenesis, two intrinsic features of MDA-7/IL-24, and a reduction in vivo in the percentage of breast cancer-initiating/stem cells. Our findings demonstrate that MDA-7/IL-24 is not only nontoxic to normal cells and normal stem cells but also can kill both unsorted cancer cells and enriched populations of cancer-initiating/stem cells, providing further documentation that MDA-7/IL-24 might be a safe and effective way to eradicate cancers and also potentially establish disease-free survival. PMID:23720015

  12. Breast cancer-associated fibroblasts: their roles in tumor initiation, progression and clinical applications.

    PubMed

    Qiao, Aixiu; Gu, Feng; Guo, Xiaojing; Zhang, Xinmin; Fu, Li

    2016-03-01

    Breast cancer is the most common malignant tumor in women, and the incidence of this disease has increased in recent years because of changes in diet, living environment, gestational age, and other unknown factors. Previous studies focused on cancer cells, but an increasing number of recent studies have analyzed the contribution of cancer microenvironment to the initiation and progression of breast cancer. Cancer-associated fibroblasts (CAFs), the most abundant cells in tumor stroma, secrete various active biomolecules, including extracellular matrix components, growth factors, cytokines, proteases, and hormones. CAFs not only facilitate the initiation, growth, angiogenesis, invasion, and metastasis of cancer but also serve as biomarkers in the clinical diagnosis, therapy, and prognosis of breast cancer. In this article, we reviewed the literature and summarized the research findings on CAFs in breast cancer. PMID:26791754

  13. Do subtle breast cancers attract visual attention during initial impression?

    NASA Astrophysics Data System (ADS)

    Nodine, Calvin F.; Mello-Thoms, Claudia; Weinstein, Susan P.; Kundel, Harold L.; Toto, Lawrence C.

    2000-04-01

    Women who undergo regular mammographic screening afford mammographers a unique opportunity to compare current mammograms with prior exams. This comparison greatly assists mammographers in detecting early breast cancer. A question that commonly arises when a cancer is detected under regular periodic screening conditions is whether the caner is new, or was it missed on the prior exam? This is a difficult question to answer by retrospective analysis, because knowledge of the status of the current exam biases the interpretation of the prior exam. To eliminate this bias and provide some degree of objectivity in studying this question, we looked at whether experienced mammographers who had no prior knowledge of a set of test cases fixated on potential cancer-containing regions on mammograms from cases penultimate to cancer detection. The results show that experienced mammographers cannot recognize most malignant cancers selected by retrospective analysis.

  14. Aspects histo-épidémiologiques des cancers génitaux de la femme dans la région du Littoral, Cameroun

    PubMed Central

    Engbang, Jean Paul Ndamba; Koh, Valère Mve; Tchente, Charlotte Nguefack; Fewou, Amadou

    2015-01-01

    Décrire les caractéristiques épidémiologiques et histopathologiques des tumeurs malignes génitales de la femme dans la région du littoral du Cameroun. Il s'agissait d'une étude rétrospective descriptive et analytique portant sur les cancers des organes génitaux de la femme, histologiquement prouvés pendant une période de 10 ans (2004-2013), répertoriés dans les registres des trois laboratoires d'anatomopathologie de la région (Hôpital Laquintinie de Douala, Hôpital Général de Douala, laboratoire Anapathos) et des services d'oncologie de ces hôpitaux. Les variables étudiées étaient: la fréquence, l’âge, le sexe, la localisation de la tumeur et le type histopathologique. Au total, 802 cas de cancers génitaux de la femme ont été recensés, soit une fréquence annuelle de 80,2 cas en moyenne. Le col utérin avec 580 cas (72,32%) a été la localisation la plus fréquente; suivi de l'endomètre (corps utérin) avec 93 cas (11,60%), puis des ovaires 91 cas (11,35%). L’âge moyen des patientes était de 50, 30±12,67 ans, avec les extrêmes allant de 14 à 85 ans. Selon le type histologique, les tumeurs épithéliales ont été les plus fréquemment rencontrées, soit 758 patientes (94,51%), les lymphomes venaient en seconde position avec 29 cas (3, 62%), les autres variétés histologiques (sarcomes, tumeurs germinales, tumeurs du mésenchyme et du cordon) représentant moins chacune de 1%. Les tumeurs malignes des organes génitaux féminins sont fréquentes dans la région du littoral du Cameroun, elles sont dominées essentiellement par le cancer du col utérin. Les tumeurs épithéliales sont le type histologique le plus fréquent. PMID:26327953

  15. Lignes directrices sur l’aiguillage des cas soupçonnés de cancer du poumon par un médecin de famille ou autre professionnel des soins primaires

    PubMed Central

    Del Giudice, M. Elisabeth; Young, Sheila-Mae; Vella, Emily T.; Ash, Marla; Bansal, Praveen; Robinson, Andrew; Skrastins, Roland; Ung, Yee; Zeldin, Robert; Levitt, Cheryl

    2014-01-01

    Résumé Objectif Les présentes lignes directrices visent à aider les médecins de famille et autres généralistes à reconnaître les manifestations cliniques devant éveiller les soupçons quant à la présence d’un cancer du poumon chez les patients. Composition du comité Les membres du comité ont été choisis parmi les leaders régionaux en soins primaires du Réseau provincial des soins primaires et de la lutte contre le cancer d’Action Cancer Ontario et parmi les membres du Groupe sur le siège de la maladie, Cancer du poumon d’Action Cancer Ontario. Méthodes Les présentes lignes directrices sont le fruit d’une revue systématique des données probantes, d’une synthèse des données et d’un examen externe formel effectué par des intervenants canadiens qui ont validé la pertinence des recommandations. Rapport Ces lignes directrices fondées sur des données probantes ont été formulées pour améliorer la prise en charge en contexte canadien des patients qui présentent des manifestations cliniques du cancer du poumon. Conclusion Le dépistage et l’aiguillage précoces des patients atteints de cancer du poumon pourraient en fin de compte aider à réduire les morbidités et mortalités liées au cancer. Ces lignes directrices pourraient aussi s’avérer utiles dans la mise sur pied de programmes de diagnostic du cancer du poumon et pour aider les décideurs à veiller à ce que les ressources appropriées soient en place.

  16. Detection of a Pancreatic Cancer-Associated Antigen (DU-PAN-2 Antigen) in Serum and Ascites of Patients with Adenocarcinoma

    NASA Astrophysics Data System (ADS)

    Metzgar, Richard S.; Rodriguez, Ned; Finn, Olivera J.; Lan, Michael S.; Daasch, Vicki N.; Fernsten, Philip D.; Meyers, William C.; Sindelar, William F.; Sandler, Robert S.; Seigler, H. F.

    1984-08-01

    A competition radioimmunoassay was developed, utilizing a murine monoclonal antibody to human pancreatic adenocarcinoma cells. Immunoblotting of a standard antigen preparation from either serum or ascites fluid after electrophoresis in 1% agarose showed that the specific DUPAN-2 activity resided in two major high molecular weight bands. DU-PAN-2 antigen levels were expressed as arbitrary units based on a standard partially purified antigen preparation. The inhibition curve with standard antigen was reproducible (SD < 10%) and essentially linear from 25 to 200 units/ml. The mean DU-PAN-2 antigen concentration for the sera from 126 normal individuals was 81 units/ml. Sera from pediatric patients with malignancy had a mean of 127 units/ml, while nasopharyngeal, stage III melanoma, and ovarian carcinoma patients had means of 89, 92, and 119 units/ml, respectively. All values in normal subjects as well as the melanoma, nasopharyngeal, ovarian, and pediatric cancer patients were less than 400 units/ml. Intermediate antigen levels were detected in patients with alimentary tract malignancies. Eight of 20 gastric cancer and 8 of 76 colorectal carcinoma patients and 3 patients with benign or nonmalig nant gastrointestinal tract disease had DU-PAN-2 values exceeding 400 units/ml. Ascites fluids from 6/6 and pancreatic juice from 2/2 pancreatic cancer patients had values greater than 750 units/ml. Serum from 68% of the 89 pancreatic cancer patients tested had DU-PAN-2 antigen levels greater than 400 units/ml. The mean serum value in this patient population was 4888 units/ml.

  17. Oncogenic KRAS activates an embryonic stem cell-like program in human colon cancer initiation

    PubMed Central

    Le Rolle, Anne-France; Chiu, Thang K.; Zeng, Zhaoshi; Shia, Jinru; Weiser, Martin R.; Paty, Philip B.; Chiu, Vi K.

    2016-01-01

    Colorectal cancer is the third most frequently diagnosed cancer worldwide. Prevention of colorectal cancer initiation represents the most effective overall strategy to reduce its associated morbidity and mortality. Activating KRAS mutation (KRASmut) is the most prevalent oncogenic driver in colorectal cancer development, and KRASmut inhibition represents an unmet clinical need. We apply a systems-level approach to study the impact of KRASmut on stem cell signaling during human colon cancer initiation by performing gene set enrichment analysis on gene expression from human colon tissues. We find that KRASmut imposes the embryonic stem cell-like program during human colon cancer initiation from colon adenoma to stage I carcinoma. Expression of miR145, an embryonic SC program inhibitor, promotes cell lineage differentiation marker expression in KRASmut colon cancer cells and significantly suppresses their tumorigenicity. Our data support an in vivo plasticity model of human colon cancer initiation that merges the intrinsic stem cell properties of aberrant colon stem cells with the embryonic stem cell-like program induced by KRASmut to optimize malignant transformation. Inhibition of the embryonic SC-like program in KRASmut colon cancer cells reveals a novel therapeutic strategy to programmatically inhibit KRASmut tumors and prevent colon cancer. PMID:26744320

  18. Octreotide in combination with AT-101 induces cytotoxicity and apoptosis through up-regulation of somatostatin receptors 2 and 5 in DU-145 prostate cancer cells.

    PubMed

    Degirmenci, Mustafa; Erdogan, Atike Pinar; Bulut, Gulcan; Atmaca, Harika; Uzunoglu, Selim; Karaca, Burcak; Karabulut, Bulent; Uslu, Ruchan

    2016-04-01

    Prostate cancer (PCa) is the most common type of cancer among males. Although survival rate of early-stage PCa is high, treatment options are very limited for recurrent disease. In this study, the possible synergistic cytotoxic and apoptotic effect of octreotide in combination with AT-101 was investigated in DU-145 hormone and drug refractory prostate cancer cell line. To enlighten the action mechanisms of the combination treatment, expression levels of somatostatin receptors 2 and 5 (SSTR2 and SSTR5) were also investigated. Cell viability was measured by XTT assay. Apoptosis was assessed through DNA fragmentation analysis and caspase 3/7 assay. mRNA and protein levels of SSTR2 and SSTR5 were evaluated by qRT-PCR and western blot analysis, respectively. Octreotide in combination with AT-101 inhibited cell viability and induced apoptosis synergistically in DU-145 cells as compared to any agent alone. Combination treatment increased both SSTR2 and SSTR5 mRNA and protein levels in DU-145 cells. The data suggest that this combination therapy may be a good candidate for patients with advanced metastatic PCa do not respond to androgen deprivation. PMID:26531719

  19. Dermatosis as the initial presentation of gastric cancer: two cases

    PubMed Central

    Ge, Wei; Teng, Bu-Wei; Yu, De-Cai; Zheng, Li-Ming; Ding, Yi-Tao

    2014-01-01

    Paraneoplastic dermatoses are known to be certain dermatosis related with tumor. The common paraneoplastic dermatoses are acanthosis nigricans, acquired ichthyosis, dermatomyositis, erythroderma, and so on. Here we report two cases of paraneoplastic dermatoses associated with gastric cancer. One case was a 57-year-old man with dermatomyositis and proved to be associated with gastric cancer through stomachoscopy. The other was a 66-year-old man with erythroderma and proved to be associated with gastric cancer through stomachoscopy. Both cases were treated with radical total gastrectomy with lymphadenectomy (D2) and esophagojejunostomy of Roux-en-Y. The skin symptom of both cases had improved a lot but still existed after operation. Paraneoplastic dermatoses can be seen as the early manifestation of visceral carcinomas. As a result, gastric cancers should be excluded in the patients with paraneoplastic dermatoses. PMID:25400431

  20. Infection par le VIH chez les patientes atteintes de cancer du sein en Guinée (Afrique de l'Ouest)

    PubMed Central

    Traore, Bangaly; Diane, Solomana; Sow, Mamadou Saliou; Keita, Mamady; Conde, Mamoudou; Traore, Fodé Amara; Kourouma, Tidiane

    2015-01-01

    L'objectif était de déterminer la prévalence de l'infection à VIH chez les patientes atteintes de cancer du sein et de comparer les caractéristiques anatomocliques et thérapeutiques de ces cancers du sein par rapports aux patientes non infectées par le VIH. Il s'agissait d'une étude rétrospective et analytique comparant les dossiers de patientes atteintes de cancers du sein histologiquement confirmés, infectées ou non par le VIH à l'unité de chirurgie oncologique de Donka, CHU de Conakry, de 2007 à 2012. Nous avons colligé 278 patientes présentant un cancer du sein dont 14 (5,0%) infectées par le VIH et 264 (95,0%) non infectées par le VIH. Les différences observées entre ces deux groupes de patientes étaient respectivement: âge médian (36,8 vs 49,0 ans), la ménopause (21,4% vs 53,4%), le nombre des patientes traitées (50,0% contre 77,1%) et la survenue de décès (78,6% vs 50,8%). Aucune différence n'a été notée dans la présentation clinique, histologique et le retard de consultation. Dans notre étude, la prévalence de l'infection à VIH chez les patients atteints de cancer du sein est élevée. L’âge jeune des patients, la faible accessibilité au traitement et la mortalité élevée doivent être confirmés par une étude sur un échantillon plus large. PMID:26523196

  1. Global Cancer Disparities and the Need for New Initiatives.

    PubMed

    LeBaron, Virginia T

    2016-01-01

    The field of oncology is evolving at breakneck speed. Keeping up with the latest research findings, clinical best practices, and new chemotherapy agents is challenging, even with the help of the Internet. These oncologic advances, however, are far from uniformly available, and disturbing global disparities persist. In much of the world, a diagnosis of cancer remains a death sentence, and too many patients struggle to obtain access to screening, treatment, and basic symptom management. The harsh reality is that patients' chances of dying from cancer depends largely on where they live.  
. PMID:26679452

  2. Cancer prevention as biomodulation: targeting the initiating stimulus and secondary adaptations.

    PubMed

    Furth, Priscilla A

    2012-10-01

    In a medical sense, biomodulation could be considered a biochemical or cellular response to a disease or therapeutic stimulus. In cancer pathophysiology, the initial oncogenic stimulus leads to cellular and biochemical changes that allow cells, tissue, and organism to accommodate and accept the oncogenic insult. In epithelial cell cancer development, the process of carcinogenesis is frequently characterized by sequential cellular and biochemical adaptations as cells transition through hyperplasia, dysplasia, atypical dysplasia, carcinoma in situ, and invasive cancer. In some cases, the adaptations may persist after the initial oncogenic stimulus is gone in a type of "hit-and-run" oncogenesis. These pathophysiological changes may interfere with cancer prevention therapies targeted solely to the initial oncogenic insult, perhaps contributing to resistance development. Characterization of these accommodating adaptations could provide insight for the development of cancer preventive regimens that might more effectively biomodulate preneoplastic cells toward a more normal state. PMID:23050958

  3. Cancer stem cells, cancer-initiating cells and methods for their detection.

    PubMed

    Akbari-Birgani, Shiva; Paranjothy, Ted; Zuse, Anna; Janikowski, Tomasz; Cieślar-Pobuda, Artur; Likus, Wirginia; Urasińska, Elżbieta; Schweizer, Frank; Ghavami, Saeid; Klonisch, Thomas; Łos, Marek J

    2016-05-01

    The cancer stem cell (CSC) hypothesis considers CSCs as the main culprits of tumor initiation, propagation, metastasis and therapy failure. CSCs represent a minority subpopulation of cells within a tumor. Their detection, characterization and monitoring are crucial steps toward a better understanding of the biological roles of these special cells in the development and propagation of tumors which, in turn, improves clinical reasoning and treatment options. Nowadays, in vitro and in vivo assays are available that address the self-renewal and differentiation potential of CSCs, and advanced in vivo molecular imaging technology facilitates the detection and provides an unprecedented in vivo observation platform to study the behavior of CSCs in their natural environment. Here, we provide a brief overview of CSCs and describe modern cellular models and labeling techniques to study and trace CSCs. PMID:26976692

  4. CDK inhibitors induce mitochondria-mediated apoptosis through the activation of polyamine catabolic pathway in LNCaP, DU145 and PC3 prostate cancer cells.

    PubMed

    Arisan, Elif Damla; Obakan, Pinar; Coker-Gurkan, Ajda; Calcabrini, Annarica; Agostinelli, Enzo; Unsal, Narcin Palavan

    2014-01-01

    Androgen signaling is critical in prostate cancer development and progression. The co-existence of hormone responsive and irresponsive cells due to functional androgen receptor (AR) in prostate gland is the major obstacle in prostate cancer therapy models. Targeting aberrant cell cycle by novel cell cycle blocking agents is a promising strategy to treat various types of malignancies. Purvalanol and roscovitine are cyclin dependent kinase (CDK) inhibitors able to activate apoptotic cell death by inducing cell cycle arrest at G1/S and G2/M phases in cancer cells. Polyamines are unique cationic amine derivatives involved in the regulation of cell proliferation. Although the elevated intracellular level of polyamines (putrescine, spermidine and spermine) is typical for prostate gland, abnormal regulation of polyamine metabolism might result in rapid cell proliferation and, thus in prostate cancer progression. Therefore, treatment with drug-induced depletion of intracellular polyamine levels through the activated polyamine catabolism is critical to achieve successful strategies for prostate cancer. In this study we aimed to investigate the apoptotic efficiency of CDK inhibitors in three prostate cancer cell lines (LNCaP, DU145 and PC3), showing different AR expression profile. We found that both purvalanol and roscovitine were able to induce apoptosis at moderate cytotoxic concentrations by decreasing mitochondria membrane potential. The apoptotic effect of both CDK inhibitors was due to activation of caspases by modulating Bcl-2 family members. The efficiency of drugs was quite similar on the three prostate cell lines used in this study. However, DU145 cells were found the least sensitive against CDK inhibitors while purvalanol was more potent than roscovitine. Similarly to classical chemotherapeutic agents, both drugs could up-regulate polyamine catabolic enzymes (SSAT, SMO and PAO) in cell type dependent manner. Transient silencing of SSAT and/or inhibition of PAO

  5. Complications de l’hormonothérapie anti-androgénique du cancer de la prostate

    PubMed Central

    Ziouziou, Imad; Karmouni, Tariq; Khader, Khalid El; Koutani, Abdellatif; Andaloussi, Ahmed Iben Attya

    2014-01-01

    Résumé Les effets indésirables de l’hormonothérapie anti-androgénique (HAA) dans le traitement du cancer de la prostate sont attribuables à la carence d’androgènes. L’HAA entraîne le syndrome de castration, qui se caractérise par une diminution de la libido, la dysfonction érectile, l’asthénie, des bouffées de chaleur, la diminution des capacités intellectuelles et la dépression. Il en résulte également une augmentation de la graisse abdominale, ce qui favorise l’insulinorésistance et le diabète. La perte de la densité minérale osseuse secondaire à l’HAA entraîne un risque fracturaire accru. Il existe de plus un risque cardiovasculaire important dû aux facteurs métaboliques. L’effet thérapeutique de l’HAA doit donc être soupesé en regard de la toxicité liée à l’hypogonadisme. PMID:24678355

  6. Benzoxazinoids from Scoparia dulcis (sweet broomweed) with antiproliferative activity against the DU-145 human prostate cancer cell line.

    PubMed

    Wu, Wan-Hsun; Chen, Tzu-Yu; Lu, Rui-Wen; Chen, Shui-Tein; Chang, Chia-Chuan

    2012-11-01

    Sweet broomweed (Scoparia dulcis) is an edible perennial medicinal herb widely distributed in tropical and subtropical regions of Asia, Africa, and the Americas. Four compounds, (2R)-7-methoxy-2H-1,4-benzoxazin-3(4H)-one 2-O-β-galactopyranoside [(2R)-HMBOA-2-O-Gal], 3,6-dimethoxy-benzoxazolin-2(3H)-one (3,6-M2BOA), 3-hydroxy-6-methoxy-2-benzoxazolinone (3-OH-MBOA), and scutellarein 7-O-β-glucuronamide, along with eight known compounds, including two 7-methoxy-1,4-benzoxazin-3(2H)-one 3-O-hexopyranosides [(2R)-HMBOA-2-O-Glc and (2R)-HDMBOA-2-O-Glc], 6-methoxy-benzoxazolin-2(3H)-one (MBOA), acteoside, sodium scutellarin, p-coumaric acid, and two monosaccharides (fructose and glucose), were isolated from the aqueous extract of S. dulcis. Antiproliferative activities of the six benzoxazinoid compounds against the DU-145 human prostate cancer cell line were assayed, and one of these displayed an IC₅₀ of 65.8 μg/mL. PMID:22944352

  7. Cancer métaplasique du sein: à propos d'un cas

    PubMed Central

    Babahabib, Moulay Abdellah; Chennana, Adil; Hachi, Aymen; Kouach, Jaoud; Moussaoui, Driss; Dhayni, Mohammed

    2014-01-01

    Les carcinomes métaplasiques du sein sont des tumeurs rares. Ils constituent un groupe hétérogène de tumeurs définis selon l'organisation mondiale de la santé comme étant un carcinome canalaire infiltrant mais comportant des zones de remaniements métaplasiques (de type épidermoïde, à cellules fusiformes, chondroïde et osseux ou mixte), qui varient de quelques foyers microscopiques à un remplacement glandulaire complet. Les aspects cliniques et radiologiques ne sont pas spécifiques. Le traitement associe la chirurgie, la radiothérapie et la chimiothérapie. L'hormonothérapie n'a pas de place. Le pronostic est sombre. L'histopathologie combinée à l'immunohistochimie permet de poser un diagnostic sure. Etant donné que la prise en charge thérapeutique est limitée, une nouvelle approche moléculaire pourrait modifier cette contribution faible et mal cernée des traitements systémiques classiques. Les patientes atteintes de carcinome métaplasique mammaire pourraient bénéficier de traitements ciblés, ce qui reste à confirmer par des essais cliniques. PMID:25870723

  8. Place du traitement chirurgical sous circulation extracorporelle à cœur battant dans les cancers du rein avec envahissement cave supra-diaphragmatique: à propos de sept cas

    PubMed Central

    Lahyani, Mounir; Karmouni, Tarik; Elkhader, Khalid; Koutani, Abdellatif; Andaloussi, Ahmed Ibn Attya

    2014-01-01

    Ce travail vise à analyser les résultats de la néphrectomie avec thrombectomie atrio-cave sous circulation extracorporelle (CEC) chez sept patients ayant un cancer du rein avec envahissement cave supra-diaphragmatique et de discuter les indications opératoires. Sept patients, six hommes et une femme dont l’âge varie entre 46ans et 65ans, ont été opérés d'un cancer du rein avec extension atrio-cave. L’écho-doppler a toujours permis la mise en évidence de l'extension veineuse mais la limite supérieure du thrombus était formellement identifiée par l'examen tomodensitométrique quatre fois, et par la résonance magnétique nucléaire dans tous les cas. Tous les patients ont été opérés sous CEC à cœur battant en normothermie. Un seul décès postopératoire est survenu. La durée du séjour en réanimation a été de 4,5 jours. Cinq patients ont eu à distance une dissémination métastatique. Cinq malades ont eu une médiane de survie de 11,5 mois (de 7 à16). Un malade a subi une métastasectomie pulmonaire 6 mois après la néphrectomie. L'exérèse des thrombi atrio-caves a été facilitée par la CEC avec une mortalité et une morbidité postopératoires acceptables mais les résultats à distance ont été décevants. Cette intervention ne peut être proposée qu'aux patients n'ayant aucune extension locorégionale et générale décelable, ce qui souligne l'importance des examens morphologiques préopératoires. PMID:25995777

  9. Initial Validation of the Sleep Disturbances in Pediatric Cancer Model.

    PubMed

    Daniel, Lauren C; Schwartz, Lisa A; Mindell, Jodi A; Tucker, Carole A; Barakat, Lamia P

    2016-07-01

    OBJECTIVE : The current study evaluates content validity of the Sleep Disturbance in Pediatric Cancer (SDPC) model using qualitative and quantitative stakeholder input.  METHODS : Parents of children (aged: 3-12 years) with acute lymphoblastic leukemia (n = 20) and medical providers (n = 6) participated in semi-structured interviews about child sleep during cancer treatment. They also rated SDPC model component importance on a 0-4 scale and selected the most relevant sleep-related intervention targets.  RESULTS : Qualitatively, parents and providers endorsed that changes in the child's psychosocial, environmental, and biological processes affect sleep. Stakeholders rated most model components (parent: 32 of 40; provider: 39 of 41) as important (>2) to child sleep. Parents were most interested in interventions targeting difficulty falling asleep and providers selected irregular sleep habits/scheduling, though groups did not differ significantly. CONCLUSIONS : Stakeholders supported SDPC content validity. The model will inform subsequent measure and intervention development focusing on biological and behavioral factors most salient to sleep disturbances in pediatric cancer. PMID:26994058

  10. Genetics and metabolic deregulation following cancer initiation: A world to explore.

    PubMed

    Araldi, Rodrigo Pinheiro; Módolo, Diego Grando; de Sá Júnior, Paulo Luiz; Consonni, Sílvio Roberto; de Carvalho, Rodrigo Franco; Roperto, Franco Peppino; Beçak, Willy; de Cassia Stocco, Rita

    2016-08-01

    Cancer is a group of highly complex and heterogeneous diseases with several causes. According to the stochastic model, cancer initiates from mutation in somatic cells, leading to genomic instability and cell transformation. This canonical pathway of carcinogenesis is related to the discovery of important mechanisms that regulate cancer initiation. However, there are few studies describing genetic and metabolic alterations that deregulate transformed cells, resulting in epithelial-mesenchymal transition (EMT) and its most dramatic consequence, the metastasis. This review summarizes the main genetics and metabolic changes induced by reactive oxygen species (ROS) that lead to EMT. PMID:27470384

  11. Epidémiologie du cancer gastrique: expérience d'un centre hospitalier marocain

    PubMed Central

    Mellouki, Ihsane; laazar, Nawal; Benyachou, Bahija; Aqodad, Nouredine; Ibrahimi, Adil

    2014-01-01

    Le cancer de l'estomac est représenté essentiellement par Les adénocarcinomes gastriques, ces derniers demeurent l'une des dix premières causes mondiales de mortalité avec un pronostic qui est péjoratif. Son incidence reste variable à travers le monde, elle est caractérisée par une importante disparité géographique. Le but de notre travail est de décrire les caractéristiques épidémiologiques de l'adénocarcinome gastrique dans notre contexte à travers une étude rétrospective, observationnelle étalée sur une période de 10 ans (Janvier 2001- Janvier 2011), incluant tous les malades admis au service d'hépato-gastroentérologie du CHU Hassan II de Fès pour prise en charge d'un adénocarcinome gastrique. Durant cette période, 343 patients étaient admis pour prise en charge d'une tumeur gastrique, dont 170 patients avaient un adénocarcinome gastrique (49.5%). L’âge moyen de ces patients était de 58±13.4 ans [16 ans-0 ans]. Dans 43.7% des cas, les patients provenaient de la région de Fès, souvent du milieu rurale. On note une nette prédominance masculine, avec une différence significative entre les 2 sexes (p < ;0.05). Les patients âgés de moins de 60ans représentaient la tranche d’âge prédominante (63%) par rapports aux patients âgés de plus de 60ans (p = 0.02). 61% des patients consultaient dans un délai allant de 1 mois à 6 mois, 30.4% des patients étaient tabagiques, ce facteur avait une relation statistiquement significative avec l'adénocarcinome gastrique (p = 0.02). la non consommation de l'alcool est inversement liée et de façon significative à l'apparition de l'adénocarcinome gastrique (p = 0.03) dans notre contexte. L'infection par Hélicobacter pylori n’était mentionnée que chez peu de malades. Les formes métastatiques au moment du diagnostic dépassaient 50% avec un taux de décès au cours de l'hospitalisation de 2.6%. Sur le plan endoscopique, la localisation antropylorique, et la forme ulc

  12. Prostate Cancer Unit Initiative in Europe: A position paper by the European School of Oncology.

    PubMed

    Valdagni, Riccardo; Van Poppel, Hendrik; Aitchison, Michael; Albers, Peter; Berthold, Dominik; Bossi, Alberto; Brausi, Maurizio; Denis, Louis; Drudge-Coates, Lawrence; De Santis, Maria; Feick, Günther; Harrison, Chris; Haustermans, Karin; Hollywood, Donal; Hoyer, Morton; Hummel, Henk; Mason, Malcolm; Mirone, Vincenzo; Müller, Stefan C; Parker, Chris; Saghatchian, Mahasti; Sternberg, Cora N; Tombal, Bertrand; van Muilekom, Erik; Watson, Maggie; Wesselmann, Simone; Wiegel, Thomas; Magnani, Tiziana; Costa, Alberto

    2015-08-01

    The Prostate Cancer Programme of the European School of Oncology developed the concept of specialised interdisciplinary and multiprofessional prostate cancer care to be formalized in Prostate Cancer Units (PCU). After the publication in 2011 of the collaborative article "The Requirements of a Specialist Prostate Cancer Unit: A Discussion Paper from the European School of Oncology", in 2012 the PCU Initiative in Europe was launched. A multiprofessional Task Force of internationally recognized opinion leaders, among whom representatives of scientific societies, and patient advocates gathered to set standards for quality comprehensive prostate cancer care and designate care pathways in PCUs. The result was a consensus on 40 mandatory and recommended standards and items, covering several macro-areas, from general requirements to personnel to organization and case management. This position paper describes the relevant, feasible and applicable core criteria for defining PCUs in most European countries delivered by PCU Initiative in Europe Task Force. PMID:26092320

  13. Delay of Treatment Initiation Does Not Adversely Affect Survival Outcome in Breast Cancer

    PubMed Central

    Yoo, Tae-Kyung; Han, Wonshik; Moon, Hyeong-Gon; Kim, Jisun; Lee, Jun Woo; Kim, Min Kyoon; Lee, Eunshin; Kim, Jongjin; Noh, Dong-Young

    2016-01-01

    Purpose Previous studies examining the relationship between time to treatment and survival outcome in breast cancer have shown inconsistent results. The aim of this study was to analyze the overall impact of delay of treatment initiation on patient survival and to determine whether certain subgroups require more prompt initiation of treatment. Materials and Methods This study is a retrospective analysis of stage I-III patients who were treated in a single tertiary institution between 2005 and 2008. Kaplan-Meier survival analysis and Cox proportional hazards regression model were used to evaluate the impact of interval between diagnosis and treatment initiation in breast cancer and various subgroups. Results A total of 1,702 patients were included. Factors associated with longer delay of treatment initiation were diagnosis at another hospital, medical comorbidities, and procedures performed before admission for surgery. An interval between diagnosis and treatment initiation as a continuous variable or with a cutoff value of 15, 30, 45, and 60 days had no impact on disease-free survival (DFS). Subgroup analyses for hormone-responsiveness, triple-negative breast cancer, young age, clinical stage, and type of initial treatment showed no significant association between longer delay of treatment initiation and DFS. Conclusion Our results show that an interval between diagnosis and treatment initiation of 60 days or shorter does not appear to adversely affect DFS in breast cancer. PMID:26511801

  14. Comparative lineage tracing reveals cellular preferences for prostate cancer initiation

    PubMed Central

    Wang, Zhu A; Shen, Michael M

    2015-01-01

    The interplay of different cell types of origin and distinct oncogenic mutations may determine the tumor subtype. We have recently found that although both basal and luminal epithelial cells can initiate prostate tumorigenesis, the latter are more likely to undergo transformation in response to a range of oncogenic events. PMID:27308462

  15. Florida Initiative for Quality Cancer Care: Improvements on Colorectal Cancer Quality of Care Indicators during a 3-Year Interval

    PubMed Central

    Siegel, Erin M; Jacobsen, Paul B; Lee, Ji-Hyun; Malafa, Mokenge; Fulp, William; Fletcher, Michelle; Smith, Jesusa Corazon R; Brown, Richard; Levine, Richard; Cartwright, Thomas; Abesada-Terk, Guillermo; Kim, George; Alemany, Carlos; Faig, Douglas; Sharp, Philip; Markham, Merry-Jennifer; Shibata, David

    2015-01-01

    BACKGROUND The quality of cancer care has become a national priority; however, there are few ongoing efforts to assist medical oncology practices in identifying areas for improvement. The Florida Initiative for Quality Cancer Care is a consortium of 11 medical oncology practices that evaluates the quality of cancer care across Florida. Within this practice-based system of self-assessment, we determined adherence to colorectal cancer quality of care indicators (QCIs) in 2006, disseminated results to each practice and reassessed adherence in 2009. The current report focuses on evaluating the direction and magnitude of change in adherence to QCIs for colorectal cancer patients between the 2 assessments. STUDY DESIGN Medical records were reviewed for all colorectal cancer patients seen by a medical oncologist in 2006 (n = 489) and 2009 (n = 511) at 10 participating practices. Thirty-five indicators were evaluated individually and changes in QCI adherence over time and by site were examined. RESULTS Significant improvements were noted from 2006 to 2009, with large gains in surgical/pathological QCIs (eg, documenting rectal radial margin status, lymphovascular invasion, and the review of ≥12 lymph nodes) and medical oncology QCIs (documenting planned treatment regimen and providing recommended neoadjuvant regimens). Documentation of perineural invasion and radial margins significantly improved; however, adherence remained low (47% and 71%, respectively). There was significant variability in adherence for some QCIs across institutions at follow-up. CONCLUSIONS The Florida Initiative for Quality Cancer Care practices conducted self-directed quality-improvement efforts during a 3-year interval and overall adherence to QCIs improved. However, adherence remained low for several indicators, suggesting that organized improvement efforts might be needed for QCIs that remained consistently low over time. Findings demonstrate how efforts such as the Florida Initiative for

  16. A hot L1 retrotransposon evades somatic repression and initiates human colorectal cancer.

    PubMed

    Scott, Emma C; Gardner, Eugene J; Masood, Ashiq; Chuang, Nelson T; Vertino, Paula M; Devine, Scott E

    2016-06-01

    Although human LINE-1 (L1) elements are actively mobilized in many cancers, a role for somatic L1 retrotransposition in tumor initiation has not been conclusively demonstrated. Here, we identify a novel somatic L1 insertion in the APC tumor suppressor gene that provided us with a unique opportunity to determine whether such insertions can actually initiate colorectal cancer (CRC), and if so, how this might occur. Our data support a model whereby a hot L1 source element on Chromosome 17 of the patient's genome evaded somatic repression in normal colon tissues and thereby initiated CRC by mutating the APC gene. This insertion worked together with a point mutation in the second APC allele to initiate tumorigenesis through the classic two-hit CRC pathway. We also show that L1 source profiles vary considerably depending on the ancestry of an individual, and that population-specific hot L1 elements represent a novel form of cancer risk. PMID:27197217

  17. California Breast Cancer Prevention Initiatives: Setting a research agenda for prevention.

    PubMed

    Sutton, P; Kavanaugh-Lynch, M H E; Plumb, M; Yen, I H; Sarantis, H; Thomsen, C L; Campleman, S; Galpern, E; Dickenson, C; Woodruff, T J

    2015-07-01

    The environment is an underutilized pathway to breast cancer prevention. Current research approaches and funding streams related to breast cancer and the environment are unequal to the task at hand. We undertook the California Breast Cancer Prevention Initiatives, a four-year comprehensive effort to set a research agenda related to breast cancer, the environment, disparities and prevention. We identified 20 topics for Concept Proposals reflecting a life-course approach and the complex etiology of breast cancer; considering the environment as chemical, physical and socially constructed exposures that are experienced concurrently: at home, in the community and at work; and addressing how we should be modifying the world around us to promote a less carcinogenic environment. Redirecting breast cancer research toward prevention-oriented discovery could significantly reduce the incidence and associated disparities of the disease among future generations. PMID:25277312

  18. Putative cancer-initiating stem cells in cell culture models for molecular subtypes of clinical breast cancer

    PubMed Central

    TELANG, NITIN

    2015-01-01

    Cancer-initiating stem cells (CISC) represent a minor subpopulation of heterogeneous breast cancer. CISC are responsible for the acquired resistance to conventional chemoendocrine therapy and eventual relapse observed in patients with breast cancer. Certain molecular subtypes of clinical breast cancer that exhibit differential expression of genes coding for hormone and growth factor receptors differ in their response to conventional chemoendocrine therapy and targeted therapeutic inhibitors. Thus, the development of reliable cell culture models for CISC may provide a valuable experimental approach for the study of stem cell-targeted therapy for the treatment of breast cancer. The present study utilized optimized cell culture systems as experimental models for different molecular subtypes of clinical breast cancer, including luminal A, human epidermal growth factor receptor (HER)-2-enriched and triple negative breast cancer. Biomarker end points, including control of homeostatic growth, cancer risk and drug resistance, were quantitatively analyzed in the selected models. The results of the analyses indicated that, compared with the non-tumorigenic controls, the cell models representing the aforementioned molecular subtypes of clinical breast cancer exhibited aberrant cell cycle progression, downregulated cellular apoptosis and loss of control of homeostatic growth, as evidenced by hyperproliferation. Additionally, these models displayed persistent cancer risk, as indicated by their high incidence and frequency of anchorage-independent (AI) colony formation in vitro and their tumor development capacity in vivo. Furthermore, in the presence of maximum cytostatic drug concentrations, the drug-resistant phenotypes isolated from the parental drug-sensitive cell lines representing luminal A, HER-2-enriched and triple negative breast cancer exhibited an 11.5, 5.0 and 6.2 fold increase in cell growth, and a 5.6, 5.4 and 4.4 fold increase in the number of AI colonies

  19. Effects of a Multikinase Inhibitor Motesanib (AMG 706) Alone and Combined with the Selective DuP-697 COX-2 Inhibitor on Colorectal Cancer Cells.

    PubMed

    Kaya, Tijen Temiz; Altun, Ahmet; Turgut, Nergiz Hacer; Ataseven, Hilmi; Koyluoglu, Gokhan

    2016-01-01

    In the present study, we investigated the effects of motesanib (AMG 706), a multikinase inhibitor alone and in combination with DuP-697, an irreversible selective inhibitor of COX-2, on cell proliferation, angiogenesis, and apoptosis induction in a human colorectal cancer cell line (HT29). Real time cell analysis (RTCA, Xcelligence system) was used to determine the effects on colorectal cancer cell proliferation. Apoptosis was assessed with annexin V staining and angiogenesis was determined with chorioallantoic membrane model. We found that motesanib alone exerted antiproliferative, antiangiogenic and apoptotic effects on HT29 colorectal cancer cells. Combination with DUP-697 increased the antiproliferative, antiangiogenic and apoptotic effects. Results of this study indicate that motesanib may be a good choice in treatment of colorectal tumors. In addition, the increased effects of combination of motesanib with DuP-697 raise the possibility of using lower doses of these drugs and therefore avoid/minimize the dose-dependent side effects generally observed. PMID:27039732

  20. Molecular genetics of bladder cancer: Emerging mechanisms of tumor initiation and progression.

    PubMed

    McConkey, David J; Lee, Sangkyou; Choi, Woonyoung; Tran, Mai; Majewski, Tadeusz; Lee, Sooyong; Siefker-Radtke, Arlene; Dinney, Colin; Czerniak, Bogdan

    2010-01-01

    Urothelial cancer has served as one of the most important sources of information about the mutational events that underlie the development of human solid malignancies. Although "field effects" that affect the entire bladder mucosa appear to initiate disease, tumors develop along 2 distinct biological "tracks" that present vastly different challenges for clinical management. Recent whole genome methodologies have facilitated even more rapid progress in the identification of the molecular mechanisms involved in bladder cancer initiation and progression. Specifically, whole organ mapping combined with high resolution, high throughput SNP analyses have identified a novel class of candidate tumor suppressors ("forerunner genes") that localize near more familiar tumor suppressors but are disrupted at an earlier stage of cancer development. Furthermore, whole genome comparative genomic hybridization (CGH) and mRNA expression profiling have demonstrated that the 2 major subtypes of urothelial cancer (papillary/superficial and non-papillary/muscle-invasive) are truly distinct molecular entities, and in recent work our group has discovered that muscle-invasive tumors express molecular markers characteristic of a developmental process known as "epithelial-to-mesenchymal transition" (EMT). Emerging evidence indicates that urothelial cancers contain subpopulations of tumor-initiating cells ("cancer stem cells") but the phenotypes of these cells in different tumors are heterogeneous, raising questions about whether or not the 2 major subtypes of cancer share a common precursor. This review will provide an overview of these new insights and discuss priorities for future investigation. PMID:20610280

  1. Colon Cancer Tumorigenesis Initiated by the H1047R Mutant PI3K.

    PubMed

    Yueh, Alexander E; Payne, Susan N; Leystra, Alyssa A; Van De Hey, Dana R; Foley, Tyler M; Pasch, Cheri A; Clipson, Linda; Matkowskyj, Kristina A; Deming, Dustin A

    2016-01-01

    The phosphoinositide 3-kinase (PI3K) signaling pathway is critical for multiple important cellular functions, and is one of the most commonly altered pathways in human cancers. We previously developed a mouse model in which colon cancers were initiated by a dominant active PI3K p110-p85 fusion protein. In that model, well-differentiated mucinous adenocarcinomas developed within the colon and initiated through a non-canonical mechanism that is not dependent on WNT signaling. To assess the potential relevance of PI3K mutations in human cancers, we sought to determine if one of the common mutations in the human disease could also initiate similar colon cancers. Mice were generated expressing the Pik3caH1047R mutation, the analog of one of three human hotspot mutations in this gene. Mice expressing a constitutively active PI3K, as a result of this mutation, develop invasive adenocarcinomas strikingly similar to invasive adenocarcinomas found in human colon cancers. These tumors form without a polypoid intermediary and also lack nuclear CTNNB1 (β-catenin), indicating a non-canonical mechanism of tumor initiation mediated by the PI3K pathway. These cancers are sensitive to dual PI3K/mTOR inhibition indicating dependence on the PI3K pathway. The tumor tissue remaining after treatment demonstrated reduction in cellular proliferation and inhibition of PI3K signaling. PMID:26863299

  2. Colon Cancer Tumorigenesis Initiated by the H1047R Mutant PI3K

    PubMed Central

    Yueh, Alexander E.; Payne, Susan N.; Leystra, Alyssa A.; Van De Hey, Dana R.; Foley, Tyler M.; Pasch, Cheri A.; Clipson, Linda; Matkowskyj, Kristina A.; Deming, Dustin A.

    2016-01-01

    The phosphoinositide 3-kinase (PI3K) signaling pathway is critical for multiple important cellular functions, and is one of the most commonly altered pathways in human cancers. We previously developed a mouse model in which colon cancers were initiated by a dominant active PI3K p110-p85 fusion protein. In that model, well-differentiated mucinous adenocarcinomas developed within the colon and initiated through a non-canonical mechanism that is not dependent on WNT signaling. To assess the potential relevance of PI3K mutations in human cancers, we sought to determine if one of the common mutations in the human disease could also initiate similar colon cancers. Mice were generated expressing the Pik3caH1047R mutation, the analog of one of three human hotspot mutations in this gene. Mice expressing a constitutively active PI3K, as a result of this mutation, develop invasive adenocarcinomas strikingly similar to invasive adenocarcinomas found in human colon cancers. These tumors form without a polypoid intermediary and also lack nuclear CTNNB1 (β-catenin), indicating a non-canonical mechanism of tumor initiation mediated by the PI3K pathway. These cancers are sensitive to dual PI3K/mTOR inhibition indicating dependence on the PI3K pathway. The tumor tissue remaining after treatment demonstrated reduction in cellular proliferation and inhibition of PI3K signaling. PMID:26863299

  3. Measuring quality in cancer care: overview of initiatives in selected countries.

    PubMed

    Wild, C; Patera, N

    2013-11-01

    To inform the Austrian National Cancer Plan on possible generic quality indicators that might be derived from routine data a systematic literature search in three databases, followed by extensive hand-searching to locate initiatives and their publications was carried out in spring 2011. Twenty-one initiatives that developed indicators for measuring quality of cancer care were identified: longer standing and decentralised initiatives are characteristics of the USA. The Canadian province of Ontario publishes the Cancer System Quality Index, centralised audit and peer review programmes are undertaken in the National Health Service in the UK. Methodologically sound cancer type-specific pilot projects in Belgium have been implemented, the Netherlands and Denmark are running national initiatives. Germany recently started quality measurement activities, too. Generic indicators often focus on end-of-life care, multidisciplinarity, advance care planning and documentation. Indicators measuring the quality of care during an entire episode of cancer are rare, as are those for less common cancers and for care in the outpatient setting. Access, equity and the patient's perspective are only beginning to be incorporated into indicators. After having identified a range of candidate indicators that can be implemented with routinely collected data alone, piloting them in Austria would be the next step to go. PMID:23808585

  4. The Haiti Breast Cancer Initiative: Initial Findings and Analysis of Barriers-to-Care Delaying Patient Presentation

    PubMed Central

    Sharma, Ketan; Costas, Ainhoa; Damuse, Ruth; Hamiltong-Pierre, Jean; Pyda, Jordan; Ong, Cecilia T.; Shulman, Lawrence N.; Meara, John G.

    2013-01-01

    Background. In Haiti, breast cancer patients present at such advanced stages that even modern therapies offer modest survival benefit. Identifying the personal, sociocultural, and economic barriers-to-care delaying patient presentation is crucial to controlling disease. Methods. Patients presenting to the Hôpital Bon Sauveur in Cange were prospectively accrued. Delay was defined as 12 weeks or longer from initial sign/symptom discovery to presentation, as durations greater than this cutoff correlate with reduced survival. A matched case-control analysis with multivariate logistic regression was used to identify factors predicting delay. Results. Of N = 123 patients accrued, 90 (73%) reported symptom-presentation duration and formed the basis of this study: 52 patients presented within 12 weeks of symptoms, while 38 patients waited longer than 12 weeks. On logistic regression, lower education status (OR = 5.6, P = 0.03), failure to initially recognize mass as important (OR = 13.0, P < 0.01), and fear of treatment cost (OR = 8.3, P = 0.03) were shown to independently predict delayed patient presentation. Conclusion. To reduce stage at presentation, future interventions must educate patients on the recognition of initial breast cancer signs and symptoms and address cost concerns by providing care free of charge and/or advertising that existing care is already free. PMID:23840209

  5. JNK Signaling in the Control of the Tumor-Initiating Capacity Associated with Cancer Stem Cells

    PubMed Central

    Sato, Atsushi; Okada, Masashi

    2013-01-01

    Deregulation of c-Jun NH2-terminal kinase (JNK) signaling occurs frequently in a variety of human cancers, yet the exact role(s) of JNK deregulation in cancer cell biology remains to be fully elucidated. Our recent demonstration that the activity of JNK is required not only for self-renewal of glioma stem cells but also for their tumor initiation has, however, identified a new role for JNK in the control of the stemness and tumor-initiating capacity of cancer cells. Significantly, transient JNK inhibition was sufficient to cause sustained loss of the tumor-initiating capacity of glioma stem cells, suggesting that the phenotype of “lost tumor-initiating capacity” may be as stable as the differentiated state and that the tumor-initiating capacity might therefore be under the control of JNK through an epigenetic mechanism that also governs stemness and differentiation. Here, in this article, we review the role and mechanism of JNK in the control of this “stemness-associated tumor-initiating capacity” (STATIC), a new hypothetical concept we introduce in this review article. Since the idea of STATIC is essentially applicable to both cancer types that do and do not follow the cancer stem cell hypothesis, we also give consideration to the possible involvement of JNK-mediated control of STATIC in a wide range of human cancers in which JNK is aberrantly activated. Theoretically, successful targeting of STATIC through JNK could contribute to long-term control of cancer. Issues to be considered before clinical application of therapies targeting this JNK-STATIC axis are also discussed. PMID:24349636

  6. The characteristics and spatial distributions of initially missed and rebiopsy-detected prostate cancers

    PubMed Central

    2016-01-01

    Purpose: The purpose of this study was to analyze the characteristics of initially missed and rebiopsy-detected prostate cancers following 12-core transrectal biopsy. Methods: A total of 45 patients with prostate cancers detected on rebiopsy and 45 patients with prostate cancers initially detected on transrectal ultrasound-guided biopsy were included in the study. For result analysis, the prostate was divided into six compartments, and the cancer positive rates, estimated tumor burden, and agreement rates between biopsy and surgical specimens, along with clinical data, were evaluated. Results: The largest mean tumor burden was located in the medial apex in both groups. There were significantly more tumors in this location in the rebiopsy group (44.9%) than in the control group (30.1%, P=0.015). The overall sensitivity of biopsy was significantly lower in the rebiopsy group (22.5% vs. 43.4%, P<0.001). The agreement rate of cancer positive cores between biopsy and surgical specimens was significantly lower in the medial apex in the rebiopsy group compared with that of the control group (50.0% vs. 65.6%, P=0.035). The cancer positive rates of target biopsy cores and premalignant lesions in the rebiopsy group were 63.1% and 42.3%, respectively. Conclusion: Rebiopsy-detected prostate cancers showed different spatial distribution and lower cancer detection rate of biopsy cores compared with initially diagnosed cancers. To overcome lower cancer detection rate, target biopsy of abnormal sonographic findings, premalignant lesions and medial apex which revealed larger tumor burden would be recommended when performing rebiopsy. PMID:27048261

  7. Radionécrose cérébrale chez des patients irradiés pour cancers du nasopharynx: à propos de 3 cas

    PubMed Central

    El Mazghi, Abderrahman; Lalya, Issam; Loukili, Kaoutar; El Kacemi, Hanan; Kebdani, Taieb; Hassouni, Khalid

    2014-01-01

    La radionécrose cérébrale est une complication tardive, iatrogène, relativement rare de la radiothérapie qui survient après plus de six mois suivant le début du traitement. Elle pourrait s'expliquer par la conjonction de lésions vasculaires, gliales et d'ordre immunologiques. Elle peut mettre en jeu le pronostic fonctionnel et vital du malade. La prévention de cette affection redoutable est fondamentale vu l'absence de traitement potentiellement efficace. Nous rapportons 03 nouveaux cas, chez des patients traités par chimiothérapie d'induction puis radio- chimiothérapie concomitante pour des cancers localement avancés du nasopharynx. Le diagnostic a été orienté par l'IRM spectroscopique et l’évolution était favorable sous corticothérapie dans les 03 cas. PMID:25722784

  8. Place de la chirurgie dans la prise en charge des cancers du sein chez la femme au Centre Hospitalier Universitaire Yalgado Ouedraogo: à propos de 81 cas

    PubMed Central

    Zongo, Nayi; Millogo-Traore, Timonga Françoise Danielle; Bagre, Sidpawalmdé Carine; Bagué, Abdoul-Halim; Ouangre, Edgar; Zida, Maurice; Bambara, Aboubacar; Bambara, Tozoula Augustin; Traoré, Si Simon

    2015-01-01

    Etudier la place de la chirurgie dans la prise en charge des cancers du sein au centre hospitalier universitaire Yalgado Ouédraogo. Nous avons réalisé une étude prospective et descriptive sur dix (10) mois portant sur la place de la chirurgie dans le cancer du sein. Elle a eu pour cadre les services de gynécologie-obstétrique et de chirurgie viscérale et digestive du centre hospitalier universitaire Yalgado Ouédraogo. Ont été pris en compte les indications, les gestes et les résultats de la chirurgie. Nous avons colligé 81 cancers mammaires. Le délai moyen de consultation a été de 14,26 mois. Les tumeurs T3 à T4 représentaient 82,71% des cas. Trente-huit patientes (46,91%) ont été opérées. La chimiothérapie néo adjuvante a été réalisée dans 29,63% des cas. Trente-quatre patientes (41,97%) étaient opérables d'emblée. Il s'agissait de mastectomie selon Madden dans 94,74% des cas et de chirurgie de propreté dans 2 cas (5,26% des cas). Une chimiothérapie adjuvante a été réalisée chez 52,63% des patientes opérées. Des complications à type de lymphocèle ont été notées dans 23,68% des cas. Leur traitement a consisté en des ponctions évacuatrices. Les indications de la chirurgie sont limitées par le retard diagnostique corollaire de stades avancés des cancers du sein. L'absence de la radiothérapie rend délicate la pratique de la chirurgie conservatrice et la mastectomie occupe toujours une place importante. Un diagnostic précoce permettrait d'augmenter les indications chirurgicales. PMID:26848364

  9. Developmental Pathways Direct Pancreatic Cancer Initiation from Its Cellular Origin

    PubMed Central

    Reichert, Maximilian; Blume, Karin; Kleger, Alexander; Hartmann, Daniel; von Figura, Guido

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDA) is characterized by an extremely poor prognosis, since it is usually diagnosed at advanced stages. In order to employ tools for early detection, a better understanding of the early stages of PDA development from its main precursors, pancreatic intraepithelial neoplasia (PanIN), and intraductal papillary mucinous neoplasm (IPMN) is needed. Recent studies on murine PDA models have identified a different exocrine origin for PanINs and IPMNs. In both processes, developmental pathways direct the initiation of PDA precursors from their cellular ancestors. In this review, the current understanding of early PDA development is summarized. PMID:26681957

  10. TARGETING THE eIF4F TRANSLATION INITIATION COMPLEX: A CRITICAL NEXUS FOR CANCER DEVELOPMENT

    PubMed Central

    Pelletier, Jerry; Graff, Jeremy; Ruggero, Davide; Sonenberg, Nahum

    2014-01-01

    Elevated protein synthesis is an important feature of many cancer cells and often arises as a consequence of increased signaling flux channeled to eukaryotic initiation factor (eIF) 4F, the key regulator of the mRNA-ribosome recruitment phase of translation initiation. In many cellular and pre-clinical models of cancer, eIF4F deregulation results in changes in translational efficiency of specific mRNA classes. Importantly, many of these mRNAs code for proteins that potently regulate critical cellular processes such as cell growth and proliferation, enhanced cell survival, and cell migration that ultimately impinge on several hallmarks of cancer, including increased angiogenesis, deregulated growth control, enhanced cellular survival, epithelial-to-mesenchymal transition, invasion and metastasis. By being positioned as the molecular nexus downstream of key oncogenic signaling pathways (e.g. Ras, PI3K/AKT/TOR, and Myc), eIF4F serves as a direct link between important steps in cancer development and translation initiation. Identification of mRNAs particularly responsive to elevated eIF4F activity that typifies tumorigenesis underscores the critical role of eIF4F in cancer and raises the exciting possibility of developing new-in-class small molecules targeting translation initiation as anti-neoplastic agents. PMID:25593033

  11. Physician-Initiated Stop-Smoking Program for Patients Receiving Treatment for Early-Stage Cancer

    ClinicalTrials.gov

    2015-10-06

    Bladder Cancer; Breast Cancer; Colorectal Cancer; Head and Neck Cancer; Lung Cancer; Lymphoma; Prostate Cancer; Testicular Germ Cell Tumor; Tobacco Use Disorder; Unspecified Adult Solid Tumor, Protocol Specific

  12. The epigenetics of tumour initiation: cancer stem cells and their chromatin.

    PubMed

    Avgustinova, Alexandra; Benitah, Salvador Aznar

    2016-02-01

    Cancer stem cells (CSCs) have been identified in various tumours and are defined by their potential to initiate tumours upon transplantation, self-renew and reconstitute tumour heterogeneity. Modifications of the epigenome can favour tumour initiation by affecting genome integrity, DNA repair and tumour cell plasticity. Importantly, an in-depth understanding of the epigenomic alterations underlying neoplastic transformation may open new avenues for chromatin-targeted cancer treatment, as these epigenetic changes could be inherently more amenable to inhibition and reversal than hard-wired genomic alterations. Here we discuss how CSC function is affected by chromatin state and epigenomic instability. PMID:26874045

  13. 5-epi-Torrubiellutin C shows antiproliferative activity on DU145 prostate cancer cells through inactivation of the AKT/mTOR pathway.

    PubMed

    Singh, Ashita; Mahipal, Bodugam; Chandrasekhar, Srivari; Ummanni, Ramesh

    2014-04-01

    Cell-based assays for evaluation of the anticancer potential of a focused small molecule library have identified a few potential hit molecules. Among the hits identified, Torrubiellutins (3a) showed good anticancer potential across the cells used in screening assays. Torrubiellutins are isolated from fungal insects Torrubiella luteorostrata and diverse pharmacological effects for these have been reported. However, it is not known as to how Torrubiellutins act through signaling pathways inhibiting the growth of eukaryotic cells. The current study aimed to determine the anticancer potential of Torrubiellutins by defining the molecular mechanism of cytotoxicity using DU145 cells. The results showed that the inhibition of prostate cancer cell growth by 3a was associated with inhibition of anchorage-independent growth, cell migration, and, to a small extent, apoptosis-mediated cell death by caspase activation. The growth-inhibitory effects of 3a are supported by inactivation of prosurvival pathways. Immunoblot analysis showed that the treatment of DU145 cells with 3a resulted in specific downregulation of AKT/mammalian target of rapamycin (mTOR) and its downstream effector proteins p70S6K, GSK3β, and STAT3. On the basis of these findings, we propose that the changes observed in the AKT/mTOR signaling axis are new targets of 3a that are involved in its inhibitory activity on the proliferation of prostate cancer cells, suggesting its potential for further investigation as a promising anticancer agent. PMID:24445589

  14. Assessing the impact of an English national initiative for early cancer diagnosis in primary care

    PubMed Central

    Rubin, G; Gildea, C; Wild, S; Shelton, J; Ablett-Spence, I

    2015-01-01

    Background: The Cancer Networks Supporting Primary Care programme was a National Health Service (NHS) initiative in England between 2011 and 2013 that aimed to better understand and improve referral practices for suspected cancer. Methods: A mixed methods evaluation using semi-structured interviews with purposefully sampled key stakeholders and an analysis of Cancer Waiting Times and Hospital Episode Statistics data for all 8179 practices in England were undertaken. We compared periods before (2009/10) and at the end (2012/13) of the initiative for practices taking up any one of four specified quality improvement initiatives expected to change referral practice in the short to medium term and those that did not. Results: Overall, 38% of general practices were involved in at least one of four quality improvement activities (clinical audit, significant event analysis, use of risk assessment tools and development of practice plans). Against an overall 29% increase in urgent cancer referrals between 2009/10 and 2012/13, these practices had a significantly higher increase in referral rate, with reduced between-practice variation. There were no significant differences between the two groups in conversion, detection or emergency presentation rates. Key features of successful implementation at practice and network level reported by participants included leadership, organisational culture and physician involvement. Concurrent health service reforms created organisational uncertainty and limited the programme's effectiveness. Conclusions: Specific primary care initiatives promoted by cancer networks had an additional and positive impact on urgent referrals for suspected cancer. Successful engagement with the programmes depended on effective and well-supported leadership by cancer networks and their general practitioner (GP) leads. PMID:25734381

  15. Nuclear interaction of Smac/DIABLO with Survivin at G2/M arrest prompts docetaxel-induced apoptosis in DU145 prostate cancer cells

    SciTech Connect

    Kim, Ji Young; Chung, Jin-Yong; Lee, Seung Gee; Kim, Yoon-Jae; Park, Ji-Eun; Yoo, Ki Soo; Yoo, Young Hyun; Park, Young Chul; Kim, Byeong Gee; Kim, Jong-Min . E-mail: jmkim7@dau.ac.kr

    2006-12-01

    Smac/DIABLO is released by mitochondria in response to apoptotic stimuli and is thought to antagonize the function of inhibitors of apoptosis proteins. Recently, it has been shown that, like XIAP, Survivin can potentially interact with Smac/DIABLO. However, the precise mechanisms and cellular location of their action have not been determined. We report for the first time that Smac/DIABLO translocates to the nucleus and is colocalized with Survivin at mitotic spindles during apoptosis resulting from G2/M arrest due to docetaxel treatment of DU145 prostate cancer cells. Our data demonstrate that the nuclear interaction of Smac/DIABLO with Survivin is an important step for suppressing the anti-apoptotic function of Survivin in Doc-induced apoptosis. This suggests that the balance between cellular Smac/DIABLO and Survivin levels could be critical for cellular destiny in taxane-treated cancer cells.

  16. Amplification of the 20q chromosomal arm occurs early in tumorigenic transformation and may initiate cancer.

    PubMed

    Tabach, Yuval; Kogan-Sakin, Ira; Buganim, Yosef; Solomon, Hilla; Goldfinger, Naomi; Hovland, Randi; Ke, Xi-Song; Oyan, Anne M; Kalland, Karl-H; Rotter, Varda; Domany, Eytan

    2011-01-01

    Duplication of chromosomal arm 20q occurs in prostate, cervical, colon, gastric, bladder, melanoma, pancreas and breast cancer, suggesting that 20q amplification may play a causal role in tumorigenesis. According to an alternative view, chromosomal imbalance is mainly a common side effect of cancer progression. To test whether a specific genomic aberration might serve as a cancer initiating event, we established an in vitro system that models the evolutionary process of early stages of prostate tumor formation; normal prostate cells were immortalized by the over-expression of human telomerase catalytic subunit hTERT, and cultured for 650 days till several transformation hallmarks were observed. Gene expression patterns were measured and chromosomal aberrations were monitored by spectral karyotype analysis at different times. Several chromosomal aberrations, in particular duplication of chromosomal arm 20q, occurred early in the process and were fixed in the cell populations, while other aberrations became extinct shortly after their appearance. A wide range of bioinformatic tools, applied to our data and to data from several cancer databases, revealed that spontaneous 20q amplification can promote cancer initiation. Our computational model suggests that 20q amplification induced deregulation of several specific cancer-related pathways including the MAPK pathway, the p53 pathway and Polycomb group factors. In addition, activation of Myc, AML, B-Catenin and the ETS family transcription factors was identified as an important step in cancer development driven by 20q amplification. Finally we identified 13 "cancer initiating genes", located on 20q13, which were significantly over-expressed in many tumors, with expression levels correlated with tumor grade and outcome suggesting that these genes induce the malignant process upon 20q amplification. PMID:21297939

  17. Amplification of the 20q Chromosomal Arm Occurs Early in Tumorigenic Transformation and May Initiate Cancer

    PubMed Central

    Buganim, Yosef; Solomon, Hilla; Goldfinger, Naomi; Hovland, Randi; Ke, Xi-Song; Oyan, Anne M.; Kalland, Karl-H.; Rotter, Varda; Domany, Eytan

    2011-01-01

    Duplication of chromosomal arm 20q occurs in prostate, cervical, colon, gastric, bladder, melanoma, pancreas and breast cancer, suggesting that 20q amplification may play a causal role in tumorigenesis. According to an alternative view, chromosomal imbalance is mainly a common side effect of cancer progression. To test whether a specific genomic aberration might serve as a cancer initiating event, we established an in vitro system that models the evolutionary process of early stages of prostate tumor formation; normal prostate cells were immortalized by the over-expression of human telomerase catalytic subunit hTERT, and cultured for 650 days till several transformation hallmarks were observed. Gene expression patterns were measured and chromosomal aberrations were monitored by spectral karyotype analysis at different times. Several chromosomal aberrations, in particular duplication of chromosomal arm 20q, occurred early in the process and were fixed in the cell populations, while other aberrations became extinct shortly after their appearance. A wide range of bioinformatic tools, applied to our data and to data from several cancer databases, revealed that spontaneous 20q amplification can promote cancer initiation. Our computational model suggests that 20q amplification induced deregulation of several specific cancer-related pathways including the MAPK pathway, the p53 pathway and Polycomb group factors. In addition, activation of Myc, AML, B-Catenin and the ETS family transcription factors was identified as an important step in cancer development driven by 20q amplification. Finally we identified 13 "cancer initiating genes", located on 20q13, which were significantly over-expressed in many tumors, with expression levels correlated with tumor grade and outcome suggesting that these genes induce the malignant process upon 20q amplification. PMID:21297939

  18. Fate of the human Y chromosome linked genes and loci in prostate cancer cell lines DU145 and LNCaP

    PubMed Central

    2013-01-01

    Background Prostate cancer is a known cause of mortality in men worldwide although the risk factor varies among different ethnic groups. Loss of the Y chromosome is a common chromosomal abnormality observed in the human prostate cancer. Results We screened 51 standard sequence tagged sites (STSs) corresponding to a male-specific region of the Y chromosome (MSY), sequenced the coding region of the SRY gene and assessed the status of the DYZ1 arrays in the human prostate cancer cell lines DU145 and LNCaP. The MSY was found to be intact and coding region of SRY showed no sequence variation in both the cell lines. However, DYZ1 arrays showed sequence and copy number variations. DU145 and LNCaP cells were found to carry 742 and 1945 copies of the DYZ1, respectively per 3.3 pg of genomic DNA. The DYZ1 copies detected in these cell lines are much below the average of that reported in normal human males. Similarly, the number of “TTCCA” repeat and its derivatives within the DYZ1 arrays showed variation compared to those of the normal males. Conclusions Clearly, the DYZ1 is maximally affected in both the cell lines. Work on additional cell lines and biopsied samples would augment our understanding about the susceptibility of this region. Based on the present work, we construe that copy number status of the DYZ1 may be exploited as a supplementary prognostic tool to monitor the occurrence of prostate cancer using biopsied samples. PMID:23663454

  19. Current trends in initial management of laryngeal cancer: the declining use of open surgery.

    PubMed

    Silver, Carl E; Beitler, Jonathan J; Shaha, Ashok R; Rinaldo, Alessandra; Ferlito, Alfio

    2009-09-01

    The role of open surgery for management of laryngeal cancer has been greatly diminished during the past decade. The development of transoral endoscopic laser microsurgery (TLS), improvements in delivery of radiation therapy (RT) and the advent of multimodality protocols, particularly concomitant chemoradiotherapy (CCRT) have supplanted the previously standard techniques of open partial laryngectomy for early cancer and total laryngectomy followed by adjuvant RT for advanced cancer. A review of the recent literature revealed virtually no new reports of conventional conservation surgery as initial treatment for early stage glottic and supraglottic cancer. TLS and RT, with or without laser surgery or CCRT, have become the standard initial treatments for T1, T2 and selected T3 laryngeal cancer. Photodynamic therapy (PDT) may have an emerging role in the treatment of early laryngeal cancer. Anterior commissure involvement presents particular difficulties in application of TLS, although no definitive conclusions have been reached with regard to optimal treatment of these lesions. Results of TLS are equivalent to those obtained by conventional conservation surgery, with considerably less morbidity, less hospital time and better postoperative function. Oncologic results of TLS and RT are equivalent for glottic cancer, but with better voice results for RT in patients who require more extensive cordectomy. The preferred treatment for early supraglottic cancer, particularly for bulkier or T3 lesions is TLS, with or without postoperative RT. The Veterans Administration Study published in 1991 established the fact that the response to neoadjuvant CT predicts the response of a tumor to RT. Patients with advanced tumors that responded either partially or completely to CT were treated with RT, and total laryngectomy was reserved for non-responders. This resulted in the ability to preserve the larynx in a significant number of patients with locally advanced laryngeal cancer, while

  20. Targeting Tumor Initiating Cells through Inhibition of Cancer Testis Antigens and Notch Signaling: A Hypothesis.

    PubMed

    Colombo, Michela; Mirandola, Leonardo; Reidy, Adair; Suvorava, Natallia; Konala, Venu; Chiaramonte, Raffaella; Grizzi, Fabio; Rahman, Rakhshanda Layeequr; Jenkins, Marjorie R; Nugyen, Diane D; Dalhbeck, Scott; Cobos, Everardo; Figueroa, Jose A; Chiriva-Internati, Maurizio

    2015-03-01

    Tumor initiating cells (TICs) differ from normal stem cells (SCs) in their ability to initiate tumorigenesis, invasive growth, metastasis and the acquisition of chemo and/or radio-resistance. Over the past years, several studies have indicated the potential role of the Notch system as a key regulator of cellular stemness and tumor development. Furthermore, the expression of cancer testis antigens (CTA) in TICs, and their role in SC differentiation and biology, has become an important area of investigation. Here, we propose a model in which CTA expression and Notch signaling interacts to maintain the sustainability of self-replicating tumor populations, ultimately leading to the development of metastasis, drug resistance and cancer progression. We hypothesize that Notch-CTA interactions in TICs offer a novel opportunity for meaningful therapeutic interventions in cancer. PMID:25901861

  1. Fumonisin-induced hepatocarcinogenesis: mechanisms related to cancer initiation and promotion.

    PubMed Central

    Gelderblom, W C; Abel, S; Smuts, C M; Marnewick, J; Marasas, W F; Lemmer, E R; Ramljak, D

    2001-01-01

    We review the hepatocarcinogenic effects of fungal cultures of Fusarium verticillioides(= Fusarium moniliforme) strain MRC 826 in male BD IX rats. Subsequent chemical analyses of the fumonisin B (FB) mycotoxin content in the culture material used and long-term carcinogenesis studies with purified FB1 provide information about dose-response effects, relevance of hepatotoxicity during FB1-induced carcinogenesis, and the existence of a no-effect threshold. Fumonisin intake levels of between 0.08 and 0.16 mg FB/100 g body weight (bw)/day over approximately 2 years produce liver cancer in male BD IX rats. Exposure levels < 0.08 mg FB/100 g bw/day fail to induce cancer, although mild toxic and preneoplastic lesions are induced. The nutritional status of the diets used in the long-term experiments was marginally deficient in lipotropes and vitamins and could have played an important modulating role in fumonisin-induced hepatocarcinogenesis. Short-term studies in a cancer initiation/promotion model in rat liver provided important information about the possible mechanisms involved during the initial stages of cancer development by this apparently nongenotoxic mycotoxin. These studies supported the findings of long-term investigations indicating that a cytotoxic/proliferative response is required for cancer induction and that a no-effect threshold exists for cancer induction. The mechanisms proposed for cancer induction are highlighted and include the possible role of oxidative damage during initiation and the disruption of lipid metabolism, integrity of cellular membranes, and altered growth-regulatory responses as important events during promotion. PMID:11359698

  2. Glutathione and thioredoxin antioxidant pathways synergize to drive cancer initiation and progression.

    PubMed

    Harris, Isaac S; Treloar, Aislinn E; Inoue, Satoshi; Sasaki, Masato; Gorrini, Chiara; Lee, Kim Chung; Yung, Ka Yi; Brenner, Dirk; Knobbe-Thomsen, Christiane B; Cox, Maureen A; Elia, Andrew; Berger, Thorsten; Cescon, David W; Adeoye, Adewunmi; Brüstle, Anne; Molyneux, Sam D; Mason, Jacqueline M; Li, Wanda Y; Yamamoto, Kazuo; Wakeham, Andrew; Berman, Hal K; Khokha, Rama; Done, Susan J; Kavanagh, Terrance J; Lam, Ching-Wan; Mak, Tak W

    2015-02-01

    Controversy over the role of antioxidants in cancer has persisted for decades. Here, we demonstrate that synthesis of the antioxidant glutathione (GSH), driven by GCLM, is required for cancer initiation. Genetic loss of Gclm prevents a tumor's ability to drive malignant transformation. Intriguingly, these findings can be replicated using an inhibitor of GSH synthesis, but only if delivered prior to cancer onset, suggesting that at later stages of tumor progression GSH becomes dispensable potentially due to compensation from alternative antioxidant pathways. Remarkably, combined inhibition of GSH and thioredoxin antioxidant pathways leads to a synergistic cancer cell death in vitro and in vivo, demonstrating the importance of these two antioxidants to tumor progression and as potential targets for therapeutic intervention. PMID:25620030

  3. Short-form Ron is a novel determinant of ovarian cancer initiation and progression.

    PubMed

    Moxley, Katherine M; Wang, Luyao; Welm, Alana L; Bieniasz, Magdalena

    2016-05-01

    Short-form Ron (sfRon) is an understudied, alternative isoform of the full-length Ron receptor tyrosine kinase. In contrast to Ron, which has been shown to be an important player in many cancers, little is known about the role of sfRon in cancer pathogenesis. Here we report the striking discovery that sfRon expression is required for development of carcinogen-induced malignant ovarian tumors in mice. We also show that sfRon is expressed in several subtypes of human ovarian cancer including high-grade serous carcinomas, which is in contrast to no detectable expression in healthy ovaries. In addition, we report that introduction of sfRon into OVCAR3 cells resulted in epithelial-to-mesenchymal transition, activation of the PI3K and PDK1 pathway, and inhibition of the MAPK pathway. We demonstrated that sfRon confers an aggressive cancer phenotype in vitro characterized by increased proliferation and migration, and decreased adhesion of ovarian cancer cells. Moreover, the in vivo studies show that OVCAR3 tumors expressing sfRon exhibit significantly more robust growth and spreading to the abdominal cavity when compared with the parental sfRon negative OVCAR3 cells. These data suggest that sfRon plays a significant role in ovarian cancer initiation and progression, and may represent a promising therapeutic target for ovarian cancer treatment. PMID:27551332

  4. Berberine-induced apoptosis in human prostate cancer cells is initiated by reactive oxygen species generation

    SciTech Connect

    Meeran, Syed M.; Katiyar, Suchitra; Katiyar, Santosh K.

    2008-05-15

    Phytochemicals show promise as potential chemopreventive or chemotherapeutic agents against various cancers. Here we report the chemotherapeutic effects of berberine, a phytochemical, on human prostate cancer cells. The treatment of human prostate cancer cells (PC-3) with berberine induced dose-dependent apoptosis but this effect of berberine was not seen in non-neoplastic human prostate epithelial cells (PWR-1E). Berberine-induced apoptosis was associated with the disruption of the mitochondrial membrane potential, release of apoptogenic molecules (cytochrome c and Smac/DIABLO) from mitochondria and cleavage of caspase-9,-3 and PARP proteins. This effect of berberine on prostate cancer cells was initiated by the generation of reactive oxygen species (ROS) irrespective of their androgen responsiveness, and the generation of ROS was through the increased induction of xanthine oxidase. Treatment of cells with allopurinol, an inhibitor of xanthine oxidase, inhibited berberine-induced oxidative stress in cancer cells. Berberine-induced apoptosis was blocked in the presence of antioxidant, N-acetylcysteine, through the prevention of disruption of mitochondrial membrane potential and subsequently release of cytochrome c and Smac/DIABLO. In conclusion, the present study reveals that the berberine-mediated cell death of human prostate cancer cells is regulated by reactive oxygen species, and therefore suggests that berberine may be considered for further studies as a promising therapeutic candidate for prostate cancer.

  5. Short-form Ron is a novel determinant of ovarian cancer initiation and progression

    PubMed Central

    Moxley, Katherine M.; Wang, Luyao; Welm, Alana L.; Bieniasz, Magdalena

    2016-01-01

    Short-form Ron (sfRon) is an understudied, alternative isoform of the full-length Ron receptor tyrosine kinase. In contrast to Ron, which has been shown to be an important player in many cancers, little is known about the role of sfRon in cancer pathogenesis. Here we report the striking discovery that sfRon expression is required for development of carcinogen-induced malignant ovarian tumors in mice. We also show that sfRon is expressed in several subtypes of human ovarian cancer including high-grade serous carcinomas, which is in contrast to no detectable expression in healthy ovaries. In addition, we report that introduction of sfRon into OVCAR3 cells resulted in epithelial-to-mesenchymal transition, activation of the PI3K and PDK1 pathway, and inhibition of the MAPK pathway. We demonstrated that sfRon confers an aggressive cancer phenotype in vitro characterized by increased proliferation and migration, and decreased adhesion of ovarian cancer cells. Moreover, the in vivo studies show that OVCAR3 tumors expressing sfRon exhibit significantly more robust growth and spreading to the abdominal cavity when compared with the parental sfRon negative OVCAR3 cells. These data suggest that sfRon plays a significant role in ovarian cancer initiation and progression, and may represent a promising therapeutic target for ovarian cancer treatment. PMID:27551332

  6. Dietary phytochemicals and cancer prevention: Nrf2 signaling, epigenetics, and cell death mechanisms in blocking cancer initiation and progression

    PubMed Central

    Lee, Jong Hun; Khor, Tin Oo; Shu, Limin; Su, Zheng-Yuan; Fuentes, Francisco; Kong, Ah-Ng Tony

    2013-01-01

    Reactive metabolites from carcinogens and oxidative stress can drive genetic mutations, genomic instability, neoplastic transformation, and ultimately carcinogenesis. Numerous dietary phytochemicals in vegetables/fruits have been shown to possess cancer chemopreventive effects in both preclinical animal models and human epidemiological studies. These phytochemicals could prevent the initiation of carcinogenesis via either direct scavenging of reactive oxygen species/reactive nitrogen species (ROS/RNS) or, more importantly, the induction of cellular defense detoxifying/antioxidant enzymes. These defense enzymes mediated by Nrf2-antioxidative stress and anti-inflammatory signaling pathways can contribute to cellular protection against ROS/RNS and reactive metabolites of carcinogens. In addition, these compounds would kill initiated/transformed cancer cells in vitro and in in vivo xenografts via diverse anti-cancer mechanisms. These mechanisms include the activation of signaling kinases (e.g., JNK), caspases and the mitochondria damage/cytochrome c pathways. Phytochemicals may also have anti-cancer effects by inhibiting the IKK/NF-κB pathway, inhibiting STAT3, and causing cell cycle arrest. In addition, other mechanisms may include epigenetic alterations (e.g., inhibition of HDACs, miRNAs, and the modification of the CpG methylation of cancer-related genes). In this review, we will discuss: the current advances in the study of Nrf2 signaling; Nrf2-deficient tumor mouse models; the epigenetic control of Nrf2 in tumorigenesis and chemoprevention; Nrf2-mediated cancer chemoprevention by naturally occurring dietary phytochemicals; and the mutation or hyper-expression of the Nrf2–Keap1 signaling pathway in advanced tumor cells. The future development of dietary phytochemicals for chemoprevention must integrate in vitro signaling mechanisms, relevant biomarkers of human diseases, and combinations of different phytochemicals and/or non-toxic therapeutic drugs, including

  7. Simultaneous radical cystectomy and colorectal cancer resection for synchronous muscle invasive bladder cancer and cT3 colorectal cancer: Our initial experience in five patients

    PubMed Central

    Liu, Zhuo; Chen, Guiping; Zhu, Yuping; Li, Dechuan

    2014-01-01

    To review cases of simultaneous radical cystectomy and colorectal cancer (CRC) resection for synchronous carcinoma of bladder and colorectum. Between May 1997 and September 2010, five patients were diagnosed with synchronous bladder cancer and CRCs. The primary colorectal tumors included three sigmoid cancers, one ascending colon cancer and one rectal cancer. All patients underwent simultaneous radical cystectomy and CRC resection. Pathologic types were confirmed by the biopsies of cystoscopy and colonoscopy. All patients were performed synchronous radical cystectomy and CRC resection. Four of them received adjuvant chemotherapies for CRC. Two of them died of liver metastasis 32.8 months and 13 months after surgery. Although patients with synchronous carcinoma of bladder and colorectum are rare, the Urologist should be alerted to this possibility when evaluating patients for the initially presenting symptoms and/or detected tumors. The simultaneous surgery is technically feasible for the selected patients. PMID:25538788

  8. Anterior prostate biopsy at initial and repeat evaluation: is it useful to detect significant prostate cancer?

    PubMed Central

    Pepe, Pietro; Pennisi, Michele; Fraggetta, Filippo

    2015-01-01

    ABSTRACT Purpose: Detection rate for anterior prostate cancer (PCa) in men who underwent initial and repeat biopsy has been prospectively evaluated. Materials and Methods: From January 2013 to March 2014, 400 patients all of Caucasian origin (median age 63.5 years) underwent initial (285 cases) and repeat (115 cases) prostate biopsy; all the men had negative digital rectal examination and the indications to biopsy were: PSA values > 10 ng/mL, PSA between 4.1-10 or 2.6-4 ng/mL with free/total PSA≤25% and ≤20%, respectively. A median of 22 (initial biopsy) and 31 cores (repeat biopsy) were transperineally performed including 4 cores of the anterior zone (AZ) and 4 cores of the AZ plus 2 cores of the transition zone (TZ), respectively. Results: Median PSA was 7.9 ng/mL; overall, a PCa was found in 180 (45%) patients: in 135 (47.4%) and 45 (36%) of the men who underwent initial and repeat biopsy, respectively. An exclusive PCa of the anterior zone was found in the 8.9 (initial biopsy) vs 13.3% (repeat biopsy) of the men: a single microfocus of cancer was found in the 61.2% of the cases; moreover, in 7 out 18 AZ PCa the biopsy histology was predictive of significant cancer in 2 (28.5%) and 5 (71.5%) men who underwent initial and repeat biopsy, respectively. Conclusions: However AZ biopsies increased detection rate for PCa (10% of the cases), the majority of AZ PCa with histological findings predictive of clinically significant cancer were found at repeat biopsy (about 70% of the cases). PMID:26689509

  9. Anticancer Effect of Fucoidan on DU-145 Prostate Cancer Cells through Inhibition of PI3K/Akt and MAPK Pathway Expression

    PubMed Central

    Choo, Gang-Sik; Lee, Hae-Nim; Shin, Seong-Ah; Kim, Hyeong-Jin; Jung, Ji-Youn

    2016-01-01

    In this study, we showed that PI3K/Akt signaling mediates fucoidan’s anticancer effects on prostate cancer cells, including suppression of proliferation. Fucoidan significantly decreased viability of DU-145 cancer cells in a concentration-dependent manner as shown by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. The drug also significantly increased chromatin condensation, which indicates apoptosis, in a concentration-dependent manner as shown by DAPI (4′,6-diamidino-2-phenylindole) staining. Fucoidan increased expression of Bax, cleaved poly-ADP ribose polymerase and cleaved caspase-9, and decreased of the Bcl-2, p-Akt, p-PI3K, p-P38, and p-ERK in a concentration-dependent manner. In vivo, fucoidan (at 5 and 10 mg/kg) significantly decreased tumor volume, and increased apoptosis as assessed by the TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) assay, confirming the tumor inhibitory effect. The drug also increased expression of p-Akt and p-ERK as shown by immunohistochemistry staining. Therefore, fucoidan may be a promising cancer preventive medicine due to its growth inhibitory effects and induction of apoptosis in human prostate cancer cells. PMID:27399727

  10. Anticancer Effect of Fucoidan on DU-145 Prostate Cancer Cells through Inhibition of PI3K/Akt and MAPK Pathway Expression.

    PubMed

    Choo, Gang-Sik; Lee, Hae-Nim; Shin, Seong-Ah; Kim, Hyeong-Jin; Jung, Ji-Youn

    2016-01-01

    In this study, we showed that PI3K/Akt signaling mediates fucoidan's anticancer effects on prostate cancer cells, including suppression of proliferation. Fucoidan significantly decreased viability of DU-145 cancer cells in a concentration-dependent manner as shown by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. The drug also significantly increased chromatin condensation, which indicates apoptosis, in a concentration-dependent manner as shown by DAPI (4',6-diamidino-2-phenylindole) staining. Fucoidan increased expression of Bax, cleaved poly-ADP ribose polymerase and cleaved caspase-9, and decreased of the Bcl-2, p-Akt, p-PI3K, p-P38, and p-ERK in a concentration-dependent manner. In vivo, fucoidan (at 5 and 10 mg/kg) significantly decreased tumor volume, and increased apoptosis as assessed by the TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) assay, confirming the tumor inhibitory effect. The drug also increased expression of p-Akt and p-ERK as shown by immunohistochemistry staining. Therefore, fucoidan may be a promising cancer preventive medicine due to its growth inhibitory effects and induction of apoptosis in human prostate cancer cells. PMID:27399727

  11. YAP forms autocrine loops with the ERBB pathway to regulate ovarian cancer initiation and progression

    PubMed Central

    He, Chunbo; Lv, Xiangmin; Hua, Guohua; Lele, Subodh M; Remmenga, Steven; Dong, Jixin; Davis, John S; Wang, Cheng

    2014-01-01

    Mechanisms underlying ovarian cancer initiation and progression are unclear. Herein, we report that the Yes-associated protein (YAP), a major effector of the Hippo tumor suppressor pathway, interacts with ERBB signaling pathways to regulate the initiation and progression of ovarian cancer. Immunohistochemistry studies indicate that YAP expression is associated with poor clinical outcomes in patients. Overexpression or constitutive activation of YAP leads to transformation and tumorigenesis in human ovarian surface epithelial cells, and promotes growth of cancer cells in vivo and in vitro. YAP induces expression of EGF receptors (EGFR, ERBB3) and production of EGF-like ligands (HBEGF, NRG1 and NRG2). HBEGF or NRG1, in turn, activates YAP and stimulates cancer cell growth. Knockdown of ERBB3 or HBEGF eliminates YAP effects on cell growth and transformation, while knockdown of YAP abrogates NRG1- and HBEGF-stimulated cell proliferation. Collectively, our study demonstrates the existence of HBEGF&NRGs/ERBBs/YAP/HBEGF&NRGs autocrine loop that controls ovarian cell tumorigenesis and cancer progression. PMID:25798835

  12. The Role of nAChR and Calcium Signaling in Pancreatic Cancer Initiation and Progression

    PubMed Central

    Schaal, Courtney; Padmanabhan, Jaya; Chellappan, Srikumar

    2015-01-01

    Pancreatic cancer shows a strong correlation with smoking and the current therapeutic strategies have been relatively ineffective in improving the survival of patients. Efforts have been made over the past many years to understand the molecular events that drive the initiation and progression of pancreatic cancer, especially in the context of smoking. It has become clear that components of tobacco smoke not only initiate these cancers, especially pancreatic ductal adenocarcinomas (PDACs) through their mutagenic properties, but can also promote the growth and metastasis of these tumors by stimulating cell proliferation, angiogenesis, invasion and epithelial-mesenchymal transition. Studies in cell culture systems, animal models and human samples have shown that nicotinic acetylcholine receptor (nAChR) activation enhances these tumor-promoting events by channeling signaling through multiple pathways. In this context, signaling through calcium channels appear to facilitate pancreatic cancer growth by itself or downstream of nAChRs. This review article highlights the role of nAChR downstream signaling events and calcium signaling in the growth, metastasis as well as drug resistance of pancreatic cancer. PMID:26264026

  13. The Interplay of Reactive Oxygen Species, Hypoxia, Inflammation, and Sirtuins in Cancer Initiation and Progression

    PubMed Central

    Sansone, Luigi; Limana, Federica; Arcangeli, Tania; De Santis, Elena; Polese, Milena; Fini, Massimo; Russo, Matteo A.

    2016-01-01

    The presence of ROS is a constant feature in living cells metabolizing O2. ROS concentration and compartmentation determine their physiological or pathological effects. ROS overproduction is a feature of cancer cells and plays several roles during the natural history of malignant tumor. ROS continuously contribute to each step of cancerogenesis, from the initiation to the malignant progression, acting directly or indirectly. In this review, we will (a) underline the role of ROS in the pathway leading a normal cell to tumor transformation and progression, (b) define the multiple roles of ROS during the natural history of a tumor, (c) conciliate many conflicting data about harmful or beneficial effects of ROS, (d) rethink the importance of oncogene and tumor suppressor gene mutations in relation to the malignant progression, and (e) collocate all the cancer hallmarks in a mechanistic sequence which could represent a “physiological” response to the initial growth of a transformed stem/pluripotent cell, defining also the role of ROS in each hallmark. We will provide a simplified sketch about the relationships between ROS and cancer. The attention will be focused on the contribution of ROS to the signaling of HIF, NFκB, and Sirtuins as a leitmotif of cancer initiation and progression. PMID:26798421

  14. Initial analyses of colon cancer-specific antigen (CCSA)-3 and CCSA-4 as colorectal cancer-associated serum markers.

    PubMed

    Leman, Eddy S; Schoen, Robert E; Weissfeld, Joel L; Cannon, Grant W; Sokoll, Lori J; Chan, Daniel W; Getzenberg, Robert H

    2007-06-15

    Colon cancer-specific antigen (CCSA)-3 and CCSA-4 are novel colon cancer markers identified by focused proteomic analysis of nuclear structural proteins. The goal of these studies was to evaluate serum-based CCSA-3 and CCSA-4 in the detection of individuals with preneoplastic and neoplastic lesions using ELISAs. Serum samples from 107 subjects undergoing colonoscopy, 28 subjects with colorectal cancer, and 125 subjects with benign disease or other types of cancer were evaluated. Individuals who underwent colonoscopy were classified into mutually exclusive categories, including normal colon, hyperplastic polyp, nonadvanced adenoma, and advanced adenoma. Sensitivity and specificity for both CCSA-3 and CCSA-4 were evaluated using receiver operating characteristic (ROC) curves. At a cutoff of 2 microg/mL for CCSA-3 and 0.3 microg/mL for CCSA-4, each marker detected all 28 colorectal cancers, for a sensitivity of 100% (lower 95% confidence bound, 89.8%). The sensitivity for detection of the combined end point of colorectal cancer and advanced adenoma for CCSA-3 was 89.1% [95% confidence interval (95% CI), 76.4-96.4%] and for CCSA-4 was 84.8% (95% CI, 71.1-93.7%) and 91.3% (95% CI, 79.2-97.6%) for either marker positive. The specificity in individuals with normal, hyperplastic polyps, or nonadvanced adenomas was 82.0% (95% CI, 72.4-89.4%) and 91.0% (95% CI, 83.0-96.0%) for CCSA-3 and CCSA-4, respectively. ROC curves for CCSA-3 and CCSA-4 reveal an area under the curve of 0.94 (95% CI, 0.90-0.98%). In these initial analyses, CCSA-3 and CCSA-4 show promise as potential serum markers for detection of colorectal cancer and advanced adenomas. PMID:17575123

  15. Endocrine therapy initiation among Medicaid-insured breast cancer survivors with hormone receptor-positive tumors

    PubMed Central

    Wheeler, Stephanie Brooke; Kohler, Racquel Elizabeth; Reeder-Hayes, Katherine Elizabeth; Goyal, Ravi K.; Lich, Kristen Hassmiller; Moore, Alexis; Smith, Timothy W.; Melvin, Cathy L.; Muss, Hyman Bernard

    2016-01-01

    Purpose Hormone receptor positive (HR+) cancers account for most breast cancer diagnoses and deaths. Among survivors with HR+ breast cancers, endocrine therapy (ET) reduces 5-year risk of recurrence by up to 40%. Observational studies in Medicare and privately-insured survivors suggest under-utilization of ET. We sought to characterize ET use in a low-income Medicaid-insured population in North Carolina. Methods Medicaid claims data were matched to state cancer registry records for survivors ages 18–64 diagnosed with stage 0-II HR+ breast cancer from 2003–2007, eligible for ET, and enrolled in Medicaid for at least 12 of 15 months post-diagnosis. We used multivariable logistic regression to model receipt of any ET medication during 15-months post-diagnosis controlling for age, race, tumor characteristics, receipt of other treatments, co-morbidity, residence, reason for Medicaid eligibility, involvement in the Breast and Cervical Cancer Control Program (BCCCP), and diagnosis year. Results Of 222 women meeting inclusion criteria, only 50% filled a prescription for ET. Involvement in BCCCP and earlier year of diagnoses were associated with significantly higher odds of initiating guideline-recommended ET (Adjusted Odds Ratio [AOR] for BCCCP: 3.76, 95%CI: 1.67–8.48; AOR for 2004 relative to 2007: 2.80, 95%CI: 1.03–7.62; AOR for 2005 relative to 2007: 2.11, 95%CI: 0.92–4.85). Conclusions Results suggest substantial under-utilization of ET in this population. Interventions are needed to improve timely receipt of ET and to better support survivors taking ET. Implications of cancer survivors Low-income survivors should be counseled on the importance of ET and offered support services to promote initiation and long-term adherence. PMID:24866922

  16. Effects of Androgen and Estrogen Receptor Signaling Pathways on Bladder Cancer Initiation and Progression

    PubMed Central

    Godoy, Guilherme; Gakis, Georgios; Smith, Carolyn L.; Fahmy, Omar

    2016-01-01

    Epidemiologic studies have long demonstrated clear differences in incidence and progression of bladder cancer between genders suggesting that the mechanisms of development and progression in these tumors have a strong association with steroid hormonal pathways. Such observations led to preclinical studies investigating the role of androgen and estrogen receptors, as well as their cognate hormones in bladder cancer initiation and progression. Using various in vitro cell line assays and in vivo mouse models, studies have elucidated different mechanisms and signaling pathways through which these steroid receptors may participate in this disease. More recently, RNA expression data from multiple studies revealed a luminal subtype of bladder cancer that exhibited an estrogen receptor signaling pathway, making it a strong candidate for further consideration of targeted therapies in the future. Despite the promising preclinical data demonstrating potential roles for both antiandrogen and antiestrogen strategies targeting these pathways in different stages of bladder cancer, only two clinical trials are currently active and accruing patients for such clinical studies. Targeted therapies in bladder cancer are a large unmet need and have the potential to change treatment paradigms and improve oncological outcomes of patients with bladder cancer. PMID:27376135

  17. Controlling female cancer in Argentina. Divergent initiatives and the road to fragmentation

    PubMed Central

    Eraso, Yolanda

    2014-01-01

    This article analyses the organisation of cancer control in Argentina, with a special focus on the initiatives, institutions, and models that targeted female or gynaecological cancers. It identifies and examines the main factors in the process of elaborating a national policy to control the disease drawing on a series of actors and instruments such as the state, medical professionals, institutions and services, and the use of technology (notably diagnostic tools) for the detection of the disease. It traces the developments in the organisation highlighting its transformations from a centralising to a decentralised model of service provision. Using the concept of «path-dependence» the article examines the continuities and changes observed in the organisation of female cancer critically signalling the particular time at which a path was taken where «fragmentation» became consolidated within the health system. It also argues that it was within the field of cancer diagnosis that Argentinian doctors first sought to create the foundational structures of cancer organisation. The article contends that the path-dependence analytical approach helps us acknowledge the importance of historical analysis in the identification of factors that led to the lack of service coordination, including the persistent strain between national/provincial states that hampered the development of comprehensive programmes, aspects that have continued to mark efforts in the elaboration of cancer policies to the present day. PMID:24944432

  18. Urinary Cadmium and Risk of Invasive Breast Cancer in the Women's Health Initiative.

    PubMed

    Adams, Scott V; Shafer, Martin M; Bonner, Matthew R; LaCroix, Andrea Z; Manson, JoAnn E; Meliker, Jaymie R; Neuhouser, Marian L; Newcomb, Polly A

    2016-05-01

    Cadmium is a widespread heavy metal pollutant that may act as an exogenous estrogenic hormone. Environmental cadmium exposure has been associated with risk of breast cancer in retrospective studies. We prospectively assessed the relationship between cadmium exposure, evaluated by creatinine-normalized urinary cadmium concentration, and invasive breast cancer among 12,701 postmenopausal women aged ≥50 years in a Women's Health Initiative study of bone mineral density. After a median of 13.2 years of follow-up (1993-2010), 508 cases of invasive breast cancer and 1,050 comparison women were identified for a case-cohort analysis. Multivariable Cox regression was used to calculate hazard ratios and 95% confidence intervals. Risk of breast cancer was not associated with urinary cadmium parameterized either in quartiles (comparing highest quartile with lowest, hazard ratio = 0.80, 95% confidence interval: 0.56, 1.14; P for trend = 0.20) or as a log-transformed continuous variable (per 2-fold higher urinary cadmium concentration, hazard ratio = 0.94, 95% confidence interval: 0.86, 1.03). We did not observe an association between urinary cadmium and breast cancer risk in any subgroup examined, including never smokers and women with body mass index (weight (kg)/height (m)(2)) less than 25. Results were consistent in both estrogen receptor-positive and estrogen receptor-negative tumors. Our results do not support the hypothesis that environmental cadmium exposure is associated with risk of postmenopausal breast cancer. PMID:27037269

  19. Treatment of PC-3 and DU145 prostate cancer cells by prenylflavonoids from hop (Humulus lupulus L.) induces a caspase-independent form of cell death.

    PubMed

    Delmulle, L; Vanden Berghe, T; Keukeleire, D De; Vandenabeele, P

    2008-02-01

    Xanthohumol (X), isoxanthohumol (IX), 8-prenylnaringenin (8PN) and 6-prenylnaringenin (6PN), prenylflavonoids from hop (Humulus lupulus L.), were investigated for their cytotoxicity and the mechanism by which they exert cell death when incubated with prostate cancer cell lines PC-3 and DU145. All compounds induced cell death in the absence of caspase-3 activation and typical apoptotic morphological features. The general pan-caspase inhibitor zVAD-fmk could not protect this form of cell death. In addition, the formation of vacuoles was observed in PC-3 cells treated with IX and 6PN, and in DU145 treated with IX, 8PN and 6PN, which could suggest the induction of autophagy and consequent cell death. The results indicate that hop-derived prenylflavanones (IX, 8PN, 6PN), but not prenylchalcones (X) induce a caspase-independent form of cell death, suggested to be autophagy. Therefore, IX, 8PN and 6PN appear to be promising candidates for further investigation in prostate anticancer therapy. PMID:17726738

  20. Florida Initiative for Quality Cancer Care: Improvements in Breast Cancer Quality Indicators During a 3-Year Interval

    PubMed Central

    Laronga, Christine; Gray, Jhanelle E; Siegel, Erin M; Lee, Ji-Hyun; Fulp, William J; Fletcher, Michelle; Schreiber, Fred; Brown, Richard; Levine, Richard; Cartwright, Thomas; Abesada-Terk, Guillermo; Kim, George; Alemany, Carlos; Faig, Douglas; Sharp, Phillip; Markham, Merry-Jennifer; Shibata, David; Malafa, Mokenge; Jacobsen, Paul B

    2015-01-01

    BACKGROUND The Florida Initiative for Quality Cancer Care (FIQCC), composed of 11 practice sites across Florida, conducted its initial evaluation of adherence to breast cancer quality of care indicators (QCI) in 2006, with feedback provided to encourage quality improvement efforts at participating sites. In this study, our objective was to reassess changes over time resulting from these efforts. STUDY DESIGN Quality care indicators were derived from the Quality Oncology Practice Initiative, the National Comprehensive Cancer Network, the American College of Surgeons, and expert panel consensus. Medical records were reviewed for breast cancer patients first seen by medical oncologists in 2009 at the FIQCC sites, using the same performance indicators as in 2006. Statistical comparisons of 2006 vs 2009 data across sites were made by Pearson chi-square exact test using Monte Carlo estimation. RESULTS Charts of 602 patients in 2006 and 636 patients in 2009 were compared. Performance on medical oncology QCI improved over time for documentation of clinical trial participation discussion (p = 0.001), documentation of consent for chemotherapy (p = 0.047), definitive surgery done after neoadjuvant chemotherapy (p = 0.017), and planned dose of chemotherapy consistent with published regimens (p = 0.02). Improvements in surgical QCI were seen for documentation of specimen orientation (p < 0.001), inking of margins (p < 0.0001), and performance of sentinel lymph node biopsy (p = 0.035). CONCLUSIONS The 2006 FIQCC study identified several medical and surgical oncology QCI improvement needs. Quality improvement efforts resulted in better performance for numerous metrics, therefore speaking to the benefits of reassessment of adherence to performance indicators to guide QCI efforts. PMID:25086813

  1. IDENTIFYING AND TARGETING TUMOR-INITIATING CELLS IN THE TREATMENT OF BREAST CANCER

    PubMed Central

    Wei, Wei; Lewis, Michael T.

    2015-01-01

    Breast cancer is the most common cancer in women (exclusive of skin cancer), and is the second leading cause of cancer-related deaths. Although conventional and targeted therapies have improved survival rates, there are still considerable challenges in treating breast cancer, including treatment resistance, disease recurrence, and metastasis. Treatment resistance can be either de novo - due to traits that tumor cells possess prior to treatment, or acquired, - due to traits that tumor cells gain in response to treatment. A recently proposed mechanism of de novo resistance invokes existence of a specialized subset of cancer cells defined as tumor-initiating cells (TICs), or cancer stem cells (CSC). TICs have the capacity to self-renew and regenerate new tumors that consist of all clonally-derived cell types present in the parental tumor. There are data to suggest that TICs are resistant to many conventional cancer therapies, and survive treatment in spite of dramatic shrinkage of the tumor. Residual TICs can then eventually regrow resulting in disease relapse. It is also hypothesized that TIC may be responsible for metastatic disease. If these hypotheses are correct, targeting TICs may be imperative to achieve cure. In this review, we discuss evidence for breast TICs and their apparent resistance to conventional chemotherapy and radiotherapy, as well as to various targeted therapies. We also address the potential impact of breast TIC plasticity and metastatic potential on therapeutic strategies. Finally, we describe several genes and signaling pathways that appear important for TIC function that may represent promising therapeutic targets. PMID:25876646

  2. Lysyl oxidase propeptide stimulates osteoblast and osteoclast differentiation and enhances PC3 and DU145 prostate cancer cell effects on bone in vivo.

    PubMed

    Alsulaiman, Mona; Bais, Manish V; Trackman, Philip C

    2016-03-01

    Lysyl oxidase pro-enzyme is secreted by tumor cells and normal cells as a 50 kDa pro-enzyme into the extracellular environment where it is cleaved into the ~30 kDa mature enzyme (LOX) and 18 kDa pro-peptide (LOX-PP). Extracellular LOX enzyme activity is required for normal collagen and elastin extracellular cross-linking and maturation of the extracellular matrix. Extracellular LOX-PP acts as a tumor suppressor and can re-enter cells from the extracellular environment to induce its effects. The underlying hypothesis is that LOX-PP has the potential to promote bone cell differentiation, while inhibiting cancer cell effects in bone. Here we investigate the effect of LOX-PP on bone marrow cell proliferation and differentiation towards osteoblasts or osteoclasts, and LOX-PP modulation of prostate cancer cell conditioned media-induced alterations of proliferation and differentiation of bone marrow cells in vitro. Effects of overexpression of rLOX-PP in DU145 and PC3 prostate cancer cell lines on bone structure in vivo after intramedullary injections were determined. Data show that prostate cancer cell conditioned media inhibited osteoblast differentiation in bone marrow-derived cells, which was reversed by rLOX-PP treatment. Prostate cancer conditioned media stimulated osteoclast differentiation which was further enhanced by rLOX-PP treatment. rLOX-PP stimulated osteoclast differentiation by inhibiting OPG expression, up-regulating CCN2 expression, and increasing osteoclast fusion. In vivo studies indicate that rLOX-PP expression by PC3 cells implanted into the tibia of mice further enhanced PC3 cell ability to resorb bone, while rLOX-PP expression in DU145 cells resulted in non-significant increases in net bone formation. rLOX-PP enhances both osteoclast and osteoblast differentiation. rLOX-PP may serve to enhance coupling interactions between osteoclasts and osteoblasts helping to maintain a normal bone turnover in health, while contributing to bone abnormalities

  3. Exercise in Regulation of Inflammation-Immune Axis Function in Cancer Initiation and Progression

    PubMed Central

    Koelwyn, Graeme J.; Wennerberg, Erik; Demaria, Sandra; Jones, Lee W.

    2016-01-01

    Pharmacologic manipulation of the immune system is emerging as a viable and robust treatment for some cancer patients. Exercise-induced modulation of the immune system may be another adjunctive strategy for inhibiting tumor initiation and progression. In healthy individuals, exercise has been shown to modulate a number of cell subsets involved in innate and adaptive immunity. Here, we provide an overview of the current state of knowledge pertaining to exercise modulation of the inflammation-immune axis in cancer. The current evidence suggests that exercise may be a promising adjunctive strategy that can favorably alter numerous components of the immune system, which, in turn, may modulate tumorigenesis. However, many important knowledge gaps are evident. To this end, we propose a framework to guide future research efforts investigating the immune effects of exercise in cancer. PMID:26676894

  4. METHADONE INITIATION AND ROTATION IN THE OUTPATIENT SETTING FOR PATIENTS WITH CANCER PAIN

    PubMed Central

    Parsons, Henrique A.; de la Cruz, Maxine; El Osta, Badi; Li, Zhijun; Calderon, Bianca; Palmer, J. Lynn

    2009-01-01

    Background Methadone is an effective and inexpensive opioid for cancer pain treatment. It has been reported as difficult to use in the outpatient setting due to its variable relative potency and long half-life. The purpose of this study was to determine the outcome of methadone initiation or rotation for cancer pain treatment in outpatient settings. Methods Chart review of 189 consecutive patients who underwent methadone initiation or rotation in our palliative care outpatient center. Data were collected regarding demographic and clinical characteristics, symptoms, and opioid side effects at baseline and for 2 follow up visits(F1,F2). Failure was defined as methadone discontinuation by the palliative care physician or patient's hospitalization for uncontrolled pain or methadone-related side effects at F1. Results 100(53%) initiations and 89(47%) rotations were conducted. Success rates for methadone initiation and rotation were 82/89(92%) and 85/100(84%) respectively. Mean(standard deviation) age was 60(11) years. 100(53%) patients were female, 138(73%) white, 182(96%) had solid cancers. The main reason for rotation was pain (65/89 patients, 47%). Median(interquartile range, IR) pain scores (Edmonton Symptom Assessment System/0–10) were 6(5–8), 4(3–6), and 3(2–5) at baseline, F1, and F2, respectively(p<0.0001). Median(IR) daily methadone dose for initiation and rotation was 10(5–15)mg and 15(10–30)mg at F1(p<0.0001) and 10(8–15)mg and 18(10–30)mg at F2(p<0.0001), respectively. Constipation and nausea improved (p<0.005) after initiation/rotation to methadone. Frequency of sedation, hallucinations, myoclonus, and delirium did not increase after initiation/rotation to methadone. Conclusions Outpatient methadone initiation and rotation for cancer pain treatment were safe, with high success rate and low side effect profile. PMID:19924788

  5. Targeting pancreatitis blocks tumor-initiating stem cells and pancreatic cancer progression.

    PubMed

    Mohammed, Altaf; Janakiram, Naveena B; Madka, Venkateshwar; Brewer, Misty; Ritchie, Rebekah L; Lightfoot, Stan; Kumar, Gaurav; Sadeghi, Michael; Patlolla, Jagan Mohan R; Yamada, Hiroshi Y; Cruz-Monserrate, Zobeida; May, Randal; Houchen, Courtney W; Steele, Vernon E; Rao, Chinthalapally V

    2015-06-20

    Recent development of genetically engineered mouse models (GEMs) for pancreatic cancer (PC) that recapitulates human disease progression has helped to identify new strategies to delay/inhibit PC development. We first found that expression of the pancreatic tumor-initiating/cancer stem cells (CSC) marker DclK1 occurs in early stage PC and in both early and late pancreatic intraepithelial neoplasia (PanIN) and that it increases as disease progresses in GEM and also in human PC. Genome-wide next generation sequencing of pancreatic ductal adenocarcinoma (PDAC) from GEM mice revealed significantly increased DclK1 along with inflammatory genes. Genetic ablation of cyclo-oxygenase-2 (COX-2) decreased DclK1 in GEM. Induction of inflammation/pancreatitis with cerulein in GEM mice increased DclK1, and the novel dual COX/5-lipoxygenase (5-LOX) inhibitor licofelone reduced it. Dietary licofelone significantly inhibited the incidence of PDAC and carcinoma in situ with significant inhibition of pancreatic CSCs. Licofelone suppressed pancreatic tumor COX-2 and 5-LOX activities and modulated miRNAs characteristic of CSC and inflammation in correlation with PDAC inhibition. These results offer a preclinical proof of concept to target the inflammation initiation to inhibit cancer stem cells early for improving the treatment of pancreatic cancers, with immediate clinical implications for repositioning dual COX/5-LOX inhibitors in human trials for high risk patients. PMID:25906749

  6. Radiation promotes colorectal cancer initiation and progression by inducing senescence-associated inflammatory responses.

    PubMed

    Kim, S B; Bozeman, R G; Kaisani, A; Kim, W; Zhang, L; Richardson, J A; Wright, W E; Shay, J W

    2016-06-30

    Proton radiotherapy is becoming more common as protons induce more precise DNA damage at the tumor site with reduced side effects to adjacent normal tissues. However, the long-term biological effects of proton irradiation in cancer initiation compared with conventional photon irradiation are poorly characterized. In this study, using a human familial adenomatous polyposis syndrome susceptible mouse model, we show that whole-body irradiation with protons are more effective in inducing senescence-associated inflammatory responses (SIRs), which are involved in colon cancer initiation and progression. After proton irradiation, a subset of SIR genes (Troy, Sox17, Opg, Faim2, Lpo, Tlr2 and Ptges) and a gene known to be involved in invasiveness (Plat), along with the senescence-associated gene (P19Arf), are markedly increased. Following these changes, loss of Casein kinase Iα and induction of chronic DNA damage and TP53 mutations are increased compared with X-ray irradiation. Proton irradiation also increases the number of colonic polyps, carcinomas and invasive adenocarcinomas. Pretreatment with the non-steroidal anti-inflammatory drug, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid-ethyl amide (CDDO-EA), reduces proton irradiation-associated SIR and tumorigenesis. Thus exposure to proton irradiation elicits significant changes in colorectal cancer initiation and progression that can be mitigated using CDDO-EA. PMID:26477319

  7. Radiation Promotes Colorectal Cancer Initiation and Progression by Inducing Senescence-Associated Inflammatory Responses

    PubMed Central

    Kim, Sang Bum; Bozeman, Ronald; Kaisani, Aadil; Kim, Wanil; Zhang, Lu; Richardson, James A.; Wright, Woodring E.; Shay, Jerry W.

    2015-01-01

    Proton radiotherapy is becoming more common since protons induce more precise DNA damage at the tumor site with reduced side effects to adjacent normal tissues. However, the long-term biological effects of proton irradiation in cancer initiation compared to conventional photon irradiation are poorly characterized. In this study, using a human familial adenomatous polyposis syndrome susceptible mouse model, we show that whole body irradiation with protons are more effective in inducing senescence-associated inflammatory responses (SIR) which are involved in colon cancer initiation and progression. After proton irradiation, a subset of SIR genes (Troy, Sox17, Opg, Faim2, Lpo, Tlr2 and Ptges) and a gene known to be involved in invasiveness (Plat), along with the senescence associated gene (P19Arf) are markedly increased. Following these changes loss of Casein kinase Iα (CKIα) and induction of chronic DNA damage and TP53 mutations are increased compared to x-ray irradiation. Proton irradiation also increases the number of colonic polyps, carcinomas and invasive adenocarcinomas. Pretreatment with the non-steroidal anti-inflammatory drug, CDDO-EA, reduces proton irradiation associated SIR and tumorigenesis. Thus, exposure to proton irradiation elicits significant changes in colorectal cancer initiation and progression that can be mitigated using CDDO-EA. PMID:26477319

  8. Paraneoplastic syndrome and underlying breast cancer: a worsening rash despite initiation of chemotherapy.

    PubMed

    Ahuja, Shradha; Makkar, Priyanka; Gupta, Sorab; Vigoda, Ivette

    2016-05-01

    Skin may show the first clinical evidence of systemic disease and can be the first clue to malignancy in 1% of cases. Dermatomyositis is an immunologically mediated inflammatory myopathy characterized by proximal muscle weakness, muscle inflammation, and characteristic skin findings. It has an incidence of 1 in 100,000 patients. In 15%-30% cases of dermatomyositis, an underlying malignancy is the cause of paraneoplastic syndrome. Ovarian and breast cancer in women and lung cancer in men are the most common malignancies associated with dermatomyositis. Here we report the case of a 55-year-old postmenopausal woman who initially presented with a facial rash. She was treated for chemical dermatitis without resolution of symptoms and was subsequently found to have dermatomyositis associated with stage IV invasive ductal carcinoma of the breast. In most cases, the skin changes resolve after treatment for the underlying malignancy has been initiated, but in this case of paraneoplastic dermatomyositis, the rash worsened with initiation of treatment for underlying breast cancer. PMID:27258056

  9. [A Case of Double Cancer of Initially Unresectable Sigmoid Colon Cancer and Advanced Gastric Cancer Treated with Curative Resection after mFOLFOX6 Therapy].

    PubMed

    Yoshikawa, Toru; Aoki, Kazunori; Mitsuhashi, Yuto; Tomiura, Satoko; Suto, Akiko; Miura, Takuya; Ikenaga, Shojirokazunori; Shibasaki, Itaru; Endo, Masaaki

    2016-03-01

    A 61-year-old man was admitted to our hospital because of a complaint of blood in stool. He was diagnosed with advanced colon and gastric cancers. Computed tomography (CT) revealed a sigmoid tumor with invasion to the bladder, a metastatic tumor in the lateral segmental branch of the left hepatic lobe, and ascites. He was diagnosed with initially unresectable double cancer. Ileostomy was performed immediately, and he was treated with modified (m) FOLFOX6 regimen (oxaliplatin in combination with infusional 5-fluorouracil/Leucovorin). After 6 courses of the mFOLFOX6 regimen, CT revealed that the primary lesion of the sigmoid colon and liver metastasis had reduced in size, and the ascites had disappeared. Gastroscopy revealed that the gastric cancer had disappeared. Biopsy results were negative. Accordingly, his gastric cancer was diagnosed as treatment effect Grade 3. After 8 courses of mFOLFOX6 therapy, sigmoidectomy, partial resection of the bladder, and partial resection of the liver were performed. Gastric cancer was not resected in accordance with his will. Although 40 months has passed after the radical resection, neither the sigmoid colon cancer nor the gastric cancer recurred. PMID:27067857

  10. Analyse des facteurs histo-pronostiques du cancer du rectum non métastatique dans une série ouest Algérienne de 58 cas au CHU-Tlemcen

    PubMed Central

    Mesli, Smain Nabil; Regagba, Derbali; Tidjane, Anisse; Benkalfat, Mokhtar; Abi-Ayad, Chakib

    2016-01-01

    Introduction L'objectif de notre travail est d'analyser les facteurs histo-pronostiques des cancers du rectum non métastatique opérés au service de chirurgie «A» de Tlemcen à ouest Algérien durant une période de six ans. Méthodes Etude rétrospective de 58 patients qui avait un adénocarcinome rectal. Le critère de jugement était la survie. Les paramètres étudiés, le sexe, l’âge, stade tumoral, et les récidives tumorales. Résultats L’âge moyen était de 58 ans. Avec 52% d'hommes contre 48% femmes avec sex-ratio (1,08). Le siège tumoral était: moyen rectum avec 41,37%, 34,48% au bas rectum et dans 24,13% au haut rectum. La classification TNM avec 17,65% au stade I, 18,61% au stade II, 53, 44% au stade III et 7,84% au stade IV. La survie médiane globale était de 40 mois ±2,937 mois. La survie en fonction du stade tumoral, le stade III et IV avait un faible taux de survie (19%) a 3 ans contre le stade I, II avait un taux de survie de (75%) (P = 0,000) (IC 95%). Les patients avec récidives tumorales avaient un taux de survie faible à 3 ans par rapport à ceux n'ayant pas eu de récidive (30,85% Vs 64,30% P = 0,043). Conclusion Dans cette série, l’étude uni varié des différents facteurs pronostiques conditionnant la survie n'a permis de retenir que trois facteurs influençant la survie, à savoir la taille tumorale, le stade, et les récidives tumorales. En analyse multi variée en utilisant le modèle Cox un seul facteur été retenu la récidive tumorale.

  11. Diagnosis and treatment of recurrent laryngeal cancer following initial nonsurgical therapy.

    PubMed

    Agra, Ivan Marcelo Gonçalves; Ferlito, Alfio; Takes, Robert P; Silver, Carl E; Olsen, Kerry D; Stoeckli, Sandro J; Strojan, Primož; Rodrigo, Juan P; Gonçalves Filho, João; Genden, Eric M; Haigentz, Missak; Khafif, Avi; Weber, Randal S; Zbären, Peter; Suárez, Carlos; Hartl, Dana M; Rinaldo, Alessandra; Kim, Kwang Hyun; Kowalski, Luiz P

    2012-05-01

    Surgery is the preferred modality for curative treatment of recurrent laryngeal cancer after failure of nonsurgical treatments. Patients with initial early-stage cancer experiencing recurrence following radiotherapy often have more advanced-stage tumors by the time the recurrence is recognized. About one third of such recurrent cancers are suitable for conservation surgery. Endoscopic resection with the CO(2) laser or open partial laryngectomy (partial vertical, supracricoid, or supraglottic laryngectomies) have been used. The outcomes of conservation surgery appear better than those after total laryngectomy, because of selection bias. Transoral laser surgery is currently used more frequently than open partial laryngectomy for treatment of early-stage recurrence, with outcomes equivalent to open surgery but with less associated morbidity. Laser surgery has also been employed for selective cases of advanced recurrent disease, but patient selection and expertise are required for application of this modality to rT3 tumors. In general, conservation laryngeal surgery is a safe and effective treatment for localized recurrences after radiotherapy for early-stage glottic cancer. Recurrent advanced-stage cancers should generally be treated by total laryngectomy. PMID:21484925

  12. Clinical trial designs for rare diseases: Studies developed and discussed by the International Rare Cancers Initiative

    PubMed Central

    Bogaerts, Jan; Sydes, Matthew R.; Keat, Nicola; McConnell, Andrea; Benson, Al; Ho, Alan; Roth, Arnaud; Fortpied, Catherine; Eng, Cathy; Peckitt, Clare; Coens, Corneel; Pettaway, Curtis; Arnold, Dirk; Hall, Emma; Marshall, Ernie; Sclafani, Francesco; Hatcher, Helen; Earl, Helena; Ray-Coquard, Isabelle; Paul, James; Blay, Jean-Yves; Whelan, Jeremy; Panageas, Kathy; Wheatley, Keith; Harrington, Kevin; Licitra, Lisa; Billingham, Lucinda; Hensley, Martee; McCabe, Martin; Patel, Poulam M.; Carvajal, Richard; Wilson, Richard; Glynne-Jones, Rob; McWilliams, Rob; Leyvraz, Serge; Rao, Sheela; Nicholson, Steve; Filiaci, Virginia; Negrouk, Anastassia; Lacombe, Denis; Dupont, Elisabeth; Pauporté, Iris; Welch, John J.; Law, Kate; Trimble, Ted; Seymour, Matthew

    2015-01-01

    Background The past three decades have seen rapid improvements in the diagnosis and treatment of most cancers and the most important contributor has been research. Progress in rare cancers has been slower, not least because of the challenges of undertaking research. Settings The International Rare Cancers Initiative (IRCI) is a partnership which aims to stimulate and facilitate the development of international clinical trials for patients with rare cancers. It is focused on interventional – usually randomised – clinical trials with the clear goal of improving outcomes for patients. The key challenges are organisational and methodological. A multi-disciplinary workshop to review the methods used in ICRI portfolio trials was held in Amsterdam in September 2013. Other as-yet unrealised methods were also discussed. Results The IRCI trials are each presented to exemplify possible approaches to designing credible trials in rare cancers. Researchers may consider these for use in future trials and understand the choices made for each design. Interpretation Trials can be designed using a wide array of possibilities. There is no ‘one size fits all’ solution. In order to make progress in the rare diseases, decisions to change practice will have to be based on less direct evidence from clinical trials than in more common diseases. PMID:25542058

  13. Neutrophils support lung colonization of metastasis-initiating breast cancer cells.

    PubMed

    Wculek, Stefanie K; Malanchi, Ilaria

    2015-12-17

    Despite progress in the development of drugs that efficiently target cancer cells, treatments for metastatic tumours are often ineffective. The now well-established dependency of cancer cells on their microenvironment suggests that targeting the non-cancer-cell component of the tumour might form a basis for the development of novel therapeutic approaches. However, the as-yet poorly characterized contribution of host responses during tumour growth and metastatic progression represents a limitation to exploiting this approach. Here we identify neutrophils as the main component and driver of metastatic establishment within the (pre-)metastatic lung microenvironment in mouse breast cancer models. Neutrophils have a fundamental role in inflammatory responses and their contribution to tumorigenesis is still controversial. Using various strategies to block neutrophil recruitment to the pre-metastatic site, we demonstrate that neutrophils specifically support metastatic initiation. Importantly, we find that neutrophil-derived leukotrienes aid the colonization of distant tissues by selectively expanding the sub-pool of cancer cells that retain high tumorigenic potential. Genetic or pharmacological inhibition of the leukotriene-generating enzyme arachidonate 5-lipoxygenase (Alox5) abrogates neutrophil pro-metastatic activity and consequently reduces metastasis. Our results reveal the efficacy of using targeted therapy against a specific tumour microenvironment component and indicate that neutrophil Alox5 inhibition may limit metastatic progression. PMID:26649828

  14. Development of cancer-initiating cells and immortalized cells with genomic instability.

    PubMed

    Yoshioka, Ken-Ichi; Atsumi, Yuko; Nakagama, Hitoshi; Teraoka, Hirobumi

    2015-03-26

    Cancers that develop after middle age usually exhibit genomic instability and multiple mutations. This is in direct contrast to pediatric tumors that usually develop as a result of specific chromosomal translocations and epigenetic aberrations. The development of genomic instability is associated with mutations that contribute to cellular immortalization and transformation. Cancer occurs when cancer-initiating cells (CICs), also called cancer stem cells, develop as a result of these mutations. In this paper, we explore how CICs develop as a result of genomic instability, including looking at which cancer suppression mechanisms are abrogated. A recent in vitro study revealed the existence of a CIC induction pathway in differentiating stem cells. Under aberrant differentiation conditions, cells become senescent and develop genomic instabilities that lead to the development of CICs. The resulting CICs contain a mutation in the alternative reading frame of CDKN2A (ARF)/p53 module, i.e., in either ARF or p53. We summarize recently established knowledge of CIC development and cellular immortality, explore the role of the ARF/p53 module in protecting cells from transformation, and describe a risk factor for genomic destabilization that increases during the process of normal cell growth and differentiation and is associated with the downregulation of histone H2AX to levels representative of growth arrest in normal cells. PMID:25815132

  15. Treating persistent distress and anxiety in parents of children with cancer: an initial feasibility trial.

    PubMed

    Warner, Carrie Masia; Ludwig, Kristy; Sweeney, Corinne; Spillane, Clare; Hogan, Laura; Ryan, Julie; Carroll, William

    2011-01-01

    Persistent anxiety is common among parents of children with cancer and may affect the family's well-being and adjustment. The goals of this pilot study are to determine the feasibility and potential efficacy of a brief cognitive-behavioral parent intervention aimed at reducing parental distress and anxiety related to their child's cancer diagnosis. Parents of children with cancer, at least 1 month postdiagnosis, were screened at an outpatient oncology clinic, and those reporting elevated levels of distress were offered a 4-session cognitive-behavioral intervention based on a modified version of the Surviving Cancer Competently Intervention Program-Newly Diagnosed. Five parents reporting persistent distress received the intervention. Results revealed decreases in parents' distress, state anxiety, and depressive symptoms, as well as in parents' feelings of burden associated with their children's cancer. This initial study suggests that identification of parents with prolonged heightened psychological distress is feasible and acceptable and that offering them a brief intervention within a pediatric oncology setting may be beneficial. PMID:21646637

  16. Does Radiotherapy for the Primary Tumor Benefit Prostate Cancer Patients with Distant Metastasis at Initial Diagnosis?

    PubMed Central

    Cho, Yeona; Chang, Jee Suk; Rha, Koon Ho; Hong, Sung Joon; Choi, Young Deuk; Ham, Won Sik; Kim, Jun Won; Cho, Jaeho

    2016-01-01

    Purpose/Objectives Treatment of the primary tumor reportedly improves survival in several types of metastatic cancer. We herein evaluated the efficacy and toxicity of radiotherapy for the primary tumor in prostate cancer with metastasis. Materials/Methods The study cohort included 140 men with metastatic prostate cancer at initial diagnosis. Metastatic sites were divided into 4 groups as follows: solitary bone, 2–4 bones, ≥5 bones, and visceral organs. Patient, tumor, and treatment characteristics, and clinical outcomes were compared between patients treated with (prostate radiotherapy [PRT] group) or without radiotherapy to the primary tumor. Results Patients in PRT group presented with a statistically significantly younger age (p = .02), whereas other characteristics showed no significant difference. Overall survival (OS) and biochemical failure-free survival (BCFFS) were improved in PRT patients (3-year OS: 69% vs. 43%, p = 0.004; 3-year BCFFS: 52% vs. 16%, p = 0.002). Multivariate analysis identified PRT as a significant predictor of both OS (hazard ratio [HR] = 0.43, p = 0.015). None of the 38 PRT patients experienced severe (grade ≥3) genitourinary or gastrointestinal toxicity. Conclusions Our data suggest that radiotherapy to the primary tumor was associated with improved OS and BCFFS in metastatic prostate cancer. The results of this study warrant prospective controlled clinical trials of this approach in stage IV prostate cancer patients with limited extent of bone metastasis and good performance status. PMID:26807740

  17. Development of cancer-initiating cells and immortalized cells with genomic instability

    PubMed Central

    Yoshioka, Ken-ichi; Atsumi, Yuko; Nakagama, Hitoshi; Teraoka, Hirobumi

    2015-01-01

    Cancers that develop after middle age usually exhibit genomic instability and multiple mutations. This is in direct contrast to pediatric tumors that usually develop as a result of specific chromosomal translocations and epigenetic aberrations. The development of genomic instability is associated with mutations that contribute to cellular immortalization and transformation. Cancer occurs when cancer-initiating cells (CICs), also called cancer stem cells, develop as a result of these mutations. In this paper, we explore how CICs develop as a result of genomic instability, including looking at which cancer suppression mechanisms are abrogated. A recent in vitro study revealed the existence of a CIC induction pathway in differentiating stem cells. Under aberrant differentiation conditions, cells become senescent and develop genomic instabilities that lead to the development of CICs. The resulting CICs contain a mutation in the alternative reading frame of CDKN2A (ARF)/p53 module, i.e., in either ARF or p53. We summarize recently established knowledge of CIC development and cellular immortality, explore the role of the ARF/p53 module in protecting cells from transformation, and describe a risk factor for genomic destabilization that increases during the process of normal cell growth and differentiation and is associated with the downregulation of histone H2AX to levels representative of growth arrest in normal cells. PMID:25815132

  18. Bioenergetic and Antiapoptotic Properties of Mitochondria from Cultured Human Prostate Cancer Cell Lines PC-3, DU145 and LNCaP

    PubMed Central

    Panov, Alexander; Orynbayeva, Zulfiya

    2013-01-01

    The purpose of this work was to reveal the metabolic features of mitochondria that might be essential for inhibition of apoptotic potential in prostate cancer cells. We studied mitochondria isolated from normal prostate epithelial cells (PrEC), metastatic prostate cancer cell lines LNCaP, PC-3, DU145; and non-prostate cancer cells - human fibrosarcoma HT1080 cells; and normal human lymphoblastoid cells. PrEC cells contained 2 to 4 times less mitochondria per gram of cells than the three PC cell lines. Respiratory activities of PrEC cell mitochondria were 5-20-fold lower than PC mitochondria, depending on substrates and the metabolic state, due to lower content and lower activity of the respiratory enzyme complexes. Mitochondria from the three metastatic prostate cancer cell lines revealed several features that are distinctive only to these cells: low affinity of Complex I for NADH, 20-30 mV higher electrical membrane potential (ΔΨ). Unprotected with cyclosporine A (CsA) the PC-3 mitochondria required 4 times more Ca2+ to open the permeability transition pore (mPTP) when compared with the PrEC mitochondria, and they did not undergo swelling even in the presence of alamethicin, a large pore forming antibiotic. In the presence of CsA, the PC-3 mitochondria did not open spontaneously the mPTP. We conclude that the low apoptotic potential of the metastatic PC cells may arise from inhibition of the Ca2+-dependent permeability transition due to a very high ΔΨ and higher capacity to sequester Ca2+. We suggest that due to the high ΔΨ, mitochondrial metabolism of the metastatic prostate cancer cells is predominantly based on utilization of glutamate and glutamine, which may promote development of cachexia. PMID:23951286

  19. Prevalence and Correlates of Postdiagnosis Initiation of Complementary and Alternative Medicine Among Patients at a Comprehensive Cancer Center

    PubMed Central

    Perlman, Adam; Lontok, Oliver; Huhmann, Maureen; Parrott, J. Scott; Simmons, Leigh Ann; Patrick-Miller, Linda

    2013-01-01

    Purpose: Patients with cancer increasingly use complementary and alternative medicine (CAM) in conjunction with conventional oncology treatments. Previous studies have not investigated postdiagnosis initiation of CAM therapies or independent correlates of use of individual CAM modalities. The purpose of this study was to determine the prevalence and correlates of individual CAM modalities initiated after cancer diagnosis. Methods: A cross-sectional survey was conducted of a random sample of adults with a cancer diagnosis (N = 1,228) seeking care at a National Cancer Institute–designated comprehensive cancer center within a 12-month period. Results: The majority of patients were female (64.7%), white (86.9%), and married (72.8%).Three-quarters (75.2%) used at least one CAM modality, and 57.6% of those using CAM initiated use after cancer diagnosis. For all CAM therapies combined, women were 1.7 times more likely than men to initiate any CAM therapy after cancer diagnosis. However, when CAM modalities were differentiated by type, men and women were equally likely to initiate all therapies except for psychotherapy and mind-body approaches. Postdiagnosis initiation of every CAM modality, except mind-body therapies, differed by cancer type. Conclusion: A significant proportion of patients initiated CAM use after diagnosis. However, specific type of CAM initiated varied by demographics and cancer type, suggesting there is not a “typology” of CAM user. Optimal comprehensive cancer treatment, palliation, and survivorship care will require patient and provider education regarding CAM use by modality type; improved provider-patient communication regarding potential benefits, limitations, and risks; and institutional policies to support integrated conventional and CAM treatment. PMID:23633969

  20. Alternative transcription initiation leads to expression of a novel ALK isoform in cancer

    PubMed Central

    Wiesner, Thomas; Lee, William; Obenauf, Anna C.; Ran, Leili; Murali, Rajmohan; Zhang, Qi Fan; Wong, Elissa W. P.; Hu, Wenhuo; Scott, Sasinya N.; Shah, Ronak H.; Landa, Iñigo; Button, Julia; Lailler, Nathalie; Sboner, Andrea; Gao, Dong; Murphy, Devan A.; Cao, Zhen; Shukla, Shipra; Hollmann, Travis J.; Wang, Lu; Borsu, Laetitia; Merghoub, Taha; Schwartz, Gary K.; Postow, Michael A.; Ariyan, Charlotte E.; Fagin, James A.; Zheng, Deyou; Ladanyi, Marc; Busam, Klaus J.; Berger, Michael F.; Chen, Yu; Chi, Ping

    2016-01-01

    Activation of oncogenes by mechanisms other than genetic aberrations such as mutations, translocations, or amplifications is largely undefined. Here we report a novel isoform of the anaplastic lymphoma kinase (ALK) that is expressed in ~ 11% of melanomas and sporadically in other human cancer types, but not in normal tissues. The novel ALK transcript initiates from a de novo alternative transcription initiation (ATI) site in ALK intron 19, and was termed ALKATI. In ALKATI-expressing tumours, the ATI site is enriched for H3K4me3 and RNA polymerase II, chromatin marks characteristic of active transcription initiation sites1. ALKATI is expressed from both ALK alleles, and no recurrent genetic aberrations are found at the ALK locus, indicating that the transcriptional activation is independent of genetic aberrations at the ALK locus. The ALKATI transcript encodes three proteins with molecular weights of 61.1, 60.8 and 58.7 kilodaltons, consisting primarily of the intracellular tyrosine kinase domain. ALKATI stimulates multiple oncogenic signalling pathways, drives growth-factor-independent cell proliferation in vitro, and promotes tumorigenesis in vivo in mouse models. ALK inhibitors can suppress the kinase activity of ALKATI, suggesting that patients with ALKATI-expressing tumours may benefit from ALK inhibitors. Our findings suggest a novel mechanism of oncogene activation in cancer through de novo alternative transcription initiation. PMID:26444240

  1. The matricellular protein CCN6 (WISP3) decreases Notch1 and suppresses breast cancer initiating cells.

    PubMed

    Huang, Wei; Martin, Emily E; Burman, Boris; Gonzalez, Maria E; Kleer, Celina G

    2016-05-01

    Increasing evidence supports that the epithelial to mesenchymal transition (EMT) in breast cancer cells generates tumor initiating cells (TICs) but the contribution of the tumor microenvironment to these programs needs further elucidation. CCN6 (WISP3) is a secreted matrix-associated protein (36.9 kDa) of the CCN family (named after CTGF, Cyr61 and Nov) that is reduced or lost in invasive carcinomas of the breast with lymph node metastasis and in inflammatory breast cancer. CCN6 exerts breast cancer growth and invasion inhibitory functions, but the mechanisms remain to be defined. In the present study we discovered that ectopic CCN6 overexpression in triple negative (TN) breast cancer cells and in cells derived from patients is sufficient to induce a mesenchymal to epithelial transition (MET) and to reduce TICs. In vivo, CCN6 overexpression in the TIC population of MDA-MB-231 cells delayed tumor initiation, reduced tumor volume, and inhibited the development of metastasis. Our studies reveal a novel CCN6/Slug signaling axis that regulates Notch1 signaling activation, epithelial cell phenotype and breast TICs, which requires the conserved thrombospondin type 1 (TSP1) motif of CCN6. The relevance of these data to human breast cancer is highlighted by the finding that CCN6 protein levels are inversely correlated with Notch1 intracellular activated form (NICD1) in 69.5% of invasive breast carcinomas. These results demonstrate that CCN6 regulates epithelial and mesenchymal states transition and TIC programs, and pinpoint one responsible mechanism. PMID:26933820

  2. Clinical and Organizational Factors in the Initial Evaluation of Patients With Lung Cancer

    PubMed Central

    Jim Yeung, Sai-Ching; Tanoue, Lynn T.; Gould, Michael K.

    2013-01-01

    Background: This guideline is intended to provide an evidence-based approach to the initial evaluation of patients with known or suspected lung cancer. It also includes an assessment of the impact of timeliness of care and multidisciplinary teams on outcome. Methods: The applicable current medical literature was identified by a computerized search and evaluated using standardized methods. Recommendations were framed using the approach described by the Guidelines Oversight Committee of the American College of Chest Physicians. Data sources included MEDLINE and the Cochrane Database of Systematic Reviews. Results: Initial evaluation should include a thorough history and physical examination; CT imaging; pulmonary function tests; and hemoglobin, electrolyte, liver function, and calcium levels. Additional testing for distant metastases and paraneoplastic syndromes should be determined on the basis of these results. Paraneoplastic syndromes may have an adverse impact on cancer treatment, so they should be controlled rapidly with the goal of proceeding with definitive cancer treatment in a timely manner. Although the relationship between timeliness of care and survival is difficult to quantify, efforts to deliver timely care are reasonable and should be balanced with the need to attend to other dimensions of health-care quality (eg, safety, effectiveness, efficiency, equality, consistency with patient values and preferences). Quality care will require multiple disciplines. Although it is difficult to assess the impact, we suggest that a multidisciplinary team approach to care be used, particularly for patients requiring multimodality therapy. Conclusions: The initial evaluation of patients with lung cancer should include a thorough history and physical examination, pulmonary function tests, CT imaging, basic laboratory tests, and selective testing for distant metastases and paraneoplastic syndromes. PMID:23649435

  3. Androgen and taxol cause cell type-specific alterations of centrosome and DNA organization in androgen-responsive LNCaP and androgen-independent DU145 prostate cancer cells

    NASA Technical Reports Server (NTRS)

    Schatten, H.; Ripple, M.; Balczon, R.; Weindruch, R.; Chakrabarti, A.; Taylor, M.; Hueser, C. N.

    2000-01-01

    We investigated the effects of androgen and taxol on the androgen-responsive LNCaP and androgen-independent DU145 prostate cancer cell lines. Cells were treated for 48 and 72 h with 0.05-1 nM of the synthetic androgen R1881 and with 100 nM taxol. Treatment of LNCaP cells with 0.05 nM R1881 led to increased cell proliferation, whereas treatment with 1 nM R1881 resulted in inhibited cell division, DNA cycle arrest, and altered centrosome organization. After treatment with 1 nM R1881, chromatin became clustered, nuclear envelopes convoluted, and mitochondria accumulated around the nucleus. Immunofluorescence microscopy with antibodies to centrosomes showed altered centrosome structure. Although centrosomes were closely associated with the nucleus in untreated cells, they dispersed into the cytoplasm after treatment with 1 nM R1881. Microtubules were only faintly detected in 1 nM R1881-treated LNCaP cells. The effects of taxol included microtubule bundling and altered mitochondria morphology, but not DNA organization. As expected, the androgen-independent prostate cancer cell line DU145 was not affected by R1881. Treatment with taxol resulted in bundling of microtubules in both cell lines. Additional taxol effects were seen in DU145 cells with micronucleation of DNA, an indication of apoptosis. Simultaneous treatment with R1881 and taxol had no additional effects on LNCaP or DU145 cells. These results suggest that LNCaP and DU145 prostate cancer cells show differences not only in androgen responsiveness but in sensitivity to taxol as well. Copyright 2000 Wiley-Liss, Inc.

  4. Racial variation in adjuvant chemotherapy initiation among breast cancer patients receiving oncotype DX testing.

    PubMed

    Roberts, Megan C; Weinberger, Morris; Dusetzina, Stacie B; Dinan, Michaela A; Reeder-Hayes, Katherine E; Troester, Melissa A; Carey, Lisa A; Wheeler, Stephanie B

    2015-08-01

    It is unknown whether racial differences exist in adjuvant chemotherapy initiation among women with similar oncotype DX (ODX) risk scores. We examined whether adjuvant chemotherapy initiation varied by race. Data come from the Phase III, Carolina Breast Cancer Study, a longitudinal, population-based study of North Carolina women diagnosed with breast cancer between 2008 and 2014. We used modified Poisson regression and report adjusted relative risk (aRR) and 95% confidence intervals (95%CI) to estimate the association between race and adjuvant chemotherapy initiation across ODX risk groups among women who received the test (n = 541). Among women who underwent ODX testing, 54.2, 37.5, and 8.3% of women had tumors classified as low-, intermediate-, and high-risk groups, respectively. We observed no racial variation in adjuvant chemotherapy initiation. Increasing ODX risk score (aRR = 1.39, 95%CI = 1.22, 1.58) and being married (aRR = 2.92, 95%CI = 1.12, 7.60) were independently associated with an increased likelihood of adjuvant chemotherapy in the low-risk group. Among women in the intermediate-risk group, ODX risk score (aRR = 1.15, 95%CI = 1.11, 1.20), younger age (aRR = 1.95, 95%CI = 1.35, 2.81), larger tumor size (aRR = 1.70, 95%CI = 1.22, 2.35), and higher income were independently associated with increased likelihood of adjuvant chemotherapy initiation. No racial differences were found in adjuvant chemotherapy initiation among women receiving ODX testing. As treatment decision-making becomes increasingly targeted with the use of genetic technologies, these results provide evidence that test results may drive treatment in a similar way across racial subgroups. PMID:26216535

  5. CXCR7 mediates TGFβ1-promoted EMT and tumor-initiating features in lung cancer.

    PubMed

    Wu, Y-C; Tang, S-J; Sun, G-H; Sun, K-H

    2016-04-21

    In the tumor microenvironment, chemokine system has a critical role in tumorigenesis and metastasis. The acquisition of stem-like properties by cancer cells is involved in metastasis and drug resistance, which are pivotal problems that result in poor outcomes in patients with lung cancer. Patients with advanced lung cancer present high plasma levels of transforming growth factor-β1 (TGFβ1), which correlate with poor prognostic features. Therefore, TGFβ1 may be important in the tumor microenvironment, where chemokines are widely expressed. However, the role of chemokines in TGFβ1-induced tumor progression still remains unclear. In our study, TGFβ1 upregulated CXC chemokine receptor expression, migration, invasion, epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) formation in lung adenocarcinoma. We found that CXCR7 was the most upregulated chemokine receptor induced by TGFβ1. CXCR7 knockdown resulted in reduction of migration, invasion and EMT induced by TGFβ1, whereas CXCR4 knockdown did not reverse TGFβ1-promoted EMT. CXCR7 silencing significantly decreased cancer sphere-forming capacity, stem-like properties, chemoresistance and TGFβ1-induced CSC tumor initiation in vivo. In clinical samples, high TGFβ1 and CXCR7 expression was significantly associated with the late stages of lung adenocarcinoma. Moreover, TGFβ1 and CXCR7 coexpression was positively correlated with the CSC marker, CD44, which is associated with lymph node metastasis. Besides, patients with high expression of both CXCR7 and TGFβ1 presented a significantly worse survival rate. These results suggest that the TGFβ1-CXCR7 axis may be a prognostic marker and may provide novel targets for combinational therapies to be used in the treatment of advanced lung cancer in the future. PMID:26212008

  6. Diet Quality and Survival After Ovarian Cancer: Results From the Women’s Health Initiative

    PubMed Central

    Crane, Tracy E.; Wertheim, Betsy C.; Neuhouser, Marian L.; Li, Wenjun; Snetselaar, Linda G.; Basen-Engquist, Karen M.; Zhou, Yang; Irwin, Melinda L.

    2014-01-01

    Background Survival after an ovarian cancer diagnosis is poor. Given the high mortality in these patients, efforts to identify modifiable lifestyle behaviors that could influence survival are needed. Earlier evidence suggests a protective role for vegetables, but no prior studies have evaluated overall dietary quality and ovarian cancer survival. The purpose of this analysis was to evaluate the role of prediagnosis diet quality in ovarian cancer survival. Methods We identified 636 centrally adjudicated cases of ovarian cancer within the Women’s Health Initiative Observational Study or Clinical Trials of 161808 postmenopausal women followed from 1995 to 2012. Dietary quality was assessed for the Healthy Eating Index (2005) using a food frequency questionnaire, covariables were obtained from standardized questionnaires, and adiposity was measured by clinic-based measurements of height, weight, and waist circumference. The association between diet quality and mortality was analyzed using Cox proportional hazards regression, adjusted for potential confounders, and stratified by waist circumference, physical activity level, and diabetes status. Tests of statistical significance were two-sided. Results Overall, higher diet quality was associated with lower all-cause mortality after ovarian cancer (hazard ratio [HR] for highest vs lowest tertile = 0.73; 95% confidence interval [CI] = 0.55 to 0.97, P trend = .03). The effect was strongest among women with waist circumference of 88cm or less and with no history of diabetes (HR = 0.73, 95% CI = 0.54 to 0.98). Physical activity level did not modify the association between diet quality and survival. Conclusion Our results suggest that overall higher prediagnosis diet quality may protect against mortality after ovarian cancer. PMID:25335480

  7. Laparoscopy Versus Robotic Surgery for Colorectal Cancer: A Single-Center Initial Experience.

    PubMed

    Ferrara, Francesco; Piagnerelli, Riccardo; Scheiterle, Maximilian; Di Mare, Giulio; Gnoni, Pasquale; Marrelli, Daniele; Roviello, Franco

    2016-08-01

    Background Minimally invasive approach has gained interest in the treatment of patients with colorectal cancer. The purpose of this study is to analyze the differences between laparoscopy and robotics for colorectal cancer in terms of oncologic and clinical outcomes in an initial experience of a single center. Materials and Methods Clinico-pathological data of 100 patients surgically treated for colorectal cancer from March 2008 to April 2014 with laparoscopy and robotics were analyzed. The procedures were right colonic, left colonic, and rectal resections. A comparison between the laparoscopic and robotic resections was made and an analysis of the first and the last procedures in the 2 groups was performed. Results Forty-two patients underwent robotic resection and 58 underwent laparoscopic resection. The postoperative mortality was 1%. The number of harvested lymph nodes was higher in robotics. The conversion rate was 7.1% for robotics and 3.4% for laparoscopy. The operative time was lower in laparoscopy for all the procedures. No differences were found between the first and the last procedures in the 2 groups. Conclusions This initial experience has shown that robotic surgery for the treatment of colorectal adenocarcinoma is a feasible and safe procedure in terms of oncologic and clinical outcomes, although an appropriate learning curve is necessary. Further investigation is needed to demonstrate real advantages of robotics over laparoscopy. PMID:26721500

  8. Initiation and promotion in cancer formation: the importance of studies on intercellular communication.

    PubMed

    Potter, V R

    1980-01-01

    Three major theories of cancer--somatic mutation, virus causation, and faulty differentiation--are proposed to involve alterations in DNA structure. Each results finally in terms of failures in the normal intercellular communication that involves feedback between differentiated cells acting on less differentiated cells still capable of proliferation. The historical background of the latter idea is traced to Osgood, Weiss and Kavanau, and to Iversen. The historical background of concepts of initiation and promotion are traced to Berenblum and Mottram and the Boutwell concept of promotion as gene activation is cited. It is proposed that gene activation by promoters is a valid concept and that it results from the blocking of the normal intercellular communication postulated by Osgood and others. The problem of explaining the low probability of cancer following initiators or promoters acting alone is cited as a problem in basic science. A hypothesis to solve the problem is proposed: Cancer results from two of more relevant mutations: promoters enhance proliferation of cells with one relevant mutation, thereby increasing the probability of obtaining a cell with two relevant mutations. A new scheme of five stages of hepatocarcinogenesis is proposed in terms of the hypothesis and available data. PMID:7013284

  9. A rare initial presentation of gastric cancer with multiple osteolytic lesions.

    PubMed

    Jehangir, Asad; Aderhold, Kim; Rajagopalan, Priya; Shogbesan, Oluwaseun; Swierczynski, Sharon; Qureshi, Anam; Jehangir, Qasim; Espana Schmidt, Christian

    2015-01-01

    Gastric cancer is the 12th leading cause of cancer-related deaths in the United States and commonly metastasizes to the bones. However, the presentation of gastric cancer as bony metastases without preceding gastrointestinal symptoms is rare which has been infrequently reported in the literature. Moreover, leptomeningeal carcinomatosis is an unusual complication of gastric cancer accounting for less than 1 percent of these patients. We present a unique case of a middle aged male who presented to the emergency department with worsening backache which started one month priorly. The only abnormal laboratory test was an elevated alkaline phosphatase of 154 IU/L. The imaging of his spine showed osteolytic lesions which on biopsy revealed signet ring cells. A small 2 cm ulcerated mass was found on esophagogastroduodenoscopy at the gastric cardia which on biopsy revealed signet ring gastric carcinoma. The patient received chemotherapy with capecitabine and oxaliplatin as well as radiation and showed a good response initially. A few months later, he presented with persistent worsening headaches and on brain imaging was found to have leptomeningeal carcinomatosis. Ten months after the diagnosis of gastric carcinoma, he passed away. PMID:25984375

  10. Current trends in initial management of oropharyngeal cancer: the declining use of open surgery.

    PubMed

    Haigentz, Missak; Silver, Carl E; Corry, June; Genden, Eric M; Takes, Robert P; Rinaldo, Alessandra; Ferlito, Alfio

    2009-12-01

    The widespread availability of novel primary treatment approaches against oropharyngeal cancers has provided several potentially curative surgical and nonsurgical treatment options for patients, generating both hope and controversy. As treatment is usually curative in intent, management considerations must include consideration of primary tumor and nodal disease control as well as long-term toxicities and functional outcomes. Anatomical and functional organ preservation (speech and deglutition) remains of paramount importance to patients with oropharyngeal cancer and the physicians involved in their care, accounting for the growing popularity of chemoradiotherapy and transoral surgical techniques for this indication. These novel approaches have greatly diminished the role of open surgery as initial therapy for oropharyngeal cancers. Open surgery which is often reserved for salvage on relapse, may still be an appropriate therapy for certain early stage primary lesions. The growing treatment armamentarium requires careful consideration for optimal individualized care. The identification of oncogenic human papillomavirus as a predictive and prognostic marker in patients with oropharyngeal cancer has great potential to further optimize the choice of treatment. In this review, novel primary therapies against oropharyngeal squamous cell carcinoma are presented in the context of anatomical, quality of life, and emerging biological considerations. PMID:19866522

  11. Oncolytic adenoviruses kill breast cancer initiating CD44+CD24-/low cells.

    PubMed

    Eriksson, Minna; Guse, Kilian; Bauerschmitz, Gerd; Virkkunen, Pekka; Tarkkanen, Maija; Tanner, Minna; Hakkarainen, Tanja; Kanerva, Anna; Desmond, Renee A; Pesonen, Sari; Hemminki, Akseli

    2007-12-01

    Cancer stem cells have been indicated in the initiation of tumors and are even found to be responsible for relapses after apparently curative therapies have been undertaken. In breast cancer, they may reside in the CD44(+)CD24(-/low) population. The use of oncolytic adenoviruses presents an attractive anti-tumor approach for eradication of these cells because their entry occurs through infection and they are, therefore, not susceptible to those mechanisms that commonly render stem cells resistant to many drugs. We isolated CD44(+)CD24(-/low) cells from patient pleural effusions and confirmed stem cell-like features including oct4 and sox2 expression and Hoechst 33342 exclusion. CD44(+)CD24(-/low) cells, including the Hoechst excluding subpopulation, could be effectively killed by oncolytic adenoviruses Ad5/3-Delta24 and Ad5.pk7-Delta24. In mice, CD44(+)CD24(-/low) cells formed orthotopic breast tumors but virus infection prevented tumor formation. Ad5/3-Delta24 and Ad5.pk7-Delta24 were effective against advanced orthotopic CD44(+)CD24(-/low)-derived tumors. In summary, Ad5/3-Delta24 and Ad5.pk7-Delta24 can kill CD44(+)CD24(-/low), and also committed breast cancer cells, making them promising agents for treatment of breast cancer. PMID:17848962

  12. Chrysanthemum indicum L. extract induces apoptosis through suppression of constitutive STAT3 activation in human prostate cancer DU145 cells.

    PubMed

    Kim, Chulwon; Kim, Moo-Chang; Kim, Sung-Moo; Nam, Dongwoo; Choi, Seung-Hoon; Kim, Sung-Hoon; Ahn, Kyoo Seok; Lee, Eun Ha; Jung, Sang Hoon; Ahn, Kwang Seok

    2013-01-01

    Chrysanthemum indicum L. has been shown to possess antiinflammatory and anticancer activities, but its molecular targets/pathways are not yet fully understood in tumor cells. In the present study, the potential effects of C. indicum on signal transducer and activator of transcription 3 (STAT3) signaling pathway in different tumor cells were examined. The solvent fractions (hexane, CH₂Cl₂, EtOAc, and BuOH,) were obtained from a crude extract (80% EOH extract) of C. indicum. The methylene chloride fraction of C. indicum (MCI) exhibited strong cytotoxic activity as compared with the other fractions and clearly suppressed constitutive STAT3 activation against both DU145 and U266 cells, but not MDA-MB-231 cells. The suppression of constitutive STAT3 activation by MCI is associated with blocking upstream JAK1 and JAK2, but not Src. MCI downregulated the expression of STAT3-regulated gene products; this is correlated with the accumulation of the cell cycle at sub-G1 phase, the induction of caspase-3 activation, and apoptosis. Moreover, the major components of the MCI were bioactive compounds such as sudachitin, hesperetin, chrysoeriol, and acacetin. Sudachitin, chrysoeriol, and acacetin also exerted significantly cytotoxicity, clearly suppressed constitutive STAT3 activation, and induced apoptosis, although hesperetin did not show any significant effect in DU145 cells. Overall, our results demonstrate that MCI could induce apoptosis through inhibition of the JAK1/2 and STAT3 signaling pathways. PMID:22438130

  13. Monitoring of environmental cancer initiators through hemoglobin adducts by a modified Edman degradation method

    SciTech Connect

    Toernqvist, M.M.; Mowrer, J.; Jensen, S.; Ehrenberg, L.

    1986-04-01

    Tissue doses of cancer initiators/mutagens are suitably monitored through hemoglobin adducts formed in vivo, but the use of this method has been hampered by a lack of sufficiently simple and fast procedures. It was previously observed that when the N-terminal amino acid in hemoglobin, valine, is alkylated it is cleaved off by the Edman sequencing reagent, phenyl isothiocyanate, in the neutral-alkaline coupling medium, as opposed to the acidic medium required by normal amino acids. Based on this principle, conditions for a functioning procedure for gas chromatography/mass spectrometry (GC/MS) determination of N-terminal alkylvalines in hemoglobin were worked out. Derivatizing the protein in formamide solution with pentafluorophenyl isothiocyanate, using a /sup 2/H-alkylated protein as internal standard, and applying on-column injection during analysis, permit reproducible determination of hydroxyethylvaline and other adducts down into the dose range where cancer risks may be considered acceptably low.

  14. Uterine cervical cancer with brain metastasis as the initial site of presentation.

    PubMed

    Sato, Yumi; Tanaka, Kei; Kobayashi, Yoichi; Shibuya, Hiromi; Nishigaya, Yoshiko; Momomura, Mai; Matsumoto, Hironori; Iwashita, Mitsutoshi

    2015-07-01

    Brain metastasis from uterine cervical cancer is rare, with an incidence of 0.5%, and usually occurs late in the course of the disease. We report a case of uterine cervical cancer with brain metastasis as the initial site of presentation. A 50-year-old woman with headache, vertigo, amnesia and loss of appetite was admitted for persistent vomiting. Contrast enhanced computed tomography showed a solitary right frontal cerebral lesion with ring enhancement and uterine cervical tumor. She was diagnosed with uterine cervical squamous cell carcinoma with parametrium invasion and no other distant affected organs were detected. The cerebral lesion was surgically removed and pathologically proved to be metastasis of uterine cervical squamous cell carcinoma. The patient underwent concurrent chemoradiotherapy, followed by cerebral radiation therapy, but multiple metastases to the liver and lung developed and the patient died 7 months after diagnosis of brain metastasis. PMID:25656985

  15. Tumour-initiating cells vs. cancer 'stem' cells and CD133: What's in the name?

    SciTech Connect

    Neuzil, Jiri; E-mail: j.neuzil@griffith.edu.au; Stantic, Marina; Zobalova, Renata; Chladova, Jaromira; Wang, Xiufang; Prochazka, Lubomir; Dong, Lanfeng; Andera, Ladislav; Ralph, Stephen J.

    2007-04-20

    Recent evidence suggests that a subset of cells within a tumour have 'stem-like' characteristics. These tumour-initiating cells, distinct from non-malignant stem cells, show low proliferative rates, high self-renewing capacity, propensity to differentiate into actively proliferating tumour cells, resistance to chemotherapy or radiation, and they are often characterised by elevated expression of the stem cell surface marker CD133. Understanding the molecular biology of the CD133{sup +} cancer cells is now essential for developing more effective cancer treatments. These may include drugs targeting organelles, such as mitochondria or lysosomes, using highly efficient and selective inducers of apoptosis. Alternatively, agents or treatment regimens that enhance sensitivity of these therapy-resistant 'tumour stem cells' to the current or emerging anti-tumour drugs would be of interest as well.

  16. HMO membership, copayment, and initiation of care for cancer: a study of working adults.

    PubMed Central

    Greenwald, H P

    1987-01-01

    This study compares diagnosis and commencement of treatment for cancer among persons with fully financed fee-for-service coverage, persons with copaid fee-for-service coverage, and persons in an HMO (health maintenance organization). A total of 242 subjects actively employed at the time of their diagnosis were interviewed, typically within six months of beginning cancer treatment. After sex, age, income, education, residence (urban vs rural), and disease site and stage had been controlled, those who made copayments were found to have waited an average of 1.25 months longer (95 per cent confidence limit (cl) +/- .88) between initial suspicion of illness and obtaining a definitive diagnosis than those with full insurance coverage. Time from diagnosis until the beginning of treatment averaged .83 months longer (95 per cent cl +/- .41) for HMO members than those in fee-for-service. These relations were strongest in income categories equal to or exceeding $20,000 per year. PMID:3826465

  17. Induction of cytotoxic T lymphocytes against ovarian cancer-initiating cells.

    PubMed

    Weng, Desheng; Song, Baizheng; Durfee, John; Sugiyama, Valerie; Wu, Zhengrong; Koido, Shigeo; Calderwood, Stuart K; Gong, Jianlin

    2011-10-15

    The majority of patients with stage III/IV ovarian carcinoma that respond initially to standard therapies ultimately undergo relapse due to the survival of small populations of cells with tumor-initiating potential. These ovarian cancer (OVCA)-initiating cells (OCIC) are sometimes called cancer stem cells (CSC) because they express stem cell markers, and can survive conventional therapies such as chemotherapy, which usually target rapidly replicating tumor cells, and give rise to recurrent tumors that are more chemo-resistant and more aggressive. Thus, it would be desirable to develop a therapy that could selectively target OCIC and be used to complement the conventional therapies. In this study, we isolated a subset of OVCA cells with a CD44(+) phenotype in samples from patients with OVCA that possess CSC properties including the formation of spheroids in culture, self-renewal and the ability to be engrafted in immune-compromised mice. We next explored the use of immunotherapy using fusions of dendritic cells and OCIC to specifically target the OCIC subpopulations. Fusion cells (FCs) prepared in this way activated T cells to express elevated levels of IFN-γ with enhanced killing of CD44(+) OVCA cells. We envision a combined approach where conventional therapies such as chemotherapy kill the bulk of tumor cells, whereas OCIC-reactive cytotoxic T lymphocytes target the resistant OCIC fraction. A combined therapy such as this may represent a promising approach for the treatment of OVCA. PMID:21154809

  18. National Cancer Institute's Precision Medicine Initiatives for the new National Clinical Trials Network.

    PubMed

    Abrams, Jeffrey; Conley, Barbara; Mooney, Margaret; Zwiebel, James; Chen, Alice; Welch, John J; Takebe, Naoko; Malik, Shakun; McShane, Lisa; Korn, Edward; Williams, Mickey; Staudt, Louis; Doroshow, James

    2014-01-01

    The promise of precision medicine will only be fully realized if the research community can adapt its clinical trials methodology to study molecularly characterized tumors instead of the traditional histologic classification. Such trials will depend on adequate tissue collection, availability of quality controlled, high throughput molecular assays, and the ability to screen large numbers of tumors to find those with the desired molecular alterations. The National Cancer Institute's (NCI) new National Clinical Trials Network (NCTN) is well positioned to conduct such trials. The NCTN has the ability to seamlessly perform ethics review, register patients, manage data, and deliver investigational drugs across its many sites including both in cities and rural communities, academic centers, and private practices. The initial set of trials will focus on different questions: (1) Exceptional Responders Initiative-why do a minority of patients with solid tumors or lymphoma respond very well to some drugs even if the majority do not?; (2) NCI MATCH trial-can molecular markers predict response to targeted therapies in patients with advanced cancer resistant to standard treatment?; (3) ALCHEMIST trial-will targeted epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) inhibitors improve survival for adenocarcinoma of the lung in the adjuvant setting?; and (4) Lung Cancer Master Protocol trial for advanced squamous cell lung cancer-is there an advantage to developing drugs for small subsets of molecularly characterized tumors in a single, multiarm trial design? These studies will hopefully spawn a new era of treatment trials that will carefully select the tumors that may respond best to investigational therapy. PMID:24857062

  19. A Role for OCT4 in Tumor Initiation of Drug-Resistant Prostate Cancer Cells

    PubMed Central

    Linn, Douglas E.; Yang, Xi; Sun, Feng; Xie, Yingqiu; Chen, Hege; Jiang, Richeng; Chen, Hegang; Chumsri, Saranya; Burger, Angelika M.; Qiu, Yun

    2010-01-01

    Drug resistance remains a clinical challenge in cancer treatment due to poor understanding of underlying mechanisms. We have established several drug-resistant prostate cancer cell lines by long-term culture in medium containing chemotherapeutic drugs. These resistant lines displayed a significant increase in side population cells due to overexpression of drug efflux pumps including ABCG2/BCRP and MDR1/Pgp. To uncover potential mechanisms underlying drug resistance, we performed microarray analysis to identify differentially expressed genes in 2 drug-resistant lines. We observed that POU5F1/OCT4, a transcription factor key to regulating pluripotency in embryonic stem cells, was upregulated in drug-resistant lines and accompanied by transcriptional activation of a set of its known target genes. Upregulation of OCT4 in drug-resistant cells was validated by RT-PCR and sequencing of PCR products as well as confirmation by Western blot and specific shRNA knockdown. Analysis of the regulatory region of POU5F1/OCT4 revealed a reduction of methylation in drug-resistant cell lines. Furthermore, these drug-resistant cells exhibited a significant increase in tumorigenicity in vivo. Subcutaneous inoculation of as few as 10 drug-resistant cells could initiate tumor formation in SCID mice, whereas no detectable tumors were observed from the parental line under similar conditions, suggesting that these drug-resistant cells may be enriched for tumor-initiating cells. Knocking down OCT4 expression by specific shRNAs attenuated growth of drug-resistant cells. Our data suggest that OCT4 re-expression in cancer cells may play an important role in carcinogenesis and provide one possible mechanism by which cancer cells acquire/maintain a drug-resistant phenotype. PMID:21779471

  20. Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells.

    PubMed

    Dowling, Ryan J O; Zakikhani, Mahvash; Fantus, I George; Pollak, Michael; Sonenberg, Nahum

    2007-11-15

    Metformin is used for the treatment of type 2 diabetes because of its ability to lower blood glucose. The effects of metformin are explained by the activation of AMP-activated protein kinase (AMPK), which regulates cellular energy metabolism. Recently, we showed that metformin inhibits the growth of breast cancer cells through the activation of AMPK. Here, we show that metformin inhibits translation initiation. In MCF-7 breast cancer cells, metformin treatment led to a 30% decrease in global protein synthesis. Metformin caused a dose-dependent specific decrease in cap-dependent translation, with a maximal inhibition of 40%. Polysome profile analysis showed an inhibition of translation initiation as metformin treatment of MCF-7 cells led to a shift of mRNAs from heavy to light polysomes and a concomitant increase in the amount of 80S ribosomes. The decrease in translation caused by metformin was associated with mammalian target of rapamycin (mTOR) inhibition, and a decrease in the phosphorylation of S6 kinase, ribosomal protein S6, and eIF4E-binding protein 1. The effects of metformin on translation were mediated by AMPK, as treatment of cells with the AMPK inhibitor compound C prevented the inhibition of translation. Furthermore, translation in MDA-MB-231 cells, which lack the AMPK kinase LKB1, and in tuberous sclerosis complex 2 null (TSC2(-/-)) mouse embryonic fibroblasts was unaffected by metformin, indicating that LKB1 and TSC2 are involved in the mechanism of action of metformin. These results show that metformin-mediated AMPK activation leads to inhibition of mTOR and a reduction in translation initiation, thus providing a possible mechanism of action of metformin in the inhibition of cancer cell growth. PMID:18006825

  1. Acoustic sensing of the initial adhesion of chemokine-stimulated cancer cells.

    PubMed

    Wei, Xiao-Lan; Zhang, Jing; Zhao, Na

    2013-11-01

    Chemokines together with their receptors play important roles in tumor metastasis. Intracellular signals stimulated by chemokines regulate the initial adhesion of cancer cells, which controls the subsequent cell spreading and migration. Until now, the nature of initial cell adhesion has been understood very poorly, since conventional assays are static and could not provide dynamic information. In order to address this issue, we adopt an acoustic sensor, quartz crystal microbalance (QCM), to monitor the attachment of chemokine-stimulated cancer cells in real-time. As a model, the chemokine CXCL12 was used to stimulate three human breast cancer cell lines expressing different levels of its receptor CXCR4, which triggers intracellular signaling pathways that activate integrins across cell membrane. Interaction between cellular integrins and adhesion molecules (CAMs) pre-coated on sensor surfaces were in situ monitored by QCM of which the frequency was sensitive to the mechanical connection of cells to the sensor surface. The ratio of frequency shift under stimulation to that without stimulation indicated the number and strength of integrin-CAM binding stimulated by the chemokine. The cell-surface binding was found to be enhanced by CXCL12, which depends on the CAM type and levels of chemokine and receptor, and was significantly inhibited by a blocker of the chemokine pathway. The binding of integrin with intercellular adhesion molecule was also found to be strong and in good correlated with the chemotactic indexes obtained by the classical Boyden chamber assay. This research suggests that acoustic sensing of initial cell adhesion could provide a dynamic insight into cell interfacial phenomena. PMID:23911626

  2. Quality Improvement in the National Cancer Institute Community Cancer Centers Program: The Quality Oncology Practice Initiative Experience

    PubMed Central

    Siegel, Robert D.; Castro, Kathleen M.; Eisenstein, Jana; Stallings, Holley; Hegedus, Patricia D.; Bryant, Donna M.; Kadlubek, Pam J.; Clauser, Steven B.

    2015-01-01

    Purpose: The National Cancer Institute (NCI) Community Cancer Centers Program (NCCCP) began in 2007; it is a network of community-based hospitals funded by the NCI. Quality of care is an NCCCP priority, with participation in the American Society of Clinical Oncology Quality Oncology Practice Initiative (QOPI) playing a fundamental role in quality assessment and quality improvement (QI) projects. Using QOPI methodology, performance on quality measures was analyzed two times per year over a 3-year period to enhance our implementation of quality standards at NCCCP hospitals. Methods: A data-sharing agreement allowed individual-practice QOPI data to be electronically sent to the NCI. Aggregated data with the other NCCCP QOPI participants were presented to the network via Webinars. The NCCCP Quality of Care Subcommittee selected areas in which to focus subsequent QI efforts, and high-performing practices shared voluntarily their QI best practices with the network. Results: QOPI results were compiled semiannually between fall 2010 and fall 2013. The network concentrated on measures with a quality score of ≤ 0.75 and planned voluntary group-wide QI interventions. We identified 13 measures in which the NCCCP fell at or below the designated quality score in fall 2010. After implementing a variety of QI initiatives, the network registered improvements in all parameters except one (use of treatment summaries). Conclusion: Using the NCCCP as a paradigm, QOPI metrics provide a useful platform for group-wide measurement of quality performance. In addition, these measurements can be used to assess the effectiveness of QI initiatives. PMID:25538082

  3. DIRAS3 regulates the autophagosome initiation complex in dormant ovarian cancer cells

    PubMed Central

    Lu, Zhen; Baquero, Maria T; Yang, Hailing; Yang, Maojie; Reger, Albert S; Kim, Choel; Levine, Douglas A; Clarke, Charlotte H; Liao, Warren S-L; Bast Jr, Robert C

    2014-01-01

    DIRAS3 is an imprinted tumor suppressor gene that is downregulated in 60% of human ovarian cancers. Re-expression of DIRAS3 at physiological levels inhibits proliferation, decreases motility, induces autophagy, and regulates tumor dormancy. Functional inhibition of autophagy with choroquine in dormant xenografts that express DIRAS3 significantly delays tumor regrowth after DIRAS3 levels are reduced, suggesting that autophagy sustains dormant ovarian cancer cells. This study documents a newly discovered role for DIRAS3 in forming the autophagosome initiation complex (AIC) that contains BECN1, PIK3C3, PIK3R4, ATG14, and DIRAS3. Participation of BECN1 in the AIC is inhibited by binding of BECN1 homodimers to BCL2. DIRAS3 binds BECN1, disrupting BECN1 homodimers and displacing BCL2. Binding of DIRAS3 to BECN1 increases the association of BECN1 with PIK3C3 and ATG14, facilitating AIC activation. Amino acid starvation of cells induces DIRAS3 expression, reduces BECN1-BCL2 interaction and promotes autophagy, whereas DIRAS3 depletion blocks amino acid starvation-induced autophagy. In primary ovarian cancers, punctate expression of DIRAS3, BECN1, and the autophagic biomarker MAP1LC3 are highly correlated (P < 0.0001), underlining the clinical relevance of these mechanistic studies. Punctate expression of DIRAS3 and MAP1LC3 was detected in only 21–23% of primary ovarian cancers but in 81–84% of tumor nodules found on the peritoneal surface at second-look operations following primary chemotherapy. This reflects a 4-fold increase (P < 0.0001) in autophagy between primary disease and post-treatment recurrence. We suggest that DIRAS3 not only regulates the AIC, but induces autophagy in dormant, nutrient-deprived ovarian cancer cells that remain after conventional chemotherapy, facilitating their survival. PMID:24879154

  4. Synchronous Diagnosis of Multiple Myeloma, Breast Cancer, and Monoclonal B-Cell Lymphocytosis on Initial Presentation

    PubMed Central

    Vennepureddy, A.; Motilal Nehru, V.; Liu, Y.; Mohammad, F.; Atallah, J. P.

    2016-01-01

    The cooccurrence of more than one oncologic illness in a patient can present a diagnostic challenge. Here we report an unusual case of concomitant existence of multiple myeloma, breast cancer, and monoclonal B-cell lymphocytosis on initial presentation. The challenge was to accurately diagnose each disease and stage in order to maximize the therapeutic regimen to achieve cure/remission. Successful management of the patient and increased life expectancy can be achieved by multidisciplinary management and patient-oriented approach in multiple primary malignant synchronous tumors. PMID:27247815

  5. Familial Clustering of Breast and Prostate Cancer and Risk of Postmenopausal Breast Cancer in the Women’s Health Initiative Study

    PubMed Central

    Beebe-Dimmer, Jennifer L.; Yee, Cecilia; Cote, Michele L.; Petrucelli, Nancie; Palmer, Nynikka; Bock, Cathryn; Lane, Dorothy; Agalliu, Ilir; Stefanick, Marcia L.; Simon, Michael S.

    2015-01-01

    BACKGROUND Evidence suggests that the risk of breast and prostate cancer is increased among those with a family history of the same disease and particularly among first-degree relatives. However, less is known about the relationship between breast and prostate cancer within families and particularly among minority populations. METHODS Analyses of participants in the Women’s Health Initiative observational cohort who were free of breast cancer at the time of their baseline examination were conducted. Subjects were followed for breast cancer through August 31, 2009. A Cox proportional hazards regression modeling approach was used to estimate the risk of breast cancer associated with a family history of prostate cancer, breast cancer, and both among first-degree relatives. RESULTS There were 78,171 eligible participants, and 3506 breast cancer cases were diagnosed during the study period. A family history of prostate cancer was associated with a modest increase in breast cancer risk after adjustments for confounders (adjusted hazard ratio [aHR], 1.14; 95% confidence interval [CI], 1.02-1.26). In a separate analysis examining the joint impact of both cancers, a family history of both breast and prostate cancer was associated with a 78% increase in breast cancer risk (aHR, 1.78; 95% CI, 1.45-2.19). Risk estimates associated with a family history of both breast and prostate cancer were higher among African American women (aHR, 2.34; 95% CI, 1.09-5.02) versus white women (aHR, 1.66; 95% CI, 1.33-2.08). CONCLUSIONS These findings suggest that prostate cancer diagnosed among first-degree family members increases a woman’s risk of developing breast cancer. Future studies are needed to determine the relative contributions of genes and a shared environment to the risk for both cancers. PMID:25754547

  6. Mortality due to respiratory cancers in the coke oven plants of the Lorraine coalmining industry (Houillères du Bassin de Lorraine).

    PubMed Central

    Bertrand, J P; Chau, N; Patris, A; Mur, J M; Pham, Q T; Moulin, J J; Morviller, P; Auburtin, G; Figueredo, A; Martin, J

    1987-01-01

    The main activity of the Houillères du Bassin de Lorraine (Lorraine Collieries), employing 23,000 operatives and executives, is coalmining. The coke production is carried out by two coke oven plants with a workforce of respectively 747 and 552 workers. The coal coking process entails the emission of noxious products such as polycyclic aromatic hydrocarbons (PAH) from the ovens. The influence of occupational exposure on mortality due to respiratory cancers, and particularly to lung and upper respiratory and alimentary tracts cancer, was investigated among a cohort of 534 male workers from the two coke oven plants who had retired from work between 1963 and 1982. The job history of each subject has been precisely reconstructed by indicating the duration of exposure on the ovens, close to the ovens, and in maintenance occupations. The cohort mortality has been analysed according to the method of indirect standardisation with reference to the French male population and by a case-control study concerning the consumption of tobacco per cohort. The mortality due to lung cancer is 2.51 times higher than expected. This excess of mortality differs, but not significantly, between the two coke oven plants (standardised mortality ratio equals 3.05 and 1.75 respectively). It is not significantly higher among subjects exposed for more than five years, directly exposed on the ovens or working near the ovens or at maintenance occupations on the ovens (SMR = 2.78), than among those exposed for less than five years (SMR = 2.35) or those not exposed at all. Even taking into account the excess of mortality due to lung cancers in the Moselle district (1.6 time that of France), the excess of lung cancers does not seem to be explained by the regional factor, or by tobacco and alcohol consumption. Although no significant relation was offered between lung cancer and the duration of exposure to PAH, even when taking smoking habits into account, the carcinogenic role of occupational nuisances

  7. Obesity and future prostate cancer risk among men after an initial benign biopsy of the prostate

    PubMed Central

    Rundle, Andrew; Jankowski, Michelle; Kryvenko, Oleksandr N.; Tang, Deliang; Rybicki, Benjamin A.

    2013-01-01

    Background In general population studies, obesity has been associated with risk of high-grade prostate cancer (PCa), but little is known about obesity and future PCa risk among men with an initial benign biopsy of the prostate; a high risk population. Methods Within a cohort of 6,692 men followed up after a biopsy or transurethral resection of the prostate (TURP) with benign findings, a nested case-control study was conducted of 494 PCa cases and controls matched on age, race, follow-up duration, biopsy vs. TURP and date of procedure. Body mass index at the time of the initial procedure was abstracted from medical records and initial biopsy specimens were reviewed for the presence of prostatic intraepithelial neoplasia (PIN). Results Obesity was associated with the presence of PIN in the initial benign specimen (OR = 2.15, 95% CI 1.13, 4.11). After adjustment for the matching variables, family history of PCa, PSA levels at the initial procedure, the number of PSA tests and DRE during follow-up, obesity (OR = 1.57, 95% CI 1.07, 2.30) at the time of the initial procedure was associated with PCa incidence during follow-up. Risk associated with obesity was confined to cases with follow-up less than 1,538 days, the median duration of follow-up among cases (OR = 1.95, 95% CI 1.09, 3.48). Conclusions Obesity is associated with the presence of PIN in benign specimens and with future PCa risk after an initial benign finding. Impact Obesity may be a factor to consider when planning clinical follow-up after a benign biopsy. PMID:23613026

  8. Obstructive jaundice at the initial presentation in small-cell lung cancer

    PubMed Central

    Ochi, Nobuaki; Takigawa, Nagio; Yasugi, Masayuki; Ishida, Etsuji; Kawamoto, Hirofumi; Taniguchi, Akihiko; Harada, Daijiro; Hayashi, Eiko; Toda, Hiroko; Yanai, Hiroyuki; Tanimoto, Mitsune; Kiura, Katsuyuki

    2010-01-01

    Obstructive jaundice sometimes may develop in association with advanced small-cell lung cancer (SCLC); however, SCLC initially presenting with obstructive jaundice is rare. This report presents the cases of two SCLC patients with obstructive jaundice at the initial diagnosis. A 64-year-old male presented with obstructive jaundice due to a tumor at the head of the pancreas. He was diagnosed with SCLC by transbronchial biopsy from a lung tumor in the left upper lobe. Another 74-year-old male was admitted with jaundice due to a tumor in the porta hepatis. He was also diagnosed with SCLC by a fine-needle aspiration biopsy of a lung tumor in the left lower lobe. Both cases were successfully treated with systemic chemotherapy after endoscopic retrograde biliary drainage. PMID:23754881

  9. The Project Data Sphere Initiative: Accelerating Cancer Research by Sharing Data

    PubMed Central

    Reeder-Hayes, Katherine E.; Corty, Robert W.; Basch, Ethan; Milowsky, Mathew I.; Dusetzina, Stacie B.; Bennett, Antonia V.; Wood, William A.

    2015-01-01

    Background. In this paper, we provide background and context regarding the potential for a new data-sharing platform, the Project Data Sphere (PDS) initiative, funded by financial and in-kind contributions from the CEO Roundtable on Cancer, to transform cancer research and improve patient outcomes. Given the relatively modest decline in cancer death rates over the past several years, a new research paradigm is needed to accelerate therapeutic approaches for oncologic diseases. Phase III clinical trials generate large volumes of potentially usable information, often on hundreds of patients, including patients treated with standard of care therapies (i.e., controls). Both nationally and internationally, a variety of stakeholders have pursued data-sharing efforts to make individual patient-level clinical trial data available to the scientific research community. Potential Benefits and Risks of Data Sharing. For researchers, shared data have the potential to foster a more collaborative environment, to answer research questions in a shorter time frame than traditional randomized control trials, to reduce duplication of effort, and to improve efficiency. For industry participants, use of trial data to answer additional clinical questions could increase research and development efficiency and guide future projects through validation of surrogate end points, development of prognostic or predictive models, selection of patients for phase II trials, stratification in phase III studies, and identification of patient subgroups for development of novel therapies. Data transparency also helps promote a public image of collaboration and altruism among industry participants. For patient participants, data sharing maximizes their contribution to public health and increases access to information that may be used to develop better treatments. Concerns about data-sharing efforts include protection of patient privacy and confidentiality. To alleviate these concerns, data sets are

  10. Regulation of Ovarian Cancer Stem Cells or Tumor-Initiating Cells

    PubMed Central

    Kwon, Mi Jeong; Shin, Young Kee

    2013-01-01

    Cancer stem cells or tumor-initiating cells (CSC/TICs), which can undergo self-renewal and differentiation, are thought to play critical roles in tumorigenesis, therapy resistance, tumor recurrence and metastasis. Tumor recurrence and chemoresistance are major causes of poor survival rates of ovarian cancer patients, which may be due in part to the existence of CSC/TICs. Therefore, elucidating the molecular mechanisms responsible for the ovarian CSC/TICs is required to develop a cure for this malignancy. Recent studies have indicated that the properties of CSC/TICs can be regulated by microRNAs, genes and signaling pathways which also function in normal stem cells. Moreover, emerging evidence suggests that the tumor microenvironments surrounding CSC/TICs are crucial for the maintenance of these cells. Similarly, efforts are now being made to unravel the mechanism involved in the regulation of ovarian CSC/TICs, although much work is still needed. This review considers recent advances in identifying the genes and pathways involved in the regulation of ovarian CSC/TICs. Furthermore, current approaches targeting ovarian CSC/TICs are described. Targeting both CSC/TICs and bulk tumor cells is suggested as a more effective approach to eliminating ovarian tumors. Better understanding of the regulation of ovarian CSC/TICs might facilitate the development of improved therapeutic strategies for recurrent ovarian cancer. PMID:23528891

  11. Oncolytic herpes simplex virus kills stem-like tumor-initiating colon cancer cells

    PubMed Central

    Warner, Susanne G; Haddad, Dana; Au, Joyce; Carson, Joshua S; O’Leary, Michael P; Lewis, Christina; Monette, Sebastien; Fong, Yuman

    2016-01-01

    Stem-like tumor-initiating cells (TICs) are implicated in cancer progression and recurrence, and can be identified by sphere-formation and tumorigenicity assays. Oncolytic viruses infect, replicate in, and kill a variety of cancer cells. In this study, we seek proof of principle that TICs are susceptible to viral infection. HCT8 human colon cancer cells were subjected to serum-free culture to generate TIC tumorspheres. Parent cells and TICs were infected with HSV-1 subtype NV1066. Cytotoxicity, viral replication, and Akt1 expression were assessed. TIC tumorigenicity was confirmed and NV1066 efficacy was assessed in vivo. NV1066 infection was highly cytotoxic to both parent HCT8 cells and TICs. In both populations, cell-kill of >80% was achieved within 3 days of infection at a multiplicity of infection (MOI) of 1.0. However, the parent cells required 2-log greater viral replication to achieve the same cytotoxicity. TICs overexpressed Akt1 in vitro and formed flank tumors from as little as 100 cells, growing earlier, faster, larger, and with greater histologic atypia than tumors from parent cells. Treatment of TIC-induced tumors with NV1066 yielded tumor regression and slowed tumor growth. We conclude that colon TICs are selected for by serum-free culture, overexpress Akt1, and are susceptible to oncolytic viral infection. PMID:27347556

  12. Predictors of Regional Lymph Node Recurrence after Initial Thyroidectomy in Patients with Thyroid Cancer

    PubMed Central

    Sharifi, Amirsina; Shojaeifard, Abolfazl; Soroush, Ahmadreza; Jafari, Mehdi; Abdehgah, Ali Ghorbani; Mahmoudzade, Hossein

    2016-01-01

    Background. Regional lymph node recurrence (RLNR) is common in patients with thyroid cancer but clinicopathological predictors are unclear. We aimed to clarify these predictors and identify patients who would benefit from prophylactic lymph node dissection the most. Method. 343 patients with different types of thyroid cancer were analyzed retrospectively. All patients underwent total thyroidectomy between 2007 and 2013. Results. The median ± interquartile range of patients' age was 40 ± 25 years. 245 (71.4%) patients were female. Regarding the risk of regional lymph node recurrence, we found that male gender, age ≥45 years, non-PTC (i.e., medullary, follicular, and anaplastic types) histopathology, T3 (i.e., tumor size >4 cm in the greatest dimension limited to the thyroid or any tumor with minimal extrathyroid extension), stage IVa, and isolated cervical lymphadenopathy as initial manifestation (ICL) are significant risk factors. T3 (p < 0.001; odds ratio = 156.41, 95% CI [55.72–439.1]) and ICL (p < 0.001; odds ratio = 77.79, 95% CI [31.55–191.81]) were the strongest predictors of regional lymph node recurrence. Conclusion. We found easily achievable risk factors for RLNR in thyroid cancers patients. We suggested that patients with specific clinicopathological features like male gender, age ≥45 years, larger tumor size, and extrathyroidal extension be considered as prophylactic lymphadenectomy candidates. PMID:27403370

  13. MicroRNAs in Breast Cancer —Our Initial Results

    PubMed Central

    Popovska-Jankovic, K; Noveski, P; Chakalova, L; Petrusevska, G; Kubelka, K; Plaseska-Karanfilska, D

    2012-01-01

    MicroRNAs (miRNAs) are small [∼21 nucleotide (nt)] non coding RNAs (ncRNAs) that regulate gene expression posttranscriptionally. About 3.0% of human genes encode for miRNAs, and up to 30.0% of human protein coding genes may be regulated by miRNAs. Currently, more than 2000 unique human mature microRNAs are known. MicroRNAs play a key role in diverse biological processes including development, cell proliferation, differentiation and apoptosis. These processes are commonly dysregulated in cancer, implicating miRNAs in carcinogenesis, where they act as tumor supressors or oncogenes. Several miRNAs are associated with breast cancer. Here we present our initial results of miRNA analyses of breast cancer tissues using quantitative real time-polymerase chain reaction (ReTi-PCR) (qPCR) involving stem-loop reverse transcriptase (RT) primers combined with TaqMan® PCR and miRNA microarray analysis. PMID:24052751

  14. Oncolytic herpes simplex virus kills stem-like tumor-initiating colon cancer cells.

    PubMed

    Warner, Susanne G; Haddad, Dana; Au, Joyce; Carson, Joshua S; O'Leary, Michael P; Lewis, Christina; Monette, Sebastien; Fong, Yuman

    2016-01-01

    Stem-like tumor-initiating cells (TICs) are implicated in cancer progression and recurrence, and can be identified by sphere-formation and tumorigenicity assays. Oncolytic viruses infect, replicate in, and kill a variety of cancer cells. In this study, we seek proof of principle that TICs are susceptible to viral infection. HCT8 human colon cancer cells were subjected to serum-free culture to generate TIC tumorspheres. Parent cells and TICs were infected with HSV-1 subtype NV1066. Cytotoxicity, viral replication, and Akt1 expression were assessed. TIC tumorigenicity was confirmed and NV1066 efficacy was assessed in vivo. NV1066 infection was highly cytotoxic to both parent HCT8 cells and TICs. In both populations, cell-kill of >80% was achieved within 3 days of infection at a multiplicity of infection (MOI) of 1.0. However, the parent cells required 2-log greater viral replication to achieve the same cytotoxicity. TICs overexpressed Akt1 in vitro and formed flank tumors from as little as 100 cells, growing earlier, faster, larger, and with greater histologic atypia than tumors from parent cells. Treatment of TIC-induced tumors with NV1066 yielded tumor regression and slowed tumor growth. We conclude that colon TICs are selected for by serum-free culture, overexpress Akt1, and are susceptible to oncolytic viral infection. PMID:27347556

  15. Characterisation of Mesothelioma-Initiating Cells and Their Susceptibility to Anti-Cancer Agents

    PubMed Central

    Pasdar, Elham Alizadeh; Smits, Michael; Stapelberg, Michael; Bajzikova, Martina; Stantic, Marina; Goodwin, Jacob; Yan, Bing; Stursa, Jan; Kovarova, Jaromira; Sachaphibulkij, Karishma; Bezawork-Geleta, Ayenachew; Sobol, Margaryta; Filimonenko, Anatoly; Tomasetti, Marco; Zobalova, Renata; Hozak, Pavel; Dong, Lan-Feng; Neuzil, Jiri

    2015-01-01

    Malignant mesothelioma (MM) is an aggressive type of tumour causing high mortality. One reason for this paradigm may be the existence of a subpopulation of tumour-initiating cells (TICs) that endow MM with drug resistance and recurrence. The objective of this study was to identify and characterise a TIC subpopulation in MM cells, using spheroid cultures, mesospheres, as a model of MM TICs. Mesospheres, typified by the stemness markers CD24, ABCG2 and OCT4, initiated tumours in immunodeficient mice more efficiently than adherent cells. CD24 knock-down cells lost the sphere-forming capacity and featured lower tumorigenicity. Upon serial transplantation, mesospheres were gradually more efficiently tumrigenic with increased level of stem cell markers. We also show that mesospheres feature mitochondrial and metabolic properties similar to those of normal and cancer stem cells. Finally, we show that mesothelioma-initiating cells are highly susceptible to mitochondrially targeted vitamin E succinate. This study documents that mesospheres can be used as a plausible model of mesothelioma-initiating cells and that they can be utilised in the search for efficient agents against MM. PMID:25932953

  16. MAPK13 is preferentially expressed in gynecological cancer stem cells and has a role in the tumor-initiation.

    PubMed

    Yasuda, Kazuyo; Hirohashi, Yoshihiko; Kuroda, Takafumi; Takaya, Akari; Kubo, Terufumi; Kanaseki, Takayuki; Tsukahara, Tomohide; Hasegawa, Tadashi; Saito, Tsuyoshi; Sato, Noriyuki; Torigoe, Toshihiko

    2016-04-15

    Cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) are defined as small subpopulation of cancer cells that are endowed with higher tumor-initiating ability. CSCs/CICs are resistant to standard cancer therapies including chemotherapy and radiotherapy, and they are thus thought to be responsible for cancer recurrence and metastasis. Therefore, elucidation of molecular mechanisms of CSCs/CICs is essential to cure cancer. In this study, we analyzed the gene expression profiles of gynecological CSCs/CICs isolated as aldehyde dehydrogenase high (ALDH(high)) cells, and found that MAPK13, PTTG1IP, CAPN1 and UBQLN2 were preferentially expressed in CSCs/CICs. MAPK13 is expressed in uterine, ovary, stomach, colon, liver and kidney cancer tissues at higher levels compared with adjacent normal tissues. MAPK13 gene knockdown using siRNA reduced the ALDH(high) population and abrogated the tumor-initiating ability. These results indicate that MAPK13 is expressed in gynecological CSCs/CICs and has roles in the maintenance of CSCs/CICs and tumor-initiating ability, and MAPK13 might be a novel molecular target for treatment-resistant CSCs/CICs. PMID:26969274

  17. IKKβ in intestinal mesenchymal cells promotes initiation of colitis-associated cancer

    PubMed Central

    Pasparakis, Manolis

    2015-01-01

    The importance of mesenchymal cells in inflammation and/or neoplastic transformation is well recognized, but their role in the initiation of these processes, particularly in the intestine, remains elusive. Using mouse models of colorectal cancer, we show that IKKβ in intestinal mesenchymal cells (IMCs) is critically involved in colitis-associated, but not spontaneous tumorigenesis. We further demonstrate that IMC-specific IKKβ is involved in the initiation of colitis-associated cancer (CAC), as in its absence mice develop reduced immune cell infiltration, epithelial cell proliferation, and dysplasia at the early stages of the disease. At the molecular level, these effects are associated with decreased early production of proinflammatory and protumorigenic mediators, including IL-6, and reduced STAT3 activation. Ex vivo IKKβ-deficient IMCs show defective responses to innate immune stimuli such as LPS, as shown by decreased NF-κB signaling and reduced expression of important NF-κB target genes. Collectively, our results reveal a hitherto unknown role of mesenchymal IKKβ in driving inflammation and enabling carcinogenesis in the intestine. PMID:26621453

  18. IKKβ in intestinal mesenchymal cells promotes initiation of colitis-associated cancer.

    PubMed

    Koliaraki, Vasiliki; Pasparakis, Manolis; Kollias, George

    2015-12-14

    The importance of mesenchymal cells in inflammation and/or neoplastic transformation is well recognized, but their role in the initiation of these processes, particularly in the intestine, remains elusive. Using mouse models of colorectal cancer, we show that IKKβ in intestinal mesenchymal cells (IMCs) is critically involved in colitis-associated, but not spontaneous tumorigenesis. We further demonstrate that IMC-specific IKKβ is involved in the initiation of colitis-associated cancer (CAC), as in its absence mice develop reduced immune cell infiltration, epithelial cell proliferation, and dysplasia at the early stages of the disease. At the molecular level, these effects are associated with decreased early production of proinflammatory and protumorigenic mediators, including IL-6, and reduced STAT3 activation. Ex vivo IKKβ-deficient IMCs show defective responses to innate immune stimuli such as LPS, as shown by decreased NF-κB signaling and reduced expression of important NF-κB target genes. Collectively, our results reveal a hitherto unknown role of mesenchymal IKKβ in driving inflammation and enabling carcinogenesis in the intestine. PMID:26621453

  19. Direct cost for initial management of prostate cancer: a systematic review

    PubMed Central

    Sanyal, C.; Aprikian, A.G.; Chevalier, S.; Cury, F.L.; Dragomir, A.

    2013-01-01

    Background Prostate cancer (pca) is the most common non-skin cancer among men in Canada and other Western countries. Increased prevalence and higher cost of newer treatments have led to a significant rise in the economic burden of pca. The objectives of the present study were to systematically review the literature on direct costs for the initial management of pca, and to examine the methodologic considerations across studies. Methods Bibliographic databases were systematically searched for peer-reviewed articles in English. Studies were reviewed for methodologic considerations and mean direct cost of active surveillance or watchful waiting (as/ww) and initial treatments. Direct cost was standardized to 2011 Canadian dollars. Results After a review of abstracts and full-text papers, seventeen articles met the eligibility criteria and were included in the review. Studies were published during 1992–2010. The studies reported on health care systems in the United States, France, the United Kingdom, German, Italy, and Spain. Our review identified a lack of methodologic consensus, leading to variation in direct costs between studies. Nevertheless, results indicate a significant direct cost of pca treatments. Conclusions The existing literature lacks methodologically rigorous studies on the direct costs of pca treatments specific to publicly funded health care systems. Additional studies are required to appreciate the direct costs of newer treatments and the impact of their adoption on the growing economic burden of pca management. PMID:24311952

  20. Endothelial cell-initiated signaling promotes the survival and self-renewal of cancer stem cells

    PubMed Central

    Krishnamurthy, Sudha; Dong, Zhihong; Vodopyanov, Dmitry; Imai, Atsushi; Helman, Joseph I.; Prince, Mark E.; Wicha, Max S.; Nör, Jacques E.

    2010-01-01

    Recent studies have demonstrated that cancer stem cells play an important role in the pathobiology of head and neck squamous cell carcinomas (HNSCC). However, little is known about functional interactions between head and neck cancer stem-like cells (CSC) and surrounding stromal cells. Here, we used Aldehyde Dehydrogenase activity and CD44 expression to sort putative stem cells from primary human HNSCC. Implantation of 1,000 CSC (ALDH+CD44+Lin−) led to tumors in 13 (out of 15) mice, while 10,000 non-cancer stem cells (NCSC; ALDH−CD44−Lin−) resulted in 2 tumors in 15 mice. These data demonstrated that ALDH and CD44 select a sub-population of cells that are highly tumorigenic. The ability to self-renew was confirmed by the observation that ALDH+CD44+Lin− cells sorted from human HNSCC formed more spheroids (orospheres) in 3-D agarose matrices or ultra-low attachment plates than controls and were serially passaged in vivo. We observed that approximately 80% of the CSC were located in close proximity (within 100-µm radius) of blood vessels in human tumors, suggesting the existence of perivascular niches in HNSCC. In vitro studies demonstrated that endothelial cell-secreted factors promoted self-renewal of CSC, as demonstrated by the upregulation of Bmi-1 expression and the increase in the number of orospheres as compared to controls. Notably, selective ablation of tumor-associated endothelial cells stably transduced with a caspase-based artificial death switch (iCaspase-9) caused a marked reduction in the fraction of CSC in xenograft tumors. Collectively, these findings indicate that endothelial cell-initiated signaling can enhance the survival and self-renewal of head and neck cancer stem cells. PMID:21098716

  1. Spontaneous initiation, promotion and progression of colorectal cancer in the novel A/J Min/+ mouse.

    PubMed

    Sødring, Marianne; Gunnes, Gjermund; Paulsen, Jan Erik

    2016-04-15

    The C57BL/6J multiple intestinal neoplasia (Min/+) mouse is a widely used murine model for familial adenomatous polyposis, a hereditary form of human colorectal cancer. However, it is a questionable model partly because the vast majority of tumors arise in the small intestine, and partly because the fraction of tumors that progress to invasive carcinomas is minuscule. A/J mice are typically more susceptible to carcinogen-induced colorectal cancer than C57BL/6J mice. To investigate whether the novel Min/+ mouse on the A/J genetic background could be a better model for colorectal cancer, we examined the spontaneous intestinal tumorigenesis in 81 A/J Min/+ mice ranging in age from 4 to 60 weeks. The A/J Min/+ mouse exhibited a dramatic increase in number of colonic lesions when compared to what has been reported for the conventional Min/+ mouse; however, an increase in small intestinal lesions did not occur. In addition, this novel mouse model displayed a continual development of colonic lesions highlighted by the transition from early lesions (flat ACF) to tumors over time. In mice older than 40 weeks, 13 colonic (95% CI: 8.7-16.3) and 21 small intestinal (95% CI: 18.6-24.3) tumors were recorded. Notably, a considerable proportion of those lesions progressed to carcinomas in both the colon (21%) and small intestine (51%). These findings more closely reflect aspects of human colorectal carcinogenesis. In conclusion, the novel A/J Min/+ mouse may be a relevant model for initiation, promotion and progression of colorectal cancer. PMID:26566853

  2. Putative CD133+ melanoma cancer stem cells induce initial angiogenesis in vivo.

    PubMed

    Zimmerer, Rüdiger M; Matthiesen, Peter; Kreher, Fritjof; Kampmann, Andreas; Spalthoff, Simon; Jehn, Philipp; Bittermann, Gido; Gellrich, Nils-Claudius; Tavassol, Frank

    2016-03-01

    Tumor angiogenesis is essential for tumor growth and metastasis, and is regulated by a complex network of various types of cells, chemokines, and stimulating factors. In contrast to sprouting angiogenesis, tumor angiogenesis is also influenced by hypoxia, inflammation, and the attraction of bone-marrow-derived cells. Recently, cancer stem cells have been reported to mimic vascularization by differentiating into endothelial cells and inducing vessel formation. In this study, the influence of cancer stem cells on initial angiogenesis was evaluated for the metastatic melanoma cell line D10. Following flow cytometry, CD133+ and CD133- cells were isolated using magnetic cell separation and different cell fractions were transferred to porcine gelatin sponges, which were implanted into the dorsal skinfold chamber of immunocompromised mice. Angiogenesis was analyzed based on microvessel density over a 10-day period using in vivo fluorescence microscopy, and the results were verified using immunohistology. CD133+ D10 cells showed a significant induction of early angiogenesis in vivo, contrary to CD133- D10 cells, unsorted D10 cells, and negative control. Neovascularization was confirmed by visualizing endothelial cells by immunohistology using an anti-CD31 antibody. Because CD133+ cells are rare in clinical specimens and hardly amenable to functional assays, the D10 cell line provides a suitable model to study the angiogenic potential of putative cancer stem cells and the leukocyte-endothelial cell interaction in the dorsal skinfold chamber in vivo. This cancer stem cell model might be useful in the development and evaluation of therapeutic agents targeting tumors. PMID:26656667

  3. Diabetes, metformin and incidence of and death from invasive cancer in postmenopausal women: Results from the women's health initiative.

    PubMed

    Gong, Zhihong; Aragaki, Aaron K; Chlebowski, Rowan T; Manson, JoAnn E; Rohan, Thomas E; Chen, Chu; Vitolins, Mara Z; Tinker, Lesley F; LeBlanc, Erin S; Kuller, Lewis H; Hou, Lifang; LaMonte, Michael J; Luo, Juhua; Wactawski-Wende, Jean

    2016-04-15

    Findings from studies of metformin use with risk of cancer incidence and outcome provide mixed results; with few studies examined associations by recency of diabetes diagnosis or duration of medication use. Thus, in the Women's Health Initiative, we examined these associations and further explored whether associations differ by recency of diabetes and duration of metformin use. Cox regression models were used to estimate hazard ratios (HR) and their 95% confidence intervals. Diabetes was associated with higher risk of total invasive cancer (HR, 1.13; p < 0.001) and of several site-specific cancers (HR, 1.2-1.4, and up to over twofold). Diabetes was also associated with higher risk of death from cancer (HR, 1.46; p < 0.001). There was no overall difference in cancer incidence by diabetes therapy (p = 0.66). However, there was a lower risk of death from cancer for metformin users, compared to users of other medications, relative to women without diabetes, overall (HRs, 1.08 vs. 1.45; p = 0.007) and for breast cancer (HRs, 0.50 vs. 1.29; p = 0.05). Results also suggested that lower cancer risk associated with metformin may be evident only for a longer duration of use in certain cancer sites or subgroup populations. We provide further evidence that postmenopausal women with diabetes are at higher risk of invasive cancer and cancer death. Metformin users, particularly long-term users, may be at lower risk of developing certain cancers and dying from cancer, compared to users of other anti-diabetes medications. Future studies are needed to determine the long-term effect of metformin in cancer risk and survival from cancer. PMID:26616262

  4. Participation du patient Marocain atteint du cancer au choix thérapeutique: résultat d'une enquête réalisée auprès de 272 patient

    PubMed Central

    Boukir, Anwar; Azghari, Ilham; El Kabous, Mustapha; Jouid, Khalid; Boutayeb, Saber; El Ghissassi, Ibrahim; Mrabti, Hind; Errrihani, Hassan

    2015-01-01

    Introduction La décision médicale partagée ‘Shared decision making’ est un concept qui se développe depuis les années 1990. Il donne aux patients le soutien nécessaire pour exprimer leurs préférences et partager la décision médicale. Cette étude cherche à estimer le degré de participation du patient Marocain atteint de cancer au choix thérapeutique. Méthodes Cette enquête a été réalisée auprès de 272 malades sous chimiothérapie pour une pathologie cancéreuse sous forme d'un entretien verbal basé sur un questionnaire. Les patients ont été sélectionnés selon un mode d’échantillonnage aléatoire, le nombre de patients a été choisi pour une marge d'erreur de 5% et un seuil de probabilité qui approxime les 90%. Résultats Seulement 5.5% des patients dans l'enquête ont participé activement dans le choix thérapeutique. Pour 94% des patients de l’échantillon la stratégie thérapeutique adoptée par le médecin est la bonne et représente l'option optimale. Les principales causes retrouvées qui expliquent la non participation à la décision thérapeutique sont le bas niveau d'instruction, la non réceptivité à l'information ainsi que des défauts majeures dans la transmission et la perception de l'information. Conclusion Ces résultats prouvent que la relation médecin malade dans notre contexte baigne toujours dans le modèle paternaliste. La responsabilité de la décision thérapeutique est le plus souvent laissée au médecin. Il est nécessaire d'informer et d'impliquer le patient de façon active dans le choix thérapeutique afin de mieux sauvegarder la relation médecin-malade qui doit être fondée sur la confiance ainsi que sur une approche participative. PMID:26918070

  5. Secretome of human bone marrow mesenchymal stem cells: an emerging player in lung cancer progression and mechanisms of translation initiation.

    PubMed

    Attar-Schneider, Oshrat; Zismanov, Victoria; Drucker, Liat; Gottfried, Maya

    2016-04-01

    Non-small cell lung cancer (NSCLC) remains the most common cause of cancer-related death worldwide. Patients presenting with advanced-stage NSCLC have poor prognosis, while metastatic spread accounts for >70 % of patient's deaths. The major advances in the treatment of lung cancer have brought only minor improvements in survival; therefore, novel strategic treatment approaches are urgently needed. Accumulating data allocate a central role for the cancer microenvironment including mesenchymal stem cells (MSCs) in acquisition of drug resistance and disease relapse. Furthermore, studies indicate that translation initiation factors are over expressed in NSCLC and negatively impact its prognosis. Importantly, translation initiation is highly modulated by microenvironmental cues. Therefore, we decided to examine the effect of bone marrow MSCs (BM-MSCs) from normal donors on NSCLC cell lines with special emphasis on translation initiation mechanism in the crosstalk. We cultured NSCLC cell lines with BM-MSC conditioned media (i.e., secretome) and showed deleterious effects on the cells' proliferation, viability, death, and migration. We also demonstrated reduced levels of translation initiation factors implicated in cancer progression [eukaryotic translation initiation factor 4E (eIF4E) and eukaryotic translation initiation factor 4GI (eIF4GI)], their targets, and regulators. Finally, we outlined a mechanism by which BM-MSCs' secretome affected NSCLC's mitogen-activated protein kinase (MAPK) signaling pathway, downregulated the cell migration, and diminished translation initiation factors' levels. Taken together, our study demonstrates that there is direct dialogue between the BM-MSCs' secretome and NSCLC cells that manipulates translation initiation and critically affects cell fate. We suggest that therapeutic approach that will sabotage this dialogue, especially in the BM microenvironment, may diminish lung cancer metastatic spread and morbidity and improve the patient

  6. Vulnerabilities in Older Patients when Cancer Treatment is Initiated: Does a Cognitive Impairment Impact the Two-Year Survival?

    PubMed Central

    Borghgraef, Cindy; Etienne, Anne-Marie; Merckaert, Isabelle; Paesmans, Marianne; Reynaert, Christine; Roos, Myriam; Slachmuylder, Jean-Louis; Vandenbossche, Sandrine; Bron, Dominique; Razavi, Darius

    2016-01-01

    Introduction Dementia is a known predictor of shorter survival times in older cancer patients. However, no empirical evidence is available to determine how much a cognitive impairment shortens survival in older patients when cancer treatment is initiated. Purpose To longitudinally investigate how much a cognitive impairment detected at the initiation of cancer treatment influences survival of older patients during a two-year follow-up duration and to compare the predictive value of a cognitive impairment on patients survival with the predictive value of other vulnerabilities associated with older age. Methods Three hundred and fifty-seven consecutive patients (≥65 years old) admitted for breast, prostate, or colorectal cancer surgeries were prospectively recruited. A cognitive impairment was assessed with the Montreal Cognitive Assessment (MoCA<26). Socio-demographic, disease-related, and geriatric vulnerabilities were assessed using validated tools. Univariate and subsequent multivariate Cox proportional hazards models stratified for diagnosis (breast/prostate cancer versus colorectal cancer) and disease status (metastatic versus non-metastatic) were used. Results A cognitive impairment was detected in 46% (n = 163) of patients. Survival was significantly influenced by a cognitive impairment (HR = 6.13; 95% confidence interval [CI] = 2.07–18.09; p = 0.001), a loss in instrumental autonomy (IADL ≤7) (HR = 3.06; 95% CI = 1.31–7.11; p = 0.009) and fatigue (Mob-T<5) (HR = 5.98; 95% CI = 2.47–14.44; p <0.001). Conclusions During the two years following cancer treatment initiation, older patients with a cognitive impairment were up to six times more likely to die than patients without. Older patients should be screened for cognitive impairments at cancer treatment initiation to enable interventions to reduce morbidity and mortality. Further studies should address processes underlying the relationship between cognitive impairments and an increased risk of dying

  7. Two Splice Variants of Y Chromosome-Located Lysine-Specific Demethylase 5D Have Distinct Function in Prostate Cancer Cell Line (DU-145).

    PubMed

    Jangravi, Zohreh; Tabar, Mehdi Sharif; Mirzaei, Mehdi; Parsamatin, Pouria; Vakilian, Haghighat; Alikhani, Mehdi; Shabani, Mohammad; Haynes, Paul A; Goodchild, Ann K; Gourabi, Hamid; Baharvand, Hossein; Salekdeh, Ghasem Hosseini

    2015-09-01

    One of the major objectives of the Human Y Chromosome Proteome Project is to characterize sets of proteins encoded from the human Y chromosome. Lysine (K)-specific demethylase 5D (KDM5D) is located on the AZFb region of the Y chromosome and encodes a JmjC-domain-containing protein. KDM5D, the least well-documented member of the KDM5 family, is capable of demethylating di- and trimethyl H3K4. In this study, we detected two novel splice variants of KDM5D with lengths of 2650bp and 2400bp that correspond to the 100 and 80 kDa proteins in the human prostate cancer cell line, DU-145. The knockdown of two variants using the short interfering RNA (siRNA) approach increased the growth rate of prostate cancer cells and reduced cell apoptosis. To explore the proteome pattern of the cells after KDM5D downregulation, we applied a shotgun label-free quantitative proteomics approach. Of 820 proteins present in all four replicates of two treatments, the abundance of 209 proteins changed significantly in response to KDM5D suppression. Of these, there were 102 proteins observed to be less abundant and 107 more abundant in KDM5D knockdown cells compared with control cells. The results revealed that KDM5D knockdown altered the abundance of proteins involved in RNA processing, protein synthesis, apoptosis, the cell cycle, and growth and proliferation. In conjunction, these results provided new insights into the function of KDM5D and its splice variants. The proteomics data are available at PRIDE with ProteomeXchange identifier PXD000416. PMID:26215926

  8. ABCG2 is a potential marker of tumor-initiating cells in breast cancer.

    PubMed

    Sicchieri, Renata Danielle; da Silveira, Willian Abraham; Mandarano, Larissa Raquel Mouro; de Oliveira, Tatiane Mendes Gonçalves; Carrara, Hélio Humberto Angotti; Muglia, Valdair Francisco; de Andrade, Jurandyr Moreira; Tiezzi, Daniel Guimarães

    2015-12-01

    The existence of tumor-initiating cells (TICs) within solid tumors has been hypothesized to explain tumor heterogeneity and resistance to cancer therapy. In breast cancer, the expression of CD44 and CD24 and the activity of aldehyde dehydrogenase 1 (ALDH1) can be used to selectively isolate a cell population enriched in TICs. However, the ideal marker to identify TICs has not been established. The aim of this study was to evaluate the expression of novel potential markers for TIC in breast carcinoma. We prospectively analyzed the expression of CD44, CD24, ABCG2, and CXCR4, and the activity of ALDH1 by using flow cytometry in 48 invasive ductal carcinomas from locally advanced and metastatic breast cancer patients who were administered primary chemotherapy. A mammosphere assay was employed in 30 samples. The relationship among flow cytometric analyses, ABCG2 gene expression, and clinical and pathological responses to therapy was analyzed. The GSE32646 database was analyzed in silico to identify genes associated with tumors with low and high ABCG2 expression. We observed that the presence of ABCG2(+) cells within the primary tumor was the only marker to predict the formation of mammospheres in vitro (R (2) = 0.15, p = 0.029). Quantitative polymerase chain reaction (qPCR) revealed a positive correlation between ABCG2 expression and the presence of ABCG2(+) cells within the primary tumor. The expression of ABCG2 was predictive of the response to neoadjuvant chemotherapy in our experiments and in the GSE32646 dataset (p = 0.04 and p = 0.002, respectively). The in silico analysis demonstrated that ABCG2(Up) breast cancer samples have a slower cell cycle and a higher expression of membrane proteins but a greater potential for chromosomal instability, metastasis, immune evasion, and resistance to hypoxia. Such genetic characteristics are compatible with highly aggressive and resistant tumors. Our results support the hypothesis that the presence of ABCG2

  9. (±)Equol inhibits invasion in prostate cancer DU145 cells possibly via down-regulation of matrix metalloproteinase-9, matrix metalloproteinase-2 and urokinase-type plasminogen activator by antioxidant activity

    PubMed Central

    Zheng, Wei; Zhang, Yumei; Ma, Defu; Shi, Yuhui; Liu, Changqiu; Wang, Peiyu

    2012-01-01

    Exposure to soy isoflavones has been associated with low mortality of prostate cancer. In this study, we examined the effects of (±)equol and two representative isoflavones, daidzein and genistein, on migration and invasion in human prostate cancer DU145 cells. First of all, the three regents did not show significant growth inhibitive effect in DU145 cells until the treatments last for 72 h. Treatment with 5 µM, 10 µM, 50 µM (±)equol, 0.5 µM, 1 µM, 5 µM daidzein and genistein for 24 h decreased cell migration and invasion significantly. (±)equol activated phosphatase and tensin homologue deleted on chromosome ten at protein level but not mRNA level, which activated antioxidants, including superoxide dismutase and nuclear factor (erythroid-derived 2)-like 2. A reduction of malondialdehyde concentration, the product of lipid per-oxidation, was observed as well. Moreover, matrix metalloproteinase-2, matrix metalloproteinase-9, and urokinase-type plasminogen activator, the crucial members in metastasis, were down-regulated. Overall, our data indicate that (±)equol, daidzein and genistein may have significant anti-invasion effect in DU145 cells (in vitro). The effects induced by (±)equol may relate to its anti-oxidant effect mediated by phosphatase and tensin homologue deleted on chromosome ten. PMID:22798715

  10. Resource Utilization and Costs during the Initial Years of Lung Cancer Screening with Computed Tomography in Canada

    PubMed Central

    Lam, Stephen; Tammemagi, Martin C.; Evans, William K.; Leighl, Natasha B.; Regier, Dean A.; Bolbocean, Corneliu; Shepherd, Frances A.; Tsao, Ming-Sound; Manos, Daria; Liu, Geoffrey; Atkar-Khattra, Sukhinder; Cromwell, Ian; Johnston, Michael R.; Mayo, John R.; McWilliams, Annette; Couture, Christian; English, John C.; Goffin, John; Hwang, David M.; Puksa, Serge; Roberts, Heidi; Tremblay, Alain; MacEachern, Paul; Burrowes, Paul; Bhatia, Rick; Finley, Richard J.; Goss, Glenwood D.; Nicholas, Garth; Seely, Jean M.; Sekhon, Harmanjatinder S.; Yee, John; Amjadi, Kayvan; Cutz, Jean-Claude; Ionescu, Diana N.; Yasufuku, Kazuhiro; Martel, Simon; Soghrati, Kamyar; Sin, Don D.; Tan, Wan C.; Urbanski, Stefan; Xu, Zhaolin; Peacock, Stuart J.

    2014-01-01

    Background: It is estimated that millions of North Americans would qualify for lung cancer screening and that billions of dollars of national health expenditures would be required to support population-based computed tomography lung cancer screening programs. The decision to implement such programs should be informed by data on resource utilization and costs. Methods: Resource utilization data were collected prospectively from 2059 participants in the Pan-Canadian Early Detection of Lung Cancer Study using low-dose computed tomography (LDCT). Participants who had 2% or greater lung cancer risk over 3 years using a risk prediction tool were recruited from seven major cities across Canada. A cost analysis was conducted from the Canadian public payer’s perspective for resources that were used for the screening and treatment of lung cancer in the initial years of the study. Results: The average per-person cost for screening individuals with LDCT was $453 (95% confidence interval [CI], $400–$505) for the initial 18-months of screening following a baseline scan. The screening costs were highly dependent on the detected lung nodule size, presence of cancer, screening intervention, and the screening center. The mean per-person cost of treating lung cancer with curative surgery was $33,344 (95% CI, $31,553–$34,935) over 2 years. This was lower than the cost of treating advanced-stage lung cancer with chemotherapy, radiotherapy, or supportive care alone, ($47,792; 95% CI, $43,254–$52,200; p = 0.061). Conclusion: In the Pan-Canadian study, the average cost to screen individuals with a high risk for developing lung cancer using LDCT and the average initial cost of curative intent treatment were lower than the average per-person cost of treating advanced stage lung cancer which infrequently results in a cure. PMID:25105438

  11. Cancer Patient and Survivor Research from the Cancer Information Service Research Consortium: A Preview of Three Large Randomized Trials and Initial Lessons Learned

    PubMed Central

    MARCUS, ALFRED C.; DIEFENBACH, MICHAEL A.; STANTON, ANNETTE L.; MILLER-HALEGOUA, SUZANNE N.; FLEISHER, LINDA; RAICH, PETER C.; MORRA, MARION E.; PEROCCHIA, ROSEMARIE SLEVIN; TRAN, ZUNG VU; BRIGHT, MARY ANNE

    2014-01-01

    Three large randomized trials are described from the Cancer Information Service Research Consortium (CISRC). Three web-based multimedia programs are being tested to help newly diagnosed prostate (Project 1) and breast cancer patients (Project 2) make informed treatment decisions and breast cancer patients prepare for life after treatment (Project 3). Project 3 is also testing a telephone callback intervention delivered by a cancer information specialist. All participants receive standard print material specific to each project. Preliminary results from the two-month follow-up interviews are reported for the initial wave of enrolled participants, most of whom were recruited from the Cancer Information Service (1-800-4-CANCER) telephone information program (Project 1 = 208, Project 2 = 340, Project 3 = 792). Self-reported use of the multimedia program was 51%, 52% and 67% for Projects 1–3, respectively. Self-reported use of the print materials (read all, most or some) was 90%, 85% and 83% for Projects 1–3, respectively. The callback intervention was completed by 92% of Project 3 participants. Among those using the CISRC interventions, perceived utility and benefit was high, and more than 90% would recommend them to other cancer patients. Five initial lessons learned are presented that may help inform future cancer communications research. PMID:23448232

  12. [PHENOTYPE OF PERIPHERAL BLOOD NEUTROPHILS IN THE INITIAL STAGE OF ENDOMETRIAL CANCER].

    PubMed

    Abakumova, T V; Antoneeva, I I; Gening, T P; Dolgova, D R; Gening, S O

    2016-01-01

    We have examined peripheral blood neutrophils from 123 patients with primary endometrial cancer at stage Ia. Receptor system and the ability of neutrophils to form extracellular traps were assessed by fluorescence microscopy, the spontaneous production of cytokines IL-2, IFN-γ, g-CSF, matrix metalloproteinases-1,9,13 by the method of enzyme-linked immunosorbent assay, phagocytic activity, myeloperoxidase activity, the level of cationic proteis activity in NBT-test were evaluated by cytochemical methods, activity of neutrophils in the spontaneous NBT-test was used to evaluate the oxygen-dependent bactericidal action of neutrophils. The topology and the rigidity of the membrane of neutrophils were assessed by scanning probe microscopy. We have shown that the increase in the relative number of neutrophils lead to a change in their receptor system, aerobic and anaerobic cytotoxicity and ability to phagocytosis are enchanced while reducing NET-activity. We have observed a change in the secretory activity of neutrophils, which is characterized by increased level of MMP-1, possibly initiated by enhanced production of reactive oxygen species, by a reduction in the IL-2 level (inductor of cytotoxic activity) and a sharp increase in the level of the G-CSF. Architectonics of neutrophils in the case of endonetrial cancer at stage Ia is characterized by changing the shape and loss of grit. The rigidity of the cell membrane decreased. Changes in the morphology of neutrophils on the background of the continuing hyperactivity suggests that a state of balance between the immune system and the tumor is already in stage Ia endometrial cancer. PMID:27220248

  13. Positron emission tomography for initial staging of esophageal cancer among medicare beneficiaries

    PubMed Central

    Varghese, Thomas K.; Flanagan, Meghan R.; Flum, David R.; Shankaran, Veena; Oelschlager, Brant K.; Mulligan, Michael S.; Wood, Douglas E.; Pellegrini, Carlos A.

    2016-01-01

    Background The role of positron emission tomography (PET) in the initial staging of esophageal cancer is to detect occult metastases, but its ability to do so has not been evaluated at the population-level. In 2001, Medicare approved reimbursement of PET for esophageal cancer staging. We hypothesized rapid adoption of PET after 2001 and a coincident increase in the prevalence of stage IV disease. Methods A retrospective cohort study [1997-2009] was conducted of 12,870 Medicare beneficiaries with esophageal cancer using the Surveillance, Epidemiology, and End-Results (SEER)-Medicare database. Results PET use increased from <3% before 2001 to 44% in 2009 (post-PET era) (P trend <0.001). Over the same period, the prevalence of stage IV disease also increased (20% in 1997 and 28% in 2009, P trend <0.001). After adjusting for changing patient characteristics over time, the rate of increase in stage IV disease in the post-PET era [relative risk (RR) =1.06; 95% confidence interval (CI), 1.00-1.13] was no different than the rate of increase in the pre-PET era (RR =1.02; 95% CI, 1.02-1.04). Over the entire study period, the prevalence of unrecorded stage decreased by more than half (43% to 18%, adjusted P trend <0.001) with coincident increases in stage 0-III (37% to 53%, adjusted P trend <0.001) as well as stage IV disease. Conclusions The increasing frequency of PET use and stage IV disease over time is more likely explained by improved documentation rather than PET’s ability to detect occult metastases. The absence of compelling population-level impact compliments previous studies, revealing an opportunity to increase value through selective use of PET. PMID:27284472

  14. Undesirable financial effects of head and neck cancer radiotherapy during the initial treatment period

    PubMed Central

    Egestad, Helen; Nieder, Carsten

    2015-01-01

    Background Healthcare cost and reforms are at the forefront of international debates. One of the current discussion themes in oncology is whether and how patients’ life changes due to costs of cancer care. In Norway, the main part of the treatment costs is supported by general taxpayer revenues. Objectives The objective of this study was to clarify whether head and neck cancer patients (n=67) in northern Norway experienced financial health-related quality of life (HRQOL) deterioration due to costs associated with treatment. Design HRQOL was examined by the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 in the beginning and in the end of radiation treatment in patients treated at the University Hospital in Northern Norway. Changes in financial HRQOL were calculated and compared by paired sample T-tests. Multiple regression analyses were used to examine correlations among gender, marital status, age and treatment with or without additional chemotherapy and changes in the HRQOL domain of financial difficulties. Results The majority of score results at both time points were in the lower range (mean 15–25), indicating limited financial difficulties. We observed no statistically significant differences by gender, marital status and age. Increasing financial difficulties during treatment were reported by male patients and those younger than 65, that is, patients who were younger than retirement age. The largest effect was seen in singles. However, differences were not statistically significant. Conclusions During the initial phase of the disease trajectory, no significant increase in financial difficulties was found. This is in line with the aims of the Norwegian public healthcare model. However, long-term longitudinal studies should be performed, especially with regard to the trends we observed in single, male and younger patients. PMID:25623815

  15. Beginner Surgeon's Initial Experience with Distal Subtotal Gastrectomy for Gastric Cancer Using a Minimally Invasive Approach

    PubMed Central

    You, Yung Hun; Ahn, Dae Ho

    2015-01-01

    Purpose Minimally invasive gastrectomy (MIG), including laparoscopic distal subtotal gastrectomy (LDG) and robotic distal subtotal gastrectomy (RDG), is performed for gastric cancer, and requires a learning period. However, there are few reports regarding MIG by a beginner surgeon trained in MIG for gastric cancer during surgical residency and fellowship. The aim of this study was to report our initial experience with MIG, LDG, and RDG by a trained beginner surgeon. Materials and Methods Between January 2014 and February 2015, a total of 36 patients (20 LDGs and 16 RDGs) underwent MIG by a beginner surgeon during the learning period, and 13 underwent open distal subtotal gastrectomy (ODG) by an experienced surgeon in Bundang CHA Medical Center. Demographic characteristics, operative findings, and short-term outcomes were evaluated for the groups. Results MIG was safely performed without open conversion in all patients and there was no mortality in either group. There was no significant difference between the groups in demographic factors except for body mass index. There were significant differences in extent of lymph node dissection (LND) (D2 LND: ODG 8.3% vs. MIG 55.6%, P=0.004) and mean operative time (ODG 178.8 minutes vs. MIG 254.7 minutes, P<0.001). The serial changes in postoperative hemoglobin level (P=0.464) and white blood cell count (P=0.644) did not show significant differences between the groups. There were no significant differences in morbidity. Conclusions This study showed that the operative and short-term outcomes of MIG for gastric cancer by a trained beginner surgeon were comparable with those of ODG performed by an experienced surgeon. PMID:26819806

  16. Hemorrhagic small intestine cancer with solitary pulmonary metastasis initially presented as suspected primary lung cancer: an autopsy report.

    PubMed

    Iwata, Takashi; Inoue, Kiyotoshi; Kiriike, Sachiko; Izumi, Nobuhiro; Mizuguchi, Shinjiro; Tsukioka, Takuma; Morita, Ryuhei; Nishiyama, Noritoshi; Takemura, Masashi; Osugi, Harusi; Wakasa, Kenichi; Suehiro, Shigefumi

    2007-12-01

    Cancer of the small intestine presenting with a solitary pulmonary metastasis is rare. Diagnosis and treatment of hemorrhagic small intestinal disease is clinically problematic due to its anatomic aspect, especially after multiple laparotomies. The case that we present here was a 79-year-old man who was initially diagnosed with suspected T2N2M0 lung cancer. After non-diagnostic results on two bronchoscopic biopsies and computed tomography-guided needle biopsy, he was admitted for thoracoscopic biopsy and possible curative operation. The patient had a history of multiple laparotomies for gastric ulcer and had no abdominal symptoms. A fecal occult blood test was positive; this was thought to be because of persistent bloody sputum. During the preoperative evaluation period, massive intestinal hemorrhage occurred. Intestinal tumor was identified by double-balloon enteroscopy and emergency laparotomy was performed to control the bleeding. The histopathological diagnosis was metastatic adenocarcinoma. However, intestinal bleeding started again. His systemic status deteriorated progressively, resulting in death. Autopsy revealed a large polypoid tumor with hemorrhagic necrosis in the jejunum that was histologically and immunohistochemically diagnosed as primary poorly differentiated adenocarcinoma in the small intestine. Multiple small submucosal tumors with central ulceration were confirmed as intramural metastases. A lung mass in the right lower lobe was diagnosed as a metastatic lesion. In the diagnosis and treatment of the disease, we faced several clinically difficult problems. We here describe in detail the clinical course and the diagnostic and therapeutic difficulties of this rare case, with some references to the literature. PMID:18432067

  17. Diet Quality and Colorectal Cancer Risk in the Women's Health Initiative Observational Study.

    PubMed

    Vargas, Ashley J; Neuhouser, Marian L; George, Stephanie M; Thomson, Cynthia A; Ho, Gloria Y F; Rohan, Thomas E; Kato, Ikuko; Nassir, Rami; Hou, Lifang; Manson, JoAnn E

    2016-07-01

    Diet quality index scores on Healthy Eating Index 2010 (HEI-2010), Alternative HEI-2010, alternative Mediterranean Diet Index, and the Dietary Approaches to Stop Hypertension (DASH) index have been inversely associated with all-cause and cancer-specific death. This study assessed the association between these scores and colorectal cancer (CRC) incidence as well as CRC-specific mortality in the Women's Health Initiative Observational Study (1993-2012), a US study of postmenopausal women. During an average of 12.4 years of follow-up, there were 938 cases of CRC and 238 CRC-specific deaths. We estimated multivariate hazard ratios and 95% confidence intervals for relationships between quintiles of diet scores (from baseline food frequency questionnaires) and outcomes. HEI-2010 score (hazard ratios were 0.81, 0.77, and 0.73 with P values of 0.04, 0.01, and <0.01 for quintiles 3-5 vs. quintile 1, respectively) and DASH score (hazard ratios were 0.72, 0.74, and 0.78 with P values of <0.01, <0.01, and 0.03 for quintiles 3-5 vs. quintile 1, respectively), but not other diet scores, were associated with a lower risk of CRC in adjusted models. No diet scores were significantly associated with CRC-specific mortality. Closer adherence to HEI-2010 and DASH dietary recommendations was inversely associated with risk of CRC in this large cohort of postmenopausal women. PMID:27267948

  18. Needs of young children with cancer during their initial hospitalization: an observational study.

    PubMed

    Björk, Maria; Nordström, Berit; Hallström, Inger

    2006-01-01

    The aim of this study was to describe young (under the age of 7) children's needs as expressed by their behavior, body language and verbal expression through observations during their initial hospitalization after being diagnosed with cancer. Twelve children under the age of seven were followed during 26 hours with non-participant unstructured observations. Field notes were written after each observation and transcribed into a narrative text, which was analyzed by content analysis at both manifest and latent level. Five themes were identified, of which "need to have the parent close by" was the most prominent. The other themes were "need to play and feel joy," "need for participation in care and treatment," "need for a good relationship with the staff," and "need for physical and emotional satisfaction." The results indicate that the children needed their parents and the parents' presence helped the children to express other needs. Professionals need to support the child and his or her parents so that the parents in their turn can support and alleviate their child's hospitalization and cancer treatment. PMID:16766686

  19. Laser immunotherapy: initial results from a human breast cancer pilot trial

    NASA Astrophysics Data System (ADS)

    Hode, Tomas; Guerra, Maria C.; Ferrel, Gabriela L.; Lunn, John A.; Adelsteinsson, Orn; Nordquist, Robert E.; Chen, Wei R.

    2010-02-01

    Laser Immunotherapy is an experimental treatment modality for late-stage, metastatic tumors, which targets solid primary and/or secondary tumors and utilizes an autologous vaccine-like approach to stimulate immune responses. Specifically, laser immunotherapy combines laser-induced in situ tumor devitalization with an immunoadjuvant for local immunostimulation. Here we report the initial results from a human breast cancer pilot trial with laser immunotherapy. Six stage III and IV cancer patients were treated, all of which were considered to be out of all other options, and preliminary data at the three-month examination are presented. The immediate goal of the trial was to determine the patient tolerance and the toxicity of the therapy, the optimal dose for the alteration of the course of the disease, and the reduction of the tumor burden. Each patient was individually evaluated for toxicity tolerance through physical exams and by appropriate supplemental and routine laboratory tests. Observable tumors in patients were followed with physical examination and radiological evaluations. Treatment efficacy was judged by the size and number of local and distant metastases before and after treatment.

  20. Long-lived intestinal tuft cells serve as colon cancer-initiating cells.

    PubMed

    Westphalen, C Benedikt; Asfaha, Samuel; Hayakawa, Yoku; Takemoto, Yoshihiro; Lukin, Dana J; Nuber, Andreas H; Brandtner, Anna; Setlik, Wanda; Remotti, Helen; Muley, Ashlesha; Chen, Xiaowei; May, Randal; Houchen, Courtney W; Fox, James G; Gershon, Michael D; Quante, Michael; Wang, Timothy C

    2014-03-01

    Doublecortin-like kinase 1 protein (DCLK1) is a gastrointestinal tuft cell marker that has been proposed to identify quiescent and tumor growth-sustaining stem cells. DCLK1⁺ tuft cells are increased in inflammation-induced carcinogenesis; however, the role of these cells within the gastrointestinal epithelium and their potential as cancer-initiating cells are poorly understood. Here, using a BAC-CreERT-dependent genetic lineage-tracing strategy, we determined that a subpopulation of DCLK1⁺ cells is extremely long lived and possesses rare stem cell abilities. Moreover, genetic ablation of Dclk1 revealed that DCLK1⁺ tuft cells contribute to recovery following intestinal and colonic injury. Surprisingly, conditional knockdown of the Wnt regulator APC in DCLK1⁺ cells was not sufficient to drive colonic carcinogenesis under normal conditions; however, dextran sodium sulfate-induced (DSS-induced) colitis promoted the development of poorly differentiated colonic adenocarcinoma in mice lacking APC in DCLK1⁺ cells. Importantly, colonic tumor formation occurred even when colitis onset was delayed for up to 3 months after induced APC loss in DCLK1⁺ cells. Thus, our data define an intestinal DCLK1⁺ tuft cell population that is long lived, quiescent, and important for intestinal homeostasis and regeneration. Long-lived DCLK1⁺ cells maintain quiescence even following oncogenic mutation, but are activated by tissue injury and can serve to initiate colon cancer. PMID:24487592

  1. Resveratrol and N-acetylcysteine block the cancer-initiating step in MCF-10F cells

    PubMed Central

    Zahid, Muhammad; Saeed, Muhammad; Beseler, Cheryl; Rogan, Eleanor G.; Cavalieri, Ercole L.

    2015-01-01

    Substantial evidence suggests that catechol estrogen-3,4-quinones react with DNA to form predominantly the depurinating adducts 4-hydroxyestrone (estradiol)-1-N3Ade [4-OHE1(E2)-1-N3Ade] and 4-OHE1(E2)-1-N7Gua. Apurinic sites resulting from these adducts generate critical mutations that can initiate cancer. The paradigm of cancer initiation is based on an imbalance in estrogen metabolism between activating pathways that lead to estrogen–DNA adducts and deactivating pathways that lead to estrogen metabolites and conjugates. This imbalance can be improved to minimize formation of adducts by using antioxidants, such as resveratrol (Resv) and N-acetylcysteine (NAcCys). To compare the ability of Resv and NAcCys to block formation of estrogen–DNA adducts, we used the human breast epithelial cell line MCF-10F treated with 4-OHE2. Resv and NAcCys directed the metabolism of 4-OHE2 toward protective pathways. NAcCys reacted with the quinones and reduced the semiquinones to catechols. This pathway was also carried out by Resv. In addition, Resv induced the protective enzyme quinone reductase, which reduces E1(E2)-3,4-quinones to 4-OHE1(E2). Resv was more effective at increasing the amount of 4-OCH3E1(E2) than NAcCys. Inhibition of estrogen–DNA adduct formation was similar at lower doses, but at higher doses Resv was about 50% more effective than NAcCys. Their combined effects were additive. Therefore, these two antioxidants provide an excellent combination to protect catechol estrogens from oxidation to catechol quinones. PMID:20934508

  2. RGD-modifided oncolytic adenovirus exhibited potent cytotoxic effect on CAR-negative bladder cancer-initiating cells

    PubMed Central

    Yang, Y; Xu, H; Shen, J; Yang, Y; Wu, S; Xiao, J; Xu, Y; Liu, X-Y; Chu, L

    2015-01-01

    Cancer-initiating cell (CIC) is critical in cancer development, maintenance and recurrence. The reverse expression pattern of coxsackie and adenovirus receptor (CAR) and αν integrin in bladder cancer decreases the infection efficiency of adenovirus. We constructed Arg-Gly-Asp (RGD)-modified oncolytic adenovirus, carrying EGFP or TNF-related apoptosis-inducing ligand (TRAIL) gene (OncoAd.RGD-hTERT-EGFP/TRAIL), and applied them to CAR-negative bladder cancer T24 cells and cancer-initiating T24 sphere cells. OncoAd.RGD-hTERT-EGFP had enhanced infection ability and cytotoxic effect on T24 cells and T24 sphere cells, but little cytoxicity on normal urothelial SV-HUC-1 cells compared with the unmodified virus OncoAd.hTERT-EGFP. Notably, OncoAd.RGD-hTERT-TRAIL induced apoptosis in T24 cells and T24 sphere cells. Furthermore, it completely inhibited xenograft initiation established by the oncolytic adenovirus-pretreated T24 sphere cells, and significantly suppressed tumor growth by intratumoral injection. These results provided a promising therapeutic strategy for CAR-negative bladder cancer through targeting CICs. PMID:25973680

  3. Genome-wide Association Studies from the Cancer Genetic Markers of Susceptibility (CGEMS) Initiative | Office of Cancer Genomics

    Cancer.gov

    CGEMS identifies common inherited genetic variations associated with a number of cancers, including breast and prostate. Data from these genome-wide association studies (GWAS) are available through the Division of Cancer Epidemiology & Genetics website.

  4. Dietary Cadmium Exposure and Risk of Breast, Endometrial, and Ovarian Cancer in the Women’s Health Initiative

    PubMed Central

    Quraishi, Sabah M.; Shafer, Martin M.; Passarelli, Michael N.; Freney, Emily P.; Chlebowski, Rowan T.; Luo, Juhua; Meliker, Jaymie R.; Mu, Lina; Neuhouser, Marian L.; Newcomb, Polly A.

    2014-01-01

    Background: In vitro and animal data suggest that cadmium, a heavy metal that contaminates some foods and tobacco plants, is an estrogenic endocrine disruptor. Elevated estrogen exposure is associated with breast, endometrial, and ovarian cancer risk. Objectives: We examined the association between dietary cadmium intake and risk of these cancers in the large, well-characterized Women’s Health Initiative (WHI). Methods: A total of 155,069 postmenopausal women, 50–79 years of age, who were enrolled in the WHI clinical trials or observational study, participated in this study. We estimated dietary cadmium consumption by combining baseline food frequency questionnaire responses with U.S. Food and Drug Administration data on food cadmium content. Participants reported incident invasive breast, endometrial, or ovarian cancer, and WHI centrally adjudicated all cases through August 2009. We applied Cox regression to estimate adjusted hazard ratios (HRs) and 95% CIs for each cancer, comparing quintiles of energy-adjusted dietary cadmium intake. Results: Over an average of 10.5 years, 6,658 invasive breast cancers, 1,198 endometrial cancers, and 735 ovarian cancers were reported. We observed no statistically significant associations between dietary cadmium and risk of any of these cancers after adjustment for potential confounders including total dietary energy intake. Results did not differ in any subgroup of women examined. Conclusions: We found little evidence that dietary cadmium is a risk factor for breast, endometrial, or ovarian cancers in postmenopausal women. Misclassification in dietary cadmium assessment may have attenuated observed associations. Citation: Adams SV, Quraishi SM, Shafer MM, Passarelli MN, Freney EP, Chlebowski RT, Luo J, Meliker JR, Mu L, Neuhouser ML, Newcomb PA. 2014. Dietary cadmium exposure and risk of breast, endometrial, and ovarian cancer in the Women’s Health Initiative. Environ Health Perspect 122:594–600; http://dx.doi.org/10

  5. Initial Treatment Patterns in Younger Adult Patients with Differentiated Thyroid Cancer in California

    PubMed Central

    Semrad, Alison M.; Farwell, D. Gregory; Chen, Yingjia; Cress, Rosemary

    2015-01-01

    Background: Differentiated thyroid cancer (DTC) is among the most common malignancies in the adolescent and young adult (age 15–39 years) population, and its incidence is rising. Younger age (<45 years) is an important prognostic indicator and is incorporated into the TNM classification system. This study hypothesized that this would result in distinct treatment patterns for younger and older patients. Methods: Using the California Cancer Registry, 24,362 patients with DTC from 2004 to 2011 were identified, and they were divided into younger (<45 years) and older (≥45 years) cohorts. Demographic and clinical variables were tabulated and then compared using chi-square tests. Treatment variables included total or near total thyroidectomy, other types of thyroid surgery, and the administration of radioiodine as part of the initial treatment. Multivariable logistic regression was used to identify independent predictors of treatment administered. Results: Younger patients were more likely to be Hispanic (32.5% vs. 21.2%) and female (82.7% vs. 74.7%), and to have papillary carcinoma (92.9% vs. 90.9%) and lymph node involvement (32.8% vs. 19.7%; p<0.0001). On multivariable analysis, younger patients (OR 1.20 [CI 1.11–1.30]), higher T-stage tumors, higher socioeconomic status (SES), and papillary carcinoma were predictors of undergoing total thyroidectomy versus less than total thyroid surgery. After adjustment, predictors of radioiodine administration included younger age (OR 1.12 [CI 1.05–1.18]), higher SES, total thyroidectomy, higher T stage, and lymph node positivity. Conclusions: Younger patients with DTC in California are more likely to be female and Hispanic with papillary histology. After adjustment for disease and demographic characteristics, younger patients are more likely to undergo total thyroidectomy as their initial surgery and are more likely to receive radioiodine. Given their excellent prognosis and the potential for adverse sequelae from initial

  6. Proteomic analysis of cancer stem cells in human prostate cancer cells

    SciTech Connect

    Lee, Eun-Kyung; Cho, Hyungdon; Kim, Chan-Wha

    2011-08-26

    Highlights: {yields} DU145 prostate cancer cell line was isolated into CD44+ or CD44- cells. {yields} We confirmed CD44+ DU145 cells are more proliferative and tumorigenic than CD44- DU145 cells. {yields} We analyzed and identified proteins that were differentially expressed between CD44+ and CD44- DU145 cells. {yields} Cofilin and Annexin A5 associated with cancer were found to be positively correlated with CD44 expression. -- Abstract: Results from recent studies support the hypothesis that cancer stem cells (CSCs) are responsible for tumor initiation and formation. Here, we applied a proteome profiling approach to investigate the mechanisms of CSCs and to identify potential biomarkers in the prostate cancer cell line DU145. Using MACS, the DU145 prostate cancer cell line was isolated into CD44+ or CD44- cells. In sphere culture, CD44+ cells possessed stem cell characteristics and highly expressed genes known to be important in stem cell maintenance. In addition, they showed strong tumorigenic potential in the clonogenic assay and soft agar colony formation assay. We then analyzed and identified proteins that were differentially expressed between CD44+ and CD44- using two-dimensional gel electrophoresis and LC-MS/MS. Cofilin and Annexin A5, which are associated with proliferation or metastasis in cancer, were found to be positively correlated with CD44 expression. These results provide information that will be important to the development of new cancer diagnostic tools and understanding the mechanisms of CSCs although a more detailed study is necessary to investigate the roles of Cofilin and Annexin A5 in CSCs.

  7. The "Win-Win" initiative: a global, scientifically based approach to resource sparing treatment for systemic breast cancer therapy

    PubMed Central

    Elzawawy, Ahmed

    2009-01-01

    Background Worldwide, breast cancer is the most frequent malignancy among females. Its incidence shows a trend towards an increase in the next decade, particularly in developing countries where less than of 5% of resources for cancer management are available. In most breast cancer cases systemic cancer treatment remains a primary management strategy. With the increasing costs of novel drugs, amidst the growing breast cancer rate, it can be safely assumed that in the next decade, newly developed cancer drugs will become less affordable and therefore will be available to fewer patients in low and middle income countries. In light of this potentially tragic situation, a pressing need emerges for science-based innovative solutions. Methods In this article, we cite examples of recently published researches and case management approaches that have been shown to lower overall treatment costs without compromising patient outcomes. The cited approaches are not presented as wholly inclusive or definitive solutions but are offered as effective examples that we hope will inspire the development of additional evidence-based management approaches that provide both efficient and effective breast cancer treatment Results We propose a "win-win" initiative, borne in the year of 2008 of strategic information sharing through preparatory communications, publications and our conference presentations. In the year 2009, ideas developed through these mechanisms can be refined through focused small pilot meetings with interested stakeholders, including the clinical, patient advocate, and pharmaceutical communities, and as appropriate (as proposed plans emerge), governmental representatives. The objective is to draw a realistic road map for feasible and innovative scientific strategies and collaborative actions that could lead to resource sparing; i.e. cost effective and tailored breast cancer systemic treatment for low and middle income countries. Conclusion The intended result would assure

  8. Long-chain ω-3 fatty acid intake and endometrial cancer risk in the Women’s Health Initiative12345

    PubMed Central

    Brasky, Theodore M; Rodabough, Rebecca J; Liu, Jingmin; Kurta, Michelle L; Wise, Lauren A; Orchard, Tonya S; Cohn, David E; Belury, Martha A; White, Emily; Manson, JoAnn E; Neuhouser, Marian L

    2015-01-01

    Background: Inflammation may be important in endometrial cancer development. Long-chain ω-3 (n–3) polyunsaturated fatty acids (LCω-3PUFAs) may reduce inflammation and, therefore, reduce cancer risk. Because body mass is associated with both inflammation and endometrial cancer risk, it may modify the association of fat intake on risk. Objective: We examined whether intakes of LCω-3PUFAs were associated with endometrial cancer risk overall and stratified by body size and histologic subtype. Design: Women were n = 87,360 participants of the Women’s Health Initiative Observational Study and Clinical Trials who were aged 50–79 y, had an intact uterus, and completed a baseline food-frequency questionnaire. After 13 y of follow-up, n = 1253 incident invasive endometrial cancers were identified. Cox regression models were used to estimate HRs and 95% CIs for the association of intakes of individual ω-3 fatty acids and fish with endometrial cancer risk. Results: Intakes of individual LCω-3PUFAs were associated with 15–23% linear reductions in endometrial cancer risk. In women with body mass index (BMI; in kg/m2) <25, those in the upper compared with lowest quintiles of total LCω-3PUFA intake (sum of eicosapentaenoic, docosapentaenoic, and docosahexaenoic acids) had significantly reduced endometrial cancer risk (HR: 0.59; 95% CI: 0.40, 0.82; P-trend = 0.001), whereas there was little evidence of an association in overweight or obese women. The reduction in risk observed in normal-weight women was further specific to type I cancers. Conclusions: Long-chain ω-3 intake was associated with reduced endometrial cancer risk only in normal-weight women. Additional studies that use biomarkers of ω-3 intake are needed to more accurately estimate their effects on endometrial cancer risk. This trial was registered at clinicaltrials.gov as NCT00000611. PMID:25739930

  9. The Relationship of Cancer Symptom Clusters to Depressive Affect in the Initial Phase of Palliative Radiation

    PubMed Central

    Francoeur, Richard Benoit

    2007-01-01

    Research on comorbidity across cancer symptoms, including pain, fatigue, and depression, could suggest if crossover effects from symptom-specific interventions are plausible. Secondary analyses were conducted on a survey of 268 cancer patients with recurrent disease from a northeastern U.S. city who were initiating palliative radiation for bone pain. Moderator regression analyses predicted variation in depressive affect that could be attributed to symptom clusters. Patients self-reported difficulty controlling each physical symptom over the past month on a Likert scale and depressive symptoms on a validated depression measure (Center for Epidemiologic Studies-Depression [CES-D]) over the past week on a four-category scale. An index of depressive affect was based on items of negative and positive affect from the CES-D. In predicting depressive affect, synergistic interactions of pain with fever, fatigue, and weight loss suggest separate pathways involving pain. A similar interaction with fever occurs when nausea was tested in place of pain. Further, the interaction between pain and fatigue is similar in form to the interaction between difficulty breathing and fatigue (when sleep is not a problem). Follow-up to the latter interaction reveals: 1) additional moderation by hypertension and palliative radiation to the hip/pelvis; and 2) a similar cluster not involving hypertension when appetite problems and weight loss were tested in place of fatigue. The significance and form of these interactions are remarkably consistent. Similar sickness mechanisms could be generating: 1) pain and nausea during fever; 2) pain and fatigue during weight loss; and 3) pain and breathing difficulty when fatigue is pronounced. Crossover effects from symptom-specific interventions appear promising. PMID:15733806

  10. La radiothérapie du cancer de l'endomètre: expérience de l'institut national d'oncologie à propos de 52 cas

    PubMed Central

    Mezouri, Imane; Berhili, Soufiane; Mouhajir, Nawal; Bellefqih, Sara; Elkacemi, Hanan; Kebdani, Tayeb; Benjaafar, Noureddine

    2016-01-01

    Le cancer de l'endomètre est le cancer gynécologique le plus fréquent en occident. Il concerne principalement les femmes ménopausées. L'objectif de notre travail est de rapporter l'expérience du service de radiothérapie à l'Institut National d'Oncologie (INO) dans la prise en charge du cancer de l'endomètre. Nous avons analysé rétrospectivement 52 cas de cancer de l'endomètre traités dans le service de radiothérapie de l'INO entre 2007 à 2009. Les données collectées à partir des dossiers médicaux de nos patientes concernaient les aspects épidémiologiques, cliniques, thérapeutiques et évolutifs de ce cancer. La médiane d’âge des patientes était de 57 ans, 87% étaient ménopausées. Le délai moyen de consultation était de six mois. Le maitre symptôme était des métrorragies chez 51 patientes. Le diagnostic histologique a été porté sur un curetage biopsique de l'endomètre dans 51% des cas. L'examen anatomopathologique a montré un adénocarcinome endométrioïde dans 92% des cas. Après le bilan, 27% des patientes étaient stade I, 30% stade II, 20% stade III et 1% stade IVA selon la classification de la Fédération Internationale de Gynécologie Obstétrique (FIGO). Après la chirurgie, 51% des patientes ont reçu une radiothérapie externe. La dose délivrée était de 46 Gray (Gy). Une curiethérapie du fond vaginal a été délivrée chez toutes les patientes. Sur le plan évolutif, 83% des patientes étaient toujours suivies en situation de bon contrôle de leur maladie, 8% ont eu une récidive locorégionale et 4% avaient des métastases à distance. Ainsi, le cancer de l'endomètre est un cancer dont le traitement repose sur la chirurgie. La radiothérapie est le traitement adjuvant principal. PMID:27279969

  11. Mesenchymal stem cells expressing GD2 and CD271 correlate with breast cancer-initiating cells in bone marrow

    PubMed Central

    Cohen, Evan N; Gao, Hui; Mego, Michal; Lee, Bang-Ning; Lodhi, Ashutosh; Cristofanilli, Massimo; Lucci, Anthony

    2011-01-01

    Purpose The bone marrow microenvironment is considered a critical component in the dissemination and fate of cancer cells in the metastatic process. We explored the possible correlation between bone marrow mesenchymal stem cells (BM-MSC) and disseminated breast cancer-initiating cells (BCIC) in primary breast cancer patients. Results The percentages of BCIC (Aldefluor+CD326+CD44+CD24−) correlated with the percentages of BM-MSC, either CD45−GD2+CD200+CD271+ (Kedall's τ = 0.684, p = 0.004) or CD45−GD2+CD271+ in the bone marrow (Kedall's τ = 0.464, p = 0.042). Experimental Design Bone marrow mononuclear cells (BM-MNC) were collected at the time of primary surgery in 12 breast cancer patients. BM-MNC was immunophenotyped and BCIC was defined as epithelial cells (CD326+CD45−) with a “stem-like” phenotype (CD44+CD24low/−, ALDH activity). BM-MSC was defined as CD34−CD45− cells that co-expressed GD2, CD271 and/or CD200 within CD326-depleted BM-MNC. Conclusions There was a positive correlation between mesenchymal stem cells expressing GD2 and CD271 and breast cancer-initiating cells in BM of patients with primary breast cancer. PMID:21358274

  12. N-Acetylcysteine blocks formation of cancer-initiating estrogen-DNA adducts in cells

    PubMed Central

    Zahid, Muhammad; Saeed, Muhammad; Ali, Mohammed F.; Rogan, Eleanor G.; Cavalieri, Ercole L.

    2010-01-01

    Catechol estrogens, especially 4-hydroxylated metabolites of 17β-estradiol (E2), are responsible for estrogen-induced carcinogenesis. 4-Hydroxyestradiol (4-OHE2), a major metabolite of E2 formed preferentially by cytochrome P-450 1B1, is oxidized to E2-3,4-quinone, which can react with DNA to yield the depurinating adducts 4-OHE2-1-N3Ade and 4-OHE2-1-N7Gua. The apurinic sites generated by the loss of these depurinating adducts induce mutations that could lead to cancer initiation. In the present study, we have evaluated the effects of N-acetycysteine (NAcCys) on the metabolism of two cell lines, MCF-10F (a normal human breast epithelial cell line) and E6 (a normal mouse mammary epithelial cell line), treated with 4-OHE2 or its reactive metabolite, E2-3,4-quinone. Extensive HPLC with electrochemical detection and UPLC-MS/MS analyses of the cell media demonstrated that the presence of NAcCys very efficiently shifted the estrogen metabolism towards protective methoxylation and conjugation pathways in multiple ways, while formation of depurinating DNA adducts was inhibited. Protection by NAcCys appears to be similar in both cell lines irrespective of their origin (human or mouse) or the presence of estrogen receptor-alpha. This finding suggests that NAcCys, a common dietary supplement, could be used as a potential chemopreventive agent to block the initial step in the genotoxicity caused by catechol estrogen quinones. PMID:20472053

  13. A new diagnostic for cancer dynamics: status and initial tests of the NANIVID

    NASA Astrophysics Data System (ADS)

    Raja, Waseem K.; Gligorijevic, Bojana; Condeelis, John S.; Castracane, James

    2009-02-01

    The Tumor MicroEnvironment for Metastasis (TMEM) is a critical determinant which will presage the evolution of primary tumors and the resulting metastatic dynamics. Primary tumor cells up and down regulate certain genes which increase motility and cause a disregard for positional information. We report on the development of a new tool for the documentation of cancer cell migration (initial targets: the rat mammary adenocarcinoma cell lines MTLn3 with an over expression of Mena+++). This tool, the NANo IntraVital Device (NANIVID), is a multi-functional nanosystem composed of a chemoattractant source (hydrogel-EGF), capsule (cell trap), counter (transparent, interdigitated electrode arrays for sensing cell arrival), and remote reporter (readout electronics). The device will be retrieved from the tumor site and the cells will be expelled for subsequent assay. The NANIVID will be used in conjunction with the current catheter-based approach in which a needle is loaded with a chemoattractant source and injected into the tumor. A major drawback in the catheter approach is the short cell collection time and lack of real time registering and reporting of cell arrival. This paper will present the current status of the NANIVID prototypes developed in which a transparent implantable device is loaded with chemoattractant source and placed near candidate mammary gland tumors in an established rat model for multiple days or weeks. This series of experiments will allow the comparison of methods and to benchmark the NANIVID for use in research. Initial results of these experiments and NANIVID design modifications will be presented.

  14. Overview of the Long Island Breast Cancer Study Project (Past Initiative)

    Cancer.gov

    The Long Island Breast Cancer Study Project is a multistudy effort to investigate whether environmental factors are responsible for breast cancer in Suffolk and Nassau counties, NY, as well as in Schoharie County, NY, and Tolland County, CT.

  15. History of periodontal disease diagnosis and lung cancer incidence in the Women’s Health Initiative Observational Study

    PubMed Central

    Mai, Xiaodan; LaMonte, Michael J.; Hovey, Kathleen M.; Nwizu, Ngozi; Freudenheim, Jo L.; Tezal, Mine; Scannapieco, Frank; Hyland, Andrew; Andrews, Christopher A.; Genco, Robert J.

    2014-01-01

    Purpose While some evidence suggests that periodontal disease (PD) might be positively associated with lung cancer, prospective studies in women are limited. Previous findings may reflect residual confounding by smoking. The study aims to determine whether history of PD diagnosis is associated with incident lung cancer in a large cohort of postmenopausal women. Methods Prospective analyses were conducted in a cohort of 77,485 postmenopausal women enrolled in the Women’s Health Initiative Observational Study. History of PD (prevalence of 26.1%) was self-reported and 754 incident lung cancer cases occurred during an average 6.8 (SD ±2.6) years of follow-up. Cox regression analysis was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results Overall, PD was positively associated with lung cancer risk after adjusting for detailed smoking history including smoking status and pack-years of smoking (HR=1.24, 95% CI: 1.07–1.45). There was a positive additive interaction between PD with pack-years of smoking (P=0.02), suggesting a potential synergistic effect between PD and smoking intensity on lung cancer. The association between PD and lung cancer was stronger in former smokers. When restricted to never-smokers, PD was not associated with lung cancer (HR=1.02, 95% CI: 0.68–1.53). Conclusions PD was not independently associated with lung cancer in non-smoking postmenopausal women. However, smoking and PD jointly increased lung cancer risk beyond that expected from the sum of the each effect separately. The potential synergism between PD and smoking on lung cancer warrants further examination. PMID:24913780

  16. Optimal Cutoffs of Obesity Measures in Relation to Cancer Risk in Postmenopausal Women in the Women's Health Initiative Study

    PubMed Central

    Kabat, Geoffrey C.; Strickler, Howard D.; Lin, Juan; Hou, Lifang; Stefanick, Marcia L.; Anderson, Garnet L.; Rohan, Thomas E.

    2015-01-01

    Abstract Background: Obesity is a risk factor for several cancers in postmenopausal women. We attempted to determine cutoffs of adiposity measures in relation to risk of obesity-related cancers among postmenopausal women and to examine the effects of hormone therapy (HT) use on the cutoffs, neither of which has been broadly studied. Methods: We used data from the Women's Health Initiative cohort (n=144,701) and applied Cox-proportional hazards regressions to each combination of 17 cancer types and 6 anthropometric measures (weight, body mass index [BMI], weight to height ratio, waist circumference, waist to hip ratio [WHR], and waist to height ratio). Interactions between the anthropometric measures and HT use were also examined. Cutoffs were determined by applying a grid search followed by a two-fold cross validation method. Survival ROC analysis of 5- and 10-year incidence followed. Results: Breast, colorectal, colon, endometrium, kidney, and all cancers combined were significantly positively associated with all six anthropometric measures, whereas lung cancer among ever smokers was significantly inversely associated with all measures except WHR. The derived cutoffs of each obesity measure varied across cancers (e.g., BMI cutoffs for breast and endometrium cancers were 30 kg/m2 and 34 kg/m2, respectively), and also depended on HT use. The Youden indices of the cutoffs for predicting 5- and 10-year cancer incidence were higher among HT never users. Conclusion: Using a panel of different anthropometric measures, we derived optimal cut-offs categorizing populations into high- and low-risk groups, which differed by cancer type and HT use. Although the discrimination abilities of these risk categories were generally poor, the results of this study could serve as a starting point from which to determine adiposity cutoffs for inclusion in risk prediction models for specific cancer types. PMID:25587642

  17. The Anger Expression Scale for Children: Initial Validation among Healthy Children and Children with Cancer

    PubMed Central

    Steele, Ric G.; Legerski, John-Paul; Nelson, Timothy D.

    2009-01-01

    Objective To evaluate the proposed structure of the Anger Expression Scale for Children (AESC) in samples of healthy children and those with cancer, and to examine correlations between AESC subscales and other indicators of anger and hostility. Method A total of 803 children from two independent studies of healthy and ill children (mean age = 12.7, SD = 3.1) completed the AESC and other measures of anger expression and hostility, and a sub-sample of 298 of their parents completed measures of anger expression and hostility. Results Results provided initial support for the proposed four-factor model of the AESC (Trait Anger, Anger Expression, Anger In, and Anger Control). Measurement invariance was established across groups using a series of nested tests. Correlations between AESC subscales and parent- and child-reported indices of anger, hostility, and aggression support the convergent validity of the scales. Conclusions Analyses supported the construct validity of the AESC and generalization of the factor structure across healthy and chronically ill children. PMID:18556672

  18. The Role of Surface Receptor Density in Surface-Initiated Polymerizations for Cancer Cell Isolation.

    PubMed

    Lilly, Jacob L; Berron, Brad J

    2016-06-01

    Fluid biopsies potentially offer a minimally invasive alternative to traditional tissue biopsies for the continual monitoring of metastatic cancer. Current established technologies for isolating circulating tumor cells (CTCs) suffer from poor purity and yield and require fixatives that preclude the collection of viable cells for longitudinal analyses of biological function. Antigen specific lysis (ASL) is a rapid, high-purity method of cell isolation based on targeted protective coatings on antigen-presenting cells and lysis depletion of unprotected antigen-negative cells. In ASL, photoinitiators are specifically labeled on cell surfaces that enable subsequent surface-initiated polymerization. Critically, the significant determinants of process yield have yet to be investigated for this emerging technology. In this work, we show that the labeling density of photoinitiators is strongly correlated with the yield of intact cells during ASL by flow cytometry analysis. Results suggest ASL is capable of delivering ∼25% of targeted cells after isolation using traditional antibody labeling approaches. Monomer formulations of two molecular weights of PEG-diacrylate (Mn ∼ 575 and 3500) are examined. The gelation response during ASL polymerization is also investigated via protein microarray analogues on planar glass. Finally, a density threshold of photoinitiator labeling required for protection during lysis is determined for both monomer formulations. These results indicate ASL is a promising technology for high yield CTC isolation for rare-cell function assays and fluid biopsies. PMID:27206735

  19. Electric blanket (EB) use and risk of thyroid cancer in the Women’s Health Initiative (WHI) observational cohort

    PubMed Central

    Kato, Ikuko; Young, Alicia; Liu, Jingmin; Abrams, Judith; Bock, Cathryn; Simon, Michael

    2016-01-01

    Thyroid cancer disproportionally affects more women than men. The aim of this study was to assess whether exposure to extremely low frequency electric magnetic fields from electric blankets (EB) was associated with development of thyroid cancer. We analyzed data from 89,527 women who participated in the Women’s Health Initiative Observational Study and who responded to questions concerning prior use of EB. During a mean follow-up of 12.2 years, we identified 190 incident cases of thyroid cancer. We estimated the hazard ratio (HR) and 95% confidence interval (CI) of incident thyroid cancer associated with EB use by Cox’s proportional hazard model, adjusted for selected covariates. A majority, 57%, of the women in the cohort reported ever use of EB while sleeping and/or for warming the bed before sleep. We found no association between ever use of EB and subsequent risk of thyroid cancer (HR= 0.98, 95% CI: 0.72–1.32). Duration of EB use measured in years, months or hours had no effect on risk. These results did not change when the cases were limited to papillary thyroid cancer, the most frequently occurring histologic type. The results of this study do not support possible health hazards of EB in regards to thyroid cancer risk. PMID:25996298

  20. Lunatic Fringe is a potent tumor suppressor in Kras-initiated pancreatic cancer.

    PubMed

    Zhang, S; Chung, W-C; Xu, K

    2016-05-12

    Notch controls pancreatic differentiation during development and is reactivated in pancreatic cancer. In recent years, the importance of Notch signaling in pancreatic tumorigenesis has become increasingly evident; however, it remains unclear how Notch activities are regulated in this context. Here we report differential regulation of Notch receptors by Lunatic Fringe (Lfng), which encodes an O-fucosylpeptide 3-β-N-acetylglucosaminyltransferase known to modify epidermal growth factor repeats in the Notch extracellular domain, during pathogenesis of Kras-induced pancreatic ductal adenocarcinoma (PDAC). We show that Lfng is uniquely expressed in a subset of acinar cells in the adult pancreas. Deletion of Lfng in the Kras(LSL-G12D/+);Pdx1-Cre mouse model caused increased activation of Notch3 throughout PDAC initiation and progression, and Notch1 after the onset of disease, associated with marked upregulation of Notch target gene Hes1. Deletion of Lfng also resulted in accumulation of Aldh1-positive cell population. We found that loss of Lfng significantly accelerated Kras-initiated PDAC development and shortened survival of the PDAC mice. Interestingly, Lfng-deficient tumors showed a propensity for a poorly differentiated state with features of epithelial-to-mesenchymal transition. Likewise, knockdown of LFNG in human PDAC cell lines caused elevated Notch activation, associated with either accelerated cell proliferation or expanded Aldh1-positive cell population. Deletion of Lfng resulted in downregulation of Tgfb1, Tgfb2 and Tgfbr2 expression in the wild-type pancreas at all ages examined, and in the Kras(LSL-G12D/+);Pdx1-Cre pancreas after PDAC onset, as well as reduced phospho-Smad2 levels in pancreatic tumors. We provide evidence that Lfng regulates transforming growth factor (TGF)-β signaling through Notch-mediated transcriptional repression of TGF-β pathway genes. Taken together, our results reveal a potent tumor-suppressive function for Lfng and crosstalk

  1. miR-17 inhibition enhances the formation of kidney cancer spheres with stem cell/tumor initiating cell properties

    PubMed Central

    Lichner, Zsuzsanna; Saleh, Carol; Subramaniam, Venkateswaran; Seivwright, Annetta; Prud'homme, Gerald Joseph; Yousef, George Makram

    2015-01-01

    Renal cell carcinoma (RCC) is an aggressive disease, with 35% chance of metastasis. The ‘cancer stem cell’ hypothesis suggests that a subset of cancer cells possess stem cell properties and is crucial in tumor initiation, metastasis and treatment resistance. We isolated RCC spheres and showed that they exhibit cancer stem cell/tumor initiating cell-like properties including the formation of self-renewing spheres, high tumorigenicity and the ability to differentiate to cell types of the original tumor. Spheres showed increased expression of stem cell-related transcription factors and mesenchymal markers.  miRNAs were differentially expressed between RCC spheres and their parental cells. Inhibition of miR-17 accelerated the formation of RCC spheres which shared molecular characteristics with the spontaneous RCC spheres. Target prediction pointed out TGFβ pathway activation as a possible mechanism to drive RCC sphere formation. We demonstrate that miR-17 overexpression interferes with the TGFβ-EMT axis and hinders RCC sphere formation; and validated TGFBR2 as a direct and biologically relevant target during this process. Thus, a single miRNA may have an impact on the formation of highly tumorigenic cancer spheres of kidney cancer. PMID:25011053

  2. Cancer-initiating cells derived from human rectal adenocarcinoma tissues carry mesenchymal phenotypes and resist drug therapies.

    PubMed

    Fan, C-W; Chen, T; Shang, Y-N; Gu, Y-Z; Zhang, S-L; Lu, R; OuYang, S-R; Zhou, X; Li, Y; Meng, W-T; Hu, J-K; Lu, Y; Sun, X-F; Bu, H; Zhou, Z-G; Mo, X-M

    2013-01-01

    Accumulating evidence indicates that cancer-initiating cells (CICs) are responsible for cancer initiation, relapse, and metastasis. Colorectal carcinoma (CRC) is typically classified into proximal colon, distal colon, and rectal cancer. The gradual changes in CRC molecular features within the bowel may have considerable implications in colon and rectal CICs. Unfortunately, limited information is available on CICs derived from rectal cancer, although colon CICs have been described. Here we identified rectal CICs (R-CICs) that possess differentiation potential in tumors derived from patients with rectal adenocarcinoma. The R-CICs carried both CD44 and CD54 surface markers, while R-CICs and their immediate progenies carried potential epithelial-mesenchymal transition characteristics. These R-CICs generated tumors similar to their tumor of origin when injected into immunodeficient mice, differentiated into rectal epithelial cells in vitro, and were capable of self-renewal both in vitro and in vivo. More importantly, subpopulations of R-CICs resisted both 5-fluorouracil/calcium folinate/oxaliplatin (FolFox) and cetuximab treatment, which are the most common therapeutic regimens used for patients with advanced or metastatic rectal cancer. Thus, the identification, expansion, and properties of R-CICs provide an ideal cellular model to further investigate tumor progression and determine therapeutic resistance in these patients. PMID:24091671

  3. STAT3 signaling is activated preferentially in tumor-initiating cells in claudin-low models of human breast cancer.

    PubMed

    Wei, Wei; Tweardy, David J; Zhang, Mei; Zhang, Xiaomei; Landua, John; Petrovic, Ivana; Bu, Wen; Roarty, Kevin; Hilsenbeck, Susan G; Rosen, Jeffrey M; Lewis, Michael T

    2014-10-01

    In breast cancer, a subset of tumor-initiating cells (TIC) or "cancer stem cells" are thought to be responsible for tumor maintenance, treatment resistance, and disease recurrence. While current breast cancer stem cell markers (e.g., CD44(high) /CD24(low/neg) , ALDH positive) have allowed enrichment for such cells, they are not universally expressed and may actually identify distinct TIC subpopulations in the same tumor. Thus, additional markers of functional stem cells are needed. The STAT3 pathway is a critical regulator of the function of normal stem cells, and evidence is accumulating for its important role in breast cancer stem cells. However, due to the lack of a method for separating live cells based on their level of STAT3 activity, it remains unknown whether STAT3 functions in the cancer stem cells themselves, or in surrounding niche cells, or in both. To approach this question, we constructed a series of lentiviral fluorescent (enhanced green fluorescent protein, EGFP) reporters that enabled flow cytometric enrichment of cells differing in STAT3-mediated transcriptional activity, as well as in vivo/in situ localization of STAT3 responsive cells. Using in vivo claudin-low cell line xenograft models of human breast cancer, we found that STAT3 signaling reporter activity (EGFP(+) ) is associated with a subpopulation of cancer cells enriched for mammosphere-forming efficiency, as well as TIC function in limiting dilution transplantation assays compared to negative or unsorted populations. Our results support STAT3 signaling activity as another functional marker for human breast cancer stem cells thus making it an attractive therapeutic target for stem-cell-directed therapy in some breast cancer subtypes. PMID:24891218

  4. Piloting an approach to rapid and automated assessment of a new research initiative: Application to the National Cancer Institute’s Provocative Questions initiative

    PubMed Central

    Hsu, Elizabeth R.; Williams, Duane E.; DiJoseph, Leo G.; Schnell, Joshua D.; Finstad, Samantha L.; Lee, Jerry S. H.; Greenspan, Emily J.; Corrigan, James G.

    2013-01-01

    Funders of biomedical research are often challenged to understand how a new funding initiative fits within the agency’s portfolio and the larger research community. While traditional assessment relies on retrospective review by subject matter experts, it is now feasible to design portfolio assessment and gap analysis tools leveraging administrative and grant application data that can be used for early and continued analysis. We piloted such methods on the National Cancer Institute’s Provocative Questions (PQ) initiative to address key questions regarding diversity of applicants; whether applicants were proposing new avenues of research; and whether grant applications were filling portfolio gaps. For the latter two questions, we defined measurements called focus shift and relevance, respectively, based on text similarity scoring. We demonstrate that two types of applicants were attracted by the PQs at rates greater than or on par with the general National Cancer Institute applicant pool: those with clinical degrees and new investigators. Focus shift scores tended to be relatively low, with applicants not straying far from previous research, but the majority of applications were found to be relevant to the PQ the application was addressing. Sensitivity to comparison text and inability to distinguish subtle scientific nuances are the primary limitations of our automated approaches based on text similarity, potentially biasing relevance and focus shift measurements. We also discuss potential uses of the relevance and focus shift measures including the design of outcome evaluations, though further experimentation and refinement are needed for a fuller understanding of these measures before broad application. PMID:24808631

  5. Call for a Computer-Aided Cancer Detection and Classification Research Initiative in Oman.

    PubMed

    Mirzal, Andri; Chaudhry, Shafique Ahmad

    2016-01-01

    Cancer is a major health problem in Oman. It is reported that cancer incidence in Oman is the second highest after Saudi Arabia among Gulf Cooperation Council countries. Based on GLOBOCAN estimates, Oman is predicted to face an almost two-fold increase in cancer incidence in the period 2008-2020. However, cancer research in Oman is still in its infancy. This is due to the fact that medical institutions and infrastructure that play central roles in data collection and analysis are relatively new developments in Oman. We believe the country requires an organized plan and efforts to promote local cancer research. In this paper, we discuss current research progress in cancer diagnosis using machine learning techniques to optimize computer aided cancer detection and classification (CAD). We specifically discuss CAD using two major medical data, i.e., medical imaging and microarray gene expression profiling, because medical imaging like mammography, MRI, and PET have been widely used in Oman for assisting radiologists in early cancer diagnosis and microarray data have been proven to be a reliable source for differential diagnosis. We also discuss future cancer research directions and benefits to Oman economy for entering the cancer research and treatment business as it is a multi-billion dollar industry worldwide. PMID:27268600

  6. Tetrandrine, a Compound Common in Chinese Traditional Medicine, Preferentially Kills Breast Cancer Tumor Initiating Cells (TICs) In Vitro

    PubMed Central

    Xu, Wei; Debeb, Bisrat G.; Lacerda, Lara; Li, Jessica; Woodward, Wendy A.

    2011-01-01

    Tetrandrine is a bisbenzylisoquinoline alkaloid found in Stephania tetrandra, a Chinese medicine commonly used as an anti-inflammatory. It has extensive pharmacological activity, including positive ion channel blockade and inhibition of multiple drug resistance proteins. These activities are very similar to that of salinomycin, a known drug targeting breast cancer initiation cells (TICs). Herein, we tested tetrandrine targeting of breast cancer TICs. SUM-149, an inflammatory breast cancer cell line and SUM-159, a non-inflammatory metaplastic breast cancer cell line were used in these studies. In proliferation assays using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS), we found that the IC50 for inhibition of proliferation is 15.3 ± 4.1 μM for SUM-149 and 24.3 ± 2.1 μM for SUM-159 cells. Tetrandrine also inhibited mammosphere formation, a surrogate for breast cancer TICs growth in vitro with IC50 around 1 μM for SUM-149 and around 2 μM for SUM-159 cells. Tetrandrine has similar effects on the mammosphere formation from cells isolated from fresh patient sample. Moreover, tetrandrine decreases the aldehyde dehydrogenase (ALDH) positive population in SUM-159 by 45% ± 5.45% P = 0.005. In summary, tetrandrine demonstrates significant efficacy against in vitro surrogates for inflammatory and aggressive breast cancer TICs. PMID:24212809

  7. Biokinetics and dosimetry of depleted uranium (DU) in rats implanted with DU fragments.

    SciTech Connect

    Guilmette, Ray A.; Hahn, Fletcher F.; Durbin, P. W.

    2004-01-01

    A number of U. S. veterans of the Persian Gulf War were wounded with depleted uranium (DU) metal fragments as a result of 'friendly fire' incidents, in which Abrams tanks and Bradley fighting vehicles were struck by DU anti-armor munitions. Some of the crew members who survived were left with multiple small fragments of DU in their muscles and soft tissues. The number, size and location of the fragments made them inoperable in general, and therefore subject to long-term retention. Because there was inadequate data to predict the potential carcinogenicity of DU fragments in soft tissues, Hahn et al. (2003) conducted a lifespan cancer study in rats. As part of that study, a number of rats were maintained to study the biokinetics and dosimetry of DU implanted intramuscularly in male Wistar rats. Typically, four metal fragments, either as cylindrical pellets or square wafers were implanted into the biceps femoris muscles of the rats. Urine samples were collected periodically during their lifespans, and DU was analyzed in kidneys and eviscerated carcass (minus the implant sites) at death. The daily DU urinary excretion rate increased steeply during the first 30 d after implantation peaking at about 90 d at 3-10 x 10{sup -3}%/d. During the first 150 d, the average excretion rate was 2.4 x 10{sup -3}%/d, decreasing thereafter to about 1 x 10{sup -3}%/d. Serial radiographs were made of the wound sites to monitor gross morphologic changes in the DU implant and the surrounding tissue. As early as 1 w after implantation, radiographs showed the presence of surface corrosion and small, dense bodies near the original implant, presumably DU. This corrosion from the surface of the implant continued with time, but did not result in an increasing amount of DU reaching the blood and urine after the first 3 mo. During this 3-mo period, connective tissue capsules formed around the implants, and are hypothesized to have reduced the access of DU to tissue fluids by limiting the diffusion

  8. Urinary Levels of Melatonin and Risk of Postmenopausal Breast Cancer: Women’s Health Initiative Observational Cohort

    PubMed Central

    Sturgeon, Susan R.; Doherty, Ashley; Reeves, Katherine W.; Bigelow, Carol; Stanczyk, Frank Z.; Ockene, Judith K.; Liu, Simin; Manson, JoAnn E.; Neuhouser, Marian L.

    2014-01-01

    Background Results from prospective studies on the association between urinary levels of melatonin and risk of postmenopausal breast cancer have been mixed. Several although not all studies have found lower urinary levels of melatonin in women who developed breast cancer compared to cancer-free women. Methods We examined the association between urinary levels of melatonin and breast cancer risk in postmenopausal women in a case-control study nested in the Women’s Health Initiative Observational Cohort. Levels of 6-sulfatoxymelatonin were measured in first morning voids from 258 women who later developed breast cancer and from 515 matched controls. Multivariable conditional logistic regression was used to calculate odds ratios and 95% confidence intervals. Results Fully adjusted risk estimates of breast cancer, relative to the lowest quartile level of creatinine-adjusted melatonin, were 1.07 (95% CI 0.67–1.71), 1.26 (95% CI 0.79–2.01), and 1.25 (95% CI 0.78–2.02) for women in the second, third and highest quartile [p for trend =.27]. Comparable results for cases diagnosed less than four years after urinary collection and matched controls were 1.0, 1.25 (95%CI 0.51–3.06, 1.85 (95%CI 0.75–4.57), and 1.94 (95%CI 0.75–5.03) [p for trend = 0.11]. Melatonin levels and breast cancer were not associated in cases diagnosed four or more years after urinary collection and matched controls [p for trend = 0.89]. Conclusions We found no evidence that higher urinary levels of melatonin are inversely associated with breast cancer risk in postmenopausal women. Impact Accumulating discrepancies in results across studies warrant further exploration. PMID:24510738

  9. Conjugated Equine Estrogens and Colorectal Cancer Incidence and Survival: The Women’s Health Initiative Randomized Clinical Trial

    PubMed Central

    Ritenbaugh, Cheryl; Stanford, Janet L.; Wu, LieLing; Shikany, James M.; Schoen, Robert E.; Stefanick, Marcia L.; Taylor, Vicky; Garland, Cedric; Frank, Gail; Lane, Dorothy; Mason, Ellen; McNeeley, S. Gene; Ascensao, Joao; Chlebowski, Rowan T.

    2010-01-01

    Background In separate Women’s Health Initiative randomized trials, combined hormone therapy with estrogen plus progestin reduced colorectal cancer incidence but estrogen alone in women with hysterectomy did not. We now analyze features of the colorectal cancers that developed and examine survival of women following colorectal cancer diagnosis in the latter trial. Participants and Methods 10,739 postmenopausal women who were 50 to 79 years of age and had undergone hysterectomy were randomized to conjugated equine estrogens (0.625 mg/day) or matching placebo. Colorectal cancer incidence was a component of the study’s monitoring global index but was not a primary study endpoint. Colorectal cancers were verified by central medical record and pathology report review. Bowel exam frequency was not protocol defined but information on their use was collected. Results After a median 7.1 years, there were 58 invasive colorectal cancers in the hormone group and 53 in the placebo group (hazard ratio [HR] 1.12, 95% Confidence Interval [CI] 0.77–1.63). Tumor size, stage, and grade were comparable in the two randomization groups. Bowel exam frequency was also comparable in the two groups. The cumulative mortality following colorectal cancer diagnosis among women in the conjugated equine estrogen group was 34 % compared to 30 % in the placebo group (HR 1.34, 95% CI 0.58–3.19). Conclusions In contrast to the preponderance of observational studies, conjugated equine estrogens in a randomized clinical trial did not reduce colorectal cancer incidence nor improve survival after diagnosis. PMID:18829444

  10. Imipenem-Cilastatin versus Sulbactam-Cefoperazone plus Amikacin in the Initial Treatment of Febrile Neutropenic Cancer Patients

    PubMed Central

    ÖZYILKAN, Özgür; YALÇINTAŞ, ÜlKü; BAŞKAN, Sezgin

    1999-01-01

    The treatment of infectious complications in cancer patients has evolved as a consequence of the developments in the chemotherapy of cancer patients. In this prospective, randomized study, we compared imipenem-cilastatin and sulbactam-cefoperazone with amikacin in the empiric therapy of febrile neutropenic (<1000/mm3) patients with liquids and solid tumours. Of 30 evaluable episodes, 15 were treated with imipenem-cilastatin and 15 were treated with sulbactam-cefoperazone plus amikacin. 73% of episodes were culture-positive; gram-positive pathogens accounted for 62% of the isolates. Bacteremia was the most frequent site of infection. The initial clinical response rate for both regimens was 60% (p>0.05). No major adverse effects occurred. This study demonstrated that imipenem-cilastatin monotherapy and combination therapy of sulbactam-cefoperazone plus amikacin were equally effective empiric therapy for febrile granulocytopenic cancer patients. PMID:10461420

  11. NOTCH Signaling Regulates Asymmetric Cell Fate of Fast- and Slow-Cycling Colon Cancer-Initiating Cells.

    PubMed

    Srinivasan, Tara; Walters, Jewell; Bu, Pengcheng; Than, Elaine Bich; Tung, Kuei-Ling; Chen, Kai-Yuan; Panarelli, Nicole; Milsom, Jeff; Augenlicht, Leonard; Lipkin, Steven M; Shen, Xiling

    2016-06-01

    Colorectal cancer cells with stem-like properties, referred to as colon cancer-initiating cells (CCIC), have high tumorigenic potential. While CCIC can differentiate to promote cellular heterogeneity, it remains unclear whether CCIC within a tumor contain distinct subpopulations. Here, we describe the co-existence of fast- and slow-cycling CCIC, which can undergo asymmetric division to generate each other, highlighting CCIC plasticity and interconvertibility. Fast-cycling CCIC express markers, such as LGR5 and CD133, rely on MYC for their proliferation, whereas slow-cycling CCIC express markers, such as BMI1 and hTERT, are independent of MYC. NOTCH signaling promotes asymmetric cell fate, regulating the balance between these two populations. Overall, our results illuminate the basis for CCIC heterogeneity and plasticity by defining a direct interconversion mechanism between slow- and fast-cycling CCIC. Cancer Res; 76(11); 3411-21. ©2016 AACR. PMID:27197180

  12. Understanding community beliefs of Chinese-Australians about cancer: initial insights using an ethnographic approach.

    PubMed

    Yeo, Soo See; Meiser, Bettina; Barlow-Stewart, Kristine; Goldstein, David; Tucker, Katherine; Eisenbruch, Maurice

    2005-03-01

    Ethnography was employed to investigate the hypothesis that the cultural meaning of cancer is one of the possible barriers to access of cancer services. The objectives were to identify indigenous terminologies, taxonomies and illness explanatory models of cancer in a community-based sample of 15 Chinese-Australians and a sample of 16 informants who had been recruited through two Sydney familial cancer clinics. Many of the informants included in their narrative terms that seemed to match Western biomedical explanations for cancer. The majority of informants also maintained traditional Chinese beliefs, despite high acculturation and beliefs in biomedical explanations about cancer. Explanations of illness including cancer, referred to the following concepts: (i) karma (yeh), (ii) retribution (bao ying), (iii) fate (ming yun) or Heaven's or God's will, (iv) geomancy (feng-shui), (v) touched evil (zhong chia), (vi) misfortune or bad luck (shui wan, dong hark); (vii) offending the gods or deities requiring prayers or offerings for appeasement; and (viii) kong-tau (spells invoked through human intervention). Taking into consideration the heterogeneity of the Chinese population, the findings provide an insight into Chinese illness conceptualization that may assist health professionals to develop an understanding of how the cultural explanatory models affect access to screening services, communication of diagnosis of cancer and management of treatment regimen. PMID:15386778

  13. Patient-Centered Cancer Care Programs in Italy: Benchmarking Global Patient Education Initiatives.

    PubMed

    Truccolo, Ivana; Cipolat Mis, Chiara; Cervo, Silvia; Dal Maso, Luigino; Bongiovanni, Marilena; Bearz, Alessandra; Sartor, Ivana; Baldo, Paolo; Ferrarin, Emanuela; Fratino, Lucia; Mascarin, Maurizio; Roncadin, Mario; Annunziata, Maria Antonietta; Muzzatti, Barbara; De Paoli, Paolo

    2016-06-01

    In Italy, educational programs for cancer patients are currently provided by the national government, scientific societies, and patient advocate organizations. Several gaps limit their effectiveness, including the lack of coordinated efforts, poor involvement of patient feedback in the planning of programs, as well as a lack of resources on innovative cancer-related topics. This process is parallel to a strong shift in the attitude of patients towards health in general and taking charge of their own health conditions in particular. The National Cancer Institute in the USA and the Organization of European Cancer Institutes encourage comprehensive cancer centers in providing educational programs conceived to overcome these gaps. The goal of this paper is to identify and describe the key elements necessary to develop a global patient education program and provide recommendations for strategies with practical examples for implementation in the daily activities of cancer institutes. A multidisciplinary committee was established for patient education, including patient representatives as equal partners, to define, implement, verify, and evaluate the fundamental steps for establishing a comprehensive education program. Six essential topics were identified for the program: appropriate communication of cancer epidemiology, clinical trial information, new therapeutic technologies, support in the use of medicines, psycho-oncological interventions, age-personalized approaches, and training programs for healthcare providers. Integration of these topics along with patient feedback is the key to a successful model for educational programs. An integrated educational program can transform a comprehensive cancer center to an institution that provides research and care for and with patients. PMID:25773134

  14. Cancer Education Program Evaluation: A Responsive Approach to Planning an Evaluation and Initial Results.

    ERIC Educational Resources Information Center

    Pearsol, James A.

    This paper describes evaluation planning for the Cancer Education Program (CEP) at Ohio State University (OSU). The three-year OSU CEP project was designed as a multidisciplinary cancer education program. A responsive method, which trades off some measurement precision in order to increase the usefulness of the findings, was employed in the…

  15. Lentivirus-mediated knockdown of eukaryotic translation initiation factor 3 subunit D inhibits proliferation of HCT116 colon cancer cells.

    PubMed

    Yu, Xiaojun; Zheng, Bo'an; Chai, Rui

    2014-01-01

    Dysregulation of protein synthesis is emerging as a major contributory factor in cancer development. eIF3D (eukaryotic translation initiation factor 3 subunit D) is one member of the eIF3 (eukaryotic translation initiation factor 3) family, which is essential for initiation of protein synthesis in eukaryotic cells. Acquaintance with eIF3D is little since it has been identified as a dispensable subunit of eIF3 complex. Recently, eIF3D was found to embed somatic mutations in human colorectal cancers, indicating its importance for tumour progression. To further probe into its action in colon cancer, we utilized lentivirus-mediated RNA interference to knock down eIF3D expression in one colon cancer cell line HCT116. Knockdown of eIF3D in HCT116 cells significantly inhibited cell proliferation and colony formation in vitro. Flow cytometry analysis indicated that depletion of eIF3D led to cell-cycle arrest in the G2/M phase, and induced an excess accumulation of HCT116 cells in the sub-G1 phase representing apoptotic cells. Signalling pathways responsible for cell growth and apoptosis have also been found altered after eIF3D silencing, such as AMPKα (AMP-activated protein kinase alpha), Bad, PRAS40 [proline-rich Akt (PKB) substrate of 40 kDa], SAPK (stress-activated protein kinase)/JNK (c-Jun N-terminal kinase), GSK3β and PARP [poly(ADP-ribose) polymerase]. Taken together, these findings suggest that eIF3D might play an important role in colon cancer progression. PMID:25370813

  16. SOX2 is a cancer-specific regulator of tumor initiating potential in cutaneous squamous cell carcinoma

    PubMed Central

    Siegle, Jasmin M.; Basin, Alice; Sastre-Perona, Ana; Yonekubo, Yoshiya; Brown, Jessie; Sennett, Rachel; Rendl, Michael; Tsirigos, Aristotelis; Carucci, John A.; Schober, Markus

    2014-01-01

    Although the principles that balance stem cell self-renewal and differentiation in normal tissue homeostasis are beginning to emerge, it is still unclear whether cancer cells with tumor initiating potential are similarly governed, or whether they have acquired distinct mechanisms to sustain self-renewal and long-term tumor growth. Here we show that the transcription factor Sox2, which is not expressed in normal skin epithelium and is dispensable for epidermal homeostasis, marks tumor initiating cells (TICs) in cutaneous squamous cell carcinomas (SCC). We demonstrate that Sox2 is required for SCC growth in mouse and human, where it enhances Nrp1/Vegf signaling to promote the expansion of TICs along the tumor-stroma interface. Our findings suggest that distinct transcriptional programs govern self-renewal and long-term growth of TICs and normal skin epithelial stem and progenitor cells. These programs present promising diagnostic markers and targets for cancer specific therapies. PMID:25077433

  17. Factors involved in the delay of treatment initiation for cervical cancer patients: A nationwide population-based study.

    PubMed

    Shen, Szu-Ching; Hung, Yao-Ching; Kung, Pei-Tseng; Yang, Wen-Hui; Wang, Yueh-Hsin; Tsai, Wen-Chen

    2016-08-01

    Cervical cancer ranks as the fourth leading cause of cancer death in women worldwide. In Taiwan, although the universal health insurance system has achieved 99.9% coverage and ensured easy access to medical care, some cervical cancer patients continue to delay initiation of definitive treatment after diagnosis. This study focused on cervical cancer patients who delayed treatment for at least 4 months, and examined the characteristics, related factors, and survival in these patients.Data on patients with a new confirmed diagnosis of cervical cancer by the International Federation of Gynecology and Obstetrics (FIGO) staging system between 2005 and 2010 were obtained from the National Health Insurance Research Database and the Taiwan Cancer Registry. Logistic regression analysis was performed to analyze the association of various factors with treatment delay. The Cox proportional hazards model was used to analyze the effects of various factors on mortality risk.The rate of treatment delay for cervical cancer decreased steadily from 6.46% in 2005 to 2.48% in 2010. Higher rates of treatment delay were observed among patients who were aged ≥75 years (9.91%), had severe comorbidity, had stage IV (9.50%), diagnosing hospital level at nonmedical center, or at public hospital ownership. Factors that correlated with treatment delay were age ≥75 years (odds ratio [OR] = 2.42), higher comorbidity Charlson comorbidity index (CCI) 4-6, or ≥7 (OR = 1.60, 2.00), cancer stage IV (OR = 2.60), the diagnosing hospital being a regional, district hospital, or other (OR = 3.00, 4.01, 4.60), and at public hospital ownership. Those who delayed treatment had 2.31 times the mortality risk of those who underwent timely treatment (P < 0.05).Delayed cervical cancer treatment in Taiwan was associated with age, comorbidity, cancer stage, diagnosing hospital level, and hospital ownership. Delaying treatment for ≥4 months substantially raised mortality risk in cervical cancer patients

  18. Tumour-initiating stem-like cells in human prostate cancer exhibit increased NF-κB signalling

    PubMed Central

    Rajasekhar, Vinagolu K.; Studer, Lorenz; Gerald, William; Socci, Nicholas D.; Scher, Howard I.

    2011-01-01

    Androgen depletion is a key strategy for treating human prostate cancer, but the presence of hormone-independent cells escaping treatment remains a major therapeutic challenge. Here, we identify a minor subset of stem-like human prostate tumour-initiating cells (TICs) that do not express prostate cancer markers, such as androgen receptor or prostate specific antigen. These TICs possess stem cell characteristics and multipotency as demonstrated by in vitro sphere-formation and in vivo tumour-initiation, respectively. The cells represent an undifferentiated subtype of basal cells and can be purified from prostate tumours based on coexpression of the human pluripotent stem cell marker TRA-1-60 with CD151 and CD166. Such triple-marker-positive TICs recapitulate the original parent tumour heterogeneity in serial xeno-transplantations indicating a tumour cell hierarchy in human prostate cancer development. These TICs exhibit increased nuclear factor-κB activity. These findings are important in understanding the molecular basis of human prostate cancer. PMID:21245843

  19. Suppression of cancer-initiating cells and selection of adipose-derived stem cells cultured on biomaterials having specific nanosegments.

    PubMed

    Kao, Ta-Chun; Lee, Henry Hsin-Chung; Higuchi, Akon; Ling, Qing-Dong; Yu, Wan-Chun; Chou, Yu-Hsuan; Wang, Pin-Yu; Suresh Kumar, S; Chang, Yu; Hung Chen, Yung; Chang, Yung; Chen, Da-Chung; Hsu, Shih-Tien

    2014-04-01

    Cancer-initiating cells [cancer stem cells (CSCs)] in colon cancer cells can be selectively suppressed when they are cultured on Pluronic (nanosegment)-grafted dishes, whereas CSCs are maintained on conventional tissue culture dishes and extracellular matrix-coated dishes. CSCs persist in tumors as a distinct population and cause relapse and metastasis by giving rise to new tumorigenic clones. The purification or depletion (suppression) of CSCs should be useful for analyzing CSC characteristics and for clinical application. CSCs can be selectively suppressed from colon cancer cells containing adipose-derived stem cells (ADSCs) on Pluronic-grafted dishes, while ADSCs remain on the dishes. ADSCs on Pluronic-grafted dishes after the suppression of the CSCs can differentiate into osteoblasts, chondrocytes, adipocytes, cardiomyocytes, and neuronal cells. The CSCs and ADSCs exhibited different characteristics. The selection of ADSCs was possible on Pluronic-grafted dishes that suppressed the CSCs from the fat tissues of cancer patients (i.e., cell-sorting dishes), which was explained by specific biomedical characteristics of Pluronic. PMID:24039170

  20. Challenges in initiating and conducting personalized cancer therapy trials: perspectives from WINTHER, a Worldwide Innovative Network (WIN) Consortium trial

    PubMed Central

    Rodon, J.; Soria, J. C.; Berger, R.; Batist, G.; Tsimberidou, A.; Bresson, C.; Lee, J. J.; Rubin, E.; Onn, A.; Schilsky, R. L.; Miller, W. H.; Eggermont, A. M.; Mendelsohn, J.; Lazar, V.; Kurzrock, R.

    2015-01-01

    Advances in ‘omics’ technology and targeted therapeutic molecules are together driving the incorporation of molecular-based diagnostics into the care of patients with cancer. There is an urgent need to assess the efficacy of therapy determined by molecular matching of patients with particular targeted therapies. WINTHER is a clinical trial that uses cutting edge genomic and transcriptomic assays to guide treatment decisions. Through the lens of this ambitious multinational trial (five countries, six sites) coordinated by the Worldwide Innovative Networking Consortium for personalized cancer therapy, we discovered key challenges in initiation and conduct of a prospective, omically driven study. To date, the time from study concept to activation has varied between 19 months at Gustave Roussy Cancer Campus in France to 30 months at the Segal Cancer Center, McGill University (Canada). It took 3+ years to be able to activate US sites due to national regulatory hurdles. Access to medications proposed by the molecular analysis remains a major challenge, since their availability through active clinical trials is highly variable over time within sites and across the network. Rules regarding the off-label use of drugs, or drugs not yet approved at all in some countries, pose a further challenge, and many biopharmaceutical companies lack a simple internal mechanism to supply the drugs even if they wish to do so. These various obstacles should be addressed to test and then implement precision medicine in cancer. PMID:25908602

  1. Challenges in initiating and conducting personalized cancer therapy trials: perspectives from WINTHER, a Worldwide Innovative Network (WIN) Consortium trial.

    PubMed

    Rodon, J; Soria, J C; Berger, R; Batist, G; Tsimberidou, A; Bresson, C; Lee, J J; Rubin, E; Onn, A; Schilsky, R L; Miller, W H; Eggermont, A M; Mendelsohn, J; Lazar, V; Kurzrock, R

    2015-08-01

    Advances in 'omics' technology and targeted therapeutic molecules are together driving the incorporation of molecular-based diagnostics into the care of patients with cancer. There is an urgent need to assess the efficacy of therapy determined by molecular matching of patients with particular targeted therapies. WINTHER is a clinical trial that uses cutting edge genomic and transcriptomic assays to guide treatment decisions. Through the lens of this ambitious multinational trial (five countries, six sites) coordinated by the Worldwide Innovative Networking Consortium for personalized cancer therapy, we discovered key challenges in initiation and conduct of a prospective, omically driven study. To date, the time from study concept to activation has varied between 19 months at Gustave Roussy Cancer Campus in France to 30 months at the Segal Cancer Center, McGill University (Canada). It took 3+ years to be able to activate US sites due to national regulatory hurdles. Access to medications proposed by the molecular analysis remains a major challenge, since their availability through active clinical trials is highly variable over time within sites and across the network. Rules regarding the off-label use of drugs, or drugs not yet approved at all in some countries, pose a further challenge, and many biopharmaceutical companies lack a simple internal mechanism to supply the drugs even if they wish to do so. These various obstacles should be addressed to test and then implement precision medicine in cancer. PMID:25908602

  2. Production of interleukin‑4 in CD133+ cervical cancer stem cells promotes resistance to apoptosis and initiates tumor growth.

    PubMed

    Liu, Chun-Tao; Xin, Ying; Tong, Chun-Yan; Li, Bing; Bao, Hong-Li; Zhang, Cai-Yun; Wang, Xue-Hui

    2016-06-01

    The cancer stem cell (CSC) theory suggests that cancer growth and invasion is dictated by the small population of CSCs within the heterogenous tumor. The aim of the present study was to elucidate the cause for chemotherapy failure and the resistance of CSCs to apoptosis. A total of ~2.3% cluster of differentiation (CD)133+ cancer stem‑like side population (SP) cells were identified in cases of uterine cervical cancer. These CD133+ SP cells were found to potently initiate tumor growth and invasion, as they exhibit transcriptional upregulation of stemness genes, including octamer‑binding transcription factor‑4, B‑cell‑specific Moloney murine leukemia virus insertion site‑1, epithelial cell adhesion molecule, (sex determining region Y)‑box 2, Nestin and anti‑apoptotic B cell lymphoma‑2. In addition, the CD133+ SP cells showed resistance to multi‑drug treatment and apoptosis. The present study further showed that the secretion of interleukin‑4 (IL‑4) in CD133+ cervical cancer SP cells promoted cell proliferation and prevented the SP cells from apoptosis. Following the neutralization of IL‑4 with anti‑IL‑4 antibody, the CD133+ SP cells were more sensitive to drug treatment and apoptosis. Therefore, the data obtained in the present study suggested that the autocrine secretion of IL‑4 promotes increased survival and resistance to cell death in CSCs. PMID:27121303

  3. Production of interleukin-4 in CD133+ cervical cancer stem cells promotes resistance to apoptosis and initiates tumor growth

    PubMed Central

    LIU, CHUN-TAO; XIN, YING; TONG, CHUN-YAN; LI, BING; BAO, HONG-LI; ZHANG, CAI-YUN; WANG, XUE-HUI

    2016-01-01

    The cancer stem cell (CSC) theory suggests that cancer growth and invasion is dictated by the small population of CSCs within the heterogenous tumor. The aim of the present study was to elucidate the cause for chemotherapy failure and the resistance of CSCs to apoptosis. A total of ~2.3% cluster of differentiation (CD)133+ cancer stem-like side population (SP) cells were identified in cases of uterine cervical cancer. These CD133+ SP cells were found to potently initiate tumor growth and invasion, as they exhibit transcriptional upregulation of stemness genes, including octamer-binding transcription factor-4, B-cell-specific Moloney murine leukemia virus insertion site-1, epithelial cell adhesion molecule, (sex determining region Y)-box 2, Nestin and anti-apoptotic B cell lymphoma-2. In addition, the CD133+ SP cells showed resistance to multi-drug treatment and apoptosis. The present study further showed that the secretion of interleukin-4 (IL-4) in CD133+ cervical cancer SP cells promoted cell proliferation and prevented the SP cells from apoptosis. Following the neutralization of IL-4 with anti-IL-4 antibody, the CD133+ SP cells were more sensitive to drug treatment and apoptosis. Therefore, the data obtained in the present study suggested that the autocrine secretion of IL-4 promotes increased survival and resistance to cell death in CSCs. PMID:27121303

  4. Hypoxia-inducing factors as master regulators of stemness properties and altered metabolism of cancer- and metastasis-initiating cells

    PubMed Central

    Mimeault, Murielle; Batra, Surinder K

    2013-01-01

    Accumulating lines of experimental evidence have revealed that hypoxia-inducible factors, HIF-1α and HIF-2α, are key regulators of the adaptation of cancer- and metastasis-initiating cells and their differentiated progenies to oxygen and nutrient deprivation during cancer progression under normoxic and hypoxic conditions. Particularly, the sustained stimulation of epidermal growth factor receptor (EGFR), insulin-like growth factor-1 receptor (IGF-1R), stem cell factor (SCF) receptor KIT, transforming growth factor-β receptors (TGF-βRs) and Notch and their downstream signalling elements such as phosphatidylinositol 3′-kinase (PI3K)/Akt/molecular target of rapamycin (mTOR) may lead to an enhanced activity of HIFs. Moreover, the up-regulation of HIFs in cancer cells may also occur in the hypoxic intratumoral regions formed within primary and secondary neoplasms as well as in leukaemic cells and metastatic prostate and breast cancer cells homing in the hypoxic endosteal niche of bone marrow. The activated HIFs may induce the expression of numerous gene products such as induced pluripotency-associated transcription factors (Oct-3/4, Nanog and Sox-2), glycolysis- and epithelial-mesenchymal transition (EMT) programme-associated molecules, including CXC chemokine receptor 4 (CXCR4), snail and twist, microRNAs and angiogenic factors such as vascular endothelial growth factor (VEGF). These gene products in turn can play critical roles for high self-renewal ability, survival, altered energy metabolism, invasion and metastases of cancer cells, angiogenic switch and treatment resistance. Consequently, the targeting of HIF signalling network and altered metabolic pathways represents new promising strategies to eradicate the total mass of cancer cells and improve the efficacy of current therapies against aggressive and metastatic cancers and prevent disease relapse. PMID:23301832

  5. Prostatic inflammation enhances basal-to-luminal differentiation and accelerates initiation of prostate cancer with a basal cell origin

    PubMed Central

    Kwon, Oh-Joon; Zhang, Li; Ittmann, Michael M.; Xin, Li

    2014-01-01

    Chronic inflammation has been shown to promote the initiation and progression of diverse malignancies by inducing genetic and epigenetic alterations. In this study, we investigate an alternative mechanism through which inflammation promotes the initiation of prostate cancer. Adult murine prostate epithelia are composed predominantly of basal and luminal cells. Previous studies revealed that the two lineages are largely self-sustained when residing in their native microenvironment. To interrogate whether tissue inflammation alters the differentiation program of basal cells, we conducted lineage tracing of basal cells using a K14-CreER;mTmG model in concert with a murine model of prostatitis induced by infection from the uropathogenic bacteria CP9. We show that acute prostatitis causes tissue damage and creates a tissue microenvironment that induces the differentiation of basal cells into luminal cells, an alteration that rarely occurs under normal physiological conditions. Previously we showed that a mouse model with prostate basal cell-specific deletion of Phosphatase and tensin homolog (K14-CreER;Ptenfl/fl) develops prostate cancer with a long latency, because disease initiation in this model requires and is limited by the differentiation of transformation-resistant basal cells into transformation-competent luminal cells. Here, we show that CP9-induced prostatitis significantly accelerates the initiation of prostatic intraepithelial neoplasia in this model. Our results demonstrate that inflammation results in a tissue microenvironment that alters the normal prostate epithelial cell differentiation program and that through this cellular process inflammation accelerates the initiation of prostate cancer with a basal cell origin. PMID:24367088

  6. CD133 initiates tumors, induces epithelial-mesenchymal transition and increases metastasis in pancreatic cancer

    PubMed Central

    Nomura, Alice; Banerjee, Sulagna; Chugh, Rohit; Dudeja, Vikas; Yamamoto, Masato; Vickers, Selwyn M.; Saluja, Ashok K.

    2015-01-01

    CD133 has been implicated as a cancer stem cell (CSC) surface marker in several malignancies including pancreatic cancer. However, the functional role of this surface glycoprotein in the cancer stem cell remains elusive. In this study, we determined that CD133 overexpression induced “stemness” properties in MIA-PaCa2 cells along with increased tumorigenicity, tumor progression, and metastasis in vivo. Additionally, CD133 expression induced epithelial-mesenchymal transition (EMT) and increased in vitro invasion. EMT induction and increased invasiveness were mediated by NF-κB activation, as inhibition of NF-κB mitigated these effects. This study showed that CD133 expression contributes to pancreatic cancer “stemness,” tumorigenicity, EMT induction, invasion, and metastasis. PMID:25829252

  7. Regional Variation in Breast Cancer Rates in the United States (Past Initiative)

    Cancer.gov

    Five institutions are being funded to conduct research using epidemiologic and statistical methods for determining whether various factors may account for the geographic differences in breast cancer rates in the United States.

  8. Cancer modelling in the NGS era - Part I: Emerging technology and initial modelling.

    PubMed

    Rovigatti, Ugo

    2015-11-01

    It is today indisputable that great progresses have been made in our molecular understanding of cancer cells, but an effective implementation of such knowledge into dramatic cancer-cures is still belated and yet desperately needed. This review gives a snapshot at where we stand today in this search for cancer understanding and definitive treatments, how far we have progressed and what are the major obstacles we will have to overcome both technologically and for disease modelling. In the first part, promising 3rd/4th Generation Sequencing Technologies will be summarized (particularly IonTorrent and OxfordNanopore technologies). Cancer modelling will be then reviewed from its origin in XIX Century Germany to today's NGS applications for cancer understanding and therapeutic interventions. Developments after Molecular Biology revolution (1953) are discussed as successions of three phases. The first, PH1, labelled "Clonal Outgrowth" (from 1960s to mid 1980s) was characterized by discoveries in cytogenetics (Nowell, Rowley) and viral oncology (Dulbecco, Bishop, Varmus), which demonstrated clonality. Treatments were consequently dominated by a "cytotoxic eradication" strategy with chemotherapeutic agents. In PH2, (from the mid 1980s to our days) the description of cancer as "Gene Networks" led to targeted-gene-therapies (TGTs). TGTs are the focus of Section 3: in view of their apparent failing (Ephemeral Therapies), alternative strategies will be discussed in review part II (particularly cancer immunotherapy, CIT). Additional Pitfalls impinge on the concepts of tumour heterogeneity (inter/intra; ITH). The described pitfalls set the basis for a new phase, PH3, which is called "NGS Era" and will be also discussed with ten emerging cancer models in the Review 2nd part. PMID:26427785

  9. Reducing the Excess Burden of Cervical Cancer Among Latinas: Translating Science into Health Promotion Initiatives

    PubMed Central

    Baezconde-Garbanati, Lourdes; Murphy, Sheila T.; Moran, Meghan Bridgid; Cortessis, Victoria K.

    2013-01-01

    Purpose Although deaths from cervical cancer are declining, Latinas are not benefiting equally in this decline. Incidence of invasive cervical cancer among Los Angeles’, California Latinas is much higher than among non-Latina Whites (14.7 versus 8.02 per 100,000). This paper examines cervical cancer screening among Latinas. Methods Ninety-seven women of Mexican origin participated in 12 focus groups exploring barriers to screening. Saturation was reached. Results All participants knew what a Pap test was and most knew its purpose. More acculturated participants understood the link between HPV and cervical cancer. More recent immigrants did not. There was confusion whether women who were not sexually active need to be screened. Most frequently mentioned barriers were lack of time and concern over missing work. Lower income and less acculturated women were less likely to be aware of free/low-cost clinics. Older and less acculturated participants held more fatalistic beliefs, were more embarrassed about getting a Pap test, were more fearful of being perceived as sexually promiscuous, and were more fearful of receiving disapproval from their husbands. Conclusions Latinas are informed regarding cervical cancer screening; rather they encounter barriers such as a lack of time, money and support. Health promotion interventions can be enhanced via peer-to-peer education, by addressing barriers to cervical cancer screening with in-language, culturally tailored interventions, and working with clinics on systemic changes, such as extended clinic hours. PMID:24587769

  10. CD133+ tumor initiating cells (TIC) in a syngenic murine model of pancreatic cancer respond to Minnelide

    PubMed Central

    Banerjee, Sulagna; Nomura, Alice; Sangwan, Veena; Chugh, Rohit; Dudeja, Vikas; Vickers, Selwyn M; Saluja, Ashok

    2014-01-01

    Purpose Pancreatic adenocarcinoma is the fourth leading cause for cancer-related mortality with a survival rate of less than 5%. Late diagnosis and lack of effective chemotherapeutic regimen contribute to these grim survival statistics. Relapse of any tumor is largely attributed to the presence of tumor-initiating cells (TIC) or cancer stem cells (CSC). These cells are considered as hurdles to cancer therapy as no known chemotherapeutic compound is reported to target them. Thus, there is an urgent need to develop a TIC-targeted therapy for pancreatic cancer. Experimental design We isolated CD133+ cells from a spontaneous PDAC mouse model and studied both surface expression, molecular markers of pancreatic TICs. We also studied tumor initiation properties by implanting low numbers of CD133+ cells in immune competent mice. Effect of Minnelide, a drug currently under Phase I clinical trial, was studied on the tumors derived from the CD133+ cells. Results Our study showed for the first time that CD133+ population demonstrated all the molecular markers for pancreatic TIC. These cells initiated tumors in immunocompetent mouse models and showed increased expression of pro-survival and pro-invasive proteins compared to the CD133− non-TIC population. Our study further showed that Minnelide, was very efficient in downregulating both CD133− and CD133+ population in the tumors, resulting in a 60% decrease in tumor volume compared to the untreated ones. Conclusion As Minnelide is currently under Phase I clinical trial, its evaluation in reducing tumor burden by decreasing TIC as well as non-TIC population suggests its potential as an effective therapy. PMID:24634377

  11. Initial Case Reports of Cancer in Naked Mole-rats (Heterocephalus glaber).

    PubMed

    Delaney, M A; Ward, J M; Walsh, T F; Chinnadurai, S K; Kerns, K; Kinsel, M J; Treuting, P M

    2016-05-01

    Naked mole-rats (NMRs;Heterocephalus glaber) are highly adapted, eusocial rodents renowned for their extreme longevity and resistance to cancer. Because cancer has not been formally described in this species, NMRs have been increasingly utilized as an animal model in aging and cancer research. We previously reported the occurrence of several age-related diseases, including putative pre-neoplastic lesions, in zoo-housed NMR colonies. Here, we report for the first time 2 cases of cancer in zoo-housed NMRs. In Case No. 1, we observed a subcutaneous mass in the axillary region of a 22-year-old male NMR, with histologic, immunohistochemical (pancytokeratin positive, rare p63 immunolabeling, and smooth muscle actin negative), and ultrastructural characteristics of an adenocarcinoma possibly of mammary or salivary origin. In Case No. 2, we observed a densely cellular, poorly demarcated gastric mass of polygonal cells arranged in nests with positive immunolabeling for synaptophysin and chromogranin indicative of a neuroendocrine carcinoma in an approximately 20-year-old male NMR. We also include a brief discussion of other proliferative growths and pre-cancerous lesions diagnosed in 1 zoo colony. Although these case reports do not alter the longstanding observation of cancer resistance, they do raise questions about the scope of cancer resistance and the interpretation of biomedical studies in this model. These reports also highlight the benefit of long-term disease investigations in zoo-housed populations to better understand naturally occurring disease processes in species used as models in biomedical research. PMID:26846576

  12. The National Cancer Institute’s Community Networks Program Initiative to Reduce Cancer Health Disparities: Outcomes and Lessons Learned

    PubMed Central

    Braun, Kathryn L.; Stewart, Susan; Baquet, Claudia; Berry-Bobovski, Lisa; Blumenthal, Daniel; Brandt, Heather M.; Buchwald, Dedra S.; Campbell, Janis E.; Coe, Kathryn; Cooper, Leslie C.; Espinoza, Paula; Henry-Tillman, Ronda; Hargreaves, Margaret; James, Aimee; Kaur, Judith Salmon; Viswanath, K.; Ma, Grace X.; Mandelblatt, Jeanne; Meade, Cathy; Ramirez, Amelie; Scarinci, Isabel; Tanjasiri, Sora Park; Thompson, Beti; Vines, Anissa I.; Dignan, Mark

    2015-01-01

    Background We describe reach, partnerships, products, benefits, and lessons learned of the 25 Community Network Programs (CNPs) that applied community-based participatory research (CBPR) to reduce cancer health disparities. Methods Quantitative and qualitative data were abstracted from CNP final reports. Qualitative data were grouped by theme. Results Together, the 25 CNPs worked with more than 2,000 academic, clinical, community, government, faith-based, and other partners. They completed 211 needs assessments, leveraged funds for 328 research and service projects, trained 719 new investigators, educated almost 55,000 community members, and published 991 articles. Qualitative data illustrated how use of CBPR improved research methods and participation; improved knowledge, interventions, and outcomes; and built community capacity. Lessons learned related to the need for time to nurture partnerships and the need to attend to community demand for sustained improvements in cancer services. Implications Findings demonstrate the value of government-supported, community–academic, CBPR partnerships in cancer prevention and control research. PMID:26213401

  13. Initial prostate cancer diagnosis and disease staging--the role of choline-PET-CT.

    PubMed

    Mapelli, Paola; Picchio, Maria

    2015-09-01

    An early and correct diagnosis together with accurate staging of prostate cancer is necessary in order to plan the most appropriate treatment strategy. Morphological imaging modalities such as transrectal ultrasonography (TRUS), CT, and MRI can have some limitations regarding their accuracy for primary diagnosis and staging of prostate cancer; for instance, they have limited specificity in differentiating cancer from benign prostatic conditions and, by using size as the only criterion to characterize lymph node metastases, they might not be accurate enough for tumour characterization. In this scenario, PET-CT with (11)C-labelled or (18)F-labelled choline derivatives provides morphological and functional characterization and could overcome the limitations of the conventional imaging techniques. PET-CT is one of the most investigated molecular imaging modalities for prostate cancer diagnosis and staging. Currently, the main investigations on the role of PET-CT in the diagnosis and staging of prostate cancer have been performed on a retrospective basis and this type of analysis might be one of the main reasons why different results regarding its diagnostic accuracy have been reported. PMID:26260884

  14. The isolation and characterization of renal cancer initiating cells from human Wilms' tumour xenografts unveils new therapeutic targets†

    PubMed Central

    Pode-Shakked, Naomi; Shukrun, Rachel; Mark-Danieli, Michal; Tsvetkov, Peter; Bahar, Sarit; Pri-Chen, Sara; Goldstein, Ronald S; Rom-Gross, Eithan; Mor, Yoram; Fridman, Edward; Meir, Karen; Simon, Amos; Magister, Marcus; Kaminski, Naftali; Goldmacher, Victor S; Harari-Steinberg, Orit; Dekel, Benjamin

    2013-01-01

    There are considerable differences in tumour biology between adult and paediatric cancers. The existence of cancer initiating cells/cancer stem cells (CIC/CSC) in paediatric solid tumours is currently unclear. Here, we show the successful propagation of primary human Wilms' tumour (WT), a common paediatric renal malignancy, in immunodeficient mice, demonstrating the presence of a population of highly proliferative CIC/CSCs capable of serial xenograft initiation. Cell sorting and limiting dilution transplantation analysis of xenograft cells identified WT CSCs that harbour a primitive undifferentiated – NCAM1 expressing – “blastema” phenotype, including a capacity to expand and differentiate into the mature renal-like cell types observed in the primary tumour. WT CSCs, which can be further enriched by aldehyde dehydrogenase activity, overexpressed renal stemness and genes linked to poor patient prognosis, showed preferential protein expression of phosphorylated PKB/Akt and strong reduction of the miR-200 family. Complete eradication of WT in multiple xenograft models was achieved with a human NCAM antibody drug conjugate. The existence of CIC/CSCs in WT provides new therapeutic targets. PMID:23239665

  15. Multiple roles of COUP-TFII in cancer initiation and progression

    PubMed Central

    Litchfield, Lacey M.; Klinge, Carolyn M.

    2012-01-01

    COUP-TFII is an orphan nuclear receptor that acts as a transcriptional activator or repressor in a cell type-dependent manner. Best characterized for its role in the regulation of angiogenesis during mouse development, COUP-TFII also plays important roles in glucose metabolism and cancer. Expression of COUP-TFII is altered in various endocrine conditions. Cell type-specific functions and the regulation of COUP-TFII expression result in its varying physiological and pathological actions in diverse systems. Evidence will be reviewed for oncogenic and tumor suppressive functions of COUP-TFII, with roles in angiogenesis, metastasis, steroidogenesis, and endocrine sensitivity of breast cancer described. The applicability of current data to our understanding of the role of COUP-TFII in cancer will be discussed. PMID:22966133

  16. Changes in Initial Treatment for Prostate Cancer Among Medicare Beneficiaries, 1999-2007

    SciTech Connect

    Dinan, Michaela A.; Robinson, Timothy J.; Zagar, Timothy M.; Scales, Charles D.; Curtis, Lesley H.; Reed, Shelby D.; Lee, W. Robert; Schulman, Kevin A.

    2012-04-01

    Purpose: In the absence of evidence from large clinical trials, optimal therapy for localized prostate cancer remains unclear; however, treatment patterns continue to change. We examined changes in the management of patients with prostate cancer in the Medicare population. Methods and Materials: We conducted a retrospective claims-based analysis of the use of radiation therapy, surgery, and androgen deprivation therapy in the 12 months after diagnosis of prostate cancer in a nationally representative 5% sample of Medicare claims. Patients were Medicare beneficiaries 67 years or older with incident prostate cancer diagnosed between 1999 and 2007. Results: There were 20,918 incident cases of prostate cancer between 1999 and 2007. The proportion of patients receiving androgen deprivation therapy decreased from 55% to 36%, and the proportion of patients receiving no active therapy increased from 16% to 23%. Intensity-modulated radiation therapy replaced three-dimensional conformal radiation therapy as the most common method of radiation therapy, accounting for 77% of external beam radiotherapy by 2007. Minimally invasive radical prostatectomy began to replace open surgical approaches, being used in 49% of radical prostatectomies by 2007. Conclusions: Between 2002 and 2007, the use of androgen deprivation therapy decreased, open surgical approaches were largely replaced by minimally invasive radical prostatectomy, and intensity-modulated radiation therapy replaced three-dimensional conformal radiation therapy as the predominant method of radiation therapy in the Medicare population. The aging of the population and the increasing use of newer, higher-cost technologies in the treatment of patients with prostate cancer may have important implications for nationwide health care costs.

  17. Changes in Initial Treatment for Prostate Cancer Among Medicare Beneficiaries, 1999-2007

    PubMed Central

    Dinan, Michaela A.; Robinson, Timothy J.; Zagar, Timothy M.; Scales, Charles D.; Curtis, Lesley H.; Reed, Shelby D.; Robert Lee, W.; Schulman, Kevin A.

    2012-01-01

    Purpose In the absence of evidence from large clinical trials, optimal therapy for localized prostate cancer remains unclear; however, treatment patterns continue to change. We examined changes in the management of patients with prostate cancer in the Medicare population. Methods and Materials We conducted a retrospective claims-based analysis of the use of radiation therapy, surgery, and androgen deprivation therapy in the 12 months after diagnosis of prostate cancer in a nationally representative 5% sample of Medicare claims. Patients were Medicare beneficiaries 67 years or older with incident prostate cancer diagnosed between 1999 and 2007. Results There were 20,918 incident cases of prostate cancer between 1999 and 2007. The proportion of patients receiving androgen deprivation therapy decreased from 55% to 36%, and the proportion of patients receiving no active therapy increased from 16% to 23%. Intensity-modulated radiation therapy replaced 3-dimensional conformal radiation therapy as the most common method of radiation therapy, accounting for 77% of external beam radiotherapy by 2007. Minimally invasive radical prostatectomy began to replace open surgical approaches, being used in 49% of radical prostatectomies by 2007. Conclusions Between 2002 and 2007, the use of androgen deprivation therapy decreased, open surgical approaches were largely replaced by minimally invasive radical prostatectomy, and intensity-modulated radiation therapy replaced 3-dimensional conformal radiation therapy as the predominant method of radiation therapy in the Medicare population. The aging of the population and the increasing use of newer, higher-cost technologies in the treatment of patients with prostate cancer may have important implications for nationwide health care costs. PMID:22331001

  18. Symptomization and triggering processes: ovarian cancer patients' narratives on pre-diagnostic sensation experiences and the initiation of healthcare seeking.

    PubMed

    Brandner, Susanne; Müller-Nordhorn, Jacqueline; Stritter, Wiebke; Fotopoulou, Christina; Sehouli, Jalid; Holmberg, Christine

    2014-10-01

    Ovarian cancer is a malignant entity typically diagnosed in advanced stages, with concomitant poor prognosis. Delayed healthcare seeking is commonly explained by the 'vague' character of the disease's symptoms combined with a lack of awareness among patients. However, research on the social contexts of ovarian cancer patients' pre-diagnostic illness experiences and healthcare seeking is scarce. To explore these topics, we initiated a qualitative interview study guided by the principles of grounded theory and based on interviews with 42 ovarian cancer patients. The study was conducted in Germany from September 2011 to February 2013. Our analysis illustrates how, in the narratives, the interviewees struggled to balance specific bodily sensations with aspects of their life-worlds prior to consulting a biomedical professional. We propose a three-phase model to capture these experiences and demonstrate how the developments of pre-diagnostic sensations were catalysed by the dynamic and complex interplay of the sensations with a variety of individual and socio-cultural factors. To conceptualize these interplays, we introduce the analytical notion of a triggering process, and we elaborate on the different ways in which such a process conditioned the transformation of a sensation into a symptom and decisions to seek healthcare. We finally discuss our findings both in relation to current research on sensations, symptoms and healthcare seeking and in their relevance for understanding diagnostic delays in ovarian cancer. PMID:25179810

  19. Dependency of colorectal cancer on a TGF-beta-driven programme in stromal cells for metastasis initiation

    PubMed Central

    Calon, Alexandre; Espinet, Elisa; Palomo-Ponce, Sergio; Tauriello, Daniele V. F.; Iglesias, Mar; Céspedes, María Virtudes; Sevillano, Marta; Nadal, Cristina; Jung, Peter; Zhang, Xiang H.-F.; Byrom, Daniel; Riera, Antoni; Rossell, David; Mangues, Ramón; Massague, Joan; Sancho, Elena; Batlle, Eduard

    2012-01-01

    SUMMARY A large proportion of colorectal cancers (CRCs) display mutational inactivation of the TGF-beta pathway yet paradoxically, they are characterized by elevated TGF-beta production. Here, we unveil a prometastatic programme induced by TGF-beta in the microenvironment that associates with a high-risk of CRC relapse upon treatment. The activity of TGF-beta on stromal cells increases the efficiency of organ colonization by CRC cells whereas mice treated with a pharmacological inhibitor of TGFBR1 are resilient to metastasis formation. Secretion of IL11 by TGF-beta-stimulated cancer-associated fibroblasts (CAFs) triggers GP130/STAT3 signalling in tumour cells. This crosstalk confers a survival advantage to metastatic cells. The dependency on the TGF-beta stromal programme for metastasis initiation could be exploited to improve the diagnosis and treatment of CRC. PMID:23153532

  20. An apoptosis-enhancing drug overcomes platinum resistance in a tumour-initiating subpopulation of ovarian cancer

    PubMed Central

    Janzen, D. M.; Tiourin, E.; Salehi, J. A.; Paik, D. Y.; Lu, J.; Pellegrini, M.; Memarzadeh, S.

    2015-01-01

    High-grade serous ovarian cancers (HGSCs) are deadly malignancies that relapse despite carboplatin chemotherapy. Here we show that 16 independent primary HGSC samples contain a CA125-negative population enriched for carboplatin-resistant cancer initiating cells. Transcriptome analysis reveals upregulation of homologous recombination DNA repair and anti-apoptotic signals in this population. While treatment with carboplatin enriches for CA125-negative cells, co-treatment with carboplatin and birinapant eliminates these cells in HGSCs expressing high levels of the inhibitor of apoptosis protein cIAP in the CA125-negative population. Birinapant sensitizes CA125-negative cells to carboplatin by mediating degradation of cIAP causing cleavage of caspase 8 and restoration of apoptosis. This co-therapy significantly improves disease-free survival in vivo compared with either therapy alone in tumour-bearing mice. These findings suggest that therapeutic strategies that target CA125-negative cells may be useful in the treatment of HGSC. PMID:26234182

  1. Delay in initiation of adjuvant trastuzumab therapy leads to decreased overall survival and relapse-free survival in patients with HER2-positive non-metastatic breast cancer.

    PubMed

    Gallagher, Christopher M; More, Kenneth; Kamath, Tripthi; Masaquel, Anthony; Guerin, Annie; Ionescu-Ittu, Raluca; Gauthier-Loiselle, Marjolaine; Nitulescu, Roy; Sicignano, Nicholas; Butts, Elizabeth; Wu, Eric Q; Barnett, Brian

    2016-05-01

    Trastuzumab reduces the risk of relapse in women with HER2-positive non-metastatic breast cancer, but little information exists on the timing of trastuzumab initiation. The study investigated the impact of delaying the initiation of adjuvant trastuzumab therapy for >6 months after the breast cancer diagnosis on time to relapse, overall survival (OS), and relapse-free survival (RFS) among patients with non-metastatic breast cancer. Adult women with non-metastatic breast cancer who initiated trastuzumab adjuvant therapy without receiving any neoadjuvant therapy were selected from the US Department of Defense health claims database from 01/2003 to 12/2012. Two study cohorts were defined based on the time from breast cancer diagnosis to trastuzumab initiation: >6 months and ≤6 months. The impact of delaying trastuzumab initiation on time to relapse, OS, and RFS was estimated using Cox regression models adjusted for potential confounders. Of 2749 women in the study sample, 79.9 % initiated adjuvant trastuzumab within ≤6 months of diagnosis and 20.1 % initiated adjuvant trastuzumab >6 months after diagnosis. After adjusting for confounders, patients who initiated trastuzumab >6 months after the breast cancer diagnosis had a higher risk of relapse, death, or relapse/death than those who initiated trastuzumab within ≤6 months of diagnosis (hazard ratios [95 % CIs]: 1.51 [1.22-1.87], 1.54 [1.12-2.12], and 1.43 [1.16-1.75]; respectively). The results of this population-based study suggest that delays of >6 months in the initiation of trastuzumab among HER2-positive non-metastatic breast cancer patients are associated with a higher risk of relapse and shorter OS and RFS. PMID:27107569

  2. Integration of Nuclear- and Extranuclear-Initiated Estrogen Receptor Signaling in Breast Cancer Cells

    ERIC Educational Resources Information Center

    Madak Erdogan, Zeynep

    2009-01-01

    Estrogenic hormones exert their effects through binding to Estrogen Receptors (ERs), which work in concert with coregulators and extranuclear signaling pathways to control gene expression in normal as well as cancerous states, including breast tumors. In this thesis, we have used multiple genome-wide analysis tools to elucidate various ways that…

  3. Evaluating the Quality of Colorectal Cancer Care in the State of Florida: Results From the Florida Initiative for Quality Cancer Care

    PubMed Central

    Siegel, Erin M.; Jacobsen, Paul B.; Malafa, Mokenge; Fulp, William; Fletcher, Michelle; Lee, Ji-Hyun; Smith, Jesusa Corazon R.; Brown, Richard; Levine, Richard; Cartwright, Thomas; Abesada-Terk, Guillermo; Kim, George; Alemany, Carlos; Faig, Douglas; Sharp, Philip; Markham, Merry-Jennifer; Shibata, David

    2012-01-01

    Purpose: The Florida Initiative for Quality Cancer Care (FIQCC) was established to evaluate the quality of cancer care at the regional level across the state of Florida. This study assessed adherence to validated quality indicators in colorectal cancer (CRC) and the variability in adherence by practice site, volume, and patient age. Methods: The FIQCC is a consortium of 11 medical oncology practices in Florida. Medical record reviews were conducted for 507 patients diagnosed with CRC and seen as new medical oncology patients in 2006. Thirty-five indicators were evaluated individually and categorized across clinical domains and components of care. Results: The mean adherence for 19 of 35 individual indicators was > 85%. Pathology reports were compliant on reporting depth of tumor invasion (96%; range, 86% to 100%), grade (93%; range, 72% to 100%), and status of proximal and distal surgical resection margins (97%; range. 86% to 100%); however, documentation of lymphovascular and perineural invasion did not meet adherence standards (76%; range, 53% to 100% and 39%; range, 5% to 83%, respectively). Among patients with nonmetastatic rectal cancer, documentation of the status of surgical radial margins was consistently low across sites (42%; range, 0% to 100%; P = .19). Documentation of planned treatment regimens for adjuvant chemotherapy was noted in only 58% of eligible patients. Conclusion: In this large regional initiative, we found high levels of adherence to more than half of the established quality indicators. Although the quality of care delivered within FIQCC practices seems to be high, several components of care were identified that warrant further scrutiny on both a systemic level and at individual centers. PMID:23180990

  4. Use of Bone Scan During Initial Prostate Cancer Workup, Downstream Procedures, and Associated Medicare Costs

    SciTech Connect

    Falchook, Aaron D.; Salloum, Ramzi G.; Hendrix, Laura H.; Chen, Ronald C.

    2014-06-01

    Purpose: For patients with a high likelihood of having metastatic disease (high-risk prostate cancer), bone scan is the standard, guideline-recommended test to look for bony metastasis. We quantified the use of bone scans and downstream procedures, along with associated costs, in patients with high-risk prostate cancer, and their use in low- and intermediate-risk patients for whom these tests are not recommended. Methods and Materials: Patients in the Surveillance, Epidemiology, and End Results (SEER)-Medicare database diagnosed with prostate cancer from 2004 to 2007 were included. Prostate specific antigen (PSA), Gleason score, and clinical T stage were used to define D'Amico risk categories. We report use of bone scans from the date of diagnosis to the earlier of treatment or 6 months. In patients who underwent bone scans, we report use of bone-specific x-ray, computed tomography (CT), and magnetic resonance imaging (MRI) scans, and bone biopsy within 3 months after bone scan. Costs were estimated using 2012 Medicare reimbursement rates. Results: In all, 31% and 48% of patients with apparent low- and intermediate-risk prostate cancer underwent a bone scan; of these patients, 21% underwent subsequent x-rays, 7% CT, and 3% MRI scans. Bone biopsies were uncommon. Overall, <1% of low- and intermediate-risk patients were found to have metastatic disease. The annual estimated Medicare cost for bone scans and downstream procedures was $11,300,000 for low- and intermediate-risk patients. For patients with apparent high-risk disease, only 62% received a bone scan, of whom 14% were found to have metastasis. Conclusions: There is overuse of bone scans in patients with low- and intermediate-risk prostate cancers, which is unlikely to yield clinically actionable information and results in a potential Medicare waste. However, there is underuse of bone scans in high-risk patients for whom metastasis is likely.

  5. "Cirque du Freak."

    ERIC Educational Resources Information Center

    Rivett, Miriam

    2002-01-01

    Considers the marketing strategies that underpin the success of the "Cirque du Freak" series. Describes how "Cirque du Freak" is an account of events in the life of schoolboy Darren Shan. Notes that it is another reworking of the vampire narrative, a sub-genre of horror writing that has proved highly popular with both adult and child readers. (SG)

  6. Cancer

    MedlinePlus

    ... Leukemia Liver cancer Non-Hodgkin lymphoma Ovarian cancer Pancreatic cancer Testicular cancer Thyroid cancer Uterine cancer ... have any symptoms. In certain cancers, such as pancreatic cancer, symptoms often do not start until the disease ...

  7. Improving Care for Children With Cancer in Low- and Middle-Income Countries--a SIOP PODC Initiative.

    PubMed

    Arora, Ramandeep Singh; Challinor, Julia M; Howard, Scott C; Israels, Trijn

    2016-03-01

    The Paediatric Oncology in Developing Countries (PODC) committee of International Society of Paediatric Oncology (SIOP) has 10 working groups that provide a forum for individuals to engage, network, and implement improvements in the care of children with cancer in low- and middle-income countries. The development of adapted guidelines (medulloblastoma, retinoblastoma, Wilms tumor, neuroblastoma, retinoblastoma, Burkitt lymphoma, supportive care), advocacy and awareness (on hospital detention and essential drugs), education and training, and global mapping (nutritional practice, abandonment rates, and twinning collaborations) have been the initial areas of focus, and the impact of some of these activities is evident, for example, in the SIOP Africa PODC Collaborative Wilms tumor project. PMID:26797891

  8. PET/MR Imaging for Chest Diseases: Review of Initial Studies on Pulmonary Nodules and Lung Cancers.

    PubMed

    Yoon, Soon Ho; Goo, Jin Mo; Lee, Sang Min; Park, Chang Min; Cheon, Gi Jeong

    2015-05-01

    PET/MR imaging, a new hybrid modality, is thought to have great potential in oncologic imaging because it provides advantages of both PET, which allows functional imaging capability, and MR imaging, which allows high spatial resolution imaging without radiation exposure. Despite the inherent weakness of MR imaging in lung imaging, initial studies on lung cancer revealed that PET/MR imaging showed highly correlated standardized uptake values of lesions and equivalent performance in terms of lesion detection and staging compared with PET/computed tomography (CT). Thus, to affirm the actual clinical benefits of dedicated PET/MR imaging over PET/CT, prospective studies with more patients are warranted. PMID:25952518

  9. Importance of dietary fat during initiation versus promotion in rat mammary cancer

    SciTech Connect

    Hasler, C.M.; Bennink, M.R.

    1986-03-05

    This study was designed to determine if the fat content of the diet would alter 7,12-dimethylbenzanthracene (DMBA) initiation of mammary carcinogenesis. Female Sprague-Dawley rats were fed the AIN-76 (high carbohydrate, HC) diet or a modified AIN-76 diet (high fat (37/sup 5/), HF) prior to initiation. The HF diet had the same energy to nutrient ratio as the HC diet. Two groups were fed either the HC or the HF diet during the initiation and promotion phase (HC-HC and HF-HF groups). A third group was fed the HF diet 20 days before and 12 days after initiation and then were fed the HC diet during the promotion phase (HF-HC group). Weight gain during promotion was similar for the HC-HC and HF-HC groups, but the HF-HF group gained 41% more weight. The HC-HC group had significantly fewer tumors than the HF-HF or HF-HC groups (HC-HC = 1.45 tumors/rat; HF-HF = 2.75 and HF-HC = 3.63). Surprisingly, feeding the HC diet during promotion did not cause a decrease in tumorigenesis (there was actually a non-significant increase). This work demonstrates that the fat (energy) content of the diet during DMBA initiation is critical. Furthermore, the fat (energy) content of the diet during initiation was more critical than during promotion.

  10. [Conversion Therapy of Initially Unresectable Rectal Cancer with Perforation via FOLFOX4 Chemotherapy].

    PubMed

    Yamada, Chizu; Ishikawa, Fumihiko; Nitta, Hiroshi; Fujita, Yoshihisa; Omoto, Hideyuki; Kamata, Shigeyuki; Ito, Hiroshi

    2015-11-01

    We describe a case of perforated rectal cancer that became curatively resectable after FOLFOX4 chemotherapy. An 81- year-old woman was transferred to our hospital with a diagnosis of bowel perforation. She underwent emergency transverse colostomy, peritoneal lavage, and the insertion of indwelling drainage tubes, because the perforated rectal cancer was considered unresectable. After recuperation, she received chemotherapy consisting of FOLFOX4 and bevacizumab. Owing to a good response to the treatment after 4 months, rectal resection was achieved curatively. Wound dehiscence occurred as a postoperative complication. The patient chose not to receive adjuvant chemotherapy. Currently, she has been alive for more than 1 year 3 months after resection without recurrence. PMID:26805353

  11. Initial Evaluation of an Electronic Symptom Diary for Adolescents with Cancer

    PubMed Central

    Gibson, Faith; Coll, Beatriz; Kletter, Richard; Zeltzer, Paul; Miaskowski, Christine

    2012-01-01

    Background The delivery of optimal care depends on accurate communication between patients and clinicians regarding untoward symptoms. Documentation of patients’ symptoms necessitates reliance on memory, which is often imprecise. We developed an electronic diary (eDiary) for adolescents and young adults (AYAs) with cancer to record symptoms. Objective The purpose of this paper is to describe the utility of an eDiary designed for AYAs with cancer, including dependability of the mobile application, the reasons for any missing recorded data, patients’ adherence rates to daily symptom queries, and patients’ perceptions of the usefulness and acceptability of symptom data collection via mobile phones. Methods Our team developed an electronic symptom diary based on interviews conducted with AYAs with cancer and their clinicians. This diary included daily severity ratings of pain, nausea, vomiting, fatigue, and sleep. The occurrence of other selected physical sequelae was assessed daily. Additionally, patients selected descriptors of their mood. A 3-week trial of the eDiary was conducted with 10 AYA cancer patients. Mobile phones with service plans were loaned to patients who were instructed to report their symptoms daily. Patients completed a brief questionnaire and were interviewed to elicit their perceptions of the eDiary and any technical difficulties encountered. Results Overall adherence to daily symptom reports exceeded 90%. Young people experienced few technical difficulties and reported benefit from daily symptom reports. Symptom occurrence rates were high and considerable inter- and intra-patient variability was noted in symptom and mood reports. Conclusions We demonstrated the utility of an eDiary that may contribute insight into patients’ symptom patterns to promote effective symptom management. PMID:23612521

  12. The Role of the Membrane-Initiated Heat Shock Response in Cancer.

    PubMed

    Bromberg, Zohar; Weiss, Yoram

    2016-01-01

    The heat shock response (HSR) is a cellular response to diverse environmental and physiological stressors resulting in the induction of genes encoding molecular chaperones, proteases, and other proteins that are essential for protection and recovery from cellular damage. Since different perturbations cause accumulation of misfolded proteins, cells frequently encounter fluctuations in the environment which alter proteostasis. Since tumor cells use their natural adaptive mechanism of coping with stress and misfolded proteins, in recent years, the proteostasis network became a promising target for anti-tumor therapy. The membrane is the first to be affected by heat shock and therefore may be the first one to sense heat shock. The membrane also connects between the extracellular and the intracellular signals. Hence, there is a "cross talk" between the HSR and the membranes since heat shock can induce changes in the fluidity of membranes, leading to membrane lipid remodeling that occurs in several diseases such as cancer. During the last decade, a new possible therapy has emerged in which an external molecule is used that could induce membrane lipid re-organization. Since at the moment there are very few substances that regulate the HSR effectively, an alternative way has been searched to modulate chaperone activities through the plasma membrane. Recently, we suggested that the use of the membrane Transient Receptor Potential Vanilloid-1 (TRPV1) modulators regulated the HSR in cancer cells. However, the primary targets of the signal transduction pathway are yet un-known. This review provides an overview of the current literature regarding the role of HSR in membrane remodeling in cancer since a deep understanding of the membrane biology in cancer and the membrane heat sensing pathway is essential to design novel efficient therapies. PMID:27200359

  13. The Role of the Membrane-Initiated Heat Shock Response in Cancer

    PubMed Central

    Bromberg, Zohar; Weiss, Yoram

    2016-01-01

    The heat shock response (HSR) is a cellular response to diverse environmental and physiological stressors resulting in the induction of genes encoding molecular chaperones, proteases, and other proteins that are essential for protection and recovery from cellular damage. Since different perturbations cause accumulation of misfolded proteins, cells frequently encounter fluctuations in the environment which alter proteostasis. Since tumor cells use their natural adaptive mechanism of coping with stress and misfolded proteins, in recent years, the proteostasis network became a promising target for anti-tumor therapy. The membrane is the first to be affected by heat shock and therefore may be the first one to sense heat shock. The membrane also connects between the extracellular and the intracellular signals. Hence, there is a “cross talk” between the HSR and the membranes since heat shock can induce changes in the fluidity of membranes, leading to membrane lipid remodeling that occurs in several diseases such as cancer. During the last decade, a new possible therapy has emerged in which an external molecule is used that could induce membrane lipid re-organization. Since at the moment there are very few substances that regulate the HSR effectively, an alternative way has been searched to modulate chaperone activities through the plasma membrane. Recently, we suggested that the use of the membrane Transient Receptor Potential Vanilloid-1 (TRPV1) modulators regulated the HSR in cancer cells. However, the primary targets of the signal transduction pathway are yet un-known. This review provides an overview of the current literature regarding the role of HSR in membrane remodeling in cancer since a deep understanding of the membrane biology in cancer and the membrane heat sensing pathway is essential to design novel efficient therapies. PMID:27200359

  14. Inactivating all three rb family pocket proteins is insufficient to initiate cervical cancer.

    PubMed

    Shin, Myeong-Kyun; Sage, Julien; Lambert, Paul F

    2012-10-15

    Human papillomavirus-16 (HPV-16) is associated etiologically with many human cervical cancers. It encodes 3 oncogenes E5, E6, and E7. Of these oncogenes, E7 has been found to be the dominant driver of cervical cancer in mice. More than 100 cellular proteins have been reported to associate with HPV-16 E7, which is thought to dysregulate the cell cycle in part by binding and inducing the degradation of pRb and its related pocket protein family members, p107 and p130. The ability of E7 to inactivate the pRb family correlates with its ability to induce head and neck cancers in mice. We previously showed that the inactivation of pRb is itself not sufficient to recapitulate the oncogenic properties of E7 in cervical carcinogenesis. In this study, we evaluated mice that were deficient in multiple pocket proteins, including mice that lacked pRb, p107, and p130. Strikingly, combined loss of two or all 3 pocket proteins resulted in development of high-grade cervical intraepithelial neoplasia, but not frank cervical carcinoma. These findings strongly argue that the oncogenic properties of HPV-16 E7 in human cervical carcinogenesis may involve disruption of E7 binding proteins beyond simply the pRb family members. PMID:22942253

  15. Tumor Initiating Cells and Chemoresistance: Which Is the Best Strategy to Target Colon Cancer Stem Cells?

    PubMed Central

    Paldino, Emanuela; Tesori, Valentina; Casalbore, Patrizia; Gasbarrini, Antonio

    2014-01-01

    There is an emerging body of evidence that chemoresistance and minimal residual disease result from selective resistance of a cell subpopulation from the original tumor that is molecularly and phenotypically distinct. These cells are called “cancer stem cells” (CSCs). In this review, we analyze the potential targeting strategies for eradicating CSCs specifically in order to develop more effective therapeutic strategies for metastatic colon cancer. These include induction of terminal epithelial differentiation of CSCs or targeting some genes expressed only in CSCs and involved in self-renewal and chemoresistance. Ideal targets could be cell regulators that simultaneously control the stemness and the resistance of CSCs. Another important aspect of cancer biology, which can also be harnessed to create novel broad-spectrum anticancer agents, is the Warburg effect, also known as aerobic glycolysis. Actually, little is yet known with regard to the metabolism of CSCs population, leaving an exciting unstudied avenue in the dawn of the emerging field of metabolomics. PMID:24527460

  16. Vulvar cancer: initial management and systematic review of literature on currently applied treatment approaches.

    PubMed

    Sznurkowski, Jacek Jan

    2016-07-01

    This review provides guidelines and aims to estimate utilisation rates of treatment modalities applied in vulvar cancer. Current standards of treatment are as follows: wide local excision instead of radical vulvectomy in the case of small tumour (T < 2 cm), no lymph node dissection in the case of a micro-invasive tumour (invasion <1 mm), unilateral lymph node dissection in the case of a lateral tumour and inguinal-femoral lymphadenectomy by separate incisions instead of en bloc inguinal-femoral lymph node excision. Implementation of sentinel lymph node biopsy in patients with tumours not exceeding 4 cm is safe and efficiently eliminates redundant groin dissections. Pre-operative treatment with chemoradiotherapy reduces tumour size and improves surgical excision of inoperable primary tumours or fixed lymph nodes, but side effects are considerable. Literature search performed using PubMed database (from: 1 June 2005 to 1 June 2015) with the terms 'consecutive', 'vulvar cancer', 'treatment' identified seven full-text manuscripts, including data on 1114 patients. Utilisation rates of neoadjuvant radiochemotherapy, chemotherapy alone, surgery, adjuvant radiotherapy and adjuvant radiochemotherapy were 5.9%, 0.3%, 89.3%, 22.6% and 0.2% respectively. An evidence-based estimation of appropriate rates of surgery, radiotherapy and chemotherapy for vulvar cancer is needed to compare management reflecting guidelines with presented here real frequency of applied modalities. PMID:26880231

  17. Intraperitoneal chemotherapy for the initial management of primary epithelial ovarian cancer

    PubMed Central

    Jaaback, Kenneth; Johnson, Nick; Lawrie, Theresa A

    2014-01-01

    Background Ovarian cancer tends to be chemosensitive and confine itself to the surface of the peritoneal cavity for much of its natural history. These features have made it an obvious target for intraperitoneal (IP) chemotherapy. Chemotherapy for ovarian cancer is usually given as an intravenous (IV) infusion repeatedly over five to eight cycles. Intraperitoneal chemotherapy is given by infusion of the chemotherapeutic agent directly into the peritoneal cavity. There are biological reasons why this might increase the anticancer effect and reduce some systemic adverse effects in comparison to IV therapy. Objectives To determine if adding a component of the chemotherapy regime into the peritoneal cavity affects overall survival, progression-free survival, quality of life (QOL) and toxicity in the primary treatment of epithelial ovarian cancer. Search methods We searched the Gynaecological Cancer Review Group’s Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) Issue 2, 2011, MEDLINE (1951 to May 2011) and EMBASE (1974 to May 2011). We updated these searches in February 2007, August 2010 and May 2011. In addition, we handsearched and cascade searched the major gynaecological oncology journals. Selection criteria The analysis was restricted to randomised controlled trials (RCTs) assessing women with a new diagnosis of primary epithelial ovarian cancer, of any FIGO stage, following primary cytoreductive surgery. Standard IV chemotherapy was compared with chemotherapy that included a component of IP administration. Data collection and analysis We extracted data on overall survival, disease-free survival, adverse events and QOL and performed meta-analyses of hazard ratios (HR) for time-to-event variables and relative risks (RR) for dichotomous outcomes using RevMan software. Main results Nine randomised trials studied 2119 women receiving primary treatment for ovarian cancer. We considered six trials to be of high quality. Women were less

  18. Eukaryotic Translation Initiation Factor 3a (eIF3a) Promotes Cell Proliferation and Motility in Pancreatic Cancer.

    PubMed

    Wang, Shu Qian; Liu, Yu; Yao, Min Ya; Jin, Jing

    2016-10-01

    Identifying a target molecule that is crucially involved in pancreatic tumor growth and metastasis is necessary in developing an effective treatment. The study aimed to investigate the role of the eukaryotic translation initiation factor 3a (eIF3a) in the cell proliferation and motility in pancreatic cancer. Our data showed that the expression of eIF3a was upregulated in pancreatic ductal adenocarcinoma as compared with its expression in normal pancreatic tissues. Knockdown of eIF3a by a specific shRNA caused significant decreases in cell proliferation and clonogenic abilities in pancreatic cancer SW1990 and Capan-1 cells. Consistently, the pancreatic cancer cell growth rates were also impaired in xenotransplanted mice. Moreover, wound-healing assay showed that depletion of eIF3a significantly slowed down the wound recovery processes in SW1990 and Capan-1 cells. Transwell migration and invasion assays further showed that cell migration and invasion abilities were significantly inhibited by knockdown of eIF3a in SW1990 and Capan-1 cells. Statistical analysis of eIF3a expression in 140 cases of pancreatic ductal adenocarcinoma samples revealed that eIF3a expression was significantly associated with tumor metastasis and TNM staging. These analyses suggest that eIF3a contributes to cell proliferation and motility in pancreatic ductal adenocarcinoma. PMID:27550487

  19. Down-regulation of epithelial cadherin is required to initiate metastatic outgrowth of breast cancer

    PubMed Central

    Wendt, Michael K.; Taylor, Molly A.; Schiemann, Barbara J.; Schiemann, William P.

    2011-01-01

    Reduced epithelial cadherin (E-cad) is a hallmark of invasive carcinomas that have acquired epithelial-mesenchymal transition (EMT) phenotypes. Here we show that down-regulated E-cad expression induced by transforming growth factor-β (TGF-β) and EMT preceded breast cancer outgrowth in three-dimensional (3D) organotypic assays and in the lungs of mice. Pharmacological inhibitors against focal adhesion kinase prevented metastatic outgrowth of newly seeded organoids, but not that of their fully established counterparts. Interrogating the D2-HAN (hyperplastic alveolar nodule) model of breast cancer dormancy and metastasis showed that dormant D2.OR cells produced branched organoid morphologies in 3D-cultures, and expressed robust quantities of E-cad that was uncoupled from regulation by TGF-β. In contrast, metastatic D2.A1 organoids were spherical and wholly lacked E-cad expression. Interestingly, D2.A1 cells engineered to re-express E-cad formed branched organoids, down-regulated β1 integrin expression, and failed to undergo metastatic outgrowth. The tumor-suppressing function of E-cad was inactivated by increased microenvironmental rigidity, and was not recapitulated by expression of an E-cad mutant lacking its extracellular domain. Twist expression, but not that of Snail, reinitiated metastatic outgrowth in dormant D2.OR cells. Our findings show that EMT and its down-regulated expression of E-cad circumvent breast cancer dormancy in part by facilitating β1 integrin expression necessary for metastatic outgrowth. PMID:21613543

  20. 31P MRSI and 1H MRS at 7 T: initial results in human breast cancer.

    PubMed

    Klomp, Dennis W J; van de Bank, Bart L; Raaijmakers, Alexander; Korteweg, Mies A; Possanzini, Cecilia; Boer, Vincent O; van de Berg, Cornelius A T; van de Bosch, Maurice A A J; Luijten, Peter R

    2011-12-01

    This study demonstrates the feasibility of the noninvasive determination of important biomarkers of human (breast) tumor metabolism using high-field (7-T) MRI and MRS. (31) P MRSI at this field strength was used to provide a direct method for the in vivo detection and quantification of endogenous biomarkers. These encompass phospholipid metabolism, phosphate energy metabolism and intracellular pH. A double-tuned, dual-element transceiver was designed with focused radiofrequency fields for unilateral breast imaging and spectroscopy tuned for optimized sensitivity at 7 T. T(1) -weighted three-dimensional MRI and (1) H MRS were applied for the localization and quantification of total choline compounds. (31) P MRSI was obtained within 20 min per subject and mapped in three dimensions over the breast with pixel volumes of 10 mL. The feasibility of monitoring in vivo metabolism was demonstrated in two patients with breast cancer during neoadjuvant chemotherapy, validated by ex vivo high-resolution magic angle spinning NMR and compared with data from an age-matched healthy volunteer. Concentrations of total choline down to 0.4 mM could be detected in the human breast in vivo. Levels of adenosine and other nucleoside triphosphates, inorganic phosphate, phosphocholine, phosphoethanolamine and their glycerol diesters detected in glandular tissue, as well as in tumor, were mapped over the entire breast. Altered levels of these compounds were observed in patients compared with an age-matched healthy volunteer; modulation of these levels occurred in breast tumors during neoadjuvant chemotherapy. To our knowledge, this is the first comprehensive MRI and MRS study in patients with breast cancer, which reveals detailed information on the morphology and phospholipid metabolism from volumes as small as 10 mL. This endogenous metabolic information may provide a new method for the noninvasive assessment of prognostic and predictive biomarkers in breast cancer treatment. PMID

  1. Initial results of the National Colorectal Cancer Screening Program in Lithuania.

    PubMed

    Poskus, Tomas; Strupas, Kestutis; Mikalauskas, Saulius; Bitinaitė, Dominyka; Kavaliauskas, Augustas; Samalavicius, Narimantas E; Saladzinskas, Zilvinas

    2015-03-01

    The aim of the present study was to review the National Colorectal Cancer Screening Program (the Program) in Lithuania according to the criteria set by the European Union. In Lithuania, screening services are provided free of charge to the population. The National Health Insurance Fund (NHIF) reimburses the institutions for performing each service; each procedure within the Program has its own administrative code. All the information about the performance of the Program is collected in one institution - the NHIF. The results of the Program were retrieved from the database of NHIF from the start of the Program from 1 July 2009 to 1 July 2012. Descriptive analysis of epidemiological indicators was carried out. Results were compared with the references in the guidelines of the European Union for quality assurance in colorectal cancer (CRC) screening and diagnosis. Information service [which involves fecal immunochemical test (FIT)] was provided to 271,396 of 890,309 50-74-year-old residents. The screening uptake was 46.0% over 3 years. During this period, 19,455 (7.2%) FITs were positive and 251,941 (92.8%) FITs were negative. Referral for colonoscopy was performed in 10,190 (52.4%) patients. Colonoscopy was performed in 12,864 (66.1%) patients. Colonoscopy did not indicate any pathological findings in 8613 (67.0%) patients. Biopsies were performed in 4251 (33.0%) patients. The rate of high-grade neoplasia reported by pathologists was 3.9%; the rate of cancer was 3.1% of all colonoscopies. The rate of CRC detected by the Program was 0.2%. The CRC screening program in Lithuania meets most of the requirements for standardized CRC screening programs. The invitation coverage and rate of referral for colonoscopy after positive FIT should be improved. PMID:25370682

  2. Single-port video-assisted thoracic surgery for early lung cancer: initial experience in Japan

    PubMed Central

    Takeuchi, Shingo; Usuda, Jitsuo

    2016-01-01

    Background Single-port video-assisted thoracic surgery (SPVATS) emerged several years ago as a new, minimally invasive surgery for diseases in the field of respiratory surgery, and is increasingly becoming a subject of interest for some thoracic surgeons in Europe and Asia. However, the adoption rate of this procedure in the United States and Japan remains low. We herein reviewed our experience of SPVATS for early lung cancer in our center, and evaluated the safety and minimal invasiveness of this technique. Methods We retrospectively analyzed patients who had undergone SPVATS for pathological stage I lung cancer in Nippon Medical School Chiba Hokusoh Hospital between September 2012 and October 2015. In SPVATS, an approximately 4-cm incision was made at the 4th or 5th intercostal space between the anterior and posterior axillary lines. A rib spreader was not used at the incision site, and surgical manipulation was performed very carefully in order to avoid contact between surgical instruments and the intercostal nerves. The same surgeon performed surgery on all patients, and analyzed laboratory data before and after surgery. Results Eighty-four patients underwent anatomical lung resection for postoperative pathological stage I lung cancer. The mean wound length was 4.2 cm. Eighty-four patients underwent lobectomy and segmentectomy, respectively. The mean preoperative forced expiratory volume in 1 second (FEV1%) was 1.85%±0.36%. Our patients consisted of 49 men (58.3%) and 35 women (41.7%), with 64, 18, 1, and 1 having adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, and small-cell lung cancer, respectively. The mean operative time was 175±21 min, operative blood loss 92±18 mL, and duration of drain placement 1.9±0.6 days. The duration of the postoperative hospital stay was 7.1±1.7 days, numeric rating scale (NRS) 1 week after surgery 2.8±0.6, and occurrence rate of allodynia 1 month after surgery 10.7%. No patient developed serious

  3. Preliminary results on the role of PET/CT in initial staging, restaging, and management of lung cancer

    NASA Astrophysics Data System (ADS)

    Malamitsi, J.; Valotassiou, B.; Iliadis, K.; Kosmidis, P.; Laspas, F.; Vasilaki, M.; Pipini, E.; Petounis, A.; Gogou, L.; Pagou, M.; Dalianis, K.; Efthimiadou, R.; Andreou, J.

    2006-12-01

    AimTo determine true-positive and true-negative rates of PET/CT studies in the staging of lung cancer as compared with conventional imaging (CT and bone scan and occasionally MRI) and the impact of PET/CT on the treatment strategy in patients with lung cancer. Materials and methodTwenty patients (21 studies) with known or suspected lung cancer (14 patients with non-small-cell lung cancer (NSCLC), three patients with small-cell lung cancer (SCLC), three patients with solitary pulmonary nodule underwent initial staging (seven studies) or restaging (14 studies) with combined FDG PET and CT scans on a PET/CT tomograph. PET/CT images were evaluated separately by two nuclear medicine physicians and two radiologists specialized on PET, CT, and MRI. Histology results and a more than 6 months follow-up served as the reference standards. ResultsAccurate diagnosis was achieved on 16 studies. Site-by-site analysis gave the following results: 16 true-positive sites (seven on histology, nine on >6 months follow-up), six true-negative sites (two on histology, four on >6 months follow-up). On PET/CT, six patients were correctly down-staged, three patients were correctly upstaged and seven patients were diagnosed correctly as being on the same stage (2/7 with increase of extent of disease, 5/7 with the same extent of disease). One patient was falsely upstaged and three patients were falsely down-staged. On the basis of PET/CT results, change of management was induced in six patients, while in 14 patients there was no change induced. In five cases PET/CT was partially accurate: on site-by-site analysis, four sites proved true positive (on histology), one site false positive (on histology), and four sites false negative (one on histology, three on >6 months follow-up). ConclusionIn our early experience, PET/CT contributed significantly to correct staging and management of patients with lung cancer.

  4. Diabetes, metformin and incidence of and death from invasive cancer in postmenopausal women: Results from the women’s health initiative

    PubMed Central

    Gong, Zhihong; Aragaki, Aaron K.; Chlebowski, Rowan T.; Manson, JoAnn E.; Rohan, Thomas E.; Chen, Chu; Vitolins, Mara Z.; Tinker, Lesley F.; LeBlanc, Erin S.; Kuller, Lewis H.; Hou, Lifang; LaMonte, Michael J.; Luo, Juhua; Wactawski-Wende, Jean

    2016-01-01

    Findings from studies of metformin use with risk of cancer incidence and outcome provide mixed results; with few studies examined associations by recency of diabetes diagnosis or duration of medication use. Thus, in the Women’s Health Initiative, we examined these associations and further explored whether associations differ by recency of diabetes and duration of metformin use. Cox regression models were used to estimate hazard ratios (HR) and their 95% confidence intervals. Diabetes was associated with higher risk of total invasive cancer (HR, 1.13; p < 0.001) and of several site-specific cancers (HR, 1.2–1.4, and up to over twofold). Diabetes was also associated with higher risk of death from cancer (HR, 1.46; p < 0.001). There was no overall difference in cancer incidence by diabetes therapy (p = 0.66). However, there was a lower risk of death from cancer for metformin users, compared to users of other medications, relative to women without diabetes, overall (HRs, 1.08 vs. 1.45; p = 0.007) and for breast cancer (HRs, 0.50 vs. 1.29; p = 0.05). Results also suggested that lower cancer risk associated with metformin may be evident only for a longer duration of use in certain cancer sites or subgroup populations. We provide further evidence that postmenopausal women with diabetes are at higher risk of invasive cancer and cancer death. Metformin users, particularly long-term users, may be at lower risk of developing certain cancers and dying from cancer, compared to users of other anti-diabetes medications. Future studies are needed to determine the long-term effect of metformin in cancer risk and survival from cancer. PMID:26616262

  5. Slug inhibits pancreatic cancer initiation by blocking Kras-induced acinar-ductal metaplasia

    PubMed Central

    Ebine, Kazumi; Chow, Christina R.; DeCant, Brian T.; Hattaway, Holly Z.; Grippo, Paul J.; Kumar, Krishan; Munshi, Hidayatullah G.

    2016-01-01

    Cells in the pancreas that have undergone acinar-ductal metaplasia (ADM) can transform into premalignant cells that can eventually become cancerous. Although the epithelial-mesenchymal transition regulator Snail (Snai1) can cooperate with Kras in acinar cells to enhance ADM development, the contribution of Snail-related protein Slug (Snai2) to ADM development is not known. Thus, transgenic mice expressing Slug and Kras in acinar cells were generated. Surprisingly, Slug attenuated Kras-induced ADM development, ERK1/2 phosphorylation and proliferation. Co-expression of Slug with Kras also attenuated chronic pancreatitis-induced changes in ADM development and fibrosis. In addition, Slug attenuated TGF-α-induced acinar cell metaplasia to ductal structures and TGF-α-induced expression of ductal markers in ex vivo acinar explant cultures. Significantly, blocking the Rho-associated protein kinase ROCK1/2 in the ex vivo cultures induced expression of ductal markers and reversed the effects of Slug by inducing ductal structures. In addition, blocking ROCK1/2 activity in Slug-expressing Kras mice reversed the inhibitory effects of Slug on ADM, ERK1/2 phosphorylation, proliferation and fibrosis. Overall, these results increase our understanding of the role of Slug in ADM, an early event that can eventually lead to pancreatic cancer development. PMID:27364947

  6. Roles of N-Myc and STAT interactor in cancer: From initiation to dissemination.

    PubMed

    Pruitt, Hawley C; Devine, Daniel J; Samant, Rajeev S

    2016-08-01

    N-myc & STAT Interactor, NMI, is a protein that has mostly been studied for its physical interactions with transcription factors that play critical roles in tumor growth, progression and metastasis. NMI is an inducible protein, thus its intracellular levels and location can vary dramatically, influencing a diverse array of cellular functions in a context-dependent manner. The physical interactions of NMI with its binding partners have been linked to many aspects of tumor biology including DNA damage response, cell death, epithelial-to-mesenchymal transition and stemness. Thus, discovering more details about the function(s) of NMI could reveal key insights into how transcription factors like c-Myc, STATs and BRCA1 are contextually regulated. Although a normal, physiological function of NMI has not yet been discovered, it has potential roles in pathologies ranging from viral infection to cancer. This review provides a timely perspective of the unfolding roles of NMI with specific focus on cancer progression and metastasis. PMID:26874464

  7. Initial Characterization of Integrase-Defective Lentiviral Vectors for Pancreatic Cancer Gene Therapy.

    PubMed

    Hanoun, Naima; Gayral, Marion; Pointreau, Adeline; Buscail, Louis; Cordelier, Pierre

    2016-02-01

    The vast majority (85%) of pancreatic ductal adenocarcinomas (PDACs) are discovered at too of a late stage to allow curative surgery. In addition, PDAC is highly resistant to conventional methods of chemotherapy and radiotherapy, which only offer a marginal clinical benefit. Consequently, the prognosis of this cancer is devastating, with a 5-year survival rate of less than 5%. In this dismal context, we recently demonstrated that PDAC gene therapy using nonviral vectors is safe and feasible, with early signs of efficacy in selected patients. Our next step is to transfer to the clinic HIV-1-based lentiviral vectors (LVs) that outshine other therapeutic vectors to treat experimental models of PDAC. However, a primary safety issue presented by LVs that may delay their use in patients is the risk of oncogenesis after vector integration in the host's cell DNA. Thus, we developed a novel anticancerous approach based on integrase-defective lentiviral vectors (IDLVs) and demonstrated that IDLVs can be successfully engineered to transiently deliver therapeutic genes to inhibit pancreatic cancer cells proliferation. This work stems for the use of therapeutic IDLVs for the management of PDAC, in forthcoming early phase gene therapy clinical trial for this disease with no cure. PMID:26731312

  8. Efficiency of Non-Contrast-Enhanced Liver Imaging Sequences Added to Initial Rectal MRI in Rectal Cancer Patients

    PubMed Central

    Kwon, Gene-hyuk; Kim, Kyung Ah; Hwang, Seong Su; Park, Soo Youn; Kim, Hyun A.; Choi, Sun Young; Kim, Ji Woong

    2015-01-01

    Purpose The purpose of this study was to estimate the value of addition of liver imaging to initial rectal magnetic resonance imaging (MRI) for detection of liver metastasis and evaluate imaging predictors of a high risk of liver metastasis on rectal MRI. Methods We enrolled 144 patients who from October 2010 to May 2013 underwent rectal MRI with T2-weighted imaging (T2WI) and diffusion-weighted imaging (DWI) (b values = 50, 500, and 900 s/mm2) of the liver and abdominopelvic computed tomography (APCT) for the initial staging of rectal cancer. Two reviewers scored the possibility of liver metastasis on different sets of liver images (T2WI, DWI, and combined T2WI and DWI) and APCT and reached a conclusion by consensus for different analytic results. Imaging features from rectal MRI were also analyzed. The diagnostic performances of CT and an additional liver scan to detect liver metastasis were compared. Multivariate logistic regression to determine independent predictors of liver metastasis among rectal MRI features and tumor markers was performed. This retrospective study was approved by the Institutional Review Board, and the requirement for informed consent was waived. Results All sets of liver images were more effective than APCT for detecting liver metastasis, and DWI was the most effective. Perivascular stranding and anal sphincter invasion were statistically significant for liver metastasis (p = 0.0077 and p = 0.0471), while extramural vascular invasion based on MRI (mrEMVI) was marginally significant (p = 0.0534). Conclusion The addition of non-contrast-enhanced liver imaging, particularly DWI, to initial rectal MRI in rectal cancer patients could facilitate detection of liver metastasis without APCT. Perivascular stranding, anal sphincter invasion, and mrEMVI detected on rectal MRI were important imaging predictors of liver metastasis. PMID:26348217

  9. Establishment of a New Prostate Cancer Multidisciplinary Clinic: Format and Initial Experience

    PubMed Central

    Sundi, Debasish; Cohen, Jason E; Cole, Alexander P; Neuman, Brian P; Cooper, John; Faisal, Farzana A; Ross, Ashley E; Schaeffer, Edward M

    2014-01-01

    Background The use of multidisciplinary clinics (MDCs) for outpatient cancer evaluation is increasing. MDCs may vary in format, and data on whether MDCs change prostate cancer (PCa) care are limited. Here we report on the setup and design of a relatively new PCa MDC clinic. Because MDC evaluation was associated with a comprehensive re-evaluation of all patients' staging and risk stratification data, we studied the frequency of changes in PCa grade and stage upon MDC evaluation, which provides a unique estimate of the magnitude of pathology, radiology, and exam-based risk stratification in a modern tertiary setting. Methods In 2008–2012, 887 patients underwent consultation for newly diagnosed PCa at the Johns Hopkins Hospital (JHH) weekly MDC. In a same-day process, patients are interviewed and examined in a morning clinic. Examination findings, radiology studies, and biopsy slides are then reviewed during a noon conference that involves real-time collaboration among JHH attending specialty physicians: urologists, radiation oncologists, medical oncologists, pathologists, and radiologists. During afternoon consultations, attending physicians appropriate to each patients' eligible treatment options individually meet with patients to discuss management strategies and/or clinical trials. Retrospective chart review identified presenting tumor characteristics based on outside assessment, which was compared with stage and grade as determined at MDC evaluation. Results Overall, 186/647 (28.7%) had a change in their risk category or stage. For example, 2.9% of men were down-classified as very-low-risk, rendering them eligible for active surveillance. 5.7% of men thought to have localized cancer were up-classified as metastatic, thus prompting systemic management approaches. Using NCCN guidelines as a benchmark, many men were found to have undergone nonindicated imaging (bone scan 23.9%, CT/MRI 47.4%). The three most chosen treatments after MDC evaluation were external beam

  10. Dynamic risk stratification for medullary thyroid cancer according to the response to initial therapy.

    PubMed

    Kwon, Hyemi; Kim, Won Gu; Jeon, Min Ji; Song, Dong Eun; Lee, Yu-Mi; Sung, Tae-Yon; Chung, Ki-Wook; Yoon, Jong Ho; Hong, Suck Joon; Baek, Jung Hwan; Lee, Jeong Hyun; Kim, Tae Yong; Kim, Won Bae; Shong, Young Kee

    2016-07-01

    Detecting persistent/recurrent disease of medullary thyroid carcinoma (MTC) is important. The tumor-node-metastasis (TNM) staging system is useful for predicting disease-specific mortality, but is a static system and does not include postoperative serum calcitonin levels. We have focused on the clinical usefulness of dynamic risk stratification (DRS) using the best response to the initial therapy in MTC patients. A total of 120 MTC patients were classified into three DRS groups based on their responses to initial therapy. Clinical outcomes were assessed according to TNM staging and DRS. In the DRS, 70, 23 and 7 % of the MTC patients were classified into excellent, biochemical incomplete, or structural incomplete response groups, respectively. On TNM staging, 37, 16, 13 and 35 % of patients were stages I-IV, respectively. There were significant differences in survivals according to TNM staging (p = 0.03) and DRS (p = 0.005). During the median follow-up of 6.2 years, 75 patients (63 %) demonstrated no evidence of disease (NED). About 60 and 17 % of patients in stages III and IV were NED, respectively. DRS predicted NED better than TNM staging according to the proportion of variance explained (PVE) (49.1 vs. 28.7 %, respectively). At the final follow-up, 88, 4 and 0 % of patients in excellent, biochemical incomplete, and structural incomplete response groups attained NED, respectively. DRS based on the best response to the initial therapy can provide useful prognostic information in addition to initial TNM staging for predicting of mortality, as well as the likelihood of NED in MTC patients. PMID:26754662

  11. Radiation induced apoptosis and initial DNA damage are inversely related in locally advanced breast cancer patients

    PubMed Central

    2010-01-01

    Background DNA-damage assays, quantifying the initial number of DNA double-strand breaks induced by radiation, have been proposed as a predictive test for radiation-induced toxicity. Determination of radiation-induced apoptosis in peripheral blood lymphocytes by flow cytometry analysis has also been proposed as an approach for predicting normal tissue responses following radiotherapy. The aim of the present study was to explore the association between initial DNA damage, estimated by the number of double-strand breaks induced by a given radiation dose, and the radio-induced apoptosis rates observed. Methods Peripheral blood lymphocytes were taken from 26 consecutive patients with locally advanced breast carcinoma. Radiosensitivity of lymphocytes was quantified as the initial number of DNA double-strand breaks induced per Gy and per DNA unit (200 Mbp). Radio-induced apoptosis at 1, 2 and 8 Gy was measured by flow cytometry using annexin V/propidium iodide. Results Radiation-induced apoptosis increased in order to radiation dose and data fitted to a semi logarithmic mathematical model. A positive correlation was found among radio-induced apoptosis values at different radiation doses: 1, 2 and 8 Gy (p < 0.0001 in all cases). Mean DSB/Gy/DNA unit obtained was 1.70 ± 0.83 (range 0.63-4.08; median, 1.46). A statistically significant inverse correlation was found between initial damage to DNA and radio-induced apoptosis at 1 Gy (p = 0.034). A trend toward 2 Gy (p = 0.057) and 8 Gy (p = 0.067) was observed after 24 hours of incubation. Conclusions An inverse association was observed for the first time between these variables, both considered as predictive factors to radiation toxicity. PMID:20868468

  12. N-Myc Drives Neuroendocrine Prostate Cancer Initiated from Human Prostate Epithelial Cells.

    PubMed

    Lee, John K; Phillips, John W; Smith, Bryan A; Park, Jung Wook; Stoyanova, Tanya; McCaffrey, Erin F; Baertsch, Robert; Sokolov, Artem; Meyerowitz, Justin G; Mathis, Colleen; Cheng, Donghui; Stuart, Joshua M; Shokat, Kevan M; Gustafson, W Clay; Huang, Jiaoti; Witte, Owen N

    2016-04-11

    MYCN amplification and overexpression are common in neuroendocrine prostate cancer (NEPC). However, the impact of aberrant N-Myc expression in prostate tumorigenesis and the cellular origin of NEPC have not been established. We define N-Myc and activated AKT1 as oncogenic components sufficient to transform human prostate epithelial cells to prostate adenocarcinoma and NEPC with phenotypic and molecular features of aggressive, late-stage human disease. We directly show that prostate adenocarcinoma and NEPC can arise from a common epithelial clone. Further, N-Myc is required for tumor maintenance, and destabilization of N-Myc through Aurora A kinase inhibition reduces tumor burden. Our findings establish N-Myc as a driver of NEPC and a target for therapeutic intervention. PMID:27050099

  13. Magnetic resonance imaging-guided brachytherapy for cervical cancer: initiating a program

    PubMed Central

    Prisciandaro, Joann I.; Soliman, Abraam; Ravi, Ananth; Song, William Y.

    2015-01-01

    Over the past decade, the application of magnetic resonance imaging (MRI) has increased, and there is growing evidence to suggest that improvements in accuracy of target delineation in MRI-guided brachytherapy may improve clinical outcomes in cervical cancer. To implement a high quality image guided brachytherapy program, a multidisciplinary team is required with appropriate expertise as well as an adequate patient load to ensure a sustainable program. It is imperative to know that the most important source of uncertainty in the treatment process is related to target delineation and therefore, the necessity of training and expertise as well as quality assurance should be emphasized. A short review of concepts and techniques that have been developed for implementation and/or improvement of workflow of a MRI-guided brachytherapy program are provided in this document, so that institutions can use and optimize some of them based on their resources to minimize their procedure times. PMID:26622249

  14. Patient Surveillance After Initial Breast Cancer Therapy: Variation by Physician Specialty

    PubMed Central

    Parmeshwar, Rina; Margenthaler, Julie A.; Allam, Emad; Chen, Ling; Virgo, Katherine S.; Johnson, Frank E.

    2016-01-01

    Background American Society of Clinical Oncology (ASCO) guidelines recommend only office visits and mammograms as the primary modalities for patient surveillance after treatment for breast carcinoma. We aimed to quantify differences in posttreatment surveillance among medical oncologists, radiation oncologists, and surgeons. Methods We emailed a survey to the 3245 ASCO members who identified themselves as having breast cancer as a major focus of their practice. Questions assessed frequency of use of 12 specific surveillance modalities for five posttreatment years. Results Of 1012 total responses, 846 were evaluable: 5% from radiation oncologists, 70% from medical oncologists and 10% from surgeons; 15% were unspecified. Marked variation in surveillance practices were noted within each specialty and among specialties. Conclusion There are notable variations in surveillance intensity. This suggests overuse and/or underuse and/or misuse of scarce medical resources. PMID:23870392

  15. Magnetic resonance imaging-guided brachytherapy for cervical cancer: initiating a program.

    PubMed

    Owrangi, Amir M; Prisciandaro, Joann I; Soliman, Abraam; Ravi, Ananth; Song, William Y

    2015-10-01

    Over the past decade, the application of magnetic resonance imaging (MRI) has increased, and there is growing evidence to suggest that improvements in accuracy of target delineation in MRI-guided brachytherapy may improve clinical outcomes in cervical cancer. To implement a high quality image guided brachytherapy program, a multidisciplinary team is required with appropriate expertise as well as an adequate patient load to ensure a sustainable program. It is imperative to know that the most important source of uncertainty in the treatment process is related to target delineation and therefore, the necessity of training and expertise as well as quality assurance should be emphasized. A short review of concepts and techniques that have been developed for implementation and/or improvement of workflow of a MRI-guided brachytherapy program are provided in this document, so that institutions can use and optimize some of them based on their resources to minimize their procedure times. PMID:26622249

  16. Adaptive Radiotherapy for Head-and-Neck Cancer: Initial Clinical Outcomes From a Prospective Trial

    SciTech Connect

    Schwartz, David L.; Garden, Adam S.; Thomas, Jimmy; Chen Yipei; Zhang Yongbin; Lewin, Jan; Chambers, Mark S.; Dong, Lei

    2012-07-01

    Purpose: To present pilot toxicity and survival outcomes for a prospective trial investigating adaptive radiotherapy (ART) for oropharyngeal squamous cell carcinoma. Methods and Materials: A total of 24 patients were enrolled in an institutional review board-approved clinical trial; data for 22 of these patients were analyzed. Daily CT-guided setup and deformable image registration permitted serial mapping of clinical target volumes and avoidance structures for ART planning. Primary site was base of tongue in 15 patients, tonsil in 6 patient, and glossopharyngeal sulcus in 1 patient. Twenty patients (91%) had American Joint Committee on Cancer (AJCC) Stage IV disease. T stage distribution was 2 T1, 12 T2, 3 T3, 5 T4. N stage distribution was 1 N0, 2 N1, 5 N2a, 12 N2b, and 2 N2c. Of the patients, 21 (95%) received systemic therapy. Results: With a 31-month median follow-up (range, 13-45 months), there has been no primary site failure and 1 nodal relapse, yielding 100% local and 95% regional disease control at 2 years. Baseline tumor size correlated with absolute volumetric treatment response (p = 0.018). Parotid volumetric change correlated with duration of feeding tube placement (p = 0.025). Acute toxicity was comparable to that observed with conventional intensity-modulated radiotherapy (IMRT). Chronic toxicity and functional outcomes beyond 1 year were tabulated. Conclusion: This is the first prospective evaluation of morbidity and survival outcomes in patients with locally advanced head-and-neck cancer treated with automated adaptive replanning. ART can provide dosimetric benefit with only one or two mid-treatment replanning events. Our preliminary clinical outcomes document functional recovery and preservation of disease control at 1-year follow-up and beyond.

  17. Obesity and colorectal cancer: Role of adipokines in tumor initiation and progression

    PubMed Central

    Riondino, Silvia; Roselli, Mario; Palmirotta, Raffaele; Della-Morte, David; Ferroni, Patrizia; Guadagni, Fiorella

    2014-01-01

    Obesity-associated diseases account for a large portion of public health challenges. Among obesity-related disorders, a direct and independent relationship has been ascertained for colorectal cancer (CRC). The evidence that adipocyte hypertrophy and excessive adipose tissue accumulation (mainly visceral) can promote pathogenic adipocyte and adipose tissue-related diseases, has led to formulate the concept of “adiposopathy”, defined as adipocyte and adipose tissue dysfunction that contributes to metabolic syndrome. Adipose tissue can, indeed, be regarded as an important and highly active player of the innate immune response, in which cytokine/adipokine secretion is responsible for a paracrine loop between adipocytes and macrophages, thus contributing to the systemic chronic low-grade inflammation associated with visceral obesity, which represents a favorable niche for tumor development. The adipocyte itself participates as a central mediator of this inflammatory response in obese individuals by secreting hormones, growth factors and proinflammatory cytokines, which are of particular relevance for the pathogenesis of CRC. Among adipocyte-secreted hormones, the most relevant to colorectal tumorigenesis are adiponectin, leptin, resistin and ghrelin. All these molecules have been involved in cell growth and proliferation, as well as tumor angiogenesis and it has been demonstrated that their expression changes from normal colonic mucosa to adenoma and adenocarcinoma, suggesting their involvement in multistep colorectal carcinogenesis. These findings have led to the hypothesis that an unfavorable adipokine profile, with a reduction of those with an anti-inflammatory and anti-cancerous activity, might serve as a prognostic factor in CRC patients and that adipokines or their analogues/antagonists might become useful agents in the management or chemoprevention of CRC. PMID:24833848

  18. Clinical impact of 18F-FDG PET/CT on initial staging and therapy planning for breast cancer

    PubMed Central

    GUNALP, BENGUL; INCE, SEMRA; KARACALIOGLU, ALPER OZGUR; AYAN, ASLI; EMER, OZDES; ALAGOZ, ENGIN

    2012-01-01

    The purpose of this study was to determine the clinical significance of 18F-FDG PET/CT on initial staging and therapy planning in patients with invasive breast cancer. One hundred and forty-one consecutive, biopsy proven preoperative and 195 postoperative high-risk breast cancer patients who were referred for PET/CT for initial staging were included in this retrospective study. The clinical stage had been determined by conventional imaging modalities prior to the PET/CT scan. Of the 141 examined preoperative patients, 19 had clinical stage I (T1N0), 51 had stage IIA (12 T2N0 and 39 T1N1), 49 had stage IIB (2 T3N0 and 47 T2N1), 12 had stage IIIA (11 T3N1, 1 T2N2), 2 had stage IIIB (2 T4N1) and 8 had stage IV. PET/CT modified the staging for 26% of stage I patients, 29% of stage IIA patients, 46% of stage IIB patients, 58% of stage IIIA patients and 100% of stage IIIB patients. PET/CT scans detected extra-axillary regional lymph nodes in 14 (9.9%) patients and distant metastasis in 41 (29%) patients. PET/CT scans detected multifocal lesions in 30 (21%) patients, multicentric lesions in 21 (14%) patients and malign foci in the contralateral breast (bilateral breast cancer) confirmed by biopsy in 5 (3.5%) patients. Of the examined 195 postoperative patients PET/CT detected axillary lymph nodes in 22 (11%) patients, extra-axillary regional lymph nodes in 21 (10%) patients and distant metastasis in 24 (12%) patients. PET/CT findings altered plans for radiotherapy in 22 (11%) patients and chemotherapy was adapted to the meta-static diseases in 24 (12%) patients. PET/CT was revealed to be superior to conventional imaging modalities for the detection of extra-axillary regional metastatic lymph nodes and distant metastases. These features make PET/CT an essential imaging modality for the primary staging of invasive breast cancer, particularly in patients with clinical stages II and III. PMID:23170128

  19. Clinical impact of (18)F-FDG PET/CT on initial staging and therapy planning for breast cancer.

    PubMed

    Gunalp, Bengul; Ince, Semra; Karacalioglu, Alper Ozgur; Ayan, Asli; Emer, Ozdes; Alagoz, Engin

    2012-10-01

    The purpose of this study was to determine the clinical significance of (18)F-FDG PET/CT on initial staging and therapy planning in patients with invasive breast cancer. One hundred and forty-one consecutive, biopsy proven preoperative and 195 postoperative high-risk breast cancer patients who were referred for PET/CT for initial staging were included in this retrospective study. The clinical stage had been determined by conventional imaging modalities prior to the PET/CT scan. Of the 141 examined preoperative patients, 19 had clinical stage I (T1N0), 51 had stage IIA (12 T2N0 and 39 T1N1), 49 had stage IIB (2 T3N0 and 47 T2N1), 12 had stage IIIA (11 T3N1, 1 T2N2), 2 had stage IIIB (2 T4N1) and 8 had stage IV. PET/CT modified the staging for 26% of stage I patients, 29% of stage IIA patients, 46% of stage IIB patients, 58% of stage IIIA patients and 100% of stage IIIB patients. PET/CT scans detected extra-axillary regional lymph nodes in 14 (9.9%) patients and distant metastasis in 41 (29%) patients. PET/CT scans detected multifocal lesions in 30 (21%) patients, multicentric lesions in 21 (14%) patients and malign foci in the contralateral breast (bilateral breast cancer) confirmed by biopsy in 5 (3.5%) patients. Of the examined 195 postoperative patients PET/CT detected axillary lymph nodes in 22 (11%) patients, extra-axillary regional lymph nodes in 21 (10%) patients and distant metastasis in 24 (12%) patients. PET/CT findings altered plans for radiotherapy in 22 (11%) patients and chemotherapy was adapted to the meta-static diseases in 24 (12%) patients. PET/CT was revealed to be superior to conventional imaging modalities for the detection of extra-axillary regional metastatic lymph nodes and distant metastases. These features make PET/CT an essential imaging modality for the primary staging of invasive breast cancer, particularly in patients with clinical stages II and III. PMID:23170128

  20. Prospective Evaluation of Dual-Energy Imaging in Patients Undergoing Image Guided Radiation Therapy for Lung Cancer: Initial Clinical Results

    SciTech Connect

    Sherertz, Tracy; Hoggarth, Mark; Luce, Jason; Block, Alec M.; Nagda, Suneel; Harkenrider, Matthew M.; Emami, Bahman; Roeske, John C.

    2014-07-01

    Purpose: A prospective feasibility study was conducted to investigate the utility of dual-energy (DE) imaging compared to conventional x-ray imaging for patients undergoing kV-based image guided radiation therapy (IGRT) for lung cancer. Methods and Materials: An institutional review board-approved feasibility study enrolled patients with lung cancer undergoing IGRT and was initiated in September 2011. During daily setup, 2 sequential respiration-gated x-ray images were obtained using an on-board imager. Imaging was composed of 1 standard x-ray image at 120 kVp (1 mAs) and a second image obtained at 60 kVp (4 mAs). Weighted logarithmic subtraction of the 2 images was performed offline to create a soft tissue-selective DE image. Conventional and DE images were evaluated by measuring relative contrast and contrast-to-noise ratios (CNR) and also by comparing spatial localization, using both approaches. Imaging dose was assessed using a calibrated ion chamber. Results: To date, 10 patients with stage IA to IIIA lung cancer were enrolled and 57 DE images were analyzed. DE subtraction resulted in complete suppression of overlying bone in all 57 DE images, with an average improvement in relative contrast of 4.7 ± 3.3 over that of 120 kVp x-ray images (P<.0002). The improvement in relative contrast with DE imaging was seen for both smaller (gross tumor volume [GTV] ≤5 cc) and larger tumors (GTV >5 cc), with average relative contrast improvement ratios of 3.4 ± 4.1 and 5.4 ± 3.6, respectively. Moreover, the GTV was reliably localized in 95% of the DE images versus 74% of the single energy (SE images, (P=.004). Mean skin dose per DE image set was 0.44 ± 0.03 mGy versus 0.43 ± 0.03 mGy, using conventional kV imaging parameters. Conclusions: Initial results of this feasibility study suggest that DE thoracic imaging may enhance tumor localization in lung cancer patients receiving kV-based IGRT without increasing imaging dose.

  1. Hypoxia-inducible factor 1α promotes primary tumor growth and tumor-initiating cell activity in breast cancer

    PubMed Central

    2012-01-01

    Introduction Overexpression of the oxygen-responsive transcription factor hypoxia-inducible factor 1α (HIF-1α) correlates with poor prognosis in breast cancer patients. The mouse mammary tumor virus polyoma virus middle T (MMTV-PyMT) mouse is a widely utilized preclinical mouse model that resembles human luminal breast cancer and is highly metastatic. Prior studies in which the PyMT model was used demonstrated that HIF-1α is essential to promoting carcinoma onset and lung metastasis, although no differences in primary tumor end point size were observed. Using a refined model system, we investigated whether HIF-1α is directly implicated in the regulation of tumor-initiating cells (TICs) in breast cancer. Methods Mammary tumor epithelial cells were created from MMTV-PyMT mice harboring conditional alleles of Hif1a, followed by transduction ex vivo with either adenovirus β-galactosidase or adenovirus Cre to generate wild-type (WT) and HIF-1α-null (KO) cells, respectively. The impact of HIF-1α deletion on tumor-initiating potential was investigated using tumorsphere assays, limiting dilution transplantation and gene expression analysis. Results Efficient deletion of HIF-1α reduced primary tumor growth and suppressed lung metastases, prolonging survival. Loss of HIF-1α led to reduced expression of markers of the basal lineage (K5/K14) in cells and tumors and of multiple genes involved in the epithelial-to-mesenchymal transition. HIF-1α also enhanced tumorsphere formation at normoxia and hypoxia. Decreased expression of several genes in the Notch pathway as well as Vegf and Prominin-1 (CD133)was observed in response to Hif1a deletion. Immunohistochemistry confirmed that CD133 expression was reduced in KO cells and in tumorspheres. Tumorsphere formation was enhanced in CD133hi versus CD133neg cells sorted from PyMT tumors. Limiting dilution transplantation of WT and KO tumor cells into immunocompetent recipients revealed > 30-fold enrichment of TICs in WT cells

  2. The du Bois sign.

    PubMed

    Voelpel, James H; Muehlberger, Thomas

    2011-03-01

    According to the current literature, the term "du Bois sign" characterizes the condition of a shortened fifth finger as a symptom of congenital syphilis, Down syndrome, dyscrania, and encephalic malformation. Modern medical dictionaries and text books attribute the eponym to the French gynecologist Paul Dubois (1795-1871). Yet, a literature analysis revealed incorrect references to the person and unclear definitions of the term. Our findings showed that the origin of the term is based on observations made by the Swiss dermatologist Charles du Bois (1874-1947) in connection with congenital syphilis. In addition, a further eponymical fifth finger sign is closely associated with the du Bois sign. In conclusion, the du Bois sign has only limited diagnostic value and is frequently occurring in the normal healthy population. PMID:21263293

  3. The potential role of COX-2 in cancer stem cell-mediated canine mammary tumor initiation: an immunohistochemical study.

    PubMed

    Huang, Jian; Zhang, Di; Xie, Fuqiang; Lin, Degui

    2015-01-01

    Increasing evidence suggests that cancer stem cells (CSCs) are responsible for tumor initiation and maintenance. Additionally, it is becoming apparent that cyclooxygenase (COX) signaling is associated with canine mammary tumor development. The goals of the present study were to investigate COX-2 expression patterns and their effect on CSC-mediated tumor initiation in primary canine mammary tissues and tumorsphere models using immunohistochemistry. Patterns of COX-2, CD44, octamer-binding transcription factor (Oct)-3/4, and epidermal growth factor receptor (EGFR) expression were examined in malignant mammary tumor (MMT) samples and analyzed in terms of clinicopathological characteristics. COX-2 and Oct-3/4 expression was higher in MMTs compared to other histological samples with heterogeneous patterns. In MMTs, COX-2 expression correlated with tumor malignancy features. Significant associations between COX-2, CD44, and EGFR were observed in low-differentiated MMTs. Comparative analysis showed that the levels of COX-2, CD44, and Oct-3/4 expression varied significantly among TSs of three histological grades. Enhanced COX-2 staining was consistently observed in TSs. Similar levels of staining intensity were found for CD44 and Oct-3/4, but EGFR expression was weak. Our findings indicate the potential role of COX-2 in CSC-mediated tumor initiation, and suggest that COX-2 inhibition may help treat canine mammary tumors by targeting CSCs. PMID:26124697

  4. Initial failure of angiography to demonstrate a bleeding pancreatic cancer: a case for provocative agents

    PubMed Central

    Lee, FYJ; Lai, PBS; Chong, KL

    2001-01-01

    Background Mesenteric angiography is commonly employed in the modern-day investigation of gastro-intestinal bleeding if the bleeding sites cannot be identified by endoscopic means. Angiography is optimally sensitive in the presence of active bleeding. However, vasospasm may occasionally account for a negative study shortly after bleeding. Case outline A 70-year-old lady with inoperable carcinoma of the pancreas presented with gastro-intestinal bleeding. Although upper endoscopy visualised active bleeding from the tumour, which had invaded into the duodenum, haemostasis could not be achieved endoscopically. Therefore, mesenteric angiography was arranged. Results The initial angiography failed to demonstrate the bleeding site, which only became obvious on a repeat study, when embolisation was performed to achieve haemostasis. Discussion Vasospasm probably accounted for the initial negative study, as the second angiography was able to demonstrate contrast extravasation without the use of any anticoagulant or thrombolytic agent. It is not our routine to give pharmacological agents to provoke bleeding after a negative angiography, but for selected patients this manoeuvre may turn out to be more cost-effective. PMID:18333021

  5. Delineation of a cellular hierarchy in lung cancer reveals an oncofetal antigen expressed on tumor-initiating cells.

    PubMed

    Damelin, Marc; Geles, Kenneth G; Follettie, Maximillian T; Yuan, Ping; Baxter, Michelle; Golas, Jonathon; DiJoseph, John F; Karnoub, Maha; Huang, Shuguang; Diesl, Veronica; Behrens, Carmen; Choe, Sung E; Rios, Carol; Gruzas, Janet; Sridharan, Latha; Dougher, Maureen; Kunz, Arthur; Hamann, Philip R; Evans, Deborah; Armellino, Douglas; Khandke, Kiran; Marquette, Kimberly; Tchistiakova, Lioudmila; Boghaert, Erwin R; Abraham, Robert T; Wistuba, Ignacio I; Zhou, Bin-Bing S

    2011-06-15

    Poorly differentiated tumors in non-small cell lung cancer (NSCLC) have been associated with shorter patient survival and shorter time to recurrence following treatment. Here, we integrate multiple experimental models with clinicopathologic analysis of patient tumors to delineate a cellular hierarchy in NSCLC. We show that the oncofetal protein 5T4 is expressed on tumor-initiating cells and associated with worse clinical outcome in NSCLC. Coexpression of 5T4 and factors involved in the epithelial-to-mesenchymal transition were observed in undifferentiated but not in differentiated tumor cells. Despite heterogeneous expression of 5T4 in NSCLC patient-derived xenografts, treatment with an anti-5T4 antibody-drug conjugate resulted in complete and sustained tumor regression. Thus, the aggressive growth of heterogeneous solid tumors can be blocked by therapeutic agents that target a subpopulation of cells near the top of the cellular hierarchy. PMID:21540235

  6. Roles of the translation initiation factor eIF2α serine 51 phosphorylation in cancer formation and treatment.

    PubMed

    Koromilas, Antonis E

    2015-07-01

    Cells respond to various forms of stress by activating anti-proliferative pathways, which allow them to correct the damage caused by stress before re-entering proliferation. If the damage, however, is beyond repair, stressed cells are eliminated from the host by undergoing death. The balance between cell survival and death is essential for cancer formation and is determined by several key pathways that impact on different stages of gene expression. In recent years, it has become evident that phosphorylation of the alpha (α) subunit of the translation initiation factor eIF2 at serine 51 (eIF2αS51P) is an important determinant of cell fate in response to stress. Induction of eIF2αS51P is mediated by a family of four kinases namely, HRI, PKR, PERK and GCN2, each of which responds to distinct forms of stress. Increased eIF2αS51P results in a global inhibition of protein synthesis but at the same time enhances the translation of select mRNAs encoding for proteins that control cell adaptation to stress. Short-term induction of eIF2αS51P has been associated with cell survival whereas long-term induction with cell death. Studies in mouse and human models of cancer have provided compelling evidence that eIF2αS51P plays an essential role in stress-induced tumorigenesis. Increased eIF2αS51P exhibits cell autonomous as well as immune regulatory effects, which can influence tumor growth and the efficacy of anti-tumor therapies. The findings suggest that eIF2αS51P may be of prognostic value and a suitable target for the design and implementation of effective anti-tumor therapies. This article is part of a Special Issue entitled: Translation and Cancer. PMID:25497381

  7. Preventive sparing of spinal cord and brain stem in the initial irradiation of locally advanced head and neck cancers.

    PubMed

    Farace, Paolo; Piras, Sara; Porru, Sergio; Massazza, Federica; Fadda, Giuseppina; Solla, Ignazio; Piras, Denise; Deidda, Maria Assunta; Amichetti, Maurizio; Possanzini, Marco

    2014-01-01

    Since reirradiation in recurrent head and neck patients is limited by previous treatment, a marked reduction of maximum doses to spinal cord and brain stem was investigated in the initial irradiation of stage III/IV head and neck cancers. Eighteen patients were planned by simultaneous integrated boost, prescribing 69.3 Gy to PTV1 and 56.1 Gy to PTV2. Nine 6 MV coplanar photon beams at equispaced gantry angles were chosen for each patient. Step-and-shoot IMRT was calculated by direct machine parameter optimization, with the maximum number of segments limited to 80. In the standard plan, optimization considered organs at risk (OAR), dose conformity, maximum dose < 45 Gy to spinal cord and < 50 Gy to brain stem. In the sparing plans, a marked reduction to spinal cord and brain stem were investigated, with/without changes in dose conformity. In the sparing plans, the maximum doses to spinal cord and brain stem were reduced from the initial values (43.5 ± 2.2 Gy and 36.7 ± 14.0 Gy), without significant changes on the other OARs. A marked difference (-15.9 ± 1.9 Gy and -10.1 ± 5.7 Gy) was obtained at the expense of a small difference (-1.3% ± 0.9%) from initial PTV195% coverage (96.6% ± 0.9%). Similar difference (-15.7 ± 2.2 Gy and -10.2 ± 6.1 Gy) was obtained compromising dose conformity, but unaffecting PTV195% and with negligible decrease in PTV295% (-0.3% ± 0.3% from the initial 98.3% ± 0.8%). A marked spinal cord and brain stem preventive sparing was feasible at the expense of a decrease in dose conformity or slightly compromising target coverage. A sparing should be recommended in highly recurrent tumors, to make potential reirradiation safer. PMID:24423836

  8. AhR ligand Aminoflavone inhibits α6-integrin expression and breast cancer sphere-initiating capacity.

    PubMed

    Brantley, Eileen; Callero, Mariana A; Berardi, Damian E; Campbell, Petreena; Rowland, Leah; Zylstra, Dain; Amis, Louisa; Yee, Michael; Simian, Marina; Todaro, Laura; Loaiza-Perez, Andrea I; Soto, Ubaldo

    2016-06-28

    Traditional chemotherapies debulk tumors but fail to produce long-term clinical remissions due to their inability to eradicate tumor-initiating cells (TICs). This necessitates therapy with activity against the TIC niche. Αlpha6-integrin (α6-integrin) promotes TIC growth. In contrast, aryl hydrocarbon receptor (AhR) signaling activation impedes the formation of mammospheres (clusters of cells enriched for TICs). We investigated the ability of AhR agonist Aminoflavone (AF) and AF pro-drug (AFP464) to disrupt mammospheres derived from breast cancer cells and a M05 mammary mouse model of breast cancer respectively. We further examined the capacity of AF and AFP464 to exhibit anticancer activity and modulate the expression of 'stemness' genes including α6-integrin using immunofluorescence, flow cytometry and qRT-PCR analysis. AF disrupted mammospheres and prevented secondary mammosphere formation. In contrast, AF did not disrupt mammospheres derived from AhR ligand-unresponsive MCF-7 cells. AFP464 treatment suppressed M05 tumor growth and disrupted corresponding mammospheres. AF and AFP464 reduced the expression and percentage of cells that stained for 'stemness' markers including α6-integrin in vitro and in vivo respectively. These data suggest AFP464 thwarts bulk breast tumor and TIC growth via AhR agonist-mediated α6-integrin inhibition. PMID:26996297

  9. Clustering of monosialyl-Gb5 initiates downstream signalling events leading to invasion of MCF-7 breast cancer cells

    PubMed Central

    van Slambrouck, Severine; Steelant, Wim F. A.

    2006-01-01

    Invasion is a complex process controlled by secretion and activation of proteases, alteration of integrin levels and GSL (glycosphingolipid) patterns. Differential organization of GSLs with specific membrane proteins and signal transducers in GEMs (GSL-enriched microdomains), initiates signalling events to modify cellular phenotype. Although the GSL monosialyl-Gb5 has been linked with invasion, its functional role in invasion is poorly described and understood. To investigate this problem, we induced the invasion of human breast cancer cells and subsequently explored the underlying mechanism. In the present study, the invasion of human MCF-7 breast cancer cells is highly dependent on clustering of monosialyl-Gb5, and the subsequent activation of monosialyl-Gb5-associated focal adhesion kinase and cSrc in GEM leading to the downstream activation of extracellular-signal-regulated kinase (ERK). As a result, we observed increased expression levels and activity of matrix metalloproteinases-2 and -9, which correlated with decreased expression of integrins α1 and β1. Together these results suggest that the organization of crucial molecules in GEMs of MCF-7 cells is critical for their invasive properties. PMID:16995838

  10. Modeling the Transcriptional Consequences of Epidermal Growth Factor Receptor Ablation in Ras-Initiated Squamous Cancer

    PubMed Central

    Wright, Lisa Nolan; Ryscavage, Andrew; Merlino, Glenn; Yuspa, Stuart H.

    2011-01-01

    Purpose EGFR targeted therapy is in clinical use to treat squamous cell carcinoma of the head and neck and other cancers of lining epithelium. Ras mutations in these tumors are a negative prognostic factor for response and skin inflammation is an adverse reaction to therapy. We investigated transcriptional and biochemical changes that could account for the confounding effects of RAS activation and inflammation in a squamous tissue. Experimental Design We performed gene expression profiling on oncogenic Ras transformed and wildtype mouse and human keratinocytes with EGFR ablated chronically by genetic deletion or acutely by drug treatment and followed leads provided by pathway analysis with biochemical studies. Results We identified a 25 gene signature specific to the Ras-EGFR ablation interaction and a distinct 19 gene EGFR ablation signature on normal keratinocytes. EGFR ablation in the context of wildtype Ras reduces ontologies favoring cell cycle control and transcription while oncogenic Ras enriches ontologies for ion channels and membrane transporters, particularly focused on calcium homeostasis. Ontologies between chronic EGFR ablation and acute pharmacological ablation were unique, both with and without Ras activation. p38α is activated in response to abrogation of EGFR signaling under conditions of Ras activation in both mouse and human keratinocytes and in RAS transformed tumor orthografts of EGFR ablated mouse keratinocytes. EGFR ablation in the absence of oncogenic Ras revealed Erk and IL-1β related pathways. Conclusion These findings reveal unrecognized interactions between Ras and EGFR signaling in squamous tumor cells that could influence the therapeutic response to EGFR ablation therapy. PMID:22068661

  11. Capecitabine Initially Concomitant to Radiotherapy Then Perioperatively Administered in Locally Advanced Rectal Cancer

    SciTech Connect

    Zampino, Maria Giulia Magni, Elena; Leonardi, Maria Cristina; Petazzi, Elena; Santoro, Luigi; Luca, Fabrizio; Chiappa, Antonio; Petralia, Giuseppe; Trovato, Cristina; Fazio, Nicola; Orecchia, Roberto; Nole, Franco; Braud, Filippo de

    2009-10-01

    Purpose: To evaluate the impact of neoadjuvant capecitabine, concomitant to radiotherapy, followed by capecitabine monotherapy, in operable locally advanced rectal cancer (LARC) by measuring pathologic response and conservative surgery rate, toxicity profile, and disease-free survival (DFS). Methods and Materials: From October 2002 to July 2006, a total of 51 patients affected by LARC (T3-T4 or any node positive tumor), received capecitabine (825 mg/m{sup 2}, orally, twice daily continuously) concomitant to radiotherapy on the pelvis (50.4 Gy/ 28 fractions), followed by two cycles of capecitabine (1,250 mg/m{sup 2}, orally, twice daily, 14 days on 7 days off) up until 2 weeks before surgery. Tailored adjuvant systemic treatment was discussed according to pathologic stage. Results: Of 51 patients, (median age 61 years, range 38-82 years; 19 women and 32 men; ECOG performance status 0/1/2: 46/4/1), 50 were evaluable for response: 18% complete pathologic remission; 12% T-downstaging, and 30% N-downstaging. One patient died before surgery from mesenteric stroke. Grade 3 acute toxicities were 2% diarrhea, 8% dermatitis, 2% liver function test elevation, and 2% hand-foot syndrome. Sphincter preservation rates for tumors {<=}6 cm from the anal verge were 62% and 80% for the whole population. Median follow up was 43.0 months (range 0.8-68.6 months). Five-years DFS was 85.4% (95% CI = 75.3-95.4%). Conclusions: Based on our study results, we conclude that this regimen is well tolerated and active and compares favorably with existing capecitabine-based approaches.

  12. Adaptive Radiotherapy for Head and Neck Cancer: Initial Clinical Outcomes from a Prospective Trial

    PubMed Central

    Schwartz, David L.; Garden, Adam S.; Thomas, Jimmy; Chen, Yipei; Zhang, Yongbin; Lewin, Jan; Chambers, Mark S.; Dong, Lei

    2011-01-01

    Purpose To present pilot toxicity and survival outcomes for a prospective trial investigating adaptive radiotherapy (ART) for oropharyngeal squamous cell carcinoma. Methods Twenty-four patients enrolled onto an IRB-approved clinical trial. Twenty-two patients were analyzed. Daily CT-guided setup and deformable image registration permitted serial mapping of CTVs and avoidance structures for ART planning. Primary site was base of tongue in 15 patients, tonsil in 6, and glossopharyngeal sulcus in 1. Twenty (91%) patients had AJCC stage IV disease. T stage distribution was 2 T1, 12 T2, 3 T3, 5 T4 and N stage distribution was 1 N0, 2 N1, 5 N2a, 12 N2b, and 2 N2c. Twenty-one (95%) patients received systemic therapy. Results With 31 month median follow up (range: 13-45), there has been no primary site failure and 1 nodal relapse, yielding 100% local and 95% regional disease control at 2 years. Baseline tumor size correlated with absolute volumetric treatment response (p = 0.018). Parotid volumetric change correlated with duration of feeding tube placement (p = 0.025). Acute toxicity was comparable to conventional IMRT results. Chronic toxicity and functional outcomes beyond 1 year were tabulated. Discussion This is the first prospective evaluation of morbidity and survival outcomes in patients with locally advanced head and neck cancer treated with automated adaptive replanning. ART can provide dosimetric benefit with only 1 or 2 mid-treatment replanning events. Our preliminary clinical outcomes document functional recovery and preservation of disease control at one-year follow-up and beyond. PMID:22138459

  13. Initial Staging of Locally Advanced Rectal Cancer and Regional Lymph Nodes

    PubMed Central

    Cerny, Milena; Dunet, Vincent; Prior, John Olivier; Hahnloser, Dieter; Wagner, Anna Dorothea; Meuli, Reto Antoine; Schmidt, Sabine

    2016-01-01

    Purpose The aim of the study was to compare diffusion-weighted MRI (DW-MRI) parameters with 18F-FDG PET/CT in primary locally advanced rectal cancer (LARC). Methods From October 2012 to September 2014, 24 patients with histologically confirmed and untreated LARC (T3–T4) prospectively underwent a pelvic 1.5-T DW-MRI (b = 0 s/mm2, b = 600 s/mm2) and a whole-body 18F-FDG PET/CT, before neoadjuvant therapy. The 2 examinations were performed on the same day. Two readers measured 18F-FDG SUVmax and SUVmean of the rectal tumor and of the pathological regional lymph nodes on PET/CT and compared these with minimum and mean values of the ADC (ADCmin and ADCmean) on maps generated from DW-MRI. The diagnostic performance of ADC values in identifying pathological lymph nodes was also assessed. Results Regarding tumors (n = 24), we found a significant negative correlation between SUVmean and corresponding ADCmean values (ρ = −0.61, P = 0.0017) and between ADCmin and SUVmax (ρ = −0.66, P = 0.0005). Regarding the lymph nodes (n = 63), there was a significant negative correlation between ADCmean and SUVmean values (ρ = −0.38, P = 0.0021), but not between ADCmin and SUVmax values (ρ = −0.11, P = 0.41). Neither ADCmean nor ADCmin values helped distinguish pathological from benign lymph nodes (AUC of 0.24 [confidence interval, 0.10–0.38] and 0.41 [confidence interval, 0.22–0.60], respectively). Conclusions The correlations between ADCmean and SUVmean suggest an association between tumor cellularity and metabolic activity in untreated LARC and in regional lymph nodes. However, compared with 18F-FDG PET/CT, ADC values are not reliable for identifying pathological lymph nodes. PMID:26828149

  14. Usefulness of low iodine diet in managing patients with differentiated thyroid cancer - initial results

    PubMed Central

    Dobrenic, Margareta; Huic, Drazen; Zuvic, Marijan; Grosev, Darko; Petrovic, Ratimir; Samardzic, Tatjana

    2011-01-01

    Background Low iodine diet (LID) is recommended in patients with differentiated thyroid cancer before radioiodine administration. Patients with increased thyroglobulin (Tg) level, but negative 131I whole body scan present diagnostic and therapeutic dilemma. This study was designed to evaluate the benefit of a two-week LID in patients with elevated serum Tg levels and negative 131I whole body scans. Patients and methods. For the impact assessment of two-week LID on radioiodine tissue avidity, radioiodine scans before and after LID were compared. Sixteen patients with serum Tg > 2 μg/L, negative Tg-antibodies, and negative radioiodine scans underwent two-week LID before the 131I administration. Fourteen patients underwent diagnostic scanning and two patients received radioiodine therapy. Iodine concentration in the morning urine specimens were measured in each patient, a day before and 15th day after starting LID. Results Following self-managed LID, patients were able to significantly reduce their iodine body content by 50% (range 28–65%, p<0,001). 13 patients (82%) accomplished mild iodine deficiency (50-99 μg/L) and one patient (6%) achieved targeted moderate iodine deficient state (<50 μg/L). All diagnostic post-LID scans were negative. Both post-therapy 131I scans showed radioiodine accumulation outside of normal 131I distribution (neck region and diffuse hepatic uptake). This study demonstrated that two-week LID is effective way to decrease total body iodine content, although without a visible effect on post-LID diagnostic 131I scans. Conclusions A more stringent dietary protocol and longer iodine restriction period are probably needed to achieve targeted moderate iodine deficiency in patients preparing for 131I administration. This might result in higher radioiodine avidity of thyroid remnant/metastases. PMID:22933955

  15. The impact of cow's milk-mediated mTORC1-signaling in the initiation and progression of prostate cancer

    PubMed Central

    2012-01-01

    Prostate cancer (PCa) is dependent on androgen receptor signaling and aberrations of the PI3K-Akt-mTORC1 pathway mediating excessive and sustained growth signaling. The nutrient-sensitive kinase mTORC1 is upregulated in nearly 100% of advanced human PCas. Oncogenic mTORC1 signaling activates key subsets of mRNAs that cooperate in distinct steps of PCa initiation and progression. Epidemiological evidence points to increased dairy protein consumption as a major dietary risk factor for the development of PCa. mTORC1 is a master regulator of protein synthesis, lipid synthesis and autophagy pathways that couple nutrient sensing to cell growth and cancer. This review provides evidence that PCa initiation and progression are promoted by cow´s milk, but not human milk, stimulation of mTORC1 signaling. Mammalian milk is presented as an endocrine signaling system, which activates mTORC1, promotes cell growth and proliferation and suppresses autophagy. Naturally, milk-mediated mTORC1 signaling is restricted only to the postnatal growth phase of mammals. However, persistent consumption of cow´s milk proteins in humans provide highly insulinotropic branched-chain amino acids (BCAAs) provided by milk´s fast hydrolysable whey proteins, which elevate postprandial plasma insulin levels, and increase hepatic IGF-1 plasma concentrations by casein-derived amino acids. BCAAs, insulin and IGF-1 are pivotal activating signals of mTORC1. Increased cow´s milk protein-mediated mTORC1 signaling along with constant exposure to commercial cow´s milk estrogens derived from pregnant cows may explain the observed association between high dairy consumption and increased risk of PCa in Westernized societies. As well-balanced mTORC1-signaling plays an important role in appropriate prostate morphogenesis and differentiation, exaggerated mTORC1-signaling by high cow´s milk consumption predominantly during critical growth phases of prostate development and differentiation may exert long

  16. Design and Focus Test of a Preconsultation Decision Aid for Breast Cancer Reconstruction Patients: A Quality Improvement Initiative

    PubMed Central

    Hui, Kenneth J.; Liu, Xiang X.; Luan, Anna

    2015-01-01

    Objective: To design, develop, and evaluate via focus group a preconsultation decision aid to improve patient satisfaction for breast reconstruction. Methods: The design of the decision aid was based on perceived patient needs, literature, existing decision aids, and current standard of breast cancer reconstruction treatment and consultation at Stanford. Our decision aid was designed to (1) reducing fear of the unknown in patients via providing a knowledge base that they can rely on, (2) helping patients identify their key breast reconstruction concerns, (3) addressing common patient concerns, (4) providing a framework to help patients identify the treatment option that may be right for them, and (5) promoting shared decision making. Physicians were consulted on the decision aid, following which a focus group was conducted for patient feedback. Results: Interviewed patients (n = 12) were supportive of the decision aid initiative. Participants were especially pleased with the side-by-side comparison of surgical options and the parsimonious way information was represented. All patients before undergoing reconstruction (n = 3) requested the decision guide to reference at home. All interviewed patients believed information level was “about right.” Conclusions: Decision aid was well received by patients in the focus group. As the initiative is for quality improvement, we saw no need to further delay the distribution of the decision aid. A pilot study will be conducted to evaluate whether our decision aid has an effect on patients’ decision regret, stress, and anxiety. PMID:26171096

  17. New ex-ovo colorectal-cancer models from different SdFFF-sorted tumor-initiating cells.

    PubMed

    Mélin, Carole; Perraud, Aurélie; Christou, Niki; Bibes, Romain; Cardot, Philippe; Jauberteau, Marie-Odile; Battu, Serge; Mathonnet, Muriel

    2015-11-01

    Despite effective treatments, relapse of colorectal cancer (CRC) is frequent, in part caused by the existence of tumor-initiating cells (TICs). Different subtypes of TICs, quiescent and activated, coexist in tumors, defining the tumor aggressiveness and therapeutic response. These subtypes have been sorted by hyperlayer sedimentation field-flow fractionation (SdFFF) from WiDr and HCT116 cell lines. On the basis of a new strategy, including TIC SdFFF sorting, 3D Matrigel amplification, and grafting of corresponding TIC colonies on the chick chorioallantoic membrane (CAM), specific tumor matrices could be obtained. If tumors had similar architectural structure with vascularization by the host system, they had different proliferative indices in agreement with their initial quiescent or activated state. Protein analysis also revealed that tumors obtained from a population enriched for "activated" TICs lost "stemness" properties and became invasive. In contrast, tumors obtained from a population enriched for "quiescent" TICs kept their stemness properties and seemed to be less proliferative and invasive. Then, it was possible to produce different kinds of tumor which could be used as selective supports to study carcinogenesis and therapy sensitivity. PMID:26427501

  18. [Effect of lidamycin on mitochondria initiated apoptotic pathway in human cancer cells].

    PubMed

    Qiu, Qiang; Wang, Zhen; Jiang, Jian-ming; Li, Dian-dong

    2007-02-01

    Although enediyne antibiotic lidamycin ( LDM) is a potent inducer of apoptosis, the underlying mechanisms of its apoptotic functions remain to be explored. Here, we aim to elucidate its possible mechanisms in mitochondria initiated apoptotic pathway involved in human BEL-7402 and MCF-7 cells. Cytochrome c released from mitchondria to cytosol fraction was detected by Western blotting. p53 and Bax, Bcl-2 expressions were detected by Western blotting and RT-PCR. MTT assay was used to detect cytotoxicity of LDM with or without caspase inhibitor z-VAD-fmk. After the BEL-7402 cells were exposed to 0. 1 micromol x L(-1) LDM within 6 h, the increase of cytochrome c in the cytosol and decrease in the mitochondria were observed when compared with untreated cells. The expression of Bax, an important proapoptotic member of the Bcl-2 family, increased gradually in the BEL-7402 cells after exposure to LDM of 0. 1 micromol x L (-1) for 2, 6, and 9 h, separately, while Bcl-2 increased at 2 and 6 h, and decreased at 9 h after LDM treatment. Enhanced protein expressions were parallel with respective increased mRNA level for Bax only, but not p53. Caspase inhibitor may inhibit partially the killing effects induced by LDM. Therefore we conclude that the rapid activation of mitochondrial pathway induced by LDM in tumor cells might contribute to its highly potent cytotoxicities. PMID:17518039

  19. Gene Knockdown by EpCAM Aptamer-siRNA Chimeras Suppresses Epithelial Breast Cancers and Their Tumor-Initiating Cells.

    PubMed

    Gilboa-Geffen, Adi; Hamar, Peter; Le, Minh T N; Wheeler, Lee Adam; Trifonova, Radiana; Petrocca, Fabio; Wittrup, Anders; Lieberman, Judy

    2015-10-01

    Effective therapeutic strategies for in vivo siRNA delivery to knockdown genes in cells outside the liver are needed to harness RNA interference for treating cancer. EpCAM is a tumor-associated antigen highly expressed on common epithelial cancers and their tumor-initiating cells (TIC, also known as cancer stem cells). Here, we show that aptamer-siRNA chimeras (AsiC, an EpCAM aptamer linked to an siRNA sense strand and annealed to the siRNA antisense strand) are selectively taken up and knock down gene expression in EpCAM(+) cancer cells in vitro and in human cancer biopsy tissues. PLK1 EpCAM-AsiCs inhibit colony and mammosphere formation (in vitro TIC assays) and tumor initiation by EpCAM(+) luminal and basal-A triple-negative breast cancer (TNBC) cell lines, but not EpCAM(-) mesenchymal basal-B TNBCs, in nude mice. Subcutaneously administered EpCAM-AsiCs concentrate in EpCAM(+) Her2(+) and TNBC tumors and suppress their growth. Thus, EpCAM-AsiCs provide an attractive approach for treating epithelial cancer. PMID:26264278

  20. Analysis of monotherapy prostate brachytherapy in patients with prostate cancer. Initial PSA and Gleason are important for recurrence?

    PubMed Central

    Galego, Pedro; Silva, Fernando C.; Pinheiro, Luís Campos

    2015-01-01

    Purpose To evaluate the clinical outcome of a cohort of localized prostate cancer patients treate with 125-I permanent brachytherapy at the São José Hospital – CHLC, Lisbon. Materials and Methods A retrospective analysis was carried out on 429 patients with low and intermediate-risk of prostate adenocarcinoma, according to the recommendations of the EORTC, who underwent 125I brachytherapies in intraoperative dosimetry “real-time” system between September 2003 and September 2013. Results The mean follow-up was 71.98 months. Biochemical relapse of disease by rising PSA (Phoenix criterion) was observed in 18 patients (4.2%). Through the application of Kaplan-Meier survival curves in this sample, the rate of survival at 6 years without biochemical relapse was higher than 95%. By Iog rank test comparing biochemical relapse with initial PSA (15-10 and <10) and Gleason values (7 and <7), there was no statistical difference (P=0.830) of the initial PSA in the probability of developing biochemical relapse. In relation to Gleason score, it was noted a statistical difference (P<0.05), demonstrating that patients with Gleason 7 are more likely to develop biochemical relapse. Conclusions Brachytherapy as monotherapy is at present an effective choice in the treatment of localized prostate adenocarcinoma. Biochemical relapses are minimal. The initial PSA showed no statistically difference in the rate of relapses, unlike the value Gleason, where it was demonstrated that patients with Gleason 7 have a higher probability of biochemical relapse. Cases with PSA bounce should be controlled before starting a salvage treatment. PMID:26005979

  1. Long-Term Outcome and Toxicity of Salvage Brachytherapy for Local Failure After Initial Radiotherapy for Prostate Cancer

    SciTech Connect

    Burri, Ryan J.; Stone, Nelson N.; Unger, Pam; Stock, Richard G.

    2010-08-01

    Purpose: To describe long-term outcomes and toxicity after salvage brachytherapy (BT) for local failure after initial radiotherapy for prostate cancer. Methods and Materials: Between 1994 and 2008, 37 men with local failure after initial prostate radiotherapy (32 external-beam radiation therapy [EBRT] and 5 BT) underwent salvage BT with {sup 103}Pd or {sup 125}I. Estimates of freedom from biochemical failure (FFbF, Phoenix definition) and cause-specific survival (CSS) were calculated using the Kaplan-Meier method. Toxicities were graded using CTCv3.0. Results: Median follow-up was 86 months (range, 2-156). The median dose to 90% of the prostate volume was 122 Gy (range, 67-166). The 10-year FFbF and CSS were 54% and 96%, respectively. On univariate analysis, prostate-specific antigen (PSA) >10 ng/mL at initial diagnosis was significantly associated with FFbF (p = 0.01), and there were trends for both age <70 years (p = 0.08) and PSA <6 ng/mL (p = 0.08) at the time of salvage BT. On multivariate analysis, only presalvage PSA <6 ng/mL (p = 0.046) was significantly associated with improved FFbF. There were three Grade 3 toxicities and one Grade 4 toxicity. Pelvic lymph node dissection before salvage BT was the only variable significantly associated with Grade {>=}2 toxicity (p = 0.03). Conclusion: With a median follow-up of 86 months, salvage prostate BT was associated with a 10-year FFbF of 54% and CSS of 96%. Improved FFbF was associated with a presalvage PSA <6 ng/mL. Toxicity was worse in patients who had undergone pelvic lymph node dissection before salvage BT. Careful patient selection for salvage BT may result in improved outcomes and reduced toxicity.

  2. Guidelines for timely initiation of chemotherapy: a proposed framework for access to medical oncology and haematology cancer clinics and chemotherapy services.

    PubMed

    Alexander, M; Beattie-Manning, R; Blum, R; Byrne, J; Hornby, C; Kearny, C; Love, N; McGlashan, J; McKiernan, S; Milar, J L; Murray, D; Opat, S; Parente, P; Thomas, J; Tweddle, N; Underhill, C; Whitfield, K; Kirsa, S; Rischin, D

    2016-08-01

    These guidelines, informed by the best available evidence and consensus expert opinion, provide a framework to guide the timely initiation of chemotherapy for treating cancer. They sit at the intersection of patient experience, state-of-the-art disease management and rational efficient service provision for these patients at a system level. Internationally, cancer waiting times are routinely measured and publicly reported. In Australia, there are existing policies and guidelines relating to the timeliness of cancer care for surgery and radiation therapy; however, until now, equivalent guidance for chemotherapy was lacking. Timeliness of care should be informed, where available, by evidence for improved patient outcomes. Independent of this, it should be recognised that shorter waiting periods are likely to reduce patient anxiety. While these guidelines were developed as part of a proposed framework for consideration by the Victorian Department of Health, they are clinically relevant to national and international cancer services. They are intended to be used by clinical and administrative staff within cancer services. Adoption of these guidelines, which are for the timely triage, review and treatment of cancer patients receiving systemic chemotherapy, aims to ensure that patients receive care within a timeframe that will maximise health outcomes, and that access to care is consistent and equitable across cancer services. Local monitoring of performance against this guideline will enable cancer service providers to manage proactively future service demand. PMID:27553996

  3. Le morte du tumour: histological features of tumor destruction in chemo-resistant cancers following intravenous infusions of pathotropic nanoparticles bearing therapeutic genes.

    PubMed

    Gordon, Erlinda M; Chan, Maria Teresa; Geraldino, Nelson; Lopez, Francisco F; Cornelio, Gerardo H; Lorenzo, Conrado C; Levy, John P; Reed, Rebecca A; Liu, Liqiong; Hall, Frederick L

    2007-06-01

    The pathotropic targeting of therapeutic nanoparticles to cancerous lesions is an innovative concept that has recently been reduced to practice in clinical trials for the treatment of metastatic cancer. Previously, we reported that intravenous infusions of Rexin-G, a pathotropic nanoparticle (or vector) bearing a cyto-ablative construct, induced tumor regression, reduced tumor burden, and improved survival, while enhancing the overall quality-of-life of patients with otherwise intractable chemotherapy-resistant cancers. In this report, we describe the major histopathological and radiologic features that are characteristic of solid tumors under the destructive influences of Rexin-G administered as a single therapeutic agent. To further promote tumor eradication and enhance cancer survival, we explored the potential of an auxiliary gene transfer strategy, specifically intended to induce a localized cancer auto-immunization in addition to assisting in acute tumor destruction. This immunization strategy uses Rexin-G in combination with Reximmune-C, a tumor targeted expression vector bearing a granulocyte macrophage-colony stimulating factor (GM-CSF) gene. Intravenous infusions of Rexin-G were given first to induce apoptosis and necrosis in the metastatic tumor nodules, thus exposing tumor neo-antigens, followed by Reximmune-C infusions, intended to recruit immune cells discretely into the same compartments (or lesions). The intent of this two-step approach is to bring a complement of cells involved in humoral and cell-mediated immunity in close proximity to the immunizing tumor antigens in a concerted effort to assist in tumor eradication and to promote a cancer vaccination in situ. Herein, we also describe the distinctive histopathologic and immunocytochemical features of tumors in terminal cancer patients who received Rexin-G infusions in combination with Reximmune-C. In addition to documenting the first histological indications of clinical efficacy achieved by this

  4. Mapping patients' experiences from initial change in health to cancer diagnosis: a qualitative exploration of patient and system factors mediating this process.

    PubMed

    Molassiotis, A; Wilson, B; Brunton, L; Chandler, C

    2010-01-01

    Delays in the diagnosis of cancer are common, and they are attributed to both patient and healthcare system factors. Minimizing such delays and improving early detection rates is a key goal of the new cancer reform strategy in England, in light of recent data showing that survival rates in the UK are low. The aim of this study was to explore the pathway from initial persistent change in health to diagnosis of cancer in a sample of patients from seven diagnostic groups in the UK and the factors mediating this process. Qualitative interviews with patients diagnosed with cancer were carried out. Seventy-five cancer patients discussed their pre-diagnosis experience as part of a broader exploration of their symptom experience for a larger study. Data were analysed by using content analysis and chart events. A broader range of mediating factors affecting and extending the patient pathway to diagnosis were reported in relation to lung, gastrointestinal and head and neck cancers and lymphoma, compared with breast, gynaecological and brain cancer patients. Many of the mediating factors were patient-related (e.g. misattribution of symptoms to common ailments, underestimation of the seriousness of the symptoms, self-medication or monitoring of symptoms, etc.). Primary care practitioner-factors were also prominent, including the exploration of firstly more common possibilities for treating the presenting symptoms without follow-up of persisting symptoms. Public health education about common cancer signs and symptoms, educational approaches in primary care to improve early diagnoses of cancer and updated guidelines for referral of suspected cancers should be enhanced before we can see any improvements in survival rates from cancer in the UK. PMID:19552730

  5. The European Medicines Agency: an overview of its mission, responsibilities, and recent initiatives in cancer drug regulation.

    PubMed

    Pignatti, Francesco; Gravanis, Iordanis; Herold, Ralf; Vamvakas, Spiros; Jonsson, Bertil; Marty, Michel

    2011-08-15

    The European Medicines Agency (EMA) is responsible for the scientific evaluation of medicines developed by pharmaceutical companies for use in the European Union (EU). Since 2005, the agency has become responsible for the approval of all new oncology drugs in the EU. In this article we describe the mission, role, and responsibilities of the EMA, and provide a brief summary of recent initiatives related to cancer drug regulation. The EMA recently published its Road Map to 2015. Over the next 5 years, the agency aims to continue to stimulate drug development in areas of unmet medical needs. Concerning drug safety, one of the priorities over the next few years will be to establish a more proactive approach in ensuring patient safety. This is the result of new EU legislation coming into force in 2012 that will strengthen the way the safety of medicines for human use is monitored in the EU. In terms of its general operation, the agency is committed to increased openness and transparency, and to build on its interactions with stakeholders, including members of academia, health care professionals, patients, and health technology assessment bodies. The agency recently created an oncology working party to expand the current guideline for the development and evaluation of cancer drugs. The guideline focuses on both exploratory and confirmatory studies for different types of agents. The current revision will address a number of topics, including the use of biomarkers as an integrated part of drug development and the use of progression-free survival as a primary endpoint in registration trials. PMID:21844037

  6. The Breast Health Global Initiative: clinical practice guidelines for management of breast cancer in low- and middle-income countries.

    PubMed

    Yip, Cheng Har; Anderson, Benjamin O

    2007-08-01

    Breast cancer is an increasingly urgent problem in low- and mid-level resource countries of the world. Despite knowing the optimal management strategy based on guidelines developed in wealthy countries, clinicians are forced to provide less-than-optimal care to patients when diagnostic and/or treatment resources are lacking. For this reason, it is important to identify which resources commonly applied in resource-abundant countries most effectively fill the healthcare needs in limited-resource regions, where patients commonly present with more advanced disease at diagnosis, and to provide guidance on how new resource allocations should be made in order to maximize improvement in outcome. Established in 2002, the Breast Health Global Initiative (BHGI) created an international health alliance to develop evidence-based guidelines for countries with limited resources (low- and middle-income countries) to improve breast health outcomes. The BHGI serves as a program for international guideline development and as a hub for linkage among clinicians, governmental health agencies and advocacy groups to translate guidelines into policy and practice. The BHGI collaborated with 12 national and international health organizations, cancer societies and nongovernmental organizations to host two BHGI international summits. The evidence-based BHGI Guidelines, developed at the 2002 Global Summit, were published in 2003 as a theoretical treatise on international breast healthcare. These guidelines were then updated and expanded at the 2005 Global Summit into a fully comprehensive and flexible framework to permit incremental improvements in healthcare delivery, based upon outcomes, cost, cost-effectiveness and use of healthcare services. PMID:18028018

  7. Cancer

    MedlinePlus

    ... body. Cancerous cells are also called malignant cells. Causes Cancer grows out of cells in the body. Normal ... of many cancers remains unknown. The most common cause of cancer-related death is lung cancer. In the U.S., ...

  8. Adult murine prostate basal and luminal cells are self-sustained lineages that can both serve as targets for prostate cancer initiation

    PubMed Central

    Choi, Nahyun; Zhang, Boyu; Zhang, Li; Ittmann, Michael; Xin, Li

    2012-01-01

    Summary The prostate epithelial lineage hierarchy and the cellular origin for prostate cancer remain inadequately defined. Using a lineage tracing approach, we show that adult rodent prostate basal and luminal cells are independently self-sustained in vivo. Disrupting the tumor suppressor Pten in either lineage led to prostate cancer initiation. However, the cellular composition and onset dynamics of the resulting tumors are distinctive. Prostate luminal cells are more responsive to Pten null-induced mitogenic signaling. In contrast, basal cells are resistant to direct transformation. Instead, loss of Pten activity induces the capability of basal cells to differentiate into transformation-competent luminal cells. Our study suggests that deregulation of epithelial differentiation is a critical step for the initiation of prostate cancers of basal cell origin. PMID:22340597

  9. Resistive index of prostatic capsular arteries as a predictor of prostate cancer in patients undergoing initial prostate biopsy.

    PubMed

    Zhang, Xuefeng; Li, Gang; Hu, Linkun; Wei, Xuedong; Zha, Yueqin; Yin, Huming; Sun, Mubin; He, Jun; Hou, Jianquan

    2014-12-01

    To evaluate the value of resistive index (RI) of prostatic capsular arteries in diagnosis and evaluation of prostate cancer (PCa) in Chinese patients undergoing initial prostate biopsy. A total of 532 consecutive patients undergoing prostate biopsy were enrolled in this study. RI was measured on the largest transverse section of prostate for each individual. The predictive value of RI was evaluated using multivariate logistic regression and receiver operating characteristic (ROC) curve analyses. PCa was identified in 217 (40.79%) patients. RI was 0.69 ± 0.08 and 0.8 ± 0.08 for patients without and with PCa (p < 0.01). On logistic regression RI was significantly associated with PCa (p < 0.01). Using ROC analysis RI outperformed tPSA in prediction of PCa in all patients [area under ROC curve (AUC) = 0.83, 0.78, respectively]. With the cutoff value of 0.73, RI discriminated PCa from non-PCa patients with 81.9% sensitivity, 75.9% specificity and 77.63% diagnostic accuracy. Furthermore, The AUC for RI in the discrimination of PCa from non-PCa patients in a subset with PSA of 4 to 10 ng/ml, high grade from non-high grade PCa patients and advanced from localized PCa patients was 0.70, 0.77 and 0.80, higher than other parameters (p < 0.05). RI is proved a practicable parameter in identifying patients at risk for PCa and predicting the grade and stage of PCa before initial prostate biopsy. The value of RI should be further explored in the future. PMID:25380843

  10. miR-21 Might be Involved in Breast Cancer Promotion and Invasion Rather than in Initial Events of Breast Cancer Development.

    PubMed

    Petrović, Nina

    2016-04-01

    Breast cancer (BC) is a heterogeneous disease that develops into a large number of varied phenotypes. One of the features used in its classification and therapy selection is invasiveness. MicroRNA-21 (miR-21) is considered to be an important element of BC invasiveness, and miR-21 levels are frequently increased in different tumor types compared with normal tissue, including the breast. Experimental and literature research has highlighted that miR-21 was always significantly elevated in every study that included invasive breast carcinomas compared with healthy breast tissue. The main goal of this research was to specify the predominant role of miR-21 in the different phases of BC pathogenesis, i.e. whether it was involved in the early (initiation), later (promotion), or late (propagation, progression) phases. Our second goal was to explain the roles of miR-21 targets in BC by an in silico approach and literature review, and to associate the importance of miR-21 with particular phases of BC pathogenesis through the action of its target genes. Analysis has shown that changes in miR-21 levels might be important for the later and/or late phases of breast cancerogenesis rather than for the initial early phases. Targets of miR-21 (TIMP3, PDCD4, PTEN, TPM1 and RECK) are also primarily involved in BC promotion and progression, especially invasion, angiogenesis and metastasis. miR-21 expression levels could perhaps be used in conjunction with the standard diagnostic parameters as an indicator of BC presence, and to indicate a phenotype likely to show early invasion/metastasis detection and poor prognosis. PMID:26891730

  11. Equol, an isoflavone metabolite, regulates cancer cell viability and protein synthesis initiation via c-Myc and eIF4G.

    PubMed

    de la Parra, Columba; Borrero-Garcia, Luis D; Cruz-Collazo, Ailed; Schneider, Robert J; Dharmawardhane, Suranganie

    2015-03-01

    Epidemiological studies implicate dietary soy isoflavones as breast cancer preventives, especially due to their anti-estrogenic properties. However, soy isoflavones may also have a role in promoting breast cancer, which has yet to be clarified. We previously reported that equol, a metabolite of the soy isoflavone daidzein, may advance breast cancer potential via up-regulation of the eukaryotic initiation factor 4GI (eIF4GI). In estrogen receptor negative (ER-) metastatic breast cancer cells, equol induced elevated levels of eIF4G, which were associated with increased cell viability and the selective translation of mRNAs that use non-canonical means of initiation, including internal ribosome entry site (IRES), ribosome shunting, and eIF4G enhancers. These mRNAs typically code for oncogenic, survival, and cell stress molecules. Among those mRNAs translationally increased by equol was the oncogene and eIF4G enhancer, c-Myc. Here we report that siRNA-mediated knockdown of c-Myc abrogates the increase in cancer cell viability and mammosphere formation by equol, and results in a significant down-regulation of eIF4GI (the major eIF4G isoform), as well as reduces levels of some, but not all, proteins encoded by mRNAs that are translationally stimulated by equol treatment. Knockdown of eIF4GI also markedly reduces an equol-mediated increase in IRES-dependent mRNA translation and the expression of specific oncogenic proteins. However, eIF4GI knockdown did not reciprocally affect c-Myc levels or cell viability. This study therefore implicates c-Myc as a potential regulator of the cancer-promoting effects of equol via up-regulation of eIF4GI and selective initiation of translation on mRNAs that utilize non-canonical initiation, including certain oncogenes. PMID:25593313

  12. IMP1 promotes tumor growth, dissemination and a tumor-initiating cell phenotype in colorectal cancer cell xenografts

    PubMed Central

    Hamilton, Kathryn E.; Noubissi, Felicite K.; Rustgi, Anil K.

    2013-01-01

    Igf2 mRNA binding protein 1 (IMP1, CRD-BP, ZBP-1) is a messenger RNA binding protein that we have shown previously to regulate colorectal cancer (CRC) cell growth in vitro. Furthermore, increased IMP1 expression correlates with enhanced metastasis and poor prognosis in CRC patients. In the current study, we sought to elucidate IMP1-mediated functions in CRC pathogenesis in vivo. Using CRC cell xenografts, we demonstrate that IMP1 overexpression promotes xenograft tumor growth and dissemination into the blood. Furthermore, intestine-specific knockdown of Imp1 dramatically reduces tumor number in the Apc Min/+ mouse model of intestinal tumorigenesis. In addition, IMP1 knockdown xenografts exhibit a reduced number of tumor cells entering the circulation, suggesting that IMP1 may directly modulate this early metastatic event. We further demonstrate that IMP1 overexpression decreases E-cadherin expression, promotes survival of single tumor cell-derived colonospheres and promotes enrichment and maintenance of a population of CD24+CD44+ cells, signifying that IMP1 overexpressing cells display evidence of loss of epithelial identity and enhancement of a tumor-initiating cell phenotype. Taken together, these findings implicate IMP1 as a modulator of tumor growth and provide evidence for a novel role of IMP1 in early events in CRC metastasis. PMID:23764754

  13. The role of maintenance proteins in the preservation of epithelial cell identity during mammary gland remodeling and breast cancer initiation

    PubMed Central

    Coradini, Danila; Oriana, Saro

    2014-01-01

    During normal postnatal mammary gland development and adult remodeling related to the menstrual cycle, pregnancy, and lactation, ovarian hormones and peptide growth factors contribute to the delineation of a definite epithelial cell identity. This identity is maintained during cell replication in a heritable but DNA-independent manner. The preservation of cell identity is fundamental, especially when cells must undergo changes in response to intrinsic and extrinsic signals. The maintenance proteins, which are required for cell identity preservation, act epigenetically by regulating gene expression through DNA methylation, histone modification, and chromatin remodeling. Among the maintenance proteins, the Trithorax (TrxG) and Polycomb (PcG) group proteins are the best characterized. In this review, we summarize the structures and activities of the TrxG and PcG complexes and describe their pivotal roles in nuclear estrogen receptor activity. In addition, we provide evidence that perturbations in these epigenetic regulators are involved in disrupting epithelial cell identity, mammary gland remodeling, and breast cancer initiation. PMID:23845141

  14. A Proposed Paradigm Shift in Initializing Cancer Predictive Models with DCE-MRI Based PK Parameters: A Feasibility Study

    PubMed Central

    Roniotis, Alexandros; Oraiopoulou, Mariam-Eleni; Tzamali, Eleftheria; Kontopodis, Eleftherios; Van Cauter, Sofie; Sakkalis, Vangelis; Marias, Kostas

    2015-01-01

    Glioblastoma multiforme is the most aggressive type of glioma and the most common malignant primary intra-axial brain tumor. In an effort to predict the evolution of the disease and optimize therapeutical decisions, several models have been proposed for simulating the growth pattern of glioma. One of the latest models incorporates cell proliferation and invasion, angiogenic net rates, oxygen consumption, and vasculature. These factors, particularly oxygenation levels, are considered fundamental factors of tumor heterogeneity and compartmentalization. This paper focuses on the initialization of the cancer cell populations and vasculature based on imaging examinations of the patient and presents a feasibility study on vasculature prediction over time. To this end, pharmacokinetic parameters derived from dynamic contrast-enhanced magnetic resonance imaging using Toft’s model are used in order to feed the model. Ktrans is used as a metric of the density of endothelial cells (vasculature); at the same time, it also helps to discriminate distinct image areas of interest, under a set of assumptions. Feasibility results of applying the model to a real clinical case are presented, including a study on the effect of certain parameters on the pattern of the simulated tumor. PMID:26085787

  15. Targeting phospholipase D1 attenuates intestinal tumorigenesis by controlling β-catenin signaling in cancer-initiating cells

    PubMed Central

    Kang, Dong Woo; Choi, Chi Yeol; Cho, Yong-Hee; Tian, Huasong; Di Paolo, Gilbert; Choi, Kang-Yell

    2015-01-01

    Expression of the Wnt target gene phospholipase D1 (PLD1) is up-regulated in various carcinomas, including colorectal cancer (CRC). However, the mechanistic significance of its elevated expression in intestinal tumorigenesis remains unknown. In this study, we show that genetic and pharmacological targeting of PLD1 disrupts spontaneous and colitis-associated intestinal tumorigenesis in ApcMin/+ and azoxymethane/dextran sodium sulfate mice models. Intestinal epithelial cell–specific PLD1 overexpression in ApcMin/+ mice accelerated tumorigenesis with increased proliferation and nuclear β-catenin levels compared with ApcMin/+ mice. Moreover, PLD1 inactivation suppressed the self-renewal capacity of colon cancer–initiating cells (CC-ICs) by decreasing expression of β-catenin via E2F1-induced microRNA (miR)-4496 up-regulation. Ultimately, low expression of PLD1 coupled with a low level of CC-IC markers was predictive of a good prognosis in CRC patients, suggesting in vivo relevance. Collectively, our data reveal that PLD1 has a crucial role in intestinal tumorigenesis via its modulation of the E2F1–miR-4496–β-catenin signaling pathway. Modulation of PLD1 expression and activity represents a promising therapeutic strategy for the treatment of intestinal tumorigenesis. PMID:26122663

  16. Docetaxel for non-small-cell lung cancer harboring the activated EGFR mutation with T790M at initial presentation.

    PubMed

    Yamane, Hiromichi; Ochi, Nobuaki; Yasugi, Masayuki; Tabayashi, Takayuki; Yamagishi, Tomoko; Monobe, Yasumasa; Hisamoto, Akiko; Kiura, Katsuyuki; Takigawa, Nagio

    2013-01-01

    A 72-year-old woman was referred to our hospital with Stage IV non-small-cell lung cancer (NSCLC). Chest computed tomography revealed a mass in the upper lobe of the right lung, with pleural effusion. Cytologic examination identified adenocarcinoma cells in the right pleural effusion. Furthermore, both a deletion mutation in exon 19 and a threonine-methionine substitution mutation at position 790 in exon 20 (T790M) were detected in the epidermal growth factor receptors (EGFR) in the malignant cells. As systemic chemotherapy consisting of carboplatin and pemetrexed or erlotinib proved ineffective, docetaxel monotherapy was initiated as a third-line treatment. Following salvage chemotherapy, her Eastern Cooperative Oncology Group performance status improved from 3 to 1, with tumor regression over 5 months. To the best of our knowledge, this is the first report of successful docetaxel treatment for a patient with NSCLC harboring the T790M EGFR-activating mutation identified before treatment with EGFR tyrosine kinase inhibitors. PMID:23493804

  17. Docetaxel for non-small-cell lung cancer harboring the activated EGFR mutation with T790M at initial presentation

    PubMed Central

    Yamane, Hiromichi; Ochi, Nobuaki; Yasugi, Masayuki; Tabayashi, Takayuki; Yamagishi, Tomoko; Monobe, Yasumasa; Hisamoto, Akiko; Kiura, Katsuyuki; Takigawa, Nagio

    2013-01-01

    A 72-year-old woman was referred to our hospital with Stage IV non-small-cell lung cancer (NSCLC). Chest computed tomography revealed a mass in the upper lobe of the right lung, with pleural effusion. Cytologic examination identified adenocarcinoma cells in the right pleural effusion. Furthermore, both a deletion mutation in exon 19 and a threonine–methionine substitution mutation at position 790 in exon 20 (T790M) were detected in the epidermal growth factor receptors (EGFR) in the malignant cells. As systemic chemotherapy consisting of carboplatin and pemetrexed or erlotinib proved ineffective, docetaxel monotherapy was initiated as a third-line treatment. Following salvage chemotherapy, her Eastern Cooperative Oncology Group performance status improved from 3 to 1, with tumor regression over 5 months. To the best of our knowledge, this is the first report of successful docetaxel treatment for a patient with NSCLC harboring the T790M EGFR-activating mutation identified before treatment with EGFR tyrosine kinase inhibitors. PMID:23493804

  18. Yttrium-90/indium-111 DOTA peptide chimeric L6; pharmacokinetics, dosimetry and initial therapeutic studies in patients with breast cancer

    SciTech Connect

    DeNardo, S.J.; Shen, S.; Richman, C.M.

    1995-05-01

    Chimeric L6 MoAb(ChL6) as I-131 ChL6 has shown therapeutic promise in breast cancer patients. To enhance this potential, we developed yttrium-90 (Y-90) and indium-111 (In-111) ChL6 radiopharmaceuticals by conjugating Y-90 and In-111 DOTA peptide ChL6. Immunoreactivity of In-111 and Y-90 ChL6 was 80-100% of ChL6. Dosimetry was calculated from pharmacokinetics obtained in four studies of patients with metastatic breast cancer using 200 mg ChL6 and 4mCi In-111/3mCi Y-90 DOTA peptide ChL6 in 3 studies and 10 mCi In-111 in one (specific activity 1.1-3.5mCi/mg). Quantitative imaging of In-111 and in vitro analysis of Y-90/In-111 blood and urine clearances and biopsies for bone and marrow uptake were performed. In-111 and Y-90 DOTA peptide ChL6 blood clearances were compared in each patient with {beta} intercepts for each initial study of 13.9/12.7, 4.9/5.8, 25.2/16.2 (%ID), and {beta} T{1/2} 32/30, 33/35, and 41/57 (h) for In- 111/Y-90, respectively. Normal organ and tumor dosimetry for Y-90 DOTA peptide ChL6 was extrapolated from the In-111 kinetics: WB 2.1-2.3, Liver 3.8-5.9, Lung 6.2-7.9, Kidney 8.1-11.3, Spleen 4.4-14.0 (cGy/mCi). Dosimetry of 13 tumored areas (1-10 g) ranged from 42-260 (mean = 103) cGy/mCi. Marrow doses calculated from Y-90 in blood ranged from 0.6-1.5. Marrow biopsies at 5 d pi showed In-111 and Y-90 (%ID/g), 1-2 x 10{sup -3} and 6-7x10{sup -4} and bone 1-3x10{sup -3} and 0.1-3x10{sup -4}, respectively. Compared to our previous I-131 ChL6 dosimetry, this study indicates that the Y-90 DOTA peptide ChL6 radiation dose to tumor is 4-8 times that of I-131 ChL6 whereas normal organs receive less than twice that of I-131 from Y-90. Based on this calculated enhancement of the therapeutic ratio, a multicycle Y-90 DOTA peptide ChL6 therapy protocol has been initiated in breast cancer patients.

  19. Carcinome colloïde du sein: à propos d'un cas

    PubMed Central

    Laabadi, Kamilia; Jayi, Sofia; Alaoui, Fatimazohra Fdili; Bouguern, Hakima; Chaara, Hikmat; Melhouf, My Abdelilah

    2013-01-01

    Nous rapportons le cas d'une tumeur colloïde du sein chez un homme. Cette situation rare interpelle par son mode de découverte. Nous avons pris en charge un homme de 60 ans atteint d'une lésion rétro-aréolaire droite classée cliniquement T4b N1 M0 et suspecte radiologiquement. L'analyse histologique (microbiopsie) a conclu à un carcinome colloïde muqueux associé à une petite composante canalaire classique de grade I de SBR du sein. Les traitements complémentaires associent mastectomie, curage, chimiothérapie, radiothérapie et hormonothérapie. Le cancer du sein est rare chez l'homme. Le carcinome colloïde est exceptionnel puisqu'il représente seulement 1 à 6% de l'ensemble des cancers du sein. Il est encore plus rare chez l'homme. Ces tumeurs touchent une population spécifique et ont un meilleur pronostic que les autres types prépondérant dans les cancers du sein chez l'homme. A travers cette observation et une revue de la littérature, nous essaierons de discuter les principales caractéristiques anatomo-cliniques et évolutives de cette forme rare du cancer du sein. PMID:24772222

  20. LKB1 is a central regulator of tumor initiation and pro-growth metabolism in ErbB2-mediated breast cancer

    PubMed Central

    2013-01-01

    Background Germline and somatic mutations in STK11, the gene encoding the serine/threonine kinase LKB1, are strongly associated with tumorigenesis. While loss of LKB1 expression has been linked to breast cancer, the mechanistic role of LKB1 in regulating breast cancer development, metastasis, and tumor metabolism has remained unclear. Methods We have generated and analyzed transgenic mice expressing ErbB2 in the mammary epithelium of LKB1 wild-type or LKB1-deficient mice. We have also utilized ErbB2-expressing breast cancer cells in which LKB1 levels have been reduced using shRNA approaches. These transgenic and xenograft models were characterized for the effects of LKB1 loss on tumor initiation, growth, metastasis and tumor cell metabolism. Results We demonstrate that loss of LKB1 promotes tumor initiation and induces a characteristic shift to aerobic glycolysis (‘Warburg effect’) in a model of ErbB2-mediated breast cancer. LKB1-deficient breast cancer cells display enhanced early tumor growth coupled with increased cell migratory and invasive properties in vitro. We show that ErbB2-positive tumors deficient for LKB1 display a pro-growth molecular and phenotypic signature characterized by elevated Akt/mTOR signaling, increased glycolytic metabolism, as well as increased bioenergetic markers both in vitro and in vivo. We also demonstrate that mTOR contributes to the metabolic reprogramming of LKB1-deficient breast cancer, and is required to drive glycolytic metabolism in these tumors; however, LKB1-deficient breast cancer cells display reduced metabolic flexibility and increased apoptosis in response to metabolic perturbations. Conclusions Together, our data suggest that LKB1 functions as a tumor suppressor in breast cancer. Loss of LKB1 collaborates with activated ErbB2 signaling to drive breast tumorigenesis and pro-growth metabolism in the resulting tumors. PMID:24280377

  1. An integrated genomic approach identifies that the PI3K/AKT/FOXO pathway is involved in breast cancer tumor initiation.

    PubMed

    Smit, Linda; Berns, Katrien; Spence, Katherine; Ryder, W David; Zeps, Nik; Madiredjo, Mandy; Beijersbergen, Roderick; Bernards, René; Clarke, Robert B

    2016-01-19

    Therapy resistance is one of the major impediments to successful cancer treatment. In breast cancer, a small subpopulation of cells with stem cell features, named breast cancer stem cells (BCSC), is responsible for metastasis and recurrence of the tumor. BCSC have the unique ability to grow under non-adherent conditions in "mammospheres". To prevent breast cancer recurrence and metastasis it will be crucial to eradicate BCSC.We used shRNA genetic screening to identify genes that upon knockdown enhance mammosphere formation in breast cancer cells. By integration of these results with gene expression profiles of mammospheres and NOTCH-activated cells, we identified FOXO3A. Modulation of FOXO3A activity results in a change in mammosphere formation, expression of mammary stem cell markers and breast cancer initiating potential. Importantly, lack of FOXO3A expression in breast cancer patients is associated with increased recurrence rate. Our findings provide evidence for a role for FOXO3A downstream of NOTCH and AKT that may have implications for therapies targeting BCSCs. PMID:26595803

  2. Supportive care during treatment for breast cancer: resource allocations in low- and middle-income countries. A Breast Health Global Initiative 2013 consensus statement.

    PubMed

    Cardoso, Fatima; Bese, Nuran; Distelhorst, Sandra R; Bevilacqua, Jose Luiz B; Ginsburg, Ophira; Grunberg, Steven M; Gralla, Richard J; Steyn, Ann; Pagani, Olivia; Partridge, Ann H; Knaul, Felicia Marie; Aapro, Matti S; Andersen, Barbara L; Thompson, Beti; Gralow, Julie R; Anderson, Benjamin O

    2013-10-01

    Breast cancer patients may have unmet supportive care needs during treatment, including symptom management of treatment-related toxicities, and educational, psychosocial, and spiritual needs. Delivery of supportive care is often a low priority in low- and middle-income settings, and is also dependent on resources available. This consensus statement describes twelve key recommendations for supportive care during treatment in low- and middle-income countries, identified by an expert international panel as part of the 5th Breast Health Global Initiative (BHGI) Global Summit for Supportive Care, which was held in October 2012, in Vienna, Austria. Panel recommendations are presented in a 4-tier resource-stratified table to illustrate how health systems can provide supportive care services during treatment to breast cancer patients, starting at a basic level of resource allocation and incrementally adding program resources as they become available. These recommendations include: health professional and patient and family education; management of treatment related toxicities, management of treatment-related symptoms of fatigue, insomnia and non-specific pain, and management of psychosocial and spiritual issues related to breast cancer treatment. Establishing supportive care during breast cancer treatment will help ensure that breast cancer patients receive comprehensive care that can help 1) improve adherence to treatment recommendations, 2) manage treatment-related toxicities and other treatment related symptoms, and 3) address the psychosocial and spiritual aspects of breast cancer and breast cancer treatments. PMID:24001709

  3. An integrated genomic approach identifies that the PI3K/AKT/FOXO pathway is involved in breast cancer tumor initiation

    PubMed Central

    Smit, Linda; Berns, Katrien; Spence, Katherine; Ryder, W. David; Zeps, Nik; Madiredjo, Mandy; Beijersbergen, Roderick; Bernards, René; Clarke, Robert B.

    2016-01-01

    Therapy resistance is one of the major impediments to successful cancer treatment. In breast cancer, a small subpopulation of cells with stem cell features, named breast cancer stem cells (BCSC), is responsible for metastasis and recurrence of the tumor. BCSC have the unique ability to grow under non-adherent conditions in “mammospheres”. To prevent breast cancer recurrence and metastasis it will be crucial to eradicate BCSC. We used shRNA genetic screening to identify genes that upon knockdown enhance mammosphere formation in breast cancer cells. By integration of these results with gene expression profiles of mammospheres and NOTCH-activated cells, we identified FOXO3A. Modulation of FOXO3A activity results in a change in mammosphere formation, expression of mammary stem cell markers and breast cancer initiating potential. Importantly, lack of FOXO3A expression in breast cancer patients is associated with increased recurrence rate. Our findings provide evidence for a role for FOXO3A downstream of NOTCH and AKT that may have implications for therapies targeting BCSCs. PMID:26595803

  4. GLI1 regulates a novel neuropilin-2/α6β1 integrin based autocrine pathway that contributes to breast cancer initiation.

    PubMed

    Goel, Hira Lal; Pursell, Bryan; Chang, Cheng; Shaw, Leslie M; Mao, Junhao; Simin, Karl; Kumar, Prashant; Vander Kooi, Craig W; Shultz, Leonard D; Greiner, Dale L; Norum, Jens Henrik; Toftgard, Rune; Kuperwasser, Charlotte; Mercurio, Arthur M

    2013-04-01

    The characterization of cells with tumour initiating potential is significant for advancing our understanding of cancer and improving therapy. Aggressive, triple-negative breast cancers (TNBCs) are enriched for tumour-initiating cells (TICs). We investigated that hypothesis that VEGF receptors expressed on TNBC cells mediate autocrine signalling that contributes to tumour initiation. We discovered the VEGF receptor neuropilin-2 (NRP2) is expressed preferentially on TICs, involved in the genesis of TNBCs and necessary for tumour initiation. The mechanism by which NRP2 signalling promotes tumour initiation involves stimulation of the α6β1 integrin, focal adhesion kinase-mediated activation of Ras/MEK signalling and consequent expression of the Hedgehog effector GLI1. GLI1 also induces BMI-1, a key stem cell factor, and it enhances NRP2 expression and the function of α6β1, establishing an autocrine loop. NRP2 can be targeted in vivo to retard tumour initiation. These findings reveal a novel autocrine pathway involving VEGF/NRP2, α6β1 and GLI1 that contributes to the initiation of TNBC. They also support the feasibility of NRP2-based therapy for the treatment of TNBC that targets and impedes the function of TICs. PMID:23436775

  5. Understanding Cancer Prognosis

    MedlinePlus Videos and Cool Tools

    ... Screening & Early Detection Treatment Cancer & Public Health Cancer Health Disparities Childhood Cancers Research Clinical Trials Global Health Key ... Screening & Early Detection Treatment Cancer & Public Health Cancer Health Disparities Childhood Cancer Clinical Trials Global Health Key Initiatives ...

  6. Ethnic differences in initiation and timing of adjuvant endocrine therapy among older women with hormone receptor-positive breast cancer enrolled in Medicare Part D

    PubMed Central

    Du, Xianglin L.

    2016-01-01

    The aim of this study was to determine whether there are racial/ethnic differences in initiation and timing of adjuvant endocrine therapy (AET) after Medicare Part D drug coverage. We conducted a retrospective cohort study using data from the Surveillance, Epidemiology, and End Results-Medicare-linked data to assess ethnic, socio-demographic, and tumor characteristic variations in the initiation of AET among patients ≥65 with hormone receptor-positive breast cancer in 2007–2009 enrolled in Medicare Part D through 2010. Logistic regression models were performed to assess the association between race/ethnicity and the initiation of tamoxifen, aromatase inhibitors (AIs), and overall AET (tamoxifen or AIs) within the first 12 months of diagnosis. Of the 12,198 women with hormone receptor-positive breast cancer, 74.8 % received AET within 12 months of diagnosis, of which 17.3 % received tamoxifen and 82.8 % received AIs. After controlling for all variables, only Asian women were found to have a greater odds of initiation of overall AET compared to non-Hispanic white women (odds ratio (OR): 1.28, 95 % CI: 1.03–1.58). Hispanic Mexicans and non-Hispanic black patients had a significantly lower odds of tamoxifen initiation (0.70, 0.54–0.91; 0.25, 0.10–0.62). For AI initiation, Hispanic Mexicans and Asians had a higher odds compared to non-Hispanic white women (2.06, 1.34–3.10; 1.33, 1.11–1.61). A suboptimal proportion of women (25.2 %) did not initiate AET within 12 months of diagnosis and therefore did not receive the full benefits of treatment to reduce the risk of breast cancer recurrence and mortality. Racial/ethnic differences in the initiation of tamoxifen and AIs have important implications that require further investigation. PMID:26786154

  7. Guidelines for locoregional therapy in primary breast cancer in developing countries: The results of an expert panel at the 8th Annual Women's Cancer Initiative – Tata Memorial Hospital (WCI-TMH) Conference

    PubMed Central

    Munshi, Anusheel; Gupta, Sudeep; Anderson, Benjamin; Yarnold, John; Parmar, Vani; Jalali, Rakesh; Sharma, Suresh Chander; Desai, Sangeeta; Thakur, Meenakshi; Baijal, Gunjan; Sarin, Rajiv; Mittra, Indraneel; Ghosh, Jaya; Badwe, Rajendra

    2012-01-01

    Background: Limited guidelines exist for breast cancer management in developing countries. In this context, the Women's Cancer Initiative - Tata Memorial Hospital (WCI-TMH) organised its 8th Annual Conference to update guidelines in breast cancer. Materials and Methods: Appropriately formulated guideline questions on each topic and subtopic in the surgical, radiation and systemic management of primary breast cancer were developed by the scientific committee and shared with the guest faculty of the Conference. Majority of the questions had multiple choice answers. The opinion of the audience, comprising academic and community oncologists, was electronically cumulated, followed by focussed presentations by eminent national and international experts on each topic. The guidelines were finally developed through an expert panel that voted on each guideline question after all talks had been delivered and audience opinion elicited. Separate panels were constituted for locoregional and systemic therapy in primary breast cancer. Results: Based on the voting results of the expert panel, guidelines for locoregional therapy of breast cancer have been formulated. Voting patterns for each question are reported. Conclusions: The updated guidelines on locoregional management of primary breast cancer in the context of developing countries are presented in this article. These recommendations have been designed to allow centers in the developing world to improve the quality of care for breast cancer patients. PMID:22988354

  8. Presence of a putative tumor-initiating progenitor cell population predicts poor prognosis in smokers with non-small cell lung cancer

    PubMed Central

    Ooi, Aik T.; Mah, Vei; Nickerson, Derek W.; Gilbert, Jennifer L.; Ha, Vi Luan; Hegab, Ahmed E.; Horvath, Steve; Alavi, Mohammad; Maresh, Erin L.; Chia, David; Gower, Adam C.; Lenburg, Marc E.; Spira, Avrum; Solis, Luisa M.; Wistuba, Ignacio I.; Walser, Tonya C.; Wallace, William D.; Dubinett, Steven M.; Goodglick, Lee; Gomperts, Brigitte N.

    2010-01-01

    Smoking is the most important known risk factor for the development of lung cancer. Tobacco exposure results in chronic inflammation, tissue injury and repair. A recent hypothesis argues for a stem/progenitor cell involved in airway epithelial repair that may be a tumor-initiating cell in lung cancer, and which may be associated with recurrence and metastasis. We used immunostaining, quantitative real-time PCR, Western blots and lung cancer tissue microarrays to identify subpopulations of airway epithelial stem/progenitor cells under steady state conditions, normal repair, aberrant repair with premalignant lesions and lung cancer and their correlation with injury and prognosis. We identified a population of keratin 14 (K14)-expressing progenitor epithelial cells that was involved in repair after injury. Dysregulated repair resulted in persistence of K14+ cells in the airway epithelium in premalignant lesions. The presence of K14+ cells in non-small cell lung cancer (NSCLC) samples predicted poorer outcomes. This was especially true in smokers where the presence of K14+ cells in NSCLC was predictive of metastasis. The presence of K14+ progenitor airway epithelial cells in NSCLC predicted a poor prognosis and this predictive value was strongest in smokers, where it also correlated with metastasis. This suggests that reparative K14+ progenitor cells may be tumor-initiating cells in this subgroup of smokers with NSCLC. PMID:20710044

  9. Translation initiation factor eIF3b expression in human cancer and its role in tumor growth and lung colonization

    PubMed Central

    Wang, Hong; Ru, Yuanbin; Sanchez-Carbayo, Marta; Wang, Xuejiao; Kieft, Jeffrey S.; Theodorescu, Dan

    2013-01-01

    Purpose Discovery transcriptomic analyses suggest eukaryotic initiation factor 3b (eIF3b) is elevated in human bladder and prostate cancer, yet its role as a prognostic factor or its requirement in the maintenance or progression of human cancer is not established. Here we determine the therapeutic potential of eIF3b by examining the clinical relevance of its expression in human cancer tissues and its role in experimental tumor models. Experimental Design We examined mRNA expression of eIF3b in bladder (N=317) and prostate (N=566) tissue samples and protein expression by immunohistochemistry in 143 bladder tumor samples as a function of clinicopathologic features. The impact of eIF3b depletion by siRNA in human cancer lines was evaluated in regards to in vitro cell growth, cell cycle, migration, in vivo subcutaneous tumor growth and lung colonization. Results eIF3b mRNA expression correlated to tumor grade, stage and survival in human bladder and prostate cancer. eIF3b protein expression stratified survival in human bladder cancer. eIF3b depletion reduced in vitro cancer cell growth; inhibited G1/S cell cycle transition by changing protein but not RNA expression of Cyclin A, E, Rb and p27Kip1; inhibited migration and disrupted actin cytoskeleton and focal adhesions. These changes were associated with decreased protein expression of integrin α5. Integrin α5 depletion phenocopied effects observed with eIF3b. eIF3b depleted bladder cancer cells formed fewer subcutaneous tumors that grew more slowly and had reduced lung colonization. Conclusion eIF3b expression relates to human bladder and prostate cancer prognosis, is required for tumor growth and thus a candidate therapeutic target. PMID:23575475

  10. Tumour-initiating cell-specific miR-1246 and miR-1290 expression converge to promote non-small cell lung cancer progression

    PubMed Central

    Zhang, Wen Cai; Chin, Tan Min; Yang, Henry; Nga, Min En; Lunny, Declan Patrick; Lim, Edwin Kok Hao; Sun, Li Li; Pang, Yin Huei; Leow, Yi Ning; Malusay, Shanneen Rossellini Y; Lim, Priscilla Xin Hui; Lee, Jeravan Zili; Tan, Benedict Jian Wei; Shyh-Chang, Ng; Lim, Elaine Hsuen; Lim, Wan Teck; Tan, Daniel Shao Weng; Tan, Eng Huat; Tai, Bee Choo; Soo, Ross Andrew; Tam, Wai Leong; Lim, Bing

    2016-01-01

    The tumour-initiating cell (TIC) model accounts for phenotypic and functional heterogeneity among tumour cells. MicroRNAs (miRNAs) are regulatory molecules frequently aberrantly expressed in cancers, and may contribute towards tumour heterogeneity and TIC behaviour. More recent efforts have focused on miRNAs as diagnostic or therapeutic targets. Here, we identified the TIC-specific miRNAs, miR-1246 and miR-1290, as crucial drivers for tumour initiation and cancer progression in human non-small cell lung cancer. The loss of either miRNA impacted the tumour-initiating potential of TICs and their ability to metastasize. Longitudinal analyses of serum miR-1246 and miR-1290 levels across time correlate their circulating levels to the clinical response of lung cancer patients who were receiving ongoing anti-neoplastic therapies. Functionally, direct inhibition of either miRNA with locked nucleic acid administered systemically, can arrest the growth of established patient-derived xenograft tumours, thus indicating that these miRNAs are clinically useful as biomarkers for tracking disease progression and as therapeutic targets. PMID:27325363

  11. Tumour-initiating cell-specific miR-1246 and miR-1290 expression converge to promote non-small cell lung cancer progression.

    PubMed

    Zhang, Wen Cai; Chin, Tan Min; Yang, Henry; Nga, Min En; Lunny, Declan Patrick; Lim, Edwin Kok Hao; Sun, Li Li; Pang, Yin Huei; Leow, Yi Ning; Malusay, Shanneen Rossellini Y; Lim, Priscilla Xin Hui; Lee, Jeravan Zili; Tan, Benedict Jian Wei; Shyh-Chang, Ng; Lim, Elaine Hsuen; Lim, Wan Teck; Tan, Daniel Shao Weng; Tan, Eng Huat; Tai, Bee Choo; Soo, Ross Andrew; Tam, Wai Leong; Lim, Bing

    2016-01-01

    The tumour-initiating cell (TIC) model accounts for phenotypic and functional heterogeneity among tumour cells. MicroRNAs (miRNAs) are regulatory molecules frequently aberrantly expressed in cancers, and may contribute towards tumour heterogeneity and TIC behaviour. More recent efforts have focused on miRNAs as diagnostic or therapeutic targets. Here, we identified the TIC-specific miRNAs, miR-1246 and miR-1290, as crucial drivers for tumour initiation and cancer progression in human non-small cell lung cancer. The loss of either miRNA impacted the tumour-initiating potential of TICs and their ability to metastasize. Longitudinal analyses of serum miR-1246 and miR-1290 levels across time correlate their circulating levels to the clinical response of lung cancer patients who were receiving ongoing anti-neoplastic therapies. Functionally, direct inhibition of either miRNA with locked nucleic acid administered systemically, can arrest the growth of established patient-derived xenograft tumours, thus indicating that these miRNAs are clinically useful as biomarkers for tracking disease progression and as therapeutic targets. PMID:27325363

  12. An Initial Look at the Associations of a Variety of Health-Related Online Activities With Cancer Fatalism.

    PubMed

    Lee, Chul-Joo; Chae, Jiyoung

    2016-11-01

    It has been an important public health goal to remove cancer fatalism because of its negative influence on both cancer screening and preventive behaviors. The present study examines roles of the Internet, as an emerging, crucial source of cancer information, in the effect of education on cancer fatalism. Based on our secondary analysis of a nationally representative survey (i.e., Health Information National Trends Survey 4 Cycle 1), we found that people with low levels of education are less likely than their more educated counterparts to engage in online health information seeking that is negatively linked to fatalistic beliefs about cancer prevention. In addition, the effect of education on online health information seeking was detected only among people who trust online health information. The implications of these findings for cancer control and for research on the digital divide and communication inequalities are discussed. PMID:27007443

  13. GALNT1-Mediated Glycosylation and Activation of Sonic Hedgehog Signaling Maintains the Self-Renewal and Tumor-Initiating Capacity of Bladder Cancer Stem Cells.

    PubMed

    Li, Chong; Du, Ying; Yang, Zhao; He, Luyun; Wang, Yanying; Hao, Lu; Ding, Mingxia; Yan, Ruping; Wang, Jiansong; Fan, Zusen

    2016-03-01

    The existence of bladder cancer stem cells (BCSC) has been suggested to underlie bladder tumor initiation and recurrence. Sonic Hedgehog (SHH) signaling has been implicated in promoting cancer stem cell (CSC) self-renewal and is activated in bladder cancer, but its impact on BCSC maintenance is unclear. In this study, we generated a mAb (BCMab1) against CD44(+) human bladder cancer cells that recognizes aberrantly glycosylated integrin α3β1. The combination of BCMab1 with an anti-CD44 antibody identified a BCMab1(+)CD44(+) cell subpopulation as BCSCs with stem cell-like properties. Gene expression analysis revealed that the hedgehog pathway was activated in the BCMab1(+)CD44(+) subpopulation and was required for BCSC self-renewal. Furthermore, the glycotransferase GALNT1 was highly expressed in BCMab1(+)CD44(+) cells and correlated with clinicopathologic features of bladder cancers. Mechanistically, GALNT1 mediated O-linked glycosylation of SHH to promote its activation, which was essential for the self-renewal maintenance of BCSCs and bladder tumorigenesis. Finally, intravesical instillation of GALNT1 siRNA and the SHH inhibitor cyclopamine exerted potent antitumor activity against bladder tumor growth. Taken together, our findings identify a BCSC subpopulation in human bladder tumors that appears to be responsive to the inhibition of GALNT1 and SHH signaling, and thus highlight a potential strategy for preventing the rapid recurrence typical in patients with bladder cancer. PMID:26676748

  14. Initial Validation and Clinical Experience with 3D Optical-Surface-Guided Whole Breast Irradiation of Breast Cancer

    PubMed Central

    Li, S.; DeWeese, T.; Movsas, B.; Frassica, Deborah; Liu, Dezhi; Kim, Jinkoo; Chen, Qing; Walker, Eleanor

    2015-01-01

    We had introduced 3D optical surface-guided radiotherapy (SGRT) of the breast cancer (BC). We then initiated the feasibility, accuracy, and precision studies of stereovision in detection of any breast displacement through the course of treatment for total thirty breasts undertaken whole breast irradiation (WBI). In the SGRT, CT-based plan data were parsed into an in-house computer program through which the reference surfaces were generated in 3D video format. When patients were positioned on treatment Tables, real-time stereovisions were rapidly acquired while the live surface tracking shown steady thorax motion. The real-time surface images were automatically aligned with the reference surface and detected shape and location changes of the breast were online corrected through the Table and beam adjustments. Accumulated dose to each patient was computed according to the frequency distribution of the measured breast locations during beam on time. Application of SGRT had diminished large skin-marking errors of >5-mm and daily breast-setup errors of >10-mm that occurred on half of cases. Accuracy (mean) and precision (two standard deviations) of the breast displacements across the tangential field edges in the (U, V) directions were improved from (−0.5 ± 8.8, 2.2 ± 10.8) mm in conventional setup to (0.4 ± 4.6, 0.7 ± 4.4) mm in the final position while intra-fractional motion contributed only (0.1 ± 2.8, 0.0 ± 2.2) mm in free breathing. Dose uniformity and coverage to targets had both been increased by up to 10% and the lung or heart intersections have been decreased by half of those volumes if they were irradiated at the initial positions. SGRT of BC appears to be feasible regardless of skin tones, as fast as a snapshot for 3D imaging, and very accurate and precise for daily setup of flexible breast targets. Importantly, the technique allows us to verify the breast shape and position during beam-on time. PMID:22181332

  15. Survival Impact of Increasing Time to Treatment Initiation for Patients With Head and Neck Cancer in the United States

    PubMed Central

    Murphy, Colin T.; Handorf, Elizabeth A.; Egleston, Brian L.; Wang, Lora S.; Mehra, Ranee; Flieder, Douglas B.; Ridge, John A.

    2016-01-01

    Purpose To estimate the overall survival (OS) impact from increasing time to treatment initiation (TTI) for patients with head and neck squamous cell carcinoma (HNSCC). Methods Using the National Cancer Data Base (NCDB), we examined patients who received curative therapy for the following sites: oral tongue, oropharynx, larynx, and hypopharynx. TTI was the number of days from diagnosis to initiation of curative treatment. The effect of TTI on OS was determined by using Cox regression models (MVA). Recursive partitioning analysis (RPA) identified TTI thresholds via conditional inference trees to estimate the greatest differences in OS on the basis of randomly selected training and validation sets, and repeated this 1,000 times to ensure robustness of TTI thresholds. Results A total of 51,655 patients were included. On MVA, TTI of 61 to 90 days versus less than 30 days (hazard ratio [HR], 1.13; 95% CI, 1.08 to 1.19) independently increased mortality risk. TTI of 67 days appeared as the optimal threshold on the training RPA, statistical significance was confirmed in the validation set (P < .001), and the 67-day TTI was the optimal threshold in 54% of repeated simulations. Overall, 96% of simulations validated two optimal TTI thresholds, with ranges of 46 to 52 days and 62 to 67 days. The median OS for TTI of 46 to 52 days or fewer versus 53 to 67 days versus greater than 67 days was 71.9 months (95% CI, 70.3 to 73.5 months) versus 61 months (95% CI, 57 to 66.1 months) versus 46.6 months (95% CI, 42.8 to 50.7 months), respectively (P < .001). In the most recent year with available data (2011), 25% of patients had TTI of greater than 46 days. Conclusion TTI independently affects survival. One in four patients experienced treatment delay. TTI of greater than 46 to 52 days introduced an increased risk of death that was most consistently detrimental beyond 60 days. Prolonged TTI is currently affecting survival. PMID:26628469

  16. A National Initiative for Women and Healthcare Providers: CDC’s Inside Knowledge: Get the Facts About Gynecologic Cancer Campaign

    PubMed Central

    Rim, Sun Hee; Polonec, Lindsey; Stewart, Sherri L.; Gelb, Cynthia A.

    2015-01-01

    The Inside Knowledge: Get the Facts About Gynecologic Cancer campaign raises awareness of the five main types of gynecologic cancer: cervical, ovarian, uterine, vaginal, and vulvar. It encourages women to pay attention to their bodies and know what is normal for them so they can recognize the warning signs of gynecologic cancers and seek medical care. This report provides an overview of the development of this national campaign. PMID:21933006

  17. Efficacy of Intra-Arterial Infusion Chemotherapy for Head and Neck Cancers Using Coaxial Catheter Technique: Initial Experience

    SciTech Connect

    Tsurumaru, Daisuke Kuroiwa, Toshiro; Yabuuchi, Hidetake; Hirata, Hideki; Higaki, Yuichiro; Tomita, Kichinobu

    2007-04-15

    The aim of this study was to evaluate the efficacy of intra-arterial infusion chemotherapy for head and neck cancers using a coaxial catheter technique: the superficial temporal artery (STA)-coaxial catheter method. Thirty-one patients (21 males and 10 females; 37-83 years of age) with squamous cell carcinoma of the head and neck (maxilla, 2; epipharynx, 4; mesopharynx, 8; oral floor, 4; tongue, 10; lower gingiva, 1; buccal mucosa, 2) were treated by intra-arterial infusion chemotherapy. Four patients were excluded from the tumor-response evaluation because of a previous operation or impossibility of treatment due to catheter trouble. Forty-eight sessions of catheterization were performed. A guiding catheter was inserted into the STA and a microcatheter was advanced into the tumor-feeding artery via the guiding catheter under angiographic guidance. When the location of the tumor or its feeding artery was uncertain on angiography, computed tomographic angiography was performed. The anticancer agent carboplatin (CBDCA) was continuously injected for 24 h through the microcatheter from a portable infusion pump attached to the patient's waist. The total administration dose was 300-1300 mg per body. External radiotherapy was administered during intra-arterial chemotherapy at a total dose of 21-70.5 Gy.The initial response was complete response in 15 patients, partial response in 7 patients, and no change in 5 patients; the overall response rate was 81.5% (22/27). Complication-related catheter maintenance was observed in 15 of 48 sessions of catheterization. Injury and dislocation of the microcatheter occurred 10 times in 7 patients. Catheter infection was observed three times in each of two patients, and catheter occlusion and vasculitis occurred in two patients. Intra-arterial infusion chemotherapy via the STA-coaxial catheter method could have potential as a favorable treatment for head and neck tumors.

  18. CD24 Is Not Required for Tumor Initiation and Growth in Murine Breast and Prostate Cancer Models

    PubMed Central

    Cremers, Natascha; Neeb, Antje; Uhle, Tanja; Dimmler, Arno; Rothley, Melanie; Allgayer, Heike; Fodde, Riccardo; Sleeman, Jonathan Paul; Thiele, Wilko

    2016-01-01

    CD24 is a small, heavily glycosylated, GPI-linked membrane protein, whose expression has been associated with the tumorigenesis and progression of several types of cancer. Here, we studied the expression of CD24 in tumors of MMTV-PyMT, Apc1572/T+ and TRAMP genetic mouse models that spontaneously develop mammary or prostate carcinoma, respectively. We found that CD24 is expressed during tumor development in all three models. In MMTV-PyMT and Apc1572T/+ breast tumors, CD24 was strongly but heterogeneously expressed during early tumorigenesis, but decreased in more advanced stages, and accordingly was increased in poorly differentiated lesions compared with well differentiated lesions. In prostate tumors developing in TRAMP mice, CD24 expression was strong within hyperplastic lesions in comparison with non-hyperplastic regions, and heterogeneous CD24 expression was maintained in advanced prostate carcinomas. To investigate whether CD24 plays a functional role in tumorigenesis in these models, we crossed CD24 deficient mice with MMTV-PyMT, Apc1572T/+ and TRAMP mice, and assessed the influence of CD24 deficiency on tumor onset and tumor burden. We found that mice negative or positive for CD24 did not significantly differ in terms of tumor initiation and burden in the genetic tumor models tested, with the exception of Apc1572T/+ mice, in which lack of CD24 reduced the mammary tumor burden slightly but significantly. Together, our data suggest that while CD24 is distinctively expressed during the early development of murine mammary and prostate tumors, it is not essential for the formation of tumors developing in MMTV-PyMT, Apc1572T/+ and TRAMP mice. PMID:26978528

  19. CD24 Is Not Required for Tumor Initiation and Growth in Murine Breast and Prostate Cancer Models.

    PubMed

    Cremers, Natascha; Neeb, Antje; Uhle, Tanja; Dimmler, Arno; Rothley, Melanie; Allgayer, Heike; Fodde, Riccardo; Sleeman, Jonathan Paul; Thiele, Wilko

    2016-01-01

    CD24 is a small, heavily glycosylated, GPI-linked membrane protein, whose expression has been associated with the tumorigenesis and progression of several types of cancer. Here, we studied the expression of CD24 in tumors of MMTV-PyMT, Apc1572/T+ and TRAMP genetic mouse models that spontaneously develop mammary or prostate carcinoma, respectively. We found that CD24 is expressed during tumor development in all three models. In MMTV-PyMT and Apc1572T/+ breast tumors, CD24 was strongly but heterogeneously expressed during early tumorigenesis, but decreased in more advanced stages, and accordingly was increased in poorly differentiated lesions compared with well differentiated lesions. In prostate tumors developing in TRAMP mice, CD24 expression was strong within hyperplastic lesions in comparison with non-hyperplastic regions, and heterogeneous CD24 expression was maintained in advanced prostate carcinomas. To investigate whether CD24 plays a functional role in tumorigenesis in these models, we crossed CD24 deficient mice with MMTV-PyMT, Apc1572T/+ and TRAMP mice, and assessed the influence of CD24 deficiency on tumor onset and tumor burden. We found that mice negative or positive for CD24 did not significantly differ in terms of tumor initiation and burden in the genetic tumor models tested, with the exception of Apc1572T/+ mice, in which lack of CD24 reduced the mammary tumor burden slightly but significantly. Together, our data suggest that while CD24 is distinctively expressed during the early development of murine mammary and prostate tumors, it is not essential for the formation of tumors developing in MMTV-PyMT, Apc1572T/+ and TRAMP mice. PMID:26978528

  20. Mise à jour sur le nouveau vaccin 9-valent pour la prévention du virus du papillome humain

    PubMed Central

    Yang, David Yi; Bracken, Keyna

    2016-01-01

    Résumé Objectif Informer les médecins de famille quant à l’efficacité, à l’innocuité, aux effets sur la santé publique et à la rentabilité du vaccin 9-valent contre le virus du papillome humain (VPH). Qualité des données Des articles pertinents publiés dans PubMed jusqu’en mai 2015 ont été examinés et analysés. La plupart des données citées sont de niveau I (essais randomisés et contrôlés et méta-analyses) ou de niveau II (études transversales, cas-témoins et épidémiologiques). Des rapports et recommandations du gouvernement sont aussi cités en référence. Message principal Le vaccin 9-valent contre le VPH, qui offre une protection contre les types 6, 11, 16, 18, 31, 33, 45, 52 et 58 du VPH, est sûr et efficace et réduira encore plus l’incidence des infections à VPH, de même que les cas de cancer lié au VPH. Il peut également protéger indirectement les personnes non immunisées par l’entremise du phénomène d’immunité collective. Un programme d’immunisation efficace peut prévenir la plupart des cancers du col de l’utérus. Les analyses montrent que la rentabilité du vaccin 9-valent chez les femmes est comparable à celle du vaccin quadrivalent original contre le VPH (qui protège contre les types 6, 11, 16 et 18 du VPH) en usage à l’heure actuelle. Toutefois, il faut investiguer plus en profondeur l’utilité d’immuniser les garçons avec le vaccin 9-valent contre le VPH. Conclusion en plus d’être sûr, le vaccin 9-valent protège mieux contre le VPH que le vaccin quadrivalent. Une analyse coûtefficacité en favorise l’emploi, du moins chez les adolescentes. Ainsi, les médecins devraient recommander le vaccin 9-valent à leurs patients plutôt que le vaccin quadrivalent contre le VPH.

  1. The Association between Dietary Inflammatory Index and Risk of Colorectal Cancer among Postmenopausal Women: Results from the Women’s Health Initiative

    PubMed Central

    Tabung, Fred K.; Steck, Susan E.; Ma, Yunsheng; Liese, Angela D.; Zhang, Jiajia; Caan, Bette; Hou, Lifang; Johnson, Karen C.; Mossavar-Rahmani, Yasmin; Shivappa, Nitin; Wactawski-Wende, Jean; Ockene, Judith K.; Hebert, James R.

    2015-01-01

    Purpose Inflammation is a process central to carcinogenesis, and in particular to colorectal cancer (CRC). Previously, we developed a dietary inflammatory index (DII) from extensive literature review to assess the inflammatory potential of diet. In the current study, we utilized this novel index in the Women’s Health Initiative (WHI) to prospectively evaluate its association with risk of CRC in postmenopausal women. Methods The DII was calculated from baseline food frequency questionnaires administered to 152,536 women aged 50–79 years without CRC at baseline between 1993 and 1998 and followed through September 30, 2010. Incident CRC cases were ascertained through a central physician adjudication process. Multiple covariate-adjusted Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (95%CI) for colorectal, colon (proximal/distal locations), and rectal cancer risk, by DII quintiles(Q). Results During an average 11.3 years of follow-up, a total of 1,920 cases of colorectal cancer (1,559 colon and 361 rectal) were identified. Higher DII scores (representing a more pro-inflammatory diet) were associated with an increased incidence of colorectal cancer (HRQ5-Q1, 1.22; 95% CI, 1.05, 1.43; Ptrend=0.02) and colon cancer, specifically proximal colon cancer (HRQ5-Q1, 1.35; 95% CI, 1.05, 1.67; Ptrend=0.01) but not distal colon cancer (HRQ5-Q1, 0.84; 95% CI, 0.61, 1.18; Ptrend=0.63) or rectal cancer (HRQ5-Q1, 1.20; 95% CI, 0.84, 1.72; Ptrend=0.65). Conclusion Consumption of pro-inflammatory diets is associated with an increased risk of CRC, especially cancers located in the proximal colon. The absence of a significant association for distal colon cancer and rectal cancer may be due to the small number of incident cases for these sites. Interventions that may reduce the inflammatory potential of the diet are warranted to test our findings, thus provide more information for colon cancer prevention. PMID:25549833

  2. Global initiatives to enhance cancer care in areas of limited resources: what ASCO members are doing and how you can become involved.

    PubMed

    Lichtman, Stuart M

    2013-01-01

    Cancer is the leading cause of death worldwide. In 2008, 7.6 million deaths were attributable to cancer, representing 13% of all deaths. It is estimated that approximately 30% of cancer deaths are attributable to the five leading behavioral and dietary risks. These include high body mass index, low fruit and vegetable intake, lack of physical activity, and tobacco and alcohol use. A number of viral infections, such as hepatitis B and C and HPV, are responsible for approximately 20% of cancer deaths. Approximately 70% of cancer deaths occurred in low- and middle-income countries. Because of the increased numbers of elderly individuals and improved control of comorbidity, deaths from cancer worldwide are projected to continue rising, with an estimated 13.1 million deaths in 2030. To meet this need, the American Society of Clinical Oncology (ASCO) has evolved into a truly international organization. Over one-third of ASCO members practice in over 100 countries, representing the world's largest collection of expertise and insight into the treatment of cancer. More than one-half of ASCO's Annual Meeting attendees come from outside the United States. The Journal of Clinical Oncology is read by more than 24,000 subscribers worldwide and is available in a number of different languages. To fulfill its mission, ASCO has a number of international programs for sharing knowledge and providing the tools to assist clinicians worldwide in treating their patients. These programs include mentoring and knowledge exchange, education initiatives, and scientific and educational meetings. This provides ample opportunity for involvement to enhance cancer care worldwide. PMID:23714562

  3. Targeting lactate dehydrogenase-A inhibits tumorigenesis and tumor progression in mouse models of lung cancer and impacts tumor initiating cells

    PubMed Central

    Xie, Han; Hanai, Jun-ichi; Ren, Jian-Guo; Kats, Lev; Burgess, Kerri; Bhargava, Parul; Signoretti, Sabina; Billiard, Julia; Duffy, Kevin J.; Grant, Aaron; Wang, Xiaoen; Lorkiewicz, Pawel K.; Schatzman, Sabrina; Bousamra, Michael; Lane, Andrew N.; Higashi, Richard M.; Fan, Teresa W.M.; Pandolfi, Pier Paolo; Sukhatme, Vikas P.; Seth, Pankaj

    2014-01-01

    Summary The lactate dehydrogenase-A (LDH-A) enzyme catalyzes the inter-conversion of pyruvate and lactate, is upregulated in human cancers and is associated with aggressive tumor outcomes. Here we use a novel inducible murine model and demonstrate that inactivation of LDH-A in mouse models of NSCLC driven by oncogenic K-RAS or EGFR leads to decreased tumorigenesis and disease regression in established tumors. We also show that abrogation of LDH-A results in reprogramming of pyruvate metabolism, with decreased lactic fermentation in vitro, in vivo, and ex vivo. This was accompanied by re-activation of mitochondrial function in vitro but not in vivo or ex vivo. Finally, using a specific small molecule LDH-A inhibitor, we demonstrated that LDH-A is essential for cancer initiating cell survival and proliferation. Thus, LDH-A can be a viable therapeutic target for NSCLC including cancer stem cell-dependent drug resistant tumors. PMID:24726384

  4. Microenvironment-Modulated Metastatic CD133+/CXCR4+/EpCAM- Lung Cancer-Initiating Cells Sustain Tumor Dissemination and Correlate with Poor Prognosis.

    PubMed

    Bertolini, Giulia; D'Amico, Lucia; Moro, Massimo; Landoni, Elena; Perego, Paola; Miceli, Rosalba; Gatti, Laura; Andriani, Francesca; Wong, Donald; Caserini, Roberto; Tortoreto, Monica; Milione, Massimo; Ferracini, Riccardo; Mariani, Luigi; Pastorino, Ugo; Roato, Ilaria; Sozzi, Gabriella; Roz, Luca

    2015-09-01

    Metastasis is the main reason for lung cancer-related mortality, but little is known about specific determinants of successful dissemination from primary tumors and metastasis initiation. Here, we show that CD133(+)/CXCR4(+) cancer-initiating cells (CIC) directly isolated from patient-derived xenografts (PDX) of non-small cell lung cancer are endowed with superior ability to seed and initiate metastasis at distant organs. We additionally report that CXCR4 inhibition successfully prevents the increase of cisplatin-resistant CD133(+)/CXCR4(+) cells in residual tumors and their metastatization. Immunophenotypic analysis of lung tumor cells intravenously injected or spontaneously disseminated to murine lungs demonstrated the survival advantage and increased colonization ability of a specific subset of CD133(+)/CXCR4(+) with reduced expression of epithelial cell adhesion molecule (EpCAM(-)), which also shows the greatest in vitro invasive potential. We next prove that recovered disseminated cells from lungs of PDX-bearing mice enriched for CD133(+)/CXCR4(+)/EpCAM(-) CICs are highly tumorigenic and metastatic. Importantly, microenvironment stimuli eliciting epithelial-to-mesenchymal transition, including signals from cancer-associated fibroblasts, are able to increase the dissemination potential of lung cancer cells through the generation of the CD133(+)/CXCR4(+)/EpCAM(-) subset. These findings also have correlates in patient samples where disseminating CICs are enriched in metastatic lymph nodes (20-fold, P = 0.006) and their detection in primary tumors is correlated with poor clinical outcome (disease-free survival: P = 0.03; overall survival: P = 0.05). Overall, these results highlight the importance of specific cellular subsets in the metastatic process, the need for in-depth characterization of disseminating tumor cells, and the potential of therapeutic strategies targeting both primary tumor and tumor-microenvironment interactions. PMID:26141860

  5. Skeletal muscle metastases as the initial manifestation of an unknown primary lung cancer detected on F-18 fluorodeoxyglucose positron emission tomography/computed tomography

    PubMed Central

    Agrawal, Kanhaiyalal; Bhattacharya, Anish; Singh, Navneet; Harisankar, Chidambaram Natarajan Balasubramanian; Mittal, Bhagwant Rai

    2013-01-01

    Skeletal muscle metastasis as the initial presentation of the unknown primary lung cancer is unusual. A 65-year-old male patient presented with pain and swelling of the right forearm. Fine needle aspiration of the swelling revealed metastatic squamous cell carcinoma. The patient underwent whole body F-18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) to identify the site of the primary malignancy. The authors present PET/CT images showing FDG-avid metastases to the skeletal muscles along with a previously unknown primary tumor in the right lung, in a patient presenting with initial muscular symptoms without any pulmonary manifestations. PMID:24019675

  6. [Standard Cancer Therapy Are Established by the Investigator-Initiated Post-Marketing Clinical Trials, Not by the Indication-Directed Clinical Trials].

    PubMed

    Shimada, Yasuhiro

    2016-04-01

    The financial supports for investigator-initiated post-marketing clinical trial in clinical oncology are reduced after scandals related to the other fields of clinical trials in Japan. These clinical trials are the essential final steps of clinical development in newer cancer therapy, which should be conducted in the investigator-initiated clinical trial groups with well-organized infrastructure and continuous financial supports. The present problems are discussed and summarized. Future perspectives with the national viewpoints needed to be included the idea of "health technology assessment". PMID:27220797

  7. Suspension survival mediated by PP2A-STAT3-Col XVII determines tumour initiation and metastasis in cancer stem cells

    PubMed Central

    Liu, Chen-Chi; Lin, Shih-Pei; Hsu, Han-Shui; Yang, Shung-Haur; Lin, Chiu-Hua; Yang, Muh-Hwa; Hung, Mien-Chie; Hung, Shih-Chieh

    2016-01-01

    Targeting tumour-initiating cells (TICs) would lead to new therapies to cure cancer. We previously demonstrated that TICs have the capacity to survive under suspension conditions, while other cells undergo anoikis. Here we show that TICs exhibit increased phosphorylation levels of S727STAT3 because of PP2A inactivation. Collagen 17 gene expression is upregulated in a STAT3-dependent manner, which also stabilizes laminin 5 and engages cells to form hemidesmosome-like junctions in response. Blocking the PP2A-S727STAT3-collagen 17 pathway inhibits the suspension survival of TICs and their ability to form tumours in mice, while activation of the same pathway increases the suspension survival and tumour-initiation capacities of bulk cancer cells. The S727STAT3 phosphorylation levels correlate with collagen 17 expression in colon tumour samples, and correlate inversely with survival. Finally, this signalling axis enhances the ability of TIC to form tumours in mouse models of malignant lung cancer pleural effusion and spontaneous colon cancer metastasis. PMID:27306323

  8. Suspension survival mediated by PP2A-STAT3-Col XVII determines tumour initiation and metastasis in cancer stem cells.

    PubMed

    Liu, Chen-Chi; Lin, Shih-Pei; Hsu, Han-Shui; Yang, Shung-Haur; Lin, Chiu-Hua; Yang, Muh-Hwa; Hung, Mien-Chie; Hung, Shih-Chieh

    2016-01-01

    Targeting tumour-initiating cells (TICs) would lead to new therapies to cure cancer. We previously demonstrated that TICs have the capacity to survive under suspension conditions, while other cells undergo anoikis. Here we show that TICs exhibit increased phosphorylation levels of S727STAT3 because of PP2A inactivation. Collagen 17 gene expression is upregulated in a STAT3-dependent manner, which also stabilizes laminin 5 and engages cells to form hemidesmosome-like junctions in response. Blocking the PP2A-S727STAT3-collagen 17 pathway inhibits the suspension survival of TICs and their ability to form tumours in mice, while activation of the same pathway increases the suspension survival and tumour-initiation capacities of bulk cancer cells. The S727STAT3 phosphorylation levels correlate with collagen 17 expression in colon tumour samples, and correlate inversely with survival. Finally, this signalling axis enhances the ability of TIC to form tumours in mouse models of malignant lung cancer pleural effusion and spontaneous colon cancer metastasis. PMID:27306323

  9. Increased expression of phosphorylated forms of RNA-dependent protein kinase and eukaryotic initiation factor 2alpha may signal skeletal muscle atrophy in weight-losing cancer patients.

    PubMed

    Eley, H L; Skipworth, R J E; Deans, D A C; Fearon, K C H; Tisdale, M J

    2008-01-29

    Previous studies suggest that the activation (autophosphorylation) of dsRNA-dependent protein kinase (PKR) can stimulate protein degradation, and depress protein synthesis in skeletal muscle through phosphorylation of the translation initiation factor 2 (eIF2) on the alpha-subunit. To understand whether these mediators are important in muscle wasting in cancer patients, levels of the phospho forms of PKR and eIF2alpha have been determined in rectus abdominus muscle of weight losing patients with oesophago-gastric cancer, in comparison with healthy controls. Levels of both phospho PKR and phospho eIF2alpha were significantly enhanced in muscle of cancer patients with weight loss irrespective of the amount and there was a linear relationship between phosphorylation of PKR and phosphorylation of eIF2alpha (correlation coefficient 0.76, P=0.005). This suggests that phosphorylation of PKR led to phosphorylation of eIF2alpha. Myosin levels decreased as the weight loss increased, and there was a linear relationship between myosin expression and the extent of phosphorylation of eIF2alpha (correlation coefficient 0.77, P=0.004). These results suggest that phosphorylation of PKR may be an important initiator of muscle wasting in cancer patients. PMID:18087277

  10. Differences among college women for breast cancer prevention acquired information-seeking, desired apps and texts, and daughter-initiated information to mothers.

    PubMed

    Kratzke, Cynthia; Amatya, Anup; Vilchis, Hugo

    2014-04-01

    The purpose of this study was to examine among college women acquired breast cancer prevention information-seeking, desired apps and texts, and information given to mothers. Using a cross-sectional study, a survey was administered to college women at a southwestern university. College women (n = 546) used the Internet (44 %) for active breast cancer prevention information-seeking and used the Internet (74 %), magazines (69 %), and television (59 %) for passive information receipt. Over half of the participants desired breast cancer prevention apps (54 %) and texts (51 %). Logistic regression analyses revealed predictors for interest to receive apps were ethnicity (Hispanic), lower self-efficacy, actively seeking online information, and older age and predictors for interest to receive texts were lower self-efficacy and higher university level. Eighteen percent of college women (n = 99) reported giving information to mothers and reported in an open-ended item the types of information given to mothers. Predictors for giving information to mothers were actively and passively seeking online information, breast self-exam practice, and higher university level. Screenings were the most frequent types of information given to mothers. Breast cancer prevention information using apps, texts, or Internet and daughter-initiated information for mothers should be considered in health promotion targeting college students or young women in communities. Future research is needed to examine the quality of apps, texts, and online information and cultural differences for breast cancer prevention sources. PMID:23979671

  11. Rupture simultanée du ligament croisé antérieur et du ligament patellaire: à propos d'un cas

    PubMed Central

    Achkoun, Abdessalam; Houjairi, Khalid; Quahtan, Omar; Hassoun, Jalal; Arssi, Mohamed; Rahmi, Mohamed; Garch, Abdelhak

    2016-01-01

    La rupture simultanée du tendon rotulien et du ligament croisé antérieur est une lésion relativement rare. Son diagnostic peut facilement manquer lors de l'examen initial. Les options de traitement incluent la réparation immédiate du tendon rotulien avec soit la reconstruction simultanée ou différée de ligament croisé antérieur. Nous rapportons le cas d'une rupture combinée du tendon rotulien et du ligament croisé antérieur chez un jeune footballeur de 22 ans. Une approche de traitement en deux temps a été effectuée avec un excellent résultat fonctionnel. PMID:27366288

  12. Seventh Joint Meeting of K-J-CaP and CaPSURE: extending the global initiative to improve prostate cancer management

    PubMed Central

    Akaza, Hideyuki; Kim, Choung Soo; Carroll, Peter; Choi, In Young; Chung, Byung Ha; Cooperberg, Matthew R.; Hirao, Yoshihiko; Hinotsu, Shiro; Horie, Shigeo; Lee, Ji Youl; Namiki, Mikio; Ng, Chi-Fai; Onozawa, Mizuki; Ozono, Seiichiro; Ueno, Satoru; Umbas, Rainy; Ye, Dingwei; Zhu, Gang

    2014-01-01

    This report summarizes the presentations and discussions that took place at the Seventh Joint Meeting of the Korea–Japan Study Group of Prostate Cancer (K-J-CaP) and the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) held in Seoul, Korea, in September 2013. The original J-CaP and CaPSURE Joint Initiative has now been established since 2007 and since the initial collaboration between research teams in the United States (US) and Japan, the project has expanded to include several other Asian countries. The objective of the initiative is to analyze and compare data for prostate cancer patients in the participating countries, looking at similarities and differences in patient management and outcomes. Until now the focus has been primarily on data generated within J-CaP and CaPSURE, both large-scale, longitudinal, observational databases of prostate cancer patients in Japan and the US, respectively. This year’s meeting was hosted for the first time in Korea which has recently established its own national database–K-CaP–to add to the wealth of data generated by J-CaP and CaPSURE. As a newly-developed database, K-CaP has also provided a valuable ‘template’ for other countries, such as China and Indonesia, planning to establish their own national databases and this will ultimately allow greater opportunities for international data comparisons. A range of topics was discussed at this Seventh Joint Meeting including comparison of outcomes following androgen deprivation therapy or radical prostatectomy in patients with localized prostate cancer, the use of active surveillance as a treatment option and the triggers for intervention when employing this regimen, patient quality of life during treatment, the impact of comorbidities on outcomes, and a comparison of recent outcomes data between J-CaP and CaPSURE. The participants recognized that prostate cancer was now a global disease and therefore major insights into understanding and improving

  13. Neural Cell Adhesion Protein CNTN1 Promotes the Metastatic Progression of Prostate Cancer.

    PubMed

    Yan, Judy; Ojo, Diane; Kapoor, Anil; Lin, Xiaozeng; Pinthus, Jehonathan H; Aziz, Tariq; Bismar, Tarek A; Wei, Fengxiang; Wong, Nicholas; De Melo, Jason; Cutz, Jean-Claude; Major, Pierre; Wood, Geoffrey; Peng, Hao; Tang, Damu

    2016-03-15

    Prostate cancer metastasis is the main cause of disease-related mortality. Elucidating the mechanisms underlying prostate cancer metastasis is critical for effective therapeutic intervention. In this study, we performed gene-expression profiling of prostate cancer stem-like cells (PCSC) derived from DU145 human prostate cancer cells to identify factors involved in metastatic progression. Our studies revealed contactin 1 (CNTN1), a neural cell adhesion protein, to be a prostate cancer-promoting factor. CNTN1 knockdown reduced PCSC-mediated tumor initiation, whereas CNTN1 overexpression enhanced prostate cancer cell invasion in vitro and promoted xenograft tumor formation and lung metastasis in vivo. In addition, CNTN1 overexpression in DU145 cells and corresponding xenograft tumors resulted in elevated AKT activation and reduced E-cadherin (CDH1) expression. CNTN1 expression was not readily detected in normal prostate glands, but was clearly evident on prostate cancer cells in primary tumors and lymph node and bone metastases. Tumors from 637 patients expressing CNTN1 were associated with prostate cancer progression and worse biochemical recurrence-free survival following radical prostatectomy (P < 0.05). Collectively, our findings demonstrate that CNTN1 promotes prostate cancer progression and metastasis, prompting further investigation into the mechanisms that enable neural proteins to become aberrantly expressed in non-neural malignancies. PMID:26795349

  14. Influence du débit et de la répartition de dose sur l'incidence des cancers pulmonaires après inhalation d'émetteurs

    NASA Astrophysics Data System (ADS)

    Fritsch, P.; Dudoignon, N.; Morlier, J. P.; Monchaux, G.; Morin, M.

    1998-04-01

    We have discussed experimental results reported on the influence of dose rate and dose distribution on the incidence of lung tumors after inhalation exposure to α emitters. New experiments have been carried out to characterize the range of tumor risk which could vary over more than a factor 20 depending on the α activity of the inhaled particles. Long term effects induced in rats after inhalation of poorly soluble 237NpO2 and industrial PuO2 with a similar granulometry will be compared, the specific activities of which varying within a factor 500. Nous avons rapporté les différentes données expérimentales de cancérogenèse pulmonaire qui montrent une variation du risque d'induction des tumeurs après inhalation de radionucléides émetteurs α selon le débit et la répartition de dose. De nouvelles expérimentations ont été initiées afin de préciser ces variations qui s'étalent sur plus d'un facteur 20. Elles consistent à comparer les effets induits chez le rat après exposition à des aérosols de 237NpO2 et de PuO2 d'origine industrielle peu solubles et de granulométrie analogue dont les activités spécifiques diffèrent d'un facteur 500.

  15. Cancer

    MedlinePlus

    ... your life Being exposed to chemicals that can cause cancer Being at risk for skin cancer Depending on ... than nonsmokers. Other forms of tobacco can also cause cancer, such as cigars, chewing tobacco and snuff. If ...

  16. Breast cancer management in middle-resource countries (MRCs): consensus statement from the Breast Health Global Initiative.

    PubMed

    Yip, Cheng-Har; Cazap, Eduardo; Anderson, Benjamin O; Bright, Kristin L; Caleffi, Maira; Cardoso, Fatima; Elzawawy, Ahmed M; Harford, Joe B; Krygier, Gabriel D; Masood, Shahla; Murillo, Raul; Muse, Ignacio M; Otero, Isabel V; Passman, Leigh J; Santini, Luiz A; da Silva, Ronaldo Corrêa Ferreira; Thomas, David B; Torres, Soledad; Zheng, Ying; Khaled, Hussein M

    2011-04-01

    In middle resource countries (MRCs), cancer control programs are becoming a priority as the pattern of disease shifts from infectious diseases to non-communicable diseases such as breast cancer, the most common cancer among women in MRCs. The Middle Resource Scenarios Working Group of the BHGI 2010 Global Summit met to identify common issues and obstacles to breast cancer detection, diagnosis and treatment in MRCs. They concluded that breast cancer early detection programs continue to be important, should include clinical breast examination (CBE) with or without mammography, and should be coupled with active awareness programs. Mammographic screening is usually opportunistic and early detection programs are often hampered by logistical and financial problems, as well as socio-cultural barriers, despite improved public educational efforts. Although multidisciplinary services for treatment are available, geographical and economic limitations to these services can lead to an inequity in health care access. Without adequate health insurance coverage, limited personal finances can be a significant barrier to care for many patients. Despite the improved availability of services (surgery, pathology, radiology and radiotherapy), quality assurance programs remain a challenge. Better access to anticancer drugs is needed to improve outcomes, as are rehabilitation programs for survivors. Focused and sustained government health care financing in MRCs is needed to improve early detection and treatment of breast cancer. PMID:21388811

  17. Clinical Experiences of Incidental Prostate Cancer after Transurethral Resection of Prostate (TURP) According to Initial Treatment: A Study of a Korean High Volume Center

    PubMed Central

    Lee, Dong Hoon; Chung, Doo Yong; Lee, Kwang-suk; Kim, In Kyong; Rha, Koon Ho; Choi, Young Deuk; Chung, Byung Ha; Hong, Sung Joon

    2014-01-01

    Purpose These are the clinical experiences of Korean incidental prostate cancer patients detected by transurethral resection of the prostate according to initial treatment: active surveillance (AS), radical prostatectomy (RP) and hormone therapy (HT). Materials and Methods We retrospectively reviewed the records of 156 incidental prostate cancer patients between 2001 and 2012. The clinicopathologic outcomes were reviewed and follow-up results were obtained. Results Among 156 patients, 97 (62.2%) had T1a and 59 (37.8%) had T1b. Forty-six (29.5%) received AS, 67 (42.9%) underwent RP, 34 (21.8%) received HT, 4 (2.6%) received radiotherapy, and 5 (3.2%) chose watchful waiting. Of 46 patients on AS, prostate-specific antigen (PSA) progression occurred in 12 (26.1%) patients. Among them, 3 patients refused treatment despite PSA progression. Five patients, who underwent RP as an intervention, all had organ-confined Gleason score ≤6 disease. In 67 patients who underwent RP, 50 (74.6%) patients had insignificant prostate cancer and 8 (11.9%) patients showed unfavorable features. During follow-up, biochemical recurrence occurred in 2 patients. Among 34 patients who received HT, 3 (8.8%) patients had PSA progression. Among 156 patients, 6 patients died due to other causes during follow-up. There were no patients who died due to prostate cancer. Conclusion The clinical outcomes of incidental prostate cancer were satisfactory regardless of the initial treatment. However, according to recent researches and guidelines, immediate definite therapy should be avoided without a careful assessment. We also believe that improved clinical staging is needed for these patients. PMID:24339290

  18. Accuracy of Computed Tomography for Predicting Pathologic Nodal Extracapsular Extension in Patients With Head-and-Neck Cancer Undergoing Initial Surgical Resection

    SciTech Connect

    Prabhu, Roshan S.; Magliocca, Kelly R.; Hanasoge, Sheela; Aiken, Ashley H.; Hudgins, Patricia A.; Hall, William A.; Chen, Susie A.; Eaton, Bree R.; Higgins, Kristin A.; Saba, Nabil F.; Beitler, Jonathan J.

    2014-01-01

    Purpose: Nodal extracapsular extension (ECE) in patients with head-and-neck cancer increases the loco-regional failure risk and is an indication for adjuvant chemoradiation therapy (CRT). To reduce the risk of requiring trimodality therapy, patients with head-and-neck cancer who are surgical candidates are often treated with definitive CRT when preoperative computed tomographic imaging suggests radiographic ECE. The purpose of this study was to assess the accuracy of preoperative CT imaging for predicting pathologic nodal ECE (pECE). Methods and Materials: The study population consisted of 432 consecutive patients with oral cavity or locally advanced/nonfunctional laryngeal cancer who underwent preoperative CT imaging before initial surgical resection and neck dissection. Specimens with pECE had the extent of ECE graded on a scale from 1 to 4. Results: Radiographic ECE was documented in 46 patients (10.6%), and pECE was observed in 87 (20.1%). Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 43.7%, 97.7%, 82.6%, and 87.3%, respectively. The sensitivity of radiographic ECE increased from 18.8% for grade 1 to 2 ECE, to 52.9% for grade 3, and 72.2% for grade 4. Radiographic ECE criteria of adjacent structure invasion was a better predictor than irregular borders/fat stranding for pECE. Conclusions: Radiographic ECE has poor sensitivity, but excellent specificity for pECE in patients who undergo initial surgical resection. PPV and NPV are reasonable for clinical decision making. The performance of preoperative CT imaging increased as pECE grade increased. Patients with resectable head-and-neck cancer with radiographic ECE based on adjacent structure invasion are at high risk for high-grade pECE requiring adjuvant CRT when treated with initial surgery; definitive CRT as an alternative should be considered where appropriate.

  19. Pc2-mediated SUMOylation of WWOX is essential for its suppression of DU145 prostate tumorigenesis.

    PubMed

    Choi, Hye-Jin; Park, Jung-Hwan; Park, Jong-Hwan; Lee, Kyung Bok; Oh, Sang-Muk

    2015-12-21

    Tumor suppressor WW domain-containing oxidoreductase (WWOX) is depleted in various cancer types. Here we report that WWOX is modified by small ubiquitin-like modifier (SUMO) proteins and represses DU145 prostate cancer tumorigenesis in a SUMOylation-dependent manner. Ectopic WWOX was shown to associate with SUMO2/3 or E2 Ubc9. Furthermore, we revealed that WWOX SUMOylation was promoted by E3 ligase polycomb2 (Pc2), and that WWOX associated with Pc2. Meanwhile, anisomycin-induced activator protein-1 (AP-1) activity was markedly diminished by co-expression of SUMO and WWOX. Also, WWOX wild type (WT), but not WWOX SUMO mutant (K176A) markedly reduced both DU145 prostate cancer cell proliferation and xenograft tumorigenesis. Collectively, our findings demonstrate that SUMO modification of WWOX is essential for its suppressive activity for DU145 prostate cancer tumorigenesis. PMID:26592150

  20. EMAST is a Form of Microsatellite Instability That is Initiated by Inflammation and Modulates Colorectal Cancer Progression

    PubMed Central

    Carethers, John M.; Koi, Minoru; Tseng-Rogenski, Stephanie S.

    2015-01-01

    DNA mismatch repair (MMR) function is critical for correcting errors coincident with polymerase-driven DNA replication, and its proteins are frequent targets for inactivation (germline or somatic), generating a hypermutable tumor that drives cancer progression. The biomarker for defective DNA MMR is microsatellite instability-high (MSI-H), observed in ~15% of colorectal cancers, and defined by mono- and dinucleotide microsatellite frameshift mutations. MSI-H is highly correlated with loss of MMR protein expression, is commonly diploid, is often located in the right side of the colon, prognosticates good patient outcome, and predicts poor efficacy with 5-fluorouracil treatment. Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) is another form of MSI at tetranucleotide repeats that has been observed in multiple cancers, but its etiology and clinical relevance to patient care has only been recently illuminated. Specifically, EMAST is an acquired somatic defect observed in up to 60% of colorectal cancers and caused by unique dysfunction of the DNA MMR protein MSH3 (and its DNA MMR complex MutSβ, a heterodimer of MSH2-MSH3), and in particular a loss-of-function phenotype due to a reversible shift from its normal nuclear location into the cytosol in response to oxidative stress and the pro-inflammatory cytokine interleukin-6. Tumor hypoxia may also be a contributor. Patients with EMAST colorectal cancers show diminished prognosis compared to patients without the presence of EMAST in their cancer. In addition to defective DNA MMR recognized by tetranucleotide (and di- and tri-nucleotide) frameshifts, loss of MSH3 also contributes to homologous recombination-mediated repair of DNA double stranded breaks, indicating the MSH3 dysfunction is a complex defect for cancer cells that generates not only EMAST but also may contribute to chromosomal instability and aneuploidy. Areas for future investigation for this most common DNA MMR defect among

  1. COLORECTAL CANCER IN RELATION TO POSTMENOPAUSAL ESTROGEN AND ESTROGEN PLUS PROGESTIN IN THE WOMEN'S HEALTH INITIATIVE CLINICAL TRIAL AND OBSERVATIONAL STUDY

    PubMed Central

    Prentice, Ross L.; Pettinger, Mary; Beresford, Shirley A. A.; Wactawski-Wende, Jean; Hubbell, F. Allan; Stefanick, Marcia L.; Chlebowski, Rowan T.

    2009-01-01

    Background Colorectal cancer incidence was reduced among women assigned to active treatment in the Women's Health Initiative (WHI) estrogen plus progestin randomized trial, but the interpretation was obscured by an associated later stage of diagnosis. In contrast the estrogen-alone trial showed no incidence reduction or differential stage at diagnosis. Here, data from the WHI observational study are considered, in conjunction with colorectal cancer mortality data from the hormone therapy trials, in an attempt to clarify postmenopausal hormone therapy effects. Participants and Methods Postmenopausal women aged 50−79 at WHI enrollment. Estrogen-alone analyses include 21,552 and 10,739 women who were post-hysterectomy from the observational study and clinical trial respectively. Estrogen plus progestin analyses include 32,084 and 16,608 observational study and clinical trial women with uterus. Colorectal cancers were verified by central medical and pathology report review. Results Hazard ratios (95% confidence intervals) from the WHI observational study were 0.80 (0.53 to 1.20) for estrogen and 1.15 (0.74 to 1.79) for estrogen plus progestin, with respectively 168 and 175 women diagnosed with colorectal cancer. Delayed diagnosis with estrogen plus progestin is not evident in the observational study. No protective effect on colorectal cancer mortality in the estrogen plus progestin trial is seen over an 8-year intervention and follow-up period. Conclusion Hazard ratio patterns in the WHI clinical trial and observational study do not provide strong evidence of a clinically important colorectal cancer benefit with either estrogen-alone or estrogen plus progestin over 7−8 years of treatment and follow-up. PMID:19423530

  2. Early initiation of salvage hormone therapy influences survival in patients who failed initial radiation for locally advanced prostate cancer: A secondary analysis of RTOG protocol 86-10

    SciTech Connect

    Shipley, William U. . E-mail: wshipley@partners.org; DeSilvio, Michelle; Pilepich, Michael V.; Roach, Mack; Wolkov, Harvey B.; Sause, William T.; Rubin, Philip; Lawton, Colleen A.

    2006-03-15

    Purpose: We examined overall and disease-specific survival outcomes both from the time of initial treatment and from the start of salvage hormone therapy (HT), by the extent of disease progression at the time salvage HT was started in patients treated on RTOG Protocol 86-10. Methods and Materials: With a median follow-up of 9.0 years, 247 patients (54%) had received subsequent salvage HT. The overall survival (OVS) and disease-specific survival (DSS) were compared by the extent of disease progression at the time salvage HT was started. Results: For those patients with distant metastases (DM) present at the start of salvage HT, the OVS and DSS were significantly reduced when compared with those with DM absent at the time salvage HT was started (OVS at 8 years, 31% vs. 58%; DSS at 8 years, 38% vs. 65%). A statistically significant increase in DSS was observed among the 143 patients with DM absent when patients with prostate-specific antigen (PSA) less than 20 were compared with those with PSA greater than 20 at the time salvage HT was started. Conclusions: The DSS and the OVS of the relapsed patient are decreased in those with more extensive disease at the time of salvage HT. However, because this protocol could not evaluate the effect of posttreatment PSA velocity on outcomes, which is likely a better predictor of long-term success with salvage HT, these results cannot be taken to demonstrate that early salvage HT in patients with long posttreatment PSA doubling times is necessary for longer survival.

  3. Rebamipide attenuates Helicobacter pylori CagA-induced self-renewal capacity via modulation of β-catenin signaling axis in gastric cancer-initiating cells.

    PubMed

    Kang, Dong Woo; Noh, Yu Na; Hwang, Won Chan; Choi, Kang-Yell; Min, Do Sik

    2016-08-01

    Rebamipide, a mucosal-protective agent, is used clinically for treatment of gastritis and peptic ulcers induced by Helicobacter pylori (H. pylori) which is associated with increased risk of gastric cancer. Although rebamipide is known to inhibit the growth of gastric cancer cells, the action mechanisms of rebamipide in gastric carcinogenesis remains elusive. Here, we show that rebamipide suppresses H. pylori CagA-induced β-catenin and its target cancer-initiating cells (C-IC) marker gene expression via upregulation of miRNA-320a and -4496. Rebamipide attenuated in vitro self-renewal capacity of H. pylori CagA-infected gastric C-IC via modulation of miRNA-320a/-4496-β-catenin signaling axis. Moreover, rebamipide enhanced sensitivity to chemotherapeutic drugs in CagA-expressed gastric C-IC. Furthermore, rebamipide suppressed tumor-initiating capacity of gastric C-IC, probably via suppression of CagA-induced C-IC properties. These data provide novel insights for the efficacy of rebamipide as a chemoprotective drug against H. pylori CagA-induced carcinogenic potential. PMID:27265143

  4. Targeting RPL39 and MLF2 reduces tumor initiation and metastasis in breast cancer by inhibiting nitric oxide synthase signaling

    PubMed Central

    Dave, Bhuvanesh; Granados-Principal, Sergio; Zhu, Rui; Benz, Stephen; Rabizadeh, Shahrooz; Soon-Shiong, Patrick; Yu, Ke-Da; Shao, Zhimin; Li, Xiaoxian; Gilcrease, Michael; Lai, Zhao; Chen, Yidong; Huang, Tim H.-M.; Shen, Haifa; Liu, Xuewu; Ferrari, Mauro; Zhan, Ming; Wong, Stephen T. C.; Kumaraswami, Muthiah; Mittal, Vivek; Chen, Xi; Gross, Steven S.; Chang, Jenny C.

    2014-01-01

    We previously described a gene signature for breast cancer stem cells (BCSCs) derived from patient biopsies. Selective shRNA knockdown identified ribosomal protein L39 (RPL39) and myeloid leukemia factor 2 (MLF2) as the top candidates that affect BCSC self-renewal. Knockdown of RPL39 and MLF2 by specific siRNA nanoparticles in patient-derived and human cancer xenografts reduced tumor volume and lung metastases with a concomitant decrease in BCSCs. RNA deep sequencing identified damaging mutations in both genes. These mutations were confirmed in patient lung metastases (n = 53) and were statistically associated with shorter median time to pulmonary metastasis. Both genes affect the nitric oxide synthase pathway and are altered by hypoxia. These findings support that extensive tumor heterogeneity exists within primary cancers; distinct subpopulations associated with stem-like properties have increased metastatic potential. PMID:24876273

  5. Pilot initiative in India to explore the gonadal function and fertility outcomes of a cohort of childhood cancer survivors

    PubMed Central

    Arora, Puneet Rana; Misra, Ruchira; Mehrotra, Sumit; Mittal, Charu; Sharma, Sonal; Bagai, Poonam; Arora, Ramandeep Singh

    2016-01-01

    CONTEXT: Steady improvement in childhood cancer outcomes has led to a growing number of survivors, many of who develop long-term sequelae. There is limited data about these sequelae (including those related to fertility) on childhood cancer survivors from India. AIMS: We undertook a prospective pilot study on childhood cancer survivors from India to assess their gonadal function and fertility. SUBJECTS AND METHODS: A pediatric oncologist and a reproductive medicine specialist assessed 21 childhood cancer survivors. The risk of infertility was established using disease and treatment variables. Current status of puberty, sexuality, and fertility were assessed using clinical and biochemical parameters. Outcomes were correlated with risk group of infertility. Information was also ascertained on counseling with regards to risk of infertility. RESULTS: The cohort included 21 survivors (71% males) with a median age of 18 years who were off treatment for a median age of 7 years. Ten (48%) survivors were at low risk for infertility, 9 (43%) at medium risk and 2 (9%) at high risk. Gonadal dysfunction was seen in 3 (14%) survivors: 0/10 (0%) low risk, 1/9 (11%) medium risk, and 2/2 (100%) high risk. None of the survivors, who are at high risk or medium risk of infertility, received any counseling before treatment. CONCLUSIONS: This prospective pilot study of a cohort of childhood cancer survivors from India demonstrates a deficiency in the information provided and counseling of patients/families at the time of diagnosis with regards to the risk of infertility. Fertility outcomes of childhood cancer survivors were congruent with recognized risk groups for infertility. Future action points have been identified. PMID:27382233

  6. The critical roles of tumor-initiating cells and the lymph node stromal microenvironment in human colorectal cancer extranodal metastasis using a unique humanized orthotopic mouse model.

    PubMed

    Margolin, David A; Myers, Tamara; Zhang, Xin; Bertoni, Danielle M; Reuter, Brian A; Obokhare, Izi; Borgovan, Theodor; Grimes, Chelsea; Green, Heather; Driscoll, Tiffany; Lee, Chung-Gi; Davis, Nancy K; Li, Li

    2015-08-01

    Colorectal cancer (CRC) is the second-most common cause of cancer-related mortality. The most important prognostic factors are lymph node (LN) involvement and extranodal metastasis. Our objective is to investigate the interactions between CD133(+)CXCR4(+) (CXC receptor 4) colorectal cancer tumor-initiating cells (Co-TICs) and the LN stromal microenvironment in human CRC extranodal metastasis. We established a unique humanized orthotopic xenograft model. Luciferase-tagged CRC cell lines and human cancer cells were injected intrarectally into nonobese diabetic/SCID mice. Mesenteric LN stromal cells, stromal cell line HK, or CXCL12 knockdown HK (HK-KD-A3) cells were coinoculated with CRC cells. Tumor growth and metastasis were monitored by bioluminescent imaging and immunohistochemistry. We found that this model mimics the human CRC metastatic pattern with CRC cell lines or patient specimens. Adding LN stromal cells promotes CRC tumor growth and extranodal metastasis (P < 0.001). Knocking down CXCL12 impaired HK cell support of CRC tumor formation and extranodal metastasis. When HK cells were added, sorted CD133(+)CXCR4(+) Co-TICs showed increased tumor formation and extranodal metastasis capacities compared to unseparated and non-Co-TIC populations. In conclusion, both Co-TIC and LN stromal factors play crucial roles in CRC metastasis through the CXCL12/CXCR4 axis. Blocking Co-TIC/LN-stromal interactions may lead to effective therapy to prevent extranodal metastasis. PMID:25962655

  7. Initial Evaluation of [18F]DCFPyL for Prostate-Specific Membrane Antigen (PSMA)-Targeted PET Imaging of Prostate Cancer

    PubMed Central

    Szabo, Zsolt; Mena, Esther; Rowe, Steven P.; Plyku, Donika; Nidal, Rosa; Eisenberger, Mario A.; Antonarakis, Emmanuel S.; Fan, Hong; Dannals, Robert F.; Chen, Ying; Mease, Ronnie C.; Vranesic, Melin; Bhatnagar, Akrita; Sgouros, George; Cho, Steve Y.; Pomper, Martin G.

    2015-01-01

    Purpose Prostate-specific membrane antigen (PSMA) is a recognized target for imaging prostate cancer. Here we present initial safety, biodistribution, and radiation dosimetry results with [18F]DCFPyL, a second-generation fluorine-18-labeled small-molecule PSMA inhibitor, in patients with prostate cancer. Procedures Biodistribution was evaluated using sequential positron-emission tomography (PET) scans in nine patients with prostate cancer. Time-activity curves from the most avid tumor foci were determined. The radiation dose to selected organs was estimated using OLINDA/EXM. Results No major radiotracer-specific adverse events were observed. Physiologic accumulation was observed in known sites of PSMA expression. Accumulation in putative sites of prostate cancer was observed (SUVmax up to >100, and tumor-to-blood ratios up to >50). The effective radiation dose from [18F]DCFPyL was 0.0139 mGy/MBq or 5 mGy (0.5 rem) from an injected dose of 370 MBq (10 mCi). Conclusions [18F]DCFPyL is safe with biodistribution as expected, and its accumulation is high in presumed primary and metastatic foci. The radiation dose from [18F]DCFPyL is similar to that from other PET radiotracers. PMID:25896814

  8. Duration of Adulthood Overweight, Obesity, and Cancer Risk in the Women’s Health Initiative: A Longitudinal Study from the United States

    PubMed Central

    Stefanick, Marcia L.; Johnson, Karen C.; Lane, Dorothy S.; LeBlanc, Erin S.; Prentice, Ross; Rohan, Thomas E.; Snively, Beverly M.; Vitolins, Mara; Zaslavsky, Oleg; Soerjomataram, Isabelle; Anton-Culver, Hoda

    2016-01-01

    Background High body mass index (BMI) has become the leading risk factor of disease burden in high-income countries. While recent studies have suggested that the risk of cancer related to obesity is mediated by time, insights into the dose-response relationship and the cumulative impact of overweight and obesity during the life course on cancer risk remain scarce. To our knowledge, this study is the first to assess the impact of adulthood overweight and obesity duration on the risk of cancer in a large cohort of postmenopausal women. Methods and Findings Participants from the observational study of the Women’s Health Initiative (WHI) with BMI information from at least three occasions during follow-up, free of cancer at baseline, and with complete covariate information were included (n = 73,913). Trajectories of BMI across ages were estimated using a quadratic growth model; overweight duration (BMI ≥ 25 kg/m2), obesity duration (BMI ≥ 30 kg/m2), and weighted cumulative overweight and obese years, which take into account the degree of overweight and obesity over time (a measure similar to pack-years of cigarette smoking), were calculated using predicted BMIs. Cox proportional hazard models were applied to determine the cancer risk associated with overweight and obesity duration. In secondary analyses, the influence of important effect modifiers and confounders, such as smoking status, postmenopausal hormone use, and ethnicity, was assessed. A longer duration of overweight was significantly associated with the incidence of all obesity-related cancers (hazard ratio [HR] per 10-y increment: 1.07, 95% CI 1.06–1.09). For postmenopausal breast and endometrial cancer, every 10-y increase in adulthood overweight duration was associated with a 5% and 17% increase in risk, respectively. On adjusting for intensity of overweight, these figures rose to 8% and 37%, respectively. Risks of postmenopausal breast and endometrial cancer related to overweight duration were much

  9. Circles of Care: Development and Initial Evaluation of a Peer Support Model for African Americans with Advanced Cancer

    ERIC Educational Resources Information Center

    Hanson, Laura C.; Armstrong, Tonya D.; Green, Melissa A.; Hayes, Michelle; Peacock, Stacie; Elliot-Bynum, Sharon; Goldmon, Moses V.; Corbie-Smith, Giselle; Earp, Jo Anne

    2013-01-01

    Peer support interventions extend care and health information to underserved populations yet rarely address serious illness. Investigators from a well-defined academic-community partnership developed and evaluated a peer support intervention for African Americans facing advanced cancer. Evaluation methods used the Reach, Efficacy, Adoption,…

  10. Nitric Oxide Inhibits Hetero-adhesion of Cancer Cells to Endothelial Cells: Restraining Circulating Tumor Cells from Initiating Metastatic Cascade

    NASA Astrophysics Data System (ADS)

    Lu, Yusheng; Yu, Ting; Liang, Haiyan; Wang, Jichuang; Xie, Jingjing; Shao, Jingwei; Gao, Yu; Yu, Suhong; Chen, Shuming; Wang, Lie; Jia, Lee

    2014-03-01

    Adhesion of circulating tumor cells (CTCs) to vascular endothelial bed becomes a crucial starting point in metastatic cascade. We hypothesized that nitric oxide (NO) may prevent cancer metastasis from happening by its direct vasodilation and inhibition of cell adhesion molecules (CAMs). Here we show that S-nitrosocaptopril (CAP-NO, a typical NO donor) produced direct vasorelaxation that can be antagonized by typical NO scavenger hemoglobin and guanylate cyclase inhibitor. Cytokines significantly stimulated production of typical CAMs by the highly-purified human umbilical vein endothelial cells (HUVECs). CAP-NO inhibited expression of the stimulated CAMs (particularly VCAM-1) and the resultant hetero-adhesion of human colorectal cancer cells HT-29 to the HUVECs in a concentration-dependent manner. The same concentration of CAP-NO, however, did not significantly affect cell viability, cell cycle and mitochondrial membrane potential of HT-29, thus excluding the possibility that inhibition of the hetero-adhesion was caused by cytotoxicity by CAP-NO on HT-29. Hemoglobin reversed the inhibition of CAP-NO on both the hetero-adhesion between HT-29 and HUVECs and VCAM-1 expression. These data demonstrate that CAP-NO, by directly releasing NO, produces vasorelaxation and interferes with hetero-adhesion of cancer cells to vascular endothelium via down-regulating expression of CAMs. The study highlights the importance of NO in cancer metastatic prevention.

  11. Kyste hydatique primitif du sein

    PubMed Central

    Mouslik, Rabii; Settaf, Abdellatif; Elalami, Yacir; Lahnini, Hicham; Lahlou, Khalid; Chad, Bouziane

    2012-01-01

    Le kyste hydatique du sein est une parasitose rare même dans les pays endémiques. Nous rapportons une nouvelle observation d'une patiente de 30 ans qui présentait une masse du sein gauche. Le diagnostic de kyste hydatique du sein a été évoqué devant les données de l'examen clinique et de la mammographie couplée à l’échographie. Le geste chirurgical a consisté en une kystectomie. L'examen anatomopathologique de la pièce opératoire a confirmé le diagnostic. PMID:23133704

  12. Metformin Inhibits Androgen-Induced IGF-IR Up-Regulation in Prostate Cancer Cells by Disrupting Membrane-Initiated Androgen Signaling

    PubMed Central

    Malaguarnera, Roberta; Sacco, Antonella; Morcavallo, Alaide; Squatrito, Sebastiano; Migliaccio, Antimo; Morrione, Andrea; Maggiolini, Marcello

    2014-01-01

    We have previously demonstrated that, in prostate cancer cells, androgens up-regulate IGF-I receptor (IGF-IR) by inducing cAMP-response element-binding protein (CREB) activation and CREB-dependent IGF-IR gene transcription through androgen receptor (AR)-dependent membrane-initiated effects. This IGF-IR up-regulation is not blocked by classical antiandrogens and sensitizes cells to IGF-I-induced biological effects. Metformin exerts complex antitumoral functions in various models and may inhibit CREB activation in hepatocytes. We, therefore, evaluated whether metformin may affect androgen-dependent IGF-IR up-regulation. In the AR+ LNCaP prostate cancer cells, we found that metformin inhibits androgen-induced CRE activity and IGF-IR gene transcription. CRE activity requires the formation of a CREB-CREB binding protein-CREB regulated transcription coactivator 2 (CRTC2) complex, which follows Ser133-CREB phosphorylation. Metformin inhibited Ser133-CREB phosphorylation and induced nuclear exclusion of CREB cofactor CRTC2, thus dissociating the CREB-CREB binding protein-CRTC2 complex and blocking its transcriptional activity. Similarly to metformin action, CRTC2 silencing inhibited IGF-IR promoter activity. Moreover, metformin blocked membrane-initiated signals of AR to the mammalian target of rapamycin/p70S6Kinase pathway by inhibiting AR phosphorylation and its association with c-Src. AMPK signals were also involved to some extent. By inhibiting androgen-dependent IGF-IR up-regulation, metformin reduced IGF-I-mediated proliferation of LNCaP cells. These results indicate that, in prostate cancer cells, metformin inhibits IGF-I-mediated biological effects by disrupting membrane-initiated AR action responsible for IGF-IR up-regulation and suggest that metformin could represent a useful adjunct to the classical antiandrogen therapy. PMID:24437490

  13. Tissue requirements in lung cancer diagnosis for tumor heterogeneity, mutational analysis and targeted therapies: initial experience with intra-operative Frozen Section Evaluation (FROSE) in bronchoscopic biopsies

    PubMed Central

    Iding, Jeffrey S.

    2016-01-01

    Background Recent advances in lung cancer treatment have changed the requirement for the amount and quality of biopsy specimens needed to characterize the tumor and select the best treatment. One adjunct to guide the bronchoscopist on the quality and quantity of specimens during bronchoscopic biopsies for the diagnosis of lung cancer is rapid on-site evaluation (ROSE) of cytological specimens. This technique has been shown to add to the diagnostic yield of bronchoscopy when obtaining adequate specimens for molecular profiling in lung cancer. ROSE is not available at all medical centers. We describe our initial experience using intra-procedural Frozen Section Evaluation (FROSE) of bronchoscopic biopsy specimens as an alternative to ROSE. Methods A retrospective analysis of all interventional pulmonology cases using FROSE between February and July 2015 was performed. Results analyzed to evaluate the success in obtaining adequate specimens for molecular profiling. Results A total of 88 interventional pulmonology cases employing a frozen section in at least one site were identified. In 94.3% of cases, a definitive diagnosis of benign or malignant was made. The concordance of frozen section diagnoses of benign or malignant was 100% with final diagnoses. Thirteen of the eighty-eight cases were ultimately sent for molecular analysis. Of these, twelve of thirteen (92.3%) cases were adequate to perform all ordered molecular testing. In all cases there was sufficient tissue to perform EGFR and ALK testing. Conclusions In medical centers where ROSE may not be available, the use of FROSE by the local pathologist can be an effective technique to obtain adequate tissue and cytological samples for the diagnosis and molecular profiling of lung cancers. Further prospective study in bronchoscopic tissue sampling techniques to obtain the optimum quantity and quality of samples for molecular profiling of lung cancers for targeted treatments is needed. PMID:27606077

  14. Pin1 Inhibitor Juglone Exerts Anti-Oncogenic Effects on LNCaP and DU145 Cells despite the Patterns of Gene Regulation by Pin1 Differing between These Cell Lines

    PubMed Central

    Kanaoka, Ryuhei; Kushiyama, Akifumi; Seno, Yasuyuki; Nakatsu, Yusuke; Matsunaga, Yasuka; Fukushima, Toshiaki; Tsuchiya, Yoshihiro; Sakoda, Hideyuki; Fujishiro, Midori; Yamamotoya, Takeshi; Kamata, Hideaki; Matsubara, Akio; Asano, Tomoichiro

    2015-01-01

    Background Prostate cancer initially develops in an androgen-dependent manner but, during its progression, transitions to being androgen-independent in the advanced stage. Pin1, one of the peptidyl-prolyl cis/trans isomerases, is reportedly overexpressed in prostate cancers and is considered to contribute to accelerated cell growth, which may be one of the major factors contributing to their androgen-independent growth. Thus, we investigated how Pin1 modulates the gene expressions in both androgen-dependent and androgen-independent prostate cancer cell lines using microarray analysis. In addition, the effects of Juglone, a commercially available Pin1 inhibitor were also examined. Methods Two prostate cancer cell-lines, LNCaP (androgen-dependent) and DU145 (androgen-independent), were treated with Pin1 siRNA and its effects on gene expressions were analyzed by microarray. Individual gene regulations induced by Pin1 siRNA or the Pin1 inhibitor Juglone were examined using RT-PCR. In addition, the effects of Juglone on the growth of LNCaP and DU145 transplanted into mice were investigated. Results Microarray analysis revealed that transcriptional factors regulated by Pin1 differed markedly between LNCaP and DU145 cells, the only exception being that Nrf was regulated in the same way by Pin1 siRNA in both cell lines. Despite this marked difference in gene regulations, Pin1 siRNA and Juglone exert a strong inhibitory effect on both the LNCaP and the DU145 cell line, suppressing in vitro cell proliferation as well as tumor enlargement when transplanted into mice. Conclusions Despite Pin1-regulated gene expressions differing between these two prostate cancer cell-lines, LNCaP (androgen-dependent) and DU145 (androgen-independent), Pin1 inhibition suppresses proliferation of both cell-lines. These findings suggest the potential effectiveness of Pin1 inhibitors as therapeutic agents for prostate cancers, regardless of their androgen sensitivity. PMID:26039047

  15. Transforming Big Data into cancer-relevant insight: An initial, multi-tier approach to assess reproducibility and relevance | Office of Cancer Genomics

    Cancer.gov

    The Cancer Target Discovery and Development (CTD^2) Network was established to accelerate the transformation of "Big Data" into novel pharmacological targets, lead compounds, and biomarkers for rapid translation into improved patient outcomes. It rapidly became clear in this collaborative network that a key central issue was to define what constitutes sufficient computational or experimental evidence to support a biologically or clinically relevant finding.

  16. Popularity of less frequent follow up for breast cancer in randomised study: initial findings from the hotline study.

    PubMed Central

    Gulliford, T.; Opomu, M.; Wilson, E.; Hanham, I.; Epstein, R.

    1997-01-01

    OBJECTIVE: To compare the experiences of patients with breast cancer who were conventionally monitored with those in whom routine follow up was restricted to the time of mammography. DESIGN: Randomisation to conventional schedule of clinic visits or to visits only after mammography. Both cohorts received identical mammography and were invited to telephone for immediate appointments if they detected symptoms. SETTING: Combined breast clinic, Chelsea and Westminster Hospital. SUBJECTS: 211 eligible outpatients with a history of breast cancer. MAIN OUTCOME MEASURES: Acceptability of randomisation, interim use of telephone and general practitioner, satisfaction with allocation to follow up. RESULTS: Of 211 eligible patients, 196 (93%) opted for randomisation in the study. Of these, 55 were under 50 years, 78 were diagnosed fewer than five years before, 90 had stage T2-4 tumours, and 71 had involved axillary nodes. Patients who did not participate were more likely to be under 50 years, to be two to five years after diagnosis, and to have had aggressive primary disease. Twice as many patients in both groups expressed a preference for reducing rather than increasing follow up. No increased use of local practitioner services or telephone triage was apparent in the cohort randomised to less frequent follow up by specialists. CONCLUSIONS: Reducing the frequency of routine follow up has so far proved popular among patients with breast cancer at standard risk in this cohort. A multicentre study is needed to determine the effectiveness and cost-effectiveness of routine follow up with respect to disease outcomes. PMID:9022429

  17. Transforming Big Data into Cancer-Relevant Insight: An Initial, Multi-Tier Approach to Assess Reproducibility and Relevance.

    PubMed

    2016-08-01

    The Cancer Target Discovery and Development (CTD(2)) Network was established to accelerate the transformation of "Big Data" into novel pharmacologic targets, lead compounds, and biomarkers for rapid translation into improved patient outcomes. It rapidly became clear in this collaborative network that a key central issue was to define what constitutes sufficient computational or experimental evidence to support a biologically or clinically relevant finding. This article represents a first attempt to delineate the challenges of supporting and confirming discoveries arising from the systematic analysis of large-scale data resources in a collaborative work environment and to provide a framework that would begin a community discussion to resolve these challenges. The Network implemented a multi-tier framework designed to substantiate the biological and biomedical relevance as well as the reproducibility of data and insights resulting from its collaborative activities. The same approach can be used by the broad scientific community to drive development of novel therapeutic and biomarker strategies for cancer. Mol Cancer Res; 14(8); 675-82. ©2016 AACR. PMID:27401613

  18. Cone beam CT for determining breast cancer margin: an initial experience and its comparison with mammography and specimen radiograph

    PubMed Central

    Yao, Juan; Shaw, Chris; Lai, CJ; Rong, John; Wang, Jian; Liu, Wenya

    2015-01-01

    Purpose: To assess the ability of cone beam CT (CBCT) in determining the breast cancer margin using, to compare the results with mammography and specimen radiography, and to explore the clinical potential of CBCT for breast imaging. Methods: Specimens of 46 breast cancer patients were imaged by using a prototype CBCT system. Each patient underwent mammography, CBCT and X-ray of breast surgical specimen within 6 months. Images of mammography, breast surgical specimen radiography and CBCT were evaluated by an experienced radiologist. Indicators, such as: morphology, glitch, density, invasion, structural distortion and calcification, were observed. Result: There was no significant difference of the calcification, glitch and morphology among three methods. However, there was significant difference in indicators of breast tumor invasion among three methods. There was statistical significance in detecting invasions of breast cancer cells in peripheral tissues among three methods. Conclusion: CBCT shows no superiority over mammography and specimen radiography in determining tumor’s outline and detecting calcification. On the other hand, CBCT demonstrates its advantage in determining the 3 dimensional position of a lesion which could be a potential clinical application in future practices of breast imaging. PMID:26629005

  19. Can exercise ameliorate treatment toxicity during the initial phase of testosterone deprivation in prostate cancer patients? Is this more effective than delayed rehabilitation?

    PubMed Central

    2012-01-01

    Background There has been substantial increase in use of androgen deprivation therapy as adjuvant management of prostate cancer. However, this leads to a range of musculoskeletal toxicities including reduced bone mass and increased skeletal fractures compounded with rapid metabolic alterations, including increased body fat, reduced lean mass, insulin resistance and negative lipoprotein profile, increased incidence of cardiovascular and metabolic morbidity, greater distress and reduced quality of life. Numerous research studies have demonstrated certain exercise prescriptions to be effective at preventing or even reversing these treatment toxicities. However, all interventions to date have been of rehabilitative intent being implemented after a minimum of 3 months since initiation of androgen deprivation, by which time considerable physical and psychological health problems have manifested. The pressing question is whether it is more efficacious to commence exercise therapy at the same time as initiating androgen deprivation, so treatment induced adverse effects can be immediately attenuated or indeed prevented. Methods/design We are proposing a multi-site randomized controlled trial with partial crossover to examine the effects of timing of exercise implementation (immediate or delayed) on preserving long-term skeletal health, reversing short- and long-term metabolic and cardiovascular risk factors, and supporting mental health in men receiving androgen deprivation therapy. 124 men who are about to initiate androgen deprivation for prostate cancer will be randomized to immediate or delayed groups. Immediate will commence a 6-month exercise program within 7–10 days of their first dose. Delayed will receive usual care for 6 months and then commence the exercise program for 6 months (partial cross-over). Immediate will be free to adopt the lifestyle of their choosing following the initial 6-month intervention. Measurements for primary and secondary endpoints will

  20. Downregulation of cytokeratin 18 is associated with paclitaxel‑resistance and tumor aggressiveness in prostate cancer.

    PubMed

    Yin, Bo; Zhang, Mo; Zeng, Yu; Li, Youqiang; Zhang, Chao; Song, Yongsheng

    2016-04-01

    Paclitaxel frequently serves as the first-line chemotherapeutic agent for castration-resistant prostate cancer (PCa) patients. However, acquired paclitaxel-resistance almost always occurs after initial responses, and the mechanisms by which this occurs remain largely unknown. The goal of the present study was to identify differentially expressed protein(s) associated with paclitaxel-resistance and further explore the potential mechanisms involved in drug resistance. By comparing the nuclear matrix protein (NMP) patterns of DU145-TxR cells, the previously established stable paclitaxel-resistant PCa cells, with that of the parental DU145 cells using two-dimensional electrophoresis, we found that cytokeratin 18 (CK18) is downregulated in DU145-TxR cells. The downregulation of CK18 in DU145-TxR cells at mRNA, NMP and total cellular protein levels was validated by real-time RT-PCR, immunoblotting and immunofluorescence, indicating that the downregulation of CK18 was a global effect in DU145-TxR cells due to paclitaxel-resistance. Furthermore, in vivo assay of xenograft transplantation confirmed the higher tumorigenicity of DU145-TxR cells, suggesting that these paclitaxel-resistant PCa cells possessed potent cancer stem cell (CSC)-like properties and eventually developed paclitaxel-resistance. Moreover, we determined by immunohistochemistry that CK18 expression in PCa tissues was inversely correlated with tumor grade in a statistically significant fashion, indicating a potential association of the downregulation of CK18 with tumor aggressiveness. Therefore, further study to define the potential role of CK18 may lead to novel therapy strategies as well as clinically useful biomarker for PCa patients. PMID:26892177

  1. Clinical outcomes of anti-androgen withdrawal and subsequent alternative anti-androgen therapy for advanced prostate cancer following failure of initial maximum androgen blockade

    PubMed Central

    MOMOZONO, HIROYUKI; MIYAKE, HIDEAKI; TEI, HIROMOTO; HARADA, KEN-ICHI; FUJISAWA, MASATO

    2016-01-01

    The present study aimed to investigate the significance of anti-androgen withdrawal and/or subsequent alternative anti-androgen therapy in patients with advanced prostate cancer (PC) who relapsed after initial maximum androgen blockade (MAB). The present study evaluated the clinical outcomes of 272 consecutive advanced PC patients undergoing anti-androgen withdrawal and/or subsequent alternative anti-androgen therapy with flutamide following the failure of initial MAB using bicalutamide. With the exception of 41 patients (15.1%) who did not undergo anti-androgen withdrawal due to the characteristics of PC suggesting aggressive diseases, prostate-specific antigen (PSA) declined from the baseline value in 83 patients (35.9%), including 18 (7.8%) with PSA decline >50%, but not in the remaining 148 (64.1%). No significant difference in the overall survival (OS) or cancer-specific survival (CSS) among the three groups was observed based on the response to anti-androgen withdrawal. Following the introduction of alternative anti-androgen therapy with flutamide, PSA decline was observed in 185 patients (68.0%), including 103 (37.9%) who achieved a PSA reduction of >50%; however, the PSA level continued to elevate in the remaining 87 (32.0%). Furthermore, of the numerous factors examined, only the duration of the initial MAB therapy was shown to be significantly correlated with the PSA decline following alternative anti-androgen therapy. Multivariate analysis of several factors identified revealed that only PSA decline following alternative anti-androgen therapy was an independent predictor of CSS and OS. If initial MAB is effective, the introduction of alternative anti-androgen therapy may be considered; however, anti-androgen withdrawal should be omitted, irrespective of the characteristics of advanced PC. PMID:27123292

  2. Refining prognosis and identifying targetable pathways for high-risk endometrial cancer; a TransPORTEC initiative.

    PubMed

    Stelloo, Ellen; Bosse, Tjalling; Nout, Remi A; MacKay, Helen J; Church, David N; Nijman, Hans W; Leary, Alexandra; Edmondson, Richard J; Powell, Melanie E; Crosbie, Emma J; Kitchener, Henry C; Mileshkin, Linda; Pollock, Pamela M; Smit, Vincent T; Creutzberg, Carien L

    2015-06-01

    This study aimed to investigate whether molecular analysis can be used to refine risk assessment, direct adjuvant therapy, and identify actionable alterations in high-risk endometrial cancer. TransPORTEC, an international consortium related to the PORTEC3 trial, was established for translational research in high-risk endometrial cancer. In this explorative study, routine molecular analyses were used to detect prognostic subgroups: p53 immunohistochemistry, microsatellite instability and POLE proofreading mutation. Furthermore, DNA was analyzed for hotspot mutations in 13 additional genes (BRAF, CDKNA2, CTNNB1, FBXW7, FGFR2, FGFR3, FOXL2, HRAS, KRAS, NRAS, PIK3CA, PPP2R1A, and PTEN) and protein expression of ER, PR, PTEN, and ARID1a was analyzed. Rates of distant metastasis, recurrence-free, and overall survival were calculated using the Kaplan-Meier method and log-rank test. In total, samples of 116 high-risk endometrial cancer patients were included: 86 endometrioid; 12 serous; and 18 clear cell. For endometrioid, serous, and clear cell cancers, 5-year recurrence-free survival rates were 68%, 27%, and 50% (P=0.014) and distant metastasis rates 23%, 64%, and 50% (P=0.001), respectively. Four prognostic subgroups were identified: (1) a group of p53-mutant tumors; (2) microsatellite instable tumors; (3) POLE proofreading-mutant tumors; and (4) a group with no specific molecular profile (NSMP). In group 3 (POLE-mutant; n=14) and group 2 (microsatellite instable; n=19) patients, no distant metastasis occurred, compared with 50% distant metastasis rate in group 1 (p53-mutant; n=36) and 39% in group 4 (NSMP; P<0.001). Five-year recurrence-free survival was 93% and 95% for group 3 (POLE-mutant) and group 2 (microsatellite instable) vs 42% (group 1, p53-mutant) and 52% (group 4, NSMP; P<0.001). Targetable FBXW7 and FGFR2 mutations (6%), alterations in the PI3K-AKT pathway (60%) and hormone receptor positivity (45%) were frequently found. In conclusion, molecular analysis

  3. Cancer

    MedlinePlus

    Cancer begins in your cells, which are the building blocks of your body. Normally, your body forms ... be benign or malignant. Benign tumors aren't cancer while malignant ones are. Cells from malignant tumors ...

  4. GLIPR1 inhibits the proliferation and induces the differentiation of cancer-initiating cells by regulating miR-16 in osteosarcoma.

    PubMed

    Dong, Jian; Bi, Binna; Zhang, Lianhai; Gao, Kaituo

    2016-09-01

    Osteosarcoma is a common, highly malignant and metastatic bone cancer. Elucidation of the molecular mechanisms of osteosarcoma may further help us to understand the pathogenesis of the disease, and offer novel targets for effective therapies. Human glioma pathogenesis-related protein 1 (GLIPR1) has been found to be downregulated in human cancers. However, its roles have not been reported in osteosarcoma. In the present study, we demonstrated that GLIPR1 protein was downregulated in osteosarcoma. Its overexpression inhibited the proliferation, migration and invasion and induced the differentiation of cancer-initiating cells (CICs) in osteosarcoma. Moreover, GLIPR1 overexpression upregulated miR-16 in osteosarcoma cells. The upregulation suppressed proliferation, migration and invasion as well as induced differentiation of CICs in osteosarcoma. Thus, we conclude that GLIPR1 inhibited the proliferation, migration and invasion and induced the differentiation of CICs by regulating miR-16 in osteosarcoma. The present study provides direct evidence that GLIPR1 is a bona fide tumor suppressor and identified GLIPR1 and miR-16 as key components for regulating the proliferation, migration, invasion and CICs in osteosarcoma. PMID:27460987

  5. Simvastatin blocks TGF-β1-induced epithelial-mesenchymal transition in human prostate cancer cells

    PubMed Central

    XIE, FENG; LIU, JIE; LI, CHENGWEN; ZHAO, YAORUI

    2016-01-01

    In recent years, the use of statins has been reported to be associated with a reduced risk of prostate cancer (PCa), particularly metastatic PCa. The mechanisms underlying these epidemiological observations are poorly understood. Epithelial-mesenchymal transition (EMT) is a critical initial step and a hallmark for cancer metastasis. In the present study, the relationship between simvastatin and EMT in PCa and the mechanism involved was investigated. It was demonstrated that simvastatin inhibited the EMT as assessed by reduced expression of N-cadherin and vimentin, and increased E-cadherin in TGF-β1 treated DU145 PCa cells. Furthermore, simvastatin inhibited TGF-β1-induced migration and invasion of DU145 cells. The TGF-β1/Smad pathway and non-Smad pathway were investigated in simvastatin-treated DU145 cells. Simvastatin had no effect on TGF-β1-induced phosphorylation of Smad2 and Smad3. In the non-Smad pathway, simvastatin reduced TGF-β1-induced p38 MAPK phosphorylation, but had no effect on TGF-β1-induced Erk1/2 phosphorylation. Simvastatin attenuated TGF-β1-induced EMT, cell migration and invasion in DU145 cells. These effects may have been mediated by the inhibition of p38 MAPK phosphorylation, not through the canonical Smad pathway. Therefore simvastatin may be a promising therapeutic agent for treating PCa. PMID:27123120

  6. Deletion of Ptp4a3 reduces clonogenicity and tumor-initiation ability of colitis-associated cancer cells in mice

    PubMed Central

    Thompson, Tim; Homanics, Gregg E.; Lazo, John S.; Lagasse, Eric

    2014-01-01

    The PTP4A3 gene is highly expressed in human colon cancer and often associates with enhanced metastatic potential. Genetic disruption of the mouse Ptp4a3 gene reduces the frequency of colon tumor formation in mice treated in a colitis-associated cancer model. In the current study, we have examined the role of Ptp4a3 in the tumor-initiating cell population of mouse colon tumors using an in vitro culture system. Tumors generated in vivo following AOM/DSS treatment were isolated, dissociated, and expanded on a feeder layer resulting in a CD133+ cell population, which expressed high levels of Ptp4a3. Tumor cells deficient for Ptp4a3 exhibited reduced clonogenicity and growth potential relative to WT cells as determined by limiting dilution analysis. Importantly, expanded tumor cells from WT mice readily formed secondary tumors when transplanted into nude mice, while tumor cells without Ptp4a3 expression failed to form secondary tumors and thus were not tumorigenic. These results demonstrate that Ptp4a3 contributes to the malignant phenotype of tumor-initiating cells and supports its role as a potential therapeutic target to inhibit tumor self-renewal and metastasis. PMID:24950307

  7. The erbB3- and IGF-1 receptor-initiated signaling pathways exhibit distinct effects on lapatinib sensitivity against trastuzumab-resistant breast cancer cells.

    PubMed

    Lyu, Hui; Yang, Xiao He; Edgerton, Susan M; Thor, Ann D; Wu, Xiaoying; He, Zhimin; Liu, Bolin

    2016-01-19

    Both erbB3 and IGF-1 receptor (IGF-1R) have been shown to play an important role in trastuzumab resistance. However, it remains unclear whether erbB3- and IGF-1R-initiated signaling pathways possess distinct effects on the sensitivity of lapatinib, a dual tyrosine kinase inhibitor against both EGFR and erbB2, in trastuzumab-resistant breast cancer. Here, we show that the trastuzumab-resistant SKBR3-pool2 and BT474-HR20 breast cancer sublines, as compared the parental SKBR3 and BT474 cells, respectively, exhibit refractoriness to lapatinib. Knockdown of erbB3 inhibited Akt in SKBR3-pool2 and BT474-HR20 cells, significantly increased lapatinib efficacy, and dramatically re-sensitized the cells to lapatinib-induced apoptosis. In contrast, specific knockdown of IGF-1R did not alter the cells' responsiveness to lapatinib. While the levels of phosphorylated Src (P-Src) were reduced upon IGF-1R downregulation, the P-Akt levels remained unchanged. Furthermore, a specific inhibitor of Akt, but not Src, significantly enhanced lapatinib-mediated anti-proliferative/anti-survival effects on SKBR3-pool2 and BT474-HR20 cells. These data indicate that erbB3 signaling is critical for both trastuzumab and lapatinib resistances mainly through the PI-3K/Akt pathway, whereas IGF-1R-initiated Src activation results in trastuzumab resistance without affecting lapatinib sensitivity. Our findings may facilitate the development of precision therapeutic regimens for erbB2-positive breast cancer patients who become resistant to erbB2-targeted therapy. PMID:26621843

  8. Potent increased risk of the initiation of DNA replication in human prostate cancer with the use of 5α-reductase inhibitors

    PubMed Central

    Kosaka, Takeo; Yasumizu, Yota; Miyazaki, Yasumasa; Miyajima, Akira; Kikuchi, Eiji; Oya, Mototsugu

    2014-01-01

    Recent clinical studies have raised the clinically important question of the relationship between dihydrotestosterone (DHT) and prostate cancer (PCa) progression. The significance of DHT or 5α-reductase inhibitors (5ARI) in PCa development and progression has not yet been fully characterized. The aim of this study was to determine whether the initiation of DNA replication was influenced by DHT in PCa. Three cell lines were used. LNCaP: a human PCa cell line that exhibits androgen-dependent proliferation, C4-2: a human PCa cell line that exhibits androgen-independent proliferation, and C4-2AT6: a castration resistant prostate cancer cell line. Two 5ARIs, finasteride and dutasteride, were used. We examined the mRNA expression of the components of pre-replication complex (Pre-RC), CDC6, CDT1, and MCM2-7. DHT induced cell proliferation of LNCaP accompanied by significantly increased CDC6, CDT1, and MCM2-7 expression. In contrast to LNCaP, DHT inhibited cell proliferation in C4-2AT6 cells accompanied by decreased expression of CDC6, CDT1, and MCM2-7. These reverse effects resemble the effects of 5ARIs in Pre-RC. Treatment with finasteride or dutasteride inhibited CDC6 expression in LNCaP, but both 5ARIs induced CDC6 expression in C4-2 and C4-2AT6 cells.These results indicate that DHT showed reversal effects on PCa cell proliferation among prostate cancer cells based on androgen-dependence, accompanied by regulation of the initiation of DNA replication. 5ARIs may modulate the DNA replication system in someaggressive PCa through up-regulation of CDC6 expression. PMID:25374915

  9. Multiparametric PET/CT-perfusion does not add significant additional information for initial staging in lung cancer compared with standard PET/CT

    PubMed Central

    2014-01-01

    Background The purpose of this study was to assess the relationship of CT-perfusion (CTP), 18F-FDG-PET/CT and histological parameters, and the possible added value of CTP to FDG-PET/CT in the initial staging of lung cancer. Methods Fifty-four consecutive patients (median age 65 years, 15 females, 39 males) with suspected lung cancer were evaluated prospectively by CT-perfusion scan and 18F-FDG-PET/CT scan. Overall, 46 tumors were identified. CTP parameters blood flow (BF), blood volume (BV), and mean transit time (MTT) of the tumor tissue were calculated. Intratumoral microvessel density (MVD) was assessed quantitatively. Differences in CTP parameters concerning tumor type, location, PET positivity of lymph nodes, TNM status, and UICC stage were analyzed. Spearman correlation analyses between CTP and 18F-FDG-PET/CT parameters (SUVmax, SUVmean, PETvol, and TLG), MVD, tumor size, and tumor stage were performed. Results The mean BF (mL/100 mL min-1), BV (mL/100 mL), and MTT (s) was 35.5, 8.4, and 14.2, respectively. The BF and BV were lower in tumors with PET-positive lymph nodes (p = 0.02). However, the CTP values were not significantly different among the N stages. The CTP values were not different, depending on tumor size and location. No significant correlation was found between CTP parameters and MVD. Conclusions Overall, the CTP information showed only little additional information for the initial staging compared with standard FDG-PET/CT. Low perfusion in lung tumors might possibly be associated with metabolically active regional lymph nodes. Apart from that, both CTP and 18F-FDG-PET/CT parameter sets may reflect different pathophysiological mechanisms in lung cancer. PMID:24450990

  10. Potent increased risk of the initiation of DNA replication in human prostate cancer with the use of 5α-reductase inhibitors.

    PubMed

    Kosaka, Takeo; Yasumizu, Yota; Miyazaki, Yasumasa; Miyajima, Akira; Kikuchi, Eiji; Oya, Mototsugu

    2014-01-01

    Recent clinical studies have raised the clinically important question of the relationship between dihydrotestosterone (DHT) and prostate cancer (PCa) progression. The significance of DHT or 5α-reductase inhibitors (5ARI) in PCa development and progression has not yet been fully characterized. The aim of this study was to determine whether the initiation of DNA replication was influenced by DHT in PCa. Three cell lines were used. LNCaP: a human PCa cell line that exhibits androgen-dependent proliferation, C4-2: a human PCa cell line that exhibits androgen-independent proliferation, and C4-2AT6: a castration resistant prostate cancer cell line. Two 5ARIs, finasteride and dutasteride, were used. We examined the mRNA expression of the components of pre-replication complex (Pre-RC), CDC6, CDT1, and MCM2-7. DHT induced cell proliferation of LNCaP accompanied by significantly increased CDC6, CDT1, and MCM2-7 expression. In contrast to LNCaP, DHT inhibited cell proliferation in C4-2AT6 cells accompanied by decreased expression of CDC6, CDT1, and MCM2-7. These reverse effects resemble the effects of 5ARIs in Pre-RC. Treatment with finasteride or dutasteride inhibited CDC6 expression in LNCaP, but both 5ARIs induced CDC6 expression in C4-2 and C4-2AT6 cells.These results indicate that DHT showed reversal effects on PCa cell proliferation among prostate cancer cells based on androgen-dependence, accompanied by regulation of the initiation of DNA replication. 5ARIs may modulate the DNA replication system in someaggressive PCa through up-regulation of CDC6 expression. PMID:25374915

  11. Iodine-131 avid distant metastasis in differentiated thyroid cancer: An initial institutional experience from the northern part of India

    PubMed Central

    Khan, Shoukat Hussain; Hassan, Masood ul; Bhau, Rajesh Singh

    2015-01-01

    Objective: The aim of the study was to study the clinical profile in patients of differentiated thyroid cancer (DTC) with Iodine-131 avid distant metastasis at presentation. The study also attempted to evaluate factors influencing survival among these patients. Material and Methods: The cohort includes 35 patients (26 Female, 9 Male) studied retrospectively and prospectively over a period of 5 years at the Sher-I-Kashmir Institute of Medical Sciences, Srinagar, India. Results: The five years cause specific survival among patients of DTC with distant metastasis in the study group was 74.3%. The mean age at presentation was 41.4 years with female patients outnumbering the male patients in a ratio of 5:1. Papillary histopathology was the commonest in 65.7% followed by Follicular in 31.4% and poorly differentiated cancer in 2.9% of patients.31.4% 0f patients presented with relatively advanced AJC/UICC tumor stage of T3-T4. Bone was the commonest site of metastasis in 42.85% of patients followed by lung in 40% 0f patients. 82.9% of patients had only single organ metastasis. Therapeutic Radioiodine was administered in 31 (88.6%) patients. On univariate analysis of various factors that may be influencing the cause specific survival at 5 years, age ≥ 45 years, T3-T4 tumor stage, regional lymph node metastasis, follicular histopathology and non administration of radioiodine revealed significant (P<0.05) association with a poor 5 year survival. However multivariate analysis identified advanced tumor stage (T3-T4) and non administration of radioiodine to be the only independent factors associated with poor survival. Conclusion: Patients of differentiated thyroid cancer with distant metastasis having advanced tumor stage (T3-T4) and those in whom therapeutic radioiodine (I-131) is not administered seem to have an unfavorable prognosis in terms of a 5 years cause specific survival. PMID:26170565

  12. Breast cancer metastasis to the vulva 20 years remote from initial diagnosis: A case report and literature review.

    PubMed

    Alligood-Percoco, Natasha R; Kessler, Meghan S; Willis, Gregory

    2015-08-01

    •This is the 20th documented case of metastatic breast carcinoma to the vulva.•Greater than 21 years have passed from initial diagnosis to vulvar metastasis.•Existing literature supports long term surveillance in women with invasive lobular carcinoma of the breast. PMID:26425717

  13. Inflammation induced NFATc1-STAT3 Transcription Complex Promotes Pancreatic Cancer initiation by KrasG12D

    PubMed Central

    Baumgart, Sandra; Chen, Nai-ming; Siveke, Jens T.; König, Alexander; Zhang, Jin-San; Singh, Shiv K.; Wolf, Elmar; Bartkuhn, Marek; Esposito, Irene; Heßmann, Elisabeth; Reinecke, Johanna; Nikorowitsch, Julius; Brunner, Marius; Singh, Garima; Fernandez-Zapico, Martin E.; Smyrk, Thomas; Bamlet, William R.; Eilers, Martin; Neesse, Albrecht; Gress, Thomas M.; Billadeau, Daniel D.; Tuveson, David; Urrutia, Raul; Ellenrieder, Volker

    2014-01-01

    Summary Cancer-associated inflammation is a molecular key feature in pancreatic ductal adenocarcinoma. Oncogenic KRAS in conjunction with persistent inflammation is known to accelerate carcinogenesis, although the underlying mechanisms remain poorly understood. Here we outline a novel pathway whereby the transcription factors NFATc1 and STAT3 cooperate in pancreatic epithelial cells to promote KrasG12D-driven carcinogenesis. NFATc1 activation is induced by inflammation and itself accelerates inflammation-induced carcinogenesis in KrasG12D mice, whereas genetic or pharmacological ablation of NFATc1 attenuates this effect. Mechanistically, NFATc1 complexes with STAT3 for enhancer-promoter communications at jointly regulated genes involved in oncogenesis, e.g. Cyclin, EGFR and WNT family members. The NFATc1-STAT3 cooperativity is operative in pancreatitis-mediated carcinogenesis as well as in established human pancreatic cancer. Together, these studies unravel new mechanisms of inflammatory driven pancreatic carcinogenesis and suggest beneficial effects of chemopreventive strategies using drugs which are currently available for targeting these factors in clinical trials. PMID:24694735

  14. [68Ga]Pentixafor-PET/CT for imaging of chemokine receptor 4 expression in small cell lung cancer - initial experience

    PubMed Central

    Rudelius, Martina; Schmid, Jan-Stefan; Schoene, Alexander; Schirbel, Andreas; Samnick, Samuel; Pelzer, Theo; Buck, Andreas K.; Kropf, Saskia; Wester, Hans-Jürgen; Herrmann, Ken

    2016-01-01

    Chemokine receptor CXCR4 is a key factor for tumor growth and metastasis in several types of human cancer. This study investigated the feasibility of CXCR4-directed imaging of small cell lung cancer (SCLC) with positron emission tomography/computed tomography (PET/CT) using the radiolabelled chemokine ligand [68Ga]Pentixafor. 10 patients with primarily diagnosed (n=3) or pre-treated (n=7) SCLC (n=9) or large cell neuroendocrine carcinoma of the lung (LCNEC, n=1) underwent [68Ga]Pentixafor-PET/CT. 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG, n=6) and/or somatostatin receptor (SSTR)-directed PET/CT with [68Ga]DOTATOC (n=5) and immunohistochemistry (n=10) served as standards of reference. CXCR4-PET was positive in 8/10 patients and revealed more lesions with significantly higher tumor-to-background ratios than SSTR-PET. Two patients who were positive on [18F]FDG-PET were missed by CXCR4-PET, in the remainder [68Ga]Pentixafor detected an equal (n=2) or higher (n=2) number of lesions. CXCR4 expression of tumor lesions could be confirmed by immunohistochemistry. Non-invasive imaging of CXCR4 expression in SCLC is feasible. [68Ga]Pentixafor as a novel PET tracer might serve as readout for confirmation of CXCR4 expression as prerequisite for potential CXCR4-directed treatment including receptor-radio(drug)peptide therapy. PMID:26843617

  15. Current controversies in the initial post-surgical radioactive iodine therapy for thyroid cancer: a narrative review.

    PubMed

    Blumhardt, Ralph; Wolin, Ely A; Phillips, William T; Salman, Umber A; Walker, Ronald C; Stack, Brendan C; Metter, Darlene

    2014-01-01

    Differentiated thyroid cancer (DTC) is the most common endocrine malignancy and the fifth most common cancer in women. DTC therapy requires a multimodal approach, including surgery, which is beyond the scope of this paper. However, for over 50 years, the post-operative management of the DTC post-thyroidectomy patient has included radioactive iodine (RAI) ablation and/or therapy. Before 2000, a typical RAI post-operative dose recommendation was 100 mCi for remnant ablation, 150 mCi for locoregional nodal disease, and 175-200 mCi for distant metastases. Recent recommendations have been made to decrease the dose in order to limit the perceived adverse effects of RAI including salivary gland dysfunction and inducing secondary primary malignancies. A significant controversy has thus arisen regarding the use of RAI, particularly in the management of the low-risk DTC patient. This debate includes the definition of the low-risk patient, RAI dose selection, and whether or not RAI is needed in all patients. To allow the reader to form an opinion regarding post-operative RAI therapy in DTC, a literature review of the risks and benefits is presented. PMID:25277792

  16. Lymphome malin non hodgkinien du cavum: protocoles thérapeutiques et facteurs pronostiques

    PubMed Central

    Ouraini, Saloua; Nakkabi, Ismail; Benariba, Fouad

    2015-01-01

    Le lymphome malin non hodgkinien est une entité histologique rare parmi les cancers du cavum, la plupart des tumeurs du nasopharynx étant des carcinomes indifférenciés ou Undifferencied Carcinoma of Nasopharyngeal Type (UCNT); Il pose souvent un problème de diagnostic positif clinique et histologique. La symptomatologie est généralement peu spécifique et la démarche étiologique repose sur la biopsie du cavum faite à l'examen endoscopique avec examen immuno-histochimique. Nous rapportons le cas d'un lymphome non hodgkinien avec atteinte du nasopharynx, l'analyse anatomopathologique est en faveur d'un lymphome malin non hodgkinien de phénotype B. Les aspects cliniques, radiologiques, histologiques et thérapeutiques sont décrits. PMID:26889334

  17. The RAS Initiative

    Cancer.gov

    NCI established the RAS Initiative to explore innovative approaches for attacking the proteins encoded by mutant forms of RAS genes and to ultimately create effective, new therapies for RAS-related cancers.

  18. [Continent esoduodenal intubation after total gastrectomy for cancer. An African experience apropos of an initial series of 17 cases].

    PubMed

    Ribault, L; Diouf, M B; Faye, M; Sarre, B; Diagne, A L; Morcillo, R; Veillard, J M

    1991-01-01

    On the basis of a series of 17 cases in which GI continuity was restored by a containing esoduodenal intubation, the authors describe the technique, which consists in the approximation of the duodenum opposite the diaphragm. Esophageal intubation in the duodenum, the margins of which have been everted, allows preserving the physiological circuit, producing a new container within 3 months and ensuring an effective protection against reflux. The 17 patients had undergone total gastrectomy for advanced cancer, Gutman's stage II in 80% of all cases and stage III or more in the other 20%. 88% of the tumors were adenocarcinomas. There were no clinical or radiological signs of reflux, and no esophagitis was noted on repeated endoscopies. The postoperative mortality rate was 5.8%. The shortest time lapse is 1 year. PMID:1842947

  19. Lack of efficacy of blueberry in nutritional prevention of azoxymethane-initiated cancers of rat small intestine and colon

    PubMed Central

    2009-01-01

    Background Blueberries may lower relative risk for cancers of the gastrointestinal tract. Previous work indicated an inhibitory effect of consumed blueberry (BB) on formation of aberrant crypt foci (ACF) in colons of male Fisher F344 rats (inbred strain). However, effects of BB on colon tumors and in both genders are unknown. Methods We examined efficacy of BB in inhibition of azoxymethane (AOM)-induced colon ACF and intestine tumors in male and female Sprague-Dawley rats (outbred strain). Pregnant rats were fed a diet with or without 10% BB powder; progeny were weaned to the same diet as their dam and received AOM as young adults. Results Male and female rats on control diet had similar numbers of ACF at 6 weeks after AOM administration. BB increased (P < 0.05) ACF numbers within the distal colon of female but not male rats. There was a significant (P < 0.05) diet by gender interaction with respect to total colon ACF number. Colon and duodenum tumor incidences were less in females than males at 17 weeks after AOM. BB tended (0.1 > P > 0.05) to reduce overall gastrointestinal tract tumor incidence in males, however, tumor incidence in females was unaffected (P > 0.1) by BB. There was a tendency (0.1 > P > 0.05) for fewer adenocarcinomas (relative to total of adenomatous polyps plus adenocarcinomas) in colons of female than male tumor-bearing rats; in small intestine, this gender difference was significant (P < 0.05). BB favored (P < 0.05) fewer adenocarcinomas and more adenomatous polyps (as a proportion of total tumor number) in female rat small intestine. Conclusion Results did not indicate robust cancer-preventive effects of BB. Blueberry influenced ACF occurrence in distal colon and tumor progression in duodenum, in gender-specific fashion. Data indicate the potential for slowing tumor progression (adenomatous polyp to adenocarcinoma) by BB. PMID:19758446

  20. High-dose chemotherapy and autologous stem cell support followed by posttransplantation doxorubicin as initial therapy for metastatic breast cancer.

    PubMed

    deMagalhaes-Silverman, M; Bloom, E; Lembersky, B; Lister, J; Pincus, S; Rybka, W; Voloshin, M; Wilson, J; Ball, E

    1997-02-01

    High-dose chemotherapy is associated with a high complete response rate and possibly some survival advantage in patients with metastatic breast cancer. We designed a clinical trial consisting of a two-step high-dose chemotherapy regimen followed by posttransplantation doxorubicin as the first chemotherapy treatment for metastatic disease. Twenty-one patients with metastatic breast cancer and no previous chemotherapy for metastatic disease were treated with high-dose cyclophosphamide (Cy; 5000 mg/m2), followed by granulocyte colony-stimulating factor. Peripheral blood stem cells were collected. Subsequently, patients received Cy (6000 mg/m2), thiotepa (500 mg/m2), and carboplatin (800 mg/m2) (CTCb) with hematopoietic rescue. Upon recovery of hematopoietic and gastrointestinal toxicity, three cycles of doxorubicin (Dox; 60 mg/m2) were delivered. After Cy, nine patients (45%) developed neutropenic fevers. There were no episodes of bacteremia. Patients received CTCb 37 days after starting Cy and had a hospital stay of 19 days. After CTCb, the median number of days to an absolute neutrophil count >5 x 10(9)/liter was 8, and the median number of days to a platelet count >20 x 10(9)/liter was 9. Neutropenic fevers occurred in 12 patients. There were no hemorrhagic complications. Fifty-five of the 63 planned courses of Dox were delivered. The median time from peripheral blood stem cell infusion to the first Dox cycle was 38 days. The median time to the second Dox cycle was 28 days, and to the last cycle was 30 days. Three episodes of neutropenic fevers were observed. Two patients developed herpes zoster. This regimen is feasible, with acceptable toxicity. PMID:9815672

  1. Initial Study of Radiological and Clinical Efficacy Radioembolization Using 188Re-Human Serum Albumin (HSA) Microspheres in Patients with Progressive, Unresectable Primary or Secondary Liver Cancers

    PubMed Central

    Nowicki, Mirosław L.; Ćwikła, Jarosław B.; Sankowski, Artur J.; Shcherbinin, Sergey; Grimes, Josh; Celler, Anna; Buscombe, John R.; Bator, Andrzej; Pech, Maciej; Mikołajczak, Renata; Pawlak, Dariusz

    2014-01-01

    Background The aim of this initial study was to evaluate the clinical and radiological effectiveness of radioembolization (RE) using 188Re-Human Serum Albumin (HSA) microspheres in patients with advanced, progressive, unresectable primary or secondary liver cancers, not suitable to any other form of therapy. Material/Methods Overall, we included 13 patients with 20 therapy sessions. Clinical and radiological responses were assessed at 6 weeks after therapy, and then every 3 months. The objective radiological response was classified according to Response Evaluation Criteria in Solid Tumors (RECIST) v.1.0 by sequential MRI. Adverse events were evaluated using NCI CTCAE v.4.03. Results There were 4 patients with hepatocellular carcinoma (HCC), 6 with metastatic colorectal cancer (mCRC), 2 with neuroendocrine carcinoma (NEC), and 1 patient with ovarian carcinoma. Mean administered activity of 188Re HSA was 7.24 GBq (range 3.8–12.4) A high microspheres labeling efficacy of over 97±2.1% and low urinary excretion of 188Re (6.5±2.3%) during first 48-h follow-up. Median overall survival (OS) for all patients was 7.1 months (CI 6.2–13.3) and progression-free survival (PFS) was 5.1 months (CI 2.4–9.9). In those patients who had a clinical partial response (PR), stable disease (SD), and disease progression (DP) as assessed 6 weeks after therapy, the median OS was 9/5/4 months, respectively, and PFS was 5/2/0 months, respectively. The treatment adverse events (toxicity) were at an acceptable level. Initially and after 6 weeks, the CTC AE was grade 2, while after 3 months it increased to grade 3 in 4 subjects. This effect was mostly related to rapid cancer progression in this patient subgroup. Conclusions The results of this preliminary study indicate that RE using 188Re HSA is feasible and a viable option for palliative therapy in patients with extensive progressive liver cancer. It was well tolerated by most patients, with a low level of toxicity during the 3 months of

  2. The novel inhibitor BRM270 downregulates tumorigenesis by suppression of NF-κB signaling cascade in MDR-induced stem like cancer-initiating cells.

    PubMed

    Mongre, Raj Kumar; Sodhi, Simrinder Singh; Ghosh, Mrinmoy; Kim, Jeong Hyun; Kim, Nameun; Park, Yang Ho; Kim, Sung Jin; Heo, Yoo Jeong; Sharma, Neelesh; Jeong, Dong Kee

    2015-01-01

    The nuclear factor κB (NF-κB) and interleukin-6 (IL-6) contribute to multidrug resistance (MDR) in tumor chemotherapy. The essential phenomenon of oncogenic activation of NF-κB in cancer-initiating cells showing MDR resulting from increased IL-6 expression is still unclear. Cancer stem cells (CSCs) have been the objective of intensive study. The aim of this study was to investigate the selective and potential efficacy of BRM270 against stem-like cancer-initiating cells (SLCICs) via the molecular mechanisms of its anticancer effects. Co-regulation of NF-κB and Cdk6 might be new arena to mitigate tumorigenesis. In the present study phyto-drug based approach provides a new avenue in understanding the amelioration and regulatory mechanisms in CSCs. In the present study, an in vivo tumor metastasis model of osteosarcoma was established by injecting Cal72 and SaOS-2 SLCICs into the right lower flank of nude mice. Later the development of tumor was analyzed by LICOR Biosciences (Pearl image analyzer). Significant suppression of activation of NF-κB and LPS-induced gene expression and apoptosis by BRM270 was confirmed by FACS, western blotting and qPCR. Further, both p65 and Cdk6 were significantly (P<0.05) overexpressed in BRM270 non-treated Cal72 SLCICs compared to treated group. BRM270 directly dephosphorylated RelA and selectively inhibited NF-κB transcriptional activity, resulting in decreased expression of interleukin-6, a cytokine implicated in cancer metastasis. BRM270-mediated cell shrinkage, pyknosis, karyorrhexis and programmed cell death (PCD) were observed by Hoechst 33342 staining while flow cytometry analysis showed significant (P<0.05) decrease in cell population from G0-G1 phases. These findings suggest that activation of the oncogenic Cdk6-NF-κB pathway, resulting from increased IL-6 expression, plays a central role in CD133 expressing SLCICs augmented MDR and neoplasia. This study proposes targeting of NF-κB, and Cdk6 with IL-6 as potential

  3. [Cancer].

    PubMed

    de la Peña-López, Roberto; Remolina-Bonilla, Yuly Andrea

    2016-09-01

    Cancer is a group of diseases which represents a significant public health problem in Mexico and worldwide. In Mexico neoplasms are the second leading cause of death. An increased morbidity and mortality are expected in the next decades. Several preventable risk factors for cancer development have been identified, the most relevant including tobacco use, which accounts for 30% of the cancer cases; and obesity, associated to another 30%. These factors, in turn, are related to sedentarism, alcohol abuse and imbalanced diets. Some agents are well knokn to cause cancer such as ionizing radiation, viruses such as the papilloma virus (HPV) and hepatitis virus (B and C), and more recently environmental pollution exposure and red meat consumption have been pointed out as carcinogens by the International Agency for Research in Cancer (IARC). The scientific evidence currently available is insufficient to consider milk either as a risk factor or protective factor against different types of cancer. PMID:27603890

  4. Safety Results of Docetaxel-(Taxotere®)-Based Chemotherapy in Early Breast Cancer Patients of Asia-Pacific Region: Asia-Pacific Breast Initiative II

    PubMed Central

    Kok, Yau Tsz; Thuan, Tran Van; Chao, Tsu-Yi; Shen, Zhen Zhou

    2015-01-01

    Purpose The goal of this registry was to collect patient characteristics and safety data from patients from the Asia-Pacific region with early breast cancer receiving adjuvant chemotherapy containing docetaxel (Taxotere®). Methods This registry was open-label, international, longitudinal, multicenter, and observational in design and included a prospective group of consecutive early breast cancer patients with an intermediate-to-high risk of recurrence being treated with various docetaxel-based (anthracycline and non-anthracycline) adjuvant chemotherapy regimens during 2009-2013 in real-world clinical settings. Results The analysis included 1,712 patients, 79% of whom received docetaxel-based, anthracycline-containing regimens, while 21% received non-anthracycline-containing regimens. Patients receiving adjuvant docetaxel-based chemotherapy were followed for 1.5 years. Chemotherapy-related adverse events (AEs) were reported by 76.2% of patients (anthracycline-containing vs. non-anthracycline-containing regimens: 76.8% vs. 74.1%). Serious AEs were reported in 12% of patients (12.3% vs. 10%). National Cancer Institute Common Terminology Criteria for Adverse Events grade 3 or higher neutropenia was reported in 20% of patients (21.6% vs. 13.9%), leukopenia in 7.4% of patients (5.4% vs. 14.8%), and vomiting in 1.6% of patients (1.8% vs. 0.6%). Treatment-related death was reported in 27 patients (1.6%), while only 3% of patients had a relapse. Low-density lipoprotein cholesterol/high-density lipoprotein cholesterol (HDL-C) and total cholesterol/HDL-C ratios increased after chemotherapy. A clinically insignificant reduction of 1.9% in left ventricular ejection fraction, from 66.43 to 64.53, was observed 1.5 years after therapy was completed. Conclusion The Asia-Pacific Breast initiative II registry identified a variety of important facts regarding patient population characteristics, disease epidemiology and treatment response for early breast cancer patients of the Asia

  5. Initial clinical evaluation of radiolabeled MX-DTPA humanized BrE-3 antibody in patients with advanced breast cancer.

    PubMed

    Kramer, E L; Liebes, L; Wasserheit, C; Noz, M E; Blank, E W; Zabalegui, A; Melamed, J; Furmanski, P; Peterson, J A; Ceriani, R L

    1998-07-01

    To evaluate radiometal-labeled humanized BrE-3 (huBrE-3) monoclonal antibody as a radioimmunolocalization and therapeutic agent in breast cancer patients, tumor localization, pharmacokinetics, radiation dosimetry, and immunogenicity of (111)In-labeled combined 1-p-isothiocyanatobenzyl 3-methyl- and 1-p-isothiocyanatobenzyl 4-methyldiethylenetriamine pentaacetic acid (MX-DTPA) huBrE-3 were studied. Seven women with BrE-3 antigen-positive, metastatic breast carcinoma underwent (111)In huBrE-3 infusion (5 mCi; 50 mg), followed by serial gamma camera imaging and plasma sampling. Region of interest analysis of images was used to make radiation absorbed dose estimates for (111)In huBrE-3. Data were extrapolated to 90Y huBrE-3. Human anti-human antibody (HAHA) response was measured in serum samples obtained up to 3 months after infusion. Patients tolerated infusions well. Seventy-six percent of 105 known sites of disease were identified on planar and single-photon emission computed tomography scans. For six of seven patients, a biexponential model fit the plasma time-activity curve best with an average T1/2alpha=10.6+/-8.5 (SD) h and average T1/2beta=114.2+/-39.2 h. Radiation absorbed dose estimates for (111)In huBrE-3 for whole body averaged 0.53+/-.08 rads/mCi. Dose estimates for 90Y huBrE-3 for marrow averaged 8.4+/-11.9 rads/mCi, and for tumors, 70+/-31.5 rads/mCi. Liver radioactivity uptake averaged 19.7+/-8.8% injected dose at 24 h after infusion, translating into an average radiation absorbed dose 21.1+/-12 rads/90Y mCi administered. Only one of seven patients demonstrated a low level of HAHA response. Although the plasma half-lives are longer and marrow dose higher for radiolabeled huBrE-3 compared with the murine construct, the excellent tumor localization, good tumor dosimetry, and low immunogenicity support the use of 90Y-huBrE-3 antibody for radioimmunotherapy of breast cancer. PMID:9676842

  6. Conceptual and practical challenges for implementing the communities of practice model on a national scale - a Canadian cancer control initiative

    PubMed Central

    2010-01-01

    Background Cancer program delivery, like the rest of health care in Canada, faces two ongoing challenges: to coordinate a pan-Canadian approach across complex provincial jurisdictions, and to facilitate the rapid translation of knowledge into clinical practice. Communities of practice, or CoPs, which have been described by Etienne Wenger as a collaborative learning platform, represent a promising solution to these challenges because they rely on bottom-up rather than top-down social structures for integrating knowledge and practice across regions and agencies. The communities of practice model has been realized in the corporate (e.g., Royal Dutch Shell, Xerox, IBM, etc) and development (e.g., World Bank) sectors, but its application to health care is relatively new. The Canadian Partnership Against Cancer (CPAC) is exploring the potential of Wenger's concept in the Canadian health care context. This paper provides an in-depth analysis of Wenger's concept with a focus on its applicability to the health care sector. Discussion Empirical studies and social science theory are used to examine the utility of Wenger's concept. Its value lies in emphasizing learning from peers and through practice in settings where innovation is valued. Yet the communities of practice concept lacks conceptual clarity because Wenger defines it so broadly and sidelines issues of decision making within CoPs. We consider the implications of his broad definition to establishing an informed nomenclature around this specific type of collaborative group. The CoP Project under CPAC and communities of practice in Canadian health care are discussed. Summary The use of communities of practice in Canadian health care has been shown in some instances to facilitate quality improvements, encourage buy in among participants, and generate high levels of satisfaction with clinical leadership and knowledge translation among participating physicians. Despite these individual success stories, more information

  7. Cancer-Associated Fibroblasts Regulate Tumor-Initiating Cell Plasticity in Hepatocellular Carcinoma through c-Met/FRA1/HEY1 Signaling.

    PubMed

    Lau, Eunice Yuen Ting; Lo, Jessica; Cheng, Bowie Yik Ling; Ma, Mark Kin Fai; Lee, Joyce Man Fong; Ng, Johnson Kai Yu; Chai, Stella; Lin, Chi Ho; Tsang, Suk Ying; Ma, Stephanie; Ng, Irene Oi Lin; Lee, Terence Kin Wah

    2016-05-10

    Like normal stem cells, tumor-initiating cells (T-ICs) are regulated extrinsically within the tumor microenvironment. Because HCC develops primarily in the context of cirrhosis, in which there is an enrichment of activated fibroblasts, we hypothesized that cancer-associated fibroblasts (CAFs) would regulate liver T-ICs. We found that the presence of α-SMA(+) CAFs correlates with poor clinical outcome. CAF-derived HGF regulates liver T-ICs via activation of FRA1 in an Erk1,2-dependent manner. Further functional analysis identifies HEY1 as a direct downstream effector of FRA1. Using the STAM NASH-HCC mouse model, we find that HGF-induced FRA1 activation is associated with the fibrosis-dependent development of HCC. Thus, targeting the CAF-derived, HGF-mediated c-Met/FRA1/HEY1 cascade may be a therapeutic strategy for the treatment of HCC. PMID:27134167

  8. Tools for assessing the quality and accessibility of online health information: initial testing among breast cancer websites.

    PubMed

    Whitten, Pamela; Nazione, Samantha; Lauckner, Carolyn

    2013-12-01

    Health websites are used frequently, but there are many concerns about their value as information sources. Additionally, there are numerous personal barriers that prevent individuals from wholly benefitting from them. In order to assess the quality of health websites and their accessibility to users, we created tools based on previous research that examine design aspects, information validity, motivational health content and literacy content. To test these tools, we examined 155 breast cancer websites and created scores for each assessment tool to describe the percent of constructs on the average website. Results demonstrated that websites performed best on the design tool followed by the information validity, motivational health content and literacy assessment tools. The average website contained the majority of the design and information validity constructs, but only about a third of the motivational health or literacy constructs. Multiple items from the motivational health content and literacy assessment tools were not found on any of the websites, and many were only represented on a handful of sites. Overall, the assessment tools were useful in evaluating the quality of websites, and could serve as valuable resources for health website developers in the future. PMID:23957628

  9. Web Services-Based Access to Local Clinical Trial Databases: A Standards Initiative of the Association of American Cancer Institutes

    PubMed Central

    Stahl, Douglas C.; Evans, Richard M.; Afrin, Lawrence B.; DeTeresa, Richard M.; Ko, Dave; Mitchell, Kevin

    2003-01-01

    Electronic discovery of the clinical trials being performed at a specific research center is a challenging task, which presently requires manual review of the center’s locally maintained databases or web pages of protocol listings. Near real-time automated discovery of available trials would increase the efficiency and effectiveness of clinical trial searching, and would facilitate the development of new services for information providers and consumers. Automated discovery efforts to date have been hindered by issues such as disparate database schemas, vocabularies, and standards for intersystem exchange of high-level data, but adequate infrastructure now exists that makes possible the development of applications for near real-time automated discovery of trials. This paper describes the current state (design and implementation) of the Web Services Specification for Publication and Discovery of Clinical Trials as developed by the Technology Task Force of the Association of American Cancer Institutes. The paper then briefly discusses a prototype web service-based application that implements the specification. Directions for evolution of this specification are also discussed. PMID:14728248

  10. Cri du Chat syndrome

    PubMed Central

    Cerruti Mainardi, Paola

    2006-01-01

    The Cri du Chat syndrome (CdCS) is a genetic disease resulting from a deletion of variable size occurring on the short arm of chromosome 5 (5p-). The incidence ranges from 1:15,000 to 1:50,000 live-born infants. The main clinical features are a high-pitched monochromatic cry, microcephaly, broad nasal bridge, epicanthal folds, micrognathia, abnormal dermatoglyphics, and severe psychomotor and mental retardation. Malformations, although not very frequent, may be present: cardiac, neurological and renal abnormalities, preauricular tags, syndactyly, hypospadias, and cryptorchidism. Molecular cytogenetic analysis has allowed a cytogenetic and phenotypic map of 5p to be defined, even if results from the studies reported up to now are not completely in agreement. Genotype-phenotype correlation studies showed a clinical and cytogenetic variability. The identification of phenotypic subsets associated with a specific size and type of deletion is of diagnostic and prognostic relevance. Specific growth and psychomotor development charts have been established. Two genes, Semaphorin F (SEMAF) and δ-catenin (CTNND2), which have been mapped to the "critical regions", are potentially involved in cerebral development and their deletion may be associated with mental retardation in CdCS patients. Deletion of the telomerase reverse transcriptase (hTERT) gene, localised to 5p15.33, could contribute to the phenotypic changes in CdCS. The critical regions were recently refined by using array comparative genomic hybridisation. The cat-like cry critical region was further narrowed using quantitative polymerase chain reaction (PCR) and three candidate genes were characterised in this region. The diagnosis is based on typical clinical manifestations. Karyotype analysis and, in doubtful cases, FISH analysis will confirm the diagnosis. There is no specific therapy for CdCS but early rehabilitative and educational interventions improve the prognosis and considerable progress has been made in

  11. Reduced-Port Laparoscopic Surgery for a Tumor-Specific Mesorectal Excision in Patients With Colorectal Cancer: Initial Experience With 20 Consecutive Cases

    PubMed Central

    Bae, Sung Uk; Baek, Se Jin; Min, Byung Soh; Baik, Seung Hyuk; Kim, Nam Kyu

    2015-01-01

    Purpose Single-port plus one-port, reduced-port laparoscopic surgery (RPLS) may decrease collisions between laparoscopic instruments and the camera in a narrow, bony, pelvic cavity while maintaining the cosmetic advantages of single-incision laparoscopic surgery. The aim of this study is to describe our initial experience with and to assess the feasibility and safety of RPLS for tumor-specific mesorectal excisions (TSMEs) in patients with colorectal cancer. Methods Between May 2010 and August 2012, RPLS for TSME was performed in 20 patients with colorectal cancer. A single port with four channels through an umbilical incision and an additional port in the right lower quadrant were used for RPLS. Results The median operation time was 231 minutes (range, 160-347 minutes), and the estimated blood loss was 100 mL (range, 50-500 mL). We transected the rectum with one laparoscopic stapler in 17 cases (85%). The median time to soft diet was 4 days (range, 3-6 days), and the length of hospital stay was 7 days (range, 5-45 days). The median total number of lymph nodes harvested was 16 (range, 7-36), and circumferential resection margin involvement was found in 1 case (5%). Seven patients (35%) developed postoperative complications, and no mortalities occurred within 30 days. During the median follow-up period of 20 months (range, 12-40 months), liver metastasis occurred in 1 patient 10 months after surgery, and local recurrence was nonexistent. Conclusion RPLS for TSME in patients with colorectal cancer is technically feasible and safe without compromising oncologic safety. However, further studies comparing RPLS with a conventional, laparoscopic low-anterior resection are needed to prove the advantages of the RPLS procedure. PMID:25745622

  12. Initiation of Metastatic Breast Carcinoma by Targeting of the Ductal Epithelium with Adenovirus-Cre: A Novel Transgenic Mouse Model of Breast Cancer

    PubMed Central

    Svoronos, Nikolaos; Tesone, Amelia J.; Stephen, Tom L.; Perales-Puchalt, Alfredo; Nguyen, Jenny; Zhang, Paul J.; Fiering, Steven N.; Tchou, Julia; Conejo-Garcia, Jose R.

    2014-01-01

    Breast cancer is a heterogeneous disease involving complex cellular interactions between the developing tumor and immune system, eventually resulting in exponential tumor growth and metastasis to distal tissues and the collapse of anti-tumor immunity. Many useful animal models exist to study breast cancer, but none completely recapitulate the disease progression that occurs in humans. In order to gain a better understanding of the cellular interactions that result in the formation of latent metastasis and decreased survival, we have generated an inducible transgenic mouse model of YFP-expressing ductal carcinoma that develops after sexual maturity in immune-competent mice and is driven by consistent, endocrine-independent oncogene expression. Activation of YFP, ablation of p53, and expression of an oncogenic form of K-ras was achieved by the delivery of an adenovirus expressing Cre-recombinase into the mammary duct of sexually mature, virgin female mice. Tumors begin to appear 6 weeks after the initiation of oncogenic events. After tumors become apparent, they progress slowly for approximately two weeks before they begin to grow exponentially. After 7-8 weeks post-adenovirus injection, vasculature is observed connecting the tumor mass to distal lymph nodes, with eventual lymphovascular invasion of YFP+ tumor cells to the distal axillary lymph nodes. Infiltrating leukocyte populations are similar to those found in human breast carcinomas, including the presence of αβ and γδ T cells, macrophages and MDSCs. This unique model will facilitate the study of cellular and immunological mechanisms involved in latent metastasis and dormancy in addition to being useful for designing novel immunotherapeutic interventions to treat invasive breast cancer. PMID:24748051

  13. Breast cancer 1 (BRCA1)-deficient embryos develop normally but are more susceptible to ethanol-initiated DNA damage and embryopathies☆

    PubMed Central

    Shapiro, Aaron M.; Miller-Pinsler, Lutfiya; Wells, Peter G.

    2015-01-01

    The breast cancer 1 (brca1) gene is associated with breast and ovarian cancers, and heterozygous (+/−) brca1 knockout progeny develop normally, suggesting a negligible developmental impact. However, our results show BRCA1 plays a broader biological role in protecting the embryo from oxidative stress. Sox2-promoted Cre-expressing hemizygous males were mated with floxed brca1 females, and gestational day 8 +/− brca1 conditional knockout embryos with a 28% reduction in protein expression were exposed in culture to the reactive oxygen species (ROS)-initiating drug ethanol (EtOH). Untreated +/− brca1-deficient embryos developed normally, but when exposed to EtOH exhibited increased levels of oxidatively damaged DNA, measured as 8-oxo-2'-deoxyguanosine, γH2AX, which is a marker of DNA double strand breaks that can result from 8-oxo-2'-deoxyguanosine, formation, and embryopathies at EtOH concentrations that did not affect their brca1-normal littermates. These results reveal that even modest BRCA1 deficiencies render the embryo more susceptible to drug-enhanced ROS formation, and corroborate a role for DNA oxidation in the mechanism of EtOH teratogenesis. PMID:26629949

  14. Evaluation of quality of life and anxiety and depression levels in patients receiving chemotherapy for colorectal cancer: impact of patient education before treatment initiation

    PubMed Central

    Polat, Ulku; Arpacı, Afey; Demir, Satı; Erdal, Sevgi; Yalcin, Şuayib

    2014-01-01

    Background As a consequence of the improved survival due to the availability of several treatment option cost-effectiveness and health-related quality of life (HRQoL) issues have gained increasing attention in colorectal cancer (CRC). In the present study, we aimed to evaluate quality of life, level of anxiety and depression before and after a 6-month follow-up period in chemotherapy receiving patients with CRC. Methods The study was conducted in 50 patients with colon or rectal cancer. All patients were informed and educated about their disease and treatment before getting the treatment and were followed for 6 months, during which they received chemotherapy. A “Questionnaire Form” to collect patient demographic characteristics; the “EORTC QLQ-C30 Scale” and “EQ-5D Scale” to evaluate patient’s quality of life; and the “Hospital Anxiety and Depression (HAD) Scale” to evaluate the level of anxiety and depression status of patients, were used as data collecting tools. Results Quality of life scores in all functional fields were high in the sixth course when compared to the first according to EORTC QLQ-C30 Scale, reaching to statistically significant level in emotional function score compared to the initial ones (P<0.05). Moreover quality of life score measured in the sixth month with EQ-5D was statistically significantly higher than the initial. Conclusions These data, shows that with proper patient management, quality of life score, and the anxiety and depression levels improve during the course of treatment. PMID:25083300

  15. L'Aventure du LHC

    ScienceCinema

    None

    2011-10-06

    Cette présentation s?adressera principalement aux personnes qui ont construit le LHC. La construction du LHC fut longue et difficile. De nombreux problèmes sont apparus en cours de route. Tous ont été résolus grâce au dévouement et à l?engagement du personnel et des collaborateurs. Je reviendrai sur les coups durs et les réussites qui ont marqués ces 15 dernières années et je vous montrerai combien cette machine, le fruit de vos efforts, est extraordinaire.

  16. L'Aventure du LHC

    SciTech Connect

    2010-06-11

    Cette présentation s’adressera principalement aux personnes qui ont construit le LHC. La construction du LHC fut longue et difficile. De nombreux problèmes sont apparus en cours de route. Tous ont été résolus grâce au dévouement et à l’engagement du personnel et des collaborateurs. Je reviendrai sur les coups durs et les réussites qui ont marqués ces 15 dernières années et je vous montrerai combien cette machine, le fruit de vos efforts, est extraordinaire.

  17. Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer

    PubMed Central

    Saloman, Jami L.; Albers, Kathryn M.; Li, Dongjun; Hartman, Douglas J.; Crawford, Howard C.; Muha, Emily A.; Rhim, Andrew D.; Davis, Brian M.

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is characterized by an exuberant inflammatory desmoplastic response. The PDAC microenvironment is complex, containing both pro- and antitumorigenic elements, and remains to be fully characterized. Here, we show that sensory neurons, an under-studied cohort of the pancreas tumor stroma, play a significant role in the initiation and progression of the early stages of PDAC. Using a well-established autochthonous model of PDAC (PKC), we show that inflammation and neuronal damage in the peripheral and central nervous system (CNS) occurs as early as the pancreatic intraepithelial neoplasia (PanIN) 2 stage. Also at the PanIN2 stage, pancreas acinar-derived cells frequently invade along sensory neurons into the spinal cord and migrate caudally to the lower thoracic and upper lumbar regions. Sensory neuron ablation by neonatal capsaicin injection prevented perineural invasion (PNI), astrocyte activation, and neuronal damage, suggesting that sensory neurons convey inflammatory signals from Kras-induced pancreatic neoplasia to the CNS. Neuron ablation in PKC mice also significantly delayed PanIN formation and ultimately prolonged survival compared with vehicle-treated controls (median survival, 7.8 vs. 4.5 mo; P = 0.001). These data establish a reciprocal signaling loop between the pancreas and nervous system, including the CNS, that supports inflammation associated with oncogenic Kras-induced neoplasia. Thus, pancreatic sensory neurons comprise an important stromal cell population that supports the initiation and progression of PDAC and may represent a potential target for prevention in high-risk populations. PMID:26929329

  18. Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer.

    PubMed

    Saloman, Jami L; Albers, Kathryn M; Li, Dongjun; Hartman, Douglas J; Crawford, Howard C; Muha, Emily A; Rhim, Andrew D; Davis, Brian M

    2016-03-15

    Pancreatic ductal adenocarcinoma (PDAC) is characterized by an exuberant inflammatory desmoplastic response. The PDAC microenvironment is complex, containing both pro- and antitumorigenic elements, and remains to be fully characterized. Here, we show that sensory neurons, an under-studied cohort of the pancreas tumor stroma, play a significant role in the initiation and progression of the early stages of PDAC. Using a well-established autochthonous model of PDAC (PKC), we show that inflammation and neuronal damage in the peripheral and central nervous system (CNS) occurs as early as the pancreatic intraepithelial neoplasia (PanIN) 2 stage. Also at the PanIN2 stage, pancreas acinar-derived cells frequently invade along sensory neurons into the spinal cord and migrate caudally to the lower thoracic and upper lumbar regions. Sensory neuron ablation by neonatal capsaicin injection prevented perineural invasion (PNI), astrocyte activation, and neuronal damage, suggesting that sensory neurons convey inflammatory signals from Kras-induced pancreatic neoplasia to the CNS. Neuron ablation in PKC mice also significantly delayed PanIN formation and ultimately prolonged survival compared with vehicle-treated controls (median survival, 7.8 vs. 4.5 mo; P = 0.001). These data establish a reciprocal signaling loop between the pancreas and nervous system, including the CNS, that supports inflammation associated with oncogenic Kras-induced neoplasia. Thus, pancreatic sensory neurons comprise an important stromal cell population that supports the initiation and progression of PDAC and may represent a potential target for prevention in high-risk populations. PMID:26929329

  19. Prognostic Factors for Survival and Resection in Patients With Initial Nonresectable Locally Advanced Pancreatic Cancer Treated With Chemoradiotherapy

    SciTech Connect

    Bjerregaard, Jon K.; Mortensen, Michael B.; Jensen, Helle A.; Nielsen, Morten; Pfeiffer, Per

    2012-07-01

    Background and Purpose: Controversies regarding the optimal therapy for patients with locally advanced pancreatic cancer (LAPC) exist. Although the prognosis as a whole remains dismal, subgroups are known to benefit from intensive therapy, including chemoradiotherapy (CRT). We describe the results in 178 patients treated from 2001 to 2010 and have developed a prognostic model for both survival and the possibility of a subsequent resection in these patients. Methods and Materials: From 2001 until 2010, 178 consecutive patients with LAPC were treated and included in the present study, with CRT consisting of 50 Gy in 27 fractions combined with tegafur-uracil(UFT)/folinic acid(FA). Results: The median survival from diagnosis was 11.5 months. Adverse events of Grade 3 or above were seen in 36% of the patients. Ninety-three percent of the patients completed all fractions. A Cox regression model for survival demonstrated resection (hazard ratio [HR] 0.12; 95% confidence interval [CI], 0.1-0.3) and pre-CRT gemcitabine-based therapy (HR 0.57; 95% CI, 0.4-0.9) as being associated with a favorable outcome, increasing gross tumor volume (HR 1.14; 95% CI, 1.0-1.3) was associated with shorter survival. A logistic regression model showed Stage III disease (odds ratio [OR] 0.16; 95% CI, 0.0-1.1) and abnormal hemoglobin (OR 0.26; 95% CI, 0.0-1.2) as being associated with lower odds of resection. Conclusion: This study confirms the favorable prognosis for patients receiving gemcitabine therapy before CRT and the poor prognosis associated with increasing tumor volume. In addition, CRT in patients with abnormal hemoglobin and Stage III disease rarely induced tumor shrinkage allowing subsequent resection.

  20. Migration and epithelial-to-mesenchymal transition of lung cancer can be targeted via translation initiation factors eIF4E and eIF4GI.

    PubMed

    Attar-Schneider, Oshrat; Drucker, Liat; Gottfried, Maya

    2016-09-01

    Metastasis underlies cancer morbidity and accounts for disease progression and significant death rates generally and in non-small cell lung cancer (NSCLC) particularly. Therefore, it is critically important to understand the molecular events that regulate metastasis. Accumulating data portray a central role for protein synthesis, particularly translation initiation (TI) factors eIF4E and eIF4G in tumorigenesis and patients' survival. We have published that eIF4E/eIF4GI activities and consequently NSCLC cell migration are modulated by bone-marrow mesenchymal stem cell secretomes, suggesting a role for TI in metastasis. Here, we aimed to expand our understanding of the TI factors significance to NSCLC characteristics, particularly epithelial-to-mesenchymal transition (EMT) and migration, supportive of metastasis. In a model of NSCLC cell lines (H1299, H460), we inhibited eIF4E/eIF4GI's expressions (siRNA, ribavirin) and assessed NSCLC cell lines' migration (scratch), differentiation (EMT, immunoblotting), and expression of select microRNAs (qPCR). Initially, we determined an overexpression of several TI factors (eIF4E, eIF4GI, eIF4B, and DHX29) and their respective targets in NSCLC compared with normal lung samples (70-350%↑, P<0.05). Knockdown (KD) of eIF4E/eIF4GI in NSCLC cell lines (70%↓, P<0.05) also manifested in decreased target levels (ERα, SMAD5, NFkB, CyclinD1, c-MYC, and HIF1α) (20-50%↓, P<0.05). eIF4E/eIF4GI KD also attenuated cell migration (60-75%↓, P<0.05), EMT promoters (15-90%↓, P<0.05), and enhanced EMT suppressors (30-380%↑, P<0.05). The importance of eIF4E KD to NSCLC phenotype was further corroborated with its inhibitor, ribavirin. Changes in expression of essential microRNAs implicated in NSCLC cell migration concluded the study (20-100%, P<0.05). In summary, targeting eIF4E/eIF4GI reduces migration and EMT, both essential for metastasis, thereby underscoring the potential of TI targeting in NSCLC therapy, especially the already

  1. MicroRNA-199a targets CD44 to suppress the tumorigenicity and multidrug resistance of ovarian cancer-initiating cells.

    PubMed

    Cheng, Weiwei; Liu, Te; Wan, Xiaoping; Gao, Yongtao; Wang, Hui

    2012-06-01

    In ovarian cancer, CD44(+) /CD117(+) stem cells, also known as cancer-initiating cells (CICs), are highly proliferative, have a low degree of differentiation, and are resistant to chemotherapeutics. Therefore, the CD44(+) /CD117(+) subpopulation is thought to be an important target for novel therapeutic strategies. In this stud