Antagonizing Self-Renewal in Acute Myeloid Leukemia: ID2 Takes the Stage

Publication date: 11 July 2016
Source:Cancer Cell, Volume 30, Issue 1
Author(s): Gauri Deb, Tim C.P. Somervaille
E proteins and their functional antagonists, the ID proteins, have significant roles in normal hematopoiesis. In this issue of Cancer Cell, Ghisi et al. show that high ID2 levels antagonize self-renewal and promote differentiation of leukemic stem cells in the MLL-translocated molecular subtype of acute myeloid leukemia.

Teaser

E proteins and their functional antagonists, the ID proteins, have significant roles in normal hematopoiesis. In this issue of Cancer Cell, Ghisi et al. show that high ID2 levels antagonize self-renewal and promote differentiation of leukemic stem cells in the MLL-translocated molecular subtype of acute myeloid leukemia.


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RIPK3 Slams the Brake on Leukemogenesis

Publication date: 11 July 2016
Source:Cancer Cell, Volume 30, Issue 1
Author(s): Francis Ka-Ming Chan
Evasion of cell death is a key hallmark of cancers. In this issue of Cancer Cell, Höckendorf and colleagues identified RIPK3, an essential kinase for necroptosis, as having a key role in inhibiting acute myeloid leukemia development.

Teaser

Evasion of cell death is a key hallmark of cancers. In this issue of Cancer Cell, Höckendorf and colleagues identified RIPK3, an essential kinase for necroptosis, as having a key role in inhibiting acute myeloid leukemia development.


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Modeling the Epigenetic Chain Reaction Downstream of DNMT3AR882H

Publication date: 11 July 2016
Source:Cancer Cell, Volume 30, Issue 1
Author(s): Tim D.D. Somerville, Christopher R. Vakoc
In this issue of Cancer Cell, Lu et al. use a mouse model of DNMT3A^R882H/NRAS^G12D acute myeloid leukemia to define a cascade of chromatin changes that emanate from DNMT3A-bound enhancers to initiate disease. The authors also reveal a chemical strategy to interrupt this process.

Teaser

In this issue of Cancer Cell, Lu et al. use a mouse model of DNMT3A^R882H/NRAS^G12D acute myeloid leukemia to define a cascade of chromatin changes that emanate from DNMT3A-bound enhancers to initiate disease. The authors also reveal a chemical strategy to interrupt this process.


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Tumor-Associated Neutrophils Show Phenotypic and Functional Divergence in Human Lung Cancer

Publication date: 11 July 2016
Source:Cancer Cell, Volume 30, Issue 1
Author(s): Shilpi Saha, Subhra K. Biswas
Studies in murine cancer models have demonstrated the phenotypic and functional divergence of neutrophils; however, their role in pro- or anti-tumor responses in human remains elusive. In this issue of Cancer Cell, Singhal et al. report the existence of specialized subsets of neutrophils in human lung cancer with diverging functions.

Teaser

Studies in murine cancer models have demonstrated the phenotypic and functional divergence of neutrophils; however, their role in pro- or anti-tumor responses in human remains elusive. In this issue of Cancer Cell, Singhal et al. report the existence of specialized subsets of neutrophils in human lung cancer with diverging functions.


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Molecular Subtypes of Non-muscle Invasive Bladder Cancer

Publication date: 11 July 2016
Source:Cancer Cell, Volume 30, Issue 1
Author(s): Seth P. Lerner, A. Gordon Robertson
In this issue of Cancer Cell, Hedegaard et al. report a comprehensive multi-center transcriptional analysis of non-muscle invasive urothelial bladder cancer. They describe three molecular subtypes similar to those seen in other cohorts, as well as a unique CIS signature associated with risk of progression to muscle invasive cancer.

Teaser

In this issue of Cancer Cell, Hedegaard et al. report a comprehensive multi-center transcriptional analysis of non-muscle invasive urothelial bladder cancer. They describe three molecular subtypes similar to those seen in other cohorts, as well as a unique CIS signature associated with risk of progression to muscle invasive cancer.


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Hunger Pains: Stimulating the Appetite of the Immune System for Cancer

Publication date: 11 July 2016
Source:Cancer Cell, Volume 30, Issue 1
Author(s): Judson M. Englert, Jonathan D. Powell
In this issue, Pietrocola et al. and Di Biase et al. independently demonstrate that caloric restriction from fasting and pharmacologic inhibition results in an enhanced immunogenic response leading to reduced tumor growth. These two studies provide an exciting connection between the emerging fields of cancer and immune metabolism.

Teaser

In this issue, Pietrocola et al. and Di Biase et al. independently demonstrate that caloric restriction from fasting and pharmacologic inhibition results in an enhanced immunogenic response leading to reduced tumor growth. These two studies provide an exciting connection between the emerging fields of cancer and immune metabolism.


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P(URI)fying Novel Drivers of NASH and HCC: A Feedforward Loop of IL17A via White Adipose Tissue

Publication date: 11 July 2016
Source:Cancer Cell, Volume 30, Issue 1
Author(s): Achim Weber, Mathias Heikenwalder
How obesity and metabolic syndrome trigger non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) remains elusive. In this issue, Gomes and colleagues describe that nutrient surplus induces hepatic URI expression, triggering genotoxicity and IL17A expression, thus leading to insulin resistance, NASH, and HCC. IL17A signaling blockers might become a readily translatable therapy.

Teaser

How obesity and metabolic syndrome trigger non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) remains elusive. In this issue, Gomes and colleagues describe that nutrient surplus induces hepatic URI expression, triggering genotoxicity and IL17A expression, thus leading to insulin resistance, NASH, and HCC. IL17A signaling blockers might become a readily translatable therapy.


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The Multifaceted Role of Perivascular Macrophages in Tumors

Publication date: 11 July 2016
Source:Cancer Cell, Volume 30, Issue 1
Author(s): Claire E. Lewis, Allison S. Harney, Jeffrey W. Pollard
Evidence has emerged for macrophages in the perivascular niche of tumors regulating important processes like angiogenesis, various steps in the metastatic cascade, the recruitment and activity of other tumor-promoting leukocytes, and tumor responses to frontline therapies like irradiation and chemotherapy. Understanding the mechanisms controlling the recruitment, retention, and function of these cells could identify important targets for anti-cancer therapeutics.

Teaser

Evidence has emerged for macrophages in the perivascular niche of tumors regulating important processes like angiogenesis, various steps in the metastatic cascade, the recruitment and activity of other tumor-promoting leukocytes, and tumor responses to frontline therapies like irradiation and chemotherapy. Understanding the mechanisms controlling the recruitment, retention, and function of these cells could identify important targets for anti-cancer therapeutics.


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RIPK3 Restricts Myeloid Leukemogenesis by Promoting Cell Death and Differentiation of Leukemia Initiating Cells

Publication date: 11 July 2016
Source:Cancer Cell, Volume 30, Issue 1
Author(s): Ulrike Höckendorf, Monica Yabal, Tobias Herold, Enkhtsetseg Munkhbaatar, Stephanie Rott, Stefanie Jilg, Johanna Kauschinger, Giovanni Magnani, Florian Reisinger, Michael Heuser, Hans Kreipe, Karl Sotlar, Thomas Engleitner, Roland Rad, Wilko Weichert, Christian Peschel, Jürgen Ruland, Mathias Heikenwalder, Karsten Spiekermann, Julia Slotta-Huspenina, Olaf Groß, Philipp J. Jost
Since acute myeloid leukemia (AML) is characterized by the blockade of hematopoietic differentiation and cell death, we interrogated RIPK3 signaling in AML development. Genetic loss of Ripk3 converted murine FLT3-ITD-driven myeloproliferation into an overt AML by enhancing the accumulation of leukemia-initiating cells (LIC). Failed inflammasome activation and cell death mediated by tumor necrosis factor receptor caused this accumulation of LIC exemplified by accelerated leukemia onset in Il1r1^−/−, Pycard^–/–, and Tnfr1/2^−/− mice. RIPK3 signaling was partly mediated by mixed lineage kinase domain-like. This link between suppression of RIPK3, failed interleukin-1β release, and blocked cell death was supported by significantly reduced RIPK3 in primary AML patient cohorts. Our data identify RIPK3 and the inflammasome as key tumor suppressors in AML.

Graphical abstract

Teaser

Höckendorf et al. demonstrate that RIPK3 restricts malignant myeloproliferation by activating the inflammasome, which promotes differentiation and cell death, and that loss of RIPK3 increases leukemic burden in mice. Reduced RIPK3 expression is observed across several human acute myeloid leukemia subtypes.


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Fasting-Mimicking Diet Reduces HO-1 to Promote T Cell-Mediated Tumor Cytotoxicity

Publication date: 11 July 2016
Source:Cancer Cell, Volume 30, Issue 1
Author(s): Stefano Di Biase, Changhan Lee, Sebastian Brandhorst, Brianna Manes, Roberta Buono, Chia-Wei Cheng, Mafalda Cacciottolo, Alejandro Martin-Montalvo, Rafael de Cabo, Min Wei, Todd E. Morgan, Valter D. Longo
Immune-based interventions are promising strategies to achieve long-term cancer-free survival. Fasting was previously shown to differentially sensitize tumors to chemotherapy while protecting normal cells, including hematopoietic stem and immune cells, from its toxic side effects. Here, we show that the combination of chemotherapy and a fasting-mimicking diet (FMD) increases the levels of bone marrow common lymphoid progenitor cells and cytotoxic CD8⁺ tumor-infiltrating lymphocytes (TILs), leading to a major delay in breast cancer and melanoma progression. In breast tumors, this effect is partially mediated by the downregulation of the stress-responsive enzyme heme oxygenase-1 (HO-1). These data indicate that FMD cycles combined with chemotherapy can enhance T cell-dependent targeted killing of cancer cells both by stimulating the hematopoietic system and by enhancing CD8⁺-dependent tumor cytotoxicity.

Graphical abstract

Teaser

Di Biase et al. show that combining a fasting-mimicking diet with chemotherapy increases the levels of bone marrow common lymphoid progenitor cells and cytotoxic CD8⁺ tumor-infiltrating lymphocytes, delaying tumor progression. In breast tumors, this effect is partially mediated by downregulating HO-1.


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Caloric Restriction Mimetics Enhance Anticancer Immunosurveillance

Publication date: 11 July 2016
Source:Cancer Cell, Volume 30, Issue 1
Author(s): Federico Pietrocola, Jonathan Pol, Erika Vacchelli, Shuan Rao, David P. Enot, Elisa E. Baracco, Sarah Levesque, Francesca Castoldi, Nicolas Jacquelot, Takahiro Yamazaki, Laura Senovilla, Guillermo Marino, Fernando Aranda, Sylvère Durand, Valentina Sica, Alexis Chery, Sylvie Lachkar, Verena Sigl, Norma Bloy, Aitziber Buque, Simonetta Falzoni, Bernhard Ryffel, Lionel Apetoh, Francesco Di Virgilio, Frank Madeo, Maria Chiara Maiuri, Laurence Zitvogel, Beth Levine, Josef M. Penninger, Guido Kroemer
Caloric restriction mimetics (CRMs) mimic the biochemical effects of nutrient deprivation by reducing lysine acetylation of cellular proteins, thus triggering autophagy. Treatment with the CRM hydroxycitrate, an inhibitor of ATP citrate lyase, induced the depletion of regulatory T cells (which dampen anticancer immunity) from autophagy-competent, but not autophagy-deficient, mutant KRAS-induced lung cancers in mice, thereby improving anticancer immunosurveillance and reducing tumor mass. Short-term fasting or treatment with several chemically unrelated autophagy-inducing CRMs, including hydroxycitrate and spermidine, improved the inhibition of tumor growth by chemotherapy in vivo. This effect was only observed for autophagy-competent tumors, depended on the presence of T lymphocytes, and was accompanied by the depletion of regulatory T cells from the tumor bed.

Teaser

Pietrocola et al. show that short-term fasting or autophagy-inducing caloric restriction mimetics, such as hydroxycitrate and spermidine, improves the antitumor efficacy of chemotherapy in vivo. The effect is specific for autophagy-competent tumors and depends on regulatory T cell depletion from the tumor bed.


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Metabolic Inflammation-Associated IL-17A Causes Non-alcoholic Steatohepatitis and Hepatocellular Carcinoma

Publication date: 11 July 2016
Source:Cancer Cell, Volume 30, Issue 1
Author(s): Ana L. Gomes, Ana Teijeiro, Stefan Burén, Krishna S. Tummala, Mahmut Yilmaz, Ari Waisman, Jean-Philippe Theurillat, Cristian Perna, Nabil Djouder
Obesity increases hepatocellular carcinoma (HCC) risks via unknown mediators. We report that hepatic unconventional prefoldin RPB5 interactor (URI) couples nutrient surpluses to inflammation and non-alcoholic steatohepatitis (NASH), a common cause of HCC. URI-induced DNA damage in hepatocytes triggers inflammation via T helper 17 (Th17) lymphocytes and interleukin 17A (IL-17A). This induces white adipose tissue neutrophil infiltration mediating insulin resistance (IR) and fatty acid release, stored in liver as triglycerides, causing NASH. NASH and subsequently HCC are prevented by pharmacological suppression of Th17 cell differentiation, IL-17A blocking antibodies, and genetic ablation of the IL-17A receptor in myeloid cells. Human hepatitis, fatty liver, and viral hepatitis-associated HCC exhibit increased IL-17A correlating positively with steatosis. IL-17A blockers may prevent IR, NASH, and HCC in high-risk patients.

Graphical abstract

Teaser

Gomes et al. show that excess nutrients lead to URI-dependent DNA damage in hepatocytes, triggering inflammation via Th17 cells and IL-17A. Suppression of Th17 cell differentiation or blocking IL-17A signaling prevents non-alcoholic steatohepatitis and subsequent hepatocellular carcinoma.


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Molecular Mechanism of SSR128129E, an Extracellularly Acting, Small-Molecule, Allosteric Inhibitor of FGF Receptor Signaling

Publication date: 11 July 2016
Source:Cancer Cell, Volume 30, Issue 1
Author(s): Corentin Herbert, Ulrich Schieborr, Krishna Saxena, Jarek Juraszek, Frederik De Smet, Chantal Alcouffe, Marc Bianciotto, Giorgio Saladino, David Sibrac, Denis Kudlinzki, Sridhar Sreeramulu, Alan Brown, Patrice Rigon, Jean-Pascal Herault, Gilbert Lassalle, Tom L. Blundell, Frederic Rousseau, Ann Gils, Joost Schymkowitz, Peter Tompa, Jean-Marc Herbert, Peter Carmeliet, Francesco Luigi Gervasio, Harald Schwalbe, Françoise Bono




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CARM1 Methylates Chromatin Remodeling Factor BAF155 to Enhance Tumor Progression and Metastasis

Publication date: 11 July 2016
Source:Cancer Cell, Volume 30, Issue 1
Author(s): Lu Wang, Zibo Zhao, Mark B. Meyer, Sandeep Saha, Menggang Yu, Ailan Guo, Kari B. Wisinski, Wei Huang, Weibo Cai, J. Wesley Pike, Ming Yuan, Paul Ahlquist, Wei Xu




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Rab1A Is an mTORC1 Activator and a Colorectal Oncogene

Publication date: 11 July 2016
Source:Cancer Cell, Volume 30, Issue 1
Author(s): Janice D. Thomas, Yan-Jie Zhang, Yue-Hua Wei, Jun-Hung Cho, Laura E. Morris, Hui-Yun Wang, X.F. Steven Zheng




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The Public Repository of Xenografts Enables Discovery and Randomized Phase II-like Trials in Mice

Publication date: 11 July 2016
Source:Cancer Cell, Volume 30, Issue 1
Author(s): Elizabeth C. Townsend, Mark A. Murakami, Alexandra Christodoulou, Amanda L. Christie, Johannes Köster, Tiffany A. DeSouza, Elizabeth A. Morgan, Scott P. Kallgren, Huiyun Liu, Shuo-Chieh Wu, Olivia Plana, Joan Montero, Kristen E. Stevenson, Prakash Rao, Raga Vadhi, Michael Andreeff, Philippe Armand, Karen K. Ballen, Patrizia Barzaghi-Rinaudo, Sarah Cahill, Rachael A. Clark, Vesselina G. Cooke, Matthew S. Davids, Daniel J. DeAngelo, David M. Dorfman, Hilary Eaton, Benjamin L. Ebert, Julia Etchin, Brant Firestone, David C. Fisher, Arnold S. Freedman, Ilene A. Galinsky, Hui Gao, Jacqueline S. Garcia, Francine Garnache-Ottou, Timothy A. Graubert, Alejandro Gutierrez, Ensar Halilovic, Marian H. Harris, Zachary T. Herbert, Steven M. Horwitz, Giorgio Inghirami, Andrew M. Intlekofer, Moriko Ito, Shai Izraeli, Eric D. Jacobsen, Caron A. Jacobson, Sébastien Jeay, Irmela Jeremias, Michelle A. Kelliher, Raphael Koch, Marina Konopleva, Nadja Kopp, Steven M. Kornblau, Andrew L. Kung, Thomas S. Kupper, Nicole R. LeBoeuf, Ann S. LaCasce, Emma Lees, Loretta S. Li, A. Thomas Look, Masato Murakami, Markus Muschen, Donna Neuberg, Samuel Y. Ng, Oreofe O. Odejide, Stuart H. Orkin, Rachel R. Paquette, Andrew E. Place, Justine E. Roderick, Jeremy A. Ryan, Stephen E. Sallan, Brent Shoji, Lewis B. Silverman, Robert J. Soiffer, David P. Steensma, Kimberly Stegmaier, Richard M. Stone, Jerome Tamburini, Aaron R. Thorner, Paul van Hummelen, Martha Wadleigh, Marion Wiesmann, Andrew P. Weng, Jens U. Wuerthner, David A. Williams, Bruce M. Wollison, Andrew A. Lane, Anthony Letai, Monica M. Bertagnolli, Jerome Ritz, Myles Brown, Henry Long, Jon C. Aster, Margaret A. Shipp, James D. Griffin, David M. Weinstock




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Compounds Triggering ER Stress Exert Anti-Melanoma Effects and Overcome BRAF Inhibitor Resistance

Publication date: 11 July 2016
Source:Cancer Cell, Volume 30, Issue 1
Author(s): Michaël Cerezo, Abdelali Lehraiki, Antoine Millet, Florian Rouaud, Magali Plaisant, Emilie Jaune, Thomas Botton, Cyril Ronco, Patricia Abbe, Hella Amdouni, Thierry Passeron, Veronique Hofman, Baharia Mograbi, Anne-Sophie Dabert-Gay, Delphine Debayle, Damien Alcor, Nabil Rabhi, Jean-Sébastien Annicotte, Laurent Héliot, Mariano Gonzalez-Pisfil, Caroline Robert, Solange Moréra, Armelle Vigouroux, Philippe Gual, Maruf M.U. Ali, Corine Bertolotto, Paul Hofman, Robert Ballotti, Rachid Benhida, Stéphane Rocchi




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The artificial ovary: current status and future perspectives

Future Oncology Ahead of Print.


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Human Cancer Models Initiative Will Create Next Generation Cancer Models That Have Genomic and Clinical Data

Experimental studies using cancer cell lines are an essential step in successful cancer research. Researchers use cell lines to discover new genes involved in cancer, test the biological function of genes, and even develop and evaluate new treatments. 

However, most cancer cell lines in use today do not provide scientists with a complete toolkit for their research. They lack the architecture and complexity of human tissue, as well as key information that can inform research, such as genomic and clinical profiles. Moreover, given the great genetic diversity of cancer, many common and rare subtypes of cancer are inadequately represented among existing cancer cell lines. That's why the NCI has joined forces with the foremost experts in novel cell culture techniques to generate new models of cancer that more accurately represent human tumors.

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D -dimer concentrations in dogs with kidney disease with or without protein-losing nephropathy

Abstract

Limited information is currently available regarding the range of D-dimer concentrations in dogs with kidney disease (KD). The objective of the present cross-sectional study was to investigate the concentration of D-dimers in dogs with KD irrelevant of the underlying cause or the time course of the KD and the potential association of D-dimers elevation with serum creatinine concentration, concurrent protein-losing nephropathy (PLN) or the age of the animals. D-dimers were measured by a semi-quantitative plasma latex agglutination assay in 31 healthy dogs (group A) and in 30 dogs with KD (group B), without evidence of concurrent extra-renal disease that may precipitate hypercoagulation. Significantly higher median D-dimer concentrations (p = 0.0133) and a higher prevalence of increased D-dimers (≥250 μg/L) (p = 0.011) were documented in dogs with KD as compared to healthy dogs, and the increased D-dimers were not associated with the serum creatinine concentration, the coexistent PLN or the age of the dogs. In conclusion, the detection of increased D-dimers in the context of impaired kidney function should be cautiously interpreted in the dog and should not be invariably assumed to imply the presence of a state of hypercoagulability.

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The effect of hydroalcoholic extract of Mangifera indica on induced osteoarthritis of knee in male guinea pigs

Abstract

Osteoarthritis (OA) is one of the top six diseases for which complementary and alternative medicine is used. Among the herbal products, mango could be regarded as a potential natural remedy for OA due to its anti-inflammatory characteristics. The aim of the present study was to evaluate the healing effect of mango on OA of the knee. Eighteen male guinea pigs were chosen, and anterior cruciate ligament transection was performed for them to induce OA for the animal models. Then, they were recruited in four treatment groups (n = 5): (a) oral treatment, (b) intra-articular injection treatment, (c) prevention, and (d) control. After 18 weeks, the outcomes were evaluated by radiologic and histopathologic assessments. Histopathological assessment of the articular cartilages showed smooth and continuous articular surface with columnar cell distribution in the injection group which were improved better than the others while the surface in the control group has an irregularity. The radiological assessment of the knee joints shows that they were improved during the second 4 weeks after treatment. Radiological findings were similar to histopathologic assessment in which the improvement of the articular cartilage was better in the injection group compared with the oral and prevention group. The control group did not change remarkably. It seems that Mangifera fruit can be regarded as an effective complementary and alternative treatment for OA of the knee.

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A five-gene expression signature to predict progression in T1G3 bladder cancer

Publication date: September 2016
Source:European Journal of Cancer, Volume 64
Author(s): Antoine G. van der Heijden, Lourdes Mengual, Juan J. Lozano, Mercedes Ingelmo-Torres, Maria J. Ribal, Pedro L. Fernández, Egbert Oosterwijk, Jack A. Schalken, Antonio Alcaraz, J. Alfred Witjes
ObjectiveThe aim of this study was to analyze tumour gene expression profiles of progressive and non-progressive T1G3 bladder cancer (BC) patients to develop a gene expression signature to predict tumour progression.MethodsRetrospective, multicenter study of 96 T1G3 BC patients without carcinoma in situ (CIS) who underwent a transurethral resection. Formalin-fixed paraffin-embedded tissue samples were collected. Global gene expression patterns were analyzed in 21 selected samples from progressive and non-progressive T1G3 BC patients using Illumina microarrays. Expression levels of 94 genes selected based on microarray data and based on literature were studied by quantitative polymerase chain reaction (qPCR) in an independent series of 75 progressive and non-progressive T1G3 BC patients. Univariate logistic regression was used to identify individual predictors. A variable selection method was used to develop a multiplex biomarker model. Discrimination of the model was measured by area under the receiver-operating characteristic curve. Interaction networks between the genes of the model were built by GeneMANIA Cytoscape plugin.ResultsA total of 1294 genes were found differentially expressed between progressive and non-progressive patients. Differential expression of 15 genes was validated by qPCR in an additional set of samples. A five-gene expression signature (ANXA10, DAB2, HYAL2, SPOCD1, and MAP4K1) discriminated progressive from non-progressive T1G3 BC patients with a sensitivity of 79% and a specificity of 86% (AUC = 0.83). Direct interactions between the five genes of the model were not found.ConclusionsProgressive and non-progressive T1G3 bladder tumours have shown different gene expression patterns. To identify T1G3 BC patients with a high risk of progression, a five-gene expression signature has been developed.



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Gray Areas in Language-Concordant Healthcare: a Graduating Medical Student’s Reflection on the Experience and Research on Language and Cultural Competence

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YPEL3 suppresses epithelial–mesenchymal transition and metastasis of nasopharyngeal carcinoma cells through the Wnt/β-catenin signaling pathway

Abstract

Background

Metastasis remains the major cause of death in nasopharyngeal carcinoma (NPC). Yippee-like 3 (YPEL3) plays an important role in tumorigenesis. However, its function and mechanism in NPC has not been systematically explored.

Methods

We evaluated YPEL3 expression in NPC cell lines and tissues using real-time PCR and western blotting. Then, we established NPC cell lines that stably overexpressed YPEL3 and knocked down YPEL3 expression to explore its function in NPC in vitro and in vivo. Additionally, we investigated the potential mechanism of YPEL3 action by identifying the Wnt/β-catenin signaling pathway downstream genes using western blotting.

Results

YPEL3 was downregulated in NPC cell lines and tissue samples. Ectopic expression of YPEL3 inhibited NPC cell migration and invasion in vitro; while silencing of YPEL3 promoted NPC cell migration and invasion. Further study indicated that overexpression of YPEL3 inhibited NPC cell epithelial–mesenchymal transition (EMT) and that silencing it enhanced EMT. Overexpression of YPEL3 suppressed NPC cell lung metastasis in vivo. The mechanism study determined that YPEL3 suppressed the expression levels of Wnt/β-catenin signaling pathway downstream genes and the nuclear translocation of β-catenin.

Conclusions

YPEL3 suppresses NPC EMT and metastasis by suppressing the Wnt/β-catenin signaling pathway, which would help better understanding the molecular mechanisms of NPC metastasis and provide novel therapeutic targets for NPC treatment.

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The anti-tumor effect of the quinoline-3-carboxamide tasquinimod: blockade of recruitment of CD11b + Ly6C hi cells to tumor tissue reduces tumor growth

Abstract

Background

Previous work has demonstrated immunomodulatory, anti-tumor, anti-metastatic and anti-angiogenic effects of the small molecule quinoline-3-carboxamide tasquinimod in pre-clinical cancer models. To better understand the anti-tumor effects of tasquinimod in transplantable tumor models, we have evaluated the impact of the compound both on recruitment of myeloid cells to tumor tissue and on tumor-induced myeloid cell expansion as these cells are known to promote tumor development.

Methods

Mice bearing subcutaneous 4 T1 mammary carcinoma tumors were treated with tasquinimod in the drinking water. A BrdU-based flow cytometry assay was utilized to assess the impact of short-term tasquinimod treatment on myeloid cell recruitment to tumors. Additionally, long-term treatment was performed to study the anti-tumor effect of tasquinimod as well as its effects on splenic myeloid cells and their progenitors. Myeloid cell populations were also immune-depleted by in vivo antibody treatment.

Results

Short-term tasquinimod treatment did not influence the proliferation of splenic Ly6C^hi and Ly6G^hi cells, but instead reduced the influx of Ly6C^hi cells to the tumor. Treatment with tasquinimod for various periods of time after tumor inoculation revealed that the anti-tumor effect of this compound mainly operated during the first few days of tumor growth. Similar to tasquinimod treatment, antibody-mediated depletion of Ly6C^hi cells within that same time frame, caused reduced tumor growth, thereby confirming a significant role for these cells in tumor development. Additionally, long-term tasquinimod treatment reduced the splenomegaly and expansion of splenic myeloid cells during a later phase of tumor development. In this phase, tasquinimod normalized the tumor-induced alterations in myeloerythroid progenitor cells in the spleen but had only limited impact on the same populations in the bone marrow.

Conclusions

Our results indicate that tasquinimod treatment reduces tumor growth by operating early after tumor inoculation and that this effect is at least partially caused by reduced recruitment of Ly6C^hi cells to tumor tissue. Long-term treatment also reduces the number of splenic myeloid cells and myeloerythroid progenitors, but these effects did not influence established rapidly growing tumors.

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Total antioxidant intake and prostate cancer in the Cancer of the Prostate in Sweden (CAPS) study. A case control study

Abstract

Background

The total intake of dietary antioxidants may reduce prostate cancer risk but available data are sparse and the possible role of supplements unclear. We investigated the potential association between total and dietary antioxidant intake and prostate cancer in a Swedish population.

Methods

We used FFQ data from 1499 cases and 1112 controls in the population based case–control study Cancer of the Prostate in Sweden (CAPS). The ferric reducing antioxidant potential (FRAP) assay was used to assess the total antioxidant capacity (TAC) of diet and supplements. We calculated odds ratios (ORs) for the risk of prostate cancer across quintiles of antioxidant intake from all foods, from fruit and vegetables only, and from dietary supplements using unconditional logistic regression.

Results

Coffee comprised 62 % of the dietary antioxidant intake, tea 4 %, berries 4 %, chocolate 2 %, and boiled potatoes 2 %. In total 19 % and 13 % of the population took multivitamins and supplemental Vitamin C respectively, on a regular basis. Antioxidant intake from all foods and from fruits and vegetables separately measured by the FRAP assay was not associated with prostate cancer risk. For antioxidant intake from supplements we found a positive association with total, advanced, localized, high grade and low grade prostate cancer in those above median supplemental TAC intake of users compared to non-users (Adjusted ORs for total prostate cancer: 1.37, 95 % CI 1.08–1.73, advanced: 1.51, 95 % CI 1.11–2.06, localized: 1.36. 95 % CI 1.06–1.76, high grade 1.60, 95 % CI 1.06–2.40, low grade 1.36, 95 % CI 1.03–1.81). A high intake of coffee (≥6 cups/day) was associated with a possible risk reduction of fatal and significantly with reduced risk for high grade prostate cancer, adjusted OR: 0.45 (95 % CI: 0.22–0.90), whereas a high intake of chocolate was positively associated with risk of total, advanced, localized and low grade disease (adjusted OR for total: 1.43, 95 % CI 1.12–1.82, advanced: 1.40, 95 % CI 1.01–1.96, localized: 1.43, 95 % CI 1.08–1.88, low-grade: 1.41, 95 % CI 1.03–1.93).

Conclusions

Total antioxidant intake from diet was not associated with prostate cancer risk. Supplement use may be associated with greater risk of disease.

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Clinical relevance of peroxisome proliferator-activated receptor-gamma expression in myxoid liposarcoma

Abstract

Background

Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcription factor that belongs to the nuclear hormone receptor superfamily. PPARγ is essential in adipocyte differentiation from precursor cells. Its antitumorigenic effects are reported in certain malignancies; however, its effects in liposarcoma are unclear.

Methods

We analyzed PPARγ expression using immunohistochemistry (IHC) in 46 patients with myxoid liposarcoma [MLS; median age, 47 years (range, 14–90 years) and mean follow-up period, 91 months (range, 13–358 months)]. PPARγ mRNA expression levels were measured by quantitative reverse transcription polymerase chain reaction. Further, we evaluated the correlation of PPARγ expression with clinical outcomes.

Results

We found that the metastasis-free survival rate was significantly higher in lower PPARγ expressers [34 patients with labeling index (LI) <50 %] than in higher expressers (12 patients with LI ≥50 %; p = 0.01). Cox multivariate analysis revealed that a higher PPARγ level was an independent predictor of metastasis (relative risk = 6.945, p = 0.026). Furthermore, using 28 fresh MLS specimens, we confirmed an increased PPARγ mRNA expression level in the higher LI group (p = 0.001).

Conclusions

In this study, higher PPARγ expression in MLS was a risk factor associated with distant metastasis; therefore, it would be a novel prognostic marker for MLS. Further analyses will help to understand the correlation between PPARγ expression and tumor malignancy in liposarcoma.

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Spinal disease in myeloma: cohort analysis at a specialist spinal surgery centre indicates benefit of early surgical augmentation or bracing

Abstract

Background

Multiple myeloma osteolytic disease affecting the spine results in vertebral compression fractures. These are painful, result in kyphosis, and impact respiratory function and quality of life. We explore the impact of time to presentation on the efficacy of spinal treatment modalities.

Methods

We retrospectively reviewed 183 patients with spinal myeloma presenting to our service over a 2 year period.

Results

Median time from multiple myeloma diagnosis to presentation at our centre was 195 days. Eighty-four patients (45.9 %) were treated with balloon kyphoplasty and the remainder with a thoracolumbar-sacral orthosis as per our published protocol. Patients presenting earlier than 195 days from diagnosis had significant improvements in patient reported outcome measures: EuroQol 5-Dimensions (p < 0.001), Oswestry Disability Index (p < 0.001), and Visual Analogue Pain Score (p < 0.001) at follow-up, regardless of treatment. Patients presenting after 195 days, however, only experienced benefit following balloon kyphoplasty, with no significant benefit from non-operative management.

Conclusion

Vertebral augmentation and thoracolumbar bracing improve patient reported outcome scores in patients with spinal myeloma. However, delay in treatment negatively impacts clinical outcome, particularly if managed non-operatively. It is important to screen and treat patients with MM and back pain early to prevent deformity and improve quality of life.

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Erlotinib plus gemcitabine versus gemcitabine for pancreatic cancer: real-world analysis of Korean national database

Abstract

Background

A randomized clinical trial has found that the addition of erlotinib to gemcitabine (GEM-E) for pancreatic cancer led to a modest increase in survival. The aim of this national population-based retrospective study was to compare the effectiveness of GEM-E to GEM alone for pancreatic cancer patients in real clinical practice.

Methods

Patients with pancreatic cancer (ICD-10: C25) with prescription claims of gemcitabine or erlotinib between Jan 1, 2007 and Dec 31, 2012 were retrospectively identified from the Korean Health Insurance claims database. To be included in the study population, patients were required to have had a histological or cytological diagnosis within one year before chemotherapy. Patients treated with prior radiotherapy, surgery, or chemotherapy were excluded to reduce heterogeneity. Overall survival from the initiation of therapy and the medical costs of GEM-E and GEM were compared.

Results

A total of 4,267 patients were included in the analysis. Overall survival was not significantly longer in patients treated with GEM-E (median 6.77 months for GEM-E vs. 6.68 months for GEM, p = 0.0977). There was also no significant difference in the respective one-year survival rates (27.0 % vs. 27.3 %; p = 0.5988). Multivariate analysis using age, gender, and comorbidities as covariates did not reveal any significant differences in survival. Based on this relative effectiveness, the incremental cost per life year gained over GEM was estimated at USD 70,843.64 for GEM-E.

Conclusions

GEM-E for pancreatic cancer is not more effective than GEM in a real-world setting, and it does not provide reasonable cost-effectiveness over GEM.

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Implementation of immunochemical faecal occult blood test in general practice: a study protocol using a cluster-randomised stepped-wedge design

Abstract

Background

Colorectal cancer is a common malignancy and a leading cause of cancer-related death. Half of patients with colorectal cancer initially present with non-specific or vague symptoms. In the need for a safe low-cost test, the immunochemical faecal occult blood test (iFOBT) may be part of the evaluation of such patients in primary care. Currently, Danish general practitioners have limited access to this test. The aim of this article is to describe a study that will assess the uptake and clinical use of iFOBT in general practice. Furthermore, it will investigate the diagnostic value and the clinical implications of using iFOBT in general practice on patients presenting with non-alarm symptoms of colorectal cancer.

Methods/Design

The study uses a cluster-randomised stepped-wedge design and is conducted in the Central Denmark Region among 836 GPs in 381 general practices. The municipalities of the Region and their appertaining general practitioners will be included sequentially in the study during the first 7 months of the 1-year study period. The following intervention has been developed for the study: a mandatory intervention providing all general practitioners with a starting package of 10 iFOBTs, a clinical instruction on iFOBT use in general practice and online information material from the date of inclusion, and an optional intervention consisting of a continuous medical education on colorectal cancer diagnostics and use of iFOBT.

Discussion

This study is among the first and largest trials to investigate the diagnostic use and the clinical value of iFOBT on patients presenting with non-alarm symptoms of colorectal cancer. The findings will be of national and international importance for the future planning of colorectal cancer diagnostics, particularly for 'low-risk-but-not-no-risk' patients with non-alarm symptoms of colorectal cancer.

Trial registration

A Trial of the Implementation of iFOBT in General Practice NCT02308384. Date of registration: 26 November 2014

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Retrospective and comparative analysis of 99m Tc-Sestamibi breast specific gamma imaging versus mammography, ultrasound, and magnetic resonance imaging for the detection of breast cancer in Chinese women

Abstract

Background

Diagnosing breast cancer during the early stage may be helpful for decreasing cancer-related mortality. In Western developed countries, mammographies have been the gold standard for breast cancer detection. However, Chinese women usually have denser and smaller-sized breasts compared to Caucasian women, which decreases the diagnostic accuracy of mammography. However, breast specific gamma imaging, a type of molecular functional breast imaging, has been used for the accurate diagnosis of breast cancer and is not influenced by breast density. Our objective was to analyze the breast specific gamma imaging (BSGI) diagnostic value for Chinese women.

Methods

During a 2-year period, 357 women were diagnosed and treated at our oncology department and received BSGI in addition to mammography (MMG), ultrasound (US) and magnetic resonance imaging (MRI) for diagnostic assessment. We investigated the sensitivity and specificity of each method of detection and compared the biological profiles of the four imaging methods.

Results

A total of 357 women received a final surgical pathology diagnosis, with 168 malignant diseases (58.5 %) and 119 benign diseases (41.5 %). Of these, 166 underwent the four imaging tests preoperatively. The sensitivity of BSGI was 80.35 and 82.14 % by US, 75.6 % by MMG, and 94.06 % by MRI. Furthermore, the breast cancer diagnosis specificity of BSGI was high (83.19 % vs. 77.31 % vs. 66.39 % vs. 67.69 %, respectively). The BSGI diagnostic sensitivity for mammographic breast density in women was superior to mammography and more sensitive for non-luminal A subtypes (luminal A vs. non-luminal A, 68.63 % vs. 88.30 %).

Conclusions

BSGI may help improve the ability to diagnose early stage breast cancer for Chinese women, particularly for ductal carcinoma in situ (DCIS), mammographic breast density and non-luminal A breast cancer.

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Osteopontin splice variants are differential predictors of breast cancer treatment responses

Abstract

Background

Osteopontin is a marker for breast cancer progression, which in previous studies has also been associated with resistance to certain anti-cancer therapies. It is not known which splice variants may mediate treatment resistance.

Methods

Here we analyze the association of osteopontin variant expression before treatment, differentiated according to immunohistochemistry with antibodies to exon 4 and to the osteopontin-c splice junction respectively, with the ensuing therapy responses in 119 Polish breast cancer patients who presented between 1995 and 2008.

Results

We found from Cox hazard models, logrank test and Wilcoxon test that osteopontin exon 4 was associated with a favorable response to tamoxifen, but a poor response to chemotherapy with CMF (cyclophosphamide, methotrexate, fluorouracil). Osteopontin-c is prognostic, but falls short of being a significant predictor for sensitivity to treatment.

Conclusions

The addition of osteopontin splice variant immunohistochemistry to standard pathology work-ups has the potential to aid decision making in breast cancer treatment.

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Population attributable fraction of Esophageal squamous cell carcinoma due to smoking and alcohol in Uganda

Abstract

Background

Despite the high rates and regional variation of esophageal squamous cell carcinoma (ESCC) in East Africa, the contributions of smoking and alcohol to the ESCC burden in the general population are unknown.

Methods

We conducted a case-control study of patients presenting for upper gastrointestinal endoscopic examination at Mbarara Regional Referral Hospital, Uganda. Sociodemographic data including smoking and alcohol intake were collected prior to endoscopy. Cases were those with histological diagnosis of ESCC and controls were participants with normal endoscopic examination and gastritis/duodentitis or normal histology. We used odds ratios associated with ESCC risk to determine the population attributable fractions for smoking, alcohol use, and a combination of smoking and alcohol use among adults aged 30 years or greater who underwent upper gastrointestinal endoscopy.

Results

Our study consisted of 67 cases and 142 controls. Median age was 51 years (IQR 40–64); and participants were predominantly male (59 %). Dysphagia and/or odynophagia as indications for endoscopy were significantly more in cases compared to controls (72 % vs 6 %, p < 0.0001). Male gender and increasing age were statistically associated with ESCC. In the unadjusted models, the population attributable fraction of ESCC due to male gender was 55 %, female gender - 49 %, smoking 20 %, alcohol 9 % and a combination of alcohol & smoking 15 %. After adjusting for gender and age, the population attributable fraction of ESCC due to smoking, alcohol intake and a combination of alcohol & smoking were 16, 10, and 13 % respectively.

Conclusion

In this population, 13 % of esophageal squamous cell carcinoma cases would be avoided if smoking and alcohol use were discontinued. These results suggest that other important risk factors for ESCC in southwestern Uganda remain unknown.

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Alveolar Rhabdomyosarcoma of the foot metastasizing to the Iris: report of a rare case

Abstract

Background

Intraocular iris rhabdomyosarcoma is extremely rare, and in the 3 cases reported to date occurred as the primary site of tumour growth. We report a case of rhabdomyosarcoma of the foot metastasizing to the iris.

Case presentation

An 18-year-old white female was referred to the London Ocular Oncology Service for management of a metastatic rhabdomyosarcomatous deposit in the iris, a metastasis from alveolar rhabdomyosarcoma of the foot. She was diagnosed nearly 2 years earlier with the primary sarcoma with extensive systemic spread and treated by resection of the foot lesion and chemotherapy, and achieved a partial remission. The left iris deposit was noted while she was receiving systemic chemotherapy, heralding a relapse. However, anterior uveitis and raised intraocular pressure developed and she was referred to our service for further management. A left iris secondary rhabdomyosarcoma deposit was noticed and in addition a lacrimal gland mass, as indicated by ultrasound B scan of the eye and orbit. The patient was treated with external beam radiotherapy to the globe and orbit, but died 2 months after treatment completion.

Conclusion

Rhabdomyosarcoma of the iris is very rare and was previously documented only as a primary malignancy in this location. We report that secondary spread to the iris can also occur, in this case as the first sign of widely disseminated systemic relapse.

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Fast-track surgery improves postoperative clinical recovery and cellular and humoral immunity after esophagectomy for esophageal cancer

Abstract

Background

Our aim was to investigate the influence of FTS on human cellular and humoral immunity using a randomized controlled clinical study in esophageal cancer patients.

Methods

Between October 2013 and December 2014, 276 patients with esophageal cancer in our department were enrolled in the study. The patients were randomized into two groups: FTS pathway group and conventional pathway group. The postoperative hospital stay, hospitalization expenditure, and postoperative complications were recorded. The markers of inflammatory and immune function were measured before operation as well as on the 1st, 3rd, and 7th postoperative days (POD), including serum level of interleukin-6 (IL-6), C-reactive protein (CRP), serum globulin, immunoglobulin G (IgG), immunoglobulin M (IgM), immunoglobulin A (IgA) and lymphocyte subpopulations (CD3 lymphocytes, CD4 lymphocytes, CD8 lymphocytes and the CD4/CD8 ratio) in the patients between the two groups.

Results

In all, 260 patients completed the study: 128 in the FTS group and 132 in the conventional group. We found implementation of FTS pathway decreases postoperative length of stay and hospital charges (P < 0.05). In addition, inflammatory reactions, based on IL-6 and CRP levels, were less intense following FTS pathway compared to conventional pathway on POD1 and POD3 (P < 0.05). On POD1 and POD3, the levels of IgG, IgA, CD3 lymphocytes, CD4 lymphocytes and the CD4/CD8 ratio in FTS group were significantly higher than those in control group (All P < 0.05). However, there were no differences in the level of IgM and CD8 lymphocytes between the two groups.

Conclusions

FTS improves postoperative clinical recovery and effectively inhibited release of inflammatory factors via the immune system after esophagectomy for esophageal cancer.

Trial registration

ChiCTR-TRC-13003562, the date of registration: August 29, 2013.

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Prognostic significance of annexin A2 and annexin A4 expression in patients with cervical cancer

Abstract

Background

The annexins (ANXs) have diverse roles in tumor development and progression, however, their clinical significance in cervical cancer has not been elucidated. The present study was to investigate the clinical significance of annexin A2 (ANXA2) and annexin A4 (ANXA4) expression in cervical cancer.

Methods

ANXA2 and ANXA4 immunohistochemical staining were performed on a cervical cancer tissue microarray consisting of 46 normal cervical epithelium samples and 336 cervical cancer cases and compared the data with clinicopathological variables, including the survival of cervical cancer patients.

Results

ANXA2 expression was lower in cancer tissue (p = 0.002), whereas ANXA4 staining increased significantly in cancer tissues (p < 0.001). ANXA2 expression was more prominent in squamous cell carcinoma (p < 0.001), whereas ANXA4 was more highly expressed in adeno/adenosquamous carcinoma (p < 0.001). ANXA2 overexpression was positively correlated with advanced cancer phenotypes, whereas ANXA4 expression was associated with resistance to radiation with or without chemotherapy (p = 0.029). Notably, high ANXA2 and ANXA4 expression was significantly associated with shorter disease-free survival (p = 0.004 and p = 0.033, respectively). Multivariate analysis indicated that ANXA2+ (HR = 2.72, p = 0.003) and ANXA2+/ANXA4+ (HR = 2.69, p = 0.039) are independent prognostic factors of disease-free survival in cervical cancer. Furthermore, a random survival forest model using combined ANXA2, ANXA4, and clinical variables resulted in improved predictive power (mean C-index, 0.76) compared to that of clinical-variable-only models (mean C-index, 0.70) (p = 0.006).

Conclusions

These findings indicate that detecting ANXA2 and ANXA4 expression may aid the evaluation of cervical carcinoma prognosis.

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Efficacy of preoperative biliary drainage in malignant obstructive jaundice: a meta-analysis and systematic review

Abstract

Background

In patients requiring surgical resection for malignant biliary jaundice, it is unclear if preoperative biliary drainage (PBD) would improve mortality and morbidity by restoration of biliary flow prior to operation. This is a meta-analysis to pool the evidence and assess the utility of PBD in patients with malignant obstructive jaundice. The primary outcome is comparing mortality outcomes in patients with malignant obstructive jaundice undergoing direct surgery (DS) versus PBD. The secondary outcomes include major adverse events and length of hospital stay in both the groups.

Methods

Studies using PBD in patients with malignant obstructive jaundice were included in this study. For the data collection and extraction, articles were searched in MEDLINE, PubMed, Embase, Cochrane Central Register of Controlled Trials & Database of Systematic Reviews, etc. Pooled proportions were calculated using both Mantel-Haenszel method (fixed effects model) and DerSimonian-Laird method (random effects model).

Results

Initial search identified 2230 reference articles, of which 204 were selected and reviewed. Twenty-six studies (N = 3532) for PBD in malignant obstructive jaundice which met the inclusion criteria were included in this analysis. The odds ratio for mortality in PBD group versus DS group was 0.96 (95 % CI = 0.71 to 1.29). Pooled number of major adverse effects was lower in the PBD group at 10.40 (95 % CI = 9.96 to 10.83) compared to 15.56 (95 % CI = 15.06 to 16.05) in the DS group. Subgroup analysis comparing internal PBD to DS group showed lower odds for major adverse events (odds ratio, 0.48 with 95 % CI = 0.32 to 0.74).

Conclusions

In patients with malignant biliary jaundice requiring surgery, PBD group had significantly less major adverse effects than DS group. Length of hospital stay and mortality rate were comparable in both the groups.

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Concept de perte de chance : une évolution majeure dans la définition du préjudice, ou comment éviter le litige pour perte de chance ?

Publication date: Available online 21 June 2016
Source:Cancer/Radiothérapie
Author(s): T.-D. Nguyen
La notion de faute médicale en droit de la responsabilité reposait jusqu'à ces dernières années sur la nécessité d'un lien de causalité direct et certain entre la faute et le préjudice. Depuis les années 1960 et en augmentation au cours de la dernière décennie, la notion de perte de chance considérée comme un nouveau et réel préjudice (en pratique un dommage réparable) a pris naissance, puis s'est trouvée l'objet de plusieurs jurisprudences de la Cour de cassation et du conseil d'État. Les justiciables sont donc actuellement en mesure de demander une réparation au titre de la perte de chance alors même qu'il existe une incertitude sur un lien de causalité entre la faute et le dommage observé. Les circonstances les plus fréquentes de litiges impliquant une perte de chance sont le défaut d'information, le défaut ou le retard du diagnostic, le retard d'intervention et le défaut de bilan. L'auteur présente à partir de cas concrets les circonstances les plus favorables à l'apparition d'un litige pour perte de chance et discute les mesures préventives à retenir.The concept of medical error in responsibility litigation was based until the past last years on a necessary direct and definite causal link between fault and injury. In France, since the 1960s and increasingly during the last decade, the idea of loss of chance arose, considered as a new and genuine prejudice (practically, a fixable damage); it became the subject of several legal precedents from the Cour de cassation and the Conseil d'État. Thus, plaintiffs may currently demand a compensation for a loss of chance even though a doubt exists on the causal link between the fault and the observed damage. The most frequent litigation circumstances implying a loss of chance are lack of information, lack or delay in diagnosis, delay in action, and default in medical assessment. Based on practical cases, the author presents the most propitious situations where litigation for loss of chance may occur and discusses possible preventive measures.



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Rac3 regulates cell proliferation through cell cycle pathway and predicts prognosis in lung adenocarcinoma

Abstract

Lung cancer is still the leading cause of malignant deaths in the world. It is of great importance to find novel functional genes for the tumorigenesis of lung cancer. We demonstrated that Rac3 could promote cell proliferation and inhibit apoptosis in lung adenocarcinoma cell line A549 previously. The aim of this study was to investigate the function and mechanism of Rac3 in lung adenocarcinoma cell lines. Immunohistochemistry staining was performed in 107 lung adenocarcinoma tissues and matched non-tumor tissues. Multivariate analysis and Kaplan-Meier analysis were used to investigate the correlation between Rac3 expression and the clinical outcomes. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, colony formation assay, and flow cytometry analysis were employed to determine the proliferative ability, cell cycle distribution, and apoptosis in H1299 and H1975 cell lines. Gene expression microarray and pathway analysis between the Rac3-siRNA group and the control group in A549 cells were performed to investigate the pathways and mechanism of Rac3 regulation. Rac3 was shown to be positively expressed in lung adenocarcinoma tissues, and the expression of Rac3 associates with longer survival in lung adenocarcinoma patients. Silencing of Rac3 significantly induced cell growth inhibition, colony formation decrease, cell cycle arrest, and apoptosis of lung adenocarcinoma cell lines, which accompanied by obvious downregulation of CCND1, MYC, and TFDP1 of cell cycle pathway involving in the tumorigenesis of lung adenocarcinoma based on the gene expression microarray. In conclusion, these findings suggest that Rac3 has the potential of being a therapeutic target for lung adenocarcinoma.

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Influence of ADORA2A gene polymorphism on leukoencephalopathy risk in MTX-treated pediatric patients affected by hematological malignancies

Abstract

Background

Methotrexate (MTX) can lead to neurotoxicity and asymptomatic leukoencephalopathy. However, the mechanism of MTX-related leukoencephalopathy is obscure. MTX and its metabolites inhibit 5-aminoimidazole-4-carboxamide ribonucleotide formiltransferase (ATIC) and promote adenosine release. Recently, it has been reported that adenosine and its receptor are related to certain central nervous system diseases. We investigated whether adenosine pathway gene polymorphisms and clinical factors were related to MTX-related leukoencephalopathy in pediatric patients affected by hematological malignancies.

Procedure

Fifty-six Japanese childhood acute lymphoblastic leukemia or lymphoma patients were investigated. Patients were evaluated by magnetic resonance imaging of the brain before maintenance therapy or stem cell transplantation. Gene polymorphisms within the adenosine pathway (ATIC, adenosine A2A receptor [ADORA2A]) and the MTX pathway (methylenetetrahydrofolate reductase [MTHFR] and ABCB1) were genotyped using TaqMan assays. Clinical data were collected by accessing the medical records. MTX-related leukoencephalopathy was evaluated by a pediatric neurologist.

Results

Twenty-one (37%) of 56 patients developed MTX-related leukoencephalopathy. Four of 21 patients developed clinical neurotoxicity. The minor allele CC genotype of rs2298383 (ADORA2A) was associated with MTX-related leukoencephalopathy (P = 0.010, odds ratio = 5.81, 95% confidence interval 1.50–22.50). High cumulative dose of systemic MTX was associated with MTX-related leukoencephalopathy after adjusting for sex, ADORA2A polymorphism, and prolonged high MTX concentration (P = 0.042, odds ratio = 1.18, 95% confidence interval 1.01–1.37).

Conclusions

ADORA2A rs2298383 and high cumulative dose of systemic MTX administration were significantly associated with MTX-related leukoencephalopathy. Our results indicate that pharmacological intervention within the adenosine pathway may be both a treatment and preventative option for MTX-related leukoencephalopathy.

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Cytopathologic features of NUT midline carcinoma: A series of 26 specimens from 13 patients

BACKGROUND

NUT midline carcinoma (NMC) is an increasingly recognized neoplasm defined by rearrangements of the nuclear protein in testis (NUT) gene (also known as NUTM1). NMC is important to diagnose for prognostic and diagnostic reasons, but to date, only a small case series and rare case reports of the cytopathologic features of NMC have been published.

METHODS

All NMC specimens (confirmed by molecular testing and/or NUT immunoreactivity) with cytopathologic material available were identified at 2 academic centers. All smears were reviewed, and the cytologic characteristics were described.

RESULTS

Twenty-six cytopathologic specimens of NMC were identified from 13 patients: 8 men and 5 women ranging in age from 16 to 68 years (mean, 35 years). The NMCs arose in the mediastinum (n = 4), sinonasal tract (n = 4), neck (n = 2), lung (n = 1), lung and mediastinum (n = 1), and kidney (n = 1). Cytologic specimens included serous cavity effusions (n = 13), fine-needle aspirates (n = 9), bronchial brushings (n = 2), bronchial lavage (n = 1), and bronchial washings (n = 1). Ancillary studies were performed on cell blocks for only 6 samples from 4 patients: immunohistochemistry (n = 6) and flow cytometry (n = 1). All 13 NMCs had corresponding surgical pathology material. The NUT rearrangement status was known in 10 cases, and in 3 cases, the diagnosis was established by immunoreactivity for NUT. On cytologic smears, the NMCs were mostly hypercellular with monotonous, small to midsize, primitive-appearing cells largely distributed singly in a discohesive pattern. The tumor cells had round to oval nuclei that appeared mostly naked and devoid of cytoplasm. The nuclei varied in chromatin density from mostly pale, open chromatin to a hyperchromatic, neuroendocrine-type appearance, often with focal cell-to-cell molding, and most examples had a distinct, small nucleolus.

CONCLUSIONS

NMC is a recently recognized tumor that should be considered in the differential diagnosis of small round cell tumors, especially but not exclusively in the mediastinum and the head and neck. The cytologic features of NMC overlap considerably with those of other neoplasms, and a definitive diagnosis depends on a demonstration of NUT translocation by either immunohistochemical or molecular means. Cancer Cytopathol 2016. © 2016 American Cancer Society.

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The temporal relationship between diabetes and cancer: A population-based study

BACKGROUND

Diabetes is associated with an increased risk of several cancers; however, greater detection of cancer around the time of diabetes diagnosis may partly contribute to this relationship. The goal of the current study was to explore the temporal relationship between diabetes and cancer incidence.

METHODS

The authors conducted a retrospective, population-based cohort study of >1 million adults living in Ontario, Canada to evaluate the association between diabetes diagnosis and the incidence of cancer in 3 time periods: within the 10 years before a diabetes diagnosis, within the first 3 months after a diabetes diagnosis, and from 3 months to 10 years after a diabetes diagnosis.

RESULTS

Individuals with diabetes were significantly more likely to have been diagnosed with cancer within the 10 years before a diabetes diagnosis compared with individuals without diabetes (odds ratio, 1.23; 95% confidence interval [95% CI], 1.19-1.27). Cancer incidence also was found to be significantly higher in individuals with diabetes within the 3-month period after a diabetes diagnosis (hazard ratio, 1.62; 95% CI, 1.52-1.74), whereas the risk was not found to be elevated in the later period (hazard ratio, 0.97; 95% CI, 0.95-0.98). Similar trends were noted for individual cancers.

CONCLUSIONS

The results demonstrated that individuals with diabetes had a significantly higher risk of most cancers, which was limited to the time periods before and immediately after a diabetes diagnosis. The highest risk period was observed within the first 3 months after a diabetes diagnosis, suggesting a partial role of detection bias in the apparent relationship between diabetes and cancer. Cancer 2016. © 2016 American Cancer Society.

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Table of Content Volume 55, Number 9, September 2016

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Profound clinical and radiological response to BRAF inhibition in a 2-month-old diencephalic child with hypothalamic/chiasmatic glioma

Abstract

Infants with low-grade glioma (LGG) have a poor survival. BRAFV600E mutation has been identified in pediatric LGG; however, the use of BRAF inhibitors in infants has never been reported. A 2-month-old with V600E mutant hypothalamic/chiasmatic glioma progressed on chemotherapy resulting in profound visual loss, massive ascites, and diencephalic syndrome. Initiation of dabrafenib resulted in rapid and sustained disappearance of clinical symptoms and a profound sustained cytoreduction. BRAF inhibition was safely tolerated with dramatic clinicoradiological response, suggesting early targeted therapy is a viable option in infants with LGG. A re-evaluation of current management paradigms in this population is warranted to leverage the potential benefit of upfront-targeted therapies.

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Clinical presentation and risk factors of serious infections in children with Down syndrome treated for acute lymphoblastic leukemia

Abstract

Background

Treatment of acute lymphoblastic leukemia (ALL) in children with Down syndrome (DS) is associated with a higher incidence of life-threatening infections compared to the overall pediatric population. The objective of this study was to describe infections and identify risk factors of microbiologically documented infections at a sterile site in children with DS during chemotherapy for ALL.

Procedure

We conducted a single-institution retrospective review of infectious episodes encountered by patients with DS during primary treatment for ALL. Correlations between features of clinical presentation and severity of microbiologically proven infections were investigated.

Results

Among 237 suspected infectious episodes encountered by 35 patients with DS and ALL (DS–ALL), a total of 40 episodes (16.9%) had the clinical presentation of a severe infection (SI). Seventeen patients had 33 (13.9%) microbiologically proven infections from a sterile site. Fever was not part of the clinical presentation in 27% of microbiologically documented infectious episodes. The odds ratio of a microbiologically proven infection at a sterile site was significantly increased during a 7-day interval after treatment with glucocorticoids (2.18; 95% CI: 1.02–4.66; P = 0.04). Neither administration of anthracyclines in the preceding 14 days nor neutropenia correlated with infections.

Conclusions

Serious infections in DS–ALL may present without typical signs such as fever. The immediate time period following administration of glucocorticoids is particularly associated with the risk of SIs.

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Premature physeal closure following 13-cis-retinoic acid and prolonged fenretinide administration in neuroblastoma

Abstract

Retinoid therapy has contributed to improved outcomes in neuroblastoma. Clinical trials of fenretinide report favorable toxicity and disease stabilization in patients with high risk (HR) neuroblastoma. Skeletal effects have been described with other retinoids, but not with fenretinide to date. Two patients with HR, metastatic, refractory neuroblastoma received protracted courses of oral fenretinide for more than 5 years' duration. Both developed premature long bone physeal closure, causing limb length discrepancies; their neuroblastoma remains in remission. The radiographic and clinical findings reported suggest these skeletal abnormalities may be a consequence of treatment with 13-cis-retinoic acid (13cisRA) followed by prolonged oral fenretinide exposure.

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A Cost-Effectiveness Analysis of Clopidogrel for Patients with Non-ST-Segment Elevation Acute Coronary Syndrome in China

Abstract

Introduction

There are a number of economic evaluation studies of clopidogrel for patients with non-ST-segment elevation acute coronary syndrome (NSTEACS) published from the perspective of multiple countries in recent years. However, relevant research is quite limited in China. We aimed to estimate the long-term cost effectiveness for up to 1-year treatment with clopidogrel plus acetylsalicylic acid (ASA) versus ASA alone for NSTEACS from the public payer perspective in China.

Methods

This analysis used a Markov model to simulate a cohort of patients for quality-adjusted life years (QALYs) gained and incremental cost for lifetime horizon. Based on the primary event rates, adherence rate, and mortality derived from the CURE trial, hazard functions obtained from published literature were used to extrapolate the overall survival to lifetime horizon. Resource utilization, hospitalization, medication costs, and utility values were estimated from official reports, published literature, and analysis of the patient-level insurance data in China. To assess the impact of parameters' uncertainty on cost-effectiveness results, one-way sensitivity analyses were undertaken for key parameters, and probabilistic sensitivity analysis (PSA) was conducted using the Monte Carlo simulation.

Results

The therapy of clopidogrel plus ASA is a cost-effective option in comparison with ASA alone for the treatment of NSTEACS in China, leading to 0.0548 life years (LYs) and 0.0518 QALYs gained per patient. From the public payer perspective in China, clopidogrel plus ASA is associated with an incremental cost of 43,340 China Yuan (CNY) per QALY gained and 41,030 CNY per LY gained (discounting at 3.5% per year). PSA results demonstrated that 88% of simulations were lower than the cost-effectiveness threshold of 150,721 CYN per QALY gained. Based on the one-way sensitivity analysis, results are most sensitive to price of clopidogrel, but remain well below this threshold.

Conclusion

This analysis suggests that treatment with clopidogrel plus ASA for up to 1 year for patients with NSTEACS is cost effective in the local context of China from a public payers' perspective.

Funding

Sanofi China.

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Sulodexide in Patients with Chronic Venous Disease of the Lower Limbs: Clinical Efficacy and Impact on Quality of Life

Abstract

Introduction

Chronic venous disease (CVD) of the lower limbs is a common problem. It is more prevalent in women than in men and has a significant impact on patients' quality of life (QoL) and on the healthcare system. The aim of this study was to evaluate the efficacy of sulodexide in adult patients with CVD of the lower limbs and its effect on patients' QoL.

Methods

Patients with CVD were treated with sulodexide [250 LSU (lipasemic units) twice daily] for 3 months in a setting of real-life clinical practice. The endpoints of this observational non-comparative, open-label prospective study were the clinical efficacy of sulodexide (evaluated by scoring objective and subjective symptoms with a Likert-type scale) and the impact of sulodexide therapy on patients' QoL [assessed using the chronic venous insufficiency quality of life questionnaire (CIVIQ)].

Results

The study included 450 patients (mean age 46.9 ± 10.5 years, range 17–78 years). A greater percentage of patients were female (65.4%). Three months of treatment with sulodexide significantly improved all objective and subjective symptoms (p < 0.0001). Overall, patients reported a significant improvement in all QoL scores (p < 0.0001). Adverse events were spontaneously reported by two patients (one case of epigastric pain and one of gastric pain with vomiting).

Conclusion

Oral sulodexide significantly improves both objective and subjective symptoms, as well as functional and psychological aspects of QoL in patients with CVD.

Funding

No funding or sponsorship was received for this study. Sponsorship for article processing charges and open access fees was provided by Alfa Wassermann.

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Assessment of Factors Related to the Understanding of Education and Knowledge of Self-Care among Patients with Diabetes Mellitus: A Cross-Sectional Prospective Study

Abstract

Introduction

The prevalence of diabetes mellitus is rapidly increasing particularly in developing countries. The aim of this study was to assess the knowledge and self-care practices of diabetes patients and to assess the contribution of the education to this knowledge level and glycemic control.

Methods

We formed patient groups consisting of 15–30 diabetic patients. First, patients were surveyed using a diabetes self-care knowledge questionnaire (DSCKQ-30). Sunsequently, a standard PowerPoint presentation about diabetes self-management was made to the patients who were then surveyed again using DSCKQ-30. All patients were invited to hospital to measure their control glycated hemoglobin (HbA1c) level 3 months later.

Results

Of the total 364 participants, 62.9% were females. Significant increases in the percentage of correct responses were determined in all components between, before and after education. There was a significant decline of 1.1 in HbA1c levels after 3 months of education. Married or active working patients had a better understanding of the education about diabetes and had a greater knowledge of self-care management regardless of their level of education or income.

Conclusion

Education about diabetes can significantly improve knowledge of self-care management and can help in achieving glycemic control. Continuing education about self-care management and complications is crucial and this should be accompanied by a regular assessment of pateients' diabetic knowledge.

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Psychosocial distress and its effects on the health-related quality of life of primary brain tumor patients

CNS Oncology Ahead of Print.


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