International Journal of Cancer

Cover image for Vol. 135 Issue 11

Early View (Online Version of Record published before inclusion in an issue)

Editor-in-Chief: Professor Peter Lichter, DKFZ, Germany

Impact Factor: 5.007

ISI Journal Citation Reports © Ranking: 2013: 34/202 (Oncology)

Online ISSN: 1097-0215

  1. Epidemiology

    1. Improvement in population-based survival of stage IV NSCLC due to increased use of chemotherapy

      Mieke J. Aarts, Ben E. van den Borne, Bonne Biesma, Jeroen S. Kloover, Joachim G. Aerts and Valery E.P.P. Lemmens

      Article first published online: 30 SEP 2014 | DOI: 10.1002/ijc.29216

      What's new?

      The addition of chemotherapy to supportive care can improve survival in patients with metastatic (stage IV) non-small cell lung cancer (NSCLC). But certain factors, such as socioeconomic status and patient age, may dictate whether patients with advanced disease use chemotherapy. This population-based study shows that chemotherapy use in stage IV NSCLC is affected by a variety of patient and tumor characteristics. Hospital of diagnosis is also a factor, with significant differences in chemotherapy use observed among hospitals. Increasing administration rates of chemotherapy over the period 2001 to 2012 resulted in an extension of median survival by three weeks.

    2. Intrauterine devices and endometrial cancer risk: A pooled analysis of the Epidemiology of Endometrial Cancer Consortium

      Ashley S. Felix, Mia M. Gaudet, Carlo La Vecchia, Christina M. Nagle, Xiao Ou Shu, Elisabete Weiderpass, Hans Olov Adami, Shirley Beresford, Leslie Bernstein, Chu Chen, Linda S. Cook, Immaculata De Vivo, Jennifer A. Doherty, Christine M. Friedenreich, Susan M. Gapstur, Dierdre Hill, Pamela L. Horn-Ross, James V. Lacey, Fabio Levi, Xiaolin Liang, Lingeng Lu, Anthony Magliocco, Susan E. McCann, Eva Negri, Sara H. Olson, Julie R. Palmer, Alpa V. Patel, Stacey Petruzella, Jennifer Prescott, Harvey A. Risch, Lynn Rosenberg, Mark E. Sherman, Amanda B. Spurdle, Penelope M. Webb, Lauren A. Wise, Yong-Bing Xiang, Wanghong Xu, Hannah P. Yang, Herbert Yu, Anne Zeleniuch-Jacquotte and Louise A. Brinton

      Article first published online: 30 SEP 2014 | DOI: 10.1002/ijc.29229

      What's new?

      Are IUDs associated with endometrial cancer? Around the world, the intrauterine device is gaining popularity as a long-term birth control strategy. Positioned as it is embedded in the uterine lining, an IUD could affect endometrial tissue. This study builds on previous work by considering the type of device used, in addition to factors such as duration of use. The authors found that women who had used an IUD, particularly an inert IUD, had less risk of endometrial cancer. The longer the device was used, they found, the more the cancer risk decreased.

    3. Colorectal cancer prevention by an optimized colonoscopy protocol in routine practice

      Sudha Xirasagar, Yi-Jhen Li, Thomas G. Hurley, Meng Han Tsai, James W. Hardin, Deborah M. Hurley, James R. Hebert and Piet C. de Groen

      Article first published online: 30 SEP 2014 | DOI: 10.1002/ijc.29228

      What's new?

      Colonoscopy screening is a promising preventative tool for colorectal cancer, but its success may be determined by how extensively precancerous polyps are cleared from the colon. Previous studies explored relative cancer hazard risks according to endoscopists' adenoma detection rates. This retrospective investigation expands on that work by quantifying the population-based cancer protection rate achieved through the use of an optimized colonoscopy protocol targeting near-complete polyp clearance. Use of the protocol was associated with reductions of more than 80% in colorectal cancer incidence and mortality, suggesting that high rates of protection from the disease are achievable in routine practice.

  2. Tumor Immunology

    1. Gene expression profiling of peripheral blood mononuclear cells during treatment with a gene-modified allogeneic tumor cell vaccine in advanced renal cell cancer: Tumor-induced immunosuppression and a possible role for NF-κB

      Anne Flörcken, Michael Grau, Annette Wolf, André Weilemann, Joachim Kopp, Bernd Dörken, Thomas Blankenstein, Antonio Pezzutto, Peter Lenz, Georg Lenz and Jörg Westermann

      Article first published online: 30 SEP 2014 | DOI: 10.1002/ijc.29230

      What's new?

      Tumor-induced immunosuppression remains a major obstacle in the development of cancer vaccines and other immunotherapies. In this study, the authors analyzed gene expression profiling (GEP) in peripheral blood mononuclear cells (PBMCs). They found that, even before treatment, PBMCs from renal-cell cancer patients expressed far lower levels of genes associated with immune function, compared to healthy controls. Inhibition of the NF-κB signaling pathway may play an important role. These results suggest that PBMC GEP? may provide a useful tool for predicting immunosuppression, and for monitoring immune responses during immunotherapy trials.

  3. Epidemiology

    1. Risk and impact of tuberculosis in patients with chronic myeloid leukemia: A nationwide population-based study in Taiwan

      Chia-Jen Liu, Ying-Chung Hong, Chung-Jen Teng, Man-Hsin Hung, Yu-Wen Hu, Fan-Chen Ku, Yung-Tai Chen, Sheng-Hsuan Chien, Chiu-Mei Yeh, Tzeng-Ji Chen, Tzeon-Jye Chiou, Jyh-Pyng Gau and Cheng-Hwai Tzeng

      Article first published online: 30 SEP 2014 | DOI: 10.1002/ijc.29201

      What's new?

      Patients with chronic myeloid leukemia (CML) are immunosuppressed but their risk of developing active tuberculosis has not been assessed. This study from Taiwan using a nationwide population-based dataset demonstrates that the incidence of tuberculosis is significantly higher in patients with CML (adjusted hazard ration of 3.76), especially in those of male sex, older age and receiving either stem cell transplantation or interferon-α treatment. Treatment with tyrosine kinase inhibitors did not increase the risk. The authors recommend intensified tuberculosis screening in CML patients, especially those with increased risk.

  4. Cancer Genetics

    1. Genome-wide CNV analysis in 221 unrelated patients and targeted high-throughput sequencing reveal novel causative candidate genes for colorectal adenomatous polyposis

      Sukanya Horpaopan, Isabel Spier, Alexander M. Zink, Janine Altmüller, Stefanie Holzapfel, Andreas Laner, Stefanie Vogt, Siegfried Uhlhaas, Stefanie Heilmann, Dietlinde Stienen, Sandra M. Pasternack, Kathleen Keppler, Ronja Adam, Katrin Kayser, Susanne Moebus, Markus Draaken, Franziska Degenhardt, Hartmut Engels, Andrea Hofmann, Markus M. Nöthen, Verena Steinke, Alberto Perez-Bouza, Stefan Herms, Elke Holinski-Feder, Holger Fröhlich, Holger Thiele, Per Hoffmann and Stefan Aretz

      Article first published online: 30 SEP 2014 | DOI: 10.1002/ijc.29215

      What's new?

      So far, two genes have been implicated in the inheritance of adenomatous polyposis, a condition that leads to colorectal cancer: APC and MAP. But disturbances in these genes only account for about half of the disease cases. In this study, the authors sought that genetic basis by performing for the first time a genome-wide investigation into copy number variations among colorectal adenomatous polyposis patients. They identified a group of candidate genes that boost the risk of hereditary colorectal tumors; several patients had disruptions in multiple genes, suggesting that a simple lab test to evaluate risk might not be forthcoming.

  5. Cancer Cell Biology

    1. You have full text access to this OnlineOpen article
      Divergence(s) in nodal signaling between aggressive melanoma and embryonic stem cells

      Zhila Khalkhali-Ellis, Dawn A. Kirschmann, Elisabeth A. Seftor, Alina Gilgur, Thomas M. Bodenstine, Andrew P. Hinck and Mary J.C. Hendrix

      Article first published online: 29 SEP 2014 | DOI: 10.1002/ijc.29198

      What's New?

      Metastatic tumor cells and embryonic stem cells employ similar signaling pathways to maintain plasticity. Both rely, for example, on Nodal, a member of the TGFβ superfamily and a key regulator of cell fate. The present study shows that Nodal signaling in metastatic melanoma cells is carried out through heterodimeric TGFβ receptor I/TGFβ receptor II signal transduction. By contrast, Nodal signaling in embryonic stem cells was governed by Activin receptors I and II. The findings shed light on the divergence of Nodal signaling mechanisms in metastatic tumor cells, with implications for the development of Nodal-targeting therapeutics.

  6. Epidemiology

    1. Total, caffeinated and decaffeinated coffee and tea intake and gastric cancer risk: Results from the EPIC cohort study

      Harinakshi Sanikini, Vincent K. Dik, Peter D. Siersema, Nirmala Bhoo-Pathy, Cuno S.P.M. Uiterwaal, Petra H.M. Peeters, Carlos A. González, Raul Zamora-Ros, Kim Overvad, Anne Tjønneland, Nina Roswall, Marie-Christine Boutron-Ruault, Guy Fagherazzi, Antoine Racine, Tilman Kühn, Verena Katzke, Heiner Boeing, Antonia Trichopoulou, Dimitrios Trichopoulos, Pagona Lagiou, Domenico Palli, Sara Grioni, Paolo Vineis, Rosario Tumino, Salvatore Panico, Elisabete Weiderpass, Guri Skeie, Tonje Braaten, José María Huerta, Emilio Sánchez-Cantalejo, Aurelio Barricarte, Emily Sonestedt, Peter Wallstrom, Lena Maria Nilsson, Ingegerd Johansson, Kathryn E Bradbury, Kay-Tee Khaw, Nick Wareham, Inge Huybrechts, Heinz Freisling, Amanda J. Cross, Elio Riboli and H. Bas Bueno-de-Mesquita

      Article first published online: 29 SEP 2014 | DOI: 10.1002/ijc.29223

      What's New?

      Can drinking coffee or tea lead to cancer? Can they protect against cancer? These popular drinks certainly contain antioxidants, but despite many investigations into the question, we still have no clear answer. A new study has plied the data from the European Prospective Investigation into Cancer and Nutrition (EPIC) in search of a link. Participants self-reported their coffee and tea consumption by questionnaire. The authors found no link between drinking tea or coffee – with or without caffeine – and overall risk of gastric cancer; they did discern a slight increase in gastric cardia cancer with consumption of caffeinated coffee.

  7. Cancer Therapy

    1. Potent antitumor activity of cabozantinib, a c-MET and VEGFR2 inhibitor, in a colorectal cancer patient-derived tumor explant model

      Eun-Kee Song, WM Tai, Wells A. Messersmith, Stacey Bagby, Alicia Purkey, Kevin S. Quackenbush, Todd M. Pitts, Guoliang Wang, Patrick Blatchford, Rachel Yahn, Jeffrey Kaplan, Aik Choon Tan, Chloe E. Atreya, Gail Eckhardt, Robin K. Kelley, Alan Venook, Eunice L. Kwak, David Ryan and John J. Arcaroli

      Article first published online: 29 SEP 2014 | DOI: 10.1002/ijc.29225

      What's New?

      Members of the MET and vascular endothelial growth factor (VEGF) signaling pathways are important targets in anticancer drug development, owing to their association with tumor progression and metastasis. Of particular interest in tumor progression is MET upregulation in response to VEGF pathway inhibition. Here, cabozantinib, a VEGFR2 and MET inhibitor, was found to exert potent antitumor activity in a preclinical colorectal cancer patient-derived tumor xenograft model. Tumors possessing a PIK3CA mutation were highly sensitive to cabozantinib. The results suggest that cabozantinib may be of value in the treatment of colorectal cancer, with PIK3CA mutation capable of predicting therapeutic sensitivity.

  8. Cancer Cell Biology

    1. USP33 mediates Slit-Robo signaling in inhibiting colorectal cancer cell migration

      Zhaohui Huang, Pushuai Wen, Ruirui Kong, Haipeng Cheng, Binbin Zhang, Cao Quan, Zehua Bian, Mengmeng Chen, Zhenfeng Zhang, Xiaoping Chen, Xiang Du, Jianghong Liu, Li Zhu, Kazuo Fushimi, Dong Hua and Jane Y. Wu

      Article first published online: 29 SEP 2014 | DOI: 10.1002/ijc.29226

      What's New?

      The Slit-Robo pathway functions in axon guidance and cell migration and influences various pathological processes outside the nervous system, including tumorigenesis. Here, the Robo ligand and putative tumor suppressor Slit2 was found to serve as an inhibitor of cell migration in colorectal cancer (CRC). Its inhibitory activity was dependent on Robo1 and was enhanced by overexpression of USP33. USP33 mediated Slit2 activity via Robo1 deubiquitination and stabilization. In addition, Slit2 and USP33 expression was reduced in human CRC tissue. The data suggest that USP33 is a tumor suppressor in CRC and that its expression is predictive of survival.

  9. Early Detection and Diagnosis

    1. Annexin-A2 as predictor biomarker of recurrent disease in endometrial cancer

      Lorena Alonso-Alconada, Maria Santacana, Pablo Garcia-Sanz, Laura Muinelo-Romay, Eva Colas, Cristina Mirantes, Marta Monge, Juan Cueva, Esther Oliva, Robert A Soslow, Maria Angeles Lopez, Jose Palacios, Jaime Prat, Joan Valls, Camilla Krakstad, Helga Salvesen, Antonio Gil-Moreno, Rafael Lopez-Lopez, Xavier Dolcet, Gema Moreno-Bueno, Jaume Reventos, Xavier Matias-Guiu and Miguel Abal

      Article first published online: 29 SEP 2014 | DOI: 10.1002/ijc.29213

      What's New?

      Endometrial carcinoma is usually diagnosed early, with a favorable prognosis. However, even in these early cases, the relapse rate can be as high as 20%. Thus it would be helpful to have a biomarker that could predict which tumors are likely to recur, and which patients might benefit from more aggressive treatment. In this clinical study, the authors found that a protein called annexin A2 (ANXA2) may provide just such a biomarker. Interestingly, they also found that ANXA2 is involved in the ability of endometrial carcinomas to metastasize.

  10. Cancer Therapy

    1. Combination therapy of oncolytic herpes simplex virus HF10 and bevacizumab against experimental model of human breast carcinoma xenograft

      Gewen Tan, Hideki Kasuya, Tevfik Tolga Sahin, Kazuo Yamamura, Zhiwen Wu, Yusuke Koide, Yoshihiro Hotta, Toshio Shikano, Suguru Yamada, Akiyuki Kanzaki, Tsutomu Fujii, Hiroyuki Sugimoto, Shuji Nomoto, Yoko Nishikawa, Maki Tanaka, Naoko Tsurumaru, Toshie Kuwahara, Saori Fukuda, Toru Ichinose, Toyone Kikumori, Shin Takeda, Akimasa Nakao and Yasuhiro Kodera

      Article first published online: 26 SEP 2014 | DOI: 10.1002/ijc.29163

      What's new?

      Oncolytic herpes simplex viruses (HSVs) are powerful tumor-killing agents that can be manipulated via mutation for desired functions, such as preferential replication in tumor cells. Their efficacy is undermined, however, by limited intratumoral viral distribution and by the production of undesirable effects, such as increased angiogenesis. The present study shows that the combination of oncolytic HF10, an HSV mutant, and the anti-VEGFA monoclonal antibody Bevacizumab enhances viral distribution and tumor hypoxia. In breast cancer tumors, populations of apoptotic cells increased with HF10 and Bevacizumab together, while in human breast carcinoma xenografts, the two agents exhibited synergistic antitumor effects.

    2. Differential cellular responses induced by dorsomorphin and LDN-193189 in chemotherapy-sensitive and chemotherapy-resistant human epithelial ovarian cancer cells

      Jennifer L. Ali, Brittany J. Lagasse, Ainsley J. Minuk, Allison J. Love, Amani I. Moraya, Linda Lam, Gilbert Arthur, Spencer B. Gibson, Ludivine Coudière Morrison, Tamra E. Werbowetski-Ogilvie, Yangxin Fu and Mark W. Nachtigal

      Article first published online: 26 SEP 2014 | DOI: 10.1002/ijc.29220

      What's new?

      Within 18 months of completing initial chemotherapy, as many as 75% of women with epithelial ovarian cancer (EOC) experience relapse with chemoresistant disease. This phenomenon may be overcome through the discovery of new therapies that are capable of restoring drug sensitivity in resistant cells. Two such agents include the multikinase inhibitor dorsomorphin and its analog LDN-193189, which are reported here to increase survival in a mouse xenograft model of EOC. The agents successfully resensitized drug-resistant ovarian cancer cells to the killing effects of platinum agents. Mechanistic evaluation revealed that dorsomorphin typically induces autophagy, whereas LDN-193189 induces apoptosis.

  11. Mini Review

    1. You have full text access to this OnlineOpen article
  12. Tumor Immunology

    1. Antibody therapy to human L1CAM in a transgenic mouse model blocks local tumor growth but induces EMT

      Kai Doberstein, Patrick N. Harter, Uwe Haberkorn, Niko P. Bretz, Bernd Arnold, Rafael Carretero, Gerhard Moldenhauer, Michel Mittelbronn and Peter Altevogt

      Article first published online: 25 SEP 2014 | DOI: 10.1002/ijc.29222

      What's new?

      L1CAM is overexpressed in many human cancers, and is associated with poor prognosis and a reduced response to chemotherapy. In this study, the authors generated both mouse tumors and transgenic mice that express human L1CAM (huL1CAM) in a pattern similar to that seen in humans. They found that monoclonal antibodies (mAb) directed against huL1CAM reduced the growth of the tumors in vivo, with few side effects. These data support L1CAM as a potential therapeutic target. The transgenic-mouse system described in this study may also be useful for preclinical evaluation of anti-L1CAM immunotherapies.

  13. Cancer Genetics

    1. A three-gene signature and clinical outcome in esophageal squamous cell carcinoma

      Ling-Ling Sun, Jian-Yi Wu, Zhi-Yong Wu, Jin-Hui Shen, Xiu-E Xu, Bo Chen, Shao-Hong Wang, En-Min Li and Li-Yan Xu

      Article first published online: 24 SEP 2014 | DOI: 10.1002/ijc.29211

      What's new?

      Epigenetic alterations that involve modifications to histones are thought to play critical roles in cancer, with effects on processes ranging from tumor development to metastasis. The present investigation focused on the expression of the histone demethylase GASC1 and its gene targets in tumors from patients with esophageal squamous cell carcinoma (ESCC). Using risk scores from immunohistochemical analyses, the authors developed a three-gene prognostic signature involving the genes PPARG, MDM2, and NANOG. The signature was associated with a reduction in overall survival of ESCC patients, suggesting that it is predictive for poor prognosis in ESCC.

  14. Cancer Therapy

    1. Lymph node count and prognosis in colorectal cancer: The influence of examination quality

      Hendrik Bläker, Bert Hildebrandt, Hanno Riess, Moritz von Winterfeld, Barbara Ingold-Heppner, Wilfried Roth, Matthias Kloor, Peter Schirmacher, Manfred Dietel, Sha Tao, Lina Jansen, Jenny Chang-Claude, Alexis Ulrich, Hermann Brenner and Michael Hoffmeister

      Article first published online: 24 SEP 2014 | DOI: 10.1002/ijc.29221

      What's new?

      Past studies have linked a low lymph node count in cancer resections with adverse outcome in colorectal cancer. It remains unclear however if a low lymph node number is a true biological risk factor justifying the international guideline to administer adjuvant chemotherapy in stage II colorectal cancers with fewer than 12 assessed lymph nodes, or if the observed association is due to false nodal-negative staging by inadequate assessment. This study shows that a lymph node count <12 has no prognostic impact when examination follows current quality standards, questioning the 12-node cutoff for risk assessment and adjuvant therapy decision-making in colorectal cancer.

  15. Epidemiology

    1. Coffee, tea and decaffeinated coffee in relation to hepatocellular carcinoma in a European population: Multicentre, prospective cohort study

      Christina Bamia, Pagona Lagiou, Mazda Jenab, Antonia Trichopoulou, Veronika Fedirko, Krasimira Aleksandrova, Tobias Pischon, Kim Overvad, Anja Olsen, Anne Tjønneland, Marie-Christine Boutron-Ruault, Guy Fagherazzi, Antoine Racine, Tilman Kuhn, Heiner Boeing, Anna Floegel, Vasiliki Benetou, Domenico Palli, Sara Grioni, Salvatore Panico, Rosario Tumino, Paolo Vineis, H.B(as) Bueno-de-Mesquita, Vincent K. Dik, Nirmala Bhoo-Pathy, Cuno S. P. M. Uiterwaal, Elisabete Weiderpass, Eiliv Lund, J. Ramón Quirós, Raul Zamora-Ros, Esther Molina-Montes, Maria-Dolores Chirlaque, Eva Ardanaz, Miren Dorronsoro, Björn Lindkvist, Peter Wallström, Lena Maria Nilsson, Malin Sund, Kay-Tee Khaw, Nick Wareham, Kathryn E. Bradbury, Ruth C. Travis, Pietro Ferrari, Talita Duarte-Salles, Magdalena Stepien, Marc Gunter, Neil Murphy, Elio Riboli and Dimitrios Trichopoulos

      Article first published online: 24 SEP 2014 | DOI: 10.1002/ijc.29214

      What's new?

      Could coffee and tea consumption protect from liver cancer? The answer is yes! In this first multi-center European cohort study, intake of coffee and, to a lesser extent, tea was associated, in a dose-dependent manner, with lower risk of hepatocellular carcinoma. For the most loyal coffee consumers, risk was reduced by 72%. No protection was observed with decaffeinated coffee. As caffeinated coffee and tea are almost universal exposures, these results may have important implications for individuals at high risk for liver cancer.

    2. Anthropometric factors and ovarian cancer risk: A systematic review and nonlinear dose-response meta-analysis of prospective studies

      Dagfinn Aune, Deborah A. Navarro Rosenblatt, Doris Sau Man Chan, Leila Abar, Snieguole Vingeliene, Ana Rita Vieira, Darren C. Greenwood and Teresa Norat

      Article first published online: 24 SEP 2014 | DOI: 10.1002/ijc.29207

      What's new?

      While past investigations of relationships between obesity and ovarian cancer yielded inconclusive results, recent cohort studies have offered new insight, warranting reassessment of potential associations. In this meta-analysis, the authors found evidence of a nonlinear positive association between ovarian cancer risk and body mass index (BMI) and weight, with a significant association for a BMI of 28 or higher. Risk also rose significantly with increasing height. Thus, strong evidence that greater body fatness increases ovarian cancer risk has amassed from cohort studies, which has important public health implications, particularly in light of rising obesity rates.

  16. Early Detection and Diagnosis

    1. DNA methylation array analyses identified breast cancer-associated HYAL2 methylation in peripheral blood

      Rongxi Yang, Katrin Pfütze, Manuela Zucknick, Christian Sutter, Barbara Wappenschmidt, Frederik Marme, Bin Qu, Katarina Cuk, Christoph Engel, Sarah Schott, Andreas Schneeweiss, Hermann Brenner, Rainer Claus, Christoph Plass, Peter Bugert, Markus Hoth, Christof Sohn, Rita Schmutzler, Claus R. Bartram and Barbara Burwinkel

      Article first published online: 24 SEP 2014 | DOI: 10.1002/ijc.29205

      What's new?

      Altered DNA methylation in peripheral blood may be indicative of early-stage breast cancer, but methylation signatures await validation. The present study is among the first to identify and validate decreased methylation at CpG site cg27091787 in the HYAL2 gene as a potential marker of breast cancer. Methylation levels at cg27091787 were inversely associated with HYAL2 expression and were found to be indicative of breast cancer stage, thus enabling discrimination of early-stage disease, as well as facilitating disease detection in women under age 50. Differential methylation at cg27091787 could serve as a blood-based marker for early breast cancer detection.

  17. Epidemiology

    1. Risk of cervical cancer in women with autoimmune diseases, in relation with their use of immunosuppressants and screening: Population-based cohort study

      Pierre-Antoine Dugué, Matejka Rebolj, Jesper Hallas, Peter Garred and Elsebeth Lynge

      Article first published online: 24 SEP 2014 | DOI: 10.1002/ijc.29209

      What's New?

      Treatment for autoimmune disease must, of course, suppress the patient's immune system. This opens them up to harmful infections, but what about cancers? Do immunosuppressive drugs taken for autoimmune disorders increase the risk of infection-caused cancers? To find out, these authors conducted a cohort study using Danish population data on cervical cancer, autoimmune diseases, and immunosuppressant intake. They found no increase in cervical cancer risk among those with autoimmune diseases. Only one immunosuppressant drug, azathioprine, appeared to be linked to higher cervical cancer risk, particularly when taken at high doses.

    2. Investigation of gene-environment interactions between 47 newly identified breast cancer susceptibility loci and environmental risk factors

      Anja Rudolph, Roger L. Milne, Thérèse Truong, Julia A. Knight, Petra Seibold, Dieter Flesch-Janys, Sabine Behrens, Ursula Eilber, Manjeet K. Bolla, Qin Wang, Joe Dennis, Alison M. Dunning, Mitul Shah, Hannah R. Munday, Hatef Darabi, Mikael Eriksson, Judith S. Brand, Janet Olson, Celine M. Vachon, Emily Hallberg, J. Esteban Castelao, Angel Carracedo, Maria Torres, Jingmei Li, Keith Humphreys, Emilie Cordina-Duverger, Florence Menegaux, Henrik Flyger, Børge G. Nordestgaard, Sune F. Nielsen, Betul T. Yesilyurt, Giuseppe Floris, Karin Leunen, Ellen G. Engelhardt, Annegien Broeks, Emiel J. Rutgers, Gord Glendon, Anna Marie Mulligan, Simon Cross, Malcolm Reed, Anna Gonzalez-Neira, José Ignacio Arias Perez, Elena Provenzano, Carmel Apicella, Melissa C. Southey, Amanda Spurdle, kConFab Investigators, AOCS Group, Lothar Häberle, Matthias W. Beckmann, Arif B. Ekici, Aida Karina Dieffenbach, Volker Arndt, Christa Stegmaier, Catriona McLean, Laura Baglietto, Stephen J. Chanock, Jolanta Lissowska, Mark E. Sherman, Thomas Brüning, Ute Hamann, Yon-Dschun Ko, Nick Orr, Minouk Schoemaker, Alan Ashworth, Veli-Matti Kosma, Vesa Kataja, Jaana M. Hartikainen, Arto Mannermaa, Anthony Swerdlow, GENICA-Network, Graham G. Giles, Hermann Brenner, Peter A. Fasching, Georgia Chenevix-Trench, John Hopper, Javier Benítez, Angela Cox, Irene L. Andrulis, Diether Lambrechts, Manuela Gago-Dominguez, Fergus Couch, Kamila Czene, Stig E. Bojesen, Doug F. Easton, Marjanka K. Schmidt, Pascal Guénel, Per Hall, Paul D. P. Pharoah, Montserrat Garcia-Closas and Jenny Chang-Claude

      Article first published online: 23 SEP 2014 | DOI: 10.1002/ijc.29188

      What's new?

      The recent discovery of 47 susceptibility loci associated with all or estrogen receptor-negative breast cancer provided new opportunities for genetic risk prediction but it remained unclear how exposure levels of environmental (non-genetic) risk factors influenced the risk assessment. In this gene-environment study, the international team examined interactions between the single nucleotide polymorphisms and 13 established environmental risk factors including parity, height and alcohol consumption. Notably, relative risks of breast cancer associated with the susceptibility loci were not strongly modified by environmental risk factors, a finding that, if confirmed, has important implications for the risk assessment in breast cancer.

    3. Increasing participation in colorectal cancer screening: Results from a cluster randomized trial of directly mailed gFOBT kits to previous nonresponders

      Jill Tinmouth, Jigisha Patel, Peter C. Austin, Nancy N. Baxter, Melissa C. Brouwers, Craig Earle, Cheryl Levitt, Yan Lu, Marnie Mackinnon, Lawrence Paszat and Linda Rabeneck

      Article first published online: 23 SEP 2014 | DOI: 10.1002/ijc.29191

      What's new?

      People are more likely to participate in colorectal-cancer (CRC) screening when they receive a written invitation. In this study, the authors found that non-responders who received a self-test kit in the mail with a second invitation were twice as likely to complete the test as those who received a second invitation but no kit. The study also found that ten kits must be sent in order to successfully screen one additional non-responder. These results may help organized CRC screening programs improve participation and reduce CRC mortality.

  18. Early Detection and Diagnosis

    1. A three-gene panel that distinguishes benign from malignant thyroid nodules

      Bing Zheng, Jun Liu, Jianlei Gu, Yao Lu, Wei Zhang, Min Li and Hui Lu

      Article first published online: 22 SEP 2014 | DOI: 10.1002/ijc.29172

      What's new?

      Today a key challenge in thyroid cancer research lies in distinguishing benign thyroid nodules from malignant tumors in order to avoid unnecessary surgery. While many researchers have focused on molecular classification based on oligonucleotide microarray gene-expression patterns, the high cost and poor reproducibility are barriers for daily clinical application. Here, using a two-step feature selection method, the authors constructed a small gene-expression set that can distinguish benign from malignant thyroid tumors with high prediction accuracy. The three-gene signature was validated experimentally. The prediction model is simpler and more affordable than microarray-based gene-expression patterns and more suitable for daily clinical application.

    2. Low serum miR-19a expression as a novel poor prognostic indicator in multiple myeloma

      Mu Hao, Meirong Zang, Erik Wendlandt, Yan Xu, Gang An, Dasen Gong, Fei Li, Fang Qi, Yanru Zhang, Ye Yang, Fenghuang Zhan and Lugui Qiu

      Article first published online: 19 SEP 2014 | DOI: 10.1002/ijc.29199

      What's New?

      Could circulating microRNAs improve diagnosis of multiple myeloma? In search of better diagnostic and prognostic tools, these authors compared miRNA expression profiles of myeloma patients with those of healthy donors. They identified 95 miRNAs that were expressed differently in the patients; measuring a combination of just two of these was sufficient to identify the disease samples. Patients who had less miR-19a had worse prognosis, with faster disease progression and lower survival. Interestingly, though, these patients with decreased miR-19a also responded better to treatment with bortezomib. Thus, microRNAs could be very useful in diagnosing multiple myeloma and determining the best treatment.

    3. Methylation of viral and host genes and severity of cervical lesions associated with human papillomavirus type 16

      Karolina Louvanto, Eduardo L. Franco, Agnihotram V. Ramanakumar, Nataša Vasiljević, Dorota Scibior-Bentkowska, Anita Koushik, Jack Cuzick, Francois Coutlée, Attila T. Lorincz and the Biomarkers of Cervical Cancer Risk Study Team

      Article first published online: 19 SEP 2014 | DOI: 10.1002/ijc.29196

      What's New?

      Cervical cancer detection in women with human papillomavirus (HPV) infection may be aided by the identification of methylation markers in host and viral DNA. In this analysis of methylation sites in human DNA and HPV16, methylation levels in both host and viral genes were found to increase with lesion severity. Methylation levels at sites in the human genes EPB41L3 and LMX1 and the HPV16 L1 gene distinguished cervical intraepithelial neoplasia (CIN) 2/3 from negative for intraepithelial lesions or malignancy (NILM)/CIN1 and cancer from CIN2/3. The methylation sites represent potential prognostic or diagnostic markers for cervical lesions in HPV-positive women.

  19. Cancer Therapy

    1. Adjuvant chemotherapy for patients with primary hepatocellular carcinoma: A meta-analysis

      Zhouying Zheng, Wenhua Liang, Dongping Wang, Paul M. Schroder, Weiqiang Ju, Linwei Wu, Zheng Zheng, Yushu Shang, Zhiyong Guo and Xiaoshun He

      Article first published online: 19 SEP 2014 | DOI: 10.1002/ijc.29203

      What's New?

      There are numerous randomized control trials and observational studies investigating the effects of adjuvant chemotherapy for hepatocellular carcinoma (HCC) patients. The results remain controversial, however. Here, the authors conduct a meta-analysis of all available studies to evaluate the efficacy of adjuvant chemotherapy in patients with primary HCC. They show that adjuvant chemotherapy can improve outcomes for HCC patients. They confirm the benefits of adjuvant transcatheter hepatic arterial chemoembolization (TACE), whereas the effects of other adjuvant chemotherapy modalities remain uncertain. Notably, adjuvant chemotherapy appeared particularly beneficial for patients with portal vein tumor thrombus as a complication of their disease.

  20. Cancer Genetics

    1. Germline polymorphisms and survival of lung adenocarcinoma patients: A genome-wide study in two European patient series

      Antonella Galvan, Francesca Colombo, Elisa Frullanti, Alice Dassano, Sara Noci, Yufei Wang, Timothy Eisen, Athena Matakidou, Luisa Tomasello, Marzia Vezzalini, Claudio Sorio, Matteo Dugo, Federico Ambrogi, Ilaria Iacobucci, Giovanni Martinelli, Matteo Incarbone, Marco Alloisio, Mario Nosotti, Davide Tosi, Luigi Santambrogio, Giuseppe Pelosi, Ugo Pastorino, Richard S. Houlston and Tommaso A. Dragani

      Article first published online: 19 SEP 2014 | DOI: 10.1002/ijc.29195

      What's New?

      Lung adenocarcinoma patients are at a high risk of poor prognosis in spite of surgical resection, and identifying the factors for individual predisposition to poor prognosis is needed to improve follow-up and therapy. Here, the authors discovered a novel genetic profile of four SNPs associated with survival. If the results are confirmed, the profile could help stratify lung adenocarcinoma patients into different prognostic groups. The strongest association was provided by rs2107561, an intronic SNP of PTPRG, whose overexpression inhibited clonogenicity and anchorage-independent growth of lung cancer cells, pointing to a functional role of PTPRG in the prognosis of lung adenocarcinoma.

  21. Cancer Cell Biology

    1. Mutant p53 promotes epithelial-mesenchymal plasticity and enhances metastasis in mammary carcinomas of WAP-T mice

      Eva Lenfert, Claudia Maenz, Christina Heinlein, Katharina Jannasch, Udo Schumacher, Klaus Pantel, Genrich V. Tolstonog, Wolfgang Deppert and Florian Wegwitz

      Article first published online: 19 SEP 2014 | DOI: 10.1002/ijc.29186

      What's new?

      Despite the loss of transcriptional activity, mutant p53 (mutp53) proteins display gain of function properties, such as the ability to contribute to tumor progression. To elucidate functional gains, the present study explored the effects of mutp53 expression in monotransgenic WAP-T mice and bitransgenic WAP-T x WAP-mutp53 mice. Mammary tumors from both models were phenotypically similar and possessed an epithelial-mesenchymal transition (EMT) gene signature associated with tumor cell plasticity. However, mammary tumors in bitransgenic mice showed enhanced metastatic potential. Additional findings from in vitro experiments indicate that the tumor microenvironment plays a key role in regulating tumor cell phenotype and invasiveness.

  22. Mini Review

    1. T cell-based targeted immunotherapies for patients with multiple myeloma

      Lei Wang, Nan Jin, Anita Schmitt, Jochen Greiner, Georg Malcherek, Michael Hundemer, Jiju Mani, Dirk Hose, Marc S Raab, Anthony D. Ho, Bao-an Chen, Hartmut Goldschmidt and Michael Schmitt

      Article first published online: 19 SEP 2014 | DOI: 10.1002/ijc.29190

  23. Early Detection and Diagnosis

    1. Epigenetic markers for noninvasive early detection of nasopharyngeal carcinoma by methylation-sensitive high resolution melting

      Xuesong Yang, Wei Dai, Dora Lai-wan Kwong, Carol Y.Y. Szeto, Elibe Hiu-wun Wong, Wai Tong Ng, Anne W.M. Lee, Roger K.C. Ngan, Chun Chung Yau, Stewart Y. Tung and Maria Li Lung

      Article first published online: 19 SEP 2014 | DOI: 10.1002/ijc.29192

      What's new?

      Tests for Epstein-Barr virus (EBV) DNA may help screen high-risk populations for nasopharyngeal carcinoma (NPC), but these tests are not very sensitive. In this study, the authors developed a panel of biomarkers that instead tests for altered methylation of tumor-suppressor genes. They found that, when plasma and swabs from early-stage NPC patients were analyzed with the methylation panel, it detected the cancer with higher sensitivity and specificity than tests for EBV DNA. Combining the two tests may enhance noninvasive screening for NPC, thus enabling more timely and effective treatments.

  24. Tumor Immunology

    1. Newcastle disease virotherapy induces long-term survival and tumor-specific immune memory in orthotopic glioma through the induction of immunogenic cell death

      Carolien A. Koks, Abhishek D. Garg, Michael Ehrhardt, Matteo Riva, Lien Vandenberk, Louis Boon, Steven De Vleeschouwer, Patrizia Agostinis, Norbert Graf and Stefaan W. Van Gool

      Article first published online: 19 SEP 2014 | DOI: 10.1002/ijc.29202

      What's new?

      Glioblastoma multiforme has a particularly grim prognosis. One potential treatment is “oncolytic virotherapy” (OVT), which relies on viruses that specifically infect and lyse tumor cells. In this study, the authors found that mice whose gliomas were injected with Newcastle-disease virus (NDV) survived significantly longer than controls. Many researchers have assumed that, in order for OVT to work, the immune system must be suppressed. Here, however, NDV actually stimulated “immunogenic cell death” (ICD) and “necroptosis” (rather than apoptosis). OVT may thus be a promising therapeutic approach in combination with therapies that stimulate the immune response.

  25. Infectious Causes of Cancer

    1. Characterization of functional domains in the Merkel cell polyoma virus Large T antigen

      Roland Houben, Sabrina Angermeyer, Sebastian Haferkamp, Annemarie Aue, Matthias Goebeler, David Schrama and Sonja Hesbacher

      Article first published online: 19 SEP 2014 | DOI: 10.1002/ijc.29200

      What's New?

      The Merkel cell polyomavirus (MCPyV) is the first virus of the polyomavirus family to be established as a causal factor of a human cancer. Merkel cell carcinoma is a rare but very aggressive skin cancer with high mortality rates. Here, the authors describe experiments defining certain domains and molecular functions of the Large T antigen encoded by MCPyV, which are either essential or dispensable for its growth-promoting function in Merkel cell carcinoma cells.

    2. Circulating Epstein–Barr virus microRNAs miR-BART7 and miR-BART13 as biomarkers for nasopharyngeal carcinoma diagnosis and treatment

      Gaohong Zhang, Jingfeng Zong, Shaojun Lin, Rob J.A. Verhoeven, Shuang Tong, Yixin Chen, Mingfang Ji, Weimin Cheng, Sai-Wah Tsao, Maria Lung, Jianji Pan and Honglin Chen

      Article first published online: 18 SEP 2014 | DOI: 10.1002/ijc.29206

      What's new?

      Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-associated tumor in which only a few viral proteins but more than 20 BART microRNAs are detected, at abundant levels. A systematic selection of extracellular BART microRNAs and evaluation of their usefulness as novel serological markers for NPC using clinical specimens is yet to be described. Here, the authors found that miR-BART7 and miR-BART13 are secreted from NPC cells into the bloodstream, with reduced plasma levels in NPC patients immediately after radiotherapy. These novel biomarkers for NPC malignancy warrant further evaluation for application in early recognition of disease onset and monitoring of treatment.

  26. Early Detection and Diagnosis

    1. Seasonal variations do not affect the superiority of fecal immunochemical tests over guaiac tests for colorectal cancer screening

      Sébastien Chausserie, Romuald Levillain, Josette Puvinel, Olivier Ferrand, Angela Ruiz, Thibaut Raginel, Olivier Lantieri, Guy Launoy and Lydia Guittet

      Article first published online: 18 SEP 2014 | DOI: 10.1002/ijc.29187

      What's new?

      Fecal immunochemical tests (FITs) for hemoglobin are expected to replace traditional guaiac based fecal occult blood tests (gFOBTs) as a screening tool for colorectal cancer. But while more sensitive than gFOBTs, some studies have suggested that FIT performance is influenced by seasonal variations in temperature, particularly during the summer season. Here, summer temperatures were found to have no effect on the gain in sensitivity of an automated quantitative FIT (OC-SENSOR, cut-off 30μg hemoglobin/g feces), despite decreased positivity rates in summer. Across the four seasons, FIT outperformed gFOBT in clinical effectiveness.

  27. Letter to the Editor

    1. HHV-8 seroprevalence in HIV-positive and HIV-negative populations

      Julia Bohlius, Mhairi Maskew, Mary-Ann Davies and Matthias Egger

      Article first published online: 18 SEP 2014 | DOI: 10.1002/ijc.29183

  28. Carcinogenesis

    1. BIRC6 promotes hepatocellular carcinogenesis: Interaction of BIRC6 with p53 facilitating p53 degradation

      Wenqing Tang, Ruyi Xue, Shuqiang Weng, Jian Wu, Ying Fang, Yi Wang, Lingling Ji, Tingting Hu, Taotao Liu, Xiaowu Huang, She Chen, Xizhong Shen, Si Zhang and Ling Dong

      Article first published online: 18 SEP 2014 | DOI: 10.1002/ijc.29194

      What's new?

      Inhibition of apoptosis proteins (IAPs) are involved in carcinogenesis, but for some, such as BIRC6, an IAP that facilitates proteasomal degradation of pro-apoptotic proteins, the mechanisms by which they facilitate tumor development remain unclear. This report sheds new light on the effect of BIRC6 on hepatocellular carcinoma (HCC) development. BIRC6 was found to influence carcinogenesis via modulation of the cell cycle, cell proliferation, and apoptosis—activities that were dependent on its interaction with p53. In addition, BIRC6 expression levels were correlated with HCC prognosis. The findings suggest that BIRC6 is a promising prognostic marker and therapeutic target in HCC.

  29. Epidemiology

    1. The relationship between blood IL-12p40 level and melanoma progression

      Shenying Fang, Yuling Wang, Yun Shin Chun, Huey Liu, Merrick I. Ross, Jeffrey E. Gershenwald, Janice N. Cormier, Richard E. Royal, Anthony Lucci, Christopher W. Schacherer, John D. Reveille, Dawen Sui, Roland L. Bassett Jr., Li-E Wang, Qingyi Wei, Christopher I. Amos and Jeffrey E. Lee

      Article first published online: 17 SEP 2014 | DOI: 10.1002/ijc.29182

      What's new?

      Immunotherapies show promising results in advanced-stage melanoma patients. The authors measured levels of IL-12p40, the common subunit of inflammation- and tumor growth-controlling cytokines IL-12 and IL-23, in the blood of melanoma patients. They correlated levels with melanoma recurrence, melanoma-specific survival and overall survival. The results indicate that IL-12p40 represents an independent marker of disease progression in early-stage melanoma patients and a possible new target for immunotherapeutic intervention.

  30. Cancer Cell Biology

    1. The biguanides metformin and phenformin inhibit angiogenesis, local and metastatic growth of breast cancer by targeting both neoplastic and microenvironment cells

      Stefania Orecchioni, Francesca Reggiani, Giovanna Talarico, Patrizia Mancuso, Angelica Calleri, Giuliana Gregato, Valentina Labanca, Douglas M. Noonan, Katiuscia Dallaglio, Adriana Albini and Francesco Bertolini

      Article first published online: 17 SEP 2014 | DOI: 10.1002/ijc.29193

      What's new?

      Undifferentiated progenitor cells in white adipose tissue (WAT) have cooperative roles in breast cancer progression. In particular, they promote local tumor growth, angiogenesis, and metastasis—three processes shown in the present study to be inhibited by the biguanide drugs metformin and phenformin. Phenformin showed the highest levels of activity. The study is among the first to suggest that the two drugs exert their effects through direct activity against breast cancer cells, as well as through anti-angiogenic activity against WAT progenitors. The conclusions were drawn from results obtained in vitro and in vivo in triple negative and HER2+ breast cancer models.

  31. Editorials

  32. Cancer Cell Biology

    1. Expression of TNF-α and CD44 is implicated in poor prognosis, cancer cell invasion, metastasis and resistance to the sunitinib treatment in clear cell renal cell carcinomas

      Shuji Mikami, Ryuichi Mizuno, Takeo Kosaka, Hideyuki Saya, Mototsugu Oya and Yasunori Okada

      Article first published online: 17 SEP 2014 | DOI: 10.1002/ijc.29137

      What's New?

      Cancer-related inflammation helps tumors spread like wildfire, and TNF-α gets that inflammation going. In some cancers, TNF-α drives cells toward metastasis and boosts expression of CD44, a marker of cancer stem cells. What is the role of TNF-α in clear cell renal cell carcinoma (ccRCC)? These authors found that TNF-α expression correlates with CD44 expression, and both are associated with tumor stage and poor prognosis. In addition, when patients were treated with sunitinib, the ones that didn't respond well to the treatment had high CD44 expression, suggesting that TNF-α can bolster chemotherapy resistance by driving up CD44 levels.

  33. Epidemiology

    1. Plasma carotenoids, vitamin C, retinol and tocopherols levels and pancreatic cancer risk within the European Prospective Investigation into Cancer and Nutrition: A nested case–control study: Plasma micronutrients and pancreatic cancer risk

      Suzanne M. Jeurnink, Martine M. Ros, Max Leenders, Franzel J.B. van Duijnhoven, Peter D. Siersema, Eugene H.J.M. Jansen, Carla H. van Gils, Marije F. Bakker, Kim Overvad, Nina Roswall, Anne Tjønneland, Marie-Christine Boutron-Ruault, Antoine Racine, Claire Cadeau, Verena Grote, Rudolf Kaaks, Krasimira Aleksandrova, Heiner Boeing, Antonia Trichopoulou, Vasiliki Benetou, Elisavet Valanou, Domenico Palli, Vittorio Krogh, Paolo Vineis, Rosario Tumino, Amalia Mattiello, Elisabete Weiderpass, Guri Skeie, José María Huerta Castaño, Eric J. Duell, Aurelio Barricarte, Esther Molina-Montes, Marcial Argüelles, Mire Dorronsoro, Dorthe Johansen, Björn Lindkvist, Malin Sund, Francesca L. Crowe, Kay-Tee Khaw, Mazda Jenab, Veronika Fedirko, E. Riboli and H. B(as) Bueno-de-Mesquita

      Article first published online: 17 SEP 2014 | DOI: 10.1002/ijc.29175

      What's new?

      Fruits and vegetables may play a role in the prevention of pancreatic cancer, but associations between the antioxidants those foods contain and disease risk remain unclear. In this study, pancreatic cancer risk was inversely associated with increased prediagnostic plasma concentrations of the antioxidants β-carotene, zeaxanthin, and α-tocopherol. Geographic variations were also detected. In Northern European countries, inverse associations with risk were found for blood levels of several carotenoids, whereas the association was strongest for γ-tocopherol in Southern European countries. The role of carotenoids and vitamins should be considered in subsequent investigations of the etiology of pancreatic cancer.

  34. Short Reports

    1. Difference in mesothelin-binding ability of serum CA125 between patients with endometriosis and epithelial ovarian cancer

      Aya Sasaki, Kaoru Akita, Fumitake Ito, Taisuke Mori, Jo Kitawaki and Hiroshi Nakada

      Article first published online: 17 SEP 2014 | DOI: 10.1002/ijc.29185

      What's new?

      Diagnostic tests using the CA125 antigen have a high false-positive rate for ovarian cancer (OC) when conditions such as endometriosis are present. Is there a way to distinguish between these two diseases? In this study, the authors developed a “sandwich” ELISA based on CA125 with mesothelin-binding ability (CA125meso). They found that serum CA125meso levels were significantly higher in patients with OC, as was the ratio of serum CA125meso to CA125 (CA125meso/CA125). This assay may thus enable a more accurate differential diagnosis between endometriosis and OC.

  35. Mini Review

    1. Viral infections and colorectal cancer: A systematic review of epidemiological studies

      Hongda Chen, Xin-Zu Chen, Tim Waterboer, Felipe Andres Castro and Hermann Brenner

      Article first published online: 17 SEP 2014 | DOI: 10.1002/ijc.29180

  36. Cancer Therapy

    1. The combination of transcatheter arterial chemoembolization and sorafenib is well tolerated and effective in Asian patients with hepatocellular carcinoma: Final results of the START trial

      Yee Chao, Young-Hwa Chung, Guohong Han, Jung-Hwan Yoon, Jijin Yang, Jianhua Wang, Guo-Liang Shao, Byung Ik Kim and Teng-Yu Lee

      Article first published online: 16 SEP 2014 | DOI: 10.1002/ijc.29126

      What's new?

      While transarterialchemoembolization (TACE) is thestandard of care for intermediate hepatocellular carcinoma (HCC), repeated treatmentoften leads to unsatisfactory clinicaloutcomes. Combining sorafenib--an effective and safe monotherapy for unresectable HCC--with TACE to decrease post-TACE angiogenesis has been proposed to improve the efficacy of TACE therapy and reduce the recurrence ofdisease. In line with the interim analysis, the final analysis presented here of a phase II trial to evaluate the combination of TACE and interrupted-dose sorafenib in patients with intermediate HCCconfirmsthat treatment with combined TACE and sorafenib is well-tolerated and efficacious in this patient population.

  37. Tumor Immunology

    1. You have full text access to this OnlineOpen article
      Wound healing-like immune program facilitates postpartum mammary gland involution and tumor progression

      Holly A. Martinson, Sonali Jindal, Clarissa Durand-Rougely, Virginia F. Borges and Pepper Schedin

      Article first published online: 15 SEP 2014 | DOI: 10.1002/ijc.29181

      What's new?

      Young women diagnosed with postpartum breast cancer have poor prognosis for unknown reasons, and in all age groups regardless of reproductive history, breast cancers characterized by high macrophage and low T cell numbers also have poor outcomes. Here, the authors show for the first time that murine postpartum mammary gland involution is characterized by an orchestrated influx of immune cells that mirror classic wound healing. They link a transient immune suppressed microenvironment of postpartum involution with tumor monocyte infiltrate and low T cells, implicating immune suppression in the poor prognosis of young women's postpartum breast cancer.

  38. Epidemiology

    1. Improving cervical cancer screening attendance in Finland

      Anni Virtanen, Ahti Anttila, Tapio Luostarinen, Nea Malila and Pekka Nieminen

      Article first published online: 15 SEP 2014 | DOI: 10.1002/ijc.29176

      What's new?

      Self-sampling for high-risk human papillomavirus (hrHPV)-testing facilitates access to cervical screening and can thereby increase screening attendance. Attendance in screening programs is also influenced, however, by invitation protocols, such as the use of reminder letters for nonattendees or prefixed appointments noted in invitations. The present study explored attendance in a routine screening setting in Finland, where program attendance is about 70%. The authors found that the combined use of personal invitations and reminder letters, scheduled appointments in invitations and letters, and self-sampling tests sent to nonattendees can potentially raise total attendance to more than 80%.

  39. Tumor Immunology

    1. Intraepithelial macrophage infiltration is related to a high number of regulatory T cells and promotes a progressive course of HPV-induced vulvar neoplasia

      Edith M.G. van Esch, Mariette I.E. van Poelgeest, J. Baptist M.Z. Trimbos, Gert Jan Fleuren, Ekaterina S. Jordanova and Sjoerd H. van der Burg

      Article first published online: 15 SEP 2014 | DOI: 10.1002/ijc.29173

      What's new?

      The infiltration of myeloid cells in human papillomavirus (HPV)-induced usual-type vulvar intraepithelial neoplasia (uVIN) may influence the uVIN microenvironment and responses to immunotherapy. In the present study, uVIN progression was characterized by increases in intraepithelial and stromal M1 and M2 macrophages and by dense intraepithelial infiltration by CD14+ macrophages. Dense CD14+ macrophage infiltration was associated with a significantly increased risk of recurrence, indicating that it is an independent prognostic factor for disease recurrence. By contrast, best recurrence free survival was associated with sparse CD14+ cell populations and an abundance of stromal CD8+TIM3+ cells.

    2. Expression of coinhibitory receptors on T cells in the microenvironment of usual vulvar intraepithelial neoplasia is related to proinflammatory effector T cells and an increased recurrence-free survival: T-cell expressed coinhibitory molecules predict for no or late recurrences

      Edith M.G. van Esch, Mariette I.E. van Poelgeest, Simone Kouwenberg, E. Michelle Osse, J. Baptist M.Z. Trimbos, Gert Jan Fleuren, Ekaterina S. Jordanova and Sjoerd H. van der Burg

      Article first published online: 15 SEP 2014 | DOI: 10.1002/ijc.29174

      What's new?

      Immunotherapy can be an effective means of treatment in usual-type vulvar intraepithelial neoplasia (uVIN), which commonly is associated with persistent high-risk human papillomavirus (HPV) infection. However, some uVIN patients are refractory to immunotherapy, for reasons that remain unclear. In this study, increased numbers of regulatory T cells and TIM3+ T cells were detected in uVIN tissues. Dense infiltration of uVIN lesions by stromal CD8+TIM3+ and CD3+NKG2A+ T cells predicted a low recurrence rate and prolonged recurrence free survival in uVIN.

  40. Cancer Cell Biology

    1. Zeb1 and Snail1 engage miR-200f transcriptional and epigenetic regulation during EMT

      Antonio Díaz-López, Juan Díaz-Martín, Gema Moreno-Bueno, Eva P. Cuevas, Vanesa Santos, David Olmeda, Francisco Portillo, José Palacios and Amparo Cano

      Article first published online: 12 SEP 2014 | DOI: 10.1002/ijc.29177

      What's new?

      Epithelial-mesenchymal transition (EMT) is involved in the initiation of metastasis and is regulated by transcription factors (EMT-TFs) that are themselves regulated by miRNAs. The roles of the different EMT-TFs and their functional relationships, however, are poorly understood. Here, the EMT-TFs Snail1 and Zeb1 were found to play an essential role in EMT induction, while mesenchymal phenotype was maintained by continuous Snail1 and Snail2 expression. Snail1 controlled and maintained the mesenchymal phenotype through CpG DNA hypermethylation of miR-200 loci. Hypermethylated miR-200 family members may serve as surrogate markers in the treatment or prognosis of carcinosarcomas.

    2. Metastasis blood test by flow cytometry: In vivo cancer spheroids and the role of hypoxia

      Viktoria Denes, Monika Lakk, Andrew Makarovskiy, Pal Jakso, Szabolcs Szappanos, Laszlo Graf, Laszlo Mandel, Istvan Karadi and Peter Geck

      Article first published online: 11 SEP 2014 | DOI: 10.1002/ijc.29155

      What's new?

      Even when malignant cells enter the bloodstream, they don't always cause metastasis, so testing for them doesn't indicate the disease will spread. Only cancer stem cells can start a new tumor, but no test can distinguish these from other circulating tumor cells. In this paper, the authors show that cancer stem cells, which normally thrive in hypoxic conditions, form spheroid bodies to protect themselves from oxygen in the bloodstream. They developed an assay to detect these spheroids, and they demonstrated that circulating spheroids always indicate metastatic disease. Thus, testing for spheroids in the bloodstream could help predict imminent metastasis.

    3. You have full text access to this OnlineOpen article
      A preclinical mouse model of glioma with an alternative mechanism of telomere maintenance (ALT)

      Maya Jeitany, Jose Ramon Pineda, Qingyuan Liu, Rosa Maria Porreca, Françoise Hoffschir, Chantal Desmaze, David C. Silvestre, Patrick Mailliet, Marie-Pierre Junier, Arturo Londoño-Vallejo, Evelyne Ségal-Bendirdjian, Hervé Chneiweiss and François D. Boussin

      Article first published online: 11 SEP 2014 | DOI: 10.1002/ijc.29171

      What's new?

      All cancerous cells share the need to maintain and elongate their telomeres. In approximately 30% of glioblastoma multiforme tumors, telomeres are not maintained by telomerase but through an alternative mechanism, termed ALT, making specific therapeutic strategies potentially interesting. Here, the authors showed that intracerebral grafts of an ALT glioma cell line called TG20 in immunodeficient mice constitute an efficient preclinical model of ALT glioblastoma multiforme, which could aid the understanding of the underlying pathogenesis. This model could also support the development of specific therapies, with the study revealing G-quadruplex ligands as a potential therapy for this specific type of tumor.

    4. The sensitivity of gastric cancer to trastuzumab is regulated by the miR-223/FBXW7 pathway

      Kojiro Eto, Masaaki Iwatsuki, Masayuki Watanabe, Takatsugu Ishimoto, Satoshi Ida, Yu Imamura, Shiro Iwagami, Yoshifumi Baba, Yasuo Sakamoto, Yuji Miyamoto, Naoya Yoshida and Hideo Baba

      Article first published online: 11 SEP 2014 | DOI: 10.1002/ijc.29168

      What's new?

      The monoclonal antibody trastuzumab is effective against HER2-positive gastric cancers (GCs). However, as with breast cancer, many GCs develop resistance to this drug. In this study, the authors found that a microRNA called “miR-233” interacts with a gene called “FBXW7” to regulate the sensitivity of HER2-positive GC cells to trastuzumab, by altering apoptosis. These results suggest that the miR-223/FBXW7 pathway may be a valuable therapeutic target to decrease resistance of GC to trastuzumab.

    5. The metastatic microenvironment: Claudin-1 suppresses the malignant phenotype of melanoma brain metastasis

      Sivan Izraely, Orit Sagi-Assif, Anat Klein, Tsipi Meshel, Shlomit Ben-Menachem, Assaf Zaritsky, Marcelo Ehrlich, Victor G. Prieto, Menashe Bar-Eli, Christine Pirker, Walter Berger, Clara Nahmias, Pierre-Olivier Couraud, Dave S.B. Hoon and Isaac P. Witz

      Article first published online: 8 SEP 2014 | DOI: 10.1002/ijc.29090

      What's new?

      Melanoma often metastasizes to the brain, but if researchers could find out how it does so, perhaps they could prevent it. Cells poised to metastasize often reveal themselves by molecular clues, and indeed, melanoma cells likely to infiltrate the brain express less of the tight-junction protein CLDN1 than other melanoma cells. In this study, the authors showed that when melanoma cells express extra CLDN1, they could not form micro-metastases in the brain – though their ability to metastasize to the lungs was not impaired. Thus, CLDN1 expression could help predict the likelihood of brain metastasis, and targeting cells expressing low levels of the protein could help prevent or treat this deadly complication.

  41. Cancer Therapy

    1. Treatment of oral leukoplakia with a low-dose of beta-carotene and vitamin C supplements: A randomized controlled trial

      Toru Nagao, Saman Warnakulasuriya, Tomoyasu Nakamura, Shinichiro Kato, Keiichi Yamamoto, Hideo Fukano, Koji Suzuki, Kazuo Shimozato and Shuji Hashimoto

      Article first published online: 5 SEP 2014 | DOI: 10.1002/ijc.29156

      What's new?

      The randomized controlled trial presented here used β-carotene among a non/ex-smoking group of patients with oral leukoplakia-a potentially malignant disorder whose management is currently not evidence based. The β-carotene dose was lower than doses used in earlier studies that may carry an increased risk of cancer in the study population. The mean follow-up period of 60 months allowed the inclusion of malignant transformation in the data analysis, unlike in earlier publications. The negative outcome from this trial strengthens previous conclusion that β-carotene, even in combination with an additional antioxidant, does not provide a significant benefit to the population studied.

  42. Mini Reviews

  43. Early Detection and Diagnosis

    1. Assessment of ovarian cancer conditions from exhaled breath

      Haitham Amal, Da-You Shi, Radu Ionescu, Wei Zhang, Qing-Ling Hua, Yue-Yin Pan, Li Tao, Hu Liu and Hossam Haick

      Article first published online: 5 SEP 2014 | DOI: 10.1002/ijc.29166

      What's New?

      Because ovarian cancer (OC) is usually not diagnosed until it reaches an advanced stage, mortality has been very high. Current diagnostic tests are expensive and cumbersome, making widespread screening impractical. In this study, the authors developed a diagnostic breath test that was able to distinguish between patients with malignant ovarian tumors and women who were tumor free. The test uses a nanoarray of sensors to measure volatile organic compounds; it showed good sensitivity (low false-negatives) and 100% specificity (no false positives). This may lead to an inexpensive, disposable alternative for earlier diagnosis of OC.

  44. Epidemiology

    1. Measuring the societal burden of cancer: The cost of lost productivity due to premature cancer-related mortality in Europe

      Paul Hanly, Isabelle Soerjomataram and Linda Sharp

      Article first published online: 4 SEP 2014 | DOI: 10.1002/ijc.29105

      What's New?

      Cancer is a costly disease for society, with potentially large affects on productivity and economy. According to this study, in 2008 premature cancer-related deaths in Europe resulted in lost productivity costs amounting to €75 billion. Costs were nearly twice as high for males compared with females. In addition, while impacts of specific cancers varied geographically across Europe, some of the most costly cancers included those of the lung, breast, and colorectum, with melanoma having the greatest cost per death. The findings provide insight into the societal impacts of cancer and could inform the prioritization of prevention strategies.

  45. Cancer Therapy

    1. Prostate cancer cells home to bone using a novel in vivo model: Modulation by the integrin antagonist GLPG0187

      Kimberley J. Reeves, Jack E. Hurrell, Marco Cecchini, Gabri van der Pluijm, Jenny M. Down, Colby L. Eaton, Freddie Hamdy, Philippe Clement-Lacroix and Nicola J. Brown

      Article first published online: 4 SEP 2014 | DOI: 10.1002/ijc.29165

      What's new?

      Early detection of bone metastasis is critical for developing new therapeutic cancer treatments. The authors developed a novel in vivo model using the dorsal skinfold window chamber with an implanted bone graft in immunodeficient mice. This window implanted onto the dorsal mouse skinfold allowed longitudinal and spatial evaluation of the early homing, adhesion and localization of fluorescently labeled prostate cancer cells, following intra-cardiac injection. Administration of the αv integrin antagonist GLPG0187 significantly reduced prostate cancer cell number and localization within the bone implant demonstrating the clinical applicability of the model.

  46. Early Detection and Diagnosis

    1. You have full text access to this OnlineOpen article
      Association of symptoms and breast cancer in population-based mammography screening in Finland

      Deependra Singh, Nea Malila, Arun Pokhrel and Ahti Anttila

      Article first published online: 4 SEP 2014 | DOI: 10.1002/ijc.29170

      What's New?

      A key component of breast cancer screening programs is the collection of data on symptoms at the time of screening visit. In many cases, however, the data are not subsequently analyzed for relationships between symptoms and breast cancer diagnosis. Based on analysis of data from 1.2 million screening visits recorded in the Finnish Cancer Registry, the present report describes a significant association between breast cancer risk and symptoms either self-reported by patients or detected by radiographers. Risk was highest for breast lumps reported at screening. Importantly, the findings also highlight limitations regarding the clinical significance of symptoms.

    2. Glutamate enrichment as new diagnostic opportunity in breast cancer

      Jan Budczies, Berit M. Pfitzner, Balazs Györffy, Klaus-Jürgen Winzer, Cornelia Radke, Manfred Dietel, Oliver Fiehn and Carsten Denkert

      Article first published online: 4 SEP 2014 | DOI: 10.1002/ijc.29152

      What's New?

      In cancer cells, glutamine isn't processed the same way it is in normal cells. These cells often overexpress an enzyme, glutaminase, that converts glutamine to glutamate, and one strategy for attacking the tumor cells is to inhibit glutaminase. Thus, the ratio of glutamate to glutamine can indicate something about whether a particular cancer would be vulnerable to treatment with glutaminase inhibitors. In this study, the authors show that breast cancer cells, particularly ER- tumor cells, do have a higher glutamate-to-glutamine ratio than normal cells, suggesting that glutaminase inhibitors would be well worth developing as a potential therapy.

    3. Hyperpolarized [1,3-13C2]ethyl acetoacetate is a novel diagnostic metabolic marker of liver cancer

      Pernille R. Jensen, Sonia Colombo Serra, Luigi Miragoli, Magnus Karlsson, Claudia Cabella, Luisa Poggi, Luca Venturi, Fabio Tedoldi and Mathilde H. Lerche

      Article first published online: 4 SEP 2014 | DOI: 10.1002/ijc.29162

      What's New?

      An emerging approach to metabolic imaging in cancer is based on 13C-hyperpolarized magnetic resonance (MR) spectroscopy. But metabolic markers specific to cancer must be identified to realize its promise. Here, metabolic conversion of hyperpolarized esters was explored as a potential means of detecting hepatocellular carcinoma (HCC). Hyperpolarized [1,3-13C2]ethyl acetoacetate (EAA) was found to be an exceptionally good substrate for carboxyl esterase-1, concentrations and activities of which are altered in cancer cells. Metabolic conversion of EAA as a substrate for 13C-hyperpolarized MR significantly enhanced the detection of implanted liver cancer in rats.

  47. Cancer Cell Biology

    1. Cell crowding induces interferon regulatory factor 9, which confers resistance to chemotherapeutic drugs

      Iryna Kolosenko, Mårten Fryknäs, Sofi Forsberg, Per Johnsson, HyeonJoo Cheon, Elise G. Holvey-Bates, Elin Edsbäcker, Paola Pellegrini, Hanif Rassoolzadeh, Slavica Brnjic, Rolf Larsson, George R. Stark, Dan Grandér, Stig Linder, Katja Pokrovskaja Tamm and Angelo De Milito

      Article first published online: 4 SEP 2014 | DOI: 10.1002/ijc.29161

      What's new?

      Drug resistance remains a major challenge in the management of cancer patients. Using a 3D model of tumor cells the authors identify cell crowding and the interferon response as important mediators of drug resistance. They demonstrate that interferon regulatory factor 9 (IRF9) and a panel of interferon-stimulated genes are induced by cell crowding in this model. These results link unexpected new molecular mechanisms with the therapy resistance of solid tumors.

  48. Early Detection and Diagnosis

    1. Evaluating tumor metastatic potential by imaging intratumoral acidosis via pH-activatable near-infrared fluorescent probe

      Lu Wang, Zhichao Fan, Jingye Zhang, Yinzhi Changyi, Cuiyun Huang, Yanjuan Gu, Ziyao Xu, Zhijia Tang, Weiyue Lu, Xunbin Wei and Cong Li

      Article first published online: 4 SEP 2014 | DOI: 10.1002/ijc.29153

      What's new?

      Acidification of extracellular pH (pHe) plays an important role in promoting tumor metastasis. The present study describes a novel pH-activated near-infrared (NIR) fluorescent probe that is capable of both visualizing tumors by sensing the acidic pHe and revealing correlations between tumor metastatic potential and intratumoral acidosis. NIR fluorescence imaging with the probe uncovered acidosis distribution to the tumor periphery in highly metastatic tumors, versus a wide distribution of acidosis in tumors with reduced metastatic potential. By delineating intratumoral acidosis, the probe could facilitate the evaluation of tumor metastatic potential and assist in the optimization of treatment strategies.

    2. Personalizing risk stratification by addition of PAK1 expression to TNM staging: Improving the accuracy of clinical decision for gastroesophageal junction adenocarcinoma

      Zongtai Li, Xiaofang Zou, Liangxi Xie, Hongcai Chen, Yuping Chen, Sai-Ching Jim Yeung and Hao Zhang

      Article first published online: 4 SEP 2014 | DOI: 10.1002/ijc.29167

      What's new?

      Gastroesophageal junction adenocarcinoma (GEJA) is an aggressive malignancy with an alarmingly rising incidence. While TNM staging is widely used by oncologists to stratify prognosis and guide therapeutic strategies, adequate lymphadenectomy in GEJA often needs to be compromised to minimize surgical complications and morbidity, which in turn limits prognosis and proper treatment. A molecular biomarker that can accurately forecast the risk of nodal metastasis in patients with inadequate lymphadenectomy is required. This study shows that PAK1 expression in primary tumors is predictive of nodal metastasis and clinical outcomes, and can be easily integrated into a clinical decision algorithm for personalized therapy.

    3. You have full text access to this OnlineOpen article
      Genome-wide small nucleolar RNA expression analysis of lung cancer by next-generation deep sequencing

      Lu Gao, Jie Ma, Kaiissar Mannoor, Maria A. Guarnera, Amol Shetty, Min Zhan, Lingxiao Xing, Sanford A. Stass and Feng Jiang

      Article first published online: 4 SEP 2014 | DOI: 10.1002/ijc.29169

      What's new?

      Small nucleolar RNAs (snoRNAs), noncoding RNAs that direct the chemical modification of other RNAs, may also direct the onset of cancer. For instance, lung cancer cells modified to produce less of certain snoRNAs lose their tumorigenicity. These authors sought snoRNAs affiliated with non-small cell lung cancer (NSCLC) to use as biomarkers for early disease detection. They profiled the expression patterns of snoRNAs in stage I NSCLCs and found 16 whose expression distinguishes lung cancer cells from normal cells. Furthermore, they identified 6 snoRNAs that correlate with overall survival, suggesting that testing for this expression profile could predict disease prognosis.

  49. Cancer Cell Biology

    1. You have full text access to this OnlineOpen article
      Novel functions and targets of miR-944 in human cervical cancer cells

      Hong Xie, Linkiat Lee, Patrick Scicluna, Ersen Kavak, Catharina Larsson, Rickard Sandberg and Weng-Onn Lui

      Article first published online: 4 SEP 2014 | DOI: 10.1002/ijc.29160

      What's new?

      While miR-944 has been shown to be associated with tumor development and progression in several tumor types, its functions and targets remain undetermined. This study stands out as the first report of miR-944 functions and targets in human cancer. The authors demonstrate that miR-944 functions as an oncogene in human cervical cancer cells by promoting cell proliferation, migration, and invasion. In addition, they identified and validated HECW2 and S100PBP as direct targets of miR-944 in human cervical cancer cells. The findings provide new insights into the biological roles of miR-944 in human cervical cancer cells.

  50. Early Detection and Diagnosis

    1. HER2-positive gastric cancer with concomitant MET and/or EGFR overexpression: A distinct subset of patients for dual inhibition therapy

      Sang Yun Ha, Jeeyun Lee, Jiryeon Jang, Jung Yong Hong, In-Gu Do, Se Hoon Park, Joon Oh Park, Min-Gew Choi, Tae Sung Sohn, Jae Moon Bae, Sung Kim, Minji Kim, Seonwoo Kim, Cheol Keun Park, Won Ki Kang and Kyoung-Mee Kim

      Article first published online: 4 SEP 2014 | DOI: 10.1002/ijc.29159

      What's new?

      Overexpression of receptor tyrosine kinases (RTKs) is widespread among cancers, and coactivation of RTKs frequently governs the response of tumors to targeted therapeutics. In the present study of gastric cancer, patient age, tumor size, intestinal histology, and survival were correlated with the number of overexpressed RTKs. Gastric cancers with HER2+ status and concomitant overexpression of EGFR and MET were particularly aggressive, and experiments in patient-derived tumor cell models revealed profound inhibition of ERK/AKT signaling with combined HER2/MET inhibition. The findings suggest that combination therapy may be a valuable treatment option in aggressive gastric cancer.

  51. Epidemiology

    1. Calcium intake and colorectal adenoma risk: Dose-response meta-analysis of prospective observational studies

      NaNa Keum, Dong Hoon Lee, Darren C. Greenwood, Xuehong Zhang and Edward L. Giovannucci

      Article first published online: 4 SEP 2014 | DOI: 10.1002/ijc.29164

      What's new?

      Calcium protects against colorectal cancer recurrence, according to a recent study. But just how much calcium is enough to achieve a protective effect? In this study, the authors analyzed a number of previous papers presenting data on calcium supplements and risk of colorectal adenomas. They showed that within the range of 333 mg/day up to 2,229 mg/day of calcium, as intake increased, risk of adenomas – particularly high-risk adenomas – decreased. Thus, calcium may continue to decrease the risk of high-risk colorectal adenomas, precursors of cancer, over a wide range of intake.

    2. HPV16 methyl-haplotypes determined by a novel next-generation sequencing method are associated with cervical precancer

      Lisa Mirabello, Marina Frimer, Ariana Harari, Thomas McAndrew, Benjamin Smith, Zigui Chen, Nicolas Wentzensen, Sholom Wacholder, Philip E. Castle, Tina Raine-Bennett, Mark Schiffman and Robert D. Burk

      Article first published online: 3 SEP 2014 | DOI: 10.1002/ijc.29119

      What's new?

      Human papillomavirus type 16 (HPV16) is the most prevalent carcinogenic HPV type, but infection progresses to cervical precancer in only a small fraction of cases. Determining whether infections will progress or clear remains an elusive goal, but this study suggests that it may be possible to distinguish between the two with a bisulfite-treated DNA next-generation sequencing (NGS) assay specific to HPV16 DNA methylation. The NGS assay performed similarly to pyrosequencing and has several advantages over traditional methods. Using HPV16 CpG methylation and methyl-haplotype biomarkers, the NGS technique could aid in risk stratification for HPV-positive women.

  52. Cancer Cell Biology

    1. Polycystin-1 and polycystin-2 are involved in the acquisition of aggressive phenotypes in colorectal cancer

      Antonios N. Gargalionis, Penelope Korkolopoulou, Elena Farmaki, Christina Piperi, Georgia Dalagiorgou, Christos Adamopoulos, Georgia Levidou, Angelica Saetta, Paraskevi Fragkou, Panagiota Tsioli, Hippokratis Kiaris, Adamantia Zizi-Serbetzoglou, Ioannis Karavokyros, Kostas A. Papavassiliou, Nikolaos Tsavaris, Efstratios Patsouris, Efthimia K. Basdra and Athanasios G. Papavassiliou

      Article first published online: 3 SEP 2014 | DOI: 10.1002/ijc.29140

      What's new?

      The behavior of cancer cells is regulated in part by mechanical stimuli. Key to the mechanosensing properties of cells are the epithelial polycystins PC1 and PC2, which the present study links to the progression of colorectal cancer (CRC). In vitro experiments show that overexpression of PC1 and PC2 are associated with aggressive CRC phenotype, while clinical analyses associate PC1 overexpression with poor recurrence-free survival and aberrant PC2 expression with poor overall survival. The data imply that the two polycystins are of clinical relevance in CRC, with potential roles as targets for the prevention of invasion and metastasis.

    2. SDF-1α stiffens myeloma bone marrow mesenchymal stromal cells through the activation of RhoA-ROCK-Myosin II

      Dong Soon Choi, Daniel J. Stark, Robert M. Raphael, Jianguo Wen, Jing Su, Xiaobo Zhou, Chung-Che Chang and Youli Zu

      Article first published online: 2 SEP 2014 | DOI: 10.1002/ijc.29145

      What's new?

      Multiple myeloma remains an uncurable disease in part because of the persistence of myeloma cancer stem cells that remain in specific niches in the bone marrow. Here, the authors established a novel function of stromal cell-derived factor (SDF)−1α in altering biomechanics of myeloma-associated bone marrow mesenchymal stromal cells through the activation of myosin II. They further determined that the altered biophysical characteristics play a critical role in regulating the interactions between the stroma and myeloma cancer stem cells. Collectively, the results suggest that matrix stiffening can occur in the bone marrow of multiple myeloma patients which in turn can promote disease pathogenesis.

  53. Cancer Therapy

    1. Sweat but no gain: Inhibiting proliferation of multidrug resistant cancer cells with “ersatzdroges”

      Yoonseok Kam, Tuhin Das, Haibin Tian, Parastou Foroutan, Epifanio Ruiz, Gary Martinez, Susan Minton, Robert J. Gillies and Robert A. Gatenby

      Article first published online: 2 SEP 2014 | DOI: 10.1002/ijc.29158

      What's new?

      A common mechanism for acquired resistance to cancer chemotherapy is upregulation of the ABCB1 pump. This study shows that the proliferation of multidrug-resistant ABCB1-expressing cells is decreased significantly with the administration of relatively nontoxic chemotherapy drug substitutes, or ersatzdroges, that serve as pump substrates. In vivo 18-FDG-PET imaging revealed increased glucose uptake by tumors in mice following systemic ersatzdroge administration. The findings suggest that ersatzdroges, by increasing the energy expenditure of resistant cells, expose resistant cell populations and reduce their fitness and ability to proliferate. Since many ersatzdroges are currently available (e.g., Verapamil), the strategy could be applied clinically.

    2. Haploidentical hematopoietic stem cell transplantation in adults with Philadelphia-negative acute lymphoblastic leukemia: No difference in the high- and low-risk groups

      Xiao-Dong Mo, Lan-Ping Xu, Xiao-Hui Zhang, Dai-Hong Liu, Yu Wang, Huan Chen, Chen-Hua Yan, Yu-Hong Chen, Wei Han, Feng-Rong Wang, Jing-Zhi Wang, Kai-Yan Liu and Xiao-Jun Huang

      Article first published online: 2 SEP 2014 | DOI: 10.1002/ijc.29146

      What's new?

      Allogeneic hematopoietic stem cell transplantation (HSCT) is the most effective post-consolidation therapy for adult patients with Philadelphia chromosome-negative (Ph-negative) acute lymphoblastic leukemia (ALL) in first complete remission (CR1). A human leukocyte antigen (HLA)-haploidentical related donor (haplo-RD) is an important alternative source for those without HLA-identical sibling donor (ISD). Here, comparable outcomes were observed among high- and low-risk Ph-negative ALL CR1 patients after haplo-HSCT, and haplo-HSCT might overcome the poor prognostic significance of a high-risk status of Ph-negative ALL CR1 at diagnosis. Haplo-RDs may thus be considered for Ph-negative ALL adult patients in CR1 as an important alternative source of donors.

  54. Epidemiology

    1. Serum 25-hydroxyvitamin D, vitamin D binding protein and risk of colorectal cancer in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial

      Stephanie J. Weinstein, Mark P. Purdue, Stephanie A. Smith-Warner, Alison M. Mondul, Amanda Black, Jiyoung Ahn, Wen-Yi Huang, Ronald L. Horst, William Kopp, Helen Rager, Regina G. Ziegler and Demetrius Albanes

      Article first published online: 2 SEP 2014 | DOI: 10.1002/ijc.29157

      What's new?

      Vitamin D possesses anticancer properties, such as an ability to inhibit cell proliferation and angiogenesis and to promote cell differentiation and apoptosis. In particular, vitamin D status may be inversely linked with colorectal cancer risk, though studies have yielded inconsistent results. The present investigation suggests that increased levels of circulating 25-hydroxyvitamin D (25[OH]D), a biomarker for vitamin D status, are associated with a substantially reduced risk of colorectal cancer. No association or modifying role was detected for circulating levels of vitamin D binding protein, the primary carrier of 25(OH)D.

  55. Cancer Cell Biology

    1. PSAT1 regulates cyclin D1 degradation and sustains proliferation of non-small cell lung cancer cells

      Yi Yang, Jueheng Wu, Junchao Cai, Zhenjian He, Jie Yuan, Xun Zhu, Yanbing Li, Mengfeng Li and Hongyu Guan

      Article first published online: 2 SEP 2014 | DOI: 10.1002/ijc.29150

      What's new?

      Metabolic enzymes play key regulatory roles in tumorigenesis, though their specific contributions to tumor cell growth and survival are unclear. This report is the first to demonstrate that phosphoserine aminotransferase 1 (PSAT1), an enzyme involved in serine biosynthesis, is overexpressed in non-small cell lung cancer (NSCLC). Elevated PSAT1 appears to enhance the proliferation of NSCLC cells by promoting cell-cycle progression, an effect associated with inhibition of cyclin D1 degradation and altered activity of the Rb-E2F pathway. The results indicate that unrestrained cell-cycle progression in NSCLC is linked to PSAT1 upregulation and constitutive activation of E2F.

  56. Cancer Genetics

    1. Modulation of chemotherapeutic drug resistance in neuroblastoma SK-N-AS cells by the neural apoptosis inhibitory protein and miR-520f

      Harry Harvey, Olga Piskareva, Laura Creevey, Leah C. Alcock, Patrick G Buckley, Maureen J. O'Sullivan, Miguel F. Segura, Soledad Gallego, Raymond L. Stallings and Isabella M. Bray

      Article first published online: 2 SEP 2014 | DOI: 10.1002/ijc.29144

      What's new?

      Just under one-third of high-risk neuroblastomas, in which drug resistance is a central feature, involve amplification of the MYCN gene. Resistance in remaining high-risk tumors may be determined by any of several non-MYCN amplification mechanisms. Here, analysis of an SK-N-AS subline (SK-N-AsCis24) lacking MYCN amplification but resistant to cisplatin and etoposide reveals a link between the development of drug resistance via apoptotic inhibition and the neural apoptosis inhibitory protein (NAIP) and its regulatory microRNA, miR-520f. NAIP upregulation was associated with DNA copy number gain on chromosome 5 and down-regulation of miRNA-520f. MiR-520f was discovered to be down-regulated post-chemotherapy.

  57. Epidemiology

    1. Which adenomas are detected by fecal occult blood testing? A state-wide analysis from Bavaria, Germany

      Hermann Brenner, Michael Hoffmeister, Berndt Birkner and Christian Stock

      Article first published online: 2 SEP 2014 | DOI: 10.1002/ijc.29148

      What's new?

      A commonly used tool in colorectal cancer screening is the guaiac-based fecal occult blood test (gFOBT), which is associated with reduced mortality from colorectal cancer, despite its limited ability to detect colorectal adenomas, the precursors of most colorectal cancers. This study identifies three key determinants of positive adenoma detection by gFOBT: adenoma size greater than 2 cm, pedunculated shape, and nontubular histology. The low proportion of large pedunculated adenomas and nontubular adenomas in the proximal colon may explain the particular poor adenoma detection rates in the proximal colon. The findings could help to refine colorectal cancer screening strategies.

    2. Age-stratified 5-year risks of cervical precancer among women with enrollment and newly detected HPV infection

      Julia C. Gage, Hormuzd A. Katki, Mark Schiffman, Barbara Fetterman, Nancy E. Poitras, Thomas Lorey, Li C. Cheung, Philip E. Castle and Walter K. Kinney

      Article first published online: 2 SEP 2014 | DOI: 10.1002/ijc.29143

      What's new?

      Screening for human papillomavirus (HPV) is typically targeted at older women, in whom persistent HPV infection is linked to progression to cervical neoplasia and cancer. However, it is unclear whether a woman's age influences her risk of progression following HPV detection. Here, women ages 30 to 64 who were HPV-positive at enrollment in an HPV and Pap co-testing screening program were discovered to have a higher 5-year risk of cervical precancer and cancer than women with newly detected HPV infection. However, HPV infection rates declined with age, and associated risks did not rise with increasing age.

  58. Cancer Therapy

    1. RIST: A potent new combination therapy for glioblastoma

      Lisa Nonnenmacher, Mike-Andrew Westhoff, Simone Fulda, Georg Karpel-Massler, Marc-Eric Halatsch, Jens Engelke, Thomas Simmet, Selim Corbacioglu and Klaus-Michael Debatin

      Article first published online: 1 SEP 2014 | DOI: 10.1002/ijc.29138

      What's New?

      If you get glioblastoma, there aren't too many effective treatment options available. This study hopes to change that with a new combination therapy, called RIST (for rapamycin, irinotecan, sunitinib, temozolomide). Both rapamycin and sunitinib hamper survival of cancer cells in culture, but did not pan out in clinical application; combined, they may be able to overcome the cancer's natural robustness. Paired with the chemotherapeutic agents, irinotecan and temozolomide, the new combo successfully increased survival time in mice and reduced tumor growth by slowing cell division and spurring apoptosis. These results suggest RIST may be a promising treatment for brain tumors.

  59. Early Detection and Diagnosis

    1. Screening for prostate cancer in the US? Reduce the harms and keep the benefit

      Tiago M. de Carvalho, Eveline A.M. Heijnsdijk and Harry J. de Koning

      Article first published online: 1 SEP 2014 | DOI: 10.1002/ijc.29136

      What's new?

      Although prostate cancer screening based on the detection of prostate-specific antigen (PSA) can reduce mortality, it can also result in overdiagnosis and possibly unnecessary treatment. To help identify scenarios in which PSA screening is beneficial, the authors of this study examined a range of alternative PSA screening algorithms, including approaches based on different start and stop ages and screening frequencies. Screening between ages 55 and 69 appears to maximize reductions in mortality and limit overdiagnosis, risk of which rises by age 70. Screening frequency based on changes in PSA value or threshold did not noticeably improve the balance of harms and benefits compared with annual screening.

  60. Cancer Genetics

    1. Comprehensive screening for mutations associated with colorectal cancer in unselected cases reveals penetrant and nonpenetrant mutations

      Cornelia Kraus, Tilman T. Rau, Philipp Lux, Katharina Erlenbach-Wünsch, Sabine Löhr, Mandy Krumbiegel, Christian T. Thiel, Robert Stöhr, Abbas Agaimy, Roland S. Croner, Michael Stürzl, Werner Hohenberger, Arndt Hartmann and André Reis

      Article first published online: 30 AUG 2014 | DOI: 10.1002/ijc.29149

      What's new?

      It's important to find out whether a colorectal tumor has arisen spontaneously or from an inherited mutation, but only those patients whose tumors match clinical criteria for a hereditary CRC syndrome get screened for germline mutations. Thus, many familial tumors may not be identified as such. This study aimed to find out whether screening newly diagnosed colorectal tumors without regard for histology would identify more hereditary disease. They found that an unbiased screening using next generation sequencing (NGS) did indeed identify more germline mutations than the traditional method; of 3 mutations discovered, 2 would have been missed by current strategies based on clinicopathological presentation. NGS does identify non-penetrant mutations, though, which could be problematic for use with patients.

  61. Short Reports

    1. Effects of the exercise-inducible myokine irisin on malignant and non-malignant breast epithelial cell behavior in vitro

      Nicholas P. Gannon, Roger A. Vaughan, Randi Garcia-Smith, Marco Bisoffi and Kristina A. Trujillo

      Article first published online: 30 AUG 2014 | DOI: 10.1002/ijc.29142

      What's new?

      A relatively little known myokine, irisin, might be a missing link between exercise and its protective effect on breast cancer. Researchers from the University of New Mexico treated several breast cancer cell lines with the myokine and observed decreased viability, proliferation and migration. These findings were linked to proapoptotic and anti-inflammatory effects involving the transcription factor NF-κB. The authors point to potential therapeutic benefits as irisin did not affect growth or survival of non-malignant cells and synergized with doxorubicin, currently widely used in breast cancer chemotherapy.

  62. Cancer Cell Biology

    1. Discoidin domain receptor 1 is a novel transcriptional target of ZEB1 in breast epithelial cells undergoing H-Ras-induced epithelial to mesenchymal transition

      Minsoo Koh, Yunjung Woo, Rajeshwari R. Valiathan, Hae Yoen Jung, So Yeon Park, Yong Nyun Kim, Hyeong-Reh Choi Kim, Rafael Fridman and Aree Moon

      Article first published online: 29 AUG 2014 | DOI: 10.1002/ijc.29154

      What's New?

      The epithelial-to-mesynchymal transition (EMT) program has emerged as a key mechanism in cancer cell invasiveness and metastasis. Here the authors uncover a new molecular mechanism of EMT by the H-Ras proto-oncogene. They show that the EMT-inducing transcription factor ZEB1 reduces expression of DDR1, a collagen-binding receptor tyrosine kinase receptor. DDR1 itself reduces the invasive phenotype of mesenchymal-like breast cancer cells in 3D cultures, indicating that ZEB1 in part induces EMT by suppressing the anti-invasive function of DDR1.

  63. Tumor Immunology

    1. MicroRNA-155 deficiency enhances the recruitment and functions of myeloid-derived suppressor cells in tumor microenvironment and promotes solid tumor growth

      Junfeng Wang, Fang Yu, Xuemei Jia, Stephen Iwanowycz, Yuzhen Wang, Shiang Huang, Walden Ai and Daping Fan

      Article first published online: 29 AUG 2014 | DOI: 10.1002/ijc.29151

      What's New?

      miR-155 functions as an oncomicroRNA in several solid tumors, hence efforts are being made to develop anti-miR-155 therapeutic strategies for cancer therapy. However, the anti-tumor effects of miR-155 expression in host immune cells have started to attract attention. For the first time, this study shows that, in mouse models, systemic or bone marrow miR-155 deficiency promotes tumor growth, by increasing the recruitment of myeloid-derived suppressor cells—an important tumor-promoting component of the tumor microenvironment—to the tumor as well as enhancing their immune-suppressive and angiogenic functions. This study further emphasizes an important anti-cancer role of immune cell miR-155 expression in tumor development.

  64. Early Detection and Diagnosis

    1. A prognosis based classification of undifferentiated uterine sarcomas: Identification of mitotic index, hormone receptors and YWHAE-FAM22 translocation status as predictors of survival

      Gabriela Gremel, Markus Liew, Farzaneh Hamzei, Elin Hardell, Jonas Selling, Mehran Ghaderi, Sten Stemme, Fredrik Pontén and Joseph W. Carlson

      Article first published online: 27 AUG 2014 | DOI: 10.1002/ijc.29141

      What's New?

      Undifferentiated uterine sarcomas are rare tumors with a heterogeneous biology and an overall poor prognosis. While attempting to subdivide them based on prognosis has been difficult, it may provide insights into their biology. This work is the first to examine the effect of clinical, pathological, biomarker and molecular changes on patient survival. It demonstrates that the tumors can be subdivided into prognostic groups using mitotic index, hormone receptor expression, and YWHAE-FAM22 translocation status, and that a group exists that may benefit from hormone therapy. This work provides survival-analysis driven recommendations for tumor sub-classification as well as possible insights for treatment.

  65. Cancer Cell Biology

    1. The expression of glucocorticoid receptor is negatively regulated by active androgen receptor signaling in prostate tumors

      Ning Xie, Helen Cheng, Dong Lin, Liangliang Liu, Ou Yang, Li Jia, Ladan Fazli, Martin E. Gleave, Yuzhuo Wang, Paul Rennie and Xuesen Dong

      Article first published online: 27 AUG 2014 | DOI: 10.1002/ijc.29147

      What's New

      Many prostate cancers (PCa) eventually develop resistance to androgen-deprivation therapy, and the androgen receptor (AR) is known to play a critical role in this process. However, even when AR signaling is blocked, PCa tumors may still recur. Some studies have suggested that the glucocorticoid receptor (GR) might be responsible for the progression to castration-resistant prostate cancer. In this study, however, the authors determined that this is not the case. They also found that GR expression is suppressed by active AR signaling, due to a “negative androgen-response element” sequence near the GR gene.

  66. Epidemiology

    1. Estimating and explaining the effect of education and income on head and neck cancer risk: INHANCE consortium pooled analysis of 31 case-control studies from 27 countries

      David I. Conway, Darren R. Brenner, Alex D. McMahon, Lorna M.D. Macpherson, Antonio Agudo, Wolfgang Ahrens, Cristina Bosetti, Hermann Brenner, Xavier Castellsague, Chu Chen, Maria Paula Curado, Otávio A. Curioni, Luigino Dal Maso, Alexander W. Daudt, José F. de Gois Filho, Gypsyamber D'Souza, Valeria Edefonti, Eleonora Fabianova, Leticia Fernandez, Silvia Franceschi, Maura Gillison, Richard B. Hayes, Claire M. Healy, Rolando Herrero, Ivana Holcatova, Vijayvel Jayaprakash, Karl Kelsey, Kristina Kjaerheim, Sergio Koifman, Carlo La Vecchia, Pagona Lagiou, Philip Lazarus, Fabio Levi, Jolanta Lissowska, Daniele Luce, Tatiana V. Macfarlane, Dana Mates, Elena Matos, Michael McClean, Ana M Menezes, Gwenn Menvielle, Franco Merletti, Hal Morgenstern, Kirsten Moysich, Heiko Müller, Joshua Muscat, Andrew F. Olshan, Mark P. Purdue, Heribert Ramroth, Lorenzo Richiardi, Peter Rudnai, Stimson Schantz, Stephen M. Schwartz, Oxana Shangina, Lorenzo Simonato, Elaine Smith, Isabelle Stucker, Erich M. Sturgis, Neonila Szeszenia-Dabrowska, Renato Talamini, Peter Thomson, Thomas L. Vaughan, Qingyi Wei, Deborah M. Winn, Victor Wunsch-Filho, Guo-Pei Yu, Zuo-Feng Zhang, Tongzhang Zheng, Ariana Znaor, Paolo Boffetta, Shu-Chun Chuang, Marianoosh Ghodrat, Yuan-Chin Amy Lee, Mia Hashibe and Paul Brennan

      Article first published online: 22 AUG 2014 | DOI: 10.1002/ijc.29063

      What's new?

      Head and neck cancer is among the most common and increasing cancers in the world. Besides smoking, alcohol drinking, and human papilloma virus infections, low socioeconomic status has been implicated as one of the most important risk factors for this cancer type. This large multinational study authoritatively confirmed that lower education status and lower income are associated with increased risk for head and neck cancer development. Smoking and alcohol consumption could not entirely explain the risk associated with low socioeconomic factors, and therefore, as the authors argue, need to be more explicitly recognized in the etiology associated with head and neck cancer.

    2. TRAIL expression levels in human hepatocellular carcinoma have implications for tumor growth, recurrence and survival

      Katja Piras-Straub, Khaleda Khairzada, Martin Trippler, Hideo A. Baba, Gernot M. Kaiser, Andreas Paul, Ali Canbay, Frank Weber, Guido Gerken and Kerstin Herzer

      Article first published online: 22 AUG 2014 | DOI: 10.1002/ijc.29139

      What's new?

      Evidence suggests that the development and outgrowth of hepatocellular carcinoma (HCC) is influenced by dysregulation of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL). Here, TRAIL expression was found to be reduced in about two-thirds of HCCs, based on analysis of tissue samples from patients who underwent liver resection or liver transplantation, either because of HCC or because of other liver disease. TRAIL expression was correlated with tumor size and stage, recurrence after resection, and survival rate. The findings suggest that TRAIL may be able to distinguish high-risk HCC patients and influence decisions about the need for additional perioperative adjuvant procedures.

  67. Cancer Therapy

    1. Monitoring oxygen levels in orthotopic human glioma xenograft following carbogen inhalation and chemotherapy by implantable resonator-based oximetry

      Huagang Hou, Venkata Krishnamurthy Nemani, Gaixin Du, Ryan Montano, Rui Song, Barjor Gimi, Harold M. Swartz, Alan Eastman and Nadeem Khan

      Article first published online: 22 AUG 2014 | DOI: 10.1002/ijc.29132

      What's new?

      Malignant glioma are therapeutically challenging due to their aggressive growth characteristics and hypoxic environment. Additionally, techniques for direct and repeated measurements of pO2 in orthotopic human glioma xenografts for translational research are lacking. In this study, a multisite Electron Paramagnetic Resonance oximetry technique using implantable resonators was implemented. The results demonstrate the application of the technique for monitoring temporal changes in brain pO2, including orthotopic glioma and the effectiveness of carbogen inhalation for hyperoxygenation. The rational combination of gemcitabine and a cell cycle checkpoint inhibitor significantly increased pO2 and inhibited glioma growth, suggesting an innovative treatment strategy.

  68. Cancer Genetics

    1. Lynch-like syndrome: Characterization and comparison with EPCAM deletion carriers

      So Young Kang, Cheol Keun Park, Dong Kyung Chang, Jong Won Kim, Hee Jung Son, Yong Beom Cho, Seong Hyeon Yun, Hee Cheol Kim, Moosik Kwon and Kyoung-Mee Kim

      Article first published online: 22 AUG 2014 | DOI: 10.1002/ijc.29133

      What's new?

      Colorectal cancers (CRCs) with MSI+ but without detectable germline mutation or hypermethylation in DNA mismatch repair (MMR) genes can be classified as Lynch-like Syndrome (LLS). The underlying mechanism and clinical significance of LLS remain largely unknown. Here, the authors identified 55 LLS patients out of a cohort of 4,765 consecutive CRC patients. Six LLS patients had variants of unknown significance in the MMR genes. Somatic mutation in POLE was identified as a rare underlying cause for MMR deficiency in LLS. LLS and LS caused by EPCAM deletion shared common clinical features, supporting LLS as a subset of familial MSI+ CRC.

  69. Epidemiology

    1. Late mortality among 5-year survivors of early onset cancer: A population-based register study

      Andreina E. Kero, Liisa S. Järvelä, Mikko Arola, Nea Malila, Laura M. Madanat-Harjuoja, Jaakko Matomäki and Päivi M. Lähteenmäki

      Article first published online: 21 AUG 2014 | DOI: 10.1002/ijc.29135

      What's new?

      In contrast to childhood and adolescent cancer survivors, data on late mortality among survivors of young adult (YA) cancers are lacking, particularly with respect to non-malignant causes of death. In this population-based study, the authors provide data regarding cause-specific mortality after early onset cancer, with an exceptionally long observation time. The results indicate that survivors of YA cancer need specific follow-up care, particularly with regard to efforts that may reduce late cardiovascular mortality.

  70. Infectious Causes of Cancer

    1. AID expression in peripheral blood of children living in a malaria holoendemic region is associated with changes in B cell subsets and Epstein-Barr virus

      Joel R. Wilmore, Amolo S. Asito, Chungwen Wei, Erwan Piriou, P. Odada Sumba, Iñaki Sanz and Rosemary Rochford

      Article first published online: 19 AUG 2014 | DOI: 10.1002/ijc.29127

      What's New?

      Activation-induced cytidine deaminase (AID) expression has been linked to translocations in the c-myc transcription factor that can cause Burkitt's lymphoma, a tumor closely associated with Epstein Barr Virus (EBV) and malaria infections. Here the authors demonstrate a first link between AID expression and exposure to malaria in the peripheral blood of children. They further show that AID expression is linked to detectable EBV in children living in a region of high malaria transmission. These findings shed new light on how malaria and EBV co-infections can increase the risk of developing Burkitt's lymphoma.

  71. Early Detection and Diagnosis

    1. p16INK4a/Ki-67 co-expression specifically identifies transformed cells in the head and neck region

      Elena-Sophie Prigge, Csaba Toth, Gerhard Dyckhoff, Steffen Wagner, Franziska Müller, Claus Wittekindt, Kolja Freier, Peter Plinkert, Jürgen Hoffmann, Svetlana Vinokurova, Jens Peter Klussmann, Magnus von Knebel Doeberitz and Miriam Reuschenbach

      Article first published online: 19 AUG 2014 | DOI: 10.1002/ijc.29130

      What's new?

      Overexpression of p16INK4a is indicative of human papillomavirus (HPV-)-induced head and neck squamous cell carcinomas (HNSCC), though its diagnostic value is limited by factors such as overexpression in non-transformed cells and in some HPV-negative HNSCCs. This study suggests that combined detection of p16INK4a and the proliferation marker Ki-67 in a single immunohistochemical staining procedure might advance the diagnostic value of p16INK4a overexpression. Combined detection was specific for transformed cells of the head and neck region. The findings could influence the assessment of p16INK4a expression in the head and neck, particularly in the context of diagnostic cytopathology.

  72. Epidemiology

    1. A novel case–control design to estimate the extent of over-diagnosis of breast cancer due to organised population-based mammography screening

      Kerri R. Beckmann, John W. Lynch, Janet E. Hiller, Gelareh Farshid, Nehmat Houssami, Stephen W. Duffy and David M. Roder

      Article first published online: 18 AUG 2014 | DOI: 10.1002/ijc.29124

      What's new?

      The detection of abnormal growths in the breast that never become clinically significant is a known limitation of mammography screening. Nonetheless, the extent to which mammography contributes to the overdiagnosis of breast cancer is unclear. Here, among women ages 45 to 85 in South Australia, the extent of overdiagnosis due to mammography screening was estimated to be 8 percent for invasive breast cancer and 14 percent for all breast cancers. The estimates decreased following adjustment for potential risk factors. The findings suggest that the risk of overdiagnosis with mammography screening is modest, particularly for invasive disease.

  73. Cancer Cell Biology

    1. Metalloproteinase-dependent and -independent processes contribute to inhibition of breast cancer cell migration, angiogenesis and liver metastasis by a disintegrin and metalloproteinase with thrombospondin motifs-15

      Richard Kelwick, Laura Wagstaff, Julie Decock, Christian Roghi, Lindsay S. Cooley, Stephen D. Robinson, Hugh Arnold, Jelena Gavrilović, Diane M. Jaworski, Kazuhiro Yamamoto, Hideaki Nagase, Bastian Seubert, Achim Krüger and Dylan R. Edwards

      Article first published online: 18 AUG 2014 | DOI: 10.1002/ijc.29129

      What's New?

      Several members of the ADAMTS family of extracellular proteinases help stave off cancer, and these genes are often silenced or altered in tumor cells. Previous work has shown that breast cancer patients whose tumours express higher levels of ADAMTS-15 have better outcomes. In this study, the authors investigated what happened when breast cancer cells lines expressed either wild-type or a metalloproteinase-deficient mutant of ADAMTS-15. They saw no effect on proliferation or apoptosis, regardless of metalloproteinase function, but both forms hampered cell migration. However, only the wild-type impeded angiogenesis. Both forms affected metastasis, but the effects varied depending on the tissue microenvironment of the target organ.

  74. Tumor Immunology

    1. 5-Fluorouracil causes leukocytes attraction in the peritoneal cavity by activating autophagy and HMGB1 release in colon carcinoma cells

      Lucia Cottone, Annalisa Capobianco, Chiara Gualteroni, Cristiana Perrotta, Marco E. Bianchi, Patrizia Rovere-Querini and Angelo A. Manfredi

      Article first published online: 18 AUG 2014 | DOI: 10.1002/ijc.29125

      What's New?

      Anti-cancer drugs can sometimes help the tumors they are meant to destroy. One reason is because stressed or dying cancer cells release molecular factors that can attract leukocytes, and some of those leukocytes can contribute to tumor survival. In this study, the authors found that this is precisely what happens during intraperitoneal treatment of colon-cancer carcinomatosis with 5-fluorouracil (5-FU). Their results suggest that blocking autophagy and the release of HMGB1 are potential therapeutic targets for enhancing standard chemotherapy.

  75. Cancer Genetics

    1. You have full text access to this OnlineOpen article
      Fine mapping of genetic susceptibility loci for melanoma reveals a mixture of single variant and multiple variant regions

      Jennifer H. Barrett, John C. Taylor, Chloe Bright, Mark Harland, Alison M. Dunning, Lars A. Akslen, Per A. Andresen, Marie-Françoise Avril, Esther Azizi, Giovanna Bianchi Scarrà, Myriam Brossard, Kevin M. Brown, Tadeusz Dębniak, David E. Elder, Eitan Friedman, Paola Ghiorzo, Elizabeth M. Gillanders, Nelleke A. Gruis, Johan Hansson, Per Helsing, Marko Hočevar, Veronica Höiom, Christian Ingvar, Maria Teresa Landi, Julie Lang, G. Mark Lathrop, Jan Lubiński, Rona M. Mackie, Anders Molven, Srdjan Novaković, Håkan Olsson, Susana Puig, Joan Anton Puig-Butille, Nienke van der Stoep, Remco van Doorn, Wilbert van Workum, Alisa M. Goldstein, Peter A. Kanetsky, Paul D. P. Pharoah, Florence Demenais, Nicholas K. Hayward, Julia A. Newton Bishop, D. Timothy Bishop, Mark M. Iles and on behalf of the GenoMEL Consortium

      Article first published online: 14 AUG 2014 | DOI: 10.1002/ijc.29099

      What's new?

      In genome-wide association studies, researchers identify genetic variants that frequently associate with a particular disease, though the variants identified may not contribute to the molecular cause of the disease. This study took a closer look at 17 regions associated with melanoma, fine mapping the regions both in people with melanoma and in healthy controls. Though single SNPs account for the association in some regions, they found that in a few regions, several SNPs – and possibly multiple genes – contributed to the association signal. These findings illustrate the importance of not overlooking the interaction between multiple genetic markers when conducting such studies.

  76. Short Reports

    1. Contact with ruminants is associated with esophageal squamous cell carcinoma risk

      Dariush Nasrollahzadeh, Weimin Ye, Ramin Shakeri, Masoud Sotoudeh, Shahin Merat, Farin Kamangar, Christian C. Abnet, Farhad Islami, Paolo Boffetta, Sanford M. Dawsey, Paul Brennan and Reza Malekzadeh

      Article first published online: 14 AUG 2014 | DOI: 10.1002/ijc.29109

      What's new?

      People across a particular part of Central Asia have an elevated risk of esophageal cancer, but no one has yet discovered quite why. This study asks how contact with animals influences risk. The authors gave a questionnaire to people in northern Iran with and without esophageal squamous cell cancer, inquiring about their contact with various animals, including horses, dogs, poultry, and ruminants, such as sheep and cattle. It turned out that contact with ruminants was associated with an 8-fold increase in risk of esophageal squamous cell carcinoma, and the longer the exposure over a lifetime, the greater the risk.

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