International Journal of Cancer

Cover image for International Journal of Cancer

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. Cancer Cell Biology

    1. Combined DNA methylation and gene expression profiling in gastrointestinal stromal tumors reveals hypomethylation of SPP1 as an independent prognostic factor

      Florian Haller, Jitao David Zhang, Evgeny A. Moskalev, Alexander Braun, Claudia Otto, Helene Geddert, Yasser Riazalhosseini, Aoife Ward, Aleksandra Balwierz, Inga-Marie Schaefer, Silke Cameron, B. Michael Ghadimi, Abbas Agaimy, Jonathan A. Fletcher, Jörg Hoheisel, Arndt Hartmann, Martin Werner, Stefan Wiemann and Özgür Sahin

      Article first published online: 1 AUG 2014 | DOI: 10.1002/ijc.29088

      What's new?

      Variations in the clinical behavior of gastrointestinal stromal tumors (GISTs) are associated with underlying variations in gene expression. But the mechanisms regulating gene expression in GIST and how they influence tumor progression remain unclear. A mechanism implicated in the present study is epigenetic dysregulation, specifically of secreted phosphoprotein 1 (SPP1), based on targeted DNA methylation profiling and genome-wide mRNA expression analysis in a cohort of GISTs. In vitro experiments indicate that SPP1 raises oncogenic potential by influencing the activation of major intracellular regulators. The findings suggest that SPP1 hypermethylation is an independent prognostic marker in GIST.

  2. Epidemiology

    1. Gamma glutamyltransferase, alanine aminotransferase and risk of cancer: Systematic review and meta-analysis

      Setor K. Kunutsor, Tanefa A. Apekey, Mieke Van Hemelrijck, Giliola Calori and Gianluca Perseghin

      Article first published online: 1 AUG 2014 | DOI: 10.1002/ijc.29084

      What's new?

      Emerging evidence indicates that the level of gamma glutamyltransferase (GGT) and the level of alanine aminotransferase (ALT)--two markers of liver dysfunction--may each be linked to cancer risk. So far, the prospective evidence on their associations has been inconsistent. However, in the review presented here, GGT level was found to be positively and log-linearly associated with overall cancer risk. The positive association was consistent for site-specific cancers. As for ALT, there were geographical variations in its association with overall cancer, and ALT was also found to be associated with an increased risk of cancers of digestive organs.

  3. Early Detection and Diagnosis

    1. Fluorescence-based endoscopic imaging of Thomsen–Friedenreich antigen to improve early detection of colorectal cancer

      Shinji Sakuma, James Y. H. Yu, Timothy Quang, Ken-Ichiro Hiwatari, Hironori Kumagai, Stephanie Kao, Alex Holt, Jalysa Erskind, Richard McClure, Michael Siuta, Tokio Kitamura, Etsuo Tobita, Seiji Koike, Kevin Wilson, Rebecca Richards-Kortum, Eric Liu, Kay Washington, Reed Omary, John C. Gore and Wellington Pham

      Article first published online: 31 JUL 2014 | DOI: 10.1002/ijc.29093

      What's New?

      Thomsen-Friedenreich (TF) antigen is commonly present in the colorectal mucous of patients with colorectal cancer. Its specificity to cancer cells and its ability to be labeled with fluorescent markers suggest that TF antigen could be useful for optical imaging modalities in cancer detection. The present study describes the development of a fluorescence nanoparticle for TF antigen imaging via fluorescence colonoscopy. The probe successfully detected TF-associated colorectal cancer in the early stage as well as the dynamic change of TF-based CRC during therapy. The nanobeacon could be a prognostic tool for the early detection of colorectal cancer.

  4. Epidemiology

    1. Long-term HPV type-specific risks of high-grade cervical intraepithelial lesions: A 14-year follow-up of a randomized primary HPV screening trial

      Vitaly Smelov, K. Miriam Elfström, Anna L.V. Johansson, Carina Eklund, Pontus Naucler, Lisen Arnheim-Dahlström and Joakim Dillner

      Article first published online: 29 JUL 2014 | DOI: 10.1002/ijc.29085

      What's new?

      High-grade cervical lesions are immediate precursors for cervical cancer but are not well detectable with current cytology testing methods. The authors examined the contribution of human papilloma virus (HPV) types to these lesions to enhance early detection. Using data from a 14-year Swedish follow-up to a randomized HPV screening trial they found markedly different contributions of different HPV types with types 16, 18, 31 and 33 carrying the greatest (28%) risk for high-grade lesions (CIN3+). These results may impact HPV screening strategies and second-generation vaccine development to include detection and prevention of high-grade lesions.

  5. Tumor Immunology

    1. An Fc-optimized NKG2D-immunoglobulin G fusion protein for induction of natural killer cell reactivity against leukemia

      Julia Steinbacher, Katrin Baltz-Ghahremanpour, Benjamin Joachim Schmiedel, Alexander Steinle, Gundram Jung, Ayline Kübler, Maya Caroline André, Ludger Grosse-Hovest and Helmut Rainer Salih

      Article first published online: 28 JUL 2014 | DOI: 10.1002/ijc.29083

      What's New?

      If antibodies could be engineered to recognize molecules that are common to many types of cancer, it could lead to new therapies. And if those antibodies could be modified so that they recruit and activate more immune cells, it could make immunotherapy far more effective. In this study, the authors developed a modified antibody-fusion protein that strongly binds to different types of NKG2DL, a class of molecules expressed by many different tumor types. This binding, in turn, activated NK cells against leukemia cells—including myeloid types, for which no antibody-based immunotherapy is yet available.

  6. Epidemiology

    1. Association of CRP genetic variants with blood concentrations of C-reactive protein and colorectal cancer risk

      Katharina Nimptsch, Krasimira Aleksandrova, Heiner Boeing, Jürgen Janke, Young-Ae Lee, Mazda Jenab, Bas H Bueno-De-Mesquita, Eugène HJM Jansen, Konstantinos K Tsilidis, Antonia Trichopoulou, Elisabete Weiderpass, Chunsen Wu, Kim Overvad, Anne Tjønneland, Marie-Christine Boutron-Ruault, Laure Dossus, Antoine Racine, Rudolf Kaaks, Federico Canzian, Pagona Lagiou, Dimitrios Trichopoulos, Domenico Palli, Claudia Agnoli, Rosario Tumino, Paolo Vineis, Salvatore Panico, Anders Johansson, Bethany Van Guelpen, Kay-Tee Khaw, Nick Wareham, Petra H Peeters, J. Ramón Quirós, Adoración Venceslá García, Esther Molina-Montes, Miren Dorronsoro, María-Dolores Chirlaque, Aurelio Barricarte Gurrea, Timothy J Key, Talita Duarte-Salles, Magdalena Stepien, Marc J. Gunter, Elio Riboli and Tobias Pischon

      Article first published online: 28 JUL 2014 | DOI: 10.1002/ijc.29086

      What's new?

      The C-reactive protein (CRP) indicates inflammation, and some data have shown an association between the presence of this protein in the blood and risk of colorectal cancer. But it's possible that other factors that might lead to cancer could also cause the uptick in circulating CRP, or that the cancer itself ups the CRP levels. This paper investigated whether the presence of genetic alleles associated with increased CRP also associate with increased colorectal cancer risk. They found that people carrying such alleles did have a higher risk of colorectal cancer, supporting the idea that circulating CRP itself contributes to carcinogenesis.

  7. Mini Reviews

    1. EUROGIN 2014 roadmap: Differences in human papillomavirus infection natural history, transmission and human papillomavirus-related cancer incidence by gender and anatomic site of infection

      Anna R. Giuliano, Alan G. Nyitray, Aimée R. Kreimer, Christine M. Pierce Campbell, Marc T. Goodman, Staci L. Sudenga, Joseph Monsonego and Silvia Franceschi

      Article first published online: 26 JUL 2014 | DOI: 10.1002/ijc.29082

  8. Early Detection and Diagnosis

    1. Determination of prognosis in metastatic melanoma through integration of clinico-pathologic, mutation, mRNA, microRNA, and protein information

      Kaushala Jayawardana, Sarah-Jane Schramm, Lauren Haydu, John F. Thompson, Richard A. Scolyer, Graham J. Mann, Samuel Müller and Jean Yee Hwa Yang

      Article first published online: 24 JUL 2014 | DOI: 10.1002/ijc.29047

      What's new?

      The use of “-omics” technologies in the investigation of tumor biomarkers has led to the generation of multiple types of data sets. But which of those sets are most useful for prognostic assessment of disease is unclear. Here, for prognostic accuracy in metastatic melanoma after resection, a combination of clinicopathologic variables and RNA expression data was found to out-perform information derived from “-omics” platforms alone. Among patients, however, the prognostic accuracy of different data types varied. The findings suggest that more data does not necessarily increase prognostic accuracy and that patient evaluation must rely on both traditional and novel approaches.

  9. Carcinogenesis

    1. Dynamic balance of multiple myeloma clonogenic side population cell percentages controlled by environmental conditions

      Jianguo Wen, Wenjing Tao, Isere Kuiatse, Pei Lin, Yongdong Feng, Richard J. Jones, Robert Z. Orlowski and Youli Zu

      Article first published online: 23 JUL 2014 | DOI: 10.1002/ijc.29078

      What's new?

      Multiple myeloma remains incurable, with patients prone to relapse and progression despite therapy. The resiliency of multiple myeloma may be linked to the existence of side population (SP) cells, which possess stem-like qualities. Here, SP and non-SP (NSP) cell percentages were found to exist in balance in multiple myeloma, with NSP populations serving as reservoirs for the generation of SP cells. Hypoxic stress enhanced the percentage of SP cells as well as TGF-β1 expression. The findings suggest that environmental factors and the TGF-β1 pathway are involved in the regulation of SP–NSP balance in multiple myeloma.

  10. Short Reports

    1. Venous thromboembolism risk prediction in ambulatory cancer patients: Clinical significance of neutrophil/lymphocyte ratio and platelet/lymphocyte ratio

      Patrizia Ferroni, Silvia Riondino, Vincenzo Formica, Vittore Cereda, Livia Tosetto, Francesca La Farina, Maria Giovanna Valente, Matteo Vergati, Fiorella Guadagni and Mario Roselli

      Article first published online: 23 JUL 2014 | DOI: 10.1002/ijc.29076

      What's new?

      Venous thromboembolism (VTE) affects a disproportionately large number of chemotherapy-treated cancer out-patients. Many of those patients may benefit from anticoagulant prophylaxis, but identifying them requires the discovery of predictive biomarkers for VTE. Here, both neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR) were found to be significantly elevated prior to the initiation of chemotherapy in cancer patients who later developed symptomatic VTE. The association was strongest for PLR and for patients identified as being at intermediate risk of VTE.

  11. Cancer Therapy

    1. Loss of expression of the tumour suppressor gene AIMP3 predicts survival following radiotherapy in muscle-invasive bladder cancer

      Pratik M.S. Gurung, Abhi Veerakumarasivam, Magali Williamson, Nicholas Counsell, James Douglas, Wei S. Tan, Andrew Feber, Simon J. Crabb, Susan C. Short, Alex Freeman, Thomas Powles, Peter J. Hoskin, Catharine M. West and John D. Kelly

      Article first published online: 22 JUL 2014 | DOI: 10.1002/ijc.29022

      What's new?

      Radical cystectomy in the treatment of muscle-invasive bladder cancer (MIBC) is associated with significant morbidity and mortality, calling for organ-preservation strategies such as radical radiotherapy with radiosensitisation and chemo-radiotherapy. This paradigm change will be accelerated with the identification of biomarkers that can reliably select patients who will respond to radiotherapy. This study tested AIMP3, an upstream regulator of DNA damage response following genotoxic stress, as a potential clinical biomarker. AIMP3 loss of expression was associated with a decrease in genomic-stability, p53-transactivity, and radiosensitivity in vitro and was predictive of overall-survival in a phase-III randomised control trial of radiotherapy in MIBC.

  12. Mini Reviews

    1. Handling chemotherapy drugs—Do medical gloves really protect?

      Lilla Landeck, Ernesto Gonzalez and Olaf Manfred Koch

      Article first published online: 22 JUL 2014 | DOI: 10.1002/ijc.29058

    2. Hippo-YAP signaling pathway: A new paradigm for cancer therapy

      Yanlei Ma, Yongzhi Yang, Feng Wang, Qing Wei and Huanlong Qin

      Article first published online: 22 JUL 2014 | DOI: 10.1002/ijc.29073

    3. Targeting the relaxin hormonal pathway in prostate cancer

      Anton Neschadim, Alastair J.S. Summerlee and Joshua D. Silvertown

      Article first published online: 22 JUL 2014 | DOI: 10.1002/ijc.29079

  13. Cancer Genetics

    1. Characterization of genomic imbalances in diffuse large B-cell lymphoma by detailed SNP-chip analysis

      René Scholtysik, Markus Kreuz, Michael Hummel, Maciej Rosolowski, Monika Szczepanowski, Wolfram Klapper, Markus Loeffler, Lorenz Trümper, Reiner Siebert, Ralf Küppers and for the “Molecular Mechanisms in Malignant Lymphomas” Network Project of the Deutsche Krebshilfe

      Article first published online: 22 JUL 2014 | DOI: 10.1002/ijc.29072

      What's new?

      In their quest to uncover new genes involved in diffuse large B-cell lymphoma (DLBCL), these authors searched for changes in copy number using an array of small nucleotide polymorphisms – a SNP-chip. They found a number of recurrent copy number changes across the entire sample of 148 tumors, and when they separated the samples by lymphoma subtype, they found some of these changes were common to the various subtypes, but some were specific to a single subtype. They also found that a third of the copy number changes did correspond to changes in gene expression. This is the first analysis to investigate subtype-specific changes in copy number, and reveal similarities and differences between the two main types.

  14. Cancer Therapy

    1. Isolated limb perfusion with melphalan, tumour necrosis factor-alpha and oncolytic vaccinia virus improves tumour targeting and prolongs survival in a rat model of advanced extremity sarcoma

      Tim D. Pencavel, Michelle J. Wilkinson, David C. Mansfield, Aadil A. Khan, Rohit Seth, Eleni M. Karapanagiotou, Victoria Roulstone, Richard J. Aguilar, Nanhai G. Chen, Aladar A. Szalay, Andrew J. Hayes and Kevin J. Harrington

      Article first published online: 22 JUL 2014 | DOI: 10.1002/ijc.29059

      What's new?

      Attacking cancer with viruses is an strategy that's been pursued for decades, with mixed results. This paper examined the effectiveness of combining oncolytic viral therapy with isolated limb perfusion (ILP), in which cancer at the extremities is isolated and subjected to high doses of chemotherapy. Adding virus to this treatment in rats with sarcoma improved the rats' survival compared with standard ILP, and delivering the virus by this method got more virus to the tumor than giving it intravenously. This harmonious combination boosts the effectiveness of both methods, and certainly warrants further investigation.

  15. Short Reports

    1. Reproductive and menstrual factors and risk of differentiated thyroid carcinoma: The EPIC study

      Raul Zamora-Ros, Sabina Rinaldi, Carine Biessy, Anne Tjønneland, Jytte Halkjær, Agnes Fournier, Marie-Christine Boutron-Ruault, Sylvie Mesrine, Kaja Tikk, Reneé T. Fortner, Heiner Boeing, Jana Förster, Antonia Trichopoulou, Dimitrios Trichopoulos, Eleni-Maria Papatesta, Giovanna Masala, Giovanna Tagliabue, Salvatore Panico, Rosario Tumino, Silvia Polidoro, Petra H.M. Peeters, H. Bas Bueno-de-Mesquita, Elisabete Weiderpass, Eiliv Lund, Marcial Argüelles, Antonio Agudo, Esther Molina-Montes, Carmen Navarro, Aurelio Barricarte, Nerea Larrañaga, Jonas Manjer, Martin Almquist, Maria Sandström, Joakim Hennings, Konstantinos K. Tsilidis, Julie A. Schmidt, Kay-Thee Khaw, Nicholas J. Wareham, Isabelle Romieu, Graham Byrnes, Marc J. Gunter, Elio Riboli and Silvia Franceschi

      Article first published online: 22 JUL 2014 | DOI: 10.1002/ijc.29067

      What's new?

      Differentiated thyroid carcinoma (TC) is three-fold more common in women than in men. This raises the question: Do female hormones play a role in the pathogenesis of TC? In this large, prospective study, the authors did not find any strong association between reproductive or menstrual factors and TC risk. They did, however, identify positive associations between infertility, recent pregnancy, or surgical menopause and TC risk, and also detected an inverse association with prolonged use of oral contraceptives.

    2. Patterns of circulating tumor cells identified by CEP8, CK and CD45 in pancreatic cancer

      Yujuan Zhang, Fei Wang, Ning Ning, Qian Chen, Zhuo Yang, Ye Guo, Danfei Xu, Donghong Zhang, Ting Zhan and Wei Cui

      Article first published online: 21 JUL 2014 | DOI: 10.1002/ijc.29070

      What's new?

      Circulating tumor cells (CTCs) enter the circulation after being shed by primary tumors, making them potential markers in the diagnosis of cancer. However, methods to detect CTCs are in need of refinement. In an attempt to improve CTC identification in pancreatic cancer, the authors of this study examined the detection potential of a combination of methods, including immunostaining, fluorescence in situ hybridization with the centromere of chromosome 8 (CEP8) probe method. Enriched cell populations were classified into five patterns, including patterns for cytokeratin-positive or -negative CTCs and diploid or hyperdiploid CTCs, warranting further investigation of CTC characteristics.

  16. Epidemiology

    1. Selenium status is associated with colorectal cancer risk in the European prospective investigation of cancer and nutrition cohort

      David J. Hughes, Veronika Fedirko, Mazda Jenab, Lutz Schomburg, Catherine Méplan, Heinz Freisling, H.B(as) Bueno-de-Mesquita, Sandra Hybsier, Niels-Peter Becker, Magdalena Czuban, Anne Tjønneland, Malene Outzen, Marie-Christine Boutron-Ruault, Antoine Racine, Nadia Bastide, Tilman Kühn, Rudolf Kaaks, Dimitrios Trichopoulos, Antonia Trichopoulou, Pagona Lagiou, Salvatore Panico, Petra H Peeters, Elisabete Weiderpass, Guri Skeie, Engeset Dagrun, Maria-Dolores Chirlaque, Maria-Jose Sánchez, Eva Ardanaz, Ingrid Ljuslinder, Maria Wennberg, Kathryn E Bradbury, Paolo Vineis, Alessio Naccarati, Domenico Palli, Heiner Boeing, Kim Overvad, Miren Dorronsoro, Paula Jakszyn, Amanda J. Cross, Jose Ramón Quirós, Magdalena Stepien, So Yeon Kong, Talita Duarte-Salles, Elio Riboli and John E. Hesketh

      Article first published online: 21 JUL 2014 | DOI: 10.1002/ijc.29071

      What's new?

      Selenium is an essential micronutrient with anti-carcinogenic properties, but its association with the development of colorectal cancer is controversial. In the present study, the authors find that the selenium status in many Western Europeans is suboptimal. Higher selenium levels were inversely associated with the risk to develop colorectal carcinoma, a finding more evident in women than in men. The authors argue that in populations where the selenium status is sub-optimal (e.g. Western Europe) increasing selenium intake may reduce colorectal carcinoma risk, while contrasting results may be obtained in regions with higher selenium intake.

    2. Risk of breast cancer following fertility treatment—A registry based cohort study of parous women in Norway

      Marte Myhre Reigstad, Inger Kristin Larsen, Tor Åge Myklebust, Trude Eid Robsahm, Nan Birgitte Oldereid, Anne Katerine Omland, Siri Vangen, Louise Annette Brinton and Ritsa Storeng

      Article first published online: 16 JUL 2014 | DOI: 10.1002/ijc.29069

      What's new?

      Assisted reproductive technology (ART) typically involves the use of hormonal therapy, suggesting possible effects on cancer risk for infertile women. But whether ART is associated with increased or decreased risk of breast cancer in particular is unclear. Here, based on data from the Cancer Registry of Norway and the Medical Birth Registry of Norway, women who give birth following ART are at increased risk of breast cancer compared with women who give birth without ART. The rise in risk was greatest amongst women who were followed for more than 10 years and women who used in-vitro fertilization specifically.

  17. Cancer Therapy

    1. Single-cell measurement of the uptake, intratumoral distribution and cell cycle effects of cisplatin using mass cytometry

      Qing Chang, Olga I. Ornatsky, Cameron J. Koch, Naz Chaudary, Delphine T. Marie-Egyptienne, Richard P. Hill, Scott D. Tanner and David W. Hedley

      Article first published online: 16 JUL 2014 | DOI: 10.1002/ijc.29074

      What's new?

      The ways in which tumors develop resistance to drugs are complex, and it would be useful if drug distribution and action could be studied in vivo at the single-cell level. In this report, the authors used a technique called mass cytometry in mice to measure the number of molecules of cisplatin and IdU taken into individual tumor cells per minute. They also used a probe molecule called EF5, which showed that cisplatin easily spreads through hypoxic regions of tumors. These results demonstrate the potential for precise measurement of drug distribution and pharmacodynamic effects in vivo.

  18. Short Reports

    1. Generalizability of established prostate cancer risk variants in men of African ancestry

      Ying Han, Lisa B. Signorello, Sara S. Strom, Rick A. Kittles, Benjamin A. Rybicki, Janet L. Stanford, Phyllis J. Goodman, Sonja I. Berndt, John Carpten, Graham Casey, Lisa Chu, David V. Conti, Kristin A. Rand, W. Ryan Diver, Anselm J.M. Hennis, Esther M. John, Adam S. Kibel, Eric A. Klein, Suzanne Kolb, Loic Le Marchand, M. Cristina Leske, Adam B. Murphy, Christine Neslund-Dudas, Jong Y. Park, Curtis Pettaway, Timothy R. Rebbeck, Susan M. Gapstur, S. Lilly Zheng, Suh-Yuh Wu, John S. Witte, Jianfeng Xu, William Isaacs, Sue A. Ingles, Ann Hsing, The PRACTICAL Consortium, The ELLIPSE GAME-ON Consortium, Douglas F. Easton, Rosalind A. Eeles, Fredrick R. Schumacher, Stephen Chanock, Barbara Nemesure, William J. Blot, Daniel O. Stram, Brian E. Henderson and Christopher A. Haiman

      Article first published online: 15 JUL 2014 | DOI: 10.1002/ijc.29066

      What's new?

      While genome-wide association studies have identified more than 80 risk variants for prostate cancer, the generalizability of the variants in non-European and non-Asian populations needs to be understood before these loci can be used widely in risk modeling. Here, in the largest study to date, the vast majority of established variants also contributed to prostate cancer risk in men of African ancestry, with a subset of variants proving informative for risk modeling in this population. Further genomic characterization is needed to understand the contribution of the loci to risk in this population, which may be influenced by linkage disequilibrium patterns.

  19. Cancer Therapy

    1. TR4 nuclear receptor promotes prostate cancer metastasis via upregulation of CCL2/CCR2 signaling

      Xianfan Ding, Dong-Rong Yang, Soo Ok Lee, Ya-Ling Chen, Liqun Xia, Shin-Jen Lin, Shicheng Yu, Yuan-Jie Niu, Gonghui Li and Chawnshang Chang

      Article first published online: 14 JUL 2014 | DOI: 10.1002/ijc.29049

      What's New?

      Testicular nuclear receptor 4 (TR4) plays protective roles against oxidative stress and DNA damage and might be involved in aging. The linkage of TR4 to tumor progression, however, remains unclear. Here, the authors found the first clinical evidence that TR4 may be related to the prostate cancer (PCa) Gleason score. Through in vitro studies and in vivo animal studies, they showed that TR4 promotes PCa and also demonstrated CCL2/CCR2 signaling as an important mediator in TR4 action. The findings indicate TR4 as a potential key player that could be used as a biomarker or therapeutic target to battle PCa metastasis.

    2. IOERT as anticipated tumor bed boost during breast-conserving surgery after neoadjuvant chemotherapy in locally advanced breast cancer—Results of a case series after 5-year follow-up

      Gerd Fastner, Roland Reitsamer, Ingrid Ziegler, Franz Zehentmayr, Christoph Fussl, Peter Kopp, Florentia Peintinger, Richard Greil, Thorsten Fischer, Heinrich Deutschmann and Felix Sedlmayer

      Article first published online: 10 JUL 2014 | DOI: 10.1002/ijc.29064

      What's New?

      Intraoperative radiotherapy with electrons (IOERT) preceding whole breast irradiation provides favorable long-term local control rate if adopted in limited-stage breast cancer patients during breast conserving surgery. Here, the authors examined the value of IOERT in locally advanced breast cancer (LABC) patients after primary systemic treatment compared to the standard procedure. A retrospective analysis was performed for local control rate, locoregional control rate, metastasis-free survival, disease-specific survival, and overall survival in both groups. The 6-year local control rate of 98.5% was by trend superior to standard treatment, and also confirms IOERT as a highly effective boost strategy in patients with LABC.

  20. Epidemiology

    1. Polymorphisms in genes of the renin-angiotensin-aldosterone system and renal cell cancer risk: Interplay with hypertension and intakes of sodium, potassium and fluid

      Ivette A. Deckers, Piet A. van den Brandt, Manon van Engeland, Frederik-Jan van Schooten, Roger W. Godschalk, András P. Keszei and Leo J. Schouten

      Article first published online: 10 JUL 2014 | DOI: 10.1002/ijc.29060

      What's new?

      The renin-angiotensin-aldosterone system (RAAS) regulates blood pressure and salt homeostasis in the kidney and may, therefore, reflect a mechanism potentially underlying associations between hypertension or sodium intake and risk of renal cell cancer (RCC). In this prospective cohort study, several polymorphisms in RAAS genes, specifically in AGT, AGTR1, and ACE, were found to be associated with RCC risk. For polymorphisms in AGT and AGTR1, associations may be modified by hypertension, while for variants in ACE, suggestive biologic interaction with sodium intake was observed.

  21. Tumor Immunology

    1. GMCSF-armed vaccinia virus induces an antitumor immune response

      Suvi Parviainen, Marko Ahonen, Iulia Diaconu, Anja Kipar, Mikko Siurala, Markus Vähä-Koskela, Anna Kanerva, Vincenzo Cerullo and Akseli Hemminki

      Article first published online: 10 JUL 2014 | DOI: 10.1002/ijc.29068

      What's new?

      Oncolytic vaccinia viruses have shown promising results in cancer treatment. Tumor oncolysis is also an immunogenic phenomenon, thus it has been proposed to enhance activation of the immune system by arming the viruses with immunostimulatory molecules like granulocyte-macrophage colony-stimulating factor (GMCSF). However, this approach has not been studied much in model systems due to species incompatibility issues, even in the case of viruses in late-stage clinical investigation like JX-594. This study provides insight into the mechanism of action of a human GMCSF-expressing Western Reserve strain double-deleted vaccinia virus as well as clues on how JX-594 exert their effects in humans.

  22. Short Reports

    1. Granulocyte colony-stimulating factor off-target effect on nerve outgrowth promotes prostate cancer development

      Kostantin Dobrenis, Laurent R. Gauthier, Vilma Barroca and Claire Magnon

      Article first published online: 9 JUL 2014 | DOI: 10.1002/ijc.29046

      What's New?

      Granulocyte Colony Stimulating Factor (G-CSF) is known to mobilize hematopoietic progenitor stem cells in the blood of donors for stem cell transplantations, but its role as a neurotrophic factor is much less well understood. Here the authors show that G-CSF potentiates tumor growth and metastasis through autonomic nerve development in prostate tumors. This raises concerns regarding the use of G-CSF in cancer patients and gives insight into the interplay between tumor nerve development and growth factors as a potential new target in cancer therapy.

  23. Epidemiology

    1. You have full text access to this OnlineOpen article
      The prognostic value of family history among patients with urinary bladder cancer

      Lieke Egbers, Anne J. Grotenhuis, Katja K. Aben, J. Alfred Witjes, Lambertus A. Kiemeney and Sita H. Vermeulen

      Article first published online: 9 JUL 2014 | DOI: 10.1002/ijc.29062

      What's new?

      If you have a family history of cancer, you have reason to be concerned. But can your family history help clinicians accurately predict the course of your disease? In this study, the authors compared the prognosis of urinary bladder cancer patients with a positive and a negative first-degree family history – the first ever such investigation. While those who had a relative with the disease did seem to have smaller tumors and slightly more favorable outcomes, the authors could claim no strong statistical correlation between family history of UBC and prognosis.

    2. Cancer survival among First Nations people of Ontario, Canada (1968–2007)

      E. Diane Nishri, Amanda J. Sheppard, Diana R. Withrow and Loraine D. Marrett

      Article first published online: 9 JUL 2014 | DOI: 10.1002/ijc.29024

      What's new?

      Historically, First Nations peoples of Ontario, Canada, experienced lower cancer incidence and higher cancer mortality rates compared with Ontario's general population. The present study examined survival disparities specifically for five major cancer types (breast, cervix, colorectal, lung, and prostate) between First Nations peoples and other populations in Ontario from 1968 to 2001. Over that time, survival improved for other Ontarians for the five cancers investigated but improved among First Nations peoples for just breast and prostate cancer. Since 1992, however, all-cause and specific-cause survival has been especially poor among First Nations peoples for all five cancer types.

  24. Cancer Cell Biology

    1. MiR-200c inhibits autophagy and enhances radiosensitivity in breast cancer cells by targeting UBQLN1

      Quanquan Sun, Tongxin Liu, Yawei Yuan, Zhenli Guo, Guozhu Xie, Shasha Du, Xiaoshan Lin, Zhixin Xu, Minfeng Liu, Wei Wang, Quan Yuan and Longhua Chen

      Article first published online: 8 JUL 2014 | DOI: 10.1002/ijc.29065

      What's New?

      As for normal cells, autophagy is critical for tumor cells to survive stressful conditions, and thus has been implicated in tumor resistance to chemotherapy and radiotherapy. The present study showed that miR-200c could sensitize breast cancer cells to radiation via a mechanism associated with inhibition of irradiation-induced autophagy. The authors also identified ubiquilin 1 (UBQLN1) as a link between miR-200c, autophagy, and radioresistance of breast cancer cells. These results provide new insights into the molecular functions of miR-200c in the radiosensitivity of breast cancer cells and offer a rationale for enhancing radiosensitivity via miR-200c for the treatment of breast cancer.

  25. Epidemiology

    1. Improved overall survival after contralateral risk-reducing mastectomy in BRCA1/2 mutation carriers with a history of unilateral breast cancer: A prospective analysis

      Bernadette A.M. Heemskerk-Gerritsen, Matti A. Rookus, Cora M. Aalfs, Margreet G.E.M. Ausems, Johanna M. Collée, Liesbeth Jansen, C. Marleen Kets, Kristien B.M.I. Keymeulen, Linetta B. Koppert, Hanne E.J. Meijers-Heijboer, Thea M. Mooij, Rob A.E.M. Tollenaar, Hans F.A. Vasen, HEBON, Maartje J. Hooning and Caroline Seynaeve

      Article first published online: 8 JUL 2014 | DOI: 10.1002/ijc.29032

      What's new?

      When diagnosed with breast cancer, women naturally worry about tumors forming in the other breast as well. Sometimes, they elect to have both breasts removed, even though cancer has been detected only in one. But does the procedure have any protective effect? For certain groups, yes. In this paper, the authors collected data on the survival of several hundred patients with BRCA1/2-associated breast cancer. Removing the non-affected breast did improve survival in BRCA1/2 carriers with a history of primary breast cancer, particularly those under age 40. These findings will help doctors provide more personalized counselling and guidance regarding these decisions.

  26. Cancer Therapy

    1. Hematologic toxicity assessment in solid tumor patients treated with cetuximab: A pooled analysis of 18 randomized controlled trials

      Ran Cui, Li Chu, Zhu-qing Liu, Yuan-yuan Xiao, Xiao-li Zhu, Yi-jing Chen and Qing Xu

      Article first published online: 8 JUL 2014 | DOI: 10.1002/ijc.29045

      What's new?

      Cetuximab, an anti-EGFR monoclonal antibody (mAb), is used in combination with chemotherapy for several types of cancer. While many studies evaluating the toxicity of mAbs have focused on fatal adverse events, less severe toxic effects can still have a major impact on patient health. In this meta-analysis, the authors found that there is a slight but significant increase in the risk of severe hematologic toxicity associated with cetuximab treatment. Rigorous hematological monitoring of a patient's peripheral hemogram is therefore warranted when cetuximab is part of a treatment regimen.

  27. Epidemiology

    1. Folate intake and the risk of oral cavity and pharyngeal cancer: A pooled analysis within the International Head and Neck Cancer Epidemiology Consortium

      Carlotta Galeone, Valeria Edefonti, Maria Parpinel, Emanuele Leoncini, Keitaro Matsuo, Renato Talamini, Andrew F. Olshan, Jose P. Zevallos, Deborah M. Winn, Vijayvel Jayaprakash, Kirsten Moysich, Zuo-Feng Zhang, Hal Morgenstern, Fabio Levi, Cristina Bosetti, Karl Kelsey, Michael McClean, Stimson Schantz, Guo-Pei Yu, Paolo Boffetta, Yuan-Chin Amy Lee, Mia Hashibe, Carlo La Vecchia and Stefania Boccia

      Article first published online: 7 JUL 2014 | DOI: 10.1002/ijc.29044

      What's new?

      Folate is essential to DNA synthesis and repair, suggesting that folate deficiency, in disrupting normal DNA processes, may facilitate the development of certain cancers, including oral and pharyngeal cancer (OPC). The relationship between folate intake and risk of OPC, however, is unclear. In this analysis of data from the International Head and Neck Cancer Epidemiology (INHANCE) Consortium, high levels of folate intake were found to be inversely associated with overall OPC risk. The association was strongest for cancer of the oral cavity. Risk of OPC was highest among heavy alcohol drinkers with low folate levels.

  28. Infectious Causes of Cancer

    1. Bidirectional regulation between TMEFF2 and STAT3 may contribute to Helicobacter pylori-associated gastric carcinogenesis

      Tian-Tian Sun, Jia-Yin Tang, Wan Du, Hui-Jun Zhao, Gang Zhao, Sheng-Li Yang, Hao-Yan Chen, Jie Hong and Jing-Yuan Fang

      Article first published online: 7 JUL 2014 | DOI: 10.1002/ijc.29061

      What's new?

      Certain tumor suppressors and signaling pathways are dysregulated following infection with Helicobacter pylori, but the molecular mechanisms by which the bacterium induces gastric cancer are not fully understood. Here, expression of TMEFF2, a transmembrane protein previously implicated in human gastric cancer, was found to be decreased in response to H. pylori infection, an effect attributed to H. pylori activation of STAT3. Reduced expression of TMEFF2 was associated with elevated STAT3 phosphorylation. Negative regulation of STAT3 by TMEFF2 likely involves interaction with SHP-1. The findings suggest that bidirectional regulation between TMEFF2 and STAT3 contributes to H. pylori-associated gastric carcinogenesis.

  29. Carcinogenesis

    1. Elevated p53 promotes the processing of miR-18a to decrease estrogen receptor-α in female hepatocellular carcinoma

      Chiao-Ling Li, Kun-Huei Yeh, Wan-Hsin Liu, Chi-Ling Chen, Ding-Shinn Chen, Pei-Jer Chen and Shiou-Hwei Yeh

      Article first published online: 7 JUL 2014 | DOI: 10.1002/ijc.29052

      What's new?

      More men than women get liver cancer, in part because of the protective effect of the estrogen pathway. Many women who do develop hepatocellular cancer have less estrogen receptor due to higher levels of miR-18a, which slows estrogen receptor production. In this paper, the authors asked, what causes the increase in miR-18a? They found that p53 participates in pumping out miR-18a, and further investigation revealed that tying up p53 decreased levels of miR-18a, while overexpressing p53 increased miR-18a. Samples taken from female HCC patients confirmed this association, suggesting that p53 could be a useful therapeutic target in female HCC.

    2. A melanin-independent interaction between Mc1r and Met signaling pathways is required for HGF-dependent melanoma

      Agnieszka Wolnicka-Glubisz, Faith M. Strickland, Albert Wielgus, Miriam Anver, Glenn Merlino, Edward C. De Fabo and Frances P. Noonan

      Article first published online: 7 JUL 2014 | DOI: 10.1002/ijc.29050

      What's new?

      Melanocortin 1 receptor (MC1R), which plays a central role in the production of melanin, is subject to marked genetic variation, with certain variants increasing melanoma risk through fair skin phenotype. Others MCR1 variants, however, influence melanoma risk through pigment-independent alterations. Such variants may include those that affect interactions between Mc1r and hepatocyte growth factor (HGF)/Met signaling, as suggested by this investigation of Mcr1 deficiency in a UV-induced melanoma mouse model. HGF has been implicated in tumor escape from B-RAF inhibitors in human melanoma, and MET is a target for melanoma therapy, suggesting potential therapeutic significance for the findings.

  30. Epidemiology

    1. Sensitivity, effect and overdiagnosis in screening for cancers with detectable pre-invasive phase

      Matti Hakama, Arun Pokhrel, Nea Malila and Timo Hakulinen

      Article first published online: 7 JUL 2014 | DOI: 10.1002/ijc.29053

      What's new?

      Substantial variation exists in the evaluation of cancer screening for pre-invasive lesions. In some instances, such as overdiagnosis in the case of nonprogressive lesions, screening may be more harmful than beneficial. The authors of this study have derived methods of estimation of sensitivity and effect, including formulae and data requirements at the level of events and person years, that are consistent with the purpose of cancer screening to prevent invasive disease. The six indicators specified in the study are useful at the levels of laboratory, clinical medicine, and public health.

  31. Cancer Cell Biology

    1. Peroxisome proliferator-activated receptor γ upregulates galectin-9 and predicts prognosis in intestinal-type gastric cancer

      Soo-Jeong Cho, Myeong-Cherl Kook, Jun Ho Lee, Ji-Young Shin, JuRi Park, Young-Ki Bae, Il Ju Choi, Keun Won Ryu and Young-Woo Kim

      Article first published online: 7 JUL 2014 | DOI: 10.1002/ijc.29056

      What's new?

      Activation of peroxisome proliferator-activated receptor γ (PPARγ) is capable of undermining certain malignant properties of gastric cancer cells in vitro, suggesting that it may be of relevance in human gastric cancers. Here, in gastric cancer cell and zebrafish models, PPARγ overexpression inhibited epithelial-mesenchymal transition and led to reductions in cell invasion and migration. The effects of PPARγ overexpression were associated with galectin-9 upregulation. In human patients with intestinal-type gastric cancer, positive PPARγ tumor status was linked to reduced overall and cancer-specific mortalities. The findings suggest that PPARγ may be a therapeutic target and prognostic factor in gastric cancer.

  32. Tumor Immunology

    1. Novel function of Oncostatin M as a potent tumour-promoting agent in lung

      Sean Lauber, Steven Wong, Jean-Claude Cutz, Minoru Tanaka, Nicole Barra, Šárka Lhoták, Ali Ashkar and Carl Douglas Richards

      Article first published online: 7 JUL 2014 | DOI: 10.1002/ijc.29055

      What's new?

      While Oncostatin M was originally identified as a cytokine with anti-proliferative properties on melanoma and other solid tumor cell lines, its in vivo function remains obscure. Here the authors show that application of Oncostatin M into the trachea of mice had unexpected growth-promoting effects on lung tumors without direct pro-proliferative effects on tumor cells ex vivo. Detailed analysis implicated non-tumor cells in the process through the recruitment of tumor promoting M2-type monocytes/macrophages. This study uncovers a complex function of Oncostatin M in cancer biology and points to a specific role in lung cancer development.

  33. Epidemiology

    1. A prospective study of one-carbon metabolism biomarkers and cancer of the head and neck and esophagus

      Anouar Fanidi, Caroline Relton, Per Magne Ueland, Øivind Midttun, Stein Emil Vollset, Ruth C. Travis, Antonia Trichopoulou, Pagona Lagiou, Dimitrios Trichopoulos, H.B(as). Bueno-de-Mesquita, Martine Ros, Heiner Boeing, Rosario Tumino, Salvatore Panico, Domenico Palli, Sabina Sieri, Paolo Vineis, María-José Sánchez, José María Huerta, Aurelio Barricarte Gurrea, Leila Luján-Barroso, J Ramón Quirós, Anne Tjønneland, Jytte Halkjær, Marie-Christine Boutron-Ruault, Françoise Clavel-Chapelon, Claire Cadeau, Elisabete Weiderpass, Mikael Johansson, Elio Riboli, Paul Brennan and Mattias Johansson

      Article first published online: 7 JUL 2014 | DOI: 10.1002/ijc.29051

      What's new?

      One-carbon metabolism (OCM) involves the transfer of a carbon unit from methyl donor nutrients to molecules involved in the synthesis and methylation of DNA. As a result, dietary imbalances or deficiencies in nutrients crucial for OCM may affect DNA replication, repair, and regulation, potentially facilitating cancer development. This analysis of circulating levels of OCM nutrients in head and neck cancer and esophageal cancer patients and matched controls reveals an association between elevated levels of the amino acid homocysteine and increased risk of squamous cell carcinoma of the head and neck. Risk was decreased slightly by elevated folate levels.

  34. Early Detection and Diagnosis

    1. Identification of microRNAs differentially expressed in prostatic secretions of patients with prostate cancer

      Esra Guzel, Omer F. Karatas, Atilla Semercioz, Sinan Ekici, Serdar Aykan, Serhat Yentur, Chad J. Creighton, Michael Ittmann and Mustafa Ozen

      Article first published online: 7 JUL 2014 | DOI: 10.1002/ijc.29054

      What's new?

      The association of microRNAs (miRNAs) with cancer initiation, progression, and metastasis has fueled increasing interest in their potential as diagnostic and therapeutic markers. The current study aimed to identify an miRNA expression signature that could be used to distinguish prostate cancer from benign prostatic hyperplasia by using prostate secretions obtained from patients. MiRNAs were found to be present in the prostate secretion samples, with altered expression detected for four miRNAs in particular. The findings suggest that certain miRNAs may be powerful tools for aiding prostate cancer diagnosis.

  35. Short Reports

    1. Absence of cytomegalovirus in high-coverage DNA sequencing of human glioblastoma multiforme

      Ka-Wei Tang, Kristoffer Hellstrand and Erik Larsson

      Article first published online: 7 JUL 2014 | DOI: 10.1002/ijc.29042

      What's new?

      While cytomegalovirus (CMV) has been functionally implicated in glioblastoma, its presence has been challenged by several reports, including lack of CMV mRNA in transcriptome studies. Here, the authors utilized deep-coverage whole-genome sequencing data to detect CMV DNA in surgically resected tumors. They found no traces of CMV in 52.6 billion DNA sequencing reads from 34 glioblastomas. Based on statistical analysis, they conclude that should the virus be present in these tumors, the average CMV level does not exceed one virus per 240,000 tumor cells (99% CI), effectively settling any remaining controversies regarding widespread presence of CMV DNA in glioblastoma.

  36. Editorial

  37. Infectious Causes of Cancer

    1. Unique recurrence patterns of cervical intraepithelial neoplasia after excision of the squamocolumnar junction

      Michael Herfs, Joan Somja, Brooke E. Howitt, Meggy Suarez-Carmona, Gaelle Kustermans, Pascale Hubert, Jean Doyen, Frederic Goffin, Frederic Kridelka, Christopher P. Crum and Philippe Delvenne

      Article first published online: 3 JUL 2014 | DOI: 10.1002/ijc.28978

      What's new?

      A discrete population of cells at the squamo-columnar junction (SCJ) of the cervix may house the cells of origin—the first to become genetically altered in cancer initiation—for cervical intraepithelial neoplasia (CIN) and cervical cancer. In the present comparison of excision margins, timing of recurrence, CIN grade, HPV types, p16 immunophenotype, and SCJ immunophenotype for recurrent and initial CIN, recurrences were found to be invariably low grade and within the ectocervix or metaplastic epithelium. Hence, successful SCJ excision appears to reduce the risk of new CIN 2/3 lesions, suggesting that SCJ cryoablation could be effective in preventing cervical cancer.

  38. Cancer Therapy

    1. Oncolytic adenovirus and doxorubicin-based chemotherapy results in synergistic antitumor activity against soft-tissue sarcoma

      Mikko Siurala, Simona Bramante, Lotta Vassilev, Mari Hirvinen, Suvi Parviainen, Siri Tähtinen, Kilian Guse, Vincenzo Cerullo, Anna Kanerva, Anja Kipar, Markus Vähä-Koskela and Akseli Hemminki

      Article first published online: 3 JUL 2014 | DOI: 10.1002/ijc.29048

      What's new?

      New treatment options are needed for patients with soft-tissue sarcomas (STS) as management of metastatic disease is currently not very successful. Here the authors develop a new line of treatment, where they add an oncolytic adenovirus, CGTG-102 (Ad5/3-D24-GMCSF) to doxorubicin and ifosfamide, the preferred chemotherapeutic regimen against most types of STS. They show in an immune-competent Syrian hamster model that this combination is effective against established STS tumors. In an additional line of research, doxorubicin without ifosfamide synergized with CGTG-102 to treat STS of human origin in a mouse xenograft tumor model. These results support a future clinical application of CGTG-102 in combination with doxorubicin-based chemotherapy for better treatment of STS.

  39. Epidemiology

    1. Variation at ABO histo-blood group and FUT loci and diffuse and intestinal gastric cancer risk in a European population

      Eric J. Duell, Catalina Bonet, Xavier Muñoz, Leila Lujan-Barroso, Elisabete Weiderpass, Marie-Christine Boutron-Ruault, Antoine Racine, Gianluca Severi, Federico Canzian, Cosmeri Rizzato, Heiner Boeing, Kim Overvad, Anne Tjønneland, Marcial Argüelles, Emilio Sánchez-Cantalejo, Saioa Chamosa, José María Huerta, Aurelio Barricarte, Kay-Tee Khaw, Nick Wareham, Rutch C. Travis, Antonia Trichopoulou, Dimitrios Trichopoulos, Nikos Yiannakouris, Domenico Palli, Claudia Agnoli, Rosario Tumino, Alessio Naccarati, Salvatore Panico, H. B(as) Bueno-de-Mesquita, Peter D. Siersema, Petra H.M. Peeters, Bodil Ohlsson, Björn Lindkvist, Ingegerd Johansson, Weimin Ye, Matthias Johansson, Claus Fenger, Elio Riboli, Núria Sala and Carlos A. González

      Article first published online: 1 JUL 2014 | DOI: 10.1002/ijc.29034

      What's New?

      Blood type A indicates a higher risk of gastric cancer, but why? This study examined the relationship between blood group genes and cancer. The authors investigated 32 variants among not only the ABO alleles, but also including the genes involved in producing the Lewis blood group antigens. They confirmed blood group A as a risk factor for diffuse-type gastric cancer, and also detected an association between certain Lewis antigen alleles and intestinal-type gastric cancer. Interestingly, these alleles also popped up among controls who harbored H. pylori infection. These associations certainly warrant further investigation into their role in gastric cancer.

  40. Early Detection and Diagnosis

    1. Serum microRNA expression signatures identified from genome-wide microRNA profiling serve as novel noninvasive biomarkers for diagnosis and recurrence of bladder cancer

      Xiumei Jiang, Lutao Du, Lili Wang, Juan Li, Yimin Liu, Guixi Zheng, Ailin Qu, Xin Zhang, Hongwei Pan, Yongmei Yang and Chuanxin Wang

      Article first published online: 1 JUL 2014 | DOI: 10.1002/ijc.29041

      What's new?

      Early diagnosis can improve survival for patients with bladder cancer, but biomarkers and noninvasive tests that are sensitive enough to detect bladder tumors, and low-grade lesions in particular, are lacking. Here, following genome-wide serum miRNA analysis by Miseq sequencing in bladder cancer patients, a six-miRNA panel for diagnosis was developed. The panel was based on a multivariate logistic regression model and showed higher sensitivity than urine cytology in bladder cancer diagnosis, especially for patients with early stage disease. Among the six miRNAs identified for the panel, miR-152 was found to independently predict recurrence in non-muscle-invasive bladder cancer.

  41. Cancer Cell Biology

    1. CK2α phosphorylates DBC1 and is involved in the progression of gastric carcinoma and predicts poor survival of gastric carcinoma patients

      Jun Sang Bae, See-Hyoung Park, Kyoung Min Kim, Keun Sang Kwon, Chan Young Kim, Hun Ku Lee, Byung-Hyun Park, Ho Sung Park, Ho Lee, Woo Sung Moon, Myoung Ja Chung, Karl G. Sylvester and Kyu Yun Jang

      Article first published online: 1 JUL 2014 | DOI: 10.1002/ijc.29043

      What's new?

      A number of proteins that are involved in tumorigenesis are influenced by the protein kinase CK2, and the expression of CK2α specifically is known to be modified in certain cancers, suggesting possible effects on tumor development and progression. The present study indicates that CK2α is an independent prognostic indicator of gastric carcinoma and is involved in tumorigenesis by regulating the phosphorylation of the potentially oncogenic protein DBC1 (deleted in breast cancer 1). Inhibition of CK2α or DBC1 attenuated proliferation and invasion activity of cancer cells, suggesting that the CK2α-DBC1 pathway may be a therapeutic target for gastric carcinoma.

  42. Mini Reviews

    1. Evolutionary mechanism unifies the hallmarks of cancer

      Steven D. Horne, Sarah A. Pollick and Henry H.Q. Heng

      Article first published online: 30 JUN 2014 | DOI: 10.1002/ijc.29031

  43. Cancer Cell Biology

    1. BYL719, a new α-specific PI3K inhibitor: Single administration and in combination with conventional chemotherapy for the treatment of osteosarcoma

      Bérengère Gobin, Marc Baud' Huin, François Lamoureux, Benjamin Ory, Céline Charrier, Rachel Lanel, Séverine Battaglia, Françoise Redini, Frédéric Lezot, Frédéric Blanchard and Dominique Heymann

      Article first published online: 30 JUN 2014 | DOI: 10.1002/ijc.29040

      What's new?

      Mutations in PIK3CA have been identified in various cancers, including osteosarcoma, a disease for which new treatments are desperately needed. One potential therapy for osteosarcoma is BYL719, a novel agent that is active against tumor cells harboring PIK3CA variants. In the present study, BYL719 was found to inhibit the migration and decrease the proliferation of osteosarcoma cells. The drug accomplished the latter by blocking the cell cycle in G0/G1. In pre-clinical mouse models of osteosarcoma, BYL719 monotherapy significantly reduced tumor progression, tumor ectopic bone formation, and tumor vascularization. Its therapeutic potential may be augmented by combined use with ifosfamide.

  44. Epidemiology

    1. You have free access to this content
      Cannabis smoking and lung cancer risk: Pooled analysis in the International Lung Cancer Consortium

      Li Rita Zhang, Hal Morgenstern, Sander Greenland, Shen-Chih Chang, Philip Lazarus, M. Dawn Teare, Penella J. Woll, Irene Orlow, Brian Cox, on behalf of the Cannabis and Respiratory Disease Research Group of New Zealand, Yonathan Brhane, Geoffrey Liu and Rayjean J. Hung

      Article first published online: 30 JUN 2014 | DOI: 10.1002/ijc.29036

      What's new?

      Due to the potential adverse effect of cannabis smoking and its popularity, an investigation of its association with lung cancer risk is essential to help support appropriate regulations as well as health and social policy responses. The analysis presented here included the largest data set on cannabis and lung cancer risk to date. Its non-linear dose-response was examined using restricted cubic spline regression, a first in this line of work. Results provide little evidence for an increased risk of lung cancer among habitual or long-term cannabis smokers, although the possibility of potential adverse effect for heavy consumption cannot be excluded.

  45. Cancer Cell Biology

    1. Interruption of KLF5 acetylation converts its function from tumor suppressor to tumor promoter in prostate cancer cells

      Xin Li, Baotong Zhang, Qiao Wu, Xinpei Ci, Ranran Zhao, Zhiqian Zhang, Siyuan Xia, Dan Su, Jie Chen, Gui Ma, Liya Fu and Jin-Tang Dong

      Article first published online: 27 JUN 2014 | DOI: 10.1002/ijc.29028

      What's New?

      The highly expressed epithelial cell transcription factor KLF5 both suppresses and promotes tumor formation, though the mechanism behind its functional switching is unknown. Here, acetylation was found to be essential for KLF5 tumor suppression, whereas deacetylation switched KLF5 to tumor-promoting activity. KLF5's tumor suppressor activity was attenuated with inhibition of TGFβ signaling. In addition, target genes of KLF5 and TGFβ showed KLF5 acetylation-responsive expression patterns, and eight molecules were identified as possible mediators of KLF5's functional reverse. The study provides a novel mechanism for KLF5 functional switching in tumorigenesis and implicates unacetylated KLF5 in TGFβ tumor promotion.

    2. Inhibition of tumor growth by U0126 is associated with induction of interferon-γ production

      Xingzhe Ma, Qixue Wang, Ying Liu, Yuanli Chen, Ling Zhang, Meixiu Jiang, Xiaoju Li, Rong Xiang, Robert Q. Miao, Yajun Duan and Jihong Han

      Article first published online: 27 JUN 2014 | DOI: 10.1002/ijc.29038

      What's new?

      Both MEK1/2 inhibitors and interferon-γ (IFN-γ) have anti-tumorigenic activity. In this study, the authors found that the MEK1/2 inhibitor U0126 decreases growth of chemically induced pulmonary carcinomas, and increases tumor-free and survival rates in mice inoculated Lewis lung carcinomas. The authors also conclude that this anti-tumorigenic action of U0126 is due, in part, to its activation of IFN-γ production, via enhanced activity of liver X receptor (LXR).

  46. Epidemiology

    1. Home kitchen ventilation, cooking fuels, and lung cancer risk in a prospective cohort of never smoking women in Shanghai, China

      Christopher Kim, Yu-Tang Gao, Yong-Bing Xiang, Francesco Barone-Adesi, Yawei Zhang, H. Dean Hosgood, Shuangge Ma, Xiao-ou Shu, Bu-Tian Ji, Wong-Ho Chow, Wei Jie Seow, Bryan Bassig, Qiuyin Cai, Wei Zheng, Nathaniel Rothman and Qing Lan

      Article first published online: 27 JUN 2014 | DOI: 10.1002/ijc.29020

      What's New?

      Where there's smoke, there's cancer. In households where cooking smoke collects in the kitchen, is there greater risk of lung cancer? These authors collected information from nonsmoking women in Shanghai about their cooking practices, then correlated those data with cases of lung cancer among the population. Inadequate kitchen ventilation, particularly combined with long term use of coal, increased the risk of lung cancer significantly. These findings could have an important impact on public health in urban China.

  47. Early Detection and Diagnosis

    1. You have full text access to this OnlineOpen article
      The novel colorectal cancer biomarkers CDO1, ZSCAN18 and ZNF331 are frequently methylated across gastrointestinal cancers

      Hege Marie Vedeld, Kim Andresen, Ina Andrassy Eilertsen, Arild Nesbakken, Raquel Seruca, Ivar P. Gladhaug, Espen Thiis-Evensen, Torleiv O. Rognum, Kirsten Muri Boberg and Guro E. Lind

      Article first published online: 27 JUN 2014 | DOI: 10.1002/ijc.29039

      What's new?

      Various types of gastrointestinal (GI) cancers display similar epigenetic aberrations. In this study, the authors examined a number of genes that have been shown to have altered methylation in cholangiocarcinoma, to see whether these genes might also be altered in other GI cancers. They found five genes that are frequently methylated in colorectal, pancreatic, and gastric cancer and cholangiocarcinoma. Methylation patterns in these genes may therefore provide biomarkers that are especially promising for colorectal cancer detection, with a high combined sensitivity (95%) and specificity (98%).

  48. Cancer Therapy

    1. Clinical importance of risk variants in the dihydropyrimidine dehydrogenase gene for the prediction of early-onset fluoropyrimidine toxicity

      Tanja K. Froehlich, Ursula Amstutz, Stefan Aebi, Markus Joerger and Carlo R. Largiadèr

      Article first published online: 27 JUN 2014 | DOI: 10.1002/ijc.29025

      What's New?

      Fluorouracil (5FU) is effective against a variety of cancers and is one of the most commonly prescribed chemotherapy drugs. But 5FU causes severe toxicity in some patients, with their susceptibility determined largely by variations in the rate-limiting enzyme dihydropyrimidine dehydrogenase (DPD), which catabolizes 5FU. This study shows that a relatively common haplotype, hapB3, which is linked to an intronic splice site mutation (c.1129–5923C>G) in the DPD-encoding gene, DPYD, is a major contributor to early-onset severe fluoropyrimidine toxicity in Caucasian carriers. Inclusion of the c.1129–5923C>G variant in DPYD genetic testing could help prevent severe toxicity associated with fluoropyrimidine-based therapies.

  49. Epidemiology

    1. HLA-A SNPs and amino acid variants are associated with nasopharyngeal carcinoma in Malaysian Chinese

      Yoon-Ming Chin, Taisei Mushiroda, Atsushi Takahashi, Michiaki Kubo, Gopala Krishnan, Lee-Fah Yap, Soo-Hwang Teo, Paul Vey-Hong Lim, Yoke-Yeow Yap, Kin-Choo Pua, Naoyuki Kamatani, Yusuke Nakamura, Choon-Kook Sam, Alan Soo-Beng Khoo, The Malaysian NPC Study Group and Ching-Ching Ng

      Article first published online: 27 JUN 2014 | DOI: 10.1002/ijc.29035

      What's new?

      Certain variants of the HLA-A gene are linked to either resistance or susceptibility in nasopharyngeal carcinoma (NPC). But which variants are most strongly associated with effects in NPC remains unclear. Here, high resolution fine-mapping of the HLA-A region was used to better understand the effects of variants on peptide loading or HLA-A expression in a Malaysian Chinese population. Variants showing potential epigenetic, peptide-loading function and T-cell immune response were correlated with the effects of HLA-A*11:01, a protective HLA-A allele. Most other HLA-A variants did not appear to possess any potential function.

  50. Cancer Cell Biology

    1. IL-6 enriched lung cancer stem-like cell population by inhibition of cell cycle regulators via DNMT1 upregulation

      Chen-Chi Liu, Jiun-Han Lin, Tien-Wei Hsu, Kelly Su, Anna Fen-Yau Li, Han-Shui Hsu and Shih-Chieh Hung

      Article first published online: 27 JUN 2014 | DOI: 10.1002/ijc.29033

      What's new?

      Dysregulation of interleukin-6 is implicated in the progression of lung cancer, but the mechanisms by which IL-6 may facilitate disease progression are not fully known. Here, in cell and tumor sphere models, cancer initiation and lung cancer stem cell (CSC) proliferation were enhanced by upregulation of DNA methyltransferase 1 (DNMT1) as a consequence of IL-6/JAK2/STAT3 pathway activity. DNMT1 upregulation resulted in DNA hypermethylation and downregulation of p53 and p21. Upon blockage of the IL-6/JAK2/STAT3 pathway and inhibition of DNMT1, the proliferation of lung CSCs, their formation of spheres, and their ability to initiate tumor growth decreased.

  51. Epidemiology

    1. Comparative performance of novel self-sampling methods in detecting high-risk human papillomavirus in 30,130 women not attending cervical screening

      Remko P. Bosgraaf, Viola M.J. Verhoef, Leon F.A.G. Massuger, Albert G. Siebers, Johan Bulten, Gabriëlle M. de Kuyper-de Ridder, Chris J.M. Meijer, Peter J.F. Snijders, Daniëlle A.M. Heideman, Joanna IntHout, Folkert J. van Kemenade, Willem J.G. Melchers and Ruud L.M. Bekkers

      Article first published online: 26 JUN 2014 | DOI: 10.1002/ijc.29026

      What's new?

      If people won't come into the clinic to get tested for HPV, send the test to them: that's the public health strategy the Netherlands will employ beginning in 2016. This study compared two methods of self-sampling for HPV, one brush based and one lavage based. The authors measured participation rates, user comfort, how often each method detected the virus, and how often neoplasias were detected. They found non-inferiority in the participation rates, and in all other measures the two methods performed equally well.

  52. Tumor Immunology

    1. IgG1 anti-epidermal growth factor receptor antibodies induce CD8-dependent antitumor activity

      Jan Kubach, Mario Hubo, Christiane Amendt, Christopher Stroh and Helmut Jonuleit

      Article first published online: 26 JUN 2014 | DOI: 10.1002/ijc.29037

      What's new?

      IgG1 anti-EGFR monoclonal antibodies like Cetuximab are commonly used for the treatment of EGFR+ solid tumors. The exact mechanisms underlying anti-EGFR mAb-mediated tumor regression and the possible involvement of innate or adaptive immunity, however, remain controversial. This study provides strong evidence that IgG1 anti-EGFR mAb induce the novel mechanism of CD8+ T cell-mediated cytotoxicity. This knowledge may be beneficial for future approaches in cancer therapy. The study also demonstrates that novel humanized mouse models allow the preclinical testing of therapeutic mAb as well as the characterization of their functional crosstalk with human immune cells in vivo.

  53. Cancer Cell Biology

    1. CD10 expression is enhanced by Twist1 and associated with poor prognosis in esophageal squamous cell carcinoma with facilitating tumorigenicity in vitro and in vivo

      Keun-Woo Lee, Chang Ohk Sung, Jeong Hoon Kim, Myungsoo Kang, Hae-Yong Yoo, Hyeon-Ho Kim, Sung-Hee Um and Seok-Hyung Kim

      Article first published online: 26 JUN 2014 | DOI: 10.1002/ijc.29006

      What's new?

      CD10, a zinc-dependent metalloprotease, is expressed on early stages of B cell development in the germinal centers of lymph nodes and is linked to several hematological cancers. Here the authors show important new roles of CD10 in the biology of esophageal squamous cell carcinoma using cell line and animal models. Mechanistically, they show that CD10 expression is directly linked to Twist1, a master regulator of epithelial-mesenchymal transition. Importantly, CD10 overexpression on cancer cells and stromal fibroblasts was an independent (poor) prognostic marker for both survival and disease-free survival in patient samples, underscoring a potential clinical value for CD10 in patients with esophageal squamous cell carcinoma.

  54. Epidemiology

    1. You have full text access to this OnlineOpen article
      Peripheral blood cells inform on the presence of breast cancer: A population-based case–control study

      Vanessa Dumeaux, Josie Ursini-Siegel, Arnar Flatberg, Hans E. Fjosne, Jan-Ole Frantzen, Marit Muri Holmen, Enno Rodegerdts, Ellen Schlichting and Eiliv Lund

      Article first published online: 25 JUN 2014 | DOI: 10.1002/ijc.29030

      What's new?

      Blood cells are dynamic warehouses of information. In the case of cancer, studies have indicated that blood cells house genetic signatures related to solid tumors. In the present study, genes in peripheral blood cells were found to be differentially expressed in women with untreated breast cancer, enabling the development of a 50-gene signature capable of identifying women with the disease. The gene signature included signals specific to immunosuppression. The association of breast cancer with the underexpression of immune-specific pathways and with MYC-driven “universal” cell programs may explain the systemic response of the host.

  55. Early Detection and Diagnosis

    1. A prognostic classifier consisting of 17 circulating cytokines is a novel predictor of overall survival for metastatic colorectal cancer patients

      Zhi-Yuan Chen, Wen-Zhuo He, Li-Xia Peng, Wei-Hua Jia, Rong-Ping Guo, Liang-Ping Xia and Chao-Nan Qian

      Article first published online: 24 JUN 2014 | DOI: 10.1002/ijc.29017

      What's new?

      Cytokines and their receptors are important regulators of the tumor microenvironment. In colorectal cancer, certain cytokines appear to be linked to poor prognosis. This study assessed the prognostic potential in colorectal cancer of 39 circulating cytokines, using samples from patients with metastatic disease. Seventeen of the cytokines studied were found to be significant risk factors for overall survival (OS). A prognostic classifier based on the 17 cytokines could be a valuable screening tool for the identification of patients who are at high risk of short OS and who may benefit from cytokine-targeted therapies.

  56. Carcinogenesis

    1. Reflux composition influences the level of NF-κB activation and upstream kinase preference in oesophageal adenocarcinoma cells

      E. McAdam, H.N. Haboubi, A.P. Griffiths, J.N. Baxter, S. Spencer-Harty, C. Davies and G.J. Jenkins

      Article first published online: 23 JUN 2014 | DOI: 10.1002/ijc.29029

      What's New?

      Gastroesophageal reflux disease is the primary cause of esophageal adenocarcinoma. But the significance of esophageal exposure to bile acids and the inflammatory processes that lead to NF-κB activation and adenocarcinoma are not fully understood. The present study shows that reflux composition influences the severity of NF-κB signaling in esophageal cell lines. For some bile acids, the extent to which NF-κB is activated is associated with the presence or absence of acid. The findings imply that the precise composition of a person's reflux, together with whether the individual is taking acid suppressants, may dictate NF-κB activation in vivo.

  57. Special Section Editorial

    1. Special section editorial

      Kari Hemminki and Richard S Houlston

      Article first published online: 19 JUN 2014 | DOI: 10.1002/ijc.29027

  58. Special Section Paper

    1. Cancer incidence, survival and mortality: Explaining the concepts

      Libby Ellis, Laura M. Woods, Jacques Estève, Sandra Eloranta, Michel P. Coleman and Bernard Rachet

      Article first published online: 19 JUN 2014 | DOI: 10.1002/ijc.28990

    2. Multiple primary cancers as a guide to heritability

      Cezary Cybulski, Safia Nazarali and Steven A. Narod

      Article first published online: 19 JUN 2014 | DOI: 10.1002/ijc.28988

  59. Letter to the Editor

    1. Judging the carcinogenicity of rare human papillomavirus types

      Jean-Damien Combes, Peng Guan, Silvia Franceschi and Gary M. Clifford

      Article first published online: 19 JUN 2014 | DOI: 10.1002/ijc.29019

  60. Cancer Cell Biology

    1. Protease-activated receptor-1 drives pancreatic cancer progression and chemoresistance

      Karla C.S. Queiroz, Kun Shi, JanWillem Duitman, Hella L. Aberson, Johanna W. Wilmink, Carel J.M. van Noesel, Dick J. Richel and C. Arnold Spek

      Article first published online: 19 JUN 2014 | DOI: 10.1002/ijc.28726

      What's new?

      Few people survive a diagnosis of pancreatic cancer. In the search for new avenues to attack the disease, researchers have noticed that the receptor PAR-1 promotes tumor growth and proliferation. It is also expressed in the tumor microenvironment, where its role is not yet fully explored. In this study, the authors showed that PAR-1 outside the tumor contributes to drug resistance by bringing monocytes onto the scene. Their results suggest that targeting PAR-1 could boost the effectiveness of chemotherapy against pancreatic cancer.

  61. Cancer Genetics

    1. Biallelic germline and somatic mutations in malignant mesothelioma: Multiple mutations in transcription regulators including mSWI/SNF genes

      Yoshie Yoshikawa, Ayuko Sato, Tohru Tsujimura, Taiichiro Otsuki, Kazuya Fukuoka, Seiki Hasegawa, Takashi Nakano and Tomoko Hashimoto-Tamaoki

      Article first published online: 19 JUN 2014 | DOI: 10.1002/ijc.29015

      What's new?

      Malignant mesotheliomas (MM) are highly aggressive neoplasms largely arising from asbestos exposure. Here, the authors investigated possible genetic causes for the low histone acetylation levels observed in MM cell lines resistant to histone deacetylase inhibitors. Using whole-exome sequencing, they are the first to present MM cases without history of familial MM with germline variants/mutations and somatic inactivation in multiple genes including mSWI/SNF. The genes containing rare germline variants/mutations were not limited to common tumor suppressor genes, and the molecular functions of these genes were related to transcriptional regulation. Such germline variants/mutations could be used as markers for MM predisposition.

  62. Cancer Therapy

    1. Antiangiogenic activity of trabectedin in myxoid liposarcoma: Involvement of host TIMP-1 and TIMP-2 and tumor thrombospondin-1

      Romina Dossi, Roberta Frapolli, Silvana Di Giandomenico, Lara Paracchini, Fabio Bozzi, Silvia Brich, Vittoria Castiglioni, Patrizia Borsotti, Dorina Belotti, Sarah Uboldi, Roberta Sanfilippo, Eugenio Erba, Raffaella Giavazzi, Sergio Marchini, Silvana Pilotti, Maurizio D'Incalci and Giulia Taraboletti

      Article first published online: 19 JUN 2014 | DOI: 10.1002/ijc.29023

      What's New?

      Trabectedin is a natural product approved in Europe for the treatment of soft tissue sarcoma and relapsed ovarian cancer. While the response of myxoid liposarcoma to trabectedin is characteristically associated with vessel regression, the underlying mechanisms remain unclear. In this study, trabectedin showed antiangiogenic activity linked to the upregulation of endogenous inhibitors of angiogenesis: endothelial cell-derived TIMP-1 and TIMP-2 and tumor cell-derived TSP-1, the latter associated with adipocytic differentiation. Such connection between differentiation and angiogenesis in myxoid liposarcoma sets the basis for new combination therapies, and points to TIMP-1, TIMP-2 and TSP-1 as potential markers of tumor response to trabectedin.

  63. Early Detection and Diagnosis

    1. MicroRNA expression signatures for the prediction of BRCA1/2 mutation-associated hereditary breast cancer in paraffin-embedded formalin-fixed breast tumors

      Miljana Tanic, Kira Yanowski, Gonzalo Gómez-López, María Socorro Rodriguez-Pinilla, Iván Marquez-Rodas, Ana Osorio, David G. Pisano, Beatriz Martinez-Delgado and Javier Benítez

      Article first published online: 19 JUN 2014 | DOI: 10.1002/ijc.29021

      What's New?

      Screening for germline mutations in BRCA1 and BRCA2 genes is indicated for breast cancer patients from high-risk breast cancer families to inform both treatment options and clinical management. However, currently only 25% of selected patients test positive for BRCA1/2 mutation, calling for additional diagnostic biomarkers. Here, BRCA1 and BRCA2 breast tumors presented highly homogeneous miRNA expression profiles and could be differentiated from familial non-BRCA1/2 (BRCAX) and sporadic breast tumors based on unique miRNA expression signatures with 92% accuracy, in routinely available FFPE breast tumors samples. These signatures may be useful for complementing current patient selection criteria for BRCA1/2 gene testing.

  64. Epidemiology

    1. Temporal changes in serum biomarkers and risk for progression of gastric precancerous lesions: A longitudinal study

      Huakang Tu, Liping Sun, Xiao Dong, Yuehua Gong, Qian Xu, Jingjing Jing, Qi Long, W. Dana Flanders, Roberd M. Bostick and Yuan Yuan

      Article first published online: 19 JUN 2014 | DOI: 10.1002/ijc.29005

      What's new?

      Effectively managing precancerous gastric lesions could reduce the incidence and mortality of gastric cancer (GC). However, only a small percentage of these lesions actually develop into GC. Specific biomarkers would thus be extremely helpful for risk stratification. In this study, the authors evaluated multiple serological markers for any association between temporal changes in these markers and risk of progression to GC. The results indicate that increased serum levels of pepsinogen II and anti-H. pylori IgG may prove useful for predicting an increased risk of progression to GC.

  65. Cancer Cell Biology

    1. Expression, regulation and roles of miR-26a and MEG3 in tongue squamous cell carcinoma

      Ling-Fei Jia, Su-Bi Wei, Ye-Hua Gan, Yong Guo, Kai Gong, Keith Mitchelson, Jing Cheng and Guang-Yan Yu

      Article first published online: 19 JUN 2014 | DOI: 10.1002/ijc.28667

      What's new?

      Tongue squamous cell carcinoma (TSCC) is a common oral cancer, for which improved prognostic markers are needed. In this investigation, gene expression of both microRNA-26a and long non-coding RNA MEG3 was found to be reduced in TSCC, with the combination of low expression levels associated with poor clinical outcome. MiR-26a was further found to inhibit the DNA methyltransferase 3B (DNMT3B) transcript, possibly accounting for MEG3 upregulation during miR-26a upregulation. The results suggest that the relationship between miR-26a and MEG3 is important in TSCC pathogenesis and that their combined expression is a potential prognostic factor for the disease.

  66. Epidemiology

    1. Vitamin E intake and the lung cancer risk among female nonsmokers: A report from the Shanghai Women's Health Study

      Qi-Jun Wu, Yong-Bing Xiang, Gong Yang, Hong-Lan Li, Qing Lan, Yu-Tang Gao, Wei Zheng, Xiao-Ou Shu and Jay H. Fowke

      Article first published online: 19 JUN 2014 | DOI: 10.1002/ijc.29016

      What's new?

      While some studies have suggested that vitamin E may reduce lung-cancer risk among non-smokers, results have been inconsistent. In this large, prospective study, the authors found that increasing vitamin E in the diet was significantly associated with a decreased risk of lung cancer. However, vitamin E from supplements was significantly associated with an increase in lung cancer risk. This suggests that caution is warranted when recommending vitamin E supplementation for lung cancer prevention among non-smoking women.

  67. Cancer Therapy

    1. Structural design of disialoganglioside GD2 and CD3-bispecific antibodies to redirect T cells for tumor therapy

      Ming Cheng, Mahiuddin Ahmed, Hong Xu and Nai-Kong V. Cheung

      Article first published online: 19 JUN 2014 | DOI: 10.1002/ijc.29007

      What's new?

      The success of cancer immunotherapies can be substantially enhanced if T cells are engaged by bispecific antibodies. Here the authors show that structural optimization based on in silico modeling can assist in designing efficient bispecific antibodies targeting disialoganglioside on tumor cells and CD3 on T cells. In vivo, optimized bispecific antibodies efficiently inhibited melanoma and neuroblastoma xenograft growth. This strategy could critically enhance the use of low affinity antibodies against carbohydrates such as disialogangliosides and realize their full clinical potential.

  68. Epidemiology

    1. MC1R variants increased the risk of sporadic cutaneous melanoma in darker-pigmented Caucasians: A pooled-analysis from the M-SKIP project

      Elena Pasquali, José C. García-Borrón, Maria Concetta Fargnoli, Sara Gandini, Patrick Maisonneuve, Vincenzo Bagnardi, Claudia Specchia, Fan Liu, Manfred Kayser, Tamar Nijsten, Eduardo Nagore, Rajiv Kumar, Johan Hansson, Peter A. Kanetsky, Paola Ghiorzo, Tadeusz Debniak, Wojciech Branicki, Nelleke A. Gruis, Jiali Han, Terry Dwyer, Leigh Blizzard, Maria Teresa Landi, Giuseppe Palmieri, Gloria Ribas, Alexander Stratigos, M. Laurin Council, Philippe Autier, Julian Little, Julia Newton-Bishop, Francesco Sera, Sara Raimondi and for the M-SKIP Study Group

      Article first published online: 18 JUN 2014 | DOI: 10.1002/ijc.29018

      What's new?

      The MC1R gene regulates production of the protective skin pigment eumelanin in response to sun exposure. In this study, the authors found that carriers of any of nine MC1R variants had a substantially increased risk of developing sporadic CM. Surprisingly, however, this increased risk was significant only for darker-pigmented Caucasians. This information is important for targeted preventive strategies, as fair-skinned people have previously been assumed to be at greatest risk for CM.

    2. Family history, body mass index and survival in Japanese patients with stomach cancer: a prospective study

      Yuko Minami, Masaaki Kawai, Tsuneaki Fujiya, Masaki Suzuki, Tetsuya Noguchi, Hideaki Yamanami, Yoichiro Kakugawa and Yoshikazu Nishino

      Article first published online: 17 JUN 2014 | DOI: 10.1002/ijc.29001

      What's new?

      How do family history and body mass index affect prognosis of stomach cancer? In this study, the authors collected data from more than 1,000 stomach cancer patients and documented deaths over a 5-year period. Family history had no apparent impact when considering all patients, but among patients under 60, family history increased the risk of death. Similarly, among patients over age 60, being overweight increased the chance of death.

  69. Mini Reviews

    1. You have full text access to this OnlineOpen article
      Human endogenous retrovirus K and cancer: Innocent bystander or tumorigenic accomplice?

      Ronan F. Downey, Francis J. Sullivan, Feng Wang-Johanning, Stefan Ambs, Francis J. Giles and Sharon A. Glynn

      Article first published online: 17 JUN 2014 | DOI: 10.1002/ijc.29003

  70. Cancer Therapy

    1. Cell-free DNA in healthy individuals, noncancerous disease and strong prognostic value in colorectal cancer

      Karen-Lise Garm Spindler, Ane L. Appelt, Niels Pallisgaard, Rikke F. Andersen, Ivan Brandslund and Anders Jakobsen

      Article first published online: 17 JUN 2014 | DOI: 10.1002/ijc.28946

      What's New?

      Circulating nucleic acids have emerged as important diagnostic and prognostic markers in cancer biology. However, many researchers have focused on identifying tumor-derived circulating DNA to study mutations. Here, the authors show that levels of total cell-free DNA (cfDNA) can predict survival in patients with metastatic colorectal cancer. The levels of cfDNA were markedly higher in cancer patients compared to healthy controls and patients with significant comorbidities. Patients with high levels had a shorter survival when treated with irinotecan, a second-line chemotherapeutic drug, supporting the notion that cfDNA may become a useful tool for prediction of outcome from chemotherapy in patients with metastatic colorectal cancer.

  71. Tumor Immunology

    1. Host STAT2/type I interferon axis controls tumor growth

      Chanyu Yue, Jun Xu, Marc Daryl Tan Estioko, Kevin P. Kotredes, Yolanda Lopez-Otalora, Brendan A. Hilliard, Darren P. Baker, Stefania Gallucci and Ana M. Gamero

      Article first published online: 17 JUN 2014 | DOI: 10.1002/ijc.29004

      What's new?

      Type I interferons (IFN-I) are used to treat cancer due to their critical immune modulatory and anti-proliferative properties. Here, the authors provide in vivo evidence that the transcription factor STAT2 plays a key role in the antitumor activity of IFN-I by controlling tumor growth and promoting tumor antigen cross-presentation. Using microarray analysis, they identified a small subset of STAT2-dependent genes that actively direct antitumor immunity. These findings identify STAT2 as a critical player in IFN-I immunotherapy and a potential target for future drug development.

  72. Carcinogenesis

    1. Large-scale profiling of metabolic dysregulation in ovarian cancer

      Chaofu Ke, Yan Hou, Haiyu Zhang, Lijun Fan, Tingting Ge, Bing Guo, Fan Zhang, Kai Yang, Jingtao Wang, Ge Lou and Kang Li

      Article first published online: 17 JUN 2014 | DOI: 10.1002/ijc.29010

      What's new?

      In this study, the authors systematically investigated ovarian cancer metabolism through the metabolic profiling of 448 plasma samples related to epithelial ovarian cancer (EOC). Numerous novel biomarkers for early EOC detection were identified, and, for the first time, the identified metabolites were able to distinguish early-stage EOC from late-stage EOC. The novel biomarkers revealed altered L-tryptophan catabolism, aggressive fatty acid β-oxidation, and abnormal phospholipid metabolism in EOC patients. Together, these metabolic pathways provide a foundation to support cancer development and progression. This study sheds light on ovarian cancer pathogenesis and could facilitate clinical diagnosis, therapy, and prognosis in the future.

  73. Cancer Therapy

    1. HIPEC ROC I: A phase i study of cisplatin administered as hyperthermic intraoperative intraperitoneal chemoperfusion followed by postoperative intravenous platinum-based chemotherapy in patients with platinum-sensitive recurrent epithelial ovarian cancer

      Oliver Zivanovic, Alina Abramian, Maximilian Kullmann, Christine Fuhrmann, Christoph Coch, Tobias Hoeller, Hauke Ruehs, Mignon Denise Keyver-Paik, Christian Rudlowski, Stefan Weber, Nicholas Kiefer, Martin L. Poelcher, Thore Thiesler, Babak Rostamzadeh, Michael Mallmann, Nico Schaefer, Maryse Permantier, Sandra Latten, Joerg Kalff, Juergen Thomale, Ulrich Jaehde and Walther C. Kuhn

      Article first published online: 17 JUN 2014 | DOI: 10.1002/ijc.29011

      What's new?

      Hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC), in which a single dose of a heated antineoplastic agent is administered at the time of cytoreductive surgery, is a novel strategy for the management of epithelial ovarian cancer (EOC). Here, the antineoplastic drug cisplatin, when administered as HIPEC, was found to have an acceptable safety profile for patients with platinum-sensitive recurrent EOC. The study shows that cisplatin induced DNA adducts in tumors, indicating that the drug successfully penetrated into and was active within tumors when given as HIPEC. The results suggest that HIPEC may be useful as a complementary treatment in EOC.

  74. Epidemiology

    1. Endogenous androgens and risk of epithelial invasive ovarian cancer by tumor characteristics in the European Prospective Investigation into Cancer and Nutrition

      Jennifer Ose, Renée T. Fortner, Sabina Rinaldi, Helena Schock, Kim Overvad, Anne Tjonneland, Louise Hansen, Laure Dossus, Agnes Fournier, Laura Baglietto, Isabelle Romieu, Elisabetta Kuhn, Heiner Boeing, Antonia Trichopoulou, Pagona Lagiou, Dimitrios Trichopoulos, Domenico Palli, Giovanna Masala, Sabina Sieri, Rosario Tumino, Carlotta Sacerdote, Amalia Mattiello, Jose Ramon Quiros, Mireia Obón-Santacana, Nerea Larrañaga, María-Dolores Chirlaque, María-José Sánchez, Aurelio Barricarte, Petra H. Peeters, H. Bas Bueno-de-Mesquita, N. Charlotte Onland-Moret, Jenny Brändstedt, Eva Lundin, Annika Idahl, Elisabete Weiderpass, Inger T. Gram, Eiliv Lund, Kay-Tee Kaw, Ruth C. Travis, Melissa A. Merritt, Marc J. Gunther, Elio Riboli and Rudolf Kaaks

      Article first published online: 16 JUN 2014 | DOI: 10.1002/ijc.29000

      What's new?

      There appear to be several types of epithelial invasive ovarian cancer (EOC), and hormone-related risk factors are poorly understood. In this study, the authors found that the impact of endogenous androgens on the risk of developing EOC differed depending upon tumor characteristics. Androgen concentrations were positively associated with the risk of low-grade and type-I carcinomas, but the study found an inverse association for high-grade tumors. These findings support a possible role for androgens in ovarian carcinogenesis, and emphasize the need for additional research.

  75. Mini Reviews

    1. You have full text access to this OnlineOpen article
      Nuclear receptors and the Warburg effect in cancer

      James L. Thorne and Moray J. Campbell

      Article first published online: 16 JUN 2014 | DOI: 10.1002/ijc.29012

  76. Cancer Therapy

    1. Facilitation of endoglin-targeting cancer therapy by development/utilization of a novel genetically engineered mouse model expressing humanized endoglin (CD105)

      Hirofumi Toi, Masanori Tsujie, Yuro Haruta, Kanako Fujita, Jill Duzen and Ben K. Seon

      Article first published online: 13 JUN 2014 | DOI: 10.1002/ijc.28994

      What's new?

      Endoglin (ENG) is a TGF-β coreceptor that is essential for vascular development and angiogenesis. A chimeric anti-human ENG (hENG) monoclonal antibody has shown promising safety and clinical efficacy in clinical trials of patients with various advanced solid tumors. Here, the authors developed a novel genetically engineered mouse model expressing a functional humanized ENG to optimize ongoing and future hENG antibody-based cancer therapy in patients. The homozygous genetically engineered mice developed normally and were healthy. Growth of established breast and colon tumors as well as metastasis and microvessel density in the mice were effectively suppressed by systemic administration of hENG mAbs.

    2. Targeting CDK9 by wogonin and related natural flavones potentiates the anti-cancer efficacy of the Bcl-2 family inhibitor ABT-263

      Gernot Polier, Marco Giaisi, Rebecca Köhler, Wolfgang W. Müller, Christoph Lutz, Eike C. Buss, Peter H. Krammer and Min Li-Weber

      Article first published online: 13 JUN 2014 | DOI: 10.1002/ijc.29009

      What's new?

      Drugs like ABT-263 fight cancer by stopping Bcl-2 from hindering apoptosis, but the accompanying drop in platelet count makes them hard to use safely in patients. In this paper, the authors show that certain flavones, such as wogonin, enhance ABT-263's ability to kill cancer cells, meaning a much lower and safer dose can be effective. Wogonin does not increase ABT-263's ability to kill normal, healthy T cells. In addition, wogonin and ABT-263 working together successfully shrank human T-cell leukemias growing in mice.

    3. Neuropilin-2 and its ligand VEGF-C predict treatment response after transurethral resection and radiochemotherapy in bladder cancer patients

      B. Keck, S. Wach, H. Taubert, S. Zeiler, O.J. Ott, F. Kunath, A. Hartmann, S. Bertz, C. Weiss, P. Hönscheid, S. Schellenburg, C. Rödel, G.B. Baretton, R. Sauer, R. Fietkau, B. Wullich, F.S. Krause, K. Datta and M.H. Muders

      Article first published online: 12 JUN 2014 | DOI: 10.1002/ijc.28987

      What's New?

      Neuropilin-2 (NRP2) and VEGF-C may play an important role in resistance to treatment. They can induce anti-apoptotic and autophagic signaling pathways, which protects cancer cells from chemotherapeutic stress in vitro. Therefore, these proteins might be useful as biomarkers for predicting a patient's response to therapy. In this study of bladder cancer patients, the authors demonstrate that NRP2 and VEGF-C expression are indeed prognostic markers. This may allow more patients to be treated with bladder-sparing surgery rather than radical cystectomy, and may also be applicable to other types of cancer.

  77. Epidemiology

    1. Variation in general practice prostate-specific antigen testing and prostate cancer outcomes: An ecological study

      Peter Hjertholm, Morten Fenger-Grøn, Mogens Vestergaard, Morten B. Christensen, Michael Borre, Henrik Møller and Peter Vedsted

      Article first published online: 12 JUN 2014 | DOI: 10.1002/ijc.29008

      What's new?

      The impact of PSA testing on diagnosis and mortality of prostate cancer is not yet clear. In this study, the authors found that patients of general practitioners (GPs) with high rates of PSA testing had a significantly increased incidence of prostate cancer, as well as greater use of diagnostic and surgical procedures. However, the mortality rate due to prostate cancer was similar to patients of GPs with low rates of PSA testing. This indicates that routine PSA testing may increase the use of diagnostic and surgical procedures with potentially harmful side effects, without actually reducing prostate cancer mortality.

  78. Letter to the Editors

    1. HPV-avertable cancer risks in India: A pooled analysis of 9 observational studies

      Jayadeep Patra, Rajesh Dikshit, Mehak Bhatia, Chinthanie Ramasundarahettige and Prabhat Jha

      Article first published online: 11 JUN 2014 | DOI: 10.1002/ijc.28998

  79. Short Reports

    1. Global burden of gastric cancer attributable to pylori

      Martyn Plummer, Silvia Franceschi, Jérôme Vignat, David Forman and Catherine de Martel

      Article first published online: 11 JUN 2014 | DOI: 10.1002/ijc.28999

      What's new?

      Some 5.2 percent of the estimated 12.7 million new cancer cases in 2008, including 75% of non-cardia gastric cancer cases (NCGC), were attributed to the bacterium Helicobacter pylori. However, those percentages may be an underestimate, given the low sensitivity of detection of anti-H. pylori antibodies. Here, using improved estimates from prospective studies based on immunoblot, the fraction of all cancers and NCGC attributable to H. pylori was found to be 6.2 and 89% percent, respectively. Our findings reinforce the significance of the bacterium as a major cause of cancer.

  80. Epidemiology

    1. Risk evaluation for the development of cervical intraepithelial neoplasia: Development and validation of risk-scoring schemes

      Chien-Hung Lee, Chiung-Yu Peng, Ruei-Nian Li, Yu-Chieh Chen, Hsiu-Ting Tsai, Yu-Hsiu Hung, Te-Fu Chan, Hsiao-Ling Huang, Tai-Cheng Lai and Ming-Tsang Wu

      Article first published online: 11 JUN 2014 | DOI: 10.1002/ijc.28982

      What's new?

      Cervical cancer is linked to various risk factors, including persistent infection with strains of high-risk human papillomavirus (HR-HPV). However, whether specific risk factor combinations place some women at greater risk than others is unclear. To find out, the authors of this study combined HR-HPV testing and verified risk factors to develop a cumulative risk score (CRS) scheme. Elevated HR-HPV DNA load was the primary predictor for cervical intraepithelial neoplasia grade 1 (CIN1) and grade 2 (CIN2), but other factors, such as marital status and smoking, also influenced risk-scoring. The CRS scheme was especially useful for CIN2+ screening.

  81. Mini Reviews

  82. Epidemiology

    1. Accuracy of visual inspection with acetic acid to detect cervical cancer precursors among HIV-infected women in Kenya

      Megan J. Huchko, Jennifer Sneden, George Sawaya, Karen Smith-McCune, May Maloba, Naila Abdulrahim, Elizabeth A. Bukusi and Craig R. Cohen

      Article first published online: 10 JUN 2014 | DOI: 10.1002/ijc.28996

      What's new?

      In sub-Saharan Africa, high rates of HIV lead to a high burden of cervical cancer. As HIV treatments become more available, the risk of death from cervical cancer has increased. Thus, there is need for inexpensive diagnostic tools to catch cervical cancer cases. This study evaluated the sensitivity, specificity, and predictive value of VIA (visual inspection with acetic acid) among HIV patients in Kenya. The test performed equally well in patients with HIV compared with previous studies in the general population. This report will help with planning and wider implementation of VIA among populations with high HIV prevalence.

  83. Cancer Therapy

    1. Inhibition of platelet activation prevents the P-selectin and integrin-dependent accumulation of cancer cell microparticles and reduces tumor growth and metastasis in vivo

      Soraya Mezouar, Roxane Darbousset, Françoise Dignat-George, Laurence Panicot-Dubois and Christophe Dubois

      Article first published online: 9 JUN 2014 | DOI: 10.1002/ijc.28997

      What's new?

      Tissue factor (TF) plays a key role in coagulation and is capable of activating inflammatory and angiogenic responses, potentially facilitating the progression of cancer. As a result, anticoagulant or antiplatelet drugs could be effective means of prevention for tumor progression and metastasis. Here, pancreatic cancer cell-derived microparticles were found to express TF and its inhibitor TFPI. The microparticles interacted with platelets, with effects on bleeding and platelet accumulation, in mice. In cancer mouse models, treatment with the antiplatelet drug clopidogrel restored hemostasis, resulted in decreased tumor size, and prevented the development of metastases.

  84. Early Detection and Diagnosis

    1. Noninvasive assessment of mitochondrial organization in three-dimensional tissues reveals changes associated with cancer development

      Joanna Xylas, Antonio Varone, Kyle P. Quinn, Dimitra Pouli, Margaret E. McLaughlin-Drubin, Hong-Thao Thieu, Maria L. Garcia-Moliner, Michael House, Martin Hunter, Karl Munger and Irene Georgakoudi

      Article first published online: 5 JUN 2014 | DOI: 10.1002/ijc.28992

      What's New?

      Mitochondrial organization is based on dynamic tubular networks and is related to mitochondrial function, such that functional changes that occur at the onset of cancer may be reflected in mitochondrial organization. This concept has not been rigorously tested, however, especially in three-dimensional tissues. Here, automated analysis of endogenous two-photon excited fluorescence (TPEF) images was used to quantify mitochondrial organization in three-dimensional specimens, revealing differences between normal and pre-cancerous tissues. The differences were associated with changes in major bioenergetic pathways. The findings suggest that mitochondrial organization may serve as a useful noninvasive diagnostic biomarker for early cancer.

  85. Infectious Causes of Cancer

    1. Epstein-Barr virus and risk of non-Hodgkin lymphoma in the cancer prevention study-II and a meta-analysis of serologic studies

      Lauren R. Teras, Dana E. Rollison, Michael Pawlita, Angelika Michel, Johannes Brozy, Silvia de Sanjose, Jennifer L. Blase and Susan M. Gapstur

      Article first published online: 5 JUN 2014 | DOI: 10.1002/ijc.28971

      What's new?

      People with weakened immune systems can fall victim to non-Hodgkin's lymphoma caused by unchecked Epstein-Barr virus. But can the virus cause cancer in people without obvious immune deficiencies? The vast majority of us harbor EBV, and it could be that even a mild immune impairment allows reactivation of the virus and increased risk of cancer. In this study, the authors examined the association between EBV antibodies and NHL risk. When considering the three most common types of NHL, they found that certain EBV antibodies did associate with increased risk, suggesting the virus may cause more cancers than previously thought.

  86. Cancer Cell Biology

    1. YM155 sensitizes triple-negative breast cancer to membrane-bound TRAIL through p38 MAPK- and CHOP-mediated DR5 upregulation

      Marzia Pennati, Stefania Sbarra, Michelandrea De Cesare, Alessia Lopergolo, Silvia L. Locatelli, Elisa Campi, Maria Grazia Daidone, Carmelo Carlo-Stella, Alessandro M. Gianni and Nadia Zaffaroni

      Article first published online: 5 JUN 2014 | DOI: 10.1002/ijc.28993

      What's new?

      In this study, a new combined treatment based on the use of the survivin inhibitor YM155 and CD34+ cells transduced with an adenovirus encoding the human TRAIL gene (CD34-TRAIL+ cells) produced synergistic effects in experimental models of triple-negative breast cancer (TNBC). Such antitumor effect relied on the ability of YM155 to up-regulate the death receptor DR5 through a p38 MAPK- and CHOP-dependent mechanism and was selectively observed in TNBC models inherently expressing DR5. The findings provide a molecular basis for a rational combination to be clinically exploited in TNBC and suggest DR5 expression as a possible marker for patient selection.

  87. Carcinogenesis

    1. UV exposure inhibits intestinal tumor growth and progression to malignancy in intestine-specific Apc mutant mice kept on low vitamin D diet

      Heggert Rebel, Celia Dingemanse-van der Spek, Daniela Salvatori, Johannes P.T.M. van Leeuwen, Els C. Robanus-Maandag and Frank R. de Gruijl

      Article first published online: 5 JUN 2014 | DOI: 10.1002/ijc.29002

      What's new

      Mortality from colorectal cancer decreases as ambient levels of UV radiation increase, suggesting that UV exposure is critical to the prevention of the disease. This study demonstrates the biological plausibility in mice of a causal relationship between moderate chronic UV irradiation or vitamin D supplementation and an impairment of outgrowth of primary intestinal cancer. While both UV irradiation and vitamin D supplementation decreased the overall area covered by tumors, only UV exposure inhibited malignant progression.

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