International Journal of Cancer

Cover image for Vol. 136 Issue 7

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: 34/203 (Oncology)

Online ISSN: 1097-0215

  1. Mini Reviews

    1. Extracellular vesicles as carriers of microRNA, proteins and lipids in tumor microenvironment

      Patrice Penfornis, Krishna C. Vallabhaneni, Jason Whitt and Radhika Pochampally

      Article first published online: 23 JAN 2015 | DOI: 10.1002/ijc.29417

  2. Early Detection and Diagnosis

    1. Is further screening of men with baseline PSA < 1 ng ml−1 worthwhile? The discussion continues—Results of the Swiss ERSPC (Aarau)

      Marco Randazzo, Josef Beatrice, Andreas Huber, Rainer Grobholz, Lukas Manka, Felix K. Chun, Luis A. Kluth, Stephen F. Wyler, Franz Recker and Maciej Kwiatkowski

      Article first published online: 23 JAN 2015 | DOI: 10.1002/ijc.29420

      What's New?

      Whether prostate cancer screening based on levels of prostate-specific antigen (PSA) is beneficial is uncertain, yet early PSA retesting is on the rise in some places, leading to increased detection of low-risk disease that may never become life-threatening. This study explores the possibility of improving early prostate cancer detection through the adjustment of PSA retest intervals. Men with baseline PSA below 1 ng ml−1 were observed over an average of 12 years. A very low risk of prostate cancer was found for baseline values below 0.4 ng ml−1, suggesting that further screening for men with such low values could be waived.

  3. Epidemiology

    1. Use of acetochlor and cancer incidence in the Agricultural Health Study

      Catherine C. Lerro, Stella Koutros, Gabriella Andreotti, Cynthia J. Hines, Aaron Blair, Jay Lubin, Xiaomei Ma, Yawei Zhang and Laura E. Beane Freeman

      Article first published online: 23 JAN 2015 | DOI: 10.1002/ijc.29416

      What's new?

      Acetochlor is a commonly used herbicide in the U.S., yet no epidemiologic research has evaluated its carcinogenicity in humans. In this study, the authors examined the relationship between occupational exposure to acetochlor and human cancer risk in a large prospective cohort. Acetochlor use was associated with an increased risk of lung and colorectal cancer, and possibly pancreatic cancer and melanoma. Use of mixtures of acetochlor and atrazine, another widely used herbicide often applied concurrently with acetochlor, was also associated with an increased risk of lung cancer.

  4. Cancer Therapy

    1. ST1926, an orally active synthetic retinoid, induces apoptosis in chronic myeloid leukemia cells and prolongs survival in a murine model

      Rihab R. Nasr, Raed A. Hmadi, Rabab M. El-Eit, Ahmad N. Iskandarani, Mark N. Jabbour, Ghazi S. Zaatari, Francois-Xavier Mahon, Claudio C.P. Pisano and Nadine D. Darwiche

      Article first published online: 21 JAN 2015 | DOI: 10.1002/ijc.29407

      What's new?

      Imatinib is the first line of treatment for chronic myeloid leukemia (CML). Unfortunately, patients develop resistance and relapse due to bcr-abl point mutations and the persistence of leukemia initiating cells (LIC). Here, the authors investigate for the first time the antitumor properties of synthetic retinoids, namely ST1926, in CML therapy. They show that ST1926 inhibits growth, induces apoptosis, and downregulates BCR-ABL signaling in CML cells. Oral treatment reduces tumor burden and prolongs survival of CML mice. However, ST1926 does not affect LIC activity. These results highlight the potential of ST1926 in CML targeted therapy, in combination with CML LIC-targeting drugs.

  5. Epidemiology

    1. Increased diagnostic activity in general practice during the year preceding colorectal cancer diagnosis

      Pernille Libach Hansen, Peter Hjertholm and Peter Vedsted

      Article first published online: 21 JAN 2015 | DOI: 10.1002/ijc.29418

      What's new?

      The sooner cancer is detected, the sooner treatment can begin which improves outcomes. This study asked whether colorectal cancer could be detected earlier in general practice. Using Danish registries, the authors looked at how often people consulted their general practitioner prior to diagnosis with colorectal cancer, compared with a reference population who did not get cancer. They discovered that colorectal cancer patients had met with their general practitioner more frequently in the year leading up to cancer diagnosis, receiving more hemorrhoid medications and hemoglobine counts. This indicates the presence of a “diagnostic time window” where an earlier diagnosis of CRC may be possible.

    2. Contraceptive methods and ovarian cancer risk among Chinese women: A report from the Shanghai Women's Health Study

      Zhezhou Huang, Yutang Gao, Wanqing Wen, Honglan Li, Wei Zheng, Xiao-Ou Shu and Alicia Beeghly-Fadiel

      Article first published online: 21 JAN 2015 | DOI: 10.1002/ijc.29412

      What's new?

      Patterns of contraceptive use are unique in China, where long-term use of intrauterine devices (IUDs) is common. But the impact of that trend on ovarian cancer risk remains unclear. In this study, 55.6% of women in the Shanghai Women's Health Study reported ever-use of IUD contraception, whereas oral contraceptive use was 20.4% and tubal ligation was 14.7%. While ever-use of any contraception had little impact on ovarian cancer risk, IUD use for more than 20 years significantly reduced risk for the disease. The high prevalence of IUD contraception may be related to China's low incidence of ovarian cancer.

  6. Cancer Genetics

    1. Aberrant methylation of imprinted genes is associated with negative hormone receptor status in invasive breast cancer

      Timothy M. Barrow, Ludovic Barault, Rachel E. Ellsworth, Holly R. Harris, Alexandra M. Binder, Allyson L. Valente, Craig D. Shriver and Karin B. Michels

      Article first published online: 21 JAN 2015 | DOI: 10.1002/ijc.29419

      What's new?

      Epigenetic regulation of imprinted genes enables monoallelic expression according to parental origin, and its disruption is implicated in many cancers. Elucidating the relationship between imprinted genes and hormone receptor status in breast cancer may provide insight into tumorigenesis and potential prognostic factors. This is the first study to identify an association between the aberrant DNA methylation of imprinted genes and negative status of the estrogen and progesterone receptors in breast cancer. Variation in methylation increases from normal tissue to benign disease to cancer. Epigenetic disruption of imprinted genes may play an important role in the development of different breast cancer subtypes.

    2. Frequency and phenotypic spectrum of germline mutations in POLE and seven other polymerase genes in 266 patients with colorectal adenomas and carcinomas

      Isabel Spier, Stefanie Holzapfel, Janine Altmüller, Bixiao Zhao, Sukanya Horpaopan, Stefanie Vogt, Sophia Chen, Monika Morak, Susanne Raeder, Katrin Kayser, Dietlinde Stienen, Ronja Adam, Peter Nürnberg, Guido Plotz, Elke Holinski-Feder, Richard P. Lifton, Holger Thiele, Per Hoffmann, Verena Steinke and Stefan Aretz

      Article first published online: 20 JAN 2015 | DOI: 10.1002/ijc.29396

      What's New?

      A substantial number of families with adenomatous polyposis and Lynch-like phenotype have no known underlying germline mutations. Recently new mutations in the genes encoding DNA polymerase epsilon and delta were identified. Here the authors characterize the frequency and phenotypic spectrum of this newly described polymerase proofreading-associated polyposis (PPAP) syndrome. They broadened the tumor spectrum to duodenal neoplasias, extraintestinal tumors and multiple colorectal carcinomas, underscoring the clinical relevance of this syndrome beyond adenomatous polyposis. In addition, they identified nine novel, potentially pathogenic variants in four polymerase genes.

  7. Cancer Therapy

    1. Antitumor activity of an anti-CD98 antibody

      Gregory M. Hayes, Lawrence Chinn, Joseph M. Cantor, Belinda Cairns, Zoia Levashova, Hoang Tran, Timothy Velilla, Dana Duey, John Lippincott, Joseph Zachwieja, Mark H. Ginsberg and Edward H. van der Horst

      Article first published online: 14 JAN 2015 | DOI: 10.1002/ijc.29415

      What's new?

      The CD98 protein is overexpressed in a wide variety of cancers, and its expression levels show positive association with tumor progression and metastasis. Both the heavy and the light chains of CD98 are of therapeutic interest. The present study reports broad and potent anti-tumor activity of the anti-CD98 humanized monoclonal antibody IGN523 in leukemic cell-line-derived xenograft models and patient-derived non-small cell lung cancer xenografts. IGN523 exhibited multiple mechanisms of action, and in vitro demonstrated antibody-dependent cellular cytotoxicity, blocked amino acid transport, and led to tumor cell apoptosis mediated via caspase-3 and caspase-7 pathways.

  8. Early Detection and Diagnosis

    1. Early recognition of lung cancer by integrin targeted imaging in K-ras mouse model

      Vladimir Ermolayev, Pouyan Mohajerani, Angelique Ale, Athanasios Sarantopoulos, Michaela Aichler, Gian Kayser, Axel Walch and Vasilis Ntziachristos

      Article first published online: 14 JAN 2015 | DOI: 10.1002/ijc.29372

      What's new?

      Integrins play an important role in lung-cancer development and metastasis, and these molecules might therefore be useful as tumor biomarkers. In this study, the authors found that targeted imaging of αvβ3-integrin may allow preclinical researchers and clinicians to detect non-small cell lung cancer (NSCLC) at an earlier stage than accepted cancer markers. This approach may also enhance monitoring of anticancer therapies in early lung cancer.

  9. Cancer Cell Biology

    1. The rarity of ALDH+ cells is the key to separation of normal versus leukemia stem cells by ALDH activity in AML patients

      Van T. Hoang, Eike C. Buss, Wenwen Wang, Isabel Hoffmann, Simon Raffel, Abraham Zepeda-Moreno, Natalia Baran, Patrick Wuchter, Volker Eckstein, Andreas Trumpp, Anna Jauch, Anthony D. Ho and Christoph Lutz

      Article first published online: 14 JAN 2015 | DOI: 10.1002/ijc.29410

      What's new?

      To understand the precise disease-driving mechanisms in acute myeloid leukemia (AML), comparison of patient-matched hematopoietic stem cells (HSC) and leukemia stem cells (LSC) is essential. This study demonstrates the relevance of aldehyde dehydrogenase (ALDH) for the prospective identification of AML cases in which separation of functionally normal HSC from LSC is possible. Increased activity of this biomarker also characterizes a subgroup of patients with adverse outcome, which might be helpful in risk stratification prior to therapy. Overall, this study demonstrates functional heterogeneity of leukemia cells and suggests divergent roles for ALDH activity in normal HSC versus leukemia-initiating cells.

  10. Early Detection and Diagnosis

    1. Multicenter analysis of soluble Axl reveals diagnostic value for very early stage hepatocellular carcinoma

      Patrick Reichl, Meng Fang, Patrick Starlinger, Katharina Staufer, Rudolf Nenutil, Petr Muller, Kristina Greplova, Dalibor Valik, Steven Dooley, Christine Brostjan, Thomas Gruenberger, Jiayun Shen, Kwan Man, Michael Trauner, Jun Yu, Chun Fang Gao and Wolfgang Mikulits

      Article first published online: 13 JAN 2015 | DOI: 10.1002/ijc.29394

      What's new?

      If diagnosed at early stages, patients with hepatocellular carcinoma (HCC) can receive curative therapies, whereas therapeutic options at later stages are limited. Detection of early stage hepatocellular carcinoma by measuring serum α-fetoprotein (AFP) however exhibits only moderate sensitivity. This study shows that serum concentrations of soluble Axl (sAxl) are increased in very early, early and advanced HCC as well as in AFP-negative HCC patients, as compared to cirrhotic controls. Assessment of sAxl levels allows accurate differential diagnosis of very early HCC versus cirrhosis and other types of cancer, suggesting that sAxl is a promising diagnostic biomarker for routine clinical use.

  11. Cancer Genetics

    1. High IDH1 expression is associated with a poor prognosis in cytogenetically normal acute myeloid leukemia

      Qiu-Ling Ma, Jing-Han Wang, Yun-Gui Wang, Chao Hu, Qi-Tian Mu, Meng-Xia Yu, Lei Wang, Dong-Mei Wang, Min Yang, Xiu-Feng Yin, Fei-Fei Chen, Sha-Sha Lu, Jian Chen, Zhi-Juan Zhu, Sai-Juan Chen and Jie Jin

      Article first published online: 13 JAN 2015 | DOI: 10.1002/ijc.29395

      What's new?

      Isocitrate dehydrogenase 1 (IDH1) is one of two enzymes that convert isocitrate to alpha-ketoglutarate and play an important role in metabolic reprogramming of tumor cells. Here the authors demonstrate that high IDH1 expression is associated with a poor prognosis for acute myeloid leukemia with normal cytogenetic status (CN-AML). In addition, they evaluated microRNAs known to regulate IDH1 status in bone marrow blasts and found an association between high IDH1 and low microRNA181 expression. These studies link tumor metabolism to the clinical prognosis in patients with CN-AML.

  12. Epidemiology

    1. Occupation and risk of oesophageal adenocarcinoma and squamous-cell carcinoma: The Nordic Occupational Cancer Study

      Catarina Jansson, Jin-Kyoung Oh, Jan Ivar Martinsen, Jesper Lagergren, Nils Plato, Kristina Kjaerheim, Eero Pukkala, Pär Sparén, Laufey Tryggvadottir and Elisabete Weiderpass

      Article first published online: 13 JAN 2015 | DOI: 10.1002/ijc.29409

      What's new?

      Certain occupations are known to influence oesophageal cancer risk, but whether risk varies according to occupation or histological type—specifically adenocarcinoma or squamous cell carcinoma—remains unknown. In the present study, the risk of oesophageal cancer was found to vary by occupation, and for most occupational categories, histological type had little influence on risk. For both sexes, risk of oesophageal cancer was found to be elevated, particularly among those who served as waiters or food workers, whereas those who worked as teachers were at reduced risk.

  13. Cancer Cell Biology

    1. MicroRNA-196a promotes an oncogenic effect in head and neck cancer cells by suppressing annexin A1 and enhancing radioresistance

      Yae-Eun Suh, Nina Raulf, Joop Gäken, Katherine Lawler, Teresa Guerrero Urbano, Jessica Bullenkamp, Stéphane Gobeil, Jacques Huot, Eddy Odell and Mahvash Tavassoli

      Article first published online: 12 JAN 2015 | DOI: 10.1002/ijc.29397

      What's new?

      There is accumulating evidence that miR-196a plays an important role in the pathogenesis of a number of cancers. Through functional studies, here the authors demonstrate that miR-196a confers an oncogenic phenotype in head and neck cancer cells, through the targeting of ANXA1. The results also show that MiR-196a modulation is associated with response to radiation. MiR-196a may therefore represent both a prognostic and a predictive biomarker in head and neck cancer. Furthermore, the data suggest that miR-196a and/or its target gene ANXA1 could represent important therapeutic targets in head and neck cancer.

  14. Cancer Genetics

    1. Identification of genomic signatures in circulating tumor cells from breast cancer

      Nisha Kanwar, Pingzhao Hu, Philippe Bedard, Mark Clemons, David McCready and Susan J. Done

      Article first published online: 12 JAN 2015 | DOI: 10.1002/ijc.29399

      What's new?

      People die of breast cancer not from the primary tumors, but because of uncontrolled metastasis, and circulating tumor cells (CTCs) could be the key to detecting it. In this paper, the authors examined the DNA of CTCs looking for identifying features that could help spot these harbingers of metastasis. They found certain copy number changes, predominantly on chromosome 19 that may indicate the cell's ability to travel. The changes fell into two categories: one associated with dormancy, the other with tumor aggressiveness. Detection of these genetic signatures could help target the most mobile cells and thwart metastasis.

  15. Epidemiology

    1. Night shift work, chronotype and prostate cancer risk in the MCC-Spain case-control study

      Kyriaki Papantoniou, Gemma Castaño-Vinyals, Ana Espinosa, Nuria Aragonés, Beatriz Pérez-Gómez, Javier Burgos, Inés Gómez-Acebo, Javier Llorca, Rosana Peiró, Jose Juan Jimenez-Moleón, Francisco Arredondo, Adonina Tardón, Marina Pollan and Manolis Kogevinas

      Article first published online: 12 JAN 2015 | DOI: 10.1002/ijc.29400

      What's new?

      Up to 20% of workers do night-shift work, which may increase the risk of some cancers. In this study, the authors found that long-term night-shift work was associated with an increased risk of prostate cancer and decreased survival. Overall risk was higher among workers with an evening chronotype (i.e., a preference for working in the evening vs. in the morning), but risk also increased for morning chronotypes if the duration of night-shift work increased. These results may improve our understanding of prostate cancer etiology and potential prevention strategies.

  16. Mini Reviews

  17. Cancer Therapy

    1. The proteasome inhibitor Bortezomib (Velcade) as potential inhibitor of estrogen receptor-positive breast cancer

      Sonja Thaler, Gitta Thiede, Jan G. Hengstler, Arno Schad, Marcus Schmidt and Jonathan P. Sleeman

      Article first published online: 8 JAN 2015 | DOI: 10.1002/ijc.29404

      What's new?

      Drugs that block estrogen receptor α (ERα) can significantly reduce breast cancer mortality. But some ERα-positive tumors are intrinsically resistant to anti-endocrine therapy, and over time, such therapy can be rendered ineffective in initially sensitive tumors. In the search for drugs to overcome resistance to anti-endocrine therapy, the proteasome inhibitor Bortezomib has emerged as a promising agent. Here, Bortezomib is reported to have anti-tumoral effects on ERα-positive breast cancer cells, independent of p53. Bortezomib activity inhibited ERα and HER2/neu expression and decreased the expression of genes linked to poor prognosis in ERα-positive breast cancer patients.

  18. Cancer Cell Biology

    1. Cell membrane gp96 facilitates HER2 dimerization and serves as a novel target in breast cancer

      Xin Li, Lu Sun, Junwei Hou, Mingming Gui, Jianming Ying, Hong Zhao, Ning Lv and Songdong Meng

      Article first published online: 8 JAN 2015 | DOI: 10.1002/ijc.29405

      What's new

      The chaperone protein gp96 normally resides in the endoplasmic reticulum, but in certain tumor cells, it may translocate to the cell membrane. In breast cancer, gp96 cell membrane expression is correlated with malignancy. In this study, cell membrane gp96 was found to promote HER2 dimerization and phosphorylation, and HER2 phosphorylation was correlated with cell membrane gp96 levels in breast cancer patients. Inhibition of gp96 suppressed HER2-driven cell growth. The findings provide insight into a possible therapeutic approach for managing HER2 overexpression in breast cancer, which is a recognized factor behind poor prognosis for patients with HER2-positive tumors.

  19. Cancer Therapy

    1. Prostaglandin d synthase is a potential novel therapeutic agent for the treatment of gastric carcinomas expressing PPARγ

      Tatsunari Fukuoka, Masakazu Yashiro, Haruhito Kinoshita, Tamami Morisaki, Tsuyoshi Hasegawa, Toshiki Hirakawa, Naoki Aomatsu, Hiroshi Takeda, Takayuki Maruyama and Kosei Hirakawa

      Article first published online: 8 JAN 2015 | DOI: 10.1002/ijc.29392

      What's new?

      Previous work suggests that prostaglandin D2 (PGD2) exerts antiproliferative effects in certain types of cancer cells. But because PGD2 is rapidly catalyzed to its inactive form, its clinical utility is limited. A possible alternative to PGD2 is PGD synthase (PGDS), which synthesizes PGD2, but whether it also possesses antitumor activity is unknown. In this study, in PPARγ-expressing gastric cancer cells, both PGD2 and PGDS were found to significantly suppress cell proliferation. In vivo, they inhibited the growth of subcutaneous tumors. Tumor volume was markedly decreased with PGDS treatment, compared with PGD2.

  20. Cancer Cell Biology

    1. Activation of aryl hydrocarbon receptor promotes invasion of clear cell renal cell carcinoma and is associated with poor prognosis and cigarette smoke

      Masaru Ishida, Shuji Mikami, Toshiaki Shinojima, Takeo Kosaka, Ryuichi Mizuno, Eiji Kikuchi, Akira Miyajima, Yasunori Okada and Mototsugu Oya

      Article first published online: 8 JAN 2015 | DOI: 10.1002/ijc.29398

      What's new?

      As excretory organs, the kidneys are prime sites of exposure to carcinogenic substances, particularly environmental pollutants. But while such pollutants are known risk factors for clear cell renal cell cancer (ccRCC), little is known about their relationship with ccRCC progression. In this study, expression of the aryl hydrocarbon receptor (AhR), a mediator of pollutant-associated carcinogenesis, was detected in high-grade ccRCCs and tumor-infiltrating lymphocytes. In cancer cells and lymphocytes, AhR expression levels were associated with pathological tumor stage, histological grade and poor prognosis. AhR activation was found to enhance ccRCC invasiveness, while AhR silencing via siRNA inhibited invasion in vitro.

  21. Tumor Immunology

    1. A novel RNA-based adjuvant combines strong immunostimulatory capacities with a favorable safety profile

      Regina Heidenreich, Edith Jasny, Aleksandra Kowalczyk, Johannes Lutz, Jochen Probst, Patrick Baumhof, Birgit Scheel, Söhnke Voss, Karl-Josef Kallen and Mariola Fotin-Mleczek

      Article first published online: 8 JAN 2015 | DOI: 10.1002/ijc.29402

      What's new?

      While adjuvants can enhance immune responses induced by peptide and protein vaccines, in cancer immunotherapy, they fail to trigger the balanced, long-lasting immunity that is needed for anti-tumor protection. That limitation may be overcome with the development of synthetic RNA molecules as adjuvants, according to the present study. In a TC-1 tumor mouse model, RNAdjuvant®, a novel synthetic RNA with a polymeric carrier, significantly enhanced immune responses associated with the administration of peptide vaccine. Profound anti-tumor effects were observed. The adjuvant acted locally, at the site of injection, without inducing systemic cytokine release.

  22. Epidemiology

    1. Consumption of salted meat and its interactions with alcohol drinking and tobacco smoking on esophageal squamous-cell carcinoma

      Sihao Lin, Xiaorong Wang, Chengyu Huang, Xudong Liu, Jin Zhao, Ignatius T.S. Yu and David C. Christiani

      Article first published online: 8 JAN 2015 | DOI: 10.1002/ijc.29406

      What's new?

      Esophageal cancer has several known risk factors, including smoking, dietary factors, and alcohol consumption. In this paper, the authors asked whether eating lots of salted meat increases cancer risk, either alone or in combination with alcohol and smoking. They assessed the diet, tobacco, and alcohol use of nearly 2,000 cases and controls from a region of China known for high rates of esophageal cancer. Salted meat consumption, they found, accompanied an increase in esophageal cancer risk. And the addition of either alcohol or smoking produced an even larger boost in risk, more than would be expected from a simple additive effect.

  23. Short Reports

    1. Dopamine is a safe antiangiogenic drug which can also prevent 5-fluorouracil induced neutropenia

      Chandrani Sarkar, Debanjan Chakroborty, Partha Sarathi Dasgupta and Sujit Basu

      Article first published online: 7 JAN 2015 | DOI: 10.1002/ijc.29414

      What's new?

      This report for the first time indicates that the anti-angiogenic dose of DA does not cause any untoward side effects commonly observed with the presently used anti-VEGF agents. In addition, DA can also prevent 5FU induced neutropenia in tumor bearing animals. Therefore this inexpensive drug which is being used in the clinics for many years for the treatment of cardiovascular and renal disorders may also be safely administered as an anti-angiogenic agent for the treatment of malignant tumors.

  24. Cancer Genetics

    1. Genetic variants associated with longer telomere length are associated with increased lung cancer risk among never-smoking women in Asia: a report from the female lung cancer consortium in Asia

      Mitchell J. Machiela, Chao Agnes Hsiung, Xiao-Ou Shu, Wei Jie Seow, Zhaoming Wang, Keitaro Matsuo, Yun-Chul Hong, Adeline Seow, Chen Wu, H. Dean Hosgood III, Kexin Chen, Jiu-Cun Wang, Wanqing Wen, Richard Cawthon, Nilanjan Chatterjee, Wei Hu, Neil E. Caporaso, Jae Yong Park, Chien-Jen Chen, Yeul Hong Kim, Young Tae Kim, Maria Teresa Landi, Hongbing Shen, Charles Lawrence, Laurie Burdett, Meredith Yeager, I-Shou Chang, Tetsuya Mitsudomi, Hee Nam Kim, Gee-Chen Chang, Bryan A. Bassig, Margaret Tucker, Fusheng Wei, Zhihua Yin, She-Juan An, Biyun Qian, Victor Ho Fun Lee, Daru Lu, Jianjun Liu, Hyo-Sung Jeon, Chin-Fu Hsiao, Jae Sook Sung, Jin Hee Kim, Yu-Tang Gao, Ying-Huang Tsai, Yoo Jin Jung, Huan Guo, Zhibin Hu, Amy Hutchinson, Wen-Chang Wang, Robert J. Klein, Charles C. Chung, In-Jae Oh, Kuan-Yu Chen, Sonja I. Berndt, Wei Wu, Jiang Chang, Xu-Chao Zhang, Ming-Shyan Huang, Hong Zheng, Junwen Wang, Xueying Zhao, Yuqing Li, Jin Eun Choi, Wu-Chou Su, Kyong Hwa Park, Sook Whan Sung, Yuh-Min Chen, Li Liu, Chang Hyun Kang, Lingmin Hu, Chung-Hsing Chen, William Pao, Young-Chul Kim, Tsung-Ying Yang, Jun Xu, Peng Guan, Wen Tan, Jian Su, Chih-Liang Wang, Haixin Li, Alan Dart Loon Sihoe, Zhenhong Zhao, Ying Chen, Yi Young Choi, Jen-Yu Hung, Jun Suk Kim, Ho-Il Yoon, Qiuyin Cai, Chien-Chung Lin, In Kyu Park, Ping Xu, Jing Dong, Christopher Kim, Qincheng He, Reury-Perng Perng, Takashi Kohno, Sun-Seog Kweon, Chih-Yi Chen, Roel C.H Vermeulen, Junjie Wu, Wei-Yen Lim, Kun-Chieh Chen, Wong-Ho Chow, Bu-Tian Ji, John K. C. Chan, Minjie Chu, Yao-Jen Li, Jun Yokota, Jihua Li, Hongyan Chen, Yong-Bing Xiang, Chong-Jen Yu, Hideo Kunitoh, Guoping Wu, Li Jin, Yen-Li Lo, Kouya Shiraishi, Ying-Hsiang Chen, Hsien-Chih Lin, Tangchun Wu, Maria Pik Wong, Yi-Long Wu, Pan-Chyr Yang, Baosen Zhou, Min-Ho Shin, Joseph F. Fraumeni Jr., Wei Zheng, Dongxin Lin, Stephen J. Chanock, Nathaniel Rothman and Qing Lan

      Article first published online: 29 DEC 2014 | DOI: 10.1002/ijc.29393

      What's new?

      The possibility for a relationship between telomere length and cancer is intriguing, but many questions remain, including whether short or long telomeres are involved. Here, a genetic risk score derived from seven telomere-length associated genetic variants revealed a positive association between telomere length and lung cancer risk in Asian women who never smoked. The genetic proxy was unaffected by reverse-causation bias or environmental exposures. The differences in telomere length captured by the variants could aid in the identification of biological mechanisms that underlie the association between longer telomere length and increased lung cancer risk.

  25. Tumor Immunology

    1. HMGB1 secretion during cervical carcinogenesis promotes the acquisition of a tolerogenic functionality by plasmacytoid dendritic cells

      Stéphanie Demoulin, Michael Herfs, Joan Somja, Patrick Roncarati, Philippe Delvenne and Pascale Hubert

      Article first published online: 27 DEC 2014 | DOI: 10.1002/ijc.29389

      What's new?

      The human immune system usually strikes with deadly efficiency. Somehow, though, tumors evade destruction, despite the presence of distinctive tumor antigens. In fact, tumors actively train the immune cells to tolerate their antigens, using plasmacytoid dendritic cells (pDCs). In this paper, the authors asked whether cervical cells send out a molecular signal that summons the pDCs and enlists them in the service of the tumor. They discovered that the protein HMGB1, produced by tumor cells, interfered with pDCs' maturation and created an immune tolerance toward the tumor. Inhibiting HMGB1 restored normal pDC function, suggesting a possible treatment angle.

  26. Cancer Therapy

    1. Inhibition of mesothelioma cancer stem-like cells with adenovirus-mediated NK4 gene therapy

      Xu-Bin Deng, Li Xiao, Yue Wu, Fang Jin, Brooke Mossman, Joseph R. Testa and Guang-Hui Xiao

      Article first published online: 27 DEC 2014 | DOI: 10.1002/ijc.29391

      What's new?

      We demonstrate that NK4, a HGF antagonist and angiogenesis inhibitor, inhibits cancer stem-like cell (CSC) properties and growth of malignant mesothelioma. In addition to inhibiting phosphorylation of Met and AKT, NK4 suppressed the active form of β-catenin, blocked its nuclear translocation, transcriptional activity, and expression of its targets Oct4 and Myc. These findings suggest that NK4 acts as a CSC inhibitor by inhibiting Met/AKT/β-catenin signaling and provide a novel mechanism for NK4's potent anti-tumor effect.

    2. A seven-gene signature can predict distant recurrence in patients with triple-negative breast cancers who receive adjuvant chemotherapy following surgery

      Yeon Hee Park, Hae Hyun Jung, In-Gu Do, Eun Yoon Cho, Insuk Sohn, Sin-Ho Jung, Won Ho Kil, Seok Won Kim, Jeong Eon Lee, Seok Jin Nam, Jin Seok Ahn and Young-Hyuck Im

      Article first published online: 24 DEC 2014 | DOI: 10.1002/ijc.29233

      What's new?

      Breast cancer lacking HER-2, estrogen or progesterone receptors (called triple negative) lack targeted therapeutic intervention and have a relatively poor prognosis. Here the authors identified a seven-gene expression signature that predicts distal recurrence of the cancer after surgery and conventional chemotherapy. This study may help molecularly classify the heterogeneous group of triple-negative breast cancer patients and to identify patients within this group that would benefit from additional chemotherapy after surgery.

  27. Cancer Cell Biology

    1. Resident microglia, and not peripheral macrophages, are the main source of brain tumor mononuclear cells

      Annett Müller, Susan Brandenburg, Kati Turkowski, Susanne Müller and Peter Vajkoczy

      Article first published online: 24 DEC 2014 | DOI: 10.1002/ijc.29379

      What's new?

      Microglia and macrophages are indistinguishable, and studies using total body irradiation to investigate the cell types in gliomas have been confounded by possible effects on blood-brain barrier (BBB) integrity. Here, to avoid potential compromise of the BBB, the precise composition of myeloid cells during glioma progression was determined using a head-protected irradiation strategy. The approach revealed that macrophages contribute to the tumor mass only at the late stage of growth and constitute merely 25% of the myeloid cell fraction. Thus, microglia are the predominant immune cell population in gliomas and may represent the more effective therapeutic target.

  28. Carcinogenesis

    1. Antibody targeting of HER2/HER3 signaling overcomes heregulin-induced resistance to PI3K inhibition in prostate cancer

      Jayakumar S. Poovassery, Jeffrey C. Kang, Dongyoung Kim, Raimund J. Ober and E. Sally Ward

      Article first published online: 19 DEC 2014 | DOI: 10.1002/ijc.29378

      What's new?

      Changes in the PI3K/Akt pathway often accompany prostate cancer. But attempts to halt the cancer by targeting this pathway are frustratingly ineffective, as they are thwarted by the HER family of kinases. This study showed that the HER3 ligand, heregulin, allows prostate cancer cells to fend off the PI3K inhibitor, GDC-0941. The authors then went on to demonstrate that they could reverse this effect; targeting HER2 and HER3 with antibodies allowed the inhibitor to again stop the growth of the cancer. Thus, antibodies to HER2 /HER3 may enhance the effectiveness of PI3K inhibitors to treat prostate cancer in patients.

  29. Short Reports

    1. Cell-surface Vimentin: A mislocalized protein for isolating csVimentin+CD133 novel stem-like hepatocellular carcinoma cells expressing EMT markers

      Abhisek Mitra, Arun Satelli, Xueqing Xia, Jeffrey Cutrera, Lopa Mishra and Shulin Li

      Article first published online: 18 DEC 2014 | DOI: 10.1002/ijc.29382

      What's new?

      While cancer stem–like cells with epithelial–mesenchymal transition (EMT) phenotypes are known to be more aggressive and cause relapse, further advances are hampered by the absence of a specific marker. This study identifies for the first time the existence of Vimentin on the surface of liver cancer stem cells (LCSCs) and presents a separation technique to enrich EMT-positive LCSCs directly from primary tumor cells. csVim+CD133- cells thus display stem-like properties, differentiation ability, and tumorigenic properties, have the EMT phenotype, and metastasize aggressively. The findings indicate that csVim+CD133- cells are promising targets for treatment and prevention of metastatic hepatocellular carcinoma.

  30. Cancer Cell Biology

    1. Ovarian cancer ascites enhance the migration of patient-derived peritoneal mesothelial cells via cMet pathway through HGF-dependent and -independent mechanisms

      Isabelle Matte, Denis Lane, Claude Laplante, Perrine Garde-Granger, Claudine Rancourt and Alain Piché

      Article first published online: 18 DEC 2014 | DOI: 10.1002/ijc.29385

      What's new?

      The majority of patients with epithelial ovarian cancer present with ascites and advanced disease with peritoneal dissemination. Ovarian cancer ascites are an accumulation of fluid in the peritoneal cavity that represents a pro-inflammatory environment and contains abundant human peritoneal mesothelial cells. This study provides first evidence that ascites not only support tumor growth but also enhance the migratory potential of cancer-associated mesothelial cells, which may in turn support cancer progression. Ascites thus constitute a complex regulatory network of soluble factors, including hepatocyte growth factor (HGF), that confer to patient-derived mesothelial cells a migratory phenotype through the activation of cMet receptor.

  31. Epidemiology

    1. Factors influencing ovulation and the risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers

      Joanne Kotsopoulos, Jan Lubinski, Jacek Gronwald, Cezary Cybulski, Rochelle Demsky, Susan L. Neuhausen, Charmaine Kim-Sing, Nadine Tung, Susan Friedman, Leigha Senter, Jeffrey Weitzel, Beth Karlan, Pal Moller, Ping Sun, Steven A. Narod and the Hereditary Breast Cancer Clinical Study Group

      Article first published online: 18 DEC 2014 | DOI: 10.1002/ijc.29386

      What's New?

      The number of ovulatory cycles a woman has in her lifetime may influence her risk for ovarian cancer, though how cancer-associated BRCA mutations factor into that relationship remains uncertain. Here, ovarian cancer risk was found to be significantly reduced among BRCA mutation carriers in the lowest quartile of ovulatory cycles. Likewise, risk was reduced in women with BRCA1 or BRCA2 mutations who used oral contraceptives for five or three years, respectively, or who breastfed for more than 12 months. The findings lend support to the idea that factors that suppress or interrupt ovulation protect against BRCA-associated ovarian cancer.

    2. Primary human papillomavirus DNA screening for cervical cancer prevention: Can the screening interval be safely extended?

      Margaretha A. Vink, Johannes A. Bogaards, Chris J.L.M. Meijer and Johannes Berkhof

      Article first published online: 17 DEC 2014 | DOI: 10.1002/ijc.29381

      What's new?

      In 2016, a high-risk human papillomavirus (hrHPV) DNA test will replace the Pap test as primary screening instrument in the Netherlands. The screening interval for hrHPV-negative women aged 40 or 50 will expand from 5 to 10 years. This study evaluates the impact of the changes to the screening program. In light of the generally slow progression of precancerous lesions, the new screening program will reduce the long-term cervical cancer risk for women irrespective of their age in 2016.

    3. Early pregnancy IGF-I and placental GH and risk of epithelial ovarian cancer: A nested case-control study

      Helena Schock, Renée T. Fortner, Heljä-Marja Surcel, Kjell Grankvist, Eero Pukkala, Matti Lehtinen and Eva Lundin

      Article first published online: 17 DEC 2014 | DOI: 10.1002/ijc.29387

      What's new?

      Childbirth provides protective benefits against epithelial ovarian cancer (EOC), possibly through an association with changes in levels of insulin-like growth factor-I (IGF-I) or growth hormone (GH). In this study, circulating pre-diagnostic IGF-I concentrations and placental GH were evaluated in pregnant women. A limited protective association was observed between increased early pregnancy IGF-I levels and overall risk of EOC and invasive tumors. No association was detected for placental GH and EOC risk. The findings suggest that IGF-1 levels during pregnancy may be related to subsequent EOC risk, though additional studies are needed in non-pregnant women of comparable age.

  32. Carcinogenesis

    1. Chemotherapy of WAP-T mouse mammary carcinomas aggravates tumor phenotype and enhances tumor cell dissemination

      Katharina Jannasch, Florian Wegwitz, Eva Lenfert, Claudia Maenz, Wolfgang Deppert and Frauke Alves

      Article first published online: 16 DEC 2014 | DOI: 10.1002/ijc.29369

      What's new?

      Despite their prognostic value in breast cancer, disseminated tumor cells (DTCs) aren't usually monitored when treatments are evaluated. In this study, the authors developed a mouse model for analyzing the effects of chemotherapy on the growth, recurrence, and dissemination of mammary tumors in vivo. They found that tumors exposed to chemotherapy often develop a more aggressive phenotype, that tumor cells with a mesenchymal phenotype often survive exposure, and that recurrence is associated with increased DTCs. Their results also indicate that neoadjuvant chemotherapy should be carefully considered.

  33. Cancer Therapy

    1. Effects of resistance exercise on fatigue and quality of life in breast cancer patients undergoing adjuvant chemotherapy: A randomized controlled trial

      Martina E. Schmidt, Joachim Wiskemann, Petra Armbrust, Andreas Schneeweiss, Cornelia M. Ulrich and Karen Steindorf

      Article first published online: 16 DEC 2014 | DOI: 10.1002/ijc.29383

      What's new?

      For cancer patients, exercise can help fight fatigue and improve quality of life, but whether those benefits stem more from physiological adaptations or psychosocial factors is unclear. Likewise, chemotherapy is a significant source of fatigue, but little is known about the effects of exercise during courses of treatment. In the case of breast cancer, the present study suggests that resistance exercise performed over the course of adjuvant chemotherapy can mitigate physical fatigue and lead to gains in quality of life. The benefits of resistance exercise exceeded those associated with the psychosocial effects provided by a supervised, group-based muscle-relaxation program.

  34. Epidemiology

    1. An evaluation and replication of miRNAs with disease stage and colorectal cancer-specific mortality

      Martha L. Slattery, Jennifer S. Herrick, Lila E. Mullany, Nicola Valeri, John Stevens, Bette J. Caan, Wade Samowitz and Roger K. Wolff

      Article first published online: 16 DEC 2014 | DOI: 10.1002/ijc.29384

      What's new?

      MicroRNAs (miRNAs) are promising prognostic biomarkers in colorectal cancer, but more work is needed to identify clinically meaningful stage- and survival-specific associations. The present study attempted to identify those associations for 121 miRNAs using population-based data for more than 1,140 colorectal cancer patients. Microarray and statistical analyses uncovered five miRNAs associated specifically with more advanced colorectal cancer. Another 25 miRNAs were linked to mortality for either colon cancer or rectal cancer. The large number of patients and the incorporation of data on tumor molecular phenotype facilitated the detection of associations for miRNAs infrequently expressed in the study population.

  35. Infectious Causes of Cancer

    1. Resistance to UV-induced apoptosis by β-HPV5 E6 involves targeting of activated BAK for proteolysis by recruitment of the HERC1 ubiquitin ligase

      Amy Holloway, Mark Simmonds, Abul Azad, Joanna L. Fox and Alan Storey

      Article first published online: 15 DEC 2014 | DOI: 10.1002/ijc.29350

      What's new?

      Cutaneous human papillomavirus (HPV) infection may act in concert with UV radiation exposure to fuel the early progression of non-melanoma skin cancer. The molecular mechanism underlying that interaction has been elusive but may involve the E3 ubiquitin ligase HERC1, according to the present study. HERC1 was discovered to associate with the E6 protein of cutaneous HPV5. E6 prevents UV-induced apoptosis by signaling for degradation of the pro-apoptotic protein BAK. The authors show that E6 targets only activated BAK for proteolysis and requires HERC1 to carry out degradation signaling.

  36. Cancer Cell Biology

    1. Interleukin-34 promotes tumor progression and metastatic process in osteosarcoma through induction of angiogenesis and macrophage recruitment

      Aude I. Ségaliny, Amel Mohamadi, Blandine Dizier, Anna Lokajczyk, Régis Brion, Rachel Lanel, Jérôme Amiaud, Céline Charrier, Catherine Boisson-Vidal and Dominique Heymann

      Article first published online: 13 DEC 2014 | DOI: 10.1002/ijc.29376

      What's new?

      The newly discovered cytokine IL-34 shares a common receptor with macrophage-colony stimulating factor (M-CSF) and is involved in the regulation of myeloid cell growth, differentiation, and survival. The present study suggests that it may have a role in osteosarcoma. In vitro and in vivo experiments indicate that IL-34 expression is regulated by TNF-α and IL-1β and that its overexpression is associated with an increase in osteosarcoma growth and metastasis. IL-34 was further found to be pro-angiogenic and to promote M2 macrophage recruitment into tumors.

    2. Paracrine regulation of glioma cells invasion by astrocytes is mediated by glial-derived neurotrophic factor

      Ayelet Shabtay-Orbach, Moran Amit, Yoav Binenbaum, Shorook Na'ara and Ziv Gil

      Article first published online: 13 DEC 2014 | DOI: 10.1002/ijc.29380

      What's new?

      Glioblastomas arise in astrocytes, the cells that support the brain, but reproduce quickly and spread to the brain itself. How do astrocytes promote this invasiveness? These authors tested the role of the signaling molecule GDNF in spurring cancer growth. They found that in an astrocyte-rich environment, cultured glioma cells migrated more than usual – but this mobility boost vanished when they prevented GDNF from binding to its receptor, RET. In mice with gliomas, blocking RET slowed the growth of the tumors considerably. This demonstrates for the first time that astrocytes promote tumor invasion via GDNF and RET, and could suggest new treatment avenues.

    3. You have full text access to this OnlineOpen article
      HPV16 E5 expression induces switching from FGFR2b to FGFR2c and epithelial-mesenchymal transition

      Danilo Ranieri, Francesca Belleudi, Alessandra Magenta and Maria Rosaria Torrisi

      Article first published online: 13 DEC 2014 | DOI: 10.1002/ijc.29373

      What's new?

      Of the fibroblast growth factor receptor (FGFR) pathways implicated in cancer, those involving the epithelial isoform FGFR2b, which is potentially tumor suppressive, and the mesenchymal isoform FGFR2c, which is potentially oncogenic, are of special interest. This study shows that a splicing switch from FGFR2b to FGFR2c occurs in the presence of the E5 oncoprotein of human papillomavirus (HPV) type 16, which downregulates FGFR2b. The switch leads to alterations in ligand specificity and cellular response, which appear to be associated with epithelial-mesenchymal transition. The findings suggest that this switching drives HPV-associated cervical transformation and tumor progression.

  37. Epidemiology

    1. The effects of population-based mammography screening starting between age 40 and 50 in the presence of adjuvant systemic therapy

      Rianne de Gelder, Eveline A.M. Heijnsdijk, Jacques Fracheboud, Gerrit Draisma and Harry J. de Koning

      Article first published online: 13 DEC 2014 | DOI: 10.1002/ijc.29364

      What's new?

      Studies conducted in the 1980's found that mammography screening could reduce breast-cancer mortality by 20%. Although treatment modalities have changed significantly, that percentage is still used today. In this study, the authors assessed the impact of adjuvant systemic therapy on mortality compared with the impact of screening. They found that therapy and screening reduced mortality by similar amounts. These results may help clinicians and policy makers better interpret earlier screening trials and balance those results with the impact of current therapies.

  38. Mini Reviews

    1. Generation of MHC class I diversity in primary tumors and selection of the malignant phenotype

      Federico Garrido, Irene Romero, Natalia Aptsiauri and Angel M. Garcia-Lora

      Article first published online: 13 DEC 2014 | DOI: 10.1002/ijc.29375

  39. Cancer Therapy

    1. Adjuvant chemotherapy in rectal cancer: Defining subgroups who may benefit after neoadjuvant chemoradiation and resection: A pooled analysis of 3,313 patients

      Monique Maas, Patty J Nelemans, Vincenzo Valentini, Christopher H. Crane, Carlo Capirci, Claus Rödel, Garrett M. Nash, Li-Jen Kuo, Rob Glynne-Jones, Julio García-Aguilar, Javier Suárez, Felipe A. Calvo, Salvatore Pucciarelli, Sebastiano Biondo, George Theodoropoulos, Doenja M.J. Lambregts, Regina G.H. Beets-Tan and Geerard L. Beets

      Article first published online: 13 DEC 2014 | DOI: 10.1002/ijc.29355

      What's new?

      Most patients with locally advanced rectal cancer receive adjuvant chemotherapy after neoadjuvant treatment and surgery. Based on a pooled analysis of individual patient data from 13 datasets, this study however shows that the benefit of adjuvant chemotherapy differs between subgroups, based on the response of patients to previous neoadjuvant chemoradiation. Patients with a complete response after chemoradiation may not benefit from adjuvant chemotherapy, whereas patients with residual tumour have superior outcomes when adjuvant chemotherapy was administered. The results support further investigation of a more individualized approach based on pathologic staging for the administration of adjuvant chemotherapy after chemoradiation and surgery.

  40. Epidemiology

    1. You have full text access to this OnlineOpen article
      25-Hydroxyvitamin D2/D3 levels and factors associated with systemic inflammation and melanoma survival in the Leeds Melanoma Cohort

      Julia A. Newton-Bishop, John R. Davies, Faheem Latheef, Juliette Randerson-Moor, May Chan, Jo Gascoyne, Saila Waseem, Susan Haynes, Charles O'Donovan and D. Timothy Bishop

      Article first published online: 13 DEC 2014 | DOI: 10.1002/ijc.29334

      What's new?

      Vitamin D is known to affect immune function and suppress inflammation. In this study, the authors found that lower vitamin D levels at diagnosis and a history of smoking are both associated with a higher incidence of ulceration of primary melanoma, as well as with decreased survival. While a causal link hasn't yet been proven, the authors conclude that it would be prudent to suggest that melanoma patients should stop smoking, and that vitamin D depletion should be avoided.

  41. Cancer Genetics

    1. You have full text access to this OnlineOpen article
      Ribose-5-phosphate isomerase A regulates hepatocarcinogenesis via PP2A and ERK signaling

      Shih-Ci Ciou, Yu-Ting Chou, Yu-Ling Liu, Yu-Chin Nieh, Jeng-Wei Lu, Shiu-Feng Huang, Yu-Ting Chou, Li-Hao Cheng, Jeng-Fan Lo, Ming-Jen Chen, Ming-Chi Yang, Chiou-Hwa Yuh and Horng-Dar Wang

      Article first published online: 12 DEC 2014 | DOI: 10.1002/ijc.29361

      What's New?

      The non-oxidative pentose phosphate pathway is known to be involved in tumorigenesis, being recruited by tumor cells to generate ribose-5-phosphate for increased nucleotide synthesis. The role of ribose-5-phosphate isomerase A (RPIA) in human hepatocellular carcinoma (HCC), however, remains unknown. Here, the authors demonstrate that RPIA expression plays a role in HCC and correlates with several clinical indicators of tumor pathology. Additionally, RPIA acts as an oncogene by modulating PP2A and ERK signaling and was shown to regulate tumor growth in nude mice. The findings shed new light on RPIA as a potential biomarker and target for liver cancer therapy.

  42. Tumor Immunology

    1. CD20 alternative splicing isoform generates immunogenic CD4 helper T epitopes

      Charline Vauchy, Clementine Gamonet, Christophe Ferrand, Etienne Daguindau, Jeanne Galaine, Laurent Beziaud, Adrien Chauchet, Carole J. Henry Dunand, Marina Deschamps, Pierre Simon Rohrlich, Christophe Borg, Olivier Adotevi and Yann Godet

      Article first published online: 12 DEC 2014 | DOI: 10.1002/ijc.29366

      What's New?

      Cancer-specific splice variants are generating interest as they may potentially be used as biomarkers and generate novel targets for therapy. Here, the authors investigate whether an alternative transcript of the B cell lineage membrane receptor CD20 could generate epitopes that are recognized by T lymphocytes and eligible as new targets for immunotherapy. They show that D393-CD20 generates promiscuous HLA-DR epitopes recognized by CD4 T cells, and that naturally occurring D393-CD20-specific T cells are present in B cell lymphoma patients. The findings support further studies on the modulation of D393-CD20-specific T cell response by Rituximab and the development of D393-CD20-specific immunotherapies.

  43. Epidemiology

    1. Safety profile of combined therapy inhibiting EFGR and VEGF pathways in patients with advanced non-small-cell lung cancer: A meta-analysis of 15 phase II/III randomized trials

      Wang Ma, Mingxin Xu, Yiqian Liu, Hao Liu, Jiale Huang, Yanjie Zhu, Li-juan Ji and Xiaolong Qi

      Article first published online: 12 DEC 2014 | DOI: 10.1002/ijc.29377

      What's new?

      Combination therapies can reduce drug resistance and improve efficacy. However, the benefits should be weighed against the disadvantages. In this meta-analysis of studies on non-small-cell lung cancer (NSCLC), the authors found that patients who were treated with inhibitors of both EGFR and VEGF suffered more adverse events and more treatment-related deaths than those treated with a single inhibitor, without any significant increase in survival. Combining these targeted therapies thus appears to offer little benefit in NSCLC, while increasing toxicity and reducing quality of life.

    2. Long-term risk of cervical intraepithelial neoplasia grade 3 or worse according to high-risk human papillomavirus genotype and semi-quantitative viral load among 33,288 women with normal cervical cytology

      Louise T. Thomsen, Kirsten Frederiksen, Christian Munk, Jette Junge, Thomas Iftner and Susanne K. Kjaer

      Article first published online: 12 DEC 2014 | DOI: 10.1002/ijc.29374

      What's new?

      Several subtypes of human papillomavirus (HPV) are known to significantly increase the risk of cervical cancer. In this study, the authors analyzed the risk of developing high-grade cervical neoplasias in women who had normal cytology at screening. Subtype HPV16 was associated with the highest absolute risk, followed by HPV18, HPV31 and HPV33. High concentrations of HPV16 at screening further increased the risk. These findings support the use of HPV genotyping during cervical cancer screening.

  44. Cancer Cell Biology

    1. CD146 mediates VEGF-induced melanoma cell extravasation through FAK activation

      Nathalie Jouve, Richard Bachelier, Nicolas Despoix, Muriel G. Blin, Maryam Khalili Matinzadeh, Stéphane Poitevin, Michel Aurrand-Lions, Karim Fallague, Nathalie Bardin, Marcel Blot-Chabaud, Frédéric Vely, Françoise Dignat-George and Aurélie S. Leroyer

      Article first published online: 11 DEC 2014 | DOI: 10.1002/ijc.29370

      What's new?

      To win the fight against metastatic melanoma—one of the most drug-resistant cancers—novel therapeutic targets must be identified. A promising candidate is melanoma cell adhesion molecule (MCAM), or CD146, which is present at both endothelial junctions and tumor-endothelial contact sites, making it well-positioned to modulate melanoma extravasation. In the present study, CD146-deficient mice are shown to experience prolonged survival during melanoma metastasis. Evaluation of signaling molecules downstream of CD146 suggests that the VEGF/CD146/FAK/Ve-cadherin network plays a key role in mediating the hematogenous spread of melanoma to the lungs.

  45. Cancer Therapy

    1. Identification of AREG and PLK1 pathway modulation as a potential key of the response of intracranial 9L tumor to microbeam radiation therapy

      Audrey Bouchet, Nathalie Sakakini, Michèle El Atifi, Céline Le Clec'h, Elke Bräuer-Krisch, Léonid Rogalev, Jean Albert Laissue, Pascal Rihet, Géraldine Le Duc and Laurent Pelletier

      Article first published online: 11 DEC 2014 | DOI: 10.1002/ijc.29318

      What's New?

      The unique irradiation geometry of synchrotron microbeam radiation therapy (MRT) allows for the delivery of very high doses of radiation to brain tumors, with limited damage to the surrounding normal tissue. Interestingly, MRT induces a wide spectrum of transcriptomic changes in tumor and normal tissue in the brain. Here, significant transcriptomic modulation was detected for 316 genes in intracranial tumor tissue following MRT. Among those genes, 30 were specific to brain tumors, remaining undetected in normal tissue before and after MRT. Mechanisms associated with changes in those transcripts may augment or limit the effectiveness of MRT.

    2. Radiation sensitivity assay with a panel of patient-derived spheroids of small cell carcinoma of the cervix

      Aya Nakajima, Hiroko Endo, Hiroaki Okuyama, Yumiko Kiyohara, Tadashi Kimura, Shoji Kamiura, Masahiro Hiraoka and Masahiro Inoue

      Article first published online: 11 DEC 2014 | DOI: 10.1002/ijc.29349

      What's new?

      So few women are diagnosed with small cell carcinoma of the uterine cervix (SCCC) that a clear approach to SCCC treatment has yet to be established. A key part of that approach could be radiation therapy, though tumor sensitivity to radiation varies significantly among patients. Here, radiation sensitivity was explored in SCCC cells isolated from six patients via the cancer tissue–originated spheroid (CTOS) method. Irradiation experiments showed variations in radiation sensitivity, both in vitro and in vivo. Elevated levels of HIF-1α were detected in radio-resistant CTOSs within hours of irradiation. With HIF-1α suppression, radiation sensitivity was restored.

  46. Epidemiology

    1. Late psychiatric morbidity in survivors of cancer at a young age: A nationwide registry-based study

      Ritva Ahomäki, Mirja E. Gunn, Laura M. Madanat-Harjuoja, Jaakko Matomäki, Nea Malila and Päivi M. Lähteenmäki

      Article first published online: 11 DEC 2014 | DOI: 10.1002/ijc.29371

      What's new?

      Can childhood cancer affect your mental health? Researchers in Finland have shown that survivors of childhood and young adult cancers have a higher incidence of psychiatric diagnoses than their cancer-free siblings. Female patients, in particular, showed an increase in psychiatric problems, including organic memory/brain disorders, mood disorders, anxiety/neuroses, eating disorders, and personality disorders. Furthermore, cranial radiation did not account for all of these psychiatric effects; even patients treated with modern chemotherapy showed an elevated incidence, suggesting more research is necessary to determine the impact of chemotherapy on lifelong mental health.

  47. Short Reports

    1. Renal cell carcinomas of chronic kidney disease patients harbor the mutational signature of carcinogenic aristolochic acid

      Bojan Jelaković, Xavier Castells, Karla Tomić, Maude Ardin, Sandra Karanović and Jiri Zavadil

      Article first published online: 10 DEC 2014 | DOI: 10.1002/ijc.29338

      What's new?

      Ingestion of aristolochic acid (AA) causes severe nephropathies and carcinomas of the upper urinary tract, and represents a significant public health problem with millions of people at risk worldwide. In this study of renal disease patients in an endemic region, the authors identified a previously unrecognized type of renal cell carcinoma that harbors the mutational signature of this potent carcinogen. Their findings suggest that the putative causal role of AA in renal cortex carcinogenesis should be broadly addressed in high-risk regions marked by inadvertent exposure to AA or widespread use of AA-containing herbal remedies.

  48. Cancer Cell Biology

    1. Negative modulation of the epigenetic regulator, UHRF1, by thyroid hormone receptors suppresses liver cancer cell growth

      Sheng-Ming Wu, Wan-Li Cheng, Chia-Jung Liao, Hsiang-Cheng Chi, Yang-Hsiang Lin, Yi-Hsin Tseng, Chung-Ying Tsai, Ching-Ying Chen, Syuan-Ling Lin, Wei-Jan Chen, Yung-Hsin Yeh, Chi-Ying F. Huang, Ming-Huang Chen, Yi-Chen Yeh and Kwang-Huei Lin

      Article first published online: 10 DEC 2014 | DOI: 10.1002/ijc.29368

      What's new?

      How does the thyroid hormone T3 regulate liver cancer? Here the author show that T3 together with its receptor negatively regulates the expression of the ubiquitin-like with PHD and ring-finger domains 1 (UHRF1), an epigenetic regulator overexpressed in various cancers. Because UHRF1 is overexpressed in subgroups of patients with liver cancer and thyroid hormone receptor levels are inversely correlated, the authors propose that T3 and its receptor suppress hepatoma cell growth via suppression of UHRF1 expression.

  49. Cancer Genetics

    1. You have full text access to this OnlineOpen article
      Influence of MDM2 SNP309 and SNP285 status on the risk of cancer in the breast, prostate, lung and colon

      Liv B. Gansmo, Stian Knappskog, Pål Romundstad, Kristian Hveem, Lars Vatten and Per E. Lønning

      Article first published online: 10 DEC 2014 | DOI: 10.1002/ijc.29358

      What's new?

      The protein MDM2 grabs on to the tumor suppressor p53, stopping its transcription activity. In this study, the authors investigated two MDM2 polymorphisms. The first, SNP309G, has been linked to increased cancer risk; the more recently identified SNP285C may modulate the effects SNP309G. After screening 7,000 cases and half as many controls, the authors found a tissue-specific effect. They report that SNP285C accompanies reduced breast cancer risk among those carrying two SNP309G alleles. No association of SNP309 allele with colon, breast, or prostate cancer risk could be detected, but they noted an association of SNP309G with reduced lung cancer risk.

  50. Cancer Therapy

    1. Delayed primary excision with subsequent modification of radiotherapy dose for intermediate-risk rhabdomyosarcoma: A report from the Children's Oncology Group Soft Tissue Sarcoma Committee

      David A. Rodeberg, Moody D. Wharam, Elizabeth R. Lyden, Julie A. Stoner, Kenneth Brown, Suzanne L. Wolden, Charles N. Paidas, Sarah S. Donaldson, Douglas S. Hawkins, Sheri L. Spunt and Carola A. Arndt

      Article first published online: 10 DEC 2014 | DOI: 10.1002/ijc.29351

      What's new?

      Over the course of their lives, about half of individuals who survive childhood sarcoma experience one or more adverse outcomes associated with the treatment of their malignancy. As a result, there is significant need for the investigation of less-toxic therapeutic strategies for pediatric cancers. This study shows that among pediatric patients with rhabdomyosarcoma (RMS), dose reduction in radiotherapy (RT) is feasible following delayed primary excision (DPE), with RT dosage determined by completeness of resection. Local control outcomes with RT dose reduction following DPE were comparable to those reported for a similar population of RMS patients treated with radiotherapy alone.

  51. Early Detection and Diagnosis

    1. Screening outcome and surgical treatment during and after the transition from screen-film to digital screening mammography in the south of The Netherlands

      Roy J.P. Weber, Joost Nederend, Adri C. Voogd, Luc J. Strobbe and Lucien E.M. Duijm

      Article first published online: 10 DEC 2014 | DOI: 10.1002/ijc.29354

      What's new?

      Full-field digital mammography (FFDM) allows for the optimization of imaging workflow and increased contrast resolution. But whether it is superior to screen-film mammography (SFM) for the detection of breast cancer is unclear. In the present investigation, the transition to digital mammography was associated with increased breast cancer detection and referral rates. Compared to SFM, FFDM resulted in greater detection of intermediate-grade ductal carcinoma in situ and smaller-sized invasive cancers. An increase in breast conserving surgery rate was also observed with FFDM. Increases in detection were accompanied by a decline in positive predictive value of referral.

  52. Short Reports

    1. A prospective study of alcohol consumption and renal cell carcinoma risk

      Sara Karami, Sarah E. Daugherty and Mark P. Purdue

      Article first published online: 10 DEC 2014 | DOI: 10.1002/ijc.29359

      What's new?

      For multiple cancers, increasing alcohol intake is associated with increasing risk, but in the case of renal cell carcinoma (RCC), the inverse may be true. The present study analyzed alcohol intake and RCC risk, taking into account various factors, including sex, smoking status, and beverage type. RCC risk was reduced markedly in association with increasing alcohol consumption, for both men and women and regardless of beverage type. Analyses of smoking status uncovered a possible interaction between RCC risk, alcohol intake, and smoking. Additional studies are needed to understand the mechanism behind the association between alcohol intake and RCC risk.

  53. Epidemiology

    1. Genetic variants of adiponectin and risk of colorectal cancer

      Mingyang Song, Jian Gong, Edward L. Giovannucci, Sonja I. Berndt, Hermann Brenner, Jenny Chang-Claude, Keith R. Curtis, Tabitha A. Harrison, Michael Hoffmeister, Li Hsu, Shuo Jiao, Loic Le Marchand, John D. Potter, Robert E. Schoen, Daniela Seminara, Martha L. Slattery, Emily White, Kana Wu, Shuji Ogino, Charles S. Fuchs, David J. Hunter, Shelley S. Tworoger, Frank B. Hu, Eric Rimm, Majken Jensen, Ulrike Peters and Andrew T. Chan

      Article first published online: 8 DEC 2014 | DOI: 10.1002/ijc.29360

      What's new?

      Obesity is a well-established risk factor for colorectal cancer, and mounting evidence suggests that the adipocyte-derived hormone adiponectin is behind that link. In the present investigation, common genetic variants in the adiponectin (ADIPOQ) gene were analyzed for potential relationships with colorectal cancer risk. However, no statistically significant associations were identified. Because common genetic determinants account for only a limited proportion of the variance in circulating adiponectin concentrations, factors that influence adiponectin receptors and other components of the adiponectin pathway should be investigated.

  54. Cancer Therapy

    1. Sphingosine kinase 1 as a potential therapeutic target in epithelial ovarian cancer

      Jeong-Won Lee, Ji-Yoon Ryu, Gun Yoon, Hye-Kyung Jeon, Young-Jae Cho, Jung-Joo Choi, Sang Yong Song, In-Gu Do, Yoo-Young Lee, Tae-Joong Kim, Chel Hun Choi, Byoung-Gie Kim and Duk-Soo Bae

      Article first published online: 8 DEC 2014 | DOI: 10.1002/ijc.29362

      What's new?

      The products of sphingolipid metabolism regulate a variety of intracellular processes, and when altered, as in the case of sphingosine kinase 1 (SK1) overexpression, those products may contribute to cancer. The present study examined the effects of SK1 inhibition in epithelial ovarian carcinoma (EOC). In EOC cell lines, SK1 inhibition with the agent FTY720 significantly reduced angiogenesis, invasion, and proliferation and increased apoptosis. Administration of FTY720 in xenograft models of ovarian cancer cell lines and patient-derived tumors yielded reductions in tumor weight. The results suggest that SK1 targeting is a potential therapeutic strategy in ovarian cancer.

  55. Short Reports

    1. PKC/MEK inhibitors suppress oxaliplatin-induced neuropathy and potentiate the antitumor effects

      Masanobu Tsubaki, Tomoya Takeda, Tadahumi Tani, Hirotaka Shimaoka, Naohiro Suzuyama, Kotaro Sakamoto, Arisa Fujita, Naoki Ogawa, Tatsuki Itoh, Motohiro Imano, Yoshinori Funakami, Seiji Ichida, Takao Satou and Shozo Nishida

      Article first published online: 8 DEC 2014 | DOI: 10.1002/ijc.29367

      What's new?

      Oxaliplatin is a key component in adjuvant and palliative therapy for colorectal cancer, but its use is limited by the development of neuropathy, which typically is unresponsive to treatment. Following on previous work in which protein kinase C (PKC) activation was implicated in oxaliplatin-induced neuropathy, the present report suggests that PKC and MEK inhibitors may be able to block the neuropathic side effects. Inhibition was effected in the lumbar spinal cords of mice, via the PKC/ERK/c-Fos pathway. PKC and MEK inhibitors were also found to act synergistically to potentiate the tumor suppressive effects of oxaliplatin.

  56. Epidemiology

    1. Nitrate and nitrite ingestion and risk of ovarian cancer among postmenopausal women in Iowa

      Maki Inoue-Choi, Rena R. Jones, Kristin E. Anderson, Kenneth P. Cantor, James R. Cerhan, Stuart Krasner, Kim Robien, Peter J. Weyer and Mary H. Ward

      Article first published online: 8 DEC 2014 | DOI: 10.1002/ijc.29365

      What's new?

      While environmental factors such as diet are thought to have a role in ovarian cancer, few such factors have been identified. In the present study, the ingestion of nitrate and nitrite was investigated for possible involvement in ovarian cancer. Among postmenopausal women, risk of ovarian cancer was found to be positively associated with elevated nitrate levels in public drinking water supplies and with nitrite intake from processed meats. Elevated nitrate levels in private well water was linked to increased ovarian cancer risk among women with reduced vitamin C intake.

  57. Early Detection and Diagnosis

    1. Cervical cancer screening in sub-Saharan Africa: A randomized trial of VIA versus cytology for triage of HPV-positive women

      Jérôme Bigoni, Mélissa Gundar, Pierre-Marie Tebeu, Adamo Bongoe, Sonja Schäfer, Joël Fokom-Domgue, Rosa Catarino, Evelyne Foguem Tincho, Stéphanie Bougel, Pierre Vassilakos and Patrick Petignat

      Article first published online: 5 DEC 2014 | DOI: 10.1002/ijc.29353

      What's new?

      In developing countries, cervical cancer is a leading cause of cancer death among women, but better screening programs could curtail mortality. Visual inspection with acetic acid (VIA) is an attractive option for use in low-resource areas, because it is easy to administer and inexpensive. However, it is highly subjective, relying on experienced personnel for interpretation. This study compared the sensitivity and specificity of VIA with cytology in HPV+ women in Cameroon. The authors found that cytology significantly outperformed VIA at detecting precancerous lesions, suggesting more work is necessary to develop an efficient screening strategy for low-resource areas.

  58. Cancer Genetics

    1. MUC5AC hypomethylation is a predictor of microsatellite instability independently of clinical factors associated with colorectal cancer

      Florence Renaud, Audrey Vincent, Christophe Mariette, Michel Crépin, Laurence Stechly, Stéphanie Truant, Marie-Christine Copin, Nicole Porchet, Emmanuelle Leteurtre, Isabelle Van Seuningen and Marie-Pierre Buisine

      Article first published online: 4 DEC 2014 | DOI: 10.1002/ijc.29342

      What's new?

      Colorectal cancers (CRC) with microsatellite instability (MSI) display unique clinicopathological features including a mucinous pattern with frequent expression of MUC2 and MUC5AC. The mechanisms underlying such altered pattern of expression, however, remain unclear. This is the first study investigating the methylation profile of mucin genes in different CRC subgroups. It shows that MUC2 and MUC5AC expression in CRC is partially regulated by DNA methylation, and that such MUC5AC regulation is specific for MSI tumors. MUC5AC hypomethylation is a strong predictor of MSI in CRC independently of other clinicopathological characteristics and may serve as a specific marker of the serrated pathway.

  59. Cancer Cell Biology

    1. Inhibitors of BCR signalling interrupt the survival signal mediated by the micro-environment in mantle cell lymphoma

      Sophie Bernard, Damien Danglade, Laura Gardano, Christelle Laguillier, Gregory Lazarian, Claudine Roger, Catherine Thieblemont, Jacek Marzec, John Gribben, Florence Cymbalista, Nadine Varin-Blank, Dominique Ledoux and Fanny Baran-Marszak

      Article first published online: 3 DEC 2014 | DOI: 10.1002/ijc.29326

      What's new?

      While there is evidence that Mantle Cell Lymphoma (MCL) cells rely on B-cell receptor (BCR)-mediated signalling pathways for their survival, the nature of such activation remains unknown. Significant progress in MCL treatment was nonetheless achieved through therapies targeting BCR-associated kinases such as Ibrutinib and Fostamatinib. Here, the authors showed that the inhibition of SYK by Fostamatinib or BTK by Ibrutinib altered BCR-induced secretion of IL1β, IL6, IL8, VEGFα, TNFα, and CCL5. These effectors could mediate survival of MCL cells through their homing and adhesion to bone marrow stromal cells. Moreover, Fostamatinib and Ibrutinib impaired NF-κB-dependent STAT3 activation, leading to apoptosis.

  60. Cancer Genetics

    1. You have full text access to this OnlineOpen article
      Comprehensive characterization of the genomic alterations in human gastric cancer

      Juan Cui, Yanbin Yin, Qin Ma, Guoqing Wang, Victor Olman, Yu Zhang, Wen-Chi Chou, Celine S. Hong, Chi Zhang, Sha Cao, Xizeng Mao, Ying Li, Steve Qin, Shaying Zhao, Jing Jiang, Phil Hastings, Fan Li and Ying Xu

      Article first published online: 3 DEC 2014 | DOI: 10.1002/ijc.29352

      What's new?

      Gastric cancer is the second leading cause of cancer deaths world-wide. Here, the authors performed whole-genome sequencing on five gastric adenocarcinomas and adjacent noncancerous tissue. More than 100,000 somatic point mutations were identified, the most recurrent ones located in genes encoding for mucins and transcription factors. The authors also report numerous genomic rearrangements including potential insertion of H. pylori, a bacterium associated with gastric cancerogenesis, into the tumor genome. These findings form the basis for interesting new hypotheses to be tested in future experiments.

  61. Cancer Therapy

    1. Serum microRNA profiles as prognostic/predictive markers in the multimodality therapy of locally advanced adenocarcinomas of the gastroesophageal junction

      Margarete Odenthal, Julia Hee, Ines Gockel, Leila Sisic, Jolly Schmitz, Nikolas H. Stoecklein, Christiane Driemel, Birte Möhlendick, Thomas Schmidt, Wolfram T. Knoefel, Hauke Lang, Reinhard Büttner, Katja Ott and Daniel Vallböhmer

      Article first published online: 3 DEC 2014 | DOI: 10.1002/ijc.29363

      What's New?

      Advanced esophageal cancer is increasingly treated through combinations of therapeutic approaches, including neoadjuvant therapies. But only certain subsets of patients benefit from multimodal strategies, which has created a need for tools capable of predicting patient response. Potential, non-invasive predictive markers include miRNAs. From microarray analyses, the authors of the present study were able to identify differential serum miRNA profiles among patients with advanced esophageal adenocarcinoma who received neoadjuvant therapy. Of six miRNAs selected for validation, two were found to be of potential prognostic significance. The findings warrant further investigation of the markers in studies with larger patient populations.

  62. Early Detection and Diagnosis

    1. Development of new non-invasive tests for colorectal cancer screening: The relevance of information on adenoma detection

      Ulrike Haug, Amy B. Knudsen, Iris Lansdorp-Vogelaar and Karen M. Kuntz

      Article first published online: 3 DEC 2014 | DOI: 10.1002/ijc.29343

      What's new?

      The development of new non-invasive tests (NITs) for colorectal cancer (CRC) screening has centered primarily on improving the detection of invasive disease. But according to this study, whether new NITs are viable alternatives to immunochemical fecal occult blood tests—already established screening tests for CRC–depends also on their ability to detect adenomas, the precursor lesions of CRC. Without that ability, immunochemical fecal occult blood tests retain their superiority over newer NITs, many of which attempt to detect biomarkers in stool or blood. The identification of adenoma-specific markers could be critical to the advance of NITs for CRC screening.

    2. Downstaging cancer in rural Africa

      Twalib Ngoma, John Mandeli and James F. Holland

      Article first published online: 3 DEC 2014 | DOI: 10.1002/ijc.29348

      What's new?

      High cancer mortality in Africa is associated with an array of factors, including deficiencies in public education and health resources, which are likely to persist for decades to come. In the interest of effecting cancer control quickly and by economically practicable means, the authors of the present investigation in Tanzania compared routine self-referral against proactive visitation by health aides trained in the identification of suspected lesions. Significant improvement toward earlier cancer diagnosis was observed in the village where proactive visitation was implemented. Proactive referral could significantly improve the effectiveness of therapy, leading to reductions in cancer mortality in Africa.

  63. Epidemiology

    1. Nonsteroidal anti-inflammatory drugs and the risk of nonmelanoma skin cancer

      Daphne Reinau, Christian Surber, Susan S. Jick and Christoph R. Meier

      Article first published online: 3 DEC 2014 | DOI: 10.1002/ijc.29357

      What's new?

      Nonsteroidal anti-inflammatory drugs (NSAIDs) could help prevent nonmelanoma skin cancer (NMSC). However, epidemiological data on the relationship between the use of systemic NSAIDs and NMSC are limited. Here, drawing on records in the Clinical Practice Research Datalink for more than 70,000 case patients in the UK, regular NSAID exposure is shown to moderately reduce NMSC risk, particularly in the case of cutaneous SCC. The findings provide additional evidence that patients predisposed to NMSC might benefit from chemoprevention with NSAIDs.

  64. Cancer Cell Biology

    1. Effects of altered expression and activity levels of CK1δ and ɛ on tumor growth and survival of colorectal cancer patients

      Julia Richter, Kalim Ullah, Pengfei Xu, Vanessa Alscher, Annette Blatz, Christian Peifer, Jakob Halekotte, Johann Leban, Daniel Vitt, Karlheinz Holzmann, Vasiliy Bakulev, Lorenzo A. Pinna, Doris Henne-Bruns, Andreas Hillenbrand, Marko Kornmann, Frank Leithäuser, Joachim Bischof and Uwe Knippschild

      Article first published online: 1 DEC 2014 | DOI: 10.1002/ijc.29346

      What's new?

      Mutations and alterations in the expression and activity of CK1 isoforms--which play important roles in many cellular processes--are known to contribute to tumorigenesis and tumor progression. The authors show that expression of CK1ɛ correlates with the survival of colorectal cancer patients. Furthermore, they identify CK1δ mutations leading to altered kinetic parameters in vitro and, when introduced into a carcinoma cell line, altered tumor growth in vivo. Since the mutant with high oncogenic potential also displays greater sensitivity to CK1-specific inhibitors, the findings underline the potential use of CK1-specific inhibitors in the treatment of colorectal cancer and personalized medicine.

  65. Early Detection and Diagnosis

    1. You have full text access to this OnlineOpen article
      Human papillomavirus testing 2007–2012: Co-testing and triage utilization and impact on subsequent clinical management

      Jack Cuzick, Orrin Myers, William C. Hunt, Debbie Saslow, Philip E. Castle, Walter Kinney, Alan Waxman, Michael Robertson, Cosette M. Wheeler and on behalf of the New Mexico HPV Pap Registry Steering Committee

      Article first published online: 1 DEC 2014 | DOI: 10.1002/ijc.29337

      What's new?

      Concurrent testing (co-testing) for cytology and human papillomavirus (HPV) has been recommended for primary cervical-cancer screening since 2002. In this study, the authors found that, although co-testing more than tripled between 2007 and 2012, it still occurs in fewer than 20% of women. On the other hand, 82% of women with ASC-US cytology were then tested for HPV. The registry used in this study (the New Mexico HPV Pap Registry) provides a model for evaluating cervical screening and follow-up outcomes and potentially the model can be translated to other cancers.

  66. Epidemiology

    1. Hyperglycemia and chronic liver diseases on risk of hepatocellular carcinoma in Chinese patients with type 2 diabetes––National cohort of Taiwan Diabetes Study

      Chia-Ing Li, Hsuan-Ju Chen, Hsueh-Chou Lai, Chiu-Shong Liu, Wen-Yuan Lin, Tsai-Chung Li and Cheng-Chieh Lin

      Article first published online: 1 DEC 2014 | DOI: 10.1002/ijc.29321

      What's new?

      This is the first study to examine whether glucose control as measured with HbA1c level and chronic liver diseases are associated with hepatocellular carcinoma (HCC) in Chinese type-2 diabetic patients. A positive association was found between HbA1c level and HCC risk, with a level of HbA1c ≥ 9% being a predictor of HCC risk. Furthermore, the level of HbA1c ≥ 9% and chronic liver diseases were significantly jointly associated with HCC risk. HCC incidence is rapidly increasing worldwide, and lifestyle or treatment interventions to maintain a satisfactory control over glycemia and chronic liver diseases may reduce the burden of HCC.

  67. Mini Reviews

    1. Role of CXCL12 and CXCR4 in normal cerebellar development and medulloblastoma

      Patricia Midori Murobushi Ozawa, Carolina Batista Ariza, Cintya Mayumi Ishibashi, Thiago Cezar Fujita, Bruna Karina Banin-Hirata, Julie Massayo Maeda Oda and Maria Angelica Ehara Watanabe

      Article first published online: 1 DEC 2014 | DOI: 10.1002/ijc.29333

  68. Mini Review

  69. Infectious Causes of Cancer

    1. You have full text access to this OnlineOpen article
      Trends in Kaposi's sarcoma-associated Herpesvirus antibodies prior to the development of HIV-associated Kaposi's sarcoma: A nested case-control study

      Katie Wakeham, W. Thomas Johnston, Angela Nalwoga, Emily L. Webb, Billy N. Mayanja, Wendell Miley, Alison M. Elliott, Denise Whitby and Robert Newton

      Article first published online: 28 NOV 2014 | DOI: 10.1002/ijc.29329

      What's New?

      Infection with Kaposi sarcoma associated-herpesvirus (KSHV) and HIV, the major risk factor for Kaposi sarcoma, is common in sub-Saharan Africa. However, little is known about the evolution of KSHV antibody responses in HIV-infected individuals prior to the clinical onset of KS. This study shows that antibody titres against KSHV antigens K8.1 and latency-associated nuclear antigen (LANA) increase significantly in the six years leading up to HIV-associated KS. Titres of K8.1, a lytic antigen, rose more than LANA titres, indicating that the activation of genes in the lytic cycle of viral replication is important in KS development.

  70. Early Detection and Diagnosis

    1. Cell-free RNA content in urine as a possible molecular diagnostic tool for clear cell renal cell carcinoma

      An Zhao, Michel Péoc'h, Michèle Cottier, Christian Genin, Nicolas Mottet and Guorong Li

      Article first published online: 28 NOV 2014 | DOI: 10.1002/ijc.29313

      What's new?

      The detection of cell-free RNA (cf-RNA) in biological fluids raises possibilities for the development of new diagnostic assays for cancer. Such an assay may be applicable particularly for clear cell renal cell carcinoma (ccRCC). In this study, the urinary cf-RNA integrity index in ccRCC patients was found to be significantly reduced compared to control subjects. However, small-sized cf-RNA fragments, including small fragments (98 bp) of VEGF mRNA, were present at increased levels in the urine of cancer patients. Additional investigation is needed to confirm the findings and to define the clinical utility of cf-RNA detection for ccRCC.

  71. Cancer Cell Biology

    1. Phosphorylation of AKT(Ser473) serves as an independent prognostic marker for radiosensitivity in advanced head and neck squamous cell carcinoma

      Christian Freudlsperger, Dominik Horn, Sebastian Weißfuß, Wilko Weichert, Klaus-Josef Weber, Daniel Saure, Sarika Sharma, Gerhard Dyckhoff, Niels Grabe, Peter Plinkert, Jürgen Hoffmann, Kolja Freier and Jochen Hess

      Article first published online: 26 NOV 2014 | DOI: 10.1002/ijc.29328

      What's new?

      Patients with head and neck squamous cell cancers often develop resistance to radiotherapy. To figure out how, these authors investigated AKT phosphorylation in the tumor cells. AKT kinase boosts cell proliferation when it is activated by phosphorylation at two possible sites. Could the location of phosphorylation predict whether the tumor will develop resistance? These results suggest it could. The authors show that patients with more phosphorylation at serine 473 had worse survival; furthermore, they showed that reducing phosphorylation at this site increased cancer cells' vulnerability to irradiation. Phosphorylation at the other site, threonine 308, did not affect survival.

  72. Cancer Therapy

    1. The combination of irreversible EGFR TKIs and SAHA induces apoptosis and autophagy-mediated cell death to overcome acquired resistance in EGFR T790M-mutated lung cancer

      Tae-Gul Lee, Eun-Hui Jeong, Seo Yun Kim, Hye-Ryoun Kim and Cheol Hyeon Kim

      Article first published online: 26 NOV 2014 | DOI: 10.1002/ijc.29320

      What's New?

      One strategy to thwart lung cancer is inhibiting the epidermal growth factor receptor, EGFR. As always, though, some cancer cells develop resistance to this treatment with the help of a mutation, T790M, in the EGFR kinase domain. In this paper, the authors describe a new way to overcome that acquired resistance. Combining next-generation EGFR inhibitors with SAHA, a histone deacetylase inhibitor, boosted cancer cell death by both apoptosis and autophagy; furthermore, the combined treatment slowed tumor growth in xenograft model better than EGFR inhibitors alone.

  73. Carcinogenesis

    1. C/EBPβ promotes angiogenesis through secretion of IL-6, which is inhibited by genistein, in EGFRvIII-positive glioblastoma

      Xujie Liu, Kaiyu Liu, Jiazhen Qin, Limin Hao, Xiaoxia Li, Yinan Liu, Xiaoyan Zhang, Xiuxiu Liu, Peng Li, Shuo Han, Zebin Mao and Li Shen

      Article first published online: 26 NOV 2014 | DOI: 10.1002/ijc.29319

      What's New?

      The purpose of this study was to explore the mechanisms of angiogenic microenvironment formation using EGFRvIII-positive glioblastoma as a model. EGFRvIII is regarded as a poor prognosis marker in gliomas because of its potential to confer enhanced tumorigenicity. Here, the authors confirm that EGFRvIII promotes a more malignant microenvironment in mice, as demonstrated by greater expression of the pro-angiogenic and tumorigenic factor VEGF. C/EBPβ-mediated regulation of IL-6 is indispensable for maintenance of this angiogenic microenvironment. In contrast, the drug genistein inhibits the development of tumor angiogenesis through a mechanism involving CHOP-mediated inhibition of C/EBPβ and the subsequent down-regulation of IL-6.

  74. Epidemiology

    1. Recent cancer survival in Germany: An analysis of common and less common cancers

      Lina Jansen, Felipe A. Castro, Adam Gondos, Agne Krilaviciute, Benjamin Barnes, Andrea Eberle, Katharina Emrich, Stefan Hentschel, Bernd Holleczek, Alexander Katalinic, Hermann Brenner and for the GEKID Cancer Survival Working Group

      Article first published online: 26 NOV 2014 | DOI: 10.1002/ijc.29316

      What's New?

      Population-based cancer registries allow researchers to evaluate current quality and recent trends in cancer care. In this study, the authors assembled a comprehensive overview of relative cancer survival in Germany from 2007 to 2010. They also compared survival rates in Germany with those in the United States, and among various age groups. They found that relative survival has improved recently for most cancers, with multiple myeloma, non-Hodgkin lymphoma, prostate cancer and colorectal cancer showing the greatest improvement.

    2. Inherited variation at MC1R and ASIP and association with melanoma-specific survival

      Nicholas J. Taylor, Anne S. Reiner, Colin B. Begg, Anne E. Cust, Klaus J. Busam, Hoda Anton-Culver, Terence Dwyer, Lynn From, Richard P. Gallagher, Stephen B. Gruber, Stefano Rosso, Kirsten A. White, Roberto Zanetti, Irene Orlow, Nancy E. Thomas, Timothy R. Rebbeck, Marianne Berwick, Peter A. Kanetsky and on behalf of the GEM Study Group

      Article first published online: 26 NOV 2014 | DOI: 10.1002/ijc.29317

      What's new?

      MC1R has important pigmentary biological functions, and inherited variations in the gene are well-known markers of melanoma risk. But whether those variants are also associated with disease survival is unknown. Here, germline variation at MC1R was associated with improved melanoma-specific survival in carriers who lacked a consensus MC1R allele. By contrast, the ASIP TG/TG diplotype, which also is known to be associated with melanoma risk, was linked to a 5-fold increase in hazard of death from melanoma. The findings indicate a complex but influential role for pigmentary genetic loci in melanoma outcomes.

  75. Tumor Immunology

    1. Identification of NY-BR-1-specific CD4+ T cell epitopes using HLA-transgenic mice

      Adriane Gardyan, Wolfram Osen, Inka Zörnig, Lilli Podola, Maria Agarwal, Sebastian Aulmann, Eliana Ruggiero, Manfred Schmidt, Niels Halama, Barbara Leuchs, Christof von Kalle, Philipp Beckhove, Andreas Schneeweiss, Dirk Jäger and Stefan B. Eichmüller

      Article first published online: 26 NOV 2014 | DOI: 10.1002/ijc.29322

      What's New?

      The differentiation antigen NY-BR-1 appears as a suitable target antigen for T cell based immunotherapy approaches against breast cancer. Although antibody titers as well as CD8+ T cell responses specific for NY-BR-1 have been described in breast cancer patients, information about NY-BR-1-specific CD4+ T cell responses is still lacking. This article presents the first NY-BR-1-specific HLA-DRB1*0301– and HLA-DRB1*04-restricted T cell epitopes and provides evidence for their clinical relevance. The paper furthermore demonstrates the suitability of murine HLA-restricted CD4+ T cell lines for the screening of CD4+ T cell epitopes processed in human target cells.

  76. Short Reports

    1. Spatially defined microsatellite analysis reveals extensive genetic mosaicism and clonal complexity in intestinal metaplastic glands

      Yan Guo, Juan Zhou, Ayuan Huang, Jianfang Li, Min Yan, Zhenggang Zhu, Xiaodong Zhao, Jianren Gu, Bingya Liu and Zhifeng Shao

      Article first published online: 26 NOV 2014 | DOI: 10.1002/ijc.29340

      What's new?

      The transformation to intestinal metaplasia (IM) is a critical step toward gastric adenocarcinoma, potentially marking the point of no return, wherein IM tissue cannot be coaxed back to its original state. While well-defined morphologically and clinically, however, the functional significance of that transformation remains uncertain. Here, detailed analysis of microsatellite markers of IM tissue from gastric cancer patients indicates that genomic alterations are prevalent and highly variable in metaplastic tissues. Hence, despite sharing traits with intestinal glands, IM tissues are functionally distinct and may provide the random and accelerated mutation background that is necessary for malignant progression.

  77. Cancer Cell Biology

    1. Wnt-3a-activated human fibroblasts promote human keratinocyte proliferation and matrix destruction

      Katrin Sobel, Marius Tham, Hans-Jürgen Stark, Hermann Stammer, Silke Prätzel-Wunder, Jackie R Bickenbach and Petra Boukamp

      Article first published online: 26 NOV 2014 | DOI: 10.1002/ijc.29336

      What's new?

      The Wnt signaling pathway plays a role in many cancers. The central player in this pathway is beta-catenin; when this protein is knocked out, tumors wither and cancer stem cells disappear. In this study, the authors found beta-catenin hanging out in the stromal fibroblasts of a quarter of skin carcinomas. The authors further showed that an active Wnt pathway in the fibroblasts would turn on various growth-promoting elements, including chemokines IL-8 and CCL-2, and matrix-degrading metalloproteinases. These results suggest that activation of the Wnt pathway in the tumor microenvironment helps spur the growth and spread of skin cancer.

  78. Epidemiology

    1. Solar elastosis and cutaneous melanoma: A site-specific analysis

      Marina Kvaskoff, Nirmala Pandeya, Adèle C. Green, Susan Perry, Catherine Baxter, Marcia B. Davis, Rohan Mortimore, Lorraine Westacott, Dominic Wood, Joe Triscott, Richard Williamson and David C. Whiteman

      Article first published online: 26 NOV 2014 | DOI: 10.1002/ijc.29335

      What's new?

      Cutaneous melanomas are caused by sunlight, but the patterns of sun exposure that lead to disease appear to vary according to host factors and the anatomic location of the melanocytes involved. Using a case-case approach, the authors of the present study explored the predictors of chronic sun damage in skin adjacent to melanomas arising on the trunk (a sun-protected site). They found that such melanomas are associated with sun-sensitive phenotype, history of sunburns, measures of cumulative sun exposure, and numbers of actinic keratoses.

    2. Dietary acrylamide and cancer risk: An updated meta-analysis

      Claudio Pelucchi, Cristina Bosetti, Carlotta Galeone and Carlo La Vecchia

      Article first published online: 26 NOV 2014 | DOI: 10.1002/ijc.29339

      What's new?

      Acrylamide is formed in a variety of foods, and some evidence suggests it may cause cancer. How dangerous is dietary acrylamide? This study collated data from 32 earlier projects evaluating the relationship between acrylamide consumed in foods and cancer risk. Of fourteen cancer sites represented, only kidney cancer showed a possible increase in risk associated with dietary acrylamide. When they narrowed the analysis to people who had never smoked, dietary acrylamide appeared to slightly increase risk of endometrial and ovarian cancer as well.

  79. Cancer Therapy

    1. A comprehensively characterized large panel of head and neck cancer patient-derived xenografts identifies the mTOR inhibitor everolimus as potential new treatment option

      Konrad Klinghammer, Jan-Dirk Raguse, Thomas Plath, Andreas E. Albers, Korinna Joehrens, Andre Zakarneh, Bernadette Brzezicha, Annika Wulf-Goldenberg, Ulrich Keilholz, Jens Hoffmann and Iduna Fichtner

      Article first published online: 26 NOV 2014 | DOI: 10.1002/ijc.29344

      What's new?

      Preclinical drug evaluation in head and neck squamous cell carcinoma (HNSCC) is challenged by the inability of established cell lines to predict clinical impact. It may be possible to overcome that problem with patient-derived xenografts (PDX), which more closely reflect tumor characteristics. Here, a large collection of PDXs were established for HNSCC and tested for therapeutic response. The mTOR inhibitor everolimus was found to be active in a majority of the models. Biomarkers capable of predicting tumor response to everolimus were not identified, though increased expression of RPS6KB1, a member of the mTOR pathway, was common among responders.

  80. Epidemiology

    1. You have full text access to this OnlineOpen article
      Markers of vitamin B6 status and metabolism as predictors of incident cancer: The Hordaland Health Study

      Hui Zuo, Per M. Ueland, Simone J.P.M. Eussen, Grethe S. Tell, Stein E. Vollset, Ottar Nygård, Øivind Midttun, Klaus Meyer and Arve Ulvik

      Article first published online: 26 NOV 2014 | DOI: 10.1002/ijc.29345

      What's new?

      Vitamin B6 status is reflected in the measure of its active form, pyridoxal 5'-phosphate (PLP). Studies disagree, however, as to whether or not PLP measures are meaningful in relation to cancer risk, which has necessitated a search for additional markers of vitamin B6 status. In this study, inflammation-related changes in vitamin B6 catabolism were captured effectively by a novel marker, the 4-pyridoxic acid (PA) /(pyridoxal (PL) + PLP) ratio (PAr). Analyses based on the detection of PAr suggest that increased vitamin B6 metabolism and disposal are linked to increased cancer risk, particularly for lung cancer.

  81. Cancer Cell Biology

    1. MiR-34a deficiency accelerates medulloblastoma formation in vivo

      Theresa Thor, Annette Künkele, Kristian W. Pajtler, Annika K. Wefers, Harald Stephan, Pieter Mestdagh, Lukas Heukamp, Wolfgang Hartmann, Jo Vandesompele, Natalie Sadowski, Lore Becker, Lillian Garrett, Sabine M. Hölter, Marion Horsch, Julia Calzada-Wack, Tanja Klein-Rodewald, Ildiko Racz, Andreas Zimmer, Johannes Beckers, Frauke Neff, Thomas Klopstock, Pasqualino De Antonellis, Massimo Zollo, Wolfgang Wurst, Helmut Fuchs, Valérie Gailus-Durner, Ulrich Schüller, Martin Hrabě de Angelis, Angelika Eggert, Alexander Schramm and Johannes H. Schulte

      Article first published online: 25 NOV 2014 | DOI: 10.1002/ijc.29294

      What's new?

      MicroRNAs (miRNAs) play an important role in cancer initiation and progression. An miRNA called “miR-34a” is downregulated in a variety of human cancers. In this study, the authors found that miR-34a acts as a tumor suppressor in genetically engineered mice, and that it appears to regulate medulloblastoma formation in vivo. Restoring expression of miR-34a in medulloblastomas or other human cancers with deregulated miR-34a might, therefore, be a promising therapeutic strategy.

  82. Short Reports

    1. Suppression of homologous recombination sensitizes human tumor cells to IGF-1R inhibition

      Kunal A. Lodhia, Shan Gao, Tamara Aleksic, Fumiko Esashi and Valentine M. Macaulay

      Article first published online: 25 NOV 2014 | DOI: 10.1002/ijc.29327

      What's new?

      Some patients have benefitted from drugs that inhibit IGF-1 receptor (IGF-1R), but there was no way to predict in advance which patients will respond. This study shows that if molecules involved in homologous recombination (HR)–such as RAD51, BRCA2, or CDK1–are blocked, cells become more sensitive to IGF-1R inhibition. Given previous work showing that IGF-1R inhibition partially suppresses HR, these data suggest that IGF-1R-inhibited cells are more dependent on residual HR to repair endogenous DNA damage, and HR-deficient tumors may be sensitive to IGF-1R inhibitory drugs.

  83. Early Detection and Diagnosis

    1. Combined evaluation of a panel of protein and miRNA serum-exosome biomarkers for pancreatic cancer diagnosis increases sensitivity and specificity

      Bindhu Madhavan, Shijing Yue, Uwe Galli, Sanyukta Rana, Wolfgang Gross, Miryam Müller, Nathalia A. Giese, Holger Kalthoff, Thomas Becker, Markus W Büchler and Margot Zöller

      Article first published online: 25 NOV 2014 | DOI: 10.1002/ijc.29324

      What's new?

      Tumor exosomes—membrane vesicles of endocytic origin abundantly secreted by tumor cells and readily detected in body fluids—have recently emerged as a potential, non-invasive diagnostic tool. This study shows that the serum of pancreatic cancer (PaCa) patients contains detectable amounts of PaCa stem cell marker-expressing exosomes. Furthermore, the miRNA profile of serum exosomes in PaCa patients differs significantly from that of healthy donors and patients with non-malignant disease. A blinded screening study of PaCa patients' serum exosomes revealed a combined evaluation of a panel of PaCa-associated miRNA and stem cell biomarkers to provide a highly sensitive, minimally-invasive diagnostic tool.

  84. Cancer Therapy

    1. Accuracy of ultrasound for predicting pathologic response during neoadjuvant therapy for breast cancer

      Michael Luke Marinovich, Nehmat Houssami, Petra Macaskill, Gunter von Minckwitz, Jens-Uwe Blohmer and Les Irwig

      Article first published online: 25 NOV 2014 | DOI: 10.1002/ijc.29323

      What's new?

      Ultrasound is commonly used to assess “early” responses to neoadjuvant chemotherapy, which is given before primary treatment of breast cancer to shrink the tumor. However, its remains unclear whether ultrasound can accurately predict the absence of all residual invasive cancer in the breast tissue (pathological complete response). The authors performed an extensive study using Response Evaluation Criteria in Solid Tumors and World Health Organization criteria for response. Accuracy was higher than previously reported, indicating that the role of ultrasound is currently underestimated in response assessment guidelines.

  85. Infectious Causes of Cancer

    1. Human papillomavirus type 197 is commonly present in skin tumors

      L. Sara Arroyo Mühr, Emilie Hultin, Davit Bzhalava, Carina Eklund, Camilla Lagheden, Johanna Ekström, Hanna Johansson, Ola Forslund and Joakim Dillner

      Article first published online: 25 NOV 2014 | DOI: 10.1002/ijc.29325

      What's New?

      Some skin cancers such as squamous cell carcinomas occur more often in immune compromised individuals, pointing to an infectious agent as cause. In an unbiased approach the authors used next-generation sequencing to examine 91 non-melanoma skin cancer lesions. Most skin lesions contained Human Papilloma Virus (HPV). The authors cloned and sequenced a new type, HPV type 197, present in 34 of the 91 skin lesions. HPV197 has only 75% similarity with the most closely related known HPV (HPV178), suggesting a possible new agent involved in the carcinogenesis of non-melanoma skin lesions.

  86. Epidemiology

    1. Dietary glycemic index and glycemic load and risk of colorectal cancer: results from the EPIC-Italy study

      S. Sieri, V. Krogh, C. Agnoli, F. Ricceri, D. Palli, G. Masala, S. Panico, A. Mattiello, R. Tumino, M.C. Giurdanella, F. Brighenti, F. Scazzina, P. Vineis and C. Sacerdote

      Article first published online: 25 NOV 2014 | DOI: 10.1002/ijc.29341

      What's new?

      Diets rich in carbohydrate trigger increases in blood glucose and insulin levels, events that may be involved in the etiology of colorectal cancer. But carbohydrates vary in their impact on blood glucose levels, reflected in their glycemic index (GI) values, and whether high GI carbohydrates raise cancer risk remains much debated. Here, high dietary GI and elevated intake of carbohydrates from high GI foods were associated with increased risk of colorectal cancer. A diet rich in low GI carbohydrates, by contrast, was associated with a reduced risk of disease.

    2. Incidence trends of human papillomavirus-related head and neck cancer in Taiwan, 1995–2009

      Tzer-Zen Hwang, Jenn-Ren Hsiao, Chia-Rung Tsai and Jeffrey S. Chang

      Article first published online: 24 NOV 2014 | DOI: 10.1002/ijc.29330

      What's new?

      Taiwan is home to one of the highest incidence rates of head and neck cancer (HNC) in the world, primarily because of betel quid chewing. In the Western world, by contrast, overall HNC incidence is decreasing, while human papillomavirus (HPV)-related HNC is accounting for a greater proportion of cases. This analysis indicates that HPV-related HNC is on the rise in Taiwan as well. Between 1995 and 2009, the country's incidence rates for HPV-related HNC rose more rapidly than HPV-unrelated HNC. The findings suggest that HPV is a global issue in HNC.

  87. Early Detection and Diagnosis

    1. MGMT promoter methylation is associated with temozolomide response and prolonged progression-free survival in disseminated cutaneous melanoma

      Rainer Tuominen, Rosalyn Jewell, Joost J. van den Oord, Pascal Wolter, Ulrika Stierner, Christer Lindholm, Carolina Hertzman Johansson, Diana Lindén, Hemming Johansson, Marianne Frostvik Stolt, Christy Walker, Helen Snowden, Julia Newton-Bishop, Johan Hansson and Suzanne Egyházi Brage

      Article first published online: 24 NOV 2014 | DOI: 10.1002/ijc.29332

      What's new?

      In spite of the advances of targeted therapies, conventional chemotherapy with DTIC or TMZ is likely to remain useful for stage IV melanoma patients who are mutation-negative or develop drug resistance. Predictive biomarkers to identify the minority of patients who benefit from DTIC/TMZ treatment are however lacking. This study reports that MGMT promoter methylation in melanoma metastases results in MGMT gene silencing. MGMT promoter methylation is associated with significantly improved response rate to DTIC/TMZ single agent therapy and longer progression-free survival in stage IV melanoma patients, suggesting its potential use as a biomarker in melanoma, as already seen in glioblastoma.

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