当前期刊: International Journal of Cancer Go to current issue    加入关注   
显示样式:        排序: 导出
我的关注
我的收藏
您暂时未登录!
登录
  • Immune checkpoint inhibitors in advanced nasopharyngeal carcinoma: beyond an era of chemoradiation?
    Int. J. Cancer (IF 4.982) Pub Date : 2020-01-17
    Liam Masterson; James Howard; Jazmina Gonzalez‐Cruz; Christopher Jackson; Catherine Barnett; Lewis Overton; Howard Liu; Rahul Ladwa; Fiona Simpson; Margie McGrath; Ben Wallwork; Terry Jones; Christian Ottensmeier; Melvin L.K. Chua; Chris Perry; Rajiv Khanna; Benedict Panizza; Sandro Porceddu; Matt Lechner

    Now is an exciting era of development in immunotherapy checkpoint inhibitors and their effect on the treatment of NPC. While the general prognosis of R/M disease is poor, immunotherapy offers some promise in a malignancy associated with EBV and characterized by a peritumoural immune infiltrate. Our study aims to review past and on‐going clinical trials of monoclonal antibody therapies against the checkpoint inhibitors (e.g. PD1 and CTLA‐4), in R/M NPC.

    更新日期:2020-01-17
  • Inflammatory potential of the diet and risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) study
    Int. J. Cancer (IF 4.982) Pub Date : 2020-01-16
    P Jakszyn; V Cayssials; G Buckland; A Perez‐Cornago; E Weiderpass; H Boeing; MM Bergmann; A Vulcan; B Ohlsson; G Masala; AJ Cross; E Riboli; F Ricceri; C Dahm; D Nyvang; VA Katzke; T Kühns; C Kyrø; A Tjønneland; HA Ward; KK Tsilidis; G Skeie; S Sieri; MJ Sanchez; JM Huerta; P Amiano; C Lasheras; E Ardanaz; Y Mahamat‐Saleh; MC Boutron‐Ruault; F Carbonnel; S Panico; E Peppa; A Trichopoulou; A Karakatsani; R Tumino; R Vermeulen; M Jenab; M Gunter; A Agudo

    Pro‐inflammatory diets are associated with risk of developing colorectal cancer (CRC), however inconsistencies exist in subsite‐ and sex‐specific associations. The relationship between CRC and combined lifestyle‐related factors that contribute towards a low‐grade inflammatory profile has not yet been explored. We examined the association between the dietary inflammatory potential and an inflammatory profile and CRC risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. This cohort included 476,160 participants followed‐up of 14 years and 5,991 incident CRC cases (3,897 colon and 2,094 rectal tumours). Dietary inflammatory potential was estimated using an Inflammatory Score of the Diet (ISD). An Inflammatory Profile Score (IPS) was constructed, incorporating the ISD, physical activity level and abdominal obesity. The associations between the ISD and CRC and IPS and CRC were assessed using multivariable regression models. More pro‐ inflammatory diets were related to a higher CRC risk, particularly for colon cancer; Hazar Ratio (HR) for highest versus lowest ISD quartile was 1.15 (95% confidence interval (CI) 1.04‐1.27) for CRC, 1.24 (95% CI 1.09‐1.41) for colon cancer and 0.99 (95% CI 0.83‐1.17) for rectal cancer. Associations were more pronounced in men and not significant in women. The IPS was associated with CRC risk, particularly colon cancer among men; HRs for the highest versus lowest IPS were 1.62 (95% CI 1.31‐ 2.01) for colon cancer overall and 2.11 (95% CI 1.50‐2.97) for colon cancer in men. This study shows that more pro‐inflammatory diets and a more inflammatory profile are associated with higher risk of CRC, principally colon cancer and in men.

    更新日期:2020-01-17
  • Postmenopausal hormone replacement therapy and colorectal cancer risk by molecular subtypes and pathways
    Int. J. Cancer (IF 4.982) Pub Date : 2020-01-14
    Efrat L Amitay; Prudence R Carr; Lina Jansen; Elizabeth Alwers; Wilfried Roth; Esther Herpel; Matthias Kloor; Hendrik Bläker; Jenny Chang‐Claude; Hermann Brenner; Michael Hoffmeister

    Postmenopausal hormone replacement therapy (HRT) was found to be associated with lower risk of colorectal cancer (CRC). However, little is known regarding associations with molecular subtypes of CRC. The current study includes female participants of a large German population‐based case–control study (922 CRC cases and 1,183 controls). Tumor tissue samples were analyzed for microsatellite instability (MSI), CpG island methylator phenotype (CIMP), BRAF and KRAS mutation status. Multivariable logistic regression models were used to assess the association of HRT use with molecular subtypes and pathways. Postmenopausal HRT use was overall associated with reduced risk of CRC (adjusted odds‐ratio (aOR) 0.62, 95% confidence interval (CI) 0.50–0.76) and no major differences were observed for molecular subtypes or for tumor marker combinations representing molecular pathways. When stratified by median age (≤/>71 years) potentially stronger risk reductions were observed in the older group for subtypes showing MSI (OR = 0.36, 95%CI 0.17–0.76), BRAF mutation (OR = 0.40, 95%CI 0.30–0.83) and CIMP‐high (OR = 0.40, 95%CI 0.21–0.73) and for CRC suggestive of the sessile serrated pathway (OR = 0.45, 95%CI 0.20–1.01). In conclusion, postmenopausal use of HRT was similarly associated with risk reduction of major molecular tumor subtypes and pathways of CRC. Potentially stronger risk reductions with CRC subtypes diagnosed at higher ages require confirmation and clarification from other studies. The current study extends the limited understanding of the mechanisms of HRT in CRC prevention.

    更新日期:2020-01-15
  • The novel pro‐autophagy anticancer drug ABTL0812 potentiates chemotherapy in adenocarcinoma and squamous Non‐Small Cell Lung Cancer
    Int. J. Cancer (IF 4.982) Pub Date : 2020-01-14
    Anna López‐Plana; Patricia Fernández‐Nogueira; Pau Muñoz‐Guardiola; Sònia Solé‐Sánchez; Elisabet Megías‐Roda; Héctor Pérez‐Montoyo; Patricia Jauregui; Marc Yeste‐Velasco; Mariana Gómez‐Ferreria; Tatiana Erazo; Elisabet Ametller; Leire Recalde‐Percaz; Núria Moragas‐Garcia; Aleix Noguera‐Castells; Mario Mancino; Teresa Morán; Ernest Nadal; José Alfón; Carles Domènech; Pere Gascon; Jose M. Lizcano; Gemma Fuster; Paloma Bragado

    Around 40% of newly diagnosed lung cancer patients are stage IV, where the improvement of survival and reduction of disease‐related adverse events is the main goal for oncologists. In this scenario, we present pre‐clinical evidences supporting the use of ABTL0812 in combination with chemotherapy for treating advanced and metastatic Non‐Small‐Cell Lung adenocarcinomas and squamous carcinomas. ABTL0812 is a new chemical entity, currently in Phase 1b/2a clinical trial for advanced squamous NSCLC in combination with paclitaxel and carboplatin (P/C), after successfully completing the first‐in‐human trial where it showed an excellent safety profile and signs of efficacy. We show here that ABTL0812 inhibits Akt/mTOR axis by inducing the overexpression of TRIB3 and activating autophagy in lung squamous carcinoma cell lines. Furthermore, treatment with ABTL0812 also induce AMPK activation and ROS accumulation. Moreover, combination of ABTL0812 with chemotherapy dramatically increases the therapeutic effect of chemotherapy without increasing toxicity. We further show that combination of ABTL0812 and chemotherapy induces non‐apoptotic cell death mediated by TRIB3 activation and autophagy induction. We also present preliminary clinical data indicating that TRIB3 could serve as a potential novel pharmacodynamic biomarker to monitor ABTL0812 activity administered alone or in combination with chemotherapy in squamous NSCLC patients. The safety profile of ABTL0812 and its good synergy with chemotherapy potentiate the therapeutic potential of current lines of treatment based on chemotherapy regimens, arising as a promising option for improving these patient's therapeutic expectancy.

    更新日期:2020-01-14
  • Assessment of long‐term survival of cancer patients using cancer registry data from eastern China: period analysis is superior to traditional methods
    Int. J. Cancer (IF 4.982) Pub Date : 2020-01-14
    Xiyi Jiang; Liangyou Wang; Yongran Cheng; Huijuan Tang; Tianhui Chen

    We aimed to provide a systematical evaluation of the performance of period analysis compared to traditional cohort and complete methods, using cancer registry data from Taizhou, eastern China. Overall 5‐year relative survival (RS) estimate was calculated using cohort analysis, complete analysis and period analysis, respectively; further analyses were stratified by sex, region, age at diagnosis and cancer sites. Deviation value (DV), defined as the deviation between the estimated 5‐year RS obtained from each method and the observed actual survival, was calculated to evaluate the accuracy of each method. Overall, 5‐year RS derived by period analysis were much closer to the observed actual survival (51.4%), compared to those by complete and cohort methods, with the estimates of 48.7% (DV: −2.7%), 43.2% (DV: −8.2%) and 36.3% (DV: −15.1%), respectively. Further stratifications by sex, age at diagnosis, region, and cancer sites also supported period analysis provided more precise estimates, compared to complete and cohort methods. We found, for first time systematically using cancer registry data from eastern China, period analysis provided more up‐to‐date precise estimates of long‐term survival for overall and stratifications by sex, age at diagnosis, region and cancer sites, compared to traditional cohort and complete methods. Nevertheless, further investigations using large cancer registry data across China are warranted for the widespread use of period analysis in China.

    更新日期:2020-01-14
  • The impact of childhood cancer on parental working status and income in Denmark: patterns over time and determinants of adverse changes
    Int. J. Cancer (IF 4.982) Pub Date : 2020-01-14
    Luzius Mader; Marie Hargreave; Pernille Envold Bidstrup; Susanne K Kjær; Thomas Tjørnelund Nielsen; Anja Krøyer; Jeanette Falck Winther; Friederike Erdmann

    Having a child with cancer may affect the socio‐economic situation of the parents. We aimed to assess the impact of childhood cancer on parental working status and income and to identify determinants of adverse changes after the child's cancer diagnosis by calendar period. We conducted a nationwide cohort study using Danish registry data. Parents of children diagnosed with cancer in 1982‐2014 (n=12418) were matched with comparison parents of cancer‐free children (n=125014). We analysed annual working status (working/not working) and annual disposable income (lowest quintile/not lowest quintile) of case and comparison parents over a period of ten years after diagnosis by calendar period (1982‐1999 vs. 2000‐2014). Logistic regression models were used to identify determinants of adverse changes after diagnosis. Mothers of children diagnosed in 1982‐1999 were more likely not working or having a low income than comparison mothers up to ten years following diagnosis. This risk of not working or low income was lower in mothers of children diagnosed in 2000‐2014 compared to 1982‐1999 in the first years following diagnosis (pinteraction<0·05). We observed no consistent patterns among fathers. Low parental education, diagnosis of lymphoid leukaemia, and younger age of the child at diagnosis were the main determinants of adverse changes in working status or income after diagnosis. Childhood cancer adversely interfered with parents' socio‐economic situation in the earlier calendar period, particularly among mothers. The absence of such an effect in more recent years emphasizes the supportive role of a countries' welfare system alongside the general advances in childhood cancer treatment.

    更新日期:2020-01-14
  • Reducing overtreatment associated with overdiagnosis in cervical cancer screening—A model‐based benefit–harm analysis for Austria
    Int. J. Cancer (IF 4.982) Pub Date : 2020-01-13
    Gaby Sroczynski; Eva Esteban; Andreas Widschwendter; Wilhelm Oberaigner; Wegene Borena; Dorothee von Laer; Monika Hackl; Gottfried Endel; Uwe Siebert

    A general concern exists that cervical cancer screening using human papillomavirus (HPV) testing may lead to considerable overtreatment. We evaluated the trade‐off between benefits and overtreatment among different screening strategies differing by primary tests (cytology, p16/Ki‐67, HPV alone or in combinations), interval, age and diagnostic follow‐up algorithms. A Markov state‐transition model calibrated to the Austrian epidemiological context was used to predict cervical cancer cases, deaths, overtreatments and incremental harm–benefit ratios (IHBR) for each strategy. When considering the same screening interval, HPV‐based screening strategies were more effective compared to cytology or p16/Ki‐67 testing (e.g., relative reduction in cervical cancer with biennial screening: 67.7% for HPV + Pap cotesting, 57.3% for cytology and 65.5% for p16/Ki‐67), but were associated with increased overtreatment (e.g., 19.8% more conizations with biennial HPV + Papcotesting vs. biennial cytology). The IHBRs measured in unnecessary conizations per additional prevented cancer‐related death were 31 (quinquennial Pap + p16/Ki‐67‐triage), 49 (triennial Pap + p16/Ki‐67‐triage), 58 (triennial HPV + Pap cotesting), 66 (biennial HPV + Pap cotesting), 189 (annual Pap + p16/Ki‐67‐triage) and 401 (annual p16/Ki‐67 testing alone). The IHBRs increased significantly with increasing screening adherence rates and slightly with lower age at screening initiation, with a reduction in HPV incidence or with lower Pap‐test sensitivity. Depending on the accepted IHBR threshold, biennial or triennial HPV‐based screening in women as of age 30 and biennial cytology in younger women may be considered in opportunistic screening settings with low or moderate adherence such as in Austria. In organized settings with high screening adherence and in postvaccination settings with lower HPV prevalence, the interval may be prolonged.

    更新日期:2020-01-13
  • Long noncoding RNA SOX2OT promotes the proliferation of pancreatic cancer by binding to FUS
    Int. J. Cancer (IF 4.982) Pub Date : 2020-01-13
    Lei Chen; Jingjing Zhang; Qun Chen; Wanli Ge; Lingdong Meng; Xumin Huang; Peng Shen; Hao Yuan; Guodong Shi; Yi Miao; Kuirong Jiang

    Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors has one of the worst prognoses, and the role of long noncoding RNAs (lncRNAs) in the biological and pathological processes of pancreatic cancer, including tumor cell proliferation, is a popular topic in tumor research. Our previous study revealed the correlation between high levels of the lncRNA‐SOX2OT (SOX2OT) with poor survival outcomes. Cell Counting Kit‐8, EdU, Flow cytometry and Colony formation assays as well as Xenograft growth of PDAC cells in mice were used for the detection of PDAC cells proliferation progression. Fluorescence in situ hybridization, RNA‐binding protein pulldown and RNA immunoprecipitation assays were also used to identify the putative mechanisms of SOX2OT participating in the tumor progression. SOX2OT and its potential downstream targets were verified by Western blot and quantitative real‐time polymerase chain reaction (qRT‐PCR). SOX2OT was confirmed to promote the proliferation of PDAC cells. It was found to directly physically bind to FUS and we also demonstrated that FUS protein stability was affected by binding with SOX2OT and FUS could suppressed PDAC tumor by regulating cell cycle‐associated factors CCND1 and p27. Our findings suggest that SOX2OT may act as a tumor promoter in PDAC through physically binding FUS and regulating its downstream cell cycle‐associated factors CCND1 and p27. It may serve as an effective target for antitumor treatment for pancreatic cancer.

    更新日期:2020-01-13
  • The impact of alcohol consumption and physical activity on breast cancer: The role of breast cancer risk
    Int. J. Cancer (IF 4.982) Pub Date : 2020-01-13
    Linda Rainey; Mikael Eriksson; Thang Trinh; Kamila Czene; Mireille J.M. Broeders; Daniëlle van der Waal; Per Hall

    High alcohol consumption and physical inactivity are known breast cancer risk factors. However, whether the association between these lifestyle factors and breast cancer is modified by a woman's additional breast cancer risk factors has never been studied. Therefore, a population‐based prospective cohort study of 57,654 Swedish women aged 40–74 years, including 957 breast cancer cases, was performed. Alcohol consumption and physical activity were measured with validated web‐based self‐report questionnaires. The Tyrer–Cuzick risk prediction model was used to determine a woman's 10‐year risk of developing breast cancer. Logistic regression models were used to explore whether the effect of alcohol consumption and physical activity on breast cancer was modified by additional breast cancer risk factors. Findings showed that increased alcohol consumption was associated with a higher breast cancer risk (OR = 1.26, 95% CI 1.01, 1.59). However, the association between lifestyle factors (alcohol consumption and physical activity) and breast cancer was generally the same for women at below average, average and above average risk of developing breast cancer. Therefore, additional breast cancer risk factors do not appear to modify the association between lifestyle (alcohol consumption and physical activity) and breast cancer. Considering the general health benefits, preventative lifestyle recommendations can be formulated about alcohol consumption and physical activity for women at all levels of breast cancer risk.

    更新日期:2020-01-13
  • Endogenous sex hormones and colorectal cancer survival among men and women
    Int. J. Cancer (IF 4.982) Pub Date : 2020-01-11
    Wanshui Yang; Edward L. Giovannucci; Susan E. Hankinson; Andrew T. Chan; Yanan Ma; Kana Wu; Charles S. Fuchs; I‐Min Lee; Howard D. Sesso; Jennifer H. Lin; Xuehong Zhang

    Although previous studies have suggested a potential role of sex hormones in the etiology of colorectal cancer (CRC), no study has yet examined the associations between circulating sex hormones and survival among CRC patients. We prospectively assessed the associations of prediagnostic plasma concentrations of estrone, estradiol, free estradiol, testosterone, free testosterone and sex hormone‐binding globulin (SHBG) with CRC‐specific and overall mortality among 609 CRC patients (370 men and 239 postmenopausal women not taking hormone therapy at blood collection) from four U.S. cohorts. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard regression. We identified 174 deaths (83 CRC‐specific deaths) in men and 106 deaths (70 CRC‐specific deaths) in women. In men, higher circulating level of free testosterone was associated with lower risk of overall (the highest vs. lowest tertiles, HR = 0.66, 95% CI, 0.45–0.99, ptrend = 0.04) and possibly CRC‐specific mortality (HR = 0.73, 95% CI, 0.41–1.29, ptrend = 0.27). We generally observed nonsignificant inverse associations for other sex steroids, and a positive association for SHBG with CRC‐specific mortality among male patients. In women, however, we found a suggestive positive association of estrone with overall (HR = 1.54, 95% CI, 0.92–2.60, ptrend = 0.11) and CRC‐specific mortality (HR = 1.96, 95% CI, 1.01–3.84, ptrend = 0.06). Total estradiol, free estradiol and free testosterone were generally suggestively associated with higher risk of mortality among female patients, although not statistically significant. These findings implicated a potential role of endogenous sex hormones in CRC prognosis, which warrant further investigation.

    更新日期:2020-01-13
  • Risk of specific types of ovarian cancer after borderline ovarian tumors in Denmark: a nationwide‐based study
    Int. J. Cancer (IF 4.982) Pub Date : 2020-01-12
    Charlotte Gerd Hannibal; Kirsten Frederiksen; Russell Vang; Robert J. Kurman; Susanne K. Kjaer

    Population‐based evidence regarding risk of ovarian cancer after a borderline ovarian tumor (BOT) is sparse. We aimed to examine the incidence of specific types of ovarian cancer in women with serous or mucinous BOTs in a nationwide cohort study with up to 36 years of follow‐up. Using the nationwide Danish Pathology Data Bank, we identified 4281 women with a BOT (2058 serous BOTs and 2223 mucinous BOTs) in Denmark during 1978–2012. We computed standardized incidence ratios (SIRs) to compare the incidence of ovarian cancer among women with BOTs compared to general population rates. We found that a serous BOT was especially and strongly associated with subsequent serous ovarian cancer (SIR=9.2; 95% CI: 6.8–12.2), and that a mucinous BOT was strongly related to mucinous ovarian cancer (SIR=18.6; 95% CI: 10.8–29.8). The SIRs remained elevated >10 years after a serous BOT and up to 5–9 years after a mucinous BOT. The increased incidence of serous ovarian cancer in women with a serous BOT was mostly pronounced in women <50 years at the serous BOT diagnosis. In conclusion, women with a serous BOT experience long‐term increased incidence of serous ovarian cancer, and women with a mucinous BOT have long‐term elevated incidence of mucinous ovarian cancer compared to the general population. This is the first population‐based study to show compelling evidence of the histo‐specific increased risk of ovarian cancer following specific types of BOTs. Thus, these results are supportive of the hypothesis that BOTs may be precursor lesions to carcinomas of the corresponding histologic type.

    更新日期:2020-01-13
  • Primary HPV testing with cytology versus cytology alone in cervical screening – a prospective randomized controlled trial (RCT) with two rounds of screening in a Chinese population
    Int. J. Cancer (IF 4.982) Pub Date : 2020-01-10
    KKL Chan; SS Liu; N Wei; SF Ngu; MMY Chu; KY Tse; LSK Lau; ANY Cheung; HYS Ngan

    We conducted a prospective randomized controlled trial with two screening rounds to evaluate the effectiveness of combining HPV testing with liquid‐based cytology (LBC) as a co‐test, compared to LBC only in cervical cancer screening of a Chinese population. First, 15,955 women aged 30–60 were randomized at a 1:1 ratio into an intervention group (Digene Hybrid Capture 2 HPV test with LBC) and a control group (LBC alone). Women in the intervention group would be referred for colposcopy and biopsy immediately if they were found to have high‐risk HPV regardless of cytology results. The detection of cervical intraepithelial neoplasia grade 2 or above (CIN2+) lesions was significantly higher in the intervention group compared to the control (0.95% vs 0.38%, OR 2.50, 95% CI 1.65–3.88). At the subsequent round of screening approximately 36 months later, CIN2+ detection was significantly lower in the intervention group (0.08% vs 0.35%, OR 0.23, CI 0.08–0.57). Over the two rounds of screening, the total detection of CIN2+ was higher in the intervention group (1.01% vs 0.66%, OR 1.53, CI 1.09–2.19). There was a four‐fold increase (10.6% vs 2.4%, p < 0.001) in the number of colposcopies performed in the intervention arm. Adding a high‐risk HPV test to cytology for primary cervical screening led to earlier detection of clinically significant pre‐invasive lesions, resulting in a reduced detection of CIN2+ lesions in subsequent rounds and an increased rate of colposcopy.

    更新日期:2020-01-11
  • Modulating Sphingosine‐1‐Phosphate receptors to improve chemotherapy efficacy against Ewing sarcoma
    Int. J. Cancer (IF 4.982) Pub Date : 2020-01-10
    Enrica Marmonti; Hannah Savage; Aiqian Zhang; Claudia Alvarez; Miriam Garcia Morrell; Avis Harden; Meridith Buzbee; Keri Schadler

    Tumor vasculature is innately dysfunctional. Poorly functional tumor vessels inefficiently deliver chemotherapy to tumor cells; vessel hyper‐permeability promotes chemotherapy delivery primarily to a tumor's periphery. Here we identify a method for enhancing chemotherapy efficacy in Ewing sarcoma (ES) in mice by modulating tumor vessel permeability. Vessel permeability is partially controlled by the G protein‐coupled Sphinosine‐1‐phosphate receptors 1 and 2 (S1PR1 and S1PR2) on endothelial cells. S1PR1 promotes endothelial cell junction integrity while S1PR2 destabilizes it. We hypothesize that an imbalance of S1PR1:S1PR2 is partially responsible for the dysfunctional vascular phenotype characteristic of ES and that by altering the balance in favor of S1PR1, ES vessel hyper‐permeability can be reversed. In this study, we demonstrate that pharmacologic activation of S1PR1 by SEW2871 or inhibition of S1PR2 by JTE‐013 caused more organized, mature, and functional tumor vessels. Importantly, S1PR1 activation or S1PR2 inhibition improved anti‐tumor efficacy. Our data suggests that pharmacologic targeting of S1PR1 and S1PR2 may be a useful adjuvant to standard chemotherapy for ES patients.

    更新日期:2020-01-11
  • Gallbladder and extrahepatic bile duct cancers in the Americas: incidence and mortality patterns and trends
    Int. J. Cancer (IF 4.982) Pub Date : 2020-01-10
    Adalberto Miranda‐Filho; Marion Piñeros; Catterina Ferreccio; Volkan Adsay; Isabelle Soerjomataram; Freddie Bray; Jill Koshiol

    Trends in Gallbladder cancer incidence and mortality in populations across the Americas can provide insight into shifting epidemiologic patterns and the current and potential impact of preventative and curative programs. Estimates of gallbladder and extrahepatic bile duct cancer incidence and mortality for the year 2018 were extracted from IARC's GLOBOCAN database for 185 countries. Recorded registry‐based incidence from 13 countries was extracted from IARC's Cancer Incidence in Five Continents series and corresponding national deaths from the WHO mortality database. Among females, the highest estimated incidence ASR for gallbladder and extrahepatic bile duct cancer in the Americas were found in Bolivia (21.0 per 100,000), Chile (11.7), and Peru (6.0). In the U.S., the highest incidence rates were observed among Hispanics (1.8). In the Chilean population, gallbladder cancer rates declined in both females and males between 1998 and 2012. Rates dropped slightly in Canada, Costa Rica, U.S. Whites, and Hispanics in Los Angeles. Gallbladder cancer mortality rates also decreased across the studied countries, although rising trends were observed in Colombia and Canada after 2010. Countries within Southern and Central America tended to have a higher proportion of unspecified biliary tract cancers. In public health terms, the decline in gallbladder cancer incidence and mortality rates is encouraging. However, the slight increases in mortality rates during recent years in Colombia and Canada warrant further attention. Higher proportions of unspecified biliary tract cancers (with correspondingly higher mortality rates) suggest more rigorous pathology procedures may be needed after surgery.

    更新日期:2020-01-11
  • The second round of the Dutch colorectal cancer screening program: Impact of an increased fecal immunochemical test cut‐off level on yield of screening
    Int. J. Cancer (IF 4.982) Pub Date : 2020-01-09
    Arthur I. Kooyker; Esther Toes‐Zoutendijk; Annemieke W.J. Opstal‐van Winden; Manon C.W. Spaander; Maaike Buskermolen; Hanneke J. van Vuuren; Ernst J. Kuipers; Folkert J. van Kemenade; Chris Ramakers; Maarten G.J. Thomeer; Evelien Dekker; Iris D. Nagtegaal; Harry J. de Koning; Monique E. van Leerdam; Iris Lansdorp‐Vogelaar

    The Dutch colorectal cancer (CRC) screening program started in 2014, inviting the target population biennially to perform a fecal immunochemical test (FIT). We obtained prospectively collected data from the national screening information‐system to present the results of the second round (2016) and evaluate the impact of increasing the FIT cut‐off halfway through the first round from 15 to 47 μg Hb/g feces on outcomes in the second round. Second round screening was done with a 47 μg Hb/g feces FIT cut‐off. Participants were classified based on first round participation status as either FIT (15,47) or FIT (47,47) participants, and previous nonparticipants. In total, 348,891 (75.9%) out of 459,740 invitees participated in the second round. Participation rates were 93.4% among previous participants and 21.0% among previous non‐participants. FIT(47,47) participants had a significantly higher detection rate of AN (15.3 vs. 10.4 per 1,000 participants) compared to FIT(15,47) participants in the second round, while their cumulative detection rate of AN over two rounds was significantly lower (45.6 vs. 52.6 per 1,000 participants). Our results showed that participation in the Dutch CRC screening program was consistently high and that second round detection rates depended on the first round FIT cut‐off. The cumulative detection over two rounds was higher among FIT(15,47) participants. These findings suggest that a substantial part of, but not all the missed findings in the first round due to the increased FIT cut‐off were detected in the subsequent round.

    更新日期:2020-01-09
  • Quality of life in the FOXFIRE, SIRFLOX and FOXFIRE‐global randomised trials of selective internal radiotherapy for metastatic colorectal cancer
    Int. J. Cancer (IF 4.982) Pub Date : 2020-01-09
    Jane Wolstenholme; Francesco Fusco; Alastair M. Gray; Joanna Moschandreas; Pradeep S. Virdee; Sharon Love; Guy Van Hazel; Peter Gibbs; Harpreet S. Wasan; Ricky A. Sharma

    Selective internal radiotherapy (SIRT) is a liver‐directed treatment involving the injection of yttrium‐90 microspheres into the blood supply of liver tumours. There are very few studies assessing health‐related quality of life (HRQOL) in patients treated with SIRT. Patients with liver metastases from colorectal cancer (CRC) were randomised in the FOXFIRE (FFr; ISRCTN83867919), SIRFLOX (SF; NCT00724503) and FOXFIRE‐Global (FFrG; NCT01721954) trials of first‐line oxaliplatin–fluorouracil (FOLFOX) chemotherapy combined with SIRT versus FOLFOX alone. HRQOL was assessed using the three‐level EQ‐5D, European Organisation for Research and Treatment of Cancer Quality of Life (EORTC QLQ‐C30) and EORTC Colorectal Liver Metastases cancer module (EORTC QLQ‐LMC21) at baseline, ≤3 months, 6 months, 12 months and annually thereafter from randomisation, and at disease progression. Analyses were conducted on an intention‐to‐treat basis. In total, 554 patients were randomised to SIRT + FOLFOX and 549 patients to FOLFOX alone. HRQOL was statistically significant lower in SIRT + FOLFOX patients ≤3 months after SIRT administration in all three instruments, particularly global health, physical and role functioning and symptoms of fatigue, nausea/vomiting and appetite loss. By accepted thresholds, these differences were deemed not clinically important. Differences between SIRT + FOLFOX and FOLFOX alone over the 2‐year follow up and at disease progression were also not clinically important. Although there is some decrease in HRQOL for up to 3 months following SIRT, the addition of SIRT to FOLFOX chemotherapy does not change HRQOL to a clinically important degree in metastatic CRC patients.

    更新日期:2020-01-09
  • Adenosine receptor 2B activity promotes autonomous growth, migration as well as vascularization of head and neck squamous cell carcinoma cells
    Int. J. Cancer (IF 4.982) Pub Date : 2020-01-09
    Max Wilkat; Hanna Bast; Robert Drees; Johannes Dünser; Amelie Mahr; Ninel Azoitei; Ralf Marienfeld; Felicia Frank; Magnus Brhel; Alexey Ushmorov; Jens Greve; Eva Goldberg‐Bockhorn; Marie‐Nicole Theodoraki; Johannes Doescher; Simon Laban; Patrick J. Schuler; Thomas K. Hoffmann; Cornelia Brunner

    Adenosine is a signaling molecule that exerts dual effects on tumor growth: while it inhibits immune cell function and thereby prevents surveillance by the immune system, it influences tumorigenesis directly via activation of adenosine receptors on tumor cells at the same time. However, the adenosine‐mediated mechanisms affecting oncogenic processes particularly in head and neck squamous cell carcinomas (HNSCC) are not fully understood. Here, we investigated the role of adenosine receptor activity on HNSCC‐derived cell lines. Targeting the adenosine receptor A2B (ADORA2B) on these cells with the inverse agonist/antagonist PSB‐603 leads to inhibition of cell proliferation, transmigration as well as VEGFA secretion in vitro. At the molecular level, these effects were associated with cell cycle arrest as well as the induction of the apoptotic pathway. In addition, shRNA‐mediated downmodulation of ADORA2B expression caused decreased proliferation. Moreover, in in vivo xenograft experiments, chemical and genetic abrogation of ADORA2B activity impaired tumor growth associated with decreased tumor vascularization. Together, our findings characterize ADORA2B as a crucial player in the maintenance of HNSCC and, therefore, as a potential therapeutic target for HNSCC treatment.

    更新日期:2020-01-09
  • A comparison of EBV serology and serum cell‐free DNA as screening tools for nasopharyngeal cancer: Results of the Singapore NPC screening cohort
    Int. J. Cancer (IF 4.982) Pub Date : 2020-01-08
    Joshua K. Tay; Chor H. Siow; Han L. Goh; Chwee M. Lim; Pon P. Hsu; Soh H. Chan; Kwok S. Loh

    We aimed to evaluate the effectiveness of nasopharyngeal cancer (NPC) screening by comprehensive clinical follow‐up and adjunctive Epstein–Barr virus (EBV) testing. In a prospective cohort study, 524 individuals with a first‐degree family history of NPC were recruited at a university clinical center in Singapore. The cohort was evaluated at baseline and at 6 monthly intervals, with a complete head and neck examination including nasopharyngeal endoscopy. Blood was taken at baseline and at yearly intervals for EBV Viral Capsid Antigen (VCA) IgA, EBV Early Antigen (EA) IgA serology and serum cell‐free EBV DNA. Nasopharyngeal biopsy was performed when any irregularity in the nasopharynx was observed, or when EBV markers were elevated. The mean duration of follow‐up was 57.7 months, with an average of 8.6 clinical visits per participant. Five participants (0.96%) were identified to have NPC, giving a prevalence of 199 per 100,000 person‐years of screening. Four of the five NPC cases identified had asymptomatic T1 disease, at an earlier stage compared to NPC patients diagnosed in the clinic during the same time period (p = 0.0297). All NPC cases identified had elevated EBV‐EA IgA titers ≥1:10, with a specificity of 94.6% and a positive predictive value of 15.2%, outperforming EBV‐VCA IgA and serum EBV DNA. Two NPC cases were biopsied only because of elevated EBV serology titers, with increasing EBV‐EA IgA titers preceding the diagnosis of NPC. In conclusion, screening for NPC is effective in identifying early‐stage disease. Adjunctive EBV‐EA IgA testing improved the effectiveness of screening.

    更新日期:2020-01-08
  • Urinary tract infections and risk of squamous cell carcinoma bladder cancer: A Danish nationwide case–control study
    Int. J. Cancer (IF 4.982) Pub Date : 2020-01-08
    Anton Pottegård; Kasper B. Kristensen; Søren Friis; Jesper Hallas; Jørgen B. Jensen; Mette Nørgaard

    Schistosoma haematobium infection can lead to squamous cell carcinomas (SCC) of the bladder. Whether this also applies to more common urinary tract infections (UTIs) is unclear. We therefore aimed to investigate the association between UTIs, reflected by the use of specific antibiotics and risk of SCC of the bladder. We conducted a Danish nationwide case–control study and identified histologically verified bladder cancer cases (2000–2015; n = 12,271) and age‐ and sex‐matched cancer‐free controls. We computed odds ratios (ORs) with 95% confidence intervals (CI) associating the use of UTI‐specific antibiotics with SCC bladder cancer, using conditional logistic regression. We applied a 2‐year lag‐time to minimize reverse causation. To aid interpretation, similar analyses were performed for other bladder cancer types and other antibiotics. We identified 333 SCC cases (2.7% of all bladder cancers). Compared to no use (0–1 prescription), high‐use (≥10 prescriptions) of UTI‐specific antibiotics was associated with SCC with an OR of 11.4 (CI 7.6–17.2) and a clear dose–response pattern (ptrend < 0.001). Use of phenoxymethylpenicillin, an antibiotic not used against UTIs, was not associated with SCC after adjustment for use of UTI‐specific antibiotics (OR 0.5). Furthermore, UTI‐specific antibiotic use was not associated with urothelial carcinomas (n = 11,029; OR 1.13; CI 0.97–1.32). Excluding patients with known urogenital disease did not influence the SCC estimates (overall OR 10.8; CI 6.2–18.9). Data on smoking were lacking, however, a quantitative bias analysis suggested this to be of limited importance. In conclusion, common UTIs are strong, dose‐dependent and specifically associated with risk of SCC of the bladder.

    更新日期:2020-01-08
  • Novel ovarian cancer maintenance therapy targeted at mortalin and mutant p53
    Int. J. Cancer (IF 4.982) Pub Date : 2020-01-08
    Satish K. Ramraj; Sugantha P. Elayapillai; Richard C. Pelikan; Yan D. Zhao; Zitha R. Isingizwe; Amy L. Kennedy; Stanley A. Lightfoot; Doris M. Benbrook

    Current ovarian cancer maintenance therapy is limited by toxicity and no proven impact on overall survival. To study a maintenance strategy targeted at missense mutant p53, we hypothesized that the release of mutant p53 from mortalin inhibition by the SHetA2 drug combined with reactivation of mutant p53 with the PRIMA‐1MET drug inhibits growth and tumor establishment synergistically in a mutant‐p53 dependent manner. The Cancer Genome Atlas (TCGA) data and serous ovarian tumors were evaluated for TP53 and HSPA9/mortalin status. SHetA2 and PRIMA‐1MET were tested in ovarian cancer cell lines and fallopian tube secretory epithelial cells using isobolograms, fluorescent cytometry, Western blots and ELISAs. Drugs were administered to mice after peritoneal injection of MESOV mutant p53 ovarian cancer cells and prior to tumor establishment, which was evaluated by logistic regression. Fifty‐eight percent of TP53 mutations were missense and there were no mortalin mutations in TCGA high‐grade serous ovarian cancers. Mortalin levels were sequentially increased in serous benign, borderline and carcinoma tumors. SHetA2 caused p53 nuclear and mitochondrial accumulation in cancer, but not in healthy, cells. Endogenous or exogenous mutant p53 increased SHetA2 resistance. PRIMA‐1MET decreased this resistance and interacted synergistically with SHetA2 in mutant and wild type p53‐expressing cell lines in association with elevated reactive oxygen species/ATP ratios. Tumor‐free rates in animals were 0% (controls), 25% (PRIMA1MET), 42% (SHetA2) and 67% (combination). SHetA2 (p = 0.004) and PRIMA1MET (p = 0.048) functioned additively in preventing tumor development with no observed toxicity. These results justify the development of SHetA2 and PRIMA‐1MET alone and in combination for ovarian cancer maintenance therapy.

    更新日期:2020-01-08
  • Small bowel adenocarcinoma: results from a nationwide prospective ARCAD‐NADEGE cohort study of 347 patients
    Int. J. Cancer (IF 4.982) Pub Date : 2020-01-07
    Thomas Aparicio; Julie Henriques; Sylvain Manfredi; David Tougeron; Olivier Bouché; Denis Pezet; Guillaume Piessen; Romain Coriat; Aziz Zaanan; Jean‐Louis Legoux; Eric Terrebone; Marc Pocard; Jean‐Marc Gornet; Thierry Lecomte; Catherine Lombard‐Bohas; Hervé Perrier; Cédric Lecaille; Sandrine Lavau‐Denes; Dewi Vernerey; Pauline Afchain;

    Small bowel adenocarcinoma (SBA) is a rare tumour. We conducted a prospective cohort to describe the prevalence, survival, and prognostic factors in unselected SBA patients. The study enrolled patients with all stages of newly diagnosed or recurrent SBA at 74 French centres between January 2009 and December 2012. In total, 347 patients were analysed; the median age was 63 years (range: 23‐90). The primary tumour was in the duodenum (60.6%), jejunum (20.7%), and ileum (18.7%). The prevalence of predisposing disease was 8.7%, 6.9%, 1.7%, 1.7%, and 0.6% for Crohn disease, Lynch syndrome, familial adenomatous polyposis, celiac disease, and Peutz‐Jeghers syndrome, respectively. At diagnosis, 58.9%, 5.5%, and 35.6% of patients had localized and resectable, locally advanced unresectable, and metastatic disease, respectively. Crohn disease was significantly associated with younger age, poor differentiation, and ileum location, whereas Lynch syndrome with younger age, poor differentiation, early stage, and duodenum location. Adjuvant chemotherapy (oxaliplatin‐based in 89.9%) was performed in 61.5% of patients with locally resected tumours. With a 54 months median follow‐up, the 5‐year overall survival (OS) was 87.9%, 78.2%, and 55.5% in stage I, II, and III, respectively. The median OS of patients with stage IV was 12.7 months. In patients with resected tumours, poor differentiation (p=0.047) and T4 stage (p=0.001) were associated with a higher risk of death. In conclusion, this study showed that the prognosis of advanced SBA remains poor. Tumour characteristics differed according to predisposing disease. In SBA resected tumours , the prognostic factors for OS were grade and T stage.

    更新日期:2020-01-08
  • G‐protein‐coupled receptor kinase 2 safeguards epithelial phenotype in head and neck squamous cell carcinomas
    Int. J. Cancer (IF 4.982) Pub Date : 2020-01-07
    Julia Palacios‐García; María Sanz‐Flores; Alejandro Asensio; Raúl Alvarado; Susana Rojo‐Berciano; Konstantinos Stamatakis; Jesús M. Paramio; Amparo Cano; M. Ángela Nieto; Ramón García‐Escudero; Federico Mayor; Catalina Ribas

    Head and neck squamous cell carcinoma (HNSCC) arises from the mucosal lining of the upper aerodigestive tract and display few treatment options in advanced stages. Despite increased knowledge of HNSCC molecular biology, the identification of new players involved in triggering HNSCC recurrence and metastatic disease is needed. We uncover that G‐protein‐coupled receptor kinase‐2 (GRK2) expression is reduced in undifferentiated, high‐grade human HNSCC tumors, whereas its silencing in model human HNSCC cells is sufficient to trigger epithelial‐to‐mesenchymal transition (EMT) phenotypic features, an EMT‐like transcriptional program and enhanced lymph node colonization from orthotopic tongue tumors in mice. Conversely, enhancing GRK2 expression counteracts mesenchymal cells traits by mechanisms involving phosphorylation and decreased functionality of the key EMT inducer Snail1. Our results suggest that GRK2 safeguards the epithelial phenotype, whereas its downregulation contributes to the activation of EMT programs in HNSCC.

    更新日期:2020-01-07
  • The immunogenic potential of bacterial flagella for Salmonella‐mediated tumor therapy
    Int. J. Cancer (IF 4.982) Pub Date : 2020-01-07
    Sebastian Felgner; Imke Spöring; Vinay Pawar; Dino Kocijancic; Matthias Preusse; Christine Falk; Manfred Rohde; Susanne Häussler; Siegfried Weiss; Marc Erhardt

    Genetically engineered Salmonella Typhimurium are potent vectors for prophylactic and therapeutic measures against pathogens as well as cancer. This is based on the potent adjuvanticity that supports strong immune responses. The physiology of Salmonella is well understood. It simplifies engineering of both enhanced immune‐stimulatory properties as well as safety features, thus, resulting in an appropriate balance between attenuation and efficacy for clinical applications. A major virulence factor of Salmonella is the flagellum. It is also a strong pathogen‐associated molecular pattern recognized by extracellular and intracellular receptors of immune cells of the host. At the same time, it represents a serious metabolic burden. Accordingly, the bacteria evolved tight regulatory mechanisms that control flagella synthesis in vivo. Here, we systematically investigated the immunogenicity and adjuvant properties of various flagella mutants of Salmonella in vitro and in a mouse cancer model in vivo. We found that mutants lacking the flagellum‐specific ATPase FliHIJ or the inner membrane ring FliF displayed the greatest stimulatory capacity and strongest antitumor effects, while remaining safe in vivo. Scanning electron microscopy revealed the presence of outer membrane vesicles in the ΔfliF and ΔfliHIJ mutants. Finally, the combination of the ΔfliF and ΔfliHIJ mutations with our previously described attenuated and immunogenic background strain SF102 displayed strong efficacy against the highly resistant cancer cell line RenCa. We thus conclude that manipulating flagella biosynthesis has great potential for the construction of highly efficacious and versatile Salmonella vector strains.

    更新日期:2020-01-07
  • Antitumour immunity invoked by hepatic arterial infusion of first‐line oxaliplatin predicts durable colorectal cancer control after liver metastasis ablation: 8–12 years of follow‐up
    Int. J. Cancer (IF 4.982) Pub Date : 2020-01-07
    Hanna Abrahamsson; Benny V. Jensen; Lise L. Berven; Dorte L. Nielsen; Jūratė Šaltytė Benth; Jakob S. Johansen; Finn O. Larsen; Julia S. Johansen; Anne H. Ree

    In colorectal cancer (CRC), hepatic arterial infusion (HAI) chemotherapy may convert primarily unresectable CRC liver metastases (CLM) into resectability, although the risk of metastatic recurrence remains high after CLM ablation. We investigated the role of antitumour immunity invoked by first‐line oxaliplatin‐HAI for long‐term CLM outcome. In a prospective study cohort of primarily unresectable CLM, we assessed patients' fms‐related tyrosine kinase 3 ligand (FLT3LG) in serum, reflecting opportune intratumoural immune activity, at baseline and following 1–3 sequences of oxaliplatin‐HAI. The end points were CLM resectability and overall survival. Patients who presented an immediate twofold increment of circulating FLT3LG during the treatment and at its completion were scored as CLM resectable (16.4% with both features), were alive at final follow‐up 8–12 years later. All patients experienced FLT3LG increase during the treatment course, but those who remained unresectable or had the disease converted but presented a slow and gradual FLT3LG accretion, later died of the metastatic disease. These data provide further support to our previous findings that tumour‐directed immunity invoked by oxaliplatin‐containing therapy predicts excellent outcome of early advanced CRC if macroscopic tumour ablation is rendered possible by the ‘classic’ tumour response to the cytotoxic treatment.

    更新日期:2020-01-07
  • Comparing the effectiveness of different EGFR‐TKIs in patients with EGFR mutant non–small‐cell lung cancer: A retrospective cohort study in Taiwan
    Int. J. Cancer (IF 4.982) Pub Date : 2020-01-07
    Yao‐Yu Hsieh; Wei‐Tse Fang; Yu‐Wen Lo; Yi‐Han Chen; Li‐Nien Chien

    The study was to compare the effectiveness of different epidermal growth factor receptor—tyrosine kinase inhibitors (EGFR‐TKIs) in patients with advanced non‐small‐cell lung cancer (NSCLC) and received EGFR‐TKIs as first‐line therapy. This retrospective cohort study was conducted using data from real‐world settings. Patients with stage IIIB and IV NSCLC and first received gefitinib, erlotinib, or afatinib between 2011 and 2015 were included. The date of the first claim for EGFR‐TKIs was set as the index date. Study endpoints were all‐cause death and treatment failure that was defined when patients added on or switched to chemotherapy or terminal care. A total of 5,940 patients, including 3,982 (67.0%) receiving gefitinib, 1,207 (20.3%) receiving erlotinib, and 751 (12.7%) receiving afatinib, were eligible for this study. The 1‐year overall survival (OS) rates for gefitinib, erlotinib, and afatinib groups were 74% (95% confidence interval [CI]: 72–75%), 75% (95% CI: 73–77%), and 80% (95% CI: 77–83%), respectively. Compared to gefitinib, afatinib was associated with a lower risk of all‐cause death (adjusted hazard ratio [aHR] = 0.82, 95% CI: 0.72–0.93) but not erlotinib (aHR = 0.95, 95% CI: 0.86–1.05). Similar results were also found regarding the effectiveness of treatment. All the three EGFR‐TKIs showed no differences for both outcomes among patients with an Eastern Cooperative Oncology Group Performance Score of 2. The real‐world data exhibited afatinib was more likely to be used for younger patients in a better condition than other EGFR inhibitors, and observed prolonged OS and treatment effectiveness compared to gefitinib after performing a multivariate Cox regression analysis.

    更新日期:2020-01-07
  • The transcription factor FLI1 promotes cancer progression by affecting cell cycle regulation
    Int. J. Cancer (IF 4.982) Pub Date : 2020-01-07
    Beiping Miao; Andrea S. Bauer; Katrin Hufnagel; Yenan Wu; Marija Trajkovic‐Arsic; Anna C. Pirona; Nathalia Giese; Jussi Taipale; Jens T. Siveke; Jörg D. Hoheisel; Smiths Lueong

    Binding of transcription factors to mutated DNA sequences is a likely regulator of cancer progression. Noncoding regulatory mutations such as those on the core promoter of the gene encoding human telomerase reverse transcriptase have been shown to affect gene expression in cancer. Using a protein microarray of 667 transcription factor DNA‐binding domains and subsequent functional assays, we looked for transcription factors that preferentially bind the mutant hTERT promoter and characterized their downstream effects. One of them, friend leukemia integration 1 (FLI1), which belongs to the E26 transforming‐specific family of transcription factors, exhibited particularly strong effects with respect to regulating hTERT expression, while the even better binding ELK3 did not. Depletion of FLI1 decreased expression of the genes for cyclin D1 (CCND1) and E2F transcription factor 2 (E2F2) resulting in a G1/S cell cycle arrest and in consequence a reduction of cell proliferation. FLI1 also affected CMTM7, another gene involved in G1/S transition, although by another process that suggests a balanced regulation of the tumor suppressor gene's activity via opposing regulation processes. FLI1 expression was found upregulated and correlated with an increase in CCND1 expression in pancreatic cancer and brain tumors. In non‐neoplastic lung cells, however, FLI1 depletion led to rapid progression through the cell cycle. This coincides with the fact that FLI1 is downregulated in lung tumors. Taken together, our data indicate a cell cycle regulatory hub involving FLI1, hTERT, CCND1 and E2F2 in a tissue‐ and context‐dependent manner.

    更新日期:2020-01-07
  • Lifestyle Factors and Risk of Myeloproliferative Neoplasms in the NIH‐AARP Diet and Health Study
    Int. J. Cancer (IF 4.982) Pub Date : 2020-01-06
    Nikolai A. Podoltsev; Xiaoyi Wang; Rong Wang; Jonathan N. Hofmann; Linda M. Liao; Amer M. Zeidan; Ruben Mesa; Xiaomei Ma

    The etiology of Philadelphia chromosome negative myeloproliferative neoplasms (MPN) is largely unknown. We assessed potential associations between lifestyle factors and MPN risk in the NIH‐AARP Diet and Health Study. In this prospective cohort with 463,049 participants aged 50‐71 years at baseline (1995‐1996) and a median follow‐up of 15.5 years, we identified 490 MPN cases, including 190 with polycythemia vera (PV) and 146 with essential thrombocythemia (ET). Multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Smoking was not associated with MPN risk in the overall cohort, but analyses stratified by sex suggested that smoking increased the risk of MPN in women (former smoker vs. non‐smokers, HR=1.43, 95% CI: 1.03‐2.00, p=0.03; current smokers vs. non‐smokers, HR=1.71, 95% CI: 1.08‐2.71, p=0.02). Coffee consumption was inversely associated with the risk of PV (high vs. low intake, HR=0.53, 95% CI: 0.33‐0.84, p‐trend<0.01), but not the risk of ET or MPN overall. Further analysis revealed an inverse association between amount of caffeine intake and PV risk (high vs. low intake, HR= 0.55, 95% CI: 0.39‐0.79, p‐trend<0.01). While the consumption of caffeinated coffee appeared to confer a protective effect against PV, the consumption of decaffeinated coffee did not. This large prospective study identified smoking as a risk factor for MPN in women and suggests that caffeine intake is associated with a lower risk of PV.

    更新日期:2020-01-06
  • Ovarian cancer‐associated mesothelial cells induce acquired platinum‐resistance in peritoneal metastasis via the FN1/Akt signaling pathway
    Int. J. Cancer (IF 4.982) Pub Date : 2020-01-06
    Masato Yoshihara; Hiroaki Kajiyama; Akira Yokoi; Mai Sugiyama; Yoshihiro Koya; Yoshihiko Yamakita; Wenting Liu; Kae Nakamura; Yoshinori Moriyama; Hiroaki Yasui; Shiro Suzuki; Yusuke Yamamoto; Carmela Ricciardelli; Akihiro Nawa; Kiyosumi Shibata; Fumitaka Kikkawa

    Peritoneal dissemination of ovarian cancer (OvCa) arises from the surface of the peritoneum, covered by monolayer of mesothelial cells (MCs). Given that both OvCa cells and MCs are present in the same peritoneal metastatic microenvironment, they may establish cell‐to‐cell crosstalk or phenotypic alterations including the acquisition of platinum‐resistance in OvCa cells. Herein, we report how OvCa‐associated mesothelial cells (OCAMs) induce platinum‐resistance in OvCa cells through direct cell‐to‐cell crosstalk. We evaluated mutual associations between OvCa cells and human primary MCs with in vitro co‐culturing experimental models and in silico omics data analysis. The role of OCAMs was also investigated using clinical samples and in vivo mice models. Results of in vitro experiments show that mesenchymal transition is induced in OCAMs primarily by TGF‐β1 stimulation. Furthermore, OCAMs influence the behavior of OvCa cells as a component of the tumor microenvironment of peritoneal metastasis. Mechanistically, OCAMs can induce decreased platinum‐sensitivity in OvCa cells via induction of the FN1/Akt signaling pathway via cell‐to‐cell interactions. Histological analysis of OvCa peritoneal metastasis also illustrated FN1 expression in stromal cells that is supposed to originate from MCs. Further, we also confirmed activation of Akt signaling in OvCa cells in contact with TGF‐β1 stimulated peritoneum, using an in vivo mice model. Our results suggest that the tumor microenvironment, enhanced by direct cell‐to‐cell crosstalk between OvCa cells and OCAMs, induces acquisition of platinum‐resistance in OvCa cells, which may serve as a novel therapeutic target for prevention of OvCa peritoneal dissemination.

    更新日期:2020-01-06
  • A Functional Variant Near XCL1 Gene Improves Breast Cancer Survival via Promoting Cancer Immunity
    Int. J. Cancer (IF 4.982) Pub Date : 2020-01-06
    Wen‐Cheng Chou; Chia‐Ni Hsiung; Wei‐Ting Chen; Ling‐Ming Tseng; Hui‐Chun Wang; Hou‐Wei Chu; Ming‐Feng Hou; Jyh‐Cherng Yu; Chen‐Yang Shen

    Most genome‐wide association studies (GWASs) identify genetic variants for breast cancer occurrence. In contrast, few are for recurrence and mortality. We conducted a GWAS on breast cancer survival after diagnosis in estrogen receptor‐positive patients, including 953 Taiwanese patients with 159 events. Through Cox proportional hazard models estimation, we identified 24 risk SNPs with P < 1 x 10‐5. Based on imputation and integrated analysis, one SNP, rs1024176 (located in 1q24.2, P = 2.43 × 10‐5) was found to be a functional variant associated with breast cancer survival and XCL1 gene expression. A series of experimental approaches, including cell‐based analyses and CRISPR/Cas9 genome‐editing system were then used and identified the transcription factor MYBL2 was able to discriminately bind to the A allele of rs1024176, the protective variant for breast cancer survival, which promoted XCL1 expression, but not to the G allele of rs1024176. The chemokine XCL1 attracts type 1 dendritic cells (DC1s) to the tumor microenvironment. In breast cancer tissues, we applied a two‐step Mendelian randomization analysis, using expression quantitative trait loci as instrument variables, to confirm higher XCL1 expression was correlated with higher DC1 signatures and favorable disease progression, through the causal effect of rs1024176‐A allele. Our study supports the genetic effect on preventing breast cancer survival through XCL1‐induced DC1 recruitment in tumor microenvironment.

    更新日期:2020-01-06
  • Reactive stroma and trastuzumab resistance in HER2‐positive early breast cancer
    Int. J. Cancer (IF 4.982) Pub Date : 2020-01-06
    Amir Sonnenblick; Mali Salmon‐Divon; Roberto Salgado; Efrat Dvash; Noam Pondé; Tamar Zahavi; Asher Salmon; Sibylle Loibl; Carsten Denkert; Heikki Joensuu; Lieveke Ameye; Gert Van den Eynden; Pirkko‐Liisa Kellokumpu‐Lehtinen; Amos Azaria; Sherene Loi; Stefan Michiels; François Richard; Christos Sotiriou

    We investigated the value of reactive stroma as a predictor for trastuzumab resistance in patients with early HER2‐positive breast cancer receiving adjuvant therapy.

    更新日期:2020-01-06
  • The Association between Fasting Blood Glucose Trajectory and Cancer Risk in Chinese Population Without Diabetes
    Int. J. Cancer (IF 4.982) Pub Date : 2020-01-04
    Xiaoshuang Feng; Gang Wang; Zhangyan Lyu; Shuohua Chen; Luopei Wei; Xin Li; Yan Wen; Yuheng Chen; Shuanghua Xie; Hong Cui; Hongda Chen; Jiang Li; Chunqing Lin; Jiansong Ren; Jufang Shi; Shouling Wu; Min Dai; Ni Li; Jie He

    To examine the associations between fasting blood glucose (FBG) trajectories, the changes in FBG over time, and the risk of cancer, particularly for gastrointestinal cancer, we enrolled 69 742 participants without diabetes from the Kailuan cohort. FBG trajectories (2006‐2010) were modeled by group‐based trajectory modeling, and five trajectories were identified: low‐increasing (n=6275), moderate‐stable (n=44 120), moderate‐increasing (n=10 149), elevated‐decreasing (n=5244), and elevated‐stable (n=3954). A total of 1364 cancer cases were accumulated between 2010 and 2015, including 472 gastrointestinal cancer cases. We used Cox proportional hazards regression models to evaluate the associations between FBG trajectory patterns and the risk of cancer. We further assessed the associations while carefully controlling for initial body mass index (BMI) in 2006 and for changes in BMI during 2006‐2010. Relative to the moderate‐stable group, we found a higher hazard ratio (HR) for overall cancer in the low‐increasing group (HR=1.26, 95% confidence interval (CI) 1.06‐1.50); and for gastrointestinal cancer in the elevated‐stable group (HR=1.66, 95% CI 1.22‐2.26). Moreover, among participants with an initial BMI ≥25 kg/m2, a positive association with the low‐increasing group was observed for both overall cancer and gastrointestinal cancer (HR=1.54, 95% CI 1.17‐2.04; HR=1.65, 95% CI 1.02‐2.66; respectively); among participants with a stable BMI (4.40% loss‐5.15% gain), a positive association with the elevated‐stable group was observed both for overall cancer and gastrointestinal cancer (HR=1.43, 95% CI 1.10‐1.87; HR=1.95, 95% CI 1.33‐2.86; respectively). This study observed that FBG trajectories were associated with cancer risk among participants without diabetes, and BMI may modify the associations.

    更新日期:2020-01-04
  • The prognostic value of the tumor‐stroma ratio is most discriminative in patients with grade III or triple negative breast cancer
    Int. J. Cancer (IF 4.982) Pub Date : 2020-01-04
    Kiki M.H. Vangangelt; Andrew R. Green; Isabelle (M) F. Heemskerk; Danielle Cohen; Gabi W. van Pelt; Marcelo Sobral‐Leite; Marjanka K. Schmidt; Hein Putter; Emad A. Rakha; Rob A.E.M. Tollenaar; Wilma E. Mesker

    The tumor‐stroma ratio (TSR) was evaluated as a promising parameter for breast cancer prognostication in clinically relevant subgroups of patients. The TSR was assessed on hematoxylin and eosin stained tissue slides of 1794 breast cancer patients from the Nottingham City Hospital. An independent second cohort of 737 patients from the Netherlands Cancer Institute to Antoni van Leeuwenhoek was used for evaluation. In the Nottingham Breast Cancer series, the TSR was an independent prognostic parameter for recurrence‐free survival (RFS) (HR 1.35, 95% CI 1.10 to 1.66, p = 0.004). The interaction term was statistically significant for grade and triple‐negative status. Multivariate Cox regression analysis showed a more pronounced effect of the TSR for RFS in grade III tumors (HR 1.89, 95% CI 1.43 to 2.51, p < 0.001) and triple‐negative tumors (HR 1.86, 95% CI 1.10 to 3.14, p = 0.020). Comparable hazard ratios and confidence intervals were observed for grade and triple‐negative status in the ONCOPOOL study. The prognostic value of TSR was not modified by age, tumor size, histology, estrogen receptor status, progesterone receptor status, human epidermal growth factor receptor 2 status or lymph node status. In conclusion, patients with a stroma‐high tumor had a worse prognosis compared to patients with a stroma‐low tumor. The prognostic value of the TSR is most discriminative in grade III tumors and triple‐negative tumors. The TSR was not modified by other clinically relevant parameters making it a potential factor to be included for improved risk stratification.

    更新日期:2020-01-04
  • Phenotype Molding of T Cells in Colorectal Cancer by Single‐cell Analysis
    Int. J. Cancer (IF 4.982) Pub Date : 2020-01-04
    Jiabo Di; Maoxing Liu; Yingcong Fan; Pin Gao; Zaozao Wang; Beihai Jiang; Xiangqian Su

    The majority of patients with microsatellite stable (MSS) colorectal cancer (CRC) do not benefit from the immunotherapies directed at rescuing T cell functions. Therefore, complete understanding of T cell phenotypes and functional status in the CRC microenvironment is desirable. Here, we applied single‐cell mass cytometry to mold the T cell phenotype in 18 patients with MSS CRC for better understanding of CRC as a systemic disease and to search for tumor‐driven T cell profile changes. We show inter‐ and intrapatient phenotypic diversity of T cell subsets. We revealed increased immunosuppressive/exhausted T cell phenotypes at tumor lesions. CD8+CD28− immunosenescent T cells with impaired proliferation capacity dominate the T cell compartment. As per the transcriptome and quantitative real time‐PCR analysis, the accumulation of immunosuppressive cells is driven by the tumor microenvironment. T cell profiles are similar between patients at early and late stages, indicating that the immunosuppressive microenvironment is formulated early during CRC development. Mapping of T cell infiltration and understanding of the mechanisms underlying their regulation may provide valuable information to boost the immune response in patients with MSS CRC.

    更新日期:2020-01-04
  • Premetastatic niches, exosomes and circulating tumor cells: Early mechanisms of tumor dissemination and the relation to surgery
    Int. J. Cancer (IF 4.982) Pub Date : 2020-01-03
    Hans Raskov; Adile Orhan; Ali Salanti; Ismail Gögenur

    The physiological stress response to surgery promotes wound healing and functional recovery and includes the activation of neural, inflammatory and proangiogenic signaling pathways. Paradoxically, the same pathways also promote metastatic spread and growth of residual cancer. Human and animal studies show that cancer surgery can increase survival, migration and proliferation of residual tumor cells. To secure the survival and growth of disseminated tumor cells, the formation of premetastatic niches in target organs involves a complex interplay between microenvironment, immune system, circulating tumor cells, as well as chemical mediators and exosomes secreted by the primary tumor. This review describes the current understanding of the early mechanisms of dissemination, as well as how surgery may facilitate disease progression.

    更新日期:2020-01-04
  • Prognostic value of DNA ploidy and automated assessment of stroma fraction in prostate cancer
    Int. J. Cancer (IF 4.982) Pub Date : 2020-01-02
    Elin Ersvær; Tarjei S. Hveem; Ljiljana Vlatkovic; Bjørn Brennhovd; Andreas Kleppe; Kari A.R. Tobin; Manohar Pradhan; Karolina Cyll; Håkon Wæhre; David J. Kerr; Håvard E. Danielsen

    The combination of DNA ploidy and automatically estimated stroma fraction has been shown to correlate with recurrence and cancer death in colorectal cancer. We aimed to extend this observation and evaluate the prognostic importance of this combined marker in prostate cancer. DNA ploidy status was determined by image cytometry and the stroma fraction was estimated automatically on hematoxylin and eosin stained sections in three tumor samples from each patient to account for tumor heterogeneity. The optimal threshold for low (≤56%) and high (>56%) stroma fraction was identified in a discovery cohort (n = 253). The combined marker was validated in an independent patient cohort (n = 259) with biochemical recurrence as endpoint. The combined marker predicted biochemical recurrence independently in the validation cohort. Multivariable analysis showed that the highest risk of recurrence was observed for patients with samples that had both non‐diploid ploidy status and a high stroma fraction (hazard ratio: 2.51, 95% confidence interval: 1.18–5.34). In conclusion, we suggest the combination of DNA ploidy and automatically estimated stroma fraction as a prognostic marker for the risk stratification of prostate cancer patients. It may also be a potential generic marker as concurrent results have been described in colorectal cancer.

    更新日期:2020-01-04
  • Antiviral therapy against chronic hepatitis C is associated with a reduced risk of oral cancer
    Int. J. Cancer (IF 4.982) Pub Date : 2020-01-02
    Tung‐Hung Su; Tai‐Chung Tseng; Chun‐Jen Liu; Shih‐Wan Chou; Chen‐Hua Liu; Hung‐Chih Yang; Pei‐Jer Chen; Ding‐Shinn Chen; Chi‐Ling Chen; Jia‐Horng Kao

    To identify the risk factors of oral cancer, we investigated the association between chronic hepatitis C (CHC) and oral cancer, and the development of oral cancer after anti‐hepatitis C virus (HCV) therapy. We conducted a nationwide, population‐based cohort study from 2004 to 2012 from the Taiwan National Health Insurance Research Database. CHC patients without anti‐HCV therapy were matched with those non‐HCV patients by age, sex and comorbidities. Moreover, CHC patients who underwent pegylated interferon and ribavirin (PegIFN/RBV) anti‐HCV therapy were matched with CHC patients without anti‐HCV therapy. A total of 100,058 patients were included in the HCV cohort and non‐HCV cohorts, respectively. Their mean age was 59 years and 50% of these were male. CHC infection significantly increased the cumulative incidence of lichen planus and oral cancer. After adjustment for confounders and competing mortality, CHC infection significantly increased the risk of oral cancer (hazard ratio [HR]: 1.677, 95% confidence interval [CI]: 1.392–2.020, p < 0.001). Another 23,735 CHC patients without anti‐HCV therapy were matched with 23,735 CHC patients in the treatment cohort. After adjustment for confounders and competing for mortality, the risk of oral cancer was significantly reduced in CHC patients receiving anti‐HCV therapy (HR: 0.652, 95% CI: 0.479–0.887, p = 0.007). To minimize the inclusion of pre‐existing unidentified oral cancer, we excluded oral cancer developed within the first year of CHC or anti‐HCV therapy and found these associations remained statistically significant. In conclusion, CHC significantly increases the risk of oral cancer. Moreover, PegIFN/RBV antiviral therapy significantly reduces the risk of HCV‐related oral cancer.

    更新日期:2020-01-04
  • Nonbreast cancer incidence, treatment received and outcomes: Are there differences in breast screening attendees versus nonattendees?
    Int. J. Cancer (IF 4.982) Pub Date : 2020-01-02
    Euan Walpole; Nathan Dunn; Philippa Youl; Hazel Harden; Colin Furnival; Julie Moore; Kate Taylor; Elizabeth Evans; Shoni Philpot

    While reductions in breast cancer mortality have been evident since the introduction of population‐based breast screening in women aged 50–74 years, participation in cancer screening programs can be influenced by several factors, including health system and those related to the individual. In our study, we compared cancer incidence and mortality for several cancer types other than breast cancer, noncancer mortality and patterns of treatment amongst women who did and did not participate in mammography screening. All women aged 50–65 years enrolled on the Queensland Electoral Roll in 2000 were included. The study population was then linked to records from the population‐based breast screening program and private fee‐for‐service screening options to establish screened and unscreened cohorts. Diagnostic details for selected cancers and cause of death were obtained from the Queensland Oncology Repository. We calculated incidence rate ratios and hazard ratios comparing screened and unscreened cohorts. Among screened compared to unscreened women, we found a lower incidence of cancers of the lung, cervix, head and neck and esophagus and an increase in colorectal cancers. Cancer mortality (excluding breast cancer) was 35% lower among screened compared to unscreened women and they were also about 23% less likely to be diagnosed with distant disease. Screened compared to unscreened women were more likely to receive surgery and less likely to receive no treatment. Our study adds further to the population data examining outcomes among women participating in mammography screening.

    更新日期:2020-01-02
  • Long term risk of colorectal cancer after screen detected adenoma: Experiences from a Danish gFOBT positive screening cohort
    Int. J. Cancer (IF 4.982) Pub Date : 2020-01-02
    Andreas Bjerrum; Jan Lindebjerg; Ole Andersen; Anders Fischer; Elsebeth Lynge

    Faecal occult blood test (FOBT) screening for colorectal cancer (CRC) is implemented in several countries. Approximately half of all FOBT positive persons have screen detected adenomas. Despite removal of these, patients with large/multiple adenomas have increased risk of later developing new advanced adenomas and CRC. International guidelines exist for colonoscopic surveillance following adenoma removal. These divide patients in to low‐, intermediate and high‐risk groups. We followed 711 FOBT positive patients with screening adenoma identified during population based CRC screening in two Danish counties in 2005‐2006. As reference population, we included 1,240,348 persons in the same age group from the rest of Denmark not included in the screening. We estimated the long‐term CRC risk stratified by adenoma findings during screening and compared with the reference group. After 12 years follow‐up, the CRC incidence among all adenoma patients was 322 cases per 100,000 person‐years (95% CI: 212‐489) ranging from 251 (95% CI: 94‐671) to 542 (95% CI: 300‐978) cases per 100,000 person‐years in the low‐risk and high‐risk groups, respectively. In the reference population, the CRC incidence was 244 (95% CI: 242‐247) per 100,000. Patients with screen detected high‐risk adenomas after a positive FOBT had an almost doubled risk of CRC compared to the reference population (aHR 1.95, 95% CI: 1.08‐3.51), and the incidence in those with no follow‐up visits was over 3.6 (aHR 3.64 ,95% CI: 1.82‐7.29) times the incidence in the reference population. The increased CRC risk could be controlled if high‐risk patients underwent follow‐up colonoscopy (aHR 0.87, 95% CI: 0.28‐2.69).

    更新日期:2020-01-02
  • Impact of screening on cervical cancer incidence: A population‐based case–control study in the United States
    Int. J. Cancer (IF 4.982) Pub Date : 2019-12-31
    Rebecca Landy; Peter D. Sasieni; Christopher Mathews; Charles L. Wiggins; Michael Robertson; Yolanda J. McDonald; Daniel W. Goldberg; Isabel C. Scarinci; Jack Cuzick; Cosette M. Wheeler;

    Cervical cancer is widely preventable through screening, but little is known about the duration of protection offered by a negative screen in North America. A case–control study was conducted with records from population‐based registries in New Mexico. Cases were women diagnosed with cervical cancer in 2006–2016, obtained from the Tumor Registry. Five controls per case from the New Mexico HPV Pap Registry were matched to cases by sex, age and place of residence. Dates and results of all cervical screening and diagnostic tests since 2006 were identified from the pap registry. We estimated the odds ratio of nonlocalized (Stage II+) and localized (Stage I) cervical cancer associated with attending screening in the 3 years prior to case‐diagnosis compared to women not screened in 5 years. Of 876 cases, 527 were aged 25–64 years with ≥3 years of potential screening data. Only 38% of cases and 61% of controls attended screening in a 3‐year period. Women screened in the 3 years prior to diagnosis had 83% lower risk of nonlocalized cancer (odds ratio [OR] = 0.17, 95% CI: 0.12–0.24) and 48% lower odds of localized cancer (OR = 0.52, 95% CI: 0.38–0.72), compared to women not screened in the 5 years prior to diagnosis. Women remained at low risk of nonlocalized cancer for 3.5–5 years after a negative screen compared to women with no negative screens in the 5 years prior to diagnosis. Routine cervical screening is effective at preventing localized and nonlocalized cervical cancers; 3 yearly screening prevents 83% of nonlocalized cancers, with no additional benefit of more frequent screening. Increasing screening coverage remains essential to further reduce cervical cancer incidence.

    更新日期:2019-12-31
  • CTLA4 blockade promotes vessel normalization in breast tumors via the accumulation of eosinophils
    Int. J. Cancer (IF 4.982) Pub Date : 2019-12-28
    Xichen Zheng; Naidong Zhang; Long Qian; Xuexiang Wang; Peng Fan; Jiajie Kuai; Siyang Lin; Changpeng Liu; Wen Jiang; Songbing Qin; Haifeng Chen; Yuhui Huang

    Immune checkpoint blockade (ICB) has shown long‐term survival benefits, but only in a small fraction of cancer patients. Recent studies suggest that improved vessel perfusion by ICB positively correlates with its therapeutic outcomes. However, the underlying mechanism of such a process remains unclear. Here, we show that anti‐cytotoxic T‐lymphocyte‐associated protein 4 (CTLA4) treatment‐induced tumor vessel normalization was accompanied by an increased infiltration of eosinophils into breast tumors. Eosinophil accumulation was positively correlated with the responsiveness of a breast tumor to anti‐CTLA4 therapy. Depletion of eosinophils subsequently negated vessel normalization, reduced antitumor immunity and attenuated tumor growth inhibition by anti‐CTLA4 therapy. Moreover, intratumoral accumulation of eosinophils relied on T lymphocytes and interferon γ production. Together, these results suggest that eosinophils partially mediate the antitumor effects of CTLA4 blockade through vascular remodeling. Our findings uncover an unidentified role of eosinophils in anti‐CTLA4 therapy, providing a potential new target to improve ICB therapy and to predict its efficacy.

    更新日期:2019-12-29
  • The relative risk of noncervical high‐risk human papillomavirus‐related (pre)malignancies after recurrent cervical intraepithelial neoplasia grade 3: A population‐based study
    Int. J. Cancer (IF 4.982) Pub Date : 2019-12-28
    Diede L. Loopik; Renée M. Ebisch; Joanna IntHout; Willem J. Melchers; Leon F. Massuger; Ruud L. Bekkers; Albert G. Siebers

    Women with cervical intraepithelial neoplasia grade 3 (CIN3) have a long‐lasting increased risk for noncervical high‐risk human papillomavirus (hrHPV)‐related (pre)malignancies. The aim of our study was to estimate this risk in women with recurrent CIN3 compared to women without a history of CIN3 and women with a single episode of CIN3. Women with a CIN3 diagnosis between 1990 and 2010 were obtained from the Dutch Pathology Registry (PALGA) and matched with a control group of women without CIN3. Analysis has been conducted in a subset of women with recurrent CIN3, defined as reoccurrence minimally 2 years post‐treatment. Cases of noncervical hrHPV‐related (pre)malignancies of the anus, vulva, vagina and oropharynx were identified until 2015 and incidence rate ratios (IRRs) were estimated. Then, 1,797 women with recurrent CIN3 were included with a median age of 34 years (range 18–76) and 31,594 person‐years of follow‐up. Women with recurrent CIN3 had an increased risk of developing noncervical hrHPV‐related (pre)malignancies compared to women without CIN3 with an IRR of 25.96 (95%CI 6.32–106.58). The IRR was 2.48 (95% CI 1.87–3.30) compared to women with a single episode of CIN3. Studies on posttreatment follow‐up and prophylactic hrHPV vaccination are warranted.

    更新日期:2019-12-29
  • Testicular cancer incidence predictions in Europe 2010–2035: A rising burden despite population ageing
    Int. J. Cancer (IF 4.982) Pub Date : 2019-12-28
    Ariana Znaor; Niels E. Skakkebæk; Ewa Rajpert‐De Meyts; Mathieu Laversanne; Tomislav Kuliš; Jason Gurney; Diana Sarfati; Katherine A. McGlynn; Freddie Bray

    Testicular cancer is the most common cancer among young men of European ancestry, with about one‐third of all cases occurring in Europe. With the historically increasing trends in some high‐incidence populations reported to have stabilised in recent years, we aimed to assess recent trends and predict the future testicular cancer incidence burden across Europe. We extracted testicular cancer (ICD‐10 C62) incidence data from Cancer Incidence in Five Continents Volumes VII–XI and complemented this with data published by registries from 28 European countries. We predicted cancer incidence rates and the number of incident cases in Europe in the year 2035 using the NORDPRED age‐period‐cohort model. Testicular cancer incidence rates will increase in 21 out of 28 countries over the period 2010–2035, with trends attenuating in the high‐incidence populations of Denmark, Norway, Switzerland and Austria. Although population ageing would be expected to reduce the number of cases, this demographic effect is outweighed by increasing risk, leading to an overall increase in the number of cases by 2035 in Europe, and by region (21, 13 and 32% in Northern, Western and Eastern Europe, respectively). Declines are however predicted in Italy and Spain, amounting to 12% less cases in 2035 in Southern Europe overall. In conclusion, the burden of testicular cancer incidence in Europe will continue to increase, particularly in historically lower‐risk countries. The largest increase in the number of testicular cancer patients is predicted in Eastern Europe, where survival is lower, reinforcing the need to ensure the provision of effective treatment across Europe.

    更新日期:2019-12-29
  • Clinical value of serum bone resorption markers for predicting clinical outcomes after use of bone modifying agents in metastatic bone tumors: A prospective cohort study
    Int. J. Cancer (IF 4.982) Pub Date : 2019-12-28
    Hiroshi Urakawa; Yuichi Ando; Tetsunari Hase; Toyone Kikumori; Eisuke Arai; Osamu Maeda; Ayako Mitsuma; Mihoko Sugishita; Tomoya Shimokata; Kunihiro Ikuta; Naoki Ishiguro; Yoshihiro Nishida

    Bone modifying agents (BMAs) have become a standard treatment to prevent skeletal‐related events (SREs) in bone metastases (BMs). The aim of our study is to determine the clinical value of serum bone resorption markers for predicting clinical outcomes after using BMAs in patients with BM. Patients were enrolled between May 2013 and October 2017 at the Nagoya University Hospital, Japan. We prospectively observed changes in pyridinoline cross‐linked carboxyterminal telopeptide of type I collagen (ICTP) and tartrate‐resistant acid phosphatase 5b (TRACP‐5b) during treatment with BMAs. The relationship between serum markers before and after treatment and clinical outcomes such as progression of bone disease (BD), SREs and overall survival (OS) were evaluated. Pearson chi‐square test and Kaplan–Meier product limit methods were used for analysis. Sixty‐seven patients were analyzed. The primary tumor sites were 21 lung, 16 breast and 30 others. Forty and 27 patients were treated with Denosumab and Zoledronic acid, respectively. Progression of BDs, SREs and death were observed in 10, 16 and 31 cases, respectively. The median follow‐up period after using BMAs was 12.3 (range 0.3–66.3) months. ICTP at 3–4 weeks was significantly correlated with increasing BD progression, SREs and death after treatment in both the whole and lung cancer cohorts. Base line ICTP and TRACP‐5b were also associated with increasing BD progression in the whole cohort. Our study showed that early posttreatment ICTP is useful for predicting BD progression, SREs and OS after use of BMAs in patients with BM and even in patients with lung cancer BM.

    更新日期:2019-12-29
  • Tobacco smoking, chewing habits, alcohol drinking and the risk of head and neck cancer in Nepal
    Int. J. Cancer (IF 4.982) Pub Date : 2019-12-27
    Chun‐Pin Chang; Bhola Siwakoti; Amir Sapkota; Dej K. Gautam; Yuan‐Chin Amy Lee; Marcus Monroe; Mia Hashibe

    Although tobacco smoking, pan chewing and alcohol drinking are important risk factors for head and neck cancer (HNC), the HNC risks conferred by products available in Nepal for these habits are unknown. We assessed the associations of tobacco smoking, chewing habits, and alcohol drinking with HNC risk in Nepal. A case–control study was conducted in Nepal with 549 incident HNC cases and 601 controls. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression adjusting for potential confounders. We observed increased HNC risk for tobacco smoking (OR: 1.54; 95% CI: 1.14, 2.06), chewing habits (OR: 2.39; 95% CI: 1.77, 3.23), and alcohol drinking (OR: 1.57; 95% CI: 1.14, 2.18). The population attributable fraction (PAF) was 24.3% for tobacco smoking, 39.9% for chewing habits and 23.0% for alcohol drinking. Tobacco smoking, chewing habits, and alcohol drinking might be responsible for 85.3% of HNC cases. Individuals who smoked tobacco, chewed products and drank alcohol had a 13‐fold increase in HNC risk (OR: 12.83; 95% CI: 6.91, 23.81) compared to individuals who did not have any of these habits. Both high frequency and long duration of these habits were strong risk factors for HNC among the Nepalese with clear dose–response trends. Preventive strategies against starting these habits and support for quitting these habits are necessary to decrease the incidence of HNC in Nepal.

    更新日期:2019-12-27
  • Discovery of rare coding variants in OGDHL and BRCA2 in relation to breast cancer risk in Chinese women
    Int. J. Cancer (IF 4.982) Pub Date : 2019-12-27
    Xingyi Guo; Jirong Long; Zhishan Chen; Xiao‐ou Shu; Yong‐Bing Xiang; Wanqing Wen; Chenjie Zeng; Yu‐Tang Gao; Qiuyin Cai; Wei Zheng

    The missing heritability of breast cancer could be partially attributed to rare variants (MAF < 0.5%). To identify breast cancer‐associated rare coding variants, we conducted whole‐exome sequencing (~50×) in genomic DNA samples obtained from 831 breast cancer cases and 839 controls of Chinese females. Using burden tests for each gene that included rare missense or predicted deleterious variants, we identified 29 genes showing promising associations with breast cancer risk. We replicated the association for two genes, OGDHL and BRCA2, at a Bonferroni‐corrected p < 0.05, by genotyping an independent set of samples from 1,628 breast cancer cases and 1,943 controls. The association for OGDHL was primarily driven by three predicted deleterious variants (p.Val827Met, p.Pro839Leu, p.Phe836Ser; p < 0.01 for all). For BRCA2, we characterized a total of 27 disruptive variants, including 18 nonsense, six frameshift and three splicing variants, whereas they were only detected in cases, but none of the controls. All of these variants were either very rare (AF < 0.1%) or not detected in >4,500 East Asian women from the genome Aggregation database (gnomAD), providing additional support to our findings. Our study revealed a potential novel gene and multiple disruptive variants of BRCA2 for breast cancer risk, which may identify high‐risk women in Chinese populations.

    更新日期:2019-12-27
  • A Prospective Observational Registry Evaluating Clinical Outcomes of Radium‐223 Treatment in a Non‐study Population
    Int. J. Cancer (IF 4.982) Pub Date : 2019-12-25
    Sushil K Badrising; Rebecca D Louhanepessy; Vincent vd Noort; Jules LLM Coenen; Paul Hamberg; Aart Beeker; Nils Wagenaar; Marnix Lam; Filiz Celik; O.J.L Loosveld; Ad Oostdijk; Hanneke Zuetenhorst; John B Haanen; Erik Vegt; Wilbert Zwart; Andries M Bergman;

    The ALSYMPCA study established a 3.6 month Overall Survival (OS) benefit in metastatic Castration Resistant Prostate Cancer (mCRPC) patients treated with Radium‐223 dichloride (Ra‐223) over placebo. Here we report clinical outcomes of Ra‐223 treatment in a non‐study population. In this prospective registry, patients from 20 Dutch hospitals were included prior to Ra‐223 treatment. Clinical parameters collected included previous treatments and Adverse Events. Primary outcome was 6 months Symptomatic Skeletal Event (SSE) free survival, while secondary outcomes included Progression‐Free Survival (PFS) and Overall Survival (OS). Of the 305 patients included, 300 were evaluable. The mean age was 73.6 years, 90% had ≥6 bone metastases and 74.1% were pretreated with Docetaxel, 19.5% with Cabazitaxel and 80.5% with Abiraterone and/or Enzalutamide. Of all patients, 96.7% were treated with Ra‐223 and received a median of 5 cycles. After a median follow‐up of 13.2 months, 6 months SSE‐free survival rate was 83%, median PFS was 5.1 months and median OS was 15.2 months. 6 months SSE‐free survival rate and OS were comparable with those reported in ALSYMPCA. ‘Previous Cabazitaxel treatment’ and ‘bone‐only metastases’ were independent predictors of a shorter and longer PFS, respectively, while above median LDH and ‘bone‐only metastases’ were independent predictors of shorter and longer OS, respectively. Toxicity was similar as reported in the ALSYMPCA trial. These results suggest that in a non‐study population, Ra‐223 treatment is well‐tolerated, equally effective as in the ALSYMPCA population and that patients not previously treated with Cabazitaxel benefit most from Ra‐223.

    更新日期:2019-12-27
  • Cumulative exposure to premenopausal obesity and risk of postmenopausal cancer: A population‐based study in Icelandic women
    Int. J. Cancer (IF 4.982) Pub Date : 2019-12-24
    Hwayoung Noh; Hadrien Charvat; Heinz Freisling; Guðríður H. Ólafsdóttir; Elínborg J. Ólafsdóttir; Laufey Tryggvadóttir; Melina Arnold; Isabelle Soerjomataram

    Obesity, often assessed at one point in time, is an established risk factor of several types of cancer, however, associations with cumulative exposure to obesity across the life course are not well understood. We investigated the relationship between combined measures of duration and intensity of premenopausal overweight and obesity and the incidence of postmenopausal breast, endometrial, and colorectal cancers in Icelandic women. Body mass index (BMI) trajectories between ages 20 and 50 of 88,809 women from the Cancer Detection Clinic Cohort were predicted using growth curve models. Indicators of overweight and obesity duration and intensity were computed and their association with risk of postmenopausal breast, endometrial, and colorectal cancers was examined using multivariate Cox models for subjects followed‐up beyond the age of 50 (n = 67,488). During a mean follow‐up of 17 years, incident events of 3,016 postmenopausal breast, 410 endometrial and 987 colorectal cancers were ascertained. Each 0.1 kg/m2 per year increase in BMI between ages 20 and 50 was positively associated with risks of postmenopausal breast, endometrium and colorectal cancers with hazard ratios equal to 1.09 (95% Confidence Interval (CI):1.04–1.13), 1.31 (95% CI: 1.18–1.44) and 1.10 (95% CI: 1.00–1.21), respectively. Compared to women who were never obese, cumulative BMI × years of obesity were linearly positively associated with risk of endometrial cancer, whereas the association with breast cancer was initially positive, but leveled off with increasing cumulative BMI × years. Cumulative exposure to obesity may provide additional insights into the etiology of cancer and should be considered in future studies that assess obesity–cancer relationships.

    更新日期:2019-12-25
  • Abdominal and gluteofemoral size and risk of liver cancer: The liver cancer pooling project
    Int. J. Cancer (IF 4.982) Pub Date : 2019-12-23
    Andrea A. Florio; Peter T. Campbell; Xuehong Zhang; Anne Zeleniuch‐Jacquotte; Jean Wactawski‐Wende; Stephanie A. Smith‐Warner; Rashmi Sinha; Tracey G. Simon; Howard D. Sesso; Catherine Schairer; Lynn Rosenberg; Thomas E. Rohan; Kim Robien; Andrew G. Renehan; Mark P. Purdue; Jenny N. Poynter; Julie R. Palmer; Christina C. Newton; Yunxia Lu; Martha S. Linet; Linda M. Liao; I‐Min Lee; Jill Koshiol; Cari M. Kitahara; Victoria A. Kirsh; Jonathan N. Hofmann; Barry I. Graubard; Edward Giovannucci; John M. Gaziano; Susan M. Gapstur; Neal D. Freedman; Jane Demuth; Dawn Q. Chong; Andrew T. Chan; Julie E. Buring; Patrick T. Bradshaw; Laura E. Beane Freeman; Katherine A. McGlynn; Jessica L. Petrick

    Obesity is known to be associated with primary liver cancer (PLC), but the separate effects of excess abdominal and gluteofemoral size are unclear. Thus, we examined the association between waist and hip circumference with risk of PLC overall and by histologic type—hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). The Liver Cancer Pooling Project is a consortium of prospective cohort studies that include data from 1,167,244 individuals (PLC n = 2,208, HCC n = 1,154, ICC n = 335). Multivariable‐adjusted hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using proportional hazards regression. Waist circumference, per 5 cm increase, was associated with an 11% increased PLC risk (HR = 1.11, 95%CI: 1.09–1.14), including when adjusted for hip circumference (HR = 1.12, 95%CI: 1.08–1.17) and also when restricted to individuals in a normal body mass index (BMI) range (18.5 to <25 kg/m2; HR = 1.14, 95%CI: 1.07–1.21). Hip circumference, per 5 cm increase, was associated with a 9% increased PLC risk (HR = 1.09, 95%CI: 1.06–1.12), but no association remained after adjustment for waist circumference (HR = 0.99, 95%CI: 0.94–1.03). HCC and ICC results were similar. These findings suggest that excess abdominal size is associated with an increased risk of liver cancer, even among individuals considered to have a normal BMI. However, excess gluteofemoral size alone confers no increased risk. Our findings extend prior analyses, which found an association between excess adiposity and risk of liver cancer, by disentangling the separate effects of excess abdominal and gluteofemoral size through utilization of both waist and hip circumference measurements.

    更新日期:2019-12-23
  • Divergent breast cancer incidence trends by hormone receptor status in the state of Sarawak, Malaysia
    Int. J. Cancer (IF 4.982) Pub Date : 2019-12-23
    Hyuna Sung; Beena C.R. Devi; Tieng S. Tang; Philip S. Rosenberg; William F. Anderson; Xiaohong R. Yang

    Recent studies from high‐risk countries such as the US, Denmark and Ireland have shown rising incidence rates of hormone receptor (HR)‐positive and falling rates of HR‐negative breast cancers (BC). However, it remains unclear whether a similar pattern occurs in low‐risk countries. Detailed clinical and risk factor data were collected from 2,977 female invasive BC patients (≥20 years) in Sarawak General Hospital, Malaysia, representing 93% of the population. The population‐at‐risk was obtained from the Department of Statistics Malaysia. Secular trends in age‐standardized incidence rates were assessed using estimated average annual percent changes. Associations between established BC risk factors and tumor subtypes defined by HR or joint human epidermal growth factor receptor 2 (HR/HER2) status were examined by case–case comparisons using logistic regression. From 2006 to 2015, incidence rates increased for HR‐positive cancers by 4.46%/year (95% CI = 2.19–6.78) and decreased for HR‐negative cancers by 2.29%/year (95% CI = −4.31 to −0.24). When further stratified by HER2, the most contrasting difference in linear trends was observed between HR+/HER2− and HR−/HER2− subtypes. After controlling for potential confounders, cases with excess body weight (ORoverweight vs. normal = 0.82; 95% CI = 0.69–0.98; ORobese vs. normal = 0.62; 95% CI = 0.48–0.80), later age at first birth (OR≥26 years vs. <23 years = 0.82; 95% CI = 0.66–1.02), nulliparity (ORnulliparous vs. <23 years = 0.74; 95% CI = 0.59–0.94) and never‐breastfeeding (ORnever vs. ever = 0.73; 95% CI = 0.55–0.97) were less frequent among HR‐negative cases than among HR‐positive cases. Diverging incidence trends by HR expression were similar in Sarawak and Western countries, possibly reflecting changes in the prevalence of risk factors with opposing effects by tumor subtypes in low‐ and high‐risk populations.

    更新日期:2019-12-23
  • Human Papillomavirus types in cervical dysplasia among young HPV‐vaccinated women: Population‐based nested case‐control study
    Int. J. Cancer (IF 4.982) Pub Date : 2019-12-23
    Hanna Kann; Maria Hortlund; Carina Eklund; Joakim Dillner; Helena Faust

    Human papillomavirus (HPV) vaccines protect against infections with the most oncogenic HPV types, cervical intraepithelial neoplasia (CIN) and cervical cancer. We investigated whether development of cervical intraepithelial neoplasia (CIN) lesions in HPV‐vaccinated women is associated with vaccine‐targeted HPV types or not. Linkage of the Swedish vaccination and cervical screening registries identified all females born 1980‐2000 who had been HPV vaccinated before 2014‐12‐31 (n=305,320) and had attended cervical screening in 2006‐2018 (N=79,491). We further selected women HPV vaccinated below 17 years of age and screened in the capital region (N=5,874). Among those, 125 developed CIN and had a cervical cryopreserved sample available (42.5 % of all eligible CIN cases). After 1:2 matching to disease‐free HPV vaccinated controls (N=242), samples were analyzed for HPV DNA and associations between HPV type and CIN diagnosis were estimated with conditional logistic regression. Vaccine‐targeted HPV types were rare among both CIN cases (2.4 % HPV16, 0.8 % HPV18) and their matched controls (0.4 % HPV16 and 18). No woman had HPV6 or 11. The CIN lesions were associated with the non‐vaccine HPV types 31, 33, 42, 45, 51, 52, 56, 59 and 66. CIN lesions among young HPV vaccinated women are mostly attributable to infection with non‐vaccine HPV types. The phenomenon may be important for surveillance and design of cervical cancer control strategies.

    更新日期:2019-12-23
  • Identification of Diagnostic Metabolic Signatures in Clear Cell Renal Cell Carcinoma Using Mass Spectrometry Imaging
    Int. J. Cancer (IF 4.982) Pub Date : 2019-12-21
    Kanchustambham Vijayalakshmi; Vishnu Shankar; Ryan M. Bain; Rosalie Nolley; Geoffrey A. Sonn; Chia‐Sui Kao; Hongjuan Zhao; Robert Tibshirani; Richard N. Zare; James D. Brooks

    Clear cell renal cell carcinoma (ccRCC) is the most common and lethal subtype of kidney cancer. Intraoperative frozen section (IFS) analysis is used to confirm the diagnosis during partial nephrectomy (PN). However, surgical margin evaluation using IFS analysis is time consuming and unreliable, leading to relatively low utilization. In this study, we demonstrated the use of desorption electrospray ionization mass spectrometry imaging (DESI‐MSI) as a molecular diagnostic and prognostic tool for ccRCC. DESI‐MSI was conducted on fresh‐frozen 23 normal‐tumor paired nephrectomy specimens of ccRCC. An independent validation cohort of 17 normal‐tumor pairs were analyzed. DESI‐MSI provides two‐dimensional molecular images of tissues with mass spectra representing small metabolites, fatty acids, and lipids. These tissues were subjected to histopathologic evaluation. A set of metabolites that distinguish ccRCC from normal kidney were identified by performing least absolute shrinkage and selection operator (Lasso) and log‐ratio Lasso analysis. Lasso analysis with leave‐one‐patient‐out cross validation selected 57 peaks from over 27,000 metabolic features across 37,608 pixels obtained using DESI‐MSI of ccRCC and normal tissues. Baseline Lasso of metabolites predicted the class of each tissue to be normal or cancerous tissue with an accuracy of 94% and 76%, respectively. Combining the baseline Lasso with the ratio of glucose to arachidonic acid could potentially reduce scan time and improve accuracy to identify normal (82%) and ccRCC (88%) tissue. DESI‐MSI allows rapid detection of metabolites associated with normal and ccRCC with high accuracy. As this technology advances, it could be used for rapid intraoperative assessment of surgical margin status.

    更新日期:2019-12-21
  • Novel engineered TRAIL‐based chimeric protein strongly inhibits tumor growth and bypasses TRAIL resistance
    Int. J. Cancer (IF 4.982) Pub Date : 2019-12-21
    Piotr Rozga; Damian Kloska; Sebastian Pawlak; Malgorzata Teska‐Kaminska; Marlena Galazka; Katarzyna Bukato; Anna Pieczykolan; Albert Jaworski; Anna Molga‐Kaczmarska; Aleksandra Kopacz; Bogna Badyra; Neli Kachamakova‐Trojanowska; Olga Zolnierkiewicz; Marta Targosz‐Korecka; Katarzyna Poleszak; Michal Szymanik; Bartlomiej Zerek; Jerzy Pieczykolan; Alicja Jozkowicz; Anna Grochot‐Przeczek

    Targeting of the TRAIL‐DR4/5 pathway was proposed as a promising approach for specific induction of apoptosis in cancer cells. Clinical trials, however, showed inadequate efficiency of TRAIL as a monotherapy. It is a widely held view that the application of multifunctional molecules or combination therapy may lead to substantial improvement. Here, we demonstrate the effectiveness and safety of a novel chimeric protein, AD‐O51.4, which is a TRAIL equipped with positively charged VEGFA‐derived effector peptides. The study was performed in multiple cancer cell line‐ and patient‐derived xenografts. A pharmacokinetic profile was established in monkeys. AD‐O51.4 strongly inhibits tumor growth, even leading to complete long‐term tumor remission. Neither mice nor monkeys treated with AD‐O51.4 demonstrate symptoms of drug toxicity. AD‐O51.4 exhibits a satisfactory half‐life in plasma and accumulates preferentially in tumors. The cellular mechanism of AD‐O51.4 activity involves both cytotoxic effects in tumor cells and antiangiogenic effects on the endothelium. The presence of DRs in cancer cells is crucial for AD‐O51.4‐driven apoptosis execution. The TRAIL component of the fusion molecule serves as an apoptosis inducer and a cellular anchor for the effector peptides in TRAIL‐sensitive and TRAIL‐resistant cancer cells, respectively. The FADD‐dependent pathway, however, seems to be not indispensable in death signal transduction; thus, AD‐O51.4 is capable of bypassing the refractoriness of TRAIL. AD‐O51.4‐driven cell death, which exceeds TRAIL activity, is achieved due to the N‐terminally fused polypeptide, containing VEGFA‐derived effector peptides. The high anticancer efficiency of AD‐O51.4 combined with its safety has led to the entry of AD‐O51.4 into toxicological studies.

    更新日期:2019-12-21
  • High RIG‐I expression in ovarian cancer associates with an immune‐escape signature and poor clinical outcome
    Int. J. Cancer (IF 4.982) Pub Date : 2019-12-19
    Dominik Wolf; Heidi Fiegl; Alain G. Zeimet; Verena Wieser; Christian Marth; Susanne Sprung; Sieghart Sopper; Gunther Hartmann; Daniel Reimer; Maximilian Boesch

    Ovarian cancer (OC) is the most lethal gynecological malignancy, with platinum‐based chemotherapy remaining the mainstay for adjuvant treatment after surgery. The lack of indication for immunotherapy may at least in part result from the lack of suitable biomarkers allowing stratification of potentially responding patients. In this monocentric study of 141 cases with OC, we used real‐time quantitative PCR to assess the expression of retinoic acid‐inducible gene‐I (RIG‐I) in primary tumor and healthy ovarian control tissues. RIG‐I expression was correlated to various clinicopathological characteristics as well as to a set of molecular and immunological markers. The prognostic significance of RIG‐I expression was queried in univariate and multivariate analyses and validated in an independent cohort. RIG‐I was overexpressed in the cancerous ovary and correlated with a higher tumor grade. The more aggressive Type‐II cancers and cancers with inactivating p53 mutations exhibited higher RIG‐I expression. RIG‐I levels were also elevated in cancers that recurred after remission or were platinum‐refractory. Survival analyses disclosed RIG‐I as an independent marker of poor outcome in OC. Continuative analyses revealed the molecular and immunological correlates of RIG‐I expression in the tumor microenvironment, including interferon production and a distinct immune‐regulatory signature involving checkpoint molecules (PD‐L1/PD‐1), the RNA‐editing enzyme ADAR1 and the regulatory T cell‐specific transcription factor FoxP3. We conclude that high RIG‐I expression associates with poor outcome in OC, which is explainable by local immunosuppression in the tumor bed. RIG‐I expression may inform checkpoint blockade and/or RIG‐I agonistic targeting in a subset of high‐risk OC patients.

    更新日期:2019-12-20
  • Next‐generation sequencing reveals a novel role of lysine‐specific demethylase 1 in adhesion of rhabdomyosarcoma cells
    Int. J. Cancer (IF 4.982) Pub Date : 2019-12-19
    Tinka Haydn; Sarah Kehr; Dominica Willmann; Eric Metzger; Roland Schüle; Simone Fulda

    Lysine‐specific demethylase 1 (LSD1), a histone lysine demethylase with the main specificity for H3K4me2, has been shown to be overexpressed in rhabdomyosarcoma (RMS) tumor samples. However, its role in RMS biology is not yet well understood. Here, we identified a new role of LSD1 in regulating adhesion of RMS cells. Genetic knockdown of LSD1 profoundly suppressed clonogenic growth in a panel of RMS cell lines, whereas LSD1 proved to be largely dispensable for regulating cell death and short‐term survival. Combined RNA and ChIP‐sequencing performed to analyze RNA expression and histone methylation at promoter regions revealed a gene set enrichment for adhesion‐associated terms upon LSD1 knockdown. Consistently, LSD1 knockdown significantly reduced adhesion to untreated surfaces. Importantly, precoating of the plates with the adhesives collagen I or fibronectin rescued this reduced adhesion of LSD1 knockdown cells back to levels of control cells. Using KEGG pathway analysis, we identified 17 differentially expressed genes (DEGs) in LSD1 knockdown cells related to adhesion processes, which were validated by qRT‐PCR. Combining RNA and ChIP‐sequencing results revealed that, within this set of genes, SPP1, C3AR1, ITGA10 and SERPINE1 also exhibited increased H3K4me2 levels at their promoter regions in LSD1 knockdown compared to control cells. Indeed, LSD1 ChIP experiments confirmed enrichment of LSD1 at their promoter regions, suggesting a direct transcriptional regulation by LSD1. By identifying a new role of LSD1 in the modulation of cell adhesion and clonogenic growth of RMS cells, these findings highlight the importance of LSD1 in RMS.

    更新日期:2019-12-20
  • Prexasertib (LY2606368) reduces clonogenic survival by inducing apoptosis in primary patient‐derived osteosarcoma cells and synergizes with cisplatin and talazoparib
    Int. J. Cancer (IF 4.982) Pub Date : 2019-12-19
    Christopher L. Heidler; Eva K. Roth; Markus Thiemann; Claudia Blattmann; Ramon L. Perez; Peter E. Huber; Michal Kovac; Beate Amthor; Gabriele Neu‐Yilik; Andreas E. Kulozik

    Progress in the systemic control of osteosarcoma has been limited over the past decades thus indicating the urgent clinical need for the development of novel treatment strategies. Therefore, we have recently developed new preclinical models to study promising novel agents for the treatment of pediatric osteosarcoma. The checkpoint kinase (chk) inhibitor prexasertib (LY2606368) and its salt form (LSN2940930) have recently been shown to be active in adult and pediatric malignancies, including sarcoma. We have now tested the potency of prexasertib in clonogenic survival assays in two new lines of primary patient‐derived osteosarcoma cells and in two established osteosarcoma cell lines as a single agent and in combination with cisplatin and the poly ADP‐ribose polymerase (PARP) inhibitor talazoparib. Prexasertib alone results in strongly reduced clonogenic survival at low nanomolar concentrations and acts by affecting cell cycle progression, induction of apoptosis and induction of double‐stranded DNA breakage at concentrations that are well below clinically tolerable and safe plasma concentrations. In combination with cisplatin and talazoparib, prexasertib acts in a synergistic fashion. Chk1 inhibition by prexasertib and its combination with the DNA damaging agent cisplatin and the PARP‐inhibitor talazoparib thus emerges as a potential new treatment option for pediatric osteosarcoma which will now have to be tested in preclinical primary patient derived in vivo models and clinical studies.

    更新日期:2019-12-20
  • Novel genetic variants in KIF16B and NEDD4L in the endosome‐related genes are associated with nonsmall cell lung cancer survival
    Int. J. Cancer (IF 4.982) Pub Date : 2019-12-19
    Sen Yang; Dongfang Tang; Yu C. Zhao; Hongliang Liu; Sheng Luo; Thomas E. Stinchcombe; Carolyn Glass; Li Su; Sipeng Shen; David C. Christiani; Qiming Wang; Qingyi Wei

    The endosome is a membrane‐bound organ inside most eukaryotic cells, playing an important role in adaptive immunity by delivering endocytosed antigens to both MHC class I and II pathways. Here, by analyzing genotyping data from two published genome‐wide association studies (GWASs), we evaluated associations between genetic variants in the endosome‐related gene‐set and survival of patients with nonsmall cell lung cancer (NSCLC). The discovery included 44,112 (3,478 genotyped and 40,634 imputed) single‐nucleotide polymorphisms (SNPs) in 220 genes in a singlelocus analysis for their associations with survival of 1,185 NSCLC patients from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. After validation of the 821 survival‐associated significant SNPs in additional 984 NSCLC patients from the Harvard Lung Cancer Susceptibility Study, 14 SNPs remained significant. The final multivariate stepwise Cox proportional hazards regression modeling of the PLCO dataset identified three potentially functional and independent SNPs (i.e., KIF16B rs1555195 C>T, NEDD4L rs11660748 A>G and rs73440898 A>G) with an adjusted hazards ratio (HR) of 0.86 (95% confidence interval [CI] = 0.79–0.94, p = 0.0007), 1.31 (1.16–1.47, p = 6.0 × 10−5) and 1.27 (1.12–1.44, p = 0.0001) for overall survival (OS), respectively. Combined analysis of the adverse genotypes of these three SNPs revealed a trend in the genotype‐survival association (ptrend < 0.0001 for OS and ptrend < 0.0001 for disease‐specific survival). Furthermore, the survival‐associated KIF16B rs1555195T allele was significantly associated with decreased mRNA expression levels of KIF16B in both lung tissues and blood cells. Therefore, genetic variants of the endosome‐related genes may be biomarker for NSCLC survival, possibly through modulating the expression of corresponding genes.

    更新日期:2019-12-20
  • Diabetes, metformin and cancer risk in myotonic dystrophy type I
    Int. J. Cancer (IF 4.982) Pub Date : 2019-12-19
    Rotana Alsaggaf; Ruth M. Pfeiffer; Youjin Wang; Diane Marie M. St. George; Min Zhan; Kathryn R. Wagner; Sania Amr; Mark H. Greene; Shahinaz M. Gadalla

    Myotonic dystrophy type I (DM1) is an autosomal dominant multisystem disorder characterized by myotonia and muscle weakness. Type 2 diabetes (T2D) and cancer have been shown to be part of the DM1 phenotype. Metformin, a well‐established agent for the management of T2D, is thought to have cancer‐preventive effects in the general population. In our study, we aimed to assess the association between T2D, metformin use and the risk of cancer in DM1 patients. We identified a cohort of 913 DM1 patients and an age‐, sex‐ and clinic‐matched cohort of 12,318 DM1‐free controls from the UK Clinical Practice Research Datalink, a large primary care records database. We used Cox regression models to assess cancer risk in T2D patients who were metformin users or nonusers compared to patients without T2D. Separate analyses were conducted for DM1 patients and controls. T2D was more prevalent in DM1 than in controls (8% vs. 3%, p < 0.0001). DM1 patients with T2D, compared to those without T2D, were more likely to develop cancer (hazard ratio [HR] = 3.60, 95% confidence interval [CI] = 1.18–10.97; p = 0.02), but not if they were treated with metformin (HR = 0.43, 95% CI = 0.06–3.35; p = 0.42). Among controls, we observed no significant associations between T2D and cancer risk in either users or nonusers of Metformin (HR = 1.28, 95% CI = 0.91–1.79; p = 0.16 and HR = 1.13, 95% CI = 0.72–1.79; p = 0.59, respectively). These results show an association between T2D and cancer risk in DM1 patients and may provide new insights into the possible benefits of Metformin use in DM1.

    更新日期:2019-12-20
  • Ponatinib therapy in recurrent Philadelphia chromosome‐positive central nervous system leukemia with T315I mutation after Allo‐HSCT
    Int. J. Cancer (IF 4.982) Pub Date : 2019-12-19
    Jia‐Bao He; Xin Zhang; Zi‐Wen Guo; Miao‐Miao Liu; Na Xu; Fen Huang; Zhi‐Ping Fan; Li Xuan; Lan Deng; Shu‐Hua Lin; Jun Xu; Jing Sun; Qi‐Fa Liu

    Central nervous system leukemia (CNSL) relapse is relatively common among Philadelphia chromosome‐positive (Ph+) leukemia patients who undergo allogeneic hematopoietic stem cell transplantation (allo‐HSCT). The prognosis of patients is dismal for those with a BCR‐ABL T315I mutation, which is resistant to TKIs including second‐generation drugs. We assessed ponatinib for nine patients with recurrent Ph+ CNSL and a T315I mutation after allo‐HSCT, including five patients with Ph+ acute lymphoblastic leukemia and four with chronic myelogenous leukemia. Five patients experienced isolated CNSL relapse, and four experienced CNSL with hematologic relapse. All patients received ponatinib combined with intrathecal chemotherapy, and four patients with hematologic relapse received systemic chemotherapy and/or donor lymphocyte infusion. All patients achieved a deep molecular response and central nervous system remission (CNSR) at a median time of 1.5 (range: 0.7–3) months after ponatinib treatment. Two patients experienced a second CNSL relapse due to ponatinib reduction, but they achieved CNSR again after an increase to the standard dosage. Six patients developed graft versus host disease. By April 1, 2019, eight patients were alive, and one died of pneumonia. The median time of survival after the first CNSL relapse posttransplantation was 18 (range: 11.2–48.5) months. Our data from a small number of samples suggests that ponatinib is effective for recurrent Ph+ CNSL patients with a BCR‐ABL T315I mutation after allo‐HSCT and warrants broader clinical evaluation.

    更新日期:2019-12-20
  • A novel circulating tumor cell subpopulation for treatment monitoring and molecular characterization in biliary tract cancer
    Int. J. Cancer (IF 4.982) Pub Date : 2019-12-19
    Carolina Reduzzi; Marta Vismara; Marco Silvestri; Luigi Celio; Monica Niger; Giorgia Peverelli; Filippo De Braud; Maria G. Daidone; Vera Cappelletti

    In biliary tract cancer (BTC), tissue biopsies to guide treatment are rarely feasible, thus implementing liquid biopsy approaches to improve patient management represents a priority. So far, studies on circulating tumor cells (CTCs) in BTC are insufficient to promote their use in patient clinical management and are limited to EpCAM‐enriched CTCs evaluated with the CellSearch. We applied a single‐cell protocol allowing identification not only of epithelial CTCs (eCTCs), but also of nonconventional CTCs (ncCTCs) lacking epithelial and leukocyte markers, but presenting aberrant genomes as confirmed by copy number alterations and therefore representing a distinct subpopulation of bona fide CTCs. In 41 blood samples longitudinally collected from 21 patients with advanced‐stage BTC, addition of ncCTC to classic eCTC led to a CTC‐positivity increase from 19% to 83%. Patients presenting with at least 1 eCTC/10 ml of blood at baseline prior to treatment start had a significantly shorter median disease‐specific survival (DSS) compared to those lacking eCTCs (9 months vs. 19 months, p = 0.03 by log‐rank test). No differences in DSS were observed according to ncCTC‐positivity, conversely, variations in ncCTC counts during, and at the end of treatment, were associated with the RECIST response supporting their role in treatment monitoring. Moreover, in 88 ncCTCs collected at different times during treatment, unsupervised clustering evidenced segregation of cells by patient's best response, allowing identification of genomic regions possibly involved in resistance mechanisms. The presence of ncCTCs beside eCTCs opens the way to exploiting liquid biopsy for optimizing clinical management in BTC.

    更新日期:2019-12-20
  • HPV circulating tumoral DNA quantification by droplet‐based digital PCR: A promising predictive and prognostic biomarker for HPV‐associated oropharyngeal cancers
    Int. J. Cancer (IF 4.982) Pub Date : 2019-12-18
    David Veyer; Maxime Wack; Marion Mandavit; Sonia Garrigou; Stéphane Hans; Pierre Bonfils; Eric Tartour; Laurent Bélec; Shu‐Fang Wang‐Renault; Pierre Laurent‐Puig; Haitham Mirghani; Bastien Rance; Valérie Taly; Cécile Badoual; Hélène Péré

    We aimed to determine whether pretherapeutic assessment of HPV circulating tumoral DNA (HPV ctDNA) by droplet‐based digital PCR (ddPCR) could constitute a predictive and prognostic biomarker for HPV‐associated oropharyngeal squamous cell carcinoma (OPSCC). A mono‐institutional prospective biomarker study on 66 patients with p16+/HPV16‐positive oropharyngeal squamous cell carcinoma (OPSCC) was conducted in European Georges Pompidou Hospital, Paris, France. Blood samples were collected at the time of diagnosis before any treatment. Optimized digital PCR assays were used to quantify HPV16 ctDNA. Forty‐seven (71%) patients showed a positive pretherapeutic HPV ctDNA at time of diagnosis. Interestingly, the quantity of HPV16 ctDNA at baseline, as assessed by ddPCR, was significantly correlated with the T/N/M status or OPSCC stages according to the 2018 new staging criteria for high‐risk human papillomavirus (HR HPV) related OPSCC from American Joint Committee on Cancer (AJCC). Moreover, all recurrences and the majority (83%) of death reported events occurred in patients with positive HPV16 ctDNA at baseline. Finally, when posttreatment blood samples were available (n = 6), the kinetic of pretreatment/posttreatment HPV16 ctDNA was clearly associated with treatment success or failure. HPV ctDNA monitoring by ddPCR could constitute a useful and noninvasive dynamic biomarker to select HR HPV‐related OPSCC patients eligible for potential treatment de‐escalation and to monitor treatment response.

    更新日期:2019-12-19
Contents have been reproduced by permission of the publishers.
导出
全部期刊列表>>
2020新春特辑
限时免费阅读临床医学内容
ACS材料视界
科学报告最新纳米科学与技术研究
清华大学化学系段昊泓
自然科研论文编辑服务
中国科学院大学楚甲祥
上海纽约大学William Glover
中国科学院化学研究所
课题组网站
X-MOL
北京大学分子工程苏南研究院
华东师范大学分子机器及功能材料
中山大学化学工程与技术学院
试剂库存
天合科研
down
wechat
bug