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  • Neighborhood Context and Non-Small Cell Lung Cancer Outcomes in Florida non-Elderly Patients by Race/Ethnicity
    Lung Cancer (IF 4.599) Pub Date : 2020-01-16
    Asal Johnson; Allen Johnson; Robert Hines; Raheleh Mohammadi

    Objective The purpose of this study was to investigate the relationship between neighborhood environment and lung cancer outcomes among Florida residents younger than 65 years of age. Methods and materials This was a retrospective cohort study that included patients diagnosed with non-small cell lung cancer (NSCLC) in Florida from January 2005 to December 2014 (n = 22,750). Multi-level, mixed-effect logistic regression models were used for two outcomes: receipt of treatment and receipt of surgery. Survival analyses, using proportional subdistribution hazard models, were conducted to examine the impact of neighborhood characteristics on risk of death due to lung cancer with adjustment for individual-level variables. Neighborhood exposures of interest were census tract level black and Hispanic segregation combined with economic deprivation. Results White patients who lived in low black segregation/high deprivation areas had 15% lower odds of receiving surgery (95% CI: 0.76-0.93). However, the likelihood of receiving surgery for black patients who lived in high black segregation/low deprivation and high black segregation/high deprivation was lower than for black patients who lived in low black segregation/low deprivation neighborhoods (level 3 AOR = 0.56 [0.38-0.85]; level 4 AOR = 0.69 [0.54-0.88]). Living in suburban and rural areas increased the risk of lung cancer death for white patients by 14% (95% CI: 1.05-1.24) and 26% (95% CI: 1.08-1.46), respectively. Living in rural areas increased the risk of death for black patients by 54% r (SHR = 1.54 [1.19-2.0]). Black patients who live in high Hispanic segregation/high deprivation had 36 % increased risk of death compared to black patients who lived in low Hispanic segregation/low deprivation areas. Conclusion This study suggests that when investigating cancer disparities, merely adjusting for race/ethnicity does not provide sufficient explanation to understand survival and treatment variations. Lung cancer outcomes are impacted by neighborhood environments that are formed based on the distribution of race, ethnicity and class.

    更新日期:2020-01-17
  • Novel cancer therapies for advanced cutaneous melanoma: The added value of radiomics in the decision making process–A systematic review
    Cancer Med. (IF 3.357) Pub Date : 2020-01-17
    Antonino Guerrisi; Emiliano Loi; Sara Ungania; Michelangelo Russillo; Vicente Bruzzaniti; Fulvia Elia; Flora Desiderio; Raffaella Marconi; Francesco Maria Solivetti; Lidia Strigari
    更新日期:2020-01-17
  • Cost‐effectiveness analysis of pembrolizumab plus chemotherapy with PD‐L1 test for the first‐line treatment of NSCLC
    Cancer Med. (IF 3.357) Pub Date : 2020-01-16
    Ning Wan; Tian‐tian Zhang; Si‐hua Hua; Zi‐luo Lu; Bo Ji; Li‐xia Li; Li‐qing Lu; Wen‐jie Huang; Jie Jiang; Jian Li
    更新日期:2020-01-17
  • The impact of squamous cell carcinoma histology on outcomes in nonmetastatic pancreatic cancer
    Cancer Med. (IF 3.357) Pub Date : 2020-01-16
    Joshua D. Gruhl; Ignacio Garrido‐Laguna; Samual R. Francis; Kajsa Affolter; Randa Tao; Shane Lloyd
    更新日期:2020-01-17
  • Elevated eosinophil level predicted long time to next treatment in relapsed or refractory myeloma patients treated with lenalidomide
    Cancer Med. (IF 3.357) Pub Date : 2020-01-16
    Kazuhito Suzuki; Kaichi Nishiwaki; Tadahiro Gunji; Mitsuji Katori; Hidekazu Masuoka; Shingo Yano
    更新日期:2020-01-17
  • Human papillomavirus insertions identify the PIM family of serine/threonine kinases as targetable driver genes in head and neck squamous cell carcinoma
    Cancer Lett. (IF 6.508) Pub Date : 2020-01-17
    Tatevik R. Broutian; Bo Jiang; Jingfeng Li; Keiko Akagi; Shanying Gui; Zhengqiu Zhou; Weihong Xiao; David E. Symer; Maura L. Gillison

    Human papillomavirus (HPV) insertions in cancer genomes have been linked to various forms of focal genomic instability and altered expression of neighboring genes. Here we tested the hypothesis that investigation of HPV insertions in a head and neck cancer squamous cell carcinoma (HNSCC) cell line would identify targetable driver genes contributing to oncogenesis of other HNSCC. In the cell line UPCI:SCC090, HPV16 integration amplified PIM1 serine/threonine kinase gene ∼16-fold, thereby increasing transcript and protein levels. We used genetic and pharmacological approaches to inhibit PIM kinases in this and other HNSCC cell lines. Knockdown of PIM1 transcripts by transfected short hairpin RNAs reduced UPCI:SCC090 viability. CRISPR/Cas9-mediated mutagenesis of PIM1 caused cell cycle arrest and apoptosis. Pharmacological inhibition of PIM family kinases decreased growth of UPCI:SCC090 and additional HNSCC cell lines in vitro and a xenograft UPCI:SCC090 model in vivo. Based on established interactions between intracellular signaling pathways and relatively high levels of gene expression in almost all HNSCC, we also evaluated combinations of PIM kinase and epidermal growth factor receptor (EGFR) inhibitors. Dual inhibition of these pathways resulted in supra-additive cell death. These data support clinical testing of PIM inhibitors alone or in combination in HNSCC.

    更新日期:2020-01-17
  • Loss of cytoskeleton protein ADD3 promotes tumor growth and angiogenesis in glioblastoma multiforme
    Cancer Lett. (IF 6.508) Pub Date : 2020-01-17
    Karrie Mei-Yee Kiang; Pingde Zhang; Ning Li; Zhiyuan Zhu; Lei Jin; Gilberto Ka-Kit Leung

    Adducin 3 (ADD3) is a crucial assembly factor in the actin cytoskeleton and has been found to be aberrantly expressed in various cancers, including glioblastoma multiforme (GBM). It has previously been studied in array-based studies with controversial findings as to its functional role in glioma. In microarray analyses of 452 glioma specimens, we found significant downregulation of ADD3 in GBM, but not in less malignant gliomas, compared to normal brain tissue, which suggests that its downregulation might underlie critical events during malignant progression. We also found that ADD3 was functionally dependent on cell-matrix interaction. In our in vivo study, the proliferative and angiogenic capacity of ADD3-depleted GBM cells was promoted, possibly through PCNA, while p53 and p21 expression was suppressed, and pro-angiogenic signals were induced through VEGF-VEGFR-2-mediated activation in endothelial cells. With correlative in vitro, in vivo, and clinical data, we provide compelling evidence on the putative tumor-suppressive role of ADD3 in modulating GBM growth and angiogenesis. As a preclinical study, our research offers a better understanding of the pathogenesis of glioma malignant progression for the benefit of future investigations.

    更新日期:2020-01-17
  • Frequency of somatic mutations in head and neck melanoma: A single institution experience
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2020-01-16
    Emi Dika; Martina Lambertini; Annalisa Patrizi; Cosimo Misciali; Annalisa Altimari; Michelangelo Fiorentino; Barbara Melotti; Barbara Corti; Mattia Riefolo; Giulia Veronesi

    Cutaneous head and neck melanoma (HNM) is a separate subgroup of cutaneous melanoma that has a worse prognosis than other primary sites. The aim of this article is to examine the status of somatic mutations (BRAF, NRAS, and KIT) of primary lesion in head and neck regions in our institution experience. Mutational status was correlated to the clinicopathological features and the disease progression. We retrospectively analyzed 76 cases of primary HNM diagnosed from January 2005 to June 2017, from the database of the Melanoma Unit, University of Bologna. The study included 19 cases with molecular assays. BRAF mutations in HNM was positive in five patients (26.3%); NRAS p.Q61L was detected in a NM of the scalp, when the other cases were wild type for the investigated gene mutations. Interestingly, we found that HNM BRAF mutations were the most representative in our cases, although BRAF mutations in the Literature are less frequently found in melanomas occurring at sites of chronic sun damage such as the head and neck. The aim of this study is to stimulate future research.

    更新日期:2020-01-17
  • Postoperative oscillatory brain activity as an add-on prognostic marker in diffuse glioma
    J Neurooncol. (IF 3.129) Pub Date : 2020-01-17
    Vera Belgers, Tianne Numan, Shanna D. Kulik, Arjan Hillebrand, Philip C. de Witt Hamer, Jeroen J. G. Geurts, Jaap C. Reijneveld, Pieter Wesseling, Martin Klein, Jolanda Derks, Linda Douw

    Progression-free survival (PFS) in glioma patients varies widely, even when stratifying for known predictors (i.e. age, molecular tumor subtype, presence of epilepsy, tumor grade and Karnofsky performance status). Neuronal activity has been shown to accelerate tumor growth in an animal model, suggesting that brain activity may be valuable as a PFS predictor. We investigated whether postoperative oscillatory brain activity, assessed by resting-state magnetoencephalography is of additional value when predicting PFS in glioma patients.

    更新日期:2020-01-17
  • 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
  • HER2-enriched subtype and pathological complete response in HER2-positive breast cancer: a systematic review and meta-analysis
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2020-01-17
    Francesco Schettini; Tomas Pascual; Benedetta Conte; Nuria Chic; Fara Brasó-Maristany; Patricia Galván; Olga Martínez; Barbara Adamo; Maria Vidal; Montserrat Muñoz; Aranzazu Fernández-Martinez; Carla Rognoni; Gaia Griguolo; Valentina Guarneri; Pier Franco Conte; Mariavittoria Locci; Jan C. Brase; Blanca Gonzalez-Farre; Aleix Prat

    Background HER2-positive (HER2+) breast cancer (BC) comprises all the four PAM50 molecular subtypes. Among these, the HER2-E appear to be associated with higher pathological complete response (pCR) rates following anti-HER2-based regimens. Here, we present a meta-analysis to validate the association of the HER2-E subtype with pCR following anti-HER2-based neoadjuvant treatments with or without chemotherapy (CT). Methods A systematic literature search was performed in February 2019. The primary objective was to compare the association between HER2-E subtype (versus others) and pCR. Selected secondary objectives were to compare the association between 1) HER2-E subtype and pCR in CT-free studies, 2) HER2-E subtype within hormone receptor (HR)-negative and HR+ disease and 3) HR-negative disease (versus HR+) and pCR in all patients and within HER2-E subtype. A random-effect model was applied. The Higgins’ I2 was used to quantify heterogeneity. Results Sixteen studies were included, 5 of which tested CT-free regimens. HER2-E subtype was significantly associated with pCR in all patients (odds ratio [OR]=3.50, p<0.001, I2=33%), in HR+ (OR=3.61, p<0.001, I2=1%) and HR-negative tumors (OR=2.28, p=0.01, I2=47%). In CT-free studies, HER2-E subtype was associated with pCR in all patients (OR=5.52, p<0.001, I2=0%) and in HR+ disease (OR=4.08, p=0.001, I2=0%). HR-negative status was significantly associated with pCR compared to HR+ status in all patients (OR=2.41, p<0.001, I2=30%) and within the HER2-E subtype (OR=1.76, p<0.001, I2=0%). Conclusions The HER2-E biomarker identifies patients with a higher likelihood of achieving a pCR following neoadjuvant anti-HER2-based therapy beyond HR status and CT use. Future trial designs to escalate or de-escalate systemic therapy in HER2+ disease should consider this genomic biomarker.

    更新日期:2020-01-17
  • How to measure tumour response in rectal cancer? An explanation of discrepancies and suggestions for improvement
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2020-01-17
    Iris D. Nagtegaal; Rob Glynne-Jones

    Various methods categorize tumour response after neoadjuvant therapy, including down-staging and tumour regression grading. Response categories allow comparison of different treatments within clinical trials and predict outcome. A reproducible response categorization could identify subgroups with high or low risk for the most appropriate subsequent treatments, like watch and wait. Lack of standardization and interpretation difficulties currently limit the usability of these approaches. In this review we describe these difficulties for the evaluation of chemoradiation in rectal cancer. An alternative approach of tumour response is based on patterns of residual disease, including fragmentation. We summarise the evidence behind this alternative method of response categorisation, which explains a number of very relevant clinical discrepancies. These issues include differences between downstaging and tumour regression, high local regrowth in advanced tumours during watchful waiting procedures, the importance of resection margins, the limited value of post-treatment biopsies and the relatively poor outcome of patients with a near complete pathological response. Recognition of these patterns of response can allow meaningful development of novel biomarkers in the future.

    更新日期:2020-01-17
  • Optimizing treatment of renal cell carcinoma with VEGFR-TKIs: a comparison of clinical pharmacology and drug-drug interactions of anti-angiogenic drugs
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2020-01-17
    Stefano Fogli; Camillo Porta; Marzia Del Re; Stefania Crucitta; Giulia Gianfilippo; Romano Danesi; Brian I. Rini; Manuela Schmidinger

    Anti-angiogenic treatment is an important option that has changed the therapeutic landscape in cancer patients, particularly those affected by renal cell carcinoma (RCC). Agents that block signaling pathways governing tumor angiogenesis have raised high expectations among clinicians. Vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) is a heterogeneous class of drugs with distinct pharmacological profiles, including potency, selectivity, pharmacokinetics and drug-drug interactions. Among them, tivozanib is one of the last TKIs introduced in the clinical practice; this drug selectively targets VEGFRs, it is characterized by a favorable pharmacokinetics and safety profile and has been approved as first-line treatment for patients with advanced RCC. In this article, we describe the clinical pharmacology of selected VEGFR-TKIs used for the treatment of RCC, highlighting the relevant differences in clinical pharmacology and we also try to define the main pharmacologic characteristics of these drugs that allow us to divide them into different generations.

    更新日期:2020-01-17
  • The PI3K subunits, P110α and P110β are potential targets for overcoming P-gp and BCRP-mediated MDR in cancer
    Mol. Cancer (IF 10.679) Pub Date : 2020-01-17
    Lei Zhang; Yidong Li; Qianchao Wang; Zhuo Chen; Xiaoyun Li; Zhuoxun Wu; Chaohua Hu; Dan Liao; Wei Zhang; Zhe-Sheng Chen

    PI3K/AKT is a vital signaling pathway in humans. Recently, several PI3K/AKT inhibitors were reported to have the ability to reverse cancer multidrug resistance (MDR); however, specific targets in the PI3K/AKT pathways and the mechanisms associated with MDR have not been found because many of the inhibitors have multiple targets within a large candidate protein pool. AKT activation is one presumed mechanism by which MDR develops during cancer treatment. The effects of inhibiting PI3K 110α and 110β by BAY-1082439 treatment and CRISPR/Cas9 knockout were examined to determine the possible functions of BAY-1082439 and the roles of PI3K 110α and 110β in the reversal of MDR that is mediated by the downregulation of P-gp and BCRP. Inhibition of AKT with GSK-2110183 showed that the downregulation of P-gp and BCRP is independent of generalized AKT inactivation. Immunofluorescence, immunoprecipitation, MTT, flow cytometry and JC-1 staining analyses were conducted to study the reversal of MDR that is mediated by P-gp and BCRP in cancer cells. An ATPase assay and a structural analysis were also used to analyze the potential mechanisms by which BAY-1082439 specifically targets PI3K 110α and 110β and nonspecifically influences P-gp and BCRP. By inhibiting the activation of the PI3K 110α and 110β catalytic subunits through both the administration of BAY-1082439 and the CRISPR/Cas9 deletion of Pik3ca and Pik3cb, the ATP-binding cassette transporters P-gp/ABCB1 and BCRP/ABCG2 were downregulated, thereby reestablishing the drug sensitivity of human epidermoid carcinoma and non-small cell lung cancer (NSCLC) MDR cells. Inhibition of AKT did not reverse the MDR mediated by P-gp or BCRP. The ABC family proteins and AKT may play MDR-enhancing roles independently. The reversal of the dual functions of ABC-transporter-mediated and AKT-activation-enhanced MDR through the inhibition or knockout of PI3K 110α or 110β promises to improve current strategies based on combined drug treatments to overcome MDR challenges.

    更新日期:2020-01-17
  • Nanoparticles guided drug delivery and imaging in gastric cancer
    Semin. Cancer Biol. (IF 9.658) Pub Date : 2020-01-16
    Ganji Purnachandra Nagaraju; Gowru Srivani; Begum Dariya; Gayathri Chalikonda; Batoul Farran; Santosh Kumar Behera; Afroz Alam; Mohammad Amjad Kamal

    Gastric cancer represents a deadly malignancy worldwide, yet current therapeutic regimens remain ineffective. Nanoparticle (NP) -based solutions could allow the design of novel therapeutic methods to eliminate this fatal disease. NPs typically carry out a significant role in multifunctional, multimodal imaging, and drug delivery carriers. In the recent decade, they have emerged as candidate approaches for the design of novel treatment strategies. Tumor nanotherapeutics characteristically possess various distinct advantages compared to conventional anti-cancer medications, which suffer from nonspecific bio-distribution, low solubility, and poor bioavailability. In this review, we will discuss the application of NPs in diagnosis and controlled drug delivery in gastric cancer (GC). We will focus on various NPs-based strategies employed against GC.

    更新日期:2020-01-17
  • Correction to: IL-33 facilitates proliferation of colorectal cancer dependent on COX2/PGE2
    J. Exp. Clin. Cancer Res. (IF 5.646) Pub Date : 2020-01-17
    Yongkui Li; Jie Shi; Shanshan Qi; Jian Zhang; Dong Peng; Zhenzhen Chen; Guobin Wang; Zheng Wang; Lin Wang

    In the original publication of this manuscript [1], there are three errors in Fig. 1. The identified errors do not affect the conclusions of the work.

    更新日期:2020-01-17
  • Musashi2 promotes EGF-induced EMT in pancreatic cancer via ZEB1-ERK/MAPK signaling
    J. Exp. Clin. Cancer Res. (IF 5.646) Pub Date : 2020-01-17
    Weiwei Sheng; Xiaoyang Shi; Yiheng Lin; Jingtong Tang; Chao Jia; Rongxian Cao; Jian Sun; Guosen Wang; Lei Zhou; Ming Dong

    Our previous study showed Musashi2 (MSI2) promoted chemotherapy resistance and pernicious biology of pancreatic cancer (PC) by down-regulating Numb and p53. We further explored the novel molecular mechanism involving its oncogenic role in PC development. We investigated the potential role and mechanism of MSI2 in EGF-induced EMT in PC in vitro and vivo. EGF enhanced EGFR (epidermal growth factor receptor) phosphorylation, induced EMT and activated ZEB1-ERK/MAPK signaling in 2 PC cells. However, MSI2 silencing reversed EGF stimulated function, including inhibiting EGF-promoted EMT-like cell morphology and EGF-enhanced cell invasion and migration. Meanwhile, MSI2 silencing inhibited EGF-enhanced EGFR phosphorylation at tyrosine 1068 and reversed EGF-induced change of the key proteins in EMT and ZEB1-ERK/MAPK signaling (ZEB1, E-cad, ZO-1, β-catenin, pERK and c-Myc). Additionally, MSI2 was co-stained and co-immunoprecipitated with ZEB1, pERK and c-Myc in PC cells by IF and co-IP, implying a close interaction between them. In vivo, MSI2 silencing inhibited pancreatic tumor size in situ and distant liver metastases. A close relationship of MSI2 with EMT and ZEB1-ERK/MAPK signaling were also observed in vivo and human PC samples, which coordinately promoted the poor prognosis of PC patients. MSI2 promotes EGF-induced EMT in PC via ZEB1-ERK/MAPK signaling.

    更新日期:2020-01-17
  • De-regulated STAT5A/miR-202-5p/USP15/Caspase-6 regulatory axis suppresses CML cell apoptosis and contributes to Imatinib resistance
    J. Exp. Clin. Cancer Res. (IF 5.646) Pub Date : 2020-01-17
    Zi-Yuan Nie; Min Yao; Zhan Yang; Lin Yang; Xiao-Jun Liu; Jing Yu; Ying Ma; Nan Zhang; Xiao-Yan Zhang; Meng-Han Liu; Ling-Ling Jiang; Jian-Min Luo

    STAT5 plays an important role in the transformation of hematopoietic cells by BCR-ABL. However, the downstream target genes activated by STAT5 in chronic myeloid leukemia (CML) cells remain largely unclear. Here, we investigated the mechanistic functional relationship between STAT5A-regulated microRNA and CML cell apoptosis. The expression of USP15, Caspase-6, STAT5A-regulated miR-202-5p and STAT5A was detected by qRT-PCR and Western blotting in CML cell lines and PBMCs of CML patients. Cell apoptosis was evaluated by flow cytometry. Both gain- and loss-of-function experiments were used to investigate the roles of USP15, miR-202-5p and STAT5A in CML. Luciferase reporter assay detected the effect of miR-202-5p on USP15 expression. Xenograft animal model was used to test the effect of anti-miR-202-5p and pimozide on K562 cell xenograft growth. USP15 expression was significantly downregulated in CML cell lines and PBMCs of CML patients. Depletion of USP15 increased, whereas overexpression of USP15 reduced the resistance of CML cells to Imatinib. Further, decreased deubiquitinating activity of USP15 by USP15 downregulation led to reduced caspase-6 level, thus attenuating CML cell apoptosis. Mechanistically, miR-202-5p was upregulated in K562G cells and negatively regulated USP15 expression by directly targeting USP15 3′-UTR. Correspondingly, upregulation of miR-202-5p enhanced the resistance of CML cells to Imatinib by inhibiting cell apoptosis. Importantly, STAT5A was upregulated in CML cells and directly activated miR-202-5p transcription by binding to the pre-miR-202 promoter. Pimozide induced CML cell apoptosis and significantly reduced K562 cell xenograft growth in vivo by blocking STAT5A/miR-202-5p/USP15/Caspase-6 regulatory axis. we provide the first evidence that de-regulated STAT5A/miR-202-5p/USP15/Caspase-6 regulatory axis suppresses the apoptosis of CML cells, targeting this pathway might be a promising therapeutic approach for the treatment of CML.

    更新日期:2020-01-17
  • Association of Early Palliative Care With Survival in Patients With Advanced Lung Cancer—Reply
    JAMA Oncol. (IF 22.416) Pub Date : 2020-01-16
    Donald R. Sullivan; Christopher G. Slatore

    In Reply We thank Skelin and colleagues for their comments regarding our study1 evaluating the association of early palliative care with survival among patients with advanced lung cancer. Performance status is an important parameter in cancer treatment decision-making, and the Eastern Cooperative Oncology Group scale is one set of criteria used to encourage standardized reporting of treatment toxic effects and response, especially in the conduct of randomized clinical trials. Unfortunately, interrater reliability is inconsistent,2 inherent clinician bias may contribute to inconsistencies,3 and missing values are common in administrative data. Instead, we included the Charlson Comorbidity Index score, which measures comorbidities, and the Functional Comorbidity Index score, which measures physical function to predict survival in modeling, as surrogates of performance status because both are well validated in administrative data. Ultimately, treatment decision-making in oncology is complex, multifactorial, and influenced by clinician-related and patient-related factors; therefore, no single measure of patient suitability for treatment is likely to be sufficient.

    更新日期:2020-01-17
  • Down-regulated lncRNA SBF2-AS1 inhibits tumorigenesis and progression of breast cancer by sponging microRNA-143 and repressing RRS1
    J. Exp. Clin. Cancer Res. (IF 5.646) Pub Date : 2020-01-17
    Wenfei Xia; Yun Liu; Teng Cheng; Tao Xu; Menglu Dong; Xiaopeng Hu

    Recently, the roles of long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) in human diseases have been unveiled, this research was conducted to explore the impacts of lncRNA SET-binding factor 2-antisense RNA1 (SBF2-AS1), miR-143 and resistance to ralstonia solanacearum 1 (RRS1) on breast cancer (BC) development. The expression of SBF2-AS1, miR-143 and RRS1 in BC tissues, as well as in MDA-MB-231 and MCF-7 cell lines were assessed. Subsequently, the cells were transfected with miR-143 mimics or/and silenced or overexpressed SBF2-AS1 plasmids, and their negative controls. Then the proliferation, colony formation ability, cell cycle arrest, apoptosis, invasion and migration of the cells were assessed through gain- and loss-of-function experiments. Furthermore, the tumor growth, ki-67 expression and apoptosis in vivo were observed by subcutaneous tumorigenesis in nude mice. Binding relation between SBF2-AS1 and miR-143, and that between miR-143 and RRS1 were confirmed. SBF2-AS1 and RRS1 were amplified, while miR-143 was reduced in BC tissues and cells. Reduced SBF2-AS1 and elevated miR-143 could repress the proliferation, invasion and migration via restraining RRS1 expression. Moreover, knockdown of SBF2-AS1 up-regulated miR-143 to promote the apoptosis of BC cells by downregulating RRS1, resulting in a prohibitive effect on the tumorigenesis and progression of BC. Results of in vivo experiments indicated that the inhibited SBF2-AS1 and overexpressed miR-143 could restrict BC cell proliferation and promote apoptosis, and decelerate tumor growth in xenografts. We have discovered in this study that down-regulated SBF2-AS1 could inhibit tumorigenesis and progression of BC by up-regulation miR-143 and repressing RRS1, which provides basic therapeutic considerations for a novel target against BC.

    更新日期:2020-01-17
  • Association of Early Palliative Care With Survival in Patients With Advanced Lung Cancer
    JAMA Oncol. (IF 22.416) Pub Date : 2020-01-16
    Marko Skelin; Eugen Javor; Marko Lucijanic

    To the Editor We have read with great interest the retrospective population-based cohort study by Sullivan et al.1 They found an association of early palliative care (received 0 to 30 days after cancer diagnosis) with decreased survival (adjusted hazard ratio, 2.13; 95% CI, 1.97-2.30) in patients with advanced lung cancer. The authors used the propensity score method for reduction of selection bias among groups. The propensity score included factors such as the Charlson Comorbidity Index score and the Functional Comorbidity Index score. However, these parameters do not represent the true performance status of patients. Performance status is one of the major factors in cancer treatment decision-making and is assessed using the Eastern Cooperative Oncology Group scale2 or the Karnofsky scale.3 In addition, performance status is also associated with specialists’ decisions to deliver palliative care. Therefore, patients with greater functional impairment are more likely to receive palliative care sooner.

    更新日期:2020-01-17
  • Optimizing Targeted Therapy for Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia
    JAMA Oncol. (IF 22.416) Pub Date : 2020-01-16
    Karen R. Rabin

    In 1996, Druker and colleagues1 published the initial report on the inhibitory effects of a compound later named imatinib, a BCR-ABL inhibitor that reduced proliferation of BCR-ABL–positive chronic myeloid leukemia (CML) cells in vitro. The concluding paragraph of their report captures the compelling promise of targeted anticancer therapy: “This compound serves as an example of a drug that was rationally designed to inhibit the function of a specific protein when the protein’s function was known to be involved in the pathogenesis of a specific disease state. It is hoped that by directing therapy toward the underlying disease mechanism, this will result in more effective and less toxic therapies.”1(p565)

    更新日期:2020-01-17
  • Can Cannabis Cure Cancer?
    JAMA Oncol. (IF 22.416) Pub Date : 2020-01-16
    Donald I. Abrams; Manuel Guzmán

    Not long ago, discussion was focused on whether cannabis caused cancer. A thorough review by the US National Academies of Sciences, Engineering, and Medicine found moderate evidence of no statistical association between cannabis use and the development of lung and head and neck cancers.1 Limited evidence of a statistical association was found between cannabis use and the development of nonseminomatous testicular carcinomas without good support for a causative effect. Throughout the past few years, the pendulum has swung to the point where many patients with cancer diagnoses are convinced, mainly by internet testimonials, that cannabis, particularly highly concentrated oils or tinctures of Δ9-tetrahydrocannabinol (THC) and/or cannabidiol (CBD), may actually cure their cancers. What is the basis of this belief?

    更新日期:2020-01-17
  • A Diffuse Medullary Hypercaptation With No Bone Lesion
    JAMA Oncol. (IF 22.416) Pub Date : 2020-01-16
    Alexia Christin; Laurence de Leval; Michel Obeid
    更新日期:2020-01-17
  • Analysis of Price Transparency via National Cancer Institute–Designated Cancer Centers’ Chargemasters for Prostate Cancer Radiation Therapy
    JAMA Oncol. (IF 22.416) Pub Date : 2020-01-16
    Ankit Agarwal; Anupriya Dayal; Sheetal M. Kircher; Ronald C. Chen; Trevor J. Royce
    更新日期:2020-01-17
  • Effect of Dasatinib vs Imatinib in the Treatment of Pediatric Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia: A Randomized Clinical Trial
    JAMA Oncol. (IF 22.416) Pub Date : 2020-01-16
    Shuhong Shen; Xiaojuan Chen; Jiaoyang Cai; Jie Yu; Ju Gao; Shaoyan Hu; Xiaowen Zhai; Changda Liang; Xiuli Ju; Hua Jiang; Runming Jin; Xuedong Wu; Ningling Wang; Xin Tian; Kaili Pan; Hui Jiang; Lirong Sun; Yongjun Fang; Chi-kong Li; Qun Hu; Minghua Yang; Yiping Zhu; Hui Zhang; Chunfu Li; Deqing Pei; Sima Jeha; Jun J Yang; Cheng Cheng; Jingyan Tang; Xiaofan Zhu; Ching-Hon Pui
    更新日期:2020-01-17
  • Comprehensive profiling of circular RNA expressions reveals potential diagnostic and prognostic biomarkers in multiple myeloma
    BMC Cancer (IF 3.288) Pub Date : 2020-01-16
    Fan Zhou; Dongjiao Wang; Wei Wei; Haimin Chen; Haotian Shi; Nian Zhou; Lixia Wu; Rong Peng

    This study aimed to explore the heterogeneity of circRNA expression pattern via microarray, and further evaluate the potential of 10 specific circRNAs as diagnostic and prognostic biomarkers in multiple myeloma (MM). In exploration stage (stage I), circRNA expression profiles were detected by the microarray in bone marrow plasma cells from 4 MM patients and 4 healthy controls (HCs), and bioinformatic analyses were performed. In validation stage (stage II), top 10 upregulated and top 10 downregulated circRNAs identified in stage I were detected in 60 MM patients and 30 HCs for further validation; the diagnostic and prognostic values of these circRNAs in MM patients were analyzed. In stage I, 122 upregulated and 260 downregulated circRNAs were identified in MM patients compared with HCs. GO, KEGG and pathway enrichment analyses revealed that these circRNAs were implicated in neoplastic pathways such as MAPK and VEGF signaling pathways. In stage II, circ-PTK2, circ-RNF217, circ-RERE, circ-NAGPA and circ-KCNQ5 were validated to be upregulated and circ-AFF2, circ-WWC3, circ-DNAJC5, circ-KLHL2, circ-IQGAP1 and circ-AL137655 were validated to be downregulated in MM compared with controls. Circ-PTK2 and circ-RNF217 were correlated with poor treatment response and survival, while circ-AFF2 predicted good treatment response and survival in MM patients. This study provides valuable reference for profound understanding about circRNA expression patterns in MM, and validates that circ-PTK2, circ-RNF217 and circ-AFF2 might serve as potential prognostic biomarkers in MM.

    更新日期:2020-01-17
  • GC-PROM: validation of a patient-reported outcomes measure for Chinese patients with gastric cancer
    BMC Cancer (IF 3.288) Pub Date : 2020-01-16
    Xiaojuan Hu; Fen Zhao; Hongmei Yu; Yanhong Luo; Jinchun Liu; Yanbo Zhang

    There is increasing recognition that PROs are important in the estimation of the burden of long-term survival among patients with gastric cancer. The study aimed to develop a disease-specific instrument to assess patient-reported outcomes for Chinese patients with gastric cancer. Following the FDA’s draft guidance for patient-reported outcome, conceptual framework and item pool were defined based on relevant existing work. A draft scale was formed after revising some items based on feedback from experts and Chinese patients with gastric cancer. The pre-survey and formal survey were conducted in eight different hospitals in Shanxi Province, and two item-selection process based on classical test theory and item response theory. Finally, the patient-reported outcomes measure for Chinese patients with gastric cancer (GC-PROM) was validated in terms of reliability, validity, and feasibility. The minimal clinically important difference was determined by distribution-based method. The final GC-PROM consisted of 38 items, 13 subdomains, and 4 domains. Reliability was verified by Cronbach’s alpha coefficient for four domains and 13 subdomains respectively. The validity results showed that the multidimensional scale fulfilled expectations. In the formal survey, the completion rate was 96.16%, and the average filling time was less than half an hour. The values of the minimal clinically important difference were 4.14, 3.41, 3.37, and 3.28 in the four domains. The GC-PROM had good reliability, validity, and feasibility and thus can be considered an effective clinical evaluation instrument for Chinese patients with gastric cancer.

    更新日期:2020-01-17
  • Correction to: Cellular immunotherapy using irradiated lung cancer cell vaccine co-expressing GM-CSF and IL-18 can induce significant antitumor effects
    BMC Cancer (IF 3.288) Pub Date : 2020-01-17
    Hongwei Tian; Gang Shi; Guoyou Yang; Junfeng Zhang; Yiming Li; Tao Du; Jianzhou Wang; Fen Xu; Lin Cheng; Xiaomei Zhang; Lei Dai; Xiaolei Chen; Shuang Zhang; Yang Yang; Dechao Yu; Yuquan Wei; Hongxin Deng

    Following publication of the original article [1], the authors reported an error in Fig 5 of this article, graphs presenting FCM and immunofluorescent for CD4T, CD8T and NK cell of the Control Groups (LL2, LL2-irradation, MCS-irradiation) were inadvertently duplicated from another parallel experiment.

    更新日期:2020-01-17
  • Extreme down-regulation of chromosome Y and cancer risk in men
    J. Natl. Cancer Inst. (IF 10.211) Pub Date : 2020-01-16
    Cáceres A, Jene A, Esko T, et al.

    BackgroundUnderstanding the biological differences between sexes in cancer is essential for personalized treatment and prevention. We hypothesized that the extreme down-regulation of chromosome Y gene expression (EDY) is a signature of cancer risk in men and the functional mediator of the reported association between the mosaic loss of chromosome Y (LOY) and cancer. MethodsWe advanced a method to measure EDY from transcriptomic data. We studied EDY across 47 nondiseased tissues from the GTEx project (n = 371) and its association with cancer status across 12 cancer studies from the Cancer Genome Atlas (TCGA) (n = 1,774), and seven other studies (n = 7,562). Associations of EDY with cancer status and presence of loss-off function mutations in chromosome X were tested with logistic regression models, while a Fisher’s test was used to assess genome-wide association of EDY with the proportion of copy number gains. All statistical tests were two-sided. ResultsEDY was likely to occur in multiple nondiseased tissues (P<0.001) and statistically significantly associated with the EGFR tyrosine kinase inhibitor resistance pathway (FDR=0.028). EDY strongly associated with cancer risk in men (OR = 3.66, 95%CI = 1.58, 8.46, P = 0.002), adjusted by LOY and age, and its variability was largely explained by several genes of the non-recombinant region (NRY) whose chromosome X homologs showed loss-of-function mutations that co-occurred with EDY during cancer (OR = 2.82, 95%CI = 1.32, 6.01, P = 0.007). EDY associated with a high proportion of EGFR amplifications (OR = 5.64, 95%CI = 3.70, 8.59, FDR<0.001) and EGFR overexpression, along with SRY hypomethylation and NRY hypermethylation, indicating alternative causes of EDY in cancer other than LOY. EDY associations were independently validated for different cancers and exposure to smoking, and its status was accurately predicted from individual methylation patterns. ConclusionsEDY is a male-specific signature of cancer susceptibility that supports the escape from X-inactivation tumor suppressor hypothesis for genes that protect females with respect to males from cancer risk.

    更新日期:2020-01-17
  • ADP-Ribosylation Levels and Patterns Correlate with Gene Expression and Clinical Outcomes in Ovarian Cancers
    Mol. Cancer Ther. (IF 4.856) Pub Date : 2020-01-01
    Lesley B. Conrad, Ken Y. Lin, Tulip Nandu, Bryan A. Gibson, Jayanthi S. Lea, W. Lee Kraus

    Inhibitors of nuclear PARP enzymes (e.g., PARP-1) have improved clinical outcomes in ovarian cancer, especially in patients with BRCA1/2 gene mutations or additional homologous recombination (HR) DNA repair pathway deficiencies. These defects serve as biomarkers for response to PARP inhibitors (PARPi). We sought to identify an additional biomarker that could predict responses to both conventional chemotherapy and PARPi in ovarian cancers. We focused on cellular ADP-ribosylation (ADPRylation), which is catalyzed by PARP enzymes and detected by detection reagents we developed previously. We determined molecular phenotypes of 34 high-grade serous ovarian cancers and associated them with clinical outcomes. We used the levels and patterns of ADPRylation and PARP-1 to distribute ovarian cancers into distinct molecular phenotypes, which exhibit dramatically different gene expression profiles. In addition, the levels and patterns of ADPRylation, PARP-1 protein, and gene expression correlated with clinical outcomes in response to platinum-based chemotherapy, with cancers exhibiting the highest levels of ADPRylation having the best outcomes independent of BRCA1/2 status. Finally, in cell culture-based assays using patient-derived ovarian cancer cell lines, ADPRylation levels correlated with sensitivity to the PARPi, Olaparib, with cell lines exhibiting high levels of ADPRylation having greater sensitivity to Olaparib. Collectively, our study demonstrates that ovarian cancers exhibit a wide range of ADPRylation levels, which correlate with therapeutic responses and clinical outcomes. These results suggest ADPRylation may be a useful biomarker for PARPi sensitivity in ovarian cancers, independent of BRCA1/2 or homologous recombination deficiency status.

    更新日期:2020-01-17
  • Predictive and Pharmacodynamic Biomarkers of Response to the Phosphatidylinositol 3-Kinase Inhibitor Taselisib in Breast Cancer Preclinical Models
    Mol. Cancer Ther. (IF 4.856) Pub Date : 2020-01-01
    Heather M. Moore, Heidi M. Savage, Carol O'Brien, Wei Zhou, Ethan S. Sokol, Michael E. Goldberg, Ciara Metcalfe, Lori S. Friedman, Mark R. Lackner, Timothy R. Wilson

    The PI3K signaling pathway serves as a central node in regulating cell survival, proliferation, and metabolism. PIK3CA , the gene encoding the PI3K catalytic subunit p110-alpha, is commonly altered in breast cancer resulting in the constitutive activation of the PI3K pathway. Using an unbiased cell line screening approach, we tested the sensitivity of breast cancer cell lines to taselisib, a potent PI3K inhibitor, and correlated sensitivity with key biomarkers ( PIK3CA , HER2, PTEN, and ESR1 ). We further assessed how taselisib modulates downstream signaling in the different genomic backgrounds that occur within breast cancer. We found that sensitivity to taselisib correlated with the presence of PIK3CA mutations, but was independent of HER2 status. We further showed that HER2-amplified/ PIK3CA wild-type cell lines are not as sensitive to taselisib when compared with HER2-amplified/ PIK3CA -mutant cell lines. In a PIK3CA- mutant/PTEN null background, PI3K downstream signaling rebounded in the presence of taselisib correlating with decreased sensitivity at later time points. Finally, we observed that PIK3CA mutations cooccurred with mutations in the estrogen receptor (ER; ESR1 ) in metastatic tumors from patients with ER+ breast cancer. However, the cooccurrence of an ESR1 mutation with a PIK3CA mutation did not affect response to taselisib in a single agent setting or in combination with fulvestrant. In summary, these data suggest that development of taselisib in breast cancer should occur in a PIK3CA -mutant setting with cotreatments determined by the specific subtypes under investigation. This article is featured in Highlights of This Issue, [p. 1][1] [1]: /lookup/volpage/19/1?iss=1

    更新日期:2020-01-17
  • Pralatrexate in Combination with Oxaliplatin in Advanced Esophagogastric Cancer: A Phase II Trial with Predictive Molecular Correlates
    Mol. Cancer Ther. (IF 4.856) Pub Date : 2020-01-01
    Usha Malhotra, Sarbajit Mukherjee, Christos Fountzilas, Patrick Boland, Austin Miller, Santosh Patnaik, Kristopher Attwood, Sai Yendamuri, Araba Adjei, Eric Kannisto, Mateusz Opyrchal, Peter Bushunow, Peter Loud, Renuka Iyer, Nikhil Khushalani

    The purpose of our study was to evaluate the efficacy of a combination of pralatrexate plus oxaliplatin in advanced esophagogastric cancer (EGC), analyze the impact of polymorphisms in folate metabolism pathway genes on toxicity and efficacy of pralatrexate, and to evaluate microRNA profile of tumor epithelium as a predictive biomarker. This was a two-stage trial with a safety lead in cohort and a primary endpoint of overall response rate (ORR). Patients received biweekly intravenous oxaliplatin (85 mg/m2) and pralatrexate (Dose level 1 [D1], 120 mg/m2; dose level-1 [D-1] 100 mg/m2). Single-nucleotide polymorphisms (SNP) in genes encoding proteins involved in pralatrexate metabolism were evaluated in germline DNA. microRNA profiling of the tumor epithelium was performed. ORR was 26%. Dose-limiting toxicities were observed in 2 of 4 patients at D1 and none at D-1. The T>C polymorphism in DHFR rs11951910 was significantly associated with lower progression-free survival (PFS; P ≤ 0.01), whereas the presence of the SLC19A1 rs2838957 G>A polymorphism was associated with improved PFS ( P = 0.02). Presence of the GGH rs3780130 A>T and SLC19A1 rs1051266 G>A polymorphisms were significantly associated with better overall survival (OS; P = 0.01), whereas GGH rs7010484 T>C polymorphism was associated significantly with reduced OS ( P = 0.04). There was no correlation between epithelial microRNA expression profile with disease progression or response. We conclude that the combination of oxaliplatin and pralatrexate is safe, is well tolerated, and has modest efficacy in advanced EGC. Pharmacogenomic analysis may be relevant to the use of pralatrexate in combination with platinum agents.

    更新日期:2020-01-17
  • Identification of Expression Profiles Defining Distinct Prognostic Subsets of Radioactive-Iodine Refractory Differentiated Thyroid Cancer from the DECISION Trial
    Mol. Cancer Ther. (IF 4.856) Pub Date : 2020-01-01
    Jaume Capdevila, Ignacio Matos, Francesco M. Mancuso, Carmela Iglesias, Paolo Nuciforo, Carles Zafon, Hector G. Palmer, Zighereda Ogbah, Laura Muiños, Jorge Hernando, Guillermo Villacampa, Carol E. Peña, Josep Tabernero, Marcia S. Brose, Martin Schlumberger, Ana Vivancos

    Several biomarkers have been suggested to have prognostic value in differentiated thyroid carcinomas (DTC) with no validation in the refractory setting, including all tumor subtypes. We aim to correlate RNA expression profiles with survival based on patients included in the DECISION trial. We obtained 247 samples from the 417 patients included in the DECISION study and performed RNAseq analysis (77 million paired-end reads for each sample on HiSeq2000). After quality control, 125 samples were included in the secondary analysis and mapped against the human reference genome (GRCh38) with STAR (v2.5.1b) using ENCODE parameter. Survival analysis was calculated using the Kaplan–Meier method and log-rank test was used for statistical comparison. In this post hoc analysis, we identified three groups of tumors based on their gene expression profile: BRAF-like, RAS-like, and non-BRAF-non-RAS-like (NoBRaL). No significant correlation with sorafenib responders was observed. However, we identified a statistically significant correlation between the RNA-expression profiles and progression-free survival. The BRAF-like profile had a significantly better outcome compared with RAS-like and NoBRaL (11.8, 6.2, and 5.5 months, respectively) [HR: 0.31, 95% confidence interval (CI), 0.17–0.60; P < 0.001 and HR: 0.36 (95% CI, 0.21–0.63); P < 0.001] and HR: 0.36 (95% CI, 0.21–0.63; P < 0.001) and maintained significance as an independent prognostic factor for overall survival in the multivariate analysis for papillary thyroid cancers. To our knowledge, this is the first comprehensive RNA-seq analysis of all histologic subtypes of DTC. The RNA expression profiles identified may suggest a new prognostic parameter to be considered before recommendation of systemic therapies or the design of stratification factors for future clinical trials.

    更新日期:2020-01-17
  • Combined CD44- and CD25-targeted Near-Infrared Photoimmunotherapy Selectively Kills Cancer and Regulatory T cells in Syngeneic Mouse Cancer Models
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2020-01-17
    Yasuhiro Maruoka; Aki Furusawa; Ryuhei Okada; Fuyuki Inagaki; Daiki Fujimura; Hiroaki Wakiyama; Takuya Kato; Tadanobu Nagaya; Peter L. Choyke; Hisataka Kobayashi

    Near-infrared photoimmunotherapy (NIR-PIT) is a newly developed and selective cancer treatment that induces necrotic and immunogenic cell death and utilizes a monoclonal antibody conjugated to a photo-absorber dye, IR700DX, activated by NIR light. Although CD44 is surface cancer marker associated with drug resistance, anti-CD44-IR700 NIR-PIT results in inhibited cell growth and prolonged survival in multiple tumor types. Meanwhile, anti-CD25-IR700-targeted NIR-PIT has been reported to achieve selective and local depletion of FOXP3+CD25+CD4+ regulatory T cells (Tregs), which are primary immunosuppressive cells in the tumor microenvironment (TME), resulting in activation of local antitumor immunity. Combined NIR-PIT with CD44- and CD25-targeted agents has the potential to directly eliminate tumor cells and also amplify the immune response by removing FOXP3+CD25+CD4+ Tregs from the TME. We investigated the difference in therapeutic effects of CD44-targeted NIR-PIT alone, CD25-targeted NIR-PIT alone, and the combination of CD44- and CD25-targeted NIR-PIT in several syngeneic tumor models, including MC38-luc, LL/2, and MOC1. The combined NIR-PIT showed significant tumor growth inhibition and prolonged survival compared with CD44-targeted NIR-PIT alone in all tumor models and showed prolonged survival compared with CD25-targeted NIR-PIT alone in MC38-luc and LL/2 tumors. Combined CD44/CD25 NIR-PIT also resulted in some complete remissions, whereas this was not achieved with either type of NIR-PIT alone. Therefore, combined NIR-PIT simultaneously targeting cancer antigens and immunosuppressive cells in the TME may be more effective than either type of NIR-PIT alone and may have potential to induce prolonged immune responses in treated tumors.

    更新日期:2020-01-17
  • Glypican-3-specific CAR T cells co-expressing IL15 and IL21 have superior expansion and antitumor activity against hepatocellular carcinoma
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2020-01-17
    Sai Arun Batra; Purva Rathi; Linjie Guo; Amy N Courtney; Julien Fleurence; Julien Balzeau; Rahamthulla S Shaik; Thao P Nguyen; Meng-Fen Wu; Shaun Bulsara; Maksim Mamonkin; Leonid S Metelitsa; Andras Heczey

    Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death in the world and curative systemic therapies are lacking. Chimeric antigen receptor (CAR)-expressing T cells induce robust antitumor responses in patients with hematologic malignancies but have limited efficacy in patients with solid tumors including HCC. IL15 and IL21 promote T cell expansion, survival and function, and can improve the antitumor properties of T cells. We explored whether transgenic expression of IL15 and/or IL21 enhanced glypican-3-CAR (GPC3-CAR) T cells' antitumor properties against HCC. We previously optimized the co-stimulation in GPC3-CARs and selected a second generation GPC3-CAR incorporating a 4-1BB costimulatory endodomain (GBBz) for development. Here, we generated constructs encoding IL15, IL21, or both with GBBz (15.GBBz, 21.GBBz, and 21.15.GBBz, respectively) and examined the ability of transduced T cells to kill, produce effector cytokines, and expand in an antigen-dependent manner. We performed gene expression and phenotypic analyses of GPC3-CAR T cells and CRISPR-Cas9 knock-out of the TCF7 gene. Finally, we measured GPC3-CAR T cell antitumor activity in murine xenograft models of GPC3+ tumors.The increased proliferation of 21.15.GBBz T cells was at least in part dependent on upregulation and maintenance of TCF-1 (encoded by TCF7) and associated with a higher percentage of stem cell memory and central memory populations after manufacturing. T cells expressing 21.15.GBBz had superior in vitro and in vivo expansion and persistence, and the most robust antitumor activity in vivo. These results provided preclinical evidence to support the clinical evaluation of 21.15.GPC3-CAR T cells in patients with HCC.

    更新日期:2020-01-17
  • Inhibition of MDR1 Overcomes Resistance to Brentuximab Vedotin in Hodgkin Lymphoma
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-17
    Robert Chen; Alex F. Herrera; Jessie Hou; Lu Chen; Jun Wu; Yuming Guo; Timothy W. Synold; Vu N. Ngo; Sandrine Puverel; Matthew Mei; Leslie Popplewell; Shuhua Yi; Joo Y. Song; Shu Tao; Xiwei Wu; Wing C. Chan; Stephen J. Forman; Larry W. Kwak; Steven T. Rosen; Edward M. Newman

    Purpose: In classical Hodgkin lymphoma, the malignant Reed–Sternberg cells express the cell surface marker CD30. Brentuximab vedotin is an antibody–drug conjugate (ADC) that selectively delivers a potent cytotoxic agent, monomethyl auristatin E (MMAE), to CD30-positive cells. Although brentuximab vedotin elicits a high response rate (75%) in relapsed/refractory Hodgkin lymphoma, most patients who respond to brentuximab vedotin eventually develop resistance. Patients and Methods: We developed two brentuximab vedotin–resistant Hodgkin lymphoma cell line models using a pulsatile approach and observed that resistance to brentuximab vedotin is associated with an upregulation of multidrug resistance-1 (MDR1). We then conducted a phase I trial combining brentuximab vedotin and cyclosporine A (CsA) in patients with relapsed/refractory Hodgkin lymphoma. Results: Here, we show that competitive inhibition of MDR1 restored sensitivity to brentuximab vedotin in our brentuximab vedotin–resistant cell lines by increasing intracellular MMAE levels, and potentiated brentuximab vedotin activity in brentuximab vedotin–resistant Hodgkin lymphoma tumors in a human xenograft mouse model. In our phase I trial, the combination of brentuximab vedotin and CsA was tolerable and produced an overall and complete response rate of 75% and 42% in a population of patients who were nearly all refractory to brentuximab vedotin. Conclusions: This study may provide a new therapeutic strategy to combat brentuximab vedotin resistance in Hodgkin lymphoma. This is the first study reporting an effect of multidrug resistance modulation on the therapeutic activity of an ADC in humans. The expansion phase of the trial is ongoing and enrolling patients who are refractory to brentuximab vedotin to confirm clinical activity in this population with unmet need.

    更新日期:2020-01-17
  • Surfactant expression defines an inflamed subtype of lung adenocarcinoma brain metastases that correlates with prolonged survival
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-17
    Kolja Pocha; Andreas Mock; Carmen Rapp; Steffen Dettling; Rolf Warta; Christoph Geisenberger; Christine Jungk; Leila R Martins; Niels Grabe; David Reuss; Jürgen Debus; Andreas von Deimling; Amir Abdollahi; Andreas Unterberg; Christel C Herold-Mende

    Purpose: To provide a better understanding of the interplay between the immune system and brain metastases (BMs) to advance therapeutic options for this life-threatening disease. Experimental Design: Tumor-infiltrating lymphocytes (TILs) were quantified by semi-automated whole slide analysis in BMs from 81 lung adenocarcinomas (LUAD). Multi-color staining enabled phenotyping of TILs (CD3, CD8, and FOXP3) on a single cell resolution. Molecular determinants of the extent of TILs in BMs were analyzed by transcriptomics in a subset of 63 patients. Findings in LUAD BMs were related to published multi-omic primary LUAD TCGA data (n=230) and single-cell RNA-seq (scRNA-seq) data (n=52,698). Results: TIL numbers within tumor islands was an independent prognostic marker in patients with LUAD BMs. Comparative transcriptomics revealed that expression of three surfactant metabolism-related genes (SFTPA1, SFTPB, and NAPSA) was closely associated with TIL numbers. Their expression was not only prognostic in BM but also in primary LUADs. Correlation with scRNA-seq data revealed that brain metastases with high expression of surfactant genes might originate from tumor cells resembling alveolar type 2 cells. Methylome-based estimation of immune cell fractions in primary LUAD confirmed a positive association between lymphocyte infiltration and surfactant expression. Tumors with a high surfactant expression displayed a transcriptomic profile of an inflammatory microenvironment. Conclusion: The expression of surfactant metabolism-related genes (SFTPA1, SFTPB, NAPSA) defines an inflamed subtype of lung adenocarcinoma brain metastases characterized by high abundance of TILs in close vicinity to tumor cells, a prolonged survival and a tumor microenvironment which might be more accessible to immunotherapeutic approaches.

    更新日期:2020-01-17
  • ONO-7475, a novel AXL inhibitor, suppresses the adaptive resistance to initial EGFR-TKI treatment in EGFR-mutated non-small lung cancer
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-17
    Naoko Okura; Naoya Nishioka; Tadaaki Yamada; Hirokazu Taniguchi; Keiko Tanimura; Yuki Katayama; Akihiro Yoshimura; Satoshi Watanabe; Toshiaki Kikuchi; Shinsuke Shiotsu; Takeshi Kitazaki; Akihiro Nishiyama; Masahiro Iwasaku; Yoshiko Kaneko; Junji Uchino; Hisaori Uehara; Mano Horinaka; Toshiyuki Sakai; Kohei Tanaka; Ryohei Kozaki; Seiji Yano; Koichi Takayama

    Purpose: Currently, an optimal therapeutic strategy comprising molecularly targeted agents for treating EGFR-mutated non-small cell lung cancer (NSCLC) patients with acquired resistance to osimertinib is not available. Therefore, the initial therapeutic intervention is crucial for the prolonged survival of these patients. The activation of anexelekto (AXL) signaling is known to be associated with intrinsic and acquired resistance to EGFR-TKIs. In this study, we investigated the best therapeutic strategy to combat AXL-induced tolerance to EGFR-TKIs using the novel AXL inhibitor ONO-7475. Experimental design: We examined the efficacy of ONO-7475 in combination with EGFR-TKIs in EGFR mutated NSCLC cells using in vitro and in vivo experiments. We investigated the correlation between AXL expression in tumors and clinical outcomes with osimertinib for EGFR mutated NSCLC patients with acquired resistance to initial EGFR-TKIs. Results: ONO-7475 sensitized AXL-overexpressing EGFR-mutant NSCLC cells to the EGFR-TKIs osimertinib and dacomitinib. In addition, ONO-7475 suppressed the emergence and maintenance of EGFR-TKI tolerant cells. In the cell line-derived xenograft models of AXL-overexpressing EGFR mutated lung cancer treated with osimertinib, initial combination therapy of ONO-7475 and osimertinib markedly regressed tumors and delayed tumor re-growth compared to osimertinib alone or the combination after acquired resistance to osimertinib. AXL expression in EGFR-TKI refractory tumors did not correlate with the sensitivity of osimertinib. Conclusion: These results demonstrate that ONO-7475 suppresses the emergence and maintenance of tolerant cells to the initial EGFR-TKIs, osimertinib or dacomitinib, in AXL-overexpressing EGFR-mutated NSCLC cells, suggesting that ONO-7475 and osimertinib is a highly potent combination for initial treatment.

    更新日期:2020-01-17
  • Determining the optimal adjuvant therapy for improving survival in elderly patients with glioblastoma: a systematic review and meta-analysis
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-17
    Farshad Nassiri; Shervin Taslimi; Justin Z Wang; Jetan H Badhiwala; Tatyana Dalcourt; Nazanin Ijad; Neda Pirouzmand; Saleh Almenawer; Roger Stupp; Gelareh Zadeh

    Purpose: Older patients with glioblastoma(GBM) are underrepresented in clinical trials. Several abbreviated and standard chemoradiotherapy regimens are advocated with no consensus on the optimal approach. Our objective was to quantitatively evaluate which of these regimens would provide the most favourable survival outcomes in older patients with GBM using a network meta-analysis. Experimental Design: MEDLINE, Embase, Google Scholar, and the Cochrane Library were searched. Patients >60 years of age with histologically confirmed GBM were included. Primary outcome of interest was the pooled hazard ratio(HR) from randomized controlled trials. Secondary outcomes of interest included pooled HR from studies controlling for MGMT promoter methylation status, and safety. Results: Fourteen studies, including 5 randomized control trials (RCTs), reporting 4561 patients were included. Using highest quality data from RCTs, our network-based approach demonstrated that standard radiotherap(SRT) and temozolomide(TMZ) provided similar survival benefit when compared to hypofractionated radiotherapy(HRT) and TMZ(HR=.90, 95%CI 0.43-1.87), TMZ alone(HR 1.25, 95%CI 0.69-2.26), HRT alone(HR 1.34, 95%CI 0.73-2.45) or SRT alone(HR 1.43, 95%CI 0.87-2.36). HRT-TMZ had the highest probability(85%) of improving survival in older GBM patients followed by SRT-TMZ(72%). Pooled analysis of trials controlling for MGMT promoter methylation status demonstrated that TMZ monotherapy confers similar survival benefit to combined chemoradiotherapy. Conclusions: Statistical comparisons using a network approach demonstrates that the common treatment regimens for older patients with GBM in previous RCTs confer similar survival benefits. Adjustments for MGMT promoter methylation status demonstrated that radiotherapy alone were inferior to TMZ-based approaches. Head-to-head comparison of TMZ monotherapy to combined TMZ and radiation are warranted.

    更新日期:2020-01-17
  • Adenosine signalling is prognostic for cancer outcome and has predictive utility for immunotherapeutic response
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-17
    Ben Sidders; Pei Zhang; Kelly Goodwin; Greg O'Connor; Deanna L. Russell; Alexandra Borodovsky; Joshua Armenia; Robert McEwen; Bolan Linghu; Johanna C. Bendell; Todd M. Bauer; Manish R. Patel; Gerald S. Falchook; Melinda Merchant; Gayle Pouliot; J. Carl Barrett; Jonathan R Dry; Richard Woessner; Kris Sachsenmeier

    Purpose: There are several agents in early clinical trials targeting components of the adenosine pathway including A2AR and CD73. The identification of cancers with a significant adenosine drive is critical to understand the potential for these molecules. However, it is challenging to measure tumour adenosine levels at scale, thus novel, clinically tractable biomarkers are needed. Experimental Design: We generate a gene expression signature for the adenosine signaling using regulatory networks derived from the literature and validate this in patients. We apply the signature to large cohorts of disease from TCGA and cohorts of immune checkpoint inhibitor treated patients. Results: The signature captures baseline adenosine levels in vivo (r2=0.92, p=0.018), is reduced after small molecule inhibition of A2AR in mice (r2 = -0.62, p=0.001) & humans (reduction in 5 of 7 patients (70%)) and is abrogated after A2AR knock-out. Analysis of TCGA confirms a negative association between adenosine and overall survival (OS, HR=0.6, p<2.2e-16) as well as progression free survival (PFS, HR=0.77, p=0.0000006). Further, adenosine signaling is associated with reduced OS (HR=0.47, p<2.2e-16) and PFS (HR=0.65, p=0.0000002) in CD8+ T-cell infiltrated tumours. Mutation of TGFβ superfamily members are associated with enhanced adenosine signaling and worse OS (HR=0.43, p<2.2e-16). Finally, adenosine signaling is associated with reduced efficacy of anti-PD1 therapy in published cohorts (HR=0.29, p=0.00012). Conclusions: These data support the adenosine pathway as a mediator of a successful anti-tumour immune response, demonstrate the prognostic potential of the signature for immuno-therapy and inform patient selection strategies for adenosine pathway modulators currently in development.

    更新日期:2020-01-17
  • Probody therapeutic design of 89Zr-CX-072 promotes accumulation in PD-L1 expressing tumors compared to normal murine lymphoid tissue
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-17
    Danique Giesen; Linda N Broer; Marjolijn N. Lub-de Hooge; Irina Popova; Bruce Howng; Margaret Nguyen; Olga Vasiljeva; Elisabeth G E de Vries; Martin Pool

    Purpose: Probody™ therapeutic CX-072 is a protease-activatable antibody that is cross-reactive with murine and human programmed death-ligand 1 (PD-L1). CX-072 can be activated in vivo by proteases present in the tumor microenvironment, thereby potentially reducing peripheral, anti-PD-L1-mediated toxicities. To study its targeting of PD-L1-expressing tissues, we radiolabeled CX-072 with the positron emission tomography (PET) isotope zirconium-89 (89Zr). Experimental Design: 89Zr-labeled CX-072, non-specific Probody control molecule (PbCtrl) and CX-072 parental antibody (CX-075) were injected in BALB/c nude mice bearing human MDA-MB-231 tumors or C57BL/6J mice bearing syngeneic MC38 tumors. Mice underwent serial PET imaging 1, 3 and 6 days post intravenous injection (pi), followed by ex vivo biodistribution. Intratumoral 89Zr-CX-072 distribution was studied by autoradiography on tumor tissue sections, which were subsequently stained for PD-L1 by immunohistochemistry. Activated CX-072 species in tissue lysates were detected by Western capillary electrophoresis. Results: PET imaging revealed 89Zr-CX-072 accumulation in MDA-MB-231 tumors with 2.1-fold higher tumor-to-blood ratios at 6 days pi compared to 89Zr-PbCtrl. Tumor tissue autoradiography showed high 89Zr-CX-072 uptake in high PD-L1-expressing regions. Activated CX-072 species were detected in these tumors, with 5.3-fold lower levels found in the spleen. Furthermore, 89Zr-CX-072 uptake by lymphoid tissues of immune-competent mice bearing MC38 tumors was low compared to 89Zr-CX-075, which lacks the Probody design. Conclusions: 89Zr-CX-072 accumulates specifically in PD-L1-expressing tumors with limited uptake in murine peripheral lymphoid tissues. Our data may enable clinical evaluation of 89Zr-CX-072 whole-body distribution as a tool to support CX-072 drug development ([NCT03013491][1]). [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03013491&atom=%2Fclincanres%2Fearly%2F2020%2F01%2F17%2F1078-0432.CCR-19-3137.atom

    更新日期:2020-01-17
  • Newly Synthesized KRASG12C Mediates Escape from KRASG12C Inhibition
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-17
    American Association for Cancer Research

    KRAS G12C-mutant cells treated with KRASG12C inhibitors quickly became either quiescent or resistant.

    更新日期:2020-01-17
  • Test for Methylated Cell-Free DNA Identifies Colorectal Cancer
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-17
    American Association for Cancer Research

    A noninvasive test for methylated cell-free DNA markers identified colorectal cancer.

    更新日期:2020-01-17
  • Algorithms May Assist Expert Pathologists in Prostate Cancer Diagnosis
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-17
    American Association for Cancer Research

    Algorithms matching the performance of expert pathologists in prostate cancer diagnosis were designed.

    更新日期:2020-01-17
  • SWI/SNF Component ARID1A Mediates Breast Cancer Treatment Response
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-17
    American Association for Cancer Research

    ARID1A is required for response of ER+ breast cancer cells to tamoxifen and fulvestrant but not JQ1.

    更新日期:2020-01-17
  • Stop-smoking services in the UK
    Lancet Oncol. (IF 35.386) Pub Date : 2020-01-16
    Talha Khan Burki
    更新日期:2020-01-17
  • Distinct genomic traits of acral and mucosal melanomas revealed by targeted mutational profiling
    Pigment Cell Melanoma Res. (IF 4.172) Pub Date : 2020-01-16
    Zhengyun Zou; Qiuxiang Ou; Yu Ren; Qing Lv; Lanqun Qin; Lianjun Zhao; Shu Su; Xue Wu; Hua Bao; Ao Wang; Dongqin Zhu; Xiaonan Wang; Yang W. Shao; Baorui Liu

    The incidence of melanoma is rising globally including China. Comparing to Caucasians, the incidence of non‐cutaneous melanomas is significantly higher in Chinese. Herein, we performed genomic profiling of 89 Chinese surgically resected primary melanomas, including acral (n = 54), cutaneous (n = 22), and mucosal (n = 13), by hybrid capture‐based next generation sequencing. We show that mucosal melanomas tended to harbor more pathogenic mutations than other types of melanoma, though the biological significance of this finding remains uncertain. Chromosomal arm‐level alterations including 6q, 9p, and 10p/q loss were highly recurrent in all subtypes, but mucosal melanoma was significantly associated with increased genomic instability. Importantly, 7p gain significantly correlated with unfavorable clinical outcomes in non‐cutaneous melanomas, representing an intriguing prognostic biomarker of those subtypes. Furthermore, focal amplification of 4q12 (KIT, KDR, and PDGFRα) and RAD51 deletion were more abundant in mucosal melanoma, while NOTCH2 amplification was enriched in acral melanoma. Additionally, cutaneous melanomas had higher mutation load than acral melanomas, while mucosal melanomas did not differ from other subtypes in mutation burden. Together, our data revealed important features of acral and mucosal melanomas in Chinese including distinctive driver mutation pattern and increased genomic instability. These findings highlight the possibilities of combination therapies in the clinical management of melanoma.

    更新日期:2020-01-16
  • A review of cancer immunotherapy toxicity
    CA: Cancer J. Clin. (IF 223.679) Pub Date : 2020-01-16
    Lucy Boyce Kennedy; April K. S. Salama

    Cancer immunotherapies, including checkpoint inhibitors and adoptive cell therapy, manipulate the immune system to recognize and attack cancer cells. These therapies have the potential to induce durable responses in multiple solid and hematologic malignancies and thus have transformed treatment algorithms for numerous tumor types. Cancer immunotherapies lead to unique toxicity profiles distinct from the toxicities of other cancer therapies, depending on their mechanism of action. These toxicities often require specific management, which can include steroids and immune‐modulating therapy and for which consensus guidelines have been published. This review will focus on the toxicities of checkpoint inhibitors and chimeric antigen receptor T cells, including pathophysiology, diagnosis, and management.

    更新日期:2020-01-16
  • Targeting the Unfolded Protein Response in Hormone-Regulated Cancers
    Trends Cancer (IF 8.884) Pub Date : 2020-01-16
    Yang Jin; Fahri Saatcioglu

    Cancer cells exploit many of the cellular adaptive responses to support their survival needs. One of these is the unfolded protein response (UPR), a highly conserved signaling pathway that is mounted in response to endoplasmic reticulum (ER) stress. Recent work showed that steroid hormones, in particular estrogens and androgens, regulate the canonical UPR pathways in breast cancer (BCa) and prostate cancer (PCa). In addition, UPR has pleiotropic effects in advanced disease and development of therapy resistance. These findings implicate the UPR pathway as a novel target in hormonally regulated cancers in the clinic. Here, we review the potential therapeutic value of recently developed small molecule inhibitors of UPR in hormone regulated cancers.

    更新日期:2020-01-16
  • Cost-effectiveness of Stereotactic Body Radiation Therapy versus Video Assisted Thoracic Surgery in medically operable stage I Non-Small Cell Lung Cancer: A modeling study
    Lung Cancer (IF 4.599) Pub Date : 2020-01-16
    Henri B. Wolff; Leonie Alberts; Naomi van der Linden; Mathilda L. Bongers; Naomi E. Verstegen; Frank J. Lagerwaard; Frederik N. Hofman; Carin A. Uyl-de Groot; Suresh Senan; Sherif Y. El Sharouni; Elisabeth A. Kastelijn; Franz M.N.H. Schramel; Veerle M.H. Coupé

    Objectives Stage I non-small cell lung cancer (NSCLC) can be treated with either Stereotactic Body Radiotherapy (SBRT) or Video Assisted Thoracic Surgery (VATS) resection. To support decision making, not only the impact on survival needs to be taken into account, but also on quality of life, costs and cost-effectiveness. Therefore, we performed a cost-effectiveness analysis comparing SBRT to VATS resection with respect to quality adjusted life years (QALY) lived and costs in operable stage I NSCLC. Materials and Methods Patient level and aggregate data from eight Dutch databases were used to estimate costs, health utilities, recurrence free and overall survival. Propensity score matching was used to minimize selection bias in these studies. A microsimulation model predicting lifetime outcomes after treatment in stage I NSCLC patients was used for the cost-effectiveness analysis. Model outcomes for the two treatments were overall survival, QALYs, and total costs. We used a Dutch health care perspective with 1.5% discounting for health effects, and 4% discounting for costs, using 2018 cost data. The impact of model parameter uncertainty was assessed with deterministic and probabilistic sensitivity analyses. Results Patients receiving either VATS resection or SBRT were estimated to live 5.81 and 5.86 discounted QALYs, respectively. Average discounted lifetime costs in the VATS group were €29,269 versus €21,175 for SBRT. Difference in 90-day excess mortality between SBRT and VATS resection was the main driver for the difference in QALYs. SBRT was dominant in at least 74% of the probabilistic simulations. Conclusion Using a microsimulation model to combine available evidence on survival, costs, and health utilities in a cost-effectiveness analysis for stage I NSCLC led to the conclusion that SBRT dominates VATS resection in the majority of simulations.

    更新日期:2020-01-16
  • Tumour-infiltrating lymphocytes (TILs) and BRCA-like status in stage III breast cancer patients randomised to adjuvant intensified platinum-based chemotherapy versus conventional chemotherapy
    Eur. J. Cancer (IF 6.680) Pub Date : 2020-01-16
    Leonora de Boo; Ashley Cimino-Mathews; Yoni Lubeck; Antonios Daletzakis; Mark Opdam; Joyce Sanders; Erik Hooijberg; Annelot van Rossum; Zuzana Loncova; Dietmar Rieder; Zlatko Trajanoski; Marieke Vollebergh; Marcelo Sobral-Leite; Koen van de Vijver; Annegien Broeks; Rianne van der Wiel; Harm van Tinteren; Sabine Linn; Marleen Kok

    Background The prognostic value of tumour-infiltrating lymphocytes (TILs) differs by breast cancer (BC) subtype. The aim of this study was to evaluate TILs in stage III BC in the context of BRCA1/2-like phenotypes and association with outcome and benefit of intensified platinum-based chemotherapy. Patients and methods Patients participated in a randomised controlled trial of adjuvant intensified platinum-based chemotherapy versus conventional anthracycline-based chemotherapy carried out between 1993 and 1999 in stage III BC. Stromal TILs were scored according to International guidelines in these human epidermal growth factor receptor 2 (HER2)-negative tumours. BRCA-profiles were determined using Comparative Genomic Hybridization. Results TIL levels were evaluated in 248 BCs. High TILs were associated with Triple Negative BC (TNBC). BRCA-like tumours harboured higher TILs compared to non-BRCA-like tumours (median TILs of 20% versus 10%, p < 0.01). TIL levels in BRCA1-like tumours were higher compared to BRCA2-like tumours (median TILs of 20% versus 10%, p < 0.001). These correlations remained significant within the oestrogen (ER)-positive subgroup, however not within the TNBC subgroup. In this stage III BC cohort, high TIL level was associated with favourable outcome (TILs per 10% increment, recurrence-free survival (RFS): multivariate hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.71–0.94, p = 0.01; overall survival (OS): multivariate HR 0.80, 95% CI 0.68–0.94, p = 0.01). There was no significant interaction between TILs and benefit of intensified platinum-based chemotherapy. Conclusion In this high-risk breast cancer cohort, high TILs were associated with TNBC and BRCA1-like status. Within the ER-positive subgroup, TIL levels were higher in BRCA1-like compared to BRCA2-like tumours. When adjusted for clinical characteristics, TILs were significantly associated with a more favourable outcome in stage III BC patients.

    更新日期:2020-01-16
  • ShRNA-based POLD2 expression knockdown Sensitizes Glioblastoma to DNA-Damaging Therapeutics
    Cancer Lett. (IF 6.508) Pub Date : 2020-01-16
    Qingfu Xu; Chengchen Hu; Yan Zhu; Kimberly Wang; Bachuchu Lal; Lichao Li; Junhai Tang; Shuang Wei; Guohao Huang; Shuli Xia; Shengqing Lv; John Laterra; Yugang Jiang; Yunqing Li

    Glioblastoma (GBM) has limited therapeutic options. DNA repair mechanisms contribute GBM cells to escape therapies and re-establish tumor growth. Multiple studies have shown that POLD2 plays a critical role in DNA replication, DNA repair and genomic stability. We demonstrate for the first time that POLD2 is highly expressed in human glioma specimens and that expression correlates with poor patient survival. siRNA or shRNA POLD2 inhibited GBM cell proliferation, cell cycle progression, invasiveness, sensitized GBM cells to chemo/radiation-induced cell death and reversed the cytoprotective effects of EGFR signaling. Conversely, forced POLD2 expression was found to induce GBM cell proliferation, colony formation, invasiveness and chemo/radiation resistance. POLD2 expression associated with stem-like cell subsets (CD133+ and SSEA-1+ cells) and positively correlated with Sox2 expression in clinical specimens. Its expression was induced by Sox2 and inhibited by the forced differentiation of GBM neurospheres. shRNA-POLD2 modestly inhibited GBM neurosphere-derived orthotopic xenografts growth, when combined with radiation, dramatically inhibited xenograft growth in a cooperative fashion. These novel findings identify POLD2 as a new potential therapeutic target for enhancing GBM response to current standard of care therapeutics.

    更新日期:2020-01-16
  • The CCR5 antagonist maraviroc causes remission of pancreatic cancer liver metastasis in nude rats based on cell cycle inhibition and apoptosis induction
    Cancer Lett. (IF 6.508) Pub Date : 2020-01-16
    Huiying Huang; Michael Zepp; Rania Georges; Mostafa Jarahian; Maryam Kazemi; Ergül Eyol; Martin R. Berger

    Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease, and novel therapeutic strategies are urgently needed. Recently, expression of the C-C chemokine receptor 5 (CCR5) and its ligands has been found to play an important role in cancer progression and metastasis. In this study, we blocked the CCR5 receptor by the FDA approved antagonist maraviroc (MVC) in Suit2-007 and MIA-PaCa-2 human PDAC cells. The treatment significantly inhibited their proliferation and induced apoptosis of exposed cells as evidenced by caspases activation and increased Bax levels. Moreover, MVC inhibited the cell cycle by down regulating the proteins of the complexes of cyclin dependent kinase (CDK) 4/6 - Cyclin D and CDK2 - Cyclin E, as well as by increasing the protein levels of CDK inhibitors p18, p21 and p27. In line with this, MVC caused significant retardation of Suit2-007 cells growing in a PDAC liver metastasis xenograft model (p<0.05). These results suggest that maraviroc could be a promising treatment strategy for PDAC patients with liver metastases.

    更新日期:2020-01-16
  • Flumethasone enhances the efficacy of chemotherapeutic drugs in lung cancer by inhibiting Nrf2 signaling pathway
    Cancer Lett. (IF 6.508) Pub Date : 2020-01-16
    Yunjiang Zhou; Yang Zhou; Keke Wang; Tao Li; Mengdi Yang; Rui Wang; Yaxin Chen; Mengran Cao; Rong Hu

    Nuclear factor erythroid-2-related factor 2 (Nrf2), a transcription factor, participates in protecting cells from electrophilic or oxidative stresses through regulating expression of cytoprotective and antioxidant genes. It has become one of the emerging targets for cancer chemosensitization, and small molecule inhibitors of Nrf2 can enhance the efficacy of chemotherapeutic drugs. Here, we found that flumethasone, a glucocorticoid, inhibited Nrf2 signaling in A549 and H460 cells by promoting Nrf2 protein degradation. Moreover, flumethasone significantly increased the sensitivity of A549 and H460 cells to chemotherapeutic drugs including cisplatin, doxorubicin and 5-FU. In mice bearing A549-shControl cells-derived xenografts, the size and weight of xenografts in the flumethasone and cisplatin combination group had a significant reduction compared with those in the cisplatin group, while in mice bearing A549-shNrf2 cells-derived xenografts, the size and weight of the xenografts in the combination group had no significant difference compared with those in the cisplatin group, demonstrating that chemosensitization effect of flumethasone is Nrf2-dependent. This work suggests that flumethasone can potentially be used as an adjuvant sensitizer to enhance the efficacy of chemotherapeutic drugs in lung cancer.

    更新日期:2020-01-16
  • First-in-human phase I study of BPI-9016M, a dual MET/Axl inhibitor, in patients with non-small cell lung cancer
    J. Hematol. Oncol. (IF 8.731) Pub Date : 2020-01-16
    Xingsheng Hu; Xin Zheng; Sheng Yang; Lin Wang; Xuezhi Hao; Xinge Cui; Lieming Ding; Li Mao; Pei Hu; Yuankai Shi

    BPI-9016M is a novel small-molecule inhibitor that simultaneously targets both c-Met and AXL tyrosine kinases. This phase I study aimed to determine the maximum tolerated dose (MTD), safety, pharmacokinetics, and antitumor activity of BPI-9016M in Chinese patients with advanced non-small cell lung cancer (NSCLC). Over the dose range of 100 mg to 800 mg, eligible patients were administered with a single dose of 9016M tablet and received 7 days of pharmacokinetics evaluation, followed by continuous dose administration (QD dosing, 28 days). Standard “3 + 3” dose escalations were performed. Twenty NSCLC patients were treated. All patients experienced at least one adverse event (AE), of which treatment-related adverse events (TRAEs) were reported in 17 (85.0%) patients. The most common TRAEs were alanine transaminase (ALT) elevation (60%), bilirubin increased (40%), dysgeusia (40%), constipation (30%), hypertension (25%), and palmar-plantar erythrodysesthesia syndrome (15%). The TRAEs of grade 3 or higher during treatment were hypertension (15%), pulmonary embolism (5%), and laryngeal pain (5%). No dose-limiting toxicity (DLT) was observed, and the MTD was not reached. The median time to Cmax ranged from 2.0 to 3.5 h, and the plasma concentration of BPI-9016M declined rapidly after Tmax fitting a single-compartment model. The mean AUC0–72 h of M1 and M2-2, main metabolites of BPI-9016M, were 4.8–6.6 folds and 4.1–9.8 folds higher than that of BPI-9016M, respectively. Exposure to BPI-9016M, M1, and M2-2 reached moderate saturation at 600 mg. Among 19 evaluable patients, 1 had a partial response and 10 patients had stable disease. BPI-9016M showed favorable safety and pharmacokinetic profiles, and no DLT was observed at doses up to 800 mg once daily. The promising antitumor activity in Chinese NSCLC patients supports further development of this tyrosine kinase inhibitor. Clinical Trial ID: NCT02478866, registered May 21, 2015.

    更新日期:2020-01-16
  • Correction to: The predictive value of dynamic monitoring of peripheral blood lymphocyte to monocyte ratio in patients with extranodal NK/T cell lymphoma
    Cancer Cell Int. (IF 3.439) Pub Date : 2020-01-16
    Shengnan Zhang; Mengjuan Li; Fangfang Yuan; Lin Chen; Ruihua Mi; Xudong Wei; Yongping Song; Qingsong Yin

    After publication of our article [1] it was highlighted by the authors that the type of this article was primary research, instead of review.

    更新日期:2020-01-16
  • Correction to: ZNF326 promotes malignant phenotype of glioma by up-regulating HDAC7 expression and activating Wnt pathway
    J. Exp. Clin. Cancer Res. (IF 5.646) Pub Date : 2020-01-16
    Xinmiao Yu; Minghao Wang; Jingjing Wu; Qiang Han; Xiupeng Zhang

    In the original publication of this manuscript [1], the author mislabeled the CTL group and ZNF326 group in Fig. 2-I,J (MTT result). The revised Fig. 2 is shown below.

    更新日期:2020-01-16
  • Bacteriocin production by mucosal bacteria in current and previous colorectal neoplasia
    BMC Cancer (IF 3.288) Pub Date : 2020-01-16
    Darina Kohoutova; Miroslava Forstlova; Paula Moravkova; Jiri Cyrany; Juraj Bosak; David Smajs; Stanislav Rejchrt; Jan Bures

    Optimal therapy for colorectal carcinoma (CRC), a frequently diagnosed malignancy, does not exist. Some of colicins and microcins, ribosomally synthesized peptides by gramnegative bacteria, have shown significant biological activity specifically against different cancer cells in vitro and in vivo conditions. The aim of this prospective study was to evaluate natural colicin and microcin production by large intestinal mucosal bacteria in each stage of colorectal neoplasia and in those with a history of colorectal neoplasia. A total of 21 patients with non-advanced adenoma (non-a-A; 16/21 with current and 5/21 with history of non-a-A), 20 patients with advanced colorectal adenoma (a-A; 11/20 with current and 9/20 with history of a-A), 22 individuals with CRC (9/22 with current and 13/22 with history of CRC) and 20 controls were enrolled. Mucosal biopsies from the caecum, transverse colon and the rectum were taken during colonoscopy in each individual. Microbiological culture followed. Production of colicins and microcins was evaluated by PCR methods. A total of 239 mucosal biopsies were taken. Production of colicins and microcins was significantly more frequent in individuals with non-a-A, a-A and CRC compared to controls. No significant difference in colicin and microcin production was found between patients with current and previous non-a-A, a-A and CRC. Significantly more frequent production of colicins was observed in men compared to women at the stage of colorectal carcinoma. A later onset of increased production of microcins during the adenoma-carcinoma sequence has been observed in males compared to females. Strains isolated from large intestinal mucosa in patients with colorectal neoplasia produce colicins and microcins more frequently compared to controls. Bacteriocin production does not differ between patients with current and previous colorectal neoplasia. Fundamental differences in bacteriocin production have been confirmed between males and females.

    更新日期:2020-01-16
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