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  • American Association for Cancer Research (AACR)  (9)
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  • American Association for Cancer Research (AACR)  (9)
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  • 1
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 4_Supplement ( 2022-02-15), p. P1-21-01-P1-21-01
    Abstract: Background: We analyzed the treatment outcome of breast cancer patients with brain metastases (BM) in Korea to identify the prognostic factors and the role of whole brain radiation therapy (WBRT). Methods: Seven hundred thirty patients of breast cancer with BM treated at 17 institutions in Korea from 2000 to 2014 were analyzed. The median follow-up duration was 12 months. The analysis consisted of three cohorts: in cohort A, a total of 730 patients were included; in cohort B, 538 patients with available follow-up imaging after initial brain-directed treatment; and in cohort C, 54 patients receiving salvage WBRT due to recurrent BM after initial Stereotactic radiosurgery or WBRT. Overall survival (OS) was calculated from BM diagnosis in cohort A or from the last day of salvage WBRT in cohort C. Results: Median OS of cohort A was 15 months. In multivariate analysis, histologic grade 3, extracranial metastasis, number of BM & gt;4, hormone receptor (HR) or HER2 negativity, and shorter time interval to diagnosis of BM were associated with inferior OS. Among 538 patients in cohort B, 201 showed subsequent development of new BM at a median of 11 months after stereotactic radiosurgery or WBRT for the management of initial BM (at 1 year, HR+/HER2- 51.9%, HER2+ 44.0%, and TNBC 69.6%, respectively; p=0.008). Upfront WBRT reduced subsequent development of new BM, which showed the significant difference among molecular subtypes (HR+/HER2-, 42% reduction at 1 year, p & lt;0.001; HER2+, 18.5%, p=0.004; TNBC, 16.9%, p=0.071). Multivariate analysis of cohort B showed that shorter time interval to BM, TNBC subtype, extracranial systemic disease, number of BM & gt;4, and involvement of both tentoria increased subsequent development of new BM. Anti-HER2 therapy for HER2+ patients and upfront WBRT significantly reduced risk of new BM. In cohort C, upfront WBRT prolonged the salvage WBRT-free duration (median 6.9 vs. 8.7 months, p=0.058). Median OS was 6.8 months after salvage WBRT. Longer interval to salvage WBRT, controlled primary tumor, high dose of salvage WBRT (BED10 & gt;37.5 Gy), and systemic treatment after salvage WBRT showed better OS. Uncontrolled extracranial systemic disease and salvage WBRT due to local progression without distant intracranial failure showed worse OS. Conclusions: The rates of new BM showed the significant differences among molecular subtypes. Upfront WBRT decreased subsequent development of new BM and this effect was dependent on the molecular subtype as well. Anti-HER2 therapy for HER2+ patients significantly decreased the subsequent development of new BM. On salvage WBRT setting, the patients having high dose of salvage WBRT, stable extracranial systemic disease and subsequent systemic therapy showed better OS. Citation Format: Jae Sik Kim, Kyubo Kim, Wonguen Jung, Kyung Hwan Shin, Seock-Ah Im, Hee-Jun Kim, Yong Bae Kim, Jee Suk Chang, Jee Hyun Kim, Doo Ho Choi, Yeon Hee Park, Dae Yong Kim, Tae Hyun Kim, Byung Ock Choi, Sea-Won Lee, Suzy Kim, Jeanny Kwon, Ki Mun Kang, Woong-Ki Chung, Kyung Su Kim, Won Sup Yoon, Jin Hee Kim, Jihye Cha, Yoon Kyeong Oh, In Ah Kim. Multicenter study for brain metastasis from breast cancer in Korea: The significance of molecular subtype (KROG 1612) [abstract] . In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-21-01.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 2
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 10, No. 11_Supplement ( 2011-11-12), p. B236-B236
    Abstract: Background: Identification of critical genes which play pivotal role in controlling tumor growth and survival will establish the basis for developing therapeutic targets. However, these approaches have not been extensively studied in gastric cancer (GC). The fibroblast growth factor receptor (FGFR) tyrosine kinase family has long been implicated in cancer. Among them, recent studies have shown that activating somatic mutations in FGFR2 are correlated with sensitivity to FGFR2 kinase inhibition in the cell lines bearing such FGFR2 mutations, implicating FGFR2 as a novel therapeutic target. Pazopanib is an orally bioavailable, ATP competitive, multi-targeted kinase inhibitor mainly targeting VEGFR2 and PDGFR tyrosine kinases, which results in selectively inhibiting VEGF-induced angiogenesis. However, the biologic sequences of pazopanib activities beyond anti-angiogenesis are poorly defined. Method and Results: Using our in vitro platform for modeling the genotype-correlated drug sensitivity in a panel of 37 GC cell lines, we performed this preclinical study to test the efficacy of pazopanib, whose clinical activity is not well recognized in gastric cancer. In growth inhibition assay, pazopanib showed differential effect on cell growth according to the genomic changes. Treatment of the KATO-III, OCUM-2M, SNU-16 and HSC-39 gastric cancer cell lines harboring FGFR2 amplification with pazopanib resulted in a marked decrease in cell survival with IC50 in ranges of 0.1 ∼ 2.0 μM, respectively, while same treatment of the cell lines without FGFR2 amplification had no growth inhibitory effect. In growth inhibition and colony formation assay using ectopic FGFR2-expressing model, treatment with the indicated concentrations of pazopanib significantly inhibited cell growth and colony formation by the FGFR2-expressing NIH 3T3 cells with WT FGFR2 and mutant FGFR2 (S252W), as compared with the NIH-3T3 cell with vector. Pazopanib also selectively suppressed the constitutive FGFR2 signaling effectively abrogated the baseline phosphorylation of downstream effectors of growth factor receptors, such as Erk and Akt in FGFR2-amplified cells. In cell cycle analysis, the FGFR2-amplified cells underwent cell cycle arrest at the G1-S phase after pazopanib treatment, whereas no significant effect on cell cycle progression in cells without FGFR2 amplification treated with pazopanib. Also, only in the FGFR2-amplified cells did pazopanib increase a substantial fraction of sub-G1. Conclusion: Taken together, our findings show activation of FGFR2 signaling by amplification may be a critical mediator of cell proliferation in the small subset of GC patients and may sensitize these cancer cells to pazopanib. Therefore these results suggest that pazopanib may provide genotype-correlated clinical benefit beyond the setting of highly vascular tumor like RCC, which should be further explored as a novel therapeutic target in prospective clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B236.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 3
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 13, No. 11 ( 2014-11-01), p. 2527-2536
    Abstract: Pazopanib is an orally bioavailable, ATP-competitive, multitargeted tyrosine kinase inhibitor mainly targeting VEGFR2 and PDGFR tyrosine kinases, but the biologic sequences of pazopanib activities beyond antiangiogenesis are poorly defined. We used a panel of 38 gastric cancer cell lines to test the efficacy of pazopanib. In a growth inhibition assay, genomic changes indicated that pazopanib had differential effects on cell growth. Treatment of the KATO-III, OCUM-2M, SNU-16, and HSC-39 gastric cancer cell lines harboring FGFR2 amplification with pazopanib resulted in marked decreases of cell survival with IC50 in ranges of 0.1 to 2.0 μmol/L, whereas the same treatment of those cell lines without FGFR2 amplification had no growth-inhibitory effects. In the ectopic FGFR2-expressing model, treatment with the indicated concentrations of pazopanib significantly inhibited cell growth and colony formation by FGFR2-expressing NIH 3T3 cells with wild-type (WT) FGFR2 and mutant FGFR2 (S252W). Pazopanib also selectively suppressed constitutive FGFR2 signaling and phosphorylation of downstream effectors. In cell-cycle analysis, FGFR2-amplified cells underwent cell-cycle arrest at the G1–S phase after pazopanib treatment, whereas there were no significant effects on cell-cycle progression in cells without FGFR2 amplification treated with pazopanib. In addition, pazopanib increased a substantial fraction of sub-G1 only in FGFR2-amplified cells. These findings show that the activation of FGFR2 signaling by amplification may be a critical mediator of cell proliferation in a small subset of gastric cancer patients and that pazopanib may provide genotype-correlated clinical benefits beyond the setting of highly vascular tumors. Mol Cancer Ther; 13(11); 2527–36. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 4
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 7 ( 2019-04-01), p. 1520-1534
    Abstract: Various miRNAs play critical roles in the development and progression of solid tumors. In this study, we describe the role of miR-204-5p in limiting growth and progression of breast cancer. In breast cancer tissues, miR-204-5p was significantly downregulated compared with normal breast tissues, and its expression levels were associated with increased survival outcome in patients with breast cancer. Overexpression of miR-204-5p inhibited viability, proliferation, and migration capacity in human and murine breast cancer cells. In addition, miR-204-5p overexpression resulted in a significant alteration in metabolic properties of cancer cells and suppression of tumor growth and metastasis in mouse breast cancer models. The association between miR-204-5p expression and clinical outcomes of patients with breast cancer showed a nonlinear pattern that was reproduced in experimental assays of cancer cell behavior and metastatic capacities. Transcriptome and proteomic analysis revealed that various cancer-related pathways including PI3K/Akt and tumor–immune interactions were significantly associated with miR-204-5p expression. PIK3CB, a major regulator of PI3K/Akt pathway, was a direct target for miR-204-5p, and the association between PIK3CB-related PI3K/Akt signaling and miR-204-5p was most evident in the basal subtype. The sensitivity of breast cancer cells to various anticancer drugs including PIK3CB inhibitors was significantly affected by miR-204-5p expression. In addition, miR-204-5p regulated expression of key cytokines in tumor cells and reprogrammed the immune microenvironment by shifting myeloid and lymphocyte populations. These data demonstrate both cell-autonomous and non-cell–autonomous impacts of tumor suppressor miR-204-5p in breast cancer progression and metastasis. Significance: This study demonstrates that regulation of PI3K/Akt signaling by miR-204-5p suppresses tumor metastasis and immune cell reprogramming in breast cancer.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 5
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 10, No. 10 ( 2011-10-01), p. 1993-1999
    Abstract: Although erlotinib has become an important therapeutic option in addition to gemcitabine, the high frequency of KRAS mutations in pancreatic cancer probably limits the benefits. We retrospectively studied 136 pancreatic cancer patients with available formalin-fixed paraffin-embedded tumor blocks from 2003 to 2009 to understand the clinical significance of KRAS mutations in pancreatic cancer patients treated with gemcitabine-based chemotherapy. KRAS mutations were analyzed by sequencing codons 12, 13, and 61. In this study, 71 (52.2%) of the 136 pancreatic adenocarcinomas examined harbored a point mutation in codons 12 (n = 70) and 61 (n = 1) of KRAS. KRAS mutation was not associated with clinicopathologic parameters. Patients with KRAS mutations showed a worse response (11.3%) than those with wild-type KRAS (26.2%) and poor survival (mutant KRAS, 5.8 months vs. wild-type KRAS, 8.0 months; P = 0.001). Multivariate analysis revealed good prognostic factors for overall survival as well to moderately differentiated histology (P & lt; 0.001; HR = 0.437, 95% CI: 0.301–0.634), locally advanced disease (P & lt; 0.001; HR = 0.417, 95% CI: 0.255–0.681), response to first-line chemotherapy (P = 0.003; HR = 0.482, 95% CI: 0.297–0.780), and wild-type KRAS (P = 0.001; HR = 0.523, 95% CI: 0.355–0.770). However, the observed survival advantage is derived from the subgroup of patients treated with gemcitabine/erlotinib (9.7 vs. 5.2 months; P = 0.002), whereas no survival difference based on KRAS mutation status is obvious in the other subgroup of patients treated without erlotinib (7.0 vs. 7.0 months; P = 0.121). These results need to be further explored in upcoming prospective studies to provide a rationale for personalized medicine in pancreatic cancer. Mol Cancer Ther; 10(10); 1993–9. ©2011 AACR.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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    SSG: 12
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  • 6
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 15, No. 2 ( 2016-02-01), p. 251-263
    Abstract: The EGFR-targeted monoclonal antibodies are a valid therapeutic strategy for patients with metastatic colorectal cancer (mCRC). However, only a small subset of mCRC patients has therapeutic benefits and there are high demands for EGFR therapeutics with a broader patient pool and more potent efficacy. In this study, we report GC1118 exhibiting a different character in terms of binding epitope, affinity, mode of action, and efficacy from other anti-EGFR antibodies. Structural analysis of the EGFR–GC1118 crystal complex revealed that GC1118 recognizes linear, discrete N-terminal epitopes of domain III of EGFR, critical for EGF binding but not overlapping with those of other EGFR-targeted antibodies. GC1118 exhibited superior inhibitory activity against high-affinity EGFR ligands in terms of EGFR binding, triggering EGFR signaling, and proliferation compared with cetuximab and panitumumab. EGFR signaling driven by low-affinity ligands, on the contrary, was well inhibited by all the antibodies tested. GC1118 demonstrated robust antitumor activity in tumor xenografts with elevated expression of high-affinity ligands in vivo, whereas cetuximab did not. Considering the significant role of high-affinity EGFR ligands in modulating tumor microenvironment and inducing resistance to various cancer therapeutics, our study suggests a potential therapeutic advantage of GC1118 in terms of efficacy and a range of benefited patient pool. Mol Cancer Ther; 15(2); 251–63. ©2015 AACR.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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    SSG: 12
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  • 7
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 18, No. 12 ( 2012-06-15), p. 3270-3280
    Abstract: Purpose: Although recent studies have suggested that chemokine (C-X-C motif) ligand 12 (CXCL12) is important in the progression of various malignancies, its role in gallbladder carcinoma (GBC) remains unknown. We investigated CXCL12 expression in GBC and its biologic and prognostic role in GBC tumorigenesis. Experimental Design: We examined CXCL12 expression in tumor specimens from 72 patients with GBC by immunohistochemistry and analyzed the correlation between CXCL12 expression and clinicopathologic factors or survival. The functional significance of CXCL12 expression was investigated by CXCL12 treatment and suppression of CXCR4, a major receptor of CXCL12, as well as by CXCL12 overexpression in in vitro and in vivo studies. Results: CXCL12 was differentially expressed in GBC tissues. CXCL12 expression was significantly associated with a high histologic grade (P = 0.042) and nodal metastasis (P = 0.015). Multivariate analyses showed that CXCL12 expression (HR, 8.675; P = 0.014) was an independent risk factor for patient survival. CXCL12 significantly increased anchorage-dependent and -independent growth, migration, invasion, adhesiveness, and survival of GBC cells in vitro, and these effects were dependent on CXCR4. Consistent with these results, overexpression of CXCL12 significantly promoted GBC tumorigenicity in a xenograft model. Conclusions: Our results indicate that GBC cells express both CXCL12 and its receptor CXCR4, and CXCL12 may have a role in GBC progression through an autocrine mechanism. In addition, CXCL12 is a novel independent poor prognostic factor in patients with GBCs. Thus, targeting CXCL12 and CXCR4 may provide a novel therapeutic strategy for GBC treatment. Clin Cancer Res; 18(12); 3270–80. ©2012 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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  • 8
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 5034-5034
    Abstract: Background: Gemcitabine forms the backbone of chemotherapy and a recent study showed small but significant clinical benefits of erlotinib combined with gemcitabine in patients with pancreatic ductal adenocarcinoma. However, the high frequency of KRAS mutations in this population probably limits the benefits of an EGFR inhibitor, and this limitation seems to be similar to that observed in colon cancer and non-small cell lung cancer. We undertook this study to understand the clinical significance of KRAS mutation in pancreatic cancer patients who were treated with gemcitabine-based chemotherapy. Patients & Methods: We retrospectively studied 136 pancreatic cancer patients with available formalin-fixed paraffin-embedded tumor blocks from 2003 to 2009. KRAS mutations were analyzed by sequencing codons 12, 13 and 61. Results: In this study, 71 (52.2%) of the 136 pancreatic adenocarcinomas examined harbored a point mutation in codon 12 (N=70) and 61 (N =1) of KRAS. Observed point mutations at codon 12 in the order of frequency were: GGT-GAT (35G & gt;A; 41 of 71 patients, 57.7 %); GGT-GTT (35G & gt;T; 19 of 71 patients, 26.8%); GGT-CGT (34G & gt;C; 7 of 71 patients, 10.0%); and GGT-TGT (34G & gt;T; 3 of 71 patients, 4%). KRAS mutation was not associated with clinicopathological parameters such as age, sex, ECOG PS, smoking, tumor location, histologic differentiation, TNM staging, level of CA19-9 and first-line chemotherapy regimens. Patients with KRAS mutations showed a worse response and disease control rate (11.3 and 35.2%) than those with wild type KRAS (26.2 and 52.3%). KRAS mutation also adversely influenced survival of pancreatic cancer patients (mutant KRAS, 5.8 months [95% C.I. 5.1-6.5] vs. wild type KRAS, 8.0 months [95% C.I. 5.8-10.2] ; p=0.001) Multivariate analysis revealed good prognostic factors for overall survival as well to moderately differentiated histology (p & lt;0.001; hazard ratio (HR) = 0.437, 95% C.I. 0.301∼0.634), locally advanced disease (p & lt;0.001; HR 0.417, 95% C.I. 0.255∼0.681), response to first-line chemotherapy (p=0.003; HR 0.482, 95% C.I. 0.297∼0.780) and wild type KRAS (p=0.001; HR 0.523, 95% C.I. 0.355∼0.70). Conclusions: Our results suggest that KRAS mutation may play an important role as a biomarker for response to erlotinib treatment and in determining prognosis in pancreatic cancer patients who were treated with gemcitabine-based chemotherapy. These findings should be further explored in preclinical and upcoming prospective clinical trials to potentially allow the development of new treatment algorithms to identify patients who are most likely to respond to treatment and provide a rationale for personalized medicine in pancreatic cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5034. doi:10.1158/1538-7445.AM2011-5034
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 9
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 2912-2912
    Abstract: Recently, the sidedness of the primary tumor (right versus left) has been investigated for its ability to prognosticate and predict outcomes. We evaluated the effect of regorafenib based on KRAS mutation status and the sidedness of the primary tumor in patients with metastatic colorectal cancer (mCRC). We analyzed 135 patients with refractory metastatic colorectal cancer (mCRC) being treated with regorafenib at Samsung Medical Center, between January 2014 and January 2018. Primary tumors originating in the splenic flexure, descending colon, sigmoid colon, rectum, or proximal third of the transverse colon were defined as left-sided CRC (LC). Primary tumors originating in the appendix, cecum, ascending colon, hepatic flexure, or distal two-thirds of the transverse colon were defined as right-sided CRC (RC). Among all 135 patients, 100 (74.1%) had left sided colon cancer and 35 (25.9%) had right-sided colon cancer. No patients achieved a complete response, but four achieved a partial response, revealing a response rate (RR) of 3.0%. Thirty-seven patients had stable disease, yielding a disease control rate (DCR) of 30.4%. There was no difference in RR or DCR according to the location of the primary tumor (LC vs. RC). A significant difference in progression free survival (PFS) with regorafenib was observed between the LC and RC groups (2.6 months; 95% CI, 2.0 to 3.1 vs. 1.9 months; 95% CI, 1.6 to 2.3; P = 0.04, respectively). In a subpopulation with wild type KRAS, PFS with regorafenib was also significantly different between the LC and RC groups (2.9 months; 95% CI, 1.5 to 4.3 vs. 2.1 months; 95% CI, 0.6 to 3.6; P= 0.04). On multivariate analysis, the sidedness of the primary tumor (LC vs. RC) and the number of metastatic sites (≤1 vs. 2 & gt;) had a prognostic effect on PFS (P = 0.01 and P = 0.01, respectively). Regorafenib is a current standard treatment for CRC, but treatment outcomes may be improved if regorafenib is administered based on the appropriate biomarker. Citation Format: Sang Eun Yoon, Joon Young Hur, Su Jin Lee, Jeeyun Lee, Se Hoon Park, Joon Oh Park, Ho Yeong Lim, Won Ki Kang, Young Suk Park, Seung Tae Kim. The impact of primary tumor sidedness on the effect of regorafenib in refractory metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2912.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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    detail.hit.zdb_id: 1432-1
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