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  • 1
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    Abstract C120: Quantitative analysis of ERK phosphorylation by single cell phospho-specific flow cytometry in colon cancer cells as an input for pharmacokinetic/pharmacodynamic modeling of U0126 concentration.
    American Association for Cancer Research (AACR) ; 2011
    In:  Molecular Cancer Therapeutics Vol. 10, No. 11_Supplement ( 2011-11-12), p. C120-C120
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 10, No. 11_Supplement ( 2011-11-12), p. C120-C120
    Abstract: Background: To evaluate intracellular levels of phosphorylated proteins in many signaling pathways, Western blot, immunohistochemical and immufluorescence have been generally used until now. However, to establish pharmacokinetics-pharmacodynamics modeling of various drugs including antitumor agents, precise quantitative measurements of intracellular level of phosphorylated signaling molecules are critically needed. Methods and Materials: In this study, we investigated the ability of single cell phospho-specific flow cytometry to detect dynamic change of intracellular level of phosphorylated-ERK (pERK) as a pharmacodynamic marker of MEK/ERK inhibitor U0126 in human colon cancer cell lines. We also measured the intracellular concentration of U0126 in the cell lines using High-performance liquid chromatography. Results: The fluorescence intensity changes by pERK-specific single cell flow cytometry after U0126 treatment was corresponded to the pattern of results obtained by Western blot and immunofluorescence staining in dose- and time-dependent manner. In HCT116 and HT-29 human colon cancer cells, the basal fluorescence intensity of pERK was inhibited with a 0.2- to-0.8 fold decrease according to increasing concentration of U0126 (0.1 − 100 uM). We detected the rapid decrease of pERK activity within 15 min after U0126 treatment; this decrease was continued to 2 hours. And we observed the gradual recovery of pERK level closely basal status until 24 hours. The concentration of U0126 in the media was associated with decreased activity of pERK but the intracellular concentration of U0126 was not. Conclusion: Our data obtained by single cell phospho-specific flow cytometry are more sensitive, rapid, and quantitative in parallel compared with western blot. This accuracy allowed us to acquire precise inputs in order to establish pharmacokinetics-pharmacodynamics modeling of various anti-tumor agents. 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 C120.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-11-C120
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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    SSG: 12
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  • 2
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    Predicting the pathologic response of locally advanced rectal cancer to neoadjuvant concurrent chemoradiation using enzyme-linked immunosorbent assays (ELISAs) for biomarkers
    Springer Science and Business Media LLC ; 2014
    In:  Journal of Cancer Research and Clinical Oncology Vol. 140, No. 3 ( 2014-3), p. 399-409
    Details
    In: Journal of Cancer Research and Clinical Oncology, Springer Science and Business Media LLC, Vol. 140, No. 3 ( 2014-3), p. 399-409
    Type of Medium: Online Resource
    ISSN: 0171-5216 , 1432-1335
    URL: Article
    DOI: 10.1007/s00432-013-1578-y
    RVK:
    XA 52301
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2014
    detail.hit.zdb_id: 1459285-X
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  • 3
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    Reduced pelvic field sparing anastomosis for postoperative radiotherapy in selected patients with mid–upper rectal cancer
    Oxford University Press (OUP) ; 2017
    In:  Journal of Radiation Research Vol. 58, No. 4 ( 2017-07-01), p. 559-566
    Details
    In: Journal of Radiation Research, Oxford University Press (OUP), Vol. 58, No. 4 ( 2017-07-01), p. 559-566
    Abstract: The aim of this study was to report the clinical results of reduced pelvic field radiotherapy (RT), excluding the anastomotic site, after total mesorectal excision in selected patients with rectal cancer. Between 2011 and 2014, 99 patients underwent upfront surgery for clinically less-advanced tumors but were finally diagnosed as pT3/N+. Among them, 50 patients with mid–upper rectal cancer who received postoperative RT with a reduced pelvic field were included in this retrospective review. This group was composed of patients with high seated tumors, complete resection with a clear circumferential resection margin, and no complication during surgery. We investigated treatment outcomes, toxicity and the effect of RT-field reduction on organs-at risk in 5 randomly selected patients. During the median follow-up period of 42 months (range: 15−59 months), tumors recurred in 9 patients (18%). The 3-year overall and disease-free survival were 98% and 81%, respectively. Distant metastasis was the dominant failure pattern (n = 8, 16%), while no recurrences occurred at or near anastomotic sites. No anastomotic complications were found on pelvic examination, images and/or colonoscopy. Reported acute and late RT-related toxicities were mostly mild to moderate, with only small numbers of Grade 3 toxicities. None of the patients developed Grade 4−5 acute or late toxicity. With a caudally reduced field, 64% reduction in absolute anastomotic exposure at the maximum dose was achieved compared with the traditional whole-pelvic field (P = 0.008). The reduced pelvic field RT was able to minimize late anastomotic complication without increasing its recurrence in selected patients with mid–upper rectal cancer in the postoperative setting.
    Type of Medium: Online Resource
    ISSN: 0449-3060 , 1349-9157
    URL: Article
    DOI: 10.1093/jrr/rrw127
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2017
    detail.hit.zdb_id: 2038914-0
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  • 4
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    Genomic analysis reveals somatic mutations of ATM gene in DNA repair confer exceptional target lesion response to radiation therapy.
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Global Oncology Vol. 5, No. suppl ( 2019-10-07), p. 130-130
    Details
    In: Journal of Global Oncology, American Society of Clinical Oncology (ASCO), Vol. 5, No. suppl ( 2019-10-07), p. 130-130
    Abstract: 130 Background: Somatic mutations of genes involved in DNA repair (e.g. ATM and BRCA1/2) may result in chemotherapy resistance and poor prognosis, but may confer sensitivity to radiation therapy. In this study, we aimed to the hypothesis that patients with such mutations may be more susceptible to radiotherapy. Methods: Using prospectively collected RT registry, we identified patients who underwent both RT to gross disease and NGS panel screening between 2013 and 2019 (N = 27,664). From a cohort of 134 patients, 33 patients with somatic mutation in ATM or BRCA 1/2 were identified and closely matched with 33 patients without mutation using propensity score based on radiation dose and histology. Results: Infield response rate was evaluated in 66 patients with 90 gross lesions (ATM mutation, 11 patients and BRCA 1/2 mutation, 22 patients). The median tumor size and RT dose was 24 mm (3-140) and 40 Gy (12-66), respectively. Stark differences were seen in infield complete response rate, overall response rate, and local control rate at target lesions by ATM mutation (mutation vs. no mutation; 50% vs. 8%, 61% vs. 24%, and 94% vs. 58%, P 〈 .05). Response duration was also longer ATM mutation (median 11 vs. 3 months, P = .001). However, RT-related toxicities were not different (17% vs. 11%, P = .515) and no severe toxicity occurred. Conclusions: ATM mutations confer exceptional responses to radiation therapy, even with palliative dose, which has potential therapeutic implications.
    Type of Medium: Online Resource
    ISSN: 2378-9506
    URL: Article
    DOI: 10.1200/JGO.2019.5.suppl.130
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
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    detail.hit.zdb_id: 2840981-4
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  • 5
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    The role of adjuvant pelvic radiotherapy in rectal cancer with synchronous liver metastasis: a retrospective study
    Springer Science and Business Media LLC ; 2010
    In:  Radiation Oncology Vol. 5, No. 1 ( 2010-12)
    Details
    In: Radiation Oncology, Springer Science and Business Media LLC, Vol. 5, No. 1 ( 2010-12)
    Abstract: Synchronous liver metastases are detected in approximately 25% of colorectal cancer patients at diagnosis. The rates of local failure and distant metastasis are substantial in these patients, even after undergoing aggressive treatments including resection of primary and metastatic liver tumors. The purpose of this study was to determine whether adjuvant pelvic radiotherapy is beneficial for pelvic control and overall survival in rectal cancer patients with synchronous liver metastasis after primary tumor resection. Methods Among rectal cancer patients who received total mesorectal excision (TME) between 1997 and 2006 at Yonsei University Health System, eighty-nine patients diagnosed with synchronous liver metastasis were reviewed. Twenty-seven patients received adjuvant pelvic RT (group S + R), and sixty-two patients were managed without RT (group S). Thirty-six patients (58%) in group S and twenty patients (74%) in group S+R received local treatment for liver metastasis. Failure patterns and survival outcomes were analyzed. Results Pelvic failure was observed in twenty-five patients; twenty-one patients in group S (34%), and four patients in group S+R (15%) ( p = 0.066). The two-year pelvic failure-free survival rates (PFFS) of group S and group S+R were 64.8% and 80.8% ( p = 0.028), respectively, and the two-year overall survival rates (OS) were 49.1% and 70.4% ( p = 0.116), respectively. In a subgroup analysis of fifty-six patients who received local treatment for liver metastasis, the two-year PFFS were 64.9% and 82.9% ( p = 0.05), respectively; the two-year OS were 74.1% and 80.0% ( p = 0.616) in group S (n = 36) and group S+R (n = 20), respectively. Conclusions Adjuvant pelvic RT significantly reduced the pelvic failure rate but its influence on overall survival was unclear. Rectal cancer patients with synchronous liver metastasis may benefit from adjuvant pelvic RT through an increased pelvic control rate and improved quality of life.
    Type of Medium: Online Resource
    ISSN: 1748-717X
    URL: Article
    DOI: 10.1186/1748-717X-5-75
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2010
    detail.hit.zdb_id: 2224965-5
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  • 6
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    VEGF-A drives TOX-dependent T cell exhaustion in anti–PD-1–resistant microsatellite stable colorectal cancers
    American Association for the Advancement of Science (AAAS) ; 2019
    In:  Science Immunology Vol. 4, No. 41 ( 2019-11)
    Details
    In: Science Immunology, American Association for the Advancement of Science (AAAS), Vol. 4, No. 41 ( 2019-11)
    Abstract: Although immune checkpoint blockade therapies have demonstrated clinical efficacy in cancer treatment, harnessing this strategy is largely encumbered by resistance in multiple cancer settings. Here, we show that tumor-infiltrating T cells are severely exhausted in the microsatellite stable (MSS) colorectal cancer (CRC), a representative example of PD-1 blockade–resistant tumors. In MSS CRC, we found wound healing signature to be up-regulated and that T cell exhaustion is driven by vascular endothelial growth factor-A (VEGF-A). We report that VEGF-A induces the expression of transcription factor TOX in T cells to drive exhaustion-specific transcription program in T cells. Using a combination of in vitro, ex vivo, and in vivo mouse studies, we demonstrate that combined blockade of PD-1 and VEGF-A restores the antitumor functions of T cells, resulting in better control of MSS CRC tumors.
    Type of Medium: Online Resource
    ISSN: 2470-9468
    URL: Article
    DOI: 10.1126/sciimmunol.aay0555
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2019
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  • 7
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    Identification of radiosensitivity predictive genes in gastric cancer cell line using gene expression profiling
    American Association for Cancer Research (AACR) ; 2010
    In:  Clinical Cancer Research Vol. 16, No. 19_Supplement ( 2010-10-01), p. A30-A30
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 16, No. 19_Supplement ( 2010-10-01), p. A30-A30
    Abstract: Background: In the post-genome era, the development of a radiation sensitivity predictive assay is significant as it could lead to better patient and dose selection in radiotherapy. Methods: To identify radiosensitivity predictive genes in gastric cancer cells, 12 gastric and 4 colorectal cancer cell lines were used. Oligonucleotide microarray was performed using a human oligo chip containing 22,740 oligonucleotide probes of 70 bases with a reference design before radiation. Clonogenic survival assays with 2Gy of radiation were performed and survival fraction at 2 Gy (SF2) was measured. Differentially expressed genes were identified through Significant analysis of microarrays (SAM) between radiosensitive and radioresistant cell lines and functional study through Ingenuity pathway analysis was conducted. Results: According to SF2, SNU-638 (0.127±0.038), MKN-1 (0.143±0.032), and HCT-116 (0.313±0.034) were classified as radiosensitive cells, whereas YCC-2 (0.609±0.046), YCC-16 (0.62±0.091), HT29 (0.641±0.070), and YCC-7 (0.667±0.192) were determined as radioresistant cells. Eighty-two up-regulated and one hundred and forty-two down-regulated genes were identified in radiosensitive cell lines compared to radioresistant cell lines. Cell death (43 genes), cellular growth and proliferation (36 genes), cell-to-cell signaling (16 genes), cell cycle (13 genes), and DNA repair (6 genes) were related with identified gene set. Genetic network via TGFB1 and TP53 showed important role in radiosensitivity. Conclusions: Our results suggest that identified genes are candidates for radiosensitivity biomarker discovery and in vitro clonogenic assay with expression analysis may assist to predict responsiveness to radiotherapy.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/DIAG-10-A30
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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  • 8
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    Abstract B8: A phase I pharmacokinetic (PK) study of TSU-68 plus S-1 and oxaliplatin (SOX) in patients with metastatic colorectal cancer (mCRC) treated with prior chemotherapy
    American Association for Cancer Research (AACR) ; 2009
    In:  Molecular Cancer Therapeutics Vol. 8, No. 12_Supplement ( 2009-12-10), p. B8-B8
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 8, No. 12_Supplement ( 2009-12-10), p. B8-B8
    Abstract: Background: TSU-68 is a novel oral multiple tyrosine kinase inhibitor that inhibits VEGFR-2, FGF and PDGF receptors. Since TSU-68 inhibit angiogenesis pathway which is important to tumor growth and metastasis in human colorectal cancer, we conducted a phase I study to evaluate the safety, tolerability and PK of TSU-68 plus S-1 and oxaliplatin (SOX) in patients with metastatic colorectal cancer (mCRC) treated with prior chemotherapy. Methods and Materials: ECOG PS 0 or 1 patients with mCRC were treated with TSU-68 400 mg/day (Level 1) or 800 mg/day (Level 2) on Days 1–21, S-1 70 mg/m2 on Days 1–14 with one week rest and oxaliplatin 130 mg/m2 IV on Day 1 repeated every 3 week. The dose escalation of TSU-68 was not done more than Level 2 based on the results of phase I studies of TSU-68 alone in Japan. Results: Eleven patients were enrolled in the study. Of 11 patients, 2 patients were excluded from DLT assessment because both patients withdrew the written informed consent (IC) without a DLT during cycle 1. Of 9 evaluable patients, initial 3 patients in Level 1 experienced no DLT. Of 3 patients in Level 2, two patients experienced a DLT (one patient: grade 3 hiccup and grade 3 rash, another one: grade 2 neutropenia which prevented the initiation of the next cycle within 14 days). According to the protocol, additional 3 evaluable patients were enrolled in Level 1, and experienced no DLT. The MTD and RD of TSU-68 in combination with SOX was 400mg. Common adverse drug reactions (ADRs) in cycle 1 included peripheral sensory neuropathy (91%), nausea (82%), anorexia (82%), fatigue (46%), vomiting (36%) and diarrhoea (36%). No patient exhibited grade 4 ADR and treatment related death. Partial response was observed in 2 patients treated with prior chemotherapy. Median PFS was 218 days. TSU-68 plasma concentrations, Cmax and AUC0-t in Level 1 were higher than those in Level 2. There was no appreciable effect of administered TSU-68 on the PK of S-1 components (FT, CDHP and Oxo) and oxaliplatin-derived platinum. Conclusions: Administration of TSU-68 in combination with SOX is generally well tolerated. The MTD and RD of TSU-68 in this study was 400mg. A multi-institutional phase II study of TSU-68 at 400mg/day in combination with SOX is planned. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B8.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-09-B8
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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  • 9
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    Application of the Western-based adjuvant online model to Korean colon cancer patients; a single institution experience
    Springer Science and Business Media LLC ; 2012
    In:  BMC Cancer Vol. 12, No. 1 ( 2012-12)
    Details
    In: BMC Cancer, Springer Science and Business Media LLC, Vol. 12, No. 1 ( 2012-12)
    Abstract: Adjuvant Online (AOL) is web-accessible risk-assessment model that predicts the mortality and the benefits of adjuvant therapy ( http://www.newadjuvantonline.com ). AOL has never been validated for Asian colon cancer patients. Methods Using the Yonsei Tumor Registry database, patients who were treated within the Yonsei University Health System between 1990 and 2005 for T1-4, N0-2, and M0 colon cancer were included in the calculations for survival. Observed and predicted 5-year overall survival was compared for each patient. Results The median age of the study population of 1431 patients was 60 years (range, 15–87 years), and the median follow-up duration was 7.9 years (range, 0.06–19.8 years). The predicted 5-year overall survival rate (77.7%) and observed survival (79.5%) was not statistically different (95% Confidential interval, 76.3–81.5) in all patients. Predicted outcomes were within 95% confidential interval of observed survival in both stage II and III disease, including most demographic and pathologic subgroups. Moreover, AOL more accurately predicted OS for patients with stage II than stage III. Conclusions AOL tended to offer reliable prediction for 5-year overall survival and could be used as a decision making tool for adjuvant treatment in Korean colon cancer patients whose prognosis is similar to other Asian patients.
    Type of Medium: Online Resource
    ISSN: 1471-2407
    URL: Article
    DOI: 10.1186/1471-2407-12-471
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2012
    detail.hit.zdb_id: 2041352-X
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  • 10
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    Prognostic Value of Mucinous Histology Depends on Microsatellite Instability Status in Patients with Stage III Colon Cancer Treated with Adjuvant FOLFOX Chemotherapy: A Retrospective Cohort Study
    Springer Science and Business Media LLC ; 2013
    In:  Annals of Surgical Oncology Vol. 20, No. 11 ( 2013-10), p. 3407-3413
    Details
    In: Annals of Surgical Oncology, Springer Science and Business Media LLC, Vol. 20, No. 11 ( 2013-10), p. 3407-3413
    Type of Medium: Online Resource
    ISSN: 1068-9265 , 1534-4681
    URL: Article
    DOI: 10.1245/s10434-013-3169-1
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2013
    detail.hit.zdb_id: 2074021-9
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