613 results on '"Sae-Won Han"'
Search Results
52. Supplementary Figure 4 from A First-Time-in-Human Study of GSK2636771, a Phosphoinositide 3 Kinase Beta-Selective Inhibitor, in Patients with Advanced Solid Tumors
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Hendrik-Tobias Arkenau, Johann S. de Bono, Li Yan, Jeffrey R. Infante, Yung-Jue Bang, Sunil Sharma, Joseph P. Eder, Hyun Cheol Chung, Sun Young Rha, Jerry M. Tolson, Rakesh Kumar, Monica Motwani, Jiuhua Wu, Shanker Kalyana-Sundaram, Deborah A. Smith, M. Phillip DeYoung, Shaun Decordova, Karen Swales, Sae-Won Han, Howard A. Burris, Charlotte Lemech, Gopinath Ganji, and Joaquin Mateo
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Supplementary Figure 4: Investigation of the p.L1049R mutation identified in a patient with castration-resistant prostate cancer.
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- 2023
53. Data from Optimal Patient Selection for Trastuzumab Treatment in HER2-Positive Advanced Gastric Cancer
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Do-Youn Oh, Yung-Jue Bang, Woo Ho Kim, Tae-You Kim, Seock-Ah Im, Sae-Won Han, Kyung-Hun Lee, Tae-Yong Kim, Jin-Soo Kim, Jin Won Kim, Keun-Wook Lee, and Chan-Young Ock
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Purpose: Chemotherapy plus trastuzumab is standard of care for HER2-positive advanced gastric cancer (AGC). However, not all patients with HER2-positive AGC seem to benefit from trastuzumab. We evaluated the association between treatment outcomes with trastuzumab and HER2 status in patients with HER2-positive AGC.Experimental Design: We enrolled 126 patients with HER2-positive AGC treated with trastuzumab plus chemotherapy in a training cohort. HER2 IHC (N = 126), HER2/CEP17 ratio (N = 66), and HER2 gene copy number (GCN; N = 59) were analyzed, and the optimal values for discriminating overall survival (OS) were determined using receiver operating characteristic (ROC) curve analysis. We validated the findings from the training cohort using an independent validation cohort (N = 72).Results: Patients with HER2 IHC 3+ showed significantly longer OS (29 vs. 15.3 months; P = 0.025) than patients with IHC ≤ 2+. An HER2/CEP17 ratio of 4.48 was the optimal cutoff for predicting longer OS (26.9 vs. 14.7 months; P = 0.027). In subgroup analysis, treatment outcomes of patients with IHC 3+ were not influenced by the level of HER2 gene amplification. However, in patients with IHC ≤ 2+, an HER2/CEP17 ratio more than 3.69 and HER2 GCN more than 7.75 were positive predictive factors for better outcomes with trastuzumab-based chemotherapy. These findings were confirmed in both the validation cohort and the combined cohort.Conclusions: HER2 IHC status, HER2/CEP17 ratio, and HER2 GCN were correlated with clinical outcomes of trastuzumab-based treatment in HER2-positive AGC. Clinical outcomes of patients with IHC ≤ 2+ were strongly dependent on the HER2/CEP17 ratio and HER2 GCN. Clin Cancer Res; 21(11); 2520–9. ©2015 AACR.
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- 2023
54. Supplementary Figure 5 from Optimal Patient Selection for Trastuzumab Treatment in HER2-Positive Advanced Gastric Cancer
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Do-Youn Oh, Yung-Jue Bang, Woo Ho Kim, Tae-You Kim, Seock-Ah Im, Sae-Won Han, Kyung-Hun Lee, Tae-Yong Kim, Jin-Soo Kim, Jin Won Kim, Keun-Wook Lee, and Chan-Young Ock
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Supplementary Figure 5. Survival analysis according to HER2 gene copy number in validation cohort
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- 2023
55. A Real-world Efficacy of Nab-paclitaxel Monotherapy in Metastatic Breast Cancer
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Seock-Ah Im, Se Hyun Kim, So Yeon Park, Tae Yong Kim, Koung Jin Suh, Han Suk Ryu, Kyung-Hun Lee, In Ae Park, Jung Sun Kim, Jee Hyun Kim, Sae-Won Han, Go-Un Woo, Miso Kim, and Dae-Won Lee
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Cancer Research ,medicine.medical_specialty ,Chemotherapy ,Paclitaxel ,business.industry ,medicine.medical_treatment ,Endocrine therapy ,Breast Neoplasms ,Retrospective cohort study ,Luminal a ,medicine.disease ,Gastroenterology ,Metastatic breast cancer ,Regimen ,Oncology ,Albumins ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Female ,business ,Objective response ,Retrospective Studies ,Nab-paclitaxel - Abstract
PurposeWe aimed to assess the real-world efficacy of nab-paclitaxel in metastatic breast cancer patients.Materials and MethodsThis is a retrospective study performed in two tertiary referral hospitals in Korea. Patients with metastatic breast cancer treated with nab-paclitaxel (Abraxane®) between March 2016 and March 2020 were enrolled.ResultsA total of 102 patients with metastatic breast cancer were included. Patients were heavily pre-treated with a median of four prior lines of chemotherapy (5 lines when including endocrine therapy in hormone-receptor-positive patients), and 66 patients (64.7%) were exposed to taxanes in the metastatic setting. According to St. Gallen molecular subtypes, 36 patients (35.3%) were luminal A, 28 (27.5%) were luminal B, 18 (17.7%) were human epidermal growth factor receptor 2–positive and 20 (19.6%) had triple-negative disease. Fifty patients (49.0%) were treated with a 3-weekly regimen (260 mg/m2 on day 1 every 3 weeks), and 52 (51.0%) were treated with a weekly regimen (100 mg/m2 every week). Objective response rate was 22.9%. After a median follow-up of 22.0 months, median progression-free survival (PFS) was 4.0 months (95% confidence interval [CI], 2.6 to 4.8) and median overall survival was 8.7 months (95% CI, 7.5 to 11.2). Patients treated with weekly regimen had longer PFS compared to 3-weekly regimen (5.5 vs. 2.3 months, p < 0.001). Multivariate analysis revealed the treatment regimen as an independent prognostic factor for PFS. There was no grade 3 or 4 hypersensitivity reaction.ConclusionThis real-world data shows that nab-paclitaxel is a reasonable treatment option in heavily pre-treated and/or taxane-exposed metastatic breast cancer patients.
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- 2022
56. Safety and effectiveness of aflibercept in combination with FOLFIRI in Korean patients with metastatic colorectal cancer who received oxaliplatin-containing regimen
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Seung-Hoon Beom, Jong Gwang Kim, Seung Hyuk Baik, Seong Hoon Shin, Inkeun Park, Young Suk Park, Myung-Ah Lee, Soohyeon Lee, So-Yeon Jeon, Sae-Won Han, Myoung Hee Kang, Jisu Oh, Jin Soo Kim, Jin Young Kim, Mi Sun Ahn, Dae Young Zang, Byung-Noe Bae, Hong Jae Jo, Hee Kyung Kim, Jung-Han Kim, Ji Ae Yoon, and Dong Han Kim
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Cancer Research ,Oncology ,General Medicine - Abstract
To evaluate the safety and effectiveness of aflibercept in combination with fluorouracil, leucovorin, and irinotecan (FOLFIRI) in Korean patients with metastatic colorectal cancer (mCRC) who progressed with oxaliplatin-containing regimen.This was a prospective observational study conducted at 22 sites across Korea between February 2018 and September 2019. Patients aged 19 years with a diagnosis of mCRC who were prescribed aflibercept plus FOLFIRI, after progression with an oxaliplatin-containing regimen were included. Disease assessment was performed every 6 weeks.A total of 185 patients were included (males, 58.9%; right-sided tumors, 23.8%; and ECOG performance factor ≥ 1, 68.6%). A total of 514 adverse events (AEs) occurred in 134 patients, of which 206 (49.2%; 95% CI 42.0%, 56.4%) events were considered as adverse drug reactions (ADRs), 172 unexpected AEs (49.7%; 95% CI 42.5%, 56.9%), and 53 serious AEs (22.2%; 95% CI16.2%, 28.2%). The most common serious ADR was pneumonia (n = 2, 1.6%). The most common all grade hematological AE and non-hematological AE were neutropenia (21.6%) and nausea (16.2%), respectively. Over a median follow-up of 5.6 months, a total of five grade 5 (1.0%) AEs were reported. Median OS was 9.4 months, and median progression-free survival (PFS) was 7.3 months. The overall response rate was 14.6%. Right-sided tumor location and prior bevacizumab treatment were independent factors of poor PFS in multivariate analysis.Aflibercept in combination with FOLFIRI was effective and showed an acceptable safety profile in Korean patients with mCRC in daily clinical practice.
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- 2022
57. Prognostic Impact of Extramural Lymphatic, Vascular, and Perineural Invasion in Stage II Colon Cancer: A Comparison With Intramural Invasion
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Sang Sik Cho, Ji Won Park, Gyeong Hoon Kang, Jung Ho Kim, Jeong Mo Bae, Sae-Won Han, Tae-You Kim, Min Jung Kim, Seung-Bum Ryoo, Seung-Yong Jeong, and Kyu Joo Park
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Gastroenterology ,General Medicine - Abstract
Lymphatic invasion, vascular invasion, and perineural invasion are prognostic factors for colon cancer. However, the prognostic significance of those factors according to the location of permeation (intramural and extramural invasion) in stage II colon cancer is still unclear.This study aims to clarify whether the location of lymphatic invasion, vascular invasion, and perineural invasion could affect survival of stage II colon cancer patients.This was a retrospective cohort study.This study took place at a university teaching hospital.A total of 1130 patients with stage II colon cancers who underwent radical surgery at the Seoul National University Hospital between July 2003 and December 2015 were included.Patients were classified according to the location of lymphatic invasion, vascular invasion, and perineural invasion. Survival outcomes were compared among those without invasion, and those with intramural and extramural invasion. Primary end point is overall survival and secondary end point is disease free survival.Disease-free survival and overall survival of patients with extramural invasion were worse than those of patients without invasion and those with intramural invasion. Multivariate analysis for survival outcomes confirmed that extramural invasion were significant independent prognostic factors. However, both disease free survival and overall survival were not significantly different between patients without invasion and those with intramural invasion.This study was limited by its retrospective design.Extramural invasion was associated with worse prognosis in stage II colon cancer, but intramural invasion was not. Therefore, pathologic reports about the location of lymphatic invasion, vascular invasion, and perineural invasion might be helpful for predicting prognosis and for determining the need of adjuvant chemotherapy in stage II colon cancers. See Video Abstract at http://links.lww.com/DCR/B939.
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- 2022
58. Sotorasib for previously treated colorectal cancers with KRASG12C mutation (CodeBreaK100): a prespecified analysis of a single-arm, phase 2 trial
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Marwan G Fakih, Scott Kopetz, Yasutoshi Kuboki, Tae Won Kim, Pamela N Munster, John C Krauss, Gerald S Falchook, Sae-Won Han, Volker Heinemann, Kei Muro, John H Strickler, David S Hong, Crystal S Denlinger, Gustavo Girotto, Myung-Ah Lee, Haby Henary, Qui Tran, Joseph K Park, Gataree Ngarmchamnanrith, Hans Prenen, and Timothy J Price
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Oncology ,Human medicine ,Biology - Abstract
Background Sotorasib, a specific, irreversible KRAS(G12C) protein inhibitor, has shown monotherapy clinical activity in KRAS(G12C)-mutated solid tumours, including colorectal cancer, in the CodeBreaK100 phase 1 trial. We aimed to investigate the activity and safety of sotorasib in phase 2 of the trial. Methods In this single-arm, phase 2 trial, adult patients with KRAS(G12C)-mutated advanced solid tumours were enrolled, from 59 medical centres in 11 countries, if they were aged 18 years or older, had at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1, and had an Eastern Cooperative Oncology Group performance status of 1 or lower. Only data for patients with colorectal cancer, enrolled at 33 medical centres in nine countries, are presented from this basket trial. To be enrolled, the patients had to have progressed after receiving fluoropyrimidine, oxaliplatin, and irinotecan treatment. These patients were administered 960 mg sotorasib orally once per day until disease progression, development of unacceptable side-effects, withdrawal of consent, or death. The primary endpoint was objective response (complete or partial response) as assessed by blinded independent central review. Response was evaluated in patients who received at least one dose of sotorasib and had at least one measurable lesion at baseline; safety was evaluated in patients who received at least one dose of sotorasib. This analysis is a prespecified analysis triggered by the phase 2 colorectal cancer cohort. This study is registered with ClinicalTrials.gov, NCT03600883, and is active but no longer recruiting. Findings On March 1, 2021, at data cutoff, 62 patients with KRAS(G12C)-mutant colorectal cancer had been enrolled between Aug 14, 2019, and May 21, 2020, and had received at least one dose of sotorasib monotherapy. Objective response was observed in six (9.7%, 95% CI 3.6-19.9) of 62 patients, all with partial response. Treatment-related adverse events at grade 3 occurred in six (10%) patients, the most common of which was diarrhoea (two [3%] of 62 patients), and at grade 4 occurred in one (2%) patient (blood creatine phosphokinase increase); no fatal events were recorded. Serious treatment-related adverse events occurred in two (3%) patients (back pain and acute kidney injury). Interpretation Although the 9.7% overall response rate did not reach the benchmark, oral administration of sotorasib once per day showed modest anti-tumour activity and manageable safety in these heavily pretreated chemorefractory patients. Sotorasib is under evaluation in combination with other therapeutics to increase potential activity and overcome potential resistance mechanisms.
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- 2022
59. Patient‐derived organoids as a preclinical platform for precision medicine in colorectal cancer
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Dong-Wook Min, Yohan An, Tae-You Kim, Jeonghwan Youk, Hwang-Phill Kim, Sheehyun Kim, Jaeyoung Chun, Jong Pil Im, Sang-Hyun Song, Young Seok Ju, Kyu Joo Park, Young-Won Cho, and Sae-Won Han
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Oncology ,Drug ,Cancer Research ,medicine.medical_specialty ,Colorectal cancer ,media_common.quotation_subject ,Antineoplastic Agents ,Internal medicine ,Genetics ,medicine ,Organoid ,Humans ,Therapy efficacy ,Precision Medicine ,Personalized therapy ,media_common ,business.industry ,Disease progression ,General Medicine ,medicine.disease ,Precision medicine ,Organoids ,Drug repositioning ,Disease Progression ,Molecular Medicine ,Colorectal Neoplasms ,business - Abstract
Patient-derived organoids are being considered as models that can help guide personalized therapy through in vitro anti-cancer drug response evaluation. However, attempts to quantify in vitro drug responses in organoids and compare them with responses in matched patients remain inadequate. In this study, we investigated whether drug responses of organoids correlate with clinical responses of matched patients and disease progression of patients. Organoids were established from 54 patients with colorectal cancer who (except for one patient) did not receive any form of therapy before, and tumor organoids were assessed through whole-exome sequencing. For comparisons of in vitro drug responses in matched patients, we developed an "organoid score" based on the variable anti-cancer treatment responses observed in organoids. Very interestingly, a higher organoid score was significantly correlated with a lower tumor regression rate after the standard-of-care treatment in matched patients. Additionally, we confirmed that patients with a higher organoid score (≥ 2.5) had poorer progression-free survival compared with those with a lower organoid score (< 2.5). Furthermore, to assess potential drug repurposing using an FDA-approved drug library, ten tumor organoids derived from patients with disease progression were applied to a simulation platform. Taken together, organoids and organoid scores can facilitate the prediction of anti-cancer therapy efficacy, and they can be used as a simulation model to determine the next therapeutic options through drug screening. Organoids will be an attractive platform to enable the implementation of personalized therapy for colorectal cancer patients.
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- 2022
60. Destabilizing NF1 variants act in a dominant negative manner through neurofibromin dimerization
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Lucy C. Young, Ruby Goldstein de Salazar, Sae-Won Han, Zi Yi Stephanie Huang, Alan Merk, Matthew Drew, Joseph Darling, Vanessa Wall, Reinhard Grisshammer, Alice Cheng, Madeline R. Allison, Matthew J. Sale, Dwight V. Nissley, Dominic Esposito, Jana Ognjenovic, and Frank McCormick
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Multidisciplinary ,Neurofibromatosis 1 ,Neurofibromin 1 ,Neurosciences ,NFI ,Neurofibromatosis ,Rare Diseases ,neurofibromatosis type I ,Mutation ,Genetics ,Humans ,cryo-EM ,2.1 Biological and endogenous factors ,Missense ,Aetiology ,Dimerization - Abstract
The majority of pathogenic mutations in the neurofibromatosis type I ( NF1 ) gene reduce total neurofibromin protein expression through premature truncation or microdeletion, but it is less well understood how loss-of-function missense variants drive NF1 disease. We have found that patient variants in codons 844 to 848, which correlate with a severe phenotype, cause protein instability and exert an additional dominant-negative action whereby wild-type neurofibromin also becomes destabilized through protein dimerization. We have used our neurofibromin cryogenic electron microscopy structure to predict and validate other patient variants that act through a similar mechanism. This provides a foundation for understanding genotype–phenotype correlations and has important implications for patient counseling, disease management, and therapeutics.
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- 2023
61. Abstract CT029: Phase Ib study of GDC-6036 in combination with cetuximab in patients with colorectal cancer (CRC) with KRAS G12C mutation
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Jayesh Desai, Sae-Won Han, Jong-Seok Lee, Einat Shacham-Shmueli, Erminia Massarelli, Andrés Cervantes, Elena Garralda, Alejandro Falcon, Wilson H. Miller, Eelke Gort, Thomas Karasic, Salvatore Siena, Rafal Stec, Laura Medina, Luis Paz-Arez, Angelo Delmonte, Adrian Sacher, Hans Prenen, Martin Forster, Tae Won Kim, Matthew G. Krebs, Rasha Cosman, Yoonha Choi, Sandhya Mandlekar, Mark T. Lin, Kenneth K. Yau, Julie Chang, Stephanie Royer-Joo, Neekesh V. Dharia, Jennifer L. Schutzman, and Manish Patel
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Cancer Research ,Oncology - Abstract
Background: GDC-6036 is an oral, highly potent and selective KRAS G12C inhibitor that demonstrated anti-tumor activity in patients with KRAS G12C-positive advanced solid tumors, including CRC. In a previously reported single-agent cohort, GDC-6036 achieved a best response of partial response or complete response in 35% (19/55) of patients, with a confirmed overall response rate (ORR) of 24% (13/55 patients) in KRAS G12C-positive CRC patients (Desai et. al., ESMO 2022). EGFR blockade may sensitize tumors to KRAS G12C inhibition and the combination of an anti-EGFR antibody (cetuximab) with a KRAS G12C inhibitor showed greater anti-tumor activity than single-agent KRAS G12C inhibition in preclinical models (Amodio et. al., 2020). Methods: In an ongoing Phase I study (NCT04449874), patients with advanced or metastatic KRAS G12C-positive CRC were administered GDC-6036 (200-400 mg orally once a day) with cetuximab (400 mg/m2 intravenously initially, then 250 mg/m2 weekly) until intolerable toxicity or disease progression. Endpoints included safety (NCI-CTCAE v5), pharmacokinetics (PK), and preliminary anti-tumor activity (RECIST v1.1). Results: As of the clinical data cut-off date of 21 Nov 2022, 29 patients (enrolled by 07 Oct 2022) had received GDC-6036 and cetuximab. The median lines of prior metastatic therapy was 2 (range 1-8) and the median time on study treatment was 5.2 (range 1.4-11.2) months. All patients experienced at least one treatment-related adverse event (TRAE); the most common TRAEs (≥15%) were rash (grouped terms), diarrhea, nausea, vomiting, dry skin, and paronychia. Grade 3-4 TRAEs occurred in 11 patients (38%). Five patients (17%) experienced at least one serious AE, none of which were treatment-related (including 2 patients who died of CRC progression during the safety follow-up). AEs led to GDC-6036 modifications (interruptions and/or reductions) in 13 (45%) patients, dose reduction in 3 (10%) patients, and no patients discontinued due to AEs. Eleven patients discontinued from study treatment (10 due to disease progression and 1 due to physician’s discretion). The PK profile of GDC-6036 (400 mg once a day) was similar in combination with cetuximab when compared with single-agent. A partial response was achieved in 66% (19/29) of patients, with a confirmed ORR of 62% (18/29 patients). Conclusions: GDC-6036 in combination with cetuximab demonstrated a manageable safety profile and promising clinical activity. These data support that the addition of anti-EGFR therapy to GDC-6036 may lead to robust clinical benefit in patients with KRAS G12C-positive CRC. Citation Format: Jayesh Desai, Sae-Won Han, Jong-Seok Lee, Einat Shacham-Shmueli, Erminia Massarelli, Andrés Cervantes, Elena Garralda, Alejandro Falcon, Wilson H. Miller, Eelke Gort, Thomas Karasic, Salvatore Siena, Rafal Stec, Laura Medina, Luis Paz-Arez, Angelo Delmonte, Adrian Sacher, Hans Prenen, Martin Forster, Tae Won Kim, Matthew G. Krebs, Rasha Cosman, Yoonha Choi, Sandhya Mandlekar, Mark T. Lin, Kenneth K. Yau, Julie Chang, Stephanie Royer-Joo, Neekesh V. Dharia, Jennifer L. Schutzman, Manish Patel. Phase Ib study of GDC-6036 in combination with cetuximab in patients with colorectal cancer (CRC) with KRAS G12C mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT029.
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- 2023
62. Phase II Trial of Postoperative Adjuvant Gemcitabine and Cisplatin Chemotherapy Followed by Chemoradiotherapy with Gemcitabine in Patients with Resected Pancreatic Cancer
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Seock-Ah Im, Jee Hyun Kim, Jin-Young Jang, Do-Youn Oh, Sae-Won Han, Yung-Jue Bang, Sung W. Ha, Sun Whe Kim, Jihyun Kwon, Eui Kyu Chie, Jae Sung Kim, Tae-You Kim, and Kyung-Hun Lee
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Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Adolescent ,Pancreatic neoplasms ,medicine.medical_treatment ,Adenocarcinoma ,Deoxycytidine ,Gastroenterology ,Young Adult ,Internal medicine ,Pancreatic cancer ,Antineoplastic Combined Chemotherapy Protocols ,Gastrointestinal Cancer ,medicine ,Clinical endpoint ,Humans ,Survival rate ,Aged ,Postoperative Care ,Chemotherapy ,business.industry ,Chemoradiotherapy ,Middle Aged ,Prognosis ,medicine.disease ,Gemcitabine ,Survival Rate ,Tolerability ,Chemotherapy, Adjuvant ,Female ,Original Article ,Cisplatin ,business ,Febrile neutropenia ,Follow-Up Studies ,medicine.drug - Abstract
Purpose Despite curative resection, the 5-year survival for patients with resectable pancreatic cancer is less than 20%. Recurrence occurs both locally and at distant sites and effective multimodality adjuvant treatment is needed.Materials and Methods Patients with curatively resected stage IB-IIB pancreatic adenocarcinoma were eligible. Treatment consisted of chemotherapy with gemcitabine 1,000 mg/m2 on days 1 and 8 and cisplatin 60 mg/m2 on day 1 every 3 weeks for two cycles, followed by chemoradiotherapy (50.4 Gy/28 fx) with weekly gemcitabine (300 mg/m2/wk), and then gemcitabine 1,000 mg/m2 on days 1 and 8 every 3 weeks for four cycles. The primary endpoint was 1-year disease-free survival rate. The secondary endpoints were disease-free survival, overall survival, and safety.Results Seventy-four patients were enrolled. One-year disease-free survival rate was 57.9%. Median disease-free and overall survival were 15.0 months (95% confidence interval [CI], 11.6 to 18.4) and 33.0 months (95% CI, 21.8 to 44.2), respectively. At the median follow-up of 32 months, 57 patients (77.0%) had recurrence including 11 patients whose recurrence was during the adjuvant treatment. Most of the recurrences were systemic (52 patients). Stage at the time of diagnosis (70.0% in IIA, 51.2% in IIB, p=0.006) were significantly related with 1-year disease-free survival rate. Toxicities were generally tolerable, with 53 events of grade 3 or 4 hematologic toxicity and four patients with febrile neutropenia.Conclusion Adjuvant gemcitabine and cisplatin chemotherapy followed by chemoradiotherapy with gemcitabine and maintenance gemcitabine showed efficacy and good tolerability in curatively resected pancreatic cancer.
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- 2021
63. Circulating tumor DNA sequencing in colorectal cancer patients treated with first-line chemotherapy with anti-EGFR
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Ji Won Park, Hyojun Han, Jun Kyu Kang, Kyu Joo Park, Yoojoo Lim, Tae-You Kim, Sheehyun Kim, Hyoki Kim, Min Jung Kim, Hwang-Phill Kim, Hoon Jang, Seung Bum Ryoo, Kyung Hun Lee, Seung-Yong Jeong, Gyeong Hoon Kang, and Sae-Won Han
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Oncology ,Neuroblastoma RAS viral oncogene homolog ,Adult ,Male ,medicine.medical_specialty ,Colorectal cancer ,medicine.medical_treatment ,Science ,Cetuximab ,medicine.disease_cause ,Article ,Circulating Tumor DNA ,Tumour biomarkers ,Tumor Status ,Germline mutation ,Antineoplastic Agents, Immunological ,Gene Frequency ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Aged ,Aged, 80 and over ,Mutation ,Chemotherapy ,Multidisciplinary ,business.industry ,High-Throughput Nucleotide Sequencing ,Middle Aged ,medicine.disease ,Progression-Free Survival ,ErbB Receptors ,ras Proteins ,Medicine ,Female ,KRAS ,business ,Colorectal Neoplasms ,Progressive disease - Abstract
Circulating tumor DNA (ctDNA) may reveal dynamic tumor status during therapy. We conducted serial ctDNA analysis to investigate potential association with clinical outcome in metastatic colorectal cancer (mCRC) patients receiving chemotherapy. Tissue KRAS/NRAS wild-type mCRC patients were enrolled and treated with first-line cetuximab-containing chemotherapy. ctDNA isolated from plasma were analyzed by next generation sequencing (NGS) with 16 targeted gene panel. Among 93 patients, 84 (90.3%) had at least 1 somatic mutation in baseline ctDNA samples (average 2.74). Five patients with KRAS or NRAS hotspot mutation in the ctDNA showed significantly worse progression-free survival (PFS) (p = 0.029). Changes in average variant allele frequency (VAF) in ctDNA showed significant correlation with tumor size change at the time of first response evaluation (p = 0.020) and progressive disease (PD) (p = 0.042). Patients whose average VAF decreased below cutoff (p p = 0.018). At the time of PD, 54 new mutations including KRAS and MAP2K1 emerged in ctDNA. ctDNA sequencing can provide mutation profile that could better reflect tumor mutation status and predict treatment outcome.
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- 2021
64. Evaluation of Lapatinib Powder-Entrapped Biodegradable Polymeric Microstructures Fabricated by X-Ray Lithography for a Targeted and Sustained Drug Delivery System
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Eun-Goo Jeong, Hyung Jung Yoo, Byeonghwa Song, Hwang-Phill Kim, Sae-Won Han, Tae-You Kim, and Dong-Il Dan Cho
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drug delivery system (DDS) ,molecular targeted therapy ,lapatinib ,gastric cancer ,sustained drug release ,biodegradable polymer ,polycaprolactone (PCL) ,Technology ,Electrical engineering. Electronics. Nuclear engineering ,TK1-9971 ,Engineering (General). Civil engineering (General) ,TA1-2040 ,Microscopy ,QH201-278.5 ,Descriptive and experimental mechanics ,QC120-168.85 - Abstract
An oral medication of a molecular targeted drug, lapatinib, is taken regularly to maintain the drug concentration within the desired therapeutic levels. To alleviate the need for such cumbersome administration schedules in several drugs, advanced drug delivery systems (DDSs), which can provide time-controlled and sustained drug release, have recently received significant attention. A biodegradable synthetic polymer, such as polycaprolactone (PCL), is usually used as a carrier material for DDSs. In this paper, lapatinib powder-entrapped, PCL microstructures were fabricated with a precise X-ray lithography-based method. In vitro experiments on HER2 positive-human gastric cancer derived NCI-N87 cells were performed to appraise the drug release characteristics of the fabricated DDSs. The in vitro results indicate that after the X-ray lithography process, the lapatinib powder is still working well and show time- and dose- dependent drug release efficiencies. The cell growth inhibition characteristics of one hundred 40-μm sized microstructures were similar to those of a 1 μM lapatinib solution for over 144 h. In conclusion, the developed lapatinib-entrapped PCL microstructures can be used in molecular targeted delivery and sustained release as effective cancer-targeted DDSs.
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- 2015
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65. A Phase II Trial of S-1 and Oxaliplatin in Patients with Metastatic Breast Cancer Previously Treated with Anthracycline and Taxane (KCSG-BR07-03)
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Dae-Won Lee, Bhumsuk Keam, Keun Seok Lee, Jin-Hee Ahn, Joohyuk Sohn, Jin Seok Ahn, Moon Hee Lee, Jee Hyun Kim, Kyung Eun Lee, Hyo Jung Kim, Si-Young Kim, Yeon Hee Park, Chan-Young Ock, Kyung-Hun Lee, Sae-Won Han, Sung-Bae Kim, Young Hyuck Im, Hyun Cheol Chung, Do-Youn Oh, and Seock-Ah Im
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Cancer Research ,Oncology - Abstract
Purpose This single-arm phase II trial investigate the efficacy and safety of S-1 plus oxaliplatin (SOX) in patients with metastatic breast cancer.Materials and Methods Patients with metastatic breast cancer previously treated with anthracyclines and taxanes were enrolled. Patients received S-1 (40-60 mg depending on patient’s body surface area, twice a day, day 1-14) and oxaliplatin (130 mg/m2, day 1) in 3 weeks cycle until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumor 1.1. Secondary endpoints included time-to-progression (TTP), duration-of-response (DoR), overall survival (OS), and adverse events.Results A total of 87 patients were enrolled from 11 institutions in Korea. Hormone receptor was positive in 54 (62.1%) patients and six (6.9%) had human epidermal growth factor receptor 2–positive disease. Forty-eight patients (85.1%) had visceral metastasis and 74 (55.2%) had more than three sites of metastases. The ORR of SOX regimen was 38.5% (95% confidence interval [CI], 26.9 to 50.0) with a median TTP of 6.0 months (95% CI, 5.1 to 6.9). Median DoR and OS were 10.3 months (95% CI, 5.5 to 15.1) and 19.4 (95% CI, not estimated) months, respectively. Grade 3 or 4 neutropenia was reported in 28 patients (32.1%) and thrombocytopenia was observed in 23 patients (26.6%).Conclusion This phase II study showed that SOX regimen is a reasonable option in metastatic breast cancer previously treated with anthracyclines and taxanes.
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- 2022
66. Standard versus longer interval of radical resection after neoadjuvant chemoradiotherapy in locally advanced rectal cancer: A 20-year single-center experiencepropensity-score matching
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Saule Khamzina, Jongoh Lee, Seung‐Bum Ryoo, Min Jung Kim, Ji Won Park, Hyun‐Cheol Kang, Eui Kyu Chie, Dae‐Won Lee, Sae‐Won Han, Tae‐You Kim, Seung‐Yong Jeong, and Kyu Joo Park
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Treatment Outcome ,Postoperative Complications ,Oncology ,Rectal Neoplasms ,Humans ,Surgery ,Neoplasms, Second Primary ,General Medicine ,Chemoradiotherapy ,Neoadjuvant Therapy ,Retrospective Studies ,Neoplasm Staging - Abstract
Despite the standard interval of 6-8 weeks between neoadjuvant chemoradiotherapy (nCRT) and surgery, it is debated whether an interval of8 weeks increases the pathologic complete response (pCR) rate. We investigated the interval between nCRT and surgery, and its impact on oncological outcomes and postoperative complications in patients with locally advanced rectal cancer.We retrospectively reviewed patients with rectal cancer who underwent total mesorectal excision after long-course nCRT between 2000 and 2020. They were divided into two groups-those who underwent surgery at 6-8 and8 weeks after nCRT. Surgical outcomes (stoma rate and postoperative complications), pCR, tumor regression grade (TRG), recurrence-free survival (RFS), and overall survival (OS) were compared.We selected 770/1153 patients with rectal cancer, including 502 and 268 patients surgically treated at 6-8 and8 weeks after nCRT, respectively. The pCR rates were similar between the two groups (14.7% vs. 15.3%, p = 0.836), while the TRG was significantly better in the8 weeks group (p = 0.267). Additionally, the postoperative complications, recurrence, 5-year RFS, and OS rates were not significantly different between the two groups.Although tumor regression increased in the8 weeks group, the oncological benefits of surgery8 weeks after nCRT remain uncertain.
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- 2022
67. Phenotype-based single cell sequencing identifies diverse genetic subclones in CD133 positive cancer stem cells
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Yoojoo Lim, Xianyu Wen, Sae-Won Han, Sungsik Kim, Sang Hyun Song, Jinhyun Kim, Sunghoon Kwon, Tae-You Kim, Young Won Cho, Gyeong Hoon Kang, Dong Wook Min, and Hwang-Phill Kim
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Male ,0301 basic medicine ,Colorectal cancer ,Population ,Gene Dosage ,Biophysics ,Cell Separation ,Biology ,Biochemistry ,Metastasis ,03 medical and health sciences ,0302 clinical medicine ,Single-cell analysis ,Cancer stem cell ,Exome Sequencing ,Genetic variation ,Biomarkers, Tumor ,medicine ,Humans ,AC133 Antigen ,Neoplasm Metastasis ,education ,Molecular Biology ,Aged ,education.field_of_study ,Lasers ,Cell Biology ,medicine.disease ,Phenotype ,030104 developmental biology ,Single cell sequencing ,030220 oncology & carcinogenesis ,Colonic Neoplasms ,Mutation ,Neoplastic Stem Cells ,Cancer research ,Single-Cell Analysis - Abstract
Tumor heterogeneity is one of the ongoing huddles in the field of colon cancer therapy. It is evident that there are countless clones which exhibit different phenotypes and therefore, single cell analysis is inevitable. Cancer stem cells (CSCs) are rare cell population within tumor which is known to function in cancer metastasis and recurrence. Although there have been trials to prove intra-tumoral heterogeneity using single cell sequencing, that of CSCs has not been clearly elucidated. Here, we articulate the presence of heterogeneous subclones within CD133 positive cancer stem cells through single cell sequencing. As a proof of principle, we performed phenotype-based high-throughput laser isolation and single cell sequencing (PHLI-seq) of CD133 positive cells in a frozen tumor tissue obtained from a patient with colorectal cancer. The result proved that CD133 positive cells were shown to be heterogeneous both in copy number and mutational profiles. Single cancer stem cell specific mutations such as RNF144A, PAK2, PARP4, ADAM21, HYDIN, KRT38 and CELSR1 could be also detected in liver metastatic tumor of the same patient. Collectively, these data suggest that single cell analysis used to spot subclones with genetic variation within rare population, will lead to new strategies to tackle colon cancer metastasis.
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- 2021
68. Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with advanced colorectal carcinoma.
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Bert H O'Neil, John M Wallmark, David Lorente, Elena Elez, Judith Raimbourg, Carlos Gomez-Roca, Samuel Ejadi, Sarina A Piha-Paul, Mark N Stein, Albiruni R Abdul Razak, Katia Dotti, Armando Santoro, Roger B Cohen, Marlena Gould, Sanatan Saraf, Karen Stein, and Sae-Won Han
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Medicine ,Science - Abstract
Colorectal cancers (CRCs) expressing programmed death ligand 1 (PD-L1) have poor prognosis. In the multicohort KEYNOTE-028 trial, the anti-PD-1 antibody pembrolizumab was evaluated in 20 PD-L1-positive advanced solid tumors. Herein, we report results for the advanced CRC cohort.Patients with advanced, treatment-resistant PD-L1-positive carcinoma of the colon or rectum were enrolled, regardless of microsatellite instability (MSI) status. Pembrolizumab 10 mg/kg was administered every 2 weeks for up to 2 years or until disease progression/unacceptable toxicity. Response was assessed every 8 weeks for the first 6 months and every 12 weeks thereafter. Primary end points were safety and overall response rate by investigator review per Response Evaluation Criteria in Solid Tumors version 1.1. Data cutoff was June 20, 2016.Of 137 patients with CRC and samples evaluable for PD-L1 expression, 33 (24%) had PD-L1-positive tumors, of which 23 were enrolled. Median follow-up was 5.3 months, and 8 patients (35%) reported treatment-related adverse events (AEs), most commonly fatigue (n = 3, 13%), stomatitis (n = 2, 9%), and asthenia (n = 2, 9%). One patient (4%) experienced grade 4 treatment-related increased blood bilirubin. No grade 3 AEs, discontinuations, or deaths were attributed to treatment. Most patients (n = 15, 65%) experienced progressive disease. One partial response occurred in a patient (4%) with MSI-high CRC.Pembrolizumab demonstrated a favorable safety profile in advanced PD-L1-positive CRC. Antitumor activity was observed in a single patient with MSI-high CRC, warranting further evaluation in this patient population. (Clinicaltrials.gov registration: NCT02054806).
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- 2017
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69. Body mass index and body weight change during adjuvant chemotherapy in colon cancer patients: results from the AVANT trial
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Aesun Shin, Sooyoung Cho, Dae Won Lee, Tae-You Kim, and Sae-Won Han
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Male ,0301 basic medicine ,medicine.medical_specialty ,Bevacizumab ,Colorectal cancer ,Population ,lcsh:Medicine ,Gastroenterology ,Disease-Free Survival ,Article ,Body Mass Index ,Gastrointestinal cancer ,03 medical and health sciences ,0302 clinical medicine ,Weight loss ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Outcome Assessment, Health Care ,Humans ,Medicine ,education ,lcsh:Science ,Aged ,Neoplasm Staging ,Proportional Hazards Models ,education.field_of_study ,Multidisciplinary ,business.industry ,Proportional hazards model ,Body Weight ,Weight change ,lcsh:R ,Middle Aged ,Prognosis ,medicine.disease ,030104 developmental biology ,Chemotherapy, Adjuvant ,030220 oncology & carcinogenesis ,Colonic Neoplasms ,Female ,lcsh:Q ,sense organs ,medicine.symptom ,business ,Body mass index ,Weight gain ,medicine.drug - Abstract
While obesity increases colorectal cancer incidence, there are inconsistent results in the prognostic role of obesity or body weight change on survival. This study investigated the prognostic impact of body weight and weight change in stage III or high risk stage II colon cancer patients. We used data from patients enrolled in the phase III AVANT trial. The AVANT trial investigated the efficacy of adding bevacizumab to standard adjuvant chemotherapy (FOFOX or XELOX). Weight change during the first 6 months of adjuvant chemotherapy was measured. Cox proportional hazard model was used to assess the prognostic influence of body weight and weight change. Among 3451 intention-to-treat population, body weight and weight change was measured in 3449 (99.9%) and 2455 (71.1%) patients, respectively. Among 2455 patients, 651 (26.5%) had weight gain over 5 kg and 179 (7.3%) had weight loss over 5 kg. Weight gain was more frequently observed in Asian and male. Neither baseline BMI nor weight change affected recurrence or survival in the Cox proportional hazard model.
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- 2020
70. A Phase II Trial of S-1 and Oxaliplatin in Patients with Metastatic Breast Cancer Previously Treated with Anthracycline and Taxane (KCSG-BR07-03).
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Dae-Won Lee, Bhumsuk Keam, Keun Seok Lee, Jin-Hee Ahn, Joohyuk Sohn, Jin Seok Ahn, Moon Hee Lee, Jee Hyun Kim, Kyung Eun Lee, Hyo Jung Kim, Si-Young Kim, Yeon Hee Park, Chan-Young Ock, Kyung-Hun Lee, Sae-Won Han, Sung-Bae Kim, Young Hyuck Im, Hyun Cheol Chung, Do-Youn Oh, and Seock-Ah Im
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METASTATIC breast cancer ,EPIDERMAL growth factor receptors ,BODY surface area ,OXALIPLATIN ,HORMONE receptors - Abstract
Purpose This single-arm phase II trial investigate the efficacy and safety of S-1 plus oxaliplatin (SOX) in patients with metastatic breast cancer. Materials and Methods Patients with metastatic breast cancer previously treated with anthracyclines and taxanes were enrolled. Patients received S-1 (40-60 mg depending on patient's body surface area, twice a day, day 1-14) and oxaliplatin (130 mg/m², day 1) in 3 weeks cycle until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumor 1.1. Secondary endpoints included time-to-progression (TTP), duration-of-response (DoR), overall survival (OS), and adverse events. Results A total of 87 patients were enrolled from 11 institutions in Korea. Hormone receptor was positive in 54 (62.1%) patients and six (6.9%) had human epidermal growth factor receptor 2-positive disease. Forty-eight patients (85.1%) had visceral metastasis and 74 (55.2%) had more than three sites of metastases. The ORR of SOX regimen was 38.5% (95% confidence interval [CI], 26.9 to 50.0) with a median TTP of 6.0 months (95% CI, 5.1 to 6.9). Median DoR and OS were 10.3 months (95% CI, 5.5 to 15.1) and 19.4 (95% CI, not estimated) months, respectively. Grade 3 or 4 neutropenia was reported in 28 patients (32.1%) and thrombocytopenia was observed in 23 patients (26.6%). Conclusion This phase II study showed that SOX regimen is a reasonable option in metastatic breast cancer previously treated with anthracyclines and taxanes. [ABSTRACT FROM AUTHOR]
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- 2023
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71. Abstract 5157: ctDNA change predicts treatment outcome of regorafenib in metastatic colorectal cancer
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Dae-Won Lee, Sae-Won Han, Yoojoo Lim, Hwang-Phill Kim, Hanseong Roh, Min Jung Kim, Seung-Bum Ryoo, Ji Won Park, Seung-Yong Jeong, Kyu Joo Park, Gyeong Hoon Kang, and Tae-You Kim
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Cancer Research ,Oncology - Abstract
Introduction: Regorafenib is a multikinase inhibitor which showed clinical benefit in patients with treatment refractory metastatic colorectal cancer. However, as only a subset of patients derives clinical benefit from regorafenib, it is essential to identify biomarker to predict therapeutic response. Circulating tumor DNA (ctDNA) is emerging as a valuable non-invasive tool to identify tumor heterogeneity and tumor burden. This study investigated ctDNA dynamics in patients with metastatic colorectal cancer treated with regorafenib. Methods: This is a prospective biomarker study including patients with refractory metastatic colorectal cancer treated with regorafenib (ClinicalTrial.gov Identifier: NCT01996969). Patients with metastatic colorectal cancer who were refractory to standard therapies (fluoropyrimidine, oxaliplatin, and irinotecan) were eligible for the current study. Patients received oral regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle and were treated until disease progression, death, unacceptable toxicity, or decision by the treating physicians. Blood samples were obtained prior to regorafenib treatment and after every two cycles of regorafenib treatment until disease progression. ctDNA was detected by AlphaLiquid® 100 target capture panel (IMBdx, Inc., Seoul, South Korea). Alphaliquid® 100 is a tumor agnostic panel consist of 106 genes, including 10 gene fusion and MSI. Variant allele frequency (VAF) amount was calculated by adding the VAF value of all altered genes. Results: A total of 110 patients were included in the present study. Baseline blood samples were successfully acquired in 107 patients (97.3%) with a total of 713 genetic alteration. Mutation was most frequently found in TP53 (76.6%) followed by APC (75.7%), KRAS (43.0%), PIK3CA (17.8%), and SMAD4 (17.8%). BRAF mutation was found in 8.4% of patients and NRAS was detected in 3.7% of patients. Blood samples after two cycle of regorafenib was acquired in 106 patients, and was acquired in 95 patients after disease progression. Among 104 patients with baseline and follow-up cfDNA, the mean VAF at baseline was 12.8% and 7.2% in follow-up. This resulted in a mean VAF change of -5.61% (absolute value) and -43.7% (relative change). VAF decreased markedly after 2 cycles of regorafenib in several genes, including CSF1R, JAK3, KIT, ROS1, and TERT. Although, VAF change of specific gene was not associated with regorafenib outcome, VAF change of whole gene was an early predictive marker for regorafenib. Reduction in VAF amount of ≥ 50% after two cycles of regorafenib were associated with a significantly improved PFS (6.1 vs. 2.7 months, p = 0.002), OS (11.3 vs. 5.9 months, p = 0.001), and higher disease control rate (86.3% vs. 51.1%, p < 0.001). Conclusions: Serial ctDNA could be used as an early predictive biomarker in metastatic colorectal cancer treated with regorafenib. Citation Format: Dae-Won Lee, Sae-Won Han, Yoojoo Lim, Hwang-Phill Kim, Hanseong Roh, Min Jung Kim, Seung-Bum Ryoo, Ji Won Park, Seung-Yong Jeong, Kyu Joo Park, Gyeong Hoon Kang, Tae-You Kim. ctDNA change predicts treatment outcome of regorafenib in metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5157.
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- 2022
72. More Accurate Prediction of Metastatic Pancreatic Cancer Patients' Survival with Prognostic Model Using Both Host Immunity and Tumor Metabolic Activity.
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Younak Choi, Do-Youn Oh, Hyunkyung Park, Tae-Yong Kim, Kyung-Hun Lee, Sae-Won Han, Seock-Ah Im, Tae-You Kim, and Yung-Jue Bang
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Medicine ,Science - Abstract
Neutrophil to lymphocyte ratio (NLR) and standard uptake value (SUV) by 18F-FDG PET represent host immunity and tumor metabolic activity, respectively. We investigated NLR and maximum SUV (SUVmax) as prognostic markers in metastatic pancreatic cancer (MPC) patients who receive palliative chemotherapy.We reviewed 396 MPC patients receiving palliative chemotherapy. NLR was obtained before and after the first cycle of chemotherapy. In 118 patients with PET prior to chemotherapy, SUVmax was collected. Cut-off values were determined by ROC curve.In multivariate analysis of all patients, NLR and change in NLR after the first cycle of chemotherapy (ΔNLR) were independent prognostic factors for overall survival (OS). We scored the risk considering NLR and ΔNLR and identified 4 risk groups with different prognosis (risk score 0 vs 1 vs 2 vs 3: OS 9.7 vs 7.9 vs 5.7 vs 2.6 months, HR 1 vs 1.329 vs 2.137 vs 7.915, respectively; P
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- 2016
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73. Korean red ginseng for cancer-related fatigue in colorectal cancer patients with chemotherapy: A randomised phase III trial
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Keon Uk Park, Jong Gwang Kim, Sang Cheul Oh, Jae Yong Cho, Sun Kyung Baek, Ik Joo Chung, Myung Ah Lee, Jaewon Lee, Joong Bae Ahn, Yeul Hong Kim, Jin Won Kim, Doyeun Oh, Byoung-Yong Shim, Kyung Hee Lee, Dongbok Shin, and Sae-Won Han
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Male ,0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,Colorectal cancer ,Panax ,Neutropenia ,Placebo ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,Internal medicine ,medicine ,Clinical endpoint ,Humans ,Adverse effect ,Cancer-related fatigue ,Fatigue ,business.industry ,Area under the curve ,Cancer ,Middle Aged ,Prognosis ,medicine.disease ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Quality of Life ,Female ,medicine.symptom ,Colorectal Neoplasms ,business - Abstract
Background Cancer-related fatigue (CRF) is a common symptom and has a negative impact on prognosis in cancer patients. CRF could be improved by Korean red ginseng (KRG). Patients and methods For this randomised and double-blinded trial, colorectal cancer patients who received mFOLFOX-6 were randomly assigned to either KRG 2000 mg/day (n = 219) or placebo (n = 219) for 16 weeks. CRF was evaluated using the mean area under the curve (AUC) change from baseline of brief fatigue inventory (BFI) as the primary endpoint. Fatigue-related quality of life, stress, and adverse events were evaluated as secondary endpoints. Results In the full analysis group, KRG up to 16 weeks improved CRF by the mean AUC change from baseline of BFI compared to placebo, particularly in “Mood” and “Walking ability” (P = 0.038, P = 0.023, respectively). In the per-protocol group, KRG led to improved CRF in the global BFI score compared with the placebo (P = 0.019). Specifically, there were improvements in “Fatigue right now,” “Mood,” “Relations with others,” “Walking ability,” and “Enjoyment of life” at 16 weeks (P = 0.045, P = 0.006, P = 0.028, P = 0.003, P = 0.036, respectively). In subgroups of female patients, ≥60 years old, with high compliance (≥80%) or more baseline fatigue, the beneficial effects of KRG were more enhanced than that of placebo. Although neutropenia was more frequent in KRG than placebo, the incidence of all adverse events was similar. Conclusions KRG could be safely combined with mFOLFOX-6 chemotherapy in colorectal cancer patients, and reduced CRF compared with placebo.
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- 2020
74. Author response for 'Patient‐derived organoids as a preclinical platform for precision medicine in colorectal cancer'
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null Young‐Won Cho, null Dong‐Wook Min, null Hwang‐Phill Kim, null Yohan An, null Sheehyun Kim, null Jeonghwan Youk, null Jaeyoung Chun, null Jong Pil Im, null Sang‐Hyun Song, null Young Seok Ju, null Sae‐Won Han, null Kyu Joo Park, and null Tae‐You Kim
- Published
- 2021
75. Phase 1 Study of No-Carrier Added (NCA) 177Lu-DOTATATE (SNU-KB-01) in Patients with Somatostatin Receptor-Positive Neuroendocrine Tumors: The First Clinical Trial of Peptide Receptor Radionuclide Therapy (PRRT) in Korea
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Hyun Gee Ryoo, Minseok Suh, Keon Wook Kang, Dae-Won Lee, Sae-Won Han, and Gi Jeong Cheon
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Cancer Research ,Oncology - Abstract
Purpose To provide a wider choice of treatment opportunities for patients with neuroendocrine tumor (NET) in Korea, we have conducted a phase 1, open-label, single-arm, dose-escalation study of SNU-KB-01, a no-carrier added (NCA) 177Lu-labeled DOTATATE.Materials and Methods Seven patients with inoperable, progressive, metastatic, or locally advanced, somatostatin receptor-positive NET with Ki67 index ≤ 20% were enrolled according to the rolling six design. The study consisted of two cohorts to receive 4 cycles of SNU-KB-01 every 8 weeks for the first dose of 5.55 GBq (n=3) and 7.40 GBq (n=4). We assessed the incidence of dose-limiting toxicity (DLT) and adverse event, absorbed dose of kidneys and bone marrow, and objective tumor response.Results Seven patients completed 4 cycles (21.3-30.1 GBq total dose) of SNU-KB-01. The mean absorbed doses to kidneys and bone marrow were 0.500 mGy/MBq and 0.053 mGy/MBq, respectively, and the total body effective dose was 0.115 mSv/MBq. No DLT was observed and the maximum tolerated dose was 7.40 GBq/cycle. Grade 3 thrombocytopenia occurred in one patient, but no other grade 3 or 4 major hematologic or renal toxicity was observed. The best objective response to SNU-KB-01 was partial response. Overall response rate was 42.9% and disease control rate was 85.7%.Conclusion Treatment with 4 cycles of SNU-KB-01 was well tolerated and resulted in control of disease in most of the patients. Our results indicate SNU-KB-01, an NCA 177Lu-labeled DOTATATE, as a potentially safe and efficacious treatment option for NET patients in Korea.
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- 2021
76. Sotorasib for previously treated colorectal cancers with KRAS
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Marwan G, Fakih, Scott, Kopetz, Yasutoshi, Kuboki, Tae Won, Kim, Pamela N, Munster, John C, Krauss, Gerald S, Falchook, Sae-Won, Han, Volker, Heinemann, Kei, Muro, John H, Strickler, David S, Hong, Crystal S, Denlinger, Gustavo, Girotto, Myung-Ah, Lee, Haby, Henary, Qui, Tran, Joseph K, Park, Gataree, Ngarmchamnanrith, Hans, Prenen, and Timothy J, Price
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Adult ,Male ,Proto-Oncogene Proteins p21(ras) ,Pyrimidines ,Pyridines ,Mutation ,Humans ,Female ,Middle Aged ,Colorectal Neoplasms ,Piperazines ,Aged - Abstract
Sotorasib, a specific, irreversible KRASIn this single-arm, phase 2 trial, adult patients with KRASOn March 1, 2021, at data cutoff, 62 patients with KRASAlthough the 9·7% overall response rate did not reach the benchmark, oral administration of sotorasib once per day showed modest anti-tumour activity and manageable safety in these heavily pretreated chemorefractory patients. Sotorasib is under evaluation in combination with other therapeutics to increase potential activity and overcome potential resistance mechanisms.Amgen.
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- 2021
77. Preclinical Characterization and Phase I Study of an Anti-HER2-TLR7 Immune-Stimulator Antibody Conjugate in Patients with HER2+ Malignancies
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Filip Janku, Sae-Won Han, Toshihiko Doi, Alessio Amatu, Jaffer A. Ajani, Yasutoshi Kuboki, Alex Cortez, Susan E. Cellitti, Ping C. Mahling, Kulandayan Subramanian, Heidi A. Schoenfeld, Sarah M. Choi, Lori A. Iaconis, Lang Ho Lee, Marc R. Pelletier, Glenn Dranoff, Vasileios Askoxylakis, and Salvatore Siena
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Cancer Research ,Immunoconjugates ,Antineoplastic Agents, Immunological ,Toll-Like Receptor 7 ,Receptor, ErbB-2 ,Neoplasms ,Immunology ,Tumor Microenvironment ,Humans ,Antineoplastic Agents - Abstract
Immune-stimulator antibody conjugates (ISAC) combining tumor-targeting monoclonal antibodies with immunostimulatory agents allow targeted delivery of immune activators into tumors. NJH395 is a novel, first-in-class ISAC comprising a Toll-like receptor 7 (TLR7) agonist conjugated to an anti-HER2 antibody via a noncleavable linker payload. Preclinical characterization showed ISAC-mediated activation of myeloid cells in the presence of antigen-expressing cancer cells, with antigen targeting and TLR7 agonism contributing to antitumor activity. Safety, efficacy, immunogenicity, pharmacokinetics, and pharmacodynamics were investigated in a phase I, multicenter, open-label study in patients with HER2+ non-breast advanced malignancies (NCT03696771). Data from 18 patients enrolled in single ascending dose escalation demonstrated delivery of the TLR7-agonist payload in HER2+ tumor cells and induction of type I IFN responses, which correlated with immune modulation in the tumor microenvironment. Cytokine release syndrome was a common, but manageable, drug-related adverse event. Antidrug antibodies and neuroinflammation at high doses represented significant clinical challenges. Data provide proof-of-mechanism and critical insights for novel immunotherapies.
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- 2021
78. Role of Dedicated Subspecialized Radiologists in Multidisciplinary Team Discussions on Lower Gastrointestinal Tract Cancers
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Sun Kyung Jeon, Se Hyung Kim, Cheong-il Shin, Jeongin Yoo, Kyu Joo Park, Seung-Bum Ryoo, Ji Won Park, Tae-You Kim, Sae-Won Han, Dae-Won Lee, Eui Kyu Chie, and Hyun-Cheol Kang
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Patient Care Team ,Radiologists ,Humans ,Radiology, Nuclear Medicine and imaging ,Lower Gastrointestinal Tract ,Middle Aged ,Aged ,Gastrointestinal Neoplasms ,Retrospective Studies - Abstract
To determine the impact of dedicated subspecialized radiologists in multidisciplinary team (MDT) discussions on the management of lower gastrointestinal (GI) tract malignancies.We retrospectively analyzed the data of 244 patients (mean age ± standard deviation, 61.7 ± 11.9 years) referred to MDT discussions 249 times (i.e., 249 cases, as five patients were discussed twice for different issues) for lower GI tract malignancy including colorectal cancer, small bowel cancer, GI stromal tumor, and GI neuroendocrine tumor between April 2018 and June 2021 in a prospective database. Before the MDT discussions, dedicated GI radiologists reviewed all imaging studies again besides routine clinical reading. The referring clinician's initial diagnosis, initial treatment plan, change in radiologic interpretation compared with the initial radiology report, and the MDT's consensus recommendations for treatment were collected and compared. Factors associated with changes in treatment plans and the implementation of MDT decisions were analyzed.Of the 249 cases, radiologic interpretation was changed in 73 cases (29.3%) after a review by dedicated GI radiologists, with 78.1% (57/73) resulting in changes in the treatment plan. The treatment plan was changed in 92 cases (36.9%), and the rate of change in the treatment plan was significantly higher in cases with changes in radiologic interpretation than in those without (78.1% [57/73] vs. 19.9% [35/176],MDT discussion involving additional review of radiology examinations by dedicated GI radiologists resulted in a change in the treatment plan in 36.9% of cases. Changes in treatment plans were significantly associated with changes in radiologic interpretation.
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- 2021
79. Skeletal Muscle Depletion Predicts the Prognosis of Patients with Advanced Pancreatic Cancer Undergoing Palliative Chemotherapy, Independent of Body Mass Index.
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Younak Choi, Do-Youn Oh, Tae-Yong Kim, Kyung-Hun Lee, Sae-Won Han, Seock-Ah Im, Tae-You Kim, and Yung-Jue Bang
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Medicine ,Science - Abstract
Body composition has emerged as a prognostic factor in cancer patients. We investigated whether sarcopenia at diagnosis and loss of skeletal muscle during palliative chemotherapy were associated with survival in patients with pancreatic cancer.We retrospectively reviewed the clinical outcomes of pancreatic cancer patients receiving palliative chemotherapy between 2003 and 2010. The cross-sectional area of skeletal muscle at L3 by computed tomography was analyzed with Rapidia 3D software. We defined sarcopenia as a skeletal muscle index (SMI)< 42.2 cm2/m2 (male) and < 33.9 cm2/m2 (female) using ROC curve.Among 484 patients, 103 (21.3%) patients were sarcopenic at diagnosis. Decrease in SMI during chemotherapy was observed in 156 (60.9%) male and 65 (40.6%) female patients. Decrease in body mass index (BMI) was observed in 149 patients (37.3%), with no gender difference. By multivariate analysis, sarcopenia (P< 0.001), decreasedBMI and SMI during chemotherapy (P = 0.002, P = 0.004, respectively) were poor prognostic factors for overall survival (OS). While the OS of male patients was affected with sarcopenia (P< 0.001) and decreased SMI (P = 0.001), the OS of female patients was influenced with overweight at diagnosis (P = 0.006), decreased BMI (P = 0.032) and decreased SMI (P = 0.014). Particularly, while the change of BMI during chemotherapy did not have impact on OS within the patients with maintained SMI (P = 0.750), decrease in SMI was associated with poor OS within the patients with maintained BMI (HR 1.502; P = 0.002).Sarcopenia at diagnosis and depletion of skeletal muscle, independent of BMI change, during chemotherapy were poor prognostic factors in advanced pancreatic cancer.
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- 2015
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80. Clinical Implication of Anti-Angiogenic Effect of Regorafenib in Metastatic Colorectal Cancer.
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Yoojoo Lim, Sae-Won Han, Jeong Hee Yoon, Jeong Min Lee, Jung Min Lee, Jin Chul Paeng, Jae-Kyung Won, Gyeong Hoon Kang, Seung-Yong Jeong, Kyu Joo Park, Kyung-Hun Lee, Jee Hyun Kim, and Tae-You Kim
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Medicine ,Science - Abstract
BACKGROUND:Regorafenib induces distinct radiological changes that represent its anti-angiogenic effect. However, clinical implication of the changes is unclear. METHODS:Tumor attenuation as measured by Hounsfield units (HU) in contrast-enhanced computed tomography (CT) and cavitary changes of lung metastases were analyzed in association with treatment outcome of metastatic colorectal cancer patients (N = 80) treated with regorafenib in a prospective study. RESULTS:141 lesions in 72 patients were analyzed with HU. After 2 cycles of regorafenib, 87.5% of patients showed decrease of HU (Median change -23.9%, range -61.5%-20.7%). Lesional attenuation change was modestly associated with metabolic changes of 18-fluoro-deoxyglucose positron emission tomography-CT (Pearson's r = 0.37, p = 0.002). Among 53 patients with lung metastases, 17 (32.1%) developed cavitary changes. There were no differences in disease control rate, progression-free survival, or overall survival according to the radiological changes. At the time of progressive disease (PD) according to RECIST 1.1, HU was lower than baseline in 86.0% (43/50) and cavitary change of lung metastasis persisted without refilling in 84.6% (11/13). CONCLUSION:Regorafenib showed prominent anti-angiogenic effect in colorectal cancer, but the changes were not associated with treatment outcome. However, the anti-angiogenic effects persisted at the time of PD, which suggests that we may need to develop new treatment strategies.
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- 2015
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81. Destabilizing NF1 variants act in a dominant negative manner through neurofibromin dimerization.
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Young, Lucy C., Goldstein de Salazar, Ruby, Sae-Won Han, Zi Yi Stephanie Huang, Merk, Alan, Drew, Matthew, Darling, Joseph, Wall, Vanessa, Grisshammer, Reinhard, Cheng, Alice, Allison, Madeline R., Sale, Matthew J., Nissley, Dwight V., Esposito, Dominic, Ognjenovic, Jana, and McCormick, Frank
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DIMERIZATION ,MISSENSE mutation ,DISEASE management ,PROTEIN expression ,ELECTRON microscopy - Abstract
The majority of pathogenic mutations in the neurofibromatosis type I (NF1) gene reduce total neurofibromin protein expression through premature truncation or microdeletion, but it is less well understood how loss-of-function missense variants drive NF1 disease. We have found that patient variants in codons 844 to 848, which correlate with a severe phenotype, cause protein instability and exert an additional dominant-negative action whereby wild-type neurofibromin also becomes destabilized through protein dimerization. We have used our neurofibromin cryogenic electron microscopy structure to predict and validate other patient variants that act through a similar mechanism. This provides a foundation for understanding genotype–phenotype correlations and has important implications for patient counseling, disease management, and therapeutics. [ABSTRACT FROM AUTHOR]
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- 2023
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82. Phase 1 Study of No-Carrier Added 177Lu-DOTATATE (SNU-KB-01) in Patients with Somatostatin Receptor–Positive Neuroendocrine Tumors: The First Clinical Trial of Peptide Receptor Radionuclide Therapy in Korea.
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Hyun Gee Ryoo, Minseok Suh, Keon Wook Kang, Dae-Won Lee, Sae-Won Han, and Gi Jeong Cheon
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PEPTIDE receptors ,NEUROENDOCRINE tumors ,SOMATOSTATIN ,RADIOISOTOPES ,CLINICAL trials - Abstract
Purpose To provide a wider choice of treatment opportunities for patients with neuroendocrine tumor (NET) in Korea, we have conducted a phase 1, open-label, single-arm, dose-escalation study of SNU-KB-01, a no-carrier added (NCA) 177Lu-labeled DOTATATE. Materials and Methods Seven patients with inoperable, progressive, metastatic, or locally advanced, somatostatin receptor-positive NET with Ki67 index ≤ 20% were enrolled according to the rolling six design. The study consisted of two cohorts to receive 4 cycles of SNU-KB-01 every 8 weeks for the first dose of 5.55 GBq (n=3) and 7.40 GBq (n=4). We assessed the incidence of dose-limiting toxicity (DLT) and adverse event, absorbed dose of kidneys and bone marrow, and objective tumor response. Results Seven patients completed 4 cycles (21.3-30.1 GBq total dose) of SNU-KB-01. The mean absorbed doses to kidneys and bone marrow were 0.500 mGy/MBq and 0.053 mGy/MBq, respectively, and the total body effective dose was 0.115 mSv/MBq. No DLT was observed and the maximum tolerated dose was 7.40 GBq/cycle. Grade 3 thrombocytopenia occurred in one patient, but no other grade 3 or 4 major hematologic or renal toxicity was observed. The best objective response to SNU-KB-01 was partial response. Overall response rate was 42.9% and disease control rate was 85.7%. Conclusion Treatment with 4 cycles of SNU-KB-01 was well tolerated and resulted in control of disease in most of the patients. Our results indicate SNU-KB-01, an NCA 177Lu-labeled DOTATATE, as a potentially safe and efficacious treatment option for NET patients in Korea. [ABSTRACT FROM AUTHOR]
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- 2023
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83. Impact of UGT1A1 genotype on the efficacy and safety of irinotecan-based chemotherapy in metastatic colorectal cancer
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Xiang Lin Yuan, Kei Muro, Satoshi Morita, Masahito Kotaka, Keun Wook Lee, Joong Bae Ahn, Sang-Hee Cho, Young Suk Park, Dong Sheng Zhang, Tomohiro Nishina, Wei Jia Fang, Ying Yuan, Hiroshi Matsuoka, Masato Nakamura, Satoru Iwasa, Li Bai, Yong Sang Hong, Junichi Sakamoto, Sae-Won Han, Tae Won Kim, and Yasuhide Yamada
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Bevacizumab ,Genotype ,Colorectal cancer ,Leucovorin ,colorectal cancer ,Gastroenterology ,Deoxycytidine ,Capecitabine ,Young Adult ,Clinical Research ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Confidence Intervals ,Humans ,Glucuronosyltransferase ,XELIRI ,irinotecan ,Aged ,Aged, 80 and over ,business.industry ,capecitabine ,Hazard ratio ,General Medicine ,Original Articles ,Middle Aged ,medicine.disease ,Prognosis ,Progression-Free Survival ,Irinotecan ,Treatment Outcome ,Oncology ,Fluorouracil ,FOLFIRI ,Camptothecin ,Female ,Original Article ,UGT1A1 ,Topoisomerase I Inhibitors ,business ,Colorectal Neoplasms ,medicine.drug - Abstract
The phase III AXEPT study showed the noninferiority of modified capecitabine plus irinotecan (mXELIRI) with or without bevacizumab relative to fluorouracil, leucovorin, and irinotecan (FOLFIRI) with or without bevacizumab as a second‐line treatment for metastatic colorectal cancer. We evaluated the associations between the UGT1A1 genotype linked to adverse events—caused by irinotecan—and the efficacy and safety of mXELIRI and FOLFIRI. The UGT1A1 genotype was prospectively determined and patients were categorized into three groups according to WT (*1/*1), single heterozygous (SH; *28/*1 or *6/*1), and double heterozygous or homozygous (DHH; *28/*28, *6/*6, or *28/*6). Overall survival (OS), progression‐free survival, response rate, and safety were assessed. The UGT1A1 genotype was available in all 650 randomized patients (WT, 309 [47.5%]; SH, 291 [44.8%]; DHH, 50 [7.7%]). The median OS was 15.9, 17.7, and 10.6 months in the WT, SH, and DHH groups, respectively, with an adjusted hazard ratio (HR) of 1.53 (95% confidence interval [CI], 1.12‐2.09; P = .008) for DHH vs WT or SH. The median OS in the mXELIRI and FOLFIRI arms was 18.1 vs 14.3 months (HR 0.80; 95% CI, 0.62‐1.03) in the WT group, 16.3 vs 18.3 months (HR 1.04; 95% CI, 0.79‐1.36) in the SH group, and 13.0 vs 9.1 months (HR 0.71; 95% CI, 0.39‐1.31) in the DHH group, respectively. Modified capecitabine plus irinotecan with or without bevacizumab could be a standard second‐line chemotherapy in terms of efficacy and safety regardless of the UGT1A1 genotype., Capecitabine plus irinotecan (XELIRI) with or without bevacizumab is noninferior to fluorouracil, leucovorin, and irinotecan (FOLFIRI) with or without bevacizumab in terms of overall survival, regardless of UGT1A1 genotype. Additionally, modified XELIRI with or without bevacizumab showed a favorable tolerability profile that was comparable to that of FOLFIRI with or without bevacizumab among all UGT1A1 genotypes.
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- 2021
84. Tumor Mutation Burden and Prognosis in Patients with Colorectal Cancer Treated with Adjuvant Fluoropyrimidine and Oxaliplatin
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Hoon Jang, Jeong Mo Bae, Seung-Yong Jeong, Hyoki Kim, Kyu Joo Park, Hyojun Han, Tae-You Kim, Gyeong Hoon Kang, Dae Won Lee, Duhee Bang, and Sae-Won Han
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Male ,0301 basic medicine ,Oncology ,Nonsynonymous substitution ,Cancer Research ,medicine.medical_specialty ,Organoplatinum Compounds ,Oxaloacetates ,Colon ,Colorectal cancer ,medicine.medical_treatment ,DNA Mutational Analysis ,Leucovorin ,Disease-Free Survival ,03 medical and health sciences ,0302 clinical medicine ,Colon surgery ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Biomarkers, Tumor ,medicine ,Humans ,Exome ,Capecitabine ,Aged ,Neoplasm Staging ,Retrospective Studies ,Chemotherapy ,business.industry ,Rectum ,High-Throughput Nucleotide Sequencing ,Microsatellite instability ,Middle Aged ,Prognosis ,medicine.disease ,Oxaliplatin ,030104 developmental biology ,Chemotherapy, Adjuvant ,030220 oncology & carcinogenesis ,Mutation ,Mutation (genetic algorithm) ,Female ,Microsatellite Instability ,Fluorouracil ,Neoplasm Recurrence, Local ,Colorectal Neoplasms ,business ,medicine.drug - Abstract
Purpose: Recent sequencing studies revealed that a subset of colorectal cancer harbors a significantly higher number of somatic mutations. These hypermutated tumors show distinct clinicopathologic features. However, the prognostic impact of the hypermutated tumors is not clearly established. Experimental Design: We analyzed tumor mutation burden (TMB) from targeted next-generation sequencing data of 40 major genes in 516 patients with colorectal cancer. TMB was defined as total number of nonsynonymous mutations per tumor. Cutoff value for TMB-high was chosen by which best discriminated relapse-free survival (RFS) using the Contal and O'Quigley method. Results: In the TCGA data, mutation count of the selected 40 genes reflected the whole exome mutation burden (Pearson correlation = 0.873, P < 0.001). In our patient cohort, 8 or more mutations in the 40 genes was defined as TMB-high, which best discriminated RFS. A total of 55 patients (10.7%) had TMB-high. TMB-high tumors were more frequently found in a proximal location (63.6%) and had a higher proportion of N0 disease (30.9%) and MSI-H (49.1%) compared with TMB-low. Most importantly, TMB-high was associated with better 5-year RFS compared with TMB-low (96.3% vs. 79.8%, P = 0.005). Although there was significant overlap between TMB-high and MSI-H, MSI-H status was not significantly associated with RFS. Multivariate analysis revealed TMB-high as an independent positive prognostic factor for RFS [adjusted HR, 0.16 (95% confidence interval, 0.04–0.66), P = 0.011]. Conclusions: TMB-high is associated with better prognosis in patients with colorectal cancer treated with curative surgery followed by adjuvant fluoropyrimidine and oxaliplatin chemotherapy.
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- 2019
85. A Single Arm, Phase II Study of Simvastatin Plus XELOX and Bevacizumab as First-Line Chemotherapy in Metastatic Colorectal Cancer Patients
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Seung Tae Kim, Won Ki Kang, Jeeyun Lee, Young Suk Park, Ho Yeong Lim, Tae Won Kim, Joong Bae Ahn, Joon Oh Park, Sae Won Han, and Y.-W. Kim
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Adult ,Male ,0301 basic medicine ,Simvastatin ,Cancer Research ,medicine.medical_specialty ,Oxaloacetates ,Bevacizumab ,Colorectal cancer ,medicine.medical_treatment ,Administration, Oral ,Phases of clinical research ,Deoxycytidine ,Gastroenterology ,Colorectal neoplasms ,Capecitabine ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Clinical endpoint ,Humans ,XELOX ,Aged ,Chemotherapy ,business.industry ,Middle Aged ,Prognosis ,medicine.disease ,Survival Analysis ,Oxaliplatin ,Treatment Outcome ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Original Article ,Administration, Intravenous ,Female ,Fluorouracil ,business ,medicine.drug - Abstract
Purpose Simvastatin has demonstrated anti-tumor activity in preclinical studies via tumor cell senescence, apoptosis, and anti-angiogenesis. This phase II trial evaluated the efficacy and toxicity profile of conventional XELOX and bevacizumab chemotherapy plus simvastatin in metastatic colorectal cancer patients (MCRC). Materials and methods Patients with MCRC received first-line XELOX in 3-week treatment cycles of intravenous oxaliplatin 130 mg/m2 plus bevacizumab 7.5 mg/kg (day 1), followed by oral capecitabine 1,000 mg/m2 twice daily (day 1-14). Simvastatin 80 mg tablets were taken orally once daily every day during the period of chemotherapy. The primary endpoint was progression-free survival (PFS). Secondary endpoints were response rate, duration of response, overall survival (OS), time to progression, and toxicity. Results From January 2014 to April 2015, 60 patients were enrolled and 55 patients were evaluable for tumor response. The median follow-up duration was 30.1 months (range, 28.5 to 31.7 months). The median PFS was 10.4 months (95% confidence interval [CI], 9.6 to 11.1). The median OS of all patients was 19.0 months (95% CI, 11.9 to 26.0). The disease-control rate and overall response rate were 88.3% (95% CI, 74 to 96) and 58.3% (95% CI, 44 to 77), respectively, by intent-to-treat protocol analysis. There was one complete response and 34 partial responses. One patient experienced grade 3 creatine kinase elevation and liver enzyme elevation. Conclusion Based on the current study, the addition of 80 mg simvastatin to XELOX and bevacizumab showed comparable clinical efficacy in patients with MCRC as first-line chemotherapy and did not increase toxicity.
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- 2019
86. Impact of Mucin Proportion in the Pretreatment MRI on the Outcomes of Rectal Cancer Patients Undergoing Neoadjuvant Chemoradiotherapy
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Gyeong Hoon Kang, Jaemoon Koh, Kyu Joo Park, Eunji Kim, Seung-Yong Jeong, Se Hyung Kim, Eui Kyu Chie, Kyubo Kim, Tae-You Kim, and Sae-Won Han
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Adult ,Male ,0301 basic medicine ,Cancer Research ,Treatment response ,medicine.medical_specialty ,Colorectal cancer ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Statistical significance ,medicine ,Humans ,Digestive System Surgical Procedures ,Aged ,Aged, 80 and over ,medicine.diagnostic_test ,Rectal Neoplasms ,business.industry ,Mucin ,Mucins ,Magnetic resonance imaging ,Chemoradiotherapy ,Middle Aged ,medicine.disease ,Adenocarcinoma, Mucinous ,Magnetic Resonance Imaging ,Survival Analysis ,Total mesorectal excision ,Neoadjuvant Therapy ,Neoadjuvant chemoradiotherapy ,Treatment Outcome ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Preoperative Period ,Mucinous rectal cancer ,Adenocarcinoma ,Original Article ,Female ,business - Abstract
Purpose The purpose of this study was to evaluate treatment response to neoadjuvant chemoradiotherapy (CRT) with regard to mucin status in pathology and pretreatment magnetic resonance imaging (MRI) in locally advanced rectal cancer. Materials and Methods Between 2003 and 2011, 306 patients with locally advanced rectal cancer received neoadjuvant CRT followed by surgery, and mucinous adenocarcinoma (MAC) was found in 27 (8.8%). All MAC patients had MRI before and after CRT and mucin proportion at MRI was measured. Therapeutic response was assessed by pathology after total mesorectal excision. To determine the optimal cut-off for mucin proportion in predicting good CRT response (near total or total regression) and negative circumferential resection margin (CRM), the receiver-operating characteristic analysis was performed. Results After neoadjuvant CRT, overall downstaging occurred in 44.4% of MAC and 72.4% of non-MAC (p=0.001), and positive CRM (≤1 mm) was observed more frequently in MAC (p
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- 2019
87. Immune recurrence score using 7 immunoregulatory protein expressions can predict recurrence in stage I–III breast cancer patients
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Han Suk Ryu, Wonshik Han, Min Sun Jin, Ahrum Min, Kyung Hun Lee, Jung Youn Kim, Tae Yong Kim, Seock-Ah Im, Do Youn Oh, Jeonghwan Youk, Koung Jin Suh, In Ae Park, Dong Young Noh, Hyeong-Gon Moon, Han-Byoel Lee, Dae Won Lee, and Sae-Won Han
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Adult ,Oncology ,Cancer Research ,medicine.medical_specialty ,Stromal cell ,Immunology ,Breast Neoplasms ,Disease ,Lower risk ,medicine.disease_cause ,Article ,B7-H1 Antigen ,Disease-Free Survival ,03 medical and health sciences ,Breast cancer ,Lymphocytes, Tumor-Infiltrating ,0302 clinical medicine ,Immune system ,Internal medicine ,medicine ,Humans ,Clinical significance ,Stage (cooking) ,Aged ,Neoplasm Staging ,business.industry ,Middle Aged ,Prognosis ,Programmed Cell Death 1 Ligand 2 Protein ,medicine.disease ,030220 oncology & carcinogenesis ,Female ,Neoplasm Recurrence, Local ,Carcinogenesis ,business - Abstract
Background Immune cells in the tumour microenvironment play an essential role in tumorigenesis. This study aimed to evaluate the immunoregulatory protein expression of breast cancer and reveal their prognostic role. Methods Expression of 10 immune markers (PD-1/PD-L1/PD-L2/IDO/TIM-3/OX40/OX40L/B7-H2/ B7-H3/B7-H4) with known/possible clinical relevance was identified in stromal tumour-infiltrating lymphocytes or tumour tissue of stage I–III breast cancer patients. Results A total of 392 patients, including 271(69.1%) luminal A, 36(9.2%) luminal B, 32(8.2%) HER2-positive and 53(13.5%) triple negative disease, were included. Expression of PD-1 and PD-L1 was higher in HER2-positive and triple negative disease. By contrast, expression of TIM-3, OX40 and OX40L were higher in luminal disease. We devised an immune recurrence score (IRS) using seven markers with prognostic value (B7-H2/B7-H3/B7-H4/OX40/OX40L/PD-L1/PD-L2). Patients were classified as high-risk (7.9%), intermediate-risk (67.6%), or low-risk (24.5%). In the multivariate analysis, IRS low-risk (adjusted HR 0.14, p = 0.001) and intermediate-risk (adjusted HR 0.32, p = 0.002) had significantly lower risk of recurrence compared with high-risk. The prognostic role of IRS was maintained in both luminal A and non-luminal A patients. Conclusions This study identified immunoregulatory protein expression of breast cancer patients using 10 immune markers. In addition, we devised an IRS which may predict recurrence in stage I-III breast cancer patients.
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- 2019
88. Prognostic role of body mass index is different according to menopausal status and tumor subtype in breast cancer patients
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Dong Young Noh, Han-Byoel Lee, Do Youn Oh, Han Suk Ryu, Seock-Ah Im, Wonshik Han, Hyeong-Gon Moon, Jung Youn Kim, Sae-Won Han, Sukil Kim, Tae Yong Kim, Ahrum Min, Kyung Hun Lee, In Ae Park, and Dae Won Lee
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0301 basic medicine ,Oncology ,Receptors, Steroid ,Cancer Research ,medicine.medical_specialty ,Receptor, ErbB-2 ,Population ,Breast Neoplasms ,Body Mass Index ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Thinness ,Internal medicine ,medicine ,Humans ,Obesity ,Stage (cooking) ,skin and connective tissue diseases ,education ,Neoplasm Staging ,education.field_of_study ,business.industry ,Prognosis ,medicine.disease ,Survival Analysis ,Tumor Subtype ,030104 developmental biology ,Premenopause ,Hormone receptor ,030220 oncology & carcinogenesis ,Female ,Underweight ,medicine.symptom ,business ,Body mass index - Abstract
Although controversial, obesity and underweight may have a negative impact on breast cancer outcome. However, the relationship between body mass index (BMI) and breast cancer outcomes according to tumor subtype and menopausal status remains unclear. This study investigated the association between BMI and breast cancer outcome in stage I–III breast cancer patients. The relationships were further evaluated according to tumor subtype and menopausal status. A total of 5919 patients, 3475 (58.7%) hormone receptor (HR)(+) human epidermal growth factor receptor 2 (HER2)(–), 608 (10.3%) HR(+)HER2(+), 621 (10.5%) HR(–)HER2(+), and 1079 (18.2%) HR(–)HER2(–) were included. Underweight and obesity had a negative impact on relapse-free survival but did not affect overall survival. Importantly, the prognostic role of BMI was different according to tumor subtype and menopausal status. In HR(+)HER2(–) patients, underweight was associated with poor relapse-free survival and overall survival in pre-menopausal women. In contrast, obesity had negative impact on relapse-free survival and overall survival in HR(+)HER2(–) post-menopausal patients. Underweight may have a negative prognostic role in HR(+)HER2(+) patients. However, BMI did not impact the outcome of HR(–)HER2(+) and HR(–)HER2(–) patients. The impact of BMI on breast cancer outcome was dependent on tumor subtype and menopausal status. In HR(+)HER2(–) patients, underweight and obesity had a negative prognostic role in pre-menopausal and post-menopausal women, respectively. These findings in Asian population should be further evaluated and compared in Western population.
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- 2019
89. p53 expression status is associated with cancer-specific survival in stage III and high-risk stage II colorectal cancer patients treated with oxaliplatin-based adjuvant chemotherapy
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Nam Yun Cho, Jeong Mo Bae, Seorin Jung, Gyeong Hoon Kang, Young Hoon Kim, Kyung Ju Kim, Hyeon Jeong Oh, Tae-You Kim, Sae-Won Han, Jung Ho Kim, and Xianyu Wen
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Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Adolescent ,Organoplatinum Compounds ,medicine.medical_treatment ,Leucovorin ,Predictive markers ,Article ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Progression-free survival ,Young adult ,Stage (cooking) ,Survival analysis ,Aged ,Neoplasm Staging ,Chemotherapy ,business.industry ,Hazard ratio ,High-Throughput Nucleotide Sequencing ,Microsatellite instability ,Middle Aged ,medicine.disease ,Colorectal cancer ,Progression-Free Survival ,digestive system diseases ,Neoplasm Proteins ,Oxaliplatin ,Gene Expression Regulation, Neoplastic ,Chemotherapy, Adjuvant ,030220 oncology & carcinogenesis ,Female ,Microsatellite Instability ,Fluorouracil ,Tumor Suppressor Protein p53 ,Colorectal Neoplasms ,business ,medicine.drug - Abstract
Background We attempted to elucidate whether p53 expression or TP53 mutation status was associated with cancer-specific survival in adjuvant FOLFOX-treated patients with stage III or high-risk stage II colorectal cancer (CRC). Methods We analysed CRCs (N = 621) for the presence of TP53 alterations and for p53 expression, using targeted resequencing and immunohistochemistry. CRCs were grouped into four subsets according to the p53 expression status, which included p53-no, mild, moderate and strong expression. Results The distributions of CRCs were 19.85, 11.05, 17.7% and 51.5% in the p53-no, mild, moderate and strong expression groups, respectively. Cases in the p53-mild to moderate expression group were associated with a more frequent proximal location, undifferentiated histology, lower N category, extraglandular mucin production, microsatellite instability, CIMP-P1, CK7 expression and decreased CDX2 expression compared with those of cases of the p53-no expression and p53-strong expression groups. According to survival analysis, the p53-mild expression group showed a poor 5-year relapse-free survival (hazard ratio (HR): 2.71, 95% confidence interval (CI) = 1.60–4.60, P
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- 2019
90. NFATC3–PLA2G15 Fusion Transcript Identified by RNA Sequencing Promotes Tumor Invasion and Proliferation in Colorectal Cancer Cell Lines
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Hwang-Phill Kim, Si Hyun Lee, Hoon Jang, Sang Hyun Song, Jee Eun Jang, Tae-You Kim, Duhee Bang, and Sae-Won Han
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0301 basic medicine ,Cancer Research ,Epithelial-Mesenchymal Transition ,Oncogene Proteins, Fusion ,RNA-sequencing ,Vimentin ,Colorectal neoplasms ,03 medical and health sciences ,symbols.namesake ,0302 clinical medicine ,Cell Movement ,Cell Line, Tumor ,Humans ,Medicine ,Neoplasm Invasiveness ,Cell Proliferation ,Sanger sequencing ,Gene knockdown ,NFATC Transcription Factors ,biology ,Sequence Analysis, RNA ,Cell growth ,business.industry ,Cell migration ,HCT116 Cells ,NFATC3 ,Gene Expression Regulation, Neoplastic ,Phospholipases A2 ,030104 developmental biology ,Oncology ,Fusion transcript ,Tumor progression ,Cell culture ,PLA2G15 ,030220 oncology & carcinogenesis ,symbols ,Cancer research ,biology.protein ,Original Article ,business ,HT29 Cells ,Acyltransferases - Abstract
Purpose This study was designed to identify novel fusion transcripts (FTs) and their functional significance in colorectal cancer (CRC) lines. Materials and methods We performed paired-end RNA sequencing of 28 CRC cell lines. FT candidates were identified using TopHat-fusion, ChimeraScan, and FusionMap tools and further experimental validation was conducted through reverse transcription-polymerase chain reaction and Sanger sequencing. FT was depleted in human CRC line and the effects on cell proliferation, cell migration, and cell invasion were analyzed. Results One thousand three hundred eighty FT candidates were detected through bioinformatics filtering. We selected six candidate FTs, including four inter-chromosomal and two intrachromosomal FTs and each FT was found in at least one of the 28 cell lines. Moreover, when we tested 19 pairs of CRC tumor and adjacent normal tissue samples, NFATC3-PLA2G15 FT was found in two. Knockdown of NFATC3-PLA2G15 using siRNA reduced mRNA expression of epithelial-mesenchymal transition (EMT) markers such as vimentin, twist, and fibronectin and increased mesenchymal-epithelial transition markers of E-cadherin, claudin-1, and FOXC2 in colo-320 cell line harboring NFATC3-PLA2G15 FT. The NFATC3-PLA2G15 knockdown also inhibited invasion, colony formation capacity, and cell proliferation. Conclusion These results suggest that that NFATC3-PLA2G15 FTs may contribute to tumor progression by enhancing invasion by EMT and proliferation.
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- 2019
91. ARAF protein kinase activates RAS by antagonizing its binding to RASGAP NF1
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Wenjing Su, Radha Mukherjee, Rona Yaeger, Jieun Son, Jianing Xu, Na Na, Neilawattie Merna Timaul, Jaclyn Hechtman, Viktoriya Paroder, Mika Lin, Marissa Mattar, Juan Qiu, Qing Chang, Huiyong Zhao, Jonathan Zhang, Megan Little, Yuta Adachi, Sae-Won Han, Barry S. Taylor, Hiromichi Ebi, Omar Abdel-Wahab, Elisa de Stanchina, Charles M. Rudin, Pasi A. Jänne, Frank McCormick, Zhan Yao, and Neal Rosen
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ErbB Receptors ,Neurofibromin 1 ,ras GTPase-Activating Proteins ,Humans ,Guanosine Triphosphate ,Cell Biology ,Proto-Oncogene Proteins A-raf ,Molecular Biology ,Article ,Protein Binding ,Signal Transduction - Abstract
RAF protein kinases are effectors of the GTP-bound form of the small guanosine triphosphatase RAS and function by phosphorylating MEK. We showed here that expression of ARAF activated RAS in a kinase-independent manner. Binding of ARAF to RAS displaced the GTPase-activating protein NF1 and antagonized NF1-mediated inhibition of RAS. This reduced ERK-dependent inhibition of RAS and increased RAS-GTP. By this mechanism, ARAF regulated the duration and consequences of RTK-induced RAS activation and supported the RAS output of RTK-dependent tumor cells. In human lung cancers with EGFR mutation, amplification of ARAF was associated with acquired resistance to EGFR inhibitors, which was overcome by combining EGFR inhibitors with an inhibitor of the protein tyrosine phosphatase SHP2 to enhance inhibition of nucleotide exchange and RAS activation.
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- 2022
92. MO41-4 Clinical utility of circulating tumor DNA (ctDNA) during disease course of metastatic colorectal cancer (mCRC)
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Yoojoo Lim, Sheehyun Kim, Jun-Kyu Kang, Hwang-Phil Kim, Hanseong Roh, Su Yeon Kim, Dongin Lee, Duhee Bang, Seung-Yong Jeong, Kyu Joo Park, Sae-Won Han, and Tae-You Kim
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Oncology ,Hematology - Published
- 2022
93. Activation of WNT/β-catenin signaling results in resistance to a dual PI3K/mTOR inhibitor in colorectal cancer cells harboringPIK3CAmutations
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Yoo Joo Lim, Tae-You Kim, Sung Jin Kim, Young Won Cho, Sae-Won Han, Sang Hyun Song, Dong Wook Min, Ye Lim Park, Kyu Joo Park, Seul Ki Cheon, and Hwang-Phill Kim
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Cancer Research ,Gene knockdown ,Chemistry ,Wnt signaling pathway ,medicine.disease_cause ,Frameshift mutation ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,GSK-3 ,030220 oncology & carcinogenesis ,Cancer research ,medicine ,Signal transduction ,Carcinogenesis ,neoplasms ,Protein kinase B ,PI3K/AKT/mTOR pathway - Abstract
PIK3CA is a frequently mutated gene in cancer, including about ~15 to 20% of colorectal cancers (CRC). PIK3CA mutations lead to activation of the PI3K/AKT/mTOR signaling pathway, which plays pivotal roles in tumorigenesis. Here, we investigated the mechanism of resistance of PIK3CA-mutant CRC cell lines to gedatolisib, a dual PI3K/mTOR inhibitor. Out of a panel of 29 CRC cell lines, we identified 7 harboring one or more PIK3CA mutations; of these, 5 and 2 were found to be sensitive and resistant to gedatolisib, respectively. Both of the gedatolisib-resistant cell lines expressed high levels of active glycogen synthase kinase 3-beta (GSK3β) and harbored the same frameshift mutation (c.465_466insC; H155fs*) in TCF7, which encodes a positive transcriptional regulator of the WNT/β-catenin signaling pathway. Inhibition of GSK3β activity in gedatolisib-resistant cells by siRNA-mediated knockdown or treatment with a GSK3β-specific inhibitor effectively reduced the activity of molecules downstream of mTOR and also decreased signaling through the WNT/β-catenin pathway. Notably, GSK3β inhibition rendered the resistant cell lines sensitive to gedatolisib cytotoxicity, both in vitro and in a mouse xenograft model. Taken together, these data demonstrate that aberrant regulation of WNT/β-catenin signaling and active GSK3β induced by the TCF7 frameshift mutation cause resistance to the dual PI3K/mTOR inhibitor gedatolisib. Cotreatment with GSK3β inhibitors may be a strategy to overcome the resistance of PIK3CA- and TCF7-mutant CRC to PI3K/mTOR-targeted therapies.
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- 2018
94. A phase 1 dose-escalation and dose-expansion study to assess the safety and efficacy of CKD-516, a novel vascular disrupting agent, in combination with Irinotecan in patients with previously treated metastatic colorectal cancer
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Hyehyun Jeong, Seung Tae Kim, Jeong Eun Kim, Sang Joon Shin, Hyeong Seok Lim, Tae Won Kim, Yong Sang Hong, Young Suk Park, Joong Bae Ahn, Tae-You Kim, and Sae-Won Han
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0301 basic medicine ,Oncology ,Adult ,Male ,medicine.medical_specialty ,Maximum Tolerated Dose ,Colorectal cancer ,Nausea ,Metabolic Clearance Rate ,Antineoplastic Agents ,Kaplan-Meier Estimate ,Neutropenia ,Irinotecan ,03 medical and health sciences ,Benzophenones ,0302 clinical medicine ,Refractory ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,Humans ,Pharmacology (medical) ,Neoplasm Metastasis ,Adverse effect ,Aged ,Pharmacology ,Dose-Response Relationship, Drug ,business.industry ,Standard treatment ,Valine ,Middle Aged ,medicine.disease ,Progression-Free Survival ,030104 developmental biology ,030220 oncology & carcinogenesis ,Area Under Curve ,Vomiting ,Female ,medicine.symptom ,business ,Colorectal Neoplasms ,medicine.drug ,Half-Life - Abstract
Introduction The combination of an anti-angiogenic agent with cytotoxic chemotherapy is a standard treatment strategy for metastatic colorectal cancer. CKD-516 is an oral vascular disrupting agent that was preliminarily shown to be safe and efficacious as a monotherapy in refractory solid cancers. We evaluated the recommended phase 2 dose, safety, and preliminary efficacy of CKD-516 in combination with irinotecan in treatment-refractory metastatic colorectal cancer. Methods This phase 1 dose-escalation and dose-expansion study included patients with treatment-refractory metastatic colorectal cancer. CKD-516 tablets were administered for five consecutive days followed by two days off in combination with intravenous irinotecan (120 mg/m2) administered on day one of each treatment cycle every two weeks. A traditional 3 + 3 dose-escalation design was used. Results In total, 16 and 23 patients were enrolled in the dose-escalation and dose-expansion cohorts, respectively. The most common adverse events included diarrhea (79%), nausea (74%), vomiting (67%), and neutropenia (62%). No dose-limiting toxicity occurred, and the recommended phase 2 dose was determined at CKD-516/irinotecan doses of 11/120 mg/m2. No cases of cardiac ischemia, cardiac dysfunction, or thromboembolism were reported. Among the 34 patients with available tumor response assessments, one patient achieved partial response (3%) and 26 patients achieved stable disease (76%). The median progression-free survival and overall survival were 4.1 and 11.6 months, respectively. Conclusion This phase 1 study showed that the combination of oral CKD-516 and irinotecan is safe and tolerable in metastatic, treatment-refractory colorectal patients and showed favorable efficacy outcomes. Further studies to confirm these preliminary findings are warranted. Trial registration number NCT03076957 (Registered at March 10, 2017).
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- 2021
95. Circulating Tumor Marker Isolation with the Chemically Stable and Instantly Degradable (CSID) Hydrogel ImmunoSpheres
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Junhong Min, Young Jun Kim, Sae-Won Han, and Young-Ho Cho
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Equilibrium swelling ,Immunoassay ,Chromatography ,Chemistry ,Alginates ,Optical Imaging ,Hydrogels ,Cell Separation ,Exosomes ,Neoplastic Cells, Circulating ,Analytical Chemistry ,Circulating tumor cell ,Polyvinyl Alcohol ,Self-healing hydrogels ,Biomarkers, Tumor ,Humans ,Liquid biopsy ,Colorectal Neoplasms ,Tumor marker - Abstract
Here, we present chemically stable and instantly degradable (CSID) hydrogel immunospheres for the isolation of circulating tumor cells (CTCs) and circulating tumor exosomes (CTXs). The CSID hydrogels, which are prepared by the hybridization of alginate and poly(vinyl alcohol), show an equilibrium swelling ratio (ESR) of at pH 7, with a highly stable pH-responsive property. The present hybrid hydrogel is not easily disassociated in the biological buffers, thus being suitable for use in "liquid biopsy", requiring a multistep, long-term incubation process with biological samples. Also, it is gradually degraded by the action of chelating agents; effortless retrieval of the circulating markers has been achieved. Then, we modified the CSID hydrogel spheres with the anti-EpCAM antibody ("C-CSID ImmunoSpheres") and the anti-CD63 antibody ("E-CSID ImmunoSpheres") to isolate two promising circulating markers in liquid biopsy: CTCs and CTXs. The immunospheres' capabilities for marker isolation and retrieval were confirmed by a fluorescence image, where the spheres successfully isolate and effortlessly retrieve the target circulating markers. Lastly, we applied the CSID hydrogel immunospheres to five blood samples from colorectal cancer patients and retrieved average 10.8 ± 5.9 CTCs/mL and average 96.5 × 106 CTXs/mL. The present CSID hydrogel immunospheres represent a simple, versatile, and time-efficient assay platform for liquid biopsy in the practical setting, enabling us to gain a better understanding of disease-related circulating markers.
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- 2020
96. 378 A first in-human, multicenter, open-label, dose-finding phase 1 study of the immune stimulator antibody conjugate NJH395 in patients with nonbreast HER2+ advanced malignancies
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Jaffer A. Ajani, Sae-Won Han, Filip Janku, Marc Pelletier, Ping Mahling, Vasileios Askoxylakis, Yasutoshi Kuboki, Toshihiko Doi, Kulandayan K. Subramanian, and Salvatore Siena
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0301 basic medicine ,medicine.medical_specialty ,Nausea ,business.industry ,medicine.disease ,Gastroenterology ,03 medical and health sciences ,Cytokine release syndrome ,030104 developmental biology ,0302 clinical medicine ,Tolerability ,Pharmacokinetics ,030220 oncology & carcinogenesis ,Pharmacodynamics ,Internal medicine ,medicine ,Clinical endpoint ,Adenocarcinoma ,medicine.symptom ,business ,Adverse effect - Abstract
Background NJH395 is a first-in-class immune stimulator antibody conjugate (ISAC) consisting of a toll-like receptor 7 (TLR7) agonist conjugated to an anti-HER2 antibody. Antibody-mediated delivery of TLR7 may limit systemic toxicities previously seen with TLR agonists, while enhancing long-lasting antitumor immune response. In preclinical studies, NJH395 showed promising activity in HER2 expressing xenograft mouse models, and demonstrated immunogenicity and cytokine release in mice and nonhuman primates. Methods This phase 1, first-in-human, open-label, multicenter study (NCT03696771) is evaluating the safety, tolerability, pharmacokinetics, and preliminary efficacy of NJH395 in patients with nonbreast HER2+ advanced malignancies. The study design includes two parts: single-ascending dose (SAD), followed by multiple-ascending dose. Primary endpoint is safety; key secondary endpoints include assessment of pharmacokinetics, immunogenicity, and overall response rate. Tumor response was evaluated 3 weeks after treatment in SAD. Evaluation of pharmacodynamic markers including tumor-infiltrating lymphocytes is the key exploratory objective. Results Here, we report the results of the SAD part of this phase 1 study. As of July 01, 2020, 18 patients (10 males, 8 females; median age, 52.5 years [range, 42–74 years]) were enrolled in 5 dose cohorts (0.1–1.6 mg/kg). The tumor types included HER2+ colorectal cancer (N=11), gastroesophageal adenocarcinoma (N=2), non–small cell lung cancer (N=1), nasopharynx adenocarcinoma (N=1), pancreatic adenocarcinoma (N=1), bladder cancer (N=1), and small intestine adenocarcinoma (N=1). Seventeen patients reported 124 treatment-related adverse events. The most common (occurring in ≥ 20%) adverse events (AEs) of any grade (G), regardless of study drug relationship were cytokine release syndrome (55.6%, G ≤ 2), pyrexia (44.4%), nausea (44.4%), vomiting (33.3%), headache (33.3%), increased aspartate aminotransferase (AST, 33.3%), increased alanine aminotransferase (ALT, 27.8%), and lymphopenia/lymphocyte count decrease (27.8%). The most common ≥ G3 AEs (occurring in ≥ 10%) were lymphopenia/lymphocyte count decrease (27.8%) and increased AST (11.1%). Five dose-limiting toxicities, all G3, were reported in 3 patients: 2 cases of AST increase (1 at 0.2 mg/kg; 1 at 1.6 mg/kg), 1 ALT increase (1.6 mg/kg), 1 aseptic meningitis (1.6 mg/kg), and 1 meningism (1.6 mg/kg). No complete/partial response was seen; 9 patients had stable disease by RECIST v1.1 at 3 weeks post treatment. An increase in CD8-positive T-cells was detected in on-treatment tumor biopsies in 5 patients. Pharmacokinetics showed a greater than dose proportional exposure of NJH395; anti-drug antibodies were detected in all tested patients (14/14). Conclusions Single dosing of NJH395 showed significant but manageable toxicities in patients with nonbreast HER2+ advanced malignancies. Biomarker analysis is ongoing. Acknowledgements The authors thank all patients who participated in the study. The authors acknowledge Kavita Garg, PhD of Novartis Healthcare Pvt Ltd for providing medical editorial assistance with this abstract. Trial Registration ClinicalTrials. gov Identifier: NCT03696771 Ethics Approval The study was performed in accordance with ethical principles of the declaration of Helsinki and good clinical practice guidelines. The protocol and its amendments were approved by institutional review boards of each participating site. Consent Written informed consent was obtained from each patient prior to enrolment in the study.
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- 2020
97. Longitudinal monitoring of circulating tumor DNA (ctDNA) during disease course of metastatic colorectal cancer (mCRC)
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Yoojoo Lim, Sheehyun Kim, Jun-Kyu Kang, Hwang-Phill Kim, Hanseong Roh, Su Yeon Kim, Dongin Lee, Duhee Bang, Seung-Yong Jeong, Kyu Joo Park, Sae-Won Han, and Tae-You Kim
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Cancer Research ,Oncology - Abstract
189 Background: ctDNA is an attractive alternative to tissue for its easy accessibility and real time representation of systemic tumor profile. We explored the utility of ctDNA profiling during the course of mCRC treatment. Methods: Serial blood samples were obtained from mCRC patients before and during first-line palliative chemotherapy at fixed intervals (after every four cycles) until confirmed disease progression. ctDNA was sequenced using targeted next-generation sequencing (NGS) platform with 106 genes. Changes of ctDNA profile and treatment outcome were comprehensively analyzed. Results: A total of 272 samples from 62 patients were analyzed. In the pre-treatment blood samples, 56 (90.3%) of patients had detectable ctDNA mutations including single nucleotide variants, short insertions/deletions and copy number changes (median 4.5 mutations/ patient, range 0 - 133). In 31 (50.0%) patients who had tissue NGS panel results performed in the clinic, overall concordance between mutations from ctDNA and tissue was 86.5%. In three patients, ctDNA mutational profiles were found to be completely different from tissue profiles. At further investigation, these patients were found to have a separate primary cancer in their colon. At the time of the first follow-up, most (98.0%) patients showed decrease of ctDNA from baseline, represented by average variant allele frequency (VAF) changes of all ctDNA mutations found. Clearance of ctDNA was achieved in 40 (78.4%) patients and was associated with longer progression-free survival (median PFS 11.8 moths in ctDNA clearance (+) vs. 4.7 months in ctDNA clearance (-), p < 0.001). The ctDNA clearance at the same time point was able to further discriminate the patients in same category by RECIST 1.1. Serial follow-up monitoring revealed three patterns of ctDNA changes at the time of clinical progressive disease (PD): 1) re-emergence or re-increase of baseline ctDNA mutations, 2) emergence of new resistance mutations, 3) radiologic PD without evidence of ctDNA progression. In the patients with detectable ctDNA at PD, the ctDNA progression preceded radiologic progression in 25 (58.1%) patients by median of 3.3 months. The patients in clinical PD without ctDNA progression showed different patterns of metastasis having mainly extrahepatic spread, while 77.8% of the patients with ctDNA progression had their progression confirmed in liver metastasis. Diverse resistant mutations and gene amplifications in PD patients were discovered by ctDNA sequencing. For seven (16.3%) of the PD patients, the newly identified mutations could be potential candidates of targeted therapy or clinical trial. Conclusions: ctDNA profile provided additional information to conventional evaluation methods and reflected dynamic changes. ctDNA monitoring may improve precise treatment decision-making for individual patients.
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- 2022
98. Skeletal muscle depletion predicts survival of patients with advanced biliary tract cancer undergoing palliative chemotherapy
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Kyung Hun Lee, Kyoung Min Cho, Do Youn Oh, Tae Yong Kim, Tae-You Kim, Seock-Ah Im, Yung-Jue Bang, Hyunkyung Park, and Sae-Won Han
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0301 basic medicine ,medicine.medical_specialty ,medicine.medical_treatment ,Subgroup analysis ,Overweight ,Gastroenterology ,03 medical and health sciences ,BMI ,0302 clinical medicine ,Internal medicine ,biliary tract cancer ,Medicine ,Chemotherapy ,Receiver operating characteristic ,business.industry ,weight change ,Weight change ,Skeletal muscle ,skeletal muscle depletion ,medicine.disease ,Obesity ,Surgery ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,prognosis ,medicine.symptom ,Clinical Research Paper ,business ,Body mass index - Abstract
// Kyoung-Min Cho 1, 3 , Hyunkyung Park 1 , Do-Youn Oh 1, 2 , Tae-Yong Kim 1 , Kyung Hun Lee 1, 2 , Sae-Won Han 1, 2 , Seock-Ah Im 1, 2 , Tae-You Kim 1, 2 and Yung-Jue Bang 1, 2 1 Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea 2 Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea 3 Department of Internal Medicine, Graduate School, Kyung Hee University, Seoul, Republic of Korea Correspondence to: Do-Youn Oh, email: ohdoyoun@snu.ac.kr Keywords: biliary tract cancer, skeletal muscle depletion, weight change, BMI, prognosis Received: December 28, 2016 Accepted: May 22, 2017 Published: June 02, 2017 ABSTRACT Background: No prior study has investigated the dynamics of body weight with body muscle mass as a prognostic factor in advanced biliary tract cancer (BTC) patients undergoing palliative chemotherapy. We investigated whether low skeletal muscle mass affects survival in patients with BTC, with a co-analysis of body weight loss and body mass index (BMI). Results: By multivariate analysis, low skeletal muscle mass at diagnosis and decreased SMI during chemotherapy ( p = 0.008 and p < 0.001, respectively) were poor prognostic factors for overall survival (OS). Subgroup analysis revealed that low skeletal muscle mass patients who were overweight or obese (BMI ≥ 25 kg/m 2 ) showed worse OS ( p < 0.001). Additionally, patients with both decreased BMI and SMI during chemotherapy had worse OS ( p < 0.001). Furthermore, patients with decreased SMI had shorter survival regardless of change in BMI. However, for patients with SMI maintained during chemotherapy, decreased BMI had no effect on survival ( p = 0.576). Materials and Methods: We consecutively enrolled 524 patients with advanced BTC who received palliative chemotherapy between 2003 and 2013. Total muscle cross-sectional area (cm 2 ) at the L3 level assessed by computed tomography was analyzed. We defined low skeletal muscle mass as a skeletal muscle index (SMI) < 48.5 cm 2 /m 2 (men) and < 39.5 cm 2 /m 2 (women) using ROC curves. Conclusions: Low skeletal muscle mass, obesity and muscle depletion during palliative chemotherapy are meaningful prognostic factors in advanced BTC. Considering muscle depletion with weight change could help to more accurately predict prognoses of patients with BTC.
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- 2017
99. Targeted sequencing of cancer-related genes in colorectal cancer using next-generation sequencing.
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Sae-Won Han, Hwang-Phill Kim, Jong-Yeon Shin, Eun-Goo Jeong, Won-Chul Lee, Kyung-Hun Lee, Jae-Kyung Won, Tae-Yong Kim, Do-Youn Oh, Seock-Ah Im, Yung-Jue Bang, Seung-Yong Jeong, Kyu Joo Park, Jae-Gahb Park, Gyeong Hoon Kang, Jeong-Sun Seo, Jong-Il Kim, and Tae-You Kim
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Medicine ,Science - Abstract
Recent advance in sequencing technology has enabled comprehensive profiling of genetic alterations in cancer. We have established a targeted sequencing platform using next-generation sequencing (NGS) technology for clinical use, which can provide mutation and copy number variation data. NGS was performed with paired-end library enriched with exons of 183 cancer-related genes. Normal and tumor tissue pairs of 60 colorectal adenocarcinomas were used to test feasibility. Somatic mutation and copy number alteration were analyzed. A total of 526 somatic non-synonymous sequence variations were found in 113 genes. Among these, 278 single nucleotide variations were 232 different somatic point mutations. 216 SNV were 79 known single nucleotide polymorphisms in the dbSNP. 32 indels were 28 different indel mutations. Median number of mutated gene per tumor was 4 (range 0-23). Copy number gain (>X2 fold) was found in 65 genes in 40 patients, whereas copy number loss (
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- 2013
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100. Neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and their dynamic changes during chemotherapy is useful to predict a more accurate prognosis of advanced biliary tract cancer
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Tae-You Kim, Seock-Ah Im, Hyun-Kyung Park, Kyoung Min Cho, Sae-Won Han, Do Youn Oh, Kyung Hun Lee, Tae Yong Kim, and Yung-Jue Bang
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Male ,0301 basic medicine ,Neutrophils ,medicine.medical_treatment ,Systemic inflammation ,Gastroenterology ,Leukocyte Count ,0302 clinical medicine ,Antineoplastic Combined Chemotherapy Protocols ,Lymphocytes ,Aged, 80 and over ,Biliary tract neoplasm ,advanced biliary tract cancer ,Middle Aged ,Prognosis ,Primary tumor ,Biliary Tract Neoplasms ,Oncology ,030220 oncology & carcinogenesis ,Predictive value of tests ,Disease Progression ,Female ,Drug Monitoring ,medicine.symptom ,Research Paper ,Adult ,Blood Platelets ,medicine.medical_specialty ,Sensitivity and Specificity ,03 medical and health sciences ,neutrophil-to-lymphocyte ratio ,Predictive Value of Tests ,Internal medicine ,medicine ,Humans ,Clinical significance ,Neutrophil to lymphocyte ratio ,Aged ,Retrospective Studies ,Chemotherapy ,business.industry ,fungi ,Reproducibility of Results ,Retrospective cohort study ,medicine.disease ,Surgery ,body regions ,030104 developmental biology ,inflammation ,business - Abstract
// Kyoung-Min Cho 1,3 , Hyunkyung Park 1 , Do-Youn Oh 1,2 , Tae-Yong Kim 1 , Kyung-Hun Lee 1,2 , Sae-Won Han 1,2 , Seock-Ah Im 1,2 , Tae-You Kim 1,2 and Yung-Jue Bang 1,2 1 Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea 2 Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea 3 Department of Internal Medicine, School of Medicine, Kyung Hee University, Seoul, Republic of Korea Correspondence to: Do-Youn Oh, email: // Keywords : inflammation, prognosis, advanced biliary tract cancer, neutrophil-to-lymphocyte ratio Received : September 06, 2016 Accepted : November 24, 2016 Published : November 30, 2016 Abstract Background and Purpose: Systemic inflammation is known to promote carcinogenesis in biliary tract cancer (BTC). Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are indicative of systemic inflammation. We evaluated the clinical significance of systemic inflammation measured by NLR and PLR in patients with advanced BTC. Additionally, we also co-analyzed the dynamics of NLR and PLR during chemotherapy. Methods: We reviewed 450 patients with unresectable BTC receiving palliative chemotherapy. NLR and PLR were obtained before initiation of palliative chemotherapy. Changes in NLR, PLR were obtained by subtracting the initial value from the value obtained after progression of chemotherapy. Results: Higher systemic inflammation status also had relation with a primary tumor site ( p = 0.003) and higher levels of CEA ( p = 0.038). The ROC cut-off values of NLR and PLR for predicting overall survival (OS) were 3.8 and 121, respectively. Patients with a high NLR or PLR had worse OS independently in multivariate analysis (6.90 vs . 9.80 months, p = 0.002; 7.83 vs . 9.90 months, p =0.041, respectively). High NLR with increased NLR after chemotherapy is associated with worse OS and progression-free survival (PFS) ( p < 0.001, p = 0.013 respectively). Results are similar for PLR. Conclusion: Systemic inflammation represented by NLR and PLR, predicts the OS of patients with advanced BTC who are receiving palliative chemotherapy. In addition, considering NLR/PLR with a dynamic change of NLR/PLR during chemotherapy might help to predict a more accurate prognosis.
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- 2016
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