Publications by authors named "Jun Eul Hwang"

76 Publications

Intravesical gemcitabine for non-muscle invasive bladder cancer.

Cochrane Database Syst Rev 2021 06 14;6:CD009294. Epub 2021 Jun 14.

Urology Section, Minneapolis VA Health Care System, Minneapolis, Minnesota, USA.

Background: It remains unclear whether people with non-muscle invasive bladder cancer (NMIBC) benefit from intravesical gemcitabine compared to other agents in the primary or recurrent setting following transurethral resection of a bladder tumor. This is an update of a Cochrane Review first published in 2012. Since that time, several randomized controlled trials (RCTs) have been reported, making this update relevant.  OBJECTIVES: To assess the comparative effectiveness and toxicity of intravesical gemcitabine instillation for NMIBC.

Search Methods: We performed a comprehensive literature search of the Cochrane Library, MEDLINE, Embase, four other databases, trial registries, and conference proceedings to 11 September 2020, with no restrictions on the language or status of publication.

Selection Criteria: We included RCTs in which participants received intravesical gemcitabine for primary or recurrent NMIBC.

Data Collection And Analysis: Two review authors independently assessed the included studies and extracted data for the primary outcomes: time to recurrence, time to progression, grade III to V adverse events determined by the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0), and the secondary outcomes: time to death from bladder cancer, time to death from any cause, grade I or II adverse events determined by the CTCAE v5.0 and disease-specific quality of life. We performed statistical analyses using a random-effects model and rated the certainty of the evidence using GRADE.

Main Results: We included seven studies with 1222 participants with NMIBC across five comparisons. This abstract focuses on the primary outcomes of the three most clinically relevant comparisons. 1. Gemcitabine versus saline: based on two years' to four years' follow-up, gemcitabine may reduce the risk of recurrence over time compared to saline (39% versus 47% recurrence rate, hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.54 to 1.09; studies = 2, participants = 734; I = 49%; low-certainty evidence), but the CI included the possibility of no effect.  Gemcitabine may result in little to no difference in the risk of progression over time compared to saline (4.6% versus 4.8% progression rate, HR 0.96, 95% CI 0.19 to 4.71; studies = 2, participants = 654; I = 53%; low-certainty evidence).  Gemcitabine may result in little to no difference in the CTCAE grade III to V adverse events compared to saline (5.9% versus 4.7% adverse events rate, risk ratio [RR] 1.26, 95% CI 0.58 to 2.75; studies = 2, participants = 668; I = 24%; low-certainty evidence).  2. Gemcitabine versus mitomycin: based on three years' follow-up (studies = 1, participants = 109), gemcitabine may reduce the risk of recurrence over time compared to mitomycin (17% versus 40% recurrence rate, HR 0.36, 95% CI 0.19 to 0.69; low-certainty evidence). Gemcitabine may reduce the risk of progression over time compared to mitomycin (11% versus  18% progression rate, HR 0.57, 95% CI 0.32 to 1.01; low-certainty evidence), but the CI included the possibility of no effect.  We are very uncertain about the effect of gemcitabine on the CTCAE grade III to V adverse events compared to mitomycin (RR 0.51, 95% CI 0.13 to 1.93; very low-certainty evidence). The analysis was only based on recurrent NMIBC. 3. Gemcitabine versus Bacillus Calmette-Guérin (BCG) for recurrent (one-course BCG failure) high-risk NMIBC: based on 6 months' to 22 months' follow-up (studies = 1, participants = 80), gemcitabine may reduce the risk of recurrence compared to BCG (41% versus 97% recurrence rate, HR 0.15, 95% CI 0.09 to 0.26; low-certainty evidence) and progression over time (16% versus 33% progression rate, HR 0.45, 95% CI 0.27 to 0.76; low-certainty evidence). We are very uncertain about the effect of gemcitabine on the CTCAE grade III to V adverse events compared to BCG (RR 1.00, 95% CI 0.21 to 4.66; very low-certainty evidence).  In addition, the review provides information on  the comparison of gemcitabine versus BCG and gemcitabine versus one-third dose BCG.  AUTHORS' CONCLUSIONS: Based on findings of this review, gemcitabine may have a more favorable impact on recurrence and progression-free survival than mitomycin but we are very uncertain as to how major adverse events compare. The same is true when comparing gemcitabine to BCG in individuals with high risk disease who have previously failed BCG. The underlying low- to very low-certainty evidence indicates that our confidence in these results is limited; the true effects may be substantially different from these findings; therefore, better quality studies are needed.
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http://dx.doi.org/10.1002/14651858.CD009294.pub3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202966PMC
June 2021

Lgals3bp suppresses colon inflammation and tumorigenesis through the downregulation of TAK1-NF-κB signaling.

Cell Death Discov 2021 Apr 6;7(1):65. Epub 2021 Apr 6.

Department of Hematology and Oncology, Chonnam National University Medical School and Hwasun Hospital, Hwasun, Republic of Korea.

Galectin 3-binding protein (LGALS3BP, also known as 90K) is a multifunctional glycoprotein involved in immunity and cancer. However, its precise role in colon inflammation and tumorigenesis remains unclear. Here, we showed that Lgals3bp mice were highly susceptible to colitis and colon tumorigenesis, accompanied by the induction of inflammatory responses. In acute colitis, NF-κB was highly activated in the colon of Lgals3bp mice, leading to the excessive production of pro-inflammatory cytokines, such as IL-6, TNFα, and IL-1β. Mechanistically, Lgals3bp suppressed NF-κB through the downregulation of TAK1 in colon epithelial cells. There was no significant difference in the pro-inflammatory cytokine levels between wild-type and Lgals3bp mice in a chronic inflammatory state, during colon tumorigenesis. Instead, Lgals3bp mice showed elevated levels of GM-CSF, compared to those in WT mice. We also found that GM-CSF promoted the accumulation of myeloid-derived suppressor cells and ultimately increased colon tumorigenesis in Lgals3bp mice. Taken together, Lgals3bp plays a critical role in the suppression of colitis and colon tumorigenesis through the downregulation of the TAK1-NF-κB-cytokine axis. These findings suggest that LGALS3BP is a novel immunotherapeutic target for colon inflammation and tumorigenesis.
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http://dx.doi.org/10.1038/s41420-021-00447-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024364PMC
April 2021

Long term complications and prognostic factors in locally advanced nasopharyngeal carcinoma treated with docetaxel, cisplatin, 5-fluorouracil induction chemotherapy followed by concurrent chemoradiotherapy: A retrospective cohort study.

Medicine (Baltimore) 2020 Dec;99(49):e23173

Department of Hematology and Oncology.

This study was conducted to evaluate the long term complications and their risk factors including of survival outcomes in patients with locally advanced nasopharyngeal cancer (NPC) treated with docetaxel, cisplatin and 5-fluorouracil (TPF) induction chemotherapy followed by concurrent chemoradiotherapy (CCRT).Among the patients who were diagnosed as NPC, we consecutively evaluated the late complications in 104 patients who completed 3 cycles of TPF induction chemotherapy followed by CCRT and received regular follow-up by otolaryngologist and oncologist. The prognostic factors for overall survival, relapse free survival and each complication were analyzed based on clinical characteristics.Over a median follow-up of 54 months (range, 7.9-152.9 months), 5-year overall survival rate was 87% for stage II, 89% for stage III, 87% for stage IV patients. The significant prognostic factor for survival is complete response rate after CCRT in multivariate analysis. The most frequent toxicity was ear complication (29.8%) including of hearing loss requiring hearing aid (6.7%) and bone necrosis (3.8%). Decreased renal function over grade 2 was occurred in only 4 patients (3.8%) regardless of the cumulative dose of cisplatin. The long term complications did not affect the survival outcome. Patients who received radiation therapy more than 5400 cGy had better survival outcome than those who did not. However, ear complication was significantly related to radiation dose (≥ 6,600 cGy) and type of radiation therapy (conventional). Age over 65 years was a significant risk factor for both ear and renal toxicity. In conclusion, close follow-up to monitor long-term complications should be performed in patients treated with TPF induction chemotherapy followed by CCRT treatment, especially in elderly patients. Reestablishing the optimal chemotherapeutic agent during CCRT and adjustment of radiation dose after induction chemotherapy could be helpful to reduce the toxicity associated with the subsequent treatment strategy for locally advance NPC patients.
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http://dx.doi.org/10.1097/MD.0000000000023173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717786PMC
December 2020

Does multidetector computed tomographic urography (MDCTU) T staging classification correspond with pathologic T staging in upper tract urothelial carcinoma?

Int Urol Nephrol 2021 Jan 28;53(1):69-75. Epub 2020 Aug 28.

Department of Urology, Chonnam National University Medical School, Seoyang-ro, Hwasun-eup, Hwasun-gun, 26458128, Jeollanam-do, Korea.

Purpose: Multidetector computed tomographic urography (MDCTU) is not yet sufficient to be used in the clinical staging of upper tract urothelial carcinoma (UTUC). This study aimed to compare the diagnostic accuracy of MDCTU T stage classification and pathologic T staging for UTUC.

Methods: We retrospectively evaluated 125 patients with UTUC who underwent preoperative MDCTU. A single radiologist classified the MDCTU pattern of the tumors as either low or advanced T stage for localized or locally advanced tumors, respectively. The diagnostic values of MDCTU for locally advanced tumors and the kappa agreement between MDCTU and pathologic T stage were investigated.

Results: Among 85 pathologic low T stage (Ta-T2) tumors, 71 low T stage tumors were correctly detected by MDCTU, while 30 out of 40 advanced T stage (T3-T4) tumors were correctly diagnosed by MDCTU. MDCTU led to under-staging in 8% (10/125) tumors and over-staging in 11.2% (14/125) tumors. Therefore, the overall accuracy of MDCTU in the diagnosis of low and advanced T stage tumors was 80.8% (101/125 patients). The sensitivity for advanced T stage tumors was 75% (30/40), the specificity was 83.5% (71/85), and the positive and negative predictive values were 68.1% (30/44) and 87.6% (71/81), respectively. The kappa agreement value between the MDCTU T stage and pathologic T stage was 0.57 (95% confidence interval (CI) 0.42-0.72), which was statistically significant (P = 0.001).

Conclusion: MDCTU T stage classification may be relatively accurate for the detection and staging of UTUC correspondence with a pathologic stage.
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http://dx.doi.org/10.1007/s11255-020-02622-8DOI Listing
January 2021

Comparison of long-term treatment outcomes of T2N0M0 laryngeal squamous cell carcinoma using different treatment methods.

Oncol Lett 2020 Jul 14;20(1):921-930. Epub 2020 May 14.

Department of Otorhinolaryngology-Head and Neck Surgery, Chonnam National University Medical School and Hwasun Hospital, Hwasun, Jeollanam 519-763, Republic of Korea.

Early [stage I and II (T2N0M0)] laryngeal cancer types are currently recommended to be treated with a single modality, consisting of definitive radiation therapy or larynx-preserving surgery. Although the treatment outcomes of stage I are good, the frequency of successful outcomes decreases with T2N0M0. Therefore, the present study investigated the treatment outcomes of different treatment methods in T2N0M0 laryngeal cancer. In total, 83 patients with previously untreated T2N0M0 laryngeal squamous cell carcinoma were enrolled. Patients were grouped by treatment method: Radiation therapy (RT; 27 patients); chemoradiotherapy (CRT; 46 patients) with cisplatin base; and surgery-based therapy (SBT; ten patients). The recurrence rates of the RT, CRT and SBT groups were 44.4, 19.6 and 50%, respectively. Moreover, the local control rates of the RT, CRT and SBT groups were 55.6, 87.0 and 80%, respectively. The CRT group had a significantly lower recurrence rate and higher local control rate compared with the RT group (P<0.05). In the survival analysis, overall and disease-specific survival rate did not differ significantly among the treatment groups. However, 3- and 5-year disease-free survival rates (DFS) of the RT group were both 55%, those of the SBT group were both 50% and those of the CRT group were both 80%. Furthermore, the DFS was significantly higher in CRT group compared with the other groups (P=0.02). Using multivariate analysis with Cox regression, it was found that the treatment method was the most important factor for DFS and had a significant impact in the CRT group. In addition, in patients with glottic cancer with anterior commissure and subglottic invasion, the CRT group had significantly improved DFS compared with the RT group, whereas there was no significant difference between the two groups in patients without subglottic invasion. According to National Cancer Institution Common Toxicity Criteria (version 5.0), more patients had toxicity in the CRT group compared with the RT group. However, in the RT and CRT groups, no patients demonstrated mortality due to toxicity, and treatment-related toxicities were manageable. Collectively, although definitive conclusions could not be established, due to the limitations of this retrospective study, the results suggest that CRT had a positive impact on the local control and DFS rates with manageable toxicity in patients with T2N0M0 laryngeal cancer.
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http://dx.doi.org/10.3892/ol.2020.11628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285832PMC
July 2020

Regorafenib in patients with advanced Child-Pugh B hepatocellular carcinoma: A multicentre retrospective study.

Liver Int 2020 10 9;40(10):2544-2552. Epub 2020 Jul 9.

Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Introduction: Regorafenib is an approved agent in patients with advanced hepatocellular carcinoma (HCC) who progressed on sorafenib, but little is known about its clinical outcomes in Child-Pugh B patients. We aimed to investigate the safety and effectiveness of regorafenib in Child-Pugh B HCC patients.

Methods: This multicentre retrospective study included 59 patients with Child-Pugh B HCC who received regorafenib. Comparative analyses were performed with an independent cohort of Child-Pugh class A patients from the same registry (n = 440).

Results: The median age was 58 years (range, 19-83). All patients had progression on prior sorafenib. Regorafenib was given as 2nd line, and 3rd-4th line systemic therapy in 37 (62.7%) and 22 (37.3%) patients respectively. Compared to Child-Pugh A cohort, grade 3-4 AEs were more common in the Child-Pugh B cohort (27.1% vs 14.1%, P = .017). The median progression-free survival (PFS) and overall survival (OS) were 1.8 and 4.6 months, respectively, and these were significantly poorer than the Child-Pugh A cohort (P = .008 and P < .001 respectively). Child-Pugh B patients with albumin-bilirubin (ALBI) grade 3 had a significantly higher frequency of increased bilirubin (P = .01 for any grade and P = .01 for grade 3-4) and showed significantly poorer OS (P = .021), compared to those with ALBI grade 1 or 2.

Conclusion: Regorafenib's poor clinical outcomes and increased frequency of severe adverse events lead us to discourage its use in the Child-Pugh B population. In particular, regorafenib should not be used in Child-Pugh B patients with ALBI grade 3.
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http://dx.doi.org/10.1111/liv.14573DOI Listing
October 2020

Fibroblast growth factor receptor 4 increases epidermal growth factor receptor (EGFR) signaling by inducing amphiregulin expression and attenuates response to EGFR inhibitors in colon cancer.

Cancer Sci 2020 Sep 20;111(9):3268-3278. Epub 2020 Jul 20.

Division of Hematology-Oncology, Department of Internal Medicine, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun, Korea.

Fibroblast growth factor receptor 4 (FGFR4) is known to induce cancer cell proliferation, invasion, and antiapoptosis through activation of RAS/RAF/ERK and PI3K/AKT pathways, which are also known as major molecular bases of colon cancer carcinogenesis related with epidermal growth factor receptor (EGFR) signaling. However, the interaction between FGFR4 and EGFR signaling in regard to colon cancer progression is unclear. Here, we investigated a potential cross-talk between FGFR4 and EGFR, and the effect of anti-EGFR therapy in colon cancer treatment. To explore the biological roles of FGFR4 in cancer progression, RNA sequencing was carried out using FGFR4 transfected colon cell lines. Gene ontology data showed the upregulation of genes related to EGFR signaling, and we identified that FGFR4 overexpression secretes EGFR ligands such as amphiregulin (AREG) with consequent activation of EGFR and ErbB3. This result was also shown in in vivo study and the cooperative interaction between EGFR and FGFR4 promoted tumor growth. In addition, FGFR4 overexpression reduced cetuximab-induced cytotoxicity and the combination of FGFR4 inhibitor (BLU9931) and cetuximab showed profound antitumor effect compared to cetuximab alone. Clinically, we found the positive correlation between FGFR4 and AREG expression in tumor tissue, but not in normal tissue, from colon cancer patients and these expressions were significantly correlated with poor overall survival in patients treated with cetuximab. Therefore, our results provide the novel mechanism of FGFR4 in connection with EGFR activation and the combination of FGFR4 inhibitor and cetuximab could be a promising therapeutic option to achieve the optimal response to anti-EGFR therapy in colon cancer.
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http://dx.doi.org/10.1111/cas.14526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469799PMC
September 2020

Observational Study of Peritoneal Washing Cytology-Positive Gastric Cancer without Gross Peritoneal Metastasis in Patients who Underwent Radical D2 Gastrectomy.

Sci Rep 2020 06 12;10(1):9549. Epub 2020 Jun 12.

Department of Hematology-Oncology, Gwangju, Korea.

Background The clinical features and therapeutic strategies for gastric cancer with positive peritoneal washing cytology but without visible gross peritoneal metastasis have not been defined. The aim of this study was to evaluate the effect and clinical prognostic value of postoperative chemotherapy in gastric cancer patients with positive peritoneal washing cytology without gross peritoneal metastasis who underwent radical D2 gastrectomy in terms of disease-free survival (DFS) and overall survival (OS). Materials and Methods Intraoperative peritoneal washing cytology was performed in 285 patients who underwent radical D2 gastrectomy between April 2004 and May 2016. Of them, 88 patients with positive cytology but without gross peritoneal metastasis were included in the study. In total, 64 patients received postoperative chemotherapy, whereas 24 patients underwent surgery only. Results Most gastric cancer patients with positive cytology without gross peritoneal metastasis demonstrated pT4 and/or pN3 disease. Postoperative chemotherapy improved DFS and OS compared to surgery only in gastric cancer patients with positive cytology without gross peritoneal metastasis (median DFS 11.63 vs. 6.98 months, p < 0.001; median OS 25.50 vs. 12.11 months, p < 0.001). In multivariate analyses of gastric cancer patients with positive cytology without gross peritoneal metastasis, no chemotherapy was the strongest clinical factor for poorer DFS (hazard ratio [HR] 3.76, p < 0.001) or OS (HR 4.37, p < 0.001). Conclusion Postoperative chemotherapy improves the survival outcome compared to surgery alone in gastric cancer patients with positive peritoneal washing cytology but without visible gross peritoneal metastasis who underwent radical D2 gastrectomy.
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http://dx.doi.org/10.1038/s41598-020-66637-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293245PMC
June 2020

Regorafenib in previously treated advanced hepatocellular carcinoma: Impact of prior immunotherapy and adverse events.

Liver Int 2020 09 25;40(9):2263-2271. Epub 2020 May 25.

Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Background & Aims: Regorafenib demonstrated a clinical benefit for patients with unresectable hepatocellular carcinoma (uHCC) in the phase III RESORCE trial. Considering the heterogeneity of uHCC and discrepancies in its characteristics between prospective trials and daily practice, real-life evidence is necessary.

Methods: This multicentre, retrospective analysis was performed by the Korean Cancer Study Group. In total, 440 patients who received regorafenib between January 2017 and November 2019 were identified in nine tertiary referral hospitals in Korea.

Results: All patients received prior sorafenib, and the median time-to-progression (TTP) on sorafenib was 3.9 months (range, 0.2-71.6). Regorafenib was used as the second, third and fourth to seventh lines of therapy in 305 (69.3%), 115 (26.1%) and 20 (4.5%) patients respectively. According to the RECIST v1.1, the overall response rate was 7.7% (n = 34), and the median progression-free survival (PFS) and overall survival (OS) were 3.2 (95% CI, 2.8-3.5) and 12.1 (95% CI, 9.7-14.5) months respectively. Immune checkpoint inhibitors (ICIs) were given in 115 patients (26.1%) prior to regorafenib. There were no differences in PFS and OS with regorafenib according to the prior use of ICIs (PFS, P = .61; OS, P = .63). The occurrence of hand-foot skin reaction (HFSR) was associated with a better OS (P < .001).

Conclusions: The real-life clinical outcomes of regorafenib for patients who progressed on prior systemic therapy including ICIs were consistent with the phase III trial results. HFSR was significantly associated with better OS with regorafenib.
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http://dx.doi.org/10.1111/liv.14496DOI Listing
September 2020

Gal-3BP Negatively Regulates NF-κB Signaling by Inhibiting the Activation of TAK1.

Front Immunol 2019 26;10:1760. Epub 2019 Jul 26.

Department of Internal Medicine, Chonnam National University Medical School, Hwasun, South Korea.

Galectin-3-binding protein (Gal-3BP) is a member of the family of scavenger receptor cysteine-rich (SRCR) domain-containing proteins, which are associated with the immune system. However, the functional roles and signaling mechanisms of Gal-3BP in host defense and the immune response remain largely unknown. Here, we identified cellular Gal-3BP as a negative regulator of NF-κB activation and proinflammatory cytokine production in lipopolysaccharide (LPS)-stimulated murine embryonic fibroblasts (MEFs). Furthermore, cellular Gal-3BP interacted with transforming growth factor β-activated kinase 1 (TAK1), a crucial mediator of NF-κB activation in response to cellular stress. Gal-3BP inhibited the phosphorylation of TAK1, leading to suppression of its kinase activity and reduced protein stability. we found that deficiency in mice enhanced LPS-induced proinflammatory cytokine release and rendered mice more sensitive to LPS-induced endotoxin shock. Overall, these results suggest that Gal-3BP is a novel suppressor of TAK1-dependent NF-κB activation that may have potential in the prevention and treatment of inflammatory diseases.
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http://dx.doi.org/10.3389/fimmu.2019.01760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677151PMC
October 2020

Immunogenicity and Optimal Timing of 13-Valent Pneumococcal Conjugate Vaccination during Adjuvant Chemotherapy in Gastric and Colorectal Cancer: A Randomized Controlled Trial.

Cancer Res Treat 2020 Jan 9;52(1):246-253. Epub 2019 Jul 9.

Division of Hematology-Oncology, Department of Internal Medicine, Chonnam National University Hwasun Hospital, Chonnam National University College of Medicine, Hwasun, Korea.

Purpose: Pneumococcal vaccination (13-valent pneumococcal conjugate vaccine [PCV13]) is recommended to cancer patients undergoing systemic chemotherapy. However, the optimal time interval between vaccine administration and initiation of chemotherapy has been little studied in adult patients with solid malignancies.

Materials And Methods: We conducted a prospective randomized controlled trial to evaluate whether administering PCV13 on the first day of chemotherapy is non-inferior to vaccinating 2 weeks prior to chemotherapy initiation. Patients were randomly assigned to two study arms, and serum samples were collected at baseline and 4 weeks after vaccination to analyze the serologic response against Streptococcus pneumoniae using a multiplexed opsonophagocytic killing assay.

Results: Of the 92 patients who underwent randomization, 43 patients in arm A (vaccination 2 weeks before chemotherapy) and 44 patients in arm B (vaccination on the first day of chemotherapy) were analyzed. Immunogenicity was assessed by geometric mean and fold-increase of post-vaccination titers, seroprotection rates (percentage of patients with post-vaccination titers > 1:64), and seroconversion rates (percentage of patients with > 4-fold increase in post-vaccination titers). Serologic responses to PCV13 did not differ significantly between the two study arms according to all three types of assessments.

Conclusion: The overall antibody response to PCV13 is adequate in patients with gastric and colorectal cancer during adjuvant chemotherapy, and no significant difference was found when patients were vaccinated two weeks before or on the day of chemotherapy initiation.
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http://dx.doi.org/10.4143/crt.2019.189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962463PMC
January 2020

Lymph-node ratio is an important clinical determinant for selecting the appropriate adjuvant chemotherapy regimen for curative D2-resected gastric cancer.

J Cancer Res Clin Oncol 2019 Aug 4;145(8):2157-2166. Epub 2019 Jul 4.

Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, 322, Seoyang-ro, Hwasun-eup, Hwasun-gun, Jeonnam, 58128, South Korea.

Purpose: Adjuvant chemotherapy for gastric cancer, particularly stage III, improves survival after curative D2 gastrectomy. We investigated the clinical value of the lymph-node ratio (LNR; number of metastatic lymph nodes/number of lymph nodes examined) for selecting the appropriate adjuvant chemotherapy regimen in patients with D2-resected stage II/III gastric cancer.

Methods: We reviewed the data of 819 patients who underwent curative D2 gastrectomy followed by adjuvant chemotherapy. Of them, 353 patients received platinum-based chemotherapy and 466 received TS-1. The patients were categorized into three groups according to their LNR (LNR 1, 0-0.1; LNR 2, > 0.1-0.25; and LNR 3, > 0.25), and their disease-free survival (DFS) was evaluated.

Results: The DFS curves of the patients were well separated according to stage and LNR. In multivariate analyses, an LNR > 0.1 was strongly associated with the 3-year DFS (hazard ratio 2.402, 95% confidence interval 1.607-3.590, P < 0.001). Platinum-based chemotherapy improved the 3-year DFS compared to TS-1 in patients with LNR 3 group in stage III gastric cancer (platinum vs. TS-1, median DFS 26.87 vs. 16.27 months, P = 0.028). An LNR > 0.1 was associated with benefiting from platinum-based adjuvant chemotherapy in stage III gastric cancer patients with lymphovascular invasion (platinum vs. TS-1, median DFS 47.57 vs. 21.77 months, P = 0.011).

Conclusions: The LNR can be used to select the appropriate adjuvant chemotherapy regimen for patients with D2-resected gastric cancer, particularly in stage III.
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http://dx.doi.org/10.1007/s00432-019-02963-7DOI Listing
August 2019

Prognostic significance of high metabolic activity in breast cancer: PET signature in breast cancer.

Biochem Biophys Res Commun 2019 03 15;511(1):185-191. Epub 2019 Feb 15.

Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address:

High metabolic activity, reflected in increased glucose uptake, is one of the hallmarks of many cancers including breast cancer. However, not all cancers avidly take up glucose, suggesting heterogeneity in their metabolic demand. Thus, we aim to generate a genomic signature of glucose hypermetabolism in breast cancer and examine its clinical relevance. To identify genes significantly associated with glucose uptake, gene expression data were analyzed together with the standardized uptake values (SUVmax) of F-fluorodeoxy-glucose on positron emission tomography (PET) for 11 breast cancers. The resulting PET signature was evaluated for prognostic significance in four large independent patient cohorts (n = 5417). Potential upstream regulators accountable for the high glucose uptake were identified by gene network analysis. A PET signature of 242 genes was significantly correlated with SUVmax in breast cancer. In all four cohorts, high PET signature was significantly associated with poorer prognosis. The prognostic value of this PET signature was further supported by Cox regression analyses (hazard ratio 1.7, confidential interval 1.48-2.02; P < 0.001). The PET signature was also strongly correlated with previously established prognostic genomic signatures such as PAM50, Oncotype DX, and NKI. Gene network analyses suggested that MYC and TBX2 were the most significant upstream transcription factors in the breast cancers with high glucose uptake. A PET signature reflecting high glucose uptake is a novel independent prognostic factor in breast cancer. MYC and TBX2 are potential regulators of glucose uptake.
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http://dx.doi.org/10.1016/j.bbrc.2019.02.035DOI Listing
March 2019

Efficacy of First-Line Targeted Therapy in Real-World Korean Patients with Metastatic Renal Cell Carcinoma: Focus on Sunitinib and Pazopanib.

J Korean Med Sci 2018 Dec 22;33(51):e325. Epub 2018 Nov 22.

Department of Urology, National Cancer Center, Goyang, Korea.

Background: To evaluate survival outcomes and prognostic factors for overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC) who received sunitinib (SU) and pazopanib (PZ) as first-line therapy in real-world Korean clinical practice.

Methods: Data of 554 patients with mRCC who received SU or PZ at eight institutions between 2012 and 2016 were retrospectively reviewed. Based on the targeted therapy, the patients were divided into SU (n = 293) or PZ (n = 261) groups, and the clinicopathological variables and survival rates of the two groups were compared. A multivariable Cox proportional hazard model was used to determine the prognostic factors for OS.

Results: The median follow-up was 16.4 months (interquartile range, 8.3-31.3). Patients in the PZ group were older, and no significant difference was observed in the performance status (PS) between the two groups. In the SU group, the dose reduction rate was higher and the incidence of grade 3 toxicity was more frequent. The objective response rates were comparable between the two groups (SU, 32.1% vs. PZ, 36.4%). OS did not differ significantly between the two groups (SU, 36.5 months vs. PZ, 40.2 months; log-rank, = 0.955). Body mass index, Eastern Cooperative Oncology Group PS > 2, synchronous metastasis, poor Heng risk criteria, and liver and bone metastases were associated with a shorter OS.

Conclusion: Our real-world data of Korean patients with mRCC suggested that SU and PZ had similar efficacies as first-line therapy for mRCC. However, PZ was better tolerated than SU in Korean patients.
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http://dx.doi.org/10.3346/jkms.2018.33.e325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291404PMC
December 2018

Genetic variations using whole-exome sequencing might predict response for neoadjuvant chemoradiotherapy in locally advanced rectal cancer.

Med Oncol 2018 Sep 11;35(11):145. Epub 2018 Sep 11.

Department of Oncology/Hematology, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, Republic of Korea.

A good pathologic response to neoadjuvant chemoradiotherapy (CRT) in locally advanced rectal cancer (LARC) is associated with a better prognosis. However, there is no effective method to predict CRT response in LARC patients. Therefore, this study used whole-exome sequencing (WES) to identify novel biomarker predicting CRT benefit in LARC. Two independent tumor tissue sets were used to evaluate the genetic differences between the good CRT response group (15 patients achieved a pathologic complete response (pCR)) and the poor CRT response group (15 patients with pathologic stage III). After applying WES to the discovery set of 30 patients, additional samples (n = 67) were genotyped for candidate variants using TaqMan or Sanger sequencing for validation. Overall, this study included a total of 97 LARC patients. In the discovery and validation set, there was no known genetic mutation to predict response between two groups, while five candidate variants (BCL2L10 rs2231292, DLC1 rs3816748, DNAH14 rs3105571, ITIH5 rs3824658, and RAET1L rs912565) were found to be significantly associated with pCR. In the dominant model, the GC/CC genotype of DLC1 rs3816748 (p = 0.032), AC/CC genotype of DNAH14 rs3105571 (p = 0.009), and TT genotype of RAET1 rs912565 (p < 0.0001) were associated with a higher pCR rate. In the recessive model, BCL2L10 rs2231292 (p = 0.036) and ITIH5 rs3824658 (p = 0.003) were significantly associated with pCR. In the co-dominant model, 4 candidate variants (DLC1 rs3816748, DNAH14 rs3105571, ITIH5 rs3824658, and RAET1L rs912565) were significantly correlated with pCR. However, none of the candidate variants was associated with relapse-free or overall survival. The present results suggest that genetic variations of the BCL2L10 rs2231292, DLC1 rs3816748, DNAH14 rs3105571, ITIH5 rs3824658, and RAET1L rs912565 genes can be used as biomarkers predicting the CRT response for patients with LARC.
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http://dx.doi.org/10.1007/s12032-018-1202-8DOI Listing
September 2018

TAp73 inhibits cell invasion and migration by directly activating KAI1 expression in colorectal carcinoma.

Cancer Lett 2018 02 6;415:106-116. Epub 2017 Dec 6.

Department of Hemato-Oncology, Chonnam National University Hwasun Hospital, Hwasun, South Korea. Electronic address:

p73 is a member of the p53 family of transcription factors and, like p53, plays a role as a tumor suppressor. p73 is involved in development, proliferation, apoptosis and metastasis. However, the precise molecular mechanisms underlying its function in inhibiting metastasis remain largely unknown. Here, we show that induction of TAp73 decreased invasion and migration activity of colorectal cancer cells, whereas knockdown of TAp73 led to increased invasion and migration activity. KAI1 was identified as a transcriptional target of TAp73 and its expression is indispensable for TAp73-mediated inhibition of cell invasion and migration. Furthermore, induction of TAp73 in colorectal cancer cells elevated KAI1 expression and decreased the frequency of hepatic metastasis in vivo. Whereas, the decreased invasion and migration activities caused by TAp73 induction were abrogated by knockdown of KAI1. Interestingly, TAp73 and KAI1 are overexpressed in primary colorectal cancers and a significant correlation between TAp73 and KAI1 expression was detected, but their expressions were significantly down-regulated in metastatic cancers. Taken together, our results support a novel role for TAp73 in controlling colorectal cancer cell invasion, migration and metastasis by regulating transcription of KAI1.
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http://dx.doi.org/10.1016/j.canlet.2017.12.002DOI Listing
February 2018

Genomic landscape associated with potential response to anti-CTLA-4 treatment in cancers.

Nat Commun 2017 10 19;8(1):1050. Epub 2017 Oct 19.

Department of Systems Biology, UT MD Anderson Cancer Center, Houston, TX, 77054, USA.

Immunotherapy has emerged as a promising anti-cancer treatment, however, little is known about the genetic characteristics that dictate response to immunotherapy. We develop a transcriptional predictor of immunotherapy response and assess its prediction in genomic data from ~10,000 human tissues across 30 different cancer types to estimate the potential response to immunotherapy. The integrative analysis reveals two distinct tumor types: the mutator type is positively associated with potential response to immunotherapy, whereas the chromosome-instable type is negatively associated with it. We identify somatic mutations and copy number alterations significantly associated with potential response to immunotherapy, in particular treatment with anti-CTLA-4 antibody. Our findings suggest that tumors may evolve through two different paths that would lead to marked differences in immunotherapy response as well as different strategies for evading immune surveillance. Our analysis provides resources to facilitate the discovery of predictive biomarkers for immunotherapy that could be tested in clinical trials.
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http://dx.doi.org/10.1038/s41467-017-01018-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5648801PMC
October 2017

The optimal chemotherapeutic regimen in D2-resected locally advanced gastric cancer: a propensity score-matched analysis.

Oncotarget 2017 Sep 16;8(39):66559-66568. Epub 2017 Mar 16.

Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Jeonnam, Korea.

Adjuvant chemotherapy using TS-1 or capecitabine plus oxaliplatin improves survival outcomes after radical gastrectomy, with both regimens showing similar efficacies. A total of 494 patients with stage II‒III gastric cancer who underwent curative D2 gastrectomy and received adjuvant chemotherapy from April 2004 to June 2014 were included in this study. 219 patients received TS-1, and 275 received platinum-based chemotherapy. The disease-free survival associated with adjuvant chemotherapy with TS-1 was compared with that associated with fluoropyrimidine plus platinum chemotherapy to identify the subgroups that would benefit most from platinum-based chemotherapy. The platinum group consisted of younger individuals, more males and more stage III patients compared with the TS-1 group. To reduce selection bias and its effects on treatment results, we performed a propensity score-matched analysis. The matched cohort consisted of 219 TS-1 and 219 platinum treatment patients, respectively. In the matched cohort, the chemotherapeutic regimen did not affect disease-free survival according to stage (stage II: platinum vs. TS-1, = 0.348; stage III: = 0.132). According to the subgroup analysis, platinum-based chemotherapy resulted in an improved 3-year disease-free survival compared with TS-1 treatment (66.8% vs. 57.8%, = 0.015) for patients with high-risk features (any two or more of pT4, pN3, and lymphovascular invasion positivity). Our results suggest that TS-1 alone is acceptable for patients without high-risk features, while platinum-based adjuvant chemotherapy should be administered to patients with high-risk features in D2-resected gastric cancer.
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http://dx.doi.org/10.18632/oncotarget.16301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5630436PMC
September 2017

Is preoperative chronic kidney disease status associated with oncologic outcomes in upper urinary tract urothelial carcinoma? A multicenter propensity score-matched analysis.

Oncotarget 2017 09 15;8(39):66540-66549. Epub 2017 Mar 15.

Department of Urology, Korea University College of Medicine, Seoul, Korea.

Purpose: The aim of this study was to determine the effect of preoperative chronic kidney disease (CKD) on the prognosis of patients with upper urinary tract urothelial carcinoma (UTUC) who had undergone radical nephroureterectomy (RNU).

Results: The median follow-up period was 31.1 months (interquartile range: 16.2-55.7 months). Among the study patients, 224 patients in the non-CKD group were selected propensity score matching. The median recurrence-free, cancer-specific, and overall survival were significantly shorter for patients with preoperative CKD than for non-CKD patients ( = 0.001, = 0.001, and = 0.001, respectively). According to multivariable Cox regression analysis, preoperative CKD was related to worse recurrence-free (hazard ratio [HR]: 1.81, 95% confidence interval [CI]: 1.15-2.86, = 0.011), cancer-specific (HR: 2.44, 95% CI: 1.44-4.14, = 0.001), and overall survival (HR: 1.66, 95% CI: 1.15-2.40, = 0.007).

Methods: A total of 566 patients who underwent RNU at 6 institutions from 2004 to 2014 were retrospectively reviewed. Of these patients, 342 had an estimated glomerular filtration rate (eGFR) ≥ 60 ml/min/1.73 m (non-CKD group) and 224 patients had an eGFR <60 ml/min/1.73 m (CKD group). To adjust for potential baseline confounders, 224 patients in the non-CKD group were selected by propensity matching. Clinicopathological variables and survival rates were compared between the 2 groups.

Conclusions: Preoperative CKD appears to be an important independent prognostic factor for oncologic outcomes in patients with UTUC.
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http://dx.doi.org/10.18632/oncotarget.16239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5630434PMC
September 2017

The role of interim FDG PET-CT after induction chemotherapy as a predictor of concurrent chemoradiotherapy efficacy and prognosis for head and neck cancer.

Eur J Nucl Med Mol Imaging 2018 Feb 22;45(2):170-178. Epub 2017 Sep 22.

Department of Hemato-Oncology, Chonnam National University Medical School, Gwangju, Republic of Korea.

Purpose: Induction chemotherapy (ICT) with docetaxel, cisplatin, and 5-fluorouracil (TPF) followed by concurrent chemoradiotherapy (CCRT) has the advantages of organ preservation and systemic control in head and neck cancer (HNC). Early prediction of CCRT efficacy may help identify patients who will benefit more from surgery than from CCRT. We investigated the role of interim 18-fluoro-2-deoxy-glucose positron emission tomography computed tomography (FDG PET-CT) after ICT to predict the efficacy of CCRT and clinical outcomes.

Methods: Tumor responses were retrospectively reviewed after CCRT based on the Response Evaluation Criteria in Solid Tumors. FDG PET-CT imaging was performed before and after three cycles of TPF. We examined the associations between the metabolic response (percentage decrease in the maximum standardized uptake value [SUVmax] and total metabolic tumor volume [MTV]) after ICT and complete response (CR) to CCRT, progression-free survival (PFS), and overall survival (OS).

Results: We studied 43 HNC patients with a median follow-up of 32.7 months. Lymph node (LN) SUVmax and total MTV decreases from baseline after ICT were greater in patients with a CR to CCRT than in non-CR patients (LN SUVmax, 88.8% vs. 62.5%, respectively; total MTV, 99.7% vs. 89.9%, respectively). Decreases in total MTV ≥ 78% and LN SUVmax ≥73% after ICT predicted CR to CCRT and longer OS and PFS.

Conclusions: Using interim FDG PET-CT to measure SUVmax and total MTV after three cycles of ICT may be a useful technique for identifying HNC patients who will benefit from CCRT and predicting survival outcomes.
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http://dx.doi.org/10.1007/s00259-017-3836-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5745569PMC
February 2018

Role of depth of response and MTHFR genotype as predictors of fluorouracil rechallenge therapy for refractory metastatic colorectal cancer.

Oncol Lett 2017 Aug 19;14(2):2491-2498. Epub 2017 Jun 19.

Department of Hemato-Oncology, Chonnam National University Medical School, Gwangju 61186, Republic of Korea.

There is limited data on the clinical and biological parameters that enable the prediction of the benefits derived from additional chemotherapy after disease progression compared with standard chemotherapy in patients with metastatic colorectal cancer (mCRC). The present study evaluated the role of tumor response as a clinical parameter and single nucleotide polymorphisms (SNPs) as a biomarker to predict the benefit of additional 5-fluorouracil (5-FU) rechallenge chemotherapy in patients with refractory mCRC. Tumor responses were retrospectively reviewed based on the Response Evaluation Criteria in Solid Tumors, early tumor shrinkage (ETS) and depth of response (DoR) following first-line chemotherapy in patients with stage IV CRC. Together with these parameters, SNPs known to be associated with the response to chemotherapy were analyzed with survival outcomes. In total, the tumor responses of 242 patients with mCRC were evaluated. Overall response and ETS were identified in 110 (45.4%) and 103 patients (42.6%), respectively, and the median DoR was 38.5±30.08%. ETS and DoR were significantly associated with survival outcomes, including progression-free survival, post-progression survival and overall survival. Among these patients, SNPs were analyzed in 171 patients. X-ray repair cross complementing 1 () (AG/AA) with a DoR >60%, good performance status and the absence of bone lesions were associated with improved overall survival. In patients receiving third-line chemotherapy with 5-FU rechallenge therapy, the methylenetretrahydrofolate reductase (MTHFR) (C677T) CC genotype and a DoR >60% were significantly associated with a good prognosis in multivariate analysis. (AG/AA) was also associated with a good prognosis in patients with mCRC. Patients with a DoR >60% following first-line chemotherapy and a MTHFR (C677T) CC genotype exhibited a survival benefit from 5-FU retreatment. Therefore, the DoR and MTHFR genotype are potential markers for selecting patients with refractory mCRC that would benefit from 5-FU rechallenge therapy.
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http://dx.doi.org/10.3892/ol.2017.6414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5530182PMC
August 2017

Clinical Significance of Four Molecular Subtypes of Gastric Cancer Identified by The Cancer Genome Atlas Project.

Clin Cancer Res 2017 Jul 26. Epub 2017 Jul 26.

Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

The Cancer Genome Atlas (TCGA) project recently uncovered four molecular subtypes of gastric cancer: Epstein-Barr virus (EBV), microsatellite instability (MSI), genomically stable (GS), and chromosomal instability (CIN). However, their clinical significances are currently unknown. We aimed to investigate the relationship between subtypes and prognosis of patients with gastric cancer. Gene expression data from a TCGA cohort ( = 262) were used to develop a subtype prediction model, and the association of each subtype with survival and benefit from adjuvant chemotherapy was tested in 2 other cohorts ( = 267 and 432). An integrated risk assessment model (TCGA risk score) was also developed. EBV subtype was associated with the best prognosis, and GS subtype was associated with the worst prognosis. Patients with MSI and CIN subtypes had poorer overall survival than those with EBV subtype but better overall survival than those with GS subtype ( = 0.004 and 0.03 in two cohorts, respectively). In multivariate Cox regression analyses, TCGA risk score was an independent prognostic factor [HR, 1.5; 95% confidence interval (CI), 1.2-1.9; = 0.001]. Patients with the CIN subtype experienced the greatest benefit from adjuvant chemotherapy (HR, 0.39; 95% CI, 0.16-0.94; = 0.03) and those with the GS subtype had the least benefit from adjuvant chemotherapy (HR, 0.83; 95% CI, 0.36-1.89; = 0.65). Our prediction model successfully stratified patients by survival and adjuvant chemotherapy outcomes. Further development of the prediction model is warranted.
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http://dx.doi.org/10.1158/1078-0432.CCR-16-2211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785562PMC
July 2017

The De Ritis (aspartate transaminase/alanine transaminase) ratio as a predictor of oncological outcomes in patients after surgery for upper urinary tract urothelial carcinoma.

Int Urol Nephrol 2017 Aug 8;49(8):1383-1390. Epub 2017 May 8.

Department of Urology, Seoul National University College of Medicine, Seoul, Korea.

Purpose: Recently, several studies have shown that the De Ritis ratio (aspartate transaminase/alanine transaminase) can be a useful prognostic biomarker for certain types of malignant tumors. However, the prognostic value of the De Ritis ratio in patients with upper tract urothelial carcinoma remains largely unknown. The aim of the present study was to evaluate the prognostic significance of the De Ritis ratio in patients who had undergone radical nephroureterectomy (RNU) for upper urinary tract urothelial carcinoma.

Methods: In total, 1049 patients who underwent RNU at eight institutions from 2004 to 2015 were reviewed retrospectively. The De Ritis ratio and conventional clinicopathological parameters were analyzed. Survival analysis was performed using the Kaplan-Meier method and log-rank test. Multivariate analysis was carried out using the Cox proportional hazards regression model. De Ritis ratio cutoff values were derived from receiver operating characteristic (ROC) curves.

Results: ROC analysis showed the cutoff De Ritis ratio for overall death to be 1.6 (p = 0.002). The cancer-specific survival (CSS) and overall survival (OS) were significantly shorter for patients with a high De Ritis ratio (>1.6). Multivariate analysis revealed an independent relationship between an increased De Ritis ratio (>1.6) and shorter CSS (hazard ratio, HR 2.49, 95% confidence interval, CI 1.70-3.64; p = 0.001) and OS (HR 1.84, 95% CI 1.34-2.52; p = 0.001).

Conclusion: The De Ritis ratio can be a significant predictor of oncological outcomes in patients with upper urinary tract urothelial carcinoma after surgery.
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http://dx.doi.org/10.1007/s11255-017-1613-zDOI Listing
August 2017

Arg388 Is Correlated with Poor Survival in Resected Colon Cancer Promoting Epithelial to Mesenchymal Transition.

Cancer Res Treat 2017 Jul 9;49(3):766-777. Epub 2016 Nov 9.

Department of Hemato-Oncology, Chonnam National University Hwasun Hospital, Hwasun, Korea.

Purpose: Fibroblast growth factor receptor 4 () plays an important role in cancer progression during tumor proliferation, invasion, and metastasis. This study evaluated the prognostic role of polymorphism in patients with resected colon cancer, including the underlying mechanism.

Materials And Methods: polymorphism was characterized in patientswho received curative resection for stage III colon cancer. -dependent signal pathways involving cell proliferation, invasion, and migration according to genotypes were also evaluated in transfected colon cancer cell lines.

Results: Among a total of 273 patients, the GG of showed significantly better overall survival than the AG or AA, regardless of adjuvant treatment. In the group of AG or AA, combination of folinic acid, fluorouracil, and oxaliplatin (FOLFOX) resulted in better survival than fluorouracil/leucovorin or no adjuvant chemotherapy. However, in GG, there was no difference among treatment regimens. Using multivariate analyses, the Arg388 carriers, together with age, N stage, poor differentiation, absence of a lymphocyte response, and no adjuvant chemotherapy, had a significantly worse OS than patients with the Gly388 allele. In transfected colon cancer cells, overexpression of Arg388 significantly increased cell proliferation and changes in epithelial to mesenchymal transition markers compared with cells overexpressing the Gly388 allele.

Conclusion: The Arg388 allele of may be a biomarker and a candidate target for adjuvant treatment of patients with resected colon cancer.
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http://dx.doi.org/10.4143/crt.2016.457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5512371PMC
July 2017

Prognostic significance of platelet-lymphocyte ratio in patients receiving first-line tyrosine kinase inhibitors for metastatic renal cell cancer.

Springerplus 2016 28;5(1):1889. Epub 2016 Oct 28.

Department of Urology, Chonnam National University Medical School, 42 Jebongro, Donggu, Gwangju, 501-757 Republic of Korea.

Background: The platelet-lymphocyte ratio (PLR) and neutrophil-lymphocyte ratio (NLR) have been reported as prognostic factors in various cancers, but their roles in metastatic renal cell cancer (mRCC) remain unclear. We investigated the significance of PLR and NLR, along with that of established prognostic factors, in mRCC patients receiving first-line tyrosine kinase inhibitors (TKI).

Methods: Data obtained from 63 mRCC patients who received first-line TKI between 2007 and 2013 were evaluated retrospectively. The association of PLR, NLR, and established prognostic factors with progression-free survival (PFS) and overall survival (OS) was analyzed using the Kaplan-Meier method. The influence of independent prognostic factors on survival was determined using multivariable Cox regression analysis.

Results: High NLR (>3.6) and PLR (>150) were related to shorter PFS (p = 0.001) and OS (p = 0.001). The presence of brain metastases [hazard ratio (HR) 4.94, 95% CI 1.75-13.9; p = 0.002] and high PLR (>150, HR 13.1, 95% CI 5.14-33.2; p = 0.001) were independently associated with PFS, and Eastern Cooperative Oncology Group Performance status ≥2 (HR 3.60, 95% CI 1.39-9.31; p = 0.008), lymph node metastasis (HR 2.76, 95% CI 1.11-6.86; p = 0.029), brain metastasis (HR 9.39, 95% CI 2.74-32.1; p = 0.001), and high PLR (>150, HR 16.1, 95% CI 4.41-58.4; p = 0.001) with OS.

Conclusions: High PLR was associated with shorter survival of mRCC patients receiving first-line TKI. The PLR may be an effective independent prognostic factor in this setting.
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http://dx.doi.org/10.1186/s40064-016-3592-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5084140PMC
October 2016

Poor Preoperative Glycemic Control Is Associated with Dismal Prognosis after Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma: A Korean Multicenter Study.

Cancer Res Treat 2016 Oct 23;48(4):1293-1301. Epub 2016 Mar 23.

Department of Urology, Korea University College of Medicine, Seoul, Korea.

Purpose: The purpose of this study is to evaluate the effect of diabetes mellitus (DM) and preoperative glycemic control on prognosis in Korean patients with upper tract urothelial carcinoma (UTUC) who underwent radical nephroureterectomy (RNU).

Materials And Methods: A total of 566 patients who underwent RNU at six institutions between 2004 and 2014 were reviewed retrospectively. Kaplan-Meier and Cox regression analyses were performed to assess the association between DM, preoperative glycemic control, and recurrence-free, cancer-specific, and overall survival.

Results: The median follow-up period was 33.8 months (interquartile range, 41.4 months). A total of 135 patients (23.8%) had DM and 67 patients (11.8%) had poor preoperative glycemic control. Patients with poor preoperative glycemic control had significantly shorter median recurrence-free, cancer-specific, and overall survival than patients with good preoperative glycemic control and non-diabetics (all, p=0.001). In multivariable Cox regression analysis, DM with poor preoperative glycemic control showed association with worse recurrence-free survival (hazard ratio [HR], 2.26; 95% confidence interval [CI], 1.31 to 3.90; p=0.003), cancer-specific survival (HR, 2.96; 95% CI, 1.80 to 4.87; p=0.001), and overall survival (HR, 2.13; 95% CI, 1.40 to 3.22; p=0.001).

Conclusion: Diabetic UTUC patients with poor preoperative glycemic control had significantly worse oncologic outcomes than diabetic UTUC patients with good preoperative glycemic control and non-diabetics. Further investigation is needed to elucidate the exact mechanism underlying the impact of glycemic control on UTUC treatment outcome.
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http://dx.doi.org/10.4143/crt.2016.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5080827PMC
October 2016

Development and Validation of a Six-Gene Recurrence Risk Score Assay for Gastric Cancer.

Clin Cancer Res 2016 Dec 21;22(24):6228-6235. Epub 2016 Sep 21.

Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: This study was aimed at developing and validating a quantitative multigene assay for predicting tumor recurrence after gastric cancer surgery.

Experimental Design: Gene expression data were generated from tumor tissues of patients who underwent surgery for gastric cancer (n = 267, training cohort). Genes whose expression was significantly associated with activation of YAP1 (a frequently activated oncogene in gastrointestinal cancer), 5-year recurrence-free survival, and 5-year overall survival were first identified as candidates for prognostic genes (156 genes, P < 0.001). We developed the recurrence risk score (RRS) by using quantitative RT-PCR to identify genes whose expression levels were significantly associated with YAP1 activation and patient survival in the training cohort.

Results: We based the RRS assay on 6 genes, IGFBP4, SFRP4, SPOCK1, SULF1, THBS, and GADD45B, whose expression levels were significantly associated with YAP1 activation and prognosis in the training cohort. The RRS assay was further validated in an independent cohort of 317 patients. In multivariate analysis, the RRS was an independent predictor of recurrence [HR, 1.6; 95% confidence interval (CI), 1.02-2.4; P = 0.03]. In patients with stage II disease, the RRS had an HR of 2.9 (95% CI, 1.1-7.9; P = 0.03) and was the only significant independent predictor of recurrence.

Conclusions: The RRS assay was a valid predictor of recurrence in the two cohorts of patients with gastric cancer. Independent prospective studies to assess the clinical utility of this assay are warranted. Clin Cancer Res; 22(24); 6228-35. ©2016 AACR.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-2468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5458637PMC
December 2016

Effect of the allelic variants of ABCB1, CYP2D6 and HTR3B on response of ramosetron to prevent chemotherapy-induced nausea and vomiting in Korean cancer patients.

Asia Pac J Clin Oncol 2017 Feb 4;13(1):53-60. Epub 2016 Aug 4.

Department of Hematology-Oncolgy, Chonnam National University Medical School, Gwangju, Korea.

Aim: Despite appropriate use of antiemetics including 5-hydroxytryptamine type 3 (5-HT ) receptor antagonists, chemotherapy-induced nausea and vomiting (CINV) is still an unsolved problem in patients with anticancer drugs. We examined whether the variants of ABCB1, CYP2D6 and HTR3B affect efficacy of ramosetron, a selective 5-HT receptor antagonist in a dose escalation clinical trial.

Methods: We conducted a clinical trial on patients who underwent FOLFOX combination chemotherapy. The participants were randomized into three groups of ramosetron: 0.3 mg (standard dose), 0.45 mg and 0.6 mg. Rhodes index of nausea, vomiting and retching were measured at 1, 6 h, day 1, day 2 and day 7 after the administration of ramosetron as a clinical parameter of CINV and polymorphism was analyzed from genomic DNA.

Results: There was a dose-dependent decrease in the nausea and vomiting scores at day 1 and day 2, not statistically significant. The Rhodes index of nausea, vomiting and retching score at day 1 in participants with HTR3B-100_-102delAAG deletion variants was significantly higher than wild type participants, regardless of dosages. However, the polymorphisms including ABCB1, CYP2D6 and other HTR3B genes did not affect response to ramosetron after chemotherapy.

Conclusion: These results suggest that the -AAG deletion variant of the 5-HT receptor gene may contribute to variability in response to antiemetic therapy for CINV regardless of dose escalation. These results suggest that carrying a -100_-102delAAG variant of 5-HT gene should be supported by alternate or additive antiemetics in addition to 5-HT antagonists to control acute emesis.
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http://dx.doi.org/10.1111/ajco.12575DOI Listing
February 2017

A phase II study of adjuvant S-1/cisplatin chemotherapy followed by S-1-based chemoradiotherapy for D2-resected gastric cancer.

Cancer Chemother Pharmacol 2016 Mar 5;77(3):605-12. Epub 2016 Feb 5.

Department of Hemato-Oncology, Chonnam National University Medical School, Hwasun-gun, Republic of Korea.

Purpose: Surgery is the only possible curative treatment for gastric cancer. However, the high recurrence rate makes gastric cancer difficult to cure by surgery alone. The present study was conducted to evaluate the clinical outcomes and toxicity of adjuvant treatment, including S-1/cisplatin chemotherapy followed by radiotherapy with concurrent S-1.

Methods: Patients with radically D2-resected adenocarcinoma of the stomach of stage IB-IV (M0) were eligible. Patients were treated with S-1 (40-60 mg depending on the patient's body surface area) twice daily for 3 weeks and cisplatin (60 mg/m(2)) intravenously on day 1 every 5 weeks. Patients received CRT (45 Gy of radiation at 1.8 Gy/day, 5 days per week, for 5 weeks with the same dose of S-1 during radiation) followed by two additional cycles of S-1/cisplatin. The primary endpoint was the 3-year disease-free survival (DFS) rate; the secondary endpoints were the 3-year overall survival rate and toxicities.

Results: Until May 2012, 46 patients were enrolled, and 34 (73.9%) completed the planned treatment. The median age was 53 years (range: 31-69 years), and the numbers of patients with stage IB, II, III and IV disease were 0, 17, 25 and 4, respectively. Main grade 3-4 toxicities were as follows: neutropenia (28.2%), nausea (17.4%), vomiting (8.7%) and anorexia (15.2%). At the time of analysis, after a median follow-up period of 56.5 months (3.03-74.0 months), 16 recurrence events and 15 deaths were reported. The estimated 3-year DFS and survival rates were 65.2 and 76.1%, respectively. The most common site of recurrence was the peritoneum (n = 12).

Conclusions: The results of this phase II study show that intensified adjuvant treatment with S-1/cisplatin chemotherapy and S-1-based chemoradiotherapy was tolerable and effective in reducing disease recurrence. The addition of radiotherapy to chemotherapy may be effective in D2-resected gastric cancer. Although the data here are promising, a randomized trial is needed between patients treated with the current regimen and an appropriate comparator arm.
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http://dx.doi.org/10.1007/s00280-016-2973-2DOI Listing
March 2016

A Prospective Multicenter Study Evaluating Secondary Adrenal Suppression After Antiemetic Dexamethasone Therapy in Cancer Patients Receiving Chemotherapy: A Korean South West Oncology Group Study.

Oncologist 2015 Dec 13;20(12):1432-9. Epub 2015 Oct 13.

Department of Internal Medicine, College of Medicine, Chungbuk National University, Cheongju, Republic of Korea

Background: In a previous pilot study, adrenal suppression was found to be common after antiemetic dexamethasone therapy in cancer patients. The objective of this large prospective multicenter study was to confirm the incidence and factors associated with secondary adrenal suppression related to antiemetic dexamethasone therapy in cancer patients receiving chemotherapy.

Methods: Chemotherapy-naïve patients who were scheduled to receive at least three cycles of highly or moderately emetogenic chemotherapy with dexamethasone as an antiemetic were enrolled. Patients with a suppressed adrenal response before chemotherapy or those administered corticosteroids within 6 months of enrollment in the study were excluded.

Results: Between October 2010 and August 2014, 481 patients receiving chemotherapy underwent the rapid adrenocorticotropic hormone (ACTH) stimulation test to assess eligibility; 350 of these patients were included in the final analysis. Fifty-six patients (16.0%) showed a suppressed adrenal response in the rapid ACTH stimulation test at 3 or 6 months after the start of the first chemotherapy. The incidence of adrenal suppression was affected by age, performance status, stage, and use of megestrol acetate in univariate analysis. Multivariate analysis revealed that secondary adrenal suppression associated with antiemetic dexamethasone therapy was significantly associated with megestrol acetate treatment (odds ratio: 3.06; 95% confidence interval: 1.60 to 5.86; p < .001).

Conclusion: This large prospective study indicates that approximately 15% of cancer patients receiving chemotherapy with a normal adrenal response show suppressed adrenal responses after antiemetic dexamethasone therapy. This result was particularly significant for patients cotreated with megestrol acetate.
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http://dx.doi.org/10.1634/theoncologist.2015-0211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4679085PMC
December 2015
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