Publications by authors named "Jung Yong Hong"

94 Publications

Prognostic Impact of Sarcopenia and Radiotherapy in Patients With Advanced Gastric Cancer Treated With Anti-PD-1 Antibody.

Front Immunol 2021 8;12:701668. Epub 2021 Jul 8.

Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.

Background: We explored the combined effects of sarcopenia (SAR) and radiotherapy (RT) on outcomes in patients with advanced gastric cancer (AGC) treated with immune-checkpoint blockade (ICB).

Methods: Among 185 patients with AGC treated with ICB, we defined SAR as skeletal muscle index <49 cm2/m2 for men and <31 cm2/m2 for women; 93 patients met criteria. We defined high neutrophil-to-lymphocyte ratio (hNLR) as NLR≥3. Palliative RT was performed in 37 patients (20%) before ICB.

Results: We frequently observed hNLR in patients with SAR (53% 35%, p = 0.02). The median overall survival (OS) for the entire cohort was 5 months. Stratification by risk factors of SAR or hNLR revealed a significant difference in median OS (0 [N = 60] 1 [N = 76] 2 [N = 49]: 7.6 6.4 2.2 months, p < 0.001). Patients with microsatellite instability-high (MSI-H, N = 19) or Epstein-Barr virus (EBV)-positive tumors (N = 13) showed favorable outcomes compared to those with microsatellite stable (MSS, N = 142) tumors (median OS, not reached 16.8 3.8 months, respectively). The benefit of RT was evident in patients with both SAR and hNLR (median OS, 3.1 1.3 months, p = 0.02) and MSS/EBV-negative tumor (median OS, 6.5 3.5 months, p = 0.03), but outcomes after RT in MSI-H tumor were not significantly different. In multivariable analysis, SAR/hNLR, molecular subtypes, and a history of RT were associated with OS (all p < 0.05).

Conclusions: We demonstrated the negative predictive value of SAR/hNLR on outcomes after ICB for AGC, and the history of RT could overcome the negative impact of SAR/hNLR and the MSS/EBV-negative subtype.
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http://dx.doi.org/10.3389/fimmu.2021.701668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298191PMC
July 2021

Long-term follow-up of oxaliplatin-induced liver damage in patients with colorectal cancer.

Br J Radiol 2021 Jun 16:20210352. Epub 2021 Jun 16.

Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.

Objectives: To report the long-term follow-up data including computed tomography (CT) findings of oxaliplatin-induced liver damage in patients with colorectal cancer.

Methods: Three hundred and fifty-six patients who underwent surgery followed by oxaliplatin-based chemotherapy (OBC) for colorectal cancer between January 2013 and December 2014 were included. Abdominal CT images and laboratory results (serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, total bilirubin, and platelet counts) were reviewed immediately before (as baseline), during, and after adjuvant OBC. Abdominal CT images were reviewed to assess the heterogeneous liver parenchyma, increase in size of the spleen, development of acute portosystemic shunts during OBC, and imaging findings of chronic portal hypertension.

Results: During OBC, 90.2% (321/356) of the patients developed parenchymal heterogeneity. Increase in the spleen size during the OBC period was seen in 62.4% (225/356) of patients. The overall rate of development of acute portosystemic shunts during OBC was 23.9% (85/356). These findings were resolved after cessation of OBC except in 1.4% (5/356) of the patients in whom chronic portal hypertension persisted even after completion of OBC. Serum AST, ALT, and total bilirubin levels increased and platelet counts decreased during OBC and returned to normal after completion of OBC; however, they did not reach the pre-OBC levels.

Conclusion: Although most changes associated with liver damage reversed to normal range after completion of OBC, some parameters did not reverse to the pretreatment level, and chronic portal hypertension developed in a small number of patients.

Advances In Knowledge: Chronic, persistent oxaliplatin-induced liver damage was not an infrequent complication after oxaliplatin-based chemotherapy for patients with colorectal cancer. It may cause non-cirrhotic portal hypertension and associated complications such as variceal bleeding.
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http://dx.doi.org/10.1259/bjr.20210352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248204PMC
June 2021

Prediction of epithelial-to-mesenchymal transition molecular subtype using CT in gastric cancer.

Eur Radiol 2021 Jun 13. Epub 2021 Jun 13.

Department of Radiology and Center for Imaging Sciences, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Korea.

Objectives: To develop a prediction model with computed tomography (CT) images and to build a nomogram incorporating known clinicopathologic variables for individualized estimation of epithelial-to-mesenchymal transition (EMT) subtype gastric cancer.

Methods: Patients who underwent primary resection of gastric cancer (GC) and molecular subgroup analysis (n = 451) were reviewed. Multivariable analysis using a stepwise variable selection method was performed to build a predictive model for EMT subtype GC. A nomogram using the results of the multivariable analysis was constructed. An optimal cutoff value of total prognostic points of the nomogram for the prediction of EMT subtype was determined. The predictive model for the EMT subtype was internally validated by bootstrap resampling method.

Results: There were 88 patients with EMT subtype and 363 patients with non-EMT subtype based on transcriptome analysis. The patient's age, Lauren classification, and mural stratification on CT were variables selected for the predictive model. The area under the curve (AUC) of the model was 0.865, and the validated AUC of the bootstrap sample was 0.860. The optimal cutoff value of total prognostic points for the prediction of EMT subtype was 94.622, with 90.9% sensitivity, 67.2% specificity, and 71.8% accuracy.

Conclusion: A predictive model using patient's age, Lauren classification, and mural stratification on CT for EMT molecular subtype GC was made. A nomogram was built which would serve as a useful screening tool for an individualized estimate of EMT subtype.

Key Points: • A predictive model for epithelial-to-mesenchymal transition (EMT) subtype incorporating patient's age, Lauren classification, and mural stratification on CT was built. • The predictive model had high diagnostic accuracy (area under the curve (AUC) = 0.865) and was validated (bootstrap AUC = 0.860). • Adding CT findings to clinicopathologic variables increases the accuracy of the predictive model than using only.
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http://dx.doi.org/10.1007/s00330-021-08094-3DOI Listing
June 2021

Real-World, Single-Center Data for Lenalidomide Plus Rituximab in Relapsed or Refractory Diffuse Large B-Cell Lymphoma and Transformed Follicular Lymphoma.

Cancer Manag Res 2021 28;13:4241-4250. Epub 2021 May 28.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Background: This study explored the efficacy of lenalidomide plus rituximab for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) including cases of secondary central nervous system (CNS) involvement and transformed follicular lymphoma (FL) in real-world context because of anti-tumor effect and blood-brain barrier permeability of lenalidomide.

Methods: Twenty-four patients including relapsed or refractory DLBCL (n = 21) including seven patients with secondary CNS involvement and transformed FL (n = 3) were retrospectively analyzed.

Results: Based on the best response, the complete response (CR) rate was 21% (5/24) and the overall response rate (ORR) was 38% (9/24). However, as all cases of transformed FL (n = 3) did not respond, all responders had DLBCL, and the CR and ORR rates of DLBCL were 24% (5/21) and 43% (9/21), respectively. The median number of treatment cycles was only two (range: 1-7) due to frequent occurrence of early progression, and 18 patients died and the cause of death was disease progression. The response rate was not significantly different among patients with and without secondary CNS involvement. The median post-treatment overall and progression-free survival were 7.3 and 1.8 months, respectively. Hematologic toxicities were common adverse events, but most hematologic toxicities were manageable. There were no serious infectious complications or treatment-related mortality.

Conclusion: Lenalidomide plus rituximab might be a salvage therapy for relapsed or refractory DLBCL, especially in case of secondary CNS involvement. However, the addition of other agents should be considered to prolong the duration of response.
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http://dx.doi.org/10.2147/CMAR.S309092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168964PMC
May 2021

Phase I Study of Ceralasertib (AZD6738), a Novel DNA Damage Repair Agent, in Combination with Weekly Paclitaxel in Refractory Cancer.

Clin Cancer Res 2021 May 11. Epub 2021 May 11.

Division of Hematology-Oncology, Department of Medicine, Sungkyunkwan University School of Medicine, Seoul, Korea.

Purpose: Ceralasertib is a potent and selective oral inhibitor of the serine/threonine protein kinase ataxia telangiectasia and Rad3-related (ATR) protein.

Patients And Methods: Eligible patients with solid tumors, enriched for melanoma, received ceralasertib in combination with a fixed dose of paclitaxel (80 mg/m on D1, D8, D15) in 28-day cycles. The dose of ceralasertib was escalated to reach an MTD in a rolling 6 design. The starting dose of ceralasertib was 40 mg QD. Fifty-seven patients (33 patients with melanoma who failed prior PD1/L1 treatment) were enrolled in 7 dose cohorts ranging from 40 mg QD to 240 mg BD plus weekly paclitaxel.

Results: The RP2D was established as ceralasertib 240 mg BD days 1-14 plus paclitaxel 80 mg/m on D1, D8, D15 every 28 days. The most common toxicities were neutropenia ( = 39, 68%), anemia ( = 25, 44%), and thrombocytopenia ( = 21, 37%). In the full analysis set of 57 patients, the overall response rate (ORR) was 22.6% (95% CI, 12.5-35.3). In 33 patients with melanoma, resistant to prior anti-PD1 therapy, the ORR was 33.3% (95% CI, 18.0-51.8). In the melanoma subset, the mPFS was 3.6 months (95% CI, 2.0-5.8), the median duration of response was 9.9 months (95% CI, 3.7-23.2), and the mOS was 7.4 months (95% CI, 5.7-11.9).

Conclusions: Ceralasertib in combination with paclitaxel was well tolerated in patients with advanced malignancies and showed evidence of antitumor activity. Durable responses were observed in patients with advanced cutaneous, acral, and mucosal melanoma resistant to anti-PD1/L1 treatment.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0251DOI Listing
May 2021

Association between non-alcoholic fatty liver disease and the risk of biliary tract cancers: A South Korean nationwide cohort study.

Eur J Cancer 2021 Jun 20;150:73-82. Epub 2021 Apr 20.

Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Seoul, Republic of Korea. Electronic address:

Aims: The association between non-alcoholic fatty liver disease (NAFLD) and cholangiocarcinoma has been previously reported only in case-control studies. Therefore, we conducted this nationwide cohort study to evaluate the longitudinal association between NAFLD and the risk of biliary tract cancer (BTC), including cholangiocarcinoma and gallbladder cancer.

Methods: We included 8,120,674 adults who underwent national health screening in 2009 based on the Korean National Health Insurance Service data. NAFLD was determined using the fatty liver index: ≥60, NAFLD; 30-59, intermediate score; <30, no NAFLD. The exclusion criteria were baseline clinical liver disease, heavy alcohol consumption and cancer. Participants were followed up until December 2017 for the development of BTC. Cox proportional hazards regression models were performed.

Results: During the median follow-up period of 7.2 years, 13,043 patients were with newly diagnosed BTC. NAFLD was associated with an increased risk of BTC (adjusted hazard ratio [aHR], 1.28; 95% CI, 1.20-1.37) compared with no NAFLD. The aHRs for the association of cholangiocarcinoma and gallbladder cancer with NAFLD were 1.33 (95% CI, 1.23-1.43) and 1.14 (95% CI, 1.003-1.29), respectively. Overall, the aHR for BTC tended to increase with the increasing fatty liver index (P for trend < 0.001). Concomitant NAFLD and diabetes were associated with an increased risk of BTC by 47% (aHR, 1.47; 95% CI, 1.35-1.60).

Conclusion: In this nationwide cohort study, NAFLD was associated with an increased risk of cholangiocarcinoma and gallbladder cancer. This finding suggests that NAFLD is a potentially modifiable risk factor for BTC.
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http://dx.doi.org/10.1016/j.ejca.2021.03.024DOI Listing
June 2021

Determinants of Response and Intrinsic Resistance to PD-1 Blockade in Microsatellite Instability-High Gastric Cancer.

Cancer Discov 2021 Apr 12. Epub 2021 Apr 12.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Samsung Medical Center, Sungkyunkwan University School of Medicine

Sequence alterations in microsatellites and an elevated mutational burden are observed in 20% of gastric cancers (GC) and associated with clinical response to anti-programmed death (PD)-1 antibodies. However, 50% of microsatellite instability-high (MSI-H) cancers are intrinsically resistant to PD-1 therapies. We conducted a phase II trial of pembrolizumab in advanced MSI-H GC patients and included serial and multi-region tissue samples in addition to serial peripheral blood analyses. The number of whole-exome sequencing (WES)-derived nonsynonymous mutations correlated with anti-tumor activity and prolonged progression-free survival (PFS). Coupling WES to single-cell RNA sequencing, we identified dynamic tumor evolution with greater on treatment collapse of mutational architecture in responders. Diverse T-cell receptor repertoire was associated with longer PFS to pembrolizumab. Additionally, increase in PD-1+ CD8+ T cells correlated with durable clinical benefit. Our findings highlight the genomic, immunologic, and clinical outcome heterogeneity within MSI-H GC and may inform development of strategies to enhance responsiveness.
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http://dx.doi.org/10.1158/2159-8290.CD-21-0219DOI Listing
April 2021

Programmed Death Ligand 1 Expression as a Prognostic Marker in Patients with Advanced Biliary Tract Cancer.

Oncology 2021 17;99(6):365-372. Epub 2021 Mar 17.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea,

Background: Biliary tract cancer (BTC) is associated with poor prognosis because of its aggressive and heterogeneous nature. Programmed death ligand 1 (PD-L1) has been considered a novel biomarker for prognosis and response of immune checkpoint inhibitors in various tumors. However, there are limited data reporting on the role of PD-L1 in advanced BTC patients.

Patients And Methods: We analyzed 186 patients with advanced BTC who received palliative gemcitabine and platinum between May 2010 and December 2019. All patients were evaluated for PD-L1 expression by combined positive score positivity.

Results: Of the 186 patients, the primary tumor location was intrahepatic cholangiocarcinoma (IHCC) in 72 (38.7%), extrahepatic cholangiocarcinoma (EHCC) in 90 (48.4%), and gallbladder (GB) cancer in 24 (12.9%). Among all the patients, 53 (28.5%) had PD-L1 positivity. The median overall survival (OS) of patients with PD-L1 positivity or negativity was 12.1 and 15.4 months, respectively. The median progression-free survival (PFS) in patients with PD-L1 positivity or negativity was 5.7 and 7.1 months, respectively. OS and PFS were not statistically different between groups. In subgroup analysis, EHCC patients with PD-L1 negativity had more favorable OS (17.2 vs. 11.6 months, p = 0.002) and PFS (7.8 vs. 5.4 months, p = 0.005) than those who were PD-L1-positive. However, this finding was not reproduced in patients with IHCC or GB cancer.

Conclusion: This study demonstrated that PD-L1 expression might be a novel prognostic biomarker in patients with EHCC but not in patients with IHCC or GB cancer.
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http://dx.doi.org/10.1159/000514404DOI Listing
June 2021

Clinical sequencing to assess tumor mutational burden as a useful biomarker to immunotherapy in various solid tumors.

Ther Adv Med Oncol 2021 26;13:1758835921992992. Epub 2021 Feb 26.

Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea.

Background: Immune checkpoint inhibitors (ICIs) have become established as a new therapeutic paradigm in various solid cancers. Predictive biomarkers to ICIs have not yet been fully established. Tumor mutational burden (TMB) has been considered as a useful marker to indicate patients who benefit from ICIs.

Methods: We performed next-generation sequencing, including TMB analysis, as a routine clinical practice in 501 patients with advanced gastrointestinal (GI), genitourinary (GU), or rare cancers. The TruSight Oncology 500 assay from Illumina was used as a cancer panel.

Results: In total, 11.6% (58/501) were identified with tumors with high TMB and MSI-high status was confirmed in seven out of 501 cases (1.4%). High TMB was observed in 11.6% of patients with various solid tumors, including: GU cancers (36.0%, 9/25), colorectal cancer (15.2%, 23/151), biliary tract cancer (14.6%, 7/48), melanoma (14.3%, 3/21), gastric cancer (11.2%, 13/116), hepatocellular carcinoma (8.3%, 1/12), other GI tract cancers (4.5%, 1/22), and sarcoma (1.7%, 1/60). The objective response rate (ORR) to ICIs was 75% (nine out of 12) in solid tumor patients with high TMB and 25% (30 out of 40) in those with non-high TMB. Patients with high TMB had better ORR to ICIs than those with non-high TMB ( = 0.004). Univariate analysis revealed that the status of PD-L1 expression and of TMB (high non-high) had significant association in response to ICIs. However, in multivariate analysis, the status of TMB (high non-high) was only significantly related to the response to ICIs ( = 0.036).

Conclusion: In the present study, we analyzed the TMB using a cancer panel for various solid tumor patients in routine clinical practice and also demonstrated the usefulness of TMB to predict the efficacy for ICIs.
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http://dx.doi.org/10.1177/1758835921992992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917846PMC
February 2021

Comprehensive molecular characterization of gastric cancer patients from phase II second-line ramucirumab plus paclitaxel therapy trial.

Genome Med 2021 Jan 25;13(1):11. Epub 2021 Jan 25.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Republic of Korea.

Background: Gastric cancer (GC) is a heterogenous disease consisted of several subtypes with distinct molecular traits. The clinical implication of molecular classification has been limited especially in association with treatment efficacy of ramucirumab or various targeted agents.

Methods: We conducted a prospective non-randomized phase II single-arm trial of ramucirumab plus paclitaxel as second-line chemotherapy in 62 patients with metastatic GC who failed to respond to first-line fluoropyrimidine plus platinum treatment. For integrative molecular characterization, all patients underwent pre-ramucirumab treatment tissue biopsy for whole-exome/whole-transcriptome sequencing to categorize patients based on molecular subtypes. We also systematically performed integrative analysis, combining genomic, transcriptomic, and clinical features, to identify potential molecular predictors of sensitivity and resistance to ramucirumab treatment.

Results: Sixty-two patients were enrolled in this study between May 2016 and October 2017. Survival follow-up in all patients was completed as of the date of cut-off on January 2, 2019. No patient attained complete response (CR), while 22 patients achieved confirmed partial response (PR), resulting in a response rate (RR) of 35.5% (95% CI, 23.6-47.4). According to TCGA molecular classification, there were 30 GS, 18 CIN, 3 EBV, and 0 MSI tumors. The RR was 33% in GS (10/30), 33% in CIN (6/18), and 100% in EBV-positive GC patients with significant statistical difference for EBV(+) against EBV(-) tumors (P = 0.016; chi-squared test). Moreover, responsive patients were marked by activation of angiogenesis, VEGF, and TCR-associated pathways, while non-responder patients demonstrated enrichments of sonic hedgehog signaling pathway and metabolism activity. Integrative multi-layer data analysis further identified molecular determinants, including EBV status, and somatic mutation in GNAQ to ramucirumab activity.

Conclusions: Prospective molecular characterization identified a subset of GC patients with distinct clinical response to ramucirumab therapy, and our results demonstrate the feasibility of personalized therapeutic opportunities in gastric cancer.

Trial Registration: The study was registered on ClinicalTrial.gov ( NCT02628951 ) on June 12, 2015.
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http://dx.doi.org/10.1186/s13073-021-00826-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836461PMC
January 2021

ATM Expression as a Prognostic Marker in Patients With Advanced Biliary Tract Cancer Treated With First-line Gemcitabine and Platinum Chemotherapy.

In Vivo 2021 Jan-Feb;35(1):499-505

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea;

Background/aim: Biliary tract cancer (BTC) has a poor prognosis due to its highly invasive and metastatic potential. Ataxia-telangiectasia mutated (ATM) is a key regulator of DNA damage response and an emerging therapeutic target; however, the association between the expression of ATM and the prognosis in advanced BTC is unknown. We aimed to identify the relationship between ATM expression, clinicopathological characteristics, and survival outcomes in patients with advanced BTC.

Patients And Methods: We analyzed 113 patients with advanced BTC who received first-line gemcitabine and platinum.

Results: The tumor location was intrahepatic cholangiocarcinoma (IH-CCC) in 43 patients, extrahepatic cholangiocarcinoma (EH-CCC) in 49, and gallbladder (GB) cancer in 21 patients. Fifty-four patients (47.8%) exhibited loss of ATM protein expression. The overall response rate (ORR) of ATM loss and intact ATM was 13.3% and 19.6%, respectively. In a subgroup analysis, EH-CCC patients with ATM loss tended to have improved PFS after platinum-based chemotherapy compared to those with intact ATM (7.9 vs. 6.2 months, respectively; p=0.050).

Conclusion: We demonstrated that ATM loss could be a prognostic marker after platinum-based chemotherapy in patients with advanced EH-CCC.
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http://dx.doi.org/10.21873/invivo.12284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880754PMC
June 2021

Prognostic Factors of Survival with Aflibercept and FOLFIRI (fluorouracil, leucovorin, irinotecan) as Second-line Therapy for Patients with Metastatic Colorectal Cancer.

J Cancer 2021 1;12(2):460-466. Epub 2021 Jan 1.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Aflibercept and fluorouracil, leucovorin, irinotecan (FOLFIRI) is commonly used as a second-line treatment for metastatic colorectal cancer (CRC). However, the biomarkers to guide the choice of this regimen from among treatment options remain unclear. We performed exploratory analyses to validate potential prognostic factors for patients receiving aflibercept plus FOLFIRI as a second-line systemic treatment for metastatic CRC between January 2015 and July 2019. Patient characteristics, histopathologic data, laboratory and radiologic data, and treatment outcomes were collected and reviewed. Included were 52 patients: 50 (96.2%) received bevacizumab plus fluorouracil, leucovorin, oxaliplatin (FOLFOX) as prior first-line treatment. Among the 52 patients receiving aflibercept and FOLFIRI, four complete responses and 21 partial responses were observed in analyzed patients for an overall response rate of 48.1%. Median progression-free survival (PFS) was 7.0 months and overall survival (OS) was 16.8 months. Response to first-line treatment (median PFS, 8.0 versus 4.2 months), left-side location of primary tumor (7.9 versus 4.9 months), low baseline CEA level (8.0 versus 5.9 months), and no RAS/RAF mutation (9.9 versus 6.4 months) were remained significant prognostic factors for PFS in the multivariate backward stepwise Cox regression model, and the latter three factors were also significantly related to OS. Significant prognostic factors for PFS with aflibercept plus FOLFIRI as second-line therapy were extracted and validated in the multivariate OS model. These findings could provide useful information for selecting patients for aflibercept plus FOLFIRI as second-line therapy.
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http://dx.doi.org/10.7150/jca.49176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739009PMC
January 2021

Impact of Radiotherapy on Kidney Function among Patients Who Received Adjuvant Treatment for Gastric Cancer: Logistic and Linear Regression Analyses.

Cancers (Basel) 2020 Dec 28;13(1). Epub 2020 Dec 28.

Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.

We investigated the incidence of renal function impairment after adjuvant treatment for gastric cancer and analyzed the impact of radiotherapy on estimated glomerular filtration rate (eGFR) five years after gastric surgery. We reviewed the medical records of 1490 patients with stomach cancer who underwent curative surgery and adjuvant treatment for gastric cancer. Finally, we included 663 patients who were followed up for ≥5 years without disease recurrence and whose baseline eGFR was ≥60 mL/min/1.73 m. Logistic and linear regression analyses were performed to determine independent factors associated with the five-year eGFR. A total of 13 (2.0%) patients developed renal function impairment (five-year eGFR <60 mL/min/1.73 m). In logistic regression analysis, the baseline eGFR was identified as a prognostic factor for renal function impairment (odds ratio (OR), 0.878; 95% confidence interval (CI), 0.831-0.927; < 0.001), but radiotherapy was not (OR, 1.130; 95% CI, 0.366-3.491; = 0.832). In linear regression analysis, age (B = -0.350, < 0.001), baseline eGFR (B = 0.576, < 0.001), cisplatin (B = -2.056, = 0.010), and radiotherapy (B = -2.628, < 0.001) were predictive variables for the five-year eGFR. Among patients who received adjuvant radiotherapy, age (B = -0.277, < 0.001), hypertension (B = -4.986, = 0.004), baseline eGFR (B = 0.665, < 0.001), and volume of the kidneys receiving ≥20 Gy (B = -0.209, = 0.012) were predictive variables for the five-year eGFR. Development of renal function impairment after adjuvant treatment for gastric cancer was rare among patients with normal baseline kidney function. While radiotherapy was negatively associated with the five-year eGFR, its impact would have been minimal if the kidneys were properly shielded. Further studies are needed to confirm the impact of radiotherapy in patients with poor kidney function.
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http://dx.doi.org/10.3390/cancers13010059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794775PMC
December 2020

Incorporating sarcopenia and inflammation with radiation therapy in patients with hepatocellular carcinoma treated with nivolumab.

Cancer Immunol Immunother 2021 Jun 24;70(6):1593-1603. Epub 2020 Nov 24.

Statistics and Data Center, Samsung Medical Center, Research Institute for Future Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Republic of Korea.

Background: We investigated the combined effects of sarcopenia and inflammation on outcomes in patients with HCC treated with nivolumab.

Materials And Methods: We reviewed 102 patients treated with nivolumab between 2017 and 2018. Sarcopenia was diagnosed when the L3 skeletal muscle indices were < 42 cm/m and < 38 cm/m in men and women, respectively. Baseline neutrophil-to-lymphocyte ratio (NLR) and absolute lymphocyte count were used as surrogate markers of inflammation and immune cell reservoir. High NLR (hNLR) was defined as NLR ≥ 3, and severe lymphopenia (sLP) was defined as lymphocyte < 800/μL. The overall survival (OS) and progression-free survival (PFS) were analyzed.

Results: With a median follow-up of 21.9 (interquartile range, 8.3-58.3) months, patients with sarcopenia showed shorter OS than those without sarcopenia (median, 2.9 vs. 7.5 months, respectively). Patients with either hNLR or sLP exhibited inferior survival than those without risk factor (median OS, 2.8 vs. 14.5 months; median PFS, 1.3 vs. 3.7 months, respectively). Among 70 patients treated with RT, benefit of RT was observed in patients with sarcopenia or those without hNLR/sLP (all p < 0.05). After multivariable analysis, RT, hNLR/sLP, albumin-bilirubin (ALBI) grade, and alpha-fetoprotein were significantly associated with OS (all p < 0.05), and hNLR/sLP was also associated with decreased PFS together with ALBI grade, alpha-fetoprotein, and RT (all p < 0.05).

Conclusion: The current study hypothetically demonstrated that the risk group stratified by hNLR/sLP outweighs the significance of sarcopenia in predicting outcomes after nivolumab. Furthermore, patients with sarcopenia might benefit from RT, especially those without risk factors of hNLR/sLP.
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http://dx.doi.org/10.1007/s00262-020-02794-3DOI Listing
June 2021

Clinical and molecular distinctions in patients with refractory colon cancer who benefit from regorafenib treatment.

Ther Adv Med Oncol 2020 5;12:1758835920965842. Epub 2020 Nov 5.

Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea.

Regorafenib (Stivarga, BAY 73-4506; Bayer Pharma AG, Berlin, Germany) is a novel oral multikinase inhibitor that blocks the activity of several protein kinases. However, few guidelines exist for novel biomarkers to select patients who will likely benefit from regorafenib treatment. Metastatic colorectal cancer (mCRC) patients treated with regorafenib were evaluated in this study. Tumor tissues of these patients were subjected to next-generation sequencing-based cancer panel tests. The relationship between molecular profiling and efficacy of regorafenib was analyzed. Among the 76 mCRC patients, the median age was 58 years (range 22-79 years), and 73.7% received regorafenib as a third-line therapy. The primary tumor locations were the right side ( = 15, 19.8%) and the left side ( = 61, 80.2%). Most patients (97.4%) had received prior anti-angiogenetic agents, and a prior anti-Epidermal Growth Factor Receptor (EGFR) agent had been administered to 32.9%. Of these 76 patients, 65 were evaluated to determine the efficacy of treatment. We observed zero complete responses, seven confirmed partial responses (PR 9.2%), 26 stable disease states (34.2%), and 32 disease progressions (42.1%). The overall confirmed response rate and the disease control rate were 9.2% and 43.4%, respectively. Genomic analysis revealed that APC mutations were significant in patients who demonstrated a tumor response to regorafenib ( < 0.05). Interestingly, FGFR1 amplification was detected in only three of 76 patients (3.9%), and these three patients achieved a PR to regorafenib. The median progression-free survival time was 2.8 months (95% Confidence Interval [CI] 1.6-4.0). Patients with BRAF mutation and/or SMAD4 mutation had significantly worse progression-free survival (PFS) than those without such a mutation. On pathway analysis, Tumor Growth Factor (TGF)-beta pathways were significantly associated with worse PFS. We found that efficacy of regorafenib might be correlated with specific genetic aberrations, such as APC mutation and FGFR1 amplification. In addition, SMAD4 mutation and TGF-beta pathway were associated with worse PFS after regorafenib. We found that efficacy of regorafenib might be correlated with specific genetic aberrations, such as APC mutation and FGFR1 amplification. In addition, SMAD4 mutation and the TGF-beta pathway were associated with worse PFS after regorafenib.
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http://dx.doi.org/10.1177/1758835920965842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649869PMC
November 2020

Prognostic significance of sarcopenia in microsatellite-stable gastric cancer patients treated with programmed death-1 inhibitors.

Gastric Cancer 2021 Mar 24;24(2):457-466. Epub 2020 Sep 24.

Department of Radiology and Center for Imaging Sciences, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Korea.

Background: Sarcopenia has been underscored as a significant predictor of poor prognosis in cancer patients undergoing immunotherapy with programmed death-1 (PD-1) inhibitors. We aimed to investigate the prognostic significance of computed tomography (CT)-determined sarcopenia in patients with microsatellite-stable (MSS) gastric cancer (GC) treated with PD-1 inhibitors.

Methods: We retrospectively assessed patients with MSS GC who had been treated with PD-1 inhibitors from March 2016 to June 2019. Pre-treatment sarcopenic status was determined by analyzing L3 skeletal muscle index with abdominal CT. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method, and the differences in survival probability according to sarcopenic status were compared using the log-rank test. Cox proportional hazards regression analyses were performed to identify predictors of PFS and OS.

Results: Of 149 patients with MSS GC (mean age, 57.0 ± 12.3 years; 93 men), 79 (53.0%) had sarcopenia. Patients with sarcopenia had significantly shorter PFS than patients without sarcopenia (median, 1.4 months vs. 2.6 months; P = 0.026). Sarcopenia was independently associated with shorter PFS (adjusted hazard ratio [HR], 1.79; 95% confidence interval [CI], 1.10-2.93; P = 0.020). Patients with sarcopenia had shorter OS than patients without sarcopenia (median, 3.6 months vs. 4.9 months; P = 0.052), but sarcopenia itself was not a significant prognostic factor for OS (adjusted HR, 1.01; 95% CI, 0.58-1.75; P = 0.974).

Conclusions: CT-determined sarcopenia is an independent prognostic factor for PFS in patients with MSS GC treated with PD-1 inhibitors.
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http://dx.doi.org/10.1007/s10120-020-01124-xDOI Listing
March 2021

Mechanisms of Acquired Resistance to Savolitinib, a Selective MET Inhibitor in -Amplified Gastric Cancer.

JCO Precis Oncol 2020 24;4. Epub 2020 Mar 24.

Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Purpose: Some gastric cancers harbor gene amplifications that can be targeted by selective MET inhibitors to achieve tumor responses, but resistance eventually develops. Savolitinib, a selective MET inhibitor, is beneficial for treating patients with MET-driven gastric cancer. Understanding the resistance mechanisms is important for optimizing postfailure treatment options.

Patients And Methods: Here, we identified the mechanisms of acquired resistance to savolitinib in 3 patients with gastric cancer and -amplified tumors who showed a clinical response and then cancer progression. Longitudinal circulating tumor DNA (ctDNA) is useful for monitoring resistance during treatment and progression when rebiopsy cannot be performed.

Results: Using a next-generation sequencing 100-gene panel, we identified the target mechanisms of resistance D1228V/N/H and Y1230C mutations or high copy number gene amplifications that emerge when resistance to savolitinib develops in patients with -amplified gastric cancer.

Conclusion: We demonstrated the utility of ctDNA in gastric cancer and confirmed this approach using baseline tumor tissue or rebiopsy.
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http://dx.doi.org/10.1200/PO.19.00386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446425PMC
March 2020

Obesity Has a Stronger Relationship with Colorectal Cancer in Postmenopausal Women than Premenopausal Women.

Cancer Epidemiol Biomarkers Prev 2020 11 31;29(11):2277-2288. Epub 2020 Aug 31.

Division of Hematology-Oncology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Background: To examine the relationship between obesity measured by waist circumference (WC) and body mass index (BMI) and the incidence of colorectal cancer in premenopausal and postmenopausal women.

Methods: A total of 1,418,180 premenopausal and 4,854,187 postmenopausal women without cancer at baseline and ages over 40 were identified using the Korean National Health Insurance System Cohort during 2009 to 2014. The hazard ratio (HR) for colorectal cancer incidence was assessed according to menopausal state using Cox proportional hazards models.

Results: During a mean follow-up period of 7.2 years, 7,094 and 57,449 colorectal cancer cases occurred in premenopausal and postmenopausal women, respectively. Compared with the reference group (WC 65-75), the HRs [95% confidence interval (CI)] of colorectal cancer in WC <65, 75-85, 85-95, and >95 groups were 1.01 (0.91-1.11), 1.02 (0.97-1.07), 1.09 (1.00-1.18), and 1.31 (1.12-1.52), respectively, in premenopausal women and 1.01 (0.95-1.17), 1.09 (1.07-1.12), 1.19 (1.00-1.18), and 1.30 (1.25-1.35), respectively, in postmenopausal women. Compared with the reference group (BMI 18.5-22.9), HRs (95% CI) for colorectal cancer in BMI <18.5, 23-25, 25-30, and >30 groups were 0.99 (0.87-1.14), 0.99 (0.94-1.06), 0.98 (0.92-1.04), and 1.06 (0.92-1.20), respectively, in premenopausal women. In postmenopausal women, those values were 0.99 (0.93-1.05), 1.05 (1.03-1.08), 1.11 (1.09-1.13), and 1.20 (1.16-1.25), respectively.

Conclusions: WC is associated with the risk of colorectal cancer in both groups of women, but this association was stronger in postmenopausal women than in premenopausal women. BMI increased the incidence of colorectal cancer only in postmenopausal women IMPACT: Obesity has a stronger relationship with colorectal cancer in postmenopausal women than in premenopausal women.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0594DOI Listing
November 2020

Effect of baseline sarcopenia on adjuvant treatment for D2 dissected gastric cancer: Analysis of the ARTIST phase III trial.

Radiother Oncol 2020 11 31;152:19-25. Epub 2020 Jul 31.

Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. Electronic address:

Background And Purpose: This study evaluated the clinical significance of preoperative sarcopenia according to adjuvant concurrent chemo-radiotherapy (XP-RT) or chemotherapy alone (XP) in the D2 dissected gastric cancer patient cohort of the ARTIST trial.

Materials And Methods: Skeletal muscles at the L3 vertebra level from preoperative computed tomography images among the ARTIST trial participants were measured using validated in-house software. Skeletal muscle index (SMI) was defined as the measured skeletal muscle area divided by the square of the height, and sarcopenia was defined according to the Korean-specific cutoff, i.e. L3 SMI ≤ 49 cm/m for men and ≤31 cm/m for women.

Results: Among the 440 patients in whom we were able to evaluate L3 SMI, 75 (17.0%) met the definition for preoperative sarcopenia. No differences in treatment-related toxicities or treatment compliance were observed according to the presence of preoperative sarcopenia in either treatment arm. In the subgroup of patients without preoperative sarcopenia, recurrence was significantly lower in the XP-RT arm than that in the XP arm (p = 0.02). Recurrence-free survival (RFS) was also significantly higher in the XP-RT arm (p = 0.02, hazard ratio 0.633, 95% confidence interval 0.433-0.926) in this subgroup. In the multivariate analysis, and after adjusting for significant prognostic factors, the superior outcome of XP-RT arm regarding RFS was maintained in the subgroup of the patients without preoperative sarcopenia.

Conclusions: Superior clinical outcomes of adjuvant XP-RT over XP were only observed in patients without preoperative sarcopenia.
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http://dx.doi.org/10.1016/j.radonc.2020.07.043DOI Listing
November 2020

Real-World Outcomes of Pazopanib Treatment in Korean Patients with Advanced Soft Tissue Sarcoma: A Multicenter Retrospective Cohort Study.

Target Oncol 2020 08;15(4):485-493

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

Background: Pazopanib is the only tyrosine kinase inhibitor approved for the treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy, but there have been limited real-world data on pazopanib for the treatment of advanced STS.

Objective: We aimed to evaluate clinical outcomes of pazopanib in patients with multiple histologic STS types in real-world settings.

Patients And Methods: We retrospectively analyzed clinical data of Korean patients with advanced STS treated with pazopanib between 2008 and 2019. Outcomes of interest included treatment response, survival according to histologic subtypes, and adverse events.

Results: The analysis included 347 STS patients. The disease control rate for all pazopanib-treated patients was 54.8% (95% confidence interval (CI) 49.5-60.0); 54 patients (15.6%) achieved a partial response and 136 (39.2%) had stable disease. Patients with alveolar soft-part sarcoma (ASPS; 90%), solitary fibrous tumor (SFT; 88.2%), synovial sarcoma (66.7%), leiomyosarcoma (61.1%), and undifferentiated pleomorphic sarcoma (59.6%) showed higher disease control rates than those with other STS subtypes. Overall, median progression-free survival (PFS) and overall survival (OS) were 5.3 months (95% CI 4.5-6.0) and 12 months (95% CI 10-14), respectively. Noticeable survival outcomes occurred in patients with ASPS and SFT, with a median PFS of 24.5 (95% CI 2.5-30.0) and 13.0 (95% CI 3.0-21.3) months, respectively. The median OS of patients with ASPS and SFT was 48 (95% CI 17-52) and 32 (95% CI 19-66) months, respectively. Adverse drug reactions occurred in 170 patients (49.0%) but were not life-threatening.

Conclusions: This real-world data analysis showed acceptable efficacy and tolerability of pazopanib in patients pretreated with cytotoxic chemotherapy for advanced STS, with favorable treatment outcomes for ASPS and SFT.
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http://dx.doi.org/10.1007/s11523-020-00731-zDOI Listing
August 2020

Quantitative analysis of tumor-specific BCL2 expression in DLBCL: refinement of prognostic relevance of BCL2.

Sci Rep 2020 06 30;10(1):10680. Epub 2020 Jun 30.

Asan Institute for Life Science, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

BCL2 overexpression has been reported to be associated with poor prognosis in patients with diffuse large B-cell lymphoma (DLBCL). However, currently there is no consensus on the evaluation of BCL2 expression and only the proportion of BCL2 positive cells are evaluated for the determination of BCL2 positivity. This study aimed to define BCL2 positivity by quantitative analysis integrating both the intensity and proportion of BCL2 expression. BCL2 expression of 332 patients (221 patients for the training set and 111 patients for the validation set) with newly diagnosed DLBCL who received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) were analyzed using the tumor-specific automated quantitative analysis (AQUA) scoring method based on multiplex immunofluorescence. In the training set, high BCL2 AQUA score (N = 86, 38.9%) was significantly associated with poor prognosis (p = 0.01, HR 2.00; 95% CI [1.15-3.49]) independent of international prognostic index, cell of origin, and MYC expression. The poor prognostic impact of the high BCL2 AQUA score was validated in the validation set. AQUA scoring of BCL2 expression incorporating both the intensity and proportion of BCL2 positive cells was independently associated with survival outcomes of patients with primary DLBCL treated with R-CHOP.
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http://dx.doi.org/10.1038/s41598-020-67738-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326926PMC
June 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

First-in-human phase I trial of anti-hepatocyte growth factor antibody (YYB101) in refractory solid tumor patients.

Ther Adv Med Oncol 2020 2;12:1758835920926796. Epub 2020 Jun 2.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea.

Background: YYB101, a humanized monoclonal antibody against hepatocyte growth factor (HGF), has shown safety and efficacy and . This is a first-in-human trial of this antibody.

Materials And Methods: YYB101 was administered intravenously to refractory cancer patients once every 4 weeks for 1 month, and then once every 2 weeks until disease progression or intolerable toxicity, at doses of 0.3, 1, 3, 5, 10, 20, 30 mg/kg, according to a 3+3 dose escalation design. Maximum tolerated dose, safety, pharmacokinetics, and pharmacodynamics were studied. HGF, MET, PD-L1, and ERK expression was evaluated for 9 of 17 patients of the expansion cohort (20 mg/kg).

Results: In 39 patients enrolled, no dose-limiting toxicity was observed at 0.3 mg/kg, and the most commonly detected toxicity was generalized edema ( = 7, 18.9%) followed by pruritis and nausea ( = 5, 13.5%, each), fatigue, anemia, and decreased appetite ( = 4, 10.8%, each). No patient discontinued treatment because of adverse events. YYB101 showed dose-proportional pharmacokinetics up to 30 mg/kg. Partial response in 1 (2.5%) and stable disease in 17 (43.5%) were observed. HGF, MET, PD-L1, and ERK proteins were not significant predictors for treatment response. However, serum HGF level was significantly lowered in responders upon drug administration. RNA sequencing revealed a mesenchymal signature in two long-term responders.

Conclusion: YYB101 showed favorable safety and efficacy in patients with refractory solid tumors. Based on this phase I trial, a phase II study on the YYB101 + irinotecan combination in refractory metastatic colorectal cancer patients is planned.

Conclusion: NCT02499224.
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http://dx.doi.org/10.1177/1758835920926796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268171PMC
June 2020

Regional Lymph Node Metastasis of Scalp Angiosarcoma: A Detailed Clinical Observation Study of 40 Cases.

Ann Surg Oncol 2020 Aug 26;27(8):3018-3027. Epub 2020 May 26.

Department of Otorhinolaryngology-Head and Neck Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.

Background: The incidence of lymph node metastasis (LNM) of angiosarcomas is reported to be less than 15%, and elective neck management has not been indicated. This study evaluated the incidence and pattern of regional LNM in patients with scalp angiosarcomas using the clinical data of its full course to understand time-event sequences of scalp angiosarcomas.

Methods: This retrospective study included all consecutive cases of pathology-confirmed angiosarcomas and analyzed 40 cases of scalp angiosarcomas. The survival plots were estimated using the Kaplan-Meier method, and the results are presented mainly in a descriptive manner.

Results: The overall survival rate for the patients was 35.8% at 2 years. In contrast to previous reports, regional LNM was observed in more than half of the patients (52.5%) with scalp angiosarcoma. Meanwhile, a direct spread to distant organs occurred in only 27.5% of the patients. Regional LNM could predict clinical manifestation of systemic disease within 3 to 6 months. No differences in survival rates between patients with and without LNM were observed in this series. Occurrence of LNM seemed to be correlated with a high mitotic rate of primary tumors, but not with tumor grade or tumor dimension. The first-echelon lymph nodes from scalp angiosarcoma were peri-parotid, post-auricular, and level 2 lymph nodes.

Conclusions: For a localized scalp angiosarcoma, it seems reasonable for initial curative surgery to include prophylactic evaluation of regional lymph nodes for pathologic nodal staging, prognosis estimation, and the decision for systemic treatments.
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http://dx.doi.org/10.1245/s10434-020-08408-7DOI Listing
August 2020

Detection of Fusion Genes Using a Targeted RNA Sequencing Panel in Gastrointestinal and Rare Cancers.

J Oncol 2020 22;2020:4659062. Epub 2020 Jan 22.

Division of Hematology-Oncology, Department of Medicine, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.

Successful identification and targeting of oncogenic gene fusion is a major breakthrough in cancer treatment. Here, we investigate the therapeutic implications and feasibility of using a targeted RNA sequencing panel to identify fusion genes in gastrointestinal and rare cancers. From February through December 2017, patients with gastrointestinal, hepatobiliary, gynecologic, sarcoma, or rare cancers were recruited for a clinical sequencing project at Samsung Medical Center (NCT #02593578). The median age of the patients was 58 years (range, 31-81 years), and the male-to-female ratio was 1.3 : 1. A total of 118 patients passed the quality control process for a next-generation sequencing- (NGS-) based targeted sequencing assay. The NGS-based targeted sequencing assay was performed to detect gene fusions in 36-53 cancer-implicated genes. The following cancer types were included in this study: 28 colorectal cancers, 27 biliary tract cancers, 25 gastric cancers, 18 soft tissue sarcomas, 9 pancreatic cancers, 6 ovarian cancers, and 9 other rare cancers. Strong fusion was detected in 25 samples (21.2%). We found that 5.9% (7/118) of patients had known targetable fusion genes involving (=3), (=3), and (=1), and 10.2% (12/118) of patients had potentially targetable fusion genes involving (=4), (=2), (=2), (=1), (=1), and (=2). Thus, we successfully identified a substantial proportion of patients harboring fusion genes by RNA panel sequencing of gastrointestinal/rare cancers. Targetable and potentially targetable involved fusion genes were , , , , , , , , and . Detection of fusion genes by RNA panel sequencing may be beneficial in refractory patients with gastrointestinal/rare cancers.
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http://dx.doi.org/10.1155/2020/4659062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204148PMC
January 2020

Impact of Prior Ramucirumab Use on Treatment Outcomes of Checkpoint Inhibitors in Advanced Gastric Cancer Patients.

Target Oncol 2020 04;15(2):203-209

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 135-710, Korea.

Background: A taxane plus ramucirumab as second-line therapy followed by a checkpoint inhibitor (CPI) in third line has become a standard treatment strategy for advanced gastric cancer.

Objective: Herein, we investigated the impact of prior ramucirumab use on the efficacy of third-line immunotherapy and performed an exploratory analysis to identify potential biomarkers for the success of immunotherapy.

Patients And Methods: We retrospectively analyzed patients receiving CPI as a third-line treatment for advanced gastric cancer between January 2015 and March 2019. Clinicopathologic data, including patient characteristics, histopathologic reports, and treatment types and outcomes, were reviewed.

Results: Of the 74 patients included in this study, 45 (61%) received nivolumab and 29 (39%) received pembrolizumab as a third-line CPI. For second-line therapy, 41 patients (55%) were treated with ramucirumab plus a taxane, and 33 (45%) received a chemotherapy regimen without ramucirumab. The disease control rates of CPIs were not statistically different according to prior use of ramucirumab. The overall survival (OS) with CPI was higher in patients receiving second-line therapy without ramucirumab compared with those receiving ramucirumab and taxane (5.6 vs 4.8 months, HR 0.56, 95% confidence interval [CI] 0.33-0.96; p = 0.03); however, this was not significant in a multivariate analysis. Patients achieving a response to second-line ramucirumab and a taxane showed greater benefit from subsequent CPI treatment compared with those not achieving a response (median OS 9.9 vs 2.3 months, HR 0.20, 95% CI 0.07-0.54; p < 0.001) as found in an exploratory analysis. Multivariate analysis also showed that prior response to ramucirumab and a taxane was an independent prognostic factor of OS with third-line CPI.

Conclusions: Response to ramucirumab and a taxane as a second-line treatment is an important prognostic marker for OS with subsequent third-line CPI. This data might provide useful information when applying CPIs as third-line therapies in advanced gastric cancer patients.
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http://dx.doi.org/10.1007/s11523-020-00713-1DOI Listing
April 2020

Association of serine/threonine kinase 11 mutations and response to programmed cell death 1 inhibitors in metastatic gastric cancer.

Pathol Res Pract 2020 Jun 11;216(6):152947. Epub 2020 Apr 11.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. Electronic address:

Programmed cell death 1 (PD-1) inhibitors have shown therapeutic efficacy in metastatic gastric cancer (mGC). However, no predictive biomarkers have been established in mGC. Inactivating mutations in serine/threonine kinase 11 (STK11) are associated with poor response to PD-1 inhibitors in KRAS-mutant lung adenocarcinoma. Therefore, we hypothesized that STK11 inactivating mutations would be associated with inferior clinical response to PD-1 inhibitors in mGC. We analyzed 59 mGC patients who had been treated with PD-1 inhibitors and whose tumors had been analyzed by targeted high-throughput sequencing. STK11 mutations were identified in 30 (50.8%) patients, and were all missense mutations. Three patients (5.1%) had STK11 gene amplification and mutation, simultaneously. Patients with STK11 mutations had prolonged overall survival (median: 19.0 vs 11.6 months, p = 0.15), and progression-free survival (4.2 vs 1.9 months, p = 0.06) when treated with PD-1 inhibitors, but these differences were not statistically significant. Patients with STK11 inactivating mutations without STK11 gene amplification had significantly prolonged progression-free survival compared to patients with wild type STK11 or STK11 gene amplification (4.8 vs 1.0 months, p = 0.04). However, in multivariate Cox regression analysis with high microsatellite instability (MSI-H), the number of tumor mutations, PD Ligand-1 (PD-L1)+, Epstein-Barr virus positivity (EBV)+, and type of PD-1 inhibitor used (pembrolizumab vs nivolumab), only MSI-H and PD-L1+ were significantly associated with longer progression-free survival. In mGC, the presence of STK11 mutation was not predictive of the response to PD-1 inhibitors. Instead, patients with MSI-H or PD-L1+ tumors displayed superior clinical responses to PD-1 inhibitors.
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http://dx.doi.org/10.1016/j.prp.2020.152947DOI Listing
June 2020

Clinical scoring system for the prediction of survival of patients with advanced gastric cancer.

ESMO Open 2020 03;5(2)

Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea

Objective: In this study, we established a risk scoring system using easily obtained clinical characteristics at the time of initiating palliative chemotherapy to predict accurate overall survival of patients with advanced gastric cancer after first-line treatment with fluoropyrimidine-platinum combination chemotherapy.

Methods: A total of 1733 patients treated at the Samsung Medical Center, Korea were included in the study, and clinicopathological and laboratory data were retrospectively analysed. The dataset was split into a training set (n=1156, 67%) and a validation set (n=577, 33%). Top-ranked variables were identified using the random forest survival algorithm and integrated into a Cox regression model, thereby constructing the scoring system for predicting the overall survival of patients with advanced gastric cancer.

Results: The following five variables were finally included in the scoring system: serum neutrophil-lymphocyte ratio, alkaline phosphatase level, albumin level, performance status and histologic differentiation. The scoring system determined four distinct risk groups in the validation dataset with median overall survival of 17.1 months (95% CI=14.9 to 20.5 months), 12.9 months (95% CI=11.4 to 14.6 months), 8.1 months (95% CI=5.3 to 12.3 months) and 3.9 months (95% CI=1.5 to 8.2 months), respectively. The area under the curve to estimate the discrimination performance of the scoring system was 66.1 considering 1 year overall survival.

Conclusions: We developed a simple and clinically useful predictive scoring model in a homogeneous population with advanced gastric cancer treated with fluoropyrimidine-containing and platinum-containing chemotherapy. However, additional independent validation will be required before the scoring model can be used commonly.
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http://dx.doi.org/10.1136/esmoopen-2020-000670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078777PMC
March 2020

Use of Gefitinib in EGFR-Amplified Refractory Solid Tumors: An Open-Label, Single-Arm, Single-Center Prospective Pilot Study.

Target Oncol 2020 04;15(2):185-192

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, South Korea.

Background: Treatment options for patients with chemotherapy-refractory solid tumors are limited.

Objective: We conducted an open-label, single-arm, single-center phase II trial to evaluate the efficacy and safety of gefitinib in patients with chemotherapy-refractory solid tumors and EGFR amplification or sensitivity to an EGFR inhibitor identified through a drug-screening platform with patient-derived tumor cells (PDCs).

Patients And Methods: EGFR amplification was detected by targeted sequencing. Sensitivity to an EGFR inhibitor was established in chemical screening using PDCs. Gefitinib (250 mg daily) was administered continuously in 28-day cycles until the occurrence of disease progression, unacceptable toxicity, or death due to any cause. The primary endpoint was the objective response rate (ORR).

Results: In total, 15 patients were assigned to the present study. The most common tumor type was glioblastoma multiforme (n = 9, 60%), followed by gastric cancer (n = 3, 20%), anal squamous cancer, rectal cancer, and sarcoma (each n = 1, 6.7%). Among 13 evaluable patients, one patient had a partial response and five had stable disease, with an ORR of 7.7% and a disease control rate of 46.1%. The median progression-free survival was 2.1 months (95% confidence interval [CI] 0.77-3.43). The most common adverse events were diarrhea (26.7%) and skin rash (26.7%).

Conclusion: Gefitinib demonstrated modest anti-tumor activity and a manageable safety profile in chemotherapy-refractory solid tumors with EGFR amplification or sensitivity to an EGFR inhibitor identified through a drug-screening platform with PDCs. CLINICALTRIALS.

Gov Identifier: NCT02447419.
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http://dx.doi.org/10.1007/s11523-020-00706-0DOI Listing
April 2020

Comprehensive pharmacogenomic characterization of gastric cancer.

Genome Med 2020 02 18;12(1):17. Epub 2020 Feb 18.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.

Background: Gastric cancer is among the most lethal human malignancies. Previous studies have identified molecular aberrations that constitute dynamic biological networks and genomic complexities of gastric tumors. However, the clinical translation of molecular-guided targeted therapy is hampered by challenges. Notably, solid tumors often harbor multiple genetic alterations, complicating the development of effective treatments.

Methods: To address such challenges, we established a comprehensive dataset of molecularly annotated patient derivatives coupled with pharmacological profiles for 60 targeted agents to explore dynamic pharmacogenomic interactions in gastric cancers.

Results: We identified lineage-specific drug sensitivities based on histopathological and molecular subclassification, including substantial sensitivities toward VEGFR and EGFR inhibition therapies in diffuse- and signet ring-type gastric tumors, respectively. We identified potential therapeutic opportunities for WNT pathway inhibitors in ALK-mutant tumors, a significant association between PIK3CA-E542K mutation and AZD5363 response, and transcriptome expression of RNF11 as a potential predictor of response to gefitinib.

Conclusions: Collectively, our results demonstrate the feasibility of drug screening combined with tumor molecular characterization to facilitate personalized therapeutic regimens for gastric tumors.
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http://dx.doi.org/10.1186/s13073-020-0717-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029441PMC
February 2020
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