바다가 보이는 응접실 : 뷔티에스 ( VTS ) 도입 기여에 보람 - 초대손님 김좌훈 [ 한국항만운송협회 전무이사 ]

김좌훈 한국해사문제연구소 1997 (月刊)海洋韓國 Vol.288 No.-

A Phase II Study of Avelumab Monotherapy in Patients with Mismatch Repair–Deficient/Microsatellite Instability–High or POLE-Mutated Metastatic or Unresectable Colorectal Cancer

김좌훈,김선영,백지연,차용준,안중배,김한상,이근욱,김지원,김태유,장원진,박준오,김지훈,김정은,홍용상,김열홍,김태원 대한암학회 2020 Cancer Research and Treatment Vol.52 No.4

Purpose We evaluated the efficacy and safety of avelumab, an anti–PD-L1 antibody, in patients with metastatic or unresectable colorectal cancer (mCRC) with mismatch repair deficiency (dMMR)/microsatellite instability-high (MSI-H) or POLE mutations. Materials and Methods In this prospective, open-label, multicenter phase II study, 33 patients with mCRC harboring dMMR/MSI-H or POLEmutations after failure of ≥ 1st-line chemotherapy received avelumab 10 mg/kg every 2 weeks. dMMR/MSI-H was confirmed with immunohistochemical staining (IHC) by loss of expression of MMR proteins or polymerase chain reaction (PCR) for microsatellite sequences. POLE mutation was confirmed by next-generation sequencing (NGS). The primary endpoint was the objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors ver. 1.1. Results The median age was 60 years, and 78.8% were male. Thirty patients were dMMR/MSI-H and three had POLE mutations. The ORR was 24.2%, and all of the responders were dMMR/MSI-H. For 21 patients with MSI-H by PCR or NGS, the ORR was 28.6%. At a median follow-up duration of 16.3 months, median progression-free survival and overall survival were 3.9 and 13.2 months in all patients, and 8.1 months and not reached, respectively, in patients with MSI-H by PCR or NGS. Dose interruption and discontinuation due to treatment- related adverse events occurred in four and two patients, respectively, with no treatment- related deaths. Conclusion Avelumab displayed antitumor activity with manageable toxicity in patients with previously treated mCRC harboring dMMR/MSI-H. Diagnosis of dMMR/MSI-H with PCR or NGS could be complementary to IHC to select patients who would benefit from immunotherapy.

Adjuvant Chemotherapy for Resected Ampulla of Vater Carcinoma: Retrospective Analysis of 646 Patients

김좌훈,정재호,류백렬,김규표,장흥문,오동욱,송태준,이상수,서동완,이성구,김명환,박예종,권재우,황대욱,이재훈,이우형,김송철,유창훈,송기병 대한암학회 2021 Cancer Research and Treatment Vol.53 No.2

Purpose This study evaluated the efficacy of adjuvant chemotherapy (AC) in patients with resected ampulla of Vater (AoV) carcinoma.Materials and Methods Data from 646 patients who underwent surgical resection at Asan Medical Center between 2000 and 2017 were retrospectively reviewed.Results The median age of the patients was 62 years, and 54.2% were male. Patients were classified into AC group (n=165, 25.5%) and no AC group (n=481, 74.5%). With a median follow-up duration of 88 months, in patients with stage I, II, III, median recurrence-free survival (RFS) was not reached, 44 months, and 15 months, respectively, and the median overall survival (OS) were not reached, 88 months and 35 months, respectively. Despite no statistical significance, RFS and OS were better in stage II patients with AC than in those without AC (median RFS, 151 months vs. 38 months; p=0.156 and median OS, 153 months vs. 74 months; p=0.299). In multivariate analysis for RFS and OS, TNM stage, R1 resection status, presence of lymphovascular invasion, and perineural invasion remained significant factors, whereas AC (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.54 to 1.00; p=0.052) was marginally related with RFS. After propensity score matching in only stage II/III patients, RFS and OS with AC were numerically longer than those without AC (HR, 0.80; 95% CI, 0.60 to 1.06; p=0.116 and HR, 0.77; 95% CI, 0.56 to 1.06; p=0.111).Conclusion AC with fluoropyrimidine did not improve survival of patients with resected AoV carcinoma. However, multivariate analysis with prognostic factors showed a marginally significant survival benefit with AC.

Phase II Study of Induction Chemotherapy with Docetaxel, Capecitabine, and Cisplatin Plus Bevacizumab for Initially Unresectable Gastric Cancer with Invasion of Adjacent Organs or Paraaortic Lymph Node Metastasis

김좌훈,박숙련,류민희,류백렬,김규표,김범수,유문원,육정환,김병식,김지훈,변선주,강윤구 대한암학회 2018 Cancer Research and Treatment Vol.50 No.2

Purpose The purpose of this study was to evaluate the efficacy and safety of induction chemotherapy with docetaxel, capecitabine, and cisplatin (DXP) plus bevacizumab (BEV) on initially unresectable locally advanced gastric cancer (LAGC) or paraaortic lymph node (PAN) metastatic gastric cancer (GC). Materials and Methods Patients with LAGC or unresectable PAN metastatic GC received six induction chemotherapy cycles (60 mg/m2 docetaxel intravenously on day 1, 937.5 mg/m2 capecitabine orally twice daily on days 1-14, 60 mg/m2 cisplatin intravenously on day 1, and 7.5 mg/kg BEV intravenously on day 1 every 3 weeks), followed by conversion surgery. The primary endpoint was R0 resection rate. Results Thirty-one patients with invasion to adjacent organs but without PAN metastasis (n=14, LAGC group) or with PAN metastasis regardless of invasion (n=17, PAN group) were enrolled between July 2010 and December 2014. Twenty-seven patients (87.1%) completed six chemotherapy cycles. The most common grade  3 toxicities were neutropenia (71%), neutropenia with fever/infection (22.6%/3.2%), and stomatitis (16.1%). The clinical response and R0 resection rates were 64.3% (95% confidence interval [CI], 46.6 to 82.0) and 64.5% (LAGC group, 71.4%; PAN group, 58.8%), respectively. The pathological complete regression rate was 12.9%. After a median follow-up of 44.5 months (range, 39.4 to 49.7 months), the median progression-free survival and overall survival were 13.1 months (95% CI, 8.9 to 17.3) and 38.6 months (95% CI, 22.0 to 55.1), respectively. Conclusion Induction chemotherapy with DXP+BEV displayed antitumor activities with encouraging R0 resection rate and manageable toxicity profiles on patients with LAGC or PAN metastatic GC.

Real-World Efficacy Data and Predictive Clinical Parameters for Treatment Outcomes in Advanced Esophageal Squamous Cell Carcinoma Treated with Immune Checkpoint Inhibitors

김좌훈,안보경,홍승모,정훈용,김도훈,최기돈,안지용,이정훈,나희경,김종훈,김용희,김형렬,이현주,김성배,박숙련 대한암학회 2022 Cancer Research and Treatment Vol.54 No.2

Purpose This study aimed to evaluate the real-world efficacy of immune checkpoint inhibitors (ICIs), and to identify clinicolaboratory factors to predict treatment outcomes in patients with advanced esophageal squamous cell carcinoma (ESCC) receiving ICIs.Materials and Methods Sixty patients with metastatic or unresectable ESCC treated with nivolumab (n=48) or pembrolizumab (n=12) as ≥ second-line treatment between 2016 and 2019 at Asan Medical Center were included.Results The median age of the patients was 68 years (range, 52 to 76 years), and 93.3% were male. Most patients had metastatic disease (81.7%) and had been previously treated with fluoropyrimidines, platinum, and taxane. In 53 patients with measurable disease, the overall response rate and disease control rate were 15.1% and 35.8%, respectively. With a median follow-up duration of 16.0 months, the median progression-free survival (PFS) and overall survival (OS) were 1.9 months (95% confidence interval [CI], 1.54 to 2.19) and 6.4 months (95% CI, 4.77 to 8.11), respectively. After multivariate analysis, recent use of antibiotics, low prognostic nutrition index (< 35.93), high Glasgow Prognosis Score (≥ 1) at baseline, and ≥ 1.4-fold increase in neutrophil-to-lymphocyte ratio after one cycle from baseline were significantly unfavorable factors for both PFS and OS. Younger age (< 65 years) was a significant factor for unfavorable PFS and hyponatremia (< 135 mmol/L) for unfavorable OS.Conclusion The use of ICIs after the failure of chemotherapy showed comparable efficacy in patients with advanced ESCC in real practice; this may be associated with host immune-nutritional status, which could be predicted by clinical and routine laboratory factors.

증례 : 혈액종양 ; 위에 발생한 투명세포육종 1예

김좌훈 ( Jwa Hoon Kim ),김범수 ( Beom Su Kim ),송준선 ( Joon Seon Song ),조형우 ( Hyungwoo Cho ),김종관 ( Jongkwan Kim ),이주희 ( Joohee Lee ),류민희 ( Min Hee Ryu ) 대한내과학회 2015 대한내과학회지 Vol.89 No.4

위에 발생한 투명세포육종은 매우 드물며 국내에서 첫 증례를 보고하는 바이다. 투명세포육종의 진단은 어렵지만 충분한 조직 검체를 이용하여 면역조직화학 검사 및 분자학적 검사를 하면 진단할 수 있고, 특히 EWS 유전자 전좌를 확인하는 것이 중요하다. 문헌 보고에 따르면 투명세포육종의 치료로서 항암화학요법의 효과는 미미하였고 아직까지 항암화학요법에 대해 일치된 의견이 없어 현재까지 수술적 절제가 권장된다. 본 증례에서 초기 유잉 육종 진단하에 항암화학요법을 적용하였는데 치료 경과가 유잉 육종과 일치하지 않아투명세포육종을 의심하에 수술적 절제로 진단 및 치료를 하였다. 수술적 절제 이후에 부종양 증후군이 호전되는 것을 확인하였고 재발 없이 추적관찰 중이다. Clear-cell sarcoma (CCS) is a rare soft tissue sarcoma that usually develops in the lower extremities of young adults. CCS of the gastrointestinal tract is extremely rare. We report here the first case of CCS of the stomach in Korea. A 28-year-old female developed a large tumor of the stomach that was initially considered Ewing sarcoma, based on the results of a needle biopsy. She had paraneoplastic syndrome; fever, anemia, and hyperglycemia. Follow-up abdominal computed tomography after four-cycles of chemotherapy with vincristine-doxorubicin-cyclophosphamide or ifosfamide-etoposide showed no tumor shrinkage and revealed a fistula between the tumor and the gastric lumen. The infected tumor prompted debulking surgery, which resulted in improvement of her symptoms. The pathologic findings were consistent with CCS, and fluorescence in situ hybridization for EWS gene rearrangement was positive, confirming the diagnosis. This case highlights the importance of clinical suspicion for CCS in chemotherapy-refractory Ewing sarcoma. (Korean J Med 2015;89:465-469)

Spatial Distribution and Prognostic Implications of Tumor-Infiltrating FoxP3– CD4+ T Cells in Biliary Tract Cancer

김형돈,김좌훈,유연미,김단비,이선민,신재훈,홍승모,김기훈,정동환,송기원,황대욱,이재훈,송기병,류백렬,정재호,김규표,김상엽,유창훈 대한암학회 2021 Cancer Research and Treatment Vol.53 No.1

Purpose The clinical implications of tumor-infiltrating T cell subsets and their spatial distribution in biliary tract cancer (BTC) patients treated with gemcitabine plus cisplatin were investigated. Materials and Methods A total of 52 BTC patients treated with palliative gemcitabine plus cisplatin were included. Multiplexed immunohistochemistry was performed on tumor tissues, and immune infiltrates were separately analyzed for the stroma, tumor margin, and tumor core. Results The density of CD8+ T cells, FoxP3– CD4+ helper T cells, and FoxP3+ CD4+ regulatory T cells was significantly higher in the tumor margin than in the stroma and tumor core. The density of LAG3– or TIM3-expressing CD8+ T cell and FoxP3– CD4+ helper T cell infiltrates was also higher in the tumor margin. In extrahepatic cholangiocarcinoma, there was a higher density of T cell subsets in the tumor core and regulatory T cells in all regions. A high density of FoxP3– CD4+ helper T cells in the tumor margin showed a trend toward better progression-free survival (PFS) (p=0.092) and significantly better overall survival (OS) (p=0.012). In multivariate analyses, a high density of FoxP3– CD4+ helper T cells in the tumor margin was independently associated with favorable PFS and OS. Conclusion The tumor margin is the major site for the active infiltration of T cell subsets with higher levels of LAG3 and TIM3 expression in BTC. The density of tumor margin-infiltrating FoxP3– CD4+ helper T cells may be associated with clinical outcomes in BTC patients treated with gemcitabine plus cisplatin.

Use of Gemcitabine plus Carboplatin is Associated with Poor Outcomes in Urothelial Carcinoma Patients with Chronic Kidney Disease Stage 4-5

김형돈,임현수,김좌훈,정혜현,윤신교,박인근,이재련 대한암학회 2021 Cancer Research and Treatment Vol.53 No.4

Purpose This study aimed to investigate the clinical outcomes with gemcitabine-carboplatin (GCb), the standard treatment for patients with advanced urothelial carcinoma (UC) who are ineligible for cisplatin-based regimens, in advanced UC patients with a glomerular filtration rate (GFR) < 30 mL/min. Materials and Methods A retrospective cohort study involving GCb-treated advanced UC patients with GFR < 60 mL/min (n=89) was performed. Clinical outcomes were compared between subgroups with GFR < 30 mL/min and GFR ≥ 30 mL/min but < 60 mL/min. Results Most baseline characteristics were comparable between the two subgroups. Patients with GFR < 30 mL/min had a significantly lower objective response rate (12.5%) compared to those with higher GFR levels (56.7%) (p=0.004). The number of GCb cycles was significantly lower in patients with GFR < 30 mL/min (median 2 cycles) than in those with higher GFR levels (median 6 cycles) (p=0.002). Compared to those with GFR ≥ 30 mL/min but < 60 mL/min, patients with GFR < 30 mL/min showed significantly worse progression-free survival (PFS) and overall survival (OS) (p < 0.001 for both). Further stratification of patient subgroups according to their GFR (i.e., GFR ≥ 45 mL/min but < 60 mL/min vs. GFR ≥ 30 mL/min but < 45 mL/min vs. GFR < 30 mL/min) revealed significantly different PFS and OS (p < 0.001 for both). Conclusion The use of GCb is discouraged in advanced UC patients with GFR < 30 mL/min. Alternative therapeutic approaches with better efficacy are warranted for these patients.

Histopathologic and Molecular Biomarkers of PD-1/PD-L1 Inhibitor Treatment Response among Patients with Microsatellite Instability‒High Colon Cancer

형재원,조은정,김지훈,김좌훈,김정은,홍용상,김태원,성창옥,김선영 대한암학회 2022 Cancer Research and Treatment Vol.54 No.4

Purpose Recent clinical trials have reported response rates < 50% among patients treated with programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors for microsatellite instability–high (MSI-H) colorectal cancer (CRC), and factors predicting treatment response have not been fully identified. This study aimed to identify potential biomarkers of PD-1/PD-L1 inhibitor treatment response among patients with MSI-H CRC. Materials and Methods MSI-H CRC patients enrolled in three clinical trials of PD-1/PD-L1 blockade at Asan Medical Center (Seoul, Republic of Korea) were screened and classified into two groups according to treatment response. Their histopathologic features and expression of 730 immune-related genes from the NanoString platform were evaluated, and a machine learning–based classification model was built to predict treatment response among MSI-H CRCs patients. Results A total of 27 patients (15 responders, 12 non-responders) were included. A high degree of lymphocytic/neutrophilic infiltration and an expansile tumor border were associated with treatment response and prolonged progression-free survival (PFS), while mucinous/signet-ring cell carcinoma was associated with a lack of treatment response and short PFS. Gene expression profiles revealed that the interferon-γ response pathway was enriched in the responder group. Of the top eight differentially expressed immune-related genes, PRAME had the highest fold change in the responder group. Higher expression of PRAME was independently associated with better PFS along with histologic subtypes in the multivariate analysis. The classification model using these genes showed good performance for predicting treatment response. Conclusion We identified histologic and immune-related gene expression characteristics associated with treatment response in MSI-H CRC, which may contribute to optimal patient stratification. Purpose Recent clinical trials have reported response rates < 50% among patients treated with programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors for microsatellite instability‒high (MSI-H) colorectal cancer (CRC), and factors predicting treatment response have not been fully identified. This study aimed to identify potential biomarkers of PD-1/PD-L1 inhibitor treatment response among patients with MSI-H CRC. Materials and Methods MSI-H CRC patients enrolled in three clinical trials of PD-1/PD-L1 blockade at Asan Medical Center (Seoul, Republic of Korea) were screened and classified into two groups according to treatment response. Their histopathologic features and expression of 730 immune-related genes from the NanoString platform were evaluated, and a machine learning–based classification model was built to predict treatment response among MSI-H CRCs patients.Results A total of 27 patients (15 responders, 12 non-responders) were included. A high degree of lymphocytic/neutrophilic infiltration and an expansile tumor border were associated with treatment response and prolonged progression-free survival (PFS), while mucinous/signet-ring cell carcinoma was associated with a lack of treatment response and short PFS. Gene expression profiles revealed that the interferon-γ response pathway was enriched in the responder group. Of the top eight differentially expressed immune-related genes, <i>PRAME</i> had the highest fold change in the responder group. Higher expression of <i>PRAME</i> was independently associated with better PFS along with histologic subtypes in the multivariate analysis. The classification model using these genes showed good performance for predicting treatment response.Conclusion We identified histologic and immune-related gene expression characteristics associated with treatment response in MSI-H CRC, which may contribute to optimal patient stratification.

The Prognosis and the Role of Adjuvant Chemotherapy for Node-Positive Bladder Cancer Treated with Neoadjuvant Chemotherapy Followed by Surgery

정혜현,박계진,이용준,김형돈,김좌훈,윤신교,홍범식,이재련 대한암학회 2022 Cancer Research and Treatment Vol.54 No.1

Purpose This study aims to evaluate the prognosis of pathologically node-positive bladder cancer after neoadjuvant chemotherapy, the role of adjuvant chemotherapy in these patients, and the value of preoperative clinical evaluation for lymph node metastases. Materials and Methods Patients who received neoadjuvant chemotherapy followed by partial/radical cystectomy and had pathologically confirmed lymph node metastases between January 2007 and December 2019 were identified and analyzed. Results A total of 53 patients were included in the study. The median age was 61 years (range, 34 to 81 years) with males comprising 86.8%. Among the 52 patients with post-neoadjuvant/pre-operative computed tomography results, only 33 patients (63.5%) were considered positive for lymph node metastasis. Sixteen patients (30.2%) received adjuvant chemotherapy (AC group), and 37 pati-ents did not (no AC group). With the median follow-up duration of 67.7 months, the median recurrence-free survival (RFS) and the median overall survival (OS) was 8.5 months and 16.2 months, respectively. The 2-year RFS and OS rates were 23.3% and 34.6%, respectively. RFS and OS did not differ between the AC group and no AC group (median RFS, 8.8 months vs. 6.8 months, p=0.772; median OS, 16.1 months vs. 16.3 months, p=0.479). Thirty-eight patients (71.7%) experienced recurrence. Distant metastases were the dominant pattern of failure in both the AC group (91.7%) and no AC group (76.9%). Conclusion Patients with lymph node-positive disease after neoadjuvant chemotherapy followed by surgery showed high recurrence rates with limited survival outcomes. Little benefit was observed with the addition of adjuvant chemotherapy.