Publications by authors named "Miso Kim"

91 Publications

A phase II study of brentuximab vedotin in patients with relapsed or refractory Epstein-Barr virus-positive and CD30-positive lymphomas.

Haematologica 2021 Apr 1. Epub 2021 Apr 1.

Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea; Seoul National University Cancer Research Institute, Seoul.

Not available.
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http://dx.doi.org/10.3324/haematol.2021.278301DOI Listing
April 2021

Programmed death-ligand 1 expression level as a predictor of EGFR tyrosine kinase inhibitor efficacy in lung adenocarcinoma.

Transl Lung Cancer Res 2021 Feb;10(2):699-711

Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.

Background: The main objective of this study was to investigate the impact of programmed death-ligand 1 (PD-L1) expression on the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in patients with advanced non-small cell lung cancer (NSCLC).

Methods: This study analyzed 108 patients with NSCLC who had received EGFR-TKI as first-line systemic treatment at Seoul National University Bundang Hospital and Seoul National University Hospital between December 2012 and October 2018. The National Cancer Center Research Institute (NCCRI) and The Cancer Genome Atlas (TCGA) datasets were analyzed to investigate the mechanisms underlying EGFR-TKI-resistance in tumors with high PD-L1 expression.

Results: Among the 108 patients, 55, 37, and 16 had negative (PD-L1 Tumor proportion score <1%), weak (1-49%), and strong (≥50%) PD-L1 expression, respectively. Patients with strong PD-L1 expression had significantly shorter median progression-free survival (PFS; 7.07 months) than patients with weak (14.73 months, P<0.001) or negative (12.70 months, P=0.001) PD-L1 expression. After adjustment for covariates by Cox regression, PD-L1 expression remained a significant indicator of adverse prognosis. In EGFR-TKI-refractory patients, the frequency of T790M mutation and the PFS following treatment with third-generation EGFR-TKI and PD-1 antibody were similar in the three groups. TCGA and NCCRI database analysis showed that high PD-L1 expression in EGFR-mutated NSCLCs correlated with IL-6/JAK/STAT3 signaling and high mutation frequency.

Conclusions: Strong PD-L1 expression in tumors might be a surrogate indicator of poor response to first-line EGFR-TKIs in NSCLC patients with sensitizing EGFR mutations, and may reflect a resistance mechanism involving JAK-STAT signaling.
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http://dx.doi.org/10.21037/tlcr-20-893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947423PMC
February 2021

Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.

N Engl J Med 2021 04 13;384(14):1289-1300. Epub 2021 Feb 13.

From Memorial Sloan Kettering Cancer Center, New York (R.M.); P. Hertsen Moscow Oncology Research Institute, Moscow (B.A.), the State Institution of Health Care Regional Clinical Oncology Dispensary, Omsk (E.K.), the State Budgetary Health Care Institution Novosibirsk Regional Clinical Oncology Dispensary, Novosibirsk (V.K.), and Prevoljskiy Region Medical Center, Novgorod (A.A.) - all in Russia; Yonsei Cancer Center, Yonsei University Health System (S.Y.R.), Seoul St. Mary's Hospital, Catholic University of Korea (S.-H.H.), and Seoul National University Hospital (M.K.), Seoul, South Korea; San Matteo University Hospital Foundation, Pavia (C.P.), Istituto Nazionale dei Tumori IRCCS, Milan (G.P.), and Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori IRCCS, Meldola (U.D.G.) - all in Italy; Kyushu University, Fukuoka (M.E.), and Tokyo Women's Medical University, Tokyo (T.T.) - both in Japan; the Royal Free NHS Trust, London (T.P.), and Eisai, Hatfield (A.D.S.) - both in the United Kingdom; University Hospital Essen, Essen (V.G.), and the University of Tübingen, Tübingen (J.B.) - both in Germany; Texas Oncology, Dallas (T.E.H.); Maimonides Institute for Biomedical Research of Cordoba Hospital Universitario Reina Sofía, Medical Oncology Department, Córdoba (M.J.M.-V.), Hospital Universitario Ramón y Cajal, Madrid (T.A.G.), and Hospital de la Santa Creu i Sant Pau, Barcelona (P.M.) - all in Spain; McMaster University, Hamilton (A.K.), and Western University, London (E.W.) - both in Ontario, Canada; the University of Miami Sylvester Comprehensive Cancer Center, Miami (J.R.M.), and Florida Cancer Specialists, Gainesville (V.P.); ICON Research, South Brisbane, and University of Queensland, St. Lucia, QLD (J.C.G.), Macquarie University, Sydney (H.G.), and Western Health, Melbourne, VIC (S.W.) - all in Australia; Rambam Health Care Campus, Haifa, Israel (A.P.); Palacky University and University Hospital Olomouc, Olomouc, Czech Republic (B.M.); Centre René Gauducheau, Saint Herblain, France (F.R.); the Department of Urology, Medical University of Vienna, Vienna (M.S.); Eisai, Woodcliff Lake (C.E.D., L.D., K.M., D.X.), and Merck, Kenilworth (R.F.P.) - both in New Jersey; and Dana-Farber Cancer Institute, Boston (T.K.C.).

Background: Lenvatinib in combination with pembrolizumab or everolimus has activity against advanced renal cell carcinoma. The efficacy of these regimens as compared with that of sunitinib is unclear.

Methods: In this phase 3 trial, we randomly assigned (in a 1:1:1 ratio) patients with advanced renal cell carcinoma and no previous systemic therapy to receive lenvatinib (20 mg orally once daily) plus pembrolizumab (200 mg intravenously once every 3 weeks), lenvatinib (18 mg orally once daily) plus everolimus (5 mg orally once daily), or sunitinib (50 mg orally once daily, alternating 4 weeks receiving treatment and 2 weeks without treatment). The primary end point was progression-free survival, as assessed by an independent review committee in accordance with Response Evaluation Criteria in Solid Tumors, version 1.1. Overall survival and safety were also evaluated.

Results: A total of 1069 patients were randomly assigned to receive lenvatinib plus pembrolizumab (355 patients), lenvatinib plus everolimus (357), or sunitinib (357). Progression-free survival was longer with lenvatinib plus pembrolizumab than with sunitinib (median, 23.9 vs. 9.2 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.32 to 0.49; P<0.001) and was longer with lenvatinib plus everolimus than with sunitinib (median, 14.7 vs. 9.2 months; hazard ratio, 0.65; 95% CI, 0.53 to 0.80; P<0.001). Overall survival was longer with lenvatinib plus pembrolizumab than with sunitinib (hazard ratio for death, 0.66; 95% CI, 0.49 to 0.88; P = 0.005) but was not longer with lenvatinib plus everolimus than with sunitinib (hazard ratio, 1.15; 95% CI, 0.88 to 1.50; P = 0.30). Grade 3 or higher adverse events emerged or worsened during treatment in 82.4% of the patients who received lenvatinib plus pembrolizumab, 83.1% of those who received lenvatinib plus everolimus, and 71.8% of those who received sunitinib. Grade 3 or higher adverse events occurring in at least 10% of the patients in any group included hypertension, diarrhea, and elevated lipase levels.

Conclusions: Lenvatinib plus pembrolizumab was associated with significantly longer progression-free survival and overall survival than sunitinib. (Funded by Eisai and Merck Sharp and Dohme; CLEAR ClinicalTrials.gov number, NCT02811861.).
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http://dx.doi.org/10.1056/NEJMoa2035716DOI Listing
April 2021

2020 Korean guidelines for the management of metastatic prostate cancer.

Korean J Intern Med 2021 Feb 10. Epub 2021 Feb 10.

Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Korea.

In 2017, Korean Society of Medical Oncology (KSMO) published the Korean management guideline of metastatic prostate cancer. This paper is the 2nd edition of the Korean management guideline of metastatic prostate cancer. We updated recent many changes of management in metastatic prostate cancer in this 2nd edition guideline. The present guideline consists of the three categories: management of metastatic hormone sensitive prostate cancer; management of metastatic castration resistant prostate cancer; and clinical consideration for treating patients with metastatic prostate cancer. In category 1 and 2, levels of evidence (LEs) have been mentioned according to the general principles of evidence-based medicine. And grades of recommendation (GR) was taken into account the quality of evidence, the balance between desirable and undesirable effects, the values and preferences, and the use of resources and GR were divided into strong recommendations (SR) and weak recommendations (WR). A total of 16 key questions are selected. And we proposed recommendations and described key evidence for each recommendation. The treatment landscape of metastatic prostate cancer is changing very rapid and many trials are ongoing. To verify the results of the future trials is necessary and should be applied to the treatment for metastatic prostate cancer patients in the clinical practice. Especially, many prostate cancer patients are old age, have multiple underlying medical comorbidities, clinicians should be aware of the significance of medical management as well as clinical efficacy of systemic treatment.
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http://dx.doi.org/10.3904/kjim.2020.213DOI Listing
February 2021

Real-World Clinical Outcomes and Prognostic Factors for Patients with Advanced Angiosarcoma who Received Systemic Treatment.

Cancer Res Treat 2021 Feb 1. Epub 2021 Feb 1.

Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.

Purpose: Angiosarcoma is a highly aggressive mesenchymal tumor. Although systemic chemotherapy is often considered for the inoperable or metastatic angiosarcoma, the outcome of such treatment is unsatisfactory and poorly delineated.

Materials And Methods: We reviewed electronic medical records of 75 patients with angiosarcoma who were treated with systemic chemotherapy for inoperable or metastatic disease. Patients were classified as having liver involvement if they had either primary or metastatic hepatic lesions.

Results: Among the patients evaluated, 51 patients were male (68%) and 24 patients (32%) had primary cutaneous angiosarcoma. Liver involvement was present in 28 patients (37.3%). A total of 59 patients received first-line weekly paclitaxel (wPac) and showed an objective response rate (ORR) of 23.7% (n=14), a median progression free survival (mPFS) of 4.0 months (95% confidence interval [CI] 3.0-6.1), and a median overall survival (mOS) of 10.2 months (95% CI 7.0-14.6). Among patients without liver involvement, patients receiving wPac (n=35) had significantly prolonged mPFS (5.8 vs. 3.2 months, respectively, p=0.014) with a tendency for prolonged mOS (13.8 vs. 11.6 months, respectively, p=0.13) than those receiving other regimens (n=12). A total of 24 patients received second- or later-line pazopanib monotherapy and showed an ORR of 16.7% (n=4), a mPFS of 2.4 months (95% CI 1.8-4.3) and a mOS of 5.4 months (95% CI 3.5-NA).

Conclusion: Treatment with first-line wPac and later-line pazopanib seems to provide survival benefit, especially for patients with advanced angiosarcoma without liver involvement.
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http://dx.doi.org/10.4143/crt.2020.1337DOI Listing
February 2021

Clinical pattern of failure after a durable response to immune check inhibitors in non-small cell lung cancer patients.

Sci Rep 2021 Jan 28;11(1):2514. Epub 2021 Jan 28.

Department of Internal Medicine, Bundang Hospital, Seoul National University College of Medicine, 82, Gumi-ro 173 beon-gil, Bundang-Gu, Seongnam, Gyeonggi-do, 13620, Republic of Korea.

Although immune checkpoint inhibitors (ICIs) can induce durable responses in non-small-cell lung cancer (NSCLC) patients, a significant proportion of responders still experience progressive disease after a period of response. Limited data are available on the clinical patterns of acquired resistance (AR) to ICIs. Clinical and radiologic data from 125 NSCLC patients treated with anti-PD-1 or PD-L1 antibodies between 2011 and 2018 at two tertiary academic institutions were retrospectively reviewed. Overall, 63 (50.4%) patients experienced AR after ICI treatment in a median of 10.7 months. Among the 13 patients with a partial response with ICI, 12 (32.4%) had only lymph node progression. Most patients (n = 52, 82.5%) had one or two sites with progression (oligo-progression). The median overall survival (OS) after progression was significantly longer in the extrathoracic group than in the thoracic and liver progression groups (30.2 months [95% confidence interval (CI), 13.4 to not reached (NR)], 11.7 months [95% CI, 9.5-21.1], and 5.4 months [95% CI, 2.6-NR], respectively, P < 0.001). Patients with oligo-progression had significantly longer OS after AR than did the multi-progression patients (18.9 months [95% CI, 10.6-NR] vs. 8.8 months [95% CI, 5.7-NR], P = 0.04). No significant difference in progression-free survival was observed between the subsequent chemotherapy and the ICI after AR groups (P = 0.723). Patients with AR after ICI treatment had a unique progression pattern with oligo-progression and high rates of progression only in the lymph nodes. Local treatment and/or continuation of ICIs beyond AR might be an effective option.
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http://dx.doi.org/10.1038/s41598-021-81666-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844257PMC
January 2021

Tumor LAG-3 and NY-ESO-1 expression predict durable clinical benefits of immune checkpoint inhibitors in advanced non-small cell lung cancer.

Thorac Cancer 2021 03 17;12(5):619-630. Epub 2021 Jan 17.

Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea.

Background: Immune checkpoint inhibitors (ICIs) are an established treatment for non-small cell lung cancer (NSCLC) that have demonstrated durable clinical benefits (DCBs). Previous studies have suggested NY-ESO-1 and LAG-3 to be surrogate markers of ICI responses in NSCLC; therefore, we explored the predictive value of their expression in NSCLC.

Methods: We retrospectively reviewed the records of 38 patients with advanced NSCLC treated with anti-PD-1 monoclonal antibodies from 2013 to 2016 at Seoul National University Hospital and Seoul National University Bundang Hospital after failed platinum-based chemotherapy. Tumor tissues from each patient were subjected to immunohistochemical analysis to determine NY-ESO-1, LAG-3, and PD-L1 expression, whose ability to predict progression-free survival (PFS) and overall survival (OS) was then analyzed alongside their positive (PPV) and negative (NPV) predictive values.

Results: NY-ESO-1 or LAG-3 expression was detected in all tumor samples from patients with high PD-L1 expression and was significantly associated with favorable outcomes, unlike PD-L1 expression. Patients with both NY-ESO-1- and LAG-3-expressing tumors had a high DCB rate and those with triple-positive PD-L1, LAG-3, and NY-ESO expression had a superior median OS and PFS than those with triple-negative expression. Furthermore, LAG-3 and NY-ESO-1 co-expression was an independent predictor of both PFS and OS, while LAG-3 displayed a good NPV.

Conclusions: Patients with NSCLC who co-express NY-ESO-1 or LAG-3 with PD-L1 exhibit greater DCBs and improved long-term survival following anti-PD-1 therapy. Moreover, NY-ESO-1 and LAG-3 could be novel predictive biomarkers of survival and should be considered in the future use of ICIs.
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http://dx.doi.org/10.1111/1759-7714.13834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919166PMC
March 2021

Discovery of acquired molecular signature on immune checkpoint inhibitors in paired tumor tissues.

Cancer Immunol Immunother 2021 Jan 3. Epub 2021 Jan 3.

Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, Republic of Korea.

Background: Immune checkpoint inhibitor (ICI) has an emerging role in several types of cancer. However, the mechanisms of acquired resistance (AR) to ICI have not been elucidated yet. To identify these mechanisms, we analyzed the pre- and post-ICI paired tumor samples in patients with AR.

Methods: Six patients with renal cell carcinoma, urothelial cell carcinoma, or head and neck cancer, who showed an initial response to ICI followed by progression and had available paired tissue samples, were retrospectively analyzed. Whole exome sequencing, RNA sequencing, and multiplex immunohistochemistry were performed on pre-treatment and resistant tumor samples.

Results: The median time to AR was 370 days (range, 210 to 739). Increased expression of alternative immune checkpoints including TIM3, LAG3, and PD-1 as well as increased CD8 tumor-infiltrating lymphocytes were observed in post-treatment tumor than in pre-treatment tumor of a renal cell carcinoma patient. In contrast, CD8 T cells and immunosuppressive markers were all decreased at AR in another patient with human papillomavirus-positive head and neck squamous cell carcinoma. This patient had an evident APOBEC-associated signature, and the tumor mutation burden increased at AR. Resistant tumor tissue of this patient harbored a missense mutation (E542K) in PIK3CA. No significant aberrations of antigen-presenting machinery or IFN-γ pathway were detected in any patient.

Conclusions: Our study findings suggest that the observed increase in immunosuppressive markers after ICI might contribute to AR. Moreover, APOBEC-mediated PIK3CA mutagenesis might be an AR mechanism. To validate these mechanisms of AR, further studies with enough sample size are required.
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http://dx.doi.org/10.1007/s00262-020-02799-yDOI Listing
January 2021

Pan-cancer methylation analysis reveals an inverse correlation of tumor immunogenicity with methylation aberrancy.

Cancer Immunol Immunother 2020 Nov 24. Epub 2020 Nov 24.

Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.

Tumor immunogenicity is driven by various genomic and transcriptomic factors but the association with the overall status of methylation aberrancy is not well established. We analyzed The Cancer Genome Atlas pan-cancer database to investigate whether the overall methylation aberrancy links to the immune evasion of tumor. We created the definitions of hypermethylation burden, hypomethylation burden and methylation burden to establish the values that represent the degree of methylation aberrancy from human methylation 450 K array data. Both hypermethylation burden and hypomethylation burden significantly correlated with global methylation level as well as methylation subtypes defined in previous literatures. Then we evaluated whether methylation burden correlates with tumor immunogenicity and found that methylation burden showed a significant negative correlation with cytolytic activity score, which represent cytotoxic T cell activity, in pan-cancer (Spearman rho = - 0.37, p < 0.001) and 30 of 33 individual cancer types. Furthermore, this correlation was independent of mutation burden and chromosomal instability in multivariate regression analysis. We validated the findings in the external cohorts and outcomes of patients who were treated with immune checkpoint inhibitors, which showed that high methylation burden group had significantly poor progression-free survival (Hazard ratio 1.74, p = 0.038). Overall, the degree of methylation aberrancy negatively correlated with tumor immunogenicity. These findings emphasize the importance of methylation aberrancy for tumors to evade immune surveillance and warrant further development of methylation biomarker.
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http://dx.doi.org/10.1007/s00262-020-02796-1DOI Listing
November 2020

Genotypic and Phenotypic Characteristics of Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome in Korean Patients.

Ann Lab Med 2021 Mar;41(2):207-213

Division of Medical Oncology, Department of Internal Medicine, Gil Medical Center, Gachon University College of Medicine, Incheon, Korea.

Background: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant cancer predisposition syndrome. HLRCC is characterized by the development of cutaneous leiomyomas, early-onset uterine leiomyomas, and HLRCC-associated renal cell cancer (RCC) and caused by germline fumarate hydratase (FH) deficiency. We investigated the genotypic and phenotypic characteristics of Korean patients with HLRCC.

Methods: We performed direct sequencing analysis of in 13 patients with suspected HLRCC and their family members. A chromosomal microarray test was performed in female patients with negative sequencing results but highly suspected HLRCC. In addition, we analyzed the clinical characteristics and evaluated the genotype-phenotype correlations in Korean patients with HLRCC.

Results: We identified six different pathogenic or likely pathogenic variants in six of the 13 patients (46.2%). The variants included two nonsense variants, two splicing variants, one frameshift variant, and one missense variant. Of the six variants, two (33.3%) were novel (c.132+1G>C, and c.243dup). RCC and early-onset uterine leiomyoma were frequently observed in families with HLRCC, while cutaneous leiomyoma was less common. No significant genotype-phenotype correlation was observed.

Conclusions: We describe the genotypic and phenotypic spectrum in a small series of Korean patients with HLRCC. Our data reveal the unique characteristics of Korean patients with HLRCC and suggest a need for establishing an optimal diagnostic approach for them.
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http://dx.doi.org/10.3343/alm.2021.41.2.207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591281PMC
March 2021

HLA-B27 association of autoimmune encephalitis induced by PD-L1 inhibitor.

Ann Clin Transl Neurol 2020 11 8;7(11):2243-2250. Epub 2020 Oct 8.

Department of Neurology, Seoul National University Hospital, Seoul, Republic of Korea.

Objective: While immune checkpoint inhibitors are increasingly used for various cancers, unpredictable immune-related adverse events (irAEs) such as autoimmune encephalitis is life-threatening. Here, we report an association between human leukocyte antigen (HLA) and atezolizumab-induced encephalitis.

Methods: From an institutional prospective cohort for encephalitis, we identified patients with autoimmune encephalitis after the use of atezolizumab, a PD-L1 (programmed death-ligand 1) inhibitor, from August 2016 to September 2019 and analyzed their HLA genotypes.

Results: A total of 290 patients received atezolizumab, and seven patients developed autoimmune encephalitis, and five of whom were enrolled for the analysis. The patients presented altered mentality, seizures, or myelitis. Three patients had the HLA-B*27:05 genotype in common (60%), which is significantly frequent given its low frequency in the general population (2.5%). After Bonferroni correction, HLA-B*27:05 was significantly associated with autoimmune encephalitis by atezolizumab (corrected P < 0.001, odds ratio 59, 95% CI = 9.0 ~ 386.9).

Interpretation: Here we found that three in five patients with autoimmune encephalitis associated with atezolizumab had the rare HLA-B*27:05 genotype. Further systematic analyses in larger cohorts are necessary to investigate the value of HLA screening to prevent the life-threatening adverse events.
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http://dx.doi.org/10.1002/acn3.51213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664281PMC
November 2020

Phase II study of durvalumab and tremelimumab in pulmonary sarcomatoid carcinoma: KCSG-LU16-07.

Thorac Cancer 2020 12 7;11(12):3482-3489. Epub 2020 Oct 7.

Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.

Background: Pulmonary sarcomatoid carcinoma (PSC) is rare with a poor outcome and is resistant to conventional cytotoxic chemotherapy. The efficacy and safety of durvalumab and tremelimumab for treating recurrent or metastatic PSCs were assessed by a nonrandomized, open-label, phase II study.

Methods: A total of 18 patients with recurrent or metastatic PSC received 1500 mg of durvalumab and 75 mg of tremelimumab every four weeks, followed by 750 mg of durvalumab every two weeks until the disease progressed, or an unacceptable toxicity level was reached. The primary endpoint was the objective response rate (ORR). The secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity. Genomic profiling of PSC by next-generation sequencing (NGS) and determination of peripheral blood lymphocyte subsets using flow cytometry were performed for exploratory analysis.

Results: A total of 15 out of 18 patients were evaluated for the analysis of the primary endpoint. At the data cutoff point, the ORR of 26.7% (95% confidence interval [CI]: 7.8-55.1) was achieved with the median follow-up duration of 12.0 months (range, 8.4-16.1). Median PFS and OS were 5.9 months (95% CI: 1.1-11.9) and 15.4 months (95% CI: 11.1-not reached), respectively. Treatment-related adverse events (AEs) of any grade were reported in 16 patients; the most common AEs were pruritus (n = 5), pneumonitis (n = 4), and rash (n = 4). Treatment was discontinued in two patients due to AEs of grade ≥ 3.

Conclusions: Durvalumab and tremelimumab demonstrated clinical benefit with a prolonged survival and manageable toxicity profile in patients with recurrent or metastatic PSC.
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http://dx.doi.org/10.1111/1759-7714.13684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7705626PMC
December 2020

Combined blockade of polo-like kinase and pan-RAF is effective against NRAS-mutant non-small cell lung cancer cells.

Cancer Lett 2020 12 23;495:135-144. Epub 2020 Sep 23.

Seoul National University Cancer Research Institute, South Korea; Department of Internal Medicine, Seoul National University Hospital, South Korea.

NRAS mutation is rarely observed in non-small cell lung cancer (NSCLC) patients, and there are no approved treatments for NRAS-mutant NSCLC. Here, we evaluated the effect of pan-RAF inhibitors on human NRAS-mutant NSCLC cell lines and performed high-throughput screening using human kinome small interfering (si)RNA or CRISPR/Cas9 libraries to identify new targets for combination NSCLC treatment. Our results indicate that human NRAS-mutant NSCLC cells are moderately sensitive to pan-RAF inhibitors. High-throughput kinome screenings further showed that G2/M arrest, particularly following knockdown of polo-like kinase 1 (PLK1), can inhibit the growth of human NRAS-mutant NSCLC cells and those treated with the type II pan-RAF inhibitor LXH254. In addition, treatment with volasertib plus LXH254, resulting in dual blockade of PLK1 and pan-RAF, was found to be more effective than LXH254 monotherapy for inhibiting long-term cell viability, suggesting that this combination therapeutic strategy may lead to promising results in the clinic.
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http://dx.doi.org/10.1016/j.canlet.2020.09.018DOI Listing
December 2020

, , and in Macrophage Response to Saturated Fatty Acids and Modified Low-Density Lipoprotein.

Korean Circ J 2021 Jan 25;51(1):68-80. Epub 2020 Aug 25.

Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.

Background And Objectives: The relationship between metabolic stress, inflammation, and cardiovascular disease is being studied steadily. The aim of this study was to evaluate the effect of palmitate (PA) and minimally modified low-density lipoprotein (mmLDL) on macrophages and to identify the associated pathways.

Methods: J774 macrophages were incubated with PA or mmLDL and lipopolysaccharide (LPS). Secretion of inflammatory chemokines and the expression of corresponding genes were determined. The phosphorylation of extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase was also assessed. RNA sequencing of macrophages was performed to identify the genes regulated by PA or mmLDL. Some of the genes regulated by the 2 agents were validated by knocking down the cells using small interfering RNA.

Results: PA or mmLDL promoted the secretion of interleukin (IL)-6 and IL-1β in LPS-stimulated macrophages, and this was accompanied by higher phosphorylation of ERK. RNA sequencing revealed dozens of genes that were regulated in this process, such as and , which were affected by PA and mmLDL, respectively. These agents also increased expression. The effect of or silencing on inflammation was modest, whereas toll-like receptor (TLR) 4 inhibition reduced a large proportion of macrophage activation.

Conclusions: We demonstrated that the proinflammatory milieu with high levels of PA or mmLDL promoted macrophage activation and the expression of associated genes such as , , and . Although the TLR4 pathway appeared to be most relevant, additional role of other genes in this process provided insights regarding the potential targets for intervention.
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http://dx.doi.org/10.4070/kcj.2020.0117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779813PMC
January 2021

Association of Insulin, Metformin, and Statin with Mortality in Breast Cancer Patients.

Cancer Res Treat 2021 Jan 23;53(1):65-76. Epub 2020 Sep 23.

Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.

Purpose: This study investigated the association of insulin, metformin, and statin use with survival and whether the association was modified by the hormone receptor status of the tumor in patients with breast cancer.

Materials And Methods: We studied 7,452 patients who had undergone surgery for breast cancer at Seoul National University Hospital from 2008 to 2015 using the nationwide claims database. Exposure was defined as a recorded prescription of each drug within 12 months before the diagnosis of breast cancer.

Results: Patients with prior insulin or statin use were more likely to be older than 50 years at diagnosis and had a higher comorbidity index than those without it (p < 0.01 for both). The hazard ratio (HR) for death with insulin use was 5.7 (p < 0.01), and the effect was attenuated with both insulin and metformin exposure with an HR of 1.2 (p=0.60). In the subgroup analyses, a heightened risk of death with insulin was further prominent with an HR of 17.9 (p < 0.01) and was offset by co-administration of metformin with an HR of 1.3 (p=0.67) in patients with estrogen receptor (ER)-negative breast cancer. Statin use was associated with increased overall mortality only in patients with ER-positive breast cancer with HR for death of 1.5 (p=0.05).

Conclusion: Insulin or statin use before the diagnosis of breast cancer was associated with an increase in all-cause mortality. Subsequent analyses suggested that metformin or statin use may have been protective in patients with ER-negative disease, which warrants further studies.
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http://dx.doi.org/10.4143/crt.2020.430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812023PMC
January 2021

Tumor immune profiles noninvasively estimated by FDG PET with deep learning correlate with immunotherapy response in lung adenocarcinoma.

Theranostics 2020 29;10(23):10838-10848. Epub 2020 Aug 29.

Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.

The clinical application of biomarkers reflecting tumor immune microenvironment is hurdled by the invasiveness of obtaining tissues despite its importance in immunotherapy. We developed a deep learning-based biomarker which noninvasively estimates a tumor immune profile with fluorodeoxyglucose positron emission tomography (FDG-PET) in lung adenocarcinoma (LUAD). A deep learning model to predict cytolytic activity score (CytAct) using semi-automatically segmented tumors on FDG-PET trained by a publicly available dataset paired with tissue RNA sequencing (n = 93). This model was validated in two independent cohorts of LUAD: SNUH (n = 43) and The Cancer Genome Atlas (TCGA) cohort (n = 16). The model was applied to the immune checkpoint blockade (ICB) cohort, which consists of patients with metastatic LUAD who underwent ICB treatment (n = 29). The predicted CytAct showed a positive correlation with CytAct of RNA sequencing in validation cohorts (Spearman rho = 0.32, 0.04 in SNUH cohort; spearman rho = 0.47, 0.07 in TCGA cohort). In ICB cohort, the higher predicted CytAct of individual lesion was associated with more decrement in tumor size after ICB treatment (Spearman rho = -0.54, 0.001). Higher minimum predicted CytAct in each patient associated with significantly prolonged progression free survival and overall survival (Hazard ratio 0.25, 0.001 and 0.18, 0.004, respectively). In patients with multiple lesions, ICB responders had significantly lower variance of predicted CytActs ( 0.005). The deep learning model that predicts CytAct using FDG-PET of LUAD was validated in independent cohorts. Our approach may be used to noninvasively assess an immune profile and predict outcomes of LUAD patients treated with ICB.
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http://dx.doi.org/10.7150/thno.50283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482798PMC
August 2020

Partitioned gradient-index phononic crystals for full phase control.

Sci Rep 2020 Sep 3;10(1):14630. Epub 2020 Sep 3.

AI Metamaterial Research Team, Korea Research Institute of Standards and Science (KRISS), 267 Gajeong-ro, Yuseong-gu, Daejeon, 34113, Republic of Korea.

Gradient-index phononic crystals (GRIN-PC), characterized by layers with spatially changing refractive indices, have recently been investigated as part of the effort to realize flat lenses in acoustic and elastic regimes. Such gradient-index lens must be inversely designed from the corresponding refractive indices in order to manipulate the target wave. Unfortunately, estimating the index of this type of lens is not straightforward and requires substantial iterative computation in general, which greatly limits the applicability of GRIN-PC to flat lenses. In this work, we propose a novel design of a GRIN-PC in which neighboring layers are separated by partitions, thus preventing waves in each layer from interacting with other layers. This partitioned GRIN-PC design enables us readily to control the phase gradient accurately at the lens' end, resulting in direct calculation of indices for target wave manipulation. A detailed methodology for partitioned GRIN-PC based collimator and Bessel-beam generator is proposed and experimentally validated to confirm the versatile use of our design in wave engineering applications.
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http://dx.doi.org/10.1038/s41598-020-71397-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471306PMC
September 2020

Temporal evolution of PD-L1 expression in patients with non-small cell lung cancer.

Korean J Intern Med 2020 Aug 13. Epub 2020 Aug 13.

Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea, Seoul, Korea.

Background/aims: PD-L1 expression, a validated predictive biomarker for anti-PD-1/PD-L1 inhibitors, is reported to change over time. This poses challenges during clinical application in non-small cell lung cancer.

Methods: This study included patients with non-small cell lung cancer who underwent surgery or biopsy and evaluation of PD-L1 expression in tumor cells via immunohistochemistry more than twice. We set the threshold of PD-L1 positivity to 10% and categorized patients into four groups according to changes in PD-L1 expression. Clinicopathologic information was collected from medical records. Statistical analyses, including Fisher's exact test and log-rank test, were performed.

Results: Of 109 patients, 38 (34.9%) and 45 (41.3%) had PD-L1 positivity in archival and recent samples, respectively. PD-L1 status was maintained in 78 (71.6%) patients, but changed in 31 (28.4%), with 19 (17.4%) from negative to positive. There were no significant differences in characteristics between patients who maintained PD-L1 negativity and whose PD-L1 status changed from negative to positive. Patients harboring PD-L1 positivity in either archival or recent samples achieved better responses (p=0.129) and showed longer overall survival than those who maintained PD-L1 negativity when they received immune checkpoint inhibitors after platinum failure (median overall survival 14.4 versus 4.93 months; hazard ratio 0.43 [95% confidence interval, 0.20-0.93]).

Conclusions: PD-L1 status changed in about one-fourth of patients. PD-L1 positivity in either archival or recent samples was predictive of better responses to immune checkpoint inhibitors. Therefore, archival samples could be used for assessment of PD-L1 status. The need for new biopsies should be decided individually.
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http://dx.doi.org/10.3904/kjim.2020.178DOI Listing
August 2020

Thermal Annealing of Molecular Layer-Deposited Indicone Toward Area-Selective Atomic Layer Deposition.

ACS Appl Mater Interfaces 2020 Sep 14;12(38):43212-43221. Epub 2020 Sep 14.

Division of Materials Science and Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 04763, Republic of Korea.

Area-selective atomic layer deposition (AS-ALD) is a promising technique for fine nanoscale patterning, which may overcome the drawbacks of conventional top-down approaches for the fabrication of future electronic devices. However, conventional materials and processes often employed for AS-ALD are inadequate for conformal and rapid processing. We introduce a new strategy for AS-ALD based on molecular layer deposition (MLD) that is compatible with large-scale manufacturing. Conformal thin films of "indicone" (indium alkoxide polymer) are fabricated by MLD using INCA-1 (bis(trimethylsily)amidodiethylindium) and HQ (hydroquinone). Then, the MLD indicone films are annealed by a thermal heat treatment under vacuum. The properties of the indicone thin films with different annealing temperatures were measured with multiple optical, physical, and chemical techniques. Interestingly, a nearly complete removal of indium from the film was observed upon annealing to ca. 450 °C and above. The chemical mechanism of the thermal transformation of the indicone film was investigated by density functional theory calculations. Then, the annealed indicone thin films were applied as an inhibiting layer for the subsequent ALD of ZnO, where the deposition of approximately 20 ALD cycles (equivalent to a thickness of approximately 4 nm) of ZnO was successfully inhibited. Finally, patterns of annealed MLD indicone/Si substrates were created on which the area-selective deposition of ZnO was demonstrated.
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http://dx.doi.org/10.1021/acsami.0c10322DOI Listing
September 2020

Anti-tumor effects of NK cells and anti-PD-L1 antibody with antibody-dependent cellular cytotoxicity in PD-L1-positive cancer cell lines.

J Immunother Cancer 2020 08;8(2)

Cancer Research Institute, Seoul National University, Seoul, Republic of Korea.

Background: Although programmed cell death-1/programmed death-ligand 1 (PD-L1) inhibitors show remarkable antitumor activity, a large portion of patients with cancer, even those with high PD-L1-expressing tumors, do not respond to their effects. Most PD-L1 inhibitors contain modified fragment crystallizable region (Fc) receptor binding sites to prevent antibody-dependent cellular cytotoxicity (ADCC) against PD-L1-expressing non-tumor cells. However, natural killer (NK) cells have specific antitumor activity in the presence of tumor-targeting antibody through ADCC, which could enhance NK cell-induced cytotoxicity. We evaluated the antitumor efficacy of ADCC via anti-PD-L1 monoclonal antibodies (mAbs) and NK cells against several PD-L1-positive cancer cell lines.

Methods: Various cancer cell lines were used as target cell lines. Surface PD-L1 expression was analyzed by flow cytometry. IMC-001 and anti-hPD-L1-hIgG1 were tested as anti-PD-L1 mAbs with ADCC and atezolizumab as an anti-PD-L1 mAb without ADCC. NK cell cytotoxicity was measured by Cr-release assay and CD107a degranulation assay. Also, live cell imaging was performed to evaluate cytotoxicity in a single-cell level. NK-92-CD16 (CD16-transduced NK-92 cell line) and peripheral blood mononuclear cells from healthy donors, respectively, were used as an effector cell. FcγRIIIa (CD16a)-V158F genotyping was performed for healthy donors.

Results: We demonstrated that the cytotoxicity of NK-92-CD16 cells toward PD-L1-positive cancer cell lines was significantly enhanced in the presence of anti-PD-L1 mAb with ADCC. We also noted a significant increase in primary human NK cell cytotoxicity against PD-L1-positive human cancer cells when cocultured with anti-PD-L1 mAb with ADCC. Moreover, NK cells expressing a high-affinity genotype displayed higher anti-PD-L1 mAb-mediated ADCC lysis of tumor cells than donors with a low-affinity genotype.

Conclusion: These results suggest that NK cells induce an ADCC response in combination with anti-PD-L1 mAbs, which helps promote ADCC antitumor activity against PD-L1-positive tumors. This study provides support for NK cell immunotherapy against high PD-L1-expressing tumors in combination with ADCC through anti-PD-L1 mAbs.
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http://dx.doi.org/10.1136/jitc-2020-000873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445348PMC
August 2020

A newly developed capture-based sequencing panel for genomic assay of lung cancer.

Genes Genomics 2020 07 24;42(7):751-759. Epub 2020 May 24.

Genomic Medicine Institute, Medical Research Center, Seoul National University, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.

Background: The increase in genetic alterations targeted by specific chemotherapy in lung cancer has led to the need for universal use of more comprehensive genetic testing, which has highlighted the development of a lung cancer diagnostic panel using next-generation sequencing.

Objective: We developed a hybridization capture-based massively parallel sequencing assay named Friendly, Integrated, Research-based, Smart and Trustworthy (FIRST)-lung cancer panel (LCP), and evaluated its performance.

Methods: FIRST-LCP comprises 64 lung cancer-related genes to test for various kinds of genetic alterations including single nucleotide variations (SNVs), insertions and deletions (indels), copy number variations (CNVs), and structural variations. To assess the performance of FIRST-LCP, we compiled test sets using HapMap samples or tumor cell lines with disclosed genetic information, and also tested our clinical lung cancer samples whose genetic alterations were known by conventional methods.

Results: FIRST-LCP accomplished high sensitivity (99.4%) and specificity (100%) of the detection of SNVs. High precision was also achieved, with intra- or inter-run concordance rate of 0.99, respectively. FIRST-LCP detected indels and CNVs close to the expected allele frequency and magnitude, respectively. Tests with samples from lung cancer patients also identified all SNVs, indels and fusions.

Conclusion: Based on the current state of the art, continuous application of the panel design and analysis pipeline following up-to-date knowledge could ensure precision medicine for lung cancer patients.
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http://dx.doi.org/10.1007/s13258-020-00949-1DOI Listing
July 2020

Prediction of pathologic complete response using image-guided biopsy after neoadjuvant chemotherapy in breast cancer patients selected based on MRI findings: a prospective feasibility trial.

Breast Cancer Res Treat 2020 Jul 16;182(1):97-105. Epub 2020 May 16.

Department of Surgery, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.

Purpose: Accurate prediction of pathologic complete response (pCR) in breast cancer using magnetic resonance imaging (MRI) and ultrasound (US)-guided biopsy may aid in selecting patients who forego surgery for breast cancer. We evaluated the accuracy of US-guided biopsy aided by MRI in predicting pCR in the breast after neoadjuvant chemotherapy (NAC).

Methods: After completion of NAC, 40 patients with near pCR (either tumor size ≤ 0.5 cm or lesion-to-background signal enhancement ratio (L-to-B SER) ≤ 1.6 on MRI) and no diffused residual microcalcifications were prospectively enrolled at a single institution. US-guided multiple core needle biopsy (CNB) or vacuum-assisted biopsy (VAB) of the tumor bed, followed by standard surgical excision, was performed. Matched biopsy and surgical specimens were compared to assess pCR. The negative predictive value (NPV), accuracy, and false-negative rate (FNR) were analyzed.

Results: pCR was confirmed in 27 (67.5%) surgical specimens. Preoperative biopsy had an NPV, accuracy, and FNR of 87.1%, 90.0%, and 30.8%, respectively. NPV for hormone receptor-negative and hormone receptor-positive tumors were 83.3% and 100%, respectively. Obtaining at least 5 biopsy cores based on tumor size ≤ 0.5 cm and an L-to-B SER of ≤ 1.6 on MRI (27 patients) resulted in 100% NPV and accuracy. No differences in accuracy were noted between CNB and VAB (90% vs. 90%).

Conclusions: Investigation using stringent MRI criteria and ultrasound-guided biopsy could accurately predict patients with pCR after NAC. A larger prospective clinical trial evaluating the clinical safety of breast surgery omission after NAC in selected patients will be conducted based on these findings.
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http://dx.doi.org/10.1007/s10549-020-05678-3DOI Listing
July 2020

Near-field sub-diffraction photolithography with an elastomeric photomask.

Nat Commun 2020 Feb 10;11(1):805. Epub 2020 Feb 10.

Department of Materials Science and Engineering, Yonsei University, Seoul, 120-749, Republic of Korea.

Photolithography is the prevalent microfabrication technology. It needs to meet resolution and yield demands at a cost that makes it economically viable. However, conventional far-field photolithography has reached the diffraction limit, which imposes complex optics and short-wavelength beam source to achieve high resolution at the expense of cost efficiency. Here, we present a cost-effective near-field optical printing approach that uses metal patterns embedded in a flexible elastomer photomask with mechanical robustness. This technique generates sub-diffraction patterns that are smaller than 1/10 of the wavelength of the incoming light. It can be integrated into existing hardware and standard mercury lamp, and used for a variety of surfaces, such as curved, rough and defect surfaces. This method offers a higher resolution than common light-based printing systems, while enabling parallel-writing. We anticipate that it will be widely used in academic and industrial productions.
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http://dx.doi.org/10.1038/s41467-020-14439-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010681PMC
February 2020

Novel Associations between Related Proteins and Cellular Effects of High-Density Lipoprotein.

Korean Circ J 2020 Mar 6;50(3):236-247. Epub 2019 Nov 6.

Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Korea.

Background And Objectives: Recent studies have examined the structure-function relationship of high-density lipoprotein (HDL). This study aimed to identify and rank HDL-associated proteins involved in several biological function of HDL.

Methods: HDLs isolated from 48 participants were analyzed. Cholesterol efflux capacity, effect of HDL on nitric oxide production, and vascular cell adhesion molecule-1 expression were assessed. The relative abundance of identified proteins in the highest vs. lowest quartile was expressed using the normalized spectral abundance factor ratio.

Results: After adjustment by multiple testing, six proteins, thyroxine-binding globulin, alpha-1B-glycoprotein, plasma serine protease inhibitor, vitronectin, angiotensinogen, and serum amyloid A-4, were more abundant (relative abundance ratio ≥2) in HDLs with the highest cholesterol efflux capacity. In contrast, three proteins, complement C4-A, alpha-2-macroglobulin, and immunoglobulin mu chain C region, were less abundant (relative abundance ratio <0.5). In terms of nitric oxide production and vascular cell adhesion molecule-1 expression, no proteins showed abundance ratios ≥2 or <0.5 after adjustment. Proteins correlated with the functional parameters of HDL belonged to diverse biological categories.

Conclusions: In summary, this study ranked proteins showing higher or lower abundance in HDLs with high functional capacities and newly identified multiple proteins linked to cholesterol efflux capacity.
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http://dx.doi.org/10.4070/kcj.2019.0195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7043958PMC
March 2020

Clinical Application of Next-Generation Sequencing-Based Panel to Wild-Type Advanced Melanoma Identifies Key Oncogenic Alterations and Therapeutic Strategies.

Mol Cancer Ther 2020 03 11;19(3):937-944. Epub 2019 Dec 11.

Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.

Molecular profiling with next-generation sequencing (NGS) has been applied in multiple solid cancers to discover potential therapeutic targets. Here, we describe the results of a clinical NGS panel in patients with advanced melanoma. Thirty-six tumor tissues from patients with wild-type melanoma at Seoul National University Hospital (SNUH; Seoul, Republic of Korea) were collected and deep-sequenced using the SNUH FIRST-Cancer NGS panel to assess single-nucleotide variants, small insertions/deletions, copy number variations, and structural variations to estimate tumor mutation burden (TMB). We discovered 106 oncogenic alterations and most of the patients ( = 33, 92%) harbored at least one oncogenic alteration, including 2 patients who were initially diagnosed as BRAF V600E-negative but were later confirmed to be positive. Altogether, 36 samples were classified into //-mutant ( = 14, 39%) or triple wild-type ( = 22, 61%) melanoma subtypes. The estimated median TMB was 8.2 mutations per Mb, ranging from 0 to 146.67 mutations per Mb. Of the 36 patients, 25 (70%) had actionable alterations with currently developed drugs, and 7 (19.4%) were enrolled in clinical trials with an RAF inhibitor, multiple receptor tyrosine kinase inhibitor, and anti-programmed cell death-1 (PD-1) antibody. TMB tended to associate with progression-free survival (PFS) of treatment with anti-PD-1/PDL-1 antibody (HR, 0.96; 95% confidence interval, 0.92-1.00; = 0.07). High-TMB (≥13) group was associated with longer PFS than the low-TMB group (median 34.0 vs. 11.0 weeks, = 0.04). Overall, the clinical use of a NGS panel in patients with advanced melanoma shows association with clinical outcomes and several therapeutic strategies.
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http://dx.doi.org/10.1158/1535-7163.MCT-19-0457DOI Listing
March 2020

Closely Packed Polypyrroles via Ionic Cross-Linking: Correlation of Molecular Structure-Morphology-Thermoelectric Properties.

ACS Appl Mater Interfaces 2020 Jan 26;12(1):1110-1119. Epub 2019 Dec 26.

Department of Chemistry, College of Science , Korea University , Seoul 02841 , Republic of Korea.

A series of ionically interconnected polypyrrole (PPy) films are fabricated through two-monomer-connected-precursor polymerization by varying diacid linkers, thereby significantly influencing the crystalline morphology and electrical properties. The structure obtained using 1,5-napthalenedisulfonic acid (PPy-Nap) as a fused aromatic linker exhibits a higher electrical conductivity (∼78 S cm) than that (6.7 S cm) without a linker (PPy-ref). Cryogenic conductivity measurements reveal that the percolation carrier transport barrier of PPy-Nap is significantly smaller than that of PPy-ref, and the calculated carrier mobility of PPy-Nap is ∼5 times higher compared to PPy-ref. The carrier transport characteristics show a good agreement with morphological data by 2D grazing-incidence X-ray scattering. All PPys have similar doped charge carrier concentrations and, thus, similar Seebeck coefficients (5-8 μV K) but very different electrical conductivities. Consequently, PPy-Nap exhibits a higher power factor than that of PPy-ref (0.21 vs 0.043 μW m K). The results show that the trade-off relationship between the Seebeck coefficient and electrical conductivity can be overcome by improving crystalline morphology and carrier transport. Thus, both the electrical conductivities and thermoelectric power factors can be improved with maintaining the Seebeck coefficients by enhancing the ordered conductive domains and carrier mobility while maintaining the doping level.
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http://dx.doi.org/10.1021/acsami.9b17009DOI Listing
January 2020

Clinical insights on outcomes of corticosteroid administration in immune checkpoint inhibitor-induced pneumonitis by retrospective case series analysis.

ESMO Open 2019 28;4(6):e000575. Epub 2019 Nov 28.

Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.

Background: For the management of immune checkpoint inhibitor (ICI)-induced pneumonitis (ICI-pneumonitis), discontinuation of ICIs and high dose corticosteroid based on grade are generally recommended. The purpose of this study is to describe management and outcome of ICI-pneumonitis and explore what to consider when managing ICI-pneumonitis with or without corticosteroids in addition to grade.

Methods: We reviewed data of 706 cancer patients who were treated with ICIs and identified radiographically proven pneumonitis. The diagnosis of ICI-pneumonitis was established after excluding alternative aetiologies either by a bronchoscopy or a thorough examination of clinical features. The evaluation of the management and outcome of pneumonitis were evaluated according to the time of corticosteroid administration.

Results: ICI-pneumonitis developed in 16 patients (2.3%); nine grade 1, four grade 2 and three grade 3. Initially, 10 patients were spared from corticosteroid administration; fourpatients eventually received corticosteroid after 4 weeks of pneumonitis diagnosis due to clinical, radiographical aggravation and/or clinicians' decision. The other sixpatients never received corticosteroid and improved or remained stable radiographically. When the four and sixpatients were compared, pneumonitis grade was similar, while the latter sixpatients had a later onset from initiation of ICIs (mean 37.48 weeksvs25.45 weeks), more prior lines of chemotherapy (median 2.5 vs 1.0 lines), higher proportion of current/ex-smokers (83.3% vs 50.0%), and fewer other accompanying immune-related adverse events (50% vs 75%). Time to improvement of pneumonitis was similar between the fourpatients who received delayed corticosteroid and fivepatients who received corticosteroid within 4 weeks(3.6 vs 2.5 weeks).

Conclusions: Our analyses provide clinical insights that stratification of the patients is important in managing ICI-pneumonitis. Along with ICI-pneumonitis grade, more factors associated with the outcome need to be unravelled in the future.
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http://dx.doi.org/10.1136/esmoopen-2019-000575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6890388PMC
June 2020

Programmed cell death ligand-1-mediated enhancement of hexokinase 2 expression is inversely related to T-cell effector gene expression in non-small-cell lung cancer.

J Exp Clin Cancer Res 2019 Nov 12;38(1):462. Epub 2019 Nov 12.

Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.

Background: We investigated the role of PD-L1 in the metabolic reprogramming of non-small cell lung cancer (NSCLC).

Methods: Changes in glycolysis-related molecules and glycolytic activity were evaluated in PD-L1 and PD-L1 NSCLC cells after transfection or knockdown of PD-L1, respectively. Jurkat T-cell activation was assessed after co-culture with NSCLC cells. The association between PD-L1 and immune response-related molecules or glycolysis were analyzed in patients with NSCLC and The Cancer Genome Atlas (TCGA).

Results: Transfecting PD-L1 in PD-L1 cells enhanced hexokinase-2 (HK2) expression, lactate production, and extracellular acidification rates, but minimally altered GLUT1 and PKM2 expression and oxygen consumption rates. By contrast, knocking-down PD-L1 in PD-L1 cells decreased HK2 expression and glycolysis by suppressing PI3K/Akt and Erk pathways. Interferon-γ (IFNγ) secretion and activation marker expression was decreased in stimulated Jurkat T-cells when co-cultured with HK2-overexpressing vector-transfected tumor cells rather than empty vector-transfected tumor cells. Immunohistochemistry revealed that PD-L1 expression was positively correlated with HK2 expression in NSCLC (p < 0.001). In TCGA, HK2 exhibited a positive linear association with CD274 (PD-L1) expression (p < 0.001) but an inverse correlation with the expression of CD4, CD8A, and T-cell effector function-related genes in the CD274 rather than CD274 group. Consistently, there were fewer CD8 T-cells in PD-L1/HK2 tumors compared to PD-L1/HK2 tumors in squamous cell carcinoma.

Conclusions: PD-L1 enhances glycolysis in NSCLC by upregulating HK2, which might dampen anti-tumor immunity. PD-L1 may contribute to NSCLC oncogenesis by inducing metabolic reprogramming and immune checkpoint.
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http://dx.doi.org/10.1186/s13046-019-1407-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6852926PMC
November 2019

Immunogenicity of Influenza Vaccination in Patients with Cancer Receiving Immune Checkpoint Inhibitors.

Clin Infect Dis 2020 07;71(2):422-425

Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.

Among prospectively enrolled adult patients with cancer receiving immune checkpoint inhibitors (ICIs; n = 46) or cytotoxic agents (n = 90), seroprotection and seroconversion rates after seasonal quadrivalent influenza vaccinations were higher with ICI than with cytotoxic chemotherapy. These results support annual influenza vaccinations for cancer patients receiving ICIs. Clinical Trials Registration clinicaltrials.gov (NCT03590808).
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http://dx.doi.org/10.1093/cid/ciz1092DOI Listing
July 2020

Development of a Nomogram to Predict the Recurrence Score of 21-Gene Prediction Assay in Hormone Receptor-Positive Early Breast Cancer.

Clin Breast Cancer 2020 04 21;20(2):98-107.e1. Epub 2019 Aug 21.

Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.

Introduction: A 21-gene prediction assay (Oncotype DX) is helpful to estimate benefit from adjuvant chemotherapy in patients with hormone receptor-positive, lymph node-negative early breast cancer. This study was conducted to develop a model to estimate high recurrence score (RS) using easily available clinicopathologic parameters in limited-resource countries.

Patients And Methods: Hormone receptor-positive, lymph node-negative early breast cancer patients who underwent Oncotype DX were enrolled onto the training set (n = 192). The risk category range of the RS was the same as in the TAILORx study. The multivariable logistic regression model was used to identify significant variables associated with high RS. The independent validation set (n = 264) was established from patients of a different time period.

Results: The median age in the training set was 47 years, and 78.0% were premenopausal. The number of patients with low RS (< 11), intermediate RS (11-25), and high RS (> 25) were 42 (22.0%), 122 (63.9%), and 27 (14.1%), respectively. High nuclear grade, no progesterone receptor expression, and high Ki-67 were associated with high RS, and these variables were used to construct the nomogram. It had significant discriminatory power in internal validation (area under the curve = 0.856) and in the validation set (area under the curve = 0.828). The calibration plot showed optimal agreement between predicted and actual probabilities in both sets.

Conclusion: A nomogram was successfully developed with 3 simple parameters. The probability of high RS can be easily and conveniently estimated using our nomogram. It might be useful to determine whether or not Oncotype DX is conducted in the TAILORx era. Future large-scale prospective studies are warranted.
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http://dx.doi.org/10.1016/j.clbc.2019.07.010DOI Listing
April 2020