Publications by authors named "Dae Seog Heo"

335 Publications

Analysis of Cancer Patient Decision-making and Health Service Utilization after Enforcement of the Life-Sustaining Treatment Decision-Making Act in Korea.

Cancer Res Treat 2021 Apr 12. Epub 2021 Apr 12.

Department of Pulmonary and Critical Care Medicine Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Purpose: This study aimed to confirm the decision-making patterns for life-sustaining treatment and analyze medical service utilization changes after enforcement of the Life-Sustaining Treatment Decision-Making Act.

Materials And Methods: Of 1,237 patients who completed legal forms for life-sustaining treatment (hereafter called the life-sustaining treatment [LST] form) at three academic hospitals and died at the same institutions, 1,018 cancer patients were included. Medical service utilization and costs were analyzed using claims data.

Results: The median time to death from completion of the LST form was three days (range, 0 to 248 days). Of these, 517 people died within two days of completing the document, and 36.1% of all patients prepared the LST form themselves. The frequency of use of the intensive care unit, continuous renal replacement therapy, and mechanical ventilation was significantly higher when the families filled out the form without knowing the patient's intention. In the top 10% of the medical expense groups, the decision-makers for LST were family members rather than patients (28% patients vs. 32% family members who knew and 40% family members who did not know the patient's intention).

Conclusion: The cancer patient's own decision-making rather than the family's decision was associated with earlier decision-making, less use of some critical treatments (except chemotherapy) and expensive evaluations, and a trend toward lower medical costs.
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http://dx.doi.org/10.4143/crt.2021.131DOI Listing
April 2021

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

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

Long-Term Outcomes and Sequelae Analysis of Intracranial Germinoma: Need to Reduce the Extended-Field Radiotherapy Volume and Dose to Minimize Late Sequelae.

Cancer Res Treat 2021 Jan 13. Epub 2021 Jan 13.

Department of Radiation Oncology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.

Purpose: We aimed to refine the radiotherapy (RT) volume and dose for intracranial germinoma considering recurrences and long-term toxicities.

Materials And Methods: Total 189 patients with intracranial germinoma were treated with RT alone (n=50) and RT with upfront chemotherapy (CRT) (n=139). All cases were confirmed histologically. RT fields comprised the extended-field and involved-field only for primary site. The extended-field, including craniospinal, whole-brain (WB), and whole-ventricle (WV) for cranial field, is followed by involved-field boost. The median follow-up duration was 115 months.

Results: The relapses developed in 13 patients (6.9%). For the extended-field, cranial RT dose down to 18 Gy exhibited no cranial recurrence in 34 patients. In CRT, 74 patients (56.5%) showed complete response to chemotherapy and no involved-field recurrence with low-dose RT of 30 Gy. WV RT with chemotherapy for the basal ganglia or thalamus germinoma showed no recurrence. Secondary malignancy developed in ten patients (5.3 %) with a latency of 20 years (range, 4-26) and caused mortalities in six. WB or craniospinal field rather than WV or involved-field significantly increased the rate of hormone deficiencies, and secondary malignancy. RT dose for extended-field correlated significantly with the rate of hormone deficiencies, secondary malignancy, and neurocognitive dysfunction.

Conclusion: Reduced dose and volume of extended-field rather than total dose or involved-field will be critical to decrease the late toxicities. Upfront chemotherapy could be beneficial for the patients with complete response to minimize the RT dose down to 30 Gy. Prospective trials focused on de-intensification of the extended-field RT are warranted.
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http://dx.doi.org/10.4143/crt.2020.1052DOI Listing
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

Treatment strategy for papillary renal cell carcinoma type 2: a case series of seven patients treated based on next generation sequencing data.

Ann Transl Med 2020 Nov;8(21):1389

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

Background: Papillary renal cell carcinoma type 2 (PRCC2) is refractory to systemic treatment and has a dismal prognosis. Previous studies showed that genetic alterations in PRCC2 were heterogeneous regardless of germline or somatic mutations. In this study, we aimed to perform precision treatment of PRCC2 based on genetic information.

Methods: We performed exome and genome sequencing of tumor tissues and matched normal samples. Based on sequencing data, we treated patients with metastatic PRCC2 using precision oncology.

Results: Four patients underwent curative surgery of PRCC2 and three patients had metastatic PRCC2. All PRCC2 heterogeneously harbored own driver mutations. Two out of the three patients with metastatic disease had fumarate hydratase () germline mutations. One patient with a germline mutation was diagnosed with hereditary leiomyomatosis RCC. He was treated with bevacizumab and erlotinib combination and showed a durable response. The other metastatic PRCC2 patient harboring a germline mutation had an additional somatic mutation and was durably controlled with pazopanib. Other metastatic PRCC2 patient with somatic and mutations had over 5 years of overall survival with axitinib treatment.

Conclusions: We performed precision systemic treatment based on genetic information. Genome sequencing could help identify candidates for targeted therapy in PRCC2, a genetically heterogeneous disease.
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http://dx.doi.org/10.21037/atm-20-3466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723617PMC
November 2020

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

Difficulties Doctors Experience during Life-Sustaining Treatment Discussion after Enactment of the Life-Sustaining Treatment Decisions Act: A Cross-Sectional Study.

Cancer Res Treat 2021 Apr 19;53(2):584-592. Epub 2020 Nov 19.

Center for Palliative Care and Clinical Ethics, Seoul National University Hospital, Seoul, Korea.

Purpose: This study aimed to investigate difficulties doctors experience during life-sustaining treatment (LST) discussion with seriously ill patients and their families after enactment of the LST Decisions Act in February 2018.

Materials And Methods: A cross-sectional survey was conducted in a tertiary hospital in the Republic of Korea in August 2019. Six hundred eighty-six doctors who care for seriously ill patients were given a structured questionnaire, and difficulties during the discussion were examined.

Results: One hundred thirty-two doctors completed the questionnaire. Eighty-five percent answered they treat cancer patients. Most (86.4%) experienced considerable difficulties during LST discussions (mean score, 7.4±1.6/10). The two most common difficulties were communication with patients and family and determining when to discuss LST. Two-thirds of doctors found direct discussions with the patient difficult and said they would initiate LST discussions only with family. LST discussions were actually initiated later than considered appropriate. When medically assessing whether the patient is imminently dying, 56% of doctors experienced disagreements with other doctors, which could affect their decisions.

Conclusion: This study found that most doctors experienced serious difficulties regarding communication with patients and family and medical assessment of dying process during LST discussions. To alleviate these difficulties, further institutional support is needed to improve the LST discussion between doctors, patients, and family.
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http://dx.doi.org/10.4143/crt.2020.735DOI Listing
April 2021

Immunophenotypic Landscape and Prognosis of Diffuse Large B-Cell Lymphoma with MYC/BCL2 Double Expression: An Analysis of A Prospectively Immunoprofiled Cohort.

Cancers (Basel) 2020 Nov 9;12(11). Epub 2020 Nov 9.

Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 03080, Korea.

Diffuse large B-cell lymphoma (DLBCL) patients with MYC/BCL2 double expression (DE) show poor prognosis and their clinical outcomes after R-CHOP therapy vary immensely. We investigated the prognostic value of DE in aggressive B-cell lymphoma patients ( = 461), including those with DLBCL ( = 417) and high-grade B-cell lymphoma (HGBL; = 44), in a prospectively immunoprofiled cohort. DE was observed in 27.8% of DLBCLs and 43.2% of HGBLs ( = 0.058). DE-DLBCL patients were older ( = 0.040) and more frequently exhibited elevated serum LDH levels ( = 0.002), higher international prognostic index (IPI; = 0.042), non-germinal-center B-cell phenotype ( < 0.001), and poor response to therapy ( = 0.042) compared to non-DE-DLBCL patients. In R-CHOP-treated DLBCL patients, DE status predicted poor PFS and OS independently of IPI ( < 0.001 for both). Additionally, in DE-DLBCL patients, older age (>60 years; = 0.017), involvement of ³2 extranodal sites ( = 0.021), bone marrow involvement ( = 0.001), high IPI ( = 0.017), CD10 expression ( = 0.006), poor performance status ( = 0.028), and elevated LDH levels ( < 0.001) were significantly associated with poor OS. Notably, DE-DLBCL patients with normal LDH levels exhibited similar PFS and OS to those of patients with non-DE-DLBCL. Our findings suggest that MYC/BCL2 DE predicts poor prognosis in DLBCL. Risk stratification of DE-DLBCL patients based on LDH levels may guide clinical decision-making for DE-DLBCL patients.
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http://dx.doi.org/10.3390/cancers12113305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697982PMC
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

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

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

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

Efficacy of cyclophosphamide, doxorubicin, and cisplatin for adenoid cystic carcinoma, and their relationship with the pre-chemotherapy tumor growth rate.

Chin Clin Oncol 2020 Apr;9(2):15

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

Background: While surgical resection is the treatment of choice for adenoid cystic carcinoma (ACC), patients with metastasis and those who cannot undergo surgery receive palliative chemotherapy. However, the role of palliative chemotherapy is not clear yet. This study aimed to evaluate the efficacy of chemotherapy with cyclophosphamide, doxorubicin, and cisplatin (CAP) for patients with ACC; and to analyze the relationship between the pre-chemotherapy tumor growth rate (P-TGR) and treatment outcomes in patients with the recurred metastatic unresectable ACC.

Methods: We retrospectively analyzed the clinical data and treatment outcomes of patients who diagnosed ACC and treated with CAP chemotherapy. Response evaluation was performed using computed tomography (CT) images obtained before and after chemotherapy according to the RECIST 1.1. P-TGR was defined as the difference of the sum of the largest diameter of the target lesion per unit of time between the pre-baseline and baseline CT images.

Results: Fourteen patients with ACC who were treated with CAP were enrolled. Median patient age was 49 years, and the patients received a median of 5 CAP treatment cycles. Two patients achieved partial response (PR) and 10 patients showed stable disease. Response rate was 14.3%, and the disease control rate was 85.7%. Median progression-free survival was 5.7 months (95% CI: 4.3 to not reached) and the median overall survival was 23.4 months (95% CI: 12.9 to not reached). A low P-TGR was associated with a good response to CAP (correlation coefficient, 0.56).

Conclusions: Palliative CAP chemotherapy demonstrated a modest anti-cancer effect for ACC. A low P-TGR was associated with a good response to CAP chemotherapy.
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http://dx.doi.org/10.21037/cco.2020.03.07DOI Listing
April 2020

Failure patterns of cervical lymph nodes in metastases of unknown origin according to target volume.

Radiat Oncol J 2020 Mar 30;38(1):18-25. Epub 2020 Mar 30.

Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea.

Purpose: This study was aim to evaluate the patterns of failure according to radiotherapy (RT) target volume for cervical lymph nodes in metastases of unknown primary origin in head and neck region (HNMUO).

Materials And Methods: Sixty-two patients with HNMUO between 1998 and 2016 were retrospectively reviewed. We analyzed the clinical outcomes and primary site failure depending on the radiation target volume. The target volume was classified according to whether the potential head and neck mucosal sites were included and whether the neck node was treated involved side only or bilaterally.

Results: Potential mucosal site RT (mucosal RT) was done to 23 patients and 39 patients did not receive mucosal RT. Mucosal RT showed no significant effect on overall survival (OS) and locoregional recurrence (LRR). The location of primary site failure encountered during follow-up period was found to be unpredictable and 75% of patients with recurrence received successful salvage therapies. No significant differences in OS and LRR were found between patients treated to unilateral (n = 35) and bilateral neck irradiation (n = 21). Treatment of both necks resulted in significantly higher mucositis.

Conclusions: We found no advantages in OS and LRR of patients with HNMUO when mucosal sites and bilateral neck node were included in the radiation target volume.
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http://dx.doi.org/10.3857/roj.2020.00108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113154PMC
March 2020

Role of concurrent chemoradiation on locally advanced unresectable adenoid cystic carcinoma.

Korean J Intern Med 2021 01 30;36(1):175-181. Epub 2020 Mar 30.

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

Background/aims: Adenoid cystic carcinoma (ACC) is a rare salivary gland tumor characterized by indolence, with a high rate of local recurrence and distant metastasis. This study aimed to investigate the effect of concurrent chemoradiation (CCRT) on locally advanced unresectable ACC.

Methods: We retrospectively analyzed clinical data from 10 patients with pathologically confirmed ACC of the head and neck who received CCRT with cisplatin in Seoul National University Hospital between 2013 and 2018.

Results: Ten patients with unresectable disease at the time of diagnosis or with positive margins after surgical resection received CCRT with weekly cisplatin. Eight patients (80%) achieved complete remission, of which three later developed distant metastases without local relapse; one patient developed distant metastasis and local relapse. Two patient achieved partial remission without progression. Patients experienced several toxicities, including dry mouth, radiation dermatitis, nausea, and salivary gland inflammation of mostly grade 1 to 2. Only one patient showed grade 3 oral mucositis. Median relapse-free survival was 34.5 months (95% confidence interval, 22.8 months to not reached).

Conclusion: CCRT with cisplatin is effective for local control of ACC with manageable toxicity and may be an effective treatment option for locally advanced unresectable ACC.
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http://dx.doi.org/10.3904/kjim.2019.104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820661PMC
January 2021

Implication of the Life-Sustaining Treatment Decisions Act on End-of-Life Care for Korean Terminal Patients.

Cancer Res Treat 2020 07 23;52(3):917-924. Epub 2020 Mar 23.

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

Purpose: Life-sustaining treatment (LST) decisions for patients and caregivers at the end-of-life (EOL) process are supported by the "Act on Hospice and Palliative Care and Decisions on LST for Patients at the EOL," enforced in February 2018. It remains unclear whether the act changes EOL decisions and LST implementation in clinical practice. For this study, we investigated patients' decision-making regarding LSTs during the EOL process since the act's enforcement.

Materials And Methods: Retrospective reviews were conducted on adult patients who were able to decide to terminate LST and died at Seoul National University Hospital between February 5, 2018, and February 5, 2019. We examined demographics, who made the decisions, the type and date of documentation confirming patient's LST, and whether the LST was withheld or withdrawn.

Results: Of 809 patients who were enrolled, 29% (n=231) completed forms regarding LST themselves, and 71% (n=578) needed family members to decide. The median time from confirmation of the EOL process to death and from the Advance Statement to death were 2 and 5 days, respectively (both ranges, 0 to 244). In total, 90% (n=727) of patients withheld treatment, and 10% (n=82)withdrew it. We found a higher withdrawal rate when family members made the decisions (13.3% vs. 1.7%, p < 0.001).

Conclusion: After the act's enforcement, withdrawing LSTs became lawful and self-determination rates increased. Family members still make 71% of decisions regarding LSTs, but these are often inconsistent with the patients' wishes; thus, further efforts are needed to integrate the new act into clinical practice.
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http://dx.doi.org/10.4143/crt.2019.740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373872PMC
July 2020

Single-agent activity of phosphatidylinositol 3-kinase inhibition with copanlisib in patients with molecularly defined relapsed or refractory diffuse large B-cell lymphoma.

Leukemia 2020 08 14;34(8):2184-2197. Epub 2020 Feb 14.

Hospices Civils de Lyon, Université de Lyon, Centre Hospitalier Lyon-Sud, Service d'hématologie, Lyon, France.

Patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) have adverse outcomes. We evaluated the efficacy and safety of the phosphatidylinositol 3-kinase inhibitor copanlisib in patients with relapsed/refractory DLBCL and assessed the relationship between efficacy and DLBCL cell of origin (COO; activated B-cell like [ABC] and germinal center B-cell like [GCB]) and other biomarkers. The primary endpoint was objective response rate (ORR) in DLBCL COO subgroups (ABC, GCB, and unclassifiable) and by CD79B mutational status (NCT02391116). Sixty-seven patients received copanlisib (ABC DLBCL, n = 19; GCB DLBCL, n = 30; unclassifiable, n = 3; missing, n = 15). The ORR was 19.4%; 31.6% and 13.3% in ABC and GCB DLBCL patients, respectively. ORR was 22.2%/20.0% for patients with/without CD79B mutations (wild type, n = 45; mutant, n = 9; missing, n = 13). Overall median progression-free survival and duration of response were 1.8 and 4.3 months, respectively. Adverse events included hypertension (40.3%), diarrhea (37.3%), and hyperglycemia (32.8%). Aberrations were detected in 338 genes, including BCL2 (53.7%) and MLL2 (53.7%). A 16-gene signature separating responders from nonresponders was identified. Copanlisib treatment demonstrated a manageable safety profile in patients with relapsed/refractory DLBCL and a numerically higher response rate in ABC vs. GCB DLBCL patients.
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http://dx.doi.org/10.1038/s41375-020-0743-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387311PMC
August 2020

Anthelmintics as Potential Anti-Cancer Drugs?

Authors:
Dae Seog Heo

J Korean Med Sci 2020 Feb 17;35(6):e75. Epub 2020 Feb 17.

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

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http://dx.doi.org/10.3346/jkms.2020.35.e75DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7025903PMC
February 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

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

Severe late dysphagia after multimodal treatment of stage III/IV laryngeal and hypopharyngeal cancer.

Jpn J Clin Oncol 2020 Feb;50(2):185-192

Department of Radiation Oncology, Seoul National University Hospital, Seoul, Korea.

Background: Long-term side effects after radiotherapy for organ preservation 'could deteriorate' the laryngeal function. This study intended to identify the incidence of severe late dysphagia following the multimodal treatment for stage III/IV laryngeal and hypopharyngeal cancer 'to evaluate the function of larynx'.

Methods: The medical records of patients successfully treated for laryngeal and hypopharyngeal cancer with a multimodal approach, including radiotherapy, were retrospectively analyzed. 'Functional larynx was defined as tolerable oral diet without severe late dysphagia or tracheostoma'.

Results: The study included 99 patients with a median follow-up period of 72 months. 'Tracheostomy during the follow-up period was required in only one patient due to aspiration pneumonia, and dysphagia is the main determinant for functional larynx'. The probability of maintaining functional larynx was 63% for 10 years, when the treatment was started with radiotherapy or concurrent chemoradiotherapy. In upfront surgery (operation first and adjuvant radiotherapy/concurrent chemoradiotherapy) group, 37% of patients required total laryngectomy as primary treatment and 43% of patients could maintain laryngeal function for 10 years. And severe late dysphagia in the latter group developed mainly after laryngeal preservation surgery. The patients aged ≥65 years showed significantly higher incidence of dysphagia. Severe late dysphagia was very rare in laryngeal cancer successfully cured with radiotherapy/concurrent chemoradiotherapy (1/25, 4%); however, it gradually increased over time in hypopharyngeal cancer patients showing a statistically significant difference from laryngeal cancer patients (P = 0.040).

Conclusion: Severe late dysphagia occurred in 19.2% of patients treated for laryngeal and hypopharyngeal cancers, regardless of whether treatment started with radiotherapy/concurrent chemoradiotherapy or surgery.
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http://dx.doi.org/10.1093/jjco/hyz158DOI Listing
February 2020

Geriatric Nutritional Risk Index as a prognostic marker in patients with extensive-stage disease small cell lung cancer: Results from a randomized controlled trial.

Thorac Cancer 2020 01 10;11(1):62-71. Epub 2019 Nov 10.

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

Background: Clinical impact of the Geriatric Nutritional Risk Index (GNRI) in patients with extensive-stage disease small cell lung cancer (ED-SCLC) have not previously been reported.

Methods: This study analyzed 352 patients enrolled in a previous randomized phase III trial comparing the efficacy of irinotecan plus cisplatin with that of etoposide plus cisplatin as the first-line therapy for ED-SCLC. GNRI values were calculated using serum albumin levels and actual and ideal bodyweights. Patients with a GNRI > 98, 92-98, and <92 were grouped into no, low, and moderate/major risk groups, respectively.

Results: The objective response rates were 63.2%, 52.6%, and 49.2% in the no, low, and moderate/major risk groups, respectively (P = 0.024). The median progression-free survival (PFS) was shorter in patients with a lower GNRI than in those with a higher GNRI (no vs. low vs. moderate/major risk group; 6.5 vs. 5.8 vs. 5.9 months, respectively; P = 0.028). There were significant differences in median overall survival (OS) according to GNRI (no vs. low vs. moderate/major risk group; 13.2 vs. 10.3 vs. 8.4 months, respectively; P < 0.001). Multivariate analysis revealed that being in the moderate/major risk group was an independent poor prognostic factor for PFS (hazard ratio [HR]: 1.300, 95% confidence interval [CI]: 1.012-1.670; P = 0.040) and OS (HR: 1.539; 95% CI: 1.069-2.216; P = 0.020).

Conclusions: This prospective study shows that a low GNRI value was associated with a poor prognosis, and it supports the relationship between systemic inflammation, nutritional status, and clinical outcomes in patients with ED-SCLC.Key points SIGNIFICANT FINDINGS OF THE STUDY: The lower GNRI group had a low response rate to chemotherapy for ED-SCLC. The HRs for PFS and OS were 1.300 and 1.539 in the patients with GNRI < 92.

What This Study Adds: Low GNRI is associated with poor prognosis in ED-SCLC.
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http://dx.doi.org/10.1111/1759-7714.13229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938749PMC
January 2020

The efficacy of immune checkpoint inhibitors in anaplastic lymphoma kinase-positive non-small cell lung cancer.

Thorac Cancer 2019 11 11;10(11):2117-2123. Epub 2019 Sep 11.

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

Background: Despite recent advances in treating non-small cell lung cancer (NSCLC) with immune checkpoint inhibitors (ICIs), their role in ALK-positive NSCLC patients is unclear. We investigated the efficacy of ICIs in patients with ALK-positive NSCLC.

Methods: Between 2011 and 2018, a total of 14 ALK-positive NSCLC patients treated with ICIs were evaluated retrospectively. Clinicopathologic features including age, PD-L1 expression, and treatment outcomes were analyzed. RNA expression level and cytolytic activity by ALK positivity were analyzed using The Cancer Genome Atlas (TCGA) and National Cancer Center Research Institute (NCCRI) data sets.

Results: A total of 13 patients (92.9%) received ALK inhibitors. Patients received a median of three (range 2-8) courses of therapy. The study included nine patients (64.3%) who were PD-L1-high (>50%) and four (28.6%) who were PD-L1-low (<50%). The objective response rate was 14.3% (2/14). The median progression-free survival time was 2.18 months (95% confidence interval [CI] 1.13 months-not reached [NR]). The median overall survival time was 5.67 months (95% CI 3.00 months-NR). RNA expression levels of CD274 were similar between the ALK-positive and negative groups in both TCGA and NCCRI datasets. RNA levels of CD8A in both TCGA and NCCRI data sets were nonsignificantly lower in the ALK-positive group. Cytolytic activity scores including interferon-γ-related response were lower in the ALK-positive group in the NCCRI but not TCGA dataset.

Conclusions: Despite high PD-L1-positive rates, ICIs show limited efficacy in ALK-positive NSCLC. Decreased interferon-γ-related response may underlie these findings.
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http://dx.doi.org/10.1111/1759-7714.13195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825904PMC
November 2019

A phase II study of pembrolizumab and paclitaxel in patients with relapsed or refractory small-cell lung cancer.

Lung Cancer 2019 10 29;136:122-128. Epub 2019 Aug 29.

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

Objective: Patients with etoposide/platinum-refractory extensive disease (ED) small-cell lung cancer (SCLC) have a dismal prognosis. We aimed to evaluate the efficacy and safety of pembrolizumab and paclitaxel combination therapy in these patients.

Methods: In this multi-center, phase II study, ED-SCLC patients who showed progression after etoposide/platinum chemotherapy received paclitaxel 175 mg/m every 3 weeks for up to six cycles. Pembrolizumab 200 mg was added from the second cycle and continued until disease progression or unacceptable toxicity. The primary endpoint was the objective response rate (ORR) and the secondary endpoints were progression-free survival (PFS), overall survival (OS), safety, and biomarker analyses including programmed death-ligand 1 (PD-L1) expression, next-generation sequencing, and flow cytometric analysis of peripheral blood cells.

Results: Of the 26 patients enrolled, the confirmed ORR was 23.1% (95%CI: 6.9%-39.3%); complete response: 3.9%, confirmed partial response [PR]: 19.2%, stable disease: 57.7%, progressive disease: 7.7%, and not evaluable: 11.5%. Including 4 cases of unconfirmed PRs, 38.5% of patients were responding and the disease control rate was 80.7%. The median PFS and OS were 5.0 months (95% CI: 2.7-6.7) and 9.1 months (95% CI: 6.5-15.0), respectively. The grade 3 or 4 adverse events observed included febrile neutropenia (7.7%), neutropenia (7.7%), asthenia (7.7%), hyponatremia (7.7%), and type I diabetes (7.7%). Targeted gene sequencing identified no specific genetic alterations correlated with the treatment, except for theMET copy number gain (PFS 10.5 versus 3.4 months, p = 0.019).

Conclusions: Pembrolizumab and paclitaxel combination therapy showed a moderate activity with acceptable toxicity in patients with refractory ED-SCLC.
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http://dx.doi.org/10.1016/j.lungcan.2019.08.031DOI Listing
October 2019

First-line Pembrolizumab Versus Pembrolizumab Plus Chemotherapy Versus Chemotherapy Alone in Non-small-cell Lung Cancer: A Systematic Review and Network Meta-analysis.

Clin Lung Cancer 2019 09 11;20(5):331-338.e4. Epub 2019 May 11.

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

Background: This study aimed to comprehensively review the available evidence regarding the efficacy of first-line pembrolizumab for advanced/metastatic non-small-cell lung cancer (NSCLC), and to compare pembrolizumab monotherapy versus pembrolizumab plus chemotherapy versus chemotherapy alone.

Materials And Methods: A search of the PubMed, EMBASE, and Cochrane Library databases was performed in July 2018, and abstracts from the American Society of Clinical Oncology meetings (2015-2018) were reviewed. Summaries of the results were pooled using a random-effect model to determine the pooled hazard ratio (HR) for progression-free survival (PFS), overall survival (OS), and their 95% confidence intervals (CIs). A network meta-analysis was used to indirectly compare pembrolizumab monotherapy with pembrolizumab plus chemotherapy.

Results: A total of 4 relevant phase III trials comprising 2754 patients were identified. Pembrolizumab (with or without chemotherapy) led to significant improvements in OS and PFS, irrespective of the programmed cell death ligand 1 (PD-L1) tumor proportion score (TPS). In particular, for the subgroup with PD-L1 TPS ≥ 50%, the HR of PFS was 0.49 (95% CI, 0.32-0.76; P = .001), and that of OS was 0.57 (95% CI, 0.45-0.73; P < .001). In terms of PFS, pembrolizumab plus chemotherapy was superior to pembrolizumab monotherapy with an HR of PFS 0.52 (95% CI, 0.27-0.99; P = .048) for the subgroup with PD-L1 TPS ≥ 50%.

Conclusions: For patients with NSCLC with PD-L1 TPS ≥ 50%, pembrolizumab plus chemotherapy has a better PFS than pembrolizumab monotherapy in this meta-analysis. To confirm this finding, a prospective phase III trial that directly compares the treatments is warranted.
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http://dx.doi.org/10.1016/j.cllc.2019.05.009DOI Listing
September 2019