Publications by authors named "Bhumsuk Keam"

210 Publications

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

Korean Version of the Patient Dignity Inventory: Translation and Validation in Patients With Advanced Cancer.

J Pain Symptom Manage 2021 Jan 20. Epub 2021 Jan 20.

Department of Family Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address:

Context: The goal of palliative care is to maximize the quality of life and thus maintain the dignity of patients facing problems associated with a life-threatening illness. The Patient Dignity Inventory (PDI) is an instrument used to measure various sources of distress that can impact patients' sense of dignity at the end of life.

Objectives: We aimed to obtain a Korean translation of the PDI (PDI-K) and evaluate its psychometric properties in patients with advanced cancer.

Methods: Translation and cultural adaptation of the PDI were performed to obtain the Korean version. In a sample of 131 inpatients and outpatients with advanced cancer, psychometric properties, including factor structure, internal consistency, and concurrent validity, were examined. Concurrent validity was evaluated using the Edmonton Symptom Assessment System, the Hospital Anxiety and Depression Scale, and the 12-item Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being.

Results: Cronbach's α for the PDI-K was 0.96. Four factors were identified by exploratory factor analysis, accounting for 68.7% of the overall variance: Dependency and Physical Symptoms, Psychological Distress, Existential Distress, and SocialSupport. Concurrent validity was confirmed by significant correlations between PDI-K and Edmonton Symptom Assessment System (r = 0.40 to 0.59, P < 0.001), Hospital Anxiety and Depression Scale (r = 0.78 to 0.81, P < 0.001), and Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being (r = -0.32 to -0.57, P < 0.001).

Conclusion: Our findings indicate that the PDI-K is a valid and reliable instrument to measure dignity-related distress in patients with advanced cancer. This tool provides a four-factor Korean language alternative to the PDI.
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http://dx.doi.org/10.1016/j.jpainsymman.2021.01.003DOI 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 Mar 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
March 2021

Newly identified members of fibroblast growth factor receptor 1 splice variants engage in crosstalk with the AXL/AKT axis in salivary adenoid cystic carcinoma.

Cancer Res 2021 Jan 6. Epub 2021 Jan 6.

Department of Otolaryngology Head and Neck Surgery, University of California, San Francisco

Adenoid cystic carcinoma (ACC) is the second most common malignancy of the salivary gland. Although characterized as an indolent tumor, ACC often leads to incurable metastatic disease. Patients with ACC respond poorly to currently available therapeutic drugs, and factors contributing to the limited response remain unknown. Determining the role of molecular alterations frequently occurring in ACC may clarify ACC tumorigenesis and advance the development of effective treatment strategies. Applying Splice Expression Variant Analysis (SEVA) and outlier statistics on RNA-sequencing of primary ACC tumors and matched normal salivary gland tissues, we identified multiple alternative splicing events (ASE) of genes specific to ACC. In ACC cells and patient-derived-xenografts, FGF receptor 1 (FGFR1) was a uniquely expressed ASE. Detailed PCR analysis identified three novel, truncated, intracellular domain-lacking FGFR1 variants (FGFR1v). Cloning and expression analysis suggested that the three FGFR1v are cell-surface proteins, that expression of FGFR1v augmented pAKT activity, and that cells became more resistant to pharmacological FGFR1 inhibitor. FGFR1v-induced AKT activation was associated with AXL function, and inhibition of AXL activity in FGFR1v-knockdown cells enhanced cytotoxicity in ACC. Moreover, cell killing was increased by dual inhibition of AXL and FGFR1 in ACC cells. This study demonstrates that these previously undescribed FGFR1v cooperate with AXL and desensitize cells to FGFR1 inhibitor, which supports further investigation into combined FGFR1 and AXL inhibition as an effective ACC therapy.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1780DOI Listing
January 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

Outcomes and Biomarkers of Immune Checkpoint Inhibitor Therapy in Patients with Refractory Head and Neck Squamous Cell Carcinoma: KCSG HN18-12.

Cancer Res Treat 2020 Dec 7. Epub 2020 Dec 7.

Department of Internal Medicine, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Korea.

Purpose: This study was conducted to determine the effectiveness of immune checkpoint inhibitors (ICIs) in recurrent or metastatic head and neck squamous cell cancer (R/M HNSCC) after platinum-containing chemotherapy. We also identified clinical biomarkers which may be predictive of patient prognosis.

Materials And Methods: We analyzed 125 patients with R/M HNSCC who received ICIs, retrospectively. Overall response rate (ORR) was the primary study outcome. Overall survival (OS) and progression-free survival (PFS) were the secondary study outcomes.

Results: The patients received anti‒programmed cell death protein-1 (PD-1) (n=73, 58%), anti‒programmed death-ligand 1 (PD-L1) (n=24, 19%), or a combination of anti-PD-1/PD-L1 and anti‒cytotoxic T-lymphocyte antigen 4 (n=28, 22%). The median age was 57 (range, 37 to 87). The location of the primary tumor was in the oral cavity in 28% of the cases, followed by oropharynx (27%), hypopharynx (20%), and larynx (12%). The ORR was 15% (19/125). With 12.3 months of median follow-up, median PFS was 2.7 months. Median OS was 10.8 months. A neutrophil-to-lymphocyte ratio (NLR) >4 was significantly associated with poor response to ICIs (odds ratio, 0.30; p=0.022). A sum of the target lesions > 40 mm (hazard ratio [HR], 1.53; p=0.046] and a NLR > 4 (HR, 1.75; p=0.009) were considered to be predictive markers of short PFS. A poor performance status (HR, 4.79; p < 0.001), a sum of target lesions > 40 mm (HR, 1.93; p=0.025), and an NLR > 4 (HR, 3.36; p < 0.001) were the significant predictors for poor survival.

Conclusion: ICIs exhibited favorable antitumor activity in R/M HNSCC. Clinically, our findings can be used to recognize patients benefit from receiving ICI.
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http://dx.doi.org/10.4143/crt.2020.824DOI Listing
December 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 2020 Nov 19. Epub 2020 Nov 19.

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

Purpose: 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. 686 doctors who care for seriously ill patients were given a structured questionnaire, and difficulties during the discussion were examined.

Results: 132 doctors completed the questionnaire. 85% 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
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 Dec 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 Dec 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

Treatment strategy and outcomes in locally advanced head and neck squamous cell carcinoma: a nationwide retrospective cohort study (KCSG HN13-01).

BMC Cancer 2020 Aug 27;20(1):813. Epub 2020 Aug 27.

Department of Internal Medicine, Chungnam National University Hospital, 282 Munhwa-ro, Jung-gu, Daejeon, 35015, Republic of Korea.

Background: By investigating treatment patterns and outcomes in locally advanced head and neck squamous cell carcinoma (LA-HNSCC), we aimed at providing valuable insights into the optimal therapeutic strategy for physicians in real-world practice.

Methods: This is a multi-institutional study enrolled the patients with stage III to IVB LA-HNSCC, except for nasopharyngeal carcinoma, from 2004 to 2015 in thirteen referral hospitals capable of multidisciplinary care.

Results: A total of 445 LA-HNSCC patients were analyzed. The median age was 61 years (range, 24-89). The primary tumor location was the oropharynx in 191 (43%), oral cavity in 106 (24%), hypopharynx in 64 (14%), larynx in 57 (13%) and other sites in 27 (6%). The most common stage was T2 in 172 (39%), and N2 in 245 (55%). Based on treatment intents, 229 (52%) of the patients received definitive concurrent chemoradiotherapy (CCRT) and 187 (42%) underwent surgery. Approximately 158 (36%) of the study population received induction chemotherapy (IC). Taken together, 385 (87%) of the patients underwent combined therapeutic modalities. The regimen for definitive CCRT was weekly cisplatin in 58%, 3-weekly cisplatin in 28% and cetuximab in 3%. The preferred regimen for IC was docetaxel with cisplatin in 49%, and docetaxel, cisplatin plus fluorouracil in 27%. With a median follow-up of 39 months, one-year and two-year survival rates were 89 and 80%, respectively. Overall survival was not significantly different between CCRT and surgery group (p = 0.620).

Conclusions: In patients with LA-HNSCC, the majority of patients received combined therapeutic modalities. Definitive CCRT, IC then definitive CCRT, and surgery followed by adjuvant CCRT or radiotherapy are the preferred multidisciplinary strategies in real-world practice.
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http://dx.doi.org/10.1186/s12885-020-07297-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450571PMC
August 2020

Correction to: Hyperprogressive disease and its clinical impact in patients with recurrent and/or metastatic head and neck squamous cell carcinoma treated with immune-checkpoint inhibitors: Korean cancer study group HN 18-12.

J Cancer Res Clin Oncol 2020 Dec;146(12):3371

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

In the original article published, the first name of the author is incorrect. The correct author name is Ji Hyun Park.
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http://dx.doi.org/10.1007/s00432-020-03342-3DOI Listing
December 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

Safety and Clinical Activity of MEDI0562, a Humanized OX40 Agonist Monoclonal Antibody, in Adult Patients with Advanced Solid Tumors.

Clin Cancer Res 2020 Oct 14;26(20):5358-5367. Epub 2020 Aug 14.

UC San Diego Moores Cancer Center, La Jolla, California, USA.

Purpose: Immune checkpoint blockade has demonstrated clinical benefits across multiple solid tumor types; however, resistance and relapse often occur. New immunomodulatory targets, which are highly expressed in activated immune cells, are needed. MEDI0562, an agonistic humanized mAb, specifically binds to the costimulatory molecule OX40. This first-in-human study evaluated MEDI0562 in adults with advanced solid tumors.

Patients And Methods: In this phase I, multicenter, open-label, single-arm, dose-escalation (3+3 design) study, patients received 0.03, 0.1, 0.3, 1.0, 3.0, or 10 mg/kg MEDI0562 through intravenous infusion every 2 weeks, until confirmed disease progression or unacceptable toxicity. The primary objective evaluated safety and tolerability. Secondary endpoints included antitumor activity, pharmacokinetics, immunogenicity, and pharmacodynamics.

Results: In total, 55 patients received ≥1 dose of MEDI0562 and were included in the analysis. The most common tumor type was squamous cell carcinoma of the head and neck (47%). Median duration of treatment was 10 weeks (range, 2-48 weeks). Treatment-related adverse events (TRAEs) occurred in 67% of patients, most commonly fatigue (31%) and infusion-related reactions (14%). Grade 3 TRAEs occurred in 14% of patients with no apparent dose relationship; no TRAEs resulted in death. Two patients had immune-related partial responses per protocol and 44% had stable disease. MEDI0562 induced increased Ki67 CD4 and CD8 memory T-cell proliferation in the periphery and decreased intratumoral OX40 FOXP3 cells.

Conclusions: MEDI0562 was safely administered at doses up to 10 mg/kg in heavily pretreated patients. On-target pharmacodynamic effects were suggested in this setting. Further evaluation with immune checkpoint inhibitors is ongoing.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3070DOI Listing
October 2020

Hyperprogressive disease and its clinical impact in patients with recurrent and/or metastatic head and neck squamous cell carcinoma treated with immune-checkpoint inhibitors: Korean cancer study group HN 18-12.

J Cancer Res Clin Oncol 2020 Dec 15;146(12):3359-3369. Epub 2020 Jul 15.

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

Purpose: Although immune-checkpoint inhibitors (ICIs) have emerged as therapeutic options for recurrent and/or metastatic head and neck squamous cell carcinoma (R/M-HNSCC), concerns have been raised on exceptional acceleration of tumor growth during treatment with ICIs, a condition described as hyperprogressive disease (HPD). This study examined the incidence, potential predictors, and clinical impact of HPD in R/M-HNSCC.

Methods: We retrospectively collected data of patients with R/M-HNSCC treated with ICIs between January 2013 and June 2018 from 11 medical centers in Korea. HPD was defined as tumor growth kinetics ratio (TGKr) > 2, which was calculated by comparing TGK on ICIs with that before treatment with ICIs.

Results: Of 125 patients, 68 (54.4%) obtained progressive disease as their best responses (progressors). HPD was identified in 18 (26.5% of progressors, 14.4% of total) patients. Relatively younger age, primary tumor of oral cavity, and previous locoregional irradiation were significant predictors of HPD according to multivariable analysis (p = 0.040, 0.027, and 0.015, respectively). Compared to patients without HPD, patients with HPD had significantly shorter median progression-free survival (PFS) (1.2 vs. 3.4 months, p < 0.001) and overall survival (OS) (3.4 vs. 10.7 months, p = 0.047). However, interestingly, HPD did not significantly affect the therapeutic benefit of post-ICIs chemotherapy.

Conclusions: Younger patients with oral cavity cancer or prior treatment with locoregional radiotherapy could be regarded potential risk groups for HPD in patients with R/M-HNSCC treated with ICIs. Although HPD could consistently predict poorer survival outcomes, patients who experienced HPD with ICIs should not be excluded from the subsequent salvage chemotherapy treatments.
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http://dx.doi.org/10.1007/s00432-020-03316-5DOI Listing
December 2020

Squamous cell carcinoma of head and neck: what internists should know.

Korean J Intern Med 2020 09 14;35(5):1031-1044. Epub 2020 Jul 14.

Department of Medicine, University of California San Francisco, San Francisco, CA, USA.

Squamous cell carcinoma of head and neck (SCCHN) is a group of cancer arising from mucosal surfaces of the head and neck. Optimal management of SCCHN requires a multidisciplinary team of surgical oncologists, radiation oncologists, medical oncologists, nutritionist, and speech-language pathologists, due to the complexity of anatomical structure and importance of functional outcome. Human papilloma virus (HPV)-related SCCHN represents a distinct subset from HPV negative SCCHN which is associated with carcinogen exposure such as cigarette smoking, betel nut use and alcohol. HPV related SCCHN responds better to concurrent chemoradiation and has better overall prognosis, compared to HPV negative SCCHN. Radiation therapy has been introduced to the treatment of SCCHN, administered concurrently with systemic chemotherapy for locoregional SCCHN, as well as a palliative measure for recurrent and/or metastatic (R/M) SCCHN. Recently, immune checkpoint inhibitors have been shown to improve overall survival in R/M-SCCHN and have been incorporated into the standard of care. Combination approaches with immune therapy and targeted therapy for biomarker enriched population based on genomics are being actively investigated and will shape the future of SCCHN treatment.
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http://dx.doi.org/10.3904/kjim.2020.078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487309PMC
September 2020

A multicenter, phase I, pharmacokinetic study of osimertinib in cancer patients with normal renal function or severe renal impairment.

Pharmacol Res Perspect 2020 08;8(4):e00613

Medical Oncology Department, Bordeaux University Hospital, Saint-André Hospital, Bordeaux, France.

Osimertinib is a third-generation, irreversible, oral epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) that potently and selectively inhibits both EGFR-TKI sensitizing and EGFR T790M and has demonstrated efficacy in non-small cell lung cancer (NSCLC) central nervous system metastases. In this phase I study, we assessed the effects of normal renal function (NRF) and severe renal impairment (SRI) on the pharmacokinetics (PK) of osimertinib in patients with solid tumors. Part A: patients with NRF (creatinine clearance [CrCL] ≥90 mL/min), and SRI, (CrCL <30 mL/min), received a single 80-mg oral dose of osimertinib and standard PK measures were assessed. Part B: patients with SRI were treated for 3 months to obtain safety data, if deemed clinically appropriate. The geometric mean osimertinib plasma concentrations were higher in patients with SRI (n = 7) vs NRF (n = 8) and were highly variable. Osimertinib exposure based on C and area under the plasma concentration-time curve, was 1.19-fold (90% CI: 0.6, 2.0) and 1.85-fold (90% CI: 0.9, 3.6), respectively, higher for patients with SRI vs patients with NRF, with no clear correlation between CrCL and exposure. No new safety signals were identified after 12 weeks of osimertinib 80 mg continuous dosing. PK parameters pooled across this study and other phase I, II, and III osimertinib clinical studies (exploratory population PK analysis), showed minimal correlation between CrCL and total clearance. In conclusion, no dose adjustment is required for osimertinib for patients with SRI.
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http://dx.doi.org/10.1002/prp2.613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7307240PMC
August 2020

Phase IA/IB study of single-agent tislelizumab, an investigational anti-PD-1 antibody, in solid tumors.

J Immunother Cancer 2020 06;8(1)

Linear Clinical Research, Nedlands, Western Australia, Australia.

Background: The programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) axis plays a central role in suppressing antitumor immunity; axis dysregulation can be used by cancer cells to evade the immune system. Tislelizumab, an investigational monoclonal antibody with high affinity and binding specificity for PD-1, was engineered to minimize binding to FcγR on macrophages to limit antibody-dependent phagocytosis, a potential mechanism of resistance to anti-PD-1 therapy. The aim of this phase IA/IB study was to investigate the safety/tolerability, antitumor effects and optimal dose and schedule of tislelizumab in patients with advanced solid tumors.

Methods: Patients (aged ≥18 years) enrolled in phase IA received intravenous tislelizumab 0.5, 2, 5 or 10 mg/kg every 2 weeks; 2 or 5 mg/kg administered every 2 weeks or every 3 weeks; or 200 mg every 3 weeks; patients in phase IB received 5 mg/kg every 3 weeks. Primary objectives were to assess tislelizumab's safety/tolerability profile by adverse event (AE) monitoring and antitumor activity using RECIST V.1.1. PD-L1 expression was assessed retrospectively with the VENTANA PD-L1 (SP263) Assay.

Results: Between May 2015 and October 2017, 451 patients (n=116, IA; n=335, IB) were enrolled. Fatigue (28%), nausea (25%) and decreased appetite (20%) were the most commonly reported AEs. Most AEs were grade 1-2 severity; anemia (4.9%) was the most common grade 3-4 AE. Treatment-related AEs led to discontinuation in 5.3% of patients. Grade 5 AEs were reported in 14 patients; 2 were considered related to tislelizumab. Pneumonitis (2%) and colitis (1%) were the most common serious tislelizumab-related AEs. As of May 2019, 18% of patients achieved a confirmed objective response in phase IA and 12% in phase IB; median follow-up duration was 13.6 and 7.6 months, respectively. Pharmacokinetics, safety and antitumor activity obtained from both phase IA and IB determined the tislelizumab recommended dose; ultimately, tislelizumab 200 mg intravenous every 3 weeks was the dose and schedule recommended to be taken into subsequent clinical trials.

Conclusions: Tislelizumab monotherapy demonstrated an acceptable safety/tolerability profile. Durable responses were observed in heavily pretreated patients with advanced solid tumors, supporting the evaluation of tislelizumab 200 mg every 3 weeks, as monotherapy and in combination therapy, for the treatment of solid tumors and hematological malignancies.

Trial Registration Number: NCT02407990.
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http://dx.doi.org/10.1136/jitc-2019-000453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295442PMC
June 2020

Cell-Mediated Immunogenicity of Influenza Vaccination in Patients With Cancer Receiving Immune Checkpoint Inhibitors.

J Infect Dis 2020 Nov;222(11):1902-1909

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

Background: We assessed cell-mediated immune (CMI) responses of influenza vaccination in patients with cancer receiving immune checkpoint inhibitors (ICIs), which remain elusive.

Methods: Vaccine-elicited CMI responses in patients receiving ICIs or cytotoxic agents were investigated by flow cytometry. Polyfunctional cells were defined as T cells that express 2 or more of interleukin 2 (IL-2), interleukin 4 (IL-4), interferon gamma (IFN-γ), and CD107a. An adequate CMI response was defined as an increase of polyfunctional T cells against both H1N1 and H3N2 strains.

Results: When comparing ICI (n = 11) and cytotoxic chemotherapy (n = 29) groups, H1N1-specific IL-4 or IFN-γ-expressing CD4+ T cells, IL-2, IL-4, IFN-γ, or CD107a-expressing CD8+ T cells, H3N2-specific IFN-γ-expressing CD4+ T cells, and CD107a-expressing CD8+ T cells were more frequent in the ICI group. Fold changes in polyfunctional H3N2-specific CD4+ (median, 156.0 vs 95.7; P = .005) and CD8+ (155.0 vs 103.4; P = .044) T cells were greater in the ICI group. ICI administration was strongly associated with an adequate CMI response for both CD4+ and CD8+ T cells (P = .003).

Conclusions: CMI responses following influenza vaccination were stronger in the ICI group than in the cytotoxic chemotherapy group. Influenza vaccination should be strongly recommended in patients with cancer receiving ICIs.
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http://dx.doi.org/10.1093/infdis/jiaa291DOI Listing
November 2020

Gene Signature for Sorafenib Susceptibility in Hepatocellular Carcinoma: Different Approach with a Predictive Biomarker.

Liver Cancer 2020 Apr 18;9(2):182-192. Epub 2020 Feb 18.

Department of Surgery, Ajou University School of Medicine, Suwon, Republic of Korea.

Background/aim: Uniform treatment of hepatocellular carcinoma (HCC) with molecular targeted drugs (e.g., sorafenib) results in a poor overall tumor response when tumor subtyping is absent. Patient stratification based on actionable gene expression is a method that can potentially improve the effectiveness of these drugs. Here we aimed to identify the clinical application of actionable genes in predicting response to sorafenib.

Methods: Through quantitative real-time reverse transcription PCR, we analyzed the expression levels of seven actionable genes (, , , , , , and ) in tumors versus noncancerous tissues from 220 HCC patients treated with sorafenib. Our analysis found that 9 responders did not have unique clinical features compared to nonresponders. A receiver operating characteristic curve evaluated the predictive performance of the treatment benefit score (TBS) calculated from the actionable genes.

Results: The responders had significantly higher TBS values than the nonresponders. With an area under the curve of 0.779, a TBS combining with , , and was the most significant predictor of response to sorafenib. When used alone, sorafenib had a 0.7-3% response rate among HCC patients, but when stratifying the patients with actionable genes, the tumor response rate rose to 15.6%. Furthermore, actionable gene expression is significantly correlated with tumor response.

Conclusions: Our findings on patient stratification based on actionable molecular subtyping potentially provide a therapeutic strategy for improving sorafenib's effectiveness in treating HCC.
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http://dx.doi.org/10.1159/000504548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206603PMC
April 2020

Impact of family caregivers' awareness of the prognosis on their quality of life/depression and those of patients with advanced cancer: a prospective cohort study.

Support Care Cancer 2021 Jan 6;29(1):397-407. Epub 2020 May 6.

Department of Family Medicine, Seoul National University Hospital, Seoul, South Korea.

Purpose: A caregiver's prognostic awareness can affect clinical decisions for the patient. The purpose of this study was to examine the impact of family caregivers' prognostic awareness on the quality of life (QOL) and emotional state of both patients with advanced cancer and their caregivers.

Methods: This prospective cohort study was conducted from December of 2016 to January of 2018. A total of 159 patients with advanced cancer and an equal number of caregivers participated. The investigation tools used include the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C15-Palliative, the McGill Quality of Life Questionnaire, and the Patient Health Questionnaire-9, and evaluation was performed at baseline, 3 months, and 6 months. Covariance analysis with a general linear modeling was used to compare changes in quality of life scores according to the caregivers' awareness of the prognosis.

Results: Mean patient overall QOL score increased in the group of caregivers who were aware of prognosis and decreased in the caregivers who were not aware of the prognosis (p = 0.018). The changes over time in the patients' QOL scores associated with symptoms improved with caregiver awareness (pain, p = 0.017; dyspnea, p = 0.048; appetite loss, p = 0.045). The percentage of depressed patients was smaller after 3 months in the group with caregivers aware of the prognosis (baseline to 3 months p = 0.028). Caregivers who did not understand their patients' prognosis exhibited better existential well-being (p = 0.036), and the incidence of depression was lower in this group at 3 months (p = 0.024).

Conclusion: Caregivers' prognostic awareness may improve the quality of life and mood in patients with advanced cancer; however, this awareness may harm the quality of life and mood of the caregivers. These results may aid in developing in-depth interventions regarding prognosis for both patients and their caregivers.
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http://dx.doi.org/10.1007/s00520-020-05489-8DOI Listing
January 2021

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