1.Histone Deacetylase as a Valuable Predictive Biomarker and Therapeutic Target in Immunotherapy for Non-Small Cell Lung Cancer
Hyun-Seock SHIN ; Juwhan CHOI ; Jinhwan LEE ; Sung Yong LEE
Cancer Research and Treatment 2022;54(2):458-468
Purpose:
Histone deacetylase inhibitors (HDACis) are epigenetic regulators and used clinically for hematopoietic malignancies. Recently, HDACis have received attention as a factor that modulates the immune system. In this study, the role of histone deacetylase (HDAC) expression as a predictive marker in lung cancer patients who were treated with immune checkpoint inhibitors (ICIs) and the role of HDACi and ICI combination treatment in the mouse tumor model were analyzed.
Materials and Methods:
The overall response rate (ORR) and progression-free survival (PFS) were analyzed by the expression of HDAC. In vitro assay, the mRNA and protein expression levels of cytokines and programmed death-ligand 1 (PD-L1) were analyzed after HDACi treatment. In vivo assay, TC-1 tumor-bearing mice were treated with HDACi and mouse programmed cell death 1 (PD-1) inhibitor.
Results:
The HDAC6 low expression group showed high ORR and prolonged PFS. When the selective HDAC6 inhibitor was administered to the A549 cell line, the levels of interleukin-1β and interleukin-6 decreased and the expression of PD-L1 was reduced. Mice that received both the mouse PD-1 inhibitor and pan-HDACi had a smaller tumor size than that of the mice from the control group. Moreover, mice treated with the mouse PD-1 inhibitor and pan-HDACi generated greater numbers of E7-specific CD8+ T cells.
Conclusion
HDAC6 expression can predict the prognosis of non–small cell lung cancerpatients who were treated with ICIs. Furthermore, co-treatment with HDACi and PD-1 inhibitor was shown to decrease the tumor growth rate and create a favorable tumor microenvironment for cytotoxic T lymphocytes in the TC-1 mouse model.
2.Clinical Characteristics and Treatment of Immune-Related Adverse Events of Immune Checkpoint Inhibitors
Immune Network 2020;20(1):9-
Immune checkpoint inhibitors (ICIs) have been changing the paradigm of cancer treatment. However, immune-related adverse effects (irAEs) have also increased with the exponential increase in the use of ICIs. ICIs can break up the immunologic homeostasis and reduce T-cell tolerance. Therefore, inhibition of immune checkpoint can lead to the activation of autoreactive T-cells, resulting in various irAEs similar to autoimmune diseases. Gastrointestinal toxicity, endocrine toxicity, and dermatologic toxicity are common side effects. Neurotoxicity, cardiotoxicity, and pulmonary toxicity are relatively rare but can be fatal. ICI-related gastrointestinal toxicity, dermatologic toxicity, and hypophysitis are more common with anti- CTLA-4 agents. ICI-related pulmonary toxicity, thyroid dysfunction, and myasthenia gravis are more common with PD-1/PD-L1 inhibitors. Treatment with systemic steroids is the principal strategy against irAEs. The use of immune-modulatory agents should be considered in case of no response to the steroid therapy. Treatment under the supervision of multidisciplinary specialists is also essential, because the symptoms and treatments of irAEs could involve many organs. Thus, this review focuses on the mechanism, clinical presentation, incidence, and treatment of various irAEs.
Autoimmune Diseases
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Cardiotoxicity
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Homeostasis
;
Incidence
;
Myasthenia Gravis
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Organization and Administration
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Specialization
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Steroids
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T-Lymphocytes
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Thyroid Gland
3.Perioperative immunotherapy in stage IB-III non-small cell lung cancer: a critical review of its rationale and considerations
Jae Kyeom SIM ; Juwhan CHOI ; Sung Yong LEE
The Korean Journal of Internal Medicine 2023;38(6):787-796
Lung cancer is a dismal disease as a leading cause of overall cancer death, but the development of immune checkpoint inhibitors (ICIs) in driver gene mutation negative metastatic non-small cell lung cancer (NSCLC) is changing the paradigm of lung cancer treatment. Recently, ICIs are expanding their treatment area to early-stage NSCLC and ICIs have also changed their treatment strategies of such patients. And it is important to appropriately select patients with resectable early-stage lung cancer through a multidisciplinary team approach and decrease the tumor relapse rate in the ICIs era. In this review article, we discuss the recently released neoadjuvant and adjuvant data of ICIs, their treatment rationale, and unmet needs in the treatment of early-stage NSCLC.
4.Clinical Characteristics and Treatment of Immune-Related Adverse Events of Immune Checkpoint Inhibitors
Immune Network 2020;20(1):e9-
Immune checkpoint inhibitors (ICIs) have been changing the paradigm of cancer treatment. However, immune-related adverse effects (irAEs) have also increased with the exponential increase in the use of ICIs. ICIs can break up the immunologic homeostasis and reduce T-cell tolerance. Therefore, inhibition of immune checkpoint can lead to the activation of autoreactive T-cells, resulting in various irAEs similar to autoimmune diseases. Gastrointestinal toxicity, endocrine toxicity, and dermatologic toxicity are common side effects. Neurotoxicity, cardiotoxicity, and pulmonary toxicity are relatively rare but can be fatal. ICI-related gastrointestinal toxicity, dermatologic toxicity, and hypophysitis are more common with anti- CTLA-4 agents. ICI-related pulmonary toxicity, thyroid dysfunction, and myasthenia gravis are more common with PD-1/PD-L1 inhibitors. Treatment with systemic steroids is the principal strategy against irAEs. The use of immune-modulatory agents should be considered in case of no response to the steroid therapy. Treatment under the supervision of multidisciplinary specialists is also essential, because the symptoms and treatments of irAEs could involve many organs. Thus, this review focuses on the mechanism, clinical presentation, incidence, and treatment of various irAEs.
5.Cardiac Dysfunction Is Not Associated with Increased Reintubation Rate in Patients Treated with Post-extubation High-Flow Nasal Cannula
Jae Kyeom SIM ; Juwhan CHOI ; Jee Youn OH ; Kyung Hoon MIN ; Gyu Young HUR ; Sung Yong LEE ; Jae Jeong SHIM ; Young Seok LEE
Tuberculosis and Respiratory Diseases 2022;85(4):332-340
Background:
Cardiac dysfunction patients have long been considered at high risk of reintubation. However, it is based on past studies in which only conventional oxygen therapy was applied after extubation. We investigated association between cardiac dysfunction and reintubation rate in situation where high-flow nasal cannula (HFNC) was widely used during post-extubation period.
Methods:
We conducted a retrospective observational cohort study of patients treated with HFNC after planned extubation in medical intensive care unit of single tertiary center. Patients were divided into normal function group (ejection fraction [EF] ≥45%) and cardiac dysfunction group (EF <45%). The primary outcome was reintubation rate within 72 hours following extubation.
Results:
Of 270 patients, 35 (13%) had cardiac dysfunction. Baseline characteristics were similar in both groups. There were no differences in the changes in vital signs between the two groups during the first 12 hours after extubation except diastolic blood pressure. The reintubation rates were 20% and 17% for cardiac dysfunction group and normal function group, respectively (p=0.637). In a multivariate Cox regression analysis, cardiac dysfunction was not associated with an increased risk of reintubation within 72 hours following extubation (hazard ratio, 1.56; p=0.292).
Conclusion
Cardiac dysfunction was not associated with increased reintubation rate within 72 hours when HFNC is immediately applied after planned extubation.
6.The Clinical Efficacy and Safety of Four-Weekly Docetaxel as First-Line Therapy in Elderly Lung Cancer Patients with Squamous Cell Carcinoma
Jong Hyun CHOI ; Juwhan CHOI ; Sang Mi CHUNG ; Jee Youn OH ; Young Seok LEE ; Kyung Hoon MIN ; Gyu Young HUR ; Jae Jeong SHIM ; Kyung Ho KANG ; Hyun Kyung LEE ; Sung Yong LEE
Tuberculosis and Respiratory Diseases 2019;82(3):211-216
BACKGROUND: Docetaxel is one of the standard treatments for advanced non-small cell lung cancer. Docetaxel is usually administered in a 3-week schedule, but there is significant toxicity. In this phase II clinical study, we investigated the efficacy and safety of a 4-weekly schedule of docetaxel monotherapy, as first-line chemotherapy for advanced squamous cell carcinoma in elderly lung cancer patients. METHODS: Patients with stage IIIB/ IV lung squamous-cell carcinoma age 70 or older, that had not undergone cytotoxic chemotherapy were enrolled. Patients received docetaxel 25 mg/m2 on days 1, 8, and 15, every 4 weeks. Primary endpoint was the objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity profiles. RESULTS: A total of 19 patients were enrolled. Among 19 patients, 17 were for evaluated efficacy and safety. In the intent-to-treat population, ORR and disease control rate (DCR) were 11.8% and 47.1%, respectively. In the response evaluable population, ORR was 16.7% and DCR was 66.7%. Median PFS and OS were 3.1 months and 3.3 months, respectively. There were three adverse grade 3/4 events. Grade 1 neutropenia was reported in one patient. CONCLUSION: Our data failed to demonstrate efficacy of a 4-weekly docetaxel regimen, in elderly patients with a poor performance status. However, incidence of side effects, including neutropenia, was lower than with a 3-week docetaxel regimen, as previously reported.
Aged
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Appointments and Schedules
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Carcinoma, Non-Small-Cell Lung
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Carcinoma, Squamous Cell
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Clinical Study
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Disease-Free Survival
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Drug Therapy
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Epithelial Cells
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Humans
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Incidence
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Lung Neoplasms
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Lung
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Neutropenia
;
Treatment Outcome
7.Clinical efficacy of adjuvant chemotherapy in stage IB (< 4 cm) non-small cell lung cancer patients with high-risk factors
Juwhan CHOI ; Jee Youn OH ; Young Seok LEE ; Kyung Hoon MIN ; Jae Jeong SHIM ; Sue In CHOI ; Dong Won PARK ; Chan Kwon PARK ; Eun Joo KANG ; Hwan Seok YONG ; Bong Kyung SHIN ; Hyun Koo KIM ; Sung Yong LEE
The Korean Journal of Internal Medicine 2022;37(1):127-136
Background/Aims:
Adjuvant chemotherapy is the standard of care for resected stage II-IIIA non-small cell lung cancer (NCSLC). The efficacy of adjuvant chemotherapy in stage IB (< 4 cm) NSCLC with high-risk factors is controversial.
Methods:
This retrospective multicenter study included 285 stage IB NSCLC patients with high-risk factors according to the 8th edition tumor, node, metastasis (TNM) classification from four academic hospitals. High-risk factors included visceral pleural invasion, vascular invasion, lymphatic invasion, lung neuroendocrine tumors, and micropapillary histology patterns.
Results:
Of the 285 patients, 127 (44.6%) were included in the adjuvant chemotherapy group and 158 (55.4%) were included in the non-adjuvant chemotherapy group. The median follow-up was 41.5 months. Patients in the adjuvant chemotherapy group had a significantly reduced recurrence rate and risk of mortality than those in the non-adjuvant chemotherapy group (hazards ratio, 0.408; 95% confidence interval, 0.221 to 0.754; p = 0.004 and hazards ratio, 0.176; 95% confidence interval, 0.057 to 0.546; p = 0.003, respectively). Adjuvant chemotherapy should be particularly considered for the high-risk factors such as visceral pleural involvement or vascular invasion. Based on the subgroup analysis, adjuvant chemotherapy should be considered when visceral pleural involvement is present, even if the tumor size is < 3 cm.
Conclusions
Adjuvant chemotherapy may be useful for patients with stage IB NSCLC with high-risk factors and is more relevant for patients with visceral pleural involvement or vascular invasion.
8.The Clinical Efficacy and Safety of Four-Weekly Docetaxel as First-Line Therapy in Elderly Lung Cancer Patients with Squamous Cell Carcinoma
Jong Hyun CHOI ; Juwhan CHOI ; Sang Mi CHUNG ; Jee Youn OH ; Young Seok LEE ; Kyung Hoon MIN ; Gyu Young HUR ; Jae Jeong SHIM ; Kyung Ho KANG ; Hyun Kyung LEE ; Sung Yong LEE
Tuberculosis and Respiratory Diseases 2019;82(3):211-216
BACKGROUND:
Docetaxel is one of the standard treatments for advanced non-small cell lung cancer. Docetaxel is usually administered in a 3-week schedule, but there is significant toxicity. In this phase II clinical study, we investigated the efficacy and safety of a 4-weekly schedule of docetaxel monotherapy, as first-line chemotherapy for advanced squamous cell carcinoma in elderly lung cancer patients.
METHODS:
Patients with stage IIIB/ IV lung squamous-cell carcinoma age 70 or older, that had not undergone cytotoxic chemotherapy were enrolled. Patients received docetaxel 25 mg/m2 on days 1, 8, and 15, every 4 weeks. Primary endpoint was the objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity profiles.
RESULTS:
A total of 19 patients were enrolled. Among 19 patients, 17 were for evaluated efficacy and safety. In the intent-to-treat population, ORR and disease control rate (DCR) were 11.8% and 47.1%, respectively. In the response evaluable population, ORR was 16.7% and DCR was 66.7%. Median PFS and OS were 3.1 months and 3.3 months, respectively. There were three adverse grade 3/4 events. Grade 1 neutropenia was reported in one patient.
CONCLUSION
Our data failed to demonstrate efficacy of a 4-weekly docetaxel regimen, in elderly patients with a poor performance status. However, incidence of side effects, including neutropenia, was lower than with a 3-week docetaxel regimen, as previously reported.
9.Severe Endobronchial Inflammation Induced by Aspiration of a Ferrous Sulfate Tablet.
Sang Youn LIM ; Sung Birm SOHN ; Jung Min LEE ; Ji Ae LEE ; Sangmi CHUNG ; Junga KIM ; Juwhan CHOI ; Sehwa KIM ; Ah Young YOO ; Jong Ah ROH ; Haein PARK ; Won Shik KIM ; Jae Kyeom SIM ; Jae Jeong SHIM ; Kyung Hoon MIN
Tuberculosis and Respiratory Diseases 2016;79(1):37-41
Iron supplements such as ferrous sulfate tablets are usually used to treat iron-deficiency anemia in some elderly patients with primary neurologic disorders or decreased gag reflexes due to stroke, senile dementia, or parkinsonism. While the aspiration of ferrous sulfate is rarely reported, it is a potentially life-threatening condition that can lead to airway necrosis and bronchial stenosis. A detailed history and high suspicion of aspiration are required to avoid delays in diagnosis and treatment. The diagnosis can be confirmed by bronchoscopic examination and a tissue biopsy. Early removal of the aspirated tablet prevents acute complications, such as bronchial necrosis, hemoptysis, and lobar consolidation. Tablet removal is also necessary to prevent late bronchial stenosis. We presented the first case in Korea of a ferrous sulfate tablet aspiration that induced severe endobronchial inflammation.
Aged
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Alzheimer Disease
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Anemia, Iron-Deficiency
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Biopsy
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Bronchi
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Bronchoscopy
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Constriction, Pathologic
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Diagnosis
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Foreign Bodies
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Hemoptysis
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Humans
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Inflammation*
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Iron
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Korea
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Necrosis
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Nervous System Diseases
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Parkinsonian Disorders
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Reflex
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Respiratory Aspiration
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Stroke
;
Tablets
10.Bacterial and Viral Identification Rate in Acute Exacerbation of Chronic Obstructive Pulmonary Disease in Korea
Juwhan CHOI ; Jee Youn OH ; Young Seok LEE ; Gyu Young HUR ; Sung Yong LEE ; Jae Jeong SHIM ; Kyung Ho KANG ; Kyung Hoon MIN
Yonsei Medical Journal 2019;60(2):216-222
PURPOSE: The most common cause of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is respiratory infection. Most studies of bacterial or viral cause in AECOPD have been conducted in Western countries. We investigated bacterial and viral identification rates in AECOPD in Korea. MATERIALS AND METHODS: We reviewed and analyzed medical records of 736 cases of AECOPD at the Korea University Guro Hospital. We analyzed bacterial and viral identification rates and classified infections according to epidemiological factors, such as Global Initiative for Chronic Obstructive Lung Disease stage, mortality, and seasonal variation. RESULTS: The numbers of AECOPD events involving only bacterial identification, only viral identification, bacterial-viral co-identification, and no identification were 200 (27.2%), 159 (21.6%), 107 (14.5%), and 270 (36.7%), respectively. The most common infectious bacteria identified were Pseudomonas aeruginosa (13.0%), Streptococcus pneumoniae (11.4%), and Haemophilus influenzae (5.3%); the most common viruses identified were influenza virus (12.4%), rhinovirus (9.4%), parainfluenza virus (5.2%), and metapneumovirus (4.9%). The bacterial identification rate tended to be higher at more advanced stages of chronic obstructive pulmonary disease (p=0.020 overall, p=0.011 for P. aeruginosa, p=0.048 for S. pneumoniae). Staphylococcus aureus and Klebsiella pneumoniae were identified more in mortality group (p=0.003 for S. aureus, p=0.009 for K. pneumoniae). All viruses were seasonal (i.e., greater prevalence in a particular season; p < 0.050). Influenza virus and rhinovirus were mainly identified in the winter, parainfluenza virus in the summer, and metapneumovirus in the spring. CONCLUSION: This information on the epidemiology of respiratory infections in AECOPD will improve the management of AECOPD using antibiotics and other treatments in Korea.
Anti-Bacterial Agents
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Bacteria
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Epidemiology
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Haemophilus influenzae
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Klebsiella pneumoniae
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Korea
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Medical Records
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Metapneumovirus
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Mortality
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Orthomyxoviridae
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Paramyxoviridae Infections
;
Prevalence
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Pseudomonas aeruginosa
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Pulmonary Disease, Chronic Obstructive
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Respiratory Tract Infections
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Rhinovirus
;
Seasons
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Staphylococcus aureus
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Streptococcus pneumoniae