• Proceedings of the KOR-BRONCHOESO Conference
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• 1993.05a
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• pp.85-85
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• 1993

The clinical staging system for laryngeal cancers is not sufficient for prognosticator due to different biologic characteristics and their microenvironment according to primary sites. For determining the prognosticators, the authors peformed immunohistochemical staining to EGFR, p53 protein, and pRB in 40 cases of surgically treated squamous cell carcinomas of larynx in our institute during the past 5 years. The results are as followings; 1. The positive expression rate of p53 protein and negative expression rate of pRB showed correlations with clinical parameters. 2. The three-year survival rate for p53 protein positive cases was worse than the p53 protein negative cases. 3. Expression rate of EGFR was not correlated with the clinical parameters. As a conclusion, expression rates of p53 protein and pRB not only reflect well the biologic behavior of laryngeal cancer, but correlate closely with the tumor factors. Therefore they may be useful as the prognosticator to predict the malignant potency of laryngeal squamous cell carcinomas.

• Journal of Breast Disease
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• v.6 no.2
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• pp.35-38
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• 2018

Purpose: The eighth American Joint Committee on Cancer staging system for breast cancer was recently published to more accurately predict the prognosis by adding biomarkers such as estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2. However, this system is very complicated and difficult to use by clinicians. The authors developed a program to aid in setting up the staging system and confirmed its usefulness by applying it to theoretical combinations and actual clinical data. Methods: The program was developed using the Microsoft Excel Macro. It was used for the anatomic, clinical and pathological prognostic staging of 588 theoretical combinations. The stages were also calculated the stages using 840 patients with breast cancer without carcinoma in situ or distant metastasis who did not undergo preoperative chemotherapy. Results: The anatomic, clinical and pathological prognostic stages were identical in 240 out of 588 theoretical combinations. In the actual patients' data, stages IB and IIIB were more frequent in clinical and pathological prognostic stages than in the anatomic stage. The anatomic stage was similar to the clinical prognostic stage in 58.2% and to the pathological prognostic stage in 61.9% of patients. Oncotype DX changed the pathological prognostic stage in 2.1% of patients. Conclusion: We developed a program for the new American Joint Committee on Cancer staging system that will be useful for clinical prognostic prediction and large survival data analysis.

• Molecules and Cells
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• v.44 no.3
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• pp.168-178
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• 2021

The retinal pigment epithelium (RPE) forms a monolayer sheet separating the retina and choroid in vertebrate eyes. The polarized nature of RPE is maintained by distributing membrane proteins differentially along apico-basal axis. We found the distributions of these proteins differ in embryonic, post-natal, and mature mouse RPE, suggesting developmental regulation of protein trafficking. Thus, we deleted tumor susceptibility gene 101 (Tsg101), a key component of endosomal sorting complexes required for transport (ESCRT), in embryonic and mature RPE to determine whether ESCRT-mediated endocytic protein trafficking correlated with the establishment and maintenance of RPE polarity. Loss of Tsg101 severely disturbed the polarity of RPE, which forms irregular aggregates exhibiting non-polarized distribution of cell adhesion proteins and activation of epidermal growth factor receptor signaling. These findings suggest that ESCRT-mediated protein trafficking is essential for the development and maintenance of RPE cell polarity.

• International Journal of Oral Biology
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• v.46 no.4
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• pp.176-183
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• 2021

Oral squamous cell carcinoma (OSCC) metastasis is characterized by distant metastasis and local recurrence. Combined chemotherapy with cisplatin and 5-fluorouracil is routinely used to treat patients with OSCC, and the combined use of gefitinib with cytotoxic drugs has been reported to enhance the sensitivity of cancer cells in vitro. However, the development of drug resistance because of prolonged chemotherapy is inevitable, leading to a poor prognosis. Therefore, understanding alterations in signaling pathways and gene expression is crucial for overcoming the development of drug resistance. However, the altered characterization of Ca²⁺ signaling in drug-resistant OSCC cells remains unclear. In this study, we investigated alterations in intracellular Ca²⁺ ([Ca²⁺]_i) mobilization upon the development of gefitinib resistance in human tongue squamous carcinoma cell line (HSC)-3 and HSC-4 using ratiometric analysis. This study demonstrated the presence of altered epidermal growth factor- and purinergic agonist-mediated [Ca²⁺]_i mobilization in gefitinib-resistant OSCC cells. Moreover, Ca²⁺ content in the endoplasmic reticulum, store-operated calcium entry, and lysosomal Ca²⁺ release through the transient receptor potential mucolipin 1, were confirmed to be significantly reduced upon the development of apoptosis resistance. Consistent with [Ca²⁺]_i mobilization, we identified modified expression levels of Ca²⁺ signaling-related genes in gefitinib-resistant cells. Taken together, we propose that the regulation of [Ca²⁺]_i mobilization and related gene expression can be a new strategy to overcome drug resistance in patients with cancer.

• Tuberculosis and Respiratory Diseases
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• v.85 no.2
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• pp.147-154
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• 2022

Background: The expression of calcium signaling pathway molecules is altered in various carcinomas, which are related to the proliferation and altered characteristics of cancer cells. However, changes in calcium signaling in anti-cancer drug-resistant cells (bearing a T790M mutation in epidermal growth factor receptor [EGFR]) remain unclear. Methods: Afatinib-mediated changes in the level of store-operated Ca²⁺ entry (SOCE)-related proteins and intracellular Ca²⁺ level in non-small cell lung cancer cells with T790M mutation in the EGFR gene were analyzed using western blot and ratiometric assays, respectively. Afatinib-mediated autophagic flux was evaluated by measuring the cleavage of LC3B-II. Flow cytometry and cell proliferation assays were conducted to assess cell apoptosis and proliferation. Results: The levels of SOCE-mediating proteins (ORAI calcium release-activated calcium modulator 1 [ORAI1], stromal interaction molecule 1 [STIM1], and sarco/endoplasmic reticulum Ca²⁺ ATPase [SERCA2]) decreased after afatinib treatment in non-small cell lung cancer cells, whereas the levels of SOCE-related proteins did not change in gefitinib-resistant non-small cell lung cancer cells (PC-9/GR; bearing a T790M mutation in EGFR). Notably, the expression level of SOCE-related proteins in PC-9/GR cells was reduced also responding to afatinib in the absence of extracellular Ca²⁺. Moreover, extracellular Ca²⁺ influx through the SOCE was significantly reduced in PC-9 cells pre-treated with afatinib than in the control group. Additionally, afatinib was found to decrease the level of SOCE-related proteins through autophagic degradation, and the proliferation of PC-9GR cells was significantly inhibited by a lack of extracellular Ca²⁺. Conclusion: Extracellular Ca²⁺ plays important role in afatinib-mediated autophagic degradation of SOCE-related proteins in cells with T790M mutation in the EGFR gene and extracellular Ca²⁺ is essential for determining anti-cancer drug efficacy.

• Journal of Physiology & Pathology in Korean Medicine
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• v.35 no.4
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• pp.117-123
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• 2021

Gefitinib, a first generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI), provides obvious clinical benefit in patients with EGFR-mutant non-small cell lung cancer (NSCLC). However, patients ultimately develop gefitinib resistance which mainly caused by EGFR T790M secondary mutation. In the current study, we investigated whether the root extract of Scutellaria baicalensis (SB) overcomes gefitinib resistance. Gefitinib-resistant H1975 human NSCLC cells (EGFR L858R/T790M double mutant) were treated with gefitinib and/or ethanol extract of SB (ESB) to evaluate the effect of ESB on the gefitinib sensitivity. The cell viability was measured by MTT assay and trypan blue exclusion assay. The colony-forming ability was evaluated by anchorage-dependent colony formation assay. Combined treatment with gefitinib and ESB markedly decreased the cell viability and colony formation than single treatment with gefitinib or ESB in H1975 cells. In addition, cells treated with both gefitinib and ESB exhibited a significant increase of sub-G1 DNA content which indicates apoptotic cells compared with those treated with gefitinib or ESB alone. As a molecular mechanism, combined treatment with gefitinib and ESB strongly downregulated the phosphorylation of ERK and JNK than single treatment with gefitinib or ESB. Taken together, our results demonstrate that ESB sensitizes H1975 cells to gefitinib treatment. We cautiously propose that ESB can be used in combination with gefitinib for the advanced NSCLC patients with acquired resistance to EGFR TKIs.

• Journal of Gastric Cancer
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• v.23 no.1
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• pp.207-223
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• 2023

Gastric cancer (GC) is the fourth leading cause of cancer-related deaths worldwide. Under the standard of care, patients with advanced GC (AGC) have a median survival time of approximately 12-15 months. With the emergence of immunotherapy as a key therapeutic strategy in medical oncology, relevant changes are expected in the systemic treatment of GC. In the phase III ATTRACTION-2 trial, nivolumab, a monoclonal anti-programmed cell death 1 (PD-1) antibody, as a third- or later-line treatment improved overall survival (OS) compared with placebo in patients with AGC. Furthermore, nivolumab in combination with 5-fluorouracil and platinum as a first-line treatment improved OS in patients with human epidermal growth factor receptor-2 (HER2)-negative AGC in the global phase III CheckMate-649 study. Another anti-PD-1 antibody, pembrolizumab, in combination with trastuzumab and cytotoxic chemotherapy as a first-line treatment, significantly improved the overall response rate in patients with HER2-positive AGC. Therefore, immune checkpoint inhibitors (ICIs) are essential components of the current treatment of GC. Subsequent treatments after ICI combination therapy, such as ICI rechallenge or combination therapy with agents having other modes of action, are being actively investigated to date. On the basis of the success of immunotherapy in the treatment of AGC, various clinical trials are underway to apply this therapeutic strategy in the perioperative and postoperative settings for patients with early GC. This review describes recent progress in immunotherapy and potential immunotherapy biomarkers for GC.

• IMMUNE NETWORK
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• v.21 no.4
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• pp.31.1-31.16
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• 2021

Gastric cancer (GC) is the fourth most common cause of cancer-related death globally. The classification of advanced GC (AGC) according to molecular features has recently led to effective personalized cancer therapy for some patients. Specifically, AGC patients whose tumor cells express high levels of human epidermal growth factor receptor 2 (HER2) can now benefit from trastuzumab, a humanized monoclonal Ab that targets HER2. However, patients with HER2^negative AGC receive limited clinical benefit from this treatment. To identify potential immune therapeutic targets in HER2^negative AGC, we obtained 40 fresh AGC specimens immediately after surgical resections and subjected the CD45⁺ immune cells in the tumor microenvironment to multi-channel/multi-panel flow cytometry analysis. Here, we report that HER2 negativity associated with reduced overall survival (OS) and greater tumor infiltration with neutrophils and non-classical monocytes. The potential pro-tumoral activities of these cell types were confirmed by the fact that high expression of neutrophil or non-classical monocyte signature genes in the gastrointestinal tumors in The Cancer Genome Atlas, Genotype-Tissue Expression and Gene Expression Omnibus databases associated with worse OS on Kaplan-Meir plots relative to tumors with low expression of these signature genes. Moreover, advanced stage disease in the AGCs of our patients associated with greater tumor frequencies of neutrophils and non-classical monocytes than early stage disease. Thus, our study suggests that these 2 myeloid populations may serve as novel therapeutic targets for HER2^negative AGC.

• Korean Journal of Radiology
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• v.20 no.5
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• pp.781-790
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• 2019

Objective: To assess the relationship between contrast-enhanced ultrasound (CEUS) parameters and perfusion CT (PCT) parameters of gastric cancers and their correlation with histologic features. Materials and Methods: This prospective study was approved by our Institutional Review Board. We included 43 patients with pathologically-proven gastric cancers undergoing CEUS using SonoVue^® (Bracco) and PCT on the same day. Correlation between the CEUS parameters (peak intensity [PI], area under the curve [AUC], rise time [RT] from 10% to 90% of PI, time to peak [TTP_US], and mean transit time [MTT_US]) and PCT parameters (blood flow, blood volume, TTP_CT, MTT_CT, and permeability surface product) of gastric cancers were analyzed using Spearman's rank correlation test. In cases of surgical resection, the CEUS and PCT parameters were compared according to histologic features using Mann-Whitney test. Results: CEUS studies were of diagnostic quality in 88.4% (38/43) of patients. Among the CEUS parameters of gastric cancers, RT and TTP_US showed significant positive correlations with TTP_CT (rho = 0.327 and 0.374, p = 0.045 and 0.021, respectively); PI and AUC were significantly higher in well-differentiated or moderately-differentiated tumors (n = 4) than poorly-differentiated tumors (n = 18) (p = 0.026 and 0.033, respectively), whereas MTT_CT showed significant differences according to histologic types (poorly cohesive carcinoma [PCC] vs. non-PCC), T-staging (≤ T2 vs. ≥ T3), N-staging (N0 vs. N-positive), and epidermal growth factor receptor expression (≤ faint vs. ≥ moderate staining) (p values < 0.05). Conclusion: In patients with gastric cancers, CEUS is technically feasible for the quantification of tumor perfusion and may provide correlative and complementary information to that of PCT, which may allow prediction of histologic features.

• Tuberculosis and Respiratory Diseases
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• v.57 no.2
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• pp.160-168
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• 2004

Background : The role of second-line chemotherapy in the treatment of advanced non-small cell lung cancer (NSCLC) is known to be limited. Recently, ZD1839, the small molecule epidermal growth factor receptor-tyrosine kinase inhibitor, has been developed and has shown anti-tumor activity in patients with solid malignant tumors including lung cancer. We evaluated the response rate and toxicities of ZD1839 in patients with advanced NSCLC which has progressed after previous chemotherapy. Patients and Methods : We examined 83 patients with advanced NSCLC treated with ZD1839 for more than 1 month in Korea Cancer Center Hospital during the period from January 2002 to September 2003. All the patients were enrolled in the international expanded access program (EAP) with ZD1839 by AstraZeneca. The administered dose of ZD1839 was 250 mg once daily. Chest radiography and laboratory tests were followed-up. We evaluated the response rate, median survival, and toxicity after treatment. Results : Median age of the patients was 59 years (range 33-76). The most predominant cell type was adenocarcinoma and the most stage of the patients was IV. ECOG performance status was as follows; grade 0-1 in 10, grade 2 in 42, and grade 3 in 31 patients. Partial response was achieved in 12 patients (14.5%). Median overall survival was 9.2 (range 1.3-21.6+) months and median time to progression was 3.1 (range 1-21.2+) months. The most common adverse effect of ZD1839 was skin eruption which developed in 25 patients (25.8%). Significantly higher response rate and survival was found in patients with adenocarcinoma or good performance status. Conclusion : ZD1839 showed modest activity and tolerable toxicity in the treatment for patients with NSCLC which has progressed after previous chemotherapy.