• IMMUNE NETWORK
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• v.14 no.6
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• pp.296-306
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• 2014

There is growing evidence that crosstalk between mantle cell lymphoma (MCL) cells and stromal microenvironments, such as bone marrow and secondary lymphoid tissues, promotes tumor progression by enhancing survival and growth as well as drug resistance of MCL cells. Recent advances in the understanding of lymphoma microenvironment have led to the identification of crucial factors involved in the crosstalk and subsequent generation of their targeted agents. In the present study, we evaluated the combinatory effect of blocking antibodies (Ab) targeting CXCR4 and VLA-4, both of which were known to play significant roles in the induction of environment-mediated drug resistance (EMDR) in MCL cell line, Jeko-1. Simultaneous treatment with anti-CXCR4 and anti-VLA-4 Ab not only reduced the migration of Jeko-1 cells into the protective stromal cells, but also enhanced sensitivity of Jeko-1 to a chemotherapeutic agent to a greater degree than with either Ab alone. These combinatorial effects were associated with decreased phosphorylation of ERK1/2, AKT and NF-${\kappa}B$. Importantly, drug resistance could not be overcome once the adhesion of Jeko-1 to the stromal occurred despite the combined use of Abs, suggesting that the efforts to mitigate migration of MCLs should be attempted as much as possible. Our results provide a basis for a future development of therapeutic strategies targeting both CXCR4 and VLA-4, such as Ab combinations or bispecific antibodies, to improve treatment outcomes of MCL with grave prognosis.

• Korean Journal of Head & Neck Oncology
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• v.37 no.1
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• pp.63-66
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• 2021

Supracricoid partial laryngectomy (SCPL) with cricohyoidoepiglottopexy (CHEP) or cricohyoidopexy (CHP) involves the removal of the whole thyroid cartilage, both true and false vocal cords, the ventricles, and the paraglottic spaces, sparing the cricoid cartilage, hyoid bone, and at least one functional and mobile cricoarytenoid unit. Reconstruction is performed by suturing of the cricoid cartilage up tightly to the hyoid bone, so trachea-releasing procedures are needed to prevent leakage at anastomosis site. In case of advanced tranglottic cancer invading tracheal tracheal wall, we need to perform additional circumferentrial circumferential tracheal wall resection. However, when we perform SCPL, circumferential resection of tracheal wall is limited because SCPL procedure itself needs releasing of tracheal length. We report a case of advanced transglottic cancer involving tracheal wall treated with induction chemotherapy and SCPL including tracheal wall resection with reconstruction of tracheal defect by sternocleidomastoid muscle flap covered with skin graft.

• Tuberculosis and Respiratory Diseases
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• v.69 no.1
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• pp.16-23
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• 2010

Background: Most lung cancer patients receive systemic chemotherapy at an advanced stage disease. Cisplatin-based chemotherapy is the main regimen for treating advanced lung cancer. Recently, autophagy has become an important mechanism of cellular adaptation under starvation or cell oxidative stress. The purpose of this study was to determine whether or not autophagy can occurred in cisplatin-treated lung cancer cells. Methods: H460 cells were incubated with RPMI 1640 and treated in $5{\mu}M$ or $20{\mu}M$ cisplatin concentrations at specific time intervals. Cells surviving cisplatin treatment were measured and compared using an MTT cell viability assay to cells that underwent apoptosis with autophagy by nuclear staining, apoptotic or autophagic related proteins, and autophagic vacuoles. The development of acidic vascular organelles was using acridine orange staining and fluorescent expression of GFP-LC3 protein in its transfected cells was observed to evaluate autophagy. Results: Lung cancer cells treated with $5{\mu}M$ cisplatin-treated were less sensitive to cell death than $20{\mu}M$ cisplatin-treated cells in a time-dependent manner. Nuclear fragmentation at $5{\mu}M$ was not detected, even though it was discovered at $20{\mu}M$. Poly (ADP-ribose) polymerase cleavages were not detected in $5{\mu}M$ within 24 hours. Massive vacuolization in the cytoplasm of $5{\mu}M$ treated cells were observed. Acridine orange stain-positive cells was increased according in time-dependence manner. The autophagosome-incorporated LC3 II protein expression was increased in $5{\mu}M$ treated cells, but was not detected in $20{\mu}M$ treated cells. The expression of GFP-LC3 were increased in $5{\mu}M$ treated cells in a time-dependent manner. Conclusion: The induction of autophagy occurred in $5{\mu}M$ dose of cisplatin-treated lung cancer cells.

• Journal of Chest Surgery
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• v.36 no.7
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• pp.489-496
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• 2003

To clarify the prognostic implication of the location and number of the metastatic mediastinal nodes in resected stage IIIA N2 non-small cell lung cancer. Material and Method: One hundred and seventy-four patients with resected non-small cell lung cancer who eventually proved to have pathologic stage IIIA N2 disease were studied. Patients who received preoperative induction therapy, non-curative operation or defined as operative mortality were excluded from this study. Result: In upper lobe tumors, there was no difference in 5-year survival according to the involvement of lower mediastinal nodes (32.3% vs 25.6%, p＝0.86). In lower lobe tumors, no difference was found in 5-year survival according to the involvement of upper mediastinal nodes (25.1% vs 14.1%, p＝0.33). There was no significant difference in 5-year survival between patients with or without metastatic subcarinal node (20.9% vs 25.6%, p＝0.364). In terms of the number of metastatic mediastinal nodes, 5-year survival was better in single station group (26.3%) than multiple station group (18.3%) (p＝0.048). In multiple station N2 group, the patients who received postoperative chemotherapy and radiation therapy had better 5-year survival (34.2%) (p＝0.01). Cox's proportional hazards model revealed that the age $\geq$60 (O.R: 1.682, p＝.006), multiple station N2 (O.R: 1.503. p＝0.021), pneumonectomy (O.R: 1.562, p＝0.018), postoperative chemotherapy and radiation therapy (O.R: 0.625, p＝0.012) were the factors affecting the postoperative survival. Conclusion: Multiple station N2 disease was the important prognostic factor for postoperative survival in resected stage IIIA N2 non-small cell lung cancer. Postoperative chemotherapy and radiotherapy were thought to improve the survival in case of multiple station N2 disease.

• Tuberculosis and Respiratory Diseases
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• v.57 no.3
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• pp.257-264
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• 2004

Background : There are many combinations of treatment for locally advanced non-small cell lung cancer (NSCLC). Recent studies have showed the efficacy of concurrent chemoradiotherapy (CCRT) in NSCLC. At present, however, there is no consensus about the optimal dosages and timing of radiation and chemotherapeutic agents. The aims of study were to determine the feasibility, toxicity, response rate, and survival rate in locally advanced NSCLC patients treated with doxetaxel and cisplatin based CCRT. Method : Sixteen patients with unresectable stage III NSCLC were evaluated from May 2000 until September 2001. Induction chemoradiotherapy consisted of 3 cycles of docetaxel (75 $mg/m^2/IV$ on day 1) and cisplatin (60 $mg/m^2/IV$ on day 1) chemotherapy every 3 weeks and concomitant hyperfractionated chest irradiation (1.15 Gy/BID, total dose of 69 Gy) in 6 weeks. Patient who had complete or partial response, and stable disease were applied consolidation chemotherapy of docetaxel and cisplatin. Results : All patients showed response to CCRT. Four patients achieved complete response (25%), partial responses in 12 patients (75%). The major common toxicities were grade III or more of neutropenia (87.3%), grade III esophagitis (68.8%), pneumonia (18.8%) and grade III radiation pneumonitis (12.5%). Thirteen patients were ceased during follow-up period. Median survival time was 19.9 months (95% CI; 4.3-39.7 months). The survival rates in one, two, and three years are 68.7%, 43.7%, and 29.1%, respectively. Local recurrence was found in 11 patients (66.8%), bone metastasis in 2, and brain metastasis in 1 patient. Conclusion : The response rate and survival time of CCRT with docetaxel/cisplatin in locally advanced NSCLC were encouraging, but treatment related toxicities were high. Further modification of therapy seems to be warranted.

• Korean Journal of Head & Neck Oncology
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• v.14 no.2
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• pp.156-163
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• 1998

Background & Objectives: Frameless fractionated stereotactic radiotherapy(FFSRT) is a modification of stereotactic radiosurgery(SRS) with radiobiologic advantage of fractionation without losing mechanical accuracy of SRS. Local recurrence of head and neck cancer at or near skull base benefit from reirradiation. Main barrier to successful palliation is dose limitation secondary to normal tissue tolerance. We try to evaluate the efficacy and safety of FFSRT as a new modality of reirradaton in these challenging patients. Materials & Methods: Seven patients with recurrent head & neck cancer involving at or near skull base received FFSRT from September 1995 to November 1997. Six patients with nasopharyngeal cancer had received induction chemotherapy and curative radiation therapy. One patient with maxillary sinus cancer had received total maxillectomy and postoperative radiation therapy as a initial treatment. Follow-up ranged from 11 to 32 months with median of 24 months. Three of 7 patients received hyperfractionated radiation therapy(1.1-1.2Gy/fraction, bid, total 19.8-24Gy) just before FFSRT. All patients received FFSRT(3-5Gy/fraction, total 15-30Gy/5-10fractions). Chemotherapy(cis-platin $100mg/m^2$) were given concurrently with FFSRT in four patients. Second course of FFSRT were given in 4 patients with progression or recurrence after initial FFSRT. Because IF(irregularity factor; ratio of surface area of target to the surface area of sphere with same volume as a target) is too big to use conventional stereotactic RT using multiple arc method for protection of radiation damage to critical normal tissue, all patients received FFSRT with conformal method using irregular static ports. Results: Five of 7 patients showed complete remission in follow-up CT &/or MRI. Three of these five patients who developed marginal, in-field, and out-field recurrences, respectively. Another one of complete responders has been dead of G-I bleeding without evidence of local recurrence. One partial responder who showed progressive disease 15 months after initial FFSRT has received additional FFSRT, and then he is well-being with symptomatic improvement. One minmal responder who showed progression of locoregional disease 9 months after $1^{st}$ FFSRT has received 2nd FFSRT, and then he is alive with stable disease. Five of 7 case had showed direct invasion to skull base and had complaint headache and various symptoms of cranial nerve involvement. Four of these five case showed improvement of neurologic symptoms after FFSRT. No significant neurologic complicaltion related to FFSRT was observed during follow-up periods. Tumor volumes were ranged from 3.9 to 50.7 cc and surface area ranged from 16.1 to $114.9cm^2$. IF ranged from 1.21 to 1.74. The average ratio of volume of prescription isodose shell to target volume was 1.02 that indicated the improvement of target coverage and dose distribution with FFSRT with conformal method compared to target coverage with FFSRT with multiple arc method. Conclusion: Our initial experience suggests that FFSRT with conformal method was relatively effective and safe modality in the treatment of recurrent head and neck cancer involving at or near skull base. Treatment benefit included good palliation of symptoms and reasonable radiographic response. However, more experience and additional follow-up are needed to better assess its ultimate role in treating these challenging patients.

• Radiation Oncology Journal
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• v.16 no.3
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• pp.259-264
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• 1998

Purpose : This study was to evaluate the effectiveness of preoperative radiotherapy in maxillary sinus cancer. Materials and Methods : A retrospective analysis was done for 42 patients with maxillary sinus cancer who were treated with radiation with or without surgery from April 1986 to September 1996. There were 27 male and 15 female patients. Patients' age ranged from 24 to 75 years (median 56 years). Stage distribution showed 2 in T2, 19 in T3, and 21 in T4 lesions The histologic type was squamous cell carcinoma in 38, undifferentiated carcinoma in 1, transitional cell carcinoma in 1, and adenoid cystic carcinoma in 2 patients. All patients were treated with radiation initially with a dosage range of 50.4-70.2 Gy (median 70.2 Gy) before further evaluation of remnant disease. Eleven patients were given induction chemotherapy (2cycles of 5-fluorouracil and cisplatin) concurrently with radiotherapy. Six to eight weeks after radiotherapy with or without chemotherapy computerized tomography (CT) of paranasal sinus was taken to evaluate remnant disease. If the CT finding showed remnant disease, a Caldwell-Luc procedure was done to get the specimen of suspicious lesions. A radical maxillectomy was done if the specimen was proven to contain malignancy. In contrast periodic follow-up examination was done without any radical surgery if the tissue showed only granulation tissue. Follow-up period ranged from 3 to 92 months with a median 16 months. Results : Nine (21.4$\%$) patients showed complete response (CR) and 33 patients (78.6$\%$) showed persistent disease (PER) to initial radiotherapy. Among the 9 CR patients, 7 patients had no evidence of disease (NED), 1 patient had local failure, and 1 patient had regional failure. Among 33 PER patients, salvage total maxillectomy was done in 10 patients, and the surgery was not feasible or refused in 23 patients. Following the salvage radical surgery, 2 patients were NED and 8 patients were PER status. Overall and disease- free survival rate at 5 years was 23.1$\%$ and 16.7$\%$, respectively. The only factors associated with the overall survival rate was the response to radiotherapy (P<0.01). Conclusion : The only factors associated with the overall survival rate was the response to radiotherapy. We could omit a radical mutilating surgery by preoperative irradiation in 7 of 42 patients (21.4$\%$) so as to preserve their facial integrity.

• Tuberculosis and Respiratory Diseases
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• v.63 no.2
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• pp.154-164
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• 2007

Background: Irinotecan hydrochloride, a topoisomerase I inhibitor, is effective against small-cell lung cancer. Irinotecan also can act as a potential radiation sensitizer along with cisplatin. To evaluate efficacy and toxicity of irinotecan plus cisplatin (IP) with concurrent thoracic radiotherapy, we conducted a phase II study of IP followed by concurrent IP plus hyperfractionated thoracic radiotherapy in patients with previously untreated limited-stage small-cell lung cancer. Methods: Twenty-four patients with previously untreated small-cell lung cancer were enrolled onto the study since November 2004. Irinotecan $60mg/m^2$ was administered intravenously on days 1 and 8 in combination with cisplatin $60mg/m^2$ on day1 every 21 days. From the first day of third cycle, twice-daily thoracic irradiation (total 45 Gy) was given. Prophylactic cranial irradiation was given to the patients who showed complete remission after concurrent chemoradiotherapy. Restaging was done after second and sixth cycle with chest CT and/or bronchosocpy. Results: Up to November 2004, 19 patients were assessable. The median follow-up time was 12.5 months. A total of 99 cycles (median 5.2 cycles per patient) were administered. The actual dose intensity values were cisplatin $19.6mg/m^2$/week and irinotecan $38.2mg/m^2$/week. Among the 19 patients, the objective response rate was 95% (19 patients), with 9 patients (47%) having a complete response (CR). The major grade 3/4 hematological toxicities were neutropenia (35% of cycles), anemia (7% of cycles), thrombocytopenia (7% of cycles). Febrile neutropenia was 4% of cycles. The predominant grade 3/4 non-hematological toxicities was diarrhea (5% of cycles). Toxicities was not significantly different with concurrent administration of irinotecan and cisplatin with radiotherapy, except grade 3/4 radiation esophagitis (10% of patients). No treatment-related deaths were observed. The 1-year and 2-year survival rate of eligible patients was 89% (16/18) and 47% (9/18), respectively. Conclusion: Three-week schedule of irinotecan plus cisplatin followed by concurrent IP plus hyperfractionated thoracic radiotherapy is an effective treatment for limited disease small-cell lung cancer, with acceptable toxicity.

• Journal of Life Science
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• v.24 no.11
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• pp.1244-1251
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• 2014

Platycodon grandiflorum (PG) has been known to possess many biological effects, including anti-inflammatory and anti-allergy activity and anti-obesity and hyperlipidemia effects. However, little research has been conducted regarding its anticancer effects, with the exception of its ability to stimulate apoptosis in skin cells. There has also been no study regarding PG-induced autophagy. The modulation of autophagy is recognized as one of the hallmarks of cancer cells. Depending on the type of cancer and the context, autophagy can suppress or help cancer cells to overcome metabolic stress and the cytotoxicity of chemotherapy. Therefore, the present study was designed to investigate whether or not extracts from PG-induced cell death were connected with autophagy and apoptosis in HCT-116 human colon cancer cells. PG stimulation decreased cell proliferation in a dose- and time-dependent manner and induced apoptosis, which was partially dependent on the activation of caspases. PG treatment also resulted in the formation of autophagic vacuoles simultaneously with regulation of autophagy-related genes. Interestingly, a PG-mediated apoptotic effect was further triggered by pretreatment with the autophagy inhibitors 3-methyladenin and bafilomycin A1. However, cell viability recovered quite well with bafilomycin A1 treatment. These findings show that PG treatment promotes both autophagy and apoptosis and that PG-induced autophagic response might play a role in the autophagic cell death of HCT-116 cells.

• Journal of Life Science
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• v.27 no.8
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• pp.958-964
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• 2017

Autophagy plays an important role in cellular homeostasis and survival for cell recycling and various stresses within the cell. Recent studies have shown that autophagy activity modulates the expression of oncogene and tumor suppressor genes, leading to the development or suppression of cancer. Induction of autophagy is involved in preventing cancer development in normal cells and plays an important role in prompting a specific cell death mechanism in cancer cells with damaged cell death function. It is also known that autophagy inhibition increases the therapeutic efficacy by sensitizing cancer cells that are resistant to chemotherapy. However, the role of autophagy has not yet been fully understood in cancer treatment. Oral squamous cell carcinoma accounts for more than 90% of oral cancer and is the sixth most common cancer in the world. The incidence of oral cancer has increased by 50% over the last 20 years and the mortality rate is over 40% within 5 years after the onset. In oral cancers, the role of autophagy are described to look for tumor inhibitory in the early stages of tumor formation, like other cancers, indicating the dual functions involved in tumor cell survival include tumor progression stages. This review summarizes the various roles of autophagy in cancer cells and suggests the possibility of autophagy as a promising target for effective oral cancer therapy.