• Molecules and Cells
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• 제38권5호
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• pp.416-425
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• 2015

NF-E2-related factor 2 (Nrf2), a basic leucine zipper transcription factor, has recently received a great deal of attention as an important molecule that enhances antioxidative defenses and induces resistance to chemotherapy or radiotherapy. In this study, we investigated the apoptosis-inducing and Nrf2- upregulating effects of quercetin on malignant mesothelioma (MM) MSTO-211H and H2452 cells. Quercetin treatment inhibited cell growth and led to upregulation of Nrf2 at both the mRNA and protein levels without altering the ubiquitination and extending the half-life of the Nrf2 protein. Following treatment with quercetin, analyses of the nuclear level of Nrf2, Nrf2 antioxidant response element-binding assay, Nrf2 promoter-luc assay, and RT-PCR toward the Nrf2-regulated gene, heme oxygenase-1, demonstrated that the induced Nrf2 is transcriptionally active. Knockdown of Nrf2 expression with siRNA enhanced cytotoxicity due to the induction of apoptosis, as evidenced by an increase in the level of proapoptotic Bax, a decrease in the level of antiapoptotic Bcl-2 with enhanced cleavage of caspase-3 and PARP proteins, the appearance of a sub-$G_0/G_1$ peak in the flow cytometric assay, and increased percentage of apoptotic propensities in the annexin V binding assay. Effective reversal of apoptosis was observed following pretreatment with the pan-caspase inhibitor Z-VAD. Moreover, Nrf2 knockdown exhibited increased sensitivity to the anticancer drug, cisplatin, presumably by potentiating the oxidative stress induced by cisplatin. Collectively, our data demonstrate the importance of Nrf2 in cytoprotection, survival, and drug resistance with implications for the potential significance of targeting Nrf2 as a promising strategy for overcoming resistance to chemotherapeutics in MM.

• 대한세포병리학회지
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• 제19권2호
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• pp.126-135
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• 2008

Malignant mesothelioma (MM) is a highly lethal neoplasm arising in pleura and the peritoneum and a rapid and accurate diagnosis is crucial for treatment of the disease. However, the sensitivity of cytological analysis using pleural or ascitic fluid is relatively low, yielding an accurate diagnosis in only $32{\sim}79%$ of cases. We tested the diagnostic value of epigenetic alterations in body fluid cytology as a supplement to conventional methods. Paraffin-embedded tissue blocks from 21 MM patients and associated body fluid cytology slides considered no evidence of malignancy were used to test for epigenetic alteration. Using methylation-specific PCR, we detected methylation of RASSF1A and p16 in 47.6% (10/21) of both surgically resected tumor samples, respectively. Body fluid samples of MM also showed abnormal methylation of RASSF1A and p16INK4a genes in 38.1% (8/21) and 33.3% (7/21) of cases. The concordance in the rates of RASSF1A and p16INK4a gene-methylation abnormalities determined from cytology samples and tissue samples were 61.9% (13/21) and 66.7% (14/21), respectively. Combining both genes increases the sensitivity of the test to 57.1 % (12 of 21) of cases. Our results suggest that testing for methylation abnormalities in selected individual genes or gene combinations has diagnostic value as an alternative or adjunct method to conventional cytological diagnosis.

• Journal of Chest Surgery
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• 제55권5호
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• pp.405-412
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• 2022

Background: Malignant pleural mesothelioma (MPM) is an aggressive pleural malignancy, and despite all multimodal treatment modalities, the 5-year overall survival rate of patients with MPM is less than 20%. In the present study, we aimed to analyze the surgical and prognostic outcomes of patients with MPM who received multimodal treatment. Methods: In this retrospective, single-center study, the records of patients who underwent surgery for MPM between January 2010 and December 2020 at our department were reviewed retrospectively. Results: Sixty-four patients were included in the study, of whom 23 (35.9%) were women and 41 (64.1%) were men. Extrapleural pneumonectomy, pleurectomy/decortication, and extended pleurectomy/decortication procedures were performed in 34.4%, 45.3%, and 20.3% of patients, respectively. The median survival of patients was 21 months, and the 5-year survival rate was 20.2%. Advanced tumor stage (hazard ratio [HR], 1.8; p=0.04), right-sided extrapleural pneumonectomy (HR, 3.1; p=0.02), lymph node metastasis (HR, 1.8; p=0.04), and incomplete multimodal therapy (HR, 1.9; p=0.03) were poor prognostic factors. There was no significant survival difference according to surgical type or histopathological subtype. Conclusion: Multimodal therapy can offer an acceptable survival rate in patients with MPM. Despite its poor reputation in the literature, the survival rate after extrapleural pneumonectomy, especially left-sided, was not as poor as might be expected.

• Molecules and Cells
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• 제40권8호
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• pp.567-576
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• 2017

The $Na^+/H^+$ exchanger is responsible for maintaining the acidic tumor microenvironment through its promotion of the reabsorption of extracellular $Na^+$ and the extrusion of intracellular $H^+$. The resultant increase in the extracellular acidity contributes to the chemoresistance of malignant tumors. In this study, the chemosensitizing effects of cariporide, a potent $Na^+/H^+-exchange$ inhibitor, were evaluated in human malignant mesothelioma H-2452 cells preadapted with lactic acid. A higher basal level of phosphorylated (p)-AKT protein was found in the acid-tolerable H-2452AcT cells compared with their parental acid-sensitive H-2452 cells. When introduced in H-2452AcT cells with a concentration that shows only a slight toxicity in H-2452 cells, cariporide exhibited growth-suppressive and apoptosis-promoting activities, as demonstrated by an increase in the cells with pyknotic and fragmented nuclei, annexin V-PE(+) staining, a $sub-G_0/G_1$ peak, and a $G_2/M$ phase-transition delay in the cell cycle. Preceding these changes, a cariporide-induced p-AKT down-regulation, a p53 up-regulation, an ROS accumulation, and the depolarization of the mitochondrial-membrane potential were observed. A pretreatment with the phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002 markedly augmented the DNA damage caused by the cariporide, as indicated by a much greater extent of comet tails and a tail moment with increased levels of the p-histone H2A.X, $p-ATM^{Ser1981}$, $p-ATR^{Ser428}$, $p-CHK1^{Ser345}$, and $p-CHK2^{Thr68}$, as well as a series of pro-apoptotic events. The data suggest that an inhibition of the PI3K/AKT signaling is necessary to enhance the cytotoxicity toward the acidtolerable H-2452AcT cells, and it underlines the significance of proton-pump targeting as a potential therapeutic strategy to overcome the acidic-microenvironment-associated chemotherapeutic resistance.

• Asian Pacific Journal of Cancer Prevention
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• 제17권8호
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• pp.4169-4173
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• 2016

Background: Mesotheliomas are relatively rare tumors in Lebanon. The only previous study goes back to 14 years ago, when we published epidemiological characteristics of mesotheliomas in Lebanon, showing that the pleural location accounted for the vast majority of cases, with clear evidence of asbestos exposure from the Eternit factory of Chekka region. The objective of this current study was to estimate the incidence of mesothelioma in the past decade and to identify its epidemiological, clinical and therapeutic characteristics, making comparisons with our first study published in 2001. Materials and Methods: Between 2002 and 2014, patients diagnosed with malignant mesothelioma at Hotel-Dieu de France University Hospital were investigated. Epidemiological data focusing on asbestos exposure history were collected from medical records and interviews with the families. Results: A total of 26 patients were diagnosed with mesothelioma, 21 of which were successfully investigated. The mean age of these 21 patients is 62.5 (19-82). Only 3 (14.29%) are women. 18 (85.71%) were smokers. Among the 21 available mesotheliomas, 15 (71.4%) are pleural, while 5 (23.8%) are peritoneal and 1 (4.8%) pericardial. Only 60% of patients with pleural mesothelioma and 50% of those with an obvious exposure to asbestos lived and/or worked in Chekka region. The mean time of asbestos exposure in patients with mesothelioma is 24.5 (1-50) years and the mean latency is 37.4 (4-61) years. Of the 21 patients, 10 (47.6%) underwent surgery during their treatment, 16 (76.2%) received chemotherapy and 3 (14.3%) received best supportive care. Conclusions: Compared to the previous study (1991-2000), substantial changes in the epidemiology of mesothelioma in Lebanon were observed, such as an increase in peritoneal localizations and a lower correlation with Chekka region asbestos contamination.

• Journal of Chest Surgery
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• 제2권1호
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• pp.49-54
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• 1969

Four cases of pleural mesothelioma were treated surgically. The tumors from all cases were microscopicaly malignant, although only in one case the tumor was found to be diffuse in growth. The diagnosis made before operation were exudative pleurisy, empyema or lung cancer with no tumor cells found in examination of pleural fluid, sputum or the specimen of pleuraI biopsy. In two cases only the tumors were resected, and in other two cases pneumonectomy and pleuropneumonectomy were performed. Irradiations added in two cases postoperatively were found not to be beneficial. Postoperative recurrence of tumor growth were found in three cases within two months after surgery, and in one case no evidence of recurrence was noted four and a half months after resection of the tumor.

• Journal of Chest Surgery
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• 제33권12호
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• pp.982-987
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• 2000

미만성 악성 중피세포종은 예후가 불량한 드문 암종으로, 아직까지 적절한 병기 분류가 없고, 병리 조직학적인 진단이 쉽지 않다. 치료에 대해서 논쟁이 많지만 선택된 환자에서 늑막 폐절제술을 시행하고 보조적인항 화학요법과 방사선 요법이 생존 기간을 연장시킬 수 잇다. 저자들은 1992년 6월부터 7년간 미만성 악성 중피세포종 환자 4례에서 늑막 폐절제술을 시행하였으며 수술후 조기 사망은 없었다. 3례의 환자에서 수술후 보조요법을 시행할 수 있었다(보조 화학요법 2례, 보조 화학요법 및 방사선 치료 1례). 그러나 한 예에서는 수술후 발생한 심장염전에 의한 저산소성 뇌손상 및 농흉으로 인하여 보조용법을 시행할 수 없었다. 저자들은 저자들의 늑막 폐 절제술의 경험 및 미만성 악성 중피세포종에 대한 논란이 되는 점을 문헌고찰과 함께 보고하는 바이다.

• Journal of Chest Surgery
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• 제37권3호
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• pp.228-234
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• 2004

원발성 심종양은 비특이적 증상을 호소하고 매우 드물게 발생하는 질환이다. 악성 종양과 양성 종양으로 구분되며 외과적 절제술과 부가적인 치료를 필요로 한다. 1995년 3월부터 2003년 3월까지 원발성 심종양으로 진단받은 21예의 환자들을 대상으로 하였다. 이 환자들을 대상으로 수술 전후의 여러 가지 인자들과 수술 후 조기 및 만기 성적에 대한 후향적 연구를 진행하였다. 6예는 남자, 15예는 여자였으며 그들의 평균 연령은 45.44$\pm$18.76세였다. 병리학적 검사 결과 21예 중에서 18예는 양성(14예의 점액종, 2예의 섬유탄력종, 1예의 혈관종, 1예의 부신경절종), 3예는 악성(1예의 혈관 육종, 1예의 중피종, 1예 점액섬유육종)종양이었다. 1예의 수술 사망이 관찰되었고, 혈관종, 중피종과 혈관육종의 경우 근치적인 수술이 불가능한 상태에서 술 후 부가적인 치료와 외래 추적 중에 사망하였다. 원발성 심종양의 치료에 있어서 수술적 치료가 중요하며 경우에 따라서 부가적인 치료도 중요하지만 악성의 결과 예후는 불량하다.

• Journal of Chest Surgery
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• 제29권12호
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• pp.1385-1391
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• 1996

흉막의 고립성 섬유성 종양은 과거 중피종의 한 형태로 알려져 있으며 중피종과 흔돈하여 쓰여 왔으나 최근에는 중피하에 존재하는 미분화 중배엽성 기원의 섬유세포에서 기원하고 있는 종양으로 해석된다. 환자는 65세 여자로 우측흉통과기침 및 호흡곤란을 주소로 본원에 입원하여 흉부 방사선 및 전산화 단층 촬영상 우측 흉강내에 고형성 종괴가 발견되었다. 수술소견상 종괴의 크기와 무게는 12$\times$12$\times$6mm, 400mm 이었으며, 폐 실질내로 침윤하였고 세기관지 내강을 따라 성장한 부분이 관찰되었다. 또한 종괴는 횡경막과 벽측 흉막 및 폐실질에 다발성으로 전이 되어 있었다. 병리학적으로, 종괴는 세포밀도가 높았고, 판상배열을 보이는 등글거나 난원형 또는 짧은 방추형의 세포로 이루어졌으며, 10배의 고배율 시야에서 3개의 유사분열이 관찰되었다. 면역조직화학 염색상 vimentin과 actin에 미만성 강양성 반응을 보였고 전자현미경적으로 조면 세포질내세망이 풍부하며 세포접합부나 미세응모는 관찰되지 않아서 악성 고립성 섬유성 종양에 합당하였다. 본 교실에서는 흉막에 발생한 악성 고립성 섬유성 종양을 경험하였기에 문헌 고찰과 함께 보고한다.

• Asian Pacific Journal of Cancer Prevention
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• 제15권1호
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• pp.363-368
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• 2014

Determination of the cause of malignant pleural effusions is important for treatment and management, especially in cases of unknown primaries. There are limited biomarkers available for prediction of the cause of malignant pleural effusion in clinical practice. Hence, we evaluated pleural levels of five tumor biomarkers (CEA, AFP, CA125, CA153 and CA199) in predicting the cause of malignant pleural effusion in a retrospective study. Kruskal-Wallis or Mann-Whitney U tests were carried out to compare levels of tumor markers in pleural effusion among different forms of neoplasia - lung squamous cell carcinoma, adenocarcinoma, or small cell carcinoma, mesothelioma, breast cancer, lymphoma/leukemia and miscellaneous. Receiver operator characteristic analysis was performed to evaluate sensitivity and specificity of biomarkers. The Kruskal-Wallis test showed significant differences in levels of pleural effusion CEA (P<0.01), AFP (P<0.01), CA153 (P<0.01) and CA199 (P<0.01), but not CA125 (P>0.05), among the seven groups. Receiver operator characteristic analysis showed that, compared with other four tumor markers, CA153 was the best biomarker in diagnosing malignant pleural effusions of lung adenocarcinoma (area under curve (AUC): 0.838 (95%confidence interval: 0.787, 0.888); cut-off value: 10.2U/ml; sensitivity: 73.2% (64.4-80.8)%, specificity: 85.2% (77.8-90.8)%), lung squamous cell carcinoma (AUC: 0.716 (0.652, 0.780); cut-off value: 14.2U/ml; sensitivity: 57.6% (50.7-64.3)%, specificity: 91.2% (76.3-98.0)%), and small-cell lung cancer (AUC: 0.812 (0.740, 0.884); cut-off value: 9.7U/ml; sensitivity: 61.5% (55.0-67.8)%, specificity: 94.1% (71.2-99.0)%); CEA was the best biomarker in diagnosing MPEs of mesothelioma (AUC: 0.726 (0.593, 0.858); cut-off value: 1.43ng/ml; sensitivity: 83.7% (78.3-88.2)%, specificity: 61.1% (35.8-82.6)%) and lymphoma/leukemia (AUC: 0.923 (0.872, 0.974); cut-off value: 1.71ng/ml; sensitivity: 82.8% (77.4-87.3)%, specificity: 92.3% (63.9-98.7)%). Thus CA153 and CEA appear to be good biomarkers in diagnosing different causes of malignant pleural effusion. Our findings implied that the two tumor markers may improve the diagnosis and treatment for effusions of unknown primaries.