Na-Hye Myong

Cyclin D1 Overexpression, p16 Loss, and pRb Inactivation Play a Key Role in Pulmonary Carcinogenesis and have a Prognostic Implication for the Long-term Survival in Non-small Cell Lung Carcinoma Patients

PURPOSE We investigated the immunoexpressions of cyclin D1, cyclin-dependent kinase inhibitor p16 and phosphorylated retinoblastoma (p-pRb) proteins in non-small cell lung carcinoma (NSCLC) to demonstrate their key roles in tumorigenesis, their relationship with the clinicopathologic factors, and their prognostic influences on the long-term survival. MATERIALS AND METHODS 115 surgically resected NSCLCs were immunohistochemically stained for the G(1)/S cell cycle proteins, with using a tissue microarray. The correlation between their immunoexpressions and the clinicopathologic prognostic factors, their inter-relationships and their single or combined effects on the long-term survival (over 5 years) were statistically analyzed by SPSS15.0. RESULTS Loss of p16 was found in 75% of the cases and cyclin D1 overexpression and phosphorylated pRb (p-pRb) were found in 64% and 46%, respectively. Cyclin D1 overexpression was correlated with the p16 loss and pRb inactivation by phosphorylation. The p16 loss was tightly associated with p-pRb. The Kaplan-Meier survival curves disclosed that the cyclin D1-positive group and the p16-negative group showed a rapid decline of survival at the point of about 5 years after surgery and thereafter. The combined actions of cyclin D1 overexpression, loss of p16 and pRb inactivation tended to have an adverse influence on the prolonged survival. CONCLUSIONS The observation that cyclin D1 overexpression, p16 loss and pRb inactivation were largely found in NSCLCs suggests that they play an important role in pulmonary carcinogenesis. Also, their inverse or positive correlations indicate that the G(1)/S cell cycle proteins may act alternatively or synergistically on the mechanisms by which tumor cells escape the G(1) restriction point. Finally, their solitary or combined actions might have a long-term effect on the survival.

Interleukin-8 Production in Tuberculous Pleurisy: Role of Mesothelial Cells Stimulated by Cytokine Network Involving Tumour Necrosis Factor-α and Interleukin-1β

Interleukin‐8 (IL‐8) plays an important role in the host immune response to Mycobacterium tuberculosis by recruiting inflammatory cells to the site of infection. Here, we investigated the role of pleural macrophages and mesothelial cells in the production of IL‐8 in tuberculous pleurisy. Large concentrations of IL‐8 were detected in tuberculous pleural effusions, but not in pleural effusions associated with congestive heart failure (CHF). Tuberculous pleural macrophages and M. tuberculosis‐infected CHF pleural macrophages produced large concentrations of IL‐8. When immunohistochemistry was performed on pleural tissues, antigenic IL‐8 was detected in the mesothelial cells lining the tuberculous pleura. Direct stimulation of cultured CHF pleural mesothelial cells with M. tuberculosis induced IL‐8 secretion. However, conditioned media from M. tuberculosis‐infected pleural macrophages (CoMTB) induced greater mesothelial cell IL‐8 secretion. Tumour necrosis factor‐α (TNF‐α) and IL‐1β induced mesothelial cell IL‐8 mRNA expression, and neutralizing anti‐TNF‐α antibody and IL‐1 receptor antagonist nearly completely obliterated CoMTB‐induced mesothelial cell IL‐8 mRNA expression and protein secretion. These findings demonstrate that both pleural macrophages and mesothelial cells produce IL‐8 in tuberculous pleurisy, and cytokines produced by M. tuberculosis‐infected macrophages mediate mesothelial cell IL‐8 production.

Effect of green tea extract microencapsulation on hypertriglyceridemia and cardiovascular tissues in high fructose-fed rats

The application of polyphenols has attracted great interest in the field of functional foods and nutraceuticals due to their potential health benefits in humans. However, the effectiveness of polyphenols depends on their bioactivity and bioavailability. In the present study, the bioactive component from green tea extract (GTE) was administrated orally (50 mg/kg body weight/day) as free or in a microencapsulated form with maltodextrin in rats fed a high fructose diet. High fructose diet induced features of metabolic syndrome including hypertriglyceridemia, hyperuricemia, increased serum total cholesterol, and retroperitoneal obesity. In addition, myocardial fibrosis was increased. In rats receiving high fructose diet, the lowering of blood triglycerides, total cholesterol, non esterified fatty acid (NEFA) and uric acid, as well as the reduction in final body weight and retroperitoneal fat weight associated with the administration of GTE, led to a reversal of the features of metabolic syndrome (P < 0.05). In particular, the administration of microencapsulated GTE decreased myocardial fibrosis and increased liver catalase activity consistent with a further alleviation of serum NEFA, and hyperuricemia compared to administration of GTE. Taken together, our results suggest that microencapsulation of the bioactive components of GTE might have a protective effect on cardiovasucular system by attenuating the adverse features of myocardial fibrosis, decreasing uric acid levels and increasing hepatic catalase activity effectively by protecting their bioactivities.

Reduced Expression of E-cadherin in Human Non-small Cell Lung Carcinoma

PURPOSE E-cadherin, a calcium-dependent cell to cell adhesion molecule, plays a key role in the maintenance of tissue integrity. Reduction or loss of E-cadherin has been reported to have a role in the development of human malignancies. The expression of E-cadherin was analyzed in human non-small cell lung carcinoma (NSCLC) to elucidate the role in pulmonary carcinogenesis and determine the relationship with several clinicopathological factors and the prognosis. MATERIALS AND METHODS Sixty five human cases of NSCLC were evaluated by immunohistochemical analysis for the expression of E-cadherin. The immunostaining results for E-cadherin were semiquantitatively interpreted, as preserved and reduced, in the tumor tissues. The E-cadherin expression was analyzed in relation to several clinicopathological data and the survival. The cell proliferation index of the tumors was evaluated by immunostaining with the Ki-67 antigen. RESULTS Reduced E-cadherin expression was found in 51 cases of NSCLC tissues (78.4%) compared to that in the normal controls. Reduced E-cadherin expression was significantly correlated with male smokers and squamous cell type of the cancer, but not with histological grade, TNM stage and survival. The E-cadherin expression showed a weak inverse relationship with the proliferative activity of tumor cells, which was measured using the Ki-67 antigen. CONCLUSION Our data support the hypothesis that reduced E-cadherin expression may play a role in the pathogenesis of human NSCLC, which might be associated with the control for cell proliferation.

Tissue Microarray Analysis of Fas and FasL Expressions in Human Non-small Cell Lung Carcinomas; with Reference to the p53 and bcl-2 Overexpressions

Lack of surface Fas expression is a main route for apoptotic resistance which is considered an important mechanism of tumorigenesis and tumor progression. Fas and FasL expressions in 110 non-small cell lung carcinomas (NSCLCs) were investigated to evaluate their roles in pulmonary carcinogenesis and to examine the clinicopathologic significance of Fas expression with its relationship with p53 and bcl-2 overexpressions. Immunohistochemical analysis using tissue microarray demonstrated that a large proportion of NSCLC patients (60%) showed lack of membranous Fas expression. The Fas-negative cases revealed the significantly lower survival rate than Fas-positive ones. Also, the loss of Fas receptor expression was found more frequently in advanced stage and higher nodal status. FasL protein was increased in most NSCLCs (89%) compared to normal lungs. p53 and bcl-2 overexpressions showed no association with Fas expression. Conclusively, reduced membranous Fas expression as a mechanism of apoptotic resistance is considered to play an important part of the pulmonary carcinogenesis, which may predict poor survival and have a bad prognostic influence. Increased FasL expression is thought to be a basis for the immune evasion in NSCLCs. The rare bcl-2 overexpression suggests that this anti-apoptotic protein is unlikely to play a role in the apoptotic resistance of NSCLCs.

Malignant glioma arising at the site of an excised cerebellar hemangioblastoma after irradiation in a von Hippel-Lindau disease patient.

We describe herein a malignant glioma arising at the site of the resected hemangioblastoma after irradiation in a patient with von Hippel-Lindau disease (VHL). The patient was a 25 year-old male with multiple hemangioblastomas at the cerebellum and spinal cord, multiple pancreatic cysts and a renal cell carcinoma; he was diagnosed as having VHL disease. The largest hemangioblastoma at the right cerebellar hemisphere was completely removed, and he received high-dose irradiation postoperatively. The tumor recurred at the same site 7 years later, which was a malignant glioma with no evidence of hemangioblastoma. The malignant glioma showed molecular genetic profiles of radiation-induced tumors because of its diffuse p53 immunostaining and the loss of p16 immunoreactivity. The genetic study to find the loss of heterozygosity (LOH) of VHL gene revealed that only the cerebellar hemangioblastoma showed allelic losses for the gene. To the best of our knowledge, this report is the first to show a malignant glioma that developed in a patient with VHL disease after radiation therapy at the site of an excised hemangioblastoma. This report also suggests that radiation therapy should be performed very carefully in VHL patients with hemangioblastomas.

Low-grade myofibroblastic sarcoma arising in fibroadenoma of the breast-A case report–

BackgroundMyofibroblastic sarcoma or myofibrosarcoma is a malignant tumor of myofibroblasts and known to develop rarely in the breast, but its underlying lesion and tumor cell origin have never been reported yet.Case presentationA 61-year-old female presented with a gradually growing breast mass with well-demarcated ovoid nodular shape. The tumor was histologically characterized by fascicular-growing spindle cell proliferation with large areas of hyalinized fibrosis and focally ductal epithelial remnants embedded in myxoid stroma, mimicking a fibroadenomatous lesion. It had frequent mitoses of 5–16/10 high-power fields, hemorrhagic necrosis, and focally pericapsular invasion. The spindle cells were diffusely immunoreactive for fibronectin, smooth muscle actin, and calponin, which suggest a myofibroblastic origin. Multiple irregularly thickened vessels with medial or pericytic cell proliferation were found to be merged with the intrinsic tumor cells. The tumor could be diagnosed low-grade myofibroblastic sarcoma arising in an old fibroadenoma.ConclusionWe report a case of a low-grade mammary myofibrosarcoma that showed a background lesion of fibroadenoma first in the worldwide literature and suggest the pericytes or medial muscle cells of the intratumoral vessels as the cell origin of the myofibroblastic sarcoma.

Recurrent Acute Myocardial Infarction Caused by Intra-cardiac Metastatic Undifferentiated Pleomorphic Sarcoma during Cancer Treatment

A 54-year-old male visited the emergency room for sudden chest pain. In his previous medical history, he had been diagnosed as left axillary undifferentiated pleomorphic sarcoma two years ago without metastasis in the heart at our hospital (Fig. 1A). Despite surgery, multiple sessions of chemotherapy and radiation therapy, the cancer had proliferated. One year after diagnosis, he had started taking pembrolizumab to target the metastasis of sarcoma. After initiation of pembrolizumab, the patient was hospitalized for sudden cardiac arrest due to acute myocardial infarction (AMI) induced by metastatic sarcoma embolus and an angioplasty had been performed at another hospital a year ago. We performed direct percutaneous coronary intervention due to ST segment elevation myocardial infarction, anterior wall and found the total occlusion of the distal left anterior descending artery (Fig. 1B). We utilized a thromboaspirate suction catheter to suction the area multiple times and obtained mucoid white tissue debris (Fig. 1C). In the final coronary angiography, the coronary flow had been completely restored (Fig. 1D). In his echocardiography six months ago, a huge mass with heterogeneous echogenicity was located in the left atrium and attached to the interatrial septum with a prolapse into the left ventricle (Fig. 2A, Supplementary Movie 1). However, the mass had significantly decreased in size on new echocardiography (Fig. 2B, Supplementary Movie 2). We compared the cytologic and immunohistochemical findings of primary axillary sarcoma with the acquired intracoronary embolus tissue. The embolus tissues were composed of discohesive round sarcoma cells and scattered pleomorphic giant cells, pISSN 1975-4612 / eISSN 2005-9655 Copyright

Altered expressions of Notch-1 signaling proteins and beta-catenin in progression of carcinoma in situ into squamous carcinoma of uterine cervix

Background: Activation of Notch-1 signaling pathway and loss of membranous beta-catenin have been known to play key roles in the progression of uterine cervix cancer and thus this study focused any alteration in the expression patterns for Notch-1, p53, and cyclin D1 as well as beta-catenin in squamous carcinoma in situ (CIS) and invasive squamous carcinomas to investigate their roles in the progression of CIS to squamous carcinomas. Materials and Methods: Three Notch-1 signaling proteins, such as Notch-1, TP53, and cyclin D1, and a component of cell adhesion complex, beta-catenin, were immunohistochemically stained in 112 uterine cervical tumors including 74 CIS and 38 invasive squamous carcinomas (11 microinvasive and 27 invasive carcinomas). Each immunohistochemical result was compared between CIS and squamous carcinoma groups and the difference was statistically analyzed. Results: Notch-1 protein expression was significantly higher in the microinvasive and invasive carcinomas than in CIS lesions (P = 0.001). Cyclin D1 and p53 immunoreactivities tended to be expressed higher in the invasive group than in CIS (P = 0.056 and 0.060). Membranous beta-catenin expression was significantly reduced in squamous carcinomas compared to CIS (P = 0.000). However, both CIS and squamous carcinoma groups revealed no interrelationship among Notch-1 signaling proteins and beta-catenin. Conclusion: Altered expressions of Notch-1 signaling proteins and beta-catenin in the progression of CIS into squamous carcinoma of uterine cervix suggests that Notch-1 signaling pathway and cell adhesiveness might play key roles in the stromal invasion of CIS cells.

[Peutz-Jeghers Syndrome with Adenomatous Change in a Fifteen-month-old Boy].

Peutz-Jeghers syndrome (PJS) is a very rare genetic disorder. PJS carries a high risk of developing gastrointestinal (GI) cancer or non-GI cancer with advancing years. However, major symptoms of PJS in childhood are obstruction, intussusception, and bleeding from hamartomatous intestinal polyps which in majority of cases are not related to cancer. Generally, first GI symptom develops by 20 years in one half of children diagnosed with PJS. Children under two years of age who had PJS polyp-related intestinal symptoms are rare, and there have been no published report on intestinal carcinoma development, adenomatous change or dysplasia of polyps in Korean children with PJS. Recently, the authors have experienced a case PJS with adenomatous polyp change in a 15-month-old boy who had STK11 gene mutation. Therefore, early evaluation could be necessary and considered in children with PJS.