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Biomedical subjects

Y J Bang

Publications and source records attributed to Y J Bang.

At least 19 recordsLinked to original sources
PubMed2006

Improved therapeutic outcomes of DLBCL after introduction of rituximab in Korean patients.

The addition of rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) has been shown to improve the outcome in all age groups with newly diagnosed diffuse large B-cell lymphoma (DLBCL). We conducted a retrospective analysis to evaluate the impact of this combination therapy on DLBCL outcomes in Korea. From October 2001 to June 2004, newly diagnosed DLBCL patients in nine Korean institutes were included. All of these 81 patients were treated with three or more cycles of rituximab plus CHOP (R-CHOP) combination chemotherapy (R group), and followed for a minimum of 12 months. For comparison, a historical cohort of patients was used and analyzed for "Clinicopathologic characteristics of Korean non-Hodgkin's lymphomas (NHLs) based on Revised American Lymphoma (REAL) classification" in 1999. Among the 1,098 NHL patients, the data of 214 DLBCL patients, who were treated with CHOP chemotherapy in first-line, were analyzed (C group). We compared outcomes between the C group and the R group. A total of 295 patients were evaluated (C group, 214; R group, 81). The complete response (CR) rate was higher in R group (73 vs 91%, p=0.001). The 2-year event-free survival (EFS) rate was significantly higher in R group (78 vs 85%, p=0.0194). This survival benefit was maintained in high-risk patients according to the international prognostic index (IPI) (p=0.0039), regardless of age. However, there was no significant difference in low-risk patients. The addition of rituximab to CHOP combination chemotherapy for DLBCLs showed improved outcomes, particularly in high-risk group according to the IPI. Long-term follow-up results will be needed to confirm these results.

Adolescent↗
PubMed2006

Antibiotic use during the last days of life in cancer patients.

The purpose of this study is to document infection and to better understand current practice relating to antibiotic use and its effect in terminal cancer patients. We retrospectively reviewed patients with terminal stage cancer who were admitted to Seoul National University Boramae Hospital for symptom control only, and who finally died between March 2003 and April 2004. A total of 141 patients were enrolled. Mean duration from admission to death was 31.2 days. A total of 104 patients (75.2%) experienced a febrile episode, and physicians considered 113 patients (80.1%) developed a clinical infection. Total 119 patients (84.4%) received antibiotics. For 90 patients (63.8%), antibiotics were used until the day of death. After using antibiotics, 48% of fevers were controlled, and 31% of organism-proven cases were resolved. Symptomatic improvement of infection was achieved in 18 patients (15.1%), but 66 patients (55.4%) showed no improvement. Improved leucocytosis was achieved by 17% and C Reactive Protein elevation by 29%. In conclusion, our study reveals a high rate of infection and a high rate of antibiotic prescription during the last month of life in cancer patients. But symptomatic improvement was not achieved in more than half of the patients. Further study should be undertaken to clarify the benefit of antibiotics in terminal stage cancer patients.

Adult↗
PubMed2005

Management of gastric lymphoma with chemotherapy alone.

PURPOSE: The optimal therapy for gastric lymphoma except MALToma has not yet been established. This study was undertaken to investigate whether gastric lymphoma can be managed effectively and safely with chemotherapy alone. PATIENTS AND METHODS: A total of 58 patients (median age 56 years) with newly diagnosed gastric lymphoma between 1989--2001 at Seoul National University Hospital and who were initially managed with chemotherapy alone were evaluated. MALToma was excluded from the pathologic review. RESULTS: All patients received initially anthracycline-containing chemotherapy. ECOG performance scale 0--1 was 88% and B symptoms were present in 41.4%. Diffuse large B cell type was the most common (74.1%). Stage IE, II1E accounted for 51.7% and II2E, IIIE, IV for 48.3%. The international prognostic index (IPI) of risk was low in 39.7%, low-intermediate in 22.4%, high-intermediate in 15.5% and high in 22.4%. The complete response rate after first-line chemotherapy was 71.4% and the partial response rate was 12.2%. (overall response rate: 83.6%). Among patients who did not reach the complete response, a further complete response was achieved by second-line chemotherapy including etoposide-based regimen. Ultimately, the maximum complete response rate by chemotherapy was 83.7% (92% in stage IE, II1E, 75% in stage II2E, IIIE, IV). Median overall survival was 47.4 months (84.7 months in stage IE, II1E, 32.5 months in stage II2E, IIIE, IV) and the 5-year survival rate was 46%. Bleeding as a complication occurred in 3 of 58 patients (5.6%) and these cases were controlled by embolization or conservative management. No perforation episode occurred and surgical intervention due to complication was not necessary. Organ preservation was possible in 57 of 58 patients (98%). The one gastrectomy was performed due to a partial clinical response to chemotherapy but the specimen showed pathologic CR. Multivariate analysis revealed that only IPI had a significant influence on survival. CONCLUSIONS: Gastric lymphoma except MALToma can be managed effectively and safely with chemotherapy alone.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Transcriptional silencing of Cyclooxygenase-2 by hyper-methylation of the 5' CpG island in human gastric carcinoma cells.

It has been well established that overexpression of Cyclooxygenase-2 (Cox-2) in epithelial cells inhibits apoptosis and increases the invasiveness of malignant cells, favoring tumorigenesis and metastasis. However, the molecular mechanism that regulates Cox-2 expression has not been well defined in gastric carcinoma. In this study, we examined whether the Cox-2 expression could be regulated by hyper-methylation of the Cox-2 CpG island (spanning from -590 to +186 with respect to the transcription initiation site) in human gastric carcinoma cell lines. By Southern analysis, we found that three gastric cells (SNU-601, -620, and -719) without Cox-2 expression demonstrated hyper-methylation at the Cox-2 CpG island. A detailed methylation pattern using bisulfite sequencing analysis revealed that all of the CpG sites were completely methylated in SNU-601. Treatment with demethylating agents effectively reactivated the expression of Cox-2 and restored IL-1beta sensitivity in the previously resistant SNU-601. By transient transfection experiments, we demonstrate that constitutively active Cox-2 promoter activities were exhibited even without an exogenous stimulation in SNU-601. Furthermore, when the motif of the nuclear factor for interleukin-6 expression site, the cyclic AMP response element, or both was subjected to point mutation, the constitutive luciferase activity was markedly reduced. In addition, Cox-2 promoter activity was completely blocked by in vitro methylation of all of the CpG sites in the Cox-2 promoter region with SssI (CpG) methylase in SNU-601. Taken together, these results indicate that transcriptional repression of Cox-2 is caused by hyper-methylation of the Cox-2 CpG island in gastric carcinoma cell lines.

Azacitidine↗
PubMed2001

A Phase I study of cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-1,3-dioxolane] platinum(II) in patients with advanced malignancies.

BACKGROUND: A Phase I study of cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-1,3-dioxolane] platinum(II) (SKI 2053R), a new platinum derivative, was performed to determine the maximum tolerated dose (MTD), the dose limiting toxicities (DLTs), and the pharmacokinetic profile of SKI 2053R in patients with advanced, refractory malignancies. METHODS: Twenty-one patients were entered into the study. SKI 2053R was administered with an intravenous infusion over 1 hour every 4 weeks. The SKI 2053R dose was escalated from 40 mg/m(2) up to 480 mg/m(2) using a modified Fibonacci scheme. Pharmacokinetic analysis was done in all patients to determine the total and ultrafiltrable platinum concentrations in both the plasma and the urine. RESULTS: All patients were evaluable for toxicity and response. There was no significant toxicity with dosages up to 360 mg/m(2). At 480 mg/m(2), two of three patients developed Grade 4 hepatotoxicity, Grade 3 leukopenia and thrombocytopenia, and Grade 2 azotemia and proteinuria. Other toxicity included nausea and emesis, but it was controlled with antiemetics. SKI 2053R did not cause significant neurotoxicity or mucositis. There were 4 patients with stable disease among the 21 patients. Plasma decay of the total and free platinum concentrations was best fitted by using a two-compartment, open model. The terminal plasma half-life of the total platinum after SKI 2053R administration ranged from 63.4 hours to 114.1 hours in dosages ranging from 40 mg/m(2) to 480 mg/m(2) without significant dose dependency. However, the terminal plasma half-life of the free platinum concentration showed a significant dose dependent, incremental pattern. The renal excretion of SKI 2053R measured as platinum ranged from 49% to 75% of the administered dose. CONCLUSIONS: The MTD of SKI 2053R was 480 mg/m(2). The major DLTs were hepatotoxicity, nephrotoxicity, and myelosuppression. The recommended starting dose for a subsequent Phase II study is 360 mg/m(2) once every 4 weeks.

Adult↗
PubMed2001

Interleukin 12 gene therapy of cancer by peritumoral injection of transduced autologous fibroblasts: outcome of a phase I study.

A phase I dose-escalation clinical trial of peritumoral injections of interleukin 12 (IL-12)-transduced autologous fibroblasts was performed in patients with disseminated cancer for whom effective treatment does not exist. The goals of this study were to assess the safety and toxicities as well as the efficacy, and ancillarily the immunomodulatory effects, of peritumoral IL-12 gene transfer. Primary dermal fibroblasts cultured from the patients were transduced with retroviral vector carrying human IL-12 genes (p35 and p40) as well as the neomycin phosphotransferase gene (TFG-hIL-12-Neo). Patients received four injections at intervals of 7 days. Nine patients were enrolled in this dose-escalation study, with secreted IL-12 doses ranging from 300 ng/24 hr for the first three patients to 1000, 3000, and 5000 ng/24 hr for two patients in each subsequent dosage level. Although a definite statement cannot be made, there appears to be perturbation of systemic immunity. Also, the locoregional effects mediated by tumor necrosis factor alpha (TNF-alpha) and CD8+ T cells were observed with tumor regression. Treatment-related adverse events were limited to mild to moderate pain at the injection site; clinically significant toxicities were not encountered. Transient but clear reductions of tumor sizes were observed at the injected sites in four of nine cases, and at noninjected distant sites in one melanoma patient. Hemorrhagic necrosis of tumors was observed in two melanoma patients. These data indicate that gene therapy by peritumoral injection of IL-12-producing autologous fibroblasts is feasible, and promising in patients with advanced cancer.

Adult↗
PubMed2001

Caspase-mediated Cdk2 activation is a critical step to execute transforming growth factor-beta1-induced apoptosis in human gastric cancer cells.

Although TGF-beta1, a growth inhibitor, is known to also induce apoptosis, the molecular mechanism of this apoptosis is largely undefined. Here, we identify the mechanism of TGF-beta1-induced apoptosis in SNU-16 human gastric cancer cells. Cell cycle and TUNEL analysis showed that, upon TGF-beta1 treatment, cells were initially arrested at the G1 phase and then driven into apoptosis. Of note, caspase-3 was activated in accordance with TGF-beta1-induced G1 arrest. Activated caspase-3 is targeted to cleave p21(cip1), p27(kip1), and Rb, which play important roles in TGF-beta-induced G1 arrest, into inactive fragments. Subsequently, Cdk2 was aberrantly activated due to the cleavage of p21 and p27. We found that the inhibition of Cdk2 activity efficiently blocks TGF-beta1-induced apoptosis, whereas it did not prevent caspase-3 activation or the subsequent cleavage of target proteins. In contrast, the suppression of caspase-3 activity inhibited the cleavage of target proteins, the activation of Cdk2, and the induction of apoptosis. Taken together, our results suggest that activation of caspase-3 by TGF-beta1 may initiate the conversion from G1 cell cycle arrest to apoptosis via the cleavage of p21, p27 and Rb, which in turn causes Cdk2 activation and, most significantly, Cdk2 activation as a downstream effector of caspase is a critical step for the execution of TGF-beta1-induced apoptosis.

Annexin A5↗
PubMed2001

CD99 regulates the transport of MHC class I molecules from the Golgi complex to the cell surface.

The down-regulation of surface expression of MHC class I molecules has recently been reported in the CD99-deficient lymphoblastoid B cell line displaying the characteristics of Hodgkin's and Reed-Sternberg phenotype. Here, we demonstrate that the reduction of MHC class I molecules on the cell surface is primarily due to a defect in the transport from the Golgi complex to the plasma membrane. Loss of CD99 did not affect the steady-state expression levels of mRNA and protein of MHC class I molecules. In addition, the assembly of MHC class I molecules and the transport from the endoplasmic reticulum to the cis-Golgi occurred normally in the CD99-deficient cells, and no difference was detected between the CD99-deficient and the control cells in the pattern and degree of endocytosis. Instead, the CD99-deficient cells displayed the delayed transport of newly synthesized MHC class I molecules to the plasma membrane, thus causing accumulation of the molecules within the cells. The accumulated MHC class I molecules in the CD99-deficient cells were colocalized with alpha-mannosidase II and gamma-adaptin in the Golgi compartment. These results suggest that CD99 may be associated with the post-Golgi trafficking machinery by regulating the transport to the plasma membrane rather than the endocytosis of surface MHC class I molecules, providing a novel mechanism of MHC class I down-regulation for immune escape.

12E7 Antigen↗
PubMed2001

Prognostic factors of Krukenberg's tumor.

OBJECTIVE: The aim of this study was to determine prognostic factors of metachronous Krukenberg's tumors of gastric origin, thereby helping to establish a therapeutic plan for this rare entity. METHODS: Thirty-four female patients who underwent curative resection of gastric carcinoma from 1987 through 1996 and subsequently developed Krukenberg's tumors were identified. The covariates used for survival analysis were patient age at the time of ovarian relapse (categorized as <50 years or >/=50 years), size of Krukenberg's tumor (categorized as </=5, 5-10, or >10 cm), initial AJCC stage of gastric carcinoma, relapse-free interval (categorized as <1, 1-2, or >/=2 years), extent of recurrent disease, and the presence of gross residual disease after treatment for Krukenberg's tumors. The influence of all covariates on the survival period was assessed using the Cox proportional hazards model. RESULTS: At a median follow-up of 32.3 months (range, 2.2-83.1), the median survival period of 34 study patients was estimated to be 7.7 months (95% confidence interval (CI), 5.8-9.6) after the diagnosis of metachronous Krukenberg's tumor. Cox-model-based survival analysis demonstrated that the absence of residual disease after treatment and limited disease extent were favorable prognostic factors. The median survival period of patients without gross residual disease was longer (10.9 months (95% CI, 4.6-17.1)) than that of patients with gross residual disease (7.5 months (95% CI, 6.6-8.3)) [P = 0.036]. Median survival periods according to the extent of metastasis were 10.9 months (95% CI, 0-23.0) for patients with disease confined to the ovaries, 13.1 months (95% CI, 5.9-20.3) for patients with disease confined to the pelvis, 7.5 months (95% CI, 6.8-8.1) for patients with intraabdominal disease, and 3.6 months (95% CI, 3.4-3.7) for patients with disease spread outside the abdomen and pelvis [P = 0.003]. In contrast, patient age, size of ovarian tumor, initial stage of gastric adenocarcinoma, and relapse-free interval were not prognostic indicators for survival after the development of ovarian metastases. CONCLUSION: The absence of residual disease after treatment and limited disease extent were favorable prognostic factors of metachronous Krukenberg's tumors of stomach origin. Our data suggest that resection might have a role in the management of Krukenberg's tumors of stomach origin if it could render patients free of gross residual disease.

Adult↗
PubMed2001

Cyclin E overexpression as an independent risk factor of visceral relapse in breast cancer.

AIM: Prognostic value of the cyclin E overexpression in breast cancer has not been clearly established, especially in relation to the pattern of recurrence. We investigated the implication of cyclin E overexpression for the pattern of recurrence in Korean breast cancer patients. METHODS: Using immunohistochemical methods, we retrospectively examined the cyclin E expression level in breast cancer specimens from 128 women who underwent curative breast surgery, and correlated the levels of expression with the pattern of relapse in patients. RESULTS: Cox model-based multivariate analysis indicated that distant relapse could be predicted by the number of positive axillary lymph nodes, high cyclin E expression, and the younger age (<35 years) of the patient. We tested further the association of cyclin E overexpression with the specific types of recurrence; multivariate analyses indicated that adjusted relative risks of bone and visceral relapse as the first events among high cyclin E group were 2.46 (95% confidence interval (CI), 0.86-7.02) (P=0.092), and 3.98 (95% CI, 1.23-12.94) (P=0.022), respectively. On the other hand, cyclin E overexpression was not associated with the risk of locoregional relapse. CONCLUSION: Our data suggest that cyclin E overexpression in primary breast carcinoma tissue could independently predict the risk of distant relapse, especially of visceral relapse, as the first failure after curative breast surgery.

Adult↗
PubMed2000

Adjuvant doxorubicin and cyclophosphamide versus cyclophosphamide, methotrexate, and 5-fluorouracil chemotherapy in premenopausal women with axillary lymph node positive breast carcinoma.

BACKGROUND: This randomized controlled trial was to determine whether a combination chemotherapy regimen that contains anthracycline (doxorubicin and cyclophosphamide [AC]) is superior to the conventional cyclophosphamide, methotrexate, and 5-fluorouracil [CMF] combination in premenopausal women with axillary lymph node positive Stage II breast carcinoma. METHODS: Premenopausal women with lymph node positive breast carcinoma were stratified according to age (younger than 35 or 35 years or older) and the number of positive axillary lymph nodes (1-3, 4-9, or >/= 10) and then randomly assigned to receive either doxorubicin 40 mg/m(2) and cyclophosphamide 600 mg/m(2) intravenously (i.v.) every 3 weeks or cyclophosphamide 100 mg/m(2) orally on Days 1 through 14, methotrexate 40 mg/m(2) and 5-fluorouracil 500 mg/m(2) i.v. on Days 1 and 8 every 4 weeks. Both arms were scheduled for six cycles. RESULTS: The median follow-up was 57 months. Eighteen of the 55 AC patients developed recurrence compared with 16 of the 69 CMF patients. The corresponding 5-year recurrence free survival rates were 64% and 78%, respectively (P = 0.12). The site of the first recurrence for AC patients was locoregional in 7%, distant in 22%, and combined in 4%. The corresponding data for the CMF arm were 4%, 16%, and 3%, respectively. Six AC patients died compared with 9 CMF patients. The corresponding 5-year survival rates were 90% and 86%, respectively (P = 0.96). More leukopenia (52%, mostly Grade 1-2) occurred in the CMF arm than in the AC arm (33%, P = 0.001), but no febrile episode was accompanied with leukopenia. CONCLUSIONS: This study showed no difference between AC and CMF with respect to both disease free and overall survival rates in premenopausal women with axillary lymph node positive breast carcinoma.

Adult↗
PubMed2000

Transforming growth factor-beta induces apoptosis in activated murine T cells through the activation of caspase 1-like protease.

Transforming growth factor-beta (TGF-beta) has been known as a potent immunosuppressive cytokine that can induce apoptosis in lymphoid cells. We established an IL-2-independent cell line, CTLL-2A, from murine T cell line CTLL-2. CTLL-2A expressed higher levels of CD95, CD69, and CD18 molecules than CTLL-2 did, suggesting a more activated state in CTLL-2A than in the CTLL-2 by phenotype. Exposing both CTLL-2 and CTLL-2A to TGF-beta results in differential apoptosis patterns defined by DNA fragmentation and plasma membrane alteration. Among the bcl-2 family members, bcl-2, bcl-w, and bcl-x(L) were also differently expressed in these two cell lines. In CTLL-2A, bcl-x(L) was amplified as a major anti-apoptotic molecule, and TGF-beta-induced cell death was more enhanced than in the original cell line. Caspase 1-like protease was activated by TGF-beta treatment and consequently it cleaved bcl-x(L) in CTLL-2A. TGF-beta-induced DNA fragmentation and cleavage of bcl-x(L) were inhibited by pretreatment with tetra peptide caspase 1 inhibitor, YVAD.cmk. These findings suggest that TGF-beta induces cell death in activated murine T cells through cleavage of bcl-x(L) via activated caspase 1-like protease, which may act as an important executor in that process.

Animals↗
PubMed2000

Methylation of specific CpG sites in the promoter region could significantly down-regulate p16(INK4a) expression in gastric adenocarcinoma.

Silencing of p16(INK4a) by methylation of the CpG islands in the promoter region has been found to be an alternative mechanism of inactivation in several tumors. However, in gastric carcinoma, the relationship between methylation status and the transcriptional silencing of the p16 gene remains to be clarified. In this study, we investigated whether methylation of a few specific CpG sites in the promoter region could significantly down-regulate p16 activity in the tumorigenesis of gastric carcinoma. By Southern analysis and bisulfite-modified genomic sequencing of 9 gastric-carcinoma cell lines, we found that the 5 cell lines (55.5%) not expressing p16 mRNA had methylated CpG sites at the promoter region of p16. In addition, we analyzed the p16-protein expression of 28 primary gastric carcinomas and their normal counterparts by immunohistochemical staining (IHC) on paraffin sections. Loss of p16 expression was detected in 6 cases (22%). In 5 out of these 6 (83%), the actual p16 gene was inactivated by de novo methylation of the promoter sites. Taken together, these results suggest a strong correlation between de novo methylation of a few specific CpG sites and transcriptional silencing of the p16 gene in gastric carcinoma.

Adenocarcinoma↗
PubMed2000

Transcriptional inactivation of the tissue inhibitor of metalloproteinase-3 gene by dna hypermethylation of the 5'-CpG island in human gastric cancer cell lines.

The tissue inhibitor of metalloproteinase-3 (TIMP-3), a recently cloned member of TIMP gene family, has been implicated in the negative regulation of tumor cell invasion and tumor growth. Down-regulation of this gene has been shown to occur in a mouse carcinogenesis model, suggesting that it might play a role in the tumor progression of some cancers. In this study, we used human gastric cancer cell lines to investigate whether TIMP-3 gene expression is suppressed in human gastric cancer. We examined whether aberrant DNA methylation of the 5'-CpG island of the TIMP-3 gene is involved in this cancer. Nine of 10 human gastric cancer cell lines completely lost TIMP-3 gene expression compared with normal samples. Southern blot analysis and bisulfite genomic sequencing revealed aberrant hypermethylation near the transcription-start site of the TIMP-3 gene in all cell lines lacking TIMP-3 expression. Treatment of these cell lines with the demethylating agent 5-aza-2'-deoxycytidine restored TIMP-3 gene expression. Our results suggest that the TIMP-3 gene is another early target of tumor-associated aberrant DNA methylation in human gastric carcinogenesis. Consequently, genetic silencing of TIMP-3 may lead to a more malignant and invasive phenotype in these cancer cells.

Animals↗
PubMed2000

Loss of TGF-beta signaling contributes to autoimmune pancreatitis.

Recent observations suggest that immune response is involved in the development of pancreatitis. However, the exact pathogenesis underlying this immune-mediated response is still under debate. TGF-beta has been known to be an important regulating factor in maintaining immune homeostasis. To determine the role of TGF-beta in the initiation or progression of pancreatitis, TGF-beta signaling was inactivated in mouse pancreata by overexpressing a dominant-negative mutant form of TGF-beta type II receptor in the pancreas, under control of the pS2 mouse trefoil peptide promoter. Transgenic mice showed marked increases in MHC class II molecules and matrix metalloproteinase expression in pancreatic acinar cells. These mice also showed increased susceptibility to cerulein-induced pancreatitis. This pancreatitis was characterized by severe pancreatic edema, inflammatory cell infiltration, T- and B-cell hyperactivation, IgG-type autoantibodies against pancreatic acinar cells, and IgM-type autoantibodies against pancreatic ductal epithelial cells. Therefore, TGF-beta signaling seems to be essential either in maintaining the normal immune homeostasis and suppressing autoimmunity or in preserving the integrity of pancreatic acinar cells.

Animals↗