Biomedical subjects

Hark Kyun Kim

Publications and source records attributed to Hark Kyun Kim.

14 recordsLinked to original sources

PubMed2026

Immune pathway activation in gastric cancers with LINE-1 retrotransposon overexpression and homologous recombination deficiency.

There are only a few whole genome sequencing studies of human gastric cancer (GC) conducted so far. We performed comprehensive whole genome, bulk RNA, and methylation sequencing analyses of 100 samples of GC and adjacent normal tissue. In a smaller non-EBV/non-MSI subset (n = 23), we also performed proteomic profiling by mass spectrometry. We validated the proteomic findings in an independent dataset. Using this unprecedented dataset of human GC samples, we examined the extent of chromothripsis, homologous recombination deficiency, and retrotransposition, and correlated these events with patient outcomes. We found that chromothripsis occurred in 22% of GCs and correlated with poor prognosis. Multichromosomal chromothripsis was associated with a particularly high risk of death. Based on copy number (CN) signature analysis, we identified a distinct non-CN9 subgroup with significantly worse outcomes. Homologous recombination deficiency was present in 4% of GCs and was associated with overexpression of immune signaling pathways. Somatic retrotransposition events were most strongly associated with global hypomethylation. We also identified BYSL as a putative oncogenic driver within the 6p21 locus whose amplification is associated with poor prognosis. Collectively, our findings provide novel insights into the dysregulation of DNA stability and repair and their clinical relevance in human GCs.

Journal Article↗

PubMed2006

Use of a combination of computed tomography and endoscopy to assess the response to 5-fluorouracil/cisplatin and predict survival in gastric cancer.

BACKGROUND: Response of metastatic sites on computed tomography (CT) has been used to assess response in metastatic gastric carcinoma (MGC); however, the role of endoscopy to evaluate the response of the primary gastric lesion is unclear. We undertook a prospective study to compare prognostic values of endoscopy-based response criteria with those of CT-based response criteria in MGC patients treated with 5-fluorouracil (5-FU) and cisplatin. METHODS: MGC patients naïve to chemotherapy were treated with 5-FU (1000 mg/m(2), days 1-5) and cisplatin (60 mg/m(2), day 1) (FP) every 21 days. Response was assessed by CT [World Health Organization (WHO) criteria/Response Evaluation Criteria In Solid Tumors (RECIST)] every three cycles and/or endoscopy after the third cycle. RESULTS: With a median follow-up of 26.2 months, 103 patients were assessed by CT and endoscopy. There was good concordance between the WHO and RECIST criteria (kappa = 0.91; P = 0.0001), but poor agreement between CT and endoscopic assessments (kappa = 0.17; P = 0.01). On multivariate analysis, both CT (WHO/RECIST) (hazard ratio, 5.20; P < 0.0001) and endoscopic response (hazard ratio, 2.78; P < 0.0001) were significantly associated with survival. The combination of CT and endoscopy defined patients into four groups with distinct prognoses according to chemotherapy response: responders on both tests, responders on CT alone, responders on endoscopy alone, and nonresponders on both tests (hazard ratio, 1.00 versus 2.87 versus 5.35 versus 12.3; P < 0.0001). CONCLUSIONS: The use of endoscopy together with CT provides a better prognostic tool than CT alone in MGC patients treated with FP.

Adult↗

PubMed2005

Assessment of lymph node metastases using 18F-FDG PET in patients with advanced gastric cancer.

PURPOSE: The aim of this study was to assess the diagnostic accuracy of (18)F-fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) with respect to lymph node (LN) metastasis in patients with advanced gastric cancer, and to ascertain the factors that affect this accuracy. METHODS: Seventy-three patients with advanced gastric cancer, verified in all cases by endoscopic biopsy, were enrolled in this prospective study. We conducted FDG PET and other routine preoperative studies, including abdominal computed tomography (CT). Patients underwent either curative-intent gastrectomy and lymphadenectomy (n = 67) or exploratory laparotomy. The Japanese system for the classification of gastric cancer was used for LN assessment. RESULTS: FDG PET was able to detect primary lesions in 70 of the 73 cases. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value of FDG PET for LN metastasis were 40%, 95%, 91% and 56%, respectively. Signet-ring cell carcinoma was associated with the lowest sensitivity (15%), whereas other cell types could be detected with moderate sensitivity (30-71%) and high specificity (93-100%). According to multiple logistic regression, the standardised uptake value for primary tumours was the only independent variable to be significantly related to sensitivity for LN metastasis (p = 0.02, odds ratio = 1.14). CT was superior to PET in terms of sensitivity (p < 0.0001), and PET was superior to CT in terms of specificity (p < 0.0001) and PPV (p = 0.05). CONCLUSION: FDG PET exhibits good specificity for LN staging of gastric cancer, and FDG uptake in the primary tumour is significantly related to the accuracy of FDG PET. Despite some clear limitations, FDG PET proved useful in the LN staging of FDG-avid gastric cancer.

Adult↗

PubMed2005

Gefitinib as a first-line therapy of advanced or metastatic adenocarcinoma of the lung in never-smokers.

PURPOSE: A subset of patients with adenocarcinoma of the lung who had never smoked cigarettes showed excellent tumor responses to gefitinib therapy. To evaluate the efficacy of gefitinib as a first-line therapy in this subgroup of patients, we conducted a phase II study. EXPERIMENTAL DESIGN: Eligible patients had no smoking history, stage IIIB or IV adenocarcinoma, Eastern Cooperative Oncology Group performance status 0 to 2, and adequate organ functions. Treatment consisted of daily oral administration ofF 250 mg gefitinib for 28 days until disease progression. Responses were assessed after every two cycles of therapy. RESULTS: Of 37 patients enrolled, 36 were assessed for response. Twenty-five patients (69%) had partial response, 4 (11%) had stable disease, and 7 (19%) had progressive disease. Of 10 patients with evaluable brain metastases, 7 had objective responses in both intracranial and extracranial lesions, 1 had stable disease in the brain and dramatic response in the extracranial lesions, and 2 had progressive disease in both sites. After a median follow-up of 48 weeks (range, 4-70 weeks), 26 patients had disease progression, with median progression-free survival of 33 weeks, and 9 patients died, all due to disease progression. The median survival time has not been reached yet but the estimated 1-year survival rate was 73%. Common toxicities were skin rash and mild diarrhea but there was no significant hematologic toxicity. CONCLUSIONS: Gefitinib showed very dramatic antitumor activity, even in the brain, with unprecedented survival outcome in never-smoker adenocarcinoma patients. These data support the use of gefitinib as a first-line therapy in this particular subgroup.

Adenocarcinoma↗

PubMed2005

Weekly docetaxel in combination with capecitabine in patients with metastatic gastric cancer.

Docetaxel (T) and capecitabine (X) are active agents against gastric cancer with synergistic antitumor effects. We conducted the current phase II study to assess the response rate and toxicity of combination TX regimen in patients with metastatic gastric cancer. Eligible patients were treated with docetaxel (36 mg/m2 intravenously) on days 1 and 8 and capecitabine (1000 mg/m2 orally twice a day) on days 1-14 of a 3-week schedule until progression occurred. From December 2001 to May 2003, 55 patients with median age of 54 years (range, 22-73 years) were enrolled; 47 patients had measurable lesions. A total of 358 courses of treatment were given, with a median of 5 (range, 1-22+) per patient. Objective responses were documented in 19 of 47 patients with measurable lesions (response rate, 40.4%; 95% confidence interval [CI], 25.9-54.9), with the median response duration of 5.6 months (range, 2.1-13.6+). At a median follow up of 15.9 months for all of 55 study patients, the median time to progression and survival were 4.5 months (95% CI, 3.4-5.6) and 12.0 months (95% CI, 7.5-16.6), respectively. Hematologic toxicities were mild to moderate, and the observed grade 3 nonhematologic toxicities, the most frequent of which was stomatitis, were generally manageable. Four patients experienced pneumonitis, but all of them responded to steroid treatment. The TX regimen was relatively well tolerated and effective against metastatic gastric cancer, with the added advantage of being an outpatient regimen.

Adult↗

PubMed2005

Phase II study of low-dose docetaxel/fluorouracil/cisplatin in metastatic gastric carcinoma.

OBJECTIVES: In several recent reports, docetaxel (75-85 mg/m2) combined with fluorouracil (5-FU) and cisplatin has shown considerable efficacy but significant toxicities, especially neutropenia, in patients with advanced gastric cancer. The authors tested the efficacy and safety of a lower dose (50 mg/m2) of docetaxel, combined with 5-FU and cisplatin, in metastatic gastric cancer (MGC). METHODS: Chemonaive patients with MGC received docetaxel (50 mg/m2 on day 1), cisplatin (80 mg/m2 on day 1), and 5-FU (1200 mg/m2 on days 1-3) every 21 days. RESULTS: Forty-seven patients with a median age of 55 years (range, 30-73 years) received a median of 4 cycles (range, 1-13+ cycles). Of the 42 efficacy-"evaluable" patients, 17 showed a partial response (response rate, 40%; 95% confidence interval [CI], 26-55) according to the independent review panel. With a median follow-up of 12.6 months for all patients, the median time to progression was 4.6 months (95% CI, 3.6-5.6 months) and overall survival was 9.7 months (95% CI, 8.4-11.0 months). Grade 3/4 neutropenia developed in 68% of patients, and febrile neutropenia/neutropenic infection occurred in 26%. The most common grade 3/4 nonhematologic toxicity was stomatitis (21%), followed by syncope (6%), diarrhea (4%), peripheral neuropathy (4%), dizziness (2%), constipation (2%), and abnormal liver function tests (2%). There was 1 possible treatment-related death. CONCLUSIONS: Lower dose (50 mg/m2) docetaxel combined with 5-FU and cisplatin was active in MGC with a tolerable toxicity profile.

Adult↗

PubMed2004

Increased expression of metallothionein is associated with irinotecan resistance in gastric cancer.

To gain insight into clinically relevant mechanisms of irinotecan resistance, we undertook oligonucleotide microarray analyses on paired malignant effusion samples obtained from eight gastric cancer patients treated with weekly irinotecan. Pretreatment and posttreatment (48 h) effusion samples were obtained for each patient, and the change in expression profile was compared between clinical responders and nonresponders. When differences in the expression of genes were examined using SAM (Significance Analysis of Microarrays) software, five isoforms of the metallothionein family were identified to have significantly higher signal log ratios in five nonresponders, compared with three responders. Compared with control cells, metallothionein 1X (MT1X)-transfected AGS cells showed a 1.4-fold higher irinotecan IC(50) by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and tended to form more colonies. These findings collectively suggest that irinotecan-induced up-regulation of metallothionein might be associated with irinotecan resistance in patients with gastric cancer, although it remains to be confirmed in a larger data set.

Adult↗

PubMed2004

DNA microarray analysis of the correlation between gene expression patterns and acquired resistance to 5-FU/cisplatin in gastric cancer.

The mechanisms of intrinsic and/or acquired anti-cancer drug resistance have been described in in vitro resistance models, but the clinical relevance has remained undefined. We undertook a prospective study to identify correlations between gene expression and clinical resistance to 5-FU/cisplatin. We compared expression profiles from gastric cancer endoscopic biopsy specimens obtained at a chemosensitive state (partial remission after 5-FU/cisplatin) with those obtained at a refractory state (disease progression), using Affymetrix oligonucleotide microarray technology (U133A). Using 119 discriminating probes and a cross-validation approach, we were able to correctly identify the chemo-responsiveness of 7 pairs of training samples and 1 independent test pair. These exploratory data demonstrate that the gene expression profiles differ between chemosensitive and refractory state gastric cancer biopsy samples.

Adult↗

PubMed2004

Decreased pyruvate kinase M2 activity linked to cisplatin resistance in human gastric carcinoma cell lines.

Resistance to anticancer drugs is a major obstacle preventing effective treatment of disseminated cancers. Understanding the molecular basis to chemoresistance is likely to provide better treatment. Cell lines resistant to cisplatin or 5-fluorouracil (5-FU) were established from human gastric carcinoma cell lines SNU-638 and SNU-620. Comparative proteomics involving 2-dimensional gel electrophoresis (2-DE) and matrix-associated laser desorption ionization-mass spectroscopy (MALDI-MS) was performed on protein extracts from these parental and drug-resistant derivative lines to screen drug resistance-related proteins. Pyruvate kinase M2 (PK-M2) was identified as a protein showing lower expression in cisplatin-resistant cells compared to parental cells. Consistent with this finding, PK-M2 activity was also lower in cisplatin-resistant cells. Suppression of PK-M2 expression by antisense oligonucleotide resulted in acquired cisplatin resistance in SNU-638 cells. Furthermore, PK-M2 activity in 11 individual human gastric carcinoma cell lines positively correlated with cisplatin sensitivity. Taken together, PK-M2 protein and activity levels were lower in cisplatin-resistant human gastric carcinoma cell lines compared to their parental cell lines. Furthermore, suppression of PK-M2 expression using antisense oligonucleotides increased cisplatin resistance. These data clearly link PK-M2 and cisplatin resistance mechanisms.

Antimetabolites, Antineoplastic↗

PubMed2004

Identification of genes with differential expression in acquired drug-resistant gastric cancer cells using high-density oligonucleotide microarrays.

PURPOSE: A major obstacle in chemotherapy is treatment failure due to anticancer drug resistance. The emergence of acquired resistance results from host factors and genetic or epigenetic changes in the cancer cells. The purpose of this study was to identify differentially expressed genes associated with acquisition of resistance in human gastric cancer cells. EXPERIMENTAL DESIGN: We performed global gene expression analysis in the acquired drug-resistant gastric cancer cell lines to the commonly used drugs 5-fluorouracil, doxorubicin, and cisplatin using Affymetrix HG-U133A microarray. The gene expression patterns of 10 chemoresistant gastric cancer cell lines were compared with those of four parent cell lines using fold-change and Wilcoxon's test for data analysis. RESULTS: We identified over 250 genes differentially expressed in 5-fluorouracil-, cisplatin-, or doxorubicin-resistant gastric cancer cell lines. Our expression analysis also identified eight multidrug resistance candidate genes that were associated with resistance to two or more of the tested chemotherapeutic agents. Among these, midkine (MDK), a heparin-binding growth factor, was overexpressed in all drug-resistant cell lines, strongly suggesting that MDK might contribute to multidrug resistance in gastric cancer cells. CONCLUSIONS: Our investigation provides comprehensive gene information associated with acquired resistance to anticancer drugs in gastric cancer cells and a basis for additional functional studies.

Antineoplastic Agents↗

PubMed2004

Weekly irinotecan in patients with metastatic gastric cancer failing cisplatin-based chemotherapy.

BACKGROUND: The goal of this study is to determine the efficacy and toxicity of weekly irinotecan as second-line chemotherapy in advanced gastric cancer after failure of cisplatin-based regimen. METHODS: Gastric cancer patients failing cisplatin-based chemotherapy received 125 mg/m(2) of irinotecan weekly for 4 weeks followed by 2-week rest, until disease progression. RESULTS: Thirty-seven patients were enrolled into this study. The objective response was documented in seven of 35 patients with measurable lesion (response rate 20%, 95% CI: 6.1-33.9). Eight patients (22.9%) had stable disease and overall tumor control rate was 42.9%. The disease remained stable in both of two patients without measurable disease. At a median follow-up duration of 15.8 months, median time to progression and overall survival were 2.6 months (95% CI: 2.4-2.8) and 5.2 months (95% CI: 3.6-6.7), respectively. Neutropenia and diarrhea were the main toxicities. Among 37 patients treated, grade 3/4 (G3/4) neutropenia occurred in 43.2/24.3% of patients, respectively, and was accompanied with fever in three patients. Non-hematologic toxicities consisted mainly of delayed diarrhea (G3/4, 18.9/0%) and nausea/vomiting (G3/4, 18.9/0%). These toxicities were manageable and there was no treatment-related death. CONCLUSIONS: This weekly schedule of irinotecan was modestly active against cisplatin-refractory gastric cancer and relatively well-tolerated with appropriate dose modification.

Adenocarcinoma↗

PubMed2003

Development and applications of a beta-catenin oligonucleotide microarray: beta-catenin mutations are dominantly found in the proximal colon cancers with microsatellite instability.

beta-catenin mutations have been identified in a variety of human malignancies; most of these are missense mutations restricted at hot-spot areas in exon 3. beta-catenin mutations are known to be highly associated with colorectal cancers with microsatellite instability (MSI). More than 70 beta-catenin mutations have been reported in colorectal cancers, and approximately 90% of beta-catenin mutations have been found in 11 codons (codons 29, 31, 32, 33, 34, 35, 37, 38, 41, 45, and 48) as missense mutations or in-frame deletions. We have developed an oligonucleotide microarray for detecting beta-catenin mutations at these 11 codons. The developed oligonucleotide microarray can detect a total of 110 types of beta-catenin mutations, including the 60 mutations reported previously. Nine beta-catenin mutations were identified in this study by five different methods, i.e., PCR- single-strand conformational polymorphism, denaturing high performance liquid chromatography, direct sequencing, cloning-sequencing, and with an oligonucleotide microarray. All nine of the mutations were identified by denaturing high performance liquid chromatography, cloning-sequencing, and by the oligonucleotide microarray. However, PCR-single-strand conformational polymorphism missed 1 beta-catenin mutation and direct sequencing missed 2. Five beta-catenin mutations from 74 colorectal carcinomas (34 proximal colon cancers and 40 distal colorectal cancers) and 4 beta-catenin mutations from 31 colorectal cancer cell lines (7 from the proximal colon, 6 from the distal colorectum, and 18 unknown) were identified. In colorectal carcinomas, all 5 of the beta-catenin mutations were found in proximal colon tumors. In colorectal cancer cell lines, 2 of 4 cell lines with beta-catenin mutations originated from the proximal colon, and the remaining 2 cell lines were simply described as having originated from the colon. Considering the relationships among beta-catenin mutations, MSI, and tumor location, the frequency of beta-catenin mutations was found to be meaningfully higher in colorectal carcinomas with MSI than in those with microsatellite stability (P < 0.001); moreover, MSI was found to be more frequent in proximal colon tumors (P < 0.01). In addition, beta-catenin mutations were also found to be associated with proximal colon cancer (P = 0.017).

Adult↗

PubMed2003

Circulating numbers of endothelial progenitor cells in patients with gastric and breast cancer.

Angiogenic factors like VEGF or G-CSF were reported to mobilize endothelial progenitor cells (EPCs) from the bone marrow. These EPCs were shown to be incorporated in the neovessels of developing tumors. Although the concentrations of angiogenic factors in the peripheral blood were reported to be elevated in cancer patients, the number of circulating EPCs has not been previously investigated. In this study, the number of EPCs circulating in the blood in 16 healthy controls and 71 newly diagnosed cancer patients was examined by a culture assay of peripheral blood mononuclear cells. The number of circulating EPCs was not found to be increased in cancer patients, although the plasma levels of VEGF were elevated. It is suggested that VEGF, at concentrations typical of those observed in the blood of cancer patients, does not mobilize EPCs into the peripheral blood.

Breast Neoplasms↗

PubMed2002

Chylothorax in Gorham's disease.

A 25-yr-old woman presented with a right pleural effusion. Destruction of 9th through 12th ribs, adjacent vertebral bodies, and transverse processes was noted on plain radiograph and a large low-attenuated, irregular shaped mass lesion with peripheral rim enhancement, destroying vertebral body and transverse process, was revealed on the computed tomographic scan. Magnetic resonance imaging showed high signal on T1- weighted image and iso- and low signal on T2-weighted image for the mass lesion replacing the vertebral bony cortex and marrow space. An open rib biopsy revealed the histopathological changes of Gorham's disease (essential osteolysis), even though only bloody fluid filling the empty space and rib and vertebral transverse process destruction were grossly observed on operation. Even though there was no definite response to radiotherapy and pleurodesis, the patient showed stable condition up to 20 months after diagnosis.

Adult↗