Yeul Hong Kim

Multicenter Study of Pain and Its Management in Patients with Advanced Cancer in Korea

The aim of this study was to evaluate the prevalence, severity, and management of pain in Korean patients with advanced cancer, and to identify the predictors of inadequate management of cancer pain in Korea. From 8 university hospitals, 655 patients with advanced cancer were surveyed. Information concerning analgesics prescribed was acquired from the medical records by the investigator. Physicians, nurses and caregivers were asked to estimate patients pain. The Korean Brief Pain Inventory and the Barrier Questionnaire were completed by the patients. The Pain Management Index was estimated. Among all patients, 70.8% (464 of 655) reported pain. Among those who had pain, 63.6% (295 of 464) reported pain rated 5 or higher on a 0-10 scale. Thirty-nine percent of the patients had not received any analgesics and 53.2% were not receiving optimal pain management. Although there was a correlation between patients pain ratings and those of doctors, nurses, and caregivers, there was no significant correlation between patients ratings and health care providers ratings at pain levels above moderate intensity. Cancer pain was more poorly managed in advanced cancer than terminal cancer patients (OR:3.20, 95%C.I, 1.83-5.60), in patients with better performance(OR:3.17, 95%C.I, 1.64-6.11), and in those patients whose pain was underestimated by the doctor (OR:2.58, 95%C.I. 1.42-4.69). Despite the high prevalence and severity of pain in cancer patients, the assessment and management of cancer pain were found to be inadequate in Korea.

Comparative Genomic Hybridization Array Analysis and Real-Time PCR Reveals Genomic Copy Number Alteration for Lung Adenocarcinomas

Genomic alterations in lung cancer tissues have been observed in various studies. To analyze the aberrations in the genome of lung cancer patients, we used array comparative genomic hybridization (array CGH) in 15 lung adenocarcinoma (AdC) tissues. Copy number gains and losses in chromosomal regions were detected and corresponding genes were confirmed by real-time polymerase chain reaction (PCR). As for the results, several frequently altered loci, including gain of 16p (46% of samples), were found, and the most common losses were found in 14q32.33 (26% of samples). High-level DNA amplifications (> 0.8 log2 ratio) were detected at 1p, 5p, 7p, 9p, 11p, 11q, 12q, 14q, 16p, 17q, 19q, 20p, 21q, and 22q. A subset of genes, gained or lost, was checked for over- or underrepresentation by means of real-time PCR. The degree of fold change was highest in ECGF1 (22q13.33), HOXA9 (7p15.2), MAFG (17q25.3), TSC2 (16p13.3), and ICAM1 (19p13.2) genes and the 16p chromosome terminal region (16p13.3pter). Taken together, these results show that array CGH could be used as a powerful tool for identification of genomic alteration for lung cancer, and the above-mentioned genes may represent potential candidate genes in the study of lung cancer pathogenesis and diagnosis.

Response to high-dose intravenous immune globulin as a valuable factor predicting the effect of splenectomy in chronic idiopathic thrombocytopenic purpura patients

This study was conducted to verify whether the response to high‐dose intravenous immune globulin (IVIG) was related to the effect of splenectomy in chronic idiopathic thrombocytopenic purpura (ITP) patients. A total of 79 patients over 16 years of age were enrolled in this study. The response to the treatment was classified on the basis of the platelet count as no response (NR, <50 × 109/l), incomplete response (IR, (50–150) × 109/l), and complete response (CR, >150 × 109/l). The response was evaluated after the infusion of high‐dose IVIG, within 2 weeks after splenectomy (immediate response), and during a follow‐up period of more than 6 months after splenectomy (sustained response), respectively. 58 patients (73.4%) showed responses (CR or IR) to high‐dose IVIG. After splenectomy, immediate responses were observed in 73 patients (92%). The response to high‐dose IVIG had no relationship with the immediate response to splenectomy (P = 0.333). A follow‐up evaluation was possible with 58 patients; 6 patients with NR in immediate responses did not show any response during the follow‐up period, and 17 patients relapsed within 6 months after immediate responses, so 35 patients (60.3%) had sustained responses. Responders to IVIG had significantly higher sustained response rates to splenectomy than non‐responders (62% vs. 38%, P = 0.001). These results indicate that the response to high‐dose IVIG could be a valuable factor predicting the sustained response to splenectomy in chronic ITP patients. Am. J. Hematol. 66:197–202, 2001.

Long-Term Engraftment Stability of Peripheral Blood Stem Cells Cryopreserved Using the Dump-Freezing Method in a −80°C Mechanical Freezer with 10% Dimethyl Sulfoxide

In this study, we summarize our long-term follow-up data of 24 patients who underwent autologous peripheral blood stem cell transplantation (PBSCT) using the dump-freezing method in a −80°C freezer. Collected peripheral blood mononuclear cells were mixed with a cryoprotectant solution consisting of autologous plasma and 20% dimethyl sulfoxide, then placed in a −80°C freezer. The recovery rate of mononuclear cells (MNCs), colony-forming unit—granulocyte/macrophage (CFU-GM) colonies, and CD34+ cells were calculated. Engraftment time (with neutrophil count > 0.5 × 109/L, platelet count > 50 ×109/L) and normal hemopoiesis (neutrophil count > 2 ×109/L, platelet count > 100 ×109/L) were evaluated. Median duration of cryopreservation was 76 days. The mean recovery rates of MNCs, CFU-GM colonies, and CD34+ cells were 93.4%, 78.4%, and 95.3%, respectively. The median engraftment times of neutrophils and platelets were 8 and 27 days, respectively. The median normal hemopoiesis times of neutrophil and platelet were 31 and 45 days, respectively. Nine patients are alive and in complete remission (CR). Seven patients in first CR sustained normal hemopoiesis with a median duration of 35 months. Two patients, who achieved second CR after salvage chemotherapy due to a leukemia relapse after PBSCT, maintained engraftment status for 24 and 28 months, and 1 reached normal hemopoiesis. These results demonstrate that PBSCT using the dump-freezing method in a −80°C freezer leads to acceptable long-term engraftment stability.

The cutoff value of serum ferritin for the diagnosis of iron deficiency in community-residing older persons

The serum ferritin assay is the best single blood test for the diagnosis of iron deficiency. Previous studies with elderly anemic patients have suggested that ferritin level less than 45xa0μg/L is indicative of iron deficiency. The subjects of these studies were hospitalized patients with anemia, however. We thus conducted a prospective study to determine the normal minimum level of serum ferritin of community-dwelling older adults by assessing the ratio of serum transferrin receptor to the log ferritin level (sTfR-F index). We conducted the anemia survey between October and November 2002. A total of 1,254 apparently healthy older adults, aged between 60 and 95 years, from three urban community dwellings participated in the survey. Among these individuals, 156 subjects who were anemic or whose serum ferritin level was less than 100xa0μg/L were selected. The soluble transferrin receptor assay was performed and the sTfR-F index was calculated. The receiver operating characteristic curve analysis was performed. Based on the data, serum ferritin level of 22xa0μg/L was selected as the cutoff value for the diagnosis of iron deficiency in community-dwelling older adults. Applying the serum ferritin cutoff of 22xa0μg/L and the sTfR-F index cutoff of 1.5, the sensitivity of the assay was 89.5% (34 of 38) and the specificity was 89.0% (105 of 118). In conclusion, for the diagnosis of iron deficiency of community-residing older adults, we suggest the serum ferritin cutoff value of 22xa0μg/L obtained by use of the sTfR-F index. The value is lower than the previous value established for hospitalized and anemic older adults.

DNA profiling by array comparative genomic hybridization (CGH) of peripheral blood mononuclear cells (PBMC) and tumor tissue cell in non-small cell lung cancer (NSCLC).

Lung tumor cell DNA copy number alteration (CNA) was expected to display specific patterns such as a large-scale amplification or deletion of chromosomal arms, as previously published data have reported. Peripheral blood mononuclear cell (PBMC) CNA however, was expected to show normal variations in cancer patients as well as healthy individuals, and has thus been used as normal control DNA samples in various published studies. We performed array CGH to measure and compare genetic changes in terms of the CNA of PBMC samples as well as DNA isolated from tumor tissue samples, obtained from 24 non-small cell lung cancer patients. Contradictory to expectations, our studies showed that the PBMC CNA also showed chromosomal variant regions. The list included well-known tumor-associated NTRK1, FGF8, TP53, and TGFβ1 genes and potentially novel oncogenes such as THPO (3q27.1), JMJD1B, and EGR1 (5q31.2), which was investigated in this study. The results of this study highlighted the connection between PBMC and tumor cell genomic DNA in lung cancer patients. However, the application of these studies to cancer prognosis may pose a challenge due to the large amount of information contained in genetic predisposition and family history that has to be processed for useful downstream clinical applications.

Phase II study with a combination of epirubicin, cisplatin, UFT, and leucovorin in advanced hepatocellular carcinoma

Purpose: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Because HCC usually presents as an advanced disease and occurs in the background of liver cirrhosis, most patients are not suitable for treatment with curative intent, thus effective systemic chemotherapy is required. However, the outcome of systemic chemotherapy has been disappointing in advanced HCC. This study was conducted to test the efficacy and toxicity of the combined regimen of epirubicin, cisplatin, and UFT moderated by leucovorin in advanced or recurrent HCC. Patients and methods: All 53 patients received epirubicin (50xa0mg/m2 i.v.) on day 1 and cisplatin (60xa0mg/m2 i.v.) after epirubicin administration. Oral UFT 400–600xa0mg/day, determined by body surface area, and leucovorin 75xa0mg/day were administered for 21 consecutive days, followed by a 7-day drug free interval. Results: Nine had a partial response, representing 16.9% of response rate (95% confidence interval rate; 7.0–26.8%) with median response duration of 17.1xa0weeks (95% CI; 5.0–29.3xa0weeks, range; 7.1–51.7xa0weeks). Fifteen patients had stable disease and the disease progressed in 26 patients. The median overall survival for the patients was 24.6xa0weeks (95% CI; 17.3–31.9xa0weeks, range; 3.0–131.3xa0weeks). The main toxicities were hematologic toxicities including neutropenia, which reached grade 3/4 in 17 patients (38.5%), and grade 3 or 4 thrombocytopenia in five patients (9.4%). Conclusion: The combination of epirubicin, cisplatin, and UFT moderated by leucovorin showed modest anti-tumor activity with relatively tolerable toxicities. However, a randomized phase III trial based on this regimen is warranted to clarify its survival benefit in patients with advanced HCC.

Hematopoietic Differentiation of Embryoid Bodies Derived from the Human Embryonic Stem Cell Line SNUhES3 in Co-culture with Human Bone Marrow Stromal Cells

Human embryonic stem (ES) cells can be induced to differentiate into hematopoietic precursor cells via two methods: the formation of embryoid bodies (EBs) and co-culture with mouse bone marrow (BM) stromal cells. In this study, the above two methods have been combined by co-culture of human ES-cell-derived EBs with human BM stromal cells. The efficacy of this method was compared with that using EB formation alone. The undifferentiated human ES cell line SNUhES3 was allowed to form EBs for two days, then EBs were induced to differentiate in the presence of a different serum concentration (EB and EB/high FBS group), or co-cultured with human BM stromal cells (EB/BM co-culture group). Flow cytometry and hematopoietic colony-forming assays were used to assess hematopoietic differentiation in the three groups. While no significant increase of CD34+/CD45- or CD34+/CD38- cells was noted in the three groups on days 3 and 5, the percentage of CD34+/CD45- cells and CD34+/CD38- cells was significantly higher in the EB/BM co-culture group than in the EB and EB/high FBS groups on day 10. The number of colony-forming cells (CFCs) was increased in the EB/BM co-culture group on days 7 and 10, implying a possible role for human BM stromal cells in supporting hematopoietic differentiation from human ES cell-derived EBs. These results demonstrate that co-culture of human ES-cell-derived EBs with human BM stromal cells might lead to more efficient hematopoietic differentiation from human ES cells cultured alone. Further study is warranted to evaluate the underlying mechanism.

Array CGH Reveals Genomic Aberrations in Human Emphysema

Emphysema is the major component of chronic obstructive pulmonary disease (COPD), which is the fourth leading cause of death in the world. Several epidemiologic studies suggest that genetic factors may have an important role in the pathogenesis of emphysema. We analyzed the gene expression profiles of chromosomal aberrations using array comparative genomic hybridization (array CGH) in 32 patients with emphysema to identify the candidate genes that might be causally involved in the pathogenesis of emphysema. Copy number gains and losses were detected in chromosomal regions, and the corresponding genes were confirmed by real-time polymerase chain reaction. Several frequently altered loci were found, including a gain at 5p15.33 (60% of the study subjects), and a loss at 7q22.1 (31% of the study subjects). DNA gains were identified at a high frequency at 1p, 5p, 11p, 12p, 15q, 17p, 18q, 21q, and 22q, whereas DNA losses were frequently found at 7q and 22q. We found that the fold change levels were highest at the CYP4B1 (1p33), JUN (1p32.1), NOTCH2 (1p12-p11.2), SDHA (5p15.33), KCNQ1 (11p15.5-p15.4), NINJ2 (12p13.33), PCSK6 (15q26.3), ABR (17p13.3), CTDP1 (18q23), RUNX1 (21q22.12) and HDAC10 (22q13.33) gene loci. We also observed losses in the MUC17 (7q22.1), COMT (22q11.21) and GSTT1 (22q11.2) genes. These studies show that array CGH is a useful tool for the identification of gene alterations in cases of emphysema and that the aforementioned genes might represent potential candidate genes involved in the pathogenesis of emphysema.

Mitomycin‐C, 5‐fluorouracil, and leucovorin as a salvage therapy in patients with metastatic colorectal adenocarcinoma

Aim:u2003 There is no further treatment option for metastatic colon patients who are refractory to standard chemotherapy and to whom novel biological agents are not available. We evaluated the outcomes of mitomycin‐C, 5‐fluorouracil (5‐FU) and leucovorin in patients with metastatic colon cancer previously treated with oxaliplatin/5‐FU/leucovorin and irinotecan/5‐FU/leucovorin.