Il-Young Choi

Telomerase activity and its clinicopathological significance in gastric cancer

In order to assess the role of telomerase in development of malignant gastric cancer, we measured the telomerase activity in gastric cancer tissues and normal tissues obtained from 95 patients by employing recently developed sensitive PCR (polymerase chain reaction)-based telomerase assay (telomeric repeat amplification protocol, TRAP). We also investigated how telomerase activity related to other clinicopathological findings including DNA ploidy and K-RAS gene point mutation. The telomerase activity was present in 85 of the 95 gastric cancer tissues, whereas we detected no telomerase activity in any normal tissue. The incidence of telomerase activity in gastric cancer tissues was not correlated to age, sex, tumour stage, histological grade, DNA ploidy or K-RAS mutation. Disease-free or overall survival of patients having tumours with detectable telomerase activity was not significantly different from that of those without telomerase activity. These findings suggest that telomerase may play a key role in the establishment and progression of the gastric cancer and further studies will be needed to elucidate the biological role of telomerase in gastric cancer.

Clinical aspects of pregnancy and delivery in patients with chronic idiopathic thrombocytopenic purpura (ITP).

Background Idiopathic thrombocytopenic purpura (ITP) is a condition that often develops in young women and, consequently, physicians should frequently manage and monitor pregnant patients with this disorder. Methods We reviewed the charts of 30 women with chronic ITP delivered in 31 pregnancies from January 1995 to December 2003. Results Fifteen patients were diagnosed with ITP before pregnancy and sixteen patients were diagnosed during pregnancy. The mean platelet counts before pregnancy, during pregnancy, and at delivery were 70,040/mm3, 83,960/mm3, and 62,680/mm3, respectively. The symptoms of hemostatic impairment were not noted in most of the pregnancies (77%, 24/31). During pregnancy and at delivery, most of the women (61%, 19/31) received various kinds of treatment to raise platelet counts. At delivery, the most commonly used therapy was platelet transfusion (48.4%, 15/31). Seven pregnancies (22.6%) were treated with corticosteroids during pregnancy and at delivery. Five pregnancies (16.1%) were treated with IV IgG during pregnancy and at delivery. Fifteen deliveries (51.7%) were performed by cesarean section and fourteen (48.3%) with vaginal delivery. Bleeding was uncommon at delivery. There were no cases of infants with any clinical signs of hemorrhage. Conclusion Our current results suggest that ITP in pregnancy can proceed safely with low hemorrhagic risk in both infants and mothers, and that mothers with ITP can deliver healthy infants without serious hemorrhagic complications

Outcome of Adult Severe or Very Severe Aplastic Anemia Treated with Immunosuppressive Therapy Compared with Bone Marrow Transplantation : Multicenter Trial

To compare survival rates and long-term complications after bone marrow transplantation (BMT) or treatment with immunosuppressive agents (ISA) in the management of adult aplastic anemia (AA) and to identify prognostic factors associated with improved survival, we evaluated 229 adult AA patients treated with ISA from 1990 to 2001 and compared the results with those for 64 BMT recipients. Of 156 patients with severe aplastic anemia (SAA) or very severe AA treated with ISA (antithymocyte globulin [ATG]or ATG plus cyclosporine), 46.8% showed complete or partial response and 7.1% had relapses. After long-term follow-up, 1 case each of acute leukemia, myelodysplastic syndrome, and paroxysmal nocturnal hemoglobinuria developed.The 6-year survival rate was 69%. Response to ISA, disease severity, and low absolute neutrophil count (ANC) (≤200/mm3) were associated with poor survival. Patient age, sex, initial platelet count, etiology, or treatment regimen did not significantly affect survival. Cox regression analysis showed low ANC to be the only pretreatment variable significantly associated with poor survival (P = .000). Of 64 BMT recipients, 82.8% had sustained engraftment, and 12.5% experienced graft failure. Twenty (31.3%) of the patients developed grade II to IV acute graft-versus-host disease (GVHD), and 12 (18.8%) of the patients developed chronic GVHD.The 6-year survival rate was 79%. Patient age and sex, disease severity, etiology,ANC, initial platelet count, and treatment regimen did not affect survival. Survival of 83 AA patients, aged 14 to 40 years, treated with ISA was not statistically significant from that of 61 adult AA patients who underwent BMT (6-year survival rate, 65% and 79%, respectively). However, BMT in adult AA achieved long-term engraftment and a lower relapse rate than ISA.These results suggest that ISA can achieve a high response rate and long-term survival among patients with adult AA,regardless of disease severity. Further studies with larger numbers of patients and long-term follow-up are needed.

Absence of Clinical Prognostic Value of Vascular Endothelial Growth Factor and Microvessel Density in Multiple Myeloma

Vascular endothelial growth factor (VEGF) is considered a potent stimulator of angiogenesis. In multiple myeloma (MM), it has been reported that bone marrow angiogenesis parallels tumor progression and correlates with a poor prognosis. To investigate the role of angiogenesis in MM, we investigated VEGF expression and microvessel density (MVD) in the bone marrow of 75 MM patients by immunohistochemical methods. VEGF expression was observed in 87.3% (62 of 71) of patients. MVD was 69.42 ± 9.67 (mean ± SE) compared with the normal control values of 26.81 ± 2.85. MVD values were 73.98 ± 11.27 and 36.04 ± 6.99 in the VEGF-positive and VEGF-negative groups, respectively. The MVD of patients in the VEGF-positive group was significantly higher than in the VEGF-negative group (P = .045). However, there were no significant differences in various clinical parameters, such as age, sex, hemoglobin, platelet count, serum levels of albumin, calcium, creatinine, and β2-microglobulin, and bone marrow plasma cell percentage, between the VEGF-positive and VEGF-negative groups. Multivariate analysis revealed that age, hemoglobin, platelet count, serum levels of albumin and creatinine, and bone marrow plasma cell percentage were correlated with overall survival, whereas VEGF expression or MVD was not. In conclusion, our results suggest that VEGF is highly expressed and that MVD is increased in MM, indicating that angiogenesis may play a role in MM. Although MVD in the bone marrow of the VEGF-positive group is significantly higher compared with the VEGF-negative group (P = .045), VEGF is not correlated with overall survival. Further studies that include other angiogenic factors are needed to determine the functional role of angiogenesis in MM. Int J Hematol. 2002;76:460-464.

Phase II Study of Irinotecan, 5-Fluorouracil, and Leucovorin in Relapsed or Metastatic Colorectal Cancer as First-line Therapy

BACKGROUND The purpose of this study was to assess the efficacy and toxicity of biweekly irinotecan plus 5-fluorouracil (FU) and leucovorin (LV) in patients with relapsed or metastatic colorectal cancer. MATERIALS AND METHODS Between March 2002 and May 2004, 24 patients with histologically confirmed relapsed or metastatic colorectal cancer were enrolled in this study. One chemotherapy cycle consisted of irinotecan 180 mg/m(2) on days 1 and 15; 5-FU 400 mg/m(2) bolus IV with 600 mg/m(2) by a 22 hour intravenous infusion on days 1, 2, 15 and 16; and leucovorin 20 mg/m(2) on days 1, 2, 15 and 16, every 4 weeks. RESULTS The median age of the 24 was 57.5 years (range, 38 approximately 69). Their metastatic sites included: the liver (62.5%), lung (20.8%), peritoneum (16.7%), lymph node (12.5%), ovary (8.3%) and pelvis/vagina (8.3%). Twenty-two patients were evaluable for a response. Six and 7 patients achieved partial responses and stable diseases, respectively. The overall response rate was 27.3% (95% Confidence interval; 10.3 approximately 44.5%). The median follow-up duration for surviving patients was 14.7 months (range, 1.7 approximately 26.5). Median overall survival (OS) and 1-year OS rates were 19 months and 86.3%, respectively. Median response duration and median progression free survival were 7.47 and 5.57 months, respectively. A total of 83 cycles (median 4 cycles) were administered. The main non-hematologic toxicities were nausea/vomiting (44.5%/18.1%) and diarrhea (8.4%). The most common hematologic toxicity was NCI grade I/II anemia (31.3%) and grade I/II neutropenia was 10.8%. There was no life-threatening toxicity. CONCLUSION The results suggested that irinotecan, 5-FU and leucovorin combination chemotherapy in a biweekly schedule is a practical and tolerable treatment option in patients with advanced colorectal cancer.

Telomerase activity in benign and malignant human thyroid nodules.

Telomerase is a ribonucleoprotein polymerase which contains an integral RNA and synthesizes TTAGGG nucleotide repeats at the ends of chromosomes in vertebrates. Accumulated evidence has indicated that telomerase is stringently repressed in normal human somatic tissues but reactivated in immortal and cancer cells, suggesting that activation of telomerase may play an important role in carcinogenesis. In order to assess the role of telomerase in the development of thyroid cancer, we measured the telomerase activity in 19 frozen samples obtained from patients with benign and malignant thyroid nodules by employing a recently developed sensitive PCR-based telomerase assay (telomeric repeat amplification protocol: TRAP). Telomerase activity was detected in all the thyroid cancer tissues (9 of 9) and 4 out of 8 benign thyroid nodules showed telomerase activity. Three of thyroid cancers with high telomerase activity had an unfavorable prognosis, whereas six cancers with low telomerase activity were associated with a favorable prognosis. interestingly, Hashimotos thyroiditis tissues also showed telomerase activity. These results indicate that telomerase may play a key role during thyroid carcinogenesis.

Radiofrequency ablation for metastatic hepatic tumor in colorectal carcinoma.

PURPOSE The purpose of this study was to assess the efficacy and safety of radiofrequency ablation (RFA) to treat hepatic metastasis in patients with colorectal carcinoma. MATERIALS AND METHODS Between May 1999 and July 2002, a total of 45 tumors in 24 patients with colorectal cancer were treated with RFA. Thirteen patients received systemic chemotherapy after the RFA procedure. The ablation was performed percutaneously under ultrasound guidance using cool-tip or expandable electrodes and an RF generator. The medical records as well as the CT scan results taken every 3 months were retrospectively reviewed. RESULTS The median follow-up duration of the surviving patients was 11.7 months (4.6 approximately 32.2 months). Complete tumor necrosis was achieved in 17 patients (70.8%) on an immediate (<24 hrs) CT scan. The median survival was 17.1 months. The 1- and 2-year survival rates were 80.5 and 25.8%, respectively. In a univariate analysis, complete necrosis, tumor size and post-RFA chemotherapy were significant factors for survival. Nineteen of the 24 patients developed a recurrence or progressed (79.2%). The median progression free survival was 5.5 months. There were no treatment related deaths or serious adverse effects, with the exception of one case of respiratory failure. CONCLUSION These results suggest that RFA is a well-tolerated and effective method to treat hepatic metastasis in colorectal carcinomas.

Thymidylate Synthase, Thymidine Phosphorylase, VEGF and p53 Protein Expression in Primary Colorectal Cancer for Predicting Response to 5-fluorouracil-based Chemotherapy

PURPOSE In the treatment of advanced metastatic colorectal cancer, several new agents, such as irinotecan and oxaliplatin, have been developed, which have improved both disease free and overall survivals. Among these agents, 5-fluorouracil (5-FU) still remains one of the most active agents, and the selection of patients who can benefit from 5-FU-based chemotherapy is still important, as those unlikely to benefit could be spared the harmful side effects. The expression levels of thymidylate synthase (TS), thymidine phosphorylase (TP) and p53 have been known to be associated with the clinical response to 5-FU-based therapy as well as the prognosis, and that of vascular endothelial growth factor (VEGF) is associated with poor survival. MATERIALS AND METHODS The relationship between the expressions of TS, TP, VEGF and p53 in primary tumors, using immunohistochemistry, and the response of 45 metastatic colorectal cancer patients (M:F=25:20, median age 59 yrs) to 5-FU-based chemotherapy were evaluated. RESULTS Thirty-seven patients were treated with 5-FU/LV/irinotecan (FOLFIRI) and 8 with 5-FU/LV/oxaplatin (FOLFOX). The overall response rate was 28.9% (13/45). When immunohistochemically analyzed with monoclonal antibodies against TS, TP, VEGF and p53, 55.6% of the patients (25/45) were positive for TS, 48.9% (22/45) for TP, 82.2% (37/45) for VEGF, and 80% (36/45) for p53. There was a significant difference in the intensity of TS expression between the clinical responders and non-responders (p=0.036). In terms of the staining pattern of TS expression, diffuse staining was correlated with a poor response (p=0.012) and poor survival (p=0.045). However, there was no correlation between the expressions of TP, VEGF or P53 and the response to chemotherapy. CONCLUSION These results suggest that the expression of TS in primary colorectal cancer might be an important prognostic factor for chemotherapy response and survival, and might be a useful therapeutic marker for the response of chemotherapy.

Combination chemotherapy of heptaplatin, paclitaxel and 5-fluorouracil in patients with advanced gastric cancer: a pilot study.

PURPOSE To evaluate the efficacy and toxicity of heptaplatin, paclitaxel, and 5-fluorouracil combination chemotherapy in patients with advanced gastric cancer. MATERIALS AND METHODS Between July 2002 and September 2003, nineteen patients were enrolled in this study. Paclitaxel 135 mg/m(2) iv on day 1, heptaplatin 400 mg/m(2) iv on day 2 and 5-fluorouracil 800 mg/m(2) on day 2 approximately 4 were administered and the regimen was repeated every 3 weeks. RESULTS The median age of the patients was 60 years (range: 32 approximately 74) and the most common sites of metastasis were liver and lymph nodes. In the 16 evaluated patients, the overall response rate was 43.8%, but this was without any complete response. The median time to disease progression was 3.93 months (range: 0.26 approximately 8.1) and the median response duration for the 7 responding patients was 3.83 months (range: 1.48 approximately 6.07). The median overall survival for 19 patients was 7.01 months (range: 0.26 approximately 17.44). A median of 3 cycles (range: 1 approximately 7) and a total of 65 cycles were administered and evaluated for toxicity. The most common hematologic toxicities were NCI grade I/II anemia (47.7%), neutropenia (9.2%) and thrombocytopenia (6.2%). The most common non-hematologic toxicities more than grade II were nausea/vomiting (30.8%/9.2%). One elderly patient with ECOG 2 had a life-threatening complication of pneumonia. CONCLUSION The combination of heptaplatin, paclitaxel, and 5-fluorouracil showed significant activity and favorable toxicity profiles in patients with advanced gastric cancer. However, one elderly patient who had poor performance experienced a life-threatening toxicity/complication. Our results suggest that the efficacy of this combination chemotherapy can be maximized when administered to the patients with good performance status. Further studies with large numbers of patients and long-term follow-up study will be needed.