A Pilot Study of Trans-Arterial Injection of 166Holmium-Chitosan Complex for Treatment of Small Hepatocellular Carcinoma

Percutaneous approaches, such as percutaneous ethanol injection and radiofrequency ablation, have been most widely used for hepatocellular carcinoma patients who were not eligible for surgery. New technologies to improve the efficacy are currently needed. 166Holmium is a neutron activated radionuclide, and has several beneficial radiophysical characteristics for internal radiation therapy. 166Holmium-Chitosan complex, in which chitosan is chelated with 166Holmium, was developed as a radiopharmaceutical for cancer therapy. We have conducted a pilot study to evaluate the clinical efficacy of transarterial administration of 166Holmium-Chitosan complex in patients with a single and small (< 3 cm) hepatocellular carcinoma. 166Holmium-Chitosan complex, at a dose of 20 mCi per cm of tumor mass-diameter, was administered through the artery that directly fed the tumor. Twelve patients were treated with a median follow-up duration of 26 (range: 12-61) months. The tumor diameter ranged between 1.5 and 2.5 cm. Ten patients (83%) had complete response and two (17%) had partial response. The median complete response duration was not reached. The median AFP level declined from 83.8 to 8.3 ng/mL within 2 months after treatment. No grade III/IV toxicity was observed. Grade I and II toxicities were observed in four patients (2 abdominal pain, 1 fever, and 1 AST/ALT elevation). No toxic death occurred. This preliminary study shows a promising and durable complete response rate with an acceptable safety profile. Further studies with greater accrual of patients are warranted.

Efficacy of Postoperative Concurrent Chemoradiation for Resectable Rectal Cancer: A Single Institute Experience / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: For patients with Dukes' stage B and C rectal cancer, surgery followed by adjuvant chemoradiotherapy is considered to be the standard treatment. However, the drugs used in combination with 5-fluorouracil (5-FU), the method of administration, duration of adjuvant therapy and the frequencies of administration presently remain controversial topics. We investigated (1) the efficacy and safety of adjuvant radiotherapy and 5-FU/leucovorin (LV) chemotherapy for patients who had undergone curative resection and (2) the effect of dose related factors of 5-FU on survival. MATERIALS AND METHODS: 130 rectal cancer patients with Dukes' B or C stage disease who were treated with curative resection were evaluated. The adjuvant therapy consisted of two cycles of 5-FU/LV chemotherapy followed by pelvic radiotherapy with chemotherapy, and then 4~10 more cycles of the same chemotherapy regimen were delivered based on the disease stage. The cumulative dose of 5-FU per body square meter (BSA), actual dose intensity and relative dose intensity were obtained. The patients were divided into two groups according to the median value of each factor, and the patients' survival rates were compared. RESULTS: With a median follow-up duration of 52 months, the 5-year disease-free survival and overall survival rates of 130 patients were 57% and 73%, respectively. Loco- regional failure occurred in 17 (13%) of the 130 patients, and the distant failure rate was 27% (35/130). The chemotherapy related morbidity was minimal, and there was no mortality for these patients. The cumulative dose of 5-FU/ BSA had a significant effect on the 5-year overall survival for Dukes' C rectal cancer patients (p=0.03). Multivariate analysis demonstrated that only the performance status affected the 5-year overall survival (p=0.003). CONCLUSION: An adjuvant therapy of radiotherapy and 5-FU/LV chemotherapy is effective and tolerable for Dukes' B and C rectal cancer patients. A rospective, multicenter, randomized study to evaluate the effects of the cumulative dose of 5-FU/BSA on survival is required.

Malignant Fibrous Histiocytoma with Type I Neurofibromatosis

Type I neurofibromatosis is an autosomal dominant disorder that occurs in 1 of 3, 000 births. It is characterized by multiple cutaneous neurofibromas, cafe-au-lait spots of the skin. Patients with neurofibromatosis are at increased risk of developing malignancies, particularly neural crest and other non-neural crest neoplasms. The term `malignant fibrous histiocytoma' was first introduced in 1963 to refer to a group of soft tissue tumors characterized by a storiform or cartwheel like growth pattern. Malignant fibrous histiocytomas are the most common type of soft tissue sarcoma that occurs in late adult life. Herein, our recent experienced a case of a malignant fibrous histiocytoma in a 28 year-old female with type I neurofibromatosis is reported, with a review of the literature.

Phase II Study of Gemcitabine and Vinorelbine as Second-Line Chemotherapy in Non-Small Cell Lung Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: With the increased use of chemotherapy for non small cell lung cancer (NSCLC), a growing group of patients can now be considered for second-line chemotherapy. However, guidelines for the second line treatment remain to be developed. The objective of this study was to evaluate the efficacy and safety of the gemcitabine and vinorelbine combination therapy in patients with advanced NSCLC, pretreated with taxane and platinum based regimens. Gemcitabine has already demonstrated activity in this patient group, with the combination therapy having been reported to be well tolerated in previous phase I/II studies. MATERIALS AND METHODS: Forty two patients with advanced NSCLC (stages III/IV), having received prior taxane and platinum based chemotherapy, with an ECOG performance status (PS) 0~2, and unimpaired hematopoietic and organ function, were treated with vinorelbine, 20 mg/m2, followed by gemcitabine, 1, 000 mg/m2, both administered on days 1, 8 and 15, every 4 weeks. RESULTS: Out of the 42 patients enrolled, 41 were evaluable for their response, and all 42 for their toxicity. The patient's characteristics were as follows; median age=60 years (42~73), median PS=1 (range 0~2), a gender ratio 31: 11 males/females, with stages IIIA, IIIB and IV in 3, 14 and 25 cases. The objective responses included a partial response (PR) 8/41 (19.5%), a stable disease 15/41 (36.6%) and a progressive disease 18/41 (43.9%). The median time-to progression (TTP) and survival were 4 months, ranging from 2 to 14 months, and 8 months, ranging from 2 to 17+ months, respectively. Grade 3 neutropenia was seen in 19% of the patient, and there was no grade 4 neutropenia or episodes of febrile neutropenia. No grade 4 thrombocytopenia or other grade 3/4 non-hematological toxicities were observed. CONCLUSION: The combination of gemcitabine/vinorelbine is active and well tolerated in patients with advanced NSCLC having failed prior taxane/platinum therapy.

Paclitaxel and Cisplatin Combination Chemotherapy in Pretreated Breast Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: A single institute trial of combination chemotherapy, with paclitaxel and cisplatin, in patients with metastatic breast cancer, having failed previous combination chemotherapy, was performed. MATERIALS AND METHODS: Patients were only eligible for this study if there disease had progressed, following treatment with previous chemotherapy, in either an adjuvant or a metastatic setting. Paclitaxel 175 mg/m2 was administered as a 3-hour continuous infusion on day 1, and cisplatin 80 mg/m2 was administered for 2 hours on day 2, with adequate hydration. This was repeated every 3 weeks, and continued until one of the following events occurred: disease progression, unacceptable adverse effect or treatment refusal by the patient. Intercurrent palliative radiotherapy, or concurrent hormonal therapy, was permitted, depending on each patient's status. All the endpoints were evaluated under the principle of intention to treat analysis. RESULTS: A total of 24 patients entered the study, and 18 had at least one measurable lesion, but 6 did not. The objective response rate of the 18 patients was 50%(9/18). Two were complete responses and seven showed partial responses. The median response duration, progression free and overall survival were 5.3 months (range, 4~18), 6 months (95% CI, 5~7) and 12 months (95% CI, 7~17), respectively. 67% of the planned dose was administered. Out of a total 135 cycles administered, about 20% of cycles showed grade 3 or 4 leukopenia and 7% showed grade 3 thrombocytopenia. Two patients suffered from pneumonia, and one experienced neutropenic fever. Mucositis, greater than grade 3, existed in three cases. No treatment related deaths were reported. CONCLUSION: The combination chemotherapy, with paclitaxel and cisplatin, was active in the treatment of metastatic breast cancer patients having failed previous chemotherapy.

Changes of Telomerase Activity and Proliferation by Inhibition of Reverse Transcriptase Activity in Human Cancer Cell / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Activation of telomerase is proposed to be an essential step in cancer cell immortalization and cancer progression. 3'-azido-2',3'-dideoxythymidine (AZT), a reverse transcriptase inhibitor, was reported to be incorporated in telomeric sequences of immortalized cells in culture and to suppress the activity of telomerase and the cell proliferation. In this study, after induction of cancer cell senescence with long-term treatment of AZT, we investigated the dynamics of telomerase subunits (hTERT, hTR, TEP), transcription factors (c-Myc, Mad1), telomerase activity, and finally, telomere length in a human breast cancer cell line. MATERIALS AND METGODS: Human breast cancer cell (MDA-MB-231) was treated with AZT. Senescence was measured by senescence-associated beta-gal staining and apoptosis was counted by dTd enzyme assay. Telomerase activity (by TRAP assay), expression of telomerase subunit genes (by RT-PCR and real-time PCR) and telomere length (by Southern blot analysis) were measured after the AZT treatment. RESULTS: We found evidences of senescence, apoptosis and growth delay after AZT treatment. In addition, AZT- treated cancer cells showed inhibition of telomerase activity and shortening of telomere length in a dose- and duration-dependent way. Among the telomerase subunits, hTERT and c-Myc were the first factors to change after AZT treatment, subsequently, followed by the changes of hTR, Mad1 and TEP. CONCLUSION: The suppression of hTERT and c-Myc by AZT treatment was the initial genetic phenomenon, subsequently followed by the changes of hTR, Mad1 and TEP.

Experimental and Clinical Studies on the Intraarterial Injection of Holmium-166 Chitosan Complex in the Treatment of Hepatocellular Carcinoma

PURPOSE: The purposes of this study were to evaluate the biodistribution and effect of Ho-166 radionuclide by intra-arterial injection of the Ho-166 chitosan complex in dogs and to assess the clinical efficacy and side effects of this complex in the treatment of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: In an experimental study, 20 mCi of Ho-166 chitosan complex was injected into the left hepatic artery of six adult dogs. The distribution of radioactivity in each organ was calculated using a gamma camera scan at regular intervals. A beta ray radioactivity count (cpm) of blood and urine was performed periodically, and hematologic and hepatic function were regularly assessed. At 4, 8 and 12 weeks after intra-arterial injection, bone marrow and liver were pathologically evaluated. Twenty-five patients with a single, nodular HCC mass 3 -9 cm in diameter were treated by intra-arterial injection of Ho-166 chitosan complex, and immediately after the procedure a gamma camera scan was obtained. A beta ray radioactivity count(cpm) of blood was performed periodically, hematologic and hepatic function were regularly evaluated, and CT scans and angiograms were obtained 3 months after the procedure. On the basis of the CT and angiographic findings, the treatment effects were classified as complete (CR), partial (PR) or non-response(NR). RESULTS: In the animal study, blood radioactivity peaked immediately after injection and then declined rapidly. Urinary excretion was 0.17%. The proportion of radioactivity in each organ per whole body was 25% in the left lobe of the liver, 7% in the right lobe, 3% in the lung, 1.4 -3% in the bladder, and 2% in bone. WBC and platelet counts declined maximally at 3 -4 weeks and recovered at 12 weeks. The cellularity of bone marrow was 25% at 4 weeks and 55% at 12 weeks, findings which correlated well with the observed hematologic changes. In the clinical study of 25 HCC patients, CR was achieved in 17 (68%) cases, PR in 5 (20%) and NR in 3 (12%). At gamma camera imaging immediately after treatment, tumor radioactivity was localized in 76% of cases. In six cases (24%) WBC and platelet counts decreased 50% or more compared with their pretreatment level. In 67 -75% of cases, SGOT and SGPT were, within 1 -3 days, 2 -3 times higher than their pre-treatment level, and recovered at post 4 weeks. CONCLUSION: Ho-166 chitosan complex administrated intra-arterially localized the target organ with minimal side effects, and we therefore suggest that it may be used in the treatment of nodular and hypervascular HCC. Further study of its dosimetry and possible hematologic side reactions is needed, however.

Differential Diagnosis By Analysis of Pleural Effusion / 결핵

BACKGROUND: Pleural effusion is one of most common clinical mainifestations associated with a variety of pulmonary disease such as malignancy, tuberculosis, and pneumonia. However, there are no useful laboratory tests to determine the specific cause of pleural effusion. Therefore, an attempt was made to analyze the various types of pleural effusion and search for useful laboratory tests for pleural effusion in order to differentiate between the disease, especially between a malignant pleural effusion and a non-malignant pleural effusion. METHODS: 93 patients with a pleural effusion, who visited the Severance hospital from January 1998 to August 1999, were enrolled in this study. Ultrasound-guided thoracentesis was done and a confirmational diagnosis was made by a gram stain, bacterial culture, Ziehl-Neelsen stain, a mycobacterial culture, a pleural biopsy and cytology. RESULTS: The male to female ratio was 56:37 and the average age was 47.1±21.8 years. There were 16 cases with a malignant effusion, 12 cases with a para-malignant effusion, 36 cases with tuberculosis, 22 cases with a para-pneumonic effusion, and 7 cases with transudate. The LDH2 fraction was significantly higher in the para-malignant effusion group compared to the para-pneumonic effusion group [30.6±64.% and 20.2±7.5%, respectively (p<0.05)] and both the LDH and LDH2 fraction was significantly in the para-malignant effusion group compared to those with tuberculosis [16.4±7.2% vs. 7.6±4.7%, and 30.6±6.4% vs. 17.6±6.3% respectively (p<0.05)]. The pleural effusion/serum LDH4 fraction ratio was significantly lower in the malignant effusion group compared to those with tuberculosis [1.5±0.8 vs. 2.1±0.6, respectively (p<0.05)]. The LDH4 fraction and the pleural effusion/serum LDH4 fraction ratio was significantly lower in the para-malignant effusion group compared to those with tuberculosis [17.0±5.8% vs. 23.5±4.6% and 1.3±0.4 vs. 2.1±0.6, respectively(p<0.05)]. CONCLUSION: These results suggest that the LDH isoenzyme was the only useful biochemical test for a differential diagnosis of the various disease. In particular, the most useful test was the pleural effusion/serum LDH4 fraction ratio to distinguish between a para-malignant effusion and a tuberculous effusion.

Squamous Cell Carcinoma of the Cornea

In this paper, a case of corneal squamous cell carcinoma is reported. Invasive squamous cell carcinoma of the cornea is a rare disorder and has not been previously described in the Korean literature. In this case, the invasive squamous cell carcinoma of the cornea was treated by complete excision and cryotherapy. No evidence of metastasis or recurrence has been found since the procedure. Complete excision and adjunctive cryotherapy has become the treatment of choice because of the higher recurrence rate following a simple excision.

A case of double primary cancer of hepatocellular carcinoma and mucoepidermoid carcinoma in the liver / 대한내과학회지

Mucoepidermoid carcinoma is a common malignant tumor of the salivary glands, but rare in other sites. Only 10 cases of mucoepidermoid carcinoma of liver have been reported, and there was 1 case of double primary cancer of hepatocellular carcinoma and mucoepidermoid carcinoma. The definite diagnosis and pathogenesis are still controversial. However, hepatocellular carcinoma is the second most common cancer in Korea. Its etiology is better known compared to mucoepidermoid carcinoma. We report a rare case of double primary cancer of mucoepidermoid carcinoma and hepatocellular carcinoma in liver.

Leptomeningeal Carcinomatosis in Solid Tumors; Clinical Manifestation and Treatment / 대한암학회지

PURPOSE: Leptomeningeal carcinomatosis occurs in about 5% of patients with solid tumor and is being diagnosed with increasing frequency as patients live longer and as neuro-imaging studies improve. In general, the most commom cancers that involved the leptomeninges are breast cancer, lung cancer, and malignant melanoma. MATERIALS AND METHODS: We investigated 25 patients presented with multiple neurologic symptoms and signs who were diagnosed with leptomeningeal carcinomatosis at the Yonsei Cancer Center from January 1990 to December 1999. RESULTS: The primary disease of leptomeningeal carcinomatosis were stomach cancer (10 cases), breast cancer (7 cases), lung cancer (5 cases), unknown primary cancer (2 cases) and common bile duct cancer (1 case). All patients were presented with multiple neurologic symptoms and signs involving the central nervous system (CNS), cranial nerve or spinal nerves. Twenty-one of twenty- five patients were treated with intrathecal chemotherapy, radiotherapy, or combination therapy. Fourteen of them (66.7%) experienced improvement or stabilization of neurologic symptom and sign. The median survival was 122 days (10-2190). CONCLUSION: In conclusion, although early diagnosis and active treatment of leptomeningeal carcinomatosis may improve the quality of life in selected patients, the median survival was relatively short. Therefore, new diagnostic and therapeutic strategy for leptomeningeal carcinomatosis were needed.

Restoration of P-glycoprotein function is involved in the increase of natural killer activity with exogenous interleukin-15 in human immunodeficiency virus-infected individuals

A depressed level of natural killer (NK) activity is one of the various immunologic abnormalities in human immunodeficiency virus (HIV) infection. Interleukin-15 (IL-15), an immunotherapeutic candidate in HIV infection, increases NK activity and induces the excretion of CC-chemokines from divergent immune cells, but the mechanisms of NK activity enhancement by IL-15 stimulation is not clearly established in HIV infection. This study examined whether CC-chemokines, which are known to increase NK activity, are secreted adequately in HIV-infected individuals, and also investigated whether P-glycoprotein is involved in NK activity enhancement after IL-15 administration. NK activity increased with IL-15 stimulation in NK cells of HIV-infected individuals, as it does in normal NK cells. IL-15 stimulates NK cells to secrete CC-chemokines, such as, macrophage inflammatory protein-1alpha (MIP-1alpha), macrophage chemotactic protein-1alpha (MCP-1alpha) and regulated upon activation, normal T cells expressed and secreted (RANTES) in both HIV-infected individuals and controls with no significant difference. P-glycoprotein expression and function is decreased in HIV-infected individuals and restored only in NK cells of HIV-infected individuals after IL-15 stimulation. P-glycoprotein may play a role in the mechanism of increased NK cell activity in HIV-infected individuals after IL-15 stimulation.

The Efficacy and Safety of Docetaxel in Patients with Anthracychne pretreated Metastatic Breast Cancer: A Multicenter Phase II Study / 대한암학회지

PURPOSE: Tbis phase II study was performed to evaluate the efficacy and safety of docetaxel in patients with anthracycline-pretreated metastatic breast cancer (MBC). MATERIALS AND METHODS: From September 1996 to January 1998, 27 patients with metastatic breast cancer from 31 to 63 years of age with a performance status of 0 to 2 were registered in the phase II trial. All patients had metastatic breast cancer which had progressed or relapsed 2 during or after treatment with an anthracycline-based regimen. Docetaxel 75 mg/m2 was ad- ministered over 1 hour every 21 days until disease progression was documented or until toxic effects precluded further therapy. All patients received dexamethasone orally at the dose of 16 mg on days -1, 0, 1 of each cycle. RESULTS: Objective responses were seen in 9 of 25 assessable patients (two complete and seven partial responses), with an overall objective response rale of 36%. The median duration of response was 36 weeks (range 19.0~40.5). The median time to progression and survival duration were 17.5 and 69 weeks, respectively, for assessable patients. One hundred fifty cycles (median, five) of docetaxel were administered. Among 27 patients assessable for toxicity, the following side effects were reported: nadir neutropenia grade 3 (4 patients) and grade 4 (22 patients); grade 2 stomatitis (6 patients); grade 2 alopecia (5 patients); grade 2 to 3 neurosensory toxicity (4 patients); no hypersensitivity reaction; mild fluid retention (4 patients). CONCLUSION: Docetaxel is an active agent in patients with antracycline-pretreated metastatic breast cancer. Docetaxel was associated with severe but reversible neutropenia. Dexamethasone prevented hypersensitivity reactions and appeared to ameliorate fluid retention.

Application of Gabexate Mesylate IC against MMP - 9 Using ex vivo Model in Gastric Cancer: Prognostic Factor and Selection Criteria for Anti - MMP Treatment / 대한암학회지

PURPOSE: Among the many biological characteristics of cancer, matrix metalloproteinases(MMPs) are essential for tumor invasion and metastasis. The correction of the imbalance between MMPs and tissue inhibitors of matrix metalloproteinase (TIMP) has been suggested as a possible goal for the control of invasive phenotype of the cancer. To test the possible inhibition of MMP-9 in ex vivo model and the selection of the patients who are sensitive to MMP inhibitory (MMPI) treatment, we evaluated IC50 of the gabexate mesylate (Foy) against MMP-9 and compared them to the clinical parameters and patients survivals. MATERIALS AND METHODS: Thirty-four paired normal and gastric cancer tissues were tested for the IC50 of the gabexate mesylate. MMP-9 activity was measured by zymography. RESULTS: MMP-9 expression (percent of sample band density to control band) (p=0.04) and IC50 (p=0.02) of cancer tissues were significantly higher than those of normal tissues. Cancer tissue IC50 was higher than that of normal tissues in cases when the tumor mass diameter was longer than 5 cm (p=0.03) as well as in higher T-stage (p=0.04), lymph node metastasis (p=0.04) and in advanced stages (p=0.04). There was a tendency of increased IC50 of diffuse and mixed type than that of intestinal type (diffuse & mixed: 11.0+-20.8 mg/ml, intestinal: 2.7+-3.9 mg/ml; p 0.07), in spite of no difference in MMP-9 expression (diffuse & mixed: 40.3+49.2%, intestinal: 51.0+-58.0%). In early gastric cancer (EGC), there was no difference in IC50 between normal and cancer tissues whereas cancer tissue IC50 was higher than that of normal tissue in advanced gastric cancer (p 0.02). There was a tendency of increment of ICo in cancer tissues of advanced gastric cancer than that of EGC whereas no difference was found in MMP-9 expression between these types of cancers. Poor prognosis was found in high IC50 patients in curatively resected patients (p=0.04). In multivariate analysis, high IC50 was suggested as a possible independent prognostic factor. CONCLUSION: We could differentiate the high risk patients using IC50 of gabexate mesylate in ex vivo model. This model can be applied in detecting patients with poor prognosis and patients who can have a possible benefit with MMPI treatment.

Clinical Significance of Urokinase - type Plasminogen Activator Receptor ( uPAR ) Expression in Breast Cancer Tissues / 대한암학회지

PURPOSE: Cancer invasion is induced by several proteolytic enzyme systems associated with the destruction of basement membrane and extracellular matrix. Urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) have been reported as prognostic factors in breast cancer patients and plasminogen activation is regulated by various factor such as uPAR and growth factor. So we examined the tissue levels of urokinase-type plasminogen activator receptor (uPAR) in breast cancer patients. MATERIALS AND METHODS: Tissue uPAR levels were measured by ELISA assay in 268 breast cancer patients. RESULTS: The median and mean values of tissue uPAR level in breast cancer were 3.5 ng/mg and 4.8+-3.6 ng/mg cytosol protein, respectively. Tissue uPAR level was the highest in T1 stage, but there was no statistical significance between T stage (p >0.05). In nodal stage, there was also no difference in the value of uPAR according to progression. And the value of uPAR expression was not associated with estrogen and progesteron receptor status, number of involved node and percent of node involvement. In TNM stage, tissue uPAR levels were higher in patients with stage I-II than in patients with stage III-IV (p=0.027). In univariate analysis, nodal factor (p=0.0023) and TNM stage (p=0.0004) were significantly associated with overall survival. But, multivariate analysis showed that TNM stage was the only significant prognostic factor (p=0.0002). CONCLUSION: These results suggest that uPAR is mainly associated with initial tumor invasion and other factors might be involved in later stages of cancer progression.

Effect of 5 - FU plus leucovorin for adjuvant chemotherapy according to dose related factors in colon cancer / 대한내과학회지

BACKGROUND: In patients with stage C colon cancer, surgery followed by adjuvant chemotherapy with 5-fluorouracil (5-FU)/leucovorin (LV) is considered to be the standard treatment. However, the objects of adjuvant therapy and the duration of treatment are still matters of controversy. We investigated the effect of dose related factor(delivered total dose of 5-FU per body square meter, actual dose intensity and relative dose intensity) of the adjuvant 5-FU/leucovorin regimen on survival in coloncancer. METHODS: Of the colon cancer patients with Duke's B2 and C stage diseases treated with curative resection from December, 1990 to December, 1996, 139 patients treated with 5-FU/LV as an adjuvant chemotherapy were evaluated. The delivered total dose of 5-FU per body square meter, actual dose intensity and relative dose intensity were obtained. The patients were divided into two groups according to the median value of each factor and the survival rates were compared. RESULTS: The total dose of 5-FU administrated per body square meter had a significant effect on the 5-year disease free and overall survival in stage B2 and C colon cancer patients(B2; p=0.025, p=0.045, respectively, C; p=0.011, p=0.0002, respectively). But survival was not affected by the dose intensity. Multivariate analysis demonstrated that only the total dose of 5-FU administrated per body surface area affected the 5-year disease free and overall survival(p=0.0016, p=0.0007, respectively). CONCLUSION: It can be concluded that the total dose of 5-FU administered is more important than the DI in adjuvant chemotherapy of colon cancer and the total dose of 5-FU had a significant effect on the survival rate in colon cancer patients. To confirm the total dose effect of 5-FU on survival in this study, multi-institutional, prospective randomized studies should be carried out.

Clinical Relevance of Urokinase-type Plasminogen Activator ( uPA ) , uPA Receptor , Plasminogen Activator Inhibitor-1 Co-expression from Tissue and Serum of Breast Cancer as Targets of Biotherapy / 대한암학회지

PURPOSE: We measured and compared the uPA, plasminogen activator inhibitor-1 (PAI-1) and uPA receptor (uPAR) levels in breast cancer tissues and blood of the patients to evaluate their clinical relevance for biotherapy. MATERIALS AND METHODS: uPA, PAI-1 (Monozyme, Netherland), uPAR (American Diagnostics, USA) levels were measured by ELISA assay in 192 breast cancer tissues, in 18 normal breast tissues and in 163 blood from breast cancer patients. RESULTS: There was a tendency of uPA increment from ductal carcinoma in situ while increment of PAI-1 and uPAR occurred from Ti. With the progression of cancer, uPA, PAI-1, uPAR tended to decrease; however, the uPA/uPAR, uPA/PAI-1 ratios remained unchanged. There was a correlation of uPA expression between normal and cancer tissues ( r(2)= 0.49). Correlation of uPA and PAI-1 was found in normal tissue and stage I cancer tissue while correlation of uPAR and PAI-1 was found with cancer progression. Between cancer tissue and blood significant correlations were found in uPA, PAI-1, uPAR levels. CONCLUSION: uPA, PAI-1, uPAR levels in cancer tissue elevated from the early stage maintaining correlative expressions with cancer progression. A positive correlation between cancer tissue and blood level suggested the applicability of the levels of uPA, PAI-1 or uPAR for detecting patients for biotherapy.

The Efficacy of Pre - operative Chamotherapy with Intra-arterial Cisplatin and Intravenous Adriamycin for High Grade Osteosarcoma / 대한암학회지

PURPOSE: Osteosarcoma is one of the most common juvenile malignant tumors in Korea. Combined modality treatment [pre-operative chemotherapy + surgery (limb salvage or amputation) + adjuvant chemotherapy] had improved the overall survival and quality of life. To improve the local control rate, we introduced pre-operative chemotherapy combined with intra-arterial (IA) cisplatin and continuous intravenous infusion (CI) of adriamycin. We evaluated the efficacy and feasibility, such as limb salvage rate, recurrence pattern and the survival impact, based on the histologic response of pre-operative chemotherapy. MATERIALS AND METHODS: Fourty-one patients with histologically-proven high grade osteosarcoma of the extremities were enrolled from January 1990 to June 1996. Pre-operative chemotherapy, cisplatin 120 mg/m2 IA and adriamycin 75 mg/m2/72hrs CI, was administered for 3 cycles with 3 week interval, followed by surgery. Post-operative chemotherapy was applied by the tumor necrosis rate. If the tumor necrosis of the specimen was more than 90%, the same regimen af the preoperative one was administered for 3 cycles. A salvage regimen (Ifosfamide 7.5 gm/m2/5d IV + high dose MTX 10 gm/m2 IV VP-16 360 mg/m2/3d IV) was administered every 3 weeks for 6 cycles if the tumor necrosis was <90%. RESULTS: Of 41 patients, 37 were evaluable for efficacy and toxicities, because 4 refused further chemotherapy after 1 or 2 cycles. Twenty-one patients were male and 16 female, with the median age of 16 years (8-41). The tumor locations were as follows: distal femur 20, proximal tibia 8, humerus 6, distal tibia 2 and 1 in proximal femur. All but one patient, who died of neutropenic sepsis, completed the planned pre-operative therapy. Of the 36 patients who received surgery, limb salvage surgery was possible in 30 patients (83.3%) and 27 patients (75%) showed a good response (10 with grade III, 27.8%; 17 with grade IV, 47.2%). With a median follow-up of 23 months, 3-year disease-free survival rate was 54.7% and overall survival rate was 78.3%. Of the 15 patients who recurred, the major metastatic site was the lungs. No operation-related mortality was observed. Most patients experienced grade III-IV nausea, vomiting and hematologic toxicities, which were reversible with supportive care. CONCLUSION: Pre-operative chemotherapy combined with IA cisplatin and CI adriamycin induced higher good response rate without survival benefits. To improve the survival rate, the design of good salvage chemotherapy with a non-cross resistant regimen should be considered.

Delayed activation-induced T lymphocytes death in aplastic anemia: related with abnormal Fas system

OBJECTIVES: To quantitate apoptosis and Fas antigen expression of T lymphocytes by activation in aplastic anemia (AA) and compare with that of normal controls and completely-recovered AA, and to investigate the apoptotic sensitivity to anti-fas antibody of activated T lymphocytes in AA. METHODS: We studied the expression of Fas antigen on fresh T lymphocytes of twenty patients with AA [13 newly diagnosed, 7 recorvered AA after immunosuppressive therapy (IST)], and investigated the activation-induced cell death (AICD) and Fas expression by activation [interleukin-2 (200 U/ml) and phytohemagglutinin (50 micrograms/ml)] in 5 newly-diagnosed AA, 5 normal controls and 5 AA in complete response (CR). Apoptotic sensitivity to anti-Fas antibody was assessed by the time-course kinetics of induction of cell death by anti-Fas antibody (500 ng/ml). RESULTS: There was no significant difference of Fas antigen expression on freshly-isolated T lymphocytes among newly-diagnosed severe AA, normal control s and patients with AA in CR after IST. In normal controls, T lymphocytes death was greatly increased at 3 days of activation, and Fas antigen expression on T lymphocytes was increased above baseline at day 1 of activation. In contrast, in newly-diagnosed AA, T lymphocytes showed delayed cell death, which correlated with a slowed increase of Fas antigen expression by activation. Also, anti-Fa s antibody sensitivity of activated T lymphocytes was decreased in newly-diagnosed AA. In completely recovered AA, these abnormal AICD and Fas antigen expressions by activation were recovered to normal range. CONCLUSIONS: Abnormal AICD plays a role in the immune pathophysiology of AA, and defective Fas system is involved in this process.

Microsatellite Instability Correlate with a Prognosis in Breast Cancer / 대한암학회지

PURPOSE: Microsatellite instability in patients with defects in the mismatch repair system resulting in RER has a high risk of accumulating mutations in oncogene and tumor suppressor gene. In this study, we evaluated the incidence of microsatellite instability in breast cancer by comparing PCR-amplified sequences from frozen samples of normal and tumor tissue fram affected patients. We also investigated whether RER was associated with TGF-beta RII mutation. MATERIALS AND METHODS: Fifty surgically resected breast cancer specimens from Jan. 1996 to June, 1997 were used for study. Microsatellite instability(referred to as replication error, RER) at three loci with BAT 26, BAT 40, TA10 was analyzed by polymerase chain reaction and the results were compared with clinicopathologic characteristics. RESULTS: Of the 50 breast cancer patients, 14(28%) were RER(+) at one or more microsatellite loci, and 4(8%) showed TGF-beta RII mutation. Microsatellite instability was significantly correlated with lymph node involvement(especially in case of 4 or more lymph nodes involvement). But we could not find any correlation between RER and other prognostic factors including tumor size, tumor grade, hormone receptor status and pathology. One of fourteen tumors with RER(+) showed TGF-beta RII mutstion. There was no signiticant correlation between RER(+) and TGF-beta type II receptor gene mutation. CONCLUSION: The findings suggest that microsatellite instability would be useful prognostic factor in unilateral breast cancer patients, and the role of targeting to gene mutation will be explored in future studies.