Arsenic trioxide induces depolymerization of microtubules in an acute promyelocytic leukemia cell line

BACKGROUND: Arsenic trioxide (As2O3) is a well-known and effective treatment that can result in clinical remission for patients diagnosed with acute promyelocytic leukemia (APL). The biologic efficacy of As2O3 in APL and solid tumor cells has been explained through its actions on anti-proliferation, anti-angiogenesis, and apoptotic signaling pathways. We theorize that As2O3 activates a pathway that disrupts microtubule dynamics forming abnormal, nonfunctioning mitotic spindles, thus preventing cellular division. In this study, we investigated how As2O3 induces apoptosis by causing microtubule dysfunction. METHODS: Cultured NB4 cells were treated with As2O3, paclitaxel, and vincristine. Flow cytometric analysis was then performed. An MTT assay was used to determine drug-mediated cytotoxicity. For tubulin polymerization assay, each polymerized or soluble tubulin was measured. Microtubule assembly-disassembly was measured using a tubulin polymerization kit. Cellular microtubules were also observed with fluorescence microscopy. RESULTS: As2O3 treatment disrupted tubulin assembly resulting in dysfunctional microtubules that cause death in APL cells. As2O3 markedly enhanced the amount of depolymerized microtubules. The number of microtubule posttranslational modifications on an individual tubulin decreased with As2O3 concentration. Immunocytochemistry revealed changes in the cellular microtubule network and formation of polymerized microtubules in As2O3-treated cells. CONCLUSION: The microtubules alterations found with As2O3 treatment suggest that As2O3 increases the depolymerized forms of tubulin in cells and that this is potentially due to arsenite's negative effects on spindle dynamics.

Prognostic Factors of Response to Laparoscopic Splenectomy in Patients with Idiopathic Thrombocytopenic Purpura

Laparoscopic splenectomy (LS) has become the treatment of choice for patients with idiopathic thrombocytopenic purpura (ITP) who do not respond to medical treatment. The aim of this study was to identify factors predictive of outcome after LS for ITP. From May 1997 to December 2002, we performed 30 LS on patients with ITP. A positive response was defined as a postoperative platelet count greater than 50,000/microliter and no requirement for maintenance therapy. Chi-square testing was performed to determine the predictive effects of the following variables: age, sex, preoperative response to steroids or immunoglobulin, duration of disease, antiplatelet antibody, platelet associated antibody, and antinuclear antibody. LS was successfully performed in all patients. For a mean follow-up interval of 24.3 months, response to LS was 73.3%. Splenectomy for steroid nonresponders resulted in an inferior complete response rate (10 of 18, 55.6%) as compared with those that experienced relapse after steroid treatment (11 of 12, 91.7%) (p=0.042). The other significant predictor of outcome by univariate analysis was the time between diagnosis and surgery (p=0.049). The other variables showed no significant correlation with successful splenectomy. We conclude that LS can be performed safely with a satisfactory remission rate in patients with ITP who do not respond to medical treatment, and that the factors most frequently associated with surgical success are a response to steroid and disease duration.

A Phase II Study of Oxaliplatin Combined with 5-Fluorouracil and Leucovorin (Mayo Clinic Regimen) in 5-Fluorouracil Refractory Colorectal Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: There are few therapeutic options in patients with colorectal cancer that have progressed or recurred following 5-fluorouracil (5-FU) based therapy. We evaluated the efficacy and toxicity of oxaliplatin, 5-FU, leucovorin (Mayo clinic regimen) in 5-FU pretreated advanced colorectal cancer patients. MATERIALS AND METGODS: Twenty-eight patients were enrolled in this study between January 1999 and May 2001. Patients were treated with oxaliplatin 150 mg/m2 on day 1 as a 2-hr infusion and 5-FU 425 mg/m2, leucovorin 20 mg/m2, bolus for 5 days. Treatment courses were repeated in 4-week intervals. RESULTS: The objective response rate was 25% for 28 assessable patients, all cases registered a partial response. Eleven patients (39%) demonstrated stable disease, and ten (36%) progressed. The median response duration was 5.5 months, and the median time to progression was 6.3 months. The median overall survival time was 13.5 months from the start of the chemotherapy. From the 120 cycles analyzed, grade 3,4 hematologic toxicities included neutropenia: 1.6%, and thrombocytopenia: 1.6%. The frequent grade 3.4 non-hematologic adverse reactions were nausea/vomiting (25.0%), diarrhea (14.3%), stomititis (3.6%), and neuropathy (3.6%). There were no treatment-related deaths. CONCLUSION: This phase II study had relatively higher toxicity than previous studies, and did not show an increased significant response rate. These high levels of toxicity suggest that the study treatment combination of oxaliplatin with a full dose Mayo clinic regimen arm is no feasible. Therefore, this regimen will be discontinued and a safer regimen will be adopted.

Salvage Treatment for Advanced Gastric Cancer Using FEP (5-FU, Etoposide, Cisplatin) Combination Chemotherapy / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: There is no effective treatment for patients with advanced gastric cancer having failed to respond to first line chemotherapy. The aim of this study was to evaluate the therapeutic activity, and safety, of a FEP regimen in patients with a recurrence of, or metastatic, gastric cancer that had been unresponsive to primary chemotherapy. MATERIALS AND METHODS: Recurred or metastatic gastric cancer patients that did not respond to a 5-fluorouracil based regimen were entered into this trial. The patients were treated with FEP (5-FU, etoposide and cisplatin) as salvage chemotherapy. The treatment regimen was 5-FU (900 mg/m2/day) by continuous infusion for 3 days, etoposide (90 mg/m2/day) on days 1, 2 and 3, and cisplatin (60 mg/m2/day) on day 2. This treatment was repeated every 3 weeks. RESULTS: Between December 1997 and October 2001, 28 patients were enrolled to the study. The response rate was 32.1% (95% CI 15.5~57.8%). The median times to progression and survival duration were 23~33 weeks, respectively. Among a total of 187 cycles of chemotherapy, the grade 3 and 4 hematological toxicities were leukopenia (6.4%), thrombocytopenia (1.6%), and grade 3 non-hematological side effects of nausea/vomiting (17.9%). CONCLUSION: FEP combination chemotherapy seems to be an effective treatment regimen for gastric cancer as salvage chemotherapy. To confirm these results, large scale of clinical trials will be required.

Torsade de Pointes in Advanced Atrioventricular Block: A Cause of Syncope

Advanced or complete atrioventricular (AV) block is frequently regarded as a cause of informed syncopal attacks even though escape rhythm is maintained. Torsades de pointes (TdP) may be a significant complication of AV block associated with QT prolongation. Maintaining ventricular rate over 70 beats/min is known to be important to normalize QT interval and to reduce the possibility of bradycardia-related TdP recurrence after pacemaker implantation. We report one case of syncopal attacks associated with TdP in a 70 year old female patient with advanced AV block and prolonged QT interval. She was referred to evaluate palpitation and syncope. Advanced AV block and QT interval prolongation were seen with electrocardiography, but junctional escape rhythm was maintained. Syncopal attacks occurred during temporary pacemaker insertion. Multiple episodes of nonsustained polymorphic ventricular tachycardia and TdP related to syncopal attacks were demonstrated by 24-hour Holter monitoring. A permanent pacemaker was implanted and ventricular rate was set over 70 beats/min resulting in no recurrence of TdP and syncope.

The Effect of Cytosine Arabinoside and Daunorubicin(AD) Combination Chemotherapy in Acute Myelogeous Leukemia / 대한암학회지

PURPOSE: Important advances in the treatment of acute myelogenous leukemia have been made with the introduction of cytosine arabinoside(ara-C) and anthracycline(daunorubicin) over the past 20 years. Currently, 50 to 85% of patients with acute myelogenous leukemia achieve complete remission with induction chemotherapy consisting of ara-C and daunorubicin. About 25% of complete responders will have extended long-term survival and may be cured. Therefore we treated patients having acute myelogenous leukemia with AD(7+3) regimen and analyzed factors complete remission rate, remission duration, and survival duration. MATERIALS AND METHODS: Induction therapy; Thirty seven patients with previously untreated acute myelogenous leukemia treated with AD(7+ 3) regimen(ara-C, 200 mg/m2/d by continuous infusion for seven days, and daunorubicin, 45 mg/m2/d for 3 days). The second course of therapy was AD(5+2), if the patients failed to enter remission. Consolidation therapy; three cycles of consolidation chemotherapy were administrated with at least 4 week interval following remission. Course 1; ara-C at 100 mg/m2 by continuous infusion every 12 hour for five days, 6-thioguanine at 100 mg/m2/day orally for 5 days. Course 2; ara-C is same as course 1, vincristine at 1.2 mg/m2(maximum 2 mg) by bolus injection for 1 day, prednisolone at 40 mg/m'(maximum 60 mg) orally for 5 days. Course 3; ara-C is same as course 1, daunorubicin at 45 mg/m2 by 1 hour infusion for 2 days. RESULT: 62.2 percent of the 37 patients entered complete remission. The remission duration for all patients in complete remission ranged from 2 months to 63+ months, with the median of 15.1 months. The median duration of survival in complete responder group was 23.3 months. Among various prognostic factors, females and groups with normal chromosome and t(8;21) or t(15;17) had significantly higher complete remission rate than males and groups with other chromosomal abnormalities, respectively. Factors influencing on survival duration were female, normal chromosome, t(8;21) or t(15;17), Auer rod-positive, and peripheral blast % less than 50% at diagonosis. Groups with Auer rod-positive, normal chromosome, and t(8;21) or t(15;17) also had significantly longer remission duration. CONCLUSION: Combination chemotherapy with cytosine arabinoside and daunorubicin is a effective regimen for acute myelogenous leukemia as much as other regimen for acute myelogenous leukemia. Further clinical trials for effective treatment regimen are necessary to increase the complete remissioin rate.

Clinical Applications of Three-Dimensional Echocardiography

BACKGROUND: Three-dimensional echocardiography has good feasibility and real image display in dynamic and spatial cardiac structures. So we designed this study to assess both the feasibility and potential role of three-dimensional echocardiography for the evaluation of cardiac structures and adjacent relationships. METHOD: We studied 25 patients with various heart structures. Cross-sectional images of specific interesting region were acquired from multiplane transesophageal echocardiography and reconstructed to three-dimensional images by TomTec image processing system. These images were presented in volume-rendered dynamic display for assessing of additonal informations. RESULTS: Three-dimensional reconstructions of usual viewpoints and interesting cut planes were possible in all patients. When compared with standard two dimensional images, additional informations were provided in all reconstructed cases. Among these images, mitral valve morphology, aortoseptal continuity and interatrial septum were the structures for which three-dimensional echocardiography were most useful. CONCLUSION: Although it was preliminary datas which needs large-scale randonmized prospective studies, three-dimensional echocardiograpy may be most potent and promising methods in evaluating anatomic and functional assessment of heart structures.

Treatment of Diaphyseal Fractures of the Radius and Ulna with Dynamic Compression Plates: A Retrospective Study of 52 Fractures in 33 Patients / 대한정형외과학회잡지

Reduction of displaced diaphyseal fractures of the radius and ulna in adult must be nearly anatomical for restoration of mormal function. Most of the fractures require operative management, and various methods of open reduction and internal fixation have been recommended. Because we believe that anatomical reduction followed by rigid internal fixation provides the most satisfactory results for these injuries, dynamic compression plating method is frequently used in our hos pi tal. We studied 52 diaphyseal fractures of the forearm bone in 33 patients treated at the S.R.C.H. from May 1980 to December 1985. Of the 33 patients, 20 had fractures of the radius and ulna; 6, fractures of the radius only; and 7, fractures of the ulna only. The fractures of both bones were treated with plate and screws in 19 patients. In another one, the ulna was treated with plate and screws and the radius was treated by screw fixation only. The results were as follows: l. Of the 52 fractures, 51(98.1%) were united after the initial operation within 23 weeks. 2. The average time for radiological union of the fracture, excluding those complicated by infection or non-union, was 11.1 weeks for 24 radii and 10.9 weeks for 25 ulnae. 3. Only one patient(3.0%) was complicated by infection and only one(1.9%) non-union of radius occurred. 4. The functional results were excellent or satisfactory in 25 patients(83.3%). 5. We have found that in adults the auto compression plating is a successful method for the diaphyseal fractures of the forearm.