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Background: Little is known about the clinical features and outcome of patients with left circumflex artery (LCX) infarct-related acute myocardial infarction (AMI). This study was conducted to investigate the clinical features and outcome of patients who underwent direct percutaneous coronary intervention (d-PCI) for AMI caused by LCX occlusion, and to discover prognostic determinants in this clinical setting., Methods and Results: Between May 1993 and October 2000, a total of 819 patients with AMI underwent d-PCI in our hospital. Sixty-seven patients (8.2%) who had LCX infarct-related AMI constituted the population of this study. Ten of 67 patients (14.9%) were in cardiogenic shock. Angiographic findings demonstrated that the incidences of triple-vessel disease, reference lumen diameter (RLD) of the LCX > or = 4.0 mm, and LCX as the dominant artery in these patients were 26.9%, 22.4%, and 34.3%, respectively. Sixteen patients (23.9%) had unsuccessful reperfusion (defined as Thrombolysis in Myocardial Infarction flow < or = 2). Univariate analysis showed that dominant LCX, RLD of the LCX > or = 4.0 mm, cardiogenic shock, precordial ST-segment depression, and complete atrioventricular block were significantly related to unsuccessful reperfusion. Multiple stepwise logistic regression analysis demonstrated that dominant LCX and cardiogenic shock were significant independent predictors of unsuccessful reperfusion. The 30-day mortality rate in the 67 patients was 14.9%. Univariate analysis demonstrated that triple-vessel disease, dominant LCX, cardiogenic shock, poor left ventricular ejection fraction, and unsuccessful reperfusion were significantly associated with 30-day mortality. By multiple stepwise logistic regression analysis, dominant LCX, cardiogenic shock, and triple-vessel disease were significant independent predictors of increased 30-day mortality., Conclusions: LCX infarct-related AMI has its unique clinical features. The presence of dominant LCX and cardiogenic shock were independent determinants of unsuccessful reperfusion, and the presence of dominant LCX, cardiogenic shock, and triple-vessel disease were independent determinants of increased 30-day mortality in this clinical setting.

Background: Patients with advanced esophageal cancer are frequently not indicated for intensive chemotherapy due to aero-digestive tract complications. In order to improve the therapeutic index of systemic chemotherapy for these patients, we designed a weekly MP-HDFL protocol, which took advantage of the low toxicity of the infusional dosing schedule for cisplatin and 5-fluorouracil (5-FU), and double biochemical modulation of 5-FU by methotrexate and leucovorin., Patients and Methods: Between April 1997 and April 2001, a total of 26 patients (M:F = 22:4) with a median age of 59.5 (range: 43-81) years were enrolled into this phase II clinical trial prospectively. There were 12 patients with de novo metastatic disease, 13 with recurrent disease (including 7 relapsed from previous concurrent chemoradiotherapy incorporating cisplatin and 5-FU), and one with locally advanced disease. The weekly MP-HDFL protocol was composed of methotrexate 40 mg/m2, i.v., on days 1, 8, 15; cisplatin 35 mg/m2, 24-hour IVF, on days 2, 9, 16; and 5-FU 2,600 mg/m2 and leucovorin 300 mg/m2, 24-hour IVF, on days 2, 9, 16; repeated every 28 days., Results: A total of 97 courses were given with an average of 3.7 courses per patient (range: 1-19). All of the patients were assessable for evaluation of toxicity. Grades 3/4 leukopenia and thrombocytopenia were noted in 13 (14%) and 17 (18%) of the treatment courses, respectively. There were 3 episodes of febrile neutropenia in 2 patients, and lethal sepsis in one patient. The Grades 3/4 non-hematological toxicities were infrequent. Among 25 patients with recurrent or metastatic disease, 7 had partial response and 12 had stable disease. The response rate for the intent- to treat group was 28% (95% C.I.:12%-49%). The median survival was 5 months (range: 1-28 months)., Conclusion: Weekly MP-HDFL combination chemotherapy is associated with mild and acceptable toxicity, and has modest palliative activity in a portion of advanced esophageal cancer patients. However, a more active and better tolerated anticancer drug combination is needed to improve the outcome of these patients.

The influence of MSI on treatment outcome of colorectal cancers remains unclear and deserves further investigation. We recruited 244 patients with stage IV sporadic colorectal cancers for our study, based on appropriate eligibility criteria. Patients were nonrandomly allocated to 2 treatment groups of either with or without high-dose 5-FU plus leucovorin chemotherapy (HDFL, 5-FU 2,600 mg/m(2) leucovorin 300 mg/m(2) maximum 500 mg). Each treatment group was further divided into 2 subgroups according to high-frequency MSI (MSI-H) status. MSI-H was defined as the appearance of MSI in at least 2 of the 5 examined chromosomal loci (BAT-25, BAT-26, D5S346, D2S123, D17S250). We compared clinicopathologic parameters, p53 overexpression and overall survival between the groups. In addition, 4 subgroups were identified as follows: MSI-H(+)HDFL(+), n = 35; MSI-H(-)HDFL(+), n = 134; MSI-H(+)HDFL(-), n = 17; MSI-H(-)HDFL(-), n = 58. There was no significant difference of background clinicopathologic data between the HDFL(+) and HDFL(-) treatment groups (p > 0.05). Survival analyses indicated that the patients of subgroup MSI-H(+)HDFL(+) survived significantly longer than those of subgroup MSI-H(-)HDFL(+), with median survival times of 24 (95% CI 20.2-27.9) and 13 (95% CI 11.6-14.4) months, respectively (p = 0.0001, log-rank test). In contrast, in patients without chemotherapy, the prognosis was poor irrespective of MSI status, with median survival times of 7.0 (95% CI 4.6-9.4) and 7.0 (95% CI 6.1-7.9) months in the MSI-H(+)HDFL(-) and MSI-H(-)HDFL(-) subgroups, respectively (p = 0.8205, log-rank test). MSI-H cancers responded significantly better to HDFL (p = 0.001), with a mean response rate of 65.71% (95% CI 49.98-81.44%) in subgroup MSI-H(+)HDFL(+) compared to 35.07% (95% CI 26.99-43.15%) in subgroup MSI-H(-)HDFL(+). There appeared to be no preferential metastatic site where response to HDFL can be predicted based on the MSI status of the primary tumor. Toxicity to HDFL was similarly minimal between MSI-H(+) and MSI-H(-) patients (p > 0.05). Multivariate analysis of all patients further indicated that MSI-H and chemotherapy were independent favorable prognostic parameters (p < 0.05). Thus, the better prognosis of stage IV sporadic colorectal cancers with MSI-H may be associated with better chemosensitivity, rather than lower aggressiveness in biologic behavior., (Copyright 2002 Wiley-Liss, Inc.)

It has long been established that advanced age is not only associated with greater myocardial infarction frequency but also greater mortality and morbidity. The treatment of acute myocardial infarction (AMI) in 80 year old patients remains problematic with conflicting results; in these patients, the risks of conservative treatment are high and the risks and benefits of thrombolytic therapy are still controversial. The purpose of this study was to evaluate whether primary angioplasty can offer an important alternative method to improve short- and long-term outcomes in octogenarian or older patients who experience AMI. Between May 1986 and March 2000, 171 consecutive 80 year old patients hospitalized for AMI were not randomized to be registered and divided into a medical therapy group (group 1: an historical control group, n=11) and a primary angioplasty group (group 2, n=60). In-hospital mortality was markedly increased with advanced Killip scores (Killip 3 or 4) in both groups. Twenty-four hours after admission, group 1 patients had a significantly higher incidence of progression to higher Killip scores than did group 2 patients (P=0.006). The 30-day overall mortality of group 2 patients was significantly lower than in group 1 patients (30.0% vs 54.1%, P=0.003). Patients without cardiogenic shock treated by primary angioplasty had a significantly lower incidence of overall mortality at 30 days than patients without cardiogenic shock treated conservatively [3.1% vs 24.3%, P=0.016 (Killip 1 and 2); 18.2% vs 52.6%, P=0.044 (Killip 3)]. However, the mortality rate of cardiogenic shock was extremely high and did not differ significantly between groups I and 2 (86.1% vs 88.2%, P=0.99). The 3-year cumulative survival rate was significantly higher in group 2 than in group 1 patients (P=0.0009). In conclusion, primary angioplasty is feasible and effective, and can improve short-and long-term mortalities in octogenarian or older patients with AMI but without cardiogenic shock.

We previously reported the therapeutic efficacy of 13-cis retinoic acid (13-cRA) in some subtypes of peripheral T-cell lymphoma (PTCL). This study sought to clarify if the addition of interferon-alpha2a (IFN-alpha2a), an agent with synergistic cytotoxicity with 13-cRA in many types of malignant cells, may be more effective in the treatment of PTCL. Eligible patients has histologically proven PTCL, which was recurrent after or refractory to anthracycline-containing systemic chemotherapy. The treatment included oral administration of 13-cRA 1 mg/kg/day, divided into three doses, and intramuscular injection of IFN-alpha2a 4.5 MU/M2, three times per week. From March 1995 to July 2000, a total of 17 patients, 10 men and 7 women, with a median age of 47 years (range, 18-77 years), were recruited. The histologic diagnosis included 7 cases of unspecified PTCL, 6 cases of Ki-1 anaplastic large cell lymphoma (ALCL), 1 case of angioimmunoblastic T-cell lymphoma, and 3 cases of angiocentric nasal NK/T cell lymphoma. They received a median of 1.7 months of treatment (range, 0.4-13.3 months). One patient refused further treatment due to toxicity. The doses of 13-cRA and IFN-alpha2a had to be decreased in 7 and 7 patients, respectively. Grade III/IV hematologic and non-hematologic toxicity developed in 2 and 5 patients, respectively. There were 5 partial responses (Ki-1, 4; unspecified PTCL, 1), with a total response rate of 31.3% (95% CI, 5.7-56.8%). The median duration of response for the responders was 2.5 months (range, 0.8-7.2 months). The median overall survival for the entire group of patients was 3.6 months. In conclusion, a combination of 13-cRA and IFN-alpha2a is a useful salvage treatment for selected patients with recurrent or refractory PTCL, particularly those with the Ki-1 subtype. However, the data does not support that addition of IFN-alpha2a is superior to 13-cRA alone.

In this study, we showed that suppression of the MEK-ERK transduction pathway by a selective inhibitor, 2'-amino-3'-methoxyflavone (PD98059), increased drug resistance of SiHa cells to cisplatin, but not to another common anticancer drug, doxorubicin. The downstream mechanism of this discrepant cellular response was investigated. Both cisplatin and doxorubicin activated nuclear ERK2 and nuclear transcription factor kappa B (NF kappa B) of SiHa cells. However, suppression of the MEK-ERK2 pathway by PD98059 resulted in a further enhancement of cisplatin-induced NF kappa B activation, while no further regulation of NF kappa B was noted in doxorubicin-treated cells. The activation of NF kappa B by cisplatin or doxorubicin was not due to the degradation of cytoplasmic I kappa B alpha, as demonstrated by western blotting. Transfection of a dominant negative I kappa B alpha resulted in a markedly diminished PD98059-induced cisplatin resistance in SiHa cells. Our results suggest that the MEK-ERK signaling pathway plays a role in the chemosensitivity of SiHa cells, and suppression of this pathway increases cisplatin resistance partly via an increase of NF kappa B activation. The mechanism responsible for the discrepant effect of PD98059 on NF kappa B activation and hence the chemosensitivity of SiHa cells towards cisplatin and doxorubicin remains to be investigated.

Our study aims to further clarify the prognostic significance of p53 overexpression in stage IV colorectal cancer. Between January 1994 and June 1997, we recruited 144 patients with stage IV colorectal cancers for our study, based on appropriate eligibility criteria. The patients were nonrandomly allocated to 2 treatment groups of either with or without high-dose 5-fluorouracil plus leucovorin chemotherapy (HDFL: 5-Fu: 2,600 mg/m(2) leucovorin 300 mg/m maximum 500 mg). Each treatment group was further divided into 2 subgroups according to the status of p53 overexpression. Therefore, 4 subgroups were allocated in our study and were designated as p53 (overexpression) HDFL (+), n = 65; p53 (normal) HDFL (+), n = 37; p53 (overexpression) HDFL (-), n = 27; and p53 (normal) HDFL (-), n = 15, respectively. All patients were prospectively followed until April 2001. There was no significant difference of the background clinicopathologic data of these 4 allocated subgroups of patients (p > 0.05). Multivariate analysis of various clinicopathologic factors of the whole group of patients indicated that age > or = 60 years, poor differentiation, mucin production, CEA > 100 ng/ml, p53 overexpression and without chemotherapy were the significant independent poor prognostic factors (p < 0.05). Survival analyses indicated that the patients of subgroup p53 (normal) HDFL (+) survived significantly longer than those of subgroup p53 (overexpression) HDFL (+), with mean survival time (95% confidence interval [CI]) of 20.24 (16.24-24.25) and 13.29 (10.98-15.60) months, respectively (p = 0.0043, log-rank test). In contrast, in patients without chemotherapy, the prognosis was poor regardless of their p53 status, with mean survival time (95% CI) of 6.85 (5.47-8.23) and 5.87 (4.48-7.26) months in p53 (overexpression) HDFL (-) and p53 (normal) HDFL (-) subgroups of patients, respectively (p = 0.2820, log-rank test). Cancers of normal p53 expression responded significantly better to HDFL (p < 0.05), with mean response rate (95% CI) being 65.57% (52.18-82.96%) in subgroup p53 (normal) HDFL (+) as compared to 35.38% (23.52-47.24%) in subgroup p53 (overexpression) HDFL (+). The toxicity to HDFL was similarly minimal between p53-normal and p53-overexpression patients (p > 0.05). We thus concluded that the poorer prognosis of stage IV colorectal cancers with p53 overexpression was associated with their poorer chemosensitivity rather than the more biologic aggressiveness., (Copyright 2001 Wiley-Liss, Inc.)

Background: While coronary artery aneurysm is an uncommon anatomic disorder and has various forms, its clinical features and outcome and its impact on thrombus formation and the no-reflow phenomenon in the clinical setting of acute myocardial infarction (AMI) undergoing primary percutaneous coronary intervention (p-PCI) have not been discussed. The purpose of this study was to evaluate whether this anatomic disorder predisposes to a high burden of thrombus formation, and subsequently leads to the no-reflow phenomenon and untoward clinical outcome in patients with AMI undergoing p-PCI., Methods and Results: In our hospital, emergency p-PCI was performed in 924 consecutive patients with AMI between May 1993 and July 2001. Of these 924 patients, 24 patients (2.6%) who had an infarct-related artery (IRA) with aneurysmal dilatation were retrospectively registered and constituted the patient population of this study. Angiographic findings demonstrated that the ectasia type (defined as diffuse dilatation of 50% or more of the length of the IRA) was found most frequently (70%), followed by the fusiform type (20%; defined as a spindle-shaped dilatation in the IRA) and the saccular type (10%; defined as a localized spherical-shaped dilatation in the IRA). The right coronary artery was the most frequently involved vessel (54.2%), followed by the left anterior descending (25.0%) and the left circumflex arteries (20.8%). Coronary angiography revealed that all of these aneurysmal IRA filled with heavy thrombus (indicated as high-burden thrombus formation). The no-reflow phenomenon (defined as

In this study, we showed that nuclear ERK2 phosphorylates p53 at Thr55 in response to doxorubicin. p53 was found to physically interact with ERK2 as evidenced by Western blotting of ERK2 coimmunoprecipitated complex. The gene fragment encoded for N-terminal 68 amino acids was subcloned and fused with 6-His. Each serine or threonine site in this fragment, the possible phosphorylation site, was mutated to alanine. The recombinant proteins were used as substrates in ERK2 kinase assay. The results show that ERK2 phosphorylated p53 at Thr55. Further, electromobility shift assay showed that the phosphorylation of p53 by nuclear ERK2 was closely related to the transactivating activity of p53. These findings suggest that ERK2 may play a role in response to DNA damage via interaction with p53., (Copyright 2001 Academic Press.)

Background: Inferior wall myocardial infarction caused by obstruction of an anomalous-origin right coronary artery (RCA) is a rare angiographic finding; primary angioplasty to an anomalous-origin RCA has never been reported., Methods: In 185 patients with acute inferior wall myocardial infarction resulting from RCA occlusion who underwent primary angioplasty, eight patients (4.3%) had anomalous-origin RCAs., Results: Coronary angiography showed that all 8 patients had a dominant RCA. Six patients (75%) had an anomalous-origin RCA arising from the anterior aspect of the ascending aorta above the sinotubular line and the other 2 patients (25%) had an anomalous-origin RCA arising from the left sinus of Valsalva with a separate ostium from the left main coronary artery. The standard Judkins right guiding catheter did not offer adequate support in these patients. In the group of 6 patients, an Amplatz guiding catheter offered good support, while a standard Judkins left guiding catheter was adequate in the other 2 patients. Obstruction of the proximal RCA occurred in 6 patients (75%). Successful reperfusion was achieved in 6 patients (75%), resulting in an uneventful clinical course and long-term survival (mean follow-up, 24.9 +/- 16.5 months). Two patients (25%) had unsuccessful reperfusion and died from cardiogenic shock., Conclusions: In this small series, anomalous-origin RCAs were the dominant artery and predisposed to atherosclerosis at the proximal portions. We suggest that appropriate guide catheter selection and careful manipulation are essential for the success of revascularization. Complete reperfusion results in an excellent clinical and long-term outcome in patients with anomalous-origin RCAs.

Cyclin E is required for S phase entry. The subsequent ubiquitin-dependent degradation of cyclin E contributes to an orderly progression of the S phase. It has been shown that phosphorylation of threonine 380 (Thr380) in cyclin E provides a signal for its ubiquitin-dependent proteolysis. We report that SKP2, an F-box protein and a substrate-targeting component of the SCF(SKP2) ubiquitin E3 ligase complex, mediates cyclin E degradation. In vitro, SKP2 specifically interacted with the cyclin E peptide containing the phosphorylated-Thr380 but not with a cognate nonphosphorylated peptide. In vivo, expression of SKP2 induced cyclin E polyubiquitination and degradation. Conversion of Thr380 into nonphosphorylatable amino acids caused significant resistance of cyclin E to SKP2. The presence of the CDK inhibitor p27(Kip1) also prevented the SKP2-dependent degradation of cyclin E. Our findings suggest that SKP2 regulates cyclin E stability, thus contributing to the control of S phase progression., (Copyright 2001 Academic Press.)

Background: While coronary dissection, which is one of the most frequently occurring complications during interventional procedures, has various forms, extensive coronary dissection retrograde to the coronary sinus of Valsalva (CSV) is very rarely observed., Methods and Results: Within the last 5 years, we retrospectively reviewed our experience with 4,700 consecutive patients who underwent angioplasty procedures, 7 of whom (0.15%) developed extensive coronary dissection retrograde to the CSV. Six of the seven patients developed retrograde dissection of the right CSV during angioplasty to the right coronary artery. One of the seven patents developed retrograde dissection of the left CSV during angioplasty to the left anterior descending artery. Retrograde dissection, which extended to the ascending aorta in two patients, was observed by transthoracic echocardiography and surgical findings, respectively. Five patients were successfully treated by coronary stenting. However, this complication caused four patients to have acute myocardial infarctions, resulting in emergency surgery for one patient and in-hospital death for another., Conclusions: Our experience increased our understanding of this very rare complication. However, this complication may be life threatening, and patients in this clinical setting may have a potential risk for acute myocardial infarction, emergency surgery, or even sudden cardiac death. Therefore, it is important to learn how to promptly diagnose and manage this complication.

We have recently demonstrated that HDFL (high-dose 5-FU 2600 mg m-2 week-1 and leucovorin 500 mg m-2 week-1, weekly 24-h infusion) is highly active in the treatment of gastric cancer. To further clarify the possible mechanism underlying the improved activity of HDFL compared with conventional 5-FU regimens, we conducted in vitro studies examining the effect of these regimens on the differential regulation of thymidylate synthase (TS) in NCI-N87, a human gastric cancer cell line. The expected serum concentrations of 5-FU are 100-200 mM (lasting for less than 30 min) and 5-10 mM (lasting for 24 h) for the conventional 5-FU regimens (bolus injection or short intravenous infusion of 5-FU 370-500 mg m-2) and the HDFL regimens, respectively. Western blot analysis revealed that 24-h exposure of NCI-N87 to 2.5-10.0 mM of 5-FU resulted in a dose-dependent depletion of free TS, lasting for more than 24 h. In contrast, 30-min exposure of NCI-N87 to 200 mM of 5-FU resulted in a less than 12-h depletion of free TS. Moreover, 24-h exposure to 5-FU resulted in a higher S-phase blockade and enhanced cytotoxicity. In both modes of 5-FU treatment, the initial rapid depletion of free TS was accompanied by a rapid increment of a higher-molecular-weight TS molecule, suggesting that rapid formation of the ternary complex was the key mechanism of 5-FU action during this period. Northern blot analysis showed that the steady-state mRNA of TS was not affected by either of the schedules. We conclude that 24-h exposure of gastric cancer cells to low concentration of 5-FU resulted in better suppression of free TS, a higher degree of S-phase blockade, and enhanced cytotoxicity compared to 30-min exposure to high concentration of 5-FU. These in vitro results may help explain the improved clinical efficacy of HDFL regimens compared to conventional 5-FU regimens., (Copyright 2000 Cancer Research Campaign.)

The development of percutaneous transluminal balloon angioplasty (PTCA) is the greatest revolution in the management of stenotic coronary artery disease. However, PTCA is limited in its application to some specific subgroups of complex lesions such as bifurcational, ostial and plaque burden lesions. For this reason, some new strategies including directional atherectomy (DCA) have been developed as advanced modalities in the treatment of these complex lesions, which if treated by PTCA would certainly yield poor outcomes. We report a case of non-Q wave myocardial infarction resulting from obstruction of the ostium of left anterior descending artery. DCA and adjunctive stenting to the lesion were successfully performed and the patient was discharged uneventfully after the procedure. We suggest that DCA is a striking method and has much merit in the treatment of complex lesions with a high rate of success. In view of consideration of restenosis remains an importantly unresolved problem in percutaneous coronary intervention in specific subgroups of complex lesions. In the future, adequate debulking by mean of DCA in combination with adjunctive stenting which recently emerges as a promising treatment in the prevention of restenosis may provide a more consistent and attractive method for prevention of restenosis in these complex lesions.

Percutaneous transluminal coronary angioplasty was first introduced in 1977 by Gruentzig and now provides the option of nonsurgical revascularization for up to 1/2 of patients who undergo diagnostic catheterization for coronary artery disease. Today, although there have been great improvements in technology and operator experience, complications still occur during coronary angiography and revascularization. Coronary dissection, one of the most frequently occurring complications during angiography and angioplasty, occurs in various forms. However, right coronary dissection and retrograde extension to the aortic sinus of Valsalva is extremely unusual during an interventional procedure. We report such an unusual complication which occurred during balloon angioplasty and which was successfully managed by coronary stenting. This unusual complication may have potential risk of quickly involving the entire aorta, causing acute severe aortic regurgitation, acute myocardial infarction, requiring emergency surgery, and even resulting in death. Therefore, prompt diagnosis and management of this complication are very important.

Although very high doses of 5-fluorouracil was used in the weekly 24-h infusion, high-dose 5-fluorouracil (2600 mg/m2/week) and leucovorin (500 mg/m2/week) protocol, myelosuppression was surprisingly low. The current study was conducted to investigate the possible mechanism underlying the low myelosuppression. To mimic the clinical situation, peripheral blood progenitor cells collected from 12 patients were used for colony forming unit-granulocyte and monocyte clonogenic assay; and 2 representative modes of 5-fluorouracil exposure (30 min. versus 24 hr) were examined for cytotoxic effects on human myeloid progenitor cells. Previous pharmacokinetic studies have estimated the concentrations of 5-fluorouracil in the bone marrow to be 200-400 microM and 1-2 microM for the 30 min. infusion (600-900 mg/m2) and the 24 hr-infusion (1000-2000 mg/m2) regimens, respectively. The results of our colony-forming unit-granulocyte and monocyte clonogenic assay showed that 24-hr exposure to 5-fluorouracil (2 microM) and 30 min. exposure to 5-fluorouracil (100 microM) resulted in 27.2% and 78.2% inhibition of the colony formation, respectively. Our data provided direct evidence which may explain why myelotoxicity is significantly less in weekly 24 hr infusion of fluorouracil than in the conventional bolus regimens.

Tissue plasminogen activator (t-PA) was administered to three patients with newly developed intracardiac thrombi. Cases 1 and 2 developed right heart thrombi after radiofrequency ablation for atrioventricular nodal reentrant tachycardia and case 3 had tachycardia-related cardiomyopathy and a left ventricular thrombus. In all three patients, the intracardiac thrombi were successfully eliminated following t-PA therapy without major bleeding complications. These observations suggest that t-PA is effective in lysing new thrombus complicating radiofrequency ablation or heart failure and may be the therapy of choice in these conditions. Cathet. Cardiovasc. Intervent. 49:91-96, 2000., (Copyright 2000 Wiley-Liss, Inc.)

Background: Concurrent chemoradiotherapy (CCRT) has recently become a promising treatment for esophageal cancer. However, most investigators have adopted the conventional or modified Wayne-State PF (cisplatin plus 5-fluorouracil) regimen, which is inevitably associated with moderate to severe treatment-related toxicities. In this pilot study, we incorporated a daily low-dose regimen of cisplatin and 5-fluorouracil into CCRT in order to improve the compliance of the patients., Patients and Methods: Between July 1993 and Dec. 1997, 25 patients with locally advanced esophageal cancer (T3, or N1 disease), received CCRT which consisted of daily low-dose cisplatin (6 mg/m2/day) and continuous infusion of 5-FU (225 mg/m2/day) with radiotherapy (fraction size = 200-250 cGy/day). Except for the initial 9 patients, for whom post-CCRT esophagectomy was compulsory, all subsequent patients underwent esophagectomy only when inadequate response to CCRT was noted. The scheduled radiation dose was 50 Gy for the first 9 patients, and 60 Gy for the rest of the patients., Results: Eighteen patients (72%) completed the CCRT without interruption. Clinically, there were 8 CR and 9 PR, with a total response rate of 68% (47-87%, 95% C.I.). All patients were evaluable for toxicity. Grade 3/4 leukopenia and thrombo-cytopenia developed in 14 (56%) and 7 (28%) patients, respectively. Grade 3/4 non-hematologic toxicity was seen in 4 (16%) patients. The median survival of the whole group was 8 months (range: 2-59+). The projected 3-year overall survival was 24%., Conclusion: We suggest that for locally advanced esophageal cancer CCRT with the aforementioned daily low-dose regimen, is a treatment with good patient compliance.

Although acute left main coronary artery (LMCA) occlusion is a rare angiographic finding, it carries a very high mortality rate and most of the patients with this clinical condition die from sudden death or cardiogenic shock due to malignant arrhythmia or pump failure. The high mortality rate and tendency to lead rapidly to death are chiefly related to extensive myocardial injury. We report a case of cardiogenic shock resulting from acute myocardial infarction. Emergency cardiac catheterization was performed and coronary angiography showed a totally occluded LMCA. Prompt revascularization by means of primary LMCA stenting was successful and the patient was discharged 2 weeks later with only mild congestive heart failure. We suggest that the rapid performance of angiographic studies in this patient with cardiogenic shock was the turning point in saving her life. We also suggest primary LMCA stenting as an effective procedure for saving lives because it may reverse cardiogenic shock and prevent a probable fatal outcome.

Background: Tamoxifen sensitizes cancer cells to chemotherapeutic agents. High dose tamoxifen has been tested in the treatment of patients with melanoma and other cancers. The authors conducted a Phase II study of high dose tamoxifen plus cisplatin and etoposide for patients with advanced, inoperable nonsmall cell lung carcinoma., Methods: Patients with Stage IIIB, Stage IV, or recurrent disease; good performance status; measurable lesions; and good organ function were eligible. Tamoxifen 150 mg/m2/day, divided into 4 doses, was given for 8 days. Cisplatin 60 mg/m2 was given on Day 4. Etoposide 60 mg/m2/day was given on Days 4-8. Patients were allowed to remain in the study until either intolerable toxicity was observed or disease progression occurred., Results: Forty patients were accrued and received a total of 191 cycles of treatment. All patients were evaluable for response and toxicity. One patient had a complete remission and 14 had a partial remission (overall response rate, 37.5%). The median survival was 47 weeks. One-year survival was 44%. Increased thrombotic episodes were noted; all were clinically manageable., Conclusions: High dose tamoxifen can be administered safely in combination with cisplatin and etoposide to patients with advanced nonsmall cell lung carcinoma. Favorable response rates and survival times were obtained. The value of high dose tamoxifen in the treatment of patients with nonsmall cell lung carcinoma can be evaluated further in randomized Phase III studies.

Many tumorigenic processes affect cell-cycle progression by their effects on the levels of the cyclin-dependent kinase inhibitor p27(Kip1) [1,2]. The phosphorylation- and ubiquitination-dependent proteolysis of p27 is implicated in control of the G1-S transition in the cell cycle [3-6]. To determine the factors that control p27 stability, we established a cell-free extract assay that recapitulates the degradation of p27. Phosphorylation of p27 at Thr187 was essential for its degradation. Degradation was also dependent on SCF(Skp2), a protein complex implicated in targeting phosphorylated proteins for ubiquitination [7-10]. Immunodepletion of components of the complex - Cul-1, Skp1, or Skp2 - from the extract abolished p27 degradation, while addition of purified SCF(Skp2) to Skp2- depleted extract restored the capacity to degrade p27. A specific association was observed between Skp2 and a p27 carboxy-terminal peptide containing phosphorylated Thr187, but not between Skp2 and the non-phosphorylated peptide. Skp2-dependent associations between Skp1 or Cul-1 and the p27 phosphopeptide were also detected. Isolated SCF(Skp2) contained an E3 ubiquitin ligase activity towards p27. Our data thus suggest that SCF(Skp2) specifically targets p27 for degradation during cell-cycle progression.

A 57-year-old man was diagnosed as primary T/NK-cell central nervous system lymphoma (CNSL) with intraocular involvement. However, review of a surgical specimen taken three years before for chronic paranasal sinusitis revealed an overlooked nasal T/NK cell lymphoma (TNKL), which showed similar histomorphology and immunophenotype with the CNS disease. Another patient, a 43-year-old woman, was initially diagnosed as a rare primary leptomeningeal T-cell lymphoma with ocular manifestation. Three years later, an isolated nasal TNKL emerged. Immunohistochemical and cytogenetic studies confirmed the same nature of the CNSL and the nasal TNKL. The nasal TNKLs of both patients had a strong expression of CD3, CD56, and Epstein-Barr virus antigens, but features of angiodestruction and mucosal ulceration were absent. We propose that: 1. a locally silent "quiescent" form of nasal TNKL may exist; and 2. a thorough examination and even blind biopsy of the nasal cavity is indicated when primary T/NK-cell CNSL is diagnosed.

Background/aims: Recent in vitro evidence has strongly suggested that most anti-cancer drugs exert their cytotoxic effects via a p53-dependent apoptosis pathway. An intact p53 molecule appears to be a prerequisite for the cancer cells to be susceptible to these drugs. In this study, we specifically examined if overexpression of p53 may confer drug resistance on human gastric cancer., Methodology: All patients were treated by an empirical HDFL regimen (weekly 24-hour infusion of 5-FU, 2,600 mg/m2 and leucovorin, 300 mg/m2) in a prospective phase II clinical trial. Among them, patients with adequate pre-chemotherapy gastric cancer tissues for immunohistochemical studies were selected for this study. A p53 DO7 monoclonal antibody was used to detect the overexpression of p53. The results were designated as "-" or "+" by the independent interpretation of two pathologists., Results: A total of 30 patients, 18 men and 12 women, with a median age of 61.5 years (range: 32-78 years), were studied. There were 15 responders and 15 non-responders to HDFL chemotherapy. The percentage of p53 overexpression with positive DO7 staining was 20.0% (6 out of 30). There were no significant differences in the pertinent clinicopathologic features between the patients with positive staining of p53 and the patients with negative staining of p53. Three out of 6 (50.0%) patients with positive staining of p53 and 12 out of 24 (50.0%) patients with negative staining of p53 responded to chemotherapy, respectively (p = 1.000 by Fisher's exact test)., Conclusions: Our data suggested that the overexpression of p53 does not predict drug resistance to 5-FU of human gastric cancer.

Background/aims: In vitro data have indicated that tamoxifen (> 2.5 uM) significantly enhances the cytotoxic effect of doxorubicin in hepatocellular carcinoma (HCC) cells. This clinical study was conducted to examine whether tamoxifen, at a dose sufficient to result in a plasma concentration of more than 2.5 uM, may improve the therapeutic efficacy of doxorubicin in patients with advanced HCC., Methodology: A prospective phase II study was conducted. Eligible patients had unresectable and non-embolizable HCC, objectively measurable tumors, adequate neogram with absolute granulocyte count > 2,000/mm3 and platelet count > 1 x 10/mm3, total serum bilirubin < 3.0 mg/dl, age > or = 75 year, and a Karnofsky performance status < or = 50%. The treatment included oral tamoxifen 40 mg/m2, q.i.d, Day 1 to 7, and intravenous doxorubicin 60 mg/m2, Day 4, repeated every 3 weeks., Results: Between May 1994 and December 1996, a total of 38 patients were enrolled in the study. Thirty-six patients were evaluable for tumor response and treatment-related toxicities. There were 32 men and 4 women, with a median age of 49 years. They received an average of 3.8 (range:1-12) courses of chemotherapy. ECOG (Eastern Cooperative Oncology Group) Grade 3-4 leucopenia and Grade 3-4 thrombocytopenia developed in 27.2% and 12.5% courses given, respectively. Gastrointestinal toxicity was generally mild. Three patients developed symptomatic cardiac toxicity. Twelve patients (33.3%, 95% confidence interval 17-51%) had achieved a partial remission (PR), with a median progression-free survival of 7 months. Median survivals of the responders and non-responders were 10 and 3 months, respectively (p<0.05). The median Karnofsky performance status of the responders improved from 74.0+/-6.3% to a post-chemotherapy value of 93.2+/-4.6% (p<0.05), Conclusions: High dose tamoxifen appears to be an effective biochemical modulator of doxorubicin in the treatment of HCC. Prospective randomized phase III studies comparing doxorubicin alone versus doxorubicin plus high-dose tamoxifen are needed.

Background: Previous studies have shown that the maze operation can restore sinus rhythm and atrial transport function in patients with chronic atrial fibrillation. The purpose of this study was to test the feasibility of the application of radiofrequency and cryoablation as an alternative to the classic maze operation., Methods: Twelve patients undergoing mitral valve procedures were included in this study. Radiofrequency and cryoablation were applied to create lesions in both atria to simulate the classic maze operation., Results: There were two surgical deaths. At the mean follow-up of 10.25 months for the remaining 10 patients; 6 were in sinus rhythm, 2 in atrial rhythm, 1 in paroxysmal atrial tachycardia, and 1 in atrial fibrillation. Doppler echocardiography at 6-month follow-up showed emergence of biatrial transport function in 3 patients and right atrial contractility in 8. At 12-month follow-up of 5 patients, Doppler echocardiography showed biatrial transport function in 3 and right atrial contractility in 4., Conclusions: Our modified maze procedure during valvular operation is effective for achieving an acceptable success rate to restore sinus rhythm and atrial transport function in patients with chronic atrial fibrillation.

The mechanism of drug resistance of gastric cancer cells has rarely been investigated. We specifically examine the magnitude and the biologic significance of multidrug resistance-1 (MDR-1) expression in human gastric cancer. All patients had previously been treated in prospective clinical trials for advanced gastric cancer in our institution. Patients with adequate prechemotherapy gastric cancer tissues for immunohistochemical studies by a C219 monoclonal antibody were selected for the determination of the expression rate of MDR-1. The results were designated as negative or positive by the independent interpretation of two pathologists. A subgroup of patients who had been treated with doxorubicin- or etoposide-containing regimens were selected for further correlation with drug sensitivity. Between 1990 and 1996, a total of 60 patients, 38 men and 22 women with a median age of 55 years, were studied. Eight (13.3%; 95% confidence interval, 6%-25%) of them had MDR-1 expression. None of the pertinent clinicopathologic features, including the histopathologic types of the tumors and the extent of the diseases, correlated with the expression of MDR-1. Among the 30 patients who had received doxorubicin- or etoposide-containing combination chemotherapy, 3 (10%; 95% confidence interval, 3%-27%) were designated positive for MDR-1 expression. None of the 3 patients responded to chemotherapy, whereas 19 (70.4%) of the 27 patients who had not expressed MDR-1 did respond (p=0.041 by Fisher's exact test). We conclude that the expression of MDR-1 in gastric cancer is relatively low. Its expression, however, is clinically relevant and is useful in predicting the chemoresistance of patients with gastric cancer receiving doxorubicin- or etoposide-containing combination chemotherapy.

High-dose therapy followed by peripheral blood stem cell (PBSC) support was performed in 29 patients with primary high-risk (Group I) or chemoresponsive metastatic (Group II) breast cancer patients. Group I patients had received PBSC mobilization within 4 weeks of modified radical mastectomy. Group II patients had to achieve minimal residual disease (MRD) by induction chemotherapy before being considered eligible for PBSC mobilization and high-dose therapy. An innovative FE120C regimen (5-FU 600 mg/m2, i.v., day 1; epirubicin 120 mg/m2, i.v., day 1; cyclophosphamide 600 mg/m2, i.v., day 1) plus G-CSF (300 microg/day, subcutaneous injection for 9 days, from day 4 post-FE120C) was used to mobilize PBSCs. After high-dose CTCb (cyclophosphamide 6,000 mg/m2, thiothepa 500 mg/m2, carboplatin 800 mg/m2, in 4 days), patients received PBSC infusion and daily C-CSF 300 microg subcutaneous injection. There were 19 and 16 patients enrolled into Group I and Group II, respectively. Ten of the Group II patients had achieved minimal residual disease (MRD) after induction chemotherapy. The median numbers of mobilized total CD34 + cells for Group I and Group II patients were 27.3 (9.2 to 114.1) x 10(6)/kg and 17.1 (5.9 to 69.1) x 10(6)/kg respectively. The median time to neutrophil recovery (ANC > or = 500/microL) was 8 and 9 days in Group I and II, respectively. The median time to platelet recovery (> or = 50,000/microL) was 10 and 15 days in Group I and II, respectively. No major treatment-related toxicities were noted. In Group I, 13 out of 19 patients (68.4%; 43-87%, 95% C.I.) remained recurrence-free with a median follow-up of 31 months (6 + to 55 + months). In Group II, 3 out of 10 patients (30%; 7-65%, 95% C.I.) remained progression-free at 33 +, 35 +, 39 + months from induction therapy. We suggest that the FE120C plus G-CSF is an effective and innovative regimen for PBSC mobilization in breast cancer patients, and high-dose CTCb therapy with PBSC support is a safe and well-tolerated treatment modality.

Background: Anecdotal reports have suggested that systemic chemotherapy with agents that better cross the blood-brain barrier may result in long term disease remission in some patients with central nervous system (CNS) lymphoma. This treatment strategy has the advantage of sparing patients the late neurologic complications from brain irradiation., Methods: Eligible patients were required to 1) have tissue-proven and measurable non-acquired immunodeficiency syndrome (AIDS)- related primary or metastatic CNS lymphoma; 2) have normal hemogram, renal function, and hepatic function; 3) be age < or = 75 years; and 4) have provided informed consent. Patients with lymphoblastic lymphoma or patients who previously had been exposed to nitrosoureas, etoposide, or high dose methotrexate were not eligible. The systemic chemotherapy (BOMES regimen) included carmustine, 65 mg/m2/day, intravenously (i.v.) on Days 1-2; vincristine, 2 mg/day, i.v. on Days 1 and 8; methotrexate, 1.5 g/m2, i.v. on day 15 followed by leucovorin rescue; etoposide, 50 mg/m2/day, i.v. on Days 1-5; and methylprednisolone, 200 mg/day, i.v. on Days 1-7; repeated every 4 weeks (BOMES regimen). Four doses of intrathecal methotrexate were given to patients who had involvement in the cerebrospinal fluid., Results: Between March 1991 and March 1997 a total of 19 patients were enrolled on the study. There were 13 men and 6 women, with a median age of 57 years. Fourteen patients had primary CNS lymphoma and 5 patients had concurrent extra-CNS lymphoma. Nine patients previously had been treated by radiotherapy (four patients), chemotherapy (three patients), or both (two patients). There were 11 complete remissions (CR) (57.9%) and 5 partial remissions (26.3%), with a total remission rate of 84.2%. One patient had had progressive brain lymphoma during systemic chemotherapy with the conventional cyclophosphamide, doxorubicin, vincristine, and prednisolone regimen, but achieved CR soon after the regimen was changed to BOMES. The median time to progression of the responders was 6 months. At last follow-up, 4 patients were alive without lymphoma at 10, 47, 64, and 66 months, respectively. There were two treatment-related deaths due to sepsis. Another two patients died of fulminant hepatitis that most likely was chemotherapy-related reactivation of chronic B viral hepatitis., Conclusions: The authors believe systemic chemotherapy alone may result in long term disease remission in some select patients with non-AIDS-related CNS lymphoma. Further investigation for better protocols is mandatory.

Background: In the past 4 years, the weekly 24-hour infusion of high dose 5-fluorouracil (5-FU) and leucovorin in the treatment of patients with advanced gastric carcinoma has been prospectively studied at the authors' institution. This has enabled them to explore the possibility that the level of expression of thymidylate synthase (TS), the target enzyme of 5-FU, is related to the drug sensitivity of gastric carcinoma to 5-FU-based chemotherapy., Methods: To be eligible for this study, patients were required to have received high dose 5-FU and leucovorin chemotherapy (weekly 24-hour infusions of 5-FU, 2,600 mg/m2, and leucovorin, 300 mg/m2) and to have had adequate prechemotherapy gastric carcinoma tissues for immunohistochemical study. TS106 monoclonal antibody was used to detect the expression of TS. A visual scoring system, which ranged from 0 to 3+, was adopted by 2 independent pathologists to semiquantitate the intensity of TS expression., Results: Between 1993 and 1996, a total of 30 patients, 18 men and 12 women, with a median age of 61.5 years, were enrolled. Of these patients, 16 (53.3%) and 14 (46.7%) had high and low expression of TS, respectively. Two of the 16 patients (12.5%) with high expression of TS and 13 of the 14 patients (92.9%) with low expression of TS responded to chemotherapy (P < 0.001, chi-square test). The median overall survival was 10 months for patients with low TS expression and 4 months for patients with high TS expression (P < 0.01, log rank test)., Conclusions: The data from this study suggest that the expression of TS, as determined by immunohistochemistry, is a relatively reliable indicator of whether 5-FU should be used in the treatment of patients with gastric carcinoma.

Purpose: To report a rare case of T-cell malignant lymphoma involving the conjunctiva., Methods: A 63-year-old woman had rapid onset of bilateral perilimbal congestion and chemosis. Perilimbal thickening with corneal infiltration developed 20 days later. Computed tomography incidentally disclosed a right maxillary sinus mass. Biopsy specimens from the maxillary sinus mass and the left limbus were subjected to histopathologic examination and immunohistochemical study., Results: T-cell malignant lymphoma of diffuse large cell type, stage IV, was diagnosed. The patient was treated with combination chemotherapy plus 13-cis-retinoic acid and remained in remission 1 1/2 years after diagnosis., Conclusion: Conjunctival involvement with T-cell lymphoma may present as episcleritis and chemosis.

Acute disseminated intravascular coagulation (DIC) is a severe complication of gastric adenocarcinoma, and most of the patients die within 1-3 weeks. We have treated five such patients with an empirical non-myelosuppressive HDFL regimen (weekly 24h infusion of high-dose 5-fluorouracil 2600 mg/m2 and leucovorin 300 mg/m2). Within 2 weeks of starting the treatment the clinical and laboratory evidence of acute DIC quickly resolved in all five patients. HDFL not only caused no further myelosuppression, but also resulted in normalization of the patient's haemogram within a few weeks. Other anti-cancer drugs could then be safely added. Three patients had a survival time of more than 6 months. We suggest that HDFL is an ideal initial treatment for gastric cancer complicated by acute DIC.

We have previously shown that weekly 24-hour infusion of high-dose 5-fluorouracil and leucovorin (HDFL), a regimen initially designed for the treatment of advanced colorectal cancer, is also effective in the treatment of gastric cancer. This HDFL regimen is unique in that it is virtually non-myelosuppressive, and thus provides a comerstone on which ideal protocols may be developed. In this prospective phase II study, we examined the efficacy and toxicity of PE (cisplatin, etoposide)-HDFL, a HDFL-based combination chemotherapy, in the treatment of advanced-gastric cancer. This regimen consisted of cisplatin 60 mg/m2, i.v., D1; etoposide 65 mg/m2, i.v., D1-3; and 5-fluorouracil 2600 mg/m2 plus leucovorin 300 mg/m2, 24-hour i.v. infusion by an ambulatory infusion pump, D2,9,16; repeated every 4 weeks. The major eligibility criteria of the patients included: a) a histologically confirmed, objectively measurable, recurrent or primary inoperable gastric adenocarcinoma; b) age > or = 75 years; c) a Karnofsky performance status > or = 50%; d) an absolute granulocyte count (AGC) > or = 2000/mm3, and a platelet count > or = 100,000/mm3; e) a serum bilirubin concentration < or = 2.0 mg/dl; f) a serum creatinine concentration < or = 1.5 mg/dl; and g) a signed informed consent. Between March 1992 and June 1996, a total of 42 patients were enrolled onto the study. There were 31 men and 11 women with a median age of 54 (24-75) years; these included 16 primary metastatic, 3 locally advanced and inoperable, and 23 postgastrectomy recurrent gastric cancer patients. ECOG (Eastern Cooperative Oncology Group) grade III/IV leukopenia and thrombocytopenia developed in 34.0% and 11.0% of a total of 229 courses given, respectively. There was no treatment-related death. Four patients developed a reversible neurotoxicity; and two of them refused further chemotherapy. Among the 40 patients evaluable for responses, 9 [22.5%; 12-38%, 95% confidence interval (C.I.)] patients achieved complete remission, and 20 [50.0%; 33-67%, 95% C.I.] patients achieved partial remission. The overall response rate was 72.5% [56-86%, 95% C.I.]. The overall median survival and median time to progression of the responders were 10 and 7 months, respectively. The overall median survival of the whole group was 9 months. We concluded that PE-HDFL is a highly effective treatment for advanced gastric cancer. The treatment-related toxicity was mild and the patients' compliance was satisfactory.

Intermediate filament cytokeratin-19 (K19) protein is expressed in normal and malignant gastrointestinal epithelial cells, but not in peripheral blood (PB). Small amount of circulating gastric cancer cells can be detected by a sensitive nested reverse transcription-polymerase chain reaction (RTPCR) with primers specific for K19 mRNA. Thirty-four PB samples obtained from patients with inoperable/metastatic gastric cancer were examined. The mononuclear cell (MNC) fraction was collected by Ficoll centrifugation, and followed by total RNA extraction by acid guanidinium thiocyanate-phenol-chloroform method. RNA from 8 gastric cancer cell lines and the mononuclear cells of 33 healthy adults were used as positive and negative controls, respectively. DNA fragment of 774 bp amplified by the internal primers was found to be a highly reliable marker for K19 mRNA expression. The sensitivity of detection was between 1 and 10 cells/10(6) normal MNCs. The K19 transcripts were detected in 20.6% (7/34; 8-37%, 95% C.I.) of PB samples. None of the other pertinent clinicopathological features, including the disease extent and the histopathologic types of the tumors, were related to the expression of K19 in PB. All 34 patients had been treated by systemic chemotherapy. Among the 17 non-responders to chemotherapy, the survival of the 4 patients with detectable K19 was significantly shorter than that of 13 patients without detectable K19 in their circulating blood (p = 0.014). However, the survival impact of K19 was less significant in the other 17 patients whose tumors had responded to systemic chemotherapy. Of the whole group of patients, the median survival of the 7 and 27 patients with and without detectable K19 in their circulating blood was 1 and 3.5 months, respectively (p = 0.368). We concluded that detecting circulating cancer cells by K19 nested RT-PCR is associated with poor prognosis of gastric cancer, particularly in those patients who are not responsive to systemic chemotherapy.

Hepatocellular carcinoma (HCC) is characterized by high drug resistance to currently available chemotherapeutic agents. In a prospective clinical study, we have demonstrated that high-dose tamoxifen significantly enhanced the therapeutic efficacy of doxorubicin in patients with far-advanced HCC. In a search for a possible mechanism, we found that tamoxifen at a clinically achievable concentration (2.5 microM) significantly enhanced doxorubicin-induced cytotoxicity and apoptosis of Hep-3B cells, a multidrug resistance (MDR)-1 expressing HCC cell line. This synergistic cytotoxic effect of tamoxifen, at this concentration, however, was not mediated by MDR inhibition. Instead, as evidenced by both western blot and immunofluorescence studies, tamoxifen inhibited the cytoplasmic-membrane translocation of protein kinase C (PKC)-alpha. 12-O-Tetradecanoylphorbol-13-acetate (TPA) restored the membrane translocation of PKC-alpha and abrogated the synergistic cytotoxicity of tamoxifen. We also showed that tamoxifen, at this concentration, did not directly affect the enzyme activity of PKC. Further, membrane translocation of other membrane-bound proteins, such as Ras protein, was similarly inhibited by tamoxifen, but could not be restored by the addition of TPA. Together, these data suggested that tamoxifen may act on the cytoplasmic membrane, and thereby inhibit PKC-alpha translocation to the membrane where it is activated. We hypothesize that high-dose tamoxifen may be an effective modulator of doxorubicin in the treatment of HCC, and suggest that biochemical modulation of PKC as a measure to improve systemic chemotherapy for HCC deserves further investigation.

Previous report suggested that weekly 24-hour infusion of high-dose 5-fluorouracil (5-FU) and leucovorin is a highly active and relatively low toxic regimen for the treatment of colorectal carcinoma (J Clin Oncol 9: 625-30, 1991). This phase II study was conducted to test this important observation by a slightly modified regimen in a larger group of patients. The weekly HDFL regimen consisted of 5-FU 2600 mg/m2/week and leucovorin 300 mg/m2/week (maximum 500 mg) in a 24-hour intravenous infusion. Between February 1992 and December 1995, a total of 42 patients with non-resectable, recurrent or metastatic colorectal adenocarcinoma were enrolled onto the study. Twenty-nine (69.0%) patients had prior exposure to lower-dose 5-FU. There were 22 men and 20 women with median age of 60 (20-75) years. They received a total of 855 and an average of 20.4 (4 to 65) courses of HDFL chemotherapy. Most patients were treated at outpatient clinics and the drugs were infused by an ambulatory pump system via a Port-A catheter. The median duration of follow-up was 22 months. ECOG Gr 2-3 stomatitis, diarrhea, nausea, and vomiting developed in 6 (14.3%), 6 (14.3%), 5 (11.9%), and 5 (11.9%) patients, respectively. Twenty (47.6%) patients had developed hand-foot syndrome. There was no hematological toxicities except 3 (7.1%) patients developed ECOG Gr 1-2 leucopenia. The overall response rate was 42.9% (28%-59%, 95% C.I.) with 2 complete responses and 16 partial responses. Eight (61.5%; 31%-86%, 95% C.I.) of 13 patients, who had no previous 5-FU exposure, responded (1 complete response, 7 partial responses). Ten (34.5%, 17%-54%, 95% C.I.) of 29 patients, who had had previous lower-dose 5-FU exposure, responded (1 complete response and 9 partial responses). The median duration of response was 5 months (1+ to 23+ months). The median overall survival of the whole group of 42 patients and the 18 responders was 10 and 22 months, respectively. Our data supported the original results of HDFL regimen in the treatment of colorectal cancers. HDFL regimen can be used either as first-line or second-line treatment for non-resectable, recurrent or metastatic colorectal cancers.

Systemic chemotherapy for advanced gastric cancer is frequently associated with significant treatment-related toxicity, which is particularly serve in patients presenting with a poor general condition. A search for effective and low-toxic regimens for this group of patients is mandatory. A weekly 24-hour infusion of high-dose 5-fluorouracil (5-FU) and leucovorin (HDFL) has previously been demonstrated to be an effective treatment for advanced colorectal cancer with minimal toxicity. In the past 3 years, this regimen has been tested at our institutes in patients with advanced gastric cancer, the general condition of whom had made the use of intensive combination chemotherapy impossible. The regimen consisted of a weekly 24-hour infusion of 2,600 mg/m2 of 5-FU and 300 mg/m2 of leucovorin. From August 1992 to December 1995, 34 patients had been treated with this regimen for a total of 488 courses (average: 14.4 per patient). Hematological toxicity of this regimen was minimal, with grade 3 or 4 leukopenia developing in only 1 (2.9%) patient. Other nonhematological toxicities were also negligible except a reversible neurotoxicity which developed in 2 patients. Twenty-five patients were eligible for response analysis. One complete response, 11 partial responses, 5 stable diseases, and 8 progressive diseases were observed. The response rate was 48% (32-72%, 95% CI). The median overall survival (OS) of the whole group was 7 months (range: 1-18+). The median OS and time to progression of the responders were 8.5 months (range: 2-18) and 5 months (range: 2-10+), respectively. The palliative effect was satisfactory with the Karnofsky performance status of the responders improving from a median of 50% (range: 20-90%) to 70% (range: 50-100%). Our retrospective data suggested that HDFL is an effective and low-toxic palliative treatment even in patients with a very poor general condition. We advocated that this regimen should be further tested in ordinary patients with advanced gastric cancer.

This project was designed to examine the epidemiology of traumatic brain injury (TBI) in Taiwan. A total of 58,563 cases of TBI was collected from 114 hospitals in Taiwan during the period July 1, 1988-June 30, 1994. Traffic accident was the major cause of TBI (69.4%), followed by falls and assaults. Motorcyclists accounted for the vast majority of TBI cases among traffic accident victims (64.5%). The Glasgow Coma Scale was used in assessing the severity. 41,646 cases (79.5%) were considered mild, 4,637 cases (8.9%) moderate, and 6,078 cases (11.6%) severe. Skull x-ray showed fracture in 7,663 cases (14.6%). Intracranial hemorrhage was identified in 28.6% of patients receiving CT scanning. Craniotomy was performed in 5,226 cases (9%). The outcome of TBI was determined by the Glasgow Outcome Scale. Death occurred in 2,621 cases (5.4%), vegetative state in 429 cases (0.9%), severe disability in 1,293 cases (2.6%), moderate disability in 1,890 cases (3.9%), and good recovery in 42,596 cases (87.2%). The severity and outcome were worse than those of Western reports. In order to alleviate this problem, a helmet use persuasion program was conducted by the Police Department in Taipei City from January to June, 1994. Results of this program showed a significant reduction of TBI-related hospitalization, severity and fatality during this period of intervention. This study points out the seriousness of TBI in Taiwan and suggests some approaches and priorities for prevention.

Adult lymphoblastic lymphoma (LBL) can be of T-cell or B-cell lineage. However, the clinical significance of immunophenotypes is largely unknown. We conducted a retrospective study to compare T-cell LBL with its B-cell counterpart. Between 1983 and 1995, 50 adult patients were diagnosed as LBL at National Taiwan University Hospital. Twenty-seven patients (T-LBL:20 and B-LBL:7) had adequate clinical information and formed the basis of final analysis. Pertinent characteristics, including sex, age, and lymphoma stages of these two groups of patients were identical. Detailed clinical features were compared. Systemic involvements of lymphoma were similar except that T-cell LBL had significantly more mediastinal involvement (T:B = 70%:14.3%, p = 0.011). CNS involvement was high in both groups (T:B = 50%:28.6%, p = NS). B-cell LBL had a better overall survival than T-cell LBL, although the survival benefit became less significant after 30 months. The median survival of T- and B-cell LBL was 8 and 31 months, respectively. Both groups taken together, patients who had received prophylactic cranial irradiation had a better overall survival (p < 0.01). We suggest that: a) B-cell LBL has a relatively favorable prognosis than T-cell LBL, at least in the initial 2 to 3 years; b) except for mediastinal involvement, the clinical presentation of T- and B-cell LBL appears to be similar; c) treatment policy, such as the need of prophylactic cranial irradiation, of these two groups may also be similar.

Thymic carcinoma is known for its poor clinical outcome and unsatisfactory response to conventional chemotherapy. A 53-year-old woman was diagnosed as having metastatic thymic carcinoma in 1989. She received systemic chemotherapy containing cisplatin, doxorubicin, and cyclophosphamide, and involved-field radiotherapy. A durable complete remission was achieved and lasted for 4 years. When the disease recurred in 1995, she was found to have an autoimmune syndrome in addition to pleural effusion, a posterior mediastinal mass and a left adrenal mass. The autoimmune manifestations were seen as scleroderma, high titers of rheumatoid factor and anti-nuclear antibody. We adopted a novel HDFL regimen, which is composed of weekly 24-hour infusion of high-dose 5-fluorouracil and leucovorin, for this patient. Complete remission was achieved again, and autoimmune syndrome was well controlled.

A 64-year-old man was diagnosed as having large cell carcinoma of lung and suffered from recurrent tumors after repeated surgical resection and local irradiation. Systemic chemotherapy with chronic oral etoposide, and then 5 courses of intravenous cisplatin and etoposide (PE) resulted in disease progression with multiple new lung nodules and a severe superior vena cava syndrome. Empirical treatment with a PET regimen, which incorporated high-dose tamoxifen (TAM) 150 mg/m2/day into original PE regimen, was tried. Nearly total tumor necrosis was achieved after 5 courses of PET with remission duration of 4.5 months. The excellent response by simple addition of TAM into a previously inactive PE regimen advocates further investigation.

Salvage chemotherapy for relapsed and refractory metastatic breast cancer is a challenging issue for oncologists. At our institution, the combination of mitomycin-C, vinblastine and cisplatin (MVP) is used for treatment. The records of 19 consecutive patients with refractory metastatic breast cancer treated with MVP between April 1992 and October 1995 were reviewed. The regimen consisted of mitomycin-C 6 mg/m2, vinblastine 6 mg/m2 and cisplatin 60 mg/m2, repeated every 3 to 4 weeks. The median age of patients was 49 years (range, 35-71 yr). All patients had clinically measurable or evaluable disease and a Karnofsky's performance status greater than or equal to 50%. The median number of prior chemotherapy regimens was two (range, 1-4). Eighteen (94.7%) patients had previously received an anthracycline/anthracenedione-containing regimen, and seven (36.9%) had progression of disease during these therapies. Sixteen patients had two or more sites of metastasis and 17 patients had visceral disease. The median duration of follow-up was 26 months. A mean of 3.5 courses (range, 1-7) was administered. One patient was lost to follow-up after one course of treatment. Of the remaining 18 patients, two complete and five partial responses were observed, for a total response rate of 37% (range, 17-61%, 95% CI). One of the partial responders had disease progression during anthracycline treatment. Treatment-related toxicities were relatively well tolerated. There were no treatment-related deaths. The median duration of response was 3 months (range, 2-11 mo). The median overall survival was 7 months (range, 1-32 mo). Our data suggest that the MVP regimen is an effective palliative treatment for patients with refractory metastatic breast cancer.

Background: Hepatocellular carcinoma (HCC) is a chemoresistant tumor that frequently expresses a high level of p 170 glycoprotein of the multidrug-resistance (MDR) gene. Preliminary data suggested that VP-16 showed modest activity in HCC. Recently, schedule-dependent cytotoxicity of VP-16 has been demonstrated. In this study, we tested the therapeutic efficacy of chronic oral VP-16 plus tamoxifen, a potential MDR-reversing agent, in patients with far-advanced HCC., Methods: A prospective single-arm study was conducted in the National Taiwan University Hospital. To be eligible, patients must have had unresectable and non-embolizable HCC, objectively measurable tumors, adequate hemogram with absolute granulocyte count greater than or equal to 2,000/mm3, and platelet count greater than or equal to 1x10 (5)/mm3, total serum bilirubin less than or equal to 3.0 mg/dl, age less than or equal to 75 years, and a Karnofsky performance status of greater then or equal to 50%. The treatment included VP-16 (Bristol-Myers-Squibb, Princeton, NJ), 50 mg/m2/day, orally, Days 1 to 21, and tamoxifen (Pharmachemie B.V. Haarlem, Netherlands), 40 mg/day, orally, Days 1 to 21; repeated every 5 weeks., Results: Between December 1990 and December 1993, a total of 33 patients were enrolled in the study. There were 28 men and 5 women, with a median age of 51 years. They received an average of 3.2 (range: 1-10) courses of chemotherapy. ECOG (Eastern Cooperative Oncology Group) Grade 3 and Grade 4 leucopenia developed in 6 patients (18.2%) and 4 (12.1%) patients, respectively. Grade 3 and 4 thrombocytopenia developed in 2 patients (6.1%). Treatment-related death occurred in one patient due to sepsis. Mild gastrointestinal toxicities were common with Grade 1 and 2 nausea. Grade 1 and 2 vomiting, Grade 1 and 2 diarrhea, and Grade 1 and 2 stomatitis, developed in 13 (39.4%), 7 (21.2%), 12 (36.4%), and 16 (48.5%) patients, respectively. Grade 3 and 4 gastrointestinal toxicities were rare. Deep vein thrombosis occurred in one patient (3.0%). Eight patients (24.2%, 95% confidence interval 11%-42%) had achieved a partial remission, with a median time-to-progression of 6 months (2-11). Median survivals of the responders and non-responders were 8.0 and 3.0 months, respectively (P < 0.05). The median Karnofsky performance status of the responders improved from 70% to 80%., Conclusions: Chronic oral VP-16 and tamoxifen has modest activity and acceptable toxicity in far-advanced HCC, and is a useful palliative treatment in about a quarter of such patients.

Objective: To examine the utility of intracardiac echocardiography in guiding complex transseptal catheterization of patients undergoing percutaneous transvenous mitral commissurotomy., Design: We assessed this procedure in high-risk patients in whom transseptal catheterization is technically complex and more demanding., Material and Methods: Fifteen patients with mitral stenosis were studied. Twelve patients had giant left atria (70 mm or more), two had atrial septal aneurysms, and one had severe kyphoscoliosis. A newly developed 8-F 10-MHz intracardiac transducer catheter was placed in the right atrium through an 8-F Mullins sheath inserted from the left femoral vein. Echocardiographic images were used to confirm the septal position of the Brockenbrough needle tip before septal punctures., Results: Transseptal puncture was successful and uncomplicated in all 15 patients. Use of intracardiac echocardiography eliminated the need for atrial angiography. Before transseptal puncture, the needle tip was identified to be in contact with the atrial septum, as an echogenic point with its acoustic shadow and septal indentation. In addition, in the two patients with aneurysms, puncture of the thin-walled aneurysms was avoided., Conclusion: Intracardiac echocardiography facilitates safe complex transseptal catheterization in patients with mitral stenosis and giant left atria, atrial septal aneurysms, or severe kyphoscoliosis.

This study presents the distribution of blood lead levels and lead in various environmental samples (water, sediments, soils, and air) near the Shing-Yie storage battery recycling plant in Taiwan before (July 1990 to June 1991) and after (July 1992 to June 1993) amelioration. Before amelioration, the average blood lead levels in the neighborhood of the plant were in the range of 10.55 +/- 5.7 to 12.28 +/- 7.9 micrograms/dl. After amelioration, relatively lower average concentrations of blood lead (range 8.35 +/- 3.0 to 9.13 +/- 2.5 micrograms/dl) were generally found; however, these averages were still higher than that (7.79 +/- 3.5 micrograms/dl) from other lead-unpolluted areas of Taiwan. An exceedingly high geometric mean (GM) lead concentration (128 micrograms/L) was found in the downstream river water of the Tawulum River passing by the plant. The concentrations of lead (GM = 372 and 418 micrograms/g) in the downstream river sediments were higher than those (GM = 123 and 158 micrograms/g) in the upstream river sediments before and after amelioration, respectively. Furthermore, lead species in river sediments were analyzed by a sequential leaching technique. The sum of phases I, II, and III accounted for 83.7% of total lead at station R2 (nearest to the plant). Maximum lead concentration (GM = 2402 micrograms/g) in dust at the soil surface from station S1 (nearest to the plant) was much higher than those from the other stations by about 18 times before amelioration. However, the maximum value dropped to 1,155 micrograms/g after amelioration. On the whole, the geometric mean concentration of lead in dust at the soil surface nearest to the plant was > 1,000 micrograms/g and decreased to < 100 micrograms/g in the 15-30 cm depth soil about 2 km away from the plant. Before amelioration, the geometric mean lead concentration of 4.57 micrograms/m3 (range 0.102-37.6 micrograms/m3) in the air near the plant was higher than that at the background locations, the geometric mean value of which was 0.08 micrograms/m3.

Percutaneous transvenous mitral commissurotomy (PTMC) was performed successfully without complications in 3 patients with severe mitral stenosis and hyperthyroidism. All 3 patients had pliable, noncalcified mitral valves. One patient who had been treated with methimazole for 6 months was still in a hyperthyroid state when she presented with intractable congestive heart failure and was found to have severe mitral stenosis. The heart failure improved immediately after PTMC, but the patient remained in New York Heart Association functional class 2 until a euthyroid state was achieved with I131 therapy. In the other 2 patients, hyperthyroidism was unsuspected at the time of PTMC. Unexpectedly suboptimal symptom improvement led to the diagnosis of hyperthyroidism 1 month after the intervention. In all 3 patients, PTMC resulted in an immediate hemodynamic and clinical improvement. However, complete clinical improvement occurred only when euthyroid state was achieved after antithyroid treatment. The present study suggests that PTMC is a safe and effective intervention modality in patients with coexisting hyperthyroidism and severe mitral stenosis. The procedure may be considered a therapeutic option in patients with hyperthyroidism and severe mitral stenosis.

Transesophageal echocardiography was performed in 7 patients with effusive-constrictive pericarditis to analyze atrial septal motion(ASM). In 3 patients, the ASM was found to be normal with atrial septum (AS) moving toward the right atrium from ventricular mid-systole to early-diastole and toward the left atrium from mid-diastole to early-systole. Respiration had little effect on the ASM. In 2 patients, a brisk inversion of ASM toward the left atrium at ventricular early-to-mid systole was noted during inspiration. In the other 2 patients, a sustained ASM toward the left atrium during ventricular systole was found. In 4 of these 7 patients, hemodynamic studies were performed simultaneously with the transesophageal echocardiography. The ASM reflected the pressure gradient between the left atrium (as measured by pulmonary arterial wedge pressure) and the right atrium. The augmented ASM toward the left atrium occurred as left atrial pressure decreased markedly during inspiration. In conclusion, the ASM in patients with effusive-constrictive pericarditis showed 3 patterns: normal, sustained systolic motion toward the left atrium and a brisk systolic displacement toward the left atrium during inspiration. The ASM reflects changes in the interatrial pressure gradient.

Primary central nervous system lymphoma (PCNSL) is rare, accounting for only 1-2% of non-Hodgkin's lymphoma, and primary isolated leptomeningeal lymphoma is even rarer. It may create a diagnostic problem, particularly when the tumor cells are of T cell lineage. We herein report a patient with primary T cell leptomeningeal lymphoma. The final diagnosis was confirmed by the cytogenetic study which revealed clonal aberration, isochromosome of long arm of chromosome 7, in the lymphoid cells from CSF. She was treated with a novel protocol of systemic chemotherapy specifically designed for the CNS lymphoma. The regimen consisted of carmustine, vincristine, high-dose methotrexate, etoposide, and methylprednisolone. A total of 5 courses were given and she was still in complete remission at the time of reporting, 21 months after the establishment of diagnosis.