Clinical characteristics and treatment outcomes of gastric cancer patients with isolated para-aortic lymph node involvement.

BACKGROUND: Although gastric cancer with isolated para-aortic lymph node (PAN) involvement is considered an advanced disease, the clinical characteristics of it have not been comprehensively elucidated. PATIENTS AND METHODS: We reviewed the medical records of 1,277 patients received palliative chemotherapy with advanced gastric cancer according to metastatic sites: PAN-only metastasis, single organ metastasis other than PAN, and multiple organ metastasis. Time to other organ metastasis (TTOM) was determined only in PAN-only metastasis group as the time interval between initial diagnosis of recurrence or de novo metastasis and confirming distant metastasis beyond PAN area. RESULTS: The median overall survival (OS) of patients with PAN-only metastasis was significantly longer than that of patients with single organ metastasis other than PAN or multiple organ metastasis (13.8 months vs. 11.4 months vs. 8.4 months; P < 0.001). In the PAN-only metastasis group, patients with recurrent diseases showed longer TTOM beyond the PAN area (10.7 vs. 7.7 months; P = 0.037) and OS (23.8 vs. 12.8 months; P = 0.010) than those with de novo metastatic disease and it was validated by multivariate analysis. CONCLUSION: Patients with isolated PAN metastasis showed an excellent prognosis compared with patients with metastasis at other sites and it was primarily evident in patients with recurrent PAN metastasis.

Clinical outcomes and prognostic factors of metastatic gastric carcinoma patients who experience gastrointestinal perforation during palliative chemotherapy.

BACKGROUND: We conducted the current study to investigate the clinical outcomes of metastatic gastric carcinoma (MGC) patients who experienced gastrointestinal (GI) perforation during palliative chemotherapy and to examine the prognostic factors associated with survival after perforation. METHODS: We reviewed the medical records of patients at the Center for Gastric Cancer of the National Cancer Center, Korea who developed GI perforation during palliative chemotherapy between January 2001 and December 2008. RESULTS: Of the 1,856 patients who received palliative chemotherapy for MGC, 32 patients (1.7%) developed GI perforation during chemotherapy. Patients with perforation at the primary gastric site were more likely to have ulcerative gastric cancer lesion (90.5 vs. 40.0%, P = 0.034) or gastric tumor bleeding (28.6 vs. 0%, P = 0.298), and less likely to have Bormann type IV (14.3 vs. 60.0%, P = 0.062), than patients with perforation at nongastric sites. In 14 patients (43.8%) who resumed chemotherapy after perforation, the disease control rate was 57.1%, and median overall survival (OS) after perforation was 7.5 months [95% confidence interval (CI), 6.0-9.0 months]. In all patients, median OS following perforation was 4.0 months (95% CI, 1.5-6.6 months), and multivariate analysis revealed that differentiated tumor histology, response to chemotherapy before perforation, and absence of septic shock at time of perforation were significantly associated with favorable OS after perforation. CONCLUSIONS: As patients experiencing GI perforation during palliative chemotherapy have heterogeneous clinical presentation, we need to adopt different approaches in the management of the patients that are compatible with the favorable prognostic factors.

Predictive factors for the efficacy of cetuximab plus chemotherapy as salvage therapy in metastatic gastric cancer patients.

PURPOSE: We performed a retrospective study to evaluate the efficacy of cetuximab plus chemotherapy in metastatic gastric cancer (MGC) patients previously treated with chemotherapy and to investigate potential predictors of treatment efficacy in those patients. METHODS: Thirty-two patients with MGC were included in this study. Cetuximab was delivered, often combined with irinotecan-based chemotherapy. Thirty patients were analyzed for K-ras mutations via direct sequencing of the tumor DNA. RESULTS: Patients were heavily pretreated with a median number of three previous lines of palliative chemotherapy (56% of the patients were refractory to all of the following drugs: fluoropyrimidines, cisplatin, irinotecan, oxaliplatin, and docetaxel) and 53% of the patients displayed poor performance status. Of 28 response-assessable patients, the overall response rate to cetuximab plus chemotherapy was 3.6% [95% confidence interval (CI) 0-10.5%] and the disease control rate was 28.6%. The median progression-free survival (PFS) was 1.7 months (95% CI 1.3-2.1 months), and the median overall survival (OS) was 3.2 months (95% CI 1.4-5.0 months). Multivariate analyses revealed that skin rash and performance status were significantly associated with PFS and OS. The presence of a K-ras mutation (13.3%) was not associated with either PFS or OS. CONCLUSION: Our study suggests that MGC patients with good performance status and skin rash benefit most from salvage cetuximab combined with chemotherapy, even in heavily pretreated status.

Association of CYP2A6 polymorphisms with S-1 plus docetaxel therapy outcomes in metastatic gastric cancer.

AIMS: S-1, an oral fluoropyrimidine, contains tegafur, which is converted to 5-fluorouracil mainly by CYP2A6. We evaluated the association between CYP2A6 polymorphisms and treatment outcome in metastatic gastric cancer patients treated with S-1 plus docetaxel. MATERIALS & METHODS: Chemonaive patients received S-1 40 mg/m(2) twice daily on days 1-14 and docetaxel 35 mg/m(2) on days 1 and 8 of a 3-week cycle. We analyzed the wild-type (W) allele (CYP2A6*1) and four variant (V) alleles that abolish or reduce enzyme activity (CYP2A6*4, *7, *9 and *10). A total of 50 patients were enrolled. RESULTS: The genotype frequencies were as follows: W/W (n=14, 28%), W/V (n=26, 52%) and V/V (n=0, 20%). Patients having fewer variant alleles had significantly better response rates (W/W vs W/V vs V/V=79 vs 65 vs 30%; p=0.04) and median progression-free survival (W/W vs W/V vs V/V=8.1 vs 6.9 vs 3.1 months; p=0.0009). CONCLUSION: Our findings showed that the CYP2A6 genotype correlated with the treatment efficacy of S-1-based chemotherapy in previously untreated metastatic gastric cancer patients.

Clinical predictors of recurrent venous thromboembolism: a single institute experience in Korea.

INTRODUCTION: Racial disparities in incidence rate as well as risk factors for venous thromboembolism (VTE) exist between Asian and Western populations. Moreover, predictors for recurrent VTE were not identified in Asians. Thus, this study was undertaken to investigate risk factors for recurrent VTE events in Korean people. MATERIALS AND METHODS: Three hundred-three patients newly diagnosed as VTE were enrolled from Seoul National University Hospital. Recurrence rate based on risk factors for VTE were investigated. Cumulative incidence of recurrent VTE was calculated by the Kaplan and Meier method. Independent predictors for VTE were determined using Cox proportional hazards model. RESULTS: After a median follow-up of 44 months, 24 (8%) of 303 patients relapsed for a total observation time of 1,217 patient-year. Cumulative incidences of recurrent VTE were 3% at 1 year, 10% at 5 years, and 18% at 8 years. Independent predictors for recurrent VTE were presence of residual thrombosis (hazard ratio [HR]=3.1, 95% confidence interval [CI] 1.0-9.3; p=0.044), antiphospholipid syndrome (APS) (HR=4.3, 95% CI 1.0-19.0; p=0.052), and age 50 years or younger (HR=2.5, 95% CI 1.0-6.6; p=0.053) by multivariate analysis. Residual thrombosis and APS remained predictive of recurrence by the anticoagulation-period stratified analysis. CONCLUSIONS: In contrast to Western populations, Korean patients with VTE had the lower recurrent rate. Extended anticoagulation is necessary for Korean patients with residual thrombosis or APS.

Metastasis-associated protein S100A4 and p53 predict relapse in curatively resected stage III and IV (M0) gastric cancer.

PURPOSE: Pathologic stage is the most important predictive factor of relapse in gastric cancer after curative resection. However, patients with the same stage often have different risks of relapse. Here, we investigated whether the expressions of molecular markers can supplement the current staging system in terms of relapse prediction. PATIENTS AND METHODS: One hundred and nine stage III or IV (M0) patients who had received curative gastrectomy followed by adjuvant 5-fluorouracil and cisplatin chemotherapy were included in this study. The expressions of molecular markers including p53, p27, COX-2, HER-2, EGFR, maspin, S100A4, E-cadherin, Sp1, and p97 were analyzed by immunohistochemistry in cancer and paired normal tissues. RESULTS: The overall relapse rate was 58.7%, and pathologic stage was a significant predictive factor of relapse (42% in stage IIIA, 48% in IIIB, 76% in IV, p = 0.005). Of the 10 markers examined, p53 and S100A4 were expressed only in tumor tissues, and S100A4 expression was significantly associated with a higher relapse rate (85% vs. 53%, p = 0.008). In multivariate analysis including tumor stage, S100A4 and p53 expression were independent predictive factors of relapse (relative risk, 6.98; 95% confidence interval [CI], 1.608-30.342, 3.49; 95% CI, 1.328-9.186, respectively). On comparing patients who expressed S100A4 or p53 with those who expressed neither, relapse rates were 58% vs. 25% in stage III (p = 0.011) and 95% vs. 59% in stage IV (M0) (p = 0.003). CONCLUSION: In addition to staging system, the expressions of S100A4 and p53 were significant predictive factors of relapse in gastric cancer after curative resection and adjuvant chemotherapy.

Phase II study of low-dose paclitaxel and cisplatin as a second-line therapy after 5-fluorouracil/platinum chemotherapy in gastric cancer.

This study was performed to evaluate the efficacy and toxicity of low-dose paclitaxel/cisplatin chemotherapy in patients with metastatic or recurrent gastric cancer that had failed 5-fluorouracil/platinum-based chemotherapy. Thirty-two patients with documented progression on or within 6 months after discontinuing 5-fluorouracil/platinum-based chemotherapy were enrolled. As a second-line treatment, paclitaxel (145 mg/m(2)) and cisplatin (60 mg/m(2)) was administered on day 1 every 3 weeks. Among 32 patients enrolled, 8 (25%) responded partially to paclitaxel/cisplatin, 8 (25%) had stable disease, and 14 (44%) had progressive disease. Two patients (6%) were not evaluable. The median time to progression (TTP) and overall survival for all patients were 2.9 months and 9.1 months, respectively. The most common hematologic toxicity was anemia (47%). Grade 3 neutropenia developed in three patients (9%), but no other grade 3/4 hematologic toxicity occurred. The most common non-hematologic toxicities were emesis (31%) and peripheral neuropathy (38%). Three cases (9%) of grade 3/4 emesis and 2 cases (6%) of grade 3 peripheral neuropathy developed. In conclusion, low-dose paclitaxel and cisplatin chemotherapy showed moderate activity with favorable toxicity profiles. However, relatively short TTP of this regimen warrants the development of more effective paclitaxel-based regimens other than combination with cisplatin in these patients as second-line therapies.

Artificial nutrition and hydration in terminal cancer patients: the real and the ideal.

INTRODUCTION: To better understand current practice relating to artificial nutrition/hydration in terminal cancer patients, we enrolled terminal cancer patients who were admitted at Seoul National University Boramae Hospital for supportive care only and who died with a duration of hospital stay to death of more than 1 week between 2003 and 2004. We detailed oral intake and intravenous nutrition/hydration status on admission, 1 week after admission, and 2 days before death. Administered calories and changes in these according to time and "DNR" (do-not-resuscitate) status were noted. RESULTS: Of the total 165 patients, oral intake was possible in 84 patients (50.9%) on admission, in 79 patients (47.8%) on 1 week after admission, and in 29 patients (17.5%) 2 days before death (p < 0.01). Intravenous nutrition/hydration was administered to 133 patients (80.6%) on admission, to 125 patients (75.7%) at 1 week, and to 137 patients (83.0%) 2 days before death (p = 0.7). The calories administered to the patient by oral intake were 393 kcal on admission, 353 kcal 1 week after admission, and 89 kcal 2 days before death. In addition, the calories delivered by intravenous fluid were 369, 386 and 465 kcal, respectively. Near to death, calories by oral intake continuously reduced (p < 0.01) and intravenous calories continuously increased (p = 0.04), but total administered calories reduced (p = 0.03). Intravenous nutrition/hydration stopped after the attainment of the advance directive of DNR in 9% of patients. CONCLUSION: This study showed the high prevalence of artificial nutrition/hydration, especially intravenous infusion, in Korean terminal cancer patients compared with situation in other countries. More studies are needed to verify the efficacy of artificial nutrition/hydration in terminal cancer patients.

Antitumor activity of SK-7041, a novel histone deacetylase inhibitor, in human lung and breast cancer cells.

BACKGROUND: A class of synthetic histone deacetylase (HDAC) inhibitors, which are hybrids of trichostatin A and MS-275 were previously developed. In this study, the antitumor effects of SK-7041, one of those novel HDAC inhibitors, was evaluated on lung and breast cancer cell lines. MATERIALS AND METHODS: Human lung and breast cancer cells, as well as normal human bronchial epithelial (NHBE) cells were treated with SK-7041, and results were compared with those of cells treated with suberoylanilide hydroxamic acid (SAHA). RESULTS: SK-7041 induced time-dependent histone hyperacetylation and showed more potent cytotoxicity than SAHA in cancer cells. These antiproliferative effects of SK-7041 were due to apoptotic cell death caused by G2/M-phase arrest and to a lesser extent to G1 arrest. Moreover, SK-7041 inhibited cancer cell proliferation more selectively than NHBE cell proliferation. CONCLUSIONS: These results suggest that SK-7041 may have potential anticancer activity.

Primary systemic anaplastic large cell lymphoma in a single Korean institution: clinical characteristics and treatment outcome.

Despite advances in the characterization of anaplastic large cell lymphoma (ALCL), little data is available on Asian patients. We report here upon single Korean institution's experience regarding the clinical characteristics and outcomes of ALCL. We performed a retrospective study of 32 adults with ALCL. Most of the patients received anthracycline-based chemotherapy. Ann Arbor stage III-IV, B symptoms, high-intermediate/ high International Prognostic Index (IPI), and extranodal disease at diagnosis were present in 56%, 44%, 41%, and 63%, respectively. Compared with Western studies, the male/female ratio (4.3) was markedly higher and skin (9%) and bone involvement (9%) were less frequent. The staining results for anaplastic lymphoma kinase were positive in 6 (33%) of 18 cases available. The complete response (CR) rate was 62% (95% CI, 44-80%). With a median follow-up of 51.0 months, 5 yr overall survival was 40+/-11%. The 3 yr relapse-free survival for the 18 patients who achieved CR was 74+/-12%. Age, performance status, lactate dehydrogenase, extranodal disease sites number, and IPI were correlated with treatment response and survival. Our data suggest that Korean ALCL patients appear to have a higher male/female ratio, less frequent skin/bone involvement, and lower CR rate compared with those of Western studies.

First-line ifosfamide, methotrexate, etoposide and prednisolone chemotherapy +/- radiotherapy is active in stage I/II extranodal NK/T-cell lymphoma.

Although most patients diagnosed with extranodal NK/T-cell lymphoma (NTCL) have localized disease, radiotherapy alone is unsatisfactory because of frequent systemic failure and conventional doxorubicin-based chemotherapy has low efficacy. Twenty-six patients with NTCL received ifosfamide, methotrexate, etoposide and prednisolone (IMEP) chemotherapy as first-line treatment [ifosfamide 1.5 g/m2 (days 1 - 3), methotrexate 30 mg/m2 (days 3 and 10), etoposide 100 mg/m2 (days 1 - 3) and prednisolone 120 mg (days 1 - 5)]. Radiotherapy was administered only to patients with Ann Arbor stage I/II that had not achieved complete remission (CR) or to those that developed local failure after completing chemotherapy. Sixteen patients (group A) had nasal or upper aerodigestive tract localization (stage I/II) and 10 (group B) had extranasal or disseminated disease. Of the 14 evaluable patients in group A, 11 (79%) achieved CR after IMEP alone and 13 (93%) after chemotherapy +/- additional radiotherapy. Although, out of the 11 patients who achieved CR with chemotherapy alone, seven developed recurrence, all recurrences were local failure and successfully treated by additional curative radiotherapy. However, patients in group B responded poorly (CR 13%). IMEP regimen was active in NTCL patients with nasal or upper aerodigestive tract localization. Considering local failure rate after IMEP alone, initial IMEP chemotherapy followed by radiotherapy may be a promising treatment strategy in this subset of NTCL.

Optimization of patient selection for gefitinib in non-small cell lung cancer by combined analysis of epidermal growth factor receptor mutation, K-ras mutation, and Akt phosphorylation.

PURPOSE: Mutations in epidermal growth factor receptor (EGFR) are strongly predictive of gefitinib efficacy in non-small-cell lung cancer. However, the presence of EGFR mutant nonresponses and nonmutant responses points out the need for more comprehensive analysis. PATIENTS AND METHODS: For 69 non-small-cell lung cancer patients treated with gefitinib, we have extended our analysis to EGFR gene copy number by fluorescence in situ hybridization, mutations in K-ras, HER2, and exon 20 of EGFR by direct sequencing, and phosphatase and tensin homologue expression by immunohistochemistry, in addition to EGFR exons 18, 19, and 21, and phosphorylations of Akt and extracellular signal-regulated kinase reported previously. RESULTS: EGFR mutation and high gene copy number were associated with better objective response in univariate analysis. However, only gefitinib-sensitive EGFR mutation was independently predictive of both response (P = 0.011) and survival (P = 0.002) in multivariate analysis. No patients with K-ras mutation, including two EGFR mutants, showed response. In EGFR nonmutants, patients with either K-ras mutation or p-Akt overexpression exhibited poor response and time-to-progression whereas patients with high gene copy number tended to have better outcomes in univariate analysis. In multivariate analysis of time-to-progression in EGFR nonmutants, K-ras mutation or p-Akt overexpression was associated with shorter time-to-progression (P = 0.017). No patient with HER2 mutation showed response to gefitinib. Reduced phosphatase and tensin homologue expression was not associated with gefitinib sensitivity. CONCLUSION: Gefitinib-sensitive EGFR mutation is the single most important predictor of gefitinib sensitivity. In addition to EGFR mutation, K-ras mutation and Akt phosphorylation aid in better prediction of gefitinib responsiveness in non-small-cell lung cancer.

CPR or DNR? End-of-life decision in Korean cancer patients: a single center's experience.

PURPOSE: Whether or not physicians should conduct cardiopulmonary resuscitation (CPR) in terminal cancer patients has long been debated. We conducted this prospective observational study to characterize current CPR and do-not-resuscitate (DNR) practice among terminal cancer patients in South Korea. MATERIALS AND METHODS: The study involved patients with terminal cancer who were admitted at the Seoul National University Boramae Hospital for supportive care only, and who died between January 1, 2003 and April 30, 2004. We investigated the practices relating to the DNR directive, i.e., how many days before death was the directive effective, and from whom was it obtained. RESULTS: Of the enrolled 165 patients, 97 were male with a mean age of 65. Median duration of admission to death was 24 days (range 7-207, mean 31.7). The DNR directive was implemented in 143 patients (86.7%). All discussions about DNR took place between physician and family members, except in only one case. DNR directives were enacted at a median of 8.0 days (range 0-79, mean 12.15) before death. For 18 patients, the DNR directive was formally taken on the day of admission. In contrast, 14 cases (9.8%) were agreed on the day of death, 18.8% within 48 h of death, and 46.8% (67 of 143) within 1 week before death, 62% before 10 days, and 71.3% within 2 weeks. The worse the performance status of the patient, the earlier the DNR discussion was issued. Also, the lower the economic and educational status of the family member, the earlier the DNR directive was attained. Of the 165 patients with terminal cancer, CPR was performed in 13 cases (7.9%): in seven cases (4.2%) CPR was requested by a family member, and in six cases arrest occurred before DNR discussion was issued. None of the resuscitated patients survived. CONCLUSION: In relation to DNR decisions in South Korean cancer patients, proxy decision-making is overwhelming and issuance of DNR discussion is raised at a late stage.

Phase II trial of low-dose paclitaxel and cisplatin in patients with advanced gastric cancer.

BACKGROUND: Paclitaxel has shown promising activity in gastric cancer and has synergism with cisplatin. This study was performed to evaluate the efficacy and toxicity of low-dose paclitaxel (145 mg/m(2)) plus cisplatin chemotherapy in metastatic or relapsed gastric cancer. METHODS: Chemotherapy-naïve patients with metastatic or relapsed gastric cancer were enrolled. Paclitaxel 145 mg/m(2) was administered intravenously over 3 h, followed by cisplatin 60 mg/m(2) on Day 1 every 3 weeks in the outpatient setting. RESULTS: Of 39 patients enrolled, 17 (44%) had partial responses. Twelve (31%) had stable disease and eight (21%) progressive disease. Two patients (5%) were not evaluable because of early drop-out. The median time to progression was 4.7 months and the median overall survival was 12.1 months. The most common hematologic toxicity was anemia (41%). Grade 3/4 neutropenia and thrombocytopenia developed in 14 and 3%, respectively. The most common non-hematologic toxicities were peripheral neuropathy (43%) and emesis (43%). Grade 3/4 non-hematologic toxicities included emesis (11%), peripheral neuropathy (3%), diarrhea (3%) and hepatotoxicity (3%). CONCLUSIONS: Low-dose paclitaxel and cisplatin chemotherapy was active and well-tolerated in chemotherapy-naïve gastric cancer patients. This regimen seems to have comparable efficacy to previously reported higher-dose paclitaxel plus cisplatin-containing regimens and fewer toxicities.

Reduced dose intensity FOLFOX-4 as first line palliative chemotherapy in elderly patients with advanced colorectal cancer.

To evaluate the toxicity and efficacy of a reduced dose intensity (mini-) FOLFOX-4 regimen as a first-line palliative chemotherapy in elderly patients (> or =70 yr of age) with advanced colorectal cancer, data from prospective databases at Seoul National University Bundang Hospital and Seoul Municipal Boramae Hospital were analyzed. A total of 20 patients were enrolled between January 2001 and August 2004, and were treated with oxaliplatin 65 mg/m2 on day 1, and with 2-hr infusions of leucovorin 150 mg/m2 followed by a 5-FU bolus (300 mg/m2) and 22-hr continuous infusions (450 mg/m2) for 2 consecutive days every 2 weeks until progression, unacceptable toxicity or patient refusal. Sixteen patients were evaluable for response with an overall response rate of 43.8%. Median progression-free survival was 4.8 months (95% CI: 3.0-6.7) and overall survival was 13.5 months (95% CI: 11.1-16.0). The main side effects were anemia and neutropenia, which were observed in 20.8% and 17.7%, respectively, of the total cycles administered. There were no grade 4 toxicities and only one patient suffered from febrile neutropenia. No grade 3 toxicities occurred except for anemia (5.2%) and vomiting (1.0%). In conclusion, the mini-FOLFOX-4 regimen was found to be well tolerated with acceptable toxicity, and to provide a benefit for elderly patients with colorectal cancer.

Local tumor invasiveness is more predictive of survival than International Prognostic Index in stage I(E)/II(E) extranodal NK/T-cell lymphoma, nasal type.

This study was launched to determine the prognostic significance of local tumor invasiveness (LTI) in 114 patients diagnosed with stage I(E)/II(E) extranodal natural killer (NK)/T-cell lymphoma, nasal type (NTCL). LTI was defined as bony invasion or destruction or tumor invasion of the skin. Complete remission (CR), overall survival (OS), and disease-free survival (DFS) were compared between each group according to LTI, Ann Arbor stage, and International Prognostic Index (IPI). LTI was observed in 23 patients. Using multivariate analysis, factors associated with low probability of CR were the presence of LTI (P < .001), the presence of B symptoms (P = .003), and single-modality chemotherapy (P = .045). The presence of LTI (relative risk [RR] = 8.4, 95% confidence interval [CI] 3.9-17.9; P < .001) and high IPI score (RR = 2.8, 95% CI 1.2-6.8; P = .019) were also predictive of OS. The presence of LTI (RR = 7.3, 95% CI 3.2-16.5; P < .001) was an independently significant factor for reduced DFS. Ann Arbor staging system did not predict CR, OS, or DFS but IPI did have predictive power with regard to survival outcome. LTI is the most important prognostic factor in predicting low probability of CR and reduced OS and DFS in nasal stage I(E)/II(E) NTCL.

A pilot study of bortezomib in Korean patients with relapsed or refractory myeloma.

Recent clinical trials showed that bortezomib, a novel proteasome inhibitor, had therapeutic activity in multiple myeloma. However, there was no data about the feasibility of bortezomib in Korean patients. We performed a pilot study of bortezomib in patients with relapsed or refractory myeloma (1.3 mg/m2 twice weekly for 2 week in a 3-week cycle). Seven patients were enrolled. The median age of patients was 59 yr. All patients previously received VAD (vincristine, doxorubicin and dexamethasone) and thalidomide chemotherapy. Three patients previously received alkylator-containing chemotherapy and 4 patients, autologous stem cell transplantation. Bortezomib monotherapy resulted in 3 partial remissions (43%), 3 no changes (43%) and 1 progressive disease (14%). One patient who had no response to bortezomib monotherapy experienced partial remission after addition of dexamethasone to bortezomib. The most common serious toxicity was thrombocytopenia (grade 3/4, 10 of 20 cycles (50%)) and grade 3 peripheral neuropathy was developed in 2 of 20 cycles (10%). Drug-related adverse event led to discontinuation of bortezomib in 1 patient. There was no treatment related mortality. Overall, bortezomib seems to be effective and feasible. Conduction of larger clinical studies on Korean patients is necessary to characterize clinical efficacy and safety of bortezomib more precisely.

The endogenous ratio of Smad2 and Smad3 influences the cytostatic function of Smad3.

Although Smad2 and Smad3, critical transcriptional mediators of transforming growth factor-beta (TGF-beta) signaling, are supposed to play a role in the TGF-beta cytostatic program, it remains unclear whether TGF-beta delivers cytostatic signals through both Smads equally or through either differentially. Here, we report that TGF-beta cytostatic signals rely on a Smad3-, but not a Smad2-, dependent pathway and that the intensity of TGF-beta cytostatic signals can be modulated by changing the endogenous ratio of Smad3 to Smad2. Depleting endogenous Smad3 by RNA interference sufficiently interfered with TGF-beta cytostatic actions in various TGF-beta-sensitive cell lines, whereas raising the relative endogenous ratio of Smad3 to Smad2, by depleting Smad2, markedly enhanced TGF-beta cytostatic response. Consistently, Smad3 activation and its transcriptional activity upon TGF-beta stimulation were facilitated in Smad2-depleted cells relative to controls. Most significantly, a single event of increasing this ratio by Smad2 depletion was sufficient to restore TGF-beta cytostatic action in cells resistant to TGF-beta. These findings suggest a new important determinant of sensitivity to TGF-beta cytostatic signaling.

Docetaxel + 5-fluorouracil + cisplatin 3-day combination chemotherapy as a first-line treatment in patients with unresectable gastric cancer.

BACKGROUND: Our objective was to verify the efficacy and safety of "docetaxel + 5-fluorouracil + cisplatin" 3-day combination chemotherapy as a first-line treatment in patients with unresectable gastric cancer. METHODS: Between January and November 2002, we enrolled 43 patients [males 31; median age 55 years (range 24-74)] with inoperable gastric cancer who had not been seen previously in Seoul National University Hospital. The regimen used was docetaxel 70 mg/m(2) on day 1, cisplatin 40 mg/m(2) on days 2 and 3, and 5-fluorouracil 1200 mg/m(2) over 10 h on days 1-3, every 3 weeks. RESULTS: A total of 168 cycles were administered. Mean cycle number per patient was 3.9. The administered dose intensity of docetaxel was 21.23 mg/m(2)/week, 5-FU 1092.14 mg/m(2)/week and cisplatin 23.82 mg/m(2)/week, which corresponded to 91.1, 91.0 and 89.5% of planned doses. Of the 43 patients, response evaluation was possible in 40 and, of these patients, 17 (42.5%) achieved a partial response, 13 (32.5%) stable disease, and 10 patients (25%) showed progressive disease. The median time to progression was 5.6 months [95% confidence interval (CI) 4.6-6.6 months]. Median overall survival was 9.0 months. (95% CI 4.8-13.2 months). Leukopenia occurred during 21.4% of cycles (36 of 168 cycles); 14.3% grade 1, 5.3% grade 2 and 1.8% grade 3. Anemia occurred in 16.7% (28 of 168 cycles); 11.3% grade 1, 4.8% grade 2 and 0.6% grade 3. Thrombocytopenia was not observed. Diarrhea, stomatitis and hypersensitivity occurred in 4.7% (two out of 43 patients), respectively. Neutropenic fever occurred in two patients (4.7%) and myalgia in three (7.0%). CONCLUSION: "Docetaxel + 5-fluorouracil + cisplatin" 3-day combination chemotherapy is an active and tolerable regimen as a first-line treatment in patients with unresectable gastric cancer.