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.

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.

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.

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.

Transforming growth factor-beta 1 induces apoptosis through Fas ligand-independent activation of the Fas death pathway in human gastric SNU-620 carcinoma cells.

To date, two major apoptotic pathways, the death receptor and the mitochondrial pathway, have been well documented in mammalian cells. However, the involvement of these two apoptotic pathways, particularly the death receptor pathway, in transforming growth factor-beta 1 (TGF-beta 1)-induced apoptosis is not well understood. Herein, we report that apoptosis of human gastric SNU-620 carcinoma cells induced by TGF-beta 1 is caused by the Fas death pathway in a Fas ligand-independent manner, and that the Fas death pathway activated by TGF-beta 1 is linked to the mitochondrial apoptotic pathway via Bid mediation. We showed that TGF-beta 1 induced the expression and activation of Fas and the subsequent caspase-8-mediated Bid cleavage. Interestingly, expression of dominant negative FADD and treatment with caspase-8 inhibitor efficiently prevented TGF-beta 1-induced apoptosis, whereas the treatment with an activating CH11 or a neutralizing ZB4 anti-Fas antibody, recombinant Fas ligand, or Fas-Fc chimera did not affect activation of Fas and the subsequent induction of apoptosis by TGF-beta 1. We further demonstrated that TGF-beta 1 also activates the mitochondrial pathway showing Bid-mediated loss of mitochondrial membrane potential and subsequent cytochrome c release associated with the activations of caspase-9 and the effector caspases. Moreover, all these apoptotic events induced by TGF-beta 1 were found to be effectively inhibited by Smad3 knockdown and also completely abrogated by Smad7 expression, suggesting the involvement of the Smad3 pathway upstream of the Fas death pathway by TGF-beta 1.

Predictive and prognostic impact of epidermal growth factor receptor mutation in non-small-cell lung cancer patients treated with gefitinib.

PURPOSE: This study was undertaken to investigate the effects of epidermal growth factor receptor (EGFR) mutation and its downstream signaling on response and survival in non-small-cell lung cancer (NSCLC) patients treated with gefitinib. PATIENTS AND METHODS: For 90 consecutive NSCLC patients who had received gefitinib, EGFR mutation was analyzed by DNA sequencing of exons 18, 19, 21, and 23 in the EGFR tyrosine kinase domain. Expressions of phosphorylated (p) -Akt and p-Erk were determined via immunohistochemistry. Response rate, time to progression (TTP), and overall survival were compared between each group according to EGFR mutation, as well as p-Akt and p-Erk expression. RESULTS: Seventeen patients (18.9%; 95% CI, 10.8 to 27.0) harbored EGFR mutations. These mutations include deletions in exon 19 in seven patients, L858R in six patients, G719A in three patients, and a novel A859T in one patient. Response rate in patients with EGFR mutation was 64.7% (11 of 17 patients; 95% CI, 42.0 to 87.4), in contrast to 13.7% (10 of 73 patients; 95% CI, 5.8 to 21.6) in patients without mutation (P < .001). Moreover, these 17 patients with EGFR mutation had significantly prolonged TTP (21.7 v 1.8 months; P < .001) and overall survival (30.5 v 6.6 months; P < .001) compared with the remaining 73 patients without mutation. Although no significant correlation was detected between EGFR mutation and expressions of p-Akt or p-Erk, p-Akt overexpression was associated with prolonged TTP in patients with EGFR mutation. CONCLUSION: Our data further support the importance of EGFR mutation with regard to gefitinib sensitivity. In addition to its predictive role, EGFR mutation confers significant survival benefits on NSCLC patients treated with gefitinib.

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.

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.

AKAP12/Gravin is inactivated by epigenetic mechanism in human gastric carcinoma and shows growth suppressor activity.

AKAP12/Gravin, one of the A-kinase anchoring proteins (AKAPs), functions as a kinase scaffold protein and as a dynamic regulator of the beta2-adrenergic receptor complex. However, the biological role of AKAP12 in cancer development is not well understood. The AKAP12 gene encodes two major isoforms of 305 and 287 kDa (designated AKAP12A and AKAP12B, respectively, in this report). We found that these two isoforms are independently expressed and that they are probably under the control of two different promoters. Moreover, both isoforms were absent from the majority of human gastric cancer cells. The results from methylation-specific PCR (MSP) and bisulfite sequencing revealed that the 5' CpG islands of both AKAP12A and AKAP12B are frequently hypermethylated in gastric cancer cells. Treatment with DNA methyltransferase inhibitor and/or histone deacetylase inhibitor efficiently restored the expression of AKAP12 isoforms, confirming that DNA methylation is directly involved in the transcriptional silencing of AKAP12 in gastric cancer cells. Hypermethylation of AKAP12A CpG island was also detected in 56% (10 of 18) of primary gastric tumors. The restoration of AKAP12A in AKAP12-nonexpressing cells reduced colony formation and induced apoptotic cell death. In conclusion, our results suggest that AKAP12A may function as an important negative regulator of the survival pathway in human gastric cancer.

Transcriptional silencing of the DLC-1 tumor suppressor gene by epigenetic mechanism in gastric cancer cells.

DLC-1 (deleted in liver cancer) gene is frequently deleted in hepatocellular carcinoma. However, little is known about the genetic status and the expression of this gene in gastric cancer. In this study, Northern and Southern analysis showed that seven of nine human gastric cancer cell lines did not express DLC-1 mRNA, but contained the DLC-1 gene. To identify the mechanism of the loss of DLC-1 mRNA expression in these cell lines, we investigated the methylation status of DLC-1 gene by using methylation-specific PCR (MSP) and Southern blot, and found that five of seven DLC-1 nonexpressing gastric cancer cell lines were methylated in the DLC-1 CpG island. Treatment with 5-aza-2'-deoxycytidine (5-Aza-dC) induced DLC-1 mRNA expression in the gastric cancer cell lines that have the methylated alleles. Studies using SNU-601 cell line with methylated DLC-1 alleles revealed that nearly all CpG sites within DLC-1 CpG island were methylated, and that the in vitro methylation of the DLC-1 promoter region is enough to repress DLC-1 mRNA expression, regardless of the presence of transcription factors capable of inducing this gene. In all, 29 of 97 (30%) primary gastric cancers were also shown to be methylated, demonstrating that methylation of the DLC-1 CpG island is not uncommon in gastric cancer. In addition, we demonstrated that DLC-1 mRNA expression was induced, and an increase in the level of acetylated H3 and H4 was detected by the treatment with trichostatin A (TSA) in two DLC-1 nonexpressing cell lines that have the unmethylated alleles. Taken together, the results of our study suggest that the transcriptional silencing of DLC-1, by epigenetic mechanism, may be involved in gastric carcinogenesis.

Aberrant methylation of integrin alpha4 gene in human gastric cancer cells.

Integrins are adhesion receptors that mediate both cell-extracellular matrix and cell-cell interactions. It has also been reported that the loss of integrin alpha4 expression might be associated with metastasis in several cancers. However, the molecular mechanism for loss of their expression in cancers has not been explored. In the present study, we found that the integrin alpha4 expression is lost in human gastric cancer cell lines and that this is recovered by treatment with DNA methyltransferase inhibitor, implying transcriptional silencing by DNA methylation. Methylation-specific PCR (MSP) and bisulfite genomic DNA sequencing demonstrated the CpG methylation-dependent silencing of integrin alpha4 expression in eight of nine (88.8%) gastric cancer cell lines and in 84.7% of 46 primary tumors. We also investigated whether the restoration of integrin alpha4 in integrin alpha4-inactivated cells affects their ability to invade extracellular matrix, using matrigel assays. Interestingly, integrin alpha4-stable transfectants had markedly less invasive ability than the parental cells. Taken together, these results suggest that the transcriptional repression of the integrin alpha4 gene is caused by aberrant DNA methylation, and that this may play an important role in human gastric carcinogenesis.

Efficacy of platinum-based chemotherapy after cranial radiation in patients with brain metastasis from non-small cell lung cancer.

This study was conducted to assess the efficacy of systemic chemotherapy in patients with brain metastasis from non-small cell lung cancer. Sixty-three consecutive patients who were diagnosed as having non-small cell lung cancer (NSCLC) with synchronous brain metastasis (BM) and had not been previously treated were included in this study. After cranial radiation therapy (RT), all patients in 'the chemotherapy arm' (CTX) were treated with platinum-based combination chemotherapy, and best supportive care was selected for patients in 'the no-chemotherapy arm' (no-CTX). Thirty-one of the 63 patients received systemic chemotherapy. The median age of all patients was 55 years. The performance status of all patients was ECOG grade 1-2. Twenty-two patients had a solitary brain metastasis, 37 patients had more than two masses, and 38 patients had extracranial metastatic lesions. In the CTX arm, a paclitaxel-based combination chemotherapy was administered in 38.7%, gemcitabine-based in 25.8%, and vinorelbine-based in 25.8% as the first-line chemotherapy. Seventeen patients were treated with a second-line chemotherapy, and paclitaxel plus gemcitabine was used in 8 patients. For the first-line and second-line chemotherapies, extracranial overall responses were 36 and 35%, the median response durations were 29.1 weeks (range: 9.1-58.1 weeks) and 30.4 weeks (range: 19.4-44.0 weeks), respectively. 'Progression of the extracranial lesion' (58.1%) was more frequent than an 'aggravation of neurologic status' (19.4%) for the pattern of treatment failure in the first-line chemotherapy. The causes of failure were identical in the second-line chemotherapy. The median survival of the CTX arm was longer than that of the no-CTX arm (58.1 vs. 19.0 weeks, p<0.001). Toxicity in the CTX arm was tolerable. The systemic chemotherapy showed an effectiveness to increase the survival of patients with BM from NSCLC, and extracranial progression was the main cause of chemotherapeutic failure, although consideration for non-randomized methods should be made in this study.

Phase I and pharmacokinetic study of Genexol-PM, a cremophor-free, polymeric micelle-formulated paclitaxel, in patients with advanced malignancies.

PURPOSE: The rationale for developing an alternative paclitaxel formulation concerns Cremophor EL-related side effects, and a novel paclitaxel delivery system might augment its therapeutic efficacy. Genexol-PM is a polymeric micelle formulated paclitaxel free of Cremophor EL. A phase I study was performed to determine the maximum tolerated dosage, dose-limiting toxicities, and the pharmacokinetic profile of Genexol-PM in patients with advanced, refractory malignancies. EXPERIMENTAL DESIGN: Twenty-one patients were entered into the study. Genexol-PM was i.v. administered over 3 h every 3 weeks without premedication. The Genexol-PM dose was escalated from 135 mg/m(2) to 390 mg/m(2). RESULTS: All of the patients were evaluable for toxicity and response. Acute hypersensitivity reactions were not observed. Neuropathy and myalgia were the most common toxicities. During cycle 1, grade 3 myalgia occurred in 1 patient at 230 and 300 mg/m(2), respectively. At 390 mg/m(2), 2 of 3 patients developed grade 4 neutropenia or grade 3 polyneuropathy. Therefore, the maximum tolerated dosage was determined to be 390 mg/m(2). There were 3 partial responses (14%) among the 21 patients. Of the 3 responders, 2 were refractory to prior taxane therapy. The paclitaxel area under the curve from time 0 to infinity and peak or maximum paclitaxel concentration seemed to increase with escalating dose, except at 230 mg/m(2), which suggests that Genexol-PM has linear pharmacokinetics. CONCLUSION: The main dose-limiting toxicities were neuropathy, myalgia, and neutropenia, and the recommended dosage for a phase II study is 300 mg/m(2). Genexol-PM is believed to be superior to conventional paclitaxel in terms of the obviation of premedication and the delivery of higher paclitaxel doses without additional toxicity.

Gastric epithelial reactive oxygen species prevent normoxic degradation of hypoxia-inducible factor-1alpha in gastric cancer cells.

The expression of hypoxia inducible factor (HIF)-1alpha protein is tightly regulated by cellular oxygen status. Namely, HIF-1alpha protein is degraded rapidly in normoxic cells, whereas hypoxia stabilizes HIF-1alpha to transactivate hypoxia-responsive genes. Here we show that HIF-1alpha protein is expressed aberrantly in gastric cancer cells under normoxia in a reactive oxygen species (ROS)-dependent manner. The normoxic expression of HIF-1alpha in concordance with its DNA binding activity enhances the transcription of target genes such as vascular endothelial growth factor. The aberrant normoxic expression of HIF-1alpha is not associated with genetic abnormalities such as the loss of von Hippel-Lindau tumor suppressor, but is well correlated with endogenous ROS (hydrogen peroxide) generation. HIF-1alpha expression is blocked by nonmitochondrial ROS inhibitors, but not by inhibitors of mitochondrial electron transfer, which indicates that nonmitochondrial ROS stabilize HIF-1alpha protein in these cells. Gastric epithelial ROS have been linked to Helicobacter pylori-induced gastric carcinogenesis. This study demonstrates for the first time that ROS from H. pylori-infected gastric epithelial cells induce HIF-1alpha expression and subsequently activate HIF-1alpha-mediated transcription. Taken together, these results provide a novel mechanism of HIF-1alpha stabilization in gastric cancer, and demonstrate that gastric epithelial ROS, endogenously generated or H. pylori-stimulated, lead to the constant expression of HIF-1alpha protein under normoxia.

Class I histone deacetylase-selective novel synthetic inhibitors potently inhibit human tumor proliferation.

We have developed previously a class of synthetic hybrid histone deacetylase (HDAC) inhibitors, which were built from hydroxamic acid of trichostatin A and pyridyl ring of MS-275. In this study we evaluated the antitumor effects of these novel hybrid synthetic HDAC inhibitors, SK-7041 and SK-7068, on human cancer cells. Both SK-7041 and SK-7068 effectively inhibited cellular HDAC activity at nanomolar concentrations and induced the time-dependent hyperacetylation of histones H3 and H4. These HDAC inhibitors preferentially inhibited the enzymatic activities of HDAC1 and HDAC2, as compared with the other HDAC isotypes, indicating that class I HDAC is the major target of SK-7041 and SK-7068. We found that these compounds exhibited potent antiproliferative activity against various human cancer cells in vitro. Growth inhibition effect of SK-7041 and SK-7068 was related with the induction of aberrant mitosis and apoptosis in human gastric cancer cells. Both compounds induced the accumulation of cells at mitosis after 6 h of treatment, which was demonstrated by accumulation of tetraploid cells, lack of G(2) cyclin/cyclin-dependent kinase inactivation, and higher mitotic index. After 12 h of treatment, apoptotic cells were increased through mitochondrial and caspase-mediated pathway. Finally, in vivo experiment showed that SK-7041 or SK-7068 was found to reduce the growth of implanted human tumors in nude mice. Therefore, based on isotype specificity and antitumor activity, SK-7041 and SK-7068 HDAC inhibitors are expected to be promising anticancer therapeutic agents and need additional clinical development.

Herpes simplex virus thymidine kinase and granulocyte macrophage colony-stimulating factor combination gene therapy in a murine CT26 cell colon cancer model.

We evaluated the antitumor effects of combination gene therapy on CT26 mouse colon cancer cells, using the genes for herpes simplex virus thymidine kinase gene HSV-TK combined with granulocyte macrophage colony-stimulating factor (GM-CSF) compared with HSV-TK alone. Cells, unmodified or retrovirally transduced with HSV-TK or GM-CSF, were inoculated subcutaneously into syngeneic BALB/c mice in various combinations. HSV-TK and GM-CSF were also delivered using different routes (in separate cells vs doubly transfected single cells). Both HSV-TK (with i.p. ganciclovir - GCV - treatment) and GM-CSF genes had independent antitumor effects, and given together they caused significant reduction in tumor volumes compared with the HSV-TK gene alone (P < 0.001). Following GCV treatment, however, the treated/control ratios for tumor volumes were not different between tumors containing either HSV-TK alone or both genes (0.27 vs 0.25, respectively). Thus, the presence of GM-CSF did not increase the bystander effect of HSV-TK. Tumors receiving genes transferred in separate cells tended to be more consistently suppressed after GCV treatment than when both genes were transferred in the same cells, although this was not statistically significant. Thus, combination GM-CSF and HSV-TK gene therapy produced greater therapeutic efficacy than HSV-TK alone, but the bystander effect was not enhanced by GM-CSF.

Efficacy of modified regimen with attenuated doses of paclitaxel plus carboplatin combination chemotherapy in elderly and/or weak patients with advanced non-small cell lung cancer.

PURPOSE: We conducted this study to evaluate the activity and toxicity of a combination regimen of paclitaxel plus carboplatin in patients with advanced NSCLC aged 65 years or older and/or in those with an ECOG performance status (PS) 2. MATERIALS AND METHODS: Chemotherapy-naive patients with unresectable pathologically-proven NSCLC and of either age >or=65 or ECOG PS 2 were eligible. Patients received modified regimen with attenuated doses of paclitaxel (135 mg/m(2) i.v. for 3 h D1) and carboplatin (AUC=5, D1) every 3 weeks. RESULTS: Thirty-five patients were enrolled. Nineteen patients were aged 65 or older (54%) and 26 patients (74%) were ECOG PS 2. The objective response rate was 40% with 14 partial responses. The median time to progression was 22 weeks. Grade 3 leucopenia occurred in 1 cycle and one case of neutropenic fever. CONCLUSIONS: The modified regimen with attenuated doses of paclitaxel plus carboplatin combination chemotherapy was effective and well tolerated in patients with advanced NSCLC aged 65 years or older and/or in those with ECOG PS 2.

Extramedullary relapse confirmed by fluorescence in situ hybridization study of an ear mass in acute promyelocytic leukemia.

A 40-year-old man with acute promyelocytic leukemia (APL) achieved complete remission after induction chemotherapy combined with all-trans-retinoic acid. A mass developed in the left ear 24 months later. Relapse of APL was suspected at morphologic examination of the biopsy specimen of the ear mass, but t(15;17) and PML/RAR alpha rearrangement were not detected by chromosomal, fluorescence in situ hybridization (FISH), or reverse transcription polymerase chain reaction analysis of bone marrow samples. FISH performed on the ear mass revealed t(15;17). To our knowledge, this case is the first reported case of extramedullary relapse of APL confirmed by FISH study of a biopsy specimen of extramedullary tissue.

Induction chemotherapy followed by radiotherapy in the treatment of anal cancer.

This study was conducted to investigate the efficacy of the induction chemotherapy followed by radiotherapy in anal cancer. Twenty-three patients diagnosed with anal cancer between March 1991 and February 1999 were treated with induction chemotherapy with 5-fluorouracil based regimens followed by external beam radiation. After a median follow-up of 78 months, the overall survival and the disease-free survival at 5 years was 71.3 and 67.5%, respectively. The colostomy-free survival at 5 years was 91%, as the inguinal lymph nodes were the most frequent site of relapse. Serious side effects did not occur and late complications did not develop either. Induction chemotherapy followed by radiotherapy in patients with anal cancer is effective in terms of its response and preserving the anal sphincter without serious acute and late complications.