Long-term efficacy and safety of tucidinostat in patients with relapsed or refractory peripheral T-cell lymphoma: final analysis of phase IIb results.

Not available.

Efficacy of Antiviral Prophylaxis up to 6 or 12 Months From Completion of Rituximab in Resolved Hepatitis B Patients: A Multicenter, Randomized Study.

BACKGROUND: Rituximab occasionally induces reactivation of hepatitis B virus (HBV) in patients with resolved HBV, at times with fatal consequences. The optimal duration of prophylactic antiviral therapy in this situation is unclear. We aimed to investigate the difference in HBV reactivation according to the duration of prophylactic tenofovir disoproxil fumarate (TDF) in patients with resolved HBV and receiving rituximab. METHODS: A multicenter, randomized, open-label, prospective study was conducted in hepatitis B surface antigen-negative and anti-HBc-positive non-Hodgkin's lymphoma patients treated with rituximab-based chemotherapy. A total of 90 patients were randomized and received prophylactic TDF from the initiation of rituximab until 6 months (the 6-month group) or 12 months (the 12-month group) after the completion of rituximab. The primary outcome was the difference in HBV reactivation and the secondary outcomes were the difference in hepatitis flare and adverse events between the two groups. RESULTS: In an intention to treat (ITT) analysis, HBV reactivation occurred in 1 of 43 patients (2.3%; 95% confidence interval [CI], 0.41-12%) at a median of 13.3 months in the 6-month group and 2 of 41 patients (4.9%; 95% CI, 1.4-16%) at a median of 13.7 months in the 12-month group. In a per protocol (PP) analysis, HBV reactivation occurred in 1 of 18 patients (5.6%; 95% CI, 0.99-26%) at 13.3 months in the 6-month group and 1 of 13 patients (7.7%; 95% CI, 1.4-33%) at 9.7 months in the 12-month group. The cumulative incidence of HBV reactivation was not significantly different between the two groups in ITT and PP analyses (P = 0.502 and 0.795, respectively). The occurrence of adverse events was not significantly different between the two groups in ITT (9.3% in the 6-month group, 22.0% in the 12-month group, P = 0.193) and PP analyses (5.6% in the 6-month group, 7.7% in the 12-month group, P > 0.999). CONCLUSION: Prophylactic TDF up to 6 months after completion of rituximab-based chemotherapy is sufficient in terms of the efficacy and safety of reducing HBV reactivation in patients with resolved HBV. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02585947.

Oral HDAC inhibitor tucidinostat in patients with relapsed or refractory peripheral T-cell lymphoma: phase IIb results.

Tucidinostat (formerly known as chidamide) is an orally available, novel benzamide class of histone deacetylase (HDAC) inhibitor that selectively blocks class I and class IIb HDAC. This multicenter phase IIb study aimed to investigate the efficacy and safety of tucidinostat, 40 mg twice per week (BIW), in patients with relapsed/refractory (R/R) peripheral T-cell lymphoma (PTCL). The primary endpoint was overall response rate (ORR) assessed by an independent overall efficacy review committee. Between March 2017 and March 2019, 55 patients were treated, and 46 and 55 were evaluated for efficacy and safety, respectively. Twenty-one of 46 patients achieved objective responses with an ORR of 46% (95% confidence interval : 30.9-61.0), including five patients with complete response (CR). Responses were observed across various PTCL subtypes. In angioimmunoblastic T-cell lymphoma, there were two CR and five partial responses (PR) among eight patients, achieving an ORR of 88%. The disease control rate (CR + PR + stable disease) was 72% (33/46). The median progression-free survival, duration of response, and overall survival were 5.6 months, 11.5 months, 22.8 months, respectively. The most common adverse events (AE) (all grades) were thrombocytopenia, neutropenia, leukopenia, anemia, and diarrhea. The grade ≥3 AE emerging in ≥20% of patients included thrombocytopenia (51%), neutropenia (36%), lymphopenia (22%), and leukopenia (20%). Importantly, most of the AE were manageable by supportive care and dose modification. In conclusion, the favorable efficacy and safety profiles indicate that tucidinostat could be a new therapeutic option in patients with R/R PTCL (clinicaltrials gov. Identifier: NCT02953652).

Treatment outcome and prognostic factors of Korean patients with chronic lymphocytic leukemia: a multicenter retrospective study.

BACKGROUND/AIMS: Compared with Western countries, chronic lymphocytic leukemia (CLL) rarely occurs in Asia and has different clinical characteristics. Thus, we aimed to evaluate the clinical characteristics, treatment outcomes, and prognostic significance of Korean patients with CLL. METHODS: We retrospectively analyzed 90 patients with CLL who had received chemotherapy at 6 centers in Korea between 2000 and 2012. RESULTS: Compared with Western patients with CLL, Korean patients with CLL express lambda (42.0%) and atypical markers such as CD22 and FMC7 (76.7% and 40.0%, respectively) more frequently. First-line chemotherapy regimens included chlorambucil (n = 43), fludarabine and cyclophosphamide (FC) (n = 20), fludarabine (n = 13), rituximab-FC (n = 4). The remaining patients were treated with other various regimens (n = 10). The 5-year overall survival (OS) and progression-free survival (PFS) rates were 79.3% and 28.1%, respectively. Multivariate analyses showed that hyperleukocytosis (≥ 100 × 103/µL), extranodal involvement, and the Binet C stage were significant negative prognostic factors for OS (hazard ratio [HR] 4.75, p = 0.039; HR 21.6, p = 0.002; and HR 4.35, p = 0.034, respectively). Cytogenetic abnormalities including complex karyotypes (≥ 3), del(11q), and del(17) had a significantly adverse impact on both OS and PFS (p < 0.001 and p = 0.010, respectively). CONCLUSION: Initial hyperleukocytosis, extranodal involvement, complex karyotype, del(17) and del(11q) need to be considered in the risk stratification system for CLL.

Optimizing Preparative Regimen for Umbilical Cord Blood Transplantation in Adult Acute Leukemia Patients: Acute Lymphoblastic Leukemia Requires Myeloablative Conditioning but Not Acute Myeloid Leukemia.

Cord blood transplantation (CBT) is a valuable alternative to bone marrow transplantation in adults without readily available donors. We conducted this study to investigate the feasibility of CBT for adult patients with acute leukemia with regards to impact of different conditioning and graft-versus-host disease (GVHD) prophylaxis regimens on clinical outcomes. From 16 centers in Korea, 41 acute myeloid leukemia (AML) and 29 ALL (acute lymphoblastic leukemia) patients undergoing CBT were enrolled. For AML patients, the neutrophil engraftment was observed in 87.5% of reduced intensity conditioning (RIC) and 72.0% of myeloablative conditioning (MAC) (p = 0.242). The median RFS was 5 months and OS 7 months. Conditioning regimen did not affect relapse free survival (RFS) or overall survival (OS). GVHD prophylaxis using calcineurin inhibitors (CNI) plus methotrexate was associated with better RFS compared to CNI plus ATG (p = 0.032). For ALL patients, neutrophil engraftment was observed in 55.6% of RIC and 90.0% of MAC (p = 0.034). The median RFS was 5 months and OS 19 months. MAC regimens, especially total body irradiation (TBI)-based regimen, were associated with both longer RFS and OS compared to other conditioning regimens. In conclusion, individualized conditioning regimens will add value in terms of enhancing safety and efficacy of CBT.

The Inhibitory Mechanisms of Tumor PD-L1 Expression by Natural Bioactive Gallic Acid in Non-Small-Cell Lung Cancer (NSCLC) Cells.

Non-small-cell lung cancer (NSCLC) is the most common lung cancer subtype and accounts for more than 80% of all lung cancer cases. Epidermal growth factor receptor (EGFR) phosphorylation by binding growth factors such as EGF activates downstream prooncogenic signaling pathways including KRAS-ERK, JAK-STAT, and PI3K-AKT. These pathways promote the tumor progression of NSCLC by inducing uncontrolled cell cycle, proliferation, migration, and programmed death-ligand 1 (PD-L1) expression. New cytotoxic drugs have facilitated considerable progress in NSCLC treatment, but side effects are still a significant cause of mortality. Gallic acid (3,4,5-trihydroxybenzoic acid; GA) is a phenolic natural compound, isolated from plant derivatives, that has been reported to show anticancer effects. We demonstrated the tumor-suppressive effect of GA, which induced the decrease of PD-L1 expression through binding to EGFR in NSCLC. This binding inhibited the phosphorylation of EGFR, subsequently inducing the inhibition of PI3K and AKT phosphorylation, which triggered the activation of p53. The p53-dependent upregulation of miR-34a induced PD-L1 downregulation. Further, we revealed the combination effect of GA and anti-PD-1 monoclonal antibody in an NSCLC-cell and peripheral blood mononuclear-cell coculture system. We propose a novel therapeutic application of GA for immunotherapy and chemotherapy in NSCLC.

Efficacy and safety of blinatumomab treatment in adult Korean patients with relapsed/refractory acute lymphoblastic leukemia on behalf of the Korean Society of Hematology ALL Working Party.

Blinatumomab, a bispecific T cell-engaging antibody, has demonstrated efficacy for relapsed or refractory acute lymphoblastic leukemia (ALL). In this study, we evaluated the efficacy and toxicity of blinatumomab in adult Korean patients with relapsed or refractory Philadelphia-negative B cell precursor ALL. A total of 50 patients received blinatumomab treatment between June 2016 and August 2017 in Korea. The median number of prior therapy was one (range, 1-4). Among the 49 evaluable patients, 22 (44.9%) achieved complete response (CR) or CR with incomplete blood count recovery, and 16 of whom subsequently underwent allogenic stem cell transplantation. Although no statistically significant differences were observed, patients with extramedullary disease and poor performance status had lower responses to blinatumomab treatment. In addition, the use of high-dose dexamethasone prior to blinatumomab treatment did not affect the response to blinatumomab. The median event-free survival and overall survival of the responders were 7.5 and 8.1 months, respectively. For non-hematologic toxicities, the most common toxicity was infection. The incidences of severe cytokine release syndrome and neurologic toxicity each was 4%. In conclusion, blinatumomab was an effective and tolerable therapy in adult Korean patients with relapsed or refractory Philadelphia-negative B cell precursor ALL.

Prognostic Impact of IPSS-R and Chromosomal Translocations in 751 Korean Patients with Primary Myelodysplastic Syndrome.

Chromosomal translocations are rare in myelodysplastic syndrome (MDS) and their impact on overall survival (OS) and response to hypomethylating agents (HMA) is unknown. The prognostic impact of the revised International Prognostic Scoring System (IPSS-R) and for chromosomal translocations was assessed in 751 patients from the Korea MDS Registry. IPSS-R effectively discriminated patients according to leukaemia evolution risk and OS. We identified 40 patients (5.3%) carrying translocations, 30 (75%) of whom also fulfilled complex karyotype criteria. Translocation presence was associated with a shorter OS (median, 12.0 versus 79.7 months, P < 0.01). Multivariate analysis demonstrated that translocations (hazard ratio [HR] 1.64 [1.06-2.63]; P = 0.03) as well as age, sex, IPSS-R, and CK were independent predictors of OS. In the IPSS-R high and very high risk subgroup (n = 260), translocations remained independently associated with OS (HR 1.68 [1.06-2.69], P = 0.03) whereas HMA treatment was not associated with improved survival (median OS, 20.9 versus 21.2 months, P = 0.43). However, translocation carriers exhibited enhanced survival following HMA treatment (median 2.1 versus 12.4 months, P = 0.03). Our data suggest that chromosomal translocation is an independent predictor of adverse outcome and has an additional prognostic value in discriminating patients with MDS having higher risk IPSS-R who could benefit from HMA treatment.

Clinical Features and Survival of Patients With Follicular Lymphoma in Korea.

BACKGROUND: The incidence of follicular lymphoma (FL) varies according to geographic location. It is the second most common non-Hodgkin lymphoma in Western countries but has a very low incidence in Asia. Thus, no representative data are available for FL. Therefore, we gathered our own data to build a foundation for FL research. PATIENTS AND METHODS: We collected a total of 343 patient records. The median age was 53 years, and the ratio of male to female patients was 1.4:1. Most patients received chemotherapy with or without rituximab. RESULTS: The incidence of grade 1 and 2 FL was 64.9% (n = 205) and of stage III and IV was 51.2% (n = 171). The grade tended to be higher and the stage to be lower compared with Western data. In the chemotherapy group, the complete response rate was 76.0%, and the partial response rate was 17.1%. The median follow-up duration was 38.1 months. The estimated 5- and 10-year progression-free survival and overall survival rates were 68.3% and 84.9% and 63.0% and 71.3%, respectively. CONCLUSION: We could not find definitive differences between our Korean data and the Western data, although we found some trends in the baseline characteristics. Therefore, we hope to develop an understanding of FL and perform more qualitative studies in the future.

Prediction of survival by applying current prognostic models in diffuse large B-cell lymphoma treated with R-CHOP followed by autologous transplantation.

BACKGROUND: Among the currently available prognostic models for diffuse large B-cell lymphoma (DLBCL), we investigated to determine which is most adoptable for DLBCL patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) followed by upfront autologous stem cell transplantation (auto-SCT). METHODS: We retrospectively evaluated survival differences among risk groups based on the International Prognostic Index (IPI), the age-adjusted IPI (aaIPI), the revised IPI (R-IPI), and the National Comprehensive Cancer Network IPI (NCCN-IPI) at diagnosis in 63 CD20-positive DLBCL patients treated with R-CHOP followed by upfront auto-SCT. RESULTS: At the time of auto-SCT, 74.6% and 25.4% of patients had achieved complete remission and partial remission after R-CHOP, respectively. As a whole, the 5-year overall (OS) and progression-free survival (PFS) rates were 78.8% and 74.2%, respectively. The 5-year OS and PFS rates according to the IPI, aaIPI, R-IPI, and NCCN-IPI did not significantly differ among the risk groups for each prognostic model (P-values for OS: 0.255, 0.337, 0.881, and 0.803, respectively; P-values for PFS: 0.177, 0.904, 0.295, and 0.609, respectively). CONCLUSION: There was no ideal prognostic model among those currently available for CD20-positive DLBCL patients treated with R-CHOP followed by upfront auto-SCT.

Azacitidine Pre-Treatment Followed by Reduced-Intensity Stem Cell Transplantation in Patients with Higher-Risk Myelodysplastic Syndrome.

Azacitidine (AZA) is commonly used in patients with myelodysplastic syndrome (MDS). To determine the role of AZA before allogeneic stem cell transplantation (allo-SCT), we conducted a prospective study of AZA pre-treatment followed by allo-SCT in patients with higher-risk MDS. Twenty-one patients who were scheduled for their third to sixth cycle of AZA pre-treatment followed by allo-SCT were enrolled. AZA pre-treatment was interrupted early in 3 patients (14.3%) because of leukaemic transformation or death. The overall response rate to AZA pre-treatment was 57.1%. There were 2 cases of complete remission, 1 case of partial remission, and 9 cases of haematologic improvement. Fourteen patients (66.7%) received the planned allo-SCT and 5 patients were alive at the last follow-up. Three-year progression-free survival (PFS) and 3-year overall survival (OS) in the 14 patients who received allo-SCT were 30.0% (95% CI 3.3-56.7) and 42.9% (95% CI 17.1-68.7), respectively. PFS and OS were not influenced by response to AZA pre-treatment (p > 0.05). In this study, AZA had a role as a bridge therapy to prevent leukaemic transformation prior to selection of a donor for allo-SCT and showed low toxicity. It may be considered in patients with higher-risk MDS.

R-CHOP chemoimmunotherapy followed by autologous transplantation for the treatment of diffuse large B-cell lymphoma.

BACKGROUND: We investigated factors that influence outcomes in diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab combined with the CHOP regimen (R-CHOP) followed by upfront autologous stem cell transplantation (Auto-SCT). METHODS: We retrospectively evaluated survival differences between subgroups based on the age-adjusted International Prognostic Index (aaIPI) and revised-IPI (R-IPI) at diagnosis, disease status, and positron emission tomographic/computerized tomographic (PET/CT) status at transplantation in 51 CD20-positive DLBCL patients treated with R-CHOP followed by upfront Auto-SCT. RESULTS: Patients had either stage I/II bulky disease (5.9%) or stage III/IV disease (94.1%). The median patient age at diagnosis was 47 years (range, 22-66 years); 53.3% and 26.7% had high-intermediate and high risks according to aaIPI, respectively. At the time of Auto-SCT, 72.5% and 27.5% experienced complete (CR) and partial remission (PR) after R-CHOP, respectively. The median time from diagnosis to Auto-SCT was 7.27 months (range, 3.4-13.4 months). The 5-year overall (OS) and progression-free survival (PFS) were 77.3% and 72.4%, respectively. The 5-year OS and PFS rates according to aaIPI, R-IPI, and PET/CT status did not differ between the subgroups. More importantly, the 5-year OS and PFS rates of the patients who achieved PR at the time of Auto-SCT were not inferior to those of the patients who achieved CR (P=0.223 and 0.292, respectively). CONCLUSION: Survival was not influenced by the aaIPI and R-IPI at diagnosis, disease status, or PET/CT status at transplantation, suggesting that upfront Auto-SCT might overcome unfavorable outcomes attributed to PR after induction chemoimmunotherapy.

Is Helicobacter Pylori associated with Her2/neu Overexpression in Gastric Cancer Patients who Underwent Curative Resection?

BACKGROUND/AIMS: Human epidermal growth factor receptor 2 (Her2/neu) is an important target for treatment of gastric cancer using trastuzumab and Helicobacter pylori is a well-known risk factor of gastric cancer. We investigated the association of Her2/neu overexpression with Helicobacter pylori and other clinicopathologic factors in gastric cancer patients who underwent curative resection. METHODOLOGY: Her2/neu immunohistochemistry was performed in gastric cancer patients who underwent curative gastrectomy or endoscopic submucosal dissection. Analysis about its associations with clinicopathologic features such as Lauren histologic types, differentiation, Helicobacter pylori infection, location, depth of invasion, lymph node metastasis, and AJCC tumor stage was performed retrospectively. RESULTS: The incidence of Her2/neu 3+, 2+, 1+ and 0 was 8.9%, 22.1%, 4.4% and 64.6% respectively. Intestinal type of gastric cancer showed higher incidence of Her2/neu 3+ than diffuse type. The score 2+ and 3+ was more common in Helicobacter pylori-positive patients than Helicobacter pylori-negative patients (p = 0.024). 7th American joint Cancer Committee Tumor stage, depth of tumor invasion and lymph node metastasis did not show correlation with the level of Her2/neu expression. CONCLUSIONS: Helicobacter pylori-positive gastric cancer showed more Her2/neu overexpression. Helicobacter pylori eradication may be necessary to avoid Her2/neu overexpression.

Clinical features and survival outcomes of patients with diffuse large B-cell lymphoma: analysis of web-based data from the Korean Lymphoma Working Party Registry.

BACKGROUND: This study aimed to survey the clinical spectrum of diffuse large B-cell lymphoma (DLBCL) in terms of epidemiology, pathologic subtypes, stage, and prognostic index as well as treatment outcomes. METHODS: In 2007-2008, 13 university hospitals evenly distributed in the Korean peninsula contributed to the online registry of DLBCL at www.lymphoma.or.kr and filed a total of 1,665 cases of DLBCL recorded since 1990. RESULTS: Our analysis showed a higher prevalence of DLBCL in male than in female individuals (M:F=958:707), and extranodal disease was more common than primary nodular disease (53% vs. 47%). Among the 1,544 patients who had been treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or rituximab-CHOP (R-CHOP) therapy with or without radiation, 993 (63.9%) were alive, with 80% free of disease, 417 were dead (26.8%), with 13% free of disease, and 144 (9.3%) were lost to follow-up, with 23% free of disease. Age below 60 years, stage at diagnosis, international prognostic index (IPI) score regardless of age, and addition of rituximab to CHOP therapy in low- and low-intermediate-risk groups according to IPI scores significantly increased survival duration. CONCLUSION: The epidemiology, clinical spectrum, and biological behavior of DLBCL in Korea are similar to those observed in Western countries, and the advent of rituximab improved survival.

The antipsychotic agent chlorpromazine induces autophagic cell death by inhibiting the Akt/mTOR pathway in human U-87MG glioma cells.

2-Chloro-10-[3(-dimethylamino)propyl]phenothiazine mono hydrochloride (chlorpromazine; CPZ) is an antipsychotic agent that was originally developed to control psychotic disorders. The cytotoxic properties of the CPZ are well known, but its mechanism of action is poorly understood. In this study, we investigated the role of apoptosis and autophagy in CPZ-induced cytotoxicity in U-87MG glioma cells. CPZ treatment inhibited cell proliferation and long-term clonogenic survival. Additionally, CPZ triggered autophagy, as indicated by electron microscopy and accumulation of the membrane form of microtubule-associated protein 1 light chain 3 (LC3-II); however, CPZ did not induce apoptosis. Inhibition of autophagy by expression of Beclin 1 small interfering RNA (siRNA) in U-87MG cells attenuated CPZ-induced LC3-II formation. Furthermore, U-87MG cells expressing Beclin 1 siRNA attenuated CPZ-induced cell death. CPZ inhibited phosphatidylinositol 3-kinase (PI3K)/AKT/ mTOR pathway in U-87MG cells. Treatment with LY294002, a PI3K inhibitor, alone increased the accumulation of LC3-II and potentiated the effect of CPZ. In contrast, exogenous expression of AKT partially inhibited CPZ-induced LC3-II formation. When U-87MG cells were implanted into the brain of athymic nude mouse, CPZ triggered autophagy and inhibited xenograft tumor growth. These results provided the first evidence that CPZ-induced cytotoxicity is mediated through autophagic cell death in PTEN (phosphatase and tensin homolog deleted on chromosome 10)-null U-87MG glioma cells by inhibiting PI3K/AKT/mTOR pathway.

Lenalidomide induces apoptosis and alters gene expression in non-small cell lung cancer cells.

Non-small cell lung cancer (NSCLC) is the most deadly type of cancer worldwide. Although a number of therapies are used in NSCLC treatment, their therapeutic efficacy remains low. Lenalidomide was originally approved for use in patients with myelodysplastic syndromes, which are associated with 5q deletions, and multiple myeloma. Recently, lenalidomide was investigated as a new NSCLC treatment, and it exerted anticancer effects. However, the primary cellular mechanism of its effects in NSCLC is largely unknown. Therefore, we attempted to elucidate a molecular portrait of lenalidomide-mediated cellular events in NSCLC. Lenalidomide reduced the viability of several NSCLC cell lines in a concentration-dependent manner. In addition, array-based gene expression analysis revealed that lenalidomide regulated the expression of several genes associated with cell survival, apoptosis and development, including BH3-interacting domain death agonist (BID), v-fos FBJ murine osteosarcoma viral oncogene homolog (FOS) and NK2 homeobox1 (NKX2-1). BID and FOS, which are known apoptosis activators, were upregulated by lenalidomide treatment, whereas NKX2-1, which is used as an immunohistochemistry marker for NSCLC, was downregulated. These results provide evidence that lenalidomide directly induces antiproliferative effects by altering the expression of genes associated with cell proliferation and apoptosis.

Comparative analysis between azacitidine and decitabine for the treatment of myelodysplastic syndromes.

The present study aimed to directly compare the efficacy and safety of azacitidine and decitabine in patients with myelodysplastic syndromes (MDS). We compared the overall response rate (ORR) (complete responses, partial responses, marrow complete responses, and haematological improvements), overall survival (OS), event-free survival (EFS), time to leukaemic transformation, and adverse outcomes between azacitidine and decitabine. To minimize the effects of treatment selection bias in this observational study, adjustments were made using the propensity-score matching method. Among 300 patients, 203 were treated with azacitidine and 97 with decitabine. Propensity-score matching yielded 97 patient pairs. In the propensity-matched cohort, there were no significant differences between the azacitidine and decitabine groups regarding ORR (44% vs. 52%), OS (26 vs. 22.9 months), EFS (7.7 vs. 7.0 months), and rate of leukaemic transformation (16% vs. 22% at 1 year). In patients ≥ 65 years of age, survival was significantly better in the azacitidine group (P = 0.017). Patients who received decitabine experienced more frequent episodes of grade 3 or 4 cytopenia and infectious episodes. We found that azacitidine and decitabine showed comparable efficacy. Among patients ≥ 65 years of age, survival was significantly better in the azacitidine group (ClinicalTrials.gov Identifier: NCT01409070).

Transcriptional regulation of the interleukin-11 gene by oncogenic Ras.

Interleukin-11 (IL-11), which belongs to a class of IL6-type cytokines, plays an important role in inflammation, motility and invasion in cancer. The ras mutation is frequently found in human cancer, but little is known regarding the transcriptional activation of the IL-11 gene by the Ras signal pathway in tumour cells. In this study, we investigated the role of Ras in the regulation of IL-11 using two different cell model systems: mouse NIH3T3 cells over-expressing oncogenic Ras with a tet-on system and Capan-1 human pancreatic carcinoma cells harbouring a K-ras mutation. We found that IL-11 expression was up-regulated at the transcriptional level by oncogenic Ras. Activation of the AP-1 response element, located between -153 and -30 in the 5'-regulatory region of the IL-11 gene, was necessary for oncogenic Ras-induced IL-11 promoter activation. AP-1 proteins, including Fra-1 and Fra-2, were up-regulated through the Raf/MEK and phosphatidylinositol 3-kinase (PI3K)/Akt pathways by oncogenic Ras. Knockdown of Fra-1 by siRNA in NIH3T3 or Capan-1 cells strongly attenuated oncogenic Ras-induced IL-11 expression. Additionally, inhibition of JNK, p38 and Stat3 abrogated oncogenic Ras-induced IL-11 expression. These results suggest that both the PI3K and Raf pathways are necessary for the expression of IL-11 in oncogenic Ras-mutated cells, and that JNK, p38 and Stat3 also contribute to oncogenic Ras-induced IL-11 expression.