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Selectively replicating recombinant adenovirus has emerged as a novel strategy for the treatment of incurable human cancers. One of the major characteristics of hepatocellular carcinoma is the transcriptional reactivation of alpha-fetoprotein (AFP). In this study, we evaluated the liver cancer-specific oncolytic potential of E1B 55kDa-deleted recombinant adenovirus (YKL-1001), which retained other E1 genes driven by the AFP promoter. Transient transfection study using luciferase indicated the selective activation of the AFP promoter only in human liver cancer cells secreting AFP (HepG2, Hep3B). YKL-1001 induced both cytopathic effects exclusively in AFP-positive liver cancer cells and the growth inhibition of pre-established Hep3B xenografts. Finally, hematoxylin-eosin staining and the immunohistochemistry to the adenoviral hexon showed a large distributed necrotic area and this implied a wide spread of YKL-1001. Therefore, the present study demonstrated that YKL-1001 holds significant promise as an oncolytic agent for hepatocellular carcinoma.

9090 Background: We identified factors associated with better OS for previously treated, PD-L1–expressing advanced NSCLC using data from KEYNOTE-010 (NCT01905657; Herbst et al. Lancet. 2016;387:1540-50), in which pembrolizumab had superior OS over docetaxel. Methods: 1033 patients were randomly assigned 1:1:1 to pembrolizumab 2 or 10 mg/kg every 3 weeks (Q3W) or docetaxel 75 mg/m2 Q3W. Response was assessed per RECIST v1.1 by independent central review. Multivariate analyses were performed using a Cox proportional hazards regression model on OS in the pembrolizumab arms. A set of variable selection methods was applied to 19 baseline demographic and disease characteristics, including smoking status, and identified 7 factors that contributed to OS. Data cut was September 30, 2016. Results: Adjusted hazard ratios (HRs) for the factors in the pembrolizumab arm from the model are shown in the Table. Updated OS with an additional 6 months of follow-up from this data lock for KEYNOTE-010 will be presented. Conclusions: While the overall result of KEYNOTE-010 revealed improved OS with pembrolizumab compared with docetaxel in previously treated patients with PD-L1–positive advanced NSCLC, exploratory, post hoc multivariate analyses showed that some laboratory and tumor characteristics such as nonsquamous histology, normal baseline lactate dehydrogenase (LDH), PD-L1 TPS ≥50%, and wild-type EGFR mutation status were associated with better OS among patients treated with pembrolizumab. Clinical trial information: NCT01905657. [Table: see text]

92 Background: Nivolumab (BMS-936558/ONO-4538), a fully human IgG4, PD-1 immune-checkpoint inhibitor antibody, has shown durable clinical activity in several tumor types. Recently, two phase III studies (CheckMate-017 and -057) demonstrated that nivolumab improved overall survival (OS) than docetaxel in second-line of squamous (SQ) and non-squamous (NSQ) Non-Small Cell Lung Cancer (NSCLC), respectively. Here, we report the results of a phase II study to evaluate the efficacy and safety of nivolumab in Korean patients (pts) with previously treated advanced SQ and NSQ NSCLC. Methods: This study requires pts aged ≥ 20 years with ECOG Performance Status (PS) of 0 or 1, stage IIIB/IV or recurrent NSCLC and at least one prior chemotherapy including platinum containing regimen. Pts received nivolumab 3 mg/kg IV Q2W until progression or unacceptable toxicity. The primary endpoint in this study was the objective response rate (ORR) (RECIST v1.1). Results: Nivolumab was administered to 100 NSCLC pts (SQ: 44, NSQ: 56), male/female: 78 (SQ: 44, NSQ: 34)/22 (SQ: 0, NSQ: 22); PS 0/1: 14 (SQ: 6, NSQ: 8)/86 (SQ: 38, NSQ: 48); aged 29 to 80 [median: 66.5] years (SQ: 40 to 80 [median: 69.5], NSQ: 29 to 77 [median: 63.5]); Stage IIIB/IV/recurrence: 6 (SQ: 5, NSQ: 1)/91 (SQ: 37, NSQ: 54)/3 (SQ: 2, NSQ: 1)). In SQ and NSQ NSCLC, ORR was 15.9% (7/44) and 23.2% (13/56), respectively. Median progression-free survival was 2.6 mo and 5.3 mo, respectively. Complete Response was observed in 2.3% (1/44) and 1.8% (1/56), respectively. Median OS was 12.3 mo and 16.3 mo, respectively. Median follow-up was 8.9 mo and 12.3 mo, respectively. Most common adverse drug reaction (ADR) was decreased appetite 15.9% (7/44), followed by pyrexia 9.1% (4/44) in SQ NSCLC, and decreased appetite 12.5% (7/56), followed by pruritus 10.7% (6/56), fatigue 8.9% (5/56), pyrexia 5.4% (3/56) and nausea 5.4% (3/56) in NSQ NSCLC. Grade 3-4 ADR was observed in 6.8% (3/44) and 10.7% (6/56) of SQ and NSQ NSCLC, respectively. No interstitial lung disease and no grade 5 ADRs were observed in this study. Conclusions: Nivolumab was considered to be effective and used safely in Korean pts with SQ and NSQ NSCLC as well as in non-Korean pts with SQ and NSQ NSCLC. Clinical trial information: NCT02175017.

We previously showed that an increase of cellular Bcl-xL mediates acquired resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and knockdown of Bcl-xL expression greatly sensitized TRAIL-induced cytotoxicity. Here, we show that Daxx downregulation increases the anti-tumorigenic activity through enhancement of viral replication and cellular arrest with combination of TRAIL/shBcl-xL-induced apoptosis. This study was conducted to determine the effect of Daxx downregulation on the anti-tumorigenesis induced by oncolytic adenovirus arming TRAIL or TRAIL/shRNA of Bcl-xL genes. Unlike the enhanced cancer cell death induced by exogenous TRAIL or TRAIL plus shRNA of Bcl-xL, oncolytic adenovirus expressing TRAIL or TRAIL plus shRNA of Bcl-xL did not show much enhanced cancer cell death compared to oncolytic adenovirus itself. On the other hand, enhanced cytotoxic cell death and viral replication was observed after infection with oncolytic adenovirus expressing TRAIL plus shRNA of Bcl-xL and shRNA of Daxx at the same construct. Then we realized that enhanced adenoviral replication through Daxx downregulation was caused by increased adenoviral E1A protein expression and Daxx downregulation also stimulated cellular arrest through p21/p53 accumulation. Taken all together, we have shown here that Daxx downregulation should be essentially needed for the increase of anti-tumor activity through enhancement of viral replication and cellular arrest with the combination of TRAIL/shBcl-xL-induced apoptosis and oncolytic adenovirus.

BackgroundInflammatory breast cancer (IBC) is the most aggressive form of breast cancer, and its molecular pathogenesis still remains to be elucidated. This study aimed to evaluate the prevalence and implication of anaplastic lymphoma kinase (ALK) copy number change in IBC patients.MethodsWe retrospectively collected formalin-fixed, paraffin-embedded tumor tissues and medical records of IBC patients from several institutes in Korea. ALK gene copy number change and rearrangement were assessed by fluorescence in situ hybridization (FISH) assay, and ALK expression status was evaluated by immunohistochemical (IHC) staining.ResultsThirty-six IBC patients including those with HER2 (+) breast cancer (16/36, 44.4%) and triple-negative breast cancer (13/36, 36.1%) were enrolled in this study. ALK copy number gain (CNG) was observed in 47.2% (17/36) of patients, including one patient who harbored ALK gene amplification. ALK CNG (+) patients showed significantly worse overall survival compared to ALK CNG (-) patients in univariate analysis (24.9 months vs. 38.1 months, p = 0.033). Recurrence free survival (RFS) after curative mastectomy was also significantly shorter in ALK CNG (+) patients than in ALK CNG (-) patients (n = 22, 12.7 months vs. 43.3 months, p = 0.016). Multivariate Cox regression analysis with adjustment for HER2 and ER statuses showed significantly poorer RFS for ALK CNG (+) patients (HR 5.63, 95% CI 1.11-28.44, p = 0.037).ConclusionThis study shows a significant presence of ALK CNG in IBC patients, and ALK CNG was associated with significantly poorer RFS.

Objectives Fibroblast growth factor receptor 1 (FGFR1) plays a critical role in many human cancers. We tried to identify the frequency of FGFR1 amplifications among Korean patients with small cell lung cancer (SCLC). Additionally, we examined the clinical significance of FGFR1 amplifications for overall survival (OS) and progression-free survival (PFS) among SCLC patients who received standard chemotherapies. Materials and methods Tumor tissues from 158 Korean patients diagnosed with SCLC from September 2009 to February 2013 were collected and analyzed using an FGFR1 FISH assay with a probe that hybridized to chromosome region 8p12–8p11.23 (Abbott Molecular, Abbott Park, IL). Results and conclusion FGFR1 amplification was detected in three patients (1.9%) harboring extensive disease (ED). A multivariate analysis showed that among the patients with ED, FGFR1 amplification was associated with shorter disease-free survival to first-line chemotherapy with etoposide plus cisplatin or carboplatin (hazard ratio [HR]=7.1; 95% confidence interval [CI]=2.0–25.4; P =0.003). The median overall survival time of the patients with ED was 8.2 and 10.2 months among patients with and without FGFR1 amplification, respectively ( P =0.37). Although FGFR1 amplification is rare in SCLC compared to non-small cell lung cancer or other malignancies with squamous histology, it is associated with poor survival following standard chemotherapy in SCLC. Further studies in large cohorts of patients with SCLC are needed to verify these results. Our results imply that FGFR1 may be a potential therapeutic target in SCLC and it could be confirmed in a clinical trial.

Gemcitabine has been used most commonly as an anticancer drug to treat advanced pancreatic cancer patients. However, intrinsic or acquired resistance of pancreatic cancer to gemcitabine was also developed, which leads to very low five-year survival rates. Here, we investigated whether cellular levels of HSP27 phosphorylation act as a determinant of cellular fate with gemcitabine. In addition we have demonstrated whether HSP27 downregulation effectively could overcome the acquisition of gemcitabine resistance by using transcriptomic analysis. We observed that gemcitabine induced p38/HSP27 phosphorylation and caused acquired resistance. After acquisition of gemcitabine resistance, cancer cells showed higher activity of NF-κB. NF-κB activity, as well as colony formation in gemcitabine-resistant pancreatic cancer cells, was significantly decreased by HSP27 downregulation and subsequent TRAIL treatment, showing that HSP27 was a common network mediator of gemcitabine/TRAIL-induced cell death. After transcriptomic analysis, gene fluctuation after HSP27 downregulation was very similar to that of pancreatic cancer cells susceptible to gemcitabine, and then in opposite position to that of acquired gemcitabine resistance, which makes it possible to downregulate HSP27 to overcome the acquired gemcitabine resistance to function as an overall survival network inhibitor. Most importantly, we demonstrated that the ratio of phosphorylated HSP27 to nonphosphorylated HSP27 rather than the cellular level of HSP27 itself acts biphasically as a determinant of cellular fate in gemcitabine-resistant pancreatic cancer cells.

Purpose Gene-attenuated replication-competent adenoviruses are emerging as a promising new modality for the treatment of cancer. In an effort to continually improve upon cancer gene therapy, we have modified gene- attenuated replication-competent adenoviruses so as to cause them to replicate efficiently and lyse the infected cancer cells more effectively. Materials and methods We modified the E1 region of the adenovirus (Ad) systematically, generating Ad-deltaE1B19, Ad-deltaE1B55, Ad-deltaE1B19/55, and Ad-WT. The cytopathic effects (CPE) and viral replication of these four gene modified adenoviruses were compared, and the morphology and DNA fragmentation of the infected cells was evaluated. Results Among the constructed adenoviruses, E1B 19kD-inactivated adenovirus (Ad-deltaE1B19) was the most potent, inducing the largest-sized plaques and markedCPE. Moreover, cells infected with Ad-deltaE1B19 showed complete cell lysis with disintegrated cellular structure whereas cells infected with Ad-WT maintained intact cellular and nuclear membrane with properly structured organelles. TUNEL assay was also used to monitor DNA integrity, and a more profound induction of apoptosis was observed in the Ad-deltaE1B19 infected cells in comparison to wild type adenovirus infected cells. Conclusion We demonstrate that the inactivation of the E1B19kD gene in a replicating adenovirus leads to increased CPE, rapid viral release, improved cell-to-cell viral spread and increased induction of apoptosis.

Background and purpose : To clarify the clinical benefit derived from the combined modality therapy (CMT) comprised of chemotherapy and involved-field radiotherapy (XRT) for stage I and II angiocentric lymphomas of the head and neck. Material and methods : Of 143 patients with angiocentric lymphoma of the head and neck treated at the Yonsei Cancer Center between 1976 and 1995, 104 patients (XRT group) received involved-field XRT alone with a median dose of 50.4 Gy (range: 20–70 Gy), while 39 patients (CMT group) received a median three cycles (range: 1–6 cycles) of chemotherapy before starting involved-field XRT. The response rate, patterns of failure, complications, and survival data of the XRT group were compared with those of the CMT group. Results : Despite a higher response rate, local failure was the most common pattern of failure in patients of the both groups. The patterns of failure, including the systemic relapse rate were not influenced by the addition of combination chemotherapy. Although both modalities were well tolerated by the majority of patients, aberrant immunologic disorders or medical illnesses, such as a hemophagocytic syndrome, sepsis, intractable hemorrhage, or the evolution of second primary malignancies were more frequently observed in patients of the CMT group. The prognosis of patients in the XRT group was relatively poor, with a 5-year overall actuarial survival rate of 38% and disease-free survival rate of 32%, respectively. However, their clinical outcome was not altered by the addition of systemic chemotherapy. Achieving complete remission was the most important prognostic factor on univariate and multivariate analyses, but treatment modality was not found to be a prognostic variable influencing survival. Conclusions : Involved-field XRT alone for angiocentric lymphoma of the head and neck was insufficient to achieve an improved survival rate, but the combination of chemotherapy and involved-field XRT failed to demonstrate any therapeutic advantage over involved-field XRT alone.

Cisplatin-based chemotherapy is being tried in the treatment of nonoperable cases of non-small-cell lung cancer (NSCLC). However, the prognosis is unfavorable and to improve survival, clinical studies using various combinations of a variety of drugs as well as experimental material are in progress. We compared the efficacy and toxicities of combination chemotherapy using different doses of vinorelbine and ifosfamide with a constant dose of cisplatin in this study. Patients diagnosed with inoperable stage III or IV NSCLC between June 1997 and December 1998 were included. Cisplatin was administered at a constant dose of 80 mg/m 2 on day 5, whereas vinorelbine on days 1 and 5 and ifosfamide on day 5 were administered in one of two different doses. In arm A, vinorelbine 25 mg/m 2 and ifosfamide 3.0 g/m 2 were administered. In arm B, vinorelbine 20 mg/m 2 and ifosfamide 2.5 g/m 2 were administered. Also, we reviewed for phase II and III studies that test 1) cisplatin, 2) vinorelbine monotherapy, and 3) vinorelbine/cisplatin/ifosfamide combination chemotherapy for stage IIIb-IV non-SCLC. Summation dose intensity (SDI) was calculated in each published and current study. Twenty patients in arm A and 35 patients in arm B were available for evaluation. There was no difference in patient activity, pathologic diagnosis, and differentiation or stage between the two arms. The median number of cycles was four in both arms. The response rate was 50% in arm A and 30% in arm B. The median survival times for arm A and B were 40 and 42 weeks, respectively, whereas the SDI was 1.94 and 1.7, respectively. More than grade III leukopenia was observed in 28.9% in arm A, which is more frequent than the 17.2% in arm B. There was a significant correlation between the SDIs and response rates and median survival (r 2 = 0.629, p = 0.001; r2 = 0.453, p = 0.001, respectively). Although the follow-up period is relatively short, the survival time was similar in both arms. Because a high response rate may not be followed by a high survival time in combination chemotherapy of NSCLC, further studies on the appropriate dose of individual agents with regard to the relationship between response rate, severity, and incidence of toxicities and survival rate should be carried out.

OBJECTIVE In this study, we investigated the feasibility of a double-suicide gene/prodrug therapy, involving direct introduction of the herpes simplex virus Type 1 thymidine kinase (TK) gene and the Escherichia coli cytosine deaminase (CD) gene, via a recombinant adenoviral vector, and ganciclovir (GCV) and/or 5-fluorocytosine (5-FC) treatment, in a rat C6 glioma model. METHODS Efficient gene transfer and transduction of C6 glioma cells via a recombinant adenovirus were evaluated by infecting cells with adenovirus bearing the beta-galactosidase gene and then staining cells with X-5-bromo-4-chloro-3-indolyl-13-D-galactoside. CD/TK expression in cells infected with adenovirus bearing the CD/TK gene (ad-CD/TK) was examined by immunoblotting analysis. For in vitro cytotoxicity experiments, the cells were infected with ad-CD/TK or ad-deltaE1 (as a control). After the addition of a variety of concentrations of GCV and 5-FC, either separately or in combination, cell viability was determined by staining the cells with crystal violet solution 6 days after infection. For in vivo antitumor experiments, 1x10(5) cells were stereotactically injected into the right caudate-putamen of female Wistar rat brains. At 3 days after implantation, 1x10(8) plaque-forming units of ad-CD/TK or ad-deltaE1 (as a control) were stereotactically injected into the tumors and GCV (25 mg/kg) and 5-FC (250 mg/kg), alone or in combination, were intraperitoneally administered. Animals were then killed, and tumor volumes were measured by determining the tumor area in every fifth section, using a light microscope. RESULTS C6 glioma cells were efficiently transduced with recombinant adenoviral vector at multiplicities of infection of 200 or more. In vitro cytotoxicity of GCV and/or 5-FC, either alone or in combination, was exclusively observed in the cells transduced with ad-CD/TK. Obvious cytotoxicity (>50% inhibition) was observed in the presence of 5-FC at concentrations greater than 30 microg/ml or GCV at concentrations greater than 0.3 microg/ml at a multiplicity of infection of 100. Additionally, cytotoxicity in the presence of both GCV and 5-FC was greater than that after single-prodrug treatments, indicating additive effects of the prodrug treatments. In in vivo experiments, the tumor volumes of the rats treated with GCV or 5-FC alone after ad-CD/TK injection (59.1+/-4.6 and 57.4+/-7.1 mm3, respectively) were significantly smaller than that of the control rats (157+/-8.9 mm3, P

YKL-1, E1B 55 kDa-deleted recombinant adenovirus vector, capable of harboring a transgene casette of up to 4.9 kb, was newly constructed by reintroducing E1A and E1B 19 kDa into E1/E3-deleted adenoviral vector with a homologous recombination in E. coli. Virus replication and cytotoxicity were dramatically attenuated in all 3 different types of normal human cells. In contrast, YKL-1 efficiently replicated and induced cytotoxicity in most cancer cells, especially Hep3B and C33A cells with an inactivating p53 mutation. However, both H460 and HepG2 exhibited intermediate sensitivity to YKL-1, which was between that of Hep3B or C33A and normal human cells. The YKL-1 and DNA damaging agent, camptothecin effectively induced p53 in H460 and HepG2 as well as in normal cells. Furthermore, YKL-1 effectively prohibited both Hep3B and C33A tumor growth in nu/nu mice in a dose-dependent manner. H/E staining and TUNEL assay indicated a largely distributed necrotic area and apoptosis on its periphery. This study, therefore, indicates that YKL-1, possesses promising potential as an oncolytic adenoviral vector, which acts partially in a p53-dependent manner. Int. J. Cancer 88:454–463, 2000. © 2000 Wiley-Liss, Inc.

Background Ramucirumab is a human IgG1 monoclonal antibody that targets the extracellular domain of VEGFR-2. We aimed to assess efficacy and safety of treatment with docetaxel plus ramucirumab or placebo as second-line treatment for patients with stage IV non-small-cell-lung cancer (NSCLC) after platinum-based therapy. Methods In this multicentre, double-blind, randomised phase 3 trial (REVEL), we enrolled patients with squamous or non-squamous NSCLC who had progressed during or after a first-line platinum-based chemotherapy regimen. Patients were randomly allocated (1:1) with a centralised, interactive voice-response system (stratified by sex, region, performance status, and previous maintenance therapy [yes vs no]) to receive docetaxel 75 mg/m 2 and either ramucirumab (10 mg/kg) or placebo on day 1 of a 21 day cycle until disease progression, unacceptable toxicity, withdrawal, or death. The primary endpoint was overall survival in all patients allocated to treatment. We assessed adverse events according to treatment received. This study is registered with ClinicalTrials.gov, number NCT01168973. Findings Between Dec 3, 2010, and Jan 24, 2013, we screened 1825 patients, of whom 1253 patients were randomly allocated to treatment. Median overall survival was 10·5 months (IQR 5·1-21·2) for 628 patients allocated ramucirumab plus docetaxel and 9·1 months (4·2-18·0) for 625 patients who received placebo plus docetaxel (hazard ratio 0·86, 95% CI 0·75-0·98; p=0·023). Median progression-free survival was 4·5 months (IQR 2·3-8·3) for the ramucirumab group compared with 3·0 months (1·4-6·9) for the control group (0·76, 0·68-0·86; p

We conducted a prospective, randomized, open, single-center, parallel group study comparing the anti-emetic efficacy and toxicity of granisetron with that of ondansetron in patients receiving moderately emetogenic chemotherapy. From December 1994 to May 1995, patients who were to receive moderately emetogenic chemotherapy for the first time or who had not received chemotherapy (80 to 100 mg/m2 of cisplatin or 40 mg/m2 of doxorubicin) within 4 weeks previously were enrolled in this study. The following anti-emetic regimens were used: 3 mg of granisetron were given intravenously before chemotherapy for a single dose; 8 mg of ondansetron were given intravenously before chemotherapy and then every 8 hours for a total of 3 doses, plus 8 mg of an oral maintenance dose every 12 hours for 5 consecutive days. We evaluated 97 patients (48 received granisetron and 49 received ondansetron). In the first 24 hours after chemotherapy, complete and major responses were achieved in 76.6% of the patients receiving granisetron and in 72.9% of patients receiving ondansetron (p = 0.9033). Additionally, there was no difference in the control of delayed nausea and vomiting between the two groups (51.1% versus 54.2%, p = 0.9200), and there were no significant adverse effects or toxicities. We have concluded that a single dose of granisetron is as effective in prophylaxis of emesis induced by moderately emetogenic chemotherapy as a triple dose of ondansetron plus oral maintenance.

We studied biological phenotypes of gastric cancer cell lines based on a novel heparin-binding growth/differentiation factor (midkine (MK)) expression. MK expression was found in 67% (6/9) of the gastric cancer cell lines and 56% (14/25) of the primary cancer tissues. Gastric cancer cell lines with MK expression showed higher colony forming activity in soft agar assay and endothelial cell growth stimulatory effect in cross-feeding assay than cells which did not express MK. However, urokinase-type plasminogen activator (uPA) expression and tumor invasiveness did not correlate with MK expression. Growth of MK expressing cells was inhibited by a heparin-binding blocking agent, pentosan polysulfate (PPS). In cancer tissues, MK expression correlated with tumor size, suggesting in vivo autocrine and paracrine activity. This proliferation promoting activity of MK can be targeted by an anti-heparin binding agent as a biotherapy model in gastric cancer.

BACKGROUND Mutations at codons 12, 13, and 61 of the three ras genes, H-ras, K-ras, and N-ras, convert these genes into active oncogenes. It appears that ras gene mutations can be found in a variety of tumor types. The purpose of this study was to evaluate the clinical significance of K-ras gene mutation in nonsmall cell lung carcinoma (NSCLC). METHODS The authors analyzed 58 NSCLC patients for mutations at codons 12, 13, and 61 of the K-ras gene and correlated the findings with the tumor stage and patient survival. Polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and the direct nucleotide sequencing method were used to detect mutations after amplification of ras specific sequences by PCR. RESULTS Fourteen mutations (24%) of ras genes were found, all at codon 12 of the K-ras gene. GGT to GAT transition was the predominant mutational pattern. There was a significant association between K-ras mutation and the tumor stage (i.e., the higher the stage, the higher the mutation rate) (P = 0.014). Using univariate analysis, the presence of K-ras mutation in paraffin embedded tissue from patients who received treatment with curative intent was associated with a shorter survival (P = 0.039). The median survival duration for patients with or without K-ras mutation was 9 and 30 months, respectively. The Cox proportional hazards model also predicted a higher risk for patients with K-ras mutations (P = 0.047). CONCLUSIONS K-ras mutations, present in a subset of NSCLC, are associated with tumor progression and shortened patient survival. Cancer 1997; 79:462-7. © 1997 American Cancer Society.

The relationship between p53 overexpression and clinicopathologic variables in gastric cancer was evaluated using 304 paraffin-embedded gastric tumor tissues. DO7, a murine monoclonal antiserum to p53 protein, was used for the immunohistochemical analysis. Positive staining was found in 129 tumors (42.2% of all tumors). Overexpression of p53 was not associated with sex, location of the tumor in the stomach or the type of Borrman's tumor. The overexpression rate of p53 protein was 30.4% (28/92) in stage II and 47.6% (101/212) in stage III (p = 0.007). While there was no significant association between p53 protein accumulation and T stage, there was a significant association with N stage, i.e. p53 overexpression was 27.4% (17/62) in the node-negative group and 46.3% (112/242) in the node-positive group (p = 0.011). In 79 patients, in whom corresponding primary gastric tumor and regional lymph node metastases were available, overexpression was found in 34 (43%) primary tumors and in 38 (48.1%) node samples, with a concordance rate of 67.1% in terms of p53 expression. Mean numbers of regional lymph node involvement by the tumor were 6.1 in the group with p53 overexpression and 5.2 in the group showing no immunoreactivity (p = 0.051). These findings suggest that p53 overexpression is related to gastric cancer progression and that immunoreactivity in the metastatic lymph nodes show the dependency on p53 expression in the primary tumor.

Epidermal growth factor receptor (EGFR) T790M mutation drives acquired drug resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in patients with EGFR-mutant lung cancer. However, it was reported that this mutation may exist before drug exposure. The objective of the current study was to evaluate whether the clinical outcomes are affected by the percentage of preexisting T790M mutations within a tumor.Pretreatment tissues were collected from 124 patients with advanced non-small cell lung cancer with sensitizing EGFR mutations that were detected by direct sequencing. Genotyping for EGFR T790M mutation was further performed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Patients who were positive for the T790M mutation were divided to 2 subgroups according to T790M mutant signal frequency.The T790M mutation was found in 31 patients (25.0%). The T790M mutation frequency at which the risk of disease progression after therapy with EGFR-TKIs begins to increase was estimated to be 3.2%. The patients with T790M-positive tumors had a shorter time to disease progression after treatment with EGFR-TKIs (median, 6.3 months vs 11.5 months; P.001) and overall survival (median, 16.1 months vs 26.5 months; P = .065) compared with those with T790M-negative tumors. Among the T790M-positive patients, the patients with high T790M frequency (9 patients) were found to have a shorter time to disease progression (median, 2.4 months vs 6.7 months; P = .009) and overall survival (median, 9.1 months vs 18.7 months; P = .018) compared with those with low T790M frequency (22 patients).A preexisting EGFR T790M mutation was noted in 25% of patients with EGFR-mutant lung cancer. Patients with a high T790M mutation frequency had worse clinical outcomes to EGFR-TKIs than patients with a low T790M mutation frequency.

Background This phase II study investigated the efficacy and safety of everolimus, an inhibitor of mammalian target of rapamycin (mTOR), in locally advanced or metastatic thyroid cancer. Patients and methods Patients with thyroid cancer of any histology that was resistant or not appropriate for 131I received everolimus 10 mg daily orally until unacceptable toxicity or disease progression. The primary end point was disease control rate [partial response (PR) + stable response ≥12 weeks]. Secondary end points included response rates, clinical benefit (PD + durable stable disease (SD)], progression-free survival (PFS), overall survival, duration of response, and safety. Results Thirty-eight of 40 enrolled patients were evaluable for efficacy. The disease control rate was 81% and two (5%) patients achieved objective response; their duration of response was 21+ and 24+ weeks. Stable disease (SD) and progressive disease was reported in 76% and 17% of patients, respectively. Seventeen (45%) patients showed durable SD (≥24 weeks) and clinical benefit was reported in 19 (50%) patients. Median PFS was 47 weeks [95% confidence interval (CI) 14.9–78.5]. Calcitonin, CEA, and thyroglobulin concentrations were ≥50% lower than baseline in three (30%) and four (44%) patients with medullary thyroid cancer and five (33%) patients with PTC, respectively. The most common treatment-related adverse events were mucositis (84%), anorexia (44%), and aspartate transaminase/alanine transaminase elevation (26%). Conclusions Everolimus had a limited activity with low response rate in locally advanced or metastatic thyroid cancer. Reasonable clinical benefit rate and safety profile may warrant further investigation. ClinicalTrials.gov number NCT01164176.

S-1 is a novel oral fluoropyrimidine anticancer agent designed to enhance clinical efficacy, reduce gastrointestinal toxicity, and enhance radiotherapy effectiveness. A phase II trial was conducted to evaluate the efficacy and safety of preoperative chemoradiation with S-1 and cisplatin in locoregionally advanced esophageal cancer.Eligible patients had stage IIA-IVA esophageal cancer. Patients received two cycles of S-1 (days 1-14 and days 22-35) and cisplatin (days 1 and 22) with concurrent radiotherapy (50.4 Gy total; 1.8 Gy/fraction). Esophagectomy was performed between weeks 12 and 18 as determined by the specialist multidisciplinary team.Sixty patients were enrolled in this study between March 2008 and August 2011, and 59 were eligible. The clinical stage was ≥T3 in 28 patients (47 %) and N1 in 43 patients (72 %), with squamous cell carcinoma histology in 58 patients (97 %). Fifty-four patients (90 %) completed the planned chemoradiation. After chemoradiation, the clinical tumor response rate was 64.4 %. The primary toxicities included neutropenia (24 %) and esophagitis (8.5 %). Three treatment-related deaths were noted. Twenty-five patients (42 %) underwent esophagectomy following chemoradiation, and 15 achieved complete pathologic regression. The estimated overall survival and progression-free survival rates after 2 years were 65 and 48 %, respectively.Concurrent chemoradiation with S-1 and cisplatin exhibited encouraging results with complete pathologic regression. The survival data were promising compared with the historical data of 5FU/cisplatin and should be confirmed in a randomized phase III trial. Toxicities were significant but clinically manageable.

Purpose Maintenance therapy is associated with improved survival in patients with non–small-cell lung cancer (NSCLC), but few studies have compared active agents in this setting. AVAPERL evaluated the safety and efficacy of bevacizumab with or without pemetrexed as continuation maintenance treatment. Patients and Methods Patients with advanced nonsquamous NSCLC received first-line bevacizumab 7.5 mg/kg, cisplatin 75 mg/m2, and pemetrexed 500 mg/m2 once every 3 weeks for four cycles. Those achieving response or stable disease were randomly assigned at a ratio of 1:1 to maintenance bevacizumab 7.5 mg/kg or bevacizumab 7.5 mg/kg plus pemetrexed 500 mg/m2 once every 3 weeks until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS) after random assignment. Results In total, 376 patients received induction treatment, 71.9% achieved disease control, and 67.3% were randomly assigned to maintenance therapy, with 125 and 128 receiving single-agent bevacizumab and bevacizumab plus pemetrexed treatment, respectively. At a median follow-up of 8.1 months, PFS from random assignment was significantly improved in the bevacizumab plus pemetrexed arm (median, 3.7 v 7.4 months; hazard ratio, 0.48; 95% CI, 0.35 to 0.66; P < .001) per a stratified model. The PFS benefit extended across age, performance status, smoking history, and induction response (stable disease v partial response) subgroups. Any grade, grade ≥ 3, and serious adverse events occurred more often with bevacizumab plus pemetrexed maintenance. No new safety signals were observed. Conclusion In an unselected population of patients with nonsquamous NSCLC who had achieved disease control with platinum-based chemotherapy plus bevacizumab, bevacizumab plus pemetrexed maintenance was associated with a significant PFS benefit compared with bevacizumab alone. The combination was well tolerated.

The secondary EGF receptor (EGFR) T790M is the most common mechanism of resistance to reversible EGFR-tyrosine kinase inhibitors (TKI) in patients with non–small cell lung cancer (NSCLC) with activating EGFR mutations. Although afatinib (BIBW2992), a second-generation irreversible EGFR-TKI, was expected to overcome the acquired resistance, it showed limited efficacy in a recent phase III clinical study. In this study, we found that the inhibition of glycolysis using 2-deoxy-d-glucose (2DG) improves the efficacy of afatinib in H1975 and PC9-GR NSCLC cells with EGFR T790M. Treatment with the combination of 2DG and afatinib induced intracellular ATP depletion in both H1975 and PC9-GR cells, resulting in activation of AMP-activated protein kinase (AMPK). AMPK activation played a central role in the cytotoxicity of the combined treatment with 2DG and afatinib through the inhibition of mTOR. The alteration of the AMPK/mTOR signaling pathway by the inhibition of glucose metabolism induced specific downregulation of Mcl-1, a member of the antiapoptotic Bcl-2 family, through translational control. The enhancement of afatinib sensitivity by 2DG was confirmed in the in vivo PC9-GR xenograft model. In conclusion, this study examined whether the inhibition of glucose metabolism using 2DG enhances sensitivity to afatinib in NSCLC cells with EGFR T790M through the regulation of the AMPK/mTOR/Mcl-1 signaling pathway. These data suggest that the combined use of an inhibitor of glucose metabolism and afatinib is a potential therapeutic strategy for the treatment of patients with acquired resistance to reversible EGFR-TKIs due to secondary EGFR T790M. Mol Cancer Ther; 12(10); 2145–56. ©2013 AACR.

PURPOSE:The main objective of this study was to evaluate the association between polymorphisms of the target genes of pemetrexed and clinical outcomes in non-small cell lung cancer (NSCLC) patients treated with pemetrexed. MATERIALS AND METHODS:We assessed polymorphisms at 8 sites in 4 genes [thymidylate synthase (TS), dihydrofolate reductase (DHFR; 1610, 680, 317, intron 1), methylenetetrahydrofolate reductase (MTHFR; 677, 1298), glycinamide ribonucleotide formyl transferase (GARFT; 2255)] associated with pemetrexed metabolism using polymerase chain reaction, gene scanning, and restriction fragment length polymorphism analysis in 90 patients with adenocarcinoma of the lung. RESULTS:Survival was significantly longer with pemetrexed in patients with TS 3RGCC/3RGCC or 3RGGC/3RGGC compared with the other groups (PFS; 5.2 months vs. 3.7 months, p=0.03: OS; 31.8 months vs. 18.5 months, p=0.001). Patients with DHFR 680CC experienced fatigue more frequently (50% vs. 8.6%, p=0.008). Polymorphisms of MTHFR and GARFT were not significantly associated with clinical outcomes of pemetrexed. CONCLUSION:The TS genotype was associated with survival and one DHFR polymorphism was associated with fatigue in NSCLC patients treated with pemetrexed. Further large prospective studies are required to identify other biomarkers that affect patients being treated with pemetrexed for adenocarcinoma of the lung.

The proteolytic processes are thought to be the critical point in tumor invasion and metastasis, mainly by matrix metalloproteinases (MMPs) and serine proteases. We measured the activity of MMP-2 from 28 normal, 12 benign and 126 breast cancer tissues using gelatin zymography. Inactive MMP-2 (72 kD) was expressed in 53.6% of the normal and 66.6% of the cancer tissues, respectively (P = 0.77), while active MMP-2 (62 kD) was expressed in 28.6% and 73.0%, respectively (P = 0.003). The enzymatic activity of active MMP-2 (62 kD) measured in the gel band area was 4.0 +/- 7.2 mm2 in normal breasts, 7.7 +/- 9.8 mm2 in benign breast diseases, 9.5 +/- 8.5 mm2 in ductal carcinoma in situ (DCIS), and 12.0 +/- 13.7 mm2 in invasive cancers. The MMP-2 activation ratio (62 kD/62 kD + 72 kD) was 0.12 +/- 0.18 in normal tissues, 0.10 +/- 0.20 in benign diseases, 0.61 +/- 0.22 in DCIS, and 0.50 +/- 0.28 in invasive cancers. In conclusion, MMP-2 activation was the main cause of the increased 62 kD MMP-2 activity during the early phase of breast cancer, while production of MMP-2 supplemented the increased 62 kD activity in the late phase. We suggest, therefore, that these differential expressions of MMP-2 activation and production during the different stages of breast cancer progression are potential therapeutic targets for biological or gene therapy under the concept of stage-oriented cancer treatment.

Although several studies demonstrated the poor prognosis of young patients with gastric cancer, there were few reports about the survival of young patients who underwent radical surgery. We retrospectively reviewed the hospital records of 697 patients with curatively resected locally advanced gastric cancer to compare the pathologic findings and prognosis of young patients (aged

An immunohistochemical stain to the c-ErbB-2 protein was performed in 225 paraffin-embedded tissue blocks from patients with locally advanced gastric cancer who underwent curative resection. The overexpression of the c-ErbB-2 protein was observed in 27.4% of the patients. The c-ErbB-2 positivity showed a statistically significant correlation with nodal status and stage. The patients with an overexpression of the c-ErbB-2 protein had a tendency to a shorter survival than those without, but it was not statistically significant (p = 0.08). The 5-year survival rate after surgery was 54% in the negative staining group to the c-ErbB-2 protein and 49% in the positive staining group. This suggests that the c-ErbB-2 protein has a possible role in lymph node metastasis. Therefore overexpression of the c-ErbB-2 protein is a useful indicator of disease progression in gastric carcinoma patients who received curative surgery.

Tumor cells secrete a variety of cytokines to outgrow and evade host immune surveillance. In this context, transforming growth factor-β1 (TGF-β1) is an extremely interesting cytokine because it has biphasic effects in cancer cells and normal cells. TGF-β1 acts as a growth inhibitor in normal cells, whereas it promotes tumor growth and progression in tumor cells. Overexpression of TGF-β1 in tumor cells also provides additional oncogenic activities by circumventing the host immune surveillance. Therefore, this study ultimately aimed to test the hypothesis that suppression of TGF-β1 in tumor cells by RNA interference can have antitumorigenic effects. However, we demonstrated here that the interrelation between TGF-β isotypes should be carefully considered for the antitumor effect in addition to the selection of target sequences with highest efficacy. The target sequences were proven to be highly specific and effective for suppressing both TGF-β1 mRNA and protein expression in cells after infection with an adenovirus expressing TGF-β1 short hairpin RNA (shRNA). A single base pair change in the shRNA sequence completely abrogated the suppressive effect on TGF-β1. Surprisingly, the suppression of TGF-β1 induced TGF-β3 upregulation, and the suppression of TGF-β2 induced another unexpected downregulation of both TGF-β1 and TGF-β3. Taken together, this information may prove useful when considering the design for a novel cancer immunogene therapy.

3030Background: In KEYNOTE-010 (NCT01905657), pembro was superior to doce for OS in patients (pts) with PD-L1–positive advanced NSCLC that progressed after ≥2 platinum-doublet chemotherapy cycles (...

9024Background: KEYNOTE-010 (NCT01905657) showed that the anti–PD-1 antibody pembrolizumab (pembro; MK-3475) at doses of 2 and 10 mg/kg Q3W provided superior OS over docetaxel in patients (pts) wit...

9055Background: T790M mediates acquired resistance to 1st/2nd generation EGFR-TKIs. BI 1482694 is a 3rd generation TKI active against mutant EGFR, including T790M. This Phase I/II trial is evaluati...

9015Background: In the phase III KEYNOTE-010 study (NCT01905657), pembrolizumab (pembro; MK-3475) provided superior OS over docetaxel (doce) in patients (pts) with previously treated, PD-L1–positiv...

Several reports have demonstrated an adverse effect of perioperative blood transfusions on the survival of patients with various solid tumors treated surgically. We retrospectively investigated the relationship between perioperative blood transfusions and the survival of 501 patients who underwent radical subtotal gastrectomy for locally advanced gastric cancer (stage II-IIIB) from January 1984 to December 1989. Three hundred and fifty-two patients (70.3%) received blood transfusions within the perioperative period. The transfused group included patients with tumors of larger size (5.1 vs. 4.4 cm, p = 0.001) and more advanced stage (stage IIIB: 27.6 vs. 10.7%, p = 0.0001) than the nontransfused group. Although the 5-year overall survival rate was significantly lower (52.9 vs. 66.7%, p = 0.026) in the transfused patients than the nontransfused, subgroup analysis according to the pathologic stage showed no statistically significant difference in survival in each stage between the two groups. In conclusion, we could not find any causal relationships between transfusion and prognosis in patients with curatively resected locally advanced gastric cancer. Circumstances such as advanced stage necessitating transfusions may be more important prognostic factors.

The aim of this study was to investigate the efficacy and safety of belotecan in combination with cisplatin in patients with previously non-treated extensive stage small cell lung cancer. A total of 42 patients were enrolled and treated with combination of belotecan 0.5mg/m2 on daily basis throughout day 1-4 and cisplatin 60 mg/m2 on day 1 of a 3-week cycle, up to 6 cycles. Treatment was continued until the completion of 6 cycles of the chemotherapy, disease progression, detection of unacceptable toxicity, withdrawal of the consent, or death of the patient. Response was assessed every 2 cycles of chemotherapy by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0. Toxicity was assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 3.0. The overall response rate was 73.8% in an intention to treat population and 83.9% in the evaluable patients. With the median follow up of 9.9 months, the median progression free survival was 6.9 months (95% CI, 6.6-7.2 months), and median overall survival was 11.2 months (95% CI, 9.9-12.5 months). The frequently reported grade ≥3 toxicities were neutropenia (90.2%), thrombocytopenia (63.4%), and anemia (34.1%). Febrile neutropenia was reported in 16 patients (39.0%). Although most of non-hematologic toxicities were grade 1 or 2, there were 4 patient deaths caused by pneumonia complicated by septic shock. Belotecan and cisplatin combination chemotherapy demonstrated a promising efficacy in ED SCLC patients. But, the hematologic toxicity of this regimen requires considerable amount of attention.

Through this study, we aimed to validate several biomarkers that have been known to possibly predict the outcomes of the trastuzumab and paclitaxel (TP). Human epidermal growth factor 2 (HER2) positive metastatic breast cancer (MBC) patients who had been treated with TP in single institute from 2006 to 2009 were included in this study. For procured formalin fixed paraffin embedded tumor tissues, HER2 amplification index (AI) and polymorphisms of the immunoglobulin G fragment C receptors (FCGR) were assessed as biomarkers to the trastuzumab and expression of class III beta tubulin (bTubIII) was evaluated as a predictive factor to the paclitaxel. Of 46 patients treated with TP, 27 patients could be evaluated for HER2 AI, 31 for bTubIII, and 26 for FCGR gene polymorphism. The median of the HER2 AI was 5.0 (range, 1.4−15.5) and a higher HER2 AI (≥5.0) was significantly correlated with better response rate (RR) (80% vs. 42%, P = 0.049) and longer progression-free survival (PFS) (13.6 vs. 6.9 months, P = 0.023). High bTubIII expression showed higher RRs than did low expression (81% vs. 40%, P = 0.040) in addition to longer PFS (16.2 months vs. 8.8 months, P = 0.04). However, polymorphisms in FCGR 2A-H131R or FCGR 3A-V158F were not predictive of RR or PFS. Our results suggest that a high HER2 AI and high bTubIII expression could be predictive of the outcomes to TP therapy but no evidence was found in terms of FCGR polymorphisms.

Background Cytological fluid from a needle aspiration biopsy (NAB) is obtained directly from tumor tissue, therefore many biomarker candidates will be present in high concentrations. The aim of this study was to prospectively assess and validate the tumor markers CYFRA 21–1, CEA, and SCC in cytological fluid obtained from NAB samples to determine if they improved the performance of NAB for diagnosing non-small cell lung cancer (NSCLC). Methods A total of 194 patients (M:F = 128:66, mean age 63.7 years) with suspected malignant pulmonary lesions were prospectively enrolled and underwent percutaneous NAB. Levels of CYFRA 21–1, CEA, and SCC were measured by immunoassay in serum and cytological fluid obtained during aspiration biopsy. Cut-off values to determined malignancy were 3.3 ng/mL in serum and 15.7 ng/mL in cytological fluid for CYFRA 21–1, 5 ng/mL and 0.6 ng/mL for CEA, and 2 ng/mL and 0.86 ng/mL for SCC. Results Of 194 patients, 139 patients (71.6%) had NSCLC and 55 (28.4%) had benign lesions. Sensitivity increased significantly for NAB combined with cytological tumor markers compared with NAB alone (CYFRA 21–1: 95% versus 83.5%, p < 0.001, CEA: 92.1% versus 83.5%, p = 0.002, SCC: 91.4% versus 83.5%, p = 0.003). Accuracy improved significantly for NAB combined with cytological CYFRA 21–1 compared with NAB alone (95.9% versus 88.1%, p < 0.001). The area under curve (AUC) of NAB with cytological CYFRA 21–1 was significantly larger than for NAB alone (0.966 versus 0.917, p = 0.009). Conclusion Of the tested tumor markers, cytological fluid measurements of CYFRA 21–1 improved the diagnostic performance of NAB for NSCLC.

The secondary T790M mutation in epidermal growth factor receptor (EGFR) is the major mechanism of acquired resistance to EGFR tyrosine kinase inhibitors (TKI) in non–small cell lung cancer (NSCLC). Although irreversible EGFR TKIs, such as afatinib or dacomitinib, have been introduced to overcome the acquired resistance, they showed a limited efficacy in NSCLC with T790M. Herein, we identified the novel de novo resistance mechanism to irreversible EGFR TKIs in H1975 and PC9-GR cells, which are NSCLC cells with EGFR T790M. Afatinib activated interleukin-6 receptor (IL-6R)/JAK1/STAT3 signaling via autocrine IL-6 secretion in both cells. Inhibition of IL-6R/JAK1/STAT3 signaling pathway increased the sensitivity to afatinib. Cancer cells showed stronger STAT3 activation and enhanced resistance to afatinib in the presence of MRC5 lung fibroblasts. Blockade of IL-6R/JAK1 significantly increased the sensitivity to afatinib through inhibition of afatinib-induced STAT3 activation augmented by the interaction with fibroblasts, suggesting a critical role of paracrine IL-6R/JAK1/STAT3 loop between fibroblasts and cancer cells in the development of drug resistance. The enhancement of afatinib sensitivity by inhibition of IL-6R/JAK1/STAT3 signaling was confirmed in in vivo PC9-GR xenograft model. Similar to afatinib, de novo resistance to dacomitinib in H1975 and PC9-GR cells was also mediated by dacomitinib-induced JAK1/STAT3 activation. Taken together, these findings suggest that IL-6R/JAK1/STAT3 signaling can be a potential therapeutic target to enhance the efficacy of irreversible EGFR TKIs in patients with EGFR T790M. Mol Cancer Ther; 11(10); 2254–64. ©2012 AACR.

We evaluated the anti-tumor activity and safety of cisplatin with irinotecan (IP) induction chemotherapy followed by chemoradiotherapy with etoposide/cisplatin (EP).Induction chemotherapy consisted of irinotecan i.v. and cisplatin i.v. and was administered on day 1 and day 8 of each cycle. Patients underwent two cycles of chemotherapy with a 3-week interval. In the absence of progressive disease, 66 Gy radiation was administered concurrently with etoposide on days 1 to 5 and 29 to 33, as well as with cisplatin on day 1, 8, 29, and 36.Twenty patients were enrolled between July 2007 and December 2009. This study was closed prematurely due to lack of efficacy in induction chemotherapy. The overall response rate was 45% [95% confidence interval (CI), 25 to 65%], which did not meet the upper limit for first stage rejection of the treatment. The rates of 3-year progression-free survival and overall survival were 17.1% (95% CI, 0 to 36.8%) and 25% (95% CI, 0.2 to 49.8%), respectively. The primary toxicities included neutropenia, diarrhea and fatigue.This study failed to demonstrate a benefit for induction chemotherapy which was characterized by suboptimal antitumor activity and was poorly tolerated, with excess treatment-related toxicity.

Previously, we showed that mitogen-activated protein kinase/extracellular signal-related kinase 4 (MEKK4) is responsible for p38 activation and that its activation during tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) treatment also increases the catalytic activity of Akt. Here, we further investigated how the TRAIL-induced MEKK4/p38/heat shock protein (HSP27)/Akt survival network is modulated by the Src/c-Cbl interacting protein of 85kDa (CIN85)/c-Cbl complex. TRAIL-induced activation of Akt catalytic activity and phosphorylation were highly correlated with p38/HSP27 phosphorylation, whereas the phosphorylation of p38/HSP27 increased further during incubation with curcumin and TRAIL, which caused significant apoptotic cell death. CIN85, a c-Cbl-binding protein, plays an essential role in connecting cell survival to cell death. The interaction of CIN85 with MEKK4 was increased during the late phase of TRAIL incubation, suggesting that sustained p38 and HSP27 phosphorylation protects cells by preventing further cell death. However, further increases in p38/HSP27 phosphorylation induced by cotreatment with curcumin and TRAIL converted cell fate to death. Taken together, these data demonstrate that phosphorylated p38/HSP27 as biphasic modulators act in conjunction with CIN85 to determine whether cells survive or die in response to apoptotic stress.

Background Nimotuzumab (TheraCIM ® ) is a humanized anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) with minimal skin toxicity. Combining a different class of anti-EGFR drug with gefitinib is a new strategy to overcome intrinsic and acquired resistance to gefitinib. The aim of this phase I trial was to determine recommended phase II dose (RPIID) and the safety of gefitinib and nimotuzumab combination treatment. Methods Patients with advanced/metastatic NSCLC were treated with escalating doses of weekly nimotuzumab (100mg or 200mg, IV) and fixed doses of daily gefitinib (250mg/day, PO) until disease progression or unacceptable toxicity. We planned to enroll 10 additional patients at RPIID to ascertain the safety of treatment. EGFR mutations and KRAS mutations were analyzed from available tumor samples. Results A total of 16 patients were enrolled (3 in 100mg cohort, 13 in 200mg cohort). Six patients (37.5%) were female, and 5 (31.3%) were never smokers. Adenocarcinoma was the major histologic type (13 patients, 81.3%). Treatment was well-tolerated without dose-limiting toxicity (DLT). Four patients (25.0%) experienced grade 2 skin toxicity (1 in 100mg cohorts, 3 in 200mg cohort). Other common grade 1/2 toxicities were fatigue (37.5%) and diarrhea (25.0%). Among 16 evaluable patients, four patients (25.0%) achieved partial response and 7 patients (43.8%) had stable disease. Two of 4 responders had EGFR mutation (exon 19 deletion). Conclusions Dual agent molecular targeting of EGFR with nimotuzumab and gefitinib in patients with advanced NSCLC is well-tolerated. The RPIID for nimotuzumab is 200mg weekly IV and for gefitinib 250mg/day PO. Based upon this phase I trial, we are planning to conduct a randomized phase II trial comparing gefitinib and nimotuzumab with gefitinib alone in patients with advanced NSCLC.

Purpose The aim of this study was to prospectively assess whether analysis of the tumor markers cytokeratin 19 fragments (CYFRA 21-1), carcinoembryonic antigen (CEA), and squamous cell carcinoma (SCC) antigen in cytological fluid can improve the performance of computed tomography (CT)-guided needle aspiration biopsy (NAB) in the diagnosis of non-small cell lung cancer (NSCLC). Methods A total of 100 patients (men:women = 41:59, mean age: 63 years) with suspected malignant pulmonary lesions were prospectively enrolled for CT-guided NAB procedures. Levels of CYFRA 21-1, CEA, and SCC in the cytological fluid were measured by immunoradiometric assays. The cutoff value for tumor markers was selected on the basis of best accuracy through receiver operating characteristic curves. The sensitivity and areas under the curve (AUC) of NAB alone were compared with those of NAB combined with cytological tumor markers (CYFRA 21-1, CEA, and SCC). Results Among 100 patients, 71 (71%) had NSCLC and 29 (29%) had benign lesions. The sensitivity, specificity, and accuracy for diagnosing NSCLC were 85.7%, 100%, and 89%, respectively, for NAB alone. The sensitivity increased significantly for NAB combined with a tumor marker compared with NAB alone (100% for CYFRA 21-1, 92.9% for CEA, and 94.2% for SCC; p = 0.001, p = 0.025, and p = 0.014, respectively). The AUC of NAB with CYFRA 21-1 was significantly larger than the AUC of NAB alone (p = 0.001). Conclusion Evaluation of tumor markers CYFRA 21-1, CEA, and SCC in the cytological fluid can improve the diagnostic performance of CT-guided NAB for NSCLC. Of these markers, CYFRA 21-1 is the most useful cytological tumor marker.

To compare the relative efficacy of bevacizumab plus cisplatin-gemcitabine chemotherapy (BevCG) with cisplatin plus pemetrexed (CP) in the first-line treatment of advanced or recurrent non-small cell lung cancer (NSCLC) in East Asian patients. In the absence of evidence from head-to-head trials, an adjusted indirect treatment comparison (ITC) approach was selected to compare these treatments.BevCG and CP treatments have been compared in their relative effects versus their common comparator, the CG treatment. Outcomes from the ITC were used in a statistical model to estimate progression-free survival (PFS) and overall survival (OS) of the two treatments. The non-proportional hazards log-logistic, accelerated failure time model was selected as it provided the best fit. The ITC hazard ratio (HR) was conservatively adjusted to match what was observed between the cumulative hazard functions until the end of the Avastin in Lung trial follow-up period.The ITC analysis suggests that patients treated with Bev-based treatment can expect more favorable outcomes in terms of both PFS and OS (PFS HR=0.71 and OS HR=0.41). Probabilistic sensitivity analyses of PFS and OS HR showed that HR values below 1 are likely to occur in 82% of patients for PFS HR and in 94% of patients for OS HR.BevCG can be considered a more effective therapy than CP for NSCLC patients in East Asia.

To indirectly compare real-life clinical effectiveness of bevacizumab + cisplatin-based therapy from the Safety of Avastin in Lung (SAiL) phase IV clinical trial with published evidence from the phase III clinical trial for pemetrexed + cisplatin among East Asian patients with non-squamous metastatic or recurrent non-small cell lung cancer (NSCLC).Survival outcomes were compared between subgroups of East Asian patients receiving treatments of either bevacizumab + cisplatin-based chemotherapy or pemetrexed + cisplatin using a matching-adjusted indirect comparison approach. Patient-level data were used to derive a new group with similar characteristics compared to those reported in a phase III clinical trial evaluating pemetrexed + cisplatin therapy. Exclusions to the SAiL data included those with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2, those with mixed cell histology, non-East Asians and those who did not receive cisplatin-based chemotherapy. In total 1000 samples of the pre-matched analysis set of the SAiL data were selected that resulted in equal distributions of the ECOG PS and gender matching variables selected and evaluated for a progression-free survival (PFS) outcome.Median PFS was longer for patients treated with bevacizumab-based therapy (7.4 months; 95% confidence interval [CI]: 6.7-8.2) versus pemetrexed + cisplatin (6.4 months; 95% CI N/A) among non-squamous East Asian NSCLC patients.The results suggest that East Asian non-squamous NSCLC patients treated with bevacizumab-based therapy have a trend toward improved PFS outcomes compared to those treated with pemetrexed + cisplatin, even after adjusting for differences between the two trial groups.

The aim of this analysis is to investigate the mean incremental costs and life expectancy associated with two first-line treatments for advanced non-squamous non-small cell lung cancer (NSCLC) in Korea and Taiwan; bevacizumab plus cisplatin and gemcitabine (BevCG) and cisplatin plus pemetrexed (CP).A health economic (area under curve) model with three health states was developed to assess health outcomes (life-years gained [LYG]), direct costs, and incremental cost-effectiveness ratio (ICER). Progression-free survival (PFS) and overall survival (OS) were derived from randomized clinical trials and used in an indirect comparison in order to estimate their cost effectiveness. A life-time horizon was used. Costs and outcomes were discounted yearly by 5% in Korea and by 3% in Taiwan.The incremental LYG for the BevCG patients compared with patients treated with CP were 1.10 (13.2 months) in Korea and 1.19 (14.3 months) in Taiwan. The incremental costs were 37,439,968 ($ 33,322) in Korea and NT$ 1,910,615 ($ 64,541) in Taiwan. The incremental cost-effectiveness ratio was 34,064,835 ($ 30,318) in Korea and NT$ 1,607,960 ($ 54,317) in Taiwan. The inputs tested in one-way sensitivity analyses had very little impact on the overall cost effectiveness.This analysis shows that BevCG is more costly but is also associated with additional life-years in Korea and Taiwan. The ICER per LYG suggests that BevCG is a cost-effective therapy when compared to CP for patients with advanced NSCLC in Korea and Taiwan.