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Background: Gastric neuroendocrine carcinomas (NET) are very rare, aggressive tumors of the stomach. The objective of this study was to examine the predictive role of pretreatment fluorine-18 fluorodeoxyglucose positron emission tomography (18F-FDG PET)-assessed metabolic parameter of the whole-body and primary tumors in patients with gastric NET Method: We conducted a retrospective review of the 25 patients with histopathologically confirmed poorly differentiated NETs of the stomach at our hospital between January 2005 and December 2012. All of the patients underwent 18F-FDG-PET examination at diagnosis. Metabolic parameters [SUVmax, SUVmean, and total lesion glycolysis (TLG)] on pretreatment 18F-FDG-PET were analyzed for survival. Results: Median follow up duration was 39.4 months (95% CI, 20.0-58.1 months) and median overall survival (OS) was 25.7 months (95% CI, 14.1-37.2 months). When subjects were divided into two groups according to TLG with a cutoff value of 500, the high TLG group showed significantly shorter OS compared to the low TLG group (p=0.006). However, SUVmean and SUVmax had no significant association OS (p = 0.258, and p = 0.52, respectively). Conclusions: Our findings suggest that TLG may be more useful than SUVmean and SUVmax for predicting OS in patient with NET. The TLG measurement on 18F-FDG-PET imaging could be routinely recommended to advanced gastric cancer with neuroendocrine carcinoma Citation Format: Minkyu Jung, Beodeul Kang, Ji Soo Park, Sun Min Lim, Hyo Song Kim, Sun Young Rha, Joong Bae Ahn, Hyun Cheol Chung, Mijin Yun, Arthur Cho. Prognostic value of total lesion glycolysis from 18F-fluorodeoxyglucose positron emission tomography patients with gastric neuroendocrine carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4662. doi:10.1158/1538-7445.AM2014-4662

Background: Fibroblast growth factor receptor 1 (FGFR1) received special attention from many clinicians according to finding that FGFR1 played a critical role in many human cancers. Some clinical trials using FGFR1 targeting agents are in progress especially in breast cancer and squamous non-small cell lung cancer. Recently, FGFR1 amplifications were also found in about 5.6-6% of small cell lung cancer (SCLC) by gene copy number analysis and FISH. Methods: Tumor tissues from 113 patients diagnosed with SCLC from October 2009 to February 2013 in YUHS, Korea were collected. FGFR1 FISH assay was performed on the tissue microarray using FISH probe that hybridized to the band 8p12-8p11.23 (FISH probes were provided by Abbott Molecular, Abbott Park, IL). Results: Thirty-two patients with limited-stage disease (LD) and eighty-one patients with extensive-stage disease (ED) were enrolled. Fourteen patients were female. Among 113 tumor samples, 5 samples (4.4%) showed FGFR1 amplification. All 5 samples were obtained from the patients with ED. The patients with FGFR1 amplification more frequently had pleural metastasis at the time of diagnosis (80% vs. 26%, P=0.022). In ED, the patients with FGFR1 amplification represented shorter disease free survival from first line chemotherapy (Hazard ratio [HR], 4.469; 95% confidence interval [CI], 1.600-12.483; P=0.004) and second line chemotherapy (HR, 6.533; 95% CI, 1.700-25.108; P=0.006) than the patients without FGFR1 amplification in multivariate analysis. Median overall survival time was 8.2 months in the patients with FGFR1 amplification and 10.2 months in the patients without FGFR1 amplifications (P=0.296). Conclusion: FGFR1 amplification is a poor potential predictive biomarker of standard chemotherapy, necessitating further research in a large cohort of SCLC. The validity of targeting FGFR1 in SCLC should be confirmed in a clinical trial. Citation Format: Ji Soo Park, Jae-Seok Lee, Hyo Sup Shim, Hye Ryun Kim, Sun Min Lim, Joo Hang Kim, Byoung Chul Cho. FGFR1 gene amplification in small cell lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4728. doi:10.1158/1538-7445.AM2014-4728

Background: Mutations in the epidermal growth factor receptor (EGFR) gene are associated with increased sensitivity of lung adenocarcinoma to tyrosine kinase inhibitor (TKI) such as gefitinib. During gefitinib treatment, however, the tumor becomes resistant by acquiring specific types of resistance via the somatic changes. Although the underlying mechanisms for acquired resistance include the amplification of c-Met gene and the secondary mutation in EGFR genes, there are still unknown mechanisms that cannot be explained by the two types of genetic changes. Here, we sought to find a novel mechanism to explain TKI-resistance of EGFR-dependent lung adenocarcinoma. Methods: We developed resistant cells (HCC827-GR) from gefitinib-sensitive HCC827 cells harboring EGFR deletion mutation by chronic exposure to increasing concentrations of gefitinib. Acquired resistance mechanisms of HCC827-GR cells were analyzed. Results: HCC827-GR showed much less phosphorylation of most receptor kinases including EGFR but higher phosphorylation of downstream signaling molecules, Erk and Akt, than its parental cell. By comparing the gene expression profiles between HCC827 and HCC827-GR, we found that cancer stem cell (CSC) markers, CD44 and ALDH1A1 genes, were highly induced in HCC827-GR compared with those in HCC827. Knockdown of CD44 and ALDH1A1 expression by RNA interference induced inactivation of both Akt and Erk phosphorylation in HCC827-GR. Furthermore, HCC827-GR displayed CSC-like functionality such as colony formation and the phenotype of epithelial-mesenchymal transition (EMT). Higher level of vimentin, ZEB1 and ZFHX4 and lower level of E-cadherin were observed in HCC827-GR together with morphological change. Interestingly, miR200c, a tumor suppressive microRNA, was dramatically decreased in HCC827-GR. Forced expression of miR200c in HCC827-GR abrogated the increased expression of ZEB1 and ALDH1A1, resulting in the restoration of E-cadherin. Conclusions: These findings imply that cancer stemness induced via CD44 and ALDH1A1 expression and EMT contribute to the acquisition of gefitinib resistance in EGFR-TKI sensitive lung adenocarcinoma. Therefore, CSC markers including CD44 and ALDH1A1 and EMT regulators such as miR200c can be used as therapeutic targets for TKI-resistant EGFR-dependent lung adenocarcinoma. Citation Format: Sun Min Lim, Hyun Jung Kim, Young Ho Ban, Sang Jun Ha, Byoung Chul Cho. Acquired resistance to gefitinib is associated with cancer stem-like phenotype and EMT in EGFR mutant lung adenocarcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4663. doi:10.1158/1538-7445.AM2013-4663 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.

The secondary epidermal growth factor receptor (EGFR) T790M is the most common mechanism of resistance to reversible EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) patients 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, which are NSCLC cells with EGFR T790M. Treatment with a 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 inhibition of mammalian target of rapamycin (mTOR). The alteration of the AMPK/mTOR signaling pathway by inhibition of glucose metabolism induced specific downregulation of Mcl-1, a member of anti-apoptotic Bcl-2 family, through translational control. The enhancement of afatinib sensitivity by treatment of 2DG was confirmed in in vivo PC9-GR xenograft model. In conclusion, this study examined whether inhibition of glucose metabolism using 2DG enhances the sensitivity to afatinib in NSCLC cells with EGFR T790M through regulation of 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 treatment of patients with acquired resistance to reversible EGFR TKIs due to secondary EGFR T790M. Citation Format: Byoung Chul Cho, Hyun-Jung Kim, Sun Min Lim. Enhancement of the anti-tumor activity of afatinib by inhibition of glycolysis in non-small cell lung cancer harboring the EGFR T790M mutation . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5408. doi:10.1158/1538-7445.AM2013-5408 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.

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 with of pemetrexed. Conclusions: 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. Citation Format: Minkyu Jung, Chul Ho Lee, Hyung Soon Park, Ji Hyun Lee, Dae Joon Kim, Sun Min Lim, Joo Hang Kim, Byoung Chul Cho. Pharmacogenomic assessment of outcomes of pemetrexed-treated patients with adenocarcinoma of the lung. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2369. doi:10.1158/1538-7445.AM2013-2369 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.

Transglutaminase 2 (TG2), a cross-linking enzyme, is involved in drug resistance and in the constitutive activation of nuclear factor kappa B (NF-κB). We investigated the association of non-small cell lung cancer (NSCLC) treatment efficacy with TG2 and NF-κB expression in 120 patients: 102 with adenocarcinoma and 18 with other histologic types. All patients underwent surgery; 88 received adjuvant chemotherapy, with 28 receiving platinum-based doublet chemotherapy as first-line treatment and 29 receiving epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy. Patients' TG2 and NF-κB expression values were calculated semiquantitatively. The median TG2 value was 50 (range, 0-300) and the median NF-κB value was 20 (range, 0-240). Disease-free survival did not differ between the low- and high-TG2 groups. Among patients who received palliative platinum-based doublet chemotherapy, progression free survival (PFS) was longer in the low-TG2 group than in the high-TG2 group (11.0 vs. 7.0 months; P=0.330). Among those who received EGFR-TKI therapy, PFS was also longer in the low-TG2 group than in the high-TG 2 group (11.0 vs. 2.0 months; P=0.013). Similarly, in EGFR wild-type patients treated with EGFR-TKI, PFS was longer in patients with low TG2 expression (9.0 vs. 2.0 months; P=0.013). TG2 expression levels can predict PFS in patients with NSCLC treated with EGFR-TKI.

e16529 Background: Family caregiver burden is emerging as an important issue as number of cancer survivors increase. We hypothesized that presence of cancer survivor may influence the health-related quality of life (HRQL) of family members. Thus, we examined the HRQL of family members with cancer survivors in comparison with general population norms. Methods: Using the Fourth Korea National Health and Nutrition Examination Surveys (KNHANES IV) (2007–2009) data, we performed matching analysis to compare characteristics of cancer family vs. non-cancer family. The primary outcomes were EQ-5D and EQ-visual analogue scale (VAS) scores and generalized linear model was used. Results: Compared with general population norms, cancer family members were less employed (57.9% vs. 63.0%, P

e14559 Background: Concurrent chemoradiation has similar efficacy as surgery for esophageal cancer. Phase II trial was carried out to evaluate the efficacy and safety of chemoradiation with S-1 and cisplatin in locoregionally advanced esophageal cancer. Methods: Eligible patients had stage IIA-IVA esophageal cancer. Patients received two cycles of S-1 (days 1 to 14 and 22 to 35) and cisplatin (day 1 and 22) with concurrent radiotherapy (50.4 Gy total: 1.8 Gy/fraction). Esophagectomy was performed between week 12 and 18 as determined by the specialist multidisciplinary team meeting. Results: Sixty patients were enrolled between March 2008 and August 2011. Of the 60 patients entered, 59 patients were eligible. Clinical stage was ≥T3 in 28 patients (47%) and N1 in 43 patients (73%), with squamous cell carcinoma histology in 57 patients (97%). Fifty-four patients (90%) completed the planned treatment. After the chemoradiation, clinical tumor response rate was 62.7%. The primary grade 3/4 toxicities included neutropenia (24%) and esophagitis (8.5%). All three patients died during chemoradiation (two from pneumonia and one from gastrointestinal origin septic shock). Twenty-five patients (42%) underwent esophagectomy following chemoradiation and 15 (60%) achieved complete pathologic regression. At the median follow-up duration of 34.6 months, the estimated overall survival and progression-free survival rate at 2-year was 56.5% and 45.9%, respectively. Conclusions: Concurrent chemoradiation with S-1 and cisplatin showed an encouraging activity with high complete pathologic regression. Survival data was promising compared with historical data with 5-FU/cisplatin and should be confirmed in a randomized phase III trial. Toxicities were significant but clinically manageable.

This prospective randomized trial in 843 patients compared the effectiveness and complications of 4 intrauterine devices. At 24 months the gross accidental pregnancy rate for the Dalkon Shield was higher than for the 7Cu200 (p less than 0.05) and the ML Cu250 (p less than 0.05). The 7Cu200 had a higher expulsion rate than the Dalkon Shield (p less than 0.01), Latex Leaf (p less than 0.001) and ML Cu250 (p less than 0.001). Use-related terminations were higher for the 7Cu200 than for the ML Cu250 (p less than 0.01). Removal for pelvic inflammatory disease was necessary in 8 women (2 for the Latex Leaf and 3 each for the 7Cu200 and Dalkon Shield). There was no significant difference in termination rates between the ML Cu250 and Latex Leaf but subsequently the Leaf has given problems with removal particularly in women who have defaulted follow-up for several years.The effectiveness and complications of 4 IUDs--Gravigard, Latex Leaf, Dalkon Shield, and Multiload Cu 250--were compared in a prospective randomized clinical trial involving 843 acceptors. A total of 14,373 woman-months of IUD use were analyzed. At 24 months, the gross accidental pregnancy rate for the Dalkon Shield (10.4/100) was significantly higher than that for the Gravigard (4.3/100) and Multiload IUD (4.2/100); the pregnancy rate for the Latex Leaf device was 5.1/100. The Gravigard device had a significantly higher expulsion rate at 24 months (15.6/100) than the Dalkon Shield (2.1/100), Latex Leaf (5.2/100), or Multiload (3.7/100) devices. Use-related terminations were 38.1 for the Gravigard, 28.9 for the Dalkon Shield, 31.1 for the Latex Leaf, and 28.6 for the Multiload devices. Removal for pelvic inflammatory disease was necessary in 8 women (2 Latex Leaf acceptors,3 Dalkon Shield users, and 3 Gravigard acceptors). There was no case of septic abortion in this series. Although the Latex Leaf performed comparatively well in this study, it was found that over time the rubber degenerates and becomes separated from the thread when removal is attempted. In general, the Multiload Cu 250 appears to be one of the best currently available IUDs, because of its low pregnancy and expulsion rates.

Purpose Pediatric-type sarcomas such as rhabdomyosarcoma (RMS), Ewing sarcoma (EWS), primitive neuroectodermal tumor (PNET), and desmoplastic small round-cell tumor (DSRCT) are rare in adults, with limited studies on their prognosis and optimal treatment strategies. We aimed to examine the outcome of children and adult patients with RMS, EWS, PNET, and DSRCT and relevant prognostic factors. Materials and Methods We retrospectively reviewed 220 pediatric-type sarcoma patients at a single institution between 1985 and 2011. Comparisons were made in order to examine differences in demographics, disease characteristics, and survival. Survival analyses were performed using the Kaplan-Meier method with log-rank tests and Cox proportional hazards models. Results A total of 220 consecutive patients were identified at our institute. Median age was 15.6 years (range, 0 to 81 years) and there were 108 children (49%) and 112 adult patients (51%). According to histological classification, 106 patients (48.2%) had RMS, 60 (27.3%) had EWS, 50 (22.7%) had PNET, and 4 (1.8%) had DSRCT. With a median follow-up period of 6.6 years, the estimated median overall survival (OS) of all patients was 75 months (95% confidence interval [CI], 27.2 to 122.8 months) and median event-free survival (EFS) for all patients was 11 months (95% CI, 8.8 to 13.2 months). No significant difference in OS and EFS was observed between adults and children. In multivariate analysis, distant metastasis (hazard ratio [HR], 1.617; 95% CI, 1.022 to 2.557; p=0.040) and no debulking surgery (HR, 1.443; 95% CI, 1.104 to 1.812; p=0.012) showed independent association with worse OS. Conclusion Metastatic disease and no surgical treatment are poor prognostic factors for OS among pediatric-type sarcomas for both adults and children.

Feasibility of sterilization with Falope ring application via culdoscopy in a series of 122 women who requested sterilization is described. In 68.9% of the women sterilized the ligation procedure was combined with pregnancy termination. It was combined with dilation and curettage in 11.5% while in 16.4% of the cases the ligation was an interval procedure without concurrent maneuver. The operation was uncomplicated in 79.9% of the women and tubal transection occurred during application of the Falope ring in 13 cases. 1 pregnancy has occurred and resulted in a normal delivery. Ligation was repeated by minilaparotomy; the Falope ring was found to be correctly placed on 1 side but was situated at the ampullary end on the other side. The series demonstrates the feasibility of application of the Falope ring via culdoscopy in spite of the 1 pregnancy and 13 tubal transections. 5 of the cases of tubal transection occurred during the 1st month of the series and careful attention to technique minimizes its chance of occurring.