Hyun Jeong Shim

chronic sun-induced damage Recent molecular classification of melanomas has revealed that BRAF and NRAS mutations are common in melanomas on skin without chronic sun-induced damage (non-CSD melanoma), whereas KIT mutations and/or increased copy number are frequently found in mucosal and acral melanomas (Davies et al., 2002Davies H. Bignell G.R. Cox C. et al.Mutations of the BRAF gene in human cancer.Nature. 2002; 417: 949-954Crossref PubMed Scopus (8265) Google Scholar; Curtin et al., 2005Curtin J.A. Fridlyand J. Kageshita T. et al.Distinct sets of genetic alterations in melanoma.N Eng J Med. 2005; 353: 2135-2147Crossref PubMed Scopus (2124) Google Scholar, Curtin et al., 2006Curtin J.A. Busam K. Pinkel D. et al.Somatic activation of KIT in distinct subtypes of melanoma.J Clin Oncol. 2006; 24: 4340-4346Crossref PubMed Scopus (1255) Google Scholar). Most previous studies have been conducted in Caucasian populations, which show different common melanoma subtypes compared with Asian populations. Mutation status may also be different in Asian populations, although few studies have examined BRAF and KIT mutations in Asian melanomas (Ashida et al., 2009Ashida A. Takata M. Murata H. et al.Pathological activation of KIT in metastatic tumors of acral and mucosal melanomas.Int J Cancer. 2009; 124: 862-868Crossref PubMed Scopus (110) Google Scholar; Terada, 2010Terada T. Low incidence of KIT gene mutations and no PDGFRA gene mutations in primary cutaneous melanoma: an immunohistochemical and molecular genetic study of Japanese cases.Int J Clin Oncol. 2010; 15: 453-456Crossref PubMed Scopus (37) Google Scholar; Kong et al., 2011Kong Y. Si L. Zhu Y. et al.Large-scale analysis of KIT aberrations in Chinese patients with melanoma.Clin Cancer Res. 2011; 17: 1684-1691Crossref PubMed Scopus (197) Google Scholar; Yun et al., 2011Yun J. Lee J. Jang J. et al.KIT amplification and gene mutations in acral/mucosal melanoma in Korea.APMIS. 2011; 119: 330-335Crossref PubMed Scopus (52) Google Scholar; Si et al., 2012Si L. Kong Y. Xu X. et al.Prevalence of BRAF V600E mutation in Chinese melanoma patients: large scale analysis of BRAF and NRAS mutations in a 432-case cohort.Eur J Cancer. 2012; 48: 94-100Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar). In the present study, we aimed to determine the incidence of melanoma subtypes in 202 Korean patients with melanomas and to analyze BRAF mutations and KIT aberrations (mutations and increased copy number) in relation to clinicopathological features and prognosis. We examined formalin-fixed, paraffin-embedded specimens from 202 Korean melanoma patients at Chonnam National University Hospital and Hwasun Hospital between May 1994 and July 2011. The study protocol was approved by the institutional review board of Chonnam National University Hwasun Hospital. Written informed patient consent was obtained, and the study was conducted according to the Declaration of Helsinki Principles. Genomic DNA was extracted from the samples. Hotspot mutations were detected by amplification of exons 11 and 15 of the BRAF gene and exons 9, 11, 13, and 17 of the KIT gene, using the primers shown in Supplementary Table S5 online. To identify the BRAF exon 15 codon 600 mutation, we performed pyrosequencing using a PSQ 96MA instrument (Biotage AB, Uppsala, Sweden) at room temperature with PyroMark Gold Q96 Reagent (Qiagen, Hilden, Germany). If the result was negative, we sequenced BRAF exons 11 and 15. For KIT mutations, we initially sequenced all of the samples. PCR products purified with Expin PCR SV (GeneAll Biotechnology, Seoul, Korea) were directly sequenced using ABI-PRISM Big Dye Terminator (ver. 3.1; Applied Biosystems, Foster City, CA). KIT copy number was assessed by quantitative real-time PCR using GAPDH as a control gene. Relative copy numbers were calculated by the ΔΔCt method (Beadling et al., 2008Beadling C. Jacobson-Dunlop E. Hodi F.S. et al.KIT gene mutations in copy number in melanoma subtypes.Clin Cancer Res. 2008; 14: 6821-6828Crossref PubMed Scopus (509) Google Scholar; Kong et al., 2011Kong Y. Si L. Zhu Y. et al.Large-scale analysis of KIT aberrations in Chinese patients with melanoma.Clin Cancer Res. 2011; 17: 1684-1691Crossref PubMed Scopus (197) Google Scholar). Statistical analyses were performed using SPSS ver. 19.0 (SPSS, Chicago, IL). A P-value <0.05 was taken to indicate statistical significance. Download .pdf (.13 MB) Help with pdf files Supplementary Information Of the 202 Korean melanomas, acral melanomas (110, 54.5%) were most common, followed by mucosal melanomas (51, 25.2%) (Supplementary Table S1 online). Non-CSD and CSD melanomas were relatively uncommon. BRAF mutations were detected in 24 patients (11.9%), all in exon 15; we found no BRAF mutations in exon 11 (Supplementary Table S2 online). BRAF mutations were most frequently detected in non-CSD melanomas (12/26, 46.2%), followed by mucosal melanomas (7/51, 13.7%). They were less common in acral and CSD melanomas. The anatomical sites for BRAF-mutated non-CSD melanomas included the scalp, ear helix, forearm, and calf, which are frequently affected areas of severe sun damage in Caucasian populations. Our results are similar to those for a Chinese Han population; the BRAF exon 15 T1799A (V600E) mutation was detected in 14.7% of 109 patients with melanomas (Qi et al., 2011Qi R.Q. He L. Zheng S. et al.BRAF exon 15 T1799A mutation is common in melanocytic nevi, but less prevalent in cutaneous malignant melanoma, in Chinese Han.J Invest Dermatol. 2011; 1311: 1129-1138Abstract Full Text Full Text PDF Scopus (45) Google Scholar). KIT mutations were detected in 11.4% of melanomas (23/202) (Supplementary Table S1 online). The KIT mutation frequency was the highest in CSD melanomas (3/12, 25%), followed by acral (13/110, 11.8%) and mucosal melanomas (3/51, 5.9%). Both BRAF and KIT mutations were detected in three patients with non-CSD melanomas. Increased KIT copy numbers were detected in 45 patients (22.3%). In acral and mucosal melanomas, the increased KIT copy number frequencies were 20.9% and 29.4%, respectively. Clinicopathological correlations of BRAF mutations and KIT aberrations are shown in Supplementary Table S4 online. We included only nonsynonymous mutations in all statistical analysis; two BRAF mutations and six KIT mutations were synonymous mutations and were excluded from analysis. The median follow-up period was 25.2 months. First, we analyzed the unadjusted univariate Cox proportional hazards regression model with comprehensive lists of clinicopathological features. Breslow thickness (T4), mitotic rate, ulceration, vertical growth phase, tumor, node, metastasis stage (I–IV), and KIT mutations were significantly associated with poor prognosis (Table 1). In a subsequent multivariate analysis with these significant covariates, except Breslow thickness, using a fully adjusted Cox proportional hazards regression model, KIT mutations were found to be an independent risk factor for poor prognosis, with a hazard ratio of 2.27 and associated 95% confidence interval of 1.27–4.04 (P=0.005). An overall survival curve revealed that patients with KIT mutations had significantly poorer survival compared with those without KIT mutations (P=0.022, Figure 1b). BRAF mutations (Figure 1a), increased KIT copy number (Supplementary Figure S1A online), and KIT aberrations (Supplementary Figure S1B online) were not significantly associated with poor survival.Table 1Cox proportional HRs for clinicopathological features, BRAF mutations, and KIT aberrations in 202 Korean melanomasFeatureMedian survival (months)Unadjusted HR (95% CI; P-value)1For 95% CIs that do not contain one, the risk was considered to be statistically significant.P for trendFully adjusted HR (95% CI; P-value)1For 95% CIs that do not contain one, the risk was considered to be statistically significant.P for trendAge25.21.01 (0.99–1.01; 0.297)Sex Male39.71.00 (reference) Female47.00.73 (0.50–1.07; 0.732)Breslow thickness<0.001 T1103.71.00 (reference) T288.31.17 (0.46–2.97; 0.746) T353.21.74 (0.78–3.89; 0.176) T423.93.50 (1.90–6.44; <0.001)Mitotic rate<0.0010.223 <1mm−288.31.00 (reference)1.00 (reference) 1–6mm−239.71.97 (1.18–3.28; 0.009)1.24 (0.68–2.26; 0.491) >6mm−220.13.37 (1.95–5.81; <0.001)1.67 (0.89–3.15; 0.111)Ulceration Absent75.41.00 (reference)1.00 (reference) Present20.12.71 (1.83–4.00; <0.001)2.13 (1.41–3.23; <0.001)Vertical growth phase Absent115.41.00 (reference)1.00 (reference) Present34.62.90 (1.51–5.58; 0.001)0.88 (0.35–2.17; 0.774)Regression Absent40.91.00 (reference) Present53.60.60 (0.30–1.18; 0.137)Microsatellites Absent43.21.00 (reference) Present18.52.45 (0.99–6.06; 0.053)TILs Absent41.01.00 (reference) Present75.40.53 (0.19–1.44; 0.531)Acral Non-acral34.61.00 (reference) Acral51.50.79 (0.54–1.16; 0.233)TNM stage<0.001<0.001 I115.41.00 (reference)1.00 (reference) II51.52.57 (1.33–4.98; 0.005)1.56 (0.62–3.94; 0.346) III20.15.25 (2.58–10.7; <0.001)3.55 (1.43–8.83; 0.006) IV8.817.5 (8.27–37.0; <0.001)12.0 (4.51–32.1; <0.001)BRAF mutation Wild type41.81.00 (reference) Mutant type56.11.15 (0.66–2.02; 0.629)KIT mutation Wild type53.21.00 (reference)1.00 (reference) Mutant type34.61.88 (1.08–3.25; 0.025)2.27 (1.27–4.04; 0.005)Increased KIT copy number No44.71.00 (reference) Yes27.11.13 (0.71–1.79; 0.601)KIT aberration No56.11.00 (reference) Yes34.61.33 (0.90–2.00; 0.155)Abbreviations: CI, confidence interval; HR, hazard ratio; TIL, tumor-infiltrating lymphocyte; TNM, tumor, node, metastasis.1 For 95% CIs that do not contain one, the risk was considered to be statistically significant. Open table in a new tab Abbreviations: CI, confidence interval; HR, hazard ratio; TIL, tumor-infiltrating lymphocyte; TNM, tumor, node, metastasis. Most studies of KIT mutations in melanomas have detected mutations in exons 11, 13, 17, and 18. Mutations in exon 9 were infrequently detected or not studied. Exon 9 is the location of about 15% of KIT mutations in gastrointestinal stromal tumors, but is known to be less frequently involved in melanomas (Woodman and Davies, 2010Woodman S.E. Davies M.A. Targeting KIT in melanoma: a paradigm of molecular medicine and targeted therapeutics.Biochem Pharmacol. 2010; 80: 568-574Crossref PubMed Scopus (108) Google Scholar). The efficacy of different tyrosine kinase inhibitors may vary according to KIT mutation status (Maleddu et al., 2011Maleddu A. Pantaleo M.A. Nannini M. et al.The role of mutational analysis of KIT and PDGFRA in gastrointestinal stromal tumors in a clinical setting.J Transl Med. 2011; 9: 75Crossref PubMed Scopus (40) Google Scholar). Surprisingly, in the present study, KIT mutations (total 18 exons in 17 patients) were most frequent in exon 13 (7/18, 38.9%), followed by exon 9 (5/18, 27.8%), exon 11 (3, 16.7%), and exon 17 (3, 16.7%) (Supplementary Table S3 online). The major limitation of this study is the short follow-up period. Long-term follow-up is needed for more precise survival analysis. In conclusion, we analyzed BRAF and KIT mutations in a large number of Korean melanomas. KIT mutations were independently linked to a poor prognosis in Korean patients with melanomas. Patients with mutations did not receive BRAF or tyrosine kinase inhibitors in our study, and this might have been associated with the poor survival. We expect that these inhibitors would produce effective treatment responses in selected Korean melanomas. This study was supported by a grant (CRI11077-21) of the Chonnam National University Hospital Research Institute of Clinical Medicine, and by the Leading Foreign Research Institute Recruitment Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (MEST) (2011-0030034). Supplementary material is linked to the online version of the paper at http://www.nature.com/jid

Abstract Background Intratumour heterogeneity is a hallmark of most solid tumours, including breast cancers. We applied spatial transcriptomics and single‐cell RNA‐sequencing on patient‐derived xenografts (PDXs) to profile spatially resolved cell populations within oestrogen receptor‐positive (ER + ) breast cancer and to elucidate their importance in oestrogen‐dependent tumour growth. Methods Two PDXs of ‘ER‐high’ breast cancers with opposite oestrogen‐mediated growth responses were investigated: oestrogen‐suppressed GS3 (80–100% ER) and oestrogen‐dependent SC31 (40–90% ER) models. The observation was validated via single‐cell analyses on an ‘ER‐low’ PDX, GS1 (5% ER). The results from our spatial and single‐cell analyses were further supported by a public ER + breast cancer single‐cell dataset and protein‐based dual immunohistochemistry (IHC) of SC31 examining important luminal cancer markers (i.e., ER, progesterone receptor and Ki67). The translational implication of our findings was assessed by clinical outcome analyses on publicly available cohorts. Results Our space‐gene‐function study revealed four spatially distinct compartments within ER + breast cancers. These compartments showed functional diversity (oestrogen‐responsive, proliferative, hypoxia‐induced and inflammation‐related). The ‘proliferative’ population, rather than the ‘oestrogen‐responsive’ compartment, was crucial for oestrogen‐dependent tumour growth, leading to the acquisition of luminal B‐like features. The cells expressing typical oestrogen‐responsive genes like PGR were not directly linked to oestrogen‐dependent proliferation. Dual IHC analyses demonstrated the distinct contribution of the Ki67 + proliferative cells toward oestrogen‐mediated growth and their response to a CDK4/6 inhibitor. The gene signatures derived from the proliferative, hypoxia‐induced and inflammation‐related compartments were significantly correlated with worse clinical outcomes, while patients with the oestrogen‐responsive signature showed better prognoses, suggesting that this compartment would not be directly associated with oestrogen‐dependent tumour progression. Conclusions Our study identified the gene signature in our ‘proliferative’ compartment as an important determinant of luminal cancer subtypes. This ‘proliferative’ cell population is a causative feature of luminal B breast cancer, contributing toward its aggressive behaviours.

This study evaluated the influence of genetic polymorphism influencing drug metabolism on survival in taxane‐ and cisplatin‐treated advanced gastric cancer (AGC). Peripheral blood samples from 207 AGC patients treated with first‐line chemotherapy of taxane and cisplatin were used. We investigated polymorphisms that influenced the metabolism of taxane (ATP‐binding cassette transporter B1 (ABCB1)), cisplatin (glutathione S‐transferase M1 (GSTM1), glutathione S‐transferase P1 (GSTP1), glutathione S‐transferase T1 (GSTT1), excision repair cross complementing 1 (ERCC1), X‐ray Cross Complementing group 3 (XRCC3), X‐ray Cross Complementing group 4 (XRCC4), X‐ray Cross Complementing group 1 (XRCC1), breast cancer (BRCA1)), and 5‐fluorouracil (methylene tetrahydrofolate reductase (MTHFR), thymidylate synthase (TYMS)). A total of 207 patients were enrolled between May 2004 and Dec 2008, and 200 patients were analyzed. The overall response rate was 38.5%. Time to progression and overall survival time were 4.3 ± 0.19 months and 11.9 ± 1.05 months, respectively. There was no significant association between genetic polymorphism and response rate. However, the BRCA1 mutant TT homozygote was associated with significant prolongation of overall survival (hazard ratio [HR] = 0.43; 95% confidence interval [CI], 0.20–0.92; P = 0.03) and progression‐free survival (HR = 0.51; 95% CI, 0.26–1.00; P = 0.05). Also, the XRCC1 194 CT genotype was associated with inferior overall survival, relative to the XRCC1 194 CC homozygotes (HR = 1.49; 95% CI, 0.11–2.07; P = 0.018).These findings suggest that BRCA1 TT and XRCC1 194 CT genotypes could be modest prognostic markers of AGC response in taxane‐ and cisplatin‐treated patients. ( Cancer Sci 2010; 101: 1247–1254)

We evaluated the potential of a thermoresponsive hydrogel consisting of conjugated linoleic acid-coupled Pluronic F-127 (Plu-CLA) as a controlled release, intraperitoneal delivery system for docetaxel with the aim of treating peritoneal dissemination of gastric cancer. Previously, we established a peritoneal metastasis model that involves the injection of BALB/c mice with TMK1 human gastric cancer cells. One week after the TMK1 cells were injected, the mice were injected intraperitoneally with docetaxel alone or docetaxel-loaded Plu-CLA. Tumor progression and response to therapy were monitored by micro-positron emission tomography. The total number of peritoneal tumors and the ascites volume were also measured. Compared with docetaxel alone, the combination of docetaxel and Plu-CLA (docetaxel-Plu-CLA) significantly and synergistically reduced tumor cell survival. Docetaxel-Plu-CLA showed excellent anti-tumor activity, inducing apoptosis more potently than docetaxel alone. Docetaxel-Plu-CLA also significantly reduced the number of peritoneal metastatic nodules and increased survival in the peritoneal gastric cancer xenograft model. Our results show that intraperitoneal administration of docetaxel-Plu-CLA synergistically inhibits peritoneal metastasis and prolongs survival in a peritoneal gastric cancer model. Therefore, Plu-CLA is a potential intraperitoneal-route carrier for hydrophobic docetaxel for the effective treatment of peritoneal metastatic gastric cancer.

This study was designed to investigate an association between the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and the risk of gastric and colorectal cancer in the Korean population.We conducted a population-based large-scale case-control study involving 2,213 patients with newly diagnosed gastric cancer, 1,829 patients with newly diagnosed colorectal cancer, and 1,700 healthy controls. Genotyping was performed with peripheral blood DNA for MTHFR C677T polymorphisms. The statistical significance was estimated by logistic regression analysis.The MTHFR C677T frequencies of CC, CT, and TT genotypes were 35.2%, 47.5%, and 17.3% among stomach cancer, 34%, 50.5%, and 15.5% in colorectal cancer, and 31.8%, 50.7%, and 17.5% in the controls, respectively. The MTHFR 677TT genotype showed a weak opposite association with colorectal cancer compared to the homozygous CC genotype [adjusted age and sex odds ratio (OR) = 0.792, 95% confidence interval (CI) = 0.638-0.984, P = 0.035]. Subjects with the MTHFR 677CT showed a significantly reduced risk of gastric cancer compared whose with the 677CC genotype (age- and sex-adjusted OR = 0.810; 95% CI = 0.696-0.942, P = 0.006). We also observed no significant interactions between the MTHFR C677T polymorphism and smoking or drinking in the risk of gastric and colorectal cancer.The T allele was found to provide a weak protective association with gastric cancer and colorectal cancer.

ContextTo respect a patient's wish for end-of-life care, “the Act on Decisions on Life-Sustaining Treatment for Patients at the End-of-Life” was enacted in South Korea in 2016. Current understanding of people who would be involved in advance care planning (ACP) is crucial to disseminate it systematically.ObjectivesThe objective of this study was to investigate awareness and attitudes toward ACP in South Korea.MethodsA multicenter, nationwide cross-sectional study was conducted a survey regarding ACP among four groups that would have different positions and experiences: 1,001 cancer patients, 1,006 family caregivers, 928 physicians, and 1,005 members of the general public.ResultsA total of 16% of the general population, 33% of the patients and caregivers, and 61% of the physicians had knowledge of advance directives. More than 63% of the general population, above 72% of the patients and caregivers, and 97% of the physicians were willing to do so when the disease status was aggravated or terminal. The possibility for changing the plan, uncertainty as to whether directives would actually be followed, and psychological discomfort were common reasons for not wanting to engage in ACP. Routine recommendations for a specific medical condition, heightened accessibility, and health insurance support were common factors that could help facilitate ACP.ConclusionOur findings suggest that strategies for promoting ACP should reflect different perspectives among the general public, patients, family caregivers, and physicians. Public advocacy, resources for approaching and integrating ACP into routine health care, as well as systematic support provisions are needed.

Abstract A recent genome‐wide association study (GWAS) identified new susceptibility single‐nucleotide polymorphisms (SNPs) rs13361707 (PRKAA1 and PTGER4 gene on 5p13.1) and rs9841504 (ZBTB20 gene on 3q13.31) that were significantly associated with non‐cardia gastric cancer. The aim of this study was to determine whether rs13361707 and rs9841504 polymorphisms are associated with the risk of gastric cancer in a Korean population. We conducted a large‐scale case–control study of 3245 gastric cancer patients and 1700 controls. The allele frequencies for rs13361707 C and rs9841504 G were 53.5% and 18.3% among gastric cancer cases, compared with 47.1% and 17.2% among controls, respectively. We found that rs13361707 TC and CC genotypes were associated with increased risk for gastric cancer (odds ratios [OR] = 1.29; 95% confidence interval [CI] = 1.11–1.51 for TC vs. TT and 1.68; 1.41–2.01 for CC vs. TT). However, we found no significant association between rs9841504 and gastric cancer risk (OR = 1.11; 0.97–1.28 for CG vs. CC; OR = 1.09; 0.77–1.53 for GG vs. CC). We observed no significant interactions between rs13361707 and rs9841504 polymorphisms and age, gender, smoking habit, alcohol consumption, and clinicopathologic characteristics such as anatomical tumor location and histological type. Our study showed that the rs13361707 polymorphism was associated with increased risk of gastric cancer in a Korean population. This finding provides further evidence that genetic variant of PRKAA1 and PTGER4 genes may contribute to the gastric carcinogenesis. However, we found no association between rs9841504 and gastric cancer risk. © 2013 Wiley Periodicals, Inc.

Almost all patients with advanced gastric cancer will eventually develop progressive disease after first-line chemotherapy. However, the role of subsequent salvage chemotherapy remains controversial. The purpose of this study was to evaluate prognostic factors for the survival of patients with advanced gastric cancer who received third-line chemotherapy.We reviewed 502 patients with advanced gastric cancer who received palliative chemotherapy at the Onocology Department of Hwasun Chonnam National University Hospital (2004-2008). Among them, 174 received third-line chemotherapy. To evaluate the clinicopathologic factors that affected overall survival, univariate and multivariate analyses were performed on the baseline factors before beginning third-line chemotherapy.Multivariate analysis found 4 prognostic factors affecting poor survival following third-line chemotherapy: performance status of 2-3 (hazard ratio [HR] 1.46, 95% confidence interval [CI] 1.06-2.02; P = 0.022), serum albumin level < 4 mg/dL (HR 1.82, 95% CI 1.32-2.53; P < 0.00), poor histologic type (HR 1.77, 95% CI 1.27-2.47; P = 0.001), and progression-free survival of <2.7 months following second-line chemotherapy (HR 1.51, 95% CI 1.09-2.08; P = 0.012). A prognostic index was constructed, dividing patients into low- (0-1 factor), intermediate- (2 or 3 risk factors), or high- (4 risk factors) risk groups. Median survival times for each group were 11.8, 6.7, and 3.3 months, respectively (P < 0.00).This analysis suggests that some clinicopathologic factors might be helpful in identifying the subgroup of patients most likely to benefit from third-line chemotherapy for advanced gastric cancer.

Genetic variants at 1q22 and 10q23 were identified as genetic markers of both gastric cancer and esophageal squamous cell carcinoma susceptibility by two genome-wide association studies. The aim of this study was to determine whether rs4072037A > G in MUC1 at 1q22 and rs2274223A > G in PLCE1 at 10q23 are associated with a risk of gastric cancer in a Korean population. We conducted a large-scale case-control study of 3,245 patients with gastric cancer and 1,700 controls. The allele frequencies of rs4072037G and rs2274223G were 11.2 and 25.5% among patients with gastric cancer, compared with 12.8 and 26.4%, respectively, among controls. We found that the rs4072037 AG genotype was significantly associated with a reduced risk of gastric cancer [odds ratios (OR) = 0.78; 95% confidence interval (CI) = 0.67-0.91 for AG vs AA]. Compared with the rs2274223 AA genotype, we found a significant association between the rs2274223 AG genotype and a weakly reduced risk of gastric cancer (OR = 0.87; 95% CI = 0.76-0.99 for AG vs AA). Our data suggest that genetic variants at 1q22 and 10q23 play a role in gastric carcinogenesis.

In this study, we evaluated the prognostic significance of the concomitant existence of lymphovascular invasion and perineural invasion in patients with advanced gastric cancer. A total of 206 consecutive patients with Stage II or III gastric cancer who underwent curative D2 gastrectomy and adjuvant chemotherapy from April 2004 to December 2011 were analyzed. Patients were classified into four groups according to the presence (+) or absence (−) of lymphovascular invasion and perineural invasion: lymphovascular invasion−/perineural invasion− (n = 33), lymphovascular invasion+/perineural invasion− (n = 31), lymphovascular invasion−/perineural invasion+ (n = 54) and lymphovascular invasion+/perineural invasion+ (n = 88). A total of 136 patients (66.0%) received 5-fluorouracil plus cisplatin adjuvant chemotherapy and 70 patients (34.0%) received TS-1. During the median follow-up period of 35.18 months, the median disease-free survival times for lymphovascular invasion−/perineural invasion−, lymphovascular invasion+/perineural invasion− and lymphovascular invasion−/perineural invasion+ were not reached at the time of analysis; however, median disease-free survival for lymphovascular invasion+/perineural invasion+ was the worst (36.73 months, P = 0.001). The median overall survival in the four groups was also not reached at the time of analysis; however, median overall survival with lymphovascular invasion+/perineural invasion+ was the poorest (P = 0.002). In a multivariate analysis, lymphovascular invasion+/perineural invasion+ was an independent prognostic factor for both disease-free survival (hazard ratio = 1.940, 95% confidence interval 1.157–3.252, P = 0.012) and overall survival (hazard ratio = 2.973, 95% confidence interval 1.561–5.662, P = 0.001). The concomitant existence of lymphovascular and perineural invasion has a significant prognostic impact on disease-free survival and overall survival in patients with Stage II or III gastric cancer.

Hypoxia-inducible factor-1α (HIF-1α) increases transcription of the vascular endothelial growth factor (VEGF) gene. Inhibition of VEGF abolishes VEGF mediated induction of HIF-1α. Recent reports suggested that HIF-1α also mediated the induction of class III β-tubulin (TUBB3) in hypoxia. TUBB3 confers resistance to taxanes. Inhibition of VEGF may decrease the expression of HIF-1α and TUBB3. This study was undertaken to investigate the roles of vascular endothelial growth factor receptor (VEGFR) in gastric cancer cell behavior and to identify methods to overcome paclitaxel resistance in vitro.The protein expression levels of HIF-1α and TUBB3 were measured in human gastric cancer cell lines (AGS) under normoxic and hypoxic conditions. The relationship between TUBB3 and paclitaxel resistance was assessed with small interfering TUBB3 RNA. AGS cells were treated with anti-VEGFR-1, anti-VEGFR-2, placental growth factor (PlGF), bevacizuamb, and paclitaxel.Hypoxia induced paclitaxel resistance was decreased by knockdown of TUBB3. Induction of HIF-1α and TUBB3 in AGS is VEGFR-1 mediated and PlGF dependent. Hypoxia-dependent upregulation of HIF-1α and TUBB3 was reduced in response to paclitaxel treatment. Expressions of HIF-1α and TUBB3 were most decreased when AGS cells were treated with a combination of paclitaxel and anti-VEGFR-1. AGS cell cytotoxicity was most increased in response to paclitaxel, anti-VEGFR-1, and anti-VEGFR-2.We suggest that blockade of VEGFR-1 and VEGFR-2 enhances paclitaxel sensitivity in TUBB3-expressing gastric cancer cells.

Accurate awareness of the prognosis is an important factor in the treatment decision of patients with advanced cancer; however, prognostic disclosure is still subject to debate because it can reduce patient's satisfaction and increase depression.The purpose of this study is to assess whether patients' prognostic awareness is associated with decreased quality of life (QoL) or increased depressive mood in patients with advanced cancer.In this cohort study, 386 patients with advanced cancer were recruited across 3 periods from December 2016 to August 2018. The outcome of this study was a change in QoL and depression according to the patients' prognostic awareness at baseline, 3 months, and 6 months.This study found significant differences in changes of QoL based on patients' prognostic awareness. From baseline to 3 months, emotional functioning (P = .039), pain (P = .042), existential well-being (P = .025), and social support (P = .038) subscale scores improved significantly more in those with lack of prognostic awareness. Over 6 months, the group without prognostic awareness improved significantly in terms of physical functioning (P = .037), emotional functioning (P = .002), nausea/vomiting (P = .048), and constipation (P = .039) subscale scores and existential well-being scores (P = .025). No significant difference between the groups was found in terms of depression.Accurate prognostic awareness may pose harm and may provide no additional benefits in terms of QoL and mood among patients with advanced cancer for a short period of time.

The active metabolite of vitamin D, 1,25-dihydroxyvitamin D(3) (calcitriol), inhibits the growth of several types of human cancer cells in vitro, but its therapeutic use is limited because it causes hypercalcemia. Among its analogs, 19-nor-1,25-dihydroxyvitamin D(2) (paricalcitol), has fewer calcemic effects and exhibits an activity equipotent to that of calcitriol. We assessed the antitumor and anti-inflammatory effects of paricalcitol in gastric cancer cells, and evaluated the potential role of vitamin D in the treatment of peritoneal metastatic gastric cancer. In this study, treatment with paricalcitol inhibited gastric cancer cell growth and induced cell cycle arrest. Paricalcitol also induced apoptosis and showed anti-inflammatory activity. Moreover, the growth of intraperitoneal metastases in vivo was reduced in mice treated with paricalcitol. (18)F-FDG uptake was significantly lower in the paricalcitol group compared to control group (SUV; control group 13.2 ± 5.3 vs paricalcitol group 4.5 ± 3.0). Intraperitoneal tumor volume was significantly lower in paricalcitol treated mice (control group 353.2 ± 22.9 mm(3) vs paricalcitol group 252.0 ± 8.4 mm(3)). These results suggest that the vitamin D analog, paricalcitol, has anticancer activity on gastric cancer cells by regulation of the cell cycle, apoptosis, and inflammation.

Objectives This study determined attitudes of four groups—Korean patients with cancer, their family caregivers, physicians and the general Korean population—towards five critical end-of-life (EOL) interventions—active pain control, withdrawal of futile life-sustaining treatment (LST), passive euthanasia, active euthanasia and physician-assisted suicide. Design and setting We enrolled 1001 patients with cancer and 1006 caregivers from 12 large hospitals in Korea, 1241 members of the general population and 928 physicians from each of the 12 hospitals and the Korean Medical Association. We analysed the associations of demographic factors, attitudes towards death and the important components of a ‘good death’ with critical interventions at EoL care. Results All participant groups strongly favoured active pain control and withdrawal of futile LST but differed in attitudes towards the other four EoL interventions. Physicians (98.9%) favoured passive euthanasia more than the other three groups. Lower proportions of the four groups favoured active euthanasia or PAS. Multiple logistic regression showed that education (adjusted OR (aOR) 1.77, 95% CI 1.33 to 2.36), caregiver role (aOR 1.67, 95% CI 1.34 to 2.08) and considering death as the ending of life (aOR 1.66, 95% CI 1.05 to 1.61) were associated with preference for active pain control. Attitudes towards death, including belief in being remembered (aOR 2.03, 95% CI 1.48 to 2.79) and feeling ‘life was meaningful’ (aOR 2.56, 95% CI 1.58 to 4.15) were both strong correlates of withdrawal of LST with the level of monthly income (aOR 2.56, 95% CI 1.58 to 4.15). Believing ‘freedom from pain’ negatively predicted preference for passive euthanasia (aOR 0.69, 95% CI 0.55 to 0.85). In addition, ‘not being a burden to the family’ was positively related to preferences for active euthanasia (aOR 1.62, 95% CI 1.39 to 1.90) and PAS (aOR 1.61, 95% CI 1.37 to 1.89). Conclusion Groups differed in their attitudes towards the five EoL interventions, and those attitudes were significantly associated with various attitudes towards death.

While the guidelines for adjuvant chemotherapy (AC) for colon cancer are relatively standardized, those for early rectal cancer are still lacking. We therefore evaluated the role of AC in clinical stage II rectal cancer treatment after preoperative chemoradiotherapy (CRT). Patients diagnosed with early rectal cancer (defined by clinical stage T3/4, N0) who completed CRT followed by surgery were enrolled in this retrospective study. To evaluate the role of AC, we analyzed the risk of recurrence and survival based on clinicopathologic parameters and adjuvant chemotherapy. Of the 112 patients, 11 patients (9.8%) experienced recurrence and five patients (4.8%) died. In a multivariate analysis, circumferential resection margin involvement (CRM+) on magnetic resonance imaging at diagnosis, CRM involvement following neoadjuvant therapy (ypCRM+), tumor regression grade (≤G1) and no-AC were considered poor prognostic factors for recurrence free survival (RFS). In addition, ypCRM+ and no-AC were associated with poor overall survival (OS) in the multivariate analysis. AC including 5-FU monotherapy demonstrated the benefits of reduced recurrence and prolonged survival in clinical stage II rectal cancer, even in pathologic stage following neoadjuvant therapy (ypStage) 0-I. Further prospective studies are needed to verify the benefit of each regimen of AC and the development of a method that can accurately predict CRM status before surgery, and a vigorous treatment that can induce CRM non-involvement (CRM-) should be considered even in early stages of rectal cancer.

Dimethylsulfoxide (DMSO) has been known to differentiate HL60 cells into neutrophil like cells. Here, we provide an evidence for the involvement of tumor suppressor PTEN, an antagonist of phosphatidylinositol 3-kinase (PI3K) in the DMSO-induced differentiation of HL60 cells. DMSO upregulated PTEN with unaffecting the expression of PI3K. The upregulation of PTEN by DMSO lead to the decrease of Akt phosphorylation, a downstream of PI3K. The DMSO-induced upregulation of PTEN might be mediated by NF-κB activation, which was evidenced by the blockage of DMSO-induced PTEN upregulation with an NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC).

Tertiary syphilis, especially in cases involving visceral gummatous disease, can be confused with cancer of the solid organs.We report a case of tertiary hepatic syphilis that manifested with intrahepatic masses in a patient who had an underlying primary peritoneal serous carcinoma (PPSC).The patient was diagnosed with PPSC and achieved a complete remission of PPSC following six cycles of platinum-based chemotherapy.Two hepatic nodules developed during the follow-up period and were initially labeled as hepatic metastases from the underlying PPSC, based on radiological find ings.A resection of hepatic nodules was performed for therapeutic and diagnostic purposes, because there were no other metastatic foci except in the liver.Unexpectedly, serology and histology confirmed tertiary syphilis.This rare case emphasizes the importance of including tertiary syphilis in the differential diagnosis of a space-occupying lesion, even with an existing diagnosis of underlying cancer.

Fibroblast growth factor receptor 4 (FGFR4) plays an important role in cancer progression during tumor proliferation, invasion, and metastasis. This study evaluated the prognostic role of FGFR4 polymorphism in patients with resected colon cancer, including the underlying mechanism.FGFR4 polymorphism was characterized in patientswho received curative resection for stage III colon cancer. FGFR4-dependent signal pathways involving cell proliferation, invasion, and migration according to genotypes were also evaluated in transfected colon cancer cell lines.Among a total of 273 patients, the GG of FGFR4 showed significantly better overall survival than the AG or AA, regardless of adjuvant treatment. In the group of AG or AA, combination of folinic acid, fluorouracil, and oxaliplatin (FOLFOX) resulted in better survival than fluorouracil/leucovorin or no adjuvant chemotherapy. However, in GG, there was no difference among treatment regimens. Using multivariate analyses, the Arg388 carriers, together with age, N stage, poor differentiation, absence of a lymphocyte response, and no adjuvant chemotherapy, had a significantly worse OS than patients with the Gly388 allele. In transfected colon cancer cells, overexpression of Arg388 significantly increased cell proliferation and changes in epithelial to mesenchymal transition markers compared with cells overexpressing the Gly388 allele.The Arg388 allele of FGFR4 may be a biomarker and a candidate target for adjuvant treatment of patients with resected colon cancer.

We report a case of severe hypothyroidism in a cholangiocarcinoma patient with metastasis to the thyroid gland. A 58-year-old man was admitted for upper abdominal discomfort and multiple palpable neck nodules. Abdominal computed tomography (CT) demonstrated the presence of a 4.7-cm tumor in the right hepatic lobe, and core needle biopsy revealed it to be cholangiocarcinoma. Neck CT showed a diffuse, low attenuation thyroid gland, and fine-needle aspiration (FNA) demonstrated metastatic adenocarcinoma. Thyroid function tests were initially normal, but the size of the thyroid gland decreased and severe hypothyroidism developed after chemotherapy was implemented for cholangiocarcinoma. In a patient with malignant disease and a goiter, the possibility of a metastatic tumor involving the thyroid should be seriously considered. Metastatic thyroid cancer and thyroid dysfunction are probably infrequent, but diagnosis is important in the institution of appropriate therapy. Key words: Cholangiocarcinoma, Thyroid metastasis, Hypothyroidism

Conjugated linoleic acid-coupled Pluronic F127 (Plu-CLA) is an effective drug delivery system with numerous advantages and anti-cancer activity. 5-FU administered in Plu-CLA hydrogel (P-FU) led to the significant enhancement of tumor growth suppression and cellular apoptosis. Moreover, growth of hepatic and intraperitoneal metastases in vivo was significantly reduced in mice treated with P-FU. Therefore, Plu-CLA could be a potential intraperitoneal carrier for hydrophilic 5-FU for the effective treatment of metastatic colon cancer.

The purpose of this study was to evaluate the efficacy and tolerability of weekly docetaxel, cisplatin, and S-1 (weekly TPS) as induction chemotherapy for patients with locally advanced head and neck squamous cell carcinoma (HNSCC).A total of 35 patients with previously untreated, locally advanced HNSCC were enrolled. Seven patients (20%) were diagnosed with stage III HNSCC and 28 patients (80%) were diagnosed with stage IV. Induction treatment included 30 mg/m(2) docetaxel on day 1 and 8, 60 mg/m(2) cisplatin on day 1, and 70 mg/m(2) S-1 on days 1 to 14. The regimen was repeated every 21 days. After three courses of induction chemotherapy, patients received concurrent chemoradiotherapy.Among the 35 patients, 30 (85.7%) completed induction chemotherapy. The response to induction chemotherapy was as follows: nine patients (25.7%) achieved a complete response (CR) and the overall response rate (ORR) was 85.7%. Grades 3-4 toxicity during induction therapy included neutropenia (28.5%), neutropenic fever (8.5%), and diarrhea (17.1%). After completion of concurrent chemoradiotherapy, the CR rate was 62.8% and the partial response (PR) was 22.8%. Estimates of progression-free and overall survival at 2 years were 73.2% and 79.3%, respectively.Weekly TPS is a promising regimen that is well-tolerated, causes minimal myelosuppression and is effective as an outpatient regimen for locally advanced HNSCC.ClinicalTrials.gov: NCT01645748.

Two recent genome-wide association studies have identified that the rs2274223 single-nucleotide polymorphism inphospholipase C epsilon 1 and the single-nucleotide polymorphism rs13042395 in C20orf54 are involved in esophageal squamous cell carcinoma (ESCC) in Chinese populations. We hypothesized that genetic polymorphisms of phospholipase C epsilon 1 and C20orf54 are also associated with ESCC in a Korean population. The rs2274223 and rs13042395 genotyping was performed using high-resolution melting analysis. The rs2274223 GG genotype was significantly associated with an increased risk of ESCC (odds ratio [OR]=1.86, 95% confidence interval [CI]=1.08-3.25) compared with the rs2274223 AA genotype. The rs13042395 G allele showed a significantly decreased risk of ESCC in the younger age group (OR=0.71, 95% CI=0.52-0.97) and no significant association in the older group (OR=1.19, 95% CI=0.87-1.62). We observed that the rs2274223 polymorphism was associated with an increased risk of ESCC in this Korean case-control study and that age may modify the association between the rs13042395 polymorphism and the risk of ESCC.

To investigate the effects of hepatic arterial infusion chemotherapy (HAIC) with or without systemic chemotherapy compared to systemic chemotherapy alone in patients with locally advanced hepatocellular carcinoma (HCC).Following a registered protocol (PROSPERO 2023 CRD42023386780 Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023386780), a comprehensive search was performed using reputable databases and registries up to December 26, 2022, with no language, publication date, or status restrictions. Only randomized controlled trials (RCTs) investigating the effects of HAIC with or without systemic chemotherapy versus systemic therapy alone were included. The primary outcomes were overall survival (OS), progression-free survival (PFS), and adverse events. The secondary outcomes included the objective response rate (ORR) and disease control rate (DCR). A random-effects model was used, and the certainty of the evidence was rated using GRADE.Seven RCTs involving 1,010 patients were included. All trials utilized sorafenib as the comparator. Five trials (690 patients) compared HAIC plus sorafenib to sorafenib alone, while two trials (320 patients) compared HAIC to sorafenib. The results indicate that HAIC, with or without sorafenib, may increase OS, PFS, and ORR compared with sorafenib alone. HAIC may enhance DCR, but the evidence is very uncertain. Adverse events were comparable between HAIC plus sorafenib and sorafenib alone. However, adverse events might be decreased in HAIC alone.HAIC with or without systemic chemotherapy may improve survival outcomes and response rates of patients with HCC. Since the current body of evidence is moderate to very low, more robust randomized trials are needed to confirm the efficacy of HAIC.https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=386780, identifier CRD42023386780.

This phase II study evaluated the efficacy and safety of combination chemotherapy with paclitaxel, cisplatin, and 5-fluorouracil (5-FU) in advanced gastric cancer. Patients with histologically confirmed gastric adenocarcinoma were eligible for the study. Paclitaxel (175 mg/m(2)) and cisplatin (75 mg/m(2)) were given as a 1-hr intravenous infusion on day 1, followed by 5-FU (750 mg/m(2)) as a 24-hr continuous infusion for 5 days. This cycle was repeated every 3 weeks. Forty-five eligible patients (median age, 56 yr) were treated in this way. Of the 41 patients in whom efficacy was evaluable, an objective response rate (ORR) was seen in 51.2% (95% CI, 0.35-0.67), a complete response in two, and a partial response in 19 patients. The median progression free survival was 6.9 months (95% CI, 5.86-7.94 months), and the median overall survival was 12.7 months (95% CI, 9.9-15.5). The main hematological toxicity was neutropenia and greater than grade 3 neutropenia was observed in twelve patients (54%). Febrile neutropenia developed in three patients (6.8%). The major non-hematological toxicities were asthenia and peripheral neuropathy, but most of patients showed grade 1 or 2. In conclusion, combination chemotherapy with paclitaxel, cisplatin, and 5-FU is a promising regimen, and was well tolerated in patients with advanced gastric cancer.

While recently extending that research, however, we discovered that 236 members of the general population were mistakenly duplicated by the investigating agency (Word Research) and 1241 were reported rather than 1005. Here, we present corrections and discuss the relevant data.

Medullary thyroid cancer (MTC) is a calcitonin (Ct)-secreting tumor of the parafollicular or C cells of the thyroid gland. Higher serum Ct levels are associated with larger tumor size, distant metastases, and prognosis. We report herein a case of prostate and multiple bone metastases of nonfamilial MTC with mildly elevated Ct levels.A 73-year-old man who was found to have a 2.5 cm MTC in the left thyroid lobe with cervical lymph node metastases presented with confused mental status because of severe hypercalcemia (albumin-modified serum calcium concentration 15.2 mg/dL) associated with multiple bone metastases. Prostate biopsy was performed because the patient had frequent urination with mildly elevated serum prostate-specific antigen (5.297 ng/mL). Histologically, the prostate was diagnosed as MTC metastasis, forming a tissue architecture closely resembling the previously diagnosed MTC, and the cells were positive for Ct, carcinoembryonic antigen, and thyroid transcription factor 1. Although the patient had multiple MTC metastases, basal and calcium-stimulated serum Ct levels were not significantly elevated, measuring 22.7 pg/mL (normal <10 pg/mL) and 22.1 pg/mL, respectively.A chronic hypercalcemic state may exhaust Ct reserves and diminish the Ct response to an acute intravenous calcium injection. Therefore, the Ct level of a patient in a hypercalcemic state should be carefully interpreted. To our knowledge, this is the first reported case in the literature in which serum Ct levels were not significantly increased when associated with hypercalcemia, and an MTC metastasis to the prostate.

Extra-pulmonary neuroendocrine carcinoma is a rare and aggressive cancer. Although several biological and histological markers have been suggested as prognostic factors for this cancer, the prognostic importance of systemic inflammatory markers, including the neutrophil-lymphocyte ratio and platelet-lymphocyte ratio, is unclear. This study aimed to evaluate the association between systemic inflammatory markers and the prognosis of extra-pulmonary neuroendocrine carcinoma. We retrospectively analyzed the clinical data of 85 patients with unresectable or metastatic extra-pulmonary neuroendocrine carcinoma who received platinum-based chemotherapy as first-line chemotherapy from August 2007 to November 2019. We used time-dependent receiver operating characteristic curve analysis to determine the cut-off values. The cut-off values for the neutrophil-lymphocyte ratio and platelet-lymphocyte ratio were 3.0 and 158.5, respectively. There was no significant difference in the Eastern Cooperative Oncology Group performance status score, Ki-67 index, or response to chemotherapy between groups. The high neutrophil-lymphocyte ratio group showed significantly worse overall survival (high vs. low, median 11.1 vs. 21.0 months, log-rank p=0.004) and shorter median progression-free survival, but the latter was not statistically significant. The high platelet-lymphocyte ratio group also showed significantly worse progression-free survival and overall survival than the low platelet-lymphocyte ratio group (high vs. low: median 5.6 vs. 9.8 months, log-rank p=0.047 and median 13.8 vs. 21.0 months, log-rank p=0.013, respectively). In multivariable analysis, a high neutrophil-lymphocyte ratio was an independent prognostic factor for overall survival. The neutrophil-lymphocyte ratio is a potent and readily available prognostic factor for extra-pulmonary neuroendocrine carcinoma.

The influence of online comment sections on the news has increased based on the development of collective online behaviors in the digitalized news media era. In this study, we focus on the effect of comment order (e.g., sorting comments by the number of likes or by the time of posting) on the formation of public opinion. We explore whether reading comments sorted by number of likes (a) induces more comments from users, (b) increases the expression of user opinions in response to others’ comments through the action of liking or disliking comments and (c) consolidates user opinion. For the empirical verification of the effects of popularity metrics, we chose a common topic (increasing minimum wage), collected actual data (reviewing 3,251 articles and the numbers of associated comments, likes, and dislikes), and compared news categories based on the existence of popularity metrics. Semantic network analysis was conducted with UCINET and python for K-means clustering, and cosine similarity. Our results show how the comment order in the internet news environment affects the commenting behavior of news consumers.

This study was conducted to evaluate the long term complications and their risk factors including of survival outcomes in patients with locally advanced nasopharyngeal cancer (NPC) treated with docetaxel, cisplatin and 5-fluorouracil (TPF) induction chemotherapy followed by concurrent chemoradiotherapy (CCRT).Among the patients who were diagnosed as NPC, we consecutively evaluated the late complications in 104 patients who completed 3 cycles of TPF induction chemotherapy followed by CCRT and received regular follow-up by otolaryngologist and oncologist. The prognostic factors for overall survival, relapse free survival and each complication were analyzed based on clinical characteristics.Over a median follow-up of 54 months (range, 7.9-152.9 months), 5-year overall survival rate was 87% for stage II, 89% for stage III, 87% for stage IV patients. The significant prognostic factor for survival is complete response rate after CCRT in multivariate analysis. The most frequent toxicity was ear complication (29.8%) including of hearing loss requiring hearing aid (6.7%) and bone necrosis (3.8%). Decreased renal function over grade 2 was occurred in only 4 patients (3.8%) regardless of the cumulative dose of cisplatin. The long term complications did not affect the survival outcome. Patients who received radiation therapy more than 5400 cGy had better survival outcome than those who did not. However, ear complication was significantly related to radiation dose (≥ 6,600 cGy) and type of radiation therapy (conventional). Age over 65 years was a significant risk factor for both ear and renal toxicity. In conclusion, close follow-up to monitor long-term complications should be performed in patients treated with TPF induction chemotherapy followed by CCRT treatment, especially in elderly patients. Reestablishing the optimal chemotherapeutic agent during CCRT and adjustment of radiation dose after induction chemotherapy could be helpful to reduce the toxicity associated with the subsequent treatment strategy for locally advance NPC patients.

The alkylating agent ifosfamide is an anti-neoplastic used to treat various pediatric and adult malignancies. Its potential urologic toxicities include glomerulopathy, tubulopathy and hemorrhagic cystitis. This report describes a case of proximal renal tubular dysfunction and hemorrhagic cystitis in a 67-year-old male given ifosfamide for epitheloid sarcoma. He was also receiving an oral hypoglycemic agent for type 2 diabetes mellitus and had a baseline glomerular filtration rate of 51.5 mL/min/1.73 m(2). Despite mesna prophylaxis, the patient experienced dysuria and gross hematuria after a single course of ifosfamide plus adriamycin. The abrupt renal impairment and serum/urine electrolyte imbalances that ensued were consistent with Fanconi's syndrome. However, normal renal function and electrolyte status were restored within 14 days, simply through supportive measures. A score of 8 by Naranjo adverse drug reaction probability scale indicated these complications were most likely treatment-related, although they developed without known predisposing factors. The currently undefined role of diabetic nephropathy in adult ifosfamide nephrotoxicity merits future investigation.

Primary non-Hodgkin's lymphoma of bone (PLB) is rare, and generally presents as a single extensive and destructive bone lesion. Histopathologically, most cases present as diffuse large B-cell lymphoma, and T-cell lymphoma is rare. By contrast, multiple myeloma is a disease defined as the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. We report a case of multiple myeloma that developed during treatment of PLB in a type of T-cell. A 48-yr-old man was diagnosed as T-cell PLB, stage IE, 18 months ago. The patient received the chemoradiotherapy and salvage chemotherapy for PLB. However, the lymphoma progressed with generalized bone pain, and laboratory findings showed bicytopenia and acute renal failure. On bone marrow biopsy, the patient was diagnosed as having multiple myeloma newly developed with primary T-cell lymphoma of bone. In spite of chemotherapy, the patient died of renal failure.

Second-generation tyrosine kinase inhibitors (second TKIs) such as nilotinib and dasatinib control the activity of most ABL kinase domain mutations observed in patients with imatinib resistance. Although in vitro data show that both agents can inhibit all mutations except T315I, some discrepancies have been observed in a small subset of mutation clones. Cytogenetic clonal evolution is the important resistance mechanism of chronic myeloid leukemia (CML). Accordingly, we observed the clinical significance of coexisting with clonal evolution and BCR-ABL mutant in CML patients treated with second TKIs.We monitored BCR-ABL transcript kinetics, interrelationship of clones expressing non-mutated and mutant transcripts and clonal aberrations within Philadelphia (Ph) positive and negative clones, respectively, in eight patients with CML receiving dasatinib or nilotinib for 3~41 months.Clinical responses were correlated with in vitro sensitivity of the BCR-ABL mutants to the second TKIs in four patients. Four patients showed resistance to the second TKIs as compared to in vitro observations; three of them developed chromosomal abnormalities in the Ph chromosome positive or negative metaphases. Another patient lost the original mutation but acquired a more resistant new mutation and became resistant to the second TKI.Cytogenetic clonal evolution is an independent poor prognostic factor in CML, which could explain the onset of mechanisms for second TKIs resistance to ABL kinase domain mutations. The results indicate that an additional evaluation of chromosomal abnormalities is warranted when BCR-ABL mutants are more resistant than indicated by in vitro data.

Background/Aims: The palliative prognostic index (PPI) was designed to predict life expectancy based on clinical symptoms. In this study, a PPI was constructed and used with other biological parameters to predict 3-week survival in patients with advanced cancer. Methods: The study included 222 patients. The PPI was constructed with five variables (performance status, oral intake, edema, dyspnea at rest, and delirium). PPI scores were grouped as follows: 4 (group 1); > 4 and ≤ 6 (group 2); and > 6 (group 3). At admission, seven biological variables (white blood cell count, lymphocyte, C-reactive protein [CRP], bilirubin, albumin, creatinine, and lactate dehydrogenase) were measured. Results: The overall survival duration was 50 days in group 1, 22 days in group 2, and 14 days in groups 3. Using the PPI, a survival of 6 and increases in serum bilirubin and CRP levels. Furthermore, the 3-week survival rate in patients with hepatopancreatobiliary cancer was more accurately predicted using a combination of the PPI, CRP, and serum bilirubin levels. Conclusions: Although a PPI has limitations, it can be quickly applied to determine survival duration in patients admitted to hospice and accurately predicts 3-week survival. Furthermore, bilirubin and CRP are useful factors for predicting 3-week survival in patients with gastrointestinal cancer, including hepatopancreatobiliary cancer. (Korean J Med 2011;81:359-365)

Adjuvant chemotherapy using TS-1 or capecitabine plus oxaliplatin improves survival outcomes after radical gastrectomy, with both regimens showing similar efficacies.A total of 494 patients with stage II-III gastric cancer who underwent curative D2 gastrectomy and received adjuvant chemotherapy from April 2004 to June 2014 were included in this study.219 patients received TS-1, and 275 received platinum-based chemotherapy.The disease-free survival associated with adjuvant chemotherapy with TS-1 was compared with that associated with fluoropyrimidine plus platinum chemotherapy to identify the subgroups that would benefit most from platinum-based chemotherapy.The platinum group consisted of younger individuals, more males and more stage III patients compared with the TS-1 group.To reduce selection bias and its effects on treatment results, we performed a propensity score-matched analysis.The matched cohort consisted of 219 TS-1 and 219 platinum treatment patients, respectively.In the matched cohort, the chemotherapeutic regimen did not affect disease-free survival according to stage (stage II: platinum vs. TS-1, P = 0.348; stage III: P = 0.132).According to the subgroup analysis, platinum-based chemotherapy resulted in an improved 3-year disease-free survival compared with TS-1 treatment (66.8% vs. 57.8%,P = 0.015) for patients with high-risk features (any two or more of pT4, pN3, and lymphovascular invasion positivity).Our results suggest that TS-1 alone is acceptable for patients without high-risk features, while platinum-based adjuvant chemotherapy should be administered to patients with high-risk features in D2-resected gastric cancer.www.impactjournals.com/oncotarget

e14613 Background: Almost all patients with advanced gastric cancer will eventually develop progressive disease after first-line chemotherapy. However, the role of subsequent salvage chemotherapy remains controversial. The purpose of this study was to evaluate the prognostic factors of the survival of advanced gastric cancer patients who received third-line chemotherapy. Methods: We reviewed 502 advanced gastric cancer patients who received palliative chemotherapy at the Onocology Department of Hwasun Chonnam National University Hospital (2004–2008). Among them, 174 received third-line chemotherapy. To evaluate the clinicopathologic factors that affect overall survival, uni- and multivariate analyses were performed on the baseline factors before beginning third-line chemotherapy. Results: Multivariate analysis found 4 prognostic factors affecting poor survival following third-line chemotherapy: a performance status of 2 to 3 (HR, 1.46; 95% CI, 1.06–2.02; P = 0.022), serum albumin level <4 mg/dL (HR, 1.82; 95% CI, 1.32–2.53; P < 0.00), poor histologic type (HR, 1.77; 95% CI, 1.27–2.47; P = 0.001), and a progression-free survival of <2.7 months following second-line chemotherapy (HR, 1.51; 95% CI, 1.09–2.08; P = 0.012). A prognostic index was constructed, dividing patients into low- (0 to 1 factor), intermediate- (2 or 3 risk factors), or high- (4 risk factors) risk groups. Median survival times for each group were 11.8, 6.7, and 3.3 months, respectively (P < 0.00). Conclusions: This analysis suggests that some clinicopathologic factors might be helpful in identifying the subgroup of patients most likely to benefit from third-line chemotherapy for advanced gastric cancer.

Abstract Background Intratumor heterogeneity is a hallmark of most solid tumors, including breast cancers. We applied spatial transcriptomics and single-cell RNA-sequencing technologies to profile spatially resolved cell populations within estrogen receptor-positive (ER + ) metastatic breast cancers and elucidate their importance in estrogen-dependent tumor growth. Methods Spatial transcriptomics and single-cell RNA-sequencing were performed on two patient-derived xenografts (PDXs) of “ER-high” metastatic breast cancers with opposite estrogen-mediated growth responses: estrogen-suppressed GS3 (80–100% ER) and estrogen-stimulated SC31 (30–75% ER) models. The analyses included samples treated with and without 17β-estradiol. The findings were validated via scRNA-seq analyses on “ER-low” estrogen-accelerating PDX, GS1 (5% ER). The results from our spatial and single-cell analyses were further supported by the analysis of a publicly available single cell dataset and a protein-based dual immunohistochemical (IHC) evaluation using three important clinical markers [i.e., ER, progesterone receptor (PR), and Ki67]. The translational implication of these results was assessed by clinical outcome analyses on public breast cancer cohorts. Results Our novel space-gene-function study revealed a “proliferative” cell population in addition to three major spatially distinct compartments within ER + metastatic breast cancers. These compartments showed functional diversity (i.e., estrogen-responsive, proliferative, hypoxia-induced, and inflammation-related). The “proliferative ( MKI67 + )” population, not “estrogen-responsive” compartment, was crucial for estrogen-dependent tumor growth, leading to the acquisition of luminal B features. The cells with induction of typical estrogen-responsive genes such as PGR were not directly linked to estrogen-dependent proliferation. Additionally, the dual IHC analyses demonstrated the distinct contribution of the Ki67 + proliferative cells toward estrogen-mediated growth and their response to palbociclib, a CDK4/6 inhibitor. The gene signatures developed from the proliferative, hypoxia-induced, and inflammation-related compartments were significantly correlated with worse clinical outcomes, while patients with the high estrogen-responsive scores showed better prognosis, confirming that the estrogen-responsive compartment would not be directly associated with estrogen-dependent tumor progression. Conclusions For the first time, our study elucidated a “proliferative” cell population distinctly distributed in ER + metastatic breast cancers. They contribute differently toward progression of these cancers, and the gene signature in the “proliferative” compartment is an important determinant of luminal cancer subtypes.

Breslow thickness, ulceration, and mitotic rate are well-known prognostic factors for sentinel lymph node (SLN) metastasis in cutaneous melanoma. We investigated risk factors, including especially the degree of pigmentation, for SLN metastasis in Korean melanoma patients. We enrolled 158, composed of Korean 107 acral and 51 non-acral melanoma patients who underwent SLN biopsy. Clinicopathologic features such as Breslow thickness, ulceration, mitotic rate, and the degree of pigmentation were evaluated. The recurrence-free survival (RFS) rate and date of recurrence were determined. Fifty-four patients (34.2%) had a positive SLN biopsy result. In a multivariate analysis, Breslow thickness (odds ratio [OR] 1.93; 95% confidence interval [CI], 1.12-3.47; p = .022) and heavy pigmentation (OR 13.14; 95% CI, 2.96-95.20, p = .002) were associated with SLN metastasis. Positive SLN patients had a higher rate of loco-regional and/or distant recurrence (hazard ratio 6.32; 95% CI, 3.39-11.79; p < .001). Heavy pigmentation was associated with poor RFS. Heavy pigmentation is an independent predictor of SLN metastasis in both acral and non-acral melanoma. Our results suggest the need for in-depth SLN evaluation of cutaneous melanoma patients with heavy pigmentation and provide clinicians with important information for determining patient prognosis.

Recombinant immunotoxins (RITs) are fusion proteins consisting of a targeting domain linked to a toxin, offering a highly specific therapeutic strategy for cancer treatment. In this study, we engineered and characterized RITs aimed at mesothelin, a cell surface glycoprotein overexpressed in various malignancies. Through an extensive screening of a large nanobody library, four mesothelin-specific nanobodies were selected and genetically fused to a truncated Pseudomonas exotoxin (PE24B). Various optimizations, including the incorporation of furin cleavage sites, maltose-binding protein tags, and tobacco etch virus protease cleavage sites, were implemented to improve protein expression, solubility, and purification. The RITs were successfully overexpressed in Escherichia coli, achieving high solubility and purity post-purification. In vitro cytotoxicity assays on gastric carcinoma cell lines NCI-N87 and AGS revealed that Meso(Nb2)-PE24B demonstrated the highest cytotoxic efficacy, warranting further characterization. This RIT also displayed selective binding to human and monkey mesothelins but not to mouse mesothelin. The competitive binding assays between different RIT constructs revealed significant alterations in IC50 values, emphasizing the importance of nanobody specificity. Finally, a modification in the endoplasmic reticulum retention signal at the C-terminus further augmented its cytotoxic activity. Our findings offer valuable insights into the design and optimization of RITs, showcasing the potential of Meso(Nb2)-PE24B as a promising therapeutic candidate for targeted cancer treatment.

This dataset includes all the relevant codes and data files associated with the paper ("Molecular features of luminal breast cancer defined through spatial and single-cell transcriptomics") in Clinical and Translational Medicine journal.

This dataset includes all the relevant codes and data files associated with the paper ("Molecular features of luminal breast cancer defined through spatial and single-cell transcriptomics") in Clinical and Translational Medicine journal.

Depression is common in terminally ill cancer patients, and the management of depression in these patients is very important because this condition is associated with distress, suicidal ideation, and decreased quality of life. Antidepressants and psychostimulants are frequently used in the pharmacological treatment of depression in terminally ill cancer patients. The effectiveness of several Selective Serotonin Reuptake Inhibitors (SSRIs) for the treatment of depression in this population has been reported; however, such improvement only occurred approximately 2-4 weeks after the medications were initiated. Psychostimulants offer the advantage of rapid action, an especially important consideration given that terminally ill patients have a short life expectancy. Moreover, methylphenidate has been reported as reversing the sedating effect of opioids, decreasing fatigue, and reducing pain. However, the adverse effect of methylphenidate must be considered. Additionally, psychotherapy also seems to improve depression and anxiety. Members of the treatment teams delivering palliative care often experience emotional burnout. Because emotional burnout results in depression and depersonalization, psychological care for the treatment team is crucial. The end-of-life period of patients is very important because it is the time at which individuals review their lives. Management of the depression in these patients will improve their quality of life and contribute to resolving their end-of-life issues. Korean J Psychopharmacol 2010;21:51-61

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Despite the increasing need for geriatric assessment prior to chemotherapy, the method for this assessment remains inadequate for older cancer patients. We aimed to propose a simple assessment method to predict the performance of adjuvant chemotherapy in older patients after colon cancer surgery.This prospective study included patients over 65 years of age who were scheduled for adjuvant chemotherapy after colon cancer surgery. Before initiating chemotherapy, their functional status was assessed on the basis of activities of daily living (ADL)/instrumental activities of daily living (IADL). These parameters were analyzed with clinical characteristics and the patterns of adjuvant chemotherapy. The focus was on the completion rate of adjuvant chemotherapy.A total of 89 patients with a median age of 72 years were analyzed. Among them, 54 (61%) were non-impaired and 35 (39%) were impaired regarding their ADL/IADL classification. Low body mass index and impairment of ADL/IADLs were significantly associated with chemotherapy interruption. Among toxicities, fatigue and hand-foot syndrome were independent prognostic factors for chemotherapy interruption. Impairments of ADL/IADL were significantly associated with fatigue regardless of age. Based on age and ADL/IADL stratification, younger patients (≤ 72 years) and/or those who were ADL/IADL non-impaired were significantly more likely to complete adjuvant chemotherapy than older patients (> 72 years) and ADL/IADL impaired patients (p = 0.038). This was regardless of the chemotherapy regimen.Functional assessment using ADL/IADL is a convenient method to predict chemotherapy toxicity and performance. These results suggested that routine screening for ADL/IADLs could guide appropriate patient selection for the completion of adjuvant chemotherapy and predict expected outcomes.

The purpose of this study was to evaluate the dosage of dexamethasone in combination with granisetron and aprepitant when used for the prevention of acute and delayed nausea and vomiting in patients receiving high-dose cisplatin chemotherapy. The study was retrospective. Ninety-two patients received cisplatin (≥50 mg/m 2 ) and either a high-dose (Group I, n=57) or low-dose (Group II, n=35) regimen of dexamethasone. The high-dose regimen consisted of intravenous administration of 20 mg on day 1 and 8 mg on days 2∼4. The low-dose regimen consisted of intravenous administration of 10 mg before cisplatin and oral dexamethasone 4 mg on days 2∼4. Both groups received granisetron and aprepitant. The primary endpoint was complete response over 5 days following cisplatin administration. In the acute phase, complete response occurred in 87.7% of Group I and 91.4% of Group II patients (p=0.58). In the delayed phase, the proportions of patients without emesis in Groups I and II were 84.2% and 65.7%, respectively (p=0.04). In the overall phase, the complete response rates in Groups I and II were 80.7% and 65.7%, respectively (p=0.11). The high-dose dexamethasone regimen is superior to the low-dose in preventing delayed chemotherapy-induced nausea and vomiting, with no significant differences evident in the acute and overall phases. The high-dose dexamethasone regimen should be considered as a standard antiemetic therapy for cisplatin-treated patients.

e21503 Background: Venous thromboembolism (VTE) is common in patients with cancer and the risk increases with advanced disease. However, no management guidelines exist specific to terminal cancer patients in hospice. We conducted a retrospective analysis to determine the patterns of anticoagulant use in hospice setting. Methods: We identified patients who were prescribed anticoagulants in the Hospice and Palliative Care Clinic at Jeonnam Regional Cancer Center from August 2008 to September 2016 in this study. Patient characteristics included age, gender, cancer diagnosis, length of hospice stay, type and duration of anticoagulation. Results: Of 1,494 consecutive patients who received hospice care in our center, 57 (3.8%) were prescribed ≥ 1 anticoagulants. Types of anticoagulants prescribed were; LMWH only (n = 44, 77.2%), warfarin only (n = 7, 12.3%), rivaroxaban (n = 2, 3.5%) and both LMWH and warfarin (n = 4, 7%). Indications for anticoagulation were DVT (n = 17, 29.8%), PTE (11 = 19.3%), clinical suspicion of DVT with leg swelling (n = 23, 40.4%) and atrial fibrillation (n = 6, 10.5%), respectively. The mean age was 65 years (range 28-84) and 37 (52.6%) were male. The mean age was 63.5 years in LMWH treated patients and 67 years in warfarin treated patients (p &lt; 0.95). The median duration of hospice stay and anticoagulation use were 18.5 days and 11.2 days. The reasons for discontinuation of anticoagulants were bleeding (n = 8, 14%), no palliative benefit (n = 10, 17.5%) and clinical signs of impending death (n = 39, 68.4%). Conclusions: In this retrospective study, anticoagulants were used in highly selected patients. In the absence of specific evidence, decisions are difficult for clinicians to initiate and stop anticoagulation treatment in hospice patients with terminal cancer. Further research is needed to determine the impact of anticoagulation on outcomes, especially cost, quality of life and complications for cancer patients in hospice.

e14549 Background: The optimal treatment of advanced esophageal cancer remains a controversial subject. To improve dysphagia, chemoradiotherapy (CRT) has been considered as a useful treatment for patients (pts) with unresectable esophageal cancer. This study was conducted to evaluate the clinical outcomes and safety of concurrent CRT with weekly docetaxel and cisplatin in advanced esophageal cancer. Methods: Patients with locally advanced or metastatic esophageal squamous cell carcinoma, who have adequate organ function were eligible. During CRT, docetaxel and cisplatin were given at a dose of 20 mg/m2 and 25 mg/m2, respectively at D1, D8, D15. The cycle of this treatment was 28 days. Two cycles of chemotherapy was done during radiotherapy. Radiotherapy was started at a dose of 200 cGy/day, up to a total of 5400 cGy. Results: Up to December 2009, 31 pts were enrolled. Among them 30 pts (97%) completed the planned CRT. The median age was 61 years (range: 45- 72); male/female = 29/2; ECOG performance status was 0/1/2 = 12/15/4; stage IIb/III/IVa/IVb = 3/16/3/9. Complete response was achieved in 7 pts (22.6%), partial response in 19 (61.3%), stable disease in 2 (6.5 %), progressive disease in 2 (6.5%) and 1 (3.2%) patient was not evaluable. Therefore, the overall response rate was 83.9% (95% CI, 70.9-96.8). The CRT related grade 3-4 hematologic toxicities were rarely observed: leucopenia (3.2%) and non-febrile neutropenia (3.2%) The most common non hematologic toxicity was esophagitis. Grade 3 or 4 of esophagitis has been developed in 5 pts (16.1%) and asthenia in 1 patient (3.2%). Improvement of dysphagia after CRT had been shown in 21 pts among 28 pts (67.7%) who had complained of dysphagia at the time of diagnosis. A clinically meaningful improvement in dysphagia was found after 27 days of the first treatment. At a mean follow-up of 16 months, the estimated 1-year progression-free survival rate and overall survival rate was 35.5% and 41.9% respectively. Conclusions: The concurrent CRT with weekly docetaxel and cisplatin was safe and well tolerated in pts with advanced esophageal cancer in the outpatient setting. This result indicated promising activity both in tumor control and in symptom control. No significant financial relationships to disclose.

The Breast JournalVolume 15, Issue 2 p. 202-203 Metastatic Breast Cancer Presenting as Cancer of Unknown Primary Associated with Superior Vena Cava Syndrome Hyun-Jeong Shim MD, PhD, Hyun-Jeong Shim MD, PhD Department of Hemato-Oncology, Chonnam National University Medical School, Gwangju, KoreaSearch for more papers by this authorSe-Ryeon Lee MD, PhD, Se-Ryeon Lee MD, PhD Department of Hemato-Oncology, Chonnam National University Medical School, Gwangju, KoreaSearch for more papers by this authorJae-Sok Ahn MD, PhD, Jae-Sok Ahn MD, PhD Department of Hemato-Oncology, Chonnam National University Medical School, Gwangju, KoreaSearch for more papers by this author Duk-Hwan Yang MD, PhD, Duk-Hwan Yang MD, PhD Department of Hemato-Oncology, Chonnam National University Medical School, Gwangju, KoreaSearch for more papers by this authorYeo-Kyeoung Kim MD, PhD, Yeo-Kyeoung Kim MD, PhD Department of Hemato-Oncology, Chonnam National University Medical School, Gwangju, KoreaSearch for more papers by this authorSang-Hee Cho MD, PhD, Sang-Hee Cho MD, PhD Department of Hemato-Oncology, Chonnam National University Medical School, Gwangju, KoreaSearch for more papers by this authorJe-Jung Lee MD, PhD, Je-Jung Lee MD, PhD Department of Hemato-Oncology, Chonnam National University Medical School, Gwangju, KoreaSearch for more papers by this authorHyeoung-Joon Kim MD, PhD, Hyeoung-Joon Kim MD, PhD Department of Hemato-Oncology, Chonnam National University Medical School, Gwangju, KoreaSearch for more papers by this author Ik-Joo Chung MD, PhD, Ik-Joo Chung MD, PhD Department of Hemato-Oncology, Chonnam National University Medical School, Gwangju, KoreaSearch for more papers by this author Hyun-Jeong Shim MD, PhD, Hyun-Jeong Shim MD, PhD Department of Hemato-Oncology, Chonnam National University Medical School, Gwangju, KoreaSearch for more papers by this authorSe-Ryeon Lee MD, PhD, Se-Ryeon Lee MD, PhD Department of Hemato-Oncology, Chonnam National University Medical School, Gwangju, KoreaSearch for more papers by this authorJae-Sok Ahn MD, PhD, Jae-Sok Ahn MD, PhD Department of Hemato-Oncology, Chonnam National University Medical School, Gwangju, KoreaSearch for more papers by this author Duk-Hwan Yang MD, PhD, Duk-Hwan Yang MD, PhD Department of Hemato-Oncology, Chonnam National University Medical School, Gwangju, KoreaSearch for more papers by this authorYeo-Kyeoung Kim MD, PhD, Yeo-Kyeoung Kim MD, PhD Department of Hemato-Oncology, Chonnam National University Medical School, Gwangju, KoreaSearch for more papers by this authorSang-Hee Cho MD, PhD, Sang-Hee Cho MD, PhD Department of Hemato-Oncology, Chonnam National University Medical School, Gwangju, KoreaSearch for more papers by this authorJe-Jung Lee MD, PhD, Je-Jung Lee MD, PhD Department of Hemato-Oncology, Chonnam National University Medical School, Gwangju, KoreaSearch for more papers by this authorHyeoung-Joon Kim MD, PhD, Hyeoung-Joon Kim MD, PhD Department of Hemato-Oncology, Chonnam National University Medical School, Gwangju, KoreaSearch for more papers by this author Ik-Joo Chung MD, PhD, Ik-Joo Chung MD, PhD Department of Hemato-Oncology, Chonnam National University Medical School, Gwangju, KoreaSearch for more papers by this author First published: 09 March 2009 https://doi.org/10.1111/j.1524-4741.2009.00698.xCitations: 1 Address correspondence and reprint requests to: Sang-Hee Cho, MD, PhD, Department of Internal Medicine, Chonnam National University Hwasun Hospital, 160, Ilsimri, Hwasun-eup, Hwasun-gun, Jeollanam-do, 519-809, Korea, or e-mail: shcho@chonnam.ac.kr. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume15, Issue2March/April 2009Pages 202-203 RelatedInformation

17010 Background: This study was performed to determine the feasibility and safety of the induction chemotherapy with docetaxel, cisplatin and 5-FU (DCF) followed by concurrent cisplatin/radiotherapy for advanced nasopharyngeal cancer. Methods: Patients with histologically confirmed nasophryngeal cancer without prior treatment, ECOG PS ≤ 2, at least one measurable lesion and adequate organ functions were eligible. Docetaxel (70 mg/m2) and cisplatin (75 mg/m2) were given as an 1-h intravenous infusion on day 1, followed by 5-FU (1,000 mg/m2) as a 24-h continuous infusion for 4 days repeated every 3 weeks and subsequently received cisplatin at a dose of 100 mg/m2 every 3 weeks with radiotherapy up to 7000 cGy. Results: Nineteen patients were enrolled and their median age was 47 years. One patient was lost of follow up after 1 cycle of chemotherapy. Four patients refused radiotherapy, fourteen patients were completed treatment. Complete response was shown in 11 patients (76.8%; 95% CI, 0.49–0.95), partial response was shown in 2 (14.3%; 95% CI, 0.02–0.42) and one patient had progressive disease (7.1%; 95% CI, 0.01–0.33). Therefore, ORR was seen in 13 (92.9%). The median time to progression was 39.4 ± 14.1 months (95% CI, 11.7–67.0), and the median overall survival was not reached. The main hematological toxicity was neutropenia and leucopenia. Greater than grade 3 neutropenia were observed in 27 cycles (50%) and 14 patients (73.7%). Febrile neutropenia developed in one patient (5.3%). The major non-hematological toxicities were asthenia and nausea, but grade 3 or 4 toxicity was not seen. Conclusions: The DCF induction chemotherapy followed by cisplatin/radiotherapy for advanced nasopharyngeal cancer is effective with manageable toxicities. No significant financial relationships to disclose.

Introduction: Epigenetic mechanisms of nuclear chromatin remodeling are increasingly recognized as crucial factors in hepatocellular carcinoma (HCC). Polycomb group members Ezh1 and Ezh2 are key epigenetic regulator of embryonic stem cell identity, but their role in liver metabolism and HCC is poorly understood. Methods: To investigate the role of EZH2 and H3K27me3, mice were generated that carried Ezh1-/- and Ezh2fl/fl alleles and an Alb-Cre transgene. Mice were examined by injection of CCl4 and partial hepatectomy (PHx), and the RNA-seq and Chip-Seq analysis was determined. We checked the expression EZH2 and H3K27me3 status in 67 human HCC samples, and the gene expression by RNA-seq based on EZH2 expression. Results: Only combined loss of EZH1 and EZH2 in mouse hepatocytes caused a depletion of global H3K27me3 marks and the specific loss over ∼1900 genes. Ezh1-/-, Ezh2fl/flAlb-Cre mice exhibited regenerative nodules and concomitant periportal fibrosis. In response to chronic treatment with CCl4, all mutant mice but none of the controls showed increased hepatic degeneration and reduced ability to proliferate. After PHx, mutant mice displayed increased liver injury and a blunted regenerative response. Genome-wide analyses identified 51 genes that had lost H3K27me3 marks and their expression was significantly increased. These genes were involved in regulation of cell survival, fibrosis, and proliferation. H3K27me3 levels and liver physiology were unaffected in mice lacking either EZH1 or EZH2. The high EZH2 expression was related with poor prognosis and the expression of EZH2 was not also correlated with H3K27me3 expression in human HCC. RNA-seq analysis showed up-regulation of cell cycle and DNA replication related genes in high EZH2 expressed HCCs. Conclusion: This work demonstrates a critical redundancy of EZH1 and EZH2 in maintaining hepatic homeostasis, and non-canonical EZH2 function in HCC. This work demonstrates candidate EZH2 target genes in human HCC.

Aim/Background: The aim of the study was to assess the clinical activity and toxicity of oxaliplatin and leucovorin in combination with bolus and continuous infusion of 5-fluorouracil treated every 2 weeks (modified FOLFOX-6 regimen) in patients with adenocardinoma of unknown primary (ACUP). Methods: Previously untreated ACUP patients were enrolled and treated with oxaliplatin 100mg/m2 and leucovorin 200mg/m2 simultaneously as 2-hour infusion followed by bolus administration of 5-fluorouracil 400mg/m2 and continuous infusion of 5-fluorouracil 2400mg/m2 every 2 weeks. Response evaluation was performed every 3 cycles according to the response assessment in solid tumours version 1.1, and toxicities were assessed using the National Cancer Institute Common Toxicity Criteria for adverse events version 3.0 every 2 weeks. Results: Data from 23 patients who had been enrolled in this multicenter phase II trial between May 2009 and Nov 2014 was collected for an interim analysis. A total of 134 cycles of modified FOLFOX-6 were treated in these 23 patients. The median number of cycles of modified FOLFOX-6 was 5 (range, 1–12). Among 20 patients whose tumor responses were evaluable, 7 patients showed partial response (no complete response), which objective response rate was 35.0% (95% confidence interval: 13.2 - 52.9). The median duration of response was 3.9 months (range, 3.0–19.8). Median progression-free survival was 3.0 months (95% CI: 1.8–6.7 months) in whole patients, which was 2.4 months for non-responders and 5.8 months for responders, respectively. Adverse events of all grade occurred in 22 patients (95.7%), and a grade ≥ 3 event occurred in 7 patients (30.4%). Grade ≥ 3 hematologic toxicities occurred in 4 patients (17.4%), and grade ≥ 3 non-hematologic toxicities occurred in 6 patients (26.1%), respectively. Most common hematologic toxicities were anemia and neutropenia (78.3% and 65.2%, respectively), while nausea was most frequent non-hematologic toxicity (47.8%). Conclusions: Modified FOLFOX-6 showed modest activity in treatment-naïve patients with ACUP. Future prospective large scale study incorporating parallel molecular prediction marker study is warranted. Clinical trial identification: WHO-ICTRP ID: KCT0000410 Disclosure: All authors have declared no conflicts of interest.

Introduction: There is a lack of data about the role of further chemotherapy after standard treatment for metastatic colorectal cancer (mCRC). Rechallenge with a prior chemotherapy could be another option for selected patients to attenuate the tumor progression, however, there is no prognostic makers to select these patients. Therefore, we evaluated early tumor shrinkage (ETS) and depth of response (DoR) as clinical decision parameters, and single-nucleotide polymorphisms (SNPs) as biomarkers to choose patients who may benefit from rechallenging prior chemotherapy. Methods: We retrospectively reviewed tumor response using the Response Evaluation Criteria in Solid Tumors (RECIST 1.1), ETS and DoR after first line chemotherapy in mCRC patients with mCRC, and the clinical factors affecting survival outcomes after more than third line chemotherapy using 5-fluoropyrimidine were analyzed. In addition, survival outcomes were analyzed and combined with clinical parameters and SNPs which are known to be associated with chemotherapy response in patients who received third line chemotherapy with previous treated agents. Results: In total, 242 patients were reviewed. Overall response and ETS were found in 100 (40%) and 103 patients (42.6%), respectively, and the median DoR was 38.5 ± 30.08%. Statistically significance significant differences between ETS, DoR and survival outcomes such as PFS, PPS and OS were found. Among these, SNPs were analyzed in 170 patients. Significantly improving OS was shown in patients with XRCC1 (G399A) AG/AA genotype, DoR over 60%, ECOG performance status 0-1 and no bone metastasis. Among these patients, 88 (51.8%) received third line chemotherapy and they almost, which mostly included fluoropyrimidine rechallenge. There was survival benefit from third line chemotherapy in patients with MTHFR (C677T) CC genotype and a DoR over 60%. Conclusion: These results suggested that XRCC1 (G399A) AG/AA genotype, DoR over 60%, ECOG performance status 0-1 and no bone metastasis showed favorable OS in patients receiving conventional chemotherapy for mCRC. In addition, patients with a DoR over 60% after first line chemotherapy and MTHFR (C677T) CC genotype could get benefit from more than third line chemotherapy using fluoropyrimidine, even though it were previously used.

Abstract Background: The molecular mechanisms underlying the development of fatty liver and hepatocellular carcinoma are not fully understood. Loss of STAT5 from liver tissue results in hepatosteatosis and hepatocellular carcinoma (HCC). Enhancer of zeste homolog 2 (EZH2) mediates epigenetic silencing of gene expression and is frequently up-regulated in human HCC. STAT5 recruits EZH2, which represses a substantial subset of genes regulated by STAT5 during B lymphopoiesis. However, it is not clear if EZH2 can affect STAT5-target genes in liver. Methods: To investigate the role of STAT5 and EZH2 in liver, mice were generated that carried EZH2fl/fl alleles, STAT5fl/fl alleles, EZH2fl/flSTAT5fl/fl alleles and an Alb-Cre transgene. Lipid analysis in serum and liver, and RNA-seq were examined at 3 &amp; 8 months of age. Mice were also examined by chronic 3 months injection by carbon tetrachloride (CCl4). Results: The deletion of STAT5 in hepatocyte caused fatty liver and increased cholesterol in serum and liver. The deletion of EZH2 did not make a difference in H3K27me3 expression, and lipid in serum and liver. However, combined loss of EZH2 and STAT5 caused severe fatty liver, increase triglyceride and the ratio liver/body weight compare to STAT5 KO mice (the ratio; 0.097 vs. 0.058, p &amp;lt; 0.05). In response to 3 months treatment with CCl4, combined loss of EZH2 and STAT5 showed accelerated development of hepatocellular carcinoma at 12 months of age. Transcriptome analysis identified the expression of several genes was significantly increased (cd36, pparγ, cyp4a14, lipoprotein lipase, fasn) and decreased (nox4, bbc3, bcl2l1, cdkn2b) which were well known as STAT5 target genes in combined loss of EZH2 and STAT5. Conclusions: This work demonstrates that loss of EZH2 in liver affects the expression of STAT5 target genes and accelerates STAT5 loss mediated fatty liver and hepatocellular carcinoma development through non-methyltransferase function. Citation Format: Woo Kyun Bae, Hyun Jeong Shim, Sang Hee Cho, Ik-Joo Chung, Kyung Keun Kim. Loss of EZH2 accelerates STAT5 loss mediated fatty liver and cancer development through non-methyltransferase function. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4477.

Abstract To investigate the role of EZH1 and EZH2 in liver homeostasis, mice were generated that carried Ezh1-/- and EZH2fl/fl alleles and an Alb-Cre transgene. Only combined loss of EZH1 and EZH2 in mouse hepatocytes caused a depletion of global H3K27me3 marks and the specific loss over ∼1900 genes at 3 months of age. Ezh1-/-,Ezh2fl/flAlb-Cre mice exhibited progressive liver abnormalities manifested by development of regenerative nodules and concomitant periportal fibrosis, inflammatory infiltration and activation of A6-positive hepatic progenitor cells at 8 months of age. In response to chronic treatment with CCl4, all experimental mice but none of the controls (n = 27 each) showed increased hepatic degeneration associated with liver dysfunction and reduced ability to proliferate. After 2/3ds partial hepatectomy, mutant mice (n = 5) displayed increased liver injury and a blunted regenerative response. Genome-wide analyses at 3-months of age identified 51 genes that had lost H3K27me3 marks and their expression was significantly increased. These genes were involved in regulation of cell survival, fibrosis, and proliferation. H3K27me3 levels and liver physiology were unaffected in mice lacking either EZH1 globally or EZH2 specifically in hepatocytes. This work demonstrates a critical redundancy of EZH1 and EZH2 in maintaining hepatic homeostasis and regeneration. Next, we checked the expression EZH2 and H3K27me3 status in 67 human hepatocellular carcinoma (HCC) samples. We also checked the gene expression by the next-generation sequencing based on EZH2 expression. This work demonstrates candidate EZH2 target genes in human HCC. Citation Format: Woo Kyun Bae, Hyun Jeong Shim, Sang Hee Cho, Ik-Joo Chung, In-Kyu Park, Lothar Hennighausen. The role of methyltransferase, enhancer of zeste homolog 2 (EZH2) in mouse hepatocyte and human hepatocellular carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2304. doi:10.1158/1538-7445.AM2015-2304

Having advantage for organ preservation and systemic control, induction chemotherapy (ICT) using docetaxel, cisplatin and 5-FU (DCF) followed concurrent chemoradiotherapy (CCRT) has been used for nonsurgical management of locally advanced head and neck squamous cell carcinoma (HNSCC). Early prediction of efficacy of CCRT could be helpful to select patients with more effective in surgery than CCRT. We evaluated the role of interim 18-fluoro-2-deoxy-glucose positron emission tomography (FDG-PET) after ICT as a prediction of the efficacy of CCRT and clinical outcomes. Tumor responses were retrospectively reviewed based on Response Evaluation Criteria in Solid Tumors after ICT and CCRT in locally advanced HNSCC. FDG-PET/CT scans were performed in all patients before and after three cycles of DCF. We examined the association of metabolic response by the percentage decrease of maximum standardized uptake value (SUVmax) after ICT with complete response (CR) to CCRT and clinical outcomes including progression-free survival (PFS) and overall survival (OS). Forty-four patients with locally advanced HNSCC were evaluated with a median follow-up of 31.7 months. The SUVmax after ICT from baseline was more decreased in CR to CCRT group than non-CR group (78.8% vs. 62.5%, p = 0.004). A 78% decrease of SUVmax after ICT from baseline predicted CR after CCRT (59.3% vs. 17.6%, p = 0.012), PFS (median, not reached vs. 15.0 months, p = 0.002) and OS (median, not reached vs. 43.3 months, p = 0.005) of the patients. The SUVmax on interim FDG-PET after ICT could be useful to select patients benefitting from CCRT in locally advanced HNSCC and to predict survival outcomes.

9605 Background: Dexamethasone has a high therapeutic index for the prevention of chemotherapy-induced nausea and vomiting; however, the chronic use of high-dose glucocorticoids is associated with adrenal insufficiency. The objective of the present study was to assess the prevalence and associated factors of adrenal suppression after antiemetic dexamethasone therapy in cancer patients receiving chemotherapy. Methods: Patients who were scheduled to receive at least three cycles of highly or moderately emetogenic chemotherapy with dexamethasone as one of antiemetics were enrolled. Patients with a suppressed baseline adrenal response before chemotherapy and those administrated corticosteroids within 6 months of study commencement were excluded. Results: Between October 2010 and August 2014, 481 patients receiving chemotherapy underwent the rapid ACTH stimulation test to assess eligibility; 350 of these patients were included in the final analysis. Fifty-six patients (16.0%) showed a suppressed adrenal response in the rapid ACTH stimulation test at 3 or 6 months after the first chemotherapy with dexamethasone as an antiemetic. Multivariate analysis revealed that the incidence of adrenal suppression was significantly associated with the duration of megestrol acetate use (P< 0.001). Adrenal suppression did not correlate with age, sex, performance status, primary tumor site, tumor stage, intent of first chemotherapy, emetic risk of first chemotherapy, chemotherapeutic agents used, or the dose and duration of dexamethasone. Conclusions: This large prospective study indicates that approximately 15% of cancer patients with a normal adrenal response showed suppressed adrenal responses after antiemetic dexamethasone therapy; this was particularly significant for patients co-treated with megestrol acetate.

Patients with neurofibromatosis type 1 (NF1) are at increased risk of developing tumors throughout the gastrointestinal tract, including neuromas, gastrointestinal stromal tumors (GISTs), and periampullary somatostatin-rich carcinoids. The simultaneous occurrence of a GIST and a well-differentiated neuroendocrine carcinoma in a patient with NF1 is very rare. Here, we report two cases of the coexistence of a low-risk GIST in the jejunum with a well-differentiated neuroendocrine carcinoma in the duodenum in patients with NF1. These cases strengthen the known association of GIST with neuroendocrine carcinoma in patients with NF1. (Korean J Med 2011;81:786-791)

Abstract Thermo-responsive hydrogel consisting of conjugated linoleic acid-coupled Pluronic F127 (Plu-CLA) is an optimized drug delivery system with anti-cancer activity for controlled release of the hydrophobic drug, docetaxel. In this study, we evaluated the effect of Plu-CLA as a potential new intraperitoneal docetaxel delivery system for peritoneal dissemination of gastric cancer. We have established a peritoneal metastasis models using BALB/c mice by injection with TMK-1 human gastric cancer cells. Mice were injected intraperitoneally with docetaxel alone and docetaxel loaded Plu-CLA at 1 week after TMK1 cells were injected. Tumor progression and response to therapy were monitored by micro-positron emission tomography. The total number of peritoneal tumors and ascites volume were also measured. Compared to docetaxel alone, the combination of docetaxel and Plu-CLA significantly and synergistically reduced cell survival. The combination of docetaxel and Plu-CLA showed excellent anti-tumor activity inducing stronger apoptosis than docetaxel alone. The combination of docetaxel and Plu-CLA also significantly reduced number of peritoneal metastatic nodules and increased the survival in the peritoneal gastric cancer xenograft model. Our results showed that intraperitoneal administration of docetaxel combined with Plu-CLA synergistically inhibited peritoneal metastasis and prolonged the survival in peritoneal gastric cancer model. Therefore, Plu-CLA could be a potential intraperitoneal carrier for hydrophobic docetaxel for the effective treatment of peritoneal metastatic gastric cancer. Citation Format: Woo Kyun Bae, Lothar Hennighausen, Ji Hee Lee, Dae Eun Kim, Jun Eul Hwang, Hyun Jeong Shim, Sang Hee Cho, In-Kyu Park, Ik-Joo Chung. Intraperitoneal administration of docetaxel loaded in thermo-responsive conjugated linoleic acid-incorporated poloxamer hydrogel for the suppression of peritoneal dissemination of gastric cancer. [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 4344. doi:10.1158/1538-7445.AM2013-4344

Abstract Background: The active metabolite of vitamin D, 1, 25-dihydroxyvitamin D3 (calcitriol), inhibits the growth of several types of human cancer cells in vitro, but its therapeutic use is limited because it causes hypercalcemia. Among its analogs, 19-nor-1, 25-dihydroxyvitamin D2 (paricalcitol) induces fewer calcemic effects and exhibits an activity that is equipotential to that of calcitriol in several in vivo and in vitro systems. We investigated the antitumor activity and mechanism of action of paricalcitol in gastric cancer cells. Methods: We examined the effects of paricalcitol on cell proliferation, cell cycle, apoptosis, and inflammation/immunity in the human gastric cancer cell lines AGS, SNU719, and MKN45. Results: In vitro treatment with paricalcitol was associated with the following: (1) a dose-dependent increase in vitamin D receptor (VDR) protein expression; (2) inhibited gastric cell growth and induced apoptosis in AGS, SNU719, and MKN45 cell lines; (3) increased expression of p21 and p27 and decreased expression of CDK2; (4) increased expression of the caspase-3 cleaved protein and decreased expression of the anti-apoptotic Bcl-2 and Bax proteins; (5) promotion of early and late apoptosis; and (6) decreased expression of STAT-3, JAK2, COX2, and NF-κB. Conclusion: The low-calcemic vitamin D analog, paricalcitol, exhibits anticancer activity against gastric cancer cells, and its mechanism of action may be mediated through the VDR. Paricalcitol is a promising agent for the prevention and treatment of gastric cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3051. doi:10.1158/1538-7445.AM2011-3051

Abstract The active metabolite of vitamin D, 1,25-dihydroxyvitamin D3 (calcitriol), inhibits the growth of several types of human cancer cells in vitro, but its therapeutic use is limited because it causes hypercalcemia. Among its analogs, 19-nor-1,25-dihydroxyvitamin D2 has fewer calcemic effects and exhibits an activity that is equipotent to that of calcitriol in several in vivo and in vitro systems. This study demonstrated that paricalcitol has antitumor activity in gastric cancer cells. Treatment with paricalcitol inhibited gastric cancer cell growth, induced G0/G1 cell cycle arrest, and decreased the expression of cycle-dependent kinase 2 (CDK2). Additionally, paricalcitol led to apoptosis via induction of caspase-3 cleavage and decreased expression of anti-apoptotic Bcl-XL. Inhibition of STAT3, COX-2, and NF-κB activities was also observed. Moreover, growth of peritoneal metastases in vivo was significantly reduced in mice treated with19-nor-1,25-dihydroxyvitamin D2. These results suggest that the vitamin D analog (19-nor-1,25-dihydroxyvitamin D2) has anti-cancer and anti-inflammatory activity in gastric cancer cells, suggesting that it holds promise as a novel therapy for the prevention and treatment of gastric cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3690. doi:1538-7445.AM2012-3690

Background/Aims: OROS hydromorphone is a synthetic opioid agent. While clinical studies have tested its effectiveness at controlling cancer-associated pain in patients who have received other strong opioids, no clinical studies have tested its effectiveness at managing cancer pain in strong opioid-naive patients. We performed the present study to evaluate the efficacy and tolerability of OROS hydromorphone in strong opioid-naive cancer patients. Methods: We administered OROS hydromorphone to patients who had not received strong opioids during the previous month. The starting dose was 8 mg/day. The dose was increased every 2 days in patients who experienced more than four episodes of breakthrough pain per day (more than four times in patients being treated with short-acting opioids). We evaluated the efficacy, safety and tolerability of ORS hydromorphone. We also evaluated patient satisfaction and investigators’ global assessments. Results: We enrolled 23 patients to the study. The decrease in the numeric rating scale (NRS) was 59%. NRS variation had decreased markedly during the previous 24 h. All patients achieved stable pain control. The side effects were similar to those of other strong opioids. In total, 26% of patients were very satisfied with the treatment and 47% satisfied, and 74% of the investigators deemed OROS hydromorphone to be very effective or effective at controlling cancer pain. Conclusions: OROS hydromorphone is an osmotically driven, controlled-release preparation that is very effective and safe when administered once daily to strong opioid-naive cancer patients. (Korean J Med 2011;80:317-322)

e13656 Background: At present, there are eight beta tubulin isotypes in mammalian cells. Among these isotypes, class III beta tubulin was shown to confer resistance to antitubulin agents, such as paclitaxel or docetaxel. Of the inducer of class III beta tubulin (TUBB3), recent report showed that HIF-1a (hypoxia inducible factor-1alpha), one of contributor to chemoresistance in gastric cancer. And HIF-1a was suppressed in addition with anti-vascular endothelial growth factor, bevacizumab, in hypoxia sensitive cell line. This study was undertaken to investigate the role of bevacizumab on expression of class III beta tubulin and HIF-1a. Methods: We evaluated TUBB3 and HIF-1a expression under normoxic and hypoxic condition in human gastric cancer cell lines. The role of TUBB3 to antitumor effect of paclitaxel was checked through knockdown of TUBB3. TUBB3 and HIF-1a were measured under blocking of VEGFR1/2 with anti-FLT1 and anti-KDR antibody. The effects of bevacizumab and paclitaxel on TUBB3 and HIF1a expression were monitored by western blot and MTT assay. Results: The chemoresistance of paclitaxel was overcome by siTUBB3. In hypoxic condition, elevated expression of TUBB3 and HIF-1a were reduced by treating with anti-KDR and anti-FLT1 antibody. Compare to paclitaxel alone, when added bevacizumab to paclitaxel, the protein expressions of TUBB3 and HIF-1a were significantly decreased. Also, cell proliferation was more reduced in bevacizumab and paclitaxel combination than paclitaxel alone. Conclusions: Previously, VEGF has been well known as a target molecule of HIF-1a downstream signals. However, we showed that VEGF can also control HIF-1a as an upstream signal. Bevacizumab, which is blocker of VEGF, and paclitaxel synergistically suppressed HIF-1a and TUBB3. This study showed the potential key role of combination chemotherapy with bevacizumab and paclitaxel in TUBB3 expressed cancer. No significant financial relationships to disclose.

3658 Background: The prognostic relevance of tumor human papillomavirus (HPV) status in patients (pts) with anal squamous cell carcinoma (SCC) has not been elucidated. Methods: We conducted a multicenter, retrospective, observational study and consecutively enrolled pts with newly-diagnosed invasive anal SCC treated with combined chemoradiotherapy (CCRT) from 1998 to 2009. The pts with recurrent/metastatic cancer or positive serology test for HIV were excluded. Tumor HPV status was determined by HPV DNA chip analysis from paraffin-embedded tumor tissues at initial diagnosis. Results: 47 anal SCC pts treated with CCRT and with available paraffin-embedded tissues were identified. The median age was 65.0 (range, 44-90) years, 18 (38.3%) pts had regional nodal disease (N-pos), and mitomycin-containing regimen was used in 40 (85.1%). 35 (74.5%) pts were HPV positive and 31 (66.0%) were type 16 (HPV16-pos). After median follow-up of 51.7 months (range, 5.1-136.0), the 4-year progression-free survival (PFS) and overall survival (OS) were 47.0% (95% confidence interval [CI], 38.7-55.2) and 69.2% (95% CI, 61.2-77.2). Pts with HPV16-pos had better 4-year PFS (63.1% [53.1- 73.1] vs. 15.6% [5.6-25.7], p < 0.001) and OS (84.6% [76.2-93.0] vs. 39.8% [26.1-53.4], p = 0.008) than those without HPV type 16 (HPV16-neg). In multivariate analysis for PFS, N-pos (hazard ratio [HR], 2.97; 95% CI, 1.19-7.43) and HPV16-pos (HR, 0.30; 95% CI, 0.12-0.74) were independent prognostic factors for PFS. For OS, N-pos (HR, 4.58; 95% CI, 1.40-14.98) was the only independent prognostic factor. Comparing patterns of failure, time to loco- regional failure was statistically superior in pts with HPV16-pos over those with HPV16-neg (HR, 0.24; 95% CI, 0.08-0.72, p = 0.006), but time to systemic failure was not different (HR, 0.37; 95% CI, 0.11-1.27, p = 0.098). Conclusions: In pts with anal SCC treated with CCRT, tumor HPV16 status as well as nodal status was a strong independent prognostic factor for PFS. Further studies to define the prognostic relevance of HPV16 status are warranted, and HPV16 status should be considered as an important stratification factor in future trials in anal SCC. No significant financial relationships to disclose.

Abstract Background: 5-Fluorouracil (5-FU) is a useful chemotherapeutic agent in the treatment of solid tumors. However, it is very short half-life in plasma circulation greatly limited the in vivo antitumor efficacy, and intravenous 5FU injection is unlikely to achieve optimal dose effectiveness within peritoneal cavity. Conjugated linoleic acid-coupled Pluronic F127 (Plu-CLA) is an effective drug delivery system with numerous advantages and has an anticancer activity. It was also shown that paclitaxel loaded in Plu-CLA demonstrated synergistic tumor suppression through robust cell cycle arrest and enhanced apoptosis in tumor compared to paclitaxel in poloxamer hydrogel. The aim of this work is to evaluate the therapeutic efficacy of Plu-CLA as a new intraperitoneal 5FU delivery system. Methods: Cytotoxicity was evaluated by using CT-26 murine colon carcinoma cell. We established peritoneal metastasis models and hepatic metastasis models for colon cancer using BALB/c mice and firefly luciferase-expressing CT-26 (CT26/Fluc) cells. Tumor progression and response to therapy were monitored by bioluminescence imaging (BLI). Results: MTT assay indicated that 5-FU loaded in Plu-CLA hydrogel (P-FU) could increase the cytotoxic activity of 5-FU in CT-26. P-FU significantly enhanced apoptosis compared with 5-FU control. It was found that Caspase 3 and p21 were up-regulated, whereas Bcl-2 was down-regulated. Moreover, growth of hepatic metastases in vivo was significantly reduced in mice treated with P-FU. Treatment with P-FU substantially delayed tumor growth of intraperitoneal metastasis greatly and tumor-bearing mice treated with P-FU showed a better survival tendency than the 5-FU alone. Conclusion: These results were attributed to the synergistic effect of Plu-CLA. 5-FU administered in Plu-CLA hydrogel led to significant enhancement of tumor growth suppression and cellular apoptosis. Therefore, Plu-CLA could be a potential intraperitoneal carrier for hydrophilic 5-FU for the effective treatment of metastatic colon cancer. . Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3682.

Background: BRAF mutation is associated with poor survival in colorectal cancer. We aimed to generate genomic signature associated with BRAF mutation that possibly predict prognosis in colorectal cancer. Methods: A gene expression signature reflecting BRAF mutation was generated in TCGA cohorts (n = 207). The colorectal cancer patients were stratified into two groups according to this signature: BRAF mutation type colorectal cancer or BRAF wild type colorectal cancer. Prognostic significance of BRAF mutation-associated gene signature was tested in two other cohorts (GSE 17538, GSE 14333). Results: The BRAF mutation signature was associated with poor prognosis in two independent cohorts (total n = 522). BRAF mutation signature was associated with poor disease-free survival (median: not reached, P = 0.0303) in GSE14333, and associated with poor overall survival (BRAF mutation vs. wild, P = 0.019 median, 37.310 vs. 134.860 months), and disease-free survival in GSE 17538 (BRAF mutation vs. wild, P = 0.027, median 36.9 months vs. not reached). In a multivariate analysis, BRAF mutation signature was independent poor prognostic factor for disease-free survival (hazard ratio 2.1; 95% CI 1.43-2.62: P = 0.001). Gene network analyses suggested epithelial-mesenchymal transition is the possible explanation for poor prognosis of BRAF mutation colorectal cancer. Conclusions: BRAF mutation signature is highly associated with poor prognosis in colorectal cancer and the molecules associated with epithelial-mesenchymal transition can be potential treatment targets in BRAF mutation colorectal cancer. Legal entity responsible for the study: Chonnam National University Hwasun Hospital Funding: None Disclosure: All authors have declared no conflicts of interest.

15626 Background: This study was performed to determine the feasibility and safety of the salvage chemotherapy with docetaxel and cisplatin in 5-FU/cisplatin pretreated refractory esophageal cancer. Methods: Patients with histologically confirmed esophageal cancer pretreated with 5-FU and cisplatin ± radiotherapy, ECOG PS ≤ 2, at least one measurable lesion and adequate organ functions were eligible. Docetaxel (70 mg/m2) and cisplatin (75 mg/m2) were given as an 1-h intravenous infusion on day 1, repeated every 3 weeks. Results: Twenty-three patients were enrolled and twenty patients were evaluable. Their median age was 65 years (male/female =23/0); ECOG performance status 0/1/2/3=0/10/12/1; dysphagia score 0/1/2/3/4=0/4/13/5/1). The median and total number of cycles delivered was 4 (range, 1–9 cycles) and 81, respectively. Partial response was shown in four patients (20%; 95% CI, 5.7- 43.7%), stable disease was shown in eight (40%; 95% CI, 16.1–63.9%) and eight patients had progressive disease (40%; 95% CI, 19.1–63.9%). Therefore, ORR was seen in 20% and disease control rate was 60%. Nine patients (45%) improved their dysphagia by more than one grade based on DeMeester symptom scores. The median time to progression was 16.9 ± 7.1 (95% CI, 3.1–30.7) weeks, and the median overall survival was 7.1 ± 2.5 (95% CI, 2.2–12.0) months. The main hematological toxicities were neutropenia and leucopenia. Greater than grade 3 neutropenia and leucopenia were developed in 8 (34.8%) and 7 patients (30.4%), respectively. There was no febrile neutropenia. Greater than grade 3 nonhematologic toxicities were asthenia ( 2 patients) and nausea (1 patient). Conclusions: The combination chemotherapy with docetaxel and cisplatin is feasible and safe in 5-FU and cisplatin pretreated esophageal cancer. No significant financial relationships to disclose.

4034 Background: Adjuvant chemotherapy in gastric cancer improves survival outcomes after curative D2 gastrectomy, especially in stage III. We investigated the clinical prognostic significance and usefulness of lymph node ratio (LNR: ratio between metastatic lymph nodes and examined lymph nodes) for selecting adjuvant chemotherapy regimen in D2 resected stage II/III gastric cancer. Methods: We reviewed the data of 741 patients who underwent curative D2 gastrectomy and received adjuvant chemotherapy. 275 patients received platinum-based chemotherapy, and 466 received TS-1 including oral 5-fluorouracil. The disease-free survival (DFS) was evaluated for the influence of LNR on the clinical outcomes, and the patients were categorized initially into 4 groups, according to LNR (0, > 0-0.1, > 0.1-025, > 0.25), then group 0 and > 0-0.1 were merged because of similar DFS of two groups (0-0.1, > 0.1-0.25, > 0.25). Results: The patients were well discriminated according to LNR irrespective of the adjuvant chemotherapy regimen and stage. On multivariate analysis, LNR was most potent independent prognostic factor for DFS (hazard ratio 2.589, 95% confidence interval 1.874-3.576, P < 0.001). Platinum-based chemotherapy improved 3-year DFS compared with oral regimen (TS-1+oral 5-fluorouracil) in stage III and LNR > 0.25 (P = 0.026). LNR > 0.1 is the discriminant factor that favor platinum-base adjuvant chemotherapy in patients with combined stage III and lymphovascular invasion positivity (P = 0.037, platinum vs. oral regimen, median DFS: 46.867 vs. 21.767 months). Conclusions: The LNR has an important clinical prognostic significance, and the easily identifiable clinical determinant for selecting adjuvant chemotherapy regimen in gastric cancer patients underwent curative D2 resection, especially in stage III gastric cancer.

The platform business has had a profound impact on traditional industries such as real estate, telecommunications, and retail. It is a type of business that makes the most of the potential of the network effect. The authors conducted the current research to contribute to understanding public perception of platform business. In this study, tweets from Twitter and news articles were collected using LexisNexis database and examined through Semantic Network Analysis (SNA). The results of the two media did not show significant differences but we may conclude that the public is still in the process of building awareness about platform business.

Abstract Background Clinical features and therapeutic strategies for peritoneal washing cytology- positive (CY+) gastric cancer without gross peritoneal metastasis have not yet been defined. The aim of the study was to evaluate the clinical prognostic impacts of postoperative chemotherapy for treating gastric cancer patients with CY+ without peritoneal metastasis. Methods Intraoperative peritoneal washing cytology was performed in 285 patients who underwent curative D2 gastrectomy between April 2004 and May 2016. Of them, 88 patients with CY+ without peritoneal metastasis were included in the study. 64 patients received postoperative chemotherapy, whereas 24 patients underwent surgery only. We combined CY + 64 patients who received postoperative chemotherapy with another cohort of stage II/III gastric cancer patients (n = 819) who received adjuvant chemotherapy, for survival comparison. Results The Disease-free survival (DFS) and overall survival (OS) curves were well separated according to stage and CY+ in combined cohort (both, P  Conclusions The prognosis of gastric cancer with CY+ without gross peritoneal metastasis is somewhat different from gastric cancer with overt peritoneal metastasis, and postoperative chemotherapy improves survival outcome in this patient group. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Leiomyoma of the bronchus is a very rare benign tumor of the lung. Most endobronchial leiomyomas occur as secondary foci of primary uterine leiomyoma. We herein report a case with endobronchial tumor that had a different pathology from a primary resected uterine leiomyoma and was therefor considered a primary endobronchial leiomyoma. A 51-year-old woman with a history of uterine myoma presented with productive cough and fever. Bronchoscopy revealed a lightly yellow colored mass lesion that totally obstructed the orifice of the left lower lobe of the lung. The diagnosis of leiomyoma was made by histological examination of the obtained specimen. We considered the possibility of a benign metastasizing pulmonary leiomyoma. For treatment and differential diagnosis, a left lower lobe lobectomy of the lung and total hysterectomy with bilateral salphingooopherectomy were performed. The differences between lung and uterine lesions were confirmed by morphologic finding and immunohistochemical staining. The pathological diagnosis was primary endobronchial leiomyoma combined with uterine myoma. (Tuberc Respir Dis 2006; 61: 490-495)

Abstract Peroxisome proliferator-activated receptor-γ (PPAR-γ), a transcriptional factor that plays an essential role in mediating the pharmacologic actions of PPAR-γ ligands, is highly expressed in normal monocytes, various leukemias, and epithelial malignancies. PPAR-γ ligands have been developed to induce differentiation, growth arrest, and apoptosis. PPAR-γ must form a heterodimer with the retinoic acid receptor (RAR) to bind DNA, and its transcriptional activity is thought to be maximal in the presence of both PPAR-γ ligand and RAR ligand. Recently, it has been shown that activated PPAR-γ and PPAR-γ ligand may influence tumor growth, directly and indirectly, through regulation of the tumor suppressor gene PTEN, a lipid phosphatase that plays a significant role in several cellular functions, including survival and proliferation, by antagonizing phosphatidylinositol 3-kinase (PI 3-kinase)-mediated signaling pathways. The human leukemia cell line HL60 displays controlled differentiation along the granulocyte or monocyte lineages in response to various inductive signals. Retinoic acid receptor ligands are inducers of HL60 granulocytic differentiation. PPAR-γ ligands and RAR ligands induced growth arrest and oxidative burst capacity in HL60 cells. Previously, we reported the induction of PTEN gene expression by the PPAR-γ ligand ciglitazone in HL60 cells in the presence of retinoic acid using northern and western blotting. Here, using RT-PCR and an AdenoVector system to examine the contribution of transcriptional control in PTEN regulation and for PTEN overexpression, we show that PPAR-g ligand and RAR ligand can synergistically upregulate PTEN in human promyeloid leukemia cells, resulting in inhibition of cell growth and cell cycle progression of acute leukemic cells. Adenovirus-delivered PTEN overexpression resulted in arrests of both cell growth and the G1 phase of the cell cycle in HL-60 cells, suggesting that the growth-suppressive effect of PTEN is associated with its ability to induce cell cycle arrest. The PPAR-γ ligand, ciglitazone, and the RAR ligand, retinoic acid, increased PTEN expression of HL-60 cells in a time- and dose-dependent manner, respectively. Upregulation of PTEN was significantly enhanced by a combination of both ciglitazone and retinoic acid. Moreover, these compounds synergistically induced arrests of both cell growth and the G1 phase of the cell cycle. These findings suggest that the activation of the PPAR-γ: RAR heterodimer represents a novel regulatory pathway for HL60 cells and there may be a possible role for PPAR-γ and RAR ligand in prophylactic and therapeutic approaches for controlling leukemia through the upregulation of PTEN.

3156 Background: Dimethylsulfoxide (DMSO) has been used in the treatment of several types of cancer for several decades. However, the mechanism(s) responsible for its anti-tumoral action remains unknown. A novel tumor suppressor gene, PTEN/MMAC, on chromosome 10q23 encodes a phosphatidylinositol-3'-phosphatase (PTEN) that dephosphorylates the D3 position of phosphatidylinositol-3,4,5-triphosphate (PIP3), the second messenger downstream from phosphoinositide 3-kinase (PI 3-kinase) and protein kinase B (PKB)/Akt. PKB/Akt is a Ser/Thr protein kinase implicated in mediating biological responses, including the inhibition of apoptosis and the stimulation of cell growth. The present study was designed to evaluate whether DMSO controls PTEN expression in malignant cell lines. Methods: HL-60 cells were treated with DMSO, and PTEN expression determined by western- and northern-blot analysis. NF-κB activation was measured by electrophoretic mobility shift assay. To investigate the prevention of DMSO-induced PTEN upregulation in HL-60 cells, we blocked NF-κB activity with a p65 antisense oligonucleotide and pyrrolidine dithiocarbamate (PDTC). Results: DMSO strongly induced PTEN expression through NF-κB activation in HL-60 cells. Treatment of HL-60 cells with DMSO caused significant NF-κB activation and induced an increase in PTEN expression in a time- and dose-dependent manner. Interestingly, blocking NF-κB activity prevented the DMSO-induced upregulation of PTEN, indicating that the upregulation of PTEN expression by DMSO is NF-κB-dependent. Conclusion: These results suggest that DMSO is an important stimulator of the tumor suppressor protein PTEN in leukemia cells. These studies form the basis for further investigations to improve the anti-tumor effects of DMSO against such cancers as leukemia and various kinds of solid tumors. No significant financial relationships to disclose.

Background Although international guidelines recommend palliative care approaches for many serious illnesses, palliative needs of patients with serious illnesses other than cancer are often unmet, mainly due to insufficient prognosis-related discussion. We investigated physicians' and general public's respective attitudes toward prognostic for several serious illnesses. Methods We conducted a cross-sectional survey of 928 physicians, sourced from 12 hospitals and Korean Medical Association, and 1,005 members of general public, sourced from all 17 administrative divisions in Korea. Results For most illnesses, most physicians (adjusted proportions - end-organ failure, 99.0%; incurable genetic or neurologic disease, 98.5%; acquired immune deficiency syndrome [AIDS], 98.4%; stroke or Parkinson's disease, 96.0%; and dementia, 89.6%) and members of general public (end-organ failure, 92.0%; incurable genetic or neurologic disease, 92.5%; AIDS, 91.5%; stroke or Parkinson's disease, 92.1%; and dementia, 86.9%) wanted to be informed if they had a terminal prognosis. For physicians and general public, primary factor to consider when disclosing terminal status was the patient's right to know his/her condition (31.0%). Yet, general public was less likely to prefer prognostic than physicians. Particularly, when their family members were patients, more than 10% of general public did not want patients to be informed of their terminal prognosis. For general public, main reason for not disclosing prognosis was psychological burden such as anxiety and depression (35.8%), while for physicians it was disclosure would have no beneficial effect (42.4%). Conclusion Most Physicians and general public agreed that of a terminal prognosis respects patient autonomy for several serious illnesses. The low response rate of physicians might limit generalizability of results.

Abstract Background Extrapulmonary neuroendocrine carcinoma (EP-NEC) is an aggressive type of cancer with poor prognosis. Although several biological and histological markers are prognostic factors in NEC, the correlation between prognosis and systemic inflammation markers, such as the neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR), is unclear. This study evaluated the association between NLR or PLR and median overall survival (OS) or progression-free survival (PFS) in EP-NEC. Methods We retrospectively analyzed the clinical data from patients with unresectable or metastatic EP-NECs who received platinum-based chemotherapy at Chonnam National University Hwasun Hospital from August 2007 to March 2019. The cut-off values for NLR and PLR were 3 and 160, respectively. Results In total, 38 patients were analyzed. Both NLR and PLR at diagnosis had no significant associations with the response to initial chemotherapy. However, in the high-PLR group, median overall survival (OS) and progression-free survival (PFS) were poorer than those in the low-PLR group (high vs. low: 10.6 vs. 17.1 months, log-rank p = 0.007 and 4.1 vs. 9.3 months, log-rank p = 0.032, respectively). However, the high-NLR group had insignificantly poorer median OS and PFS than the low-NLR group. In the multivariate analysis, high PLR and LDH were independent prognostic factors for median OS and PFS. Conclusions High PLR was associated with shorter survival of EP-NEC patients receiving platinum-based chemotherapy. Therefore, PLR may be an independent prognostic factor in EP-NEC.

Abstract One of the human leukemia treatment methods is to differentiate leukemia cells into mature cells. Because differentiated cells lose their proliferative and tumor-forming abilities, differentiation inducers may be useful for the treatment of leukemia. Differentiation of leukemia cells has been studied using HL60 cells, a human promyelocytic leukemia cell line, which can be differentiated into granulocyte-like or monocyte/macrophage-like cells by various pharmacological agents such as dimethyl sulfoxide (DMSO), retinoic acid and phorbol myristic acetate (PMA). We previously reported that nuclear factor - kB (NF-kB) activation plays the important role in DMSO-induced differentiation of HL60 cells. Thus, we hypothesized that NF-kB activators could enhance DMSO-induced differentiation of HL60 cells. Here we examine whether tumor necrosis factor-a (TNF-a), a potent NF-kB inducer, enhance DMSO-induced differentiation of HL60 cells. TNF-a was found to enhance HL60 cell differentiation induced by DMSO. CD11b, a differentiation marker, was increased in 0.5 % DMSO-treated cells compared to control cells. When TNF-a was added to the same condition, CD11b expression was further enhanced in a dose and a time dependent manners. We also found that nitro blue tetrazolium (NBT) reducing activity, a marker for granulocytic differentiation, was further increased in DMSO plus TNF-a treated cells compared to only DMSO- treated cells. However, TNF-a alone had no effect on CD11b expression and NBT reducing activity. The enhancement of DMSO-induced HL60 differentiation by TNF-a was offset by NF-kB inhibition. Interestingly, retinoic acid- induced differentiation of HL60 cells showed no enhancing effect of TNF--a on the differentiation. These findings indicate that TNF--a might affect only NF-kB dependent differentation of HL60 cells. Taken together, we demonstrated that TNF-a enhances DMSO-induced differentiation of HL60 cells by stimulating NF-kB activation. Our results suggest that NF-kB inducers such as TNF-a are useful for the treatment of leukemia in combination with DMSO.

Open innovation (OI) is a crucial strategy regardless of sector, public or private, or academic or practical. However, the concept itself is often considered abstract and broad. Therefore, this study explored the coauthorship network and its groups to empirically observe the phenomenon of an open innovation. It also examined the semantic network of subject fields in open innovation research. We used coauthorship data to observe collaboration among authors. To examine how an open innovation is conceptualised and explained in academia, we used the abstracts of papers and the classification data of the journals where the papers were published. The results of the analysis found a mainstream group, which is a small group-to-group connection. We observed that the small groups are connected by key authors. We found that a social network of authorship and a semantic network of abstracts are both closely related. Our results provide a deeper understanding of an open innovation.