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Hypoxia-inducible factor-1 alpha (HIF-1α) is an important marker of hypoxia in human tumors and has been implicated in tumor progression. Drugs targeting HIF-1α are being developed, but the ability to measure drug-induced changes in HIF-1α is limited by the lability of the protein in normoxia. Our goal was to devise methods for specimen collection and processing that preserve HIF-1α in solid tumor tissues and to develop and validate a two-site chemiluminescent quantitative enzyme-linked immunosorbent assay (ELISA) for HIF-1α. We tested various strategies for HIF-1α stabilization in solid tumors, including nitrogen gas-purged lysis buffer, the addition of proteasome inhibitors or the prolyl hydroxylase inhibitor 2-hydroxyglutarate, and bead homogenization. Degassing and the addition of 2-hydroxyglutarate to the collection buffer significantly increased HIF-1α recovery, whereas bead homogenization in sealed tubes improved HIF-1α recovery and reduced sample variability. Validation of the ELISA demonstrated intra- and inter-assay variability of less than 15% and accuracy of 99.8±8.3% as assessed by spike recovery. Inter-laboratory reproducibility was also demonstrated (R(2)=0.999). Careful sample handling techniques allow us to quantitatively detect HIF-1α in samples as small as 2.5μg of total protein extract, and this method is currently being applied to analyze tumor biopsy specimens in early-phase clinical trials.

Background Proper evaluation and management of chemotherapy-related toxicity (CRT) is critical to cancer patients. We aimed to assess the clinical utility of STAF in patients with breast cancer receiving chemotherapy. Methods The STAF is a systematic form including common CRT lists and grades to help clinicians to assess CRT comprehensively as opposed to assessing CRT individually by cases. Using data from clinical data warehouse, the CRT profile was analyzed in patients with breast cancer receiving adjuvant or neoadjuvant therapy during two time periods; before (n = 1874) and after (n = 981) using STAF in the clinic at Asan Medical Center. The two cohorts were matched by age and chemotherapy, leaving conventional practice (A; n = 333) and STAF (B; n = 333) groups. The rates of unscheduled hospital utilization (outpatient department [OPD], emergency room [ER] and hospitalization) were compared between group A and B. Results No significant differences were noted in baseline characteristics between the two groups, except for a higher proportion of patients living near the hospital in group A compared to group B (67.0 vs 56.2%; P = 0.004). The completion rate of planned chemotherapy was 96.7% and 97.6% (P = 0.704), and the rate of dose reduction was 12.3% and 10.8% (P = 0.473), respectively, in group A and B. The median dose intensity was lower in group A than group B (0.92 vs. 0.95; P Table . 1788P Unscheduled utilization since cycle 2 of chemotherapy Group A (n = 333, %) Group B (n = 333, %) P OPD 22 (6.6) 11 (3.3) 0.050 ER 56 (16.8) 32 (9.6) 0.006 Hospitalization 42 (12.6) 28 (8.4) 0.077 Conclusions Using the STAF may facilitate to capture CRT in clinical practice and reduce the rates of unscheduled hospital utilization in patients with breast cancer receiving adjuvant or neoadjuvant therapy. Legal entity responsible for the study The authors. Funding Korean Foundation for Cancer Research. Disclosure All authors have declared no conflicts of interest.

Background Although, previous studies reported that metabolic response (MR) assessed by post-CRT 18FDG-PET was associated with survival outcomes in ESCC treated with dCRT, there are few data on the prognostic value of each metabolic response category after induction chemotherapy prior to dCRT and after completion of dCRT. Methods In this retrospective study, we evaluated prognostic value of MR after completion of induction chemotherapy and after completion of dCRT in 382 localized ESCC pts receiving induction chemotherapy followed by dCRT from January 2012 to February 2018 at Asan Medical Center in Korea. MR was assessed by EORTC criteria. Results MR after induction chemotherapy was significantly associated with progression-free survival (PFS) and overall survival (OS). MR after dCRT was also significantly associated with PFS and OS. MR after either induction chemotherapy or dCRT remained significant after adjusting for other prognostic factors such as clinical TNM stage, sex, and ECOG performance status. Whereas pts achieving mCR/mPR or mPD after either induction chemotherapy or dCRT had good prognosis or poor prognosis, respectively, the prognostic value of mSD was different between post-induction chemotherapy and post-dCRT; it was similar to that of mPR after induction chemotherapy, but it was similar to that of mPD after dCRT. Poorer MR to induction chemotherapy could predict the lack of MR after dCRT; the proportion of mSD/mPD after dCRT was 7.7% in pts with post-induction mCR vs. 16.0% in pts with vs. 40.0% in pts with post-induction mSD vs. 100% in pts with post-induction mPD (p = 0.001). Table . 762P Post induction chemotherapy Post-dCRT metabolic response N HR for PFS (95% CI) P-value HR for OS (95% CI) P-value N HR for PFS (95% CI) P-value HR for OS (95% CI) P-value mCR 13 1 1 150 1 1 mPR 106 3.348 (1.221-9.181) 0.019 2.498 (1.008 - 6.192) 0.048 164 2.182 (1.646-2.892) 0.000 2.224 (1.694-2.919) 0.000 mSD 10 6.008 (1.179-20.150) 0.004 3.640 (1.186-11.171) 0.024 7 11.251 (5.088-24.878) 0.000 9.659 (4.393-21.236) 0.000 mPD 2 59.209 (9.430-371.767) 0.000 14.495 (2.676-78.503) 0.002 39 21.768 (14.020-33.797) 0.000 10.592 (7.016-15.989) 0.000 diffuse esophagitis 3 1.729 (0.193-15.482) 0.624 1.103 (0.129-9.453) 0.929 22 1.169 (0.651-2.098) 0.601 1.482 (0.856-2.566) 0.160 Total 134 0.000 0.027 382 0.000 0.000 Conclusions MR after induction chemotherapy and after CRT had independent prognostic value with different prognostication between each other in ESCC pts receiving induction chemotherapy followed by dCRT. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

e15578 Background: Although dCRT is the standard treatment for pts who have locally advanced unresectable EC or refuse surgery, the prognosis of these pts remains dismal. There are urgent needs to develop the novel treatment strategy based on prognostic stratification after dCRT. Methods: A total of 382 pts with locoregional EC without distant metastasis except for supraclavicular lymph node who received dCRT at Asan Medical Center in South Korea from 2006 to 2015 were included. Overall survival (OS) and progression-free survival (PFS) were analyzed using Kaplan-Meier method. Risk factors were analyzed using Cox regression. Risk scores were calculated by multiplying coefficients in Cox proportional hazard model. Results: Baseline characteristics were as follows: median age = 66 yrs (range: 40-85); male = 359 pts (94.0%); squamous cell carcinoma = 375 (98.2%); cTNM stage (AJCC 8th) I = 40 (10.5%), II = 122 (31.9%), III = 128 (33.5%), IV = 92 (24.1%). During median follow-up of 52.9 mo, median PFS was 13.5 mo (95% CI, 10.9-16.1), and median OS was 26.7 mo (95% CI, 19.8-33.7). In the univariate analyses, sex (only for PFS), weight loss (≥ 5 kg) during dCRT, cT stage, cN stage, cTNM stage, clinical response after dCRT, reason for dCRT were significant prognostic factors for PFS and OS. In the multivariate analyses, clinical response after dCRT, cTNM stage, and weight loss were independent prognostic factors for PFS and OS (Table). Risk-scoring model using these factors stratified pts into four groups: for median PFS (p < 0.0001), group 1 = 58.2 mo (95% CI, 43.5-73.0), group 2 = 17.0 mo (95% CI, 11.9-22.1), group 3 = 9.0 mo (95% CI, 7.0-11.1), and group 4 = 3.9 mo (95% CI, 3.7-4.2); for median OS (p < 0.0001), group 1 = 106.2 mo (95% CI, 44.9-167.6), group 2 = 38.0 mo (95% CI, 24.4-51.5), group 3 = 13.0 mo (95% CI, 8.5-17.6), and group 4 = 8.0 mo (95% CI, 7.4-8.6). Conclusions: In dCRT-treated locoregional EC pts, survival outcome significantly varied according to baseline clinical stage, treatment response, and dynamic change in body weight. Different treatment and surveillance strategies based on the risk score might be needed in these pts.[Table: see text]

e15582 Background: Although neoadjuvant chemoradiation (nCRT) plus surgery or definitive CRT (dCRT) are the standard treatment for locally advanced ESCC, there are no reliable clinical tools for predicting prognosis or monitoring treatment response for CRT in ESCC. We aimed to identify a biomarker for predicting outcomes using cfDNA in ESCC patients (pts) receiving CRT. Methods: This prospective biomarker study analyzed pretreatment plasma cfDNA from pts with nCRT plus surgery (n = 23) and pts with dCRT for locally advanced ESCC (n = 17) at Asan Medical Center in South Korea from Jul. 2017 to Jun. 2018. Low depth whole-genome sequencing of cfDNA was used to identify CNA and I-score was developed to express genomic instability. I-score was defined as the sum of absolute Z-scores of sequenced reads on each chromosome. Results: The pathologic complete response (pCR) was achieved in 7 pts (30.4%) in the nCRT group, and the clinical complete response (cCR) was achieved in 3 pts (17.6%) and clinical partial response (cPR) in 8 pts (47.1%) in the dCRT. The baseline cfDNA concentrations were no significant association with the clinical T stage (cT 1-2 vs. cT 3-4; 0.27 vs. 0.28 ng/μL; p = 0.752), pathologic response (pCR vs. non-pCR; 0.26 vs. 0.30 ng/μL; p = 0.270), ypT stage (ypT 0-2 vs. ypT 3-4; 0.28 vs. 0.36 ng/μL; p = 0.161) and ypTNM stage (ypTNM 1 vs. ypTNM 2-4; 0.26 vs. 0.36 ng/μL; p = 0.065). When analyzing cfDNA concentration before and after CRT, cfDNA concentration was significantly increased after CRT (0.31 vs. 0.55 ng/μL; p = 0.007). The baseline I-score was not associated with baseline clinical stage, but was significantly associated with ypT stage (ypT 1-2 vs. 3-4; 30.4 vs 839.1; p = 0.009), time to progression (median TTP; 11.8 mo in the I-score-low group vs. 6.1 mo in the I-score-high group; p = 0.036), and overall survival (median OS; not reached vs. 10.4 mo; p = 0.046) in the nCRT group. In the dCRT group, I-score was significantly associated with higher disease progression rate (33.3 vs. 58.8%; p = 0.024) with tendency of distant metastasis (33.5 vs. 57.1%; p = 0.490), and short response duration (median, 5.7 mo in the I-score-high group vs not reached in the I-score-low group). Conclusions: The cfDNA concentration is not a good biomarker for prognostication and monitoring the course of treatment in ESCC pts treated with CRT. But the I-score, an indicator of genomic instability in ctDNA, was a significant predictor of poor prognosis.

PURPOSE: Hypoxia-inducible factor-1 (HIF-1) facilitates the adaptation of normal and tumor tissues to oxygen deprivation. HIF-1 is frequently overexpressed in cancer cells, where it is involved in the upregulation of many genes necessary for survival. EZN-2968 is an antisense oligodeoxynucleotide that specifically targets HIF-1α, one of the subunits of HIF-1. We conducted a trial of EZN-2968 in patients with refractory solid tumors to evaluate antitumor response and to measure modulation of HIF-1α mRNA and protein levels as well as HIF-1 target genes. METHODS: Adult patients with refractory advanced solid tumors were administered EZN-2968 as a 2-h IV infusion at a dose of 18 mg/kg once a week for three consecutive weeks followed by 3-week off; in a 6-week cycle. Tumor biopsies and dynamic contrast enhanced MRI (DCE-MRI) were performed at baseline and after the third dose. RESULTS: Ten patients were enrolled, of whom all were evaluable for response; one patient with a duodenal neuroendocrine tumor had prolonged stabilization of disease (24 weeks). Reduction in HIF-1α mRNA levels compared to baseline was demonstrated in 4 of 6 patients with paired tumor biopsies. Reductions in levels of HIF-1α protein and mRNA levels of some target genes were observed in two patients. Quantitative analysis of DCE-MRI from two patients revealed changes in K(trans) and k(ep). The trial was closed prematurely when the sponsor suspended development of this agent. CONCLUSION: This trial provides preliminary proof of concept for modulation of HIF-1α mRNA and protein expression and target genes in tumor biopsies following the administration of EZN-2968.

Summary Gastric cancer is the fourth most common cancer globally, and is the second most common cause of death from cancer worldwide. About three-quarters of newly diagnosed cases in 2008 were from Asian countries. With a high mortality-to-incidence ratio, management of gastric cancer is challenging. We discuss evidence for optimum management of gastric cancer in aspects of screening and early detection, diagnosis, and staging; endoscopic and surgical intervention; and the concepts of perioperative, postoperative, and palliative chemotherapy and use of molecularly targeted therapy. Recommendations are formulated on the basis of the framework provided by the Breast Health Global Initiative, using the categories of basic, limited, enhanced, and maximum level. We aim to provide a stepwise strategy for management of gastric cancer applicable to different levels of health-care resources in Asian countries.

Background We evaluated the maximum tolerated dose (MTD) and safety of sunitinib plus capecitabine/cisplatin (XP) or capecitabine/oxaliplatin (XELOX) in Korean patients with advanced gastric cancer (GC). Methods Sunitinib (37.5 or 25 mg/day) was administered on a 2-week-on/1-week-off schedule with chemotherapy. Assessments included dose-limiting toxicity (DLT), safety, pharmacokinetics, and antitumor activity. Results Twenty-eight patients received sunitinib/XP; 48 received sunitinib/XELOX. The MTDs were: sunitinib 25 mg/day, cisplatin 80 mg/m2, and capecitabine 1,000 mg/m2; sunitinib 37.5 mg/day, oxaliplatin 110 mg/m2, and capecitabine 800 mg/m2; and sunitinib 25 mg/day, oxaliplatin 110 mg/m2, and capecitabine 1,000 mg/m2. DLTs at the MTDs comprised grade (G) 4 febrile neutropenia plus G3 diarrhea (n = 1; sunitinib/XP), dose delays due to hematologic toxicity (n = 2; both sunitinib/XP), G3 bleeding (menorrhagia; n = 1; sunitinib/XELOX), and G3 increased alanine aminotransferase levels (n = 1; sunitinib/XELOX). There was a high frequency of G3/4 hematologic adverse events observed with both treatment regimens, particularly with sunitinib/XP. Frequent non-hematologic, G3/4 adverse events were nausea, stomatitis, and hypophosphatemia with sunitinib/XP and hypophosphatemia and pulmonary embolism with sunitinib/XELOX. No drug–drug interactions were apparent. At the MTDs, median progression-free survival was 6.4 months and 5.5–8.0 months for sunitinib/XP and sunitinib/XELOX, respectively; and the objective response rate was 46.7 % and 43.5–45.5 % for sunitinib/XP and sunitinib/XELOX, respectively. Conclusions At the MTD, sunitinib/XELOX had an acceptable safety profile in patients with advanced GC.

The plethora of novel molecular-targeted agents (MTAs) has provided an opportunity to selectively target pathways involved in carcinogenesis and tumour progression. Combination strategies of MTAs are being used to inhibit multiple aberrant pathways in the hope of optimizing antitumour efficacy and to prevent development of resistance. While the selection of specific agents in a given combination has been based on biological considerations (including the role of the putative targets in cancer) and the interactions of the agents used in combination, there has been little exploration of the possible enhanced toxicity of combinations resulting from alterations in multiple signalling pathways in normal cell biology. Owing to the complex networks and crosstalk that govern normal and tumour cell proliferation, inhibiting multiple pathways with MTA combinations can result in unpredictable disturbances in normal physiology. This Review focuses on the main toxicities and the lack of tolerability of some common MTA combinations, particularly where evidence of enhanced toxicity compared to either agent alone is documented or there is development of unexpected toxicity. Toxicities caused by MTA combinations highlight the need to introduce new preclinical testing paradigms early in the drug development process for the assessment of chronic toxicities resulting from such combinations.

AIM To investigated the incidence and risk factors of venous thromboembolism (VTE) in patients with advanced gastric cancer (AGC) receiving chemotherapy. METHODS All consecutive chemotherapy-naïve patients with AGC who would receive palliative chemotherapy between November 2009 and April 2012 in our hospital were recruited. Their pretreatment clinical and laboratory variables, including D-dimer, were recorded. The frequency of VTE development and survival rates during each chemotherapy cycle and regularly thereafter were assessed. RESULTS A total of 241 patients enrolled between November 2009 and April 2012 were analyzed. During a median follow-up duration of 10.8 mo (95%CI: 9.9-11.7), 27 patients developed VTE and the incidence of VTE was 17.5% (95%CI: 10.5-24.0, 12.0 events/100 person-years). The 6-mo and 1-year cumulative incidences were 7.8% (95%CI: 4.2%-11.4%) and 12.4% (95%CI: 7.3-17.2), respectively. Thirteen (48.1%) patients were symptomatic and the other 14 (51.9%) patients were asymptomatic. In multivariate analysis, pretreatment D-dimer level was the only marginally significant risk factor associated with VTE development (hazard ratio = 1.32; 95%CI: 1.00-1.75, P = 0.051). CONCLUSION The incidence of VTE is relatively high in patients with AGC receiving chemotherapy, and pretreatment D-dimer level might be a biomarker for risk stratification of VTE.

// Yeonjung Ha 1,2 , Danbi Lee 1 , Ju Hyun Shim 1 , Young-Suk Lim 1 , Han Chu Lee 1 , Young-Hwa Chung 1 , Yung Sang Lee 1 , Sook Ryun Park 3 , Min-Hee Ryu 3 , Baek-Yeol Ryoo 3 , Yoon-Koo Kang 3 and Kang Mo Kim 1 1 Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Republic of Korea 2 Department of Gastroenterology, CHA Bundang Medical Center, CHA University, Republic of Korea 3 Department of Oncology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Republic of Korea Correspondence to: Kang Mo Kim, email: // Keywords : hepatocellular carcinoma; portal vein invasion; sorafenib; overall survival; transarterial chemoembolization Received : May 05, 2016 Accepted : July 19, 2016 Published : August 02, 2016 Abstract Background: Although sorafenib is considered standard therapy for advanced hepatocellular carcinoma (HCC), actual treatments vary. We evaluated the effects of different treatment strategies on overall survival. Methods: A retrospective study of sorafenib-treated patients with advanced HCC was conducted. The primary outcome was overall survival. Prognostic factors were analyzed using multivariate Cox-proportional hazards model. Results: A total of 658 patients (mean age, 54.5 years; 83.3% male) were analyzed; 293, 129, and 236 patients were treated with sorafenib, a combination therapy of sorafenib and transarterial chemoembolization (TACE), and TACE followed by sorafenib, respectively. Overall, 51.2% of patients treated under the combination strategy had portal vein invasion, whereas 89.9% of patients receiving sorafenib monotherapy had distant metastasis. Median overall survival durations were comparable (11.8 months for sorafenib, 16.2 months for the combination therapy, and 13.5 months for TACE followed by sorafenib; P = 0.13). However, among portal vein invasion cases, combination (25.7 months, P = 0.002) and TACE followed by sorafenib (14.0 months, P = 0.030) treatments were associated with longer overall survival duration compared with than sorafenib monotherapy (5.5 months). In a multivariate model, sorafenib duration (hazard ratio [HR], 0.96, P < 0.001) and TACE (HR, 0.24, P < 0.001) along with Child-Pugh stage (HR, 1.83, P = 0.005) were associated with better survival. Conclusions: In patients with portal vein invasion, TACE performed concurrently with or before sorafenib administration is associated with better survival.

To evaluate the efficacy and safety of 2-year adjuvant imatinib for patients at high risk of recurrence after complete resection of localized gastrointestinal stromal tumor with KIT exon 11 mutation.Imatinib 400 mg/d was administered until disease recurrence, intolerable toxicities, or for 2 years. The primary end point was recurrence-free survival.Patients (n = 47) from 4 centers in Korea were enrolled. Treatment was well tolerated. Grade 3-4 toxicities included neutropenia (27.7%), skin rash (8.5%), anorexia (4.3%), and constipation (2.1%). At a median follow-up of 56.7 months, 19 patients had recurrences. Median recurrence-free survival was 58.9 months, which was significantly longer than 22.7 months from historical data of 27 patients in the pre-imatinib era (P0.0001). Imatinib was rechallenged for 15 patients with recurrence after completion of adjuvant imatinib. Thirteen patients had partial response, and two had stable disease. There was only one death so far.Postoperative adjuvant imatinib for 2 years was safe and could prolong the recurrence-free survival in patients with a high risk of recurrence after complete resection of localized KIT exon 11 mutated gastrointestinal stromal tumor. Reintroduction of imatinib after recurrence appears to be effective if the recurrence develops after completion of adjuvant imatinib.

Purpose: The aim of the present study was to assess the association between the pre-operative plasma fibrinogen level and the adjacent organ involvement in advanced gastric cancer. Materials and Methods: A total of 923 pre-operative plasma samples were obtained from 923 patients diagnosed clinically as having advanced gastric cancer, and fibrinogen levels were measured by immunoassay. Associations between fibrinogen levels and clinicopathologic findings (depth of tumor, adjacent organ involvement, and lymph node metastasis), along with survival were examined by univariate and multivariate analyses. Results: Tumor size, tumor depth, and the presence of lymph node metastasis were found to be positively correlated with the preoperative plasma fibrinogen levels (P

Purpose To evaluated the efficacy and safety of sorafenib in patients with advanced gastrointestinal stromal tumors (GIST) who failed to previous standard treatments. Experimental Design Thirty-one patients with measurable metastatic GIST who failed both imatinib and sunitinib were accrued. Sorafenib was administered orally at 400 mg twice daily until disease progression or development of intolerance. The primary endpoint was disease control rate (response + stable disease, DCR) at 24 weeks. Results Sorafenib was well tolerated, with hand-foot skin reaction, fatigue, hypertension, and abdominal pain being the most frequent adverse events. The relative dose intensity of sorafenib during the first 6 months was >80%. Four patients achieved partial response (response rate 13%, 95% CI 1–25%), and 16 (52%) had stable disease. DCR at 24 weeks was measured as 36% (95% CI 19–52%). Median progression-free and overall survivals were 4.9 and 9.7 months, respectively. Progression-free survival of patients with prior use of nilotinib (P = .0085) and with primary genotypes other than KIT exon 11 mutation (P = .0341) was significantly shorter than that of patients without. Conclusions Sorafenib showed antitumor activity in this population of imatinib and sunitinib pretreated GIST. With sorafenib, about one third of patients can maintain disease control for more than 24 weeks.

Background The purpose of this study was to compare the clinical usefulness of the seventh Union Internationale Contre le Cancer/American Joint Committee on Cancer (AJCC/UICC) staging system vs the sixth AJCC/UICC staging system in patients with gastric cancer. Study Design Included were 1,799 patients who underwent surgery for gastric cancer between January 2001 and June 2005 at the National Cancer Center (South Korea). For the sixth and seventh AJCC/UICC staging systems, survival outcomes stratified by stage, by T classification, and by N classification were summarized using Kaplan-Meier curves and compared statistically using a log rank test; survival differences were quantified using hazard ratios estimated from a Cox regression model. The 2 systems were compared in terms of prognostic performances using the linear trend chi-square test, likelihood ratio chi-square test, and Akaike information criterion (AIC) in the Cox regression analysis. Results Significant survival differences between each stage were not found using the seventh staging system, especially for stages IB, IIA, and IIB (p = 0.14 and p=0.11). The sixth staging system had higher linear trend chi-square score and likelihood ratio chi-square score, which means better discriminatory ability, monotonicity, and homogeneity, and had smaller AIC, which indicates better optimistic prognostic stratification, especially in the N classification. The modified staging system combining the T classification of the seventh AJCC/UICC system and the N classification of the sixth system showed better prognostic performance compared with each separate version (sixth or seventh) of the staging system. Conclusions The seventh AJCC/UICC staging system is not more clinically useful than the sixth system in surgically treated patients with gastric cancer because of an inappropriate N classification. A new TNM system is required with a different N classification.

Background: Many patients near death report an interest in knowing their prognoses. Patients’ awareness of disease status may lead to more appropriate care and maintained or improved quality of life. However, it is not known whether advanced cancer patients’ awareness of disease status is associated with patients’ quality of life. Aim: We aimed to examine the effect of patients’ awareness of disease status on the health-related quality of life (HRQOL) among advanced cancer patients undergoing palliative chemotherapy. Design: In this prospective cohort study, patients were followed-up at 4–6 weeks and 2–3 months after the initial palliative chemotherapy. Patients’ awareness of disease status, and demographic and clinical characteristics were assessed at baseline, and depression and anxiety using the Hospital Anxiety and Depression Scale (HADS) and HRQOL using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) were assessed three times. Setting / participants: In total, 100 patients with advanced cancer starting palliative chemotherapy were recruited from two tertiary university hospitals and from the Korea National Cancer Center. Results: Patients with advanced cancer undergoing palliative chemotherapy experienced deteriorated HRQOL. Of these, the patients who were aware of their disease status as incurable had significantly higher role ( p=0.002), emotional ( p=0.025), and social functioning ( p=0.002), and lower fatigue ( p=0.008), appetite loss ( p=0.039), constipation ( p=0.032), financial difficulties ( p=0.019), and anxiety ( p=0.041) compared with patients unaware of disease status. Conclusion: Our findings demonstrate the importance of patients’ awareness of disease status to HRQOL.

Purpose We conducted this study to evaluate the validity of the perception that awareness of their terminal prognosis and use of palliative care or nonuse of an intensive care unit (ICU) causes patients to die sooner than they would otherwise. Patients and Methods In this prospective cohort study at 11 university hospitals and the National Cancer Center in Korea, we administered questionnaires to 619 consecutive patients immediately after they were determined by physicians to be terminally ill. We followed patients during 6 months after enrollment and assessed how their survival was affected by the disclosure of terminal illness and administration of palliative care or nonuse of the ICU. Results In a follow-up of 481 patients and 163.8 person-years, we identified 466 deceased patients. Nineteen percent of the patients died within 1 month, while 41.3% lived for 3 months, and 17.7% lived for 6 months. Once the cancer was judged terminal, the median survival time was 69 days. On multivariate analysis, neither patient awareness of terminal status at baseline (adjusted hazard ratio [aHR], 1.20; 95% CI, 0.96 to 1.51), use of a palliative care facility (aHR, 0.96; 95% CI, 0.76 to 1.21), nor general prostration (aHR, 1.23; 95% CI, 0.96 to 1.57) was associated with reduced survival. Use of the ICU (aHR, 1.47; 95% CI, 1.06 to 2.05) and poor Eastern Cooperative Oncology Group performance status (aHR, 1.37; 95% CI, 1.10 to 1.71) were significantly associated with poor survival. Conclusion Patients' being aware that they are dying and entering a palliative care facility or ICU does not seem to influence patients' survival.

Background and Aim: Helicobacter pylori infection is a risk factor for gastric cancer. We evaluated whether H. pylori infection and premalignant histological changes are more prevalent in siblings of young gastric cancer patients. Methods: Young (age ≤ 40) gastric cancer patients (n = 185), their young siblings (n = 130), and young control participants (n = 287) were recruited. H. pylori infection and histological changes were assessed using the updated Sydney system in biopsy specimens from three regions. We analyzed the association of H. pylori infection and histological changes with gastric cancer using logistic regression analysis. Results: The H. pylori infection rate was significantly higher in young cancer patients than their siblings (odds ratio [OR] = 2.42, P = 0.001) or control participants (OR = 3.60, P

Background: We evaluated the association between polymorphisms of cytochrome P450 2A6 (CYP2A6)/excision repair cross-complementation group 1 (ERCC1)/X-ray repair cross-complementing group 1(XRCC1) and treatment outcomes of metastatic gastric cancer (MGC) patients treated with S-1/cisplatin. Methods: Among MGC patients (n=108), who received S-1 (40 mg m−2 b.i.d., days 1–14) and cisplatin (60 mg m−2, day 1) every 3 weeks, we analysed the wild-type allele (W) and variants (V) of CYP2A6 (*4, *7, *9, *10), and the polymorphisms of ERCC1 (rs11615, rs3212986) and XRCC1 (rs25487). Results: Patients having fewer CYP2A6 variants had better response rates (W/W vs W/V other than *1/*4 vs V/V or *1/*4=66.7 vs 58.3 vs 32.3% P=0.008), time to progression (TTP) (7.2 vs 6.1 vs 3.5 months, P=0.021), and overall survival (23.2 vs 15.4 vs 12.0 months, P=0.004). ERCC1 19442C>A (rs3212986) was also associated with response rate (C/C, 46.7% vs C/A, 55.3% vs A/A, 87.5%) (P=0.048) and TTP (4.4 vs 7.6 vs 7.9 months) (P=0.012). Patients carrying both risk genotypes of CYP2A6 (V/V or 1/*4) and ERCC1 19442C>A (C/C) vs those carrying none showed an adjusted odds ratio of 0.113 (P=0.004) for response, and adjusted hazard ratios of 3.748 (P=0.0001) for TTP and 2.961 (P=0.006) for death. Conclusion: Polymorphisms of CYP2A6 and ERCC1 19442C>A correlated with the efficacy of S-1/cisplatin.

Background & Aims Two major types of gastric cancer, intestinal and diffuse, develop through distinct mechanisms; the diffuse type is considered to be more influenced by genetic factors, although the mechanism is unknown. Our previous genome-wide association study associated 3 single nucleotide polymorphisms (SNPs) with diffuse-type gastric cancer (DGC); 1 was a functional SNP (rs2294008) in prostate stem cell antigen ( PSCA ), but the loci of the other 2 were not investigated. Methods We performed high-density mapping to explore a linkage disequilibrium status of the 2 SNPs at chromosome 1q22. A DGC case-control study was conducted using DNA from 606 cases and 1264 controls (all Japanese individuals) and validated using DNA from Japanese (304 cases, 1465 controls) and Korean (452 cases, 372 controls) individuals. The effects of SNPs on function were analyzed by reporter assays and analyses of splice variants. Results A region of a strong linkage disequilibrium with the 2 SNPs contained mucin 1 ( MUC1 ) and other 4 genes and SNPs significantly associated with DGC (rs2070803: P = 4.33 × 10 −13 ; odds ratio [OR], 1.71 by meta-analysis of the studies on the 3 panels) but not with intestinal-type gastric cancer. Functional studies demonstrated that rs4072037 ( P = 1.43 × 10 −11 ; OR, 1.66 by meta-analysis) in MUC1 affects promoter activity and determines the major splicing variants of MUC1 in the gastric epithelium. Individuals that carry both SNPs rs2294008 in PSCA and rs4072037 in MUC1 have a high risk for developing DGC (OR, 8.38). Conclusions MUC1 is the second major DGC susceptibility gene identified. The SNPs rs2070803 and rs4072037 in MUC1 might be used to identify individuals at risk for this type of gastric cancer.

While clinicians routinely follow up gastric cancer patients after curative resection to detect recurrence, the effectiveness of regular follow-up has not been proven, and no consensus has been reached regarding follow-up programs. Of the 1,767 patients who underwent curative resection for gastric cancer from 2001 to 2004, 310 (17.5%) developed recurrence during follow-up. The oncologic effectiveness of follow-up was evaluated using recurrence detection rates during follow-up and survivals. Clinicopathologic characteristics, the detection tools used, and times lapsed between recurrence and previous examinations were also investigated. Two hundred thirty-three (75.2%) of the 310 patients who developed recurrence were detected by regular follow-up (detected group). The frequencies of undifferentiated and diffuse-type recurrences were higher in patients with recurrence detected based on patient-initiated findings (undetected group) than in the detected group. Computed tomography and tumor markers were the first detection tools that yielded positive findings. Times between recurrence detection and previous examinations ranged from 2.8 to 5.3 months over the first 2 years. No difference in overall survival was found between the detected and undetected groups (log rank, P = 0.2). The oncologic effectiveness of regular follow-up after curative resection for gastric cancer was found to be unsatisfactory. A large-scale randomized controlled trial is required to identify the effectiveness of regular follow-up in terms of its oncologic, functional, psychological, and economical aspects.

Purpose: We evaluated the potential role of Vascular Endothelial Growth Factor-A (VEGFA) amplification and genome-wide copy number variations (CNVs) using circulating cell-free DNA (cfDNA) as predictors of treatment outcome in hepatocellular carcinoma (HCC) patients treated with first-line sorafenib. Methods: Among 184 patients from a prospective biomarker cohort, who had started sorafenib between April 2015 and May 2016, 151 eligible patients were included in the analysis. Plasma cfDNA was extracted from peripheral blood in patients before starting sorafenib or healthy donors. Plasma VEGFA-to-EIF2C1 ratios (the VEGFA ratios) were determined using droplet digital polymerase chain reaction. We applied low depth whole genome sequencing in cfDNA to find CNVs and developed I-score to express genomic instability, which was defined as the sum of absolute Z-scores of sequenced reads on each chromosome. Results: The cfDNA concentrations were significantly higher in HCC patients than in healthy controls (0.71 vs. 0.34 ng/μL; p Citation Format: Sook Ryun Park, Chung Ryul Oh, Sun-Young Kong, Min Kyeong Kim, Kyong-Ah Yoon, Eun-Hae Cho, Junnam Lee, Jihoon Kang, Baek-Yeol Ryoo. Biomarker analysis in circulating cell-free DNA in patients treated with sorafenib for advanced hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4600.

Although gastric cancer with isolated para-aortic lymph node (PAN) involvement is considered an advanced disease, the clinical characteristics of it have not been comprehensively elucidated.We reviewed the medical records of 1,277 patients received palliative chemotherapy with advanced gastric cancer according to metastatic sites: PAN-only metastasis, single organ metastasis other than PAN, and multiple organ metastasis. Time to other organ metastasis (TTOM) was determined only in PAN-only metastasis group as the time interval between initial diagnosis of recurrence or de novo metastasis and confirming distant metastasis beyond PAN area.The median overall survival (OS) of patients with PAN-only metastasis was significantly longer than that of patients with single organ metastasis other than PAN or multiple organ metastasis (13.8 months vs. 11.4 months vs. 8.4 months; P0.001). In the PAN-only metastasis group, patients with recurrent diseases showed longer TTOM beyond the PAN area (10.7 vs. 7.7 months; P = 0.037) and OS (23.8 vs. 12.8 months; P = 0.010) than those with de novo metastatic disease and it was validated by multivariate analysis.Patients with isolated PAN metastasis showed an excellent prognosis compared with patients with metastasis at other sites and it was primarily evident in patients with recurrent PAN metastasis.

In the era of pre- or perioperative therapy for gastric cancer, clinical staging before treatment appears to be increasingly important for prognosis, yet there are no data on the subject for resectable gastric cancer patients.To evaluate the prognostic role of preoperative locoregional staging in gastric cancer patients undergoing curative resection.We reviewed 1964 gastric cancer patients who underwent curative resection without preoperative therapy from 2001 to 2005. We performed computed tomography and clinical staging according to both the International Union Against Cancer (UICC)/American Joint Committee on Cancer (AJCC) (sixth edition) classification system, which bases N stage on the number of involved nodes, and the Japanese Classification of Gastric Carcinoma (JCGC) system, which bases N stage on node location.The 5-year survival rates for patients with clinical T1, T2, T3, and T4 disease were 94.5%, 83.6%, 57.7%, and 35.5%, respectively (P0.001). The 5-year survival rates were 89.4% and 68.3%, respectively, for patients with clinical UICC/AJCC N0 and N1 disease (P0.001) and 89.4%, 72.4%, 61.0%, and 41.9%, respectively, for patients with clinical JCGC n0, n1, n2, and n3 disease (P0.001). When the JCGC system was applied within the UICC/AJCC N1 category, the 5-year survival rates significantly decreased, going from n1 (72.4%) to n2 (61.0%) to n3 (38.2%) (P0.001). In multivariate analysis, clinical T and N stage remained significant prognostic factors for overall survival.Clinical stage is an independent predictor of long-term survival in the preoperative setting. It should be incorporated as a stratification factor in a randomized clinical trial of preoperative therapy for gastric cancer patients.

Cetuximab is a monoclonal antibody targeting epidermal growth factor receptor (EGFR). The present study investigated the association between germline genetic polymorphisms and the treatment outcome of cetuximab plus modified leucovovin, fluorouracil, and oxaliplatin (FOLFOX)6 chemotherapy in advanced gastric cancer (AGC). DNA from peripheral blood mononuclear cells of 38 patients enrolled in a phase II study of cetuximab plus modified FOLFOX6 were analyzed for 16 polymorphisms in eight genes (EGFR, epidermal growth factor, transforming growth factor-alpha (TGFA), thymidylate synthase, excision repair cross-complementation group 1, Xeroderma pigmentosum group D, and fragment c gamma receptors (FCGR)2A and 3A). The EGFR intron 1 CA repeat polymorphism was associated with survival. Twenty-one patients had low repeats (sum of both allelesor=37), and 17 patients had high repeats (sumor=38). Patients with low CA repeats had longer progression-free survival (adjusted hazard ratio [HR] 0.42 [95% confidence interval [CI] 0.19-0.96], P = 0.040) and overall survival (adjusted HR 0.40 [95% CI 0.16-0.99], P = 0.048) compared with patients with high CA repeats. In addition, the tumor EGFR expression was higher in patients with a lower number of CA repeats. The association between the CA repeat status and survival was not found in a separate cohort of AGC patients (n = 68) treated only with modified FOLFOX6. These results suggest that the EGFR intron 1 CA repeat polymorphism could be a useful, predictive biomarker of cetuximab efficacy in AGC and merits further investigation in randomized studies.

Aims: The aim of the study was to characterize recurrence patterns and identify predictors of recurrence after curative resection. Methods: Of 2,786 patients that underwent curative resection for gastric cancer from 2001 to 2006 at the Korean National Cancer Center, 439 (15.8%) experienced recurrence. Patterns of recurrence, clinicopathological characteristics, and therapeutic modalities were compared between 251 patients who had recurrence within 1 year (the early recurrence group) and 188 patients who had recurrence after more than a year (the late recurrence group). Multivariate analysis was performed to identify independent factors associated with the timing of recurrence. Results: In the early recurrence group, the most common pattern was hematogenous metastasis, and in the late recurrence group, the most common pattern was locoregional and peritoneal recurrence. The early recurrence group was characterized by a larger tumor, frequent lymph node (LN) metastasis, and venous, and perineural invasion. Multivariate analysis showed that LN metastasis and venous invasion were independent predictors of early recurrence. Median survival after recurrence was significantly shorter in the early recurrence group (p < 0.001). Conclusion: Hematogeneous metastasis was more common in the early recurrence group and LN metastasis and venous invasion were independent predictors of the timing of recurrence.

Novel phytosphingosine derivatives have been developed based on the inhibition of sphingosine kinase, which has been implicated in cell growth and inhibition of ceramide-mediated apoptosis. This study evaluated the cytotoxic effects and underlying mechanisms of action of novel phytosphingosine derivatives, including N-monomethylphytosphingosine (MMPH) and N,N-dimethylphytosphingosine (DMPH) and the pegylated forms MMPH-PEG and DMPH-PEG, in human leukemia HL60 cells. In viability and proliferation assays using WST-1, all four drugs induced suppression of cell growth and viability in a concentration-dependent manner. Among them, DMPH had the highest antileukemic activity and induced apoptosis via caspase-8, caspase-3, and caspase-9 activation. The apoptotic effect was also associated with Fas/FasL upregulation, Bid cleavage, Bcl-2 downregulation, Bax upregulation, mitochondrial membrane depolarization, and cytochrome c release. DMPH decreased the phosphorylation of ERK and inhibited daunorubicin-induced ERK activation. Furthermore, DMPH displayed synergistic cytotoxicity with daunorubicin in a sequence-dependent manner. Our findings indicate that DMPH has potential as an effective cytotoxic agent for leukemia.

The aim of this study was to assess the prognostic significance of intraoperatively estimated surgical stage (sStage) as a complementary role for pathologic stage (pStage) in gastric cancer.This was a retrospective study of 1,543 patients who underwent curative resection for gastric cancer. Clinicopathologic and therapeutic factors, including sStage, were analyzed for prognostic significance. Prognosis was stratified by sStage and pStage, and the prognoses of patients with an overestimated sStage were compared with those with a nonoverestimated sStage in the same pStage.Overall accuracy of sStage versus pStage was 39% (T stage, 73.0%; N stage, 43.5%). Survival curves were obviously stratified by sStage and pStage: Ia (97.5% versus 97.9%), Ib (94.3% versus 92.4%), II (89.6% versus 84.2%), IIIa (74.2% versus 69.3%), IIIb (54.4% versus 50.4%), and IV (55.6% versus 36.7%), respectively (p0.001). In addition to pStage, age and sStage were found to be significantly associated with overall survival by univariate and multivariate analysis. In pStages II, IIIa, and IIIb, intraoperatively overestimated patients had significantly poorer survival than nonoverestimated patients.sStage should be considered as a complementary prognostic factor for pStage in gastric cancer after curative resection, especially in stages II and III patients.

Background and Objective Only a few surgeons with much experience of laparoscopic surgery perform laparoscopy-assisted total gastrectomy (LATG), because of its technical difficulty and concern about subsequent complications. The aim of this study was to evaluate the technical feasibility and safety of LATG as compared with laparoscopy-assisted distal gastrectomy (LADG) in gastric cancer. Methods From January 2002 to December 2007, LADG was performed in 473 patients and LATG in 67 patients at the Korean National Cancer Center. Surgical procedures and short-term surgical outcomes of LATG were analyzed. Results D2 lymph node dissection was performed in 35 LATG (52.2%) cases and in 274 LADG (57.9%) cases (P = 0.378). Mean blood losses during operation were 156.8 ± 158.0 ml and 190.7 ± 176.2 ml, respectively (P = 0.114). The open conversion rate for LATG was higher than LADG without significance (4.3% vs. 1.7%, P = 0.153). Complications occurred in 18 LATG cases (26.9%) and 38 LADG cases (8.0%) (P

This study was designed to identify the characteristics of patients with early gastric cancers that have skip metastases.The possibility of lymph node metastasis is the most important factor to consider when deciding on the resection procedure for patients with early gastric cancer.From February 2003 through July 2008, 739 patients with early gastric adenocarcinoma underwent gastric resection at the National Cancer Center, Korea, and were included in this study. Patients with skip metastases were analyzed and compared with those without skip metastases.Skip metastases were found in 2.8% of patients with early gastric cancer. Tumor size and the presence of lymphatic invasion were associated with skip metastases by both univariate and multivariate analysis. All skip metastases were metastases to the extraperigastric lymph nodes that skipped across the perigastric lymph nodes. Sixteen patients (66.7%) with these metastases had metastatic lymph nodes at No. 7, 8, and 9 stations.Tumor size should be considered during sentinel lymph node mapping to prevent false-negative results in patients with early gastric cancer. If sentinel nodes are not found in the perigastric lymph nodes, No. 7, 8, and 9 stations should be explored for prevention of false-negative sentinel node mapping results.

This prospective study was conducted with the Korean Cancer Study Group to evaluate the efficacy and safety of cetuximab combined with modified FOLFOX6 (mFOLFOX6) as first-line treatment in recurrent or metastatic gastric cancer and to identify potential predictive biomarkers. Patients received cetuximab 400 mg m(-2) at week 1 and 250 mg m(-2) weekly thereafter until disease progression. Oxaliplatin (100 mg m(-2)) and leucovorin (100 mg m(-2)) were administered as a 2-h infusion followed by a 46-h continuous infusion of 5-fluorouracil (2400 mg m(-2)) every 2 weeks for a maximum of 12 cycles. Biomarkers potentially associated with efficacy were analysed. Among 38 evaluable patients, confirmed response rate (RR) was 50.0% (95% CI 34.1-65.9). Median time-to-progression (TTP) was 5.5 months (95% CI 4.5-6.5) and overall survival (OS) 9.9 months. Eleven patients having tumour EGFR expression by immunohistochemistry with low serum EGF and TGF-alpha levels showed a 100% RR compared to 37.0% in the remaining 27 patients (P0.001). Moreover, ligand level increased when disease progressed in seven out of eight patients with EGFR expression and low baseline ligand level. No patient exhibited EGFR amplification or K-ras mutations. Gastric cancer patients with EGFR expression and low ligand levels had better outcomes with cetuximab/mFOLFOX6 treatment.

Benign strictures at esophagojejunostomy sites may develop after total gastrectomy, and through-the-scope balloon dilation (TTS-BD) can relieve them. The aim of this study was to evaluate effective and safe balloon diameter for benign stricture after total gastrectomy.From June 2001 to December 2006, 930 gastric cancer patients underwent total gastrectomy with Roux-en-Y esophagojejunostomy in a cancer center hospital. We performed TTS-BD when benign strictures developed. Initial success rate, complication rate, and restenosis rate were evaluated. We classified the patients into three groups according to final dilation diameter and number of sessions.A total of 58 patients (6.2%) developed a benign stricture at the esophagojejunostomy site. We classified them into three groups based on the final luminal diameter of the balloon used and the number of sessions, as follows: group A (n = 20), 13.5-15 mm in one or two sessions; group B (n = 13), 16.5-20 mm in one session; group C (n = 25), 16.5-20 mm in two sessions. The initial success rates were 100% for groups A and B and 96% for group C. A perforation occurred in one patient (7.7%) in group B. Restenosis occurred in two patients (10%) in group A, one patient (7.7%) in group B, and in no patients in group C (p = 0.29). Restenosis was resolved by one or two further TTS-BDs.TTS-BD to 15 mm was a safe and effective treatment for benign esophagojejunostomy strictures following total gastrectomy. Restenosis was not common and could be resolved by one or two further TTS-BD sessions.

This randomised multicentre phase II study was conducted to investigate the activity and safety of two oral fluoropyrimidines, capecitabine or S-1, in elderly patients with advanced gastric cancer (AGC). Elderly (>or=65 years) chemo-naive patients with AGC were randomly assigned to receive capecitabine 1250 mg m(-2) two times daily on days 1-14 every 3 weeks or S-1 40-60 mg two times daily according to body surface area on days 1-28 every 6 weeks. Ninety-six patients were enrolled and 91 patients were randomised to capecitabine (N=46) or S-1 (N=45). Overall response rate, the primary end point, was 27.2% (95% CI, 14.1-40.4, 12 of 44 assessable patients) with capecitabine and 28.9% (95% CI, 15.6-42.1, 13 of 45) with S-1. Median times to progression and overall survival in the capecitabine arm (4.7 and 9.5 months, respectively) were similar to those in the S-1 arm (4.2 and 8.2 months, respectively). The incidence of grade 3-4 granulocytopenia was 6.8% with capecitabine and 4.8% with S-1. Grade 3-4 nonhaematologic toxicities were: asthenia (9.1% with capecitabine vs 7.1% with S-1), anorexia (6.8 vs 9.5%), diarrhoea (2.3 vs 0%), and hand-foot syndrome (6.8 vs 0%). Both capecitabine and S-1 monotherapies were active and tolerable as first-line treatment for elderly patients with AGC.

Gastric cancer is classified into intestinal and diffuse types, the latter including a highly malignant form, linitis plastica. A two-stage genome-wide association study (stage 1: 85,576 SNPs on 188 cases and 752 references; stage 2: 2,753 SNPs on 749 cases and 750 controls) in Japan identified a significant association between an intronic SNP (rs2976392) in PSCA (prostate stem cell antigen) and diffuse-type gastric cancer (allele-specific odds ratio (OR) = 1.62, 95% CI = 1.38-1.89, P = 1.11 x 10(-9)). The association was far less significant in intestinal-type gastric cancer. We found that PSCA is expressed in differentiating gastric epithelial cells, has a cell-proliferation inhibition activity in vitro and is frequently silenced in gastric cancer. Substitution of the C allele with the risk allele T at a SNP in the first exon (rs2294008, which has r(2) = 0.995, D' = 0.999 with rs2976392) reduces transcriptional activity of an upstream fragment of the gene. The same risk allele was also significantly associated with diffuse-type gastric cancer in 457 cases and 390 controls in Korea (allele-specific OR = 1.90, 95% CI = 1.56-2.33, P = 8.01 x 10(-11)). The polymorphism of the PSCA gene, which is possibly involved in regulating gastric epithelial-cell proliferation, influences susceptibility to diffuse-type gastric cancer.

We designed a phase I/II trial of S-1 combined with weekly docetaxel to determine the maximum tolerated dose (MTD) and recommended dose (RD) and to evaluate the efficacy and toxicity in metastatic gastric carcinoma (MGC). Patients with measurable disease received S-1 orally b.i.d. on days 1-14 and docetaxel intravenously on days 1 and 8 every 3 weeks. In phase I (n=30), each cohort received escalating doses of S-1 (30-45 mg m(-2) b.i.d.) and docetaxel (25-40 mg m(-2)); MTD was 45 mg m(-2) b.i.d. S-1/35 mg m(-2) docetaxel and RD was 40 mg m(-2) b.i.d. S-1/35 mg m(-2) docetaxel. Dose-limiting toxicities included grade 3 elevated liver enzymes, gastric perforation, grade 3 diarrhoea/fatigue, febrile neutropenia with grade 3 anorexia/fatigue, and neutropenic infection with grade 3 stomatitis/anorexia. In phase II (n=52), the overall response rate was 66.7% (95% confidence interval (CI): 53.8-79.6%) and the median time to progression and overall survival were 6.5 months (95% CI: 4.9-8.1) and 13.7 months (95% CI: 9.9-17.5), respectively. The most common grade 3/4 toxicity was neutropenia (29.4%), and febrile neutropenia/neutropenic infection occurred in 19.6% of patients. Non-haematological toxicities were generally mild. There was one treatment-related death due to pneumonitis. S-1 combined with weekly docetaxel is active in MGC with moderate toxicities.

BACKGROUND. The objective of the current study was to assess the staging accuracy and prognostic role of preoperative endoscopic ultrasound (EUS) and computed tomography (CT) in patients with locally advanced gastric cancer (LAGC) after neoadjuvant chemotherapy. METHODS. Presurgical LAGC patients underwent EUS and CT before and after 3 cycles of neoadjuvant chemotherapy. Chemotherapy was comprised of docetaxel (at a dose of 36 mg/m2) and cisplatin (at a dose of 40 mg/m2) on Days 1 and 8 of a 3-week cycle. RESULTS. Forty patients were enrolled in the study. After chemotherapy, the accuracy of EUS and CT was found to be 47% and 57%, respectively for T classification (P = .22) and 39% and 37%, respectively for N classification (P > .99). The 3-year overall survival (OS) rate for patients downstaged with EUS for T and/or N classification was greater than that for nondownstaged patients (69% vs 41%; P = .05). The 2-year recurrence-free survival (RFS) rate was also better for the EUS-downstaged patients than for the nondownstaged patients (77% vs 47%; P = .04). On multivariate analysis, EUS downstaging was found to be correlated with OS (hazards ratio [HR] of 0.12; P = .04), and was correlated with RFS with borderline statistical significance (HR of 0.27; P = .07). The differences in OS and RFS between the patients downstaged with CT and those not downstaged were not found to be statistically significant. CONCLUSIONS. Restaging by EUS and CT after neoadjuvant chemotherapy in patients with LAGC was found to be inaccurate. However, T and/or N downstaging by EUS was found to be correlated with better OS and RFS. Thus, downstaging by EUS may be a useful clinical parameter with which to predict a better outcome for LAGC patients. Cancer 2008. © 2008 American Cancer Society.

Pemetrexed is a multitargeted antifolate enzyme inhibitor, which has activity against a variety of tumors, including advanced gastric cancer (AGC). The aim of this study was to assess efficacy and safety of pemetrexed plus cisplatin (PemCis) combination in the treatment of AGC in Korean patients.This was a multicenter, single arm, open label study. Patients with no prior palliative chemotherapy received pemetrexed 500 mg/m(2) and cisplatin 75 mg/m(2) day 1, every 3 weeks plus folic acid and vitamin B(12) supplementation. Response rate was assessed according to response evaluation criteria in solid tumors (RECIST) criteria.Of the 50 patients evaluable for efficacy, 13 had partial response for an overall response rate of 26% (95% CI, 14.6-40.3%) and 15 (30%) had stable disease. Median time to progression was 2.8 months (95%CI, 2.2-4.4 months), and median overall survival was 6.6 months (95% CI, 4.8-10.4 months). Of the 51 patients evaluable for safety, the most frequent NCI-CTC grade 3/4 toxicities were neutropenia in 49% of patients (25% of cycles) and anorexia in 10% of patients (4% of cycles).PemCis has a modest activity and acceptable toxicity profile in patients with AGC. Clinical trials with different combinations and dose regimens are, therefore, warranted.

Objectives: Fibroblast growth factor receptor 2 (FGFR2) amplification has been reported to be a target for treatment in gastric cancer. However, an optimal tissue source and method for evaluating FGFR2 have yet to be established. Methods: Copy numbers were compared by quantitative polymerase chain reaction (qPCR) using frozen vs formalin-fixed, paraffin-embedded (FFPE) tissue and biopsy vs surgical specimens. We correlated the results of qPCR and immunohistochemistry (IHC) with fluorescence in situ hybridization (FISH) using stage IV gastric cancer biopsy specimens and validated the results in surgical specimens. Results: FFPE tissues were suitable for qPCR, and biopsy specimens were equivalent to or better than surgical specimens. qPCR and IHC results exhibited an excellent correlation with FISH at eight or more copies by qPCR in any kind of tissue, 5% or more by IHC in biopsy specimens, and 10% or more by IHC in surgical specimens. FGFR2 amplification was 6.6% in stage IV gastric cancers, and 42% of these showed heterogeneous amplification and overexpression. IHC indicated a good correlation with FISH even in the heterogeneous cases. Conclusions: FFPE biopsy tissues are an adequate source for FGFR2 evaluation in gastric carcinomas, and a qPCR-based copy number assay can be used for screening. IHC is also a valid and practical method for evaluating FGFR2 , considering frequent heterogeneity.

Purpose The intratumoural heterogeneity of human epidermal growth factor receptor 2 (HER2) expression in gastric cancer is a major challenge when identifying patients who might benefit from HER2-targeting therapy. We investigated the significance of re-evaluation of HER2 status in primary sites and metastatic or recurrent sites in advanced gastric cancer patients whose primary tumours were initially HER2-negative. Patients and methods In part I of this study, we evaluated the significance of repeat endoscopic biopsy in unresectable or metastatic gastric cancer patients whose tumours were initially HER2-negative. In part II, we examined the HER2 positivity rate in metastatic or recurrent sites in patients whose primary tumours were HER2-negative in biopsy or surgical specimens. Results In part I (n = 183), we identified patients with HER2-positive tumours for a rescued HER2 positivity rate of 8.7% (95% confidence interval [CI], 4.6–12.8%) that was associated with tumour location (diffuse stomach versus other = 0% versus 11.7%, P = 0.013), Bormann type (IV versus others = 0% versus 11.7%, P = 0.013), and initial biopsy HER2 immunohistochemistry score (0 versus 1 versus 2=6.7% versus 15.4% versus 25.0%, P = 0.028). Part II (n = 175) resulted in HER2 positivity of 5.7% (95% CI 2.3–9.1%) that was significantly associated with metastatic site (liver versus others = 17.2% versus 3.4%, P = 0.012). When compared with a historical control that showed HER2 positivity on initial assessment, patients who had rescued HER2 positivity had similar treatment benefits from trastuzumab-containing first-line chemotherapy. Conclusion Repeat HER2 assessment in primary and metastatic or recurrent sites is recommended in patients with advanced gastric cancer whose primary tumour is initially HER2-negative.

Background Everolimus (RAD001) is an orally administered mTOR inhibitor that is well known for its antitumor efficacy and that has been approved for the treatment of several solid tumors, including renal cell carcinoma. In gastric cancer (GC), despite previous preclinical and phase I/II studies suggesting the promising efficacy of everolimus in previously treated AGC, more recent trials revealed that only certain subsets of patients might benefit from treatment with everolimus. Case presentation A 26-year-old man with metastatic gastric cancer with multiple liver lesions was treated with everolimus after failure of 1st-line and 2nd-line chemotherapy. A durable partial response was achieved for over 2 years. After progression from initial everolimus treatment, sequential cytotoxic chemotherapies were tried but failed rapidly. Everolimus was re-tried as salvage chemotherapy (re-treatment), and the patient achieved stable disease for 1 year until his death. Subsequent mutational analysis and immunohistochemical (IHC) staining with the tumor tissues just before re-treatment with everolimus revealed a PIK3CA hotspot mutation and pS6 overexpression in the primary tumor. After two cycles of everolimus re-treatment, the overexpression of pS6 became nearly absent in follow-up IHC staining. Conclusions Everolimus monotherapy was satisfactory in a patient with refractory metastatic GC harboring PIK3CA and pS6 aberrations. These molecular alterations might be potential biomarkers that can predict the treatment response of everolimus, particularly in the terms of durable disease control. This case suggests and emphasizes that close evaluation of biomarkers in tumor tissue may be essential for identifying highly favorable groups among various subpopulations with AGC.

S-1 is an oral 5-fluorouracil agent containing tegafur, 5-chloro-2, 4-dihydroxypyridine (CDHP), and potassium oxonate. This study explored the pharmacokinetics of S-1 and pharmacokinetic changes after gastric surgery in patients with resectable gastric cancer who received pre- and postoperative S-1 plus docetaxel. Serial blood was drawn before and after gastrectomy from 37 patients for pharmacokinetic analysis. The pharmacokinetics of tegafur, 5-fluorouracil, and CDHP were analyzed by noncompartmental analysis (NCA) methods and by modeling. In modeling analysis, CHDP concentrations were incorporated in the model as a time-varying covariate that inhibits the clearance of 5-fluorouracil following an inhibitory Emax model. In NCA, the pharmacokinetics of tegafur and 5-FU before and after gastric surgery were similar, although average maximum concentrations of 5-FU were decreased with statistical significance after gastrectomy. Median Tmax of tegafur was shorter after surgery without statistical significance. In modeling analysis, tegafur was best fitted by mixed zero and first-order absorption. The only difference in the final pharmacokinetic model around gastrectomy was the presence of an absorption lag of 0.23 hours before surgery. Incorporation of CDHP concentrations significantly improved the model. Although some pharmacokinetic results showed statistically significant changes after gastrectomy, these differences seem to be too small to have any clinical implication.

This study was conducted to evaluate the leaning curve of D2 lymph node dissection for patients with gastric cancer in a high-volume center. The authors prospectively reviewed the data of all patients who underwent total gastrectomy with D2 lymph node dissection during a 4-year period. Retrieved lymph node number was used as a surrogate marker of oncological outcome. The retrieved lymph node number cut-off value required for satisfactory D2 lymph node dissection was defined as >25. Cumulative sum analysis was used to examine the learning curves of individual surgeons at target accuracy rates of 85%, 90%, 92.5%, 95%, and 98%. Two junior staff surgeons performed 198 curative-intent total gastrectomies with D2 lymph node dissections during the study period; their success rates exceeded 90%. Operating time decreased with operative experience (Pearson correlation coefficient = −0.515, P < 0.001). The learning period for total gastrectomy with D2 lymph node dissection for these two junior members of staff was calculated as 23–35 cases, presuming a 92.5% success rate. The current study suggests that the surgical learning period for D2 lymph node dissection extends to at least 23 cases or 8 months. In clinical trials containing gastric cancer surgery, the learning curve for qualified surgery from the standpoint of oncological outcome should be considered to minimize bias due to surgeon-associated factors.

Despite advances in the characterization of anaplastic large cell lymphoma (ALCL), little data is available on Asian patients. We report here upon single Korean institution's experience regarding the clinical characteristics and outcomes of ALCL. We performed a retrospective study of 32 adults with ALCL. Most of the patients received anthracycline-based chemotherapy. Ann Arbor stage III-IV, B symptoms, high-intermediate/ high International Prognostic Index (IPI), and extranodal disease at diagnosis were present in 56%, 44%, 41%, and 63%, respectively. Compared with Western studies, the male/female ratio (4.3) was markedly higher and skin (9%) and bone involvement (9%) were less frequent. The staining results for anaplastic lymphoma kinase were positive in 6 (33%) of 18 cases available. The complete response (CR) rate was 62% (95% CI, 44-80%). With a median follow-up of 51.0 months, 5 yr overall survival was 40+/-11%. The 3 yr relapse-free survival for the 18 patients who achieved CR was 74+/-12%. Age, performance status, lactate dehydrogenase, extranodal disease sites number, and IPI were correlated with treatment response and survival. Our data suggest that Korean ALCL patients appear to have a higher male/female ratio, less frequent skin/bone involvement, and lower CR rate compared with those of Western studies.