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In this paper, the development of a spliced girder which is called ‘SegBeam’ is introduced. SegBeam use the ‘joint block’ which composes the splicing end part of a segment and is made of higher strength concrete than the other part of segment. The joint block is used for easy match casting and resisting the stress concentration during splicing process with post tensioning. Also, joint block enables to make a variable length of segment as the joint block fabricated in advance can be moved in the form of the segment. To verify the performance, full-scale load test of a 60m-long SegBeam is carried out. The structural safety of SegBeam is guaranteed under the load exceeding the ultimate design load of the girder. The applications of the SegBeam in the real construction field are also introduced.

Background Bevacizumab has been extensively investigated in combination with various standard chemotherapies in the treatment of metastatic colorectal cancer (mCRC). However, a comparison to irinotecan + infusional 5-fluorouracil/leucovorin (FOLFIRI) is lacking. Objective To explore clinical effectiveness and cost-effectiveness of adding bevacizumab to a regimen of FOLFIRI for the first-line treatment of mCRC in the Republic of Korea by conducting an indirect treatment comparison. Methods A health-economic model was developed to investigate the possible health outcomes (life-years gained [LYG]), direct costs, and incremental cost-effectiveness ratio (ICER) of adding bevacizumab to a FOLFIRI regimen. Data on progression-free and overall survival were derived from randomized clinical trials and were used in the indirect treatment comparison. The annual discount rate for costs and outcomes was 5%. A lifetime horizon of 8 years was used. Sensitivity analyses were carried out on all pivotal model assumptions. Results Incremental mean overall survival among patients treated with bevacizumab + FOLFIRI varied between 8.6 and 15.7 months compared with patients treated with FOLFIRI alone. The deterministic base-case result was 1.177 LYG. The discounted ICERs ranged from μ31.8 to μ39.5 million/LYG, with the base-case result being μ34.5 million/LYG. Treatment effect had the most impact on the outcomes in this model. Conclusions Although there is no formal threshold for ICER per LYG in Korea, funding may be considered for bevacizumab + FOLFIRI, particularly if the severity and end-of-life nature of mCRC is taken into account.

Purpose The ARTIST (Adjuvant Chemoradiation Therapy in Stomach Cancer) trial was the first study to our knowledge to investigate the role of postoperative chemoradiotherapy therapy in patients with curatively resected gastric cancer with D2 lymph node dissection. This trial was designed to compare postoperative treatment with capecitabine plus cisplatin (XP) versus XP plus radiotherapy with capecitabine (XP/XRT/XP). Patients and Methods The XP arm received six cycles of XP (capecitabine 2,000 mg/m2 per day on days 1 to 14 and cisplatin 60 mg/m2 on day 1, repeated every 3 weeks) chemotherapy. The XP/XRT/XP arm received two cycles of XP followed by 45-Gy XRT (capecitabine 1,650 mg/m2 per day for 5 weeks) and two cycles of XP. Results Of 458 patients, 228 were randomly assigned to the XP arm and 230 to the XP/XRT/XP arm. Treatment was completed as planned by 75.4% of patients (172 of 228) in the XP arm and 81.7% (188 of 230) in the XP/XRT/XP arm. Overall, the addition of XRT to XP chemotherapy did not significantly prolong disease-free survival (DFS; P = .0862). However, in the subgroup of patients with pathologic lymph node metastasis at the time of surgery (n = 396), patients randomly assigned to the XP/XRT/XP arm experienced superior DFS when compared with those who received XP alone (P = .0365), and the statistical significance was retained at multivariate analysis (estimated hazard ratio, 0.6865; 95% CI, 0.4735 to 0.9952; P = .0471). Conclusion The addition of XRT to XP chemotherapy did not significantly reduce recurrence after curative resection and D2 lymph node dissection in gastric cancer. A subsequent trial (ARTIST-II) in patients with lymph node–positive gastric cancer is planned.

The aim of this phase I study was to investigate the optimal dose of S-1 and oxaliplatin with concurrent radiotherapy in a preoperative setting for locally advanced gastric cancer.Twelve patients with histologically confirmed clinical stage T2N+ or T3-T4 gastric adenocarcinoma received dose level -1 (oral S-1 at 60 mg/m(2)/day + oxaliplatin 40 mg/m(2) intravenously on days 1, 8, 15 and 22) or dose level 1 (S-1 80 mg/m(2)/day + oxaliplatin 40 mg/m(2)), with concurrent radiotherapy at daily fractions of 1.8 Gy 5 days per week, to a total dose of 41.4 Gy. Surgical resection, including D2 dissection, was performed within 4 weeks after the last day of chemotherapy.Chemoradiotherapy was generally well tolerated, with the most common dose-related grade 1 or 2 adverse events being anemia, nausea, vomiting, anorexia and abdominal pain. Two DLTs (prolonged thrombocytopenia and stomach perforation) were observed at dose level 1 (n = 6) and resulted in dose de-escalation to level -1. The recommended dose for future study is dose level -1, at which 1 of 6 patients developed grade 3 vomiting and anorexia. R0 resection was possible in 11 patients. Pathologic down-staging was observed in 6 patients, including one complete response. No clinically relevant postoperative complications occurred.The activity of preoperative concurrent chemoradiotherapy with S-1 (60 mg/m(2)/day for 28 consecutive days) and oxaliplatin (40 mg/m(2) on days 1, 8, 15 and 22) will be explored more extensively in a phase II study in patients with locally advanced GC.

We studied to identify the clinicopathological features, treatment outcome, and prognostic factors for patients with gastrointestinal and hepatopancreaticobiliary neuroendocrine tumor (NET).Between February 2001 and May 2006, a total of 470 patients were diagnosed with NET arising from the gastrointestinal tract, pancreas, and hepatobiliary system. The retrospective patient cohort was obtained and analyzed.The male to female ratio was 1.5:1, and the median age was 55 years (range, 16-81). The most common primary site was the rectum (55.8%). Overall 29 (6.2%) originated from the hepatobiliary system. At initial presentation, 60 patients (12.8%) showed distant metastases. Curative surgery or endoscopic resection was performed in 401 patients. Histopathological distributions were as follows: well differentiated tumor (82.1%), well differentiated carcinoma (10.2%) and poorly differentiated carcinoma (7.7%). The frequency of the poorly differentiated type was somewhat higher in the hepatobiliary system than in the pancreas and gastrointestinal tract (44.8, 15.4 and 2.8%, respectively, P0.05). The estimated 5-year overall survival rate for all patients was 89.6%. Multivariate analysis showed that distant metastases (P = 0.018), origin from the hepatobiliary system (P0.001) and poorly differentiated neuroendocrine carcinoma (P0.001) were independent predictors for poor survival outcome.Patients with locoregional NET had a favorable long-term survival after curative resection. Distant metastases, hepatobiliary localization and a poor degree of tumor cell differentiation were poor prognostic factors. Further investigational approaches for treatment of advanced disease are needed.

PURPOSE To evaluate clinical outcomes and safety of adjuvant chemoradiation therapy (CRT) with capecitabine after resection of pancreatic adenocarcinoma at a single institution. PATIENTS AND METHODS A retrospective analysis of patients undergoing adjuvant CRT with capecitabine after resection of pancreatic ductal adenocarcinoma between 2004 and 2007 yielded a total of 55 patients. Capecitabine was administered at 850 mg/m(2) twice daily every day per week radiotherapy (45 Gy in 25 fractions) over the 5 weeks. Sixteen percent of patients (N=9) went on to receive gemcitabine. RESULTS Of 55 patients, 42 had curative (R0) resection and 13 had incomplete resection (R1). Median overall survival (OS) and progression free survival were 18.3 and 8.0 months for all patients, respectively. Patients receiving additional gemcitabine after adjuvant CRT with capecitabine showed better OS and progression free survival than those not receiving additional gemcitabine (P

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the third most common cause of cancer-related death [1]. More than 75% of cases occur in the Asian-Pacific region, largely in association with chronic hepatitis B virus (HBV) infection, and 360,000 patients in Eastern Asia die from this disease each year [1]. Diagnosed at early stages, it is potentially curable by surgery and by locoregional procedures. However, disease that is diagnosed at an advanced stage or continues to progress after locoregional therapy has a dismal prognosis because of underlying liver cirrhosis and lack of effective alternative treatments. Sorafenib (Nexavar; Bayer, West Haven, CT, USA and Onyx, Emeryville, CA, USA) is an oral multitargeted tyrosine kinase inhibitor (TKI) and the first agent shown to improve overall survival (OS) in advanced HCC [2, 3]. Sorafenib inhibits angiogenesis by targeting receptors for VEGF (VEGFR2 and VEGFR3) and blocks tumor cell proliferation by inhibiting RAF/MEK/ERK signaling [4]. This combined inhibition of VEGF and PDGF pathways decreases tumor vascularization and endothelial cell proliferation and thus retards tumor progression. Sunitinib malate (Sutent; Pfizer, New York, NY, USA) is another oral, multitargeted TKI that acts on VEGFR-1, VEGFR-2, and VEGFR-3, PDGFR-α and PDGFR-β, and partially overlaps with sorafenib in its target inhibition profile [5]. Sunitinib is approved for the treatment of renal cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal tumors (GIST) [6]. Observational phase II studies suggest that sunitinib has antitumor activity in patients with advanced HCC, and a multicenter phase III clinical trial to compare its effectiveness with that of sorafenib in advanced HCC is in progress. Improving treatment outcomes for patients with advanced HCC requires development of alternative agents and regimens that are active, tolerable and safe. Further knowledge of drug mechanisms, and of biomarkers to predict tumor response and/or resistance are also needed. At present we have no standardized second-line regimen in HCC patients after progression on first line sorafenib. In metastatic RCC patients, sorafenib and sunitinib are currently used in sequence. Observational studies on the efficacy and cross-resistance of these drugs in RCC patients failed to define optimal strategy of sequential treatment [7– 13], however data for sequential treatment with these two TKIs in advanced HCC patients are lacking. We performed this retrospective study to evaluate the efficacy and safety of sequential administration of sunitinib following failure of sorafenib in advanced HCC patients.

The 2010 NCCN clinical practice guidelines recommend radiation as a part of the standard adjuvant or neoadjuvant treatment for stage IV rectal cancer patients. This study evaluated the oncologic efficacy of postoperative radiotherapy (RTx) in loco-regional control after complete removal of primary and metastatic lesions in stage IV rectal cancer.Sixty-eight patients with metastatic rectal cancer were enrolled and analyzed. Twenty-eight of the enrolled patients received concurrent postoperative RTx with chemotherapy (RTx group) and the remaining 40 received only postoperative systemic chemotherapy (CTx) without RTx (non-RTx group). The eligibility criteria were as follows: a primary rectal tumor located in the low or mid-rectum, no postoperative macroscopic and microscopic evidence of residual tumor in primary and metastatic sites, and no history of prior CTx or pelvic RTx.The recurrence rates were 75.0% in the RTx group and 72.5% in the non-RTx group. Local recurrence rates were 7.1% (RTx group) and 22.5% (non-RTx group) (P = 0.108). There were no differences in overall survival (OS), local recurrence-free survival, and disease-free survival between the two groups. The 2-year OS rates were 78.9% (RTx group) and 74.1% (non-RTx group) (P = 0.395).Survival benefit of postoperative RTx in stage IV rectal cancer after complete removal of tumors was not apparent. RTx could be recommended for selected patients at high risk of local recurrence or for palliation of symptoms.

The aim of this study was to identify subgroups that benefit from preoperative or postoperative chemoradiotherapy (CRT) for rectal cancer of intermediate stage.Between 1999 and 2004, 118 and 177 patients matched with respect to clinical T stage, circumferential tumor extent (= 60% /60%), lymph node metastasis, and lymph node size (1 cm / ≥ 1 cm), were allocated to preoperative CRT and postoperative CRT, respectively. In preoperative CRT, a total of 45 Gy was delivered with chemotherapy, and then surgery followed. In postoperative CRT, 45-51 Gy was delivered with chemotherapy following primary surgery.Local recurrence, distant metastasis, disease-free survival, and disease-specific survival were not different between the two schemes. For a circumferential tumor extent of = 60%, local recurrence in preoperative CRT (3.6%) was lower than in postoperative CRT (11.9%) (p = 0.084, hazard ratio (HR) = 0.274, 95% confidence interval (CI) = 0.058-1.032). For a tumor located5cm from the anal verge, distant metastasis in preoperative CRT (18.9%) was lower than in postoperative CRT (34.4%) (p = 0.061, HR = 0.444, 95% CI = 0.188- 1.047), and 5-year disease-free survival rates in preoperative and postoperative CRT were 72.0 and 59.0%, respectively (p = 0.078).Our findings suggest that preoperative CRT might be appropriate in rectal cancer involving the limited circumferential lumen and located in the low rectum. However, further prospective studies are required.

Background To confirm the efficacy and toxicity of Erlotinib in combination with Gemcitabine and Capecitabine when used as a first-line therapy in metastatic/recurrent pancreatic cancer (PC). Methods Locally advanced PC was excluded. Erlotinib was given at a dose of 100 mg daily from D1 to D28. 1000 mg/m2 of gemcitabine was given on D1,8,15 and 1660 mg/m2/day of capecitabine was given from D1 to 21, repeated every 4 weeks. Response was assessed every 8 weeks. Results A total of 47 patients were enrolled. Response rate and disease control rate was 32.6% (95% CI, 18.6–46.6%) and 83.7% (95% CI, 72.7–94.7%) respectively. The PFS was 6.5 months (95% CI, 3.4–9.7) and OS was 12.0 months (95% CI, 8.6–15.9). The Gr 3/4 toxicities were: neutropenia (6.8%), thrombocytopenia (3.2%), anemia (1.6%). nausea (1.6%), vomiting (1.6%), anorexia (5.3%), rash (2.4%). The EGFR expression was associated with shorter OS and ERCC2 expression was associated with longer PFS and OS. PFS and OS were not different according to K-RAS mutation or polymorphism of RRM1 and CDA. Conclusions Erlotinib, gemcitabine and capecitabine combination showed promising efficacy and good tolerability in metastatic PC. This efficacy was observed irrespective of K-RAS mutation, and EGFR expression was poor prognostic factor for OS.

Identification of critical genes which play pivotal roles in controlling tumor growth and survival will establish the basis for developing therapeutic targets. With the aim of establishing personalized medicine for treatment of solid tumors, we focused on MET amplification in gastric cancer patients, given the extreme sensitivity to c-Met inhibitor in MET amplified gastric cancer cell lines. We tested MET amplification and activation of c-Met in various gastric cancer cell lines and tissue samples from 482 gastric cancer patients who underwent curative surgery. Gastric cancer cell lines with MET amplification by quantitative real-time PCR (qPCR) and FISH predicted sensitivity to PHA-665,752, a selective c-Met kinase inhibitor. Of the 472 patients who had DNA sample available for qPCR analysis, 100 patients (21.2%) had a MET copy number greater than 4.0 copies and demonstrated poorer survival following curative surgery with statistical significance (5-year OS; 50.0 vs. 59.1%; MET amplification (+) vs. MET amplification (-); P = 0.0134). These results suggest that the increased MET copy number measured by qPCR plays an important role in determining prognosis in gastric cancer patients. However, the predictive role of MET amplification for treatment response should be further explored in upcoming clinical trials.

Background: Sorafenib, a multitargeted tyrosine kinase inhibitor, is now the treatment of choice for systemic therapy of patients with advanced hepatocellular carcinoma (HCC). Herein, we present the clinical characteristics and outcomes of patients with advanced HCC who were treated with sorafenib. Methods: Data of 201 sorafenib-treated, metastatic HCC patients were collected from a single institution tumor registry. The primary and secondary endpoints were overall survival (OS) and failure-free survival (FFS). Results: Chronic hepatitis B was the predominant cause of HCC (84%). Of 162 evaluable patients, 4 partial responses were recorded. With a median follow-up of 15.7 months, the median FFS and OS were 2.5 months (95% CI 2.3–2.7) and 5.3 months (95% CI 4.4–6.3), respectively. In multivariate analysis, the prognostic factors associated with FFS were the presence of ascites, portal venous thrombosis, serum α-fetoprotein ≧400 ng/ml, albumin, bilirubin, tumor size and number, and performance status. Likewise, the presence of ascites, portal venous thrombosis, tumor size and number, performance status and baseline levels of α-fetoprotein, albumin and bilirubin were significantly related with OS. After adjusting for performance status, the Cancer of the Liver Italian Program scoring system and Okuda stages can better predict the hazard of failure or death than the Child-Pugh classification. Conclusions: Our results suggest that Cancer of the Liver Italian Program scores or Okuda stages, along with performance status, can be useful in stratifying patients with advanced HCC treated with sorafenib.

The purpose of the study was to evaluate the efficacy and tolerability of S-1 monotherapy in metastatic colorectal cancer (CRC) patients who have failed the standard oxaliplatin-based or irinotecan-based chemotherapy. From 2007 to 2010, metastatic CRC patients who received S-1 monotherapy as salvage treatment were identified from tumor registry at Samsung Medical Center. All patients received ≥ second-line treatment for CRC. S-1 was administered orally from day 1 to day 14, every 3 weeks. The dose of S-1 for each patient was determined according to body surface area (BSA) as follows: for BSA1.25 m(2), 80 mg/day; for 1.25 m(2)BSA1.5 m(2), 100 mg/day; and for BSA1.5 m(2), 120 mg/day divided by 2 doses. The median age of the 19 patients was 59 years (range: 33-77). Fourteen (73.7%) of 19 patients received S-1 monotherapy as third-line treatment after failing oxaliplatin-based or irinotecan-based chemotherapy. Previous regimens prior to S-1 therapy were as follows: FOLFOX, XELOX, FOLFIRI, XELOX + avastin, and cetuximab + irinotecan. The median number of administered S-1 courses given in the entire studied population was 3 cycles (1-10 cycles). Three patients had confirmed partial response (PR) after 3 cycles of S-1 treatment. After a follow-up duration of 22.3 months (range: 6.7-32.6 months), median time to progression (TTP) was 2.1 (95% CI, 1.8-4.2) months. Median overall survival was 11.3 months (95% CI, 8.8-16.8) from the time of S-1 chemotherapy administration. Two patients had grade 1 hand-foot syndrome (HFS) after first and 2nd cycles of treatments, respectively, but treatments were continued without developing further adverse events. The salvage S-1 monotherapy in metastatic colorectal cancer patients who failed irinotecan-based or oxaliplatin-based chemotherapy was moderately effective and well tolerated.

Both docetaxel-based and irinotecan-based chemotherapy has been demonstrated as active combination regimen in either first-line or second-line setting for metastatic gastric cancer. The purpose of this trial was to evaluate the two active regimens, docetaxel/cisplatin and FOLFIRI, as first- and second-line chemotherapy and to compare the sequence of the two regimens in terms of efficacy and tolerability.Eligible patients were randomized to receive one of the two treatment arms: Arm A-DP (docetaxel 75 mg/m(2) D1, cisplatin 75 mg/m(2) D1 repeated every 3 weeks) until progression or unacceptable toxicity as the first-line treatment which was followed by FOLFIRI (irinotecan 150 mg/m(2) D1, leucovorin 100 mg/m(2) D1, 5-fluorouracil 3,000 mg/m(2) D1-2 for 48 h every 2 weeks) upon disease progression as second-line chemotherapy; Arm B-FOLFIRI as the first-line treatment until disease progression or unacceptable toxicity then followed by DP as the second-line treatment upon documented disease progression.Between April 2005 and Aug 2008, 58 patients were enrolled (Arm A, n = 28; Arm B, n = 30). Median follow-up was 38.2 months. The overall response rate (ORR) of the first-line chemotherapy was 25.0% with DP (Arm A1) and 13.3 with FOLFIRI (Arm B1) (P = 0.322). The tumor control rate (TCR) of first-line chemotherapy was 82.1% with DP and 66.7% with FOLFIRI (P = 0.209). The median first progression-free survival (1st PFS) was 4.3 months with DP and 3.4 months with FOLFIRI (P = 0.547). The overall response rate of second-line chemotherapy was 20.0% with FOLFIRI (Arm A2) and 27.2% with DP (Arm B2) (P = 0.296). The tumor control rate of second-line chemotherapy was 46.7% with FOLFIRI and 50.0% with DP. The median second progression-free survival (2nd PFS) was 8.1 months with Arm A and 6.7 months with Arm B (P = 0.865). The median overall survival was 12.5 months (95% CI 8.17-16.83) in Arm A and 13.4 months (95% CI 9.99-16.81) in Arm B (P = 0.674). In safety profile, the incidence of neutropenic fever was comparable among the 4 arms ranging from 0 to 3.9%.The ORR, TCR of Arm A (DP → FOLFIRI) were not different from those of Arm B (FOLFIRI → DP). There was no statistically significant difference in 1st PFS, 2nd PFS, and OS of both arms. Although the trial was terminated early due to poor patient accrual, we found that both DP and FOLFIRI regimens were tolerable with comparable efficacies regardless of the sequence administered.

Background: Understanding the effect of adverse events from commonly used agents such as sunitinib in hemodialyzed renal cell carcinoma (RCC) patients is important in clinical practice. Despite its clinical relevance, little information has been provided on the safety and toxicity profile of sunitinib when administered in hemodialyzed patients with RCC. Methods: Six patients undergoing hemodialysis were treated with sunitinib for metastatic RCC between February 2007 and May 2009. We retrospectively reviewed the medical records of these patients and examined the administered dose of sunitinib, treatment-related toxicity, and the clinical response to therapy. Results: The initial dose of sunitinib was 25 mg (cases 1 and 5), 37.5 mg (cases 2 and 3), and 50 mg (cases 4 and 6), respectively. Toxicities greater than grade 3 were observed in cases 3 and 6, and subsequently the dose was reduced in case 6. No patient had to stop sunitinib due to toxicities. Among the 6 patients, 3 (cases 2, 3, and 5) had disease progression after 1, 2, and 2 cycles of sunitinib, respectively. Three patients (cases 1, 4, and 6) had stable disease after 12, 5, and 4 cycles of treatment, respectively, and 2 of them (cases 4 and 6) were still on sunitinib 8 and 7 months, respectively, after the start of treatment. Conclusions: The toxicity of and response to sunitinib in dialyzed patients seem to be comparable to those in patients with normal renal function. However, due to the limitations of this study, i.e. a small number of participants and lack of pharmacokinetic data, prospective clinical trials with pharmacokinetic studies in a larger cohort of patients are required.

It is well known that CPT-11 (irinotecan) is biotransformed to its active metabolite, SN-38, by carboxylesterase in the liver and other tissues. However, little is known about its pharmacokinetics (PK) when administered intraperitoneally. The aim of our study was to develop a population pharmacokinetic model for CPT-11 and SN-38 following the intraperitoneal (IP) administration of CPT-11.Pharmacokinetic data obtained from 16 gastric adenocarcinoma patients with peritoneal seeding were used. Administered doses ranged from 50 to 250 mg/m(2). To measure CPT-11 and SN-38 levels, we collected samples of peritoneal fluid, plasma and urine 0, 0.5, 1.5, 2, 3.5, 8, 12, 25.5, 49 and 56 h after IP infusion. Several multicompartmental pharmacokinetic models were tested for CPT-11 and SN-38 in the sampled peritoneal fluid, plasma and urine. NONMEM ver. 6 was used throughout the model-building process.Peak concentrations were achieved earlier for peritoneal SN-38 than for plasma SN-38. The apparent metabolic clearance of peritoneal and plasma CPT-11 to peritoneal and plasma SN-38 accounted for 0.2 and 7.3% of the total clearance of peritoneal and plasma CPT-11, respectively. The typical values of steady-state volume of distribution (Vss) (46.6 L/m(2)), inter-compartment clearance (6.70 L/h/m(2)) and clearance (16.0 L/h/m(2)) for plasma CPT-11 were estimated in a two-compartment PK model.Our results demonstrate that a small fraction of intraperitoneally administered CPT-11 was metabolized in situ to active SN-38 and that the Vss of plasma CPT-11 following IP administration in our patient cohort was lower than that estimated in previous reports following the intravenous administration of CPT-11.

Purpose: The aim of this study was to determine whether the ERCC1 expression is effective to predict the clinical outcomes of patients with advanced gastric cancer (AGC) and who were treated with cisplatin-based first-line chemotherapy. Materials and Methods: A total of 89 measurable AGC patients received cisplatin and capecitabine, with or without epirubicin, as a part of a randomized phase II study. Patients were included for the current molecular analysis if they had received two or more cycles of chemotherapy, their objective tumor responses were measured and if their paraffin-embedded tumor samples were available. The ERCC1 expression was examined by performing immunohistochemical (IHC) staining, and the patients were divided into two groups (positive or negative) according to the presence of IHC staining of the tumor cell nuclei. Results: Of the 32 eligible patients, 21 patients (66%) had tumor with a positive expression of ERCC1 and the remaining 11 patients had tumor with a negative ERCC1-expression. The ERCC1-negative patients achieved a higher response rate than that of the ERCC1-positive patients (44% vs. 28%, respectively), although the difference was not statistically significant (p=0.42). The median survival time for the all patients was 14.6 months (95% CI: 13.6 to 15.6 months). The one-year survival rate was similar for the ERCC1-negative patients (61%) and the ERCC-1-positive patients (70%). Conclusion: In the current study, the tumor ERCC1 expression by IHC staining could not predict the clinical response or survival of AGC patients who were treated with cisplatin-based first-line chemotherapy. The ERCC1 protein expression does not appear to be a useful tool for the selection of tailored chemotherapy for these patients.

Background Both cisplatin/capecitabine (CX) and epirubicin plus CX (ECX) have clearly demonstrated efficacy against advanced gastric cancer (AGC). Methods Chemotherapy-naive patients with histologically confirmed, measurable AGC were randomised to receive CX (cisplatin 75 mg/m 2 iv on day 1 and capecitabine 1000 mg/m 2 bid po on days 1–14) or ECX (epirubicin 50 mg/m 2 plus CX) every 3 weeks. The primary endpoint was progression-free survival (PFS). Results Of the 91 registered patients, 45 patients were treated with CX and 44 with ECX. A total of 241 CX (median, 6; range, 1–12) and 201 ECX (median, 5; range, 1–11) cycles were delivered. Treatment duration was similar for both arms (4.4 for CX versus 4.2 months for ECX). There was no relevant difference in the occurrence of overall grade 3 or 4 toxicities between the CX and ECX arms (80% versus 78%, respectively; P = 0.516). However, none in the CX and 12% in the ECX arm discontinued treatment because of toxicity. There were no significant differences in therapeutic efficacy between CX and ECX with respect to the response rate (38% versus 37%, respectively) and PFS (6.4 versus 6.5 months). Conclusion Both CX and ECX appear to be active as first-line chemotherapy for AGC, and the safety profiles are acceptable. Given the comparable efficacy results, CX could be a reasonable standard chemotherapy for untreated AGC patients.

Colon cancer with DNA mismatch repair (MMR) defects reveals distinct clinical and pathologic features, including a better prognosis but reduced response to 5-fluorouracil (5-FU)-based chemotherapy. A current standard treatment for recurrent or metastatic colon cancer uses capecitabine plus oxaliplatin (CAPOX), or continuous-infusion fluorouracil plus oxaliplatin (FOLFOX). This study investigated the effect of MMR status on the treatment outcomes for CAPOX and FOLFOX as first-line combination chemotherapy in recurrent or metastatic colon cancer. We analyzed 171 patients who had been treated with CAPOX or FOLFOX as first-line combination chemotherapy in recurrent or metastatic colon adenocarcinoma between February 2004 and July 2008. Tumor expression of the MMR proteins, MLH1 and MSH2, was detected by immunohistochemistry (IHC) in surgically resected tumor specimens. The microsatellite instability (MSI) was analyzed by polymerase chain reaction (PCR) amplification, using fluorescent dye-labeled primers specific to microsatellite loci. Tumors with MMR defect were defined as those demonstrating a loss of MMR protein expression (MMR-D) and/or a microsatellite instability-high (MSI-H) genotype. In all, 75 patients (44%) received FOLFOX, and 96 patients (56%) received CAPOX as first-line combination chemotherapy. The incidence of colon cancer with MMR defect was 10/171 (6%). Colon cancers with MMR defect (MSI-H and/or MMR-D) are more commonly located in proximal to the splenic flexure (p = 0.03). The MMR status did not significantly influence the overall response (p = 0.95) to first-line CAPOX or FOLFOX treatment in patients with recurrent or metastatic colon cancer. According to the MMR status, there was no significant difference for PFS (p = 0.50) and OS (p = 0.47) in patients with recurrent or metastatic colon cancer treated with first-line CAPOX or FOLFOX. In colon cancers with MMR defect, there was no significant difference for PFS (p = 0.48) and OS (p = 0.56) between CAPOX and FOLFOX as first-line combination chemotherapy. However, in MMR intact, there was significant difference for OS between CAPOX and FOLFOX (p = 0.04). OS was significantly better in patients treated with CAPOX when compared to patients with FOLFOX. The MMR status does not predict the effect of oxaliplatin-based combination chemotherapy as 1st line in recurrent or metastatic colon cancers. CAPOX in the first-line treatment of recurrent or metastatic colon cancer with MMR intacts showed a superior OS compared with FOLFOX unlike colon cancer with MMR defects.

We evaluated safety and efficacy of concurrent chemoradiotherapy (CCRT) with capecitabine in patients with locally advanced pancreatic cancer (LAPC). Between January 2004 and January 2008, 39 patients with LAPC treated with capecitabine CCRT were reviewed. Capecitabine was administered at 850 mg/m twice daily every day with 5 days per week radiotherapy (1.8 Gy fractions) over the 5 weeks. Thirty-seven (94.8%) patients completed CCRT. Of the 36 evaluable patients, 15 (41.7%) and 13 (36.1%) patients achieved partial response and stable disease, and eight (28.6%) among them received gemcitabine-based post-CCRT chemotherapy without dose reduction or delay. The overall survival was 14.3 months [95% confidence interval (CI): 10.6-17.9 months]. Median progression-free survival was 11.1 months for all patients, and 7.9 months for those patients who had not received post-CCRT chemotherapy. Eight patients (21.6%) had severe grade 3 toxicities, seven (18.9%) with gastrointestinal toxicity, and one (2.7%) with hematologic toxicity. Prognostic factors for survival were serum albumin (P = 0.014; relative risk: 3.4; 95% CI: 1.4-9.7), and adjuvant gemcitabine treatment (P=0.005; relative risk: 3.5; 95% CI: 1.2-10.6). Combined therapy with capecitabine CCRT was well tolerated and seems to be a promising regimen, in terms of response, survival, and adverse effects.

Colon cancer with DNA mismatch repair (MMR) defects reveals indistinguishable clinical and pathologic aspects, including better prognosis and reduced response to 5-fluorouracil (5-FU)-based chemotherapy. There has been no consensus for p53 as a prognostic marker in colorectal cancer. This study investigated the clinical implication of MSI-H/MMR-D and p53 expression in R0-resected colon cancer patients who received adjuvant oxaliplatin/5-FU/leucovorin (FOLFOX) therapy. We analyzed 135 patients, who had been treated by adjuvant chemotherapy containing 5-FU and oxaliplatin (FOLFOX) after curative resection (R0) for colon adenocarcinoma between May 2004 and November 2007. Tumor expression of the MMR proteins, MLH1 and MSH2, was detected by immunohistochemistry (IHC) in surgically resected tumor specimens. MSI was analyzed by polymerase chain reaction (PCR) amplification using fluorescent dye-labeled primers specific for microsatellite loci. Tumors with MMR defects were defined as those demonstrating loss of MMR protein expression (MMR-D) and/or microsatellite instability high (MSI-H) genotype. Expression patterns of p53 were determined in a semiquantitative manner by light microscopy. There were 13 (9.6%) patients with stage II, 108 (80%) with stage III, and 14 (10.4%) with stage IV. Fourteen patients with stage IV (10.3%) had metastases to liver only, all of whom underwent complete metastasectomy for liver metastases. In total, 134 tumor specimens were genotyped, 115 specimens were tested by IHC and 113 cases had both genotyping and IHC results available for analysis. Genotyping results demonstrated that 12 (9.0%) cases were MSI-H and 122 (91.0%) were MSI-L/S. By IHC, 11 (9.6%) patients were MMR-D and 104 (90.4%) were MMR-I. The methods were in agreement in 108 patients (94.7%). We assessed 114 patients for p53 expression by immunostaining. MMR status was not significantly associated with DFS (P = 0.56) or OS (P = 0.61) in patients with colon cancer (n = 135) receiving adjuvant FOLFOX. According to p53 status, there was also no significant difference for DFS (P = 0.11) and OS (P = 0.94). For patients with genotyping/IHC agreement (n = 108), there was no difference in DFS (P = 0.57) and OS (P = 0.98) between patients with MSI-H/MMR-D and MSI-L/S/MMR-I tumors. The MMR status or p53 positivity was not significantly associated with outcomes to FOLFOX as adjuvant chemotherapy in colon cancer patients with R0 resection. Adding oxaliplatin in adjuvant chemotherapy may overcome negative impact of 5-FU on colon cancers with MSI-H/MMR-D.

A recent study demonstrated that colorectal cancer (CRC) with ovarian metastases was less responsive to chemotherapy compared with extraovarian metastases. Hence, the ovary may actually represent a "sanctuary" for metastatic cells from CRC. The aim of the study was to investigate the impact of ovarian metastatectomy on survival of CRC patients with ovarian metastasis.Between 1996 and 2008, 83 CRC patients underwent an oophorectomy. For the historical control, 47 CRC patients with ovarian metastasis without resection were included in the analysis.The median age was younger (48 years) in the oophorectomy group compared with the historical control (54 years; P = 0.012). The proportion of synchronous metastasis was higher in the oophorectomy group than in the control group (57 vs. 30%; P = 0.003). After a median follow-up duration of 60.8 months (range of 7.4-169.7 months), the median OS was significantly longer in the oophorectomy group (28.1 vs. 21.2 months, oophorectomy vs. non-oophorectomy; P = 0.038). For ovary-specific survival (date of ovarian metastasis diagnosis to death), CRC patients with an oophorectomy showed a significantly more favorable survival rate than the control group (20.8 vs. 10.9 months; P0.001). In univariate analyses, oophorectomy (P = 0.038), unilaterality of ovarian metastasis (P = 0.032), metastasis confined to ovaries (P0.001), normal CEA level (P0.001), good performance status (P = 0.001), palliative chemotherapy (P = 0.001), and primary disease resection (P = 0.005) were identified as significantly good prognostic factors for overall survival. The oophorectomy, chemotherapy, metastasis confined to ovaries, normal CEA level, and good performance status retained statistical significance at the multivariate level (P = 0.003, P = 0.004, P = 0.005, P = 0.015, and P = 0.029, respectively).Based on this retrospective analysis, the ovarian metastatectomy significantly prolonged survival in CRC patients with ovarian metastases. The potential role of an ovarian metastatectomy in the management of CRC should be prospectively studied.

Purpose. This study analyzed the relationship between treatment outcome and kinase mutational status in Korean patients with advanced gastrointestinal stromal tumors (GISTs). Experimental Design. Clinical data were collected from 113 consecutive patients with metastatic or unresectable GISTs treated with imatinib from June 2001 through June 2005 at five institutions in Korea. KIT exons 9, 11, 13, and 17 and PDGFRA exons 12 and 18 were examined. Results. The median patient age was 57 years (range, 31–82 years). The overall response rate was 67.2%. KIT mutations were found in exon 11 (n = 92, 81.4%) and exon 9 (n = 10, 8.8%). One patient had a PDGFRA exon 18 mutation. The overall mutation rate was 91.2%. Response rates were 68.4%, 50.0%, and 80.0% in patients with KIT exon 11 mutations, KIT exon 9 mutations, and no kinase mutations, respectively. With a median follow-up of 49.0 months, the median progression-free survival (PFS) time was 42.0 months and median overall survival (OS) time was not reached. PFS and OS times did not differ significantly according to KIT genotype. Conclusion. This study was unable to find an association between KIT mutational status and clinical outcome of imatinib in Korean patients with advanced GISTs. There was a trend toward better outcomes for patients with wild-type KIT or exon 11 mutations compared with exon 9 mutations, although this was not statistically significant. Compared with previous studies in western populations, these results suggest that ethnic differences may influence the relationship between KIT genotype and clinical outcome to imatinib.

Simvastatin has demonstrated anti-tumor activity in preclinical studies via tumor cell senescence, anti-angiogenesis, and apoptosis. This phase II trial evaluated the efficacy and toxicity profile of conventional FOLFIRI chemotherapy plus simvastatin in metastatic colorectal cancer patients.Patients received irinotecan 180 mg/m(2) as a 90-min infusion followed by leucovorin 200 mg/m(2) in a 2-h infusion, and then 5-FU 400 mg/m(2) bolus injection followed by 2,400 mg/m(2) as a 46-h continuous infusion. Treatment cycles were repeated every 2 weeks until documented disease progression, unacceptable toxicity, or patient's refusal. Simvastatin 40 mg tablet was given once daily per oral everyday during the period of chemotherapy without a rest.From October 2005 to June 2006, 49 patients were enrolled. The overall response rate (ORR) was 46.9% (95% CI, 31.0-58.8) by intent-to-treat analysis and 45.8% (95% CI, 33.3-62.8) by per-protocol analysis. There were one complete response (CR) and 22 partial responses (PRs). Both CR and PRs were confirmed at least 4 weeks later. The disease-control rate was 83.7% (95% CI, 73.4-94.0). The median follow-up duration was 25.6 months (range, 20.9-28.8 months). The median survival of all patients was 21.8 months (95% CI, 14.4, 29.2). The median TTP was 9.9 months (95% CI, 6.4, 13.3). No patients experienced additional adverse effect that was definitely caused by simvastatin drug therapy in this trial.The combination of simvastatin plus FOLFIRI was a feasible regimen with promising antitumor activity.

Background Because treatment of advanced gastric cancer (AGC) patients after failure with first-line chemotherapy remains controversial, we performed this retrospective analysis based on the data obtained from 1455 patients registered in a first-line treatment cohort with respect to receiving or not receiving subsequent chemotherapy. Methods The decision for administering second-line chemotherapy was, in most cases, at the discretion of the physician. Seven-hundred twenty-five (50%) received second-line chemotherapy after first-line failure. Univariate and multivariate analyses were performed on the recognized baseline parameters for survival. Results At the time of initiating second-line chemotherapy, the patients' median age was 56 years (range, 22 to 86) and 139 (19%) had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or more. Seven (1%) complete and 108 (15%) partial responses to second-line chemotherapy were observed for an overall response rate of 16% (95% confidence interval [CI], 13 to 19%). The median progression-free and overall survivals, calculated from the start of second-line chemotherapy, were 2.9 months (95% CI, 2.6 to 3.3) and 6.7 months (95% CI, 5.8 to 7.5), respectively. Multivariate analysis revealed that low baseline hemoglobin level (hazard ratio [HR], 0.74; 95% CI 0.61–0.90) and a poor performance status (HR, 0.66; 95% CI, 0.52–0.83) were independent negative prognostic factors for overall survival. Conclusion Performance status, along with baseline hemoglobin level, could be used to identify the subgroup of patients most likely to benefit from second-line chemotherapy for AGC.

We designed this phase I/II study of docetaxel-oxaliplatin combination chemotherapy to determine the dose-limiting toxicity (DLT), maximum tolerated dose and efficacy as a first-line treatment in patients with advanced gastric cancer.Patients with histologically proven, chemo-naive gastric adenocarcinoma were eligible. For the phase I part, three dose levels of oxaliplatin and docetaxel every 3 weeks were tested in a cohort of three patients for each level (respectively, 100 and 60 mg/m(2), 100 and 75 mg/m(2), 130 and 75 mg/m(2)). Patients were treated up to a maximum of nine cycles of oxaliplatin and docetaxel unless there was documented disease progression, an unacceptable adverse event, or withdrawal of consent.No DLT was observed at any of the three levels tested in the phase I portion. Therefore, oxaliplatin 130 mg/m(2) and docetaxel 75 mg/m(2) were recommended for the phase II study. All 47 patients were evaluable for toxicity and treatment response. The overall response rate was 55.3% (95% CI, 40.6-70.1%) and median duration of response was 4.2 months (range 0.9-9.5 months). After a median follow-up duration of 13.3 months, median overall survival was 12.7 months (95% CI: 10.4-14.9). The median time to progression was 5.0 months (95% CI, 3.4-6.5 months). The main toxicities (grade 3 or 4) were febrile neutropenia (14.9%), neutropenia (23.4%), diarrhea (10.6%) and neurotoxicity (8.5%).The combination of docetaxel and oxaliplatin was feasible with favorable toxicity profile and showed a promising anti-tumor activity in unresectable, metastatic gastric cancer patients.

Objectives: This prospective, multicenter, phase 2 study evaluated the efficacy and safety of imatinib mesylate and assessed KIT and PDGFRA gene mutation status in Korean patients with gastrointestinal stromal tumors (GISTs). Methods: Forty-seven patients with pathologically proven KIT-positive metastatic or unresectable GISTs were accrued from eight institutions in Korea. Imatinib was administered orally at 400 mg once daily. In case of disease progression, the dose was escalated to 600 mg once daily, then 400 mg twice daily. KIT and PDGFRA mutations were analyzed in 29 of the 47 patients. Results: Imatinib produced partial responses in 30 patients (63.8%; 95% confidence interval, 50.1–77.6%) and stable disease in 13 patients (27.7%). The median time to response was 2.6 months (range, 1.0–6.2 months). With a median follow-up of 62 months (range, 32–67 months), 4-year progression-free survival and overall survival rates were 50 and 65%, respectively. The most common adverse events were anemia, neutropenia, edema, and skin rash (predominantly of grade 1–2). There were no treatment-related deaths. In the subset evaluated for mutational status, 24 patients (82.8%) had KIT exon 11 mutations and 1 (3.4%) had a KIT exon 9 mutation. Conclusions: Imatinib is effective and safe in Korean patients with metastatic or unresectable GIST.

Purpose To retrospectively compare immediate and long-term outcome of central venous infusion port inserted via right high versus low jugular vein approaches. Materials and methods The study included 163 patients (125 women patients, 38 men patients; age range, 18–79 years; mean age, 53 years); 142 patients underwent port insertion with low jugular vein approach and 21 patients with high jugular vein approach. The causes of high jugular vein puncture were metastatic lymphadenopathy (n = 7), operation scar (n = 6), radiation scar (n = 5), failure of low jugular vein puncture (n = 2), and abnormal course of right subclavian artery (n = 1). Medical records and radiologic studies were reviewed retrospectively to determine and compare the outcome and the occurrence of complication related to port. Results The procedure-related complications were all minor (n = 14, 8.6%) in both groups; hematoma (n = 4, 2.8% in low jugular puncture group and n = 1, 4.8% in high jugular puncture group, p = 0.6295), air embolism (n = 2, 1.4% in low jugular puncture group and n = 0 in high jugular puncture group, p = 0.5842) and minor bleeding (n = 5, 3.5% in low jugular vein puncture group and n = 2, 9.5% in high jugular vein puncture group, p = 0.2054). The average length of follow-up was 431 days for low jugular vein puncture group and 284 days for high jugular vein puncture group. The difference between two groups was significant (p = 0.0349). The reasons for catheter removal were patients’ death (59 in low jugular puncture group and 14 in high jugular puncture group, p = 0.0465), suspected infection (11 in low jugular vein puncture group and 2 in high jugular vein puncture group, p = 0.8242), catheter occlusion (four in low jugular vein puncture group and one in high jugular vein puncture group, p = 0.6583). The catheter tip migrated upward an average of 1.86 cm (range, −0.5 to 5.0 cm) in low jugular vein puncture group and 1.56 cm (range, 0–3.6 cm) in high jugular vein puncture group and there was no significant difference (p = 0.4232). Conclusions Right high jugular vein approach can be a feasible alternative to right low jugular vein approach.

Purpose: There are no reliable prognostic markers that identify gastric cancer patients who may benefit from adjuvant chemoradiation therapy. E2F-1 was shown to be associated with radiosensitivity and chemosensitivity in certain tumor types. Therefore, we analyzed expression and prognostic significance of E2F-1 along with thymidylate synthase (TS) in R0-resected gastric adenocarcinoma patients, who underwent adjuvant chemoradiation therapy with 5-fluorouracil (5-FU) and leucovorin. Experimental Design: The chemosensitivity to 5-FU and radiosensitivity were tested in three E2F-1–overexpressed gastric cancer cell lines in vitro. The expressions of TS and E2F-1 were analyzed in 467 R0-resected primary gastric cancer patients, who received adjuvant chemoradiation therapy with 5-FU and leucovorin using tissue microarray. Results: The E2F-1 immunopositivity rate was 22.2% (103 of 465 samples) with a cutoff value of 5% immunoreactivity, whereas the TS-positive expression occurred in 19.0% of the 463 tumors tested. Using stepwise Cox proportional hazards regression modeling, multivariate analyses showed that the E2F-1 immunopositivity predicted more favorable survival as compared with the E2F-1 immunonegativity with borderline statistical significance [P = 0.050, hazard ratio (HR) = 0.702, 95% confidence interval, 0.487, 1.013]. However, the E2F-1 immunopositivity did not retain its statistical significance at multivariate analysis for predicting disease-free survival (data not shown, P = 0.270), but stage was the only influential factor for disease-free survival in stages IB to IV (M0) patients (P < 0.001). TS immunopositivity did not influence survival (P = 0.459) or disease-free survival (P = 0.447). Conclusion: E2F-1 is a potentially novel independent prognostic factor that may identify gastric cancer patients who will likely benefit from adjuvant chemoradiation therapy following curative resection.

Background and Aim: The resection of synchronous or metachronous pulmonary and liver metastasis is an aggressive treatment option for patients with stage IV colorectal cancer and has been shown to yield acceptable long-term survival. We reviewed our experience with colorectal cancer patients with both liver and lung resections to determine the efficacy of surgical resections. Methods: We performed a single institution, retrospective analysis of all patients who underwent surgical hepatic and pulmonary resection for metastatic colorectal cancer between 1995 and 2004. Results: A total of 32 patients underwent resection of both hepatic and pulmonary metastases secondary to colorectal cancer. The 5-year overall survival from initial operation was 60.8%. The disease-free interval was 44.3 months (95% confidence interval: 24.7 and 63.8, respectively). Neither the number of pulmonary lesions nor the time interval between the primary surgery and the metastasectomy had a significant impact on survival (P = 0.134). Conclusion: An aggressive surgical treatment of selected colorectal cancer patients with lung and liver metastases resulted in prolonged survival. The 5-year survival rate of 60.8% with no perioperative mortality was observed in our study.

Background: Gastric cancer with bone marrow metastases is known to pursue a rapidly deteriorating clinical course. We conducted a retrospective analysis to evaluate clinical manifestations and prognosis of gastric cancer patients with bone marrow metastases. Methods: Between September 1994 and February 2006, 39 gastric cancer patients with pathologically confirmed bone marrow dissemination were selected. Results: The majority of the patients showed younger age, poorly differentiated adenocarcinoma or signet ring cell carcinoma, thrombocytopenia, anemia, elevated lactate dehydrogenase and alkaline phosphatase. Poor prognostic factors for survival were serum sodium ≤133 mmol/l [relative risk (RR) 4.57; 95% CI 1.99–10.52; p < 0.001], the presence of lung metastasis (RR 3.47; 95% CI 1.48–8.15; p = 0.007) and the presence of peritoneal seeding (RR 2.17; 95% CI 1.06–4.43; p = 0.036). Median survival durations after bone marrow metastases for patients without any adverse factors (n = 19, 48.7%) and those with 1–3 adverse factors (n = 20, 51.3%) were 67 and 23 days, respectively (p = 0.013). Patients without any adverse factors did benefit from palliative chemotherapy (p = 0.048). Conclusion: We suggest that gastric cancer patients with bone marrow metastases should receive more tailored therapies according to different risk factors in order to enhance survival.

BACKGROUND. Erlotinib, in combination with gemcitabine, has shown clinical benefits in pancreatic adenocarcinoma patients. The presence of EGFR mutations and increased EGFR copy numbers in pancreatic adenocarcinoma was explored. METHODS. Sixty-six pancreatic cancer patients were included in the analysis. The EGFR mutation was analyzed by DNA sequencing of exons 18–21 in the tyrosine kinase domain. KRAS mutation was analyzed by sequencing codons 12, 13, and 61. Quantitative real-time polymerase chain reaction was performed to analyze the copy number of EGFR. RESULTS. In the current study the EGFR mutation was harbored in only 1 (1.5%) of the 66 inoperable or metastatic pancreatic adenocarcinoma patients. Amino acid substitution was detected in exon 20 of the EGFR gene. Increased EGFR copy numbers (≥3.0 per cell) were detected in 26 (41%) patients. There was only 1 patient, who had a highly increased EGFR copy number (≥6.0 per cell), who died, 2.1 months from the date of diagnosis. The EGFR amplification did not significantly influence survival in pancreatic adenocarcinoma patients (P = .935). Thirty-two (49%) of the 65 pancreatic adenocarcinomas examined harbored a point mutation in codons 12 (n = 31) and 61 (n = 1) of the KRAS gene. The presence of a point mutation in codon 12 adversely influenced survival of pancreatic cancer patients (P = .030). CONCLUSIONS. The incidence of somatic mutations in the tyrosine kinase domains of EGFR was very low and the increased gene copy number of EGFR did not significantly influence survival. Cancer 2007. © 2007 American Cancer Society.

e22241 Background: Recent advances in translational research have been largely accompanied by improvement of tumor cell model. In this study, we established the patient-derived cell (PDC) models fr...

3576 Background: The purpose of this randomized phase III trial was to evaluate the addition of synthetic 3-hydroxy-3methyglutaryl coenzyme A (HMG-CoA) reductase inhibitor, simvastatin to XELIRI/FO...

4049 Background: We designed a single-arm, open label phase II study to determine the efficacy and toxicity of the combination of pazopanib with CapeOx (capecitabine and oxaliplatin) in metastatic ...

2522 Background: Tanibirumab is a fully human monoclonal antibody to the vascular endothelial growth factor receptor 2 (VEGFR-2). We conducted a first-in-human phase I study of Tanibirumab in patie...

3600 Background: The aim of this study was to investigate the association between initial irinotecan dose and UGT1A1 genotype, dose intensity, response rate, neutropenia and survival in advanced co...

TPS228 Background: Treatment of gastric cancer (GC) has some notable differences between Asia and Western countries including the extent of surgery and the type of adjuvant therapy. In ARTIST trial comparing adjuvant chemotherapy involving capecitabine plus cisplatin with chemoradiotherapy, we reported comparable disease-free survival (DFS) in Korean patients with D2-resected GC. In subset analyses, patients with node-positive disease and intestinal type GC may have benefit with the addition of radiotherapy to adjuvant chemotherapy. Methods: ARTIST 2 (ClinicalTrials.gov, NCT0176146) is a 3-arm, multi-center, open-label phase III trial comparing adjuvant chemotherapy involving S-1 (40 mg/m2 bid 4-weeks-on/2-weeks-off) for one year (arm A) with S-1 plus oxaliplatin (SOX, S-1 40 mg/m2 bid 2-weeks-on/1-week-off plus oxaliplatin 130 mg/m2 iv on day 1) for 8 cycles (arm B) and chemoradiotherapy (arm C). Arm C patients receive SOX for 2 cycles, then concurrent chemoradiotherapy 45 Gy with S-1 40 mg bid daily, followed by additional SOX for 4 more cycles. Patients are randomized 1:1:1 with 3 strata: stage (II or III), type of surgery (subtotal or total gastrectomy) and Lauren classification (diffuse or intestinal type). Eligibility criteria include gastric or gastro-esophageal junction adenocarcinoma, D2 or higher surgery with no residual disease, pathologic stages 2 or 3, lymph node positive disease. Primary endpoint is DFS, and secondary endpoints include overall survival, safety, QOL and molecular biomarkers. To test if experimental arms (arm B or C) lower the hazard of recurrence by 50% (i.e., HR 1.5) compared to arm A, we need 900 patients (300 per arm) with 90% of overall statistical power. First patient entered onto the study in Feb 2013. As of Aug 2014, a total of 118 (13% of target) patients were recruited by 8 Korean tertiary centers. Clinical trial information: NCT0176146.

185 Background: Trastuzumab-based chemotherapy became the standard option for patients with HER2 (+) metastatic gastric cancer after ToGA study. However, the OS benefit was not found in Asian and diffuse-type cancer patients. The aim of the current study is to analyze whether Asian ethnicity or poorly differentiated histology (PDH) affects the clinical outcomes of patients who were treated with trastuzumab-based chemotherapy. Methods: We collected the medical records of the patients with HER2 (+) (IHC3+ or IHC2+&FISH+) gastric/GEJ cancer who were treated with trastuzumab-based chemotherapy. The ORR, PFS, and OS were compared according to the patients’ clinicopathologic features and data from ToGA trial. Results: From March 2012 to June 2014, data of 163 Asian patients from 11 institutes in South Korea were collected. The median age was 60 (range 27-85) and the male:female ratio was 116 (71.2%):47 (28.8%). 157 (96.3%) had stomach cancer and 6 (3.7%) had GEJ cancer. Fourteen (8.6%), 62 (38.0%), 71 (43.6%) and 11 (6.7%) patients had well, moderately, poorly differentiated tubular adenocarcinoma (TAC) and signet ring cell carcinoma (SRC), respectively. The ORR was 52.7% (86/163) which is similar to that of the ToGA trial. (47%) The median PFS was 9.8 months (95% CI 8.6 – 11.0 and the median OS was 18.5 months. (95% CI 16.5 – 20.5) These numerical data are slightly better than those of the ToGA trial. (PFS, 6.7 months; OS, 16.0 months) Next, we investigated if PDH (poorly differentiated TAC + SRC) affected on clinical outcomes. The ORR (50.0% vs. 56.6%, p = 0.408) and the PFS (8.8 months vs. 11.2 months, p = 0.109) were slightly inferior in PDH patients but still, they were better than that of the ToGA trial. The median OS was significantly shorter for PDH patients (14.1 months vs. 19.0 months, p = 0.046). Conclusions: While subset analysis of ToGA trial has demonstrated that trastuzumab-based chemotherapy may not be beneficial for Asian ethnicity and poorly differentiated histology, our real world data suggested that even in Asian and patients with PDH, trastuzumab-based chemotherapy is associated with improved clinical outcomes in patients with HER2 (+) gastric cancer.

Purpose The expression of p53 in patients with rectal cancer who underwent preoperative chemoradiationand and its potential prognostic significance were evaluated. Materials and Methods p53 expression was examined using immunohistochemistry in pathologic specimens from 210 rectal cancer patients with preoperative chemoradiotherapy and radical surgery. All patients were classified into two groups according to the p53 expression: low p53 (

Purpose: The purpose of this study was to identify the effects of emotional labor and self-efficacy on psychosocial stress of nurses. Methods: A cross-sectional correlation study design was used. The participants were 186 nurses from two general hospitals in Jeju Island, South Korea. A self-report questionnaire was used to collect data including data on emotional labor, self-efficacy, and psychosocial stress. Data were analyzed using descriptive statistics, Pearson correlation coefficient, t-test, ANOVA, and hierarchical multiple regression. Results: Approximately 98% of the participants were categorized as having potential and high risk stress levels. Hierarchical multiple regression showed that employment status, surface-acting, and self-efficacy explained 37.0% of psychosocial stress and self-efficacy was the main factor influencing psychosocial stress. Conclusion: Nursing administrators should understand that nurses suffer from high risk stress and emotional labor. To reduce the psychosocial stress of nurses, there is needed to improve stressful work conditions such as irregular employment, decrease surface-acting, and improve

Purpose Although several studies report risk factors for anastomotic leakage after gastrectomy for gastric cancer, they have yielded conflicting results. The present retrospective cohort study was performed to identify risk factors that are consistently associated with anastomotic leakage after gastrectomy for stomach cancer. Materials and Methods All consecutive patients who underwent gastrectomy at a single gastric surgical unit between May 2003 and December 2012 were identified retrospectively. The associations between anastomotic leakage and 23 variables related to patient history, diagnosis, and surgery were assessed and analyzed with logistic regression. Results In total, 3,827 patients were included. The rate of anastomotic leakage was 1.88% (72/3,827). Multiple regression analysis showed that male sex (P=0.001), preoperative/intraoperative transfusion (P

The aim of the study was to identify reliable predictive biological markers for treatment outcome following neoadjuvant adriamycin/docetaxel (AT) chemotherapy in locally advanced breast cancer patients.This study was a phase II study on AT neoadjuvant chemotherapy in locally advanced breast cancer patients. Patients received 50 mg/m(2) of doxorubicin intravenously (IV) over 15 min followed by docetaxel 75 mg/m(2) infused over 1 h, repeated every 3 weeks for three cycles. Surgery was performed within 3-4 weeks following the last cycle of chemotherapy. We analyzed the pre-treatment and post-treatment expression levels of ER, PgR, HER-2, Ki-67 proliferation index, and p53 and examined the correlation between the markers and clinical parameters with treatment response, overall survival and relapse-free survival following neoadjuvant treatment.From July 2001 to September 2004, 61 patients were enrolled. The meaningful parameters adversely influencing survival were post-treatment ER(-) status (P = 0.013) and post-treatment Ki-67 index above 1.0% (P = 0.013). At the multivariate level, the post-treatment Ki-67 proliferation indexor = 1.0 was the only meaningful prognostic factor for better survival (P = 0.033). Notably, tumors with Ki-67 indexor = 1.0 were more likely to express ER with statistical significance (P = 0.002). Tumors with ER(+) and Ki-67 indexor = 1.0 showed the highest survival rate, followed by ER(+) and Ki-67 index1.0%, ER(-) and Ki-67or = 1.0%, and ER(-) and Ki-671.0% with the worst survival (P = 0.033).Collectively, post-treatment ER status and Ki-67 proliferation index were prognostic of overall survival following neoadjuvant AT chemotherapy.

Biliary tract cancer is one of the most aggressive and chemotherapy-refractory tumors. Although only curative treatment modality is surgery, most patients are not suitable for surgery due to advanced stage of the disease at diagnosis. Thus most patients with biliary tract cancer are possible candidates for palliative chemotherapy. The standard chemotherapeutic regimen is still to be defined, however. We performed a phase II study of combination chemotherapy with capecitabine and cisplatin in these patients to evaluate efficacy and toxicity of the regimen. Patients with previously untreated metastatic, recurrent, or inoperable biliary tract cancer were enrolled. Eligible patients were screened as following: (1) histologically confirmed, (2) age between 18 and 75 years, (3) at least one measurable lesion according to RECIST criteria, (4) ECOG performance status ≤2, (5) a life expectancy of at least 3 months, and (6) adequate laboratory values. Patients received capecitabine (2,500 mg/m2/day, days 1 to 14) and cisplatin (60 mg/m2, day 1) every 3 weeks. Response was assessed for every two cycles of chemotherapy and treatment was stopped when tumor had progressed or stable with no further response. Thirty-two patients were enrolled, 20 (62.5%) were male and 12 (37.5%) were female and the median age was 54 years (33–71 years). Fifteen patients (46.9%) had gallbladder cancer, 13 (40.6%) had intrahepatic cholangiocarcinoma, and 4 (12.5%) had extrahepatic biliary cancer. The most frequent metastatic sites were lymph nodes (20/32, 62.5%) and liver (28/32, 56.3%). No complete response was observed and partial response was observed in 13/32 patients. By the intent-to-treat analysis, the overall response rate was 40.6% (95% CI, 23.7–59.4) with 0 CR and 13 PRs. Stable disease was observed in 3 patients (9.4%), and 11 patients (34.4%) had progressive disease. The median time to progression was 3.5 months (95% CI, 1.3–5.8), and the median overall survival was 12.4 months (95% CI, 6.3–18.5) after the median follow-up duration of 9.5 months (4.8–26.1 months). A total of 108 cycles of chemotherapy was delivered. Grade 3 hematologic toxicities included neutropenia (5, 15.6%), anemia (1, 3.1%), and thrombocytopenia (1, 3.1%) per patient, and no grade 4 hematologic toxicities were observed. Grade 3 non-hematologic toxicities included hyperbilirubinemia (2, 6.3%), increase of alkaline phosphatase (2, 6.3%), hand–foot syndrome (2, 6.3%), anorexia, and diarrhea (1, 3.1%) per patient, respectively. There was no treatment-related death. The combination chemotherapy of capecitabine and cisplatin demonstrated a promising antitumor activity with mild toxicity profile in patients with advanced biliary tract cancer.

The current study demonstrates that COX-2 expression is positively regulated by IFN-alpha, which is mediated by activation of STAT1 in A549 cells. The IFN-alpha-induced COX-2 expression and STAT1 activation were markedly inhibited by the addition of curcumin to the IFN-alpha-pretreated cells. While IFN-alpha or COX-2 inhibitors alone did not result in growth inhibition of A549 cells, the combination of IFN-alpha and celecoxib or curcumin resulted in a significant growth inhibition of A549 cells, which was associated with down-regulation of CDK2, 4, and 6 and up-regulation of p27. We demonstrate that the expression of COX-2 was induced by IFN-alpha possibly via STAT1 activation in the A549 human non-small cell lung cancer cell line, which may partly account for its IFN-alpha resistance. The addition of curcumin or celecoxib to the IFN-alpha-pretreated A549 cells altered the IFN-alpha sensitivity of cell growth inhibition.

The current study demonstrates that COX-2 expression is positively regulated by IFN-alpha, which is mediated by activation of STAT1 in A549 cells. The IFN-alpha-induced COX-2 expression and STAT1 activation were markedly inhibited by the addition of curcumin to the IFN-alpha-pretreated cells. While IFN-alpha or COX-2 inhibitors alone did not result in growth inhibition of A549 cells, the combination of IFN-alpha and celecoxib or curcumin resulted in a significant growth inhibition of A549 cells, which was associated with down-regulation of CDK2, 4, and 6 and up-regulation of p27. We demonstrate that the expression of COX-2 was induced by IFN-alpha possibly via STAT1 activation in the A549 human non-small cell lung cancer cell line, which may partly account for its IFN-alpha resistance. The addition of curcumin or celecoxib to the IFN-alpha-pretreated A549 cells altered the IFN-alpha sensitivity of cell growth inhibition.

The authors performed a Phase II study of combination chemotherapy with gemcitabine and cisplatin in patients with inoperable biliary tract cancer to evaluate efficacy and toxicity of this combination. In addition, the correlation between the CA 19-9 response and clinical outcome was analyzed.The eligibility criteria for this study were 1) histologically or cytologically confirmed inoperable biliary tract cancer in patients with metastatic or recurrent disease; 2) age between 18 and 70 years; 3) at least 1 measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria; 4) an Eastern Cooperative Oncology Group (ECOG) performance statusor = 2; 5) a life expectancy of at least 3 mos; and 6) adequate bone marrow, hepatic, and renal function. The patients received gemcitabine (1250 mg/m(2), Days 1 and 8) and cisplatin (60 mg/m(2), Day 1) every 3 weeks. Tumor response was assessed by RECIST criteria every 2 cycles of chemotherapy. Treatment was continued until progression of disease was documented.Twenty-nine patients were enrolled. The median age of these patients was 52 years (range, 37 to 69 yrs), and the median ECOG performance status was 1. No complete response was observed, and 10 of 29 patients had partial responses. The overall response rate was 34.5% (95% confidence interval [CI], 17.9-54.3) for the intent-to-treat analysis. Stable disease was observed in 4 (13.8%) patients and progressive disease in 13 (44.8%) patients. The median follow-up time was 10.0 months (95% CI, 7.2-12.8). The median time to progression (TTP) was 3.0 months (95% CI, 2.12-3.88), and the median overall survival was 11 months (95% CI, 5.49-16.5). Although these results showed a better response rate (57.1 % vs. 27.3%) and survival (12 vs. 10 mos) in patients with a decline in CA 19-9 of at least 25%, these data were statistically not significant. In addition, there was a significant positive correlation between the increment in CA 19-9 values and tumor progression as determined with RECIST criteria (r = 0.96, P0.01). However, there was no definite correlation between the CA 19-9 response and the response according to RECIST criteria (P = 0.087). National Cancer Institute (NCI) common toxicity criteria (CTC) Grade 3 or 4 hematologic toxicities included neutropenia in 4 (14%) patients and anemia in 1 (3%) patient. Two of 4 patients with Grade 3 or 4 neutropenia had febrile episodes (7%) and required hospital admissions. NCI-CTC Grade 3 or 4 nonhematologic toxicity included nausea in 1 (3%) patient. There were no treatment-related deaths.The combination chemotherapy with gemcitabine and cisplatin in inoperable biliary tract cancer was tolerable for most patients and showed modest response rates. The role of CA 19-9 monitoring as a surrogate biomarker in patients with BTC treated with gemcitabine chemotherapy should be further investigated.