bluuebunny/crossref_metadata_2025_split huggingface dataset:
Search for biomarkers of stage II/III gastric cancer and development of individualized therapy.
Authors: Oshima Takashi , Sakamoto Naoya , Yoshikawa Takaki , Rino Yasushi , Kunisaki Chikara , Yasui Wataru , Imada Toshio , Masuda Munetaka 
Published: March 2020

4068 Background: Standard therapy for stage II/III gastric cancer is curative resection followed by adjuvant chemotherapy. Treatment outcomes are expected to be further improved by the development of individualized therapy based on new biomarkers. We have extracted mRNA from frozen specimens of gastric cancer to construct a cDNA bank and searched for new biomarkers of stage II/III gastric cancer. We report currently available results. Methods: The study group comprised 256 patients with stage II/III gastric cancer in whom at least 5 years had passed since surgery (among whom 149 received S-1 as adjuvant chemotherapy). A total of 130 genes were selected on the basis of the results of comprehensive DNA microarray analyses and extraction from serial analysis of gene expression (SAGE) libraries, and other studies. Relative expression levels of each gene in gastric cancer tissue and adjacent normal mucosa were measured by quantitative PCR, and the relations between clinicopathological factors and treatment outcomes were studied. In addition, using 9 types of gastric cancer cell lines, we knocked down the new cancer biomarkers obtained in this study with small interfering RNA (siRNA) and performed functional analysis. Results: In patients with resected stage II/III gastric cancer, INHBA, IGF-1R, CLDN7, and DPD genes were independent prognostic factors. In the subgroup of patients who received S-1-based adjuvant chemotherapy, IGF-1R, INHBA, SULF1, REG4, MMP11, and KIAA1199 genes were independent prognostic factors. Knockdown of the KIAA1199 gene with siRNA markedly inhibited the proliferative and invasive activities of the gastric cancer cell lines and lowered resistance to 5-fluorouracil. Conclusions: Investigatory studies of new biomarkers of gastric cancer identified prognostic factors for patients with resected stage II/III gastric cancer and those who received adjuvant chemotherapy with S-1. At present, the development of small molecule drugs that target KIAA1199 and the joint development of risk stratification tools with the goal of individualized therapy for stage II/III gastric cancer are ongoing.
A phase ll study of new combination regimen with trastuzumab, S-1, and CDDP in HER2-positive advanced gastric cancer (HERBIS-1).
Authors: Koeda Keisuke , Sugimoto Naotoshi , Tanaka Junji , Tsuda Masahiro , Okamoto Wataru , Okuda Hiroyuki , Imamura Hiroshi , Matsuyama Jin , Shimokawa Toshio , Sakai Daisuke , Fukushima Norimasa , Kurokawa Yukinori , Komatsu Yoshito , Tsujinaka Toshimasa , Furukawa Hiroshi 
Published: March 2020

4072 Background: S-1, a novel oral fluoropyrimidine, plus cisplatin (SP) regimen is one of the standard chemotherapy as first-line for advanced gastric cancer. ToGA study demonstrated that trastuzumab (T-mab) combination regimen improved the overall survival of patients with HER2-positive advanced gastric cancer. However, there was no study evaluating the efficacy and the safety of T-mab in combination with S-1 plus cisplatin (SP) regimen. Therefore, we planned this study to examine the efficacy and the safety of the SP plus T-mab. Methods: Patients confirmed to be HER2-positive by IHC and/or FISH (IHC 3+ or IHC 2+ and FISH positive) received S-1 at 80 mg/m2 po, day 1-14, and cisplatin 60 mg/m2 iv, day 1 plus trastuzumab 8 mg/kg iv, day 1 (6 mg/kg iv, d1 from 2nd course), repeated every 3 weeks until disease progression. Primary endpoint was response rate (RR). Secondary endpoints were progression-free survival, overall survival and safety. The threshold response rate was defined as 35%, and the expected rate was set at 50% with a 80% power and a 1-sided alpha value of 0.1 and the calculated sample size was 50 patients. Results: A total of 56 patients (median age 66) were enrolled in this study. The efficacy and the safety analyses were conducted in the full analysis set of 53 patients. (Two patients were excluded for ineligibility and one was for no treatment). The confirmed RR assessed by the independent review committee was 67.9% (95% CI: 53.7 – 80.1), and the disease control rate was 94.3%. The median PFS was 7.1 months (95% CI: 6.0 – 10.1). The median OS was not reached. (The median follow-up time: 9.2 months) The main grade 3/4 adverse events were as follows: neutropenia 34%, leucopenia 8%, anorexia 23%, diarrhea 8%, hypoalbuminemia 4%, vomiting 6%, and increased creatinine 6%. Conclusions: This tri-week regimen with SP plus T-mab showed promising results in patients with HER2-positive advanced gastric cancer. Clinical trial information: UMIN000005739.
Prognostic impact of human epidermal growth factor-2 (HER2) status on overall survival (OS) of advanced gastric cancer (AGC) patients (pts) treated with standard chemotherapy without trastuzumab as a first-line treatment: A Japanese multicenter collaborative retrospective study.
Authors: Nishina Tomohiro , Fuse Nozomu , Kuwata Takeshi , Kadowaki Shigenori , Shinozaki Eiji , Machida Nozomu , Yuki Satoshi , Ooki Akira , Kajiura Shinya , Goji Takahiro , Yamanaka Takeharu , Sasaki Takahide , Shitara Kohei , Kuboki Yasutoshi , Yoshino Takayuki , Ochiai Atsushi , Ohtsu Atsushi 
Published: March 2020

4075 Background: The prognostic impact of HER2 status on OS of AGC pts treated with standard chemotherapy without trastuzumab for first-line treatment remains controversial. This study investigated whether HER2 status is an independent prognostic factor for AGC pts. Methods: Formalin-fixed paraffin-embedded tumor samples from 293 eligible pts were examined for HER2 by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH). Eligible criteria included: 1) histologically confirmed gastric or gastroesophageal junction adenocarcinoma, 2) unresectable or recurrent cancer, 3) treated with S-1 plus cisplatin as first-line chemotherapy, 4) age: ≥20, 5) ECOG performance status score: 0-2 and 6) with archived tumor sample. HER2+ was defined as IHC 3+ or IHC 2+/FISH+. Results: Of 293 pts, 43 (15%) were HER2+. Baseline pt characteristics between HER2+ and HER2- pts were significantly different by histology (intestinal/diffuse, 65%/35% vs. 39%/61%; p=0.001), measurable disease by RECIST v1.0 (91% vs. 69%; p=0.003), No. of metastatic sites (≥2, 72% vs. 46%; p=0.003) and presence of liver metastasis (56% vs. 31%; p=0.003). After median follow-up time of 48.9 months with 270 (92%) death events, there was no significant difference in OS between HER2+ and HER2- pts (median, 11.7 vs. 13.7 months; hazard ratio [HR] 1.11, 95% CI 0.79–1.55; log rank p=0.550). After adjusting other prognostic factors with Cox hazard model, HER2+ was still not prognostic for OS (HR 0.890, 95% CI 0.627–1.262, p=0.513). Conclusions: HER2 status has no significant prognostic impact on OS of AGC pts treated with S-1 plus cisplatin without trastuzumab as a first-line treatment.
Randomized phase II study comparing dose-escalated weekly paclitaxel versus standard dose weekly paclitaxel for patients with previously treated advanced gastric cancer.
Authors: Shitara Kohei , Yuki Satoshi , Takahari Daisuke , Nakamura Michio , Kondo Chihiro , Tsuda Takashi , Kii Takayuki , Tsuji Yasushi , Utsunomiya Setsuo , Ichikawa Daisuke , Hosokawa Ayumu , Ishiguro Atsushi , Sakai Daisuke , Hironaka Shuichi , Oze Isao , Matsuo Keitaro , Muro Kei 
Published: March 2020

4076 Background: Retrospective analyses of neutropenia during chemotherapy of weekly paclitaxel (wPTX) suggested better overall survival (OS) among patients with neutropenia. We conducted a randomized phase II trial comparing dose-escalated wPTX with dose adjustments determined by degree of neutropenia versus standard-dose wPTX for patients with previously treated advanced gastric cancer (AGC). Methods: Ninety-patients with AGC that progressed during one or more previous chemotherapy regimens were randomized to a standard dose of wPTX (80 mg/m2, standard dose arm) or an escalated dose of wPTX (80 mg/m2 on day 1, 100 mg/m2 on day 8, and 120 mg/m2 on day 15 unless severe toxicity nor neutropenia<1.5 x 109/L is observed, escalated dose arm) to assess superiority with a one-sided alpha of 0.3 and a power of 0.8. Results: The primary endpoint of median OS showed a trend towards longer survival in the dose-escalated arm (11.8 vs. 9.6 months; hazard ratio [HR], 0.75; 95% CI, 0.45-1.22; one-sided P=0.12). Median progression-free survival (PFS) was significantly longer in the dose-escalated arm (4.3 vs. 2.5 months, HR, 0.55; 95% CI, 0.34-0.90; P=0.017). Objective response rate was 30.3% with dose-escalation and 17.1% with standard dose (P=0.2). The disease control rate (DCR) was significantly higher with dose-escalation (78.8% vs. 48.6%, P=0.009). Subset-analysis according to stratification factors including ECOG PS, presence of measurable lesions and lines of previous chemotherapy indicated that OS benefit of the dose escalation is more prominent in PS 0-1 patients (N=81, median 13.6 vs. 9.8 months, HR 0.68, 95% CI 0.41-1.11) than PS2 patients with significant interaction (p=0.01) Conclusions: Dose escalated wPTX was associated with sufficiently longer OS in patients with pretreated AGC. In addition, significant longer PFS and higher DCR associated with dose-escalation and subset analysis according PS warrant further investigations in phase III trials, especially in patients with favorable PS patients. Clinical trial information: UMIN000004055.
Comprehensive genetic mutation analysis of human gastric adenocarcinomas.
Authors: Chen Jinfei , Xu Zhi , Huo Xinying , Gu Dongying , Wang Meilin , Tang Cuiju , Ye Hua , Zhang Zhengdong , Chen Si-Yi 
Published: March 2020

4106 Background: Gastric cancer is the one of the major cause of cancer-related death, especially in Asia. Gastric adenocarcinoma, the most common type of gastric cancer, is heterogeneous and its incidence and cause varies widely with geographical regions, gender, ethnicity, and diet. Since unique mutations have been observed in individual human cancer sample, identification and characterization of the molecular alterations underlying individual gastric adenocarcinoma is a critical step for developing more effective, personalized therapies. Until recently, identifying genetic mutations in an individual basis by DNA sequencing remains a daunting task. The recent advance of new next-generation DNA sequencing technologies, such as the semiconductor-based Ion Torrent sequencing platform, makes DNA sequencing cheaper, faster and more reliable. Methods: In this study, we aim to identify genetic mutations in the genes, which are targeted by drugs in the clinical use or under development, in individual human adenocarcinoma sample by using Ion Torrent sequencing. We sequenced 739 loci from 46 cancer-related genes in 242 human gastric adenocarcinoma samples using the Ion Torrent Ampliseq Cancer Panel. Results: The sequencing analysis revealed frequent mutations in MLH1 (8.3%), MET (11.2%), KIT (21.5%), and PIK3CA (40.5%) genes in the human gastric adenocarcinomic samples. Many mutations that are not previously reported in gastric adenocarcinomas were also identified. Moreover, distinctive patterns and the combination of mutations in various sets of genes, including HER2, EGFR, MET, FGFR, PI3K/MTOR, MLH1, MET, KIT, PIK3CA, and P53, were also identified in these gastric adenocarcinoma samples. Conclusions: Thus, this study indicates the necessity of sequencing individual human adenocarcinoma in order to match the use of personalized single targeted drugs or two or more targeted drugs in combination against individual adenocarcinoma-specific mutations.
Association of YAP1 activation with poor patient prognosis and effect on chemoresistance in gastric cancer.
Authors: Lee Sung Sook , Oh Sang Cheul , Jeong Woojin , Lee Sang Ho , Kim Sang-Bae , Park Yun-Yong , Sohn Bo Hwa , Cheong Jae-Ho , Cho Jae Yong , Lim Jae Yun , Park Eun Sung , Jang You-Jin , Mok Young-Jae , Jung WonKyung , Kim Baek-Hui , Lee Keun-Wook , Tan Patrick , Noh Sung Hoon , Ajani Jaffer A. , Lee Ju-Seog 
Published: March 2020

4113 Background: Clinical heterogeneity in gastric cancer is likely due to biological differences among patients. Molecular subtypes and their associated biomarkers need to be established to improve treatment of this disease. We aimed to uncover subgroups of gastric cancer that have distinct biological characteristics associated with clinical outcome and to identify potential best treatments or therapeutic targets for each subgroup. Methods: We analyzed gene expression profiling data from gastric cancer cell lines and 267 patients with gastric cancer to uncover tumor subtypes and identify a gene expression signature associated with prognosis and response to adjuvant chemotherapy. The association of the signature with prognosis was validated in an independent cohort of 200 patients, and its association with response to adjuvant therapy was validated by cell culture experiments. Results: We identified an expression signature of 88 genes that specifically reflected activation of the oncogene YAP1. Compared with patients without this signature, patients with the YAP1 signature had significantly poorer prognosis. In multivariate analysis, the signature was the strongest indicator of overall survival among all demographic and clinical variables examined together (hazard ratio, 2.1; 95% confidence interval, 1.3-3.3;P = .002). Activation of YAP1 was significantly associated with resistance to adjuvant chemotherapy. We also demonstrated that the Notch pathway is a potential therapeutic target for overcoming chemoresistance mediated by YAP1. Conclusions: Activation of the oncogene YAP1 is significantly associated with poorer survival of patients with gastric cancer and induces chemoresistance to this disease. Therefore, YAP1 may be highly attractive therapeutic target for patients with gastric cancer resistant to standard chemotherapy.
Gemcitabine and oxaliplatin (GEMOX) alone or with cetuximab in first-line treatment of advanced biliary cancers (ABC): Exploratory analyses according to tumor KRAS/BRAF mutations and EGFR expression in a randomized phase II trial (BINGO).
Authors: Malka David , Cervera Pascale , Heurteau-Foulon Stephanie , Wendum Dominique , Trarbach Tanja , De La Fouchardiere Christelle , Boucher Eveline , Fartoux Laetitia , Faivre Sandrine J. , Pignon Jean-Pierre , Rosmorduc Olivier , Greten Tim F. 
Published: March 2020

4127 Background: Gemcitabine-platinum regimens are the standard of care for ABC. Whether GEMOX-cetuximab may be beneficial in ABC patients (pts) was tested in BINGO, an international, open-label, randomized phase II study (ASCO 2012). With a 4-month progression-free survival (PFS) rate of 63% [CI: 52-74], the primary endpoint was met (target, ≥60%; GEMOX, 54% [43-65]). However, median PFS (6.1 vs. 5.5 months) and overall survival (OS) (11.0 vs. 12.4 months) were similar in both arms. Available data on KRAS/BRAF mutation rates in ABC pts are sparse. Methods: Planned exploratory endpoints included tumor KRAS/BRAF mutational status (high-resolution melting and DNA sequencing) and EGFR expression score (immunohistochemistry [IHC]), and their impact on patient outcome according to treatment arm. Results: Tumor samples were collected for 91 (61%) consenting pts among the 150 randomized pts, and were suitable for DNA analysis and IHC in 75 (50%) and 77(51%) pts, respectively. Tumor KRAS and BRAF mutations (MT) were found in 14 (19%) and 4 (5%) pts, respectively. High EGFR score (≥ 200) was observed in 18 (23%) pts. 4-month PFS rates did not differ according to tumor KRAS MT (wild-type [WT] vs. MT: 62% vs. 57%, p=0.72), BRAF MT (61% vs. 75%, p=1.00) or EGFR score (≥ vs. <200: 56% vs. 63%, p=0.42) overall, or according to treatment arm (table). PFS and OS (log rank test) also did not significantly differ according to these biomarkers, overall or between treatment arms. Conclusions: Tumor KRAS/BRAF mutations and EGFR overexpression were found in 24% and 23% of pts respectively. With the limit of statistical power in these exploratory analyses, they had no statistically significant prognostic or predictive impact. Clinical trial information: 2007-001200-20. [Table: see text]
Use of the mitotic kinase aurora-A activation to predict outcome for primary duodenal adenocarcinoma.
Authors: Chen Jie , Wen Jing-Yun , Chen Zhan-Hong , Lin Qu , Ma Xiao-Kun , Wei Li , Li Xing , Wang Tian tian , Ruan Dan-Yun , Lin Ze-Xiao , Wan XiangBo , Liu Quentin , Wu Xiang-Yuan 
Published: March 2020

4131 Background: We and others had proved that hypoxia-inducible factor-1α (HIF-1α) and transcriptionally upregulated Aurora-A were required for disease progression in several tumors. Methods: We addressed the clinicopathologic value of HIF-1α and Aurora-a in primary duodenal adenocarcinoma (PDA). Aurora-a and HIF-1α expression were semi-quantitative evaluated by immunohistochemistry in 140 PDA. Among which, 76 patients from one institute acted as training set, and 64 cases from another two institutes were used as testing set to validate the prognostic effect of Aurora-a and HIF-1α. Results: We found that Aurora-a was high or sufficient expressed in tumor zone, whereas low-expressed in the normal adjacent epithelia. Moreover, Aurora-a high expression, classified by training set ROC analysis-generated cutoff score, predicted an inferior overall survival both in testing set and training set. Multivariate Cox regression confirmed that Aurora-a was indeed an independent prognostic factor (Table). Contrary to previous studies, we did not detect any correlation between Aurora-a and HIF-1α in PDA. Additionally, survival analysis showed that HIF-1α level was not correlated with patient outcome (p = 0.466). Conclusions: Activation of Aurora-A, an independent negative prognostic biomarker, might be used to identify particular patients for more selective therapy. [Table: see text]
Cost-effectiveness and optimal diagnostic sequence of CT, MRI, and PET-CT in the management of colorectal liver metastases.
Authors: Yip Vincent S. , Colins Brendan , Koay Mei Y. , Tang Joseph , Wieshmann Hulya , Fenwick Stephen W. , Poston Graeme John , Malik Hassan Zakria 
Published: March 2020

4132 Background: CT, PET-CT and MRI play a role in the decision making process in managing colorectal liver metastases (CRLM). This study aimed to determine the optimal sequence of these investigations in order to reduce the rate of futile laparotomy and improve cost effectiveness of treatment. Methods: All patients referred to our specialist multidisciplinary team (sMDT) with CRLM were reviewed to investigate specific reason(s) for not offering potentially curative surgery. Clinical parameters were recorded for analysis. Three hypothetical scenarios were derived for cost-effectiveness analyses: 1) “up-front” with all imaging prior to sMDT, 2) “sequential”, with individual imaging following each sMDT, and 3) “hybrid” with PET-CT and MRI after review of the initial CT scan. Results: 644 consecutive patients were reviewed. Following assessment of initial CT, 165 patients (26%) were referred for palliative chemotherapy. After further evaluation by PET +/- MRI, 307 patients proceeded for potentially curative resection. Of those excluded from surgery, 48% were following PET-CT. Median overall survival (OS) for the resection and palliative groups were 46 and 14 months respectively (p<0.001). Futile laparotomy rate was 5.5%.The optimum strategy of lowest average time to decision, and lowest average cost is the hybrid model. Cost-utility analyses demonstrated a saving of approx. £319 (USD$ 515) per patient compared to the other 2 models. Conclusions: Decision making regarding further imaging after initial CT scan for CRLM should be performed at the sMDT to minimise delays and maximise efficiency of resources allocation. Triple assessment with CT, PET and MRI and sMDT decision process may reduce risk of futile laparotomy. A hybrid model using PET and MRI following a sMDT discussion of the initial CT provides the most cost effective algorithm for the management of CRLM.
Treatment of liver metastases in patients with neuroendocrine tumors: A National Comprehensive Cancer Network analysis.
Authors: Choti Michael A. , Bobiak Sarah , Bloomston Mark , Zornosa Carrie C. , Bergsland Emily K. , Strosberg Jonathan R. , Benson Al Bowen , Kulke Matthew , Shah Manisha H. , Nakakura Eric K. , Yao James C. 
Published: March 2020

4143 Background: The choice of therapy in patients with hepatic metastases from neuroendocrine tumors is controversial. The purpose of this study was to describe the utilization of liver resection and other locoregional therapies in the management of NET hepatic metastases in NCCN centers. Methods: The National Comprehensive Cancer Network (NCCN) Neuroendocrine Tumor Database tracks longitudinal care for patients treated at seven specialty cancer centers in the U.S. from 2004 to 2010. Patient and tumor characteristics, as well as the use of liver-directed therapy (LDT) in patients with neuroendocrine liver metastases (NELM) were evaluated. Results: Among 907 patients presenting with metastatic disease, 606 patients presenting with newly diagnosed disease or previously diagnosed disease with first distant recurrence of NELM were evaluated. LDT was used during some component of the patient care in only 43% of patients with NELM, the remainder received only systemic or no therapy. LDT varied by extent of disease (p=0.002) with a higher proportion of patients with liver-only disease receiving LDT (45%) compared to those with liver and extrahepatic disease (26%). There was a significant difference in LDT by functional tumor status (Χ2=6.84, p=0.03) and primary site of disease (Χ2=14.95, p=0.001) where a higher proportion of patients with hormonally functional tumors received LDT when compared to non-functional tumors (48% vs 42%) as well as those with primary small bowel carcinoid vs pancreatic NET (56% vs 39%). Among those treated with LDT, 39% underwent surgical resection, 57% intra-arterial therapy (IAT), and 4% ablation alone. Major hepatectomy was performed in 21%, multiple resections in 13%, and resection combined with ablation in 24% of patients receiving surgical therapy. Among the 147 patients treated with IAT, 52% received standard chemoembolization, 23% bland embolization, and 18% yttrium-90 therapy. Conclusions: Even at specialty centers less than half of patients received LDT, among which one-fifth had a hepatic resection. Future studies on this cohort will measure outcomes based on type of LDT.