bluuebunny/crossref_metadata_2025_split huggingface dataset:
KRAS gene amplification to define a distinct molecular subgroup of gastroesophageal adenocarcinoma.
Authors: Henderson Les , Xu Peng , O'Day Emily , Cecchi Fabiola , Blackler Adele , Liao Wei-Li , Hembrough Todd A. , Catenacci Daniel V.T. 
Published: February 2017

74 Background: KRAS mutation is rare ( < 5%) in gastroesophageal cancer (GEC). However, the incidence of KRAS gene amplification (amp+), consequent protein levels, and prognostic and/or therapeutic implications are unknown. Methods: 410 GEC samples and 30 cell lines were assessed for KRAS gene copy number (GCN) by fluorescence in situ hybridization (FISH) (n = 90), Kras expression by selected reaction monitoring mass spectrometry (Kras-SRM-MS) (n = 393), and Kras-SRM level evaluated for correlation with KRAS amp+ status (n = 73). Survival analysis was performed comparing KRAS amp+ versus non-amp+ patients. When possible, concurrent 315 gene next-generation sequencing was also performed. Four KRAS-amplified xenograft lines (CAT-2,12,14,15) were established from malignant effusions. Tumorigenic activity of KRAS amp+ lines (CAT lines, MKN-1) were assessed using MTT and soft agar assays in vitro and subcutaneous xenograft models, compared to non-amp+ lines. Inhibitory assays were performed using KRAS siRNA and CRIPSR, and commercial inhibitors targeting downstream effectors MEK and/or PIK3CA. Results: KRAS FISH revealed clustered gene amp+ in 28.9% (26/90); these patients had worse prognosis than non-amp+ patients. GCN significantly correlated with Kras expression. All KRAS amp+ cell lines significantly overexpressed Kras protein and were tumorigenic in xenograft subcutaneous models. KRAS siRNA and KRAS CRISPR of KRAS amp+ cell lines demonstrated inhibition in MTT viability and soft agar assays, compared to appropriate controls, and demonstrated significant and durable xenograft growth reduction. Conversely, inhibition using MEK and/or PI3K inhibitors demonstrated only transient growth reduction in vivo. Conclusions: KRAS gene amp+ was observed in a large subset (26%) of GEC patients, which correlated with extreme expression by mass spectrometry. Established xenograft lines serve as models to investigate therapeutic strategies for KRAS amp+ patients. Inhibition using MEK/PIK3CA inhibitors provided transient benefit for KRAS amp+ tumors while durable inhibition was observed with Kras protein knockdown, suggesting potential benefit from novel siRNA therapeutics currently in development.
Observational cohort study of 1st line bevacizumab combined with chemotherapy in metastatic colorectal cancer (HGCSG0802): Sub-group analysis by the GERCOR index.
Authors: Muto Osamu , Yuki Satoshi , Muranaka Tetsuhito , Kato Takashi , Meguro Takashi , Nakamura Michio , Sato Atsushi , Iwanaga Ichiro , Uebayashi Minoru , Tateyama Miki , Hatanaka Kazuteru , Eto Kazunori , Okuda Hiroyuki , Sogabe Susumu , Abe Masakazu , Kato Kanji , Kato Sosuke , Miyashita Kencho , Sakata Yuh , Komatsu Yoshito 
Published: February 2017

743 Background: The GERCOR index based on performance status and serum LDH was reported to be useful to predict survival for patients with previously untreated mCRC. However, the validity of the GERCOR index has not been reported in patients treated with bevacizumab (Bev)-based first line chemotherapy. Methods: 115 patients with mCRC treated with Bev contained first line chemotherapy were registered from 15 centers in Japan. Univariate and multivariate analysis for overall survival (OS) were performed using patient characteristics. Survival analyses were performed with the Kaplan-Meier method, log-rank test and the Cox proportional hazards model. The analysis was also designed to determine whether the GERCOR index could be extended to progression-free survival (PFS). Results: All data were available for prognostic categorization in 108 patients. Patients with the GERCOR index of low, intermediate and high risk were 45, 57, and 6, respectively. The pts characteristics between low risk (L) and intermediate/high risk (I/H) were generally balanced except for prior colorectomy (75.6% in L, 54.0% in I/H; p = 0.027), based cytotoxic agent (oxaliplatin) (80.0% in L, 93.7% in I/H; p = 0.039), liver metastasis (53.3% in L, 79.4% in I/H; p = 0.006) and median number of metastatic organ (1 in L, 2 in I/H; p = 0.024). The distribution and median OS / PFS for the GERCOR index were as follows: L (n = 45; 29.9/10.0 months), I/H (n = 63; 17.0/8.5 months). For OS, there was significant difference between L and I/H (p = 0.003). For PFS, there was not significant difference between L and I/H (p = 0.522). In the Cox multivariate analysis, GI did not show an independent prognostic impact (L vs I/H ; HR 1.499, p = 0.120) and predictive impact (L vs I/H ; HR 0.922, p = 0.733). Conclusions: In this analysis, the GERCOR index might be neither the predictive nor prognostic factor in the bevacizumab combined first line chemotherapy for patients with mCRC.
Phase I dose-escalation study of sorafenib plus S-1 in refractory solid tumors.
Authors: Tsai Hui-Jen , Chiang Nai-Jung , Shiah Her-Shyong , Chang Kwang-Yu , Su Wu-Chou , Chang Jang-Yang , Chen Li-Tzong 
Published: February 2017

745 Background: S-1 is a new oral fluoropyrimidine-derived combo and has been shown activity in patients with various cancers in phase II/III studies. Sorafenib is an oral multikinase inhibitor with anti-proliferative and anti-angiogenesis activities and has been approved for the first-line treatment of advanced HCC, RCC and radioactive iodine-resistant thyroid cancer. In xenograft mouse models, sorafenib showed its activity to enhance the cytotoxicity of chemotherapeutic agents. Therefore, a phase I dose-escalation study to determine the dose-limiting toxicity and maximum dose of S-1 in combination with standard dosing of sorafenib in patients with refractory solid tumors was conducted. Methods: Eligible patients would receive escalating dose (30, 35 and 40 mg/m2, twice daily) of S-1 in a standard 3+3 phase I study design. Treatment was consisted of continuous sorafenib 400 mg bid plus S-1 30-40mg/m2 bid, D1-14, every 21 days per cycle. DLTs were assessed during the first two cycles of treatment, and treatment would be continued until disease progression, the occurrence of unacceptable toxicity or consent withdrawal. Results: A total of 13 patients were included, 7 in 30 mg/m2 dose level and 6 in 35 mg/m2 dose level. DLT occurred in 2 of 6 patients with 35 mg/m2 twice daily, manifested as grade 3 skin rash and prolonged grade 2 hand-foot-skin reaction in one each; while there was no DLT observed in 30 mg/m2 cohort. Seven patients achieved durable tumor control, included one pancreatic neuroendocrine tumor patient who had a sustained PR for 27.9 months, and durable stable diseases (>6 months of progression-free survival) in 3 out of 4 colorectal cancer patients, 2 of 2 biliary tract cancer patients and 1 of 2 pancreatic cancer patients. Conclusions: The recommended dose of S-1 in this combination was 30mg/m2 bid. Preliminary results suggested sorafenib/S-1 combination is feasible and deserves for further exploration in refractory advanced gastrointestinal tract cancers. Clinical trial information: NCT01128998.
Pre-treatment serum folate levels and toxicity in colorectal cancer patients treated with 5-fluorouracil and folinic acid.
Authors: Yan Michael , Vincent Mark David , Ho Cheryl , Winquist Eric , Jonker Derek J. , Rayson Daniel 
Published: February 2017

755 Background: 5-fluorouracil (5-FU) chemotherapy is associated with severe and unpredictable toxicity in a significant proportion of patients.We hypothesized that susceptibility to 5-FU toxicity might be related to individual differences in components of reduced folate metabolism affecting intracellular 5,10-MTHF levels, detectable in blood prior to treatment. Methods: A prospective cohort of chemo-naive colorectal cancer patients planned to receive IV 5-FU and folinic acid for five consecutive days every four weeks were studied. Baseline clinical and laboratory data were collected prior to treatment. Biochemical data associated with folate metabolism was also collected and not revealed to treating physicians. The primary endpoint was occurrence of > grade 3 toxicity and/or toxicity mandating dose delay or reduction. Results: Of 78 eligible patients studied, 68% experienced > grade 3 toxicity, 69% had schedule modification, and 81% had either or both. Multivariable analyses identified only a higher pre-treatment serum folate level as an independent predictor of toxicity > grade 3 and/or mandating schedule modification (p = 0.016). An increasing toxicity trend was observed amongst folate-stratified patient cohorts, with an odds ratio of 2.87 (p = 0.09) comparing the highest and lowest quartiles. Concurrently, overall survival and relapse-free rates also increased with pretreatment folate levels in the adjuvant cohort with log rank values of 3.60 (p = 0.06) and 7.20 (p = 0.007) between the highest quartile and the lower quartiles, respectively. Conclusions: The incidence of severe toxicity with this schedule of 5-FU and folinic acid was high and positively correlated with the pretreatment serum folate level. Interestingly, a concurrent increase in overall and relapse free survival is observed with increasing serum folate levels. These results suggest that an optimal pretreatment folate level exists that balances chemotherapy treatment efficacy and toxicity.
A phase I study of combination of panitumumab and bevacizumab in KRAS wild-type colorectal cancer patients who were previously treated with fluoropyrimidine, oxaliplatin, irinotecan, and bevacizumab.
Authors: Takahashi Naoki , Iwasa Satoru , Tachikawa Masanori , Fukahori Masaru , Sudo Kazuki , Sasaki Yusuke , Shoji Hirokazu , Honma Yoshitaka , Okita Natsuko , Takashima Atsuo , Hamaguchi Tetsuya , Boku Narikazu , Shimada Yasuhiro , Yamagiwa Koki , Ebata Yuka , Uchida Yasuo , Honda Kazufumi , Terasaki Tetsuya , Yamada Yasuhide 
Published: February 2017

759 Background: Clinical benefit of combination of panitumumab and bevacizumab (PB) based on the BBP strategy in third-line chemotherapy is unclear. There was no prospective data about the pharmacokinetic interaction between bevacizumab and panitumumab. Methods: This study composed two parts; 1) PB part: phase I study of PB to estimate its recommended dose, 2) CPB part: feasibility study to investigate the safety in combination of bevacizumab and panitumumab at the recommended dose in the phase I part with irinotecan (CPT-11) at the dose used in the prior chemotherapy. Inclusion criteria was as follows; 1) Age: ≥ 20 and < 76 years old, 2) performance status ≤ 1, 3) histologically colorectal adenocarcinoma with KRASwild-type, 4) patients who previously received fluoropyrimidine, oxaliplatin, CPT-11 and bevacizumab for unresectable metastatic disease. Three dose levels of panitumumab (Level 1: 6mg/kg, Level 0: 5mg/kg, Level -1: 4mg/kg) was set in PB part and starting dose level was Level 0. Bevacizumab was administered at fixed-dose of 5mg/kg regardless of dose levels of panitumumab. All drugs were administered on day1 and repeated every 2 weeks. Definition of dose limiting toxicity (DLT) was grade 4 hematological adverse events or ≥ grade3 non-hematological adverse events despite the supportive care observed in 28 days from day1 of cycle 1. Results: There were no cases showing DLT at level 0 (n = 3) and level 1 (n = 3) in the PB part and recommend dose was determined as panitumumab 6mg/kg and bevacizumab 5mg/kg. In the whole treatment course at level 1, grade 3 rash acneiform was observed in 2 patients and 2 patients achieved partial response. In six patients (CPT-11 150mg/m2, biweekly n = 3, 120mg/m2n = 3) enrolled in the CBP part, grade 3 toxicities were leukopenia/neutropenia (n = 1), mucositis (n = 1), diarrhea (n = 1), rash acneiform (n = 1), thromboembolic event (n = 1). Two out of 6 patients achieved partial response in CPB regimen. Conclusions: The recommended dose of PB regimen were panitumumab 6mg/kg and bevacizumab 5mg/kg. Combination of panitumumab and bevacizumab showed manageable toxicity. Clinical trial information: UMIN000009362.
Effect of regorafenib and TAS-102 in metastatic colorectal cancer (mCRC) patients on survival in salvage line with different toxicity profile.
Authors: Sugimoto Naotoshi , Yoshinami Tetsuhiro , Yamamoto Sachiko , Yagi Toshinari , Imamura Fumio 
Published: February 2017

763 Background: In the CORRECT study, regorafenib has survival benefits in patients with metastatic colorectal cancer (mCRC) in salvage line. In the J-003 and RECOURSE study, TAS-102 has also survival benefit in them, too. But no randomized study is existed about the comparison between regorafenib and TAS-102. So we retrospectively compared the efficacy and toxicity of regorafenib and TAS-102 in patients with mCRC for salvage line in our hospital. Methods: The selection criteria were pathologically proven mCRC; 20 years or older; had a previous treatment history of two or more regimens of standard chemotherapy; no prior regorafenib and TAS-102 therapy; performance status 0-1; able to oral intake; and adequate organ functions. The patients in regorafenib group, regorafenib 160mg/body was given orally once daily for 21days followed by a 7-day rest. In TAS-102 group, TAS-102 35mg/m2 was given orally twice daily 5 days of treatment followed by a 2-day rest period, and then a 14-day rest period. Results: The analysis covered 51 patients over the period from October 2009 to June 2015.The median age was 67 years (range 33-79); 29 males and 22 females; PS 0/1 score 19/32; 23 patients were treated regorafenib and 28 patients were treated TAS-102.Progression-free survival and overall survival were 2.6 and 10.6 months with regorafenib and 3.2 and 9.7 months with TAS-102 (no significant difference). The rate of grade 3-4 toxicity were hypertension (35%), hand-foot syndrome(35%), AST/ALT increased(12%) in regorafenib group, and leucopenia (15%), neutropenia (35%), anemia(10%) in TAS-102 group. There was no treatment death in both groups. Conclusions: Both regorafenib and TAS-102 give mCRC patients survival benefit in salvage line with different toxicity profile.
Impact of blue 465nm LED on suppression of cancer growth.
Authors: Yoshikawa Kozo , Shimada Mitsuo , Higashijima Jun , Nakao Toshihiro , Nishi Masaaki , Kashihara Hideya , Takasu Chie 
Published: February 2017

767 Background: Recent studies demonstrate the efficacy of irradiation from light emitting diodes (LED) for wound healing and anti-inflammation and anti-cancertherapies. In this study, the blue LED (465nm) suppressed the tumor growth in various cancers. Methods: < Experiment 1, Effect of blue LED on colon cancer > Human colon cancer cells (HT29 or HCT116) were seeded onto laboratory dishes that were put on LED irradiation equipment with a blue LED (465 nm). Irradiation at 15 or 30 mW was performed 10 min/day, each day for 5 days. Cell counting kit8 was then used to measure cell viability. Apoptosis and expression of several mRNAs (caspase, MAPK and autophagy pathway) in HT29 cultures irradiated with 465 nm LED were evaluated via AnnexinV/PI and RT-PCR, respectively. < Experiment 2, Effect of blue LED on pancreas cancer > Human colon cancer cells (SUIT2) were examined by same way and additionally cell cycle was checked. < Experiment 3, Effect of LED on CSCs > Cancer sphere were seeded onto laboratory dishes that were then put on LED irradiation equipment with a 465 nm-LED. Stemness gene and cell surface markers of CSCs expressions were analyzed by RT-PCR. Results: < Experiment 1 > Viability of HT29 and HCT116 cells was lower in blue LED irradiated cultures than in control cultures. Moreover, the expression of FAS, caspase3, capase8, and JUK were significantly higher in 465 nm-LED irradiated cultures than in control cultures, and expression of ERK1/2 and LC3 was lower in blue LED-irradiated cells. < Experiment 2 > Viability of SUIT2 cells was lower in blue LED irradiated cultures than in control cultures. And the CCND1 mRNA expression was significantly lower in blue LED group (p < 0.05). The cells of phase G2/M was decreased. < Experiment 3 > Cell viability of cancer sphere were significantly decreased by LED irradiation(p < 0.05). And, stemness gene and cell surface markers of CSCs expressions were significantly decreased by LED irradiation (p < 0.05) Conclusions: Blue LED irradiation inhibited tumor growth in various cancer cell lines.
Metastasectomy or radiofrequency ablation for treatment for colorectal cancer liver metastasis: Comparison of recurrence rates and identification of risk factors for local recurrence.
Authors: Vietti-Violi Naik , Bize Pierre E. , Duran Rafael , Demartines Nicolas , Halkic Nermin , Knebel Jean-Francois , Denys Alban 
Published: February 2017

769 Background: Metastasectomy and radiofrequency ablation (RFA) are currently use for treatment of colorectal cancer (CRC) liver metastasis aiming for total tumor ablation with sparing liver parenchyma. Literature is lacking of studies comparing results and risk of recurrence between both techniques. We aim to compare recurrence rate after RFA and metastasectomy for CRC liver metastasis and to define which lesion is the best candidate for each treatment. Methods: By a lesion-by-lesion analysis, we reviewed 121 metastases treated by metastasectomy (43 patients, median follow up 798 days) and 110 metastases treated by RFA (60 patients, median follow up 590 days). Rate of local recurrence (LR) and hepatic recurrence (HR) were compared. We analyzed patients and primary tumor characteristics, looked for predictive factors for recurrence in metastasis data: size, deepness in liver, distance to hepatic veins, pathological resection margins in case of surgery. Analysis were performed using Chi Square and logistic regression in uni and multivariate analysis. Results: Patients and primary tumor characteristics were similar. Metastasis size was larger in metastasectomy group (18mm, range 2-90mm and 15mm, range 3-55mm; p = 0.03). Lesions were located deeper in the liver parenchyma in RFA group (20mm, range 3-51mm and 26mm, range 6-59mm; p < 0.001). Rate of LR and HR were nearly statistically different in favor of RFA: LR was 19% for metastasectomy group and 10% for RFA group (p = 0.06, delay: 245 and 289 days, p = 0.56), HR were 78% for metastasectomy and 66% for RFA (p = 0.054, delay: 226 and 235 days, p = 0.81). Predictive factors for recurrence in metastasectomy group: R1 status (p = 0.03) and metastasis deepness (p = 0.02). Metastasis deepness and proximity to hepatic veins increased risk for R1 (p = 0.04 and p < 0.001 respectively). We found no predictive factor for recurrence in RFA group. Conclusions: Pending proper selection (small lesions visible under imaging guidance), RFA tends to have a lower recurrence rate than metastasectomy. Lesions localized in depth in the liver parenchyma, close to hepatic veins are at risk of LR after metastasectomy.
Epidemiology and survival of metastatic gastrointestional stromal tumor: A Surveillance, Epidemiology, and End Results (SEER) database review.
Authors: Sundararajan Srinath , Kumar Abhijeet , Kanaan Mohammed Nawaf , Cui Haiyan , Elquza Emad , Patel Hitendra 
Published: February 2017

86 Background: Metastatic gastrointestinal stromal tumor (MGIST) is a rare disease with limited data available on its epidemiology and survival. We aimed to study the epidemiology and survival pattern of M-GIST by reviewing the Survival, Epidemiology and End Result (SEER) database. Methods: SEER database was reviewed for patients (pts) with histologically confirmed GIST between 2002 and 2007. Variables included were age, race, gender, date of diagnosis (DOD), stage, location of primary tumor, and disease specific survival (DSS). The association between survival and race, gender, and site of disease for metastatic GIST patients was investigated. Primary outcome was 3-year DSS. Survival rate was estimated using the Kaplan–Meier method and the difference in 3-years survival was tested by log-rank test. Cox proportional hazard regression model was employed to test the association between survival and age. Results: A total of 653 patients with MGIST pts were identified and 602 were included for analyses. The distribution of MGIST according to primary site was as follows: gastric (42%), small intestine (26.2%), colorectal (4.6%), peritoneal (4.5%), NOS (17%) and other sites (5.9%). The mean age of diagnosis was 61 years. Caucasians to African-American (AA) ratio was 3.5:1 and male to female ratio was 1.3:1. Three-year DSS was 56.5% for Caucasians compared to 62.9% in AA (p = 0.25). Three-year DSS was 57.8% for males compared to 58.6% in females (p = 0.88). Small intestine MGIST had the best 3-Year DSS of 73.8% compared to gastric MGIST, which had a 3-year DSS of 50.7%(p < 0.0001). Peritoneal MGIST had the worst prognosis with 3-year DSS of 34.4%. Conclusions: MGIST had significant difference in survival based on the location of primary tumor. In contrary to the findings of previous studies, small intestine MGIST had superior 3-year DSS compared gastric primary M-GIST. There was no statistically significant difference in survival based on gender or race. [Table: see text]
Notch and wnt-beta catenin pathways as targets of γ-secretase inhibitor IX (GSI) mediated therapy in CD44+ gastric cancer (GC) cells.
Authors: Plentz Ruben R , Barat Samarpita , Chen Xi , Bui Cuong , Bozko Przemyslaw , Malek Nisar P 
Published: February 2017

99 Background: GC is the second most common cause of cancer related death worldwide. New palliative therapeutic approaches to treat GC are of urgent need. Targeting cancer stem cells (CSC) could be an effective approach to treat GC. Recent studies have indicated that Notch signaling and wnt-beta-catenin pathways are crucial for CSC development. In this study, we mainly focused on inactivation of both Notch and wnt-beta-catenin pathways in CSC CD44+ GC cells using GSI. Methods: For our experiments we have used the GC cell line MKN45, as it showed expression of both targets (CD44,Hes1). For in vitro experiments proliferation, wound healing, invasion and tumorsphere assays were performed to analyze the migration, invasive and tumorigenic potential of CD44+ sorted GC initiating cells after GSI treatment. Western blot analyses of downstream signaling targets of Notch and wnt-beta catenin were tested after GSI treatment. SiRNA experiments for Notch1 and CD44 were also performed in order to confirm the Notch and wnt-beta-catenin pathway crosstalk. For in vivo analysis sorted CD44+ cells were subcutaneously injected into NMRI-nu/numice and were treated with vehicle or GSI. Results: CD44+ sorted MKN45 cells showed high expression of Hes1 as compared to the CD44- cell population. GSI treatment showed effective inhibition of cell proliferation, migration, invasion and tumor sphere formation of CD44+ cells. Interestingly, amongst all Notch receptors, Notch1 was found to be important in mediating the crosstalk between Notch and wnt-beta-catenin signaling cascades in CD44+ GC cells. Moreover, upon silencing of both CD44 and Notch1 by SiRNA showed effective inhibition of downstream targets and reconfirmed the proposed hypothesis of CD44 mediated Notch and wnt/beta-catenin crosstalk in GC cells. Conclusions: Our study highlights the crosstalk between Notch and wnt-beta-catenin in GC CD44+ cells. GSI could be an alternative drug to treat human GC as it effectively targets the CD44+ GC cells thus, completely reducing all the chances of relapse and metastasis associated with GC. Therefore, GSI therapy can open up new avenues for GC treatment with improved / better clinical outcome.