bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular mechanism of secondary-resistant for trastuzumab in gastric cancer.
Authors: Iwatsuki Masaaki , Kojiro Eto , Baba Hideo 
Published: February 2017

58 Background: The ToGA trial demonstrated the significant efficacy of trastuzumab combined with chemotherapy in patients with HER2-positive GC. Although trastuzumab has become a key drug in cancer treatment, the resistance of breast cancer to trastuzumab is a major problem in clinical practice. The aim of this study was to identify molecular mechanism that regulates the sensitivity of HER2-positive GC cells to trastuzumab. Methods: (i) Establishment of trastuzumab-resistant GC cell: We cultured the HER2-positive cell line in the presence of trastuzumab (ii) microRNA array: We examined the miR expression profile in the parent and resistant cells using miR array analysis. (iii) Identification of novel miR-gene pathway: We focused on miR-223-FBXW7 pathway based on miRarray analysis. Results: (i) We established resistant cell without significant changes in HER2 or p-HER2 in the presence of trastuzumab continuously for 6 months. (IC 50: 0.17 vs. 988.8μg/ml) (ii) We identified 23 miRs up-regulated in the resistant cells as compared with the parental cells. Of these identified miR, 40% miRs are located on 19q13.42. (iii) the miR-223/FBXW7 pathway regulates the sensitivity of a HER2-positive gastric cancer cell line to trastuzumab through the modulation of apoptosis. Conclusions: This study suggested that the miR-223-FBXW7 pathway can be a crucial clue to the mechanism of resistance to trastuzumab in GC, leading to the development of individualized treatment in clinical practice.
The occurrence of mutant KRAS clones in the blood of RAS wild type colorectal cancer patients: Impact of response or failure under anti-EGFR therapy.
Authors: Berger Andreas W. , Schwerdel Daniel , Welz Hanna , Ettrich Thomas Jens , Moeller Peter , Seufferlein Thomas 
Published: February 2017

600 Background: Colorectal cancer (CRC) is characterized by a high level of genetic heterogeneity. In addition, changes in the genetic profile induced by chemotherapy affect treatment results. Acquired resistance of tumors is defined as a result of clonal evolution and clonal selection under systemic chemotherapy. Repeated tumor tissue biopsies are difficult to obtain and cannot be easily used for dynamic monitoring of therapy response or failure due to marked tumor heterogeneity. Promising data for circulating cell-free tumor DNA (ctDNA) as a tool for studying tumor evolution were recently published. Methods: In this study we analyzed ctDNA from patients with metastatic CRC during treatment with anti-epidermal growth factor receptor (EGFR) antibodies (cetuximab/panitumumab). By droplet digital PCR we performed genotyping of CRC tissue and tracking of clonal evolution of the most frequent KRAS mutations (G12A, G12C, G12D, G12R, G12S, G12V, G13C, G13D, Q61R, A146T and A59T) in plasma ctDNA. Results: In initial KRAS wild type tumors several mutated KRAS clones occurred in plasma under the course of anti-EGFR-therapy indicating an increasing acquired resistance to the given therapy leading to a disease progression. Some of these mutations declined upon discontinuation of anti-EGFR therapy. Conclusions: Based on these results we hypothesize that the initial state of KRAS wild type situation seems to be restored in some cases. This opens up the possibility to reinduce anti-EGFR therapy in later therapy lines.
Trifluridine to enhance cytotoxicity by DNA mismatch repair deficiency and subsequent MBD4 frameshift mutation in colorectal cancer.
Authors: Suzuki Satoshi , Iwaizumi Moriya , Hamaya Yasushi , Takagaki Kosuke , Osawa Satoshi , Furuta Takahisa , Sugimoto Ken 
Published: February 2017

608 Background: TAS-102 is composed of trifluridine (FTD) and tipiracil hydrochloride and was shown to prolong survival of patients with refractory metastatic colorectal cancer (CRC). FTD is the active antitumor component of TAS102 and its metabolite TF-TTP chemically resembles 5FU-derived metabolite FdUTP in that both of them are misincorporated into DNA and lead to cytotoxicity. Several groups have reported that stage II-III colorectal cancer patients with tumors that lost DNA mismatch repair (MMR) function do not derive a benefit from 5-FU based chemotherapy. Although FTD is reported to be misincorporated into DNA, it is not known if MMR deficient CRC cells have chemoresistance for FTD. Methods: We first utilized human colorectal cancer cell lines HCT-116 (hMLH1-deficient cells) and HCT116+ch3 (hMLH1-retained cells), and compared cytotoxicity for FTD by clonogenic assay. To further analyze if 5FU refractory CRC cells have chemosensitivity for FTD, we established 5FU refractory HCT116 cells by continuous 5FU treatment for 10 month and analyzed cytotoxicity for FTD. Finally we constructed an expression plasmid of truncated DNA grycosylase MBD4, (MBD4tru) by frameshift mutation with MMR deficiency and stably transfected the construct into HCT116 CRC cells and selected HCT116MBD4tru cell clones. The HCT116MBD4tru cells were treated with FTD and analyzed for cytotoxicity by clonogenic assay. Results: In hMLH1-deficient cells, the number of colony was reduced by FTD treatment to a same degree of hMLH1-proficient cells whereas the number of colony by 5FU treatment is higher in hMLH1-deficitent cells than hMLH1-retained cells (p< 0.05). In 5FU refractory cells, treatment of FTD showed cytotoxicity to the same degree of non-5FU refractory cells. Interestingly, HCT116MBD4tru cells led to cytotoxicity with a higher sensitivity than control cells (p< 0.05). Conclusions: FTD induces cytotoxisity independently of MMR status as well as under 5FU refractory condition, and MBD4 frameshift mutation by MMR deficiency enhances FTD sensitivity. These results suggest that FTD may be useful for patients with MSI-H/MBD4 mutant CRC as well as for those with 5FU refractory CRC.
A pooled analysis of the secondary resection for colorectal cancer liver metastases: Comparison of bevacizumab (Bmab) and anti-EGFRs.
Authors: Ichikawa Wataru , Sunakawa Yu , Nakayama Hirofumi , Ikusue Toshikazu , Kaneta Toshikado , Imataka Hiromi , Sekikawa Takashi , Sasaki Yasutsuna 
Published: February 2017

610 Background: Systemic chemotherapies can convert irresectable liver metastases (LM) to resectable in some cases of metastatic colorectal cancer (mCRC). Secondary surgical resection is now considered to be a worthwhile therapeutic aim in mCRC with LM. There is a clear correlation between radiological response and secondary resection rate (SRR) (Jones RP et al. Eur J Cancer 2014). However, it remains unclear which monoclonal antibodies contribute the improvement of SRR, Bmab or anti-EGFRs. Methods: We performed a systematic review of literature published between Jan 1998 and Aug 2015 to analyze the relationship between SRR and antibodies in mCRC treated with 1st-line chemotherapy. Phase II or III trials which obtained the information of response rate (RR) and resection of LM were included in this analysis. The RR, SRR, and R0 SRR were compared between Bmab- and anti-EGFR (cetuximab or panitumumab)-containing regimen groups using Mann–Whitney U test. The correlation between RR and R0 SRR was assessed by Spearman's rank correlation coefficient. Results: A total of 40 studies were enrolled: 33 treatment arms from 16 trials for liver-limited disease (LLD) and 31 arms from 24 trials for non-LLD. The result is shown below. No difference was observed in SRR and R0 SRR between Bmab and anti-EGFR groups. In addition, a preliminary analysis showed that RR had significantly positive association with R0 SRR in anti-EGFR group (R2 0.74, P=0.027 for non-LLD; R2 0.88, P=0.018 for LLD) but not in Bmab group (P=0.27 for non-LLD, P=0.12 for LLD). Conclusions: The SRR and R0 SRR were comparable between Bmab and anti-EGFRs, even in mCRC with LLD, while RR correlated with R0 SSR in anti-EGFRs but not in Bmab. These findings warrant validation in ongoing trials to compare the targeted-agents. [Table: see text]
Association of isocitrate dehydorgenase-1 (IDH-1) mutations with elevated oncometabolite 2-hydroxyglutarate (2HG) in advanced colorectal cancer.
Authors: Fallah-Rad Nazanin , Bedard Philippe L. , Siu Lillian L. , Kamel-Reid Suzanne , Chow Helen , Weijiang Zhang , Jang Raymond , Krzyzanowska Monika K. , Razak Albiruni R. A. , Chen Eric Xueyu 
Published: February 2017

627 Background: IDH-1 mutations are common in AML, gliomas, and intrahepatic cholangiocarcinoma. The enzyme product of the IDH-1 R132 variant preferentially catalyzes the NADPH-dependent reduction of alpha-ketoglutarate to the oncometabolite R-2-Hydroxyglutarate (R-2HG), resulting in accumulation of R-2HG, relative to its enantiomer, S-2HG. Elevated plasma levels of 2HG and/or higher ratios of R/S have been observed in AML and intrahepatic cholangiocarinoma, but not in gliomas. Only a few cases of IDH-1/2 mutations have been reported in advanced colorectal cancers (CRC). We investigated plasma levels of 2HG and relative ratios of R/S in CRC patients harboring IDH-1/2mutations. Methods: Between 2012 and 2015, 428 patients with advanced CRC were molecularly profiled through the COMPACT and IMPACT programs at the Princess Margaret Cancer Centre. Tumor DNAs were isolated from FFPE archived samples and genotyped using a customized Sequenom panel or Illumina MiSeq TruSeq Amplicon Cancer Panel in a CLIA-certified laboratory. Plasma samples from patients harboring IDH-1/2mutations and 4 gender/age matched control patients were analyzed for 2HG, R-2HG and S-2HG using HPLC tandem mass spectrometry coupled with a CHIROBIOTIC R column. Results: Of 428 patients with advanced CRC, 4 (0.9%) patients were identified to harbor IDH-1 mutation. No IDH-2 mutations were detected. The variants identified were R132C (2 patients), R132S, and R132H. 3 of 4 patients also harbored KRAS mutations. Patients with IDH-1 mutations had higher levels of 2HG (319 ± 102 ng/ml vs 195 ± 43 ng/ml, p = 0.043). The ratio of R/S were 0.44, 0.75, 1.59, and 2.60 in 4 patients with IDH-1 mutations and 1.3, 0.90, 0.41 and 0.67 in 3 patients without IDH-1mutations. Conclusions: IDH-1 mutations are rare in advanced CRC. 3 of 4 patients in our study had concurrent KRAS mutations. Patients with IDH-1 mutations had higher levels of oncometabolite 2HG compared with controls with no difference in R/S ratio.
Evaluation of circulating VEGF based biomarkers in INTEGRATE: A randomized phase II double-blind placebo-controlled study of regorafenib in refractory advanced oesophagogastric cancer (AOGC)—A study by the Australasian Gastrointestinal Trials Group (AGITG).
Authors: Yip Sonia , Harvie Rozelle , Martin Andrew James , Sjoquist Katrin Marie , Tsobanis Eric , Kang Yoon-Koo , Bang Yung-Jue , Alcindor Thierry , O'Callaghan Christopher J. , Burnell Margot J. , Tebbutt Niall C. , Rha Sun Young , Lee Jeeyun , Cho Jae Yong , Lipton Lara Rachel , Strickland Andrew , Zalcberg John Raymond , Simes John , Goldstein David , Pavlakis Nick 
Published: February 2017

64 Background: The INTEGRATE study evaluated activity of regorafinib (REG) v placebo (PBO) in 147 eligible patients with refractory AOGC. REG was highly effective in prolonging progression free survival (PFS). Differences between regions (i.e. Australia New Zealand/Canada (ANZ/CAN) vs Korea) were found in the magnitude of effect, but REG was effective across all regions and subgroups. We report on an exploratory analysis of VEGF biomarkers to identify predictive/prognostic markers. Methods: Protein biomarkers IL8, VEGF-A,-B,-C-D, soluble(s)VEGFR-1,-2-3 were analysed in plasma at baseline (BL) by multiplex immunoassays (Bio-Plex,BioRad) or ELISA (Abnova). Spearman statistics were used to quantify correlations between markers. Wilcoxon Rank-Sum tests were used to compare markers across regions. The prognostic and predictive value of markers was determined using cox proportional hazards analysis of PFS. Results: There were moderate-to-strong correlations between BL levels of IL8 and VEGF-C (ρ = 0.68), IL8 and VEGF-D (ρ = 0.66), VEGF-A and VEGF-C (ρ = 0.68), VEGF-A and sVEGFR-1 (ρ = 0.54); and a modest negative correlation between VEGF-D and sVEGRF-1 (ρ = -0.33). The regions differed according to BL levels of: VEGF-A (higher in ANZ/CAN; p = 0.0015), VEGF-B (higher in Korea; p = 0.0003), VEGF-D (higher in Korea; p <.0001), and sVEGFR-1 (higher in ANZ/CAN; p <.0001). Adjusting for treatment group, there were statistically significant negative associations between PFS and BL IL8 (p = 0.047), VEGF-A (p = 0.037) and sVEGFR-1 (p = 0.045). There was no convincing statistical evidence that any BL plasma biomarker modified the effect of REG. The effect of region on effectiveness of REG was maintained when evaluated in conjunction with BL biomarkers individually and in combination. Conclusions: Highplasma IL8, VEGF-A and sVEGFR-1 may be adverse prognostic factors. A predictive VEGF blood based biomarker remains elusive. A broader biomarker study including markers beyond the VEGF axis and tissue based markers is ongoing. Clinical trial information: ACTRN12612000239864.
How are colorectal cancer (CRC) patients treated following cancer recurrence during follow-up?
Authors: Van Loon Katherine , Hu Chung-Yuan , Cuddy Amanda , Bekaii-Saab Tanios S. , Benson Al Bowen , Hall Michael J. , Lai Lily L. , Nurkin Steven J. , Skibber John Michael , Weiser Martin R. , Schrag Deborah , Chang George J. 
Published: February 2017

645 Background: A major goal of surveillance following curative resection for CRC is identification of treatable recurrence. However, there is a paucity of data regarding optimal frequency or duration of surveillance or potential for salvage therapy following detection of recurrence. The aim of this study was to examine treatment patterns following recurrence of CRC. Methods: Patients ≥ 18 years who presented to 8 participating NCCN institutions between 2005-2012 with resected stage I, II, or III CRC were identified. Time to recurrence was determined by the Kaplan-Meier method and descriptive statistics were used to report treatments following recurrence. Results: Of 5653 patients who underwent resection for locoregional CRC (2984 colon, 2669 rectal and rectosigmoid), median age was 60 [IQR: 50-70]. 53.5% were male. With a median follow-up time after diagnosis of 23.5 months (11.0-45.2), 641 recurrences (6.9% local; 93.1% distant) were identified. Median time to local recurrence was 16.1 months [IQR: 12.5-27.3]. Median time to distant recurrence was 15.6 months [IQR: 11.2-23.9]. Among 325 recurrences of a colon primary, 18 (5.5%) were local and 307 (94.5%) were distant; liver and lung were most common sites (30.8% and 13.9%, respectively). Among 316 recurrences of a rectal primary, 26 (8.2%) were local and 290 (91.8%) were distant; lung and liver were most common sites (35.8% and 21.8%, respectively). Of 597 patients who developed a metastatic recurrence, 227 (38.0%) underwent metastectomy (79 liver and 76 lung resections) and 26 (4.3%) underwent ablation. 414 (64.6%) received chemotherapy and 64 (10%) received radiation. 133 (20.7%) died without treatment < 1 year after recurrence. Of 641 patients,113 (17.6%) had synchronous sites of recurrence and 152 (23.7%) developed recurrence at a second site within 12 months. Conclusions: A high rate of metastectomy was observed following detection of recurrence within the NCCN hospitals. However, a significant proportion of patients had a second site of recurrence < 12 months after initial recurrence. Further inquiry into optimal surveillance and management of recurrence for patients following curative resection of CRC is needed. (Support: U10CA180821, CE-1304-6543).
Phase III RECOURSE trial of TAS-102 versus placebo with best supportive care in patients with metastatic colorectal cancer: Geographic subgroups.
Authors: Ohtsu Atsushi , Yoshino Takayuki , Wahba Mona M. , Benedetti Fabio M. , Falcone Alfredo , Garcia-Carbonero Rocio , Tabernero Josep , Sobrero Alberto F. , Peeters Marc , Zaniboni Alberto , Shimada Yasuhiro , Yamazaki Kentaro , Komatsu Yoshito , Hochster Howard S. , Lenz Heinz-Josef , Tran Ben , Mayer Robert J. , Van Cutsem Eric ,   on behalf of the RECOURSE Study Group
Published: February 2017

646 Background: TAS-102 is comprised of an antineoplastic thymidine-based nucleoside analog, trifluridine, and the thymidine phosphorylase inhibitor, tipiracil hydrochloride, at a molar ratio of 1:0.5 (weight ratio, 1:0.471). The efficacy and safety of TAS-102 in patients (pts) with metastatic colorectal cancer refractory/intolerant to standard therapies were evaluated in the RECOURSE trial; enrollment criteria included ≥ 2 prior lines of standard chemotherapy. Primary results of RECOURSE demonstrated a significant improvement in overall survival (OS) and progression-free survival (PFS) with TAS-102 vs placebo (PBO) (hazard ratio [HR] = 0.68 and 0.48 for OS and PFS, respectively; both P< 0.0001). Methods: RECOURSE data were evaluated for efficacy and safety, including rate of hospitalizations, of TAS-102 vs PBO by each geographic subgroup of US, EU, and Japan (JP). Results: Of 768 pts, 99 US (mean age, 60 y), 403 EU (mean age, 62 y), and 266 JP (mean age, 62 y) pts were randomized to receive TAS-102 or PBO. Median OS with TAS-102 vs PBO was 6.5 mo vs 4.3 mo in US pts, 6.8 mo vs 4.9 mo in EU pts, and 7.8 mo vs 6.7 mo in JP pts. HRs for OS and PFS for US, EU, and JP pts all favored TAS-102 (Table). There were no marked differences among the US, EU, and JP subgroups with respect to overall incidence of adverse events (AEs), ≥ Grade 3 AEs, serious AEs (SAEs), or hospitalizations. Conclusions: Similar to the overall RECOURSE population, OS and PFS benefits were observed in each geographic subgroup randomized to TAS-102 vs PBO, with an acceptable safety profile. Clinical trial information: NCT01607957. [Table: see text] [Table: see text]
Outcomes after noncurative locoregional treatment in patients with unresectable metastatic colorectal carcinoma.
Authors: Yang Qiong , Liao Fangxin , Liu Shousheng , Jiang Chang , He Wen-zhuo , Xia Liang-ping 
Published: February 2017

654 Background: A curative hepatic or pulmonary metastasectomy for colorectal carcer is a generally accepted procedure. However, the value of noncurative locoregional therapy for unresectable metastatic colorectal carcer was not well defined. Methods: Of 1,174 patients with unresectable colorectal cancer from 2003 to 2014 retrospectively reviewed, 62 patients received curative regional treatment, 290 patients received locoregional therapy, and 822 patients received standard chemotherapy. Propensity score matching was used to adjust the balance of baseline data between locoregional therapy arm and chemotherapy arm. Kaplan-Meier survival analyses were based on data after propensity score matching. Factors possibly influencing survival were evaluated by univariate and subsequently by multivariate analyses. Results: After propensity score matching, 544 patients were included in this study, 272 in locoregional therapy arm and 272 in chemotherapy arm, respectively. Locoregional therapy included metastasectomy, radiofrequency ablation, percutaneous microwave coagulation therapy and radioactive particle implantation. The addition of locoregional therapy to chemotherapy significantly improved the overall survival with median overall survival 38.73 months (95%CI 34.93-42.54 months) in locoregional therapy arm versus 19.8 months (95%CI 18.06-21.54 months) in chemotherapy arm, respectively, p<0.001. 9 factors were associated with overall survival by univariate analysis, which include primary tumor site, initial stage at first diagnosis, pathological grading, target organ of regional treatment, CA199 and LDH at diagnosis of advanced disease, CEA, CA199 and LDH before regional treatment. Furthermore, CEA (>5ng/ml) and LDH (>245U/L) before regional treatment were identified as independent poor prognostic factors by multivariate analysis. Median overall survival according to the presence of 0, 1, or 2 factors was 49.4 months, 35.7 months, and 27 months. Conclusions: Unresectable metastatic colorectal cancer also benefited from locoregional therapy. Two pre-locoregional treatment risk factors could select the patients most likely to benefit from this strategy.
Multiple immunological mechanisms of cancer cachexia in patients with solid tumors.
Authors: Gonda Kenji , Shibata Masahiko , Nakamura Izumi , Ohki Shinji , Kono Koji , Shimura Tatsuo , Takenoshita Seiichi 
Published: February 2017

667 Background: Cancer cachexia is a mixed and multiple factorial condition and commonly seen in patients with advanced cancer, and has long been reported that host-immune function is critically participated. Chronic inflammation plays a key role in the progress of malignant diseases and has been reported to relate with immune suppression and nutritional impairment seen in patients with advanced diseases. Methods: Peripheral blood mononuclear cells (PBMC) were collected from 18 normal healthy volunteers and 112 patients with gastrointestinal cancer. These cells were used for the detection of MDSC (myeloid-derived suppressor cells: CD11b+CD14-CD33+) by flow cytometry. PBMC was also used for the PHA-blastogenesis of lymphocytes which is a marker of cell mediated immunity (stimulation indices: SI) and for the production assay of cytokines including IFN-G, IL-6 and IL-10. Serum levels of soluble cytokine receptors including sIL-2R and sTNF-R1, and anti-inflammatory molecules such as IL-10 and IL-1 receptor antagonist (IL-1RA) were also measured. For the evaluation of nutritional status, serum concentrations of rapid turnover protein (RTP) including prealbumin, transferrin and retinol binding protein was measured. NLR (neutrophil/lymphocyte ratio) was calculated and used as a marker of chronic inflammation. Results: The circulating levels of MDSC was significantly increased in esophageal, gastric and colorectal carcinomas than in normal volunteer and significantly inversely correlated with serum concentration of RTP and with SI, and correlated with markers for inflammation. The levels of sIL-2R and sTNF-R1 were increased in patients with gastric and colorectal and inversely correlated with the levels of RTP and SI. In patients with cachexia, serum concentrations of IL-10 were increased and the production of IFN-G was decreased. Conclusions: It is suggested that suppression of cell-mediated immune function exists in patients with cancer cachexia and the immunological mechanisms of nutritional damages in these patients are even partially driven by Th2-dominant condition of CD4(+) cells and MDSC. These complicated mechanisms are also involved in inflammation-related immunological condition such as SIRS and CARS.