bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I/II study of azacitidine and capecitabine/oxaliplatin (CAPOX) in refractory metastatic colorectal cancer.
Authors: Overman Michael J. , Eng Cathy , Kee Bryan K. , Fogelman David R. , Fark Christine , Hippert Rick , Holter Scott , Issa Jean-Pierre , Hamilton Stanley R. , Kopetz Scott 
Published: February 2017

450 Background: Hypermethylation of promoter CpG islands (CIMP) has been strongly implicated in chemotherapy resistance and both clinical and preclinical studies have shown the ability to restore platinum sensitivity with the reversal of hypermethylation. CIMP is implicated in the pathogenesis of a subset of colorectal cancers termed CIMP-high. We sought to explore the safety and efficacy of the hypomethylator, azacitidine, in combination with CAPOX. Methods: We report the results of the phase I portion of a prospective phase I/II study in fluoropyrimidine and oxaliplatin refractory metastatic colorectal cancer (mCRC). The primary objectives were to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) of this combination. Two dose levels were explored with a standard 3+3 design of azacitidine (75 mg/m2, SQ D1-5), oxaliplatin (90 and 110 mg/m2 IV D2), and capecitabine (1500 mg/m2/d, PO divided BID, D1-14) every 3 weeks, followed by an expansion of 6 patients at the MTD to evaluate for delayed hematological toxicity. The phase II portion is restricted to patients with CIMP-high (≥ 2/6 methylation-specific PCR markers: hMLH1, P16, P14, MINT1, MINT2, and MINT31). Results: 15 pts [M/F 8/7, median age: 60 yrs (range: 34-73), ECOG PS 0/1: 1/14] were enrolled from 8/2010 to 4/2011. Prior progression on fluoropyrimidine/oxaliplatin-based treatment met RECIST criteria in 13 pts. All pts were evaluable for toxicity and 13 for response. Twelve pts were treated at the highest dose level with no DLTs. Common grade 3-4 treatment-related toxicities were: neutropenia in 5 (33%), diarrhea in 2 (13%), oxaliplatin hypersensitivity reaction in 2 (13%). Best response was SD in 7 pts (54%) with a median duration of SD of 3.2 months (range: 2.2-6.9 months). Two pts remain on treatment. Two of 14 tested pts had CIMP-high tumors and both had progressive disease. Conclusions: Azacitidine and CAPOX was well tolerated in an unenriched oxaliplatin-refractory mCRC population. The recommended phase II dose of azacitidine with CAPOX is 75mg/m2, D1-5. Enrollment in the phase II cohort continues in fluoropyrimidine and oxaliplatin refractory CIMP-high metastatic colorectal cancer.
Discovery of microRNAs in tumor tissue predictive of time to progression and overall survival in patients with colorectal cancer treated with first-line capecitabine, oxaliplatin, and bevacizumab.
Authors: Boisen Mogens Karsboel , Dehlendorff Christian , Linnemann Dorte , Ranc Kristina , Jensen Benny V. , Høgdall Estrid V. , Larsen Jim S. , Nielsen Svend Erik , Andersen Klaus Kaae , Johansen Julia S. 
Published: February 2017

461 Background: The aim was to identify predictive and prognostic microRNAs (miRNAs) in cancer tissue samples from patients with metastatic colorectal cancer (mCRC) treated with 1.-line capecitabine, oxaliplatin, and bevacizumab (CapOxBev). Methods: Patients with mCRC treated with 1.-line CapOxBev were identified from 7 hospital databases and clinical and pathological data was extracted retrospectively. Formalin-fixed paraffin-embedded (FFPE) tissue samples from primary tumors were collected and RNA was purified from 3 x 10 µm sections, without micro-dissection. MiRNA expression was measured using TaqMan® Array Human MicroRNA A and B cards (Applied Biosystems) profiling 754 miRNAs. Raw miRNA expression values were checked for outliers and data was corrected using spike-in values. In a univariate selection method, each miRNA was related to time-to-progression (TTP) and overall survival (OS) using Cox proportional hazards model (threshold p < 0.001). Candidate miRNAs were tested using Akaike’s Information Criterion in a multivariate analysis corrected for age, sex, histology, number of metastatic sites, primary location, and prior adjuvant treatment. Results: Samples from 212 patients were profiled and 205 and 192 had acceptable miRNA and outcome data available for final analysis of OS and TTP, respectively. Four miRNAs were found to be predictive for TTP and two for OS. Higher expression of miRNAs A, B, and C and lower expression of miRNA D was predictive of longer TTP, and higher expression of miRNAs E and F predicted longer OS. Conclusions: Four miRNAs measured in archival FFPE samples of primary CRC tumors from patients treated with 1.-line CapOxBev were predictors of TTP and two others of OS. Three of the miRNAs found have reported roles in angiogenesis pathways indicating that they may be biomarkers for bevacizumab efficacy. A validation study in 500 patients is on-going. [Table: see text]
PKM2 mRNA expression to predict disease recurrence in patients with stage II or III colon cancer treated with oxaliplatin in combination with fluoropyrimidines.
Authors: Papadaki Chara , Sfakianaki Maria , Saridaki Zacharenia , Giagas Georgios , Mpananis Kyriakos , Tzardi Maria , Tsakalaki Eleftheria , Trypaki Maria , Georgoulias Vassilis , Sougklakos Ioannis 
Published: February 2017

468 Background: Tumor cells have been shown to express exclusively the embryonic M2 isoform of pyruvate kinase (PKM2), which is a key enzyme that regulates aerobic glycolysis in tumor cells. Use of RNA interfering (RNAi) targeting PKM2 significantly inhibits tumor growth when combined with cisplatin in xenograft models. We evaluated the predictive significance of PKM2 in patients with “high” risk stage II or stage III colon cancer treated with oxaliplatin-fluoropyrimidines chemotherapy adjuvant treatment. Methods: FFPE primary tumours from 261 patients with stage II or III colon cancer with colon cancer were analyzed for PKM2 mRNA expression by RT-qPCR. All patients had received adjuvant treatment with an oxaliplatin and fluoropyrimidine combination. Also, match normal mucosas from 50 of these patients have been analyzed. Finally, 50 polyps (20 with low grade dysplasia, 20 high grade dysplasia and 10 serrated adenomas) from non-colon cancer patients were included in the for PKM2 mRNA expression by RT-qPCR. The analysis was performed with a set of primers and probes which amplify only the M2 isoform. Results: PKM2 mRNA expression was significantly higher in tumor areas in comparison with normal mucosa (p=0.001) and low-grade adenomas (p=0.001) as well as in tumors with BRAF mutations (p=0.001). Adenomas with high-grade dysplasia (p=0.002) and serrated adenomas (p=0.001) presented significantly higher PKM2 mRNA expression. Overexpression of PKM2 was associated with significantly lower Disease Free (p=0.018) and Overall Survival (p=0.031). Multivariate analysis revealed PKM2 high mRNA expression as independent prognostic factors for decreased DFS (HR: 2.1, p=0.003) and OS (HR: 1.8, p=0.019). Conclusions: These results provide evidence that the PKM2 mRNA expression could be used as prognostic/predictive marker for disease recurrence in patients with operable colon cancer. Analysis of the PKM2 mRNA expression in patients treated with non-oxaliplatin containing adjuvant treatment is currently performed.
Tesetaxel, a novel oral taxane, as second-line therapy for advanced gastroesophageal cancer: Activity in a dose-ranging study.
Authors: Ajani Jaffer A. , Sun Weijing , Rha Sun Young , Baker Jackie S. , Mulcahy Mary Frances 
Published: February 2017

47 Background: Standard taxanes require extended IV infusion and are associated with potentially severe hypersensitivity and cumulative neuropathy. Tesetaxel is a structurally novel orally active taxane with potent and superior antitumor activity relative to standard taxanes in human tumor xenografts that overexpress P-glycoprotein. Tesetaxel is not associated with hypersensitivity, thus eliminating the need for both premedication and extended medical/nursing observation. A prior study showed an overall major response rate (ORR) of 20% as 2nd-line therapy in pts with advanced gastric cancer. Since pharmacokinetic and safety data suggested that flat dosing of tesetaxel might be feasible, we evaluated both flat and weight-based dosing in a new dose-ranging study. Methods: Eligibility: adenocarcinoma (stomach or GE junction); treatment with 1 fluoropyrimidine/platinum analog regimen; ECOG PS 0-1; and adequate organ function. Tesetaxel was administered Q3 weeks at flat starting doses (40 mg and 50 mg) in Cohorts 1 and 2, respectively. When flat dosing proved impractical, a weight-based dose was used for Cohort 3 (27 mg/m2 with escalation to 35 mg mg/m2 pending tolerability). ORR was the primary endpoint. Results: To date, 36 pts (29 men, 7 women; median age, 58 years [range: 25-81]) have been enrolled in this ongoing study, with results as shown below. Median survival is 7.8 and 7.5 months in Cohorts 1 and 2, respectively, and is too early to estimate in Cohort 3. Uncomplicated neutropenia was the most common ≥ 3 event (13%). Conclusions: Extreme body weight differences resulted in marked underdosing and precluded flat dosing. Our data confirm that tesetaxel is active against gastroesophageal cancers in the 2nd-line setting using the weight-based Q3 week regimen. [Table: see text]
Using deep sequencing of formalin-fixed paraffin embedded (FFPE) rectal cancer biopsy tissue to analyze miRNA expression in patients with rectal cancer.
Authors: Chen Zhenbin , Gao Harry , Mu Bing , Wang Jinhui , Wu Xiwei , Qin Hanjun , Li Wenyan , Garcia-Aguilar Julio 
Published: February 2017

487 Background: miRNAs have been shown to be involved in tumor initiation, progression and metastasis in many cancers including colorectal cancer. However, miRNA profiling specifically in rectal cancer is not well characterized. Our objective was to generate a miRNA expression profile in locally advanced rectal cancer using formalin fixed paraffin embedded (FFPE) biopsy tissue collected from patients with locally advanced rectal cancer. Methods: We collected pre-treatment biopsy tissue and matched normal tissue from 40 rectal cancer patients treated with pre-operative chemoradiation (CRT) and total mesorectal excision (TME). We extracted 50-1000ng of total RNA from FFPE biopsies and optimized small RNA sample preparation for deep-sequencing. We then performed deep sequencing on biopsy and matched normal tissue and compared miRNA expression in biopsy and normal tissues using paired T-test and multiple testing (Q-bound <0.05) to determine significant miRNA expression changes in rectal cancer. Results: 182 miRNAs were differentially expressed in tumor versus normal tissues (Q-bound <0.05); 15 of these miRNAs showed a greater than 2-fold change in expression in tumor tissue; mir-18a, mir-135b, mir-503, mir-584, mir-106b, mir-224, mir-92a, mir-181d were up-regulated and mir-375, mir-378, mir-378c, mir-137, mir-378, mir-147b, mir-30a were down-regulated. miRNA mir-31 showed the highest up-regulation in tumor tissue (16-fold increase) while mir-215 expression decreased 8-fold in tumor compared to normal tissue. Tumor and normal tissues were completely separated by hierarchical cluster analysis based on their distinctive miRNA profiles. Conclusions: We optimized small RNA sample preparation for deep sequencing of miRNAs, an approach which may be useful for quantifying miRNA expression in tissues with limited starting material. We also identified a novel miRNA expression profile in rectal cancer that may be useful as a diagnostic biomarker of disease.
Efficacy of vemurafenib (V), a selective V600EBRAF inhibitor, as monotherapy or in combination with erlotinib (Erl) or erbitux (Erb) and irinotecan (Iri) doublets and triplets in a colorectal cancer (CRC) xenograft model.
Authors: Higgins Brian , Kolinsky Kenneth Daniel , Schostack Kathleen , Bollag Gideon , Lee Richard J. , Su Fei , Packman Kathryn 
Published: February 2017

494 Background: B-Raf mutations, particularly at V600 occur in 10% of CRCs resulting in constitutive activation of the MAPK pathway. V (RG7204, PLX4032) is a first-in-class, V600B-Raf-selective small molecule inhibitor previously shown to potentiate anti-tumor effects in the V600E CRC xenograft model HT29 in combination (combo) with capecitabine ± bevacizumab (ASCO GI, 2008). V600E CRC respond poorly to EGFR inhibition (EGFRi) both preclinically and clinically. We aimed to determine whether antitumor activity could be potentiated by combining V with EGFRi. Methods: The monotherapy (mono) activities of V, Erl, Erb and Iri were compared to combo of these agents in the HT29 model. V was tested as a mono at its optimal dose (OD), Erl was tested at its MTD or 2/3 MTD, and a combo of V OD + 2/3 MTD Erl were tested. V was subsequently tested as mono or combo at the OD and suboptimal-OD with OD Erb. A final study included Iri as mono, doublets of Iri + V or Erb, and triplet combo of Iri, V, and Erb. Results: Tumor growth inhibition (TGI) and increase in life span (ILS) for combo of OD V + 2/3 MTD Erl was superior to all mono arms. TGI in mono arms was equivalent for V, Erb and Iri. ILS was better for V vs Iri and Erb mono, while Iri vs Erb ILS were equivalent. TGI and ILS for Iri + Erb doublet was equivalent to V mono. Otherwise, TGI and ILS in all other doublets and triplets were superior to mono groups. TGI in V + Erb and V + Iri were equivalent, but ILS was better for V + Iri. TGI and ILS for V + Iri was better than Iri + Erb. TGI in V + Erb was better than Iri + Erb, but ILS was equivalent. TGI in the triplet was superior to all doublets except V + Erb, however ILS was superior to all doublets tested. Conclusions: V potentiates anti-tumor activity in a V600E CRC model when used in combo with Erl, Erb and Iri. Although a V + Erb doublet provided impressive TGI equivalent to a triplet with Iri, the triplet yielded sustained antitumor activity as demonstrated by a significant increase in survival as compared to the doublet. Combo with V may afford V600E CRC patients a differential response to what is seen traditionally with single agent EGFi and is worthy of clinical exploration.
Expression of the nuclear receptor, FXR, as CRC progresses from primary to lymph node to liver metastases.
Authors: Lai Lily L. , Ohanian Armond , Smith David D. , Liu Xiyong 
Published: February 2017

497 Background: Farnesoid X Receptor (FXR) is a nuclear receptor critical for cholesterol, triglyceride and glucose metabolism. In mouse models, loss of FXR results in tumorigenesis. FXR expression decreases from normal epithelium to cancer. Clinical studies identify FXR as a novel prognostic and predictive biomarker in CRC. We sought to further characterize FXR expression with clinical CRC progression. Methods: Under institutional approval, we reviewed the FFPE tissues from 20 St. IV CRC patients who underwent synchronous resection of previously untreated primary cancers, lymph nodes (LN), and liver metastases (Met) from 2000-2005. FXR expression, determined using immunohistochemical techniques, was scored on a 3-point scale (0 = no expression, 1 = moderate expression, 2 = high expression). Pair-wise differences were tested using two-tailed t-tests. Results: All 20 sets included tissues from 3 sites. We found that FXR protein levels decreased along the continuum of disease from primary to LN and from LN to Met in 15 of 20 sets of tissues. In 4 sets, there was no change in FXR expression. In 1 patient, FXR increased in the LN and Met. Overall, FXR expression decreased from primary to LN (**p<0.001), from LN to Met (**p<0.001) and from primary to Met (***p<0.0001). Conclusions: FXR expression decreases as disease advances from primary to LN to Met. Our findings suggest that FXR regulation of metabolism in the cancer cell may be lost in CRC progression. Further studies are needed to determine if upregulation of FXR activity in localized CRC can inhibit progression to metastases.
A pilot study evaluating peripheral blood lymphocyte telomere length in elderly versus young patients with colorectal cancer (CRC).
Authors: Dotan Efrat , Nicolas Emmanuelle , Devarajan Karthik , Beck Robert J , Cohen Steven J. 
Published: February 2017

512 Background: Telomere length (TL) is associated with aging as well as high cancer incidence. We conducted a pilot study to assess the TL of younger versus older (≥70 years) patients with CRC and its effect on survival. Methods: QPCR was used to analyze the relationship between telomere repeat copy number and single gene copy number (T/S ratio) on peripheral blood lymphocytes DNA of 94 CRC patients, and used as a surrogate value for relative TL. The primary aim of the study was to evaluate differences in TL between different age groups. Correlation with overall survival (OS) was the secondary aim. Samples were run in triplicate, and a standard curve was used to calculate the relative T/S ratio and account for plate to plate variability. Univariate statistical analyses were performed using the Mann-Whitney test for continuous variables and the log-rank test for OS. Multivariable analyses were performed using the Classification and Regression Trees methodology. A Type I error of 5% was used to determine statistical significance. Results: The mean relative TL was 0.95 (range 0.64-1.84). The assay demonstrated high correlation of technical replicates between plates (Pearson correlation: 0.96 and 0.81, for sample and control). Comparing patient under and over 70 years of age revealed a borderline significant difference in TL between the groups (mean TL 0.981 versus 0.925 respectively; p=0.067). Assessment using 4 age groups (50-60, 60-70, 70-80, >80) demonstrated a statistically significant difference in TL between the youngest and the oldest age groups (mean TL 1.022 versus 0.874 respectively; p=0.02) with evidence of shorter TL with advanced age. Marginal relationship was seen between OS and age (p-value=0.066) with older patients exhibiting slightly poorer survival (hazard ratio of 1.03, 95% confidence interval (0.998, 1.065)). No correlation was noted between relative TL and OS in univariate and multivariable analysis. Conclusions: These results validate the ability of a qPCR-based assay to differentiate between younger and older CRC patients by TL. Ongoing studies are utilizing this methodology to evaluate the relationship of TL to treatment tolerance in elderly CRC patients.
The efficacy of antiepidermal growth factor receptor monoclonal antibodies for patients with KRAS G13D mutations and chemorefractory metastatic colorectal cancer.
Authors: Akiyoshi Kohei , Yamada Yasuhide , Takahashi Naoki , Honma Yoshitaka , Iwasa Satoru , Kato Ken , Hamaguchi Tetsuya , Shimada Yasuhiro 
Published: February 2017

527 Background: The treatment benefits of epidermal growth factor receptor (EGFR) monoclonal antibodies for patients with KRAS mutations have not been demonstrated. However, some studies have suggested that all KRAS mutations are not equivalent, and that KRAS G13D mutations might have some survival benefit. Methods: We retrospectively analyzed the efficacy and toxicity of treatment with EGFR monoclonal antibody in 8 patients with KRAS G13D mutations and 5-FU/oxaliplatin/irinotecan (CPT) refractory metastatic colorectal cancer compared with 94 KRAS wild type patients at the National Cancer Center Hospital. Results: Eight patients with KRAS G13D mutations were treated with anti-EGFR monoclonal antibodies between July, 2009 and July, 2011. The median age was 66 (42-70); male/female 6/2; PS was 0/1/2, 2/5/1; treatment regimen was cetuximab/ cetuximab+CPT/ panitumumab+CPT, 2/5/1. Response rate (RR) was 12.5% and disease control rate (DCR) was 50.0% with 1 PR, 3 SD, and 4 PD. The PR case treated with cetuximab+CPT showed marked regression of tumor and long duration of treatment (9 months). The progression free survival (PFS) of 2 SD cases was 4.2 and 3.9 months. The other SD case is now on treatment. The median PFS of the 8 patients was 2.1 months (95% confidence interval [CI]: 0.0-5.2). The median overall survival (OS) has not been reached. Grade 3/4 toxicities included 1 hypomagnesemia G4 and 1 rash acneiform G3. Meanwhile, 94 KRAS wild type patients treated with anti EGFR monoclonal antibodies had an RR of 22.3% and DCR was 66.0% with 21 PR, 41 SD, 30 PD, and 2 NE. PFS was 5.6 months (95% CI: 4.9-6.3) and OS was 8.6 months (95% CI: 6.5-10.7). Conclusions: In this analysis, we identified one PR to anti-EGFR monoclonal antibody in a patient with KRAS G13D mutation and chemo-refractory metastatic colorectal cancer. However, we were unable to demonstrate equivalent efficacy in patients with KRAS G13D mutations and KRAS wild type patients. Further studies are needed to evaluate the efficacy and prognosis for this treatment.
Action of SDF-1/CXCR4 axis in liver metastasis of colorectal cancer.
Authors: Yamada Shinichiro , Shimada Mitsuo , Utsunomiya Toru , Imura Satoru , Morine Yuji , Ikemoto Tetsuya , Mori Hiroki , Hanaoka Jun , Saito Yu , Asanoma Michihito , Miyake Hidenori 
Published: February 2017

530 Background: It has recently been suggested that the SDF-1/CXCR4 axis is involved in tumor progression, angiogenesis, metastasis, and survival in various cancer. In this study, we investigate the possible role of SDF-1/CXCR4 axis in colorectal liver metastasis. Methods: Both primary colorectal tumors and liver metastatic tumors were obtained from 12 patients with colorectal liver metastasis. Expression levels of CXCR4 and SDF-1 were determined using RT-PCR. In 4 patients with benign liver disease, the expression level of SDF-1 in normal liver tissues was also determined. We divided the 12 patients into two groups; high expression group (n=6) and low expression group (n=6) according to each expression level of SDF-1 and CXCR4, and compared the clinicopathological factors between the two groups. Results: 1. CXCR4 expression levels in primary tumor: The frequency of the peritoneal dissemination in the CXCR4 high expression group was higher than in the low expression group (p=0.07). Moreover, overall survival rate in the CXCR4 high expression group was significantly lower than that in the low expression group (3 year-survival rate: 67% vs. 100%, p<0.05). 2. CXCR4 in metastatic tumor tissues and SDF-1 in non-tumor liver tissues: The expression level of SDF-1 in non-tumor liver tissues was significantly higher than that in normal liver tissues (p<0.01). A significant correlation between the CXCR4 expression levels in metastatic tumor tissues and SDF-1 expression levels of non-tumor liver tissues (p<0.05). The number of metastatic liver tumors in the SDF-1 high expression group tended to be larger than that in the low expression group (p=0.12). Conclusions: The present data suggest that there is a significant association of the SDF-1/CXCR4 axis with enhanced liver metastasis and poor prognosis of the patients with colorectal liver metastasis. Furthermore, an enhanced expression of SDF-1 in non-tumor liver tissues may have an important role in the formation of liver metastasis.