bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparative effectiveness of treatment options in elderly patients with colon cancer receiving adjuvant chemotherapy.
Authors: Satram-Hoang Sacha , Ramanan Devi , Lee Luen F. , Yu Shui , Reyes Carolina M. , McKenna Edward 
Published: February 2017

470 Background: While colon cancer (CC) is predominantly a disease of the elderly, older patients are underrepresented in clinical trials. We sought to evaluate whether the treatment patterns and benefits realized by trial participants pertain to older patients in the real-world setting. Methods: Using the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database, we conducted a retrospective cohort analysis of 3390 stage II and III CC patients diagnosed between 1/1/ 2004 to 12/31/2007, who were >66 years, enrolled in Medicare Parts A and B, and received adjuvant treatment with 5FU/LV (n=1368), FOLFOX (n=1398), CAP (capecitabine; n=507), and CAPOX (CAP + oxaliplatin; n=117) within 3 months after surgery. Date of last follow-up was 12/31/2007. Chi-square test and ANOVA or t-test assessed differences in patient and disease characteristics by treatment. Propensity score weighted Cox regression assessed the relative risk of death by treatment. Results: Patients treated with CAP were older (mean age 77 years; p<.0001), more likely female (61%; p<.05), more likely non-white (19%; p<.05) and had higher co-morbidity score (p<.0001) compared to the other treatment groups. The mean time to chemo initiation after surgery were similar between the groups (mean 46-49 days) while mean duration of treatment were longer for 5FU/LV (149 days) and FOLFOX (144 days), compared to CAP (121 days) and CAPOX (111 days); p<.0001. The incidence of adverse events (AEs) within 180 days after initiation of treatment were higher in patients treated with FOLFOX (82%) and 5FU/LV (78%) compared to CAP (74%) and CAPOX (71%); p=0.0002. Propensity score adjusted multivariate analysis demonstrated comparable survival for CAP-based regimens vs. 5-FU/LV- based regimens ( table ). Conclusions: Treatment outcomes for elderly patients observed in routine clinical practice were comparable between CAP-based and 5FU/LV-based regimens and consistent with results reported in randomized clinical trials. AEs associated with medical resource utilization were less frequent with CAP-based regimens. [Table: see text]
Conversion to complete surgical treatment using hepatic artery infusional chemotherapy in patients with unresectable liver metastases from colorectal cancer.
Authors: Ammori John Brian , Kemeny Nancy E. , Cercek Andrea , DeMatteo Ronald P. , Allen Peter J , Paty Philip , Fong Yuman , Jarnagin William R. , D'Angelica Michael Ian 
Published: February 2017

472 Background: Hepatic artery infusional (HAI) chemotherapy effectively treats colorectal liver metastases (CRLM). This study analyzes the combination of HAI and systemic chemotherapy for treating unresectable CRLM, focusing on the conversion to complete resection and/or ablation (R/A) and long term outcomes. Methods: All patients with initially unresectable CRLM treated with HAI and systemic chemotherapy from 2000-2009 were included. Patients who responded sufficiently to undergo complete R/A were compared to those who did not convert. Results: 373 patients were included. 296 (79 %) were previously treated and 77 (21 %) were chemo naïve. 115 (31 %) were on protocol and 258 (69 %) were not on protocol. 93 patients (25%) subsequently underwent complete R/A (conversion group). Of the 115 protocol patients, 47 (41 %) underwent complete R/A. The percentage of patients submitted to complete R/A increased from 16% during 2000-2003 to 30% during 2004-2009. 43% of patients who were chemotherapy-naïve prior to HAI therapy eventually underwent complete R/A, compared to 15% who were initially treated with systemic therapy (p<0.001). Factors associated with conversion on multivariate analysis were more recent treatment (2004-2009), no prior chemotherapy, and a clinical risk score < 3. Overall survival was greater in the conversion group, with a median and predicted 5-year survival from the time of HAI pump placement of 54 months and 49%, compared to 19 months and 6%, respectively (p<0.001). Conclusions: One-quarter of patients with unresectable CRLM responded sufficiently to undergo complete R/A following HAI plus systemic chemotherapy. Conversion was more likely in patients who were chemotherapy-naïve (43 %), had a clinical risk score < 3, and were treated in the more recent era. Survival in the conversion group was significantly better.
Early outcome of a phase I study of interrupted pulse dosed axitinib combined with FOLFOX or FOLFIRI in refractory metastatic colorectal cancer.
Authors: Roeland Eric , Shimabukuro Kelly Anne , Fanta Paul Timothy , Parker Bethany H. , Hwang Michael , Reid Tony R. 
Published: February 2017

473 Background: In mCRC, bevacizumab studies have shown improved survival in 5-FU based chemotherapy. Therapeutic inhibition of angiogenesis pathways may improve response of chemotherapy refractory malignancies. We evaluated the combination of axitinib, a VEGF receptor inhibitor, used intermittently with 5-FU based chemotherapy for refractory mCRC. We hypothesized that intermittent pulse dosed axitinib may improve response by delivering chemotherapy during tumor reperfusion after release from angiogenesis inhibition. We present preliminary data of the Phase I portion evaluating the safety and efficacy of interrupted pulse dosed axitinib + FOLFIRI. Methods: Initially, Pfizer A4061020 was a phase IB study of axitinib + bevacizumab + FOLFOX vs. FOLFIRI to evaluate potential overlapping toxicities. In cohorts 8 and 9, A4061020 was expanded to determine the MTD of 7 days of intermittent pulse dosed axitinib at 14mg vs. 20mg + FOLFIRI or FOLFOX. Enrollment was open to mCRC with progression on both oxaliplatin and irinotecan-based regimens. The primary outcome was MTD; while secondary outcomes included: PFS, TTP, and OS. Results: Preliminary data of 10 mCRC subjects show intermittent pulse dosed axitinib at 14mg and 20mg in combination treatment is safe and tolerable (few grade 3 and one grade 4 AE). We observed PFS up to 16.8 mos (avg 8.7 mos, 6 subjects) and TTP up to 17.1 mos (avg 11.8 mos, 4 subjects) vs. average 6 mos on the last line of chemotherapy. To date, the OS endpoint has not been achieved ( Table ). Conclusions: In 10 heavily pre-treated mCRC subjects, intermittent pulse dosed axitinib demonstrates safety, tolerability, and improved PFS and TTP. Intermittent pulse-dosed VEGF receptor inhibition may enhance tumor response that warrants further exploration. [Table: see text]
Phase II multicenter study of second-line FOLFIRI plus cetuximab (FLIER) in patients with KRAS wild-type metastatic colorectal cancer: Final analysis of survival and additional analysis of BRAF, PI3CA mutations.
Authors: Miyake Yasuhiro , Iwamoto Shigeyoshi , Hazama Shoichi , Goda Fuminori , Matsuda Chu , Amagai Kenji , Bandou HIroyuki , Fukunaga Mutsumi , Nagata Naoki , Sakamoto Junichi , Mishima Hideyuki 
Published: February 2017

481 Background: Survival advantage of second line FOLFIRI plus cetuximab in patients with KRAS wild-type metastatic colorectal cancer has not been well reported. Since mutations in codons 12 and 13 of the KRAS gene predict lack of response to Cetuximab, mutations of V600E BRAF and PI3CA have been controversial. Methods: The aim of this study was to assess the efficacy of second-line FOLFIRI plus cetuximab in KRAS wt mCRC. Primary endpoint was response rate, other secondary endpoints were PFS, OS and safety. KRAS, BRAF, PI3CA tests by direct sequence were performed in Yamaguchi University. The starting dose of irinotecan was 150mg/ m2 (approved dose in Japan), but decreased to 100mg/m2 with UGT1A1 *28,*6 homozygous or both heterozygous. Results: From December 2008 to November 2009, 112 pts were preregistered. 67 (59.8%) pts were KRAS codon 12, 13 wt, and 60 pts were enrolled: 39 males (65%), 21 females (35%); median age was 62 years (range 37-82). The incidence of UGT1A1*28, *6 homozygous was 2.8%, 4.7% respectively. Grade 3/4 adverse events were leucopenia 26.7%, neutropenia 43.3%, paronychia 10.0%, skin toxity (fissure) 10.0% and acne 5.0%. The confirmed response rate (RECIST) was 31.7% (19/60). The median progression free survival and overall survival were 7.5 (C.I. 5.2-10.1) and 19.5 (C.I. 11.7-22.2) months respectively. Three pts had BRAF mutations and tumor shirinkage were +50.9%, +12%, +85.6% respectively. Two pts had PI3CA mutations and tumor shirinkage were +4%, +44%, respectively. Conclusions: FLIER was the first multicenter phase II trial with prospective analysis of KRAS as a predictive biomarker for cetuximab in second-line mCRC in Japan. Second-line FOLFIRI+cetuximab is well-tolerated and active. Mutations in BRAF and PI3CA gene seemed to be lack of response to cetuximab.
Effect of PIK3CA and KRAS mutations on sensitivity to ATP-competitive mTOR inhibitors in a primary xenograft model of colorectal carcinoma.
Authors: Ducker Gregory S. , Atreya Chloe Evelyn , Simko Jeffrey , Nakakura Eric K. , Bergsland Emily K. , Donner David B. , Shokat Kevan M. , Warren Robert S. 
Published: February 2017

483 Background: The mammalian target of rapamycin (mTOR) regulates cell growth by integrating nutrient and growth factor signaling and has been strongly implicated in cancer. Mutations in KRAS and the PI3K pathway are upstream of mTOR and are common in colorectal carcinoma (CRC). Currently approved mTOR inhibitors are derivatives of the natural product rapamycin and have shown little clinical efficacy in CRC. A new and potentially more efficacious class of ATP-competitive mTOR inhibitors has now entered clinical trials. Methods: Seeking a more representative preclinical model of CRC, we generated primary xenografts in nude mice of surgically resected specimens of human hepatic colorectal cancer metastases. We then treated xenograft tumors with the selective ATP-competitive mTOR inhibitor PP242 and monitored response by inhibition of tumor growth, changes in histopatholgy, and alterations in signaling pathways. Cell line experiments were performed to support observations made in the patient derived xenografts. Results: We demonstrate that in contrast to rapamycin, the mTOR inhibitor PP242 is highly effective at inhibiting tumor growth in both the primary xenograft model and in colorectal cancer cell lines. The inhibition of tumor growth in the xenografts and cell lines depended upon the strong inhibition of phosphorylation of mTOR substrate eIF4E binding protein 1 (4EBP1) but was not correlated with inhibition of phosphorylation of S6 kinase (S6K). Cells with mutant KRAS were relatively resistant to PP242 induced growth inhibition and this correlated with reduced inhibition of 4EBP1 phosphorylation. However, these effects were partially rescued in cells in which a co-mutation in PIK3CA resulted in AKT activation. Conclusions: Our studies reveal the first mTOR inhibitor resistant cell line, the genetic basis for its resistance and most importantly, these findings were revealed through the use of a primary xenograft mouse model which recapitulates morphologically the features of the tumors isolated from patients. We believe ATP-competitive inhibitors may be of limited clinical utility in mutant KRAS tumors, except for those that have concomitant activation of AKT.
The prognostic implication of phosphoinositide 3-kinase/Akt pathway in gastric carcinomas.
Authors: Begnami Maria D. , Chiappini Paula , Costa Jr. Wilson L. , Fregnani José Humberto , Coimbra Felipe José Fernandez , Diniz Alessandro Landskron , Pinto Clovis 
Published: February 2017

49 Background: The phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B, PKB) signaling pathway plays a critical role in cell growth and survival. Dysregulation of this pathway has been found in a variety of cancer cells. Recently, constitutively active PI3K/Akt signaling has been firmly established as a major determinant for cell growth and survival in an array of cancers. Blocking the constitutively active PI3K/AKT signaling pathway provides a new strategy for targeted cancer therapy. The purpose of our present study was to investigate the expression of activated mTOR (p-mTOR), PTEN, and pAKT in non-neoplastic gastric tissue and in gastric cancer patients to determine their pattern of expression in gastric tumors and their prognostic significance. Methods: The expression of p-mTOR, pAKT, and PTEN was detected in specimens of 239 gastric cancers who underwent radical resection (R0) and in 200 non-neoplastic gastric tissues by immunohistochemistry. Slides were scanned and analyzed with an automated cellular imaging system (ACIS III, Dako). The correlation of p-mTOR, pAKT, and PTEN expression to clinicopathologic features and survival of gastric cancer was studied. Results: Overexpression of pMTOR in the cytoplasmic pattern, nuclear pAKT, and nuclear PTEN was observed in the non-neoplastic tissues when compared with gastric tumor tissues (all, p<0.001). Overexpression of pmTOR, pAKT, and PTEN in gastric tumors was closely correlated with pTNM stage (p<0.001, p=0.008, p=0,036, respectively). Patients with p-AKT positive showed significantly longer disease-free survival (DFS) and overall survival (OS) rates than those with pAKT-negative tumors in univariable analyses. In multivariable analyses, higher expression rates of pMTOR and losses of PTEN were significantly associated with worse overall survival. Conclusions: Taken together, the observations indicate the PI3K/Akt pathway plays an important role in the gastric carcinogenesis. A new strategy for combined chemotherapy of gastric cancer should be designed to more specifically block PI3K/Akt pathway for selected patients.
Copy number differences in EGFR and other amplicons between primary colon tumors and paired lymph node metastasis.
Authors: Tsikitis Vassiliki Liana , Larson David , Preece Christina , Tsavaridis Spyros , Thompson Patricia 
Published: February 2017

498 Background: Prior study, demonstrating differential immunohistochemical EGFR expression between the primary colon cancer and the liver metastasis, suggested possible molecular differences between the two tumor sites. This questions the relevance of obtaining genomic information from the primary tumor to guide adjuvant treatment. In this study we examine whether there are genomic differences specific to metastatic nodes versus the paired colon primary samples. Methods: Using 30 primary and lymph node metastasis pairs (dissected for >80% tumor from paraffin embedded tissue), we obtained a dataset of copy number derived from the Affymetrix Oncoscan Molecular Inversion Probe platform. Using the Nexus Copy Number software for processing, we used the default automatic segmentation of the copy number data with a threshold for calling copy number gains/losses of 2.3/1.7. Subsequently we applied the Wilcoxon signed-rank test in order to find regions showing copy number imbalance that differ between the paired nodes and tumors correcting for multiple comparisons by performing permutation-based estimation of the false discovery rate permuting the samples 100 times. Results: Using 40 ng of total DNA from paraffin embedded tumor from primary and tumor in positive nodes, we obtained high quality, genome wide copy number data. Using FDR < 0.1, we identified four chromosomal segments that showed statistically significant increased likelihood of copy number gains in the primary tumor compared to the tumor-containing node. Thirty five percent of tumor-bearing lymph nodes were copy number normal at the EGFR locus whereas the corresponding primary tumor showed amplification at 7p11.2 (includes the EGFR gene). A similar pattern was observed for 8q24, 14q11.2, and 20q12-q13; regions associated with aggressive tumor behavior. Conclusions: Our results demonstrate four significant differences between the primary tumor and lymph node metastasis and in all cases the metastasis were copy number normal compared to the copy number gain observed in the primary tumor. These results support the importance to examine differences at the genome level between the metastatic tumor site and the primary.
Gene expression analysis of EAC in association with PET response.
Authors: Wayte Nicola , Nancarrow Derek , Walpole Euan Thomas , Lampe Guy , Gotley David , Smithers Bernard Mark , Barbour Andrew 
Published: February 2017

50 Background: Esophagectomy with preoperative chemotherapy or chemoradiotherapy are standard treatment regimens for localized esophageal adenocarcinoma (EAC). Early metabolic response to preoperative therapy (determined by FDG-PET scan) has been shown to predict histological response and survival. We present preliminary data from a randomized phase II trial of pre-operative cisplatin (C), 5-fluorouracil (F) and docetaxel ± radiotherapy based on early response to standard chemotherapy for resectable EAC. We present gene expression data for 22 patients with early FDG-PET response. Methods: Samples that were histologically proven invasive EAC and clinical stage T2/3 tumors were included in the analysis. All patients received C (day1) and F (days 1-4) chemotherapy. Early metabolic response was defined as >35% reduction in SUVmax on day 14 FDG-PET scan compared with baseline scan. Whole genome mRNA expression was obtained for pre-treatment biopsies using HumanHT-12v4 expression chips. Expression data was log2 transformed prior to robust spline normalization conducted with the lumi R package. Statistical analysis was performed in BRBarray. Results: There were 8 early PET responders and 14 early nonresponders to CF chemotherapy. Differentially expressed genes among PET responders and non-responders were identified using a random-variance t-test; 57 genes were identified as significantly differentially expressed between the two classes (p ≤ 0.001). A global test indicated significantly different expression profiles between the classes (p = 0.031). A gene classifier to predict PET response was explored and Support Vector Machines correctly classified 82% of samples with the prediction error estimated using leave-one-out cross-validation (p = 0.05). Epigenetic and apoptotic processes were significantly overrepresented in the gene list based on Gene Ontology analysis. Conclusions: This preliminary work supports a biological basis for the association between early metabolic PET response to preoperative therapy and survival in EAC patients. The list of differentially expressed genes may include potential biomarkers of treatment response and requires further investigation at the maturation of the phase II clinical trial for EAC.
New biomarkers to predict response to oxaliplatin-based chemotherapy in metastatic colorectal cancer: KRAS and ERCC1.
Authors: Strippoli Antonia , Basso Michele , Orlandi Armando , Schinzari Giovanni , Calegari Alessandra , Cursio Olga Elisabetta , Barile Rosalba , Amoruso Alessia , Pozzo Carmelo , Cassano Alessandra , Barone Carlo 
Published: February 2017

500 Background: In the present study we have evaluated the possibility that KRAS mutational status might be predictive of the efficacy of oxaliplatin-based chemotherapy. In addition, we explored the possible role of excision repair cross complementing group-1 (ERCC-1) that is envolved in repair of oxaliplatin (OXA) produced DNA-adducts. Methods: We performed a retrospective analysis of 90 patients with metastatic colorectal cancer, who received FOLFOX-6 schedule and FOLFIRI schedule ± Bevacizumab, in first or second line therapy. In sixty out of 90 patients the expression of ERCC-1 was also determined by fluorescence-based real-time detection method. Results: Among 90 patients, 42 (47%) wild-type (wt) and 48 (53%) mutated (mt) KRAS tumors were found. Twenty-two out of 42 wt KRAS patients received FOLFOX-6 as first-line therapy and the other 20 patients as second-line treatment; in the mt KRAS population, 27 and 21 patients received FOLFOX-6 as front-line or second-line, respectively. One complete response (CR) and 10 partial responses (PR) were observed in the wt KRAS group (RR 26%), whereas 2 CR and 25 PR were obtained in the mt KRAS group (56%); the difference is statistically significant in the total sample (p=0.003) and when only patients receiving FOLFOX-6 in first-line are considered (p=0006). PFS was longer in mt than in wt KRAS patients in the entire group of patients (10 vs 8 months, respectively; p=0.001) and in those treated in front-line (10 vs 8 months, respectively; p=0.003). ERCC-1 was over-expressed in 30 out of 60 patients, but the efficacy of FOLFOX-6 was not different in patient showing high ERCC-1 levels in comparison to those with low level of the gene. In ERCC-1 over-expressing patients, however, RR and PFS were higher in mt than in wt patients (40% vs 13% and 10 vs 8 months, respectively); a similar, not significant, trend was also observed in patients not over-expressing ERCC-1. Conclusions: Our data, if confirmed in larger series and in a prospective setting, suggest that activating mutation of KRAS oncogene could be a predictive biomarker of response to oxaliplatin. Basal tumor expression of ERCC-1 doesn’t explain the high efficacy of FOLFOX-6 in mt KRAS patients.
The expression of multiple proteins as prognostic factors in human colorectal cancer: The correlation between cathepsin D, p53, Cox-2, EGFR, C-erbB2, and Ki-67 expression.
Authors: Lee In Kyu , Kim Hyung Jin 
Published: February 2017

502 Background: This study aimed to establish a correlation between the expression of cathepsin D; p53; Cox-2; EGFR; C-erbB2; Ki-67 protein and the prognosis of colorectal cancer patients. Methods: Tissue samples were collected from 266 patients who underwent surgery for colorectal cancer from January 2006 to December 2007. The expression of the six proteins was determined using immunohistochemical staining of paraffin-embedded tissue specimens. Results: Cathepsin D, p53, Cox-2, EGFR, C-erbB2, and Ki-67 expression was detected in 38.7%, 60.9%, 37.6%, 35.7%, 30.1%, and 74.4% of the samples, respectively. The expression of cathepsin D was significantly correlated with reduced cancer-free survival (p=0.036) and overall survival (p=0.003), whereas the expression of the other proteins could not be correlated. In a multivariate analysis, after adjusting for age, sex, and stage, cathepsin D expression was found to be an independent prognostic factor for a short overall survival(HR=8.55, 95% CI 1.07–68.49). Furthermore, patients with tumors expressing four or more of the proteins had a significantly decreased cancer-free survival rate (p=0.006) and overall survival rate (p=0.002), when compared with patients expressing fewer than four of the proteins Conclusions: In this study, the expression of CD was correlated with a poor prognosis in terms of the cancer-free survival and the overall survival rate. Importantly, the high hazard ratio (HR=8.55) associated with CD expression from the multivariate analysis, even after adjusting for the tumor stage, demonstrates its potential as an independent, single-gene prognostic factor. The expression of four or more of the examined proteins was significantly correlated with a poor prognosis, even after adjusting for the stage. Currently, the prognostic value of a single gene marker in CRCA is very controversial, but based on these results, we believe that the number of expressed genes/proteins may be helpful in identifying patients with both early-stage cancer and a potentially poor prognosis, which will help to determine if adjuvant chemotherapy is necessary.