bluuebunny/crossref_metadata_2025_split huggingface dataset:
A single-arm trial of panitumumab in cetuximab refractory KRAS wild-type colorectal cancer.
Authors: Wadlow R. C. , Hezel A. F. , Wolpin B. M. , Allen J. N. , Blaszkowsky L. S. , Kwak E. L. , Wang R. , Zhu A. X. , Ryan D. P. , Clark J. W. 
Published: February 2017

428 Background: While FOLFOX or FOLFIRI with bevacizumab are the standard first-line regimens in the treatment of metastatic colorectal cancer, a role for epidermal growth factor receptor inhibitiion in KRAS wild-type colorectal cancer has been established in the second and third line setting. Cetuximab is a chimeric antibody that consists of approximately 30% murine protein, and panitumumab is a fully human monoclonal antibody. Correspondingly, the rates of severe hypersensitivity reactions are somewhat increased with cetuximab (3%) compared to panitumumab (1%). Presently, cetuximab is typically used in combination with irinotecan in the second or third line setting, and panitumumab is occasionally substituted if hypersensitivity occurs. The value of panitumumab as a salvage agent in cetuximab-resistant colorectal cancer is unknown. Methods: Panitumumab (6 mg/kg every 14 days) was administered to patients with KRAS wild-type metastatic colorectal cancer that had progressed on prior cetuximab. Treatment was continued until disease progression, death, inability to tolerate panitumumab, or study withdrawal. The primary endpoint was response rate (RR). Twenty patients were enrolled in the first stage and, if at least one responded, 12 additional patients were to be enrolled in a second stage. This two-stage design tested the null hypothesis that the RR is less than or equal to 1% versus greater than or equal to 10% with a type I error of 3.6% and 80% power. Blood samples were collected at baseline and prior to cycles 2 and 3 to evaluate for the presence of anti-cetuximab and anti-panitumumab antibodies using the Biacore immunoassay. Results: 22 patients with ECOG PS 0-2 were treated for a median of two cycles. The best response was stable disease (45%) and the RR was 0%. There were a total of 266 toxicities reported, the majority of which were mild (n = 184, 69%) or moderate (n = 63, 24%) in severity. There were 19 grade 3 and 0 grade 4 toxicities. Median overall survival was 1.9 months. Immunologic data will be reported at the time of presentation. Conclusions: Panitumumab is not active as salvage therapy for patients with cetuximab-resistant, KRAS wild-type metastatic colorectal cancer. [Table: see text]
Preclinical development of small-molecule CRM1 inhibitors as novel therapy for the treatment of colorectal cancer (CRC).
Authors: Shacham S. , Kauffman M. , Sandanayaka V. , Draetta G. , Shechter S. , Williams J. , Nir R. 
Published: February 2017

430 Background: CRM1 (XPO1) is a key nuclear export protein which controls the location of multiple tumor suppressor (TSP) and growth regulatory (GRP) proteins including p53, PI3K/AKT, Wnt/ß-catenin and NF-kB. Forced nuclear expression of TSP and GRP by CRM1 inhibition can lead to apoptosis in cancer cells while sparing normal cells. Methods: Novel small-moleculeCRM1 inhibitors were synthesized and nuclear distribution studies were performed in cells transfected with HIV-rev GFP proteins. Cell proliferation studies were performed in 16 CRC cell lines: LS-123, SW-626, Colo-201, Colo-205, Colo-320DM, Colo-320HSR, Lovo, DLD-1, HCT-15, WiDi, LS-174T, LS-180, SW-620, C2BBe1, HCT-8, HCT-116, and in human peripheral leukocytes (PBMC). Cellular distribution and apoptosis assays were performed on HCT-116. Antitumor activity is assessed in human HCT-116 xenografts in scid-mice. Results: The lead CRM1 inhibitor, KPT-0127, blocks CRM1 mediated nuclear export of HIV-Rev-GFP, FOXO, and p53 with an IC50 of ∼300 nM. KPT-0127 is cytotoxic to various CRC cell lines with EC50s of 0.07-1.1 μM; in 9 CRC lines EC50s were < 0.3 mM. In contrast, normal cell lines and PBMCs had EC50 > 5-20 μM. In HCT- 116 cells, KPT-0127 induces cell cycle arrest at both G1/S and G2/M checkpoints and dose dependently increases nuclear p53, followed by an increase in caspase 3. KTP-0127 10μM shows no significant effect on 37 proteins including several cysteine proteases. In mice, KPT-0127 given by SC injection of 30-100 mg/kg leads to serum levels exceeding the effective CRM1 inhibitory concentration for at least 4 hours and is well tolerated. KPT-0127 given SC to mice bearing HCT-116 colon xenografts results in dose-dependent antitumor activity. Conclusions: The novel small- molecule CRM1 inhibitor KTP-0127 kills CRC lines with multiple TSP, GRP, and oncogenic abnormalities, including p53 mutations/deletions and PTEN deficiency/AKT activation, while sparing normal cells. This likely reflects the ability of CRM1 inhibition to affect multiple critical and non-redundant regulatory pathways. These results support the development of CRM1 inhibitors for the treatment of CRC. IND-enabling CMC and toxicology work are in preparation. [Table: see text]
External validation of a tumor-derived 5-gene prognostic signature for recurrence (R) of stages I/II colon and stage I rectal cancer following potentially curative resection.
Authors: Lenehan P. F. , Boardman L. A. , Fry D. W. , Heyman E. R. , Ohrnberger J. , Worzel W. P. 
Published: February 2017

437 Background: Optimizing post-operative clinical management for early-stage (I/II) colorectal cancer (CRC) patients (pts) is a significant unmet medical need. We hypothesized that a molecular prognostic test using primary CRC tissue would better predict the chances of tumor R within 36 months (mo) than current NCCN Clinical Practice Guidelines (NCCN). Methods: Pts had tumor R by 36 mo (n=46) or confirmed non-recurrence (NR) for ≥36 mo (n=69) after surgery; none had received neoadjuvant or adjuvant therapy. Archival formalin-fixed paraffin-embedded primary adenocarcinoma tissues (median storage 7 years; range 4-15) obtained at initial surgical resection with curative intent were retrieved for 86 stage I/II (pT1-4 pN0 M0) colon cancer and 29 stage I (pT1-2, pN0 M0) rectal cancer pts from 2 US and 2 European sites that were different from those previously used to generate the molecular test. Tumor gene expression was assessed by qRT-PCR with custom 384- well TaqMan Low Density Arrays (Applied Biosystems) using RNA that had satisfied a set of rigorous quality control parameters. Results: For stages I/II CRC (n=115), the dichotomous rule correctly classified 32/46 R and 38/69 NR pts: sensitivity (S) 0.70, specificity (SP) 0.55. High-risk pts had a significantly higher probability of R by 36 mo than low-risk pts: PPV 0.51, NPV 0.73; hazard ratio (HR) 2.06 (95% CI: 1.10 to 3.86; p=0.020). NCCN (V.1.2011) was not able to differentiate 36-mo R vs NR in this population: S 0.72, SP 0.42, PPV 0.45, NPV 0.69; HR 1.38 (95% CI: 0.73 to 2.63; p=0.315). The SP of the molecular test was significantly greater than that for NCCN (p=0.05). For stage I pts (n=29; 13R, 16NR), the prognostic accuracy of the test (0.79; 23/29) surpassed that for NCCN (0.55; 16/29). Conclusions: External validation of a 5-gene prognostic rule confirmed its ability to differentiate early stage CRC pts at high risk vs low risk for R within 36 mo after surgery better than current NCCN Guidelines, especially for stage I. The improved specificity and high sensitivity of the molecular test confirm its potential utility for optimizing post-op clinical management of early stage CRC. [Table: see text]
Feasibility of combining EGFR- and VEGF(R)-targeted agents in colorectal cancer.
Authors: Larsen A. K. , Poindessous V. , Ouaret D. , El Ouadrani K. , Megalophonos V. F. , Batistella A. , Petitprez A. , Escargueil A. E. , Tournigand C. , De Gramont A. 
Published: February 2017

443 Background: The extensive cross-talk between EGFR and VEGF(R) argues for joint targeting of the two signaling pathways. Unexpectedly, large clinical trials with combinations of EGFR-targeted antibodies and bevacizumab, a VEGF-blocking antibody, showed no added benefit in colorectal cancer (CRC) patients compared to bevacizumab alone. One difference between the antibodies and the small molecule tyrosine kinase inhibitors (TKIs) is the potential of the TKIs to inhibit intracellular signaling pathways. Methods: We here characterize the activity of two TKIs, the irreversible EGFR/HER2 inhibitor BIBW2992 (B2) and the VEGFR/PDGFR/FGFR inhibitor BIBF1120 (B1) toward human CRC models in vitro and in vivo. Results: B1 and B2 together showed strong activity toward HT-29 CRC xenografts, compared to either drug alone, and was associated with increased tumor cell death. In comparison, cetuximab and bevacizumab together were no more active than either drug alone and showed exclusively cytostatic activity. Recent findings provide evidence for intracellular VEGF-signaling in epithelial tumors which synergizes with EGFR for proliferation and survival (Cell 140:268, 2010). In agreement, HT-29 tumors expressed abundant intracellular VEGFR1 as shown by immunohistochemistry. Furthermore, targeted knock-down of VEGFR1 in cellular models was accompanied by increased sensitivity to B1 and B2 combinations thereby confirming the relevance of intracellular VEGFR1 signaling for CRC survival. Conclusions: Combinations of B1 and B2 show synergistic activity in CRC models. These findings favor clinical studies with combinations of the two agents and suggest that rationally selected EGFR- and VEGF-targeted agents can be combined for clinical benefit. [Table: see text]
Establishment of primary human esophageal xenografts: Rationale for selection and cancer model.
Authors: Dodbiba L. , Teichman J. , Ramjaun A. , Li M. , Sun B. , Chen Z. , Renouf D. J. , Tsao M. S. , Ailles L. , Liu G. 
Published: February 2017

45 Background: New animal models of esophageal cancer are required to accelerate research into novel treatment strategies. Mouse xenografts used in pre-clinical drug testing are typically derived from cell lines, but several esophageal cancer cell lines have been contaminated (PMID 20075370). Xenografts implanted from surgically resected human tumors are a potentially viable model, and may better recapitulate the characteristics of the original tumor. We describe the feasibility of such an approach. Methods: 2-10 mm esophageal carcinoma fragments obtained from resected patient tumors were implanted directly into NOD/SCID mice. Tumors that grew beyond 1.5 cm in diameter were passaged serially. Pathologic properties were assessed from passage to passage. Potential clinicopathological predictors of engraftment were evaluated. Results: Of the 63 patients with tumors used for implantation, 67% were male; median age 66 (range 31-89); 31% node negative disease; 69% node positive disease; 12% metastatic; 55% received neoadjuvant therapy; 12% had prior Barrett's esophagus; 46% had pre-existing heartburn; 88% were distal esophageal/GE junction cancers. Engraftment occurred in 14/43 (33%) adeno-, 1/14 (7%) squamous, and 1/1 adenosquamous carcinomas (p=0.05; 5 others were rare tumors e.g. granular or small cell). Engraftment occurred in 6/31 well/moderately vs 7/18 poorly differentiated tumors (p=0.08). Because we amended our implantation procedures, we compared engraftment rates pre- (7/39; 18%) and post-amendment (8/23; 35%; p=0.13). The primary architecture of the xenografted tissue remained similar pathologically for up to 5+ passages. None of the following variables predicted for engraftment (p>0.20 each comparison): cancer location, age, gender, history of heartburn, pre-operative therapy, presence of Barrett's esophagus, disease stage, or recurrence of primary cancer. Conclusions: Creation of esophageal cancer xenografts from primary human resected specimens is feasible. Adenocarcinomas, higher tumor grade, and newer implantation strategies were associated with improved engraftment. We are treating these models with chemotherapy to discover new pharmacogenomic predictive biomarkers. No significant financial relationships to disclose.
Retrospective study to elucidate a K-ras phenotype in patients with colorectal cancer.
Authors: Garrido-Laguna I. , Janku F. , Falchook G. S. , Naing A. , Fu S. , Wheler J. , Tsimberidou A. M. , Hong D. S. , Kurzrock R. 
Published: February 2017

462 Background: Activating mutations of the K-ras oncogene in colorectal cancer (CRC) are associated with resistance to EGFR antibodies and poor prognosis. Clinical and pathological characteristics associated with K-ras mutations have not been systematically analyzed. Methods: Patients with CRC referred to the phase I program for targeted therapy were analyzed for K-ras mutations using PCR-based DNA sequencing. Patients with mutant K-ras were matched with wild-type (wt) K-ras controls. Multiple clinical and pathological characteristics were analyzed to determine, whether there is a phenotype associated with K-ras mutations. Results: A total of 107 patients with CRC were identified; 58 with K-ras mutations; and 49 with wt K-ras. Patients with K-ras mutations compared with wt K-Ras had more frequently lung metastases (80% vs. 57%, p = 0.013). There was a trend towards higher number of metastatic sites in K-ras mutant patients compared with wt K-ras (3.16 vs. 2.69; p = 0.07). There were no associations between K-ras mutations and gender, age at diagnosis, liver metastases, peritoneal metastases, and lymphatic involvement. The median time from diagnosis to development of metastatic disease was similar in K-ras mutant and K-ras wt patients (194 vs. 196 weeks, p = 0.43). The median survival from diagnosis was also similar in K-ras mutant and K-ras wt patients (254 vs. 223 weeks, p = 0.32). There was no difference in the median survival from diagnosis in patients with different types of K-ras mutations (codon 12, codon 13, and codon 61). Dukes staging was the only statistically significant prognostic factor on multivariate analysis (p < 0.05). Conclusions: K-ras mutations in CRC in comparison with wt K-ras were associated with more frequent lung metastases. K-ras mutations did not impact survival. No significant financial relationships to disclose.
Novel multiphoton microscopy probe and feasibility study for colon cancer: Probe on trace elements–related antioxidant.
Authors: Kim E. , Jeen Y. , Cho H. , Keum B. , Kim Y. , Lee H. , Chun H. , Kim C. , Ryu H. 
Published: February 2017

463 Background: Multiphoton microscopy (MPM) has gained increasing popularity during the past few years because of the distinct advantages over single-photon microscopy, which includes increased penetration depth and low out-of-focus photodamage. However, there had been no report on multiphoton probes for malignancy. Previous studies reported that Zn and Cu ions which are co-factor of antioxidants such as superoxide dismutase (SOD), altered in malignancy tissue. The aim of this study was to evaluate application of the multiphoton (MP) probe of Zn and Cu for colon cancer tissues. Methods: We monitored the Zn/Cu ions in the colon cancer cell lines with multiphoton probe Microscopy. The multiphoton probe AZn2+ (C38H38N6O3) and ACu+ (C34H47N3O3S4), we developed and obtained the patent on it, were stained in live cancer cell lines. The tissues of colon cancer, adenoma and normal mucosa were obtained by biopsy during colonoscopy. Then the tissues were stained with 20μM of the MP probes for Zn/Cu ions. The distribution and concentration of zinc and copper ions were monitored by MPM by following the change in MPEF along the depth of tissue. Results: The majority of Zn2+ and Cu+ ions distributed in cytosole. The average multi-photon excited fluorescence (MPEF) intensities due to Cu, Zn, and Cu/Zn ratio were remarkably different between the normal mucosa and adenoma/adenocarcinoma tissues. The Zn2+ content was significantly lower and the Cu2+ content was significantly higher to result in a much lower the Zn/Cu ratio in adenoma/adenocarcinoma than in normal mucosa tissues. Conclusions: We have obtained multiphoton microscopy images of normal and cancer cell lines as well as mucosa and adenoma/adenocarcinoma tissues labeled with newly developed MP probes AZn1 and ACu1. No significant financial relationships to disclose.
Pooled safety results from SPIRITT: A multicenter, open-label, randomized, phase II study of FOLFIRI with panitumumab (pmab) or bevacizumab (bev) as second-line treatment (tx) in patients (pts) with metastatic colorectal cancer (mCRC).
Authors: Hecht J. R. , Dakhil S. R. , Saleh M. N. , Piperdi B. , Cline-Burkhardt M. , Kocs D. M. , DeMarco L. C. , Chen L. , Krishnan K. , Cohn A. L. 
Published: February 2017

477 Background: Pmab is a fully human monoclonal antibody against the epidermal growth factor receptor (EGFR) approved as monotherapy in pts with chemorefractory mCRC. Many pts with mCRC who have progressed on a bev-containing regimen receive second-line bev + chemotherapy despite the lack of prospective, randomized data supporting this approach. A phase III study recently showed that pmab + second-line FOLFIRI improved progression-free survival (PFS) in pts with wild-type (WT) KRAS tumors vs chemotherapy alone. This study was amended after enrollment began to focus hypothesis testing on the WT KRAS population and is evaluating the safety and efficacy of pmab + FOLFIRI vs bev + FOLFIRI in pts who received first-line therapy with an oxaliplatin-based regimen + bev. Methods: This is a randomized, phase II, open-label study in pts with mCRC with disease progression or intolerability after ≥ 4 doses of first-line oxaliplatin-based chemotherapy + bev. Pts are randomized 1:1 to receive either 6 mg/kg pmab Q2W + FOLFIRI or bev (given at institutional standard dose Q2W) + FOLFIRI. Tx is administered until disease progression (PD), death, or withdrawal from study. The primary endpoint is PFS in patients with WT KRAS tumors. Other endpoints include objective response rate, overall survival, safety, and patient-reported outcomes. Results: At the time of data cutoff, 216 of 277 planned pts were enrolled. 175 (81%) pts discontinued study tx and 39 (18%) pts remain on tx. Any grade adverse events (AEs) were reported in 197 (92%) pts. 38 (18%) pts had AEs that led to withdrawal from tx or study. Serious AEs were reported in 66 (31%) pts and included gastrointestinal disorders (13%), infections and infestations (8%), respiratory disorders (7%), and metabolism and nutrition disorders (7%). Fatal AEs were reported in 18 (8%) pts of which 9 (4%) were related to disease progression. Conclusions: The aggregate safety profile is consistent with expected toxicities of FOLFIRI in combination with an anti-EGFR or an anti-VEGF targeted therapy in second-line mCRC. Detailed pooled safety results will be presented at the meeting. [Table: see text]
Complete pathologic response after combined-modality treatment for rectal cancer and long-term survivals: A meta-analysis.
Authors: Zorcolo L. , Rosman A. S. , Restivo A. , Pisano M. , Nigri G. R. , Fancellu A. , Melis M. 
Published: February 2017

479 Background: Recent literature suggests that a complete pathologic response (CPR) following neoadjuvant chemoradiotherapy (combined modality treatment, CMT) for rectal cancer is associated with improved survivals compared to partial or no response (NPR). However, previous reports have been limited by small sample size and single-institution design. To overcome these limitations, we performed a meta- analysis of studies evaluating the prognostic value of CPR. Methods: A systematic literature review was conducted to detect studies comparing long-term results of patients with CPR or NPR after CMT for rectal cancer. Variables were pooled only if evaluated by 3 or more studies. Both qualitative and quantitative data were pooled using a random-effects model. Study endpoints included rates of complete pathological response, local recurrence (LR), distant recurrence (DR), as well as 5-year overall (OS) and disease-free survival (DFS). Results: There were 13 studies suitable for the meta-analysis, that overall reported on outcomes of 2030 patient with rectal cancer treated with CMT. CPR was achieved in 332 patients (16.4%). CPR and NPR patients groups were similar with respect to age, male gender, tumor size, distance of tumor from the anus and pre- treatment stage (p > 0.3 for all comparisons). Median follow-up ranged from 23.5 to 46 months. CPR patients had lower rates of LR (0.7% vs. 2.6%; odds ratio [OR]=0.45, 95% CI 0.22–0.90), DR (5.3% vs. 24.1%; OR=0.15, 95% CI 0.07–0.31) and LR+DR (0.7% vs. 4.8%; OR=0.32, 95% CI 0.13–0.79). OS was 92.6% for CPR vs. 73.2% for NPR (OR=3.6, 95% CI 1.84–7.06), and DFS was 89.1% vs. 64.3% (OR=4.3, 95% CI 1.8-10.1). Conclusions: Our meta-analysis confirms that a CPR following CMT for rectal cancer is associated with an improved local and distal control as well enhanced OS and DFS. No significant financial relationships to disclose.
Similarities in treatment (Tx) patterns and clinical outcomes (CO) in patients (pts) with metastatic colorectal cancer (mCRC) initially treated with FOLFOX/BV or FOLFIRI/BV: Results from ARIES, a bevacizumab (BV) observational study.
Authors: Bendell J. C. , Bekaii-Saab T. S. , Cohn A. L. , Hurwitz H. , Kozloff M. , Tezcan H. , Feng S. , Flick E. D. , Sing A. , Grothey A. 
Published: February 2017

480 Background: COs associated with varying Tx patterns in mCRC pts are poorly understood because patterns diverge from the randomized trials (RCT). The RCTs of BV (Avastin) plus chemotherapy (CT) in mCRC pts continued BV until progressive disease (PD), even if CT was stopped/changed. Some RCTs of BV+CT in mCRC show ∼50% of pts stopping Tx early for reasons other than PD with possible lessening of benefit. It is unclear if this is due to use of a particular CT regimen or other practice pattern. While the beneficial effect of post-PD BV Tx has been shown in ARIES (HR 0.52 BBP vs No BBP) [A Cohn, ASCO 2010], the effect of stopping BV or CT before PD is unclear. ARIES, a community based observational study with a large cohort of 1st line BV-treated mCRC pts, will assess the COs associated with different 1st line Tx patterns (BV and CT) based on real world practice. Methods: ARIES enrolled mCRC pts receiving first- or second-line CT+BV. No Tx regimens or assessments are protocol specified. Data are collected prospectively at baseline (BL) and quarterly. Analyses included first-line pts with PD. Tx patterns of pts initially treated with FOLFOX/BV or FOLFIRI/BV are described and preliminary COs (PFS and OS) are estimated from K-M curves. Tx duration is calculated from enrollment date. Results: As of 2/5/10, 1,548 first-line mCRC pts enrolled (median follow up = 21 m); 1,133 pts had PD. Of 1,133 pts with PD, most had FOLFOX/BV (63%) or FOLFIRI/BV (16%) as first CT. BL characteristics were similar, but the FOLFOX/BV group had more stage 4 pts (74%). Main reasons for stopping BV include AE, max benefit achieved and CT holiday. Tx patterns and COs are in the table. Conclusions: ARIES first-line mCRC pts treated with FOLFOX/BV or FOLFIRI/BV had similar Tx patterns and COs despite the common opinion that they may differ in tolerability and possibly effectiveness. Additional analyses will assess the impact of stopping BV and/or CT before PD. [Table: see text] [Table: see text]