bluuebunny/crossref_metadata_2025_split huggingface dataset:
IMMU-130, a unique antibody-drug conjugate (ADC) of SN-38 targeting CEACAM5 antigen: Preclinical basis for clinical activity in metastatic colorectal cancer (mCRC).
Authors: Govindan Serengulam V. , Cardillo Thomas M. , Rossi Edmund A. , McBride William J. , Sharkey Robert M. , Goldenberg David M. 
Published: February 2017

625 Background: IMMU-130 is a CEACAM5-targeted ADC, labetuzumab-SN-38, with the drug being the active form of the topoisomerase I inhibitor, CPT-11, and substituted at 7-8 moles/mole of IgG. This agent is in phase I/II clinical trials in patients with relapsed mCRC (NCT01270698; NCT01605318). Methods: Therapy experiments were conducted in female athymic nude mice (n=5-10 per group), 4-6 weeks of age, bearing s.c. LS174T human colon carcinoma xenografts of ~0.2 cm3 size, or 2 weeks after lung metastases were generated by i.v. injection of GW-39 human colon carcinoma cells. Untreated controls, including a non-targeting ADC, were included. Biodistribution was examined in the s.c model using a single 12.5-mg/kg dose of the ADC or unconjugated labetuzumab, each spiked with 111In-labeled substrate. Tolerability studies were conducted in white New Zealand rabbits. Results: In the metastatic model, fractionated dosing of a total of 50 mg/kg of ADC showed that 2 × the schedules of twice-weekly × 2 weeks with 1 week off and once-weekly × 2 weeks with 1 week off doubled the median survival vs. untreated mice, and were better than a 25-mg/kg dose given on days 1 and 15 (p < 0.0474; log-rank). Pre-dosing with as much as twice the dose of labetuzumab as the ADC dose in the metastatic model did not affect median survival (p > 0.15). Therapy experiments in the s.c. model revealed that IMMU-130, with 50% of drug released in ~20 h, was superior to the conjugate with an ultrastable linker, that the ADC was better than an MTD of 5FU/leucovorin chemotherapy (p < 0.0001), and that the ADC could be combined with bevacizumab for improved efficacy (p < 0.031). Significantly better efficacy for the specific ADC vs. nonspecific ADC was observed. Pharmacokinetics in mice indicated ~25% longer half-life for the unconjugated MAb vs. ADC, but with minimal impact on tumor uptake. A tolerability study in rabbits showed the NOAEL to be the human equivalent dose of 40-60 mg/kg, given as two doses. Conclusions: Preclinical data show an excellent therapeutic window for IMMU-130, which appears to be translated into the clinical experience thus far. The potential for combination therapy is also indicated.
The chemokines CXCL9 and CXCL13 as prognostic markers for metastasis and survival in rectal cancer patients after neoadjuvant chemoradiation.
Authors: Sprenger Thilo , Behnes Carl Ludwig , Conradi Lena-Christin , Kauffels Anne , Wolff Hendrik A. , Ghadimi Michael , Liersch Torsten , Wirtz Ralph M 
Published: February 2017

627 Background: Distant metastasis is a challenging problem in multimodal treatment of rectal cancer. Valid prognostic markers for the occurrence of metachronous metastasis could help to stratify patients who qualify for adjuvant chemotherapy and intensified follow-up procedures after preoperative chemoradiotherapy (CRT). Methods: We analysed 9 different genes known to prominently figure in crucial pathways of the tumor cell metabolism. mRNA was isolated and quantified from surgical specimens of 77 rectal cancer patients undergoing neoadjuvant CRT. The panel contains genes with relevant function in apoptosis (Birc5, XIAP, SMAC) and epithelial-mesenchymal transitions (SNAI2) as well as the cancer stem-cell marker CD133, the transcription factor ESR1 and the lymphocyte-chemokines CXCL9 and 13. The expression levels in post-CRT rectal cancers were correlated with the development of distant metastasis and with disease-free (DFS) and cancer-specific overall survival (CSS). Results: Intratumoral mRNA expression of the T-cell chemokine CXCL9 (p<0.001) and the B-cell chemokine CXCL13 (p<0.01) was inversely correlated with the occurrence of distant metastasis. Patients with isolated high CXCL9 (p<0.0001) and CXCL13 levels (p<0.01) had a significantly prolonged DFS. Patients with simultaneous expression of CXCL9 and 13 had an excellent DFS compared to patients without expression of any of the chemokines (p<0.0001). Additionally, CXCL9 expression was correlated with an improved CSS (p<0.05). There was no significant correlation between expression levels of the other genes tested and metastasis or survival. Conclusions: The post-CRT expression of the lymphocyte-chemokines CXCL9 and 13 is associated with reduced rates of distant metastases and improved survival in rectal cancers after CRT. Further investigations are needed to prospectively validate these results and characterize the underlying cellular and molecular mechanisms.
KRAS mutation in colorectal cancer and its association with a stromal-derived gene signature.
Authors: Pelossof Raphael , Elkabets Moshe , Chow Oliver S , Fairchild Lauren , Chen Chin-Tung , Setty Manu , Smith Jesse Joshua , Dow Lukas E. , O'Rourke Kevin P. , Lowe Scott W. , Leslie Christina S , Garcia-Aguilar Julio 
Published: February 2017

628 Background: KRAS mutation in colorectal cancer (CRC) is characterized by an altered transcriptional profile when compared to wild-type KRAS tumors. The list of differentially expressed genes overlaps significantly with a stromal fibroblast activation (SFA) signature present across multiple carcinomas. We have reported low expression of SFA genes in KRAS mutant CRC compared to KRAS wild type tumors. Here we sought to confirm the variation of the SFA signature with KRAS mutation and infer its origin in the stromal component of the tumor using experimental models. Methods: The SFA signature was assessed in an inducible-KRAS murine CRC model using RNA-sequencing, and in a CRC cell line with and without a transduced KRAS mutant vector by microarray analysis. Finally, RNA-sequencing of CRC patient-derived xenografts (PDXs) was used to determine whether the SFA signature was being expressed in the tumor epithelium or the surrounding stroma by leveraging the ability to align sequenced reads to the mouse and human genomes separately. Results: The SFA signature was identified in the inducible-KRAS mouse model, matching human cohort observations of decreased SFA gene expression in KRAS mutant CRC. On the other hand, KRAS transduction did not recapitulate the SFA signature in a CRC cell line, suggesting that the presence of stroma may be required for the expression of the SFA signature. Finally, RNA-seq reads for SFA signature genes in CRC PDXs immediately after implantation aligned primarily to the human genome but in later passages of the same PDXs aligned only to the mouse genome. These data suggest that the SFA transcriptional program is associated with the stroma rather than the epithelial tumor cells. Conclusions: KRAS mutation in CRC is associated with a gene expression signature derived from the tumor stroma. These findings suggest that KRAS mutation in the epithelial tumor cells may impact the tumor microenvironment in CRC.
A phase I/II study of OTSGC-A24 combined peptide vaccine in advanced gastric cancer.
Authors: Yong Wei-Peng , Katsuda Masahiro , Kono Koji , Yamaue Hiroki , Rha Sun Young 
Published: February 2017

65 Background: The aim of this study was to evaluate the safety and optimal dosing schedule of a HLA-restricted cancer vaccine cocktail, OTSGC-A24 targeting novel specific tumor antigens FOXM1, DEPDC1, KIF20A, URLC10 and VEGFR1 in advanced gastric cancer patients with HLA-2402 haplotype. Methods: The vaccine was administered subcutaneously at 3-weekly, 2-weekly and weekly interval. In the first phase, 3 evaluable patients were treated in each dose cohort. The decision to expand the 2-weekly and weekly cohort to 10 patients per cohort was based on specific cytotoxic T-lymphocyte (CTL) induction rate using ELISPOT assay 4 weeks after vaccination. Results: The vaccine was well tolerated at all dose cohorts. The most common toxicity seen was skin induration at the injection sites. No DLT was observed. One patient developed G2 interstitial pneumonitis, 6 months after initiation of treatment. Stable disease was seen in 4 of 9 evaluable patients. The specific CTL induction can be observed at 4 weeks post vaccination with the highest (>2 of 3) observed in the weekly and 2-weekly cohorts. One of 3 patients in the 3-weekly cohort achieved specific CTL response at 4 weeks post vaccination, although all patients attained specific CTL response by 12 weeks after vaccination. Conclusions: OTSGC-A24 combined peptide vaccine was well tolerated. At 4 weeks post vaccination, the CTL induction rate is superior in the weekly and 2-weekly cohort. Efficacy data of the expanded cohorts will be presented. Clinical trial information: NCT01227772.
Quantitative gene expression underlying 18f-fluorodeoxyglucose uptake in colon cancer.
Authors: Engelmann Bodil E. , Binderup Tina , Kjær Andreas , Loft Annika , Gerds Thomas A. , Berthelsen Anne Kiil , Brinch Kim , Latocha Jan E. , Sloth Carsten , Højgaard Liselotte 
Published: February 2017

653 Background: Positron emission tomography (PET) with the glucose analogue 18F-fluorodeoxyglucose (FDG) is widely used in oncologic imaging. This study examines the molecular mechanism underlying the detection of colon cancer (CC) by FDG-PET. Methods: Pre-operative PET/CT scans and tissue samples from primary CC and surrounding normal mucosa were obtained from 42 patients. FDG uptake was quantified using maximal standardized uptake value (SUVmax). The expression of ki67, glucose transporter 1 (GLUT-1), hexokinase 1 (HK1), hexokinase 2 (HK2), vascular endothelial growth factor (VEGF), hypoxia-inducible factor 1α (HIF1α) and carbonic anhydrase IX (CaIX) mRNA was examined by quantitative real time reverse transcriptase-polymerase chain reaction. Results: All primary tumours showed increased uptake of FDG. The mean SUVmax was 15.0 (range 5.3 – 37.8). No correlation was found between tumour size and SUVmax. Mean gene expression levels of GLUT1, HK2, ki67, HIF1α, VEGF and CaIX, but not HK1, were significantly higher in primary tumours than in surrounding normal colonic mucosa. Linear regressions pairing tumour SUVmax with gene expression levels showed significant correlations between SUVmax and HK2, ki67 and CaIX, respectively. Conclusions: These results confirm FDG PET/CT as a functional imaging method in CC, and that FDG accumulation reflects molecular events related to glycolysis, cell proliferation, hypoxia, but not angiogenesis.
A randomized, double-blind, phase II study of first-line FOLFOX plus bevacizumab with onartuzumab versus placebo in patients with metastatic colorectal cancer (mCRC).
Authors: Bendell Johanna C. , Hochster Howard S. , Hart Lowell L. , Firdaus Irfan , Mace Joseph Ronald , McFarlane Joshua Jemison , Kozloff Mark , Catenacci Daniel Virgil Thomas , Hsu Jessie J. , Hack Stephen Paul , Shames David S. , Phan See-Chun , Cohn Allen Lee 
Published: February 2017

663 Background: In mCRC, MET overexpression has been associated with poor prognosis and resistance to anti-VEGF therapy. We initiated a phase II study to evaluate the combination of onartuzumab (O), a ligand-blocking monoclonal antibody directed against the MET receptor, plus bevacizumab and FOLFOX, in first-line mCRC (GO27827; NCT01418222). Methods: This double-blind, randomized, multicenter phase II study randomized patients 1:1 to receive O (10 mg/kg iv) or placebo (P), plus mFOLFOX6 and bevacizumab (5 mg/kg iv). Stratification was by prior adjuvant therapy. All treatments were given on day 1–3 of a 2-week cycle. Oxaliplatin was given for up to 8–12 cycles; all other agents were continued until progression, unacceptable toxicity or death. Primary endpoint was progression-free survival (PFS) in ITT and MET+ subgroup by immunohistochemistry (IHC). MET status was determined by central laboratory IHC evaluation, with scores of 2+ or 3+ considered MET+. Results: From September 2011 to November 2012, 194 patients were enrolled. A recommendation was made to stop O after an interim efficacy and safety analysis in September 2013, due to lack of efficacy. The final analysis (cut-off Feb 2014) found that O did not improve PFS vs. P in the ITT (HR 0.75 [0.52–1.08]; p=0.12) or MET IHC+ populations (n=79; HR 1.03 [0.56–1.89]; p=0.93), although improvement was noted in the MET IHC− population (n=108; HR 0.60 [0.37–0.97]; p=0.03). Neither overall survival (OS) nor response rate (RR) was improved with O vs. P in any of the groups (OS HR 0.96 [0.61–1.50], p=0.85 for ITT; OS HR 1.24 [0.63–2.43], p=0.54 for MET IHC+; OS HR 0.83 [0.44–1.56], p=0.56 for MET IHC−; RR 57.3% vs. 57.7% for ITT, 43.2% vs. 57.1% for MET IHC+, 66.1% vs. 60.8% for MET IHC−). More edema (65.7% vs. 12.9%) and venous thromboembolic events (30.3% vs. 16.1%) were seen with O vs. P, respectively. Grade ≥3 events were similar (86.9% vs. 84.9%) and events leading to discontinuation were increased (48.5% vs. 37.6%) with O vs. P. Conclusions: Adding onartuzumab to FOLFOX/bevacizumab did not prolong PFS in first-line unselected or MET IHC+ mCRC. A trend towards PFS benefit was seen in those with MET IHC− mCRC, contrary to prior reports in other tumor types. Clinical trial information: NCT01418222.
GAIN-(C): Efficacy and safety analysis of imgatuzumab (GA201), a novel dual-acting monoclonal antibody (mAb) designed to enhance antibody-dependent cellular cytotoxicity (ADCC), in combination with FOLFIRI compared to cetuximab plus FOLFIRI in second-line KRAS exon 2 wild type (e2WT) or with FOLFIRI alone in mutated (e2MT) metastatic colorectal cancer (mCRC).
Authors: Bridgewater John A. , Cervantes Andres , Markman Ben , Siena Salvatore , Cubillo Antonio , Carbonero Rocio Garcia , Sigal Darren , Aprile Giuseppe , Cunningham David , Nadal Cristina , Pericay Carles , Samuel Leslie M. , Hochhauser Daniel , Perez-Fidalgo Jose Alejandro , Strickland Andrew , Guizani Cecile , Golding Sophie , Lopez Valverde Vanesa , Ott Marion Gabriele , Tabernero Josep 
Published: February 2017

669 Background: Imgatuzumab, a humanized engineered IgG1 anti-Epidermal Growth Factor Receptor (EGFR) mAb designed to enhance ADCC, showed promising clinical activity in a phase I trial including KRAS MT mCRC. This multicenter phase II study (NCT01326000) aimed to compare the combination of imgatuzumab with FOLFIRI to cetuximab plus FOLFIRI or FOLFIRI alone as second-line treatment in patients with both KRAS e2WT or e2MT mCRC. Methods: Patients underwent a mandatory fresh tumor biopsy at screening to assess KRAS exon 2 status. KRAS e2WT patients were randomized (1:1) to treatment groups 1 or 2 to receive imgatuzumab (1,400 mg IV on day 1 and 8 then q2-weekly) or cetuximab (400 mg/m2 IV on day 1 followed by 250 mg/m2 IV q-weekly) respectively plus FOLFIRI (standard IV chemotherapy). KRAS e2MT patients were randomized to groups 3 and 4 to receive imgatuzumab plus FOLFIRI or FOLFIRI alone respectively. Patients were stratified by EGFR expression, time to disease progression on first line treatment and prior treatment with bevacizumab. A run-in phase (n=6/group) was performed to confirm tolerability before recruitment proceeded. Results: 169 patients with an evaluable fresh tumor biopsy were randomized. Median PFS (Investigator reported) was 7.3 months in group 1 versus 6.1 in group 2 (HR, 1.13; 95% CI 0.69-1.86) and 5.2 months in group 3 versus 4.3 in group 4 (HR, 0.94; 95% CI 0.57-1.54). Adverse events of ≥ grade 3 included rash (42.5%, 9.8%, 31.8%, 0% in groups 1, 2, 3 and 4 respectively), hypomagnesemia (30.0%, 4.9%, 22.7%, 0% respectively) and neutropenia (20.0%, 29.3%, 25.0%, 21.4% respectively). Conclusions: The outcome was negative with respect to the primary efficacy endpoint (PFS) with no benefit seen for the addition of imgatuzumab to FOLFIRI in second-line in both KRAS e2WT and e2MT populations. We demonstrated that collection of fresh tumor biopsy is feasible in pretreated CRC. Clinical trial information: NCT01326000.
Raltitrexed in the management of metastatic colorectal cancer: The COMET study.
Authors: Desramé Jérôme , Dourthe Louis-Marie , Debourdeau Philippe , Mille Dominique , Artru Pascal , Albrand Helene 
Published: February 2017

677 Background: Raltitrexed, indicated for palliative treatment of advanced colorectal cancer (CRC), may be useful for patients (pts) with cardiovascular (CV) risk factors, or cardiotoxicity/disease progression with prior chemotherapy (CT). The COMET study, conducted in France, described the characteristics of pts with metastatic CRC (mCRC) treated with raltitrexed, focusing on pts with cardiotoxicity or disease progression with prior 5-fluorouracil (5FU)/folinic acid. Methods: A national, multicentred, cross-sectional, non-interventional study to describe the profiles of pts with mCRC treated with raltitrexed. Pts (≥18 years) with mCRC, treated with raltitrexed as a single agent or in combination therapy, were included. Following patient consent, retrospective data were recorded during a single inclusion visit based on pt medical files; during the study, data were recorded prospectively. Results: 414 pts with mCRC were analysed; 84.8% had ≥1 prior CT, 60.9% had CV risk factors and 35.2% had CV history (angina: 11.8%; myocardial infarction: 11.8%). Overall, 79.5% of pts had received a prior 5FU-based CT. Reasons for switching to raltitrexed included short 15-min infusion duration (34.8%), treatment failure (49.8%) and acute cardiotoxicity with 5FU (8.9%). After switching, 57.2% of pts received raltitrexed as combination therapy. Mean initial dosage of raltitrexed was 2.6±0.6 mg/m2. Of those who had CV risk factors (n=73) or CV history (n=67), 69.0% and 72.7% received raltitrexed after CV toxicity, respectively. Of the pts treated with second-line raltitrexed and assessed with prior acute CV events (45/414), 88.9% (40/45) had no cardiac toxicity during treatment with raltitrexed. Of those (n=206) receiving raltitrexed due to treatment failure, 62.7% had received 5FU/folinic acid during their last CT. Of the pts assessed for tumour response (183/206), tumour progression was controlled with raltitrexed in 25.7% of cases (stable disease: 18.0%; partial response: 7.7%; progressive disease: 56.3%). Conclusions: Raltitrexed appears to be effective in heavily pretreated pts with mCRC and tumour progression after 5FU therapy and could be a safe therapeutic alternative to 5FU for pts with mCRC and prior cardiac toxicity.
Statin use and mortality in patients with colorectal cancer: A systematic review and meta-analysis of observational studies.
Authors: Gupta Arjun , Singh Siddharth , Singh Preet Paul 
Published: February 2017

686 Background: Preclinical evidence suggests that statins have anti-neoplastic properties by inhibiting cell proliferation, and inducing apoptosis. Statins may be associated with reduced risk of colorectal cancer (CRC), but their effect on CRC related mortality is unclear. We performed a meta-analysis of published observational studies evaluating statin use in patients with CRC and its association with overall and CRC-specific mortality. Methods: Through a systematic search upto August 2014, we identified 7 observational studies (64,773 patients with CRC;19.5% statin users) reporting the association between statin use and mortality in patients with CRC. Summary hazard ratio (HR) with 95% confidence intervals (CI) was estimated using the random effects model, and heterogeneity was measured using the inconsistency index (I2). Results: On meta-analysis, statin use was associated with a 26% reduction in all-cause mortality in CRC patients as compared to non-use (6 studies; adjusted HR, 0.74; 95% CI, 0.67-0.83) with minimal heterogeneity (I2=18%), after adjusting for age, sex and CRC stage. Only one study adjusted for concomitant metformin use. Five studies evaluated CRC-specific mortality; on meta-analysis, use of statins (vs non-use) was also associated with decreased CRC-specific mortality (adjusted HR, 0.74; 95% CI, 0.70-0.83; minimal heterogeneity, I2=17%). On limiting analysis to statin use after diagnosis of CRC, use of statins remained significantly associated with reduced CRC-specific mortality (3 studies; adjusted HR, 0.70; 95% CI, 0.60-0.81), but not overall mortality (4 studies; adjusted HR, 0.82; 95% CI, 0.64-1.05). On restricting analysis to studies, which adjusted for concomitant use of aspirin/NSAID, the inverse association between statin use and overall- (5 studies; adjusted HR, 0.74; 95% CI, 0.66-0.84) and CRC-specific mortality (4 studies; adjusted HR, 0.76; 95% CI, 0.69-0.84) remained significant. Conclusions: Based on this meta-analysis, statin use in patients with CRC may be associated with reduced all-cause and CRC-specific mortality. This observation merits prospective investigation of statins’ effect on outcome in CRC patients.
Survival for patients with resectable lung metastatic colorectal cancer (mCRC).
Authors: Price Timothy Jay , Tomita Yoko , Beeke Carol , Padbury Robert , Townsend Amanda Rose , Maddern Guy , Roy Amitesh , Roder David , Karapetis Christos Stelios 
Published: February 2017

708 Background: Hepatic resection for CRC metastasis is now considered a standard of care and perioperative chemotherapy may improve outcomes. Resection of metastasis isolated to lung is also considered potentially curable, although there is still some variation in recommendations and no evidence for perioperative or adjuvant chemotherapy. Here, we explore patient characteristics and outcomes for patients undergoing lung resection for mCRC, with the liver resection group as the comparator. Methods: SA mCRC registry data were analysed to assess patient characteristics and survival outcomes between patients suitable for lung or liver resection. K-M survival analysis was used to assess OS. Results: 3,241 patient are registered on the database. 102 (3.1%) patients were able to undergo a lung resection compared to 420 (12.9%) a liver resection. Of the lung resection patients, 21% initially presented with liver only disease, 11% both lung and liver, and 7% brain or pelvic disease. 62 (61%) presented with lung only disease. Of these patients, 79% went straight to surgery and 34% had lung resection as the only intervention. When comparing the groups, they were balanced for age and sex, liver v lung; 67.7 years v 69.5 years, 63.6% v 57.8% male. There was no difference in pathological grade or KRAS MT rate when tested (36% liver v 32% lung). Compared to patients undergoing liver resection, those having lung resection were more likely to be metachronous (75.5% v 44%, p=<0.0001) and have a rectal primary (43.1% v 30.7%, p=0.017). Chemotherapy for metastatic disease was given more often in liver resection patients (76.9% v 53.9%, p=0.17). Median overall survival is not reached for both arms and the lower hazard rate for lung than liver resection does not approach statistical significance (HR 0.82, 95% CI 0.54-1.24, p=0.33). The 3 and 5 year survival liver v lung as follows; 77% v 81% and 62% v 70%. Conclusions: Lung resection occurs less frequently than liver resection for metastatic disease as expected. There was no statistical difference in overall survival in patients suitable for lung or liver resection. These data support the potential for long term survival with resection of both lung and liver metastasis in mCRC.