bluuebunny/crossref_metadata_2025_split huggingface dataset:
Presentation, management, and outcome of the pregnant female with colorectal cancer.
Authors: Kachikwu E. L. , Leong L. A. , Lai L. L. 
Published: February 2017

389 Background: Most patients diagnosed with colorectal cancer (CRC) are older than 60 years old. However, there remains a population of women of reproductive age (17-49) who develop CRC. Few publications have described the presentation, management and outcome of patients who initially present while pregnant.The objective of this study is to assess the presentation, management and outcome of women aged 17-49 with a particular focus on the pregnant patient. Presenting symptoms, time from presentation to diagnosis, management of disease, and overall survival were the main endpoints of this study. Methods: A retrospective chart review was conducted of 72 women aged 18-49 who were treated for CRC between 2005 and 2009 at a single institution. We compared the non-pregnant women (n = 66, group A) with the pregnant women (n = 6, group B). Results: The median age at presentation was 43 and 36.5 years in group A and group B, respectively. All six patients in group B presented with significant anemia, severe abdominal pain, and bright red blood per rectum during pregnancy while 25% of group A were asymptomatic. Although all 6 of the group B patients presented while pregnant, five patients were diagnosed in the postpartum period. Only 1/6 patients were diagnosed while pregnant, in the 3rd trimester. Median time from presentation to diagnosis was 10 days in group A, and 175 days in group B. Definitive treatment for the group B women included resection with C-section (n = 1), resection followed by systemic chemotherapy (n = 3), and resection only (n = 2). 72% of group A and 100% of group B patients presented with advanced disease (stages III and IV). Median overall survival for the entire cohort was 24.4 months; 26.1 months for group A and 7.8 months for group B. There was one long-term survivor amongst the group B patients (5.3 years), who has had two recurrences. Conclusions: Overall, the majority of women aged 18-49 presented with advanced stages of CRC. Specifically, 5/6 pregnant women presented with stage IV disease. Given that many of the symptoms of CRC mimic symptoms of pregnancy, a higher index of suspicion of CRC may minimize the delay in diagnosis, decrease the proportion of higher stage cancers, and improve the cancer outcome in this cohort of patients. No significant financial relationships to disclose.
Development of a new stool biomarker ELISA for the early detection of colorectal cancer.
Authors: Luka J. , Arlen P. M. , Bristol J. A. 
Published: February 2017

390 Background: An ELISA was developed using NPC-1C, a novel antibody that reacts with an antigen expressed specifically by human colorectal and pancreatic tumor tissues and cell lines. The target antigen that NPC-1C recognizes was shown to be related to MUC5AC, a member of the mucin family of glycoproteins. NPC-1C reacts with neither normal tissues from healthy donors (rare, weak binding to normal colon and esophagus), nor cell lines derived from other tumor types, thereby providing the basis for a proof of concept comparative evaluation with stool from normal healthy donors. Methods: An ELISA that uses NPC-1C antibody as both capture and detection reagent was developed. Samples of stool collected during colonoscopy from colorectal cancer patients (n = 4), stool from people with small polyps (n = 4), stool from people with multiple polyps (n = 2), stool from people with large polyps (n = 3), and stool from healthy adults (n = 13) were applied to the ELISA. A soluble extract of stool was prepared by detergent lysis and centrifugation. The level of NPC-1C-specific MUC5AC antigen measured in this ELISA was compared among all groups. Results: Preliminary results demonstrated that healthy people did not express NPC-1C antigen in their stool. The signal in the assay was similar to background levels (average 723 units). In contrast, people with small polyps had higher levels (average 3,819 units); people with multiple polyps expressed higher levels (average 7,369 units); people with large polyps had even higher levels (average 10,189 units); and colon cancer patients had the highest levels (average 175,983 units), more than 240 times the level of MUC5AC-related antigen compared with healthy people. Conclusions: The proof of concept has been established to correlate the level of NPC-1C reactive antigen, measured by a novel stool-based ELISA, with colon cancer disease progression. The level of NPC-1C-specific MUC5AC detected increased concomitantly with the number and size of polyps observed during colonoscopy, and reached the highest levels in patients with colon cancer. Our goal is to apply this ELISA test for early noninvasive diagnostic screening for colorectal cancer, an area of still largely unmet need. [Table: see text]
Use of preoperative liver biopsy to predict livers that have avoided chemotherapy-induced liver injury.
Authors: Belghiti J. , Genser L. , Fuks D. , Dokmak S. , Faivre S. J. , Paradis V. 
Published: February 2017

393 Background: Liver parenchymal damage caused by neoadjuvant chemotherapy may increase the surgical risk. The aim of the present study was to assess the performance of preoperative liver biopsy (PLB) in predicting the status of the liver parenchyma at the time of resection. Methods: Among 40 patients who underwent liver resection after neoadjuvant chemotherapy for colorectal liver metastases (CLM) in 2009, 28 had percutaneous PLB from 2 to 6 weeks after onset of the treatment. Patients underwent a mean number of 9 cycles of chemotherapy (range 4-22). Chemotherapy included oxaliplatin (n=22), irinotecan (n=10), and bevacizumab (n=12). PLB and surgical specimens were compared according to the presence and rate of steatosis, sinusoidal obstruction syndrome (SOS) and chemotherapy-associated steatohepatitis (CASH). Results: Surgical specimen analysis showed steatosis in 12 (43%) patients (ranging from 5 to 80%), SOS in 12 patients (43%) and CASH in 1 patient (3%). The sensitivity, specificity, positive predictive value and negative predictive value of PLB for steatosis were 67%, 81%, 73% and 77%, respectively. It was 50%, 94%, 86% and 71%, respectively for SOS and 0%, 100%, 0% and 96%, respectively for CASH. Performance of PLB was not related to the type of chemotherapy. Among the 28 patients, 8 patients had no abnormalities on PLB. In 7 of them, surgical specimen analysis was considered normal. Conclusions: The accuracy of PLB in predicting chemotherapy- induced liver injury appears to be low. It is useful, however, given its high specificity when the PBL is normal, for encouraging hepatic resection without delay. No significant financial relationships to disclose.
Use of co-expression of HGF and c-Met to predict peritoneal dissemination established by autocrine HGF/c-Met signaling in gastric cancer.
Authors: Toiyama Y. , Tanaka K. , Yasuda H. , Saigusa S. , Fujikawa H. , Mohri Y. , Inoue Y. , Miki C. , Tabata T. , Kusunoki M. 
Published: February 2017

40 Background: Epithelial mesencymal transition (EMT) promotes facilitates migration and invasion of epithelial tumour cells. EMT is induced by growth factors implicated in theses process such as hepatocyte growth factor (HGF). Our aim of this study is whether HGF/c-Met pathway is associated with metastasis of gastric cancer (GC), especially in peritoneal dissemination (PD). Methods: HGF and c-Met expression and EMT related molecules were evaluated using real-time PCR and immunohistochemistry in GC tissues. The role of HGF/c-Met pathway for EMT and anoikis was determined and c-Met TKI (SU11274) was tested for their ability to block HGF-induced biological effects in vitro and vivo. Results: In HGF(-)c-Met(+) GC cells,recombinant HGF promoted EMT phenotype characterized by morphology, impaired E-cadherin and induction of Vimentin. HGF promoted cell growth, invasiveness, migration ability and inhibition of anoikis. SU11274 blocked HGF-induced EMT and the biological effects in vitro. In contrast of HGF(+)c-Met(+) GC cells, HGF exposure was not affected biological outcome of EMT and anoikis but SU11274 blocked biological effect as same as in HGF(-)c-Met(+) GC cells. In vivo, HGF(+)c-Met(+) GC cell line only established PD and SU11274 intraperitoneally caused an inhibition of PD growth. Clinically, HGF expression was significantly positive correlated with c-Met expression in GC specimens. Increased HGF and c-Met demonstrated a significantly associated with poor prognosis and can predict PD, respectively. Furthermore, HGF was one of the independent factors for predicting PD. Immunohistochemical analysis showed HGF and c-Met were predominantly co-expressed in cancer cell of both primary GC and PD. Conclusions: We have demonstrated that HGF/c-Met pathway as an inducer of EMT and anoikis inhibition in GC cell. Co-expression of HGF and c-Met implicates its potential to promote PD in GC. Blocking the autocrine HGF/c-Met pathway may be clinically useful for the treatment of PD in GC. No significant financial relationships to disclose.
The role of HER-3 expression in the prediction of clinical outcome for advanced colorectal cancer patients receiving irinotecan/cetuximab.
Authors: Scartozzi M. , Mandolesi A. , Giampieri R. , Zaniboni A. , Galizia E. , Giustini L. , Silva R. R. , Berardi R. , Bearzi I. , Cascinu S. 
Published: February 2017

404 Background: Preclinical data suggested that in presence of HER3 altered activation colorectal cancer cells may escape anti-EGFR mediated cell death. HER3 overexpression may then represent a key factor for resistance to anti-EGFR antibodies in colorectal cancer. The aim of our analysis was to investigate a possible correlation between HER3 expression and clinical outcome in KRAS wild-type advanced colorectal cancer receiving cetuximab and irinotecan. Methods: We retrospectively analyzed immunoreactivity for HER3 in KRAS wild-type advanced colorectal cancer patients receiving irinotecan-cetuximab. Results: Eighty-four advanced KRAS wild- type colorectal cancer patients were available for HER3 analysis. Forty patients (48%) showed HER3 negative colorectal tumor, whereas the remaining 44 cases (52%) were deemed HER3 positive. In HER3 negative and HER3 positive tumors we observed a partial response in 17 (42%) and 8 (18%) patients respectively (p = 0.04). Progressive disease was obtained in 11 (35%) and 26 (53%) patients with respectively HER3 negative and positive tumor (p = 0.007). No differences were observed for stable disease. Median PFS was 6.3 months in patients showing HER3 negative tumors and 2.8 months for those who had HER3 overexpressing tumors (p < 0.0001). Median overall survival was 13.6 months in patients showing HER3 negative tumors and 10.5 months for those who had HER3-expressing tumors (p = 0.01). Conclusions: HER3 proved to be a predictive factor for clinical outcome in KRAS wild-type colorectal cancer patients treated with cetuximab. Combined HER3 and KRAS analysis may represent an effective strategy for a better selection of responding colorectal tumors. Furthermore besides identifying colorectal cancer patients refractory to EGFR directed treatment, HER3 overexpression may also represent a potential biological indicator for the development of a new class of antineoplastic agents in this setting. No significant financial relationships to disclose.
Association of circulating cytokine and angiogenic factors (CAFs) with outcomes to second-line FOLFOX plus bevacizumab or cediranib in metastatic colorectal cancer.
Authors: Kopetz S. , Tran H. T. , Cunningham D. , Mookerjee B. , Pike L. , Jurgensmeier J. , Heymach J. 
Published: February 2017

406 Background: Chemotherapy combined with inhibitors of VEGF signaling is associated with improved outcomes, but biomarkers of therapeutic benefit have been elusive. Cediranib (Ced) is an oral VEGFR tyrosine kinase inhibitor that has been investigated as a treatment for metastatic colorectal cancer (mCRC). Methods: 215 patients with progressive disease and no prior VEGF inhibitor therapy were enrolled in a randomized phase II study of FOLFOX + Ced 20mg/d, Ced 30mg/d or bevacizumab (Bev) 10mg/kg (Cunningham D, et al. J Clin Oncol 26: 2008 (May 20 suppl; abstr 4028). 36 CAFs were analyzed at 3 time points (baseline, wk 4, wk 8). Groups were dichotomized by median CAF value. Hazard ratios (HRs) were estimated from a Cox model with a single term. Results: Data were available for > 85% patients for each CAF. When pooled across all arms, several baseline CAFs including VEGF, interleukin (IL)-2Rα, IL-8 and PDGF were associated with improved PFS (Table). Low and high baseline CAF subgroups were evaluated for potential predictive CAFs. Pts with elevated baseline IL-8 did better with Ced 30mg/d than Bev (HR 0.6 for PFS, CI 0.3-1.0) while low IL-8 was associated with greater benefit from Bev than Ced (HR 2.1, CI 1.0 to 4.2). For Ced 20mg/d, PFS HRs were 0.9 (CI 0.5, 1.6) and 1.7 (CI 0.9, 3.2) for elevated and low baseline IL-8 respectively. Hepatocyte-growth factor (HGF) demonstrated a similar relationship, while a trend for the inverse association was seen with IP-10. Distinct patterns of cytokine modulation were seen between Ced and Bev during the 8 wks, including decreases of sVEGFR2, IL-13 and increases in osteopontin. Conclusions: Several potential prognostic factors for second-line mCRC therapy were identified including VEGF and IL-8. Further work in larger placebo-controlled studies is required to further evaluate predictive markers for VEGF signaling inhibitors. [Table: see text] [Table: see text]
Use of genetic variants in formyl peptide receptor 2 (FPR2) to predict tumor recurrence in stage II colon cancer.
Authors: Zhang W. , Labonte M. J. , Yang D. , Ning Y. , Gerger A. , Bohanes P. O. , Winder T. , El-Khoueiry A. B. , Iqbal S. , Lenz H. 
Published: February 2017

408 Background: The formyl peptide receptor (FPR) is a G-protein-coupled receptor (GPCR) that mediates chemotaxis of phagocytic leucocytes induced by bacterial and host-derived chemotactic peptides. Recent studies found that it is selectively expressed in highly malignant gliomas and contributes to tumor growth and angiogenesis by mediating tumor cell chemotaxis, proliferation and production of chemokines and VEGF. Previously we demonstrated that polymorphisms in the VEGF pathway predict tumor recurrence in adjuvant colon cancer. Here we tested the hypothesis that two genetic variants in the FPR2 gene (rs17834679 and rs17694990) may predict tumor recurrence in a cohort of adjuvant colon cancer patients. Methods: Between 1992 and 2007, blood samples were obtained from 234 adjuvant colon caner patients (109 with stage II and 125 with stage III) at the USC medical facilities. Genomic DNA was extracted from peripheral blood and two potentially functional genotypes (rs17834679 and rs17694990) within the FPR2 gene were determined utilizing the PCR-RFLP technique. The median follow-up was 4.4 years (range: 0.3- 16.8). Ninety of 234 patients (38.5%) developed tumor recurrence with a 3-year probability of 0.34 ± 0.05. Results: In multivariable Cox proportional hazards regression analysis, FPR2 polymorphism rs17834679 was significantly associated with time to tumor recurrence (TTR) in stage II colon cancer (adjusted P = 0.027). Patients with CC genotype were at greatest risk of developing tumor recurrence (adjusted hazard ratio [HR]: 2.819 [95%CI: 1.127-7.051]) compared to those with GC and GG genotypes. In the dominant inheritance model, patients with any G allele had longer TTR (16.8 years+, median was not reached) compared to those with CC genotype (median TTR 5.4 years [95%CI: 3.2-10.7]; p=0.007, log-rank test). There are no significantly associations between FPR2 polymorphisms and TTR in stage III colon cancer. Conclusions: Polymorphisms in the FPR2 gene may serve as molecular markers for tumor recurrence in stage II colon cancer, indicating that the analysis of genetic variants of FPR2 may help to identify patient subgroups at high risk for tumor recurrence. No significant financial relationships to disclose.
Phase II trial of sorafenib in esophageal (E) and gastroesophageal junction (GEJ) cancer: Response observed in adenocarcinoma.
Authors: Ilson D. , Janjigian Y. Y. , Shah M. A. , Tang L. H. , Kelsen D. P. , Campbell J. , Fuqua L. 
Published: February 2017

41 Background: Sorafenib is a tyrosine kinase inhibitor targeting VEGFr, PDGFr, Raf and other pathways. Encouraging response and survival were observed in a phase II trial combining sorafenib with chemotherapy in GE cancer (J Clin Oncol 27:2947;2010). We are studying single agent sorafenib in a phase II trial with the primary endpoint to assess progression free survival (PFS). Secondary endpoints include response and therapy tolerance. Methods: Patients (pts) with measurable metastatic E and GEJ cancer with no more than 3 prior chemotherapy regimens were treated with sorafenib 400 mg BID. CT scans were performed monthly for the first 2 months, then every 2 months. Results: Sixteen of 35 pts have been accrued and 14 are currently evaluable. 13 male, 3 female, median KPS 80%, age 58, GEJ 7, E 9, squamous 2, adenocarcinoma (AC)14. An ongoing complete response (11+ months) was observed in a pt with biopsy proven metastatic neck lymphadenopathy (E primary AC, recurrence after prior chemoradiotherapy and surgery). A second pt (GEJ AC) had protracted stable disease in bulky celiac node disease (15+ months). Grade 3 toxicity was limited to skin rash (1 pt), hand foot reaction (1 pt), and fatigue (1 pt). Only 3 of 14 pts (21%) had early disease progression at 2 months or less. Median PFS 4 mos, 4 patients (29%) continue on therapy for more than 7 months. The majority of tumors tested positive for phospho-erk by immunohistochemistry (11/14, 79%). Conclusions: The observation of a durable complete response and protracted stable disease to sorafenib in E cancer is remarkable. Further accrual continues to define PFS. Supported by a grant from Bayer. [Table: see text]
Expression of dUTP nucleotidohydrolase (dUTPase) and thymidylate synthase (TS) in stage III colon cancer patients treated with either bolus 5-FU or infusional 5-FU in the adjuvant setting: Results of a translational study of the PETACC-2 trial.
Authors: Stoehlmacher J. , Kohne C. , Mauer M. , Goekkurt E. , Lutz M. P. , Aust D. E. , Carrato A. , Bedenne L. , Popov I. , Ladner R. D. 
Published: February 2017

417 Background: Pts with stage III colon cancer have been treated with either infusional 5-FU or bolus 5- FU in the adjuvant setting (PETACC-2 trial). DUTPase and TS demonstrated potential as predictive markers for 5-FU efficacy in pts with advanced colorectal cancer. Here we aimed to explore whether TS or dUTPase protein levels may predict recurrence of disease for stage III colon pts treated with 5-FU. Methods: Tumor (T) blocks of 324 pts were analyzed for protein expression of dUTPase and TS. For analysis monoclonal antibodies DUT415 and TS106 were used. T were evaluated by two investigators as follows. Only nuclear staining for both, TS and dUTPase, was analyzed. If tumor cells (TC) showed a nuclear dUTPase expression in >10% of cells, the sample was scored positive. Positive nuclear staining for >20% of TC, when using the TS antibody, determined a positive sample. Results: Analysis for dUTPase was successful in 308 samples (95.1%, 308/324). 263 out of those 308 pts showed a positive dUTPase expression (85.3%). 297/324 samples (91.7%) could be evaluated for TS. In the TS group 62.3% (185/297) showed a positive expression for TS protein. In 281 cases analyses were successful for both TS and dUTPase. We observed a significant association between dUTPase and TS expression with a majotity of 71.4% (172/241) dUTPase positive T also being positive for TS as compared to 32.5% (13/40) of dUTPase negative T that showed positivity for TS protein expression (p< 0.0001). Of pts with dUTPase positive T 64.7% showed no recurrence of disease as compared to 44.7% of those with dUTPase negative T 5 years after completion of therapy (HR 0.61 [95% CI 0.36, 1.03], p=0.06). No associations between TS and DFS were observed. Both TS and dUTPase expression did not correlate with OS in this patient cohort. Conclusions: High TS protein levels appeared to be significantly correlated with high protein levels of dUTPase in stage III colon cancer pts. Neither dUTPase nor TS protein levels appeared to be significantly associated with DFS or OS of stage III colon cancer pts that received adjuvant chemotherapy with 5-FU. No significant financial relationships to disclose.
Evaluation of antiproliferative and apoptotic effects of the rational combination of the MEK1/2 inhibitor selumetinib (AZD6244) and inhibitors of the hedgehog pathway in colorectal cancer (CRC) cell lines.
Authors: Spreafico A. , Tentler J. J. , Tan A. , Pitts T. M. , Kachaeva M. I. , Selby H. M. , Eckhardt S. G. 
Published: February 2017

422 Background: The MAPK pathway is a crucial regulator of cell proliferation, survival, and resistance to apoptosis. Hyperactivation of this pathway due to mutations in KRAS have been reported in up to 50% of CRC cases. Clinical trials have shown that KRAS patients do not benefit from therapies targeting EGFR, highlighting the need for new therapeutic options. Utilizing differential gene array analyses, we have identified the hedgehog (HH) signaling pathway as a potential mediator of resistance to AZD6244. Based on these results, we tested the rational combination of selumetinib and the HH inhibitor, cyclopamine against human CRC cell lines. Methods: CRC cell lines were exposed to varying concentrations of selumetinib and cyclopamine. For AZD6244, cell lines with IC50≤ 0.1 μM were considered extremely sensitive (ES) and those with IC50≥ 1μM were deemed extremely resistant (ER). Four KRAS mutant cell lines (2ES, 2ER) were selected for combination studies. The antiproliferative effects were assessed using the sulforhodamine B (SRB) cell viability assay, and potential synergy was evaluated using the Chou and Talalay method. Apoptosis was analyzed using bioluminescent caspase 3/7 detection. Results: In all four cell lines tested, synergistic antiproliferative effects of selumetinib and cyclopamine were observed, including resistant lines to selumetinib. We observed significant induction of apoptosis when cell lines were exposed to the combination treatment, independent of their responsiveness to selumetinib in the SRB assay. Conclusions: Treatment of KRAS mutant CRC cell lines with selumetinib and cyclopamine resulted in synergistic inhibition of proliferation, regardless of sensitivity to selumetinib. Interestingly, a significant increase in apoptosis was observed in response to the combination, which may explain the synergy observed by the combination index (CI). In vivo analyses of this combination in cell lines and human CRC explants are ongoing to further validate these results. These preclinical data may suggest a rational combination strategy for patients with KRAS mutant CRC. No significant financial relationships to disclose.