bluuebunny/crossref_metadata_2025_split huggingface dataset:
TP53 mutations in irinotecan-refractory KRAS wt-BRAF wt metastatic colorectal cancer patients treated with cetuximab-based chemotherapy.
Authors: Di Fiore F. , Lamy A. , Blanchard F. , Oden-Gangloff A. , Sesboüé R. , Sabourin J. , Frébourg T. , Michel P. , Laurent-Puig P. 
Published: February 2017

426 Background: Anti-EGFR antibodies are more efficient when EGFR pathway is activated without mutations on downstream effectors such as KRAS and BRAF (Lievre et al. Cancer Res. 2008 and Khambata-Ford et al. J Clin Oncol. 2007). Moreover, tumor growth from EGFR activation may required inactivation of the molecular brake p53 suggesting that anti-EGFR therapy should be more efficient if p53 is inactivated (Oden-Gangloff et al. Br J Cancer. 2008). The aim of the study was to evaluate, in an independent series, the impact of p53 mutations in irinotecan-refractory KRAS wt-BRAF wt MCRC patients treated with anti- EGFR. Methods: A total of 100 MCRC patients treated with cetuximab-based CT were included. KRAS and BRAF mutational status were determined using SNaPshot or allelic discrimination methods. TP53 mutations within exons 5 to 8 were detected using direct sequencing. Response to cetuximab, based on RECIST criteria, was evaluated according to molecular analysis using the Fischer exact test. Progression- free survivals (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method and compared with log-rank test. Results: Objective response (OR = partial and complete response) was observed in 40% and control disease (CD = OR+stable disease) in 74% of patients. Median PFS and OS was 12 weeks and 12 months, respectively. TP53 mutations were detected in 66% of patients and were not significantly associated with OR and CD. In contrast, patients with KRAS wt-BRAF wt and TP53 mutation had significantly longer PFS as compared to KRAS wt–BRAF wt and TP53 non mutated patients (32 weeks vs. 21 weeks, respectively; p = 0.01). There was a trend but not significant increased OS in patients with TP53 mutations (16 months vs. 13 months) Conclusions: In this independent study, our results confirm that TP53 mutation was significantly associated with an increase PFS in irinotecan-refrcatory KRAS wt-BRAF wt MCRC patients treated with anti-EGFR. [Table: see text]
Use of circulating endothelial cells to predict response to FOLFOX4 plus bevacizumab in metastatic colorectal cancer.
Authors: Matsusaka S. , Mizunuma N. , Suenaga M. , Chin K. , Shinozaki E. , Watanabe T. , Kawazoe Y. , Kuboki Y. , Terui Y. , Hatake K. 
Published: February 2017

427 Background: The purpose of this study was to identify CEC threshold proposal for determining response to FOLFOX4 plus bevacizumab in metastatic colorectal cancer (mCRC). Methods: All patients were enrolled using institutional review board-approved protocols at the Cancer Institute Hospital and provided informed consent. From July 2007 to June 2008, 33 patients treated with FOLFOX4 plus bevacizumab were enrolled in a prospective study. From January 2007 to June 2007, before bevacizumab was approved by the government in Japan, 31 patients treated with FOLFOX4 as a control were enrolled. The study population consisted of patients aged 18 years or older with histologically proven mCRC. Other inclusion criteria were Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, adequate organ function. CECs of whole blood at the baseline, day 4, 2 weeks after initiation of chemotherapy were isolated and counted using immunomagnetics. Results: There was no correlation between CEC levels and the outcome in the FOLFOX4. In the FOLFOX4 plus bevacizumab, CEC levels at the baseline were significantly associated with the outcome. Patients with 65 or more CECs at the baseline had shorter median PFS (9.2 months), than the median PFS of fewer than 65 CECs at the baseline (18.9 months) in the FOLFOX4 plus bevacizumab (p = 0.003). Patients with 65 or more CECs at the baseline had shorter median OS (23.3 months), than the median OS of fewer than 65 CEC s at the baseline in the FOLFOX4 plus bevacizumab (p = 0.027). In the univariate analysis, lung metastasis, lymph node metastasis, and CEC levels at the baseline predicted PFS. In the univariate Cox regression analyses, peritoneal metastasis, CEC levels at the baseline were associated with OS. In order to evaluate the independent predictive effect of FOLFOX4 plus bevacizumab, multivariate Cox regression analysis was carried out. CEC levels at the baseline were the strongest predictor. Conclusions: A threshold of lower than 65 CEC/4mL at the baseline was a significant predictor of the outcome for colorectal cancer patients treated with FOLFOX4 plus bevacizumab. No significant financial relationships to disclose.
Effect of miR-21 on resistance to 5-fluorouracil and regulation of MSH2.
Authors: Valeri N. , Gasparini P. , Braconi C. , Lovat F. , Paone A. , Fabbri M. , Nuovo G. , Fishel R. , Croce C. M. 
Published: February 2017

431 Background: MicroRNAs are small non coding RNAs controlling cell homeostasis. Defects in mismatch repair (MMR) genes cause resistance to 5-fluorouracil (5FU). miR-21 is up-regulated in colorectal cancer (CRC) and is associated with poor benefit from adjuvant 5FU. We aimed at studying if miR-21 may induce 5FU resistance by down-regulating MSH2. Methods: Fresh frozen (32) and paraffin-embedded (50) cases of CRC and matched normal tissues were studied for miR-21 expression (Northern Blotting and in situ Hybridization) and MSH2 expression (Western Blotting and Immunohistochemistry). CRC Colo-320DM, SW620 and isogenic Lovo cells with [Lovo(MSH2+)] and without MSH2 [Lovo(MSH2-)] were used. Pre-miR-21 was used for over-expression experiments. Luciferase vectors with MSH2 (Luc-MSH2) and MSH6 (Luc-MSH6) 3'UTRs downstream of the Luciferase gene were used. Cell cycle modifications after 5FU (10uM) were assessed by FACS analysis. Lentiviral vectors encoding for miR-21 or siRNA to MSH2 or empty vectors were used for stable infection. Stable clones were injected in the flank of nude mice. Mice were treated with 5FU i.p. for 2 weeks. Tumor volume was measured once a week and calculated according to the formula Volume=LxW2/2. Results: A statistically significant inverse correlation between miR-21 and MSH2 expression was observed by Parson's test in the two CRC cohorts. miR-21 over-expression caused reduction in MSH2 and MSH6 protein expression and in Luciferase activity after transfection with Luc-MSH2 or Luc-MSH6 vectors confirming that miR-21 directly regulates MSH2 and MSH6. miR-21 up-regulation reduced 5FU induced apoptosis and G2/M arrest at the same extent of siRNA to MSH2 in all MMR proficient cells while no significant effect was observed in Lovo(MSH2-). Complementation experiments with plasmid encoding for MSH2 promoted 5FU induced apoptosis that was inhibited by co-transfection with miR-21. Xenograft tumors over-expressing miR-21 or siRNA anti MSH2 achieved the same response to 5FU and both showed to be less responsive to 5FU than controls. Conclusions: miR-21 causes resistance to 5FU in a MSH2 dependent manner and might be a useful marker in predicting therapeutic outcome in CRC patients. No significant financial relationships to disclose.
Identification of unique gene expression signatures in colon cancer stroma using microarray technology.
Authors: Wang S. X. , Wang J. , Ozhegov E. , Srinivasan R. , Olowokure O. O. , Qu A. X. , Aronow B. , Bogdanov V. 
Published: February 2017

447 Background: Microarrays are widely used to study gene expression patterns in cancer. In colorectal cancer, it has proven useful to predict recurrence. The majority of expression profiles are generated from the cancer itself. Given the increasing evidence of importance of the microenvironment for tumor invasion, progression and metastasis, we explored tumor stroma gene signature using microarrays. Methods: Four formalin-fixed paraffin embedded (FFPE) colon cancer specimen carrying a pathological stage of T3-4/N0-2 were retrieved. Tumor stroma and normal stroma were separated using microdissection technology. Random sampling was used to minimize sampling bias. Total RNA was extracted, amplified, and labeled using Nugene FFPE kit, with array analysis using Affymetrix Human Gene 1.0. Eight samples, four normal stroma and four tumor stroma, were analyzed and compared. Array data were balanced and analyzed using standard software. To identify gene signature differences in tumor vs normal stroma, ComparativeMarker analysis and unsupervised cluster analysis were carried out. Results: We identified a 969 Affymetrix probe set as a signature that is highly expressed in tumor stroma. The top 117 genes were further analyzed to carry out a pathway analysis. We found a strong signature evident in tumor stroma, and much of this signature comprised the genes of the extracellular matrix. The pathway analysis revealed evidence of the generalized IGF1/TGFbeta/CTGF/activin mediated effect on the stroma, raising the possibility that some of this derives from, or is accompanied by, angiotensin receptor signaling. Through literature search, we found that several upregulated genes (e.g., FAP) were reported to be associated with stroma activation in vitro and in vivo. Conclusions: In this study, we successfully applied microarrays to study reactive colon tumor stroma in FFPE samples. We identified a specific gene signature reflecting stromal reaction to tumor invasion. We further identified the potential pathway that was activated in the reactive tumor stroma. We provide evidence that microarrays are useful in stroma analysis and may help identify new stromal pathways with potential diagnostic and therapeutic value. No significant financial relationships to disclose.
Can molecular markers help predict outcome in pseudomyxoma peritonei?
Authors: Beg M. S. , Wang J. , Ahmad S. A. , Wang X. , Olowokure O. O. 
Published: February 2017

455 Background: Pseudomyxoma peritonei (PMP) is a rare malignancy characterized by mucinous ascites and peritoneal tumors. Cytoreductive surgery (CRS) with or without intraperitoneal hyperthermic perfusion (IPHP) is considered the mainstay of therapy, but prognosis is variable. Due to its rarity, data on molecular phenotype is lacking and the impact on outcome is unknown. The goal of our study is to correlate molecular markers with outcome in PMP. Methods: A retrospective analysis of cases treated at the University of Cincinnati was performed and tumors analyzed. Medical records were reviewed for clinical, demographic and outcome data. Immunohistochemical studies were performed on formalin fixed paraffin embedded tissue using antibodies to Ki-67, cyclin D, and EGFR. Tumor cells were microdissected from H&E stained sections using laser capture microdissection and DNA was extracted. Exon 1 of K-ras gene was amplified by PCR and then directly sequenced. Data were analyzed using SPSS. Results: Of 22 patients (pts) included in this study 16 (73%) had an appendix primary and 6 (27%) colon. There were 12 females (55%) and 20 (90%) pts were white. Mean age was 53 (29-74) years. Most pts had prior surgery (18, 82%). Complete resection (>99% of visible disease) was achieved in 15 (68%) pts while 17 pts (77%) underwent IPHP. Nine pts had known recurrence (41%) and median time to recurrence (TTR) was 21(+/- 0.398) months (mo). There was one confirmed death and median survival could not be calculated. K-ras mutation was seen in 13 (60%), cyclin-D1 in 9 (41%) and EGFR in 10 (45%) cases. High Ki-67 (>51%) was seen in 8 cases. On univariate analysis median TTR was 15 and 43 mo for pts with high and low Ki-67 (p=0.1); 21 and 43 mo for K-ras positive and negative mutation (p=0.16), 43 and 15 mo for EGFR positive and negative tumors (p=0.6). TTR was 21 mo for cyclin D1 positive as well as negative. Conclusions: Pts with PMP who have undergone CRS and IPHP can have prolonged survival but relapses are common. Our study highlights the possible role of molecular markers such as EGFR and K-ras in tumorigenesis. A potential role in prognosis is being validated in a larger study. Future treatment strategies should incorporate molecular testing to enhance our understanding of PMP. No significant financial relationships to disclose.
Systemic inflammatory response in predicting survival in patients with operable colorectal cancer.
Authors: Kwon K. A. , Oh S. , Kim S. , Lee S. , Han J. , Choi H. , Park K. , Roh M. , Kim H. , Kwon H. 
Published: February 2017

456 Background: Several inflammatory response materials could be biomarkers for prediction of prognosis of cancer patients; elevated C-reactive protein (CRP), increased white cell, neutrophil, platelet, and decreased albumin. The Glasgow Prognostic Score (GPS) combines circulating CRP and albumin level, the neutrophil/lymphocyte ratio (NLR), and the platelet/lymphocyte ratio (PLR) has been introduced for prognostic scoring system in colorectal cancer (CRC). Thus, in this study, we attempted to identify an more adequate prognostic model related with systemic inflammatory response for CRC. Methods: Between Mar 2005 and Dec 2008, 200 patients who underwent curative resection for colorectal cancer were enrolled in this study. Systemic inflammatory parameters (CRP, albumin, neutrophil, lymphocyte, and platelet count) were checked for making 3 scoring systems. Based on clinical survival data, we then compared PFS and OS with GPS, NLR, and PLR. Results: Male to female were 123:77. Median age of the patients was 64 years (range, 26-83 years). Median follow-up duration was 27.2 months (range 7.8-52.7 months). 36 patients were observed disease progression or death. 19 patients were passed away during follow-up duration. 3 year PFS and OS were 72% and 86%, respectively. Numbers of GPS 0,1, and 2 patients were 154 (77%), 44 (22%), and 2 (1%), respectively. Survival analysis according to GPS, PFS and OS could not be able to show the prognostic significance (P=0.313 and P=263). Cut-off value of NLR and PLR were determined 3 and 180 by ROC curve. Both of NLR and PLR were observed as a good prognostic biomarker of PFS and OS (P=0.009 and P<0.001 in PFS, P=0.006 and P=0.001 in OS). Conclusions: Although GPS, NLR, and PLR were introduced as prognostic scoring systems for operable CRC, PLR which is constructed of platelet/lymphocyte count may represent a useful prognostic index for the prediction of PFS and OS in operable CRC. No significant financial relationships to disclose.
Role of matrix metalloproteinase-8 in the modulation of systemic 5-fluorouracil pharmacokinetics by local irradiation.
Authors: Hsieh C. , Liu C. , Hsieh Y. , Tai H. , Wang L. , Tsai T. , Chen Y. 
Published: February 2017

466 Background: Concurrent chemoradiation with 5-fluorouracil (5-FU) is widely accepted for cancer treatment. However, the interactions between radiation and 5-FU remain unclear. We evaluated the influence of local irradiation on the pharmacokinetics of 5-FU in rats. Methods: The single-fraction radiation was delivered to the whole pelvic fields of Sprague-Dawley rats from a linear accelerator after computerized tomography-based planning. 5-FU at 100 mg/kg was intravenously infused 24 hours after radiation. A high-performance liquid chromatography system equipped with a UV detector was used to measure 5-FU in the blood. Matrix metalloproteinase-8 (MMP-8) inhibitor I was administered to the rats to examine whether or not RT modulation of 5-FU pharmacokinetic parameters could be blocked. Results: Compared with sham-irradiated controls, whole pelvic irradiation reduced the area under the concentration versus time curve (AUC) of 5-FU in plasma and, in contrast, increased the AUC in bile in a radiation dose-dependent manner. Based on protein array analysis, the amount of plasma MMP-8 was increased by whole pelvic irradiation (2.8-fold by 0.5 Gy and 5.3-fold by 2 Gy) in comparison with controls. Pretreatment with MMP-8 inhibitor reversed the effect of irradiation on AUC of 5-FU in plasma. Conclusions: Local irradiation may modulate the systemic pharmacokinetics of 5-FU through stimulating the release of MMP-8. This unexpected influence is worthy of further investigation and for consideration in clinical practice of radiotherapy for cancer. No significant financial relationships to disclose.
Patient-reported toxicity after colorectal cancer (CRC) treatment.
Authors: Hill-Kayser C. E. , Vachani C. , Hampshire M. K. , Di Lullo G. A. , Metz J. M. 
Published: February 2017

484 Background: Colorectal cancer patients may be at risk for myriad late effects after multimodality therapy, the impact of which may difficult to evaluate using conventional methods. This Internet-based study evaluates patient perceptions of toxicity after treatment for CRC. Methods: Patient-reported data was gathered via a convenience sample frame from CRC survivors voluntarily utilizing a publically available, free, Internet-based tool for creation of survivorship care plans. Available at www.livestrongcareplan.com and through the OncoLink website, the tool allows survivors to enter data regarding diagnosis, demographics, and treatments, and provides customized guidelines for future care. During use of the tool, CRC survivors are queried regarding late effects associated with specific treatments, and asked to answer “yes,” “no,” or “I don't know.” They are also asked to score GI toxicity using WHO criteria. All data have been maintained with IRB approval. Results: 148 CRC survivors answered queries regarding late effects; 64% were female and 82% Caucasian. Median diagnosis age was 50 (24-76) and median current age 54 (24-77). Most reported having had multimodality therapy - 97% surgery, 89% chemotherapy, and 37% radiation. When queried regarding GI toxicity, 51% reported chronic changes in bowel patterns, 34% chronic diarrhea, 12% bowel obstruction, 18% hernia development, 8% radiation colitis, and 2% fistula formation. Of 18 survivors who graded GI toxicity, 27% reported 4-6 stools per day, and 22% > 6 stools per day or incontinence. When queried regarding sexual function, 31% of men reported worse erectile function than pre-treatment, and 39% of women reported sexual changes such as vaginal dryness. Perceived cognitive decline since diagnosis of cancer was reported by 57%. Conclusions: Survivors using this tool anonymously and voluntarily report significant GI toxicity after cancer treatment. Approximately 1/3 of male and female survivors report impact on sexual function, and more than 50% report perceived cognitive decline. This tool offers a unique way for survivors to report their experiences; the data reported here may be of significant impact in future study of quality of life, as well as patient counseling and survivor care. No significant financial relationships to disclose.
Analysis of oxaliplatin-induced sensory neurotoxicity (sNT) in patients receiving FIREFOX, alternating regimen of mFOLFOX-6 and FOLFIRI, with metastatic colorectal cancer (MCRC): Results from combined analysis of KSCC0501 and KSCC0701.
Authors: Kusumoto T. , Emi Y. , Kakeji Y. , Akagi Y. , Samura H. , Baba H. , Natsugoe S. , Tokunaga S. , Maehara Y. ,   Kyushu Study Group of Clinical Cancer (KSCC)
Published: February 2017

492 Background: The Kyushu Study Group of Clinical Cancer (KSCC) conducted two phase II trials (KSCC0501 and KSCC0701, Akagi et al. J Clin Oncol. 28:15s, 2010, UMIN ID: 000001342) to evaluate the efficacy and safety of first-line oxaliplatin-based chemotherapy for MCRC. This combined analysis was performed to compare the incidence of oxaliplatin-induced sNT between the two trials. Methods: Patients (pts) were accrued from 2005 to 2007 in KSCC0501 and from 2007 to 2008 in KSCC0701. Sixty pts received FOLFOX-4 in KSCC0501 and 47 pts received FIREFOX(4 cycles of mFOLFOX-6 alternating with 4 cycles of FOLFIRI) in KSCC0701. All pts were reviewed for efficacy and toxicity (NCI-CTCAEv3.0). Kaplan-Meier analysis was performed to assess the incidence of sNT. Results: The incidence of sNT was 71.4% with FOLFOX-4 and 36.2% with FIREFOX (Table). The ORR was 34.5% (95% CI F22.5-48.1%) for FOLFOX4 and 58.7% (43.9-73.5%) for FIREFOX. Median PFS was 7.0 M (5.1-9.8 M) with FOLFOX-4 and 10.3 M (7.5-11.9 M) with FIREFOX. MST and 2-year survival were respectively 31.5 M (18.1-40.1 M) and 58.0% for FOLFOX4, versus not determined and 57.1% for FIREFOX. The median no. of treatment cycles was 9 for FOLFOX-4 and 12 for FIREFOX. After 4, 8, and 12 cumulative treatment cycles, the incidence of grade 2+sNT was respectively 24.0%, 30.7%, and 60.5% with FOLFOX-4 versus 6.5%, 6.5%, and 16.0% with FIREFOX. Conclusions: As first-line oxaliplatin-based chemotherapy for MCRC, FIREFOX caused less oxaliplatin-induced sNT and prolonged the duration of treatment. We have now finished enrollment for study KSCC 0801 (KSCC 0701+bevacizumab) and are following the pts. [Table: see text] [Table: see text]
A randomized pilot study comparing safety and efficacy of irinotecan plus S-1 (IRIS) plus bevacizumab (BV) and modified (m) FOLFIRI plus BV in patients (pts) with metastatic colorectal cancer (mCRC): First report of T-CORE0702.
Authors: Kato S. , Andoh H. , Gamoh M. , Yamaguchi T. , Murakawa Y. , Sasaki Y. , Takahashi S. , Shimodaira H. , Yoshioka T. , Ishioka C. ,   Tohoku Clinical Oncology Research and Education Society (T-CORE)
Published: February 2017

496 Background: Sequential combination with irinotecan (CPT-11) and S-1 (IRIS) is active and safe regimen against mCRC (ASCO2008, abstract #4107, T. Yoshioka et al. Br J Cancer 101: 1972-77, 2009). The aim of this prospective randomized pilot study was to compare safety (CTCAE v3.0, primary endpoint) and efficacy (RR and PFS, secondary endpoint) of IRIS with mFOLFIRI when these were used with BV. Methods: Sixty pts with mCRC were randomized to compare 30 pts for IRIS+BV (CPT-11 150 mg/m2 infusion on day 1, S-1 80 mg/m2 orally on day 3-16, q3w) with 30 pts for mFOLFIRI+BV (CPT-11 150mg/m2). 57 pts (IRIS arm 29, mFOLFIRI arm 28) were evaluable. Most of them were treated as first-line therapy. Results: Background of pts was well balanced among two arms. Although G3/4 hematological AEs profiles were similar between two arms, G2-4 neutropenia was significantly lower in IRIS arm than mFOLFIRI arm (56.6%, vs. 88.9%, p=0.01, χ2test). Among G3/4 nonhematological AEs, gastrointestinal toxicities were lower in IRIS arm than mFOLFIRI arm (anorexia: 3.5% vs. 17.9%, nausea: 0% vs. 7.1%, diarrhea: 6.9% vs. 14.3%, stomatitis: 0% vs. 3.6%). By χ2 test, nausea, vomiting and hair loss were significantly lower in IRIS arm than mFOLFIRI arm (p<0.05). GI-perforation, a BV-related severe AE, occurred in 2 pts only from mFOLFIRI arm and one of them was died as TRD. RRs (institutional evaluation) were 58.6% in IRIS (CR 2, PR 15, SD 11, and PD 1) and 55.1% in mFOLFIRI arm (CR 0, PR 16, SD 10, PD 2, and not evaluable 1). Our independent review committee will clarified definite RR and median PFS near future. Conclusions: Our IRIS+BV regimen is well tolerated, effective and appears to be a promising choice for pts with mCRC. [Table: see text]