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

463 Background: The management of metastatic colorectal cancer (mCRC) has evolved considerably with advances in chemotherapeutic agents that have led to improved outcomes. Less is known about the benefits of newer agents in the real-world setting. The objective of this study was to evaluate treatment patterns and survival in older, demographically diverse mCRC patients. Methods: Using the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database, we conducted a retrospective cohort analysis of 5931 stage IIIB, IIIC and IV CRC patients diagnosed between 1/1/ 2000 – 12/31/2007, who were >66 years, enrolled in Medicare Parts A and B, and received first-line treatment with 5FU/LV (n=2907), CAP (capecitabine; n=963), FOLFOX (n=1856) or CAPOX (CAP + oxaliplatin; n=205). Date of last follow-up was 12/31/2009. Statistical comparisons were made between 5FU/LV vs. CAP and FOLFOX vs. CAPOX. Cox regression with backward elimination estimated the relative risk of death, adjusting for demographic and clinical factors. Results: Compared to 5FU/LV, patients treated with CAP were older (>80 years) at diagnosis (36% vs. 22%; p<.0001) and more likely female (59% vs. 53%; p=.0025), while patients receiving CAPOX were older (>80 years: 12% vs 8%; p<0.05) compared to FOLFOX. The mean time to chemotherapy initiation after diagnosis was similar between CAP and 5FU/LV (76 vs. 71 days) and between FOLFOX and CAPOX (75 vs. 70 days). The mean duration of treatment was longer for 5FU/LV (144 days) vs. CAP (122 days; p<.0001) and comparable between CAPOX (144 days) and FOLFOX (150 days; p=0.2139). The incidence of adverse events (AE) within 180 days after initiation of treatment were higher in patients treated with 5FU/LV (37%) vs. CAP (9%); p<.0001 and in FOLFOX (58%) vs. CAPOX (44%); p<0.0001. In multivariate analysis there were no significant differences in risk of death between CAP and 5FU/LV, and between CAPOX and FOLFOX ( table ). Conclusions: Overall survival was comparable between CAP and 5FU/LV and between CAPOX and FOLFOX with fewer AEs associated with CAP and CAPOX. This provides real-world confirmation of clinical trial data. [Table: see text]
TOP1 gene copy number in stage III colorectal cancer (CRC) samples: Association to prognosis.
Authors: Nygaard Sune Boris , Rømer Maria Unni , Christensen Ib Jarle , Nielsen Signe Lykke , Smith David Hersi , Nielsen Kirsten Vang , Müller Sven , Vainer Ben , Nielsen Hans J. , Brünner Nils 
Published: February 2017

475 Background: TOP1 inhibitor treatment is frequently being used in combination therapy of metastatic CRC. This study aims to reveal whether TOP1 gene copy number associates with patient prognosis, since such a relationship may have significant implications for future studies aiming at validating the predictive value of TOP1 gene copy number. Methods: The study included TOP1 and CEN-20 FISH analyses (DAKO A/S Denmark) on FFPE tissue sections from 154 stage III CRC patients who did not receive adjuvant chemotherapy. TOP1 gene copy number, CEN-20 copy number and the TOP1/CEN-20 ratios were analyzed and correlated to overall survival (OS), to time to recurrence (TTR) of patients with CRC and to local recurrence (LR) in patients with rectal cancer (RC). Results: TOP1 copy number counts and the TOP1/CEN-20 ratios, age, gender and primary tumor location were separately added into a multivariate analysis as continuous variables. For OS and LR, TOP1 copy number was significant and the ratio was borderline significant with higher copy number associated with longer OS or longer time to LR. When the patients were dichotomized using the TOP1 median copy number, we found that patients with high TOP1 copy number in their tumor cells had a significant longer OS (HR: 0.68; 95% CI: 0.47-0.98; p = 0.04) compared to patients with low TOP1 copy number. Using the median TOP1/CEN-20 ratio to dichotomize, no significant differences were observed between patients with levels above or below the median ratio number for OS (HR: 0.76; 95% CI: 0.53-1.10; p = 0.14). TOP1 copy number divided the RC patients into two groups with a trend towards a significant difference in time to LR (HR: 0.56; 95% CI: 0.27-1.16; p = 0.11) with higher copy number. If the median ratio was used, a significant association with longer time to LR (HR: 0.43; 95% CI: 0.20-0.92; p = 0.03) was found. No significant associations between TOP1 copy number or ratio and TTR were observed. Conclusions: Increased TOP1 copy number is associated with longer OS in CRC patients and fewer LR in RC patients. Thus, future studies analyzing the association between TOP1 copy number and response to therapy in CRC patients should be planned in such a way that a prognostic and a predictive value of TOP1 can be separated.
A novel and simple KRAS mutation detection method, FRET-Based Preferential Homoduplex Formation Assay (f-PHFA): Results from a multicenter, clinical evaluation trial.
Authors: Yamaguchi Kensei , Akagi Kiwamu , Kakuta Miho , Kurosumi Masafumi , Nishimura Yoji , Saito Norio , Kojima Motohiro , Ochiai Atsushi , Ohtsu Atsushi , Yoshino Takayuki 
Published: February 2017

476 Background: KRAS gene mutation in colorectal tumors is predictive of nonresponse to anti-epidermal growth factor receptor (EGFR) antibodies in patients with metastatic colorectal cancer (CRC). The F-PHFA has been developed as a simple and accurate mutation detection assay especially for somatic mutations. In this study, we evaluated KRAS mutation detection by F-PHFA which detects 7 common mutations in codon 12 and 13. This study was a multicenter, clinical evaluation trial designed to evaluate the efficacy of the F-PHFA method forKRAS testing in patients with CRC. Primary endpoint was the concordance rate of KRAS mutation between F-PHFA and direct sequencing with manual micro-dissection (MMD) to enrich the tumor concentration. Secondary endpoints included the concordance rate between F-PHFA and direct sequencing without MMD. Methods: The key eligibility criteria included histologically confirmed colorectal adenocarcinoma with adequate tumor samples. The materials were formalin-fixed paraffin-embedded (FFPE) 8 unstained slides at 10 um and 2 matching hematoxylin-eosin (HE)-stained slide, which were sent to the central pathology review to confirm the tumor content and to mark the tumor area. Genomic DNA was extracted using QIAamp DNA FFPE Tissue from both whole tissue of slide and tissue with MMD. F-PHFA and direct sequencing were conducted independently in two laboratories. Results: FFPE specimens from 165 patients with colorectal adenocaricinoma were registered. Success rates on KRAS tests of F-PHFA both of with or without MMD were 100% (165/165). However, those of direct sequencing were 99.4% (164/165). The concordance rate between F-PHFA and direct sequencing were 99.4% (163/164) for both of with MMD and without MMD. Only one discordant sample had a rare mutation other than the 7 common mutations. Total assay time was about 3.5 hrs. Also 20 ng of DNA was enough to examine 7 types of KRAS mutations. Conclusions: We confirmed that F-PHFA and direct sequencing shows high concordance rate regardless of MMD. F-PHFA for KRAS mutation detection method is very suitable for clinical use in terms of easiness and accuracy.
Effect of stents on radiation dosimetry for esophageal cancer.
Authors: Francis Samual Roberts , Anker Christopher James , Wang Brian , Williams Greg V. , Adler Douglas G. , Salter Bill J. 
Published: February 2017

48 Background: To evaluate how self-expanding metal stents (SEMS) affect esophageal cancer radiation planning target volumes (PTVs) and dose delivered to surrounding organs-at-risk (OARs). Methods: Ten patients were evaluated for whom a SEMS was placed before radiation. A CT scan obtained before stent placement was fused to the post-stent CT simulation scan. Three methods were used to represent pre-stent PTVs: 1) Image Fusion (IF) - PTVs were contoured based on the pre-stent CT, 2) Volume Approximation (VA) - the post-stent PTV was altered to approximate the pre-stent PTV based on differences in esophageal volumes between scans, and 3) Diameter Approximation (DA) - the post-stent PTV was altered based on differences in esophageal diameters. PTVs and OARs were contoured per RTOG 1010 protocol using Eclipse Treatment Planning software. Post-stent dosimetry for each patient was compared to approximated pre-stent dosimetry. Results: For the IF, VA, and DA methods, the post-stent PTVs were larger than pre-stent PTVs by an average of 155, 68, and 67 cm3, respectively. Pre-stent heart and lung doses were less than post-stent using VA and DA; however, IF only yielded a significantly lower heart V40 (Table). Liver, spinal cord, and kidney doses were not significantly different between planning methods. Conclusions: Placement of an esophageal SEMS increased the PTV size for radiation planning, causing a statistically significant increase in heart and lung radiation doses, although the absolute dose increase was relatively small. Most patients receiving stents will have no increased risk of radiation-induced toxicity. In patients where one anticipates difficulty meeting crucial dose constraints, it may be preferable to consider avoidance of stenting before radiotherapy. [Table: see text]
Use of colorectal cancer subtypes identified through iterative clustering to predict response to therapy.
Authors: Schlicker Andreas , Beran Garry , Chresta Christine M , McWalter Gael , Pritchard Alison , Weston Susie , Runswick Sarah , Davenport Sara , Heathcote Kerry , Alferez Castro Denis , Orphanides George , French Tim , Wessels Lodewyk F A 
Published: February 2017

482 Background: Colorectal cancer (CRC) is generally stratified based on genetic and epigenetic features, such as KRAS mutation and microsatellite instability status. In order to facilitate the development of new targeted drugs and treatment regimens, it is important to redefine CRC at the molecular level by identifying subtypes that are relevant for response to targeted therapy. Methods: We applied a new unsupervised approach for iteratively stratifying tumor samples using genome-wide mRNA expression data. The resulting gene expression signatures were used to subtype CRC cell line panels and publicly available CRC tumor datasets. We employed pharmacological data on the cell line panels to link the subtypes to therapy response. Results: Starting from a gene expression dataset of 63 CRC tumor samples, we employed non-negative matrix factorization (NMF) and identified two dominant CRC subtypes. In agreement with previously published results, one of the types showed a mesenchymal and the other an epithelial-like gene expression pattern. In a second step, we applied NMF on these two dominant subtypes and further stratified them into two and three subtypes, respectively. The resulting five CRC subtypes show many differences, most notably activation of specific signaling pathways. Importantly, we recovered these five subtypes in several independent, publicly available CRC datasets. This strongly suggests that the signatures capture disease-relevant features of CRC. Furthermore, we found that the different subtypes corresponded to different cell lines in a panel of CRC cell lines. The clustered CRC cell lines displayed differential responses to a number of targeted compounds, indicating that the new CRC clusters may represent disease subtypes that of differential drug sensitivity. Conclusions: The CRC subtypes discovered using our new method offer new insights into the functional and molecular processes driving CRC. Furthermore, the evidence suggests that these subtypes may differ in activated pathway status and the response to some targeted inhibitors, indicating that targeting pathways conserved in these subtypes may provide new drug discovery opportunities.
Characterization of serum proteome in patients with metastatic colorectal cancer responsive and nonresponsive to bevacizumab using 2 d-DIGE.
Authors: Martin Petra , Noonan Sinead , Nolan Blathnaid , Scaife Caitriona , Elia Giuliano , O'Donoghue Diarmuid , Fennelly David William , O'Sullivan Jacintha 
Published: February 2017

484 Background: Treatment of patients with metastatic colorectal cancer includes chemotherapy and a monoclonal antibody (cetuximab or bevacizumab). Patients who have k-ras mutated tumors are given bevacizumab. However, no biomarker exists to determine those patients who will respond to this targeted treatment. The objective of this study was to investigate the differential protein expression between patients who do and do not respond to bevacizumab and also compare this with normal controls. Methods: Serum from 24 patients diagnosed with metastatic colorectal cancer and 11 normal controls were collected pre-treatment. All patients received bevacizumab along with chemotherapy. Progression free and overall survival data was collected on all patients. Serum was depleted of high abundant proteins and protein expression analysed using fluorescence two-dimensional differential in-gel electrophoresis (2 D-DIGE). Gels were scanned using a Typhoon 9410 Variable Mode Imager (GE Healthcare) and exported into Progenesis SameSpots v3.3 (Nonlinear Dynamics, UK) for quantitative analysis. Selected differentially expressed were excised, digested with trypsin and analysed using the LTQ-Orbitrap XL mass spectrometer. Results: 66 proteins were identified to be statistically expressed between the responders and non-responding group (p<0.05). 30 proteins were differentially expressed between the cancer and normal group (p<0.05). Conclusions: There is a significant difference in protein expression patterns between responders and non responders to bevacizumab. Further screening required to assess for instability proteins that may have functional importance in governing treatment resistance.
Phase I study of capecitabine, oxaliplatin, bevacizumab, and everolimus in advanced solid tumors.
Authors: Rangwala Fatima A. , Bendell Johanna C. , Kozloff Mark , Arrowood Christy , Meadows Jennifer , Tourt-Uhlig Sandra Ellen , Murphy Jennifer , Meadows Kellen , Morse Michael , Uronis Hope Elizabeth , Hsu Shiaowen David , Zafar Yousuf , Hurwitz Herbert 
Published: February 2017

490 Background: Everolimus (E), an oral rapamycin analogue, is a potent mTOR inhibitor. Combined inhibition of VEGF and mTOR pathways may increase anti-angiogenic and anti-tumor activity. We evaluated E in combination with capecitabine (C), oxaliplatin (O), and bevacizumab (B) in a phase I dose escalation study. Methods: Eligible patients (pts) had advanced solid tumors, adequate organ function and no increased risk for class-related toxicities. B and O were given intravenously; C and E were orally administered. Cycle length was 21 days. Doses for level 1: C 850 mg/m2 on days 1-14; O 130 mg/m2 on day one; B 7.5 mg/kg on day one; and E 5 mg three times a week. Doses for level -1: C 680 mg/m2, O100mg/m2. An intermediate dose level (-1b) of E escalated to 5 mg five times weekly was added to maximize dose intensity. Dose limiting toxicity (DLT) was assessed in cycle 1. Concomitant administration of CYP3A4 substrates, inhibitors or inducers was prohibited. Results: Dose escalation is complete with 27 pts evaluable for toxicity and 24 evaluable for efficacy. Two DLTs (grade 2 intolerable fatigue, anorexia, vomiting and grade 3 diarrhea) were observed in 6 pts in cohort 1. No DLTs were observed in cohort -1; one DLT (rectovaginal fistula) was observed in the -1b cohort. Possible grade ≥3 treatment-related adverse events any time on study (n=1 except as indicated) included diarrhea (n=2), intestinal perforation/fistula, rectovaginal fistula, hypertriglyceridemia (n=3), hyperglycemia, hypoalbuminemia, hyponatremia, peripheral neuropathy, neutropenia (n=2), lymphopenia, thrombocytopenia, hypertension (n=3), deep vein thrombosis, and arterial thrombosis. Adverse events were consistent with known class-related toxicities. For efficacy, 10 pts had a partial response (PR); 10 had stable disease as best response. Of 13 pts with chemorefractory metastatic colorectal cancer (mCRC), 5 had a PR. Of 8 pts with chemonaive mCRC, 5 had a PR. Conclusions: E in combination with full dose C, O and B was associated with unacceptable toxicity, primarily GI toxicity. E at 5mg five times weekly, C at 680 mg/m2 on days 1-14, O at 100 mg/m2 and B at 7.5 mg/kg on day one appears well tolerated. Activity was noted in chemorefractory and chemonaive mCRC patients.
Survival analysis according to disease subtype in AVAGAST: First-line capecitabine and cisplatin plus bevacizumab (bev) or placebo in patients (pts) with advanced gastric cancer.
Authors: Shah Manish A. , Van Cutsem Eric , Kang Yoon-Koo , Dakhil Shaker R. , Satoh Taroh , Chin Keisho , Bang Yung-Jue , Bu Lilian , Bilic Grozdana , Ohtsu Atsushi 
Published: February 2017

5 Background: Gastric cancer (GC) is a heterogeneous disease that may be divided into distinct subtypes with different epidemiology, risk factors, and molecular expression profiles: proximal non-diffuse GC (type 1), diffuse GC (type 2), and distal non-diffuse GC (type 3). In clinical practice, GC subtypes are treated as a single disease. Regional efficacy differences were seen in AVAGAST: pts in Americas and Europe showed more evidence of benefit than Asia-Pacific pts. We analyzed outcomes in the phase III AVAGAST study according to GC subtype and region in order to test if GC subtype was prognostic of outcome and predictive of bev benefit. Methods: Pts were randomized and treated as previously described. The effect of treatment on overall survival (OS), measured by hazard ratio, was examined in an unplanned exploratory analysis using Cox proportional hazards models. Median OS was estimated using the Kaplan-Meier method. Results: 733 of 774 AVAGAST pts were included. Type 2 GC (52.1%) was more common than type 1 (9.5%) or type 3 (38.3%). Irrespective of treatment, pts with type 2 GC had worse outcome than type 3 GC (median OS 10.3 vs 11.7 mo; HR=0.82; 95% CI 0.68–1.00); non-Asian pts had the most dismal prognosis (8.0 vs 11.1 mo; HR=0.68; 95% CI 0.53–0.89). The table below describes the bev effect according to subtype. Non-Asian pts with GC type 2 and 3 appear to benefit from bev. Conclusions: In all regions, pts with type 3 GC had a better prognosis than type 2 GC. Bev therapy appeared to improve outcomes in non-Asian pts with type 2 and 3 GC. These data suggest that GC subtypes may be important predictors of pt outcome and warrant further prospective evaluation. [Table: see text]
Cetuximab-based or bevacizumab-based first-line treatment in patients with KRAS p.G13D mutated metastatic colorectal cancer (mCRC)? A meta-analysis of 54 cases.
Authors: Heinemann Volker , Reinacher-Schick Anke , Stintzing Sebastian , Giessen Clemens Albrecht , Tannapfel Andrea , Laubender Ruediger P. , Brodowicz Thomas , Knittelfelder Regina , Vrbanec Damir , Schmiegel Wolff , Modest Dominik Paul , Zielinski Christoph 
Published: February 2017

511 Background: KRAS p.G13D mutant metastatic colorectal cancer (mCRC) has been identified to represent a cetuximab-sensitive subtype of KRAS mutant mCRC. This analysis aims to answer the question whether first-line treatment of p.G13D mCRCs should contain cetuximab or bevacizumab. Methods: Fifty-four patients with p.G13D mutant mCRC were pooled in this analysis. All patients underwent systemic 1st-line treatment with a fluoropyrimidine and oxaliplatin/irinotecan that was combined with either cetuximab or bevacizumab. Results: Overall response rate was comparable between cetuximab- and bevacizumab-based regimens (58% vs 57%). Progression-free survival was comparable (8.0 months-cetuximab-group vs 8.7 months bevacizumab-group). Overall survival (OS) was longer in patients treated with cetuximab as first-line therapy (20.1 months vs 14.9 months). Logistic regressions modelling OS revealed oxaliplatin-based first-line treatment to correlate significantly with poor outcome (p=0.03). Moreover, a strong trend in favour of capecitabine compared to infusional 5-FU (p=0.06) was seen.. Responders among our cohort showed a benefit concerning PFS and OS undergoing cetuximab- but not bevacizumab-based regimen. Conclusions: This retrospective pooled analysis suggests that cetuximab-based first-line therapy in p.G13D mutant mCRC shows similar activity compared to bevacizumab-containing regimen. Infusional 5-FU and oxaliplatin may represent inferior options compared to capecitabine and irinotecan in p.G13D mutant mCRC 1st-line treatment.
Pretreatment levels of serum lactate dehydrogenase (LDH) and clinical outcome in metastatic colorectal cancer patients receiving first-line chemotherapy and bevacizumab.
Authors: Maccaroni Elena , Giampieri Riccardo , Scartozzi Mario , Del Prete Michela , Faloppi Luca , Bianconi Maristella , Bittoni Alessandro , Galizia Eva , Loretelli Cristian , Belvederesi Laura , Cascinu Stefano 
Published: February 2017

514 Background: No predictive marker for efficacy of a Bevacizumab-based therapy has been identified in metastatic colorectal cancer. Soluble LDH levels seem to be related to increased angiogenesis. The focus of this analysis is whether high levels of LDH can be related to higher benefit of bevacizumab-based therapy in this setting. Methods: Eligible patients were metastatic colorectal cancer patients treated in 1st line setting with a chemotherapy doublet and bevacizumab in the last year. A historical control group was also formed by collecting data of patients treated with only a chemotherapy doublet. Pre-treatment LDH serum levels were collected for all patients. Cut-off level for soluble LDH was determined via ROC curve. Primary end-point was difference in progression free survival between the two groups. Secondary end-points were overall survival and response rates. Results: 82 patients treated with first line containing bevacizumab were eligible for our analysis. 138 patients were identified as control group. The two groups were comparable for major clinical characteristics. LDH cut-off level was stated at 588 mg/dl. In the control group PFS of 4.2 and 8 months were observed for LDH high and low levels (p=0.0003,HR:0.2973,95%CI:0.0318 to 0.3543). OS were 19.6 and 34.9 months (p=0.0014,HR:0.2484,95%CI: 0.0188 to 0.3884). No significant differences were seen for response rates (with 20% vs 39% partial responses, p=0.1671). In the group of patients treated with Bevacizumab, PFS of 8.5 and 7.3 months were observed respectively for LDH high and low levels (p=0.2,HR:0.6360,95%CI:0.2528 to 1.4185). OS were 26.6 and 22 months (p=0.7,HR:0.8480,95%CI:0.2307 to 2.9563). Improved response rate for LDH high patients could be seen (58% vs 14% partial responses, p=0.0243). Conclusions: These data confirm the role of soluble LDH as marker of worse outcome for unselected patients and also suggest a role as potential marker of increased effectiveness of Bevacizumab based therapy.