bluuebunny/crossref_metadata_2025_split huggingface dataset:
The in situ local immune response, tumour senescence, and proliferation in colorectal cancer.
Authors: Roxburgh Campbell SD , Richards Colin H , Powell Arfon , Mcmillan Donald C. , Edwards Joanne E. , Horgan Paul G. , Shiels Paul G. 
Published: February 2017

412 Background: Immune cell infiltrates play a key role in determining colorectal cancer outcome. It is unclear whether they are tumour or host specific. Increased immunogenicity may relate to senescence or proliferation. Senescence, a state of cell-cycle arrest, slows tumour progression. In animal models, senescence associated regression is mediated by upregulated antitumour immune responses. High proliferation may provoke immune responses. Relationships between senescence, proliferation and immune cell infiltrates have not previously been studied. We explore whether p16ink4a associated senescence relates to T cell infiltrates in colorectal tumours and whether p16ink4a expression, proliferation and T cell infiltrates confer similar survival relationships. Methods: Immunostaining of nuclear p16inka and Ki67 was performed using a tissue microarray. Nuclear p16inkaand Ki67 were scored as high or low expression. (T cell markers CD3/CD45RO/CD8/FOXP3) were scored high/low grade on corresponding full sections (margin/stroma/ cancer cell nest). Results: 230 Stage I-III cancers were studied. High nuclear p16ink4a was expressed in 63% and high proliferation (Ki67 >15% ) in 61%. P16ink4a expression related to reduced margin, stroma and cancer cell nest (CCN) CD45RO cells (P=0.054, P=0.062, P=0.025) and reduced margin CD8 cells (P=0.016). High Ki67 labeling related to increased margin, and CCN CD3 cells (P=0.017, P<0.001), increased margin and CCN CD45RO cells (P=0.023, P<0.001), increased margin, stroma and CCN FOXP3 cells (P<0.001, P=0.001, P<0.001) and increased margin and CCN CD8 cells (P=0.026, P=0.001). On multivariate analysis, TNM stage (P<0.001), low margin CD3 (P=0.014), low margin CD8 (P=0.037), low proliferation (Ki67) (P=0.013) and low senescence (P16ink4a) (P=0.002) conferred poorer cancer survival. Conclusions: p16ink4a expression, proliferation and immune cell infiltrates are independent prognostic factors in colorectal cancer. Proliferation relates to increasing T cell infiltrates but independently influences survival. P16ink4a associated senescence does not appear to mediate improved outcome by upregulating T cell responses. Relationships observed here suggest the opposite.
Association of telomere length (TL) with clinical outcomes in patients with colorectal carcinoma (CRC).
Authors: Baig Mahadi Ali , Merla Amartej , Augustine Titto A , Atzmon Gil , Budagov Temuri , Goel Sanjay , Maitra Radhashree 
Published: February 2017

418 Background: Telomeres (T) consist of thousands of copies of TTAGGG tandem repeats capping the ends of the chromosome. T along with enzyme telomerase provides protection against any threats to the genome that might arise as a consequence of “end replication problem.” During aberrant cell proliferations the normal check points of cell cycle is compromised leading to unrestricted cell division with extremely short T and subsequent genomic instability. Studies have linked short TL with premalignant and malignant stages of CRC carcinogenesis. However, the relation of TL to the clinical outcomes has not been conclusively determined. In this study we evaluated the association of TL with clinical outcomes in a cohort of 75 CRC patients. Methods: Tumor DNA was isolated from formalin fixed paraffin embedded specimens. TL was measured by using a qRT-PCR method that provided the relative T copy number, compared to reference copy number of the housekeeping gene, β-Globin, which resulted in a T/S ratio. One T/S ratio unit is equivalent to a mean TL of 4,270 base pairs (BP). Results: From 75 patients, 122 tissue samples were identified (66 primary, 52 metastases, 29 matched pairs). Age at diagnosis (>/< median) had a statistically significant difference in TL (mean BP 4700 vs. 4374; p=0.05) with shorter TL in the advanced age. Females had longer TL compared to men (mean BP 4722 vs. 3669 respectively; p=0.04). Shorter TL was associated with shorter progression free survival (PFS) for patients treated with cetuximab/panitumumab (3963 vs. 5295 p=0.04). There was a trend towards increased overall survival (>/< median) with longer TL (4934 vs. 4117; p=0.08). We failed to find a difference in the TL between primary and metastatic sites in the 29 patients with paired samples. Conclusions: TL is a potential biomarker predictive of clinical outcome (PFS) for patients treated with cetuximab/panitumumab. Tumor TL reduces with advancing age and appears to be sex dependent. Further studies to validate TL’s predictive role in patient outcomes are underway.
Global profiling of fecal and tissue mirnas in Asian Chinese colorectal cancer patients.
Authors: Phua Lee Cheng , Koh Poh Koon , Cheah Peh Yean , Chan Eric Chun Yong , Ho Han Kiat 
Published: February 2017

439 Background: Fecal miRNAs are increasingly explored as non-invasive diagnostic markers of colorectal cancer (CRC). However, a holistic understanding of the global fecal miRNA profile in CRC patients is lacking, particularly in Asian patients. Also, it remains to be determined if the fecal miRNA profile mirrors the tumor profile. Here, we assayed the global human fecal miRNAs in Asian Chinese CRC patients to elucidate relevant diagnostic fecal markers. The disease-related profiles between feces and resected tumor of matched patients were also compared. Methods: MiRNAs were extracted from the feces of sporadic CRC patients (stage B – C, n=8) and healthy subjects (n=8) recruited into the study from September 2011 – July 2012. MiRNA expression profile was analyzed on Agilent miRNA array (miRBase Release 16.0). Biopsied tumor tissue (n=8) and matched normal mucosae (n=8) from the same CRC patients were also analyzed. Results: Univariate tests uncovered novel fecal markers (p<0.05) characterizing CRC (e.g. elevated miR-3619-5p and miR-4269; decreased miR-3164 and miR-3917), even though global fecal miRNA profiles did not differentiate CRC patients from healthy subjects. Fecal miR-223 was appreciably higher in CRC patients, corroborating with Caucasian studies. Tumor miRNA signature was clearly distinct from matched normal mucosa (PLS-DA Q2=0.883). Discriminating tumor miRNAs (p<0.05) included previously unreported (e.g. miR-874 and miR-4290) and known oncogenic miRNAs (e.g. miR-17-92 cluster and miR-135b) in the context of CRC. Notably, the global fecal miRNA profile was markedly different from that of tissue, suggesting that miRNA aberrations within CRC tumor did not significantly influence the fecal miRNA profile. Conclusions: A global profiling approach identified novel sets of differentially expressed miRNAs at the fecal and tissue level that may complement existing diagnostic markers and provide new insights into CRC pathogenesis. Interestingly, dysregulated miRNAs in the feces were different from the tumor, suggesting the presence of other contributors to the fecal miRNA profile. There is a need to reconsider using tissue biomarkers indiscriminately in different biological matrices.
Circulating tumor cells as predictive marker in panitumumab after progression of cetuximab in Japanese patients with KRAS wild-type metastatic colorectal cancer.
Authors: Ohhara Yoshihito , Matsusaka Satoshi , Shinozaki Eiji , Suenaga Mitsukuni , Mizunuma Nobuyuki , Hatake Kiyohiko , Yamaguchi Toshiharu 
Published: February 2017

440 Background: Panitumumab has a high affinity for epidermal growth factor receptor. Its utility as a salvage therapy is unknown in cetuximab-resistant colorectal cancer. We assessed the prognostic and predictive role of circulating tumor cells (CTC) in KRAS wild-type metastatic colorectal cancer (mCRC) patients treated with panitumumab after progression of cetuximab. Methods: Panitumumab (6 mg/kg, every 2 weeks) was administered as a salvage therapy to cetuximab-resistant mCRC. CTCs of whole blood at baseline were isolated and enumerated using immunomagnetics. Results: Nineteen patients were enrolled in this prospective study between July 2010 and March 2011. Five patients had stable disease (SD) with a response rate of 0%. Four patients reached long SD, which was defined as continuous SD of more than 120 days. All of the four patients had <2 CTC. <2 CTC showed an independent predictive role for progression-free survival (PFS) at multivariate analysis (HR; 7.275, p=0.013). Patients with >2 CTC had shorter median PFS than those with <2 CTC (1.8 and 3.6 months, p=0.008). There was no statistical significance in median OS between patients with <2 CTC and those with >2 CTC (3.2 and 6.7 months, p=0.164). Conclusions: Panitumumab may be effective for patients with <2 CTC, KRAS-wild-type mCRC after progression of cetuximab.
Validation of TPX2 as a novel prognostic marker for malignant progression and metastasis of colon cancer.
Authors: Wei Ping , Li Dawei , Xu Ye , Cai Sanjun 
Published: February 2017

442 Background: We previously identified aberrant overexpression of TPX2 in colon cancer by using a genome-wide gene expression profiling analysis. Here, we aimed to investigate its expression pattern, clinical significance, and biological function in colon cancer. Methods: The expression of TPX2 was analyzed in human colon cancer cell lines and tumor samples. The effect of TPX2 on cell proliferation, tumorigenesis and metastasis was examined in vitro and in vivo. Results: Overexpression of TPX2 was found in metastatic lesion of colon cancer, significantly higher than primary cancererous tissue and normal colon mucosa. Overexpression of TPX2 was significantly associated with the clinical staging, vessel invasion and metastasis. In survival analyses, patients with TPX2 expression had worse overall survival and metastasis free survival, suggesting that deregulation of TPX2 may contribute to the metastasis of colon cancer. Consistently, Silencing TPX2 inhibited proliferation and tumorigenicity of colon cancer cells both in vitro and in vivo. Strikingly, we found that TPX2 knockdown significantly attenuated the migration and invasion ability of colon cancer cells, which was further shown to be mechanistically associated with AKT mediated MMP9 activity. Conclusions: These findings suggest that TPX2 plays an important role in promoting tumorigenesis and metastasis of human colon cancer and may represent a novel prognostic biomarker and therapeutic target for the disease.
Bevacizumab (Bev) with or without erlotinib as maintenance therapy, in patients (pts) with metastatic colorectal cancer (mCRC): Exploratory analysis according to KRAS status in the gercor DREAM phase III trial.
Authors: Samson Benoit , Tournigand Christophe , Scheithauer Werner , Lledo Gérard , Viret Frédéric , André Thierry , Ramée Jean François , Tubiana-Mathieu Nicole , Dauba Jérôme , Dupuis Olivier , Rinaldi Yves , Mabro May , Aucoin Nathalie , Khalil Ahmed , Latreille Jean , Louvet Christophe , Brusquant David , Bonnetain Franck , Chibaudel Benoist , De Gramont Aimery 
Published: February 2017

448 Background: In the GERCOR-DREAM trial, maintenance therapy (MT) with bev + EGFR tyrosine kinase inhibitor erlotinib (E) after a first-line Bev-based induction therapy (IT) in pts with mCRC significantly improved PFS compared with bev alone. Here we explore the influence of KRAS status on erlotinib efficacy. Methods: Pts with previously untreated and unresectable mCRC were eligible. After a Bev-based IT with FOLFOX or XELOX or FOLFIRI, pts without disease progression were randomized to MT between Bev alone (Bev 7.5 mg/kg q3w; arm A) or Bev+E (Bev 7.5 mg/kg q3w, E 150 mg/day continuously; arm B). KRAS determination was established by local assessment in each center. Results: Among the 452 randomized patients, KRAS status was available in 403 pts (89%): 234 pts (58%) KRAS wt and 169 pts (42%) KRAS mut. Clinical characteristics were similar between both populations. For the whole population of randomized patients (n=452), median PFS from inclusion were 9.33m and 10.55m in arm A and B, respectively (HR=0.76 [0.61-0.94], p=0.011). For KRAS wt population, median PFS from inclusion was 9.66 m and 10.94 m in arm A and B, respectively (HR=0.80 [0.59-1.08], p=0.141). For KRAS mut population, median PFS from inclusion was 9.79 m and 9.79 m in arm A and B, respectively (HR=0.86 [0.61-1.22], p=0.393). In KRAS wt pts treated with erlotinib, cutaneous toxicity was predictive of PFS: mPFS was 9.66m in pts with grade 0 (n=101) and 10.91m in pts with grade ≥1 (n=114) (HR=0.69 [0.51-0.95], p=0.0186). Conclusions: The addition of erlotinib to bevacizumab as maintenance treatment in first-line metastatic colorectal cancer significantly improves progression-free survival from inclusion. However, in both wt and mut KRAS pts, difference was not statistically significant. Unlike anti-EGFR monoclonal antibodies, the addition of erlotinib to bevacizumab does not appear to be antagonist in KRAS mutant patients. Clinical trial information: NCT00265824.
Analysis of overall survival and safety during the course of the phase III VELOUR trial comparing FOLFIRI and aflibercept or placebo in patients with mCRC that progressed on prior oxaliplatin treatment.
Authors: Ruff Paul , Lakomy Radek , Prausová Jana , Van Hazel Guy , Moiseyenko Vladimir Mikhailovich , Bhargava Pankaj , Tabernero Josep , Van Cutsem Eric 
Published: February 2017

451 Background: VELOUR is a large international, randomized placebo-controlled study that compared the efficacy and safety of FOLFIRI with aflibercept (ziv-aflibercept in the US) or with placebo in 1,226 mCRC patients who received prior oxaliplatin treatment. Aflibercept demonstrated statistically significant and clinically meaningful improvements in median OS (13.5 vs 12.06 months; HR=0.817, p=0.0032) as well as PFS and response rate. (Van Cutsem et al., J Clin Oncol. 2012). This analysis estimates the treatment effect and safety over the time course of the study. Methods: Hazard ratios (HR) by 6-month time periods were estimated using a piecewise Cox proportional hazard model. NCI-CTCAE version 3.0 was used to grade the severity of AEs. Results: There was improvement in the HR over time (Table) consistent with the survival curves that continue to separate past the median time point, indicating that the magnitude of the aflibercept treatment effect continues to increase over time. Incidence of grade 3 AEs (45.1% vs. 62.0%) was higher in the aflibercept + FOLFIRI arm; grade 4 AEs were placebo 17.4% vs. 21.4% aflibercept. More common AEs only occurred in a small proportion of aflibercept + FOLFIRI cycles (e.g., grade >3 hypertension and diarrhea occurred in 3.6% and 2.8% of treatment cycles, respectively). The majority of grade 3-4 AEs occurred in early treatment cycles (first 3-4 cycles). Most patients experienced only a single episode of grade ≥3 AEs with aflibercept + FOLFIRI. Importantly, AEs in VELOUR did not impact patients’ ability to receive chemotherapy. Conclusions: Treatment with aflibercept plus FOLFIRI showed a continuous and consistent improvement in OS over time. Although combined grade 3-4 AEs were higher with aflibercept, AEs occurred early in treatment, in a small proportion of total cycles administered, and the majority were single episode in nature. Clinical trial information: NCT00561470. [Table: see text]
Progression-free survival in metastatic, BRAF-mutated colorectal cancer.
Authors: Morris Van Karlyle , Overman Michael J. , Maru Dipen M , Kopetz Scott 
Published: February 2017

458 Background: BRAF mutations occur in 5-8% of metastatic colorectal cancers and are associated with a significantly worse overall prognosis relative to patients with BRAF wild-type tumors. However, the outcomes with standard chemotherapy of a large cohort of patients with BRAF mutant tumors have not been described. Methods: We searched the MD Anderson Cancer Center databases for colorectal cancer patients with identified BRAF mutations between December 2003 and May 2012. Patients were analyzed for clinical characteristics, progression-free survival, and chemotherapeutic agents used. Survival was estimated according to the Kaplan-Meier method. Results: Among the 1567 patients tested for BRAF mutations at our institution, 127 (8.1%) had tumors with BRAF mutations. The average age was 59.6 years at the time of diagnosis, and 65/127 patients (51.2%) were male. The 71 patients who presented with metastatic disease received a median of 2 lines of chemotherapy. For the first three lines of chemotherapy, median progression-free survival was 5.6 months (n=69 patients), 3.9 months (n=58), and 3.4 months (n=31), respectively. Median PFS was not affected by the backbone chemotherapeutic agent in the first-line setting, whether oxaliplatin-based or irinotecan-based (6.1 months vs. 5.1 months, respectively, p-value = 0.78). Conclusions: Progression-free survival is expectedly poor for patients with BRAF-mutated metastatic colorectal cancer. Despite the ascertainment bias present in this cohort (with testing preferentially performed in patients suitable for clinical trials in refractory disease), fewer than half of patients with metastatic disease received more than 2 lines of therapy. This data not only provides historic controls suitable for future study design in this population but also supports the idea that novel therapeutic options are essential for this group of patients.
Validation of the survival benefit from metformin use in patients with type 2 diabetes and colorectal cancer.
Authors: Sahin Ibrahim Halil , Hassabo Hesham Mohamed , Shen Yehua , Kee Bryan K. , Hassan Manal , Garrett Chris R. 
Published: February 2017

462 Background: We previously reported improved overall survival (OS) associated with metformin usage in a retrospective study of type 2 diabetes mellitus (DM) patients with colorectal (CRC) (Br J Cancer 2012;106:1374-8). We sought to determine whether this effect could be validated in an independent data set. Methods: Under an IRB-approved protocol, 6,128 patients with CRC based on ICD-9 billing codes diagnosed between 1995-2005 were reviewed; of these 683 were determined to have type 2 DM. Results: Of the 683 diabetic CRC patients, 407 (59.5%) were male. The patient’s stage at diagnosis was: stage I (67, 9.8%), II (162, 23.7%), III (247, 36.1%), IV (166, 24.3%) and unknown stage (41, 6%). The number of patients using metformin at the time of first evaluation was 146 (21.3%). A significantly better median OS was observed in CRC patients with metformin use in both all-stage and stage III groups (p = 0.017, p = 0.029 respectively); median OS results demonstrated in table below. Conclusions: This independent retrospective data set validated the OS benefit associated with metformin use previously reported in patients with type 2 DM and CRC. Future prospective studies will be required to confirm the benefit of metformin in this clinical setting. [Table: see text]
North American (NA) subgroup results from VELOUR: Ziv-aflibercept versus placebo (pbo) plus FOLFIRI in mCRC that is resistant to or has progressed after an oxaliplatin-containing regimen.
Authors: Mitchell Edith P. , Guarino Michael J. , Allegra Carmen Joseph , Boelle Emmanuelle , Andria Michael L. , Bhargava Pankaj , Kirshner Jeffrey J. 
Published: February 2017

465 Background: Ziv-aflibercept (trade name ZALTRAP; known outside the US as aflibercept) is a new multiple angiogenic inhibitor that prevents VEGF-A, VEGF-B and PLGF from binding their receptors. Ziv-aflibercept was recently approved by the FDA in combination with FOLFIRI for patients with mCRC that is resistant to or has progressed after an oxaliplatin-containing regimen. Approval was based on the multinational phase III VELOUR trial (N=1226) which showed statistically significant improvements in overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) with aflibercept + FOLFIRI. Detailed analyses of the NA subgroup are presented here. Methods: Patients were randomized 1:1 to ziv-aflibercept (4 mg/kg) + FOLFIRI or pbo + FOLFIRI every 2 wk. Patients had ECOG performance status (PS) ≤2, 1 prior oxaliplatin-based regimen, and prior bevacizumab (bev) was allowed. Primary endpoint was OS. The NA analysis was pre-specified, but not powered, to compare within or between subgroups. Results: NA patients (N=138) were randomized to ziv-aflibercept + FOLFIRI (n=63) or pbo + FOLFIRI (n=75). Baseline characteristics were similar in both arms (ziv-aflibercept: median 61 yrs; 60% male; 96% PS 0-1; 56% >1 metastatic organ; 74% prior bev). Ziv-aflibercept vs pbo improved median OS (17.94 vs 12.88 mos; HR=0.691, 95% CI: 0.442-1.079), median PFS (6.01 vs 4.17 mos; HR=0.536, 99.9% CI: 0.222-1.296) and ORR (12% vs 9%). Patients on average received more cycles (median 8.5 vs 7.0) and had longer duration of exposure (median 20 vs 14 wk), but had more treatment modifications with ziv-aflibercept vs pbo. Most of the severe AEs (grade ≥3) with ziv-aflibercept were grade 3 including hypertension, venous thromboembolic events, proteinuria, diarrhea, fatigue/asthenia, infection, stomatitis/ulceration and neutropenia. There were few grade 4 AEs. Conclusions: Ziv-aflibercept + FOLFIRI in NA mCRC patients previously treated with an oxaliplatin-based regimen (with or without prior bev) resulted in improved OS, PFS, and ORR, with an acceptable safety profile. The NA results are consistent with the VELOUR worldwide population. Clinical trial information: NCT00561470.
HPV in upper aerodigestive tract tumors in southern Brazil.
Authors: Antunes Luis Carlos Moreira , Muller Leandro Bizarro , Lopes Antonio de Barros , Fagundes Renato Borges 
Published: February 2017

47 Background: The highest rates of esophageal cancer in Brazil occur in Rio Grande do Sul (18/100,000/year for men), where squamous cell carcinoma is the most common. Furthermore, the incidence of head and neck squamous cell carcinoma (HNSCC) is significant in this region (11/100,000/year for cancer of the oral cavity and 10/100,000/year for laryngeal cancer in men). Tobacco smoking and alcohol consumption are the major risk factors for esophageal squamous cell carcinoma (ESCC) and HNSCC. The role of HPV in the development of ESCC remains controversial. Otherwise, there are some evidence that HPV-related HNSCC is a distinct entity compared with HNSCC associated with smoking and alcohol consumption. Methods: Polymerase chain reaction (PCR) was used to evaluate the presence of Human Papillomavirus from 218 samples from three groups of patients. Group 1 comprised 51 patients with ESCC who underwent esophagectomy, in which two samples from each patient were analyzed: one sample of the tumor and another of normal esophageal mucosa distant from the tumor. Group 2 comprised 37 patients with HNSCC who underwent Lugol chromoendoscopy. In this group, samples were analyzed from the primary tumor, the stained areas of mucosa from the middle esophagus, and, when present, discolored and tumoral areas of the esophageal mucosa. Thirty-seven dyspeptic patients, not exposed to smoking or alcohol consumption, comprised Group 3, in which one sample per patient of mucosa with normal appearance from the middle esophagus was evaluated. Nested-PCR with MY09/11 and GP5/6 L1 primers was used to detect HPV L1 in samples fixed in formalin and stored in paraffin blocks. Results: Of a total of 224 samples fixed in formalin and stored in paraffin, only 6 samples had insufficient material for PCR analysis: one sample from normal distal epithelium in Group 1, one sample from a stained area and 2 samples from unstained areas in Group 2 and two samples from normal esophageal mucosa in Group 3. PCR was positive for one of conserved genes GAPDH, G3PDH or B-globin and negative for HPV DNA in all the 118 samples tested. Conclusions: There is no evidence that HPV is involved in carcinogenesis of the upper aerodigestive tract in southern Brazil.