bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic value of PD-L1 expression in colorectal cancer.
Authors: Lin Albert Y. , Kouzminova Natalia B. , Chou Thomas 
Published: March 2017

610 Background: Growing evidence have shown promise for targeting programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) signaling in several tumors. However, the role of PD-L1 expression in colorectal cancer (CRC) tumor cells and its interaction with other clinicopathologic factors remain elusive. Methods: We constructed a tissue microarray with paraffin-embedded primary colon cancer tissue (n=103; stage I, 22; II: 44; III: 37). Expression levels of biomarkers (PD-L1, EGFR, p53, Ki67, LEF1, VEGF, COX2, MMR – by IHC, and MiR-34a - by in situ hybridization), clinicopathologic variables and clinical outcomes were investigated. H-score evaluation of PD-L1 was performed. Tumors with an H score >55, derived using Cutoff Finder, were considered PD-L1 positive for use in Kaplan-Meier survival analysis with log-rank test and in Cox regression models for recurrence-free survival (RFS) and overall survival (OS). Results: Median follow-up time for the entire cohort was 4.7 years (range 0.1-20.8). Positive PLD1 was identified in 89% of cases. As a group, cases with positive PD-L1 expression had better OS than those with negative expressions (12.2 vs 3.3 years) (p = 0.043), especially in cases with mismatch repair proficiency (MMR-P, 12.1 vs 1.0 years) (p <0.001). Negative PD-L1 expression in cases who had no chemotherapy was associated with worse outcome for OS (p=0.001) and RFS (p=0.008). There was no significant association between PD-L1 expression and gender, age, tumor size, pathologic stage or tumor grade. However, PD-L1 expression was significantly associated with MiR-34a (p<0.001) and p53 overexpression (p=0.008) with a trend toward association in cases with mismatch repair proficiency (MMR-P, p=0.053). Conclusions: Our results suggest that negative PD-L1 expression appears to have negative prognostic value with worse RFS and OS in stage I - III CRC patients, especially those who had not received any chemotherapy. Given a recent study suggesting p53/miR-34a/PD-L1 axis as a novel mechanism of immune evasion, and strong correlation in the PD-L1/p53 and PD-L1/miR-334a expressions in our cohort, further investigation of their interactions is warranted that may lead to identifying their predictive value for immuno/chemotherapy.
Magnetic resonance Imaging (MRI), liquid biopsies, and patient derived organoids (PDOs) as biomarkers of response to regorafenib (REG) in treatment-refractory metastatic colorectal cancer (mCRC) patients (pts).
Authors: Khan Khurum Hayat , Rata Mihaela , Koh Dow-Mu , Tunariu Nina , Vlachogiannis George , Hahne Jens , Jamin Yann , Collins David J. , Chau Ian , Rao Sheela , Watkins David J. , Starling Naureen , Kalaitzaki Eleftheria , Fotiadis Nicos , Begum Ruwaida , Temple Eleanor , Fassan Matteo , Braconi Chiara , Cunningham David , Valeri Nicola 
Published: March 2017

613 Background: REG demonstrated efficacy in pre-treated mCRC pts. Lack of predictive biomarkers, potential toxicities and cost/effectiveness concerns highlight the unmet need for better patient selection. Methods: RAS mutant mCRC pts with biopsiable metastases were enrolled in this phase II trial. Tissue biopsies (6-12 cores) were obtained at baseline (BL), after 2 months if stable disease (SD) and at disease progression (PD). Dynamic contrast enhanced (DCE) MRI was acquired pre and at day 15 post-treatment. Median values of volume transfer constant (Ktrans) and enhancing fraction (EF) [K-trans*EF/100] were generated. Circulating tumour (ct)DNA was collected monthly until PD and tested for clonal RAS mutations by digital droplet PCR. PDOs derived from responders and non-responders pts were implanted orthotopically in the liver of mice and treated with REG for 5 days. Changes in tumour and fractional blood volume (fBV) were monitored by oxygen-enhanced MRI. Results: mCRC pts (n = 27) with paired MRI scans were analysed; a single target lesion per pt was chosen (25 liver and 2 pelvic metastases). Median K-trans*EF/100 product decrease was 58.2%. In the 23 analysable pts (4 received < 1 cycle of treatment due to toxicities), > 70% drop in K-trans*EF/100 (8/23) was associated with higher disease control rate (6/6 vs. 0/6, p = 0.048) measured by RECIST 1.1 at 2 months, improved progression free survival (PFS) [HR = 0.24 (0.07-0.86), p = 0.03], and 4-month PFS (58.3% VS 21.2%). Sequential tissue biopsies analysis confirmed reduction in CD31 in pts with K-trans*EF/100 drop. RAS mutant clones decay in ctDNA after 8 weeks of treatment was associated with better PFS [HR = 0.25 (0.08 - 0.83), p = 0.02] independently of K-trans*EF/100 drop. PDOs xeno-transplants treated with REG compared to controls had significant lower tumour fBV (4.5 VS 10.6, p = 0.03) and lower microvascular density measured by CD31 staining (4.3 VS 8.9, p = 0.02). Conclusions: Combining DCE MRI and ctDNA predicts depth and duration of anti-angiogenic response to REG monotherapy and may improve pt selection with potential health/economic implications. Clinical trial information: 201400357951.
Gaining biomarker insights from existing stage II colorectal cancer (CRC) patient cohorts in the United Kingdom: Using real-world data to guide treatment decisions.
Authors: Fleming Sarah Jane , Morris Eva , Shires Mike , Hemmings Gemma , Wang Lisa , Muranyi Andrea , Singh Shalini , McCusker Margaret Elizabeth , Shanmugam Kandavel , Quirke Philip 
Published: March 2017

614 Background: Trial data, while valuable, does not reflect the importance of a biomarker or treatment in the general population as trials generally exclude patients (pts) due to age or comorbidities. We used merged large population datasets to validate a linked anonymized stage II CRC pt cohort as representative of the population to identify the prognostic and predictive value of deficient mismatch repair (MMR) and a new biomarker Ga-interacting vesicle-associated protein (GIV). Methods: English national data on stage II CRC pts surgically treated from 2001-2015, n = 92,147, were analyzed for survival and clinicopathological parameters. Anonymized data were then linked to pathology and a subset of 405 unselected pts surgically treated from 1990-2003 at the Leeds Teaching Hospitals NHS Trust. These were investigated for 5 antibodies. 4 identified deficient MMR status and one was a new marker; GIV. Results: Population data vs the cohort of 405 pts showed a median age of 73 vs 74 yrs, M:F 55%:45% vs. 53%:47%. These are older than seen in most clinical trials and more reflective of the general stage II CRC population. The median survivals of 108 vs 92 months are as expected based on relative time periods covered. 374 patients yielded valid MMR status on immunohistochemistry (92%); 17% were dMMR and 83% were proficient. dMMR vs pMMR pts did not differ in age (median age 75 vs 74.5) or distribution of T3 (69% vs 66%), but were more likely to be female (71% vs 42%), sited in the right colon (76% vs 30%) and poorly differentiated (42% vs 8%). 11% of dMMR and 8% of pMMR received adjuvant chemotherapy in this cohort. GIV scoring status was also evaluated (405): 30% (121) were negative, 65% (264) positive and 5% (20) were not scored. Survival and risk scores by MMR and GIV status will be presented. Conclusions: Population based data has been created to validate the representativeness of a stage II biomarker cohort. This approach using large, population based data-sets provides opportunities to understand the generalizability of biomarker cohorts. The creation and expansion of such cohorts will more effectively validate existing and new biomarkers and treatments in real-world populations.
Tumor heterogeneity in anal cancer assessed with diffusion-weighted (DW) and T2-weighted MRI: Potential biomarker of treatment outcome.
Authors: Owczarczyk Kasia M. , Prezzi Davide , Siddique Muhammad , Stirling James , Cook Gary J. R. , Glynne-Jones Robert , Gaya Andrew M. , Leslie Martin , Goh Vicky 
Published: March 2017

617 Background: Despite advances in the management of anal squamous cell carcinoma (ASCC), roughly 25% of patients undergoing chemoradiotherapy (CRT) will experience a disease recurrence. Currently, there is no validated way to predict treatment failure and guidance on the timing of follow-up scans differs. This study was carried out to assess the role of statistical and fractal heterogeneity parameters from pre-treatment and early post-CRT T2- and diffusion-weighted MR in predicting disease outcome. Methods: Baseline and follow-up MR scans from patients with histologically proven non-metastatic ASCC undergoing radical CRT were included in this study. T2-W and DWI MR images were analyzed by two readers, blinded to clinical data. Statistical and fractal heterogeneity parameters were derived using in-house software. Results: 40 patients were included in the final analysis. Follow-up MRI scan was performed at a median of 15 weeks from the start of radiotherapy. 31/40 patients achieved a radiological complete response (CR) and a further 7/40 partial response (PR). Median follow-up was 34.5 months. During the course of follow-up, 12 patients experienced disease recurrence (30%). Radiological CR was not significantly associated with disease outcome. First order statistical heterogeneity analysis demonstrated a significantly lower ROI Skewness (median -0.05±0.49 vs 0.45±1.04 p=0.01) on baseline T2-W imaging as well as lower ROI Entropy (3.95±0.46 vs 4.45±0.49, p=0.01) and higher ROI Energy (0.07±0.03 vs 0.03±0.03, p=0.01) on follow-up T2-W imaging in subjects who experienced disease recurrence. In these patients T2-W Homogeneity derived from Grey-Level Co-occurrence Matrices (GLCM) was lower at baseline (0.41±0.12 vs 0.58 ±0.15 p=0.02) and associated with a higher T2-W Sum Average (median 35±7 vs median 29±7 p=0.01), whereas T2-W Contrast and ADC Correlation derived from GLCM were lower on follow-up imaging (30±11 vs 38 ±35, p=0.01 and 0.77±0.12 vs 0.88±0.12 p=0.04, respectively). Conclusions: First order statistical and fractal heterogeneity analysis of baseline and early post CRT MR scans in patients with ASCC might have a role in predicting long-term disease outcome.
National trends in local excision and esophagectomy for cT1N0 esophageal cancer.
Authors: Sturm Emily C. , Zahnd Whitney , Mellinger John D. , Ganai Sabha 
Published: March 2017

62 Background: Esophageal cancer management has evolved due to improvements in staging and treatment strategies. Endoscopic local excision presents an attractive option for definitive management of T1 cancers, avoiding the morbidity of esophagectomy. We hypothesized that for cT1N0 cancers, patients who underwent local excision would have lower survival compared to esophagectomy due to potential discordant staging. Methods: The National Cancer Database was queried for esophageal squamous cell carcinoma (SCC) and adenocarcinoma (AC) with AJCC T1N0 clinical stage who underwent local excision (n = 1625) or esophagectomy (n = 3255) between 1998 and 2012. Chi-square analysis was used to compare demographic and clinical characteristics by procedure. Chi-square trend analysis was performed to assess trends in procedure type over time. Cox Regression analysis was performed to assess survival by procedure controlling for demographic and clinical characteristics. Results: Between 1998 and 2012, the proportion of patients who underwent local excision increased from 12% to 50% for all patients (p < 0.001); from 17% to 40% for SCC patients (p < 0.001); and from 9% to 51% for AC patients (p < 0.001). Surgical procedure varied significantly by demographic, socioeconomic status, facility, and tumor-related factors. 65% of cT1N0 cancers had concordant clinical and pathological staging after esophagectomy, with 11% having positive nodal disease; 44% were concordant after local excision. While no significant difference was seen in unadjusted survival, adjusted Cox Regression analysis indicated worse survival after esophagectomy compared to local excision for all cases (HR 1.67; 95% CI, 1.40-2.00) and for ACs with concordant staging (HR 1.54; 95% CI, 1.11-2.14). Conclusions: Local excision for cT1N0 esophageal cancer has increased over time. Staging concordance for esophagectomy is seen in two-thirds of cases. Contrary to our hypothesis, patients undergoing local excision for T1N0 cancers have better overall survival than those undergoing esophagectomy, which may reflect early differences in mortality and/or selection bias. As this study was unable to distinguish T1a from T1b, further analysis is warranted.
A prospective, multicenter, randomized clinical trial of UGT1A1 promoter polymorphism for irinotecan dose escalation in metastatic colorectal cancer patients treated with bevacizumab plus FOLFIRI as the first-line setting (PURE FIST).
Authors: Wang Jaw-Yuan 
Published: March 2017

625 Background: The polymorphisms of genes encoding drug-metabolizing enzymes can play a crucial role in the increased susceptibility of patients to chemotherapy. This study is a prospective, multicenter, randomized clinical trial to compare the clinical outcomes and adverse events in metastatic colorectal cancer (mCRC) patients treated with bevacizumab plus 5-fluorouracil/leucovorin/irinotecan (FOLFIRI) with or without UGT1A1genotyping and irinotecan dose escalation as the first-line setting (NCT02256800). Methods: The enrolled patients were randomly assigned to one of two groups on the basis of receiving UGT1A1 genotyping or not. The study group receives a biweekly FOLFIRI plus bevacizumab, with irinotecan dose escalation based on UGT1A1 genotyping; whereas the control group receives the conventional biweekly FOLFIRI plus bevacizumab without UGT1A1 genotyping. The primary endpoint was the overall response rate (ORR), and the second endpoint was progression-free survival (PFS), overall survival (OS) and toxicities between the two groups. Results: BetweenAugust 2013 and May 2016, eighty-eight mCRC patients were enrolled, including 45 patients in the study group and 43 patients in the control group. With a median follow up time of 12.5 months (range, 5-30), the ORR was 71.4% vs. 44.2% ( P = 0.011). The PFS was 14.04 ± 1.44 vs. 9.08 ± 0.58 months in study group and control group ( P = 0.195), OS was 19.12 ± 1.24 vs. 14.16 ± 1.04 months ( P = 0.098), and ≥ Gr. III anemia was 2.2% vs. 23.3% ( P= 0.002) in study group and control group, respectively. However, there were no significant differences in ≥ Gr. III leukopenia or diarrhea even though the 1.36 fold relative dose intensity (RDI) in the study group. Conclusions: In the current study, patients with mCRC undergoing UGT1A1 genotyping may receive escalated doses of irinotecan for a potentially more favorable clinical response and outcome, in addition to acceptable toxicities. Such a personalized medicine based on genotyping may be feasible for potentially clinical practice. Clinical trial information: NCT02256800.
Tumor mutational burden of microsatellite stable metastatic colorectal tumors by patient factors and KRAS, BRAF, and PIK3CA mutation status.
Authors: Gong Jun , Sy Marvin , Fakih Marwan 
Published: March 2017

627 Background: Microsatellite instability (MSI) can predict response to pembrolizumab in metastatic colorectal cancer (mCRC). Benefit to PD-1 blockade is limited in microsatellite stable (MSS) mCRC yet MSS tumors represent >95% of all mCRC cases. Evidence suggests that high mutational load remains an important predictor of benefit to checkpoint inhibition across several tumors. We aimed to explore associations between tumor mutational burden (TMB) and various patient factors and mutations of interest to identify features of patients (pts) with MSS mCRC of potential significance to prognosis and PD-1 targeting. Methods: We conducted a retrospective study based on next-generation sequencing (NGS) of MSS metastatic colorectal tumors at our single institution using FoundationOne. TMB was categorized as high ≥ 20 mutations/megabase (Mb), intermediate 6-19 mutations/Mb, and low ≤ 5 mutations/Mb. TMB frequencies were analyzed according to age (≤50, >50, >65, and >70 years old), gender, race, location of primary tumor, and KRAS, BRAF, and PIK3CA mutations. Results: Among 194 MSS tumors with available TMB data, frequencies of tumors with intermediate TMB were significantly different in pts ≤50 years (24.6%, n=69) than in pts >65 (48.9%, n=47, Fisher’s exact (two-tailed) p=0.0096) and >70 (53.1%, n=32, p=0.0067). Frequencies of tumors with low TMB were significantly different in pts ≤50 years (75.4%, n=69) than in pts >65 (46.8%, n=47, p=0.0029) and >70 (43.8%, n=32, p=0.0032). Frequencies of high TMB tumors by age were 0% (≤50 years), 1.6% (>50), 4.3% (>65), and 3.1% (>70) and did not reach significance. Frequencies of high, intermediate, or low TMB tumors were not significantly different based on gender, race, and location of primary tumor. Frequencies of KRAS, BRAF, and PIK3CA mutations were similar across all TMB categories (p=0.7995, 0.8774, and 0.053, respectively). Conclusions: Older individuals with mCRC are less likely to have a low mutation burden by FoundationOne assay. Further validation of these findings in larger cohorts may indicate a potential higher likelihood for elderly colorectal cancer patients to benefit from immune-based strategies.
The relationship between the non-canonical NF-κB pathway, tumour microenvironment, systemic inflammation and survival in patients undergoing surgery for colorectal caner.
Authors: Patel Meera , Bennett Lindsay , Quinn Jean A , van Wyk Hester Catharina , Horgan Paul G. , McMillan Donald C , Roseweir Antonia K , Park James Hugh , Edwards Joanne 
Published: March 2017

631 Background: In patients with colorectal cancer (CRC) the local and systemic inflammatory responses (LIR and SIR) are important determinants of disease progression. The present study examines the association of transcription factor RelB, a key member of the non-canonical NF-κB pathway and its association with LIR and SIR in patients undergoing resection of CRC. Methods: Patients with stage I-III CRC who underwent curative resection in a single institution and were in a previously constructed tissue microarray were studied. IHC was utilised to examine cytoplasmic and nuclear RelB expression. The relationship between RelB, clinicopathological characteristics, LIR (Klintrup-Mäkinen (KM) grade, CD3+ and CD8+T-cell density), SIR and cancer-specific survival (CSS) was examined. Results: 208 patients were included in the analysis. Cytoplasmic RelB (cyto-RelB) was associated with nuclear RelB ( p=0.006). High expression of cyto-RelB was associated with MMR competence ( p=0.010) but not with TNM stage ( p=0.468), venous invasion ( p=0.973), tumour budding ( p=0.068), tumour necrosis ( p=0.786), tumour cell proliferation ( p=0.907), BRAF V600E mutation ( p=0.585) or administration of adjuvant chemotherapy ( p=0.853). High cyto-RelB was inversely associated with mGPS (mGPS >1: low cyto-RelB – 19% vs. high cyto-RelB – 8%, p=0.017). Also, cyto-RelB was inversely associated with tumour inflammatory cell infiltrate at the margin, Klintrup-Mäkinen grade ( p=0.059), (CD3+ p=0.010, CD8+ p=0.007) and in the tumour (CD3+ p=0.002) and a trend with tumour stroma percentage ( p=0.079). High expression of cyto-RelB was not significantly associated with CSS ( p=0.052). Conclusions: In patients undergoing CRC resection, high expression of cyto-RelB was associated with an adverse host local inflammatory response. Up-regulation of the non-canonical NF- κB pathway may be an important mechanism whereby the tumour deregulates local inflammatory responses and evades host immunosurveillance. Further investigation of inflammation based signal transduction pathways in patients with colorectal cancer is warranted.
Anti-KRAS siRNA nanoparticles for targeted colorectal cancer therapy.
Authors: Krasnick Bradley , Strand Matthew S. , Bi Ye , Goedegebuure Peter S. , Fleming Timothy , Wickline Samuel A. , Pan Hua , Fields Ryan C 
Published: March 2017

636 Background: Standard treatment for metastatic colorectal cancer (mCRC) is systemic chemotherapy with anti-EGFR treatment, depending on KRAS mutational status. However, tumors harboring a KRAS mutation do not respond to existing targeted therapy. Moreover, targeting mutant KRAS has, to date, not been possible. Herein, we explore using a KRAS inhibitory nanoparticle (NP), to directly knock down mutant KRAS. Methods: Utilizing fluorescent-labeled small interfering RNA (siRNA) NPs, uptake was assessed via fluorescent microscopy. KRAS mutant CT26 and wild-type MC38 CRC cell lines were incubated with either scramble (Sc) sequence siRNA NP, KRAS siRNA NP, or FOLFOX (fluorouracil + oxaliplatin) chemotherapy ± KRAS siRNA NP. Cell viability was assessed via a luminescent viability assay. KRAS and cleaved caspase 3 protein expression were assessed using western blotting. Results: Fluorescent NP uptake was demonstrated in CT26 cells as early as 260 minutes post treatment, with increased uptake through 780 minutes. Decreased cellular viability was seen with KRAS siRNA NP treated CT26 cells, as compared to both Sc siRNA NP and non-treated CT26 cells (both p < 0.0001). Cell viability was significantly diminished with FOLFOX combined with KRAS siRNA NP as compared to FOLFOX alone for CT26 cells ( p = 0.0003), but not MC38 cells (p = 0.2259). Western blot demonstrated decreased KRAS and increased cleaved caspase 3 expression in CT26 cells treated with KRAS siRNA NP. Conclusions: A KRAS siRNA tagged NP was internalized by the CRC cells in vitro, and induced cellular death via apoptosis in mutant type KRAS CRC. In addition, KRAS siRNA NP acted synergistically with FOLFOX chemotherapy to enhance cell death. We believe KRAS inhibition based NP treatment is a promising target for mutant type KRAS CRC. [Table: see text]