bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of routine image follow-up in nonmetastatic colorectal cancer after curative surgical resection.
Authors: Diniz Lara Azevedo , Karani Amanda , De Brito Sales Diogo , Machado Larissa , Barros Milton Jose 
Published: January 2019

524 Background: Follow-up surveillance is performed after primary treatment in colorectal cancer (CRC), but it is controversial in the literature the real benefit of an intensive examination in terms of outcomes and resources. Intensive follow-up after surgery for colorectal cancer has been challenged by some new published data (CEA watch trial and FACS trial). These new data suggest that a less intensive follow-up program based on carcinoembryonic antigen (CEA) measurements or CEA-Triggered imaging would be enough to detected most of the recurrences. We believe that there is a high percentage of patients with recurrence disease and normal CEA value, for whom image screening would be necessary to detect early disease recurrence suitable to metastasectomy with curative intention. Methods: This is a retrospective study that included 372 patients from a tertiary cancer center in São-Paulo (Brazil) diagnosed with colorectal adenocarcinoma stages I to III. We observed, after primary treatment, a pattern of recurrence detected either by CT (computed tomography) imaging only or CEA elevation and CT image in combination. Results: Out of the 372 patients analyzed, 110 (29,5%) had recurrent disease with a median follow-up time of 34 months. Of the 110 recurrences detected, 75 (68,18%) were detected by CEA elevation in combination with CT image, 33 (30%) were detected only by CT image and 2 (1,81%) neither by CT nor by CEA alteration. There was no clinic feature that would predict pattern of recurrence when analyzed by qui square test. Metastasectomy rate from this analysis 53,6% and it was similar among both groups. Recurrence rate after metastasectomy was 59,3%. There is a 5-year overall survival difference between patients that underwent or not metastasectomy (79,4% vs. 54%, p 0,01). Conclusions: CEA-based follow-up program and CEA-triggered imaging failed to detect early recurrence in almost 30% of cases. We believe that this number is high enough to allow us to continue to perform image test during CRC follow-up.
The incidence of infusion reactions associated with monoclonal antibody drugs targeting the epidermal growth factor receptor in metastatic colorectal cancer patients: A systematic literature review and meta-analysis.
Authors: Lowe Kimberly , Bylsma Lauren C , Dean Rebecca , Gillezeau Christina , Sangaré Laura , Alexander Dominik D , Fryzek Jon 
Published: January 2019

526 Background: Infusion reactions have been reported in studies of metastatic colorectal cancer (mCRC) patients treated with anti-EGFR therapies, including cetuximab and panitumumab, with incidences ranging from 0-33%. A systematic literature review and meta-analysis were conducted to estimate the incidence of infusion reactions in this population and identify variations in this incidence by patient and study characteristics. Methods: Multiple scientific databases were searched to identify observational studies or clinical trials of mCRC patients treated with anti-EGFR therapies that reported rates of infusion reactions, hypersensitivity, or allergy/anaphylaxis. Random effects models were used to meta-analyze the incidence of infusion reactions overall and stratified by therapy, study design, geographic location, KRAS mutation status, and grade of reaction severity. Results: Among 48 studies included in this meta-analysis, the pooled estimate for infusion reaction incidence was 0.049 (95% CI: 0.036 – 0.065), or nearly 5%. Reactions of grades 1 or 2 were more common than reactions of grades 3-5 (0.089 vs. 0.028) No significant variations in infusion reaction incidence were observed by study design, KRAS status, or study location. Conclusions: Infusion reactions occur in approximately 5% of mCRC patients treated with anti-EGFR therapies and the incidence varies significantly by grade and severity. Future studies should consider investigating survival outcomes for only those patients with infusion reactions to determine its prognostic relevance.
Genomic and immune infiltration differences between MSI and MSS GI tumors.
Authors: Newton Yulia , Golovato Justin , Tan Iain Beehuat , Lam Justina Yick Ching , Yu Guo , Koo Si-Lin , Chua Clarinda , Yeong Joe Poh Sheng , Ping Christine , Skanderup Anders , Göke Jonathan , Johnson Mark , Rabizadeh Shahrooz , Sanborn J Zachary , Benz Stephen Charles , Vaske Charles Joseph , Szeto Christopher 
Published: January 2019

528 Background: Dysregulation of DNA mismatch repair pathway can lead to microsatellite instability in many GI tumors, and microsatellite instability is an important diagnostic and prognostic marker. Microsatellite instable (MSI) tumors comprise about 15% of colorectal malignancies and can be found in other gastrointestinal (GI) tumor types. We present results of analysis of genomic and immune infiltration differences between MSI and microsatellite stable (MSS) GI tumors spanning multiple cancer types. Methods: A total of 521 GI patients with deep whole exome sequencing (WES) of tumor and blood samples, and whole transcriptomic sequencing (RNA-Seq) (∼200M reads per tumor) were available for this analysis from a commercial database. Variant calling was performed through joint probabilistic analysis of tumor and normal DNA reads, with germline status of variants being determined by heterozygous or homozygous alternate allele fraction in the germline sample. Results: Gene expression and pathway analysis found significantly higher immune signaling in MSI cohort and higher metabolic signaling in MSS cohort. We also found upregulation of structural cellular integrity pathways in MSI tumors. Per-sample deconvolution of immune infiltration using cell type gene markers shows some MSI samples with high CD8 T-cells. Co-expression analysis of checkpoint and TME genes shows higher correlation of FOXP3 and CTLA4 in the MSS cohort compared to the MSI samples, whereas correlation between FOXP3 and PDL1 is decreased. TIM3, LAG3, and OX40 are significantly more expressed in MSI samples than MSS samples. Within the subset of colorectal tumors, additional checkpoints are significantly differentially overexpressed in MSI malignancies. 50 somatic variants are significantly differential in MSI tumors. Conclusions: MSI tumors demonstrably exhibit higher immune signaling, with many immune and checkpoint markers expressed at higher levels in MSI tumors. Some cellular integrity pathways also appear to be up in MSI cohort. A number of potentially important somatic variants are associated with MSI samples.
Assessment of systemic and metastatic neutrophilic inflammation in synchronously resected colorectal cancer and liver metastases.
Authors: Steele Colin William , Roxburgh Campbell SD , McMillan Donald C , Horgan Paul G. , Samson Owen J 
Published: January 2019

534 Background: Immunotherapy has proven a largely ineffective treatment for MMR proficient colorectal cancer (CRC). Resistance to immunotherapy is due to the immunosuppressive microenvironment of colorectal cancer, with CMS4 disease proving most aggressive. Using a cohort of synchronously resected CRC and metastases we examine the relationships between common immune cells in the circulation and microenvironment of primary and secondary CRC to assess microenvironmental determinants of outcome in metastatic CRC. Methods: 46 patients that had synchronous resection of primary CRC and liver metastasis at Glasgow Royal Infirmary were included. The relationships between Neutrophil lymphocyte ratios (NLR), tissue MPO and CXCR2 positive neutrophils, CD68 positive macrophages, and CD8 positive effector T cells and Klintrup-Makinen (KM) scores were quantified. Results: There was correlation between MPO and CXCR2 positive neutrophils (r = 0.668, P = 0.014) within metastases and both of these factors were independently associated with poor outcome ( P < 0.001, P = 0.002 respectively). High CD8+ T cells numbers and KM grade in both primary and metastatic niches were independently associated with better outcome following synchronous resection (P < 0.01). High systemic neutrophil counts (NLR) were associated with poor outcome in patients having synchronous resection (P = 0.001) and correlated with neutrophil numbers in metastases (r = 0.329, P = 0.05). MPO (P < 0.001) and CXCR2 (P = 0.004) positive neutrophils within the metastatic niche and KM grade of the primary tumour (P = 0.002) remained negative prognostic indicators on multivariate analysis. Conclusions: While CD8+ T cells impact positively on prognosis, the negative impact of neutrophils within the metastatic niche is the strongest determinant of outcome in synchronously resected CRC. This study raises questions as to the heterogeneity of neutrophils within primary and metastatic colorectal cancer and whether negatively prognostic neutrophils can be phenotyped and therapeutically targeted.
CEA expression patterns determine response and resistance to the CEA-TCB bispecific immunotherapy antibody in colorectal cancer patient derived organoids.
Authors: Gonzalez Exposito Reyes , Semmianikova Maria , Griffiths Beatrice , Khan Khurum Hayat , Barber Louise J , Woolston Andrew , Spain Georgia , von Loga Katharina , Swain Amanda , Thomas Janet , Bryant Annette , Mansfield David , Rao Sheela , Watkins David J. , Chau Ian , Starling Naureen , Matthews Nik , Wallberg Fredrik , Cunningham David , Gerlinger Marco 
Published: January 2019

535 Background: The bispecific antibody CEA-TCB binds Carcino-Embryonic Antigen (CEA) on cancer cells and CD3 on T cells. This triggers T cell killing of colorectal cancer cell lines expressing moderate to high levels of CEA at the cell surface (Bacac, Clin Cancer Res 2016). Patient derived organoids (PDOs) may more accurately represent patient tumors than established cell lines. Yet, determinants of CEA-TCB resistance have not been studied in PDOs. Methods: PDOs were established from biopsies of eight multidrug-resistant metastatic CRCs, GFP labelled and adapted to 2D culture. Allogenic CD8 T cells and CEA-TCB or a non-targeting control antibody were added and cancer cell killing and growth were monitored for 10 days. CEA expression of PDOs was determined by FACS. Results: CRC PDOs could be categorized into three groups based on CEA cell-surface expression: CEAhigh (n = 3), CEAlow (n = 2), and CEA heterogeneous PDOs (n = 3) that stably maintained populations of both CEAhigh and CEAlow cells, which has not previously been described in CRC cell lines. Heterogeneity of cell-surface CEA expression is common in CRC cells in patients, supporting that PDOs may better represent these tumors than established cell lines. CEAhigh cells were sensitive whereas CEAlow cells showed resistance to CEA-TCB. All PDOs with heterogeneous CEA expression were resistant to CEA-TCB, suggesting that CEA-negative cells maintain cancer cell growth. Culture of FACS sorted CEAhigh and CEAlow cells from PDOs with heterogeneous CEA expression demonstrated high plasticity of CEA expression which may contribute to rapid resistance acquisition through CEA antigen loss. Conclusions: These results suggest that cell-surface CEA expression is a major determinant of CEA-TCB sensitivity and resistance in PDOs. In addition, we identified heterogeneous CEA expression in several PDOs and demonstrated that this could confer CEA-TCB resistance in vitro. These PDO models are likely to provide insights into the mechanism of CEA loss and may inform therapeutic opportunities to counter CEA-TCB resistance. RNA-sequencing and functional experiments are ongoing to investigate this and will be presented.
Activation of central/effector memory T cells in advanced gastric cancer patients treated with antiprogrammed death-1 antibody.
Authors: Ohmura Hirofumi , Yamaguchi Kyoko , Hanamura Fumiyasu , Ito Mamoru , Makiyama Akitaka , Uchino Keita , Shimokawa Hozumi , Esaki Taito , Mitsugi Kenji , Shibata Yoshihiro , Oda Hisanobu , Tsuchihashi Kenji , Ariyama Hiroshi , Kusaba Hitoshi , Akashi Koichi , Baba Eishi 
Published: January 2019

54 Background: Anti-programmed death-1 (PD-1) monoclonal antibody, nivolumab, enhances antitumor activity by inhibiting the interaction of PD-1 and programmed death-1 ligand 1 (PD-L1) and has shown efficacy for advanced gastric cancer (AGC) in the salvage line. However, specific subsets of immune cells predominantly activated during the period of anti-PD-1 therapy for AGC have not been clarified. Methods: Peripheral blood mononuclear cells of 20 AGC patients treated with nivolumab were prospectively obtained before the initial and second administrations of nivolumab, and at the time of progressive disease (PD). The proportion of immune cell subsets were systematically analyzed by flow cytometry, including the expression of costimulatory and coinhibitory molecules such as T-cell immunoglobulin and mucin domain 3 (TIM-3), Lymphocyte-activation gene 3 (LAG-3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), cytotoxic T cell antigen-4 (CTLA-4), CD28, OX40, and inducible T cell costimulator (ICOS). Association between changes in the proportion of the subsets and therapeutic effect were analyzed. Results: Median progression free survival (PFS) of the whole patients was 51 days (95% CI 35–83). After a single course of nivolumab, patients showed a significant increase in activated effector memory and activated effector subsets of CD4+/CD8+ T cells (p = 0.018, 0.018, 0.032, 0.024). At the time of PD, proportions of myeloid dendritic cell, IgM memory B cell and Tfh-Th1/17 cell subsets decreased (p = 0.024, 0.013, 0.0039). On the other hand, LAG3 positive CD4+/CD8+ T cells, TIM-3 positive CD4+/CD8 T cells increased at the time of PD (p = 0.013, 0.032, 0.042, 0.042). Significant positive correlations were found between PFS and the proportion of LAG3 positive CD4+/CD8+ T cells (p = 0.0056, 0.0054), OX 40 positive CD4+/CD8+ T cells (p = 0.0034, 0.0006) prior to the initial nivolumab therapy. Conclusions: Nivolumab therapy enhances activation of effector memory and effector subsets of CD4+/CD8+ T cells. The expression level of LAG3 and OX40 on T cells might be correlated with efficacy of nivolumab therapy.
Pretreatment metabolomic markers associated with therapeutic responses to FOLFOX with bevacizumab in chemotherapy-naive patients with colorectal cancer.
Authors: Tanigawara Yusuke , Sugimoto Shinji , Muro Kei 
Published: January 2019

540 Background: FOLFOX with bevacizumab (BV) is a standard treatment for metastatic colorectal cancer (mCRC); however, its clinical response is around 50% and there is no way to predict responders prior to therapy. In this study, we attempted to identify new biomarkers associated with positive therapeutic responses by means of a comprehensive metabolomic analysis of patient serum. Methods: Serum collected from 68 mCRC patients, who were registered in a phase II study of first-line FOLFOX with BV treatment (Nishina, JJCO 2013) was used to conduct a comprehensive metabolomic quantification analysis using a capillary electrophoresis time-of-flight mass spectrometry. Responders (Rs: n = 37) and non-responders (NRs: n = 31) were defined as those achieving a status of CR/PR and SD/PD, respectively, which were assessed by an extramural review board using RECIST. Statistical analyses were performed using a logistic regression model for treatment response and Cox proportional hazard analysis for overall survival (OS). Results: Among 470 annotated endogenous metabolites, cysteine-glutathione disulphide (CSG), gamma-glutamyl cysteine (gGC) and hypoxanthine (HPX) were identified as significant (p < 0.05) metabolites associated with positive therapeutic responses by both response and survival analyses. Patients were divided into two groups according to cutoff values of pretreatment serum levels of these metabolites. The actual response rate in the high CSG, gGC and HPX group were 86, 69 and 8% whereas those in the low group were 40, 26 and 64%, respectively. The hazard ratio (HR) for OS in CSG, gGC and HPX were 0.28 (p < 0.01), 0.37 (p < 0.01) and 2.39 (p < 0.05), respectively. Using CSG, gGC and HPX, we have developed a multivariate logistic regression model to predict Rs/NRs and survival benefit based on the three metabolite levels in pretreatment serum. Sensitivity, specificity, ROC AUC and HR of OS between Rs and NRs were 89%, 65%, 0.83 and 0.36 (p = 0.002), respectively. Conclusions: We identified three novel pretreatment serum metabolomic markers that are associated with treatment response to FOLFOX with BV in chemotherapy-naive mCRC patients. Clinical trial information: UMIN000001490.
The parametric estimation procedure to predict long-term efficacy on survival from publication data of clinical trials for metastatic colorectal cancer (mCRC).
Authors: Pak Kyongsun , Sunakawa Yu , Takeuchi Masahiro , Ichikawa Wataru , Fujii Masashi 
Published: January 2019

541 Background: In comparative clinical trials with time-to-event outcomes, the long-term treatment effect profile is clinically crucial. The conventional non-parametric measures, i.e., the median survival times and the t-year survival rates are informative but sometimes cannot be observed due to the limited study follow-up. For example, in the PEAK trial (Schwartzberg LS et al. J Clin Oncol 2014), the group contrast over 3 years could not be adequately confirmed due to the short follow-up. To predict the subsequent survival prognosis with the limited outcome data, one may estimate the survival curve using a parametric model. Here, we illustrate the parametric estimation procedure to predict long-term efficacy using the results of two randomized controlled trials for the patients with wild-type KRAS mCRC, i.e., PRIME (Douillard JY et al. J Clin Oncol 2010, Douillard JY et al. Ann Oncol 2014) and PEAK trials. Methods: We considered both the primary and updated results for the PRIME to assess the validity of the procedure, and then estimated the long-term efficacy in the two trials. We used the reconstructed overall survival (OS) data obtained by scanning the Kaplan-Meier curves in the literature. Fitting the data to the Weibull distribution, we estimated the parametric group contrast measures including the difference in the 3- and 5-years restricted mean survival times and mean survival times. Results: The extrapolated parametric OS curves from the primary PRIME results fitted well with the observed Kaplan-Meier curves for OS in the updated results. The parametric estimations demonstrated that, in the PRIME trial, panitumumab plus FOLFOX arm increased 2.0 (95% CI: 0.1-4.0), 4.0 (0.5-7.5), and 5.4 (0.3-10.5) months in survival on average over 3-, 5-years and the entire time, respectively, compared to FOLFOX arm. In PEAK trial, compared to bevacizumab plus FOLFOX arm, panitumumab plus FOLFOX arm increased 3.6 (0.7-6.5), 7.9 (2.1-13.7), and 12.8 (0.5-25.1) months in survival on average, respectively. Conclusions: The estimators for parametric survival curve would provide the informative summaries for long-term survival profile to the clinicians and patients.
Prospective analysis of microRNA 31-3p (miR31-3p) as a predictive biomarker of response to anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies (mABs) in patients with metastatic colorectal cancer (mCRC).
Authors: Anandappa Gayathri , Lampis Andrea , Cunningham David , Kouvelakis Kyriakos , Khan Khurum , Vlachogiannis George , Tunariu Nina , Rao Sheela , Watkins David , Starling Naureen , Braconi Chiara , Peckitt Clare , Thomas Janet , Rana Isma , Begum Ruwaida , Bryant Annette , Hahne Jens , Chau Ian , Fassan Matteo , Valeri Nicola ,   Julie Duncan, The Royal Marsden Hospital NHS Foundation Trust
Published: January 2019

548 Background: RAS status in tissue and/or liquid biopsies and tumour location (sidedness) are predictive markers of patients’ response to anti-EGFR mABs. MiR-31-3p expression has been correlated with clinical benefit from anti-EGFR mABs with chemotherapy. We aimed to validate the predictive power of miR-31-3p in a prospective cohort of chemo-refractory mCRC patients treated with single agent anti-EGFR mABs in the PROSPECT-C trial (NCT02994888). Methods: MiR-31-3p was tested by in-situ hybridization in 91 pre-treatment (PT) core biopsies from 45 mCRC patients. Sequential tissue biopsies obtained PT, at time of best response and at disease progression were tested to monitor changes in miR-31-3p expression over treatment. In 34 patients miR-31-3p, gender, sidedness, previous lines of treatment and RAS status in PT cell free (cf) DNA were evaluated in multivariate Cox and logistic regression models. Results: Patients with low miR-31-3p expression in PT biopsies showed better overall response rate (ORR: 58.3% vs 22.2%), median progression free survival (mPFS: 4.21 vs 2.27 months) and overall survival (mOS: 4.21 vs 2.27 mo) compared to those with high miR-31-3p expression (Hazard Ratio for PFS high vs low: 1.96; 95% CI: 0.98-3.88; p: 0.06 and HR for OS high vs low: 2.14; 95% CI: 1.04- 4.40; p: 0.04) adjusting for age, gender and sidedness. There was significant association between ORR and miR-31-3p expression (χ2 test p: 0.029). MiR-31-3p expression was an independent predictor of response, adjusting for gender, previous treatment lines and RAS (odds ratio: 0.14; 95% CI: 0.02-1.00, p: 0.048). A trend towards improved mPFS (5.10 vs 2.27 mo) and mOS (15.23 vs 4.67 mo) was noted in miR31-3p low vs high group in cfDNA RAS wild-type patients. No significant change in miR-31-3p expression were observed in archival tissue and sequential tissue biopsies. Conclusions: Our study validates the role of miR-31-3p as potential predictive biomarker of selection for anti-EGFR mABs. Further studies are needed to test if miR-31-3p combined with cfDNA RAS test can identify best responders in specific clinical niches.