bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prospective analysis of UGT1A1 genotyping for predicting toxicities in advanced colorectal cancer (aCRC) treated with irinotecan (IRI)-based regimens: Interim safety analysis of a Japanese observational study.
Authors: Ichikawa Wataru , Uehara Keisuke , Minamimura Keisuke , Tanaka Chihiro , Takii Yasumasa , Sadahiro Sotaro , Miyauchi Hideaki , Shinozaki Katsunori , Miyagaki Takuya , Otsuji Toshio , Kambara Takeshi , Morita Satoshi , Ando Yuichi , Okutani Yukihiro , Sugihara Masahiro , Sugiyama Toru , Ohashi Yasuo , Sakata Yuh 
Published: March 2020

3535 Background: UGT1A1*6 and UGT1A1*28 are risk factors for severe IRI-related toxicities in Asians, but recommended IRI doses based on UGT1A1 genotypes and other risk factors are unclear. We conducted a prospective analysis to examine the correlation between UGT1A1 genotypes and the efficacy and safety of IRI-based regimens in Japanese aCRC patients (pts), (NCT 01039506). Methods: Pts who had histologically confirmed aCRC, PS of 0–2, received IRI-based regimens (FOLFIRI, IRI+S-1, IRI monotherapy), were UGT1A1 genotyped, and provided written informed consent were included. UGT1A1 polymorphisms were analyzed and categorized into 3 groups: wild (*1/*1), hetero (*1/*6, *1/*28), and homo (*6/*6, *6/*28, *28/*28). Detailed toxicities in the first 3 months of treatment were prospectively recorded. For interim safety analysis, incidences of grade 3–4 (severe) toxicities were compared among UGT1A1 genotypes and a logistic regression model was used to predict the risk of severe toxicities. Severe toxicities and associated risk factors were predicted using a nomogram and bootstrap validation was performed. Results: We enrolled 1376 pts between October 2009 and March 2012. At the time of abstract submission, toxicity data of 504 pts were available; 46% pts had wild, 44% hetero, and 11% homo polymorphisms. FOLFIRI was administered to 63% pts. Severe neutropenia developed during the first 3 months of treatment in 33% pts: 36% in hetero [OR, 1.5; 95% CI, 1.0–2.3], 47% in homo (OR, 2.3; 95% CI, 1.2–4.4), and 28% in wild. Severe diarrhea incidence was 5%, which did not correlate with UGT1A1 genotypes. Multiple logistic regression model included regimen, initial IRI dose, gender, age, UGT1A1 genotype, and PS as predictors of severe neutropenia in the first treatment cycle. The resulting nomogram demonstrated good accuracy in predicting severe neutropenia, with a bootstrap-corrected concordance index of 0.74. Conclusions: Considering UGT1A1 genotype along with other clinical factors is important for managing pts undergoing IRI-based regimens. Our presentation will provide analysis of data from more than 1000 pts. Clinical trial information: NCT01039506.
Using quantitative sensory testing as an early predictor of chronic oxaliplatin neuropathy in gastrointestinal cancer patients.
Authors: Reddy Sangeetha Meda , Kwon Nancy , Helenowski Irene B. , Harden Robert Norm , Paice Judith A. , Nimeiri Halla Sayed , Mulcahy Mary Frances , Benson Al B. , Vergo Maxwell Thomas 
Published: March 2020

3540 Background: Acute oxaliplatin neurotoxicity has been shown to be predictive of chronic neuropathy, a devastating irreversible adverse effect of oxaliplatin. Our study was designed to test the utility of quantitative sensory testing (QST) to measure acute oxaliplatin neurotoxicity at early time points to identify those at risk for developing chronic neuropathy. Methods: Gastrointestinal cancer patients receiving 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy were evaluated over a 1 year period for development of acute and chronic oxaliplatin neurotoxicity: before starting FOLFOX, 1 hour into oxaliplatin infusion, before cycles 2, 4 and 12, and 1 year after start of treatment. Patients underwent QST to measure thermal and mechanical sensitivities, vibration detection, pain sensation, and fine motor skills. Chronic neuropathy was measured using National Cancer Institute Common Toxicity Criteria for Adverse Events version 4. Results: We conducted analysis of 18 patients that have reached the 1 year followup period. We found thermal QST measured during cycle 1 infusion, which is indicative of acute neurotoxicity, to be predictive of 1 year neuropathy. Decreased cold detection intrainfusion during cycle 1 relative to baseline scores yielded a significant correlation to chronic neuropathy scores (rs= -0.53, p=0.03) and predicted grade 2 or 3 neuropathy (p=0.048). Furthermore, decreased cold detection scores intrainfusion showed trend towards correlation to neuropathy scores (rs= -0.45, p=0.07) and prediction of grade 2 or 3 neuropathy (p=0.07). Additionally, patients with higher tolerance to cold and heat intrainfusion were at higher risk for grade 1 or higher neuropathy (p=0.057 for cold pain, p=0.03 for heat pain). We also found decreased mechanical detection scores using von frey filaments as early as cycle 2 were correlated to 1 year neuropathy scores (rs=0.52, p=0.03) and predicted development of grade 2 or 3 neuropathy (p=0.008). Conclusions: We can use QST to identify high risk patients that are likely to develop chronic neuropathy at 1 year, allowing for targeted use of preventive measures to decrease the incidence of this debilitating adverse effect.
Association between c-Met expression and tumor recurrence in colorectal cancer patients after liver resection.
Authors: Shoji Hirokazu , Yamada Yasuhide , Taniguchi Hirokazu , Okita Natsuko , Takashima Atsuo , Honma Yoshitaka , Iwasa Satoru , Kato Ken , Hamaguchi Tetsuya , Shimada Yasuhiro 
Published: March 2020

3559 Background: c-Met is a receptor for hepatocyte growth factor that has been implicated in the pathogenesis and growth of a wide variety of human malignancies, including colorectal cancer (CRC). The aim of the present study was to clarify the correlation between c-Met protein expression in the primary lesion and relapse-free survival (RFS) in patients who had undergone curative hepatectomy for colorectal metastases. Methods: Between January 2004 and December 2009, formalin-fixed paraffin-embedded sections of surgical specimens from 108 CRC patients who had undergone hepatectomy were obtained at a single center. We performed immunohistochemical staining to detect c-Met expression. c-Met expression levels were scored dependent on staining intensity; 0, negative; 1, weak; 2, moderate; 3, strong. We defined scores 0 and 1 as c-Met-low, and scores 2 and 3 as c-Met-high. The Kaplan-Meier method and Cox proportional hazards model were used to investigate relationships between c-Met expression, patient characteristics, and RFS. Results: We identified 65 males and 43 females with a median age of 62 years. A total of 53% of patients underwent simultaneous resection of primary and metastatic liver lesions, and the others underwent metachronous resection. High levels of c-Met expression (c-Met-high) in the primary tumor were observed in 52% of patients. There were no differences in terms of size or number of metastatic liver lesions between the c-Met-low patients and the c-Met-high patients. RFS was significantly shorter in the c-Met-high patients (9.7 months) than that in the c-Met-low patients (21.1 months) in primary tumors (p=0.013). Multivariate analyses demonstrated that c-Met-high (hazards ratio [HR], 1.73; 95% confidence interval [95% CI], 1.08-2.79 for c-Met-high vs. c-Met-low) and hepatic resection for synchronous disease (HR, 2.17; 95% CI, 1.36-3.46 for synchronous vs. metachronous resection) were associated with worse RFS. Conclusions: High levels of c-Met expression in the primary tumor were associated with shorter RFS after hepatic metastasectomy.
Tumor perivascular PDGFBR as an independent prognostic factor in metastatic colorectal cancer.
Authors: Lindh Maja Bradic , Mezheyeuski Artur , Glimelius Bengt , Pfeiffer Per , Kure Elin , Ikdahl Tone , Skovlund Eva , Sorbye Halfdan , Tveit Kjell Magne , Pietras Kristian , Birgisson Helgi , Mulder Jan , Guren Tormod Kyrre , Ostman Arne 
Published: March 2020

3571 Background: New vessel formation is an essential factor for tumor growth and metastasis. Tumor vessels show reduced and variable pericyte coverage. Several pericyte markers have been identified, including platelet-derived growth factor receptor beta (PDGFbR), smooth muscle α-actin (ASMA) and desmin. Variability in pericyte status and its prognostic significance remains largely uncharacterized in colorectal cancer (CRC). The aim of the present study was to perform a preliminary analysis of the variability in expression of the three pericyte markers and to investigate the potential prognostic significance of perivascular PDGFbR (PV-PDGFbR). Methods: A population-based cohort was used for double-staining, performed on 100 tumors with CD34 and above-named pericyte markers. For the rest of the study a metastatic CRC (mCRC) collection from the phase III NORDIC-VII study was used. Analyses were performed on a tissue microarray with tumor material from 328 out of the 566 patients in the intention to treat population. All tumors and corresponding normal tissue were scored by immunohistochemistry (IHC) with regard to PV-PDGFbR. 255 and 97 cases were analyzed by IHC with regard to perivascular ASMA and microvessel density (MVD), respectively. Results: Analyses of the double-staining revealed independent and variable expressions of all three pericyte markers. Analyses of the NORDIC-VII cohort revealed two prognostic groups with low and high PV-PDGFbR expression. Median OS was 14.3 mo for PV-PDGFbR-low tumors (N=22) vs. 22.9 mo for PV-PDGFbR-high (N=306) tumors (HR=1.95; 95% CI 1.20-3.16; log-rank p=0.007). Multivariate analysis, including WHO performance status, alkaline phosphatase level and BRAF mutation status confirmed PV-PDGFbR as an independent prognostic factor of OS (HR=1.75; 95% CI 1.07-2.84; p=0.025). PV-PDGFbR was not significantly linked to perivascular ASMA or MVD. PV-PDGFbR in normal tissue was not associated with survival. Conclusions: CRC display a previously un-recognized variability in pericyte characteristics. Low tumor PV-PDGFbR level is associated with worse prognosis in patients with mCRC, in a manner independent of performance status, alkaline phosphatase levels and BRAF status.
Primary tumor resection in metastatic colorectal cancer (mCRC): A prospective cohort study.
Authors: Wong Shu Fen , Field Kathryn M , Kosmider Suzanne , Tie Jeanne , Wong Hui-li , Tran Ben , Tacey Mark , Shapiro Jeremy , McKendrick Joseph , Gibbs Peter 
Published: March 2020

3584 Background: The role of primary tumor resection in patients presenting with mCRC remains controversial. Previously reported survival benefits associated with primary tumor resection may not translate in the modern era of systemic therapies. We examined the impact of primary tumor resection on survival in a modern cohort of mCRC patients. Methods: Patients were identified using a clinician-designed mCRC registry involving 15 participating Australian sites from mid 2009. Patients were excluded if planned for curative metastasectomy or had incomplete data. Univariate logistic regression and multivariate cox regression was utilized to identify significant associations between resection, clinical variables and survival outcomes. Results: We identified 682 mCRC patients with median follow up 20 months. 40% (n = 275) had their primary in-situ. Rates of primary resection were higher for age > 70 years (OR 1.66 95% CI [1.22 – 2.26], p = 0.001) and Charlson score ≥3 (OR 1.50 [1.10 – 2.06], p = 0.011). Lower resection rates were observed for rectal v colon primary (OR 0.39 [0.28 – 0.55], p < 0.001), liver metastases (OR 0.59 [0.42 – 0.82], p = 0.002) and ECOG 2 - 4 (OR 0.64 [0.45 – 0.92], p = 0.015). There was a significant survival advantage for pts with primary tumor resection (median OS 21.3 vs 16.8 months; HR 0.63, p < 0.001), even when adjusting for known prognostic factors in a multivariate analysis (HR 0.56 [0.44 – 0.72], p < 0.001). Multivariate analyses also demonstrated that age > 70 years (HR 1.32 [1.03 – 1.71], p = 0.031) and ECOG ≥ 2 (HR 3.17 [2.43 – 4.15], p < 0.001) were significantly associated with poorer outcomes; whereas chemotherapy use (HR 0.61 [0.45 – 0.84], p = 0.002), bevacizumab use (HR 0.68 [0.52 – 0.89], p = 0.005) and rectal primary (HR 0.69 [0.53 – 0.91], p = 0.009) predicted improved survival. Conclusions: Our study suggests that primary tumor resection is associated with significant survival advantages for mCRC patients in the modern era of systemic therapies. The 40% of primary cancers in-situ is higher than previous mCRC studies and suggests a tendency for non-operative intervention in Australia. Further analysis aimed at examining the impact of other confounding variables such as tumor burden is ongoing and will be presented.
Peripheral blood monocytes as biomarkers for colorectal cancer.
Authors: Prenen Hans , Hamm Alexander , Wenes Mathias , Delamarre Estelle , D'Hoore Andre , Hendlisz Alain , Rothe Francoise , Sarmiento Roberta , Tejpar Sabine , Van Cutsem Eric , Schmidt Thomas , Gasparini Giampietro , Weitz Juergen , Mazzone Massimiliano 
Published: March 2020

3588 Background: Peripheral blood monocytes (PBM) represent a reservoir of inflammatory cells that contribute to cancer progression. When recruited into tumors, monocytes give rise to either macrophages or dendritic cells. Tumor-derived soluble factors can influence the differentiation of tumor-associated macrophages (TAMs) and drive their phenotype to either tumoricidal (M1) or pro-tumorigenic macrophages (M2). We hypothesized that PBM might change their phenotype already when in circulation and can be used as potential markers for early diagnosis of colorectal cancer (CRC) and its progression to metastatic disease. Methods: Monocytes were isolated by using magnetic microbeads conjugated to antibodies against CD14. In a monocentric training set we included 55 (27 non metastatic (NM), 38 metastatic (M)) untreated CRC patients. The third group included age and gender matched healthy volunteers (HV). Following RNA extraction, gene expression profiles of PBM were investigated by high throughput screening using Illumina. Statistical analysis was done on the microarray expression data to delineate a disease specific signature. A cut off was set to select the genes showing a minimum fold change of 1,5. A validation study was performed in three additional major oncological centers throughout Europe. Results: There was a broad overlap in the gene signature of PBM from NM and M patients, indicating that this signature already exists in an early stage. Then we assessed the performance of the gene signature of cancer versus HV as diagnostic tool, in particular the sensitivity and specificity, which were remarkably high in the ROC analysis. Out of 40 differentially expressed genes, 21 genes were confirmed by qRT-PCR analysis on samples processed independently. In the validation study the number of genes was downsized to a 12 gene signature without loss of specificity and sensitivity. Conclusions: This first biomarker study of PBM in CRC suggests an ‘imprinting’ of PBM by the tumor in CRC patients. Since the imprinting profile might also be reversed, the PBM signature might not only be useful in CRC diagnosis, but also for the follow-up of treated CRC patients. Overall, our data offer new opportunities to develop a non-invasive test for CRC detection and monitoring.
Association of body mass index (BMI) with overall survival (OS) in patients (pts) with metastatic colorectal cancer (mCRC) who received targeted therapies (TT).
Authors: Patel Gargi Surendra , Ullah Shahid , Beeke Carol , Hakendorf Paul , Padbury Rob , Price Timothy Jay , Karapetis Christos Stelios 
Published: March 2020

3592 Background: Preclinical data suggest that adiposity activates pro-inflammatory and insulin-dependent pathways which may lead to resistance to TT, e.g., bevacizumab (Bev) or cetuximab (Cet). Only two retrospective trials have studied the relationship between BMI and outcome for mCRC pts who received TT, with conflicting results. Our aim was to compare OS across BMI groups for mCRC pts treated with TT. Methods: Retrospective data, pertaining to clinical characteristics and outcome, were obtained from the South Australian Registry for mCRC from Feb 2006-Oct 2012. The BMI at first treatment was grouped as Normal (N) = 18.5- <25, Overweight (OW) = 25- <30, Obese I(Ob1) = 30- <35, Obese II (Ob2)≥35. Results: Of 1,174 pts, 39% were OW, 15% Ob1 and 7% Ob2. 352 pts received chemo+TT (Bev, Cet, panitumumab (Pan) and/or regorafenib) and 814 chemo alone. Baseline characteristics were similar across all BMI groups except for type of mCRC: N pts were more likely than obese pts to have synchronous CRC (77.9% vs 56-69.7% for obese). On adjustment for age, sex, synchronous disease, metastatic sites, number of lines of chemo and TT, median OS was longer for N versus OW or Ob1 pts with chemo+TT (35.4 vs 24.9 or 22.7 mons, Table) with no difference in OS for chemo alone. Only N gp pts had an improvement in OS on the addition of TT to chemo. On breakdown by type of TT, OW and Ob1 pts had a poorer outcome with Bev but not with EGFR TT. Conclusions: The BMI is an independent predictor for a poorer outcome for OW and OB1 pts with chemo+TT, specifically for pts receiving Bev. The OW and OB1 patients may be a target group for lifestyle and nutrition advice to improve OS with TT. Prospective studies are required to validate this finding. [Table: see text]
A French multifactorial prospective study of tumor protein and genetic markers in stage I-III colorectal cancer (CRC): Highlight on molecular characteristics related to mismatch repair (MMR) status.
Authors: Milano Gerard , Chazal Maurice , Laurent-Puig Pierre , Olschwang Sylviane , Gaub Marie-Pierre , Formento Jean-Louis , Formento Patricia , Abderrahim-Ferkoune Anissa , Benchimol Daniel , André Thierry , Houry Sydney , Faucheron Jean-Luc , Letoublon Christian , Gilly Francois-Noel , Delpero Jean-Robert , Lasser Philippe , Pradere Bernard , Pezet Denis , Etienne-Grimaldi Marie-Christine 
Published: March 2020

3596 Background: There is still a need to identify prognostic markers in stage II CRC for setting up adjuvant treatment. The prognostic value of tumor genetic and protein markers was analyzed in CRC patients, as well as relationships between markers. Given the strong prognostic and predictive value of deficient MMR (dMMR), we examined whether dMMR tumors had a distinct protein profile as compared to proficient (pMMR) tumors. Methods: This prospective multicentric study involved 251 stage I-II-III CRC patients with complete surgical resection. Primary end-point was disease free survival (DFS, 60 events, median follow-up 88 months). Biomarkers analyzed on frozen primary tumors were: MMR status (bat 25, bat 26), mutations of KRAS (codons 12-13), BRAF (V600E), PIK3CA (exons 9 and 20), APC (exon 15) and P53 (exons 4-9), CIMP status, ploidy, S-phase fraction, LOH (8p, 17p, 18q), EGFR (ligand-binding assay), VEGFA expression (Elisa), thymidylate synthase (TS) enzyme activity and expression (RT-PCR), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) expressions (RT-PCR). Results: 30 stages I, 116 stages II and 105 stages III were included (FUFOL adjuvant treatment in 30 stages II and 61 stages III). 14% were dMMR. Multivariate Cox analyses showed that tumor staging was the only significant predictor of DFS. Log Rank analyses restricted to stage III showed tendencies for a shorter DFS in KRAS-mutated (p=0.005), BRAF wt (p=0.009) and pMMR tumors (p=0.036). dMMR tumors significantly expressed elevated TS (median 3.1 vs 1.4) and TP (median 5.8 vs 3.5) expression relative to pMMR (p<0.001) and tended to express higher DPD expression (median 14.9 vs 7.9, p=0.027) and EGFR content (median 69 vs 38, p=0.037) relative to pMMR. Conclusions: The present data, suggesting for the first time that both TS (5FU target) and DPD (FU catabolism enzyme) are overexpressed in dMMR tumors, bring strong arguments to explain the resistance of dMMR CRC tumors to FU-based therapy. The fact that dMMR tumors tend to express elevated EGFR levels and are prone to be KRAS wt suggests that anti-EGFR may be a relevant therapy in these patients. Clinical trial information: 1997.CHUNice-948.
Circulating angiogenic factors as predictors of benefit from bevacizumab (bev) beyond progression in metastatic colorectal cancer (mCRC): Traslational analyses from the phase III BEBYP trial.
Authors: Antoniotti Carlotta , Loupakis Fotios , Cremolini Chiara , Bocci Guido , Fioravanti Anna , Masi Gianluca , Salvatore Lisa , Marmorino Federica , Orlandi Paola , Schirripa Marta , Bergamo Francesca , Zoratto Federica , Di Desidero Teresa , Canu Bastianina , Danesi Romano , Falcone Alfredo 
Published: March 2020

3603 Background: TML and BEBYP trials demonstrated that the strategy of prosecuting bev beyond progression is effective in mCRC. Previous analyses from phase II studies showed that a modulation of plasma angiogenic factors occurs during 1st-line treatment with chemotherapy (CT) + bev and a wide variability in soluble Vascular Endothelial Growth Factor Receptor-2 (sVEGFR-2) levels was observed at the time of progression. Moving from preliminary analyses in murine models we selected a pool of candidate ligands to be tested in the clinical setting. Methods: sVEGFR2, Placental Growth Factor (PlGF), Platelet-Derived Growth Factor-C, basic Fibroblast Growth Factor, Angiopoietin-2 and soluble Tie-2 were assessed by ELISA on plasma samples collected at baseline in a cohort of 59 patients enrolled in phase III BEBYP trial of 2nd-line CT ± bev beyond progression to a bev-containing first-line regimen. Plasma levels were defined high or low adopting the median values as cut-off. Results: A significant interaction between treatment arm and baseline sVEGFR-2 levels was observed (p=0.036). Among 30 patients with high sVEGFR-2 levels, the prosecution of bev was associated with a significant benefit in terms of PFS (median: 10.4 vs 3.4 months, HR 0.37 [95%CI 0.10-0.58], p=0.0015), that was not evident among 29 patients with low sVEGFR-2 levels (5.4 vs 5.0 months, HR 0.98 [95%CI 0.45-2.11], p=0.956). Despite a trend towards a greater benefit from bev among 30 patients with high PlGF levels (HR 0.45 [95%CI 0.13-0.86]), no interaction between treatment arm and baseline PlGF levels was observed (p=0.210). Combined analysis of sVEGFR-2 and PlGF showed that prosecuting bev provided a substantial benefit in PFS in the subgroup with high levels of both ligands (10.5 vs 2.3 months, HR 0.25 [95%CI 0.01-0.45], p=0.043). Conclusions: sVEGFR-2 levels at the time of first progression may predict benefit from prosecuting bev. Interesting results from simultaneous analysis of sVEGFR-2 and PlGF may be affected by a pronounced subgrouping and should be considered cautiously. Given their potential clinical value, these data need prospective confirmation. Clinical trial information: NCT00720512.