bluuebunny/crossref_metadata_2025_split huggingface dataset:
Surgeon specific effects on the postoperative systemic inflammatory response and complications following surgery for colorectal cancer.
Authors: McSorley Stephen Thomas , Roxburgh Campbell SD , McMillan Donald C , Horgan Paul G. 
Published: January 2019

799 Background: The present study examined the impact of surgeon specific differences on the postoperative systemic inflammatory response (SIR) as measured by postoperative C-reactive protein (CRP), and complications, following elective surgery for colorectal cancer. Methods: 684 patients who underwent elective colorectal cancer resection performed by 10 consultant surgeons at single centre between 2008 and 2016 were included. Exceeding the established C-reactive protein (CRP) threshold of 150mg/L on postoperative days (POD) 3 and 4 was used to identify outliers by funnel plot analysis. Surgeons with significant differences in the proportion of patients exceeding POD 3 CRP 150mg/L were compared. Significantly different perioperative variables amongst surgeons, and the surgeons themselves, were then entered into a multivariate binary logistic regression model to asses association with POD 3 CRP. Results: Perioperative factors were compared between 3 surgeons with the highest volumes and greatest difference in the proportion of patients exceeding POD 3 CRP 150mg/L (Figure 1); (35% of 137, 50% of 117, 60% of 92, p < 0.001). Amongst the 3 surgeons there were significant differences in comorbid state (p = 0.042), the proportion of patients undergoing minimally invasive surgery (p < 0.001), or surgery lasting over 4 hours (p < 0.001), requiring blood transfusion (p = 0.038), epidural anaesthesia (p < 0.001), and receiving perioperative steroids (p < 0.001). When those factors which were significantly different between surgeons were entered into a multivariate binary logistic regression model to predict exceeding the POD 3 CRP threshold of 150mg/L, only perioperative dexamethasone (OR 0.40, 95% CI 0.19-0.82, p = 0.012), and postoperative complications (OR 2.22, 95% CI 1.14-4.32, p = 0.018), remained independently associated whilst the surgeons themselves were not significantly associated (OR 1.16, 95% CI 0.59-2.30, p = 0.663). Conclusions: This study suggests that surgeon specific difference in the magnitude of the postoperative systemic inflammatory response are related to differences in surgical approach, anaesthetic technique and complications.
Claudin 18.2 expression in various tumor types and its role as a potential target in advanced gastric cancer.
Authors: Cho Jang Ho , Lim Sung Won , Kim Seung Tae , Lee Jeeyun , Park Se Hoon , Park Joon Oh , Park Young Suk , Lim Ho Yeong , Kang Won Ki 
Published: January 2019

80 Background: Alterations in claudin expression can impair tight junction functioning, influence signaling pathways, and act as a tumor promoting event in some epithelial cancers. Recently, IMAB362, a highly potent and tumor cell-selective therapeutic antibody to claudin 18.2, has been developed and investigated in clinical trials. Methods: We prospectively conducted claudin 18.2 immunohistochemistry on 430 consecutive patients with advanced gastrointestinal, genitourinary, or rare cancers between June 2012 and March 2016. Results: Most patients (414/430, 96.2%) were evaluable for claudin 18.2 expression by immunohistochemistry. In total, 4.1% (17/414) were deemed claudin 18.2+, including patients with pancreatic (16.7%, 1 of 6), gastric (14.1%, 12 of 85), biliary tract (6.3%, 1 of 16), genitourinary/miscellaneous (2.2%, 1 of 46), and colorectal (0.9%, 2 of 203) cancers. Twelve of 17 patients positive for claudin 18.2 had gastric cancers; this subgroup showed no statistical difference by gender, age, disease extent, primary tumor site, pathologic differentiation, HER2 status, or EBV status with or without claudin 18.2 expression. However, claudin 18.2 was more frequently positive in intestinal-type compared to diffuse-type by Lauren classification (p = 0.026). There was no significant difference in overall survival between patients with and without claudin 18.2 expression (p = 0.101). Conclusions: Our results add to the emerging literature on claudin 18.2 expression in various cancer types and support the need for extended clinical exploration of IMAB362.
Cost-effectiveness of FOLFIRI + cetuximab vs FOLFIRI + bevacizumab in the first-line (1L) treatment of RAS wild-type (wt) metastatic colorectal cancer (mCRC) in Germany: Data from the FIRE-3 (AIO KRK-0306) study.
Authors: Stintzing Sebastian , van Oostrum Ilse , Pescott Chris , Steinbach-Buechert Alma Katharina , Heeg Bart , Heinemann Volker 
Published: January 2019

800 Background: The randomized, phase 3 FIRE-3 trial evaluated 1L FOLFIRI + cetuximab or bevacizumab in patients with RAS wt mCRC; overall survival favored FOLFIRI + cetuximab by > 8 months. The purpose of this analysis was to evaluate the cost-effectiveness of FOLFIRI + cetuximab vs that of FOLFIRI + bevacizumab as 1L treatment for patients in Germany with RAS wt mCRC (including the patient subgroup with RAS wt, left-sided [LS] primary tumors, as LS is a predictive factor). Methods: A standard oncology 3–health-state partitioned survival cost-utility model was developed to analyze the costs and health benefits of FOLFIRI + cetuximab vs those of FOLFIRI + bevacizumab from a German payer perspective based on data from FIRE-3 and the literature. Health outcomes were reported in life-years (LYs) and quality-adjusted life-years (QALYs) gained. A 3.5% discounting rate was applied to the modeled costs and outcomes. Results: Discounted costs, health gains, and incremental cost-effectiveness ratios (ICERs) for patients with RAS wt (base case) and patients with RAS wt, LS (subgroup) mCRC are summarized in the Table. Probabilistic sensitivity analyses showed that at relevant European willingness-to-pay (WTP) thresholds of €55,000 and €80,000, FOLFIRI + cetuximab had a 64.0% and 81.6% (base case) and 80.5% and 92.4% (subgroup) probability of being cost-effective vs FOLFIRI + bevacizumab, respectively. Clinical trial information: NCT00433927. Conclusions: Based on our analyses, FOLFIRI + cetuximab is cost-effective compared with FOLFIRI + bevacizumab in patients in Germany with RAS wt mCRC at official WTP thresholds applied by relevant European health technology assessment agencies. The cost-effectiveness of FOLFIRI + cetuximab is more pronounced in the subgroup of patients with RAS wt, LS tumors.[Table: see text]
Clinical significance of morphologic response and tumor shrinkage as predictive factors of Capeox+bevacizumab in 1st line treatment of metastatic colorectal cancer.
Authors: Nagaoka Tomoyuki , Shinozaki Eiji , Watanabe Ryosuke , Ueno Eiko , Ota Yumiko , Osumi Hiroki , Nakayama Izuma , Wakatsuki Takeru , Ogura Mariko , Suenaga Mitsukuni , Ichimura Takashi , Takahari Daisuke , Chin Keisho , Yamaguchi Kensei 
Published: January 2019

805 Background: Capeox + bevacizumab (BV) is one of the standard treatment for metastatic colorectal cancer (mCRC) and well known to sometimes cause morphologic response (MR). However, it is not well known the predictive value of MR in palliative chemotherapy of Capeox + BV as 1st line. The aim of this study was to investigate the clinical significance of MR and tumor shrinkage as predictive factors of Capeox+BV in 1st line treatment of mCRC. Methods: A total of 159 patients with CLM were selected from 316 mCRC patients treated with Capeox+BV as 1st line chemotherapy from February 2006 to August 2016. Among these patients, 92 patients were enrolled in the this study, who satisfied following criteria; (1) tumor responce was assesed by enhanced computed tomography (CT) images every 2-3 months, and (2) dose intensity of BV at first 4 courses were above 80%. Tumor response of RECIST1.1 and MR were evaluated by 2 radiologists. They classified them as optimal, incomplete or no morphologic response according to the morphologic criteria. Results: An optimal morphologic response (OR) was observed in 34% of all patients. The median progression-free survival (mPFS) was 9.3 months in this cohort, 13.5 months in patients with OR and 11.6 months in those with incomplete/no morphologic response. And the median overall survival (mOS) was 19.5 months, 30.3 months and 23.8 months, respectively. There were no statistical significance between OR and the other, irrespective of mPFS and mOS. On the other hand, mPFS was 14.6 months in responder as CR or PR of RECIST and 8.6 months in non responder as SD or PD (p < 0.0001). Furthermore, mOS, 31.9 months and 18.5 months, respectively (p < 0.0001). Besides in 17 patients fulfilled both responder of RECIST and OR, the mOS reached 45.4 months, which was remarkably longer compared to the other groups ( < 0.0001). Conclusions: Among mCRC patients with CLM treated with Capeox+BV as the 1st line, the response of RECIST well reflected the therapeutic effect. On the other hand, MR solely was not a predictor of therapeutic effect in this study. However, both responder of RECIST and OR may be on-treatment predictors to identify excellent prognostic group.
Microsatellite instability as a predictive marker for response to neoadjuvant chemoradiation in locally advanced rectal cancer.
Authors: Shulman Rebecca Maria , Avkshtol Vladimir , DeMora Lyudmila , Esnaola Nestor F. , Hall Michael J. , Handorf Elizabeth , Meyer Joshua E. 
Published: January 2019

806 Background: Microsatellite instability (MSI) is a marker for hypermutability due to impaired DNA mismatch repair and has been shown to be a favorable prognostic marker in colon cancer. We examined the role of MSI in locally advanced rectal cancer (LARC) as a predictive marker for response to neoadjuvant chemoradiation (CRT). Methods: We identified T3-T4 or ≥ N1 rectal cancer with reported MSI status in the National Cancer Data Base from 2007 – 2012. Patients were eligible if they were treated with CRT followed by surgical resection. Squamous cell and carcinoid histologies were excluded. The primary outcome was neoadjuvant rectal (NAR) score, categorized as low ( < 8), intermediate (8-16), and high ( > 16), representing a good, intermediate, and poor response to CRT, respectively. The secondary outcomes were complete pathologic response (ypCR) rate and overall survival (OS). Chi-square, Fisher’s exact, and independent sample t-tests were used to compare MSI status. Multivariable logistic regression models were used to examine factors associated with increasing level of NAR score and ypCR. OS was examined using multivariable Cox proportional hazards models. Results: A total of 1849 patients were eligible for the study and were classified as MSI-high (n = 52) or MSI-low/stable (n = 1797). Patients in the MSI-high group were younger (median age 50.5 vs 57.0, p = 0.005) and had higher rates of mucinous and signet ring histology (p < 0.001), clinical T4 disease (p = 0.001), and clinically positive lymph nodes (p = 0.049). The two groups did not differ in gender, race, grade, or resection margin status. While clinical T and N stage, histology, LVI, tumor grade, and PNI were correlated with the NAR score groups, MSI-high status was not significantly associated with a higher NAR score group on multivariable analysis (OR 1.168, 95% CI 0.673 – 2.028). The MSI-high group also did not differ significantly from MSI-low/stable group in ypCR rate (OR 0.748, 95% CI 0.179 – 3.115) or OS (HR 1.727, 95% CI 0.864 – 3.453) on multivariable analysis. Conclusions: MSI status in LARC was not associated with NAR score, ypCR rate, or OS. Our results do not support the use of MSI status as a predictive marker for response to CRT in LARC.
Lymphocyte-to-monocyte ratio (LMR) compared to sidedness of primary tumor to predict outcome of anti-EGFR monotherapy in metastatic colorectal cancer.
Authors: Wyrwicz Lucjan , Temnyk Maciej , Rybski Sebastrian , Winiarek Mariola , Kokoszyńska Katarzyna 
Published: January 2019

809 Background: In RAS-wild type metastatic colorectal cancer (mCRC) treatment with cetuximab or panitumumab is the standard of care. Previously, the association between overall survival (OS) and inflamatory biomarkers were reported in several studies in mCRC (NLR, LMR). According to recent observations, primary site location can predict the superior outcome of anti-EGFR agents in first line of treatment. Here we test the relationship between inflamatory biomarkers and sidedness on outcomes of anti-EGFR therapy. Methods: Total 186 consecutive patients treated with panitumumab (n = 106) or cetuximab (n = 80) in monotherapy in third or following lines of palliative treatment were identified via electronic survey of medical records of Maria Sklodowska-Curie Memorial Cancer Center, Poland. All identified patients were treated within the state reimbursment programme with pre-specified inclusion criteria (including ECOG 0-2 mCRC, failure of previous irinotecan, oxaliplatin and fluoropiridine, all RAS-wt tumors) and treatment was administered until RECIST progression. The pretreatment inflamatory biomarkers (NLR, dNLR, LMR, PLR) were obtained for all patients. Results: Median overall survival of the cohort was 31.5 months when calculated from the start of treatment, with no difference for left- and right-sided tumors (31.8 m. vs 29.5 m.; p = 0.58). In third line treatment no difference in PFS between left- and right-sided tumors were observed (p = 0.22; PFSleft 4.82 m. vs PFSright 3.44 m.). No prognostic effect of either biomarker was noted on OS or time to failure of first two lines of treatment. Only a high lymphocyte-to-monocyte ratio (LMR > 2.6) and low derived neutrocyte-to-lymphocyte ratio (dNLR < 3.0) were associated with longer PFS on anti-EGFR treatment (5.5 m. in LMR > 2.6; 2.5 m. in LMR < 2.6; HR 0.53; p = 0.008). Notable, the patients with LMR > 2.6 were more likely to be diagnosed with left sided tumor (p < 0.001; 54% and 15% of left- and right-sided tumors respectively). Conclusions: High limfocyte-to-monocyte ratio may indicate the potential subpopulation of patients which can benefit mostly from anti-EGFR treatment in monotherapy in the refractory setting.
Plasma biomarker analysis of ramucirumab in Japanese patients with advanced gastric cancer.
Authors: Takahari Daisuke , Wakatsuki Takeru , Mashima Tetsuo , Chin Keisho , Ichimura Takashi , Ogura Mariko , MATSUSHIMA TOMOHIRO , Osumi Hiroki , Nakayama Izuma , Ota Yumiko , Shinozaki Eiji , Suenaga Mitsukuni , Kawata Naomi , Horiike Yuki , Seimiya Hiroyuki , Fujita Naoya , Yamaguchi Kensei 
Published: January 2019

81 Background: Ramucirumab, anti-VEGFR2 receptor antibody, showed significantly improved survivals of gastric cancer in the second line with paclitaxel or single use. Recently we reported early elevation of plasma VEGF-A was associated with shorter survival as a preliminary result. We will report the results of final analysis. Methods: Patients with advanced gastric cancer who received ramucirumab combined with paclitaxel or single use were enrolled. Plasma samples were collected at pre-treatment and day 8 after administration. Nine kinds of plasma biomarker involved in angiogenesis, VEGF-A, C, D, PlGF, VEGFR1, 2, Angiopoietin 1, stromal cell derived factor-1α (SDF1α), and Neuropirin-1, were measured by means of ELISA. Patients were dichotomized by optimal cut-off value. Univariate and multivariate analysis were done by Cox proportion hazard model. Results: Forty-one patients were enrolled. Thirty-nine patients (95.1%) received ramucirumab with paclitaxel. Plasma VEGF-A, D, PlGF, and VEGFR2 levels were significantly increased one week after administration compared with baseline levels, while plasma VEGFR1 and NRP1levels were significantly decreased. Median PFS and OS were 5.6 (95% CI 4.66-6.54) and 9.8 (95% CI 5.41-14.19) months, respectively. In univariate analysis, higher baseline SDF1α and PlGF levels resulted in shorter OS with HR 2.71 95% CI 1.23-6.00, p =0.013 for SDF1α and HR 2.78 95% CI 1.16-6.65, p =0.022 for PlGF. Higher D8 VEGF-A was associated with shorter PFS with HR 2.77 95% CI 1.39-5.51, p =0.004. While higher D8 VEGF-D was associated with better PFS with HR 0.39 95% CI 0.20-0.77, p =0.007. In multivariate analysis, higher baseline SDF1α and PlGF were independent negative prognostic factor for OS with HR 2.45 95% CI 1.10-5.42, p =0.028 for SDF1α and HR 2.48 95% CI 1.03-5.96, p =0.043. With respect to PFS, higher D8 VEGF-A was also independent negative prognostic factor with HR 2.32 95% CI 1.13-4.77, p =0.022, while higher D8 VEGF-D was favorable predictor for PFS with HR 0.47 95% CI 0.23-0.96, p =0.038. Conclusions: Higher base line SDF1α and PlGF levels may be negative prognostic marker. While early VEGF-A and D elevation after ramucirumab administration may be predictive marker of ramucirumab.
Clinical outcomes of anti-EGFR antibody treatment for right-sided colon cancer patients without RAS, BRAF, and PIK3CA mutations in the later line.
Authors: Ushida Yuta , Shinozaki Eiji , Chin Keisho , Suenaga Mitsukuni , Takahari Daisuke , Ozaka Masato , Ogura Mariko , Ichimura Takashi , Wakatsuki Takeru , MATSUSHIMA TOMOHIRO , Osumi Hiroki , Ota Yumiko , Yamaguchi Kensei 
Published: January 2019

812 Background: Several studies have reported that patients with right-sided colon cancers (RCC) have more unfavorable responses to anti-epidermal growth factor receptor (EGFR) antibody therapy than those with left-sided colon cancers (LCC). One of the causes is that RCC have more frequently genetic mutations such as RAS, BRAF, and PIK3CA than LCC. We investigated clinical outcomes of RCC patients treated with anti-EGFR antibody in the later line without these mutations. Methods: We reviewed 653 cases of colorectal cancer treated with anti-EGFR antibody from October 2009 to July 2017. There were 150 cases of RCC patients. Among them, 32 patients without KRAS status and 54 patients without enough genetic samples for gene re-analysis were excluded. We extracted 64 patients with status on RAS, BRAF, and PIK3CA , and finally enrolled 25 patients treated with anti-EGFR antibody plus irinotecan or anti-EGFR antibody alone in the later line. We analyzed the relationship of molecular status with clinical outcomes; overall response rate (RR), overall survival (OS) and progression-free survival (PFS) in this retrospective study. Results: Overall, there were 48% of cases with any mutations; among them 8.0% for KRAS, 4.0% for NRAS, 24.0% for BRAF and 4.0% for PIK3CA. Twenty percent of patients were treated as 2nd line therapy, while 72%, 16% treated as 3rd, 4th line therapy. RR of all cases, those whom without KRAS, RAS, RAS or BRAF, any mutations were 16.0%, 19.1%, 20.0%, 28.6%, 30.8%. The median OS and PFS in all wild-type patients were tended to be better than in those of all cases (OS; 14.9 vs. 11.6 months, hazard ratio = 0.70, p = 0.30, PFS; 8.17 vs. 5.37 months, hazard ratio = 0.67, p = 0.24). Conclusions: Even if primary tumors are in right-sided colon, in the enriched and selected patients anti-EGFR antibody therapy showed enough antitumor activity. Anti-EGFR antibody for RCC cases without using it at the front line is an effective option in the later line.
Impact of UGT1A1 gene polymorphism on survival in metastatic colorectal cancer patients treated with irinotecan-containing therapy.
Authors: Shirasu Hiromichi , Yamazaki Kentaro , Furuta Mitsuhiro , Kawahira Masahiro , Kawakami Takeshi , Yoshida Yukio , Kawai Sadayuki , Hamauchi Satoshi , Todaka Akiko , Tsushima Takahiro , Machida Nozomu , Yokota Tomoya , Fukutomi Akira , Onozawa Yusuke , Yasui Hirofumi 
Published: January 2019

813 Background: UGT1A1 polymorphisms have been reported to be associated with increased irinotecan (IRI)-induced toxicity. However, influence of the polymorphisms on survival in metastatic colorectal cancer (mCRC) patients (pts) treated with IRI-containing therapy remains controversial. Methods: We retrospectively reviewed data of consecutive mCRC pts who received FOLFIRI/IRI with or without an anti-VEGF agent as 2nd line therapy at the Shizuoka Cancer Center between April 2008 and December 2015. The primary selection criteria were histologically confirmed adenocarcinoma, prior history of oxaliplatin-containing therapy, and adequate organ function. UGT1A1 polymorphisms were screened and pts with homozygous (*6/*6, *28/*28) or compound heterozygous (*6/*28) were excluded. Results: Among 103 pts found eligible for this analysis, 63 were wild type (W) (−/−) for UGT1A1, and 40 were heterozygous type (H) (-/*6, -/*28), with the following characteristics: median age (range), 60 (30–77) vs 67 (37–84); male/female, 41/22 vs 18/22; PS 0/1/2, 40/21/2 vs 21/18/1; tumor location right/left, 16/47 vs 9/31; peritoneal metastasis −/+, 49/14 vs 33/7; disease status metastasis/recurrence, 49/14 vs 23/17; RAS wild type/mutant, 25/37 vs 18/21; IRI regimen doublet/mono, 51/12 vs 33/7; anti-VEGF agent use −/+, 16/47 vs 12/28; and median IRI dose intensity, 63.7 vs 60 mg/m2/week. Incidences of grade 3/4 neutropenia, febrile neutropenia, and diarrhea in W/H pts were 36%/48%, 5%/9%, 5%/13% (initial IRI dose 180 mg/m2). Median PFS was 6.2 M in W, and 3.9 M in H (p = 0.36). Median OS was 12.1 M in W and 10.9 M in H (p = 0.86). RR was 13% in W, and 10% in H (p = 0.68). DCR was 81% in W, and 58% in H (p = 0.012). Multivariate analysis identified no liver-limited disease, disease status (metastatic), UGT1A1 H type, IRI monotherapy, and no anti-VEGF as independent predictors of poorer PFS (HR 1.76, 2.01, 1.67, 2.17, 2.58), and initial dose of CPT < 180mg/m2 and no anti-VEGF as independent predictors of poorer OS (HR 1.85 and 1.85). UGT1A1 polymorphism was not detected as an independent predictor of RR or DCR. Conclusions: UGT1A1 polymorphism may be useful in predicting PFS in mCRC pts treated with IRI-containing therapy.
Feasibility and value of incorporating pharmacogenomic testing for genetic variants in UGT1A1 and DPYD genes in patients receiving irinotecan and/or 5-fluorouracil chemotherapy.
Authors: Baldeo Candice , Hughes Caren , Kasi Pashtoon Murtaza 
Published: January 2019

814 Background: The importance of pharmacogenomics in optimizing drug doses and avoiding adverse events is increasingly being recognized. The FDA has listed pharmacogenomic biomarkers as part of drug labeling in many medications including chemotherapies such as 5-fluorouracil and irinotecan. Pharmacogenomics may enable selection of the most tolerable treatment without compromising treatment success. Variation in the dihydropyrimidine dehydrogenase ( DPYD) and UGT1A1 gene mutations can increase the risk of 5-FU and irinotecan based chemotherapy respectively. Also, the feasibility of testing in real-time and incorporating results into management has not been demonstrated. The focus of our study was to demonstrate this in the real world scenario as a quality improvement project. Methods: In July-August 2017, 89 patients who were on irinotecan and/or 5-FU chemotherapy were tested for DPYD and UGT1A1 genetic variations at Mayo Clinic Florida. Testing was done through blood sample which was collected at routine clinic visit prior to starting therapy or in patients already receiving chemotherapy. Pharmacy electronic consultation was obtained for recommendations regarding current and/or future chemotherapy regimens, based on pharmacogenomics results. A medication therapy management (MTM) consultation from the pharmacist was incorporated and included into the patient’s chart. Results: Total number of patients who has some variation in the UGT1A1 and/or DPYD gene was 60 (67%). Specifically, there were 12 patients who were homozygous for the UGT1A1 gene and 3 homozygous for DPYD gene. Both genes were affected in 3 patients. One patient was triple heterozygous for DPYD and homozygous for UGT1A1. Pharmacogenomic results were obtained for these patients within 5 business days. Conclusions: A higher prevalence of UGT1A1 and DPYD variants were reported in our patient cohort tested than what is reported in the literature. Additionally, we were able to obtain results for these patients in a timely fashion. This was then further incorporated into medication therapy management consultation from the pharmacist, which added further value.