bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single center analysis of immunotherapy in mCRC patients.
Authors: Ruckser Reinhard , Hoenigschnabl Selma , Kitzweger Elvira , Tatzreiter Georg , Kier Peter , Habertheuer Karlheinz , Zelenka Peter , Buxhofer-Ausch Veronika , Reiner-Concin Angelika , Sebesta Christian 
Published: March 2020

e14087 Background: Immunotherapy in real-life, unselected patients with metastatic colorectal cancer (mCRC) was analyzed retrospectively at a single center in Austria. Methods: We have treated 137 mCRC patients with at least one antibody containing therapy since 2004 at our center based at data available at that time and patient eligibility. Results: Most mCRC patients were between 55 and 75 years old. The KRAS mutation testing performed routinely from 2008 onwards shows a distribution of 55 % wildtype (wt) and 45% mutant (mut) KRAS. Median overall survival (OS) was 24 months (n=82) with a trend towards greater benefit for KRAS wt patients compared to KRAS mut (26.8 vs. 20.9 months, respectively). Most patients received between 3 and 5 treatment lines. 40% of patients were treated with 5 therapies and 8% reached treatment line 8. The median OS correlated with the number of therapy lines. Chemotherapy alone regimens are decreasing constantly due to the establishment of biomarker analysis based treatment decisions and the increase in available antibodies for immunotherapy in mCRC. Based on direct positive experience with various antibodies, we were successfully treating patients repeatedly with the same antibodies in non-consecutive treatment lines. 75.7% of all patients treated with Cetuximab received the antibody only once during 3.8 therapy lines. 13% of patients who obtained the agent in two lines received on average 5.7 treatment lines resulting in improved OS. This was even more prominent in 8.5% patients receiving Cetuximab in 3 lines with a trend towards further OS benefit. These data describe that multiple applications of the same antibody is not only feasible but also very effective. Conclusions: By taping the full potential of treatment options, optimizing their usage and expanding the number of treatment lines we could achieve a median OS in real-life patients similar to that previously described in large phase III studies. Our analysis describes the following key factors for reproducing clinical benefits reported in large trials: biomarker assessment, early and if possible multiple applications of available therapeutic antibodies, treatment until progression and use of supportive therapy to alleviate possible toxicities.
The impact of TP53 mutation on high-risk rectal cancer patients treated within the EXPERT-C trial, a randomized phase II study of neoadjuvant oxaliplatin/capecitabine (CAPOX) and chemoradiation (CRT) with or without cetuximab.
Authors: Dewdney Alice , Chau Ian , Capdevila Jaume , Glimelius Bengt , Cervantes-Ruiperez Andres , Tait Diana M. , Brown Gina , Wotherspoon Andrew , Gonzalez de Castro David , Hulkki Wilson Sanna , Chua Yu Jo , Wong Rachel , Barbachano Yolanda , Oates Jacqueline Rose , Cunningham David 
Published: March 2020

e14088 Background: The EXPERT-C trial randomised 165 patients into neoadjuvant CAPOX and CRT ± cetuximab and demonstrated a significant increase in radiological response (RR) and overall survival (OS) with cetuximab in KRAS/BRAF wild type (WT) rectal cancer (Dewdney et al JCO in press). TP53 mutation has been associated with worse CRT response and survival in rectal cancer and could lead to stimulation of PI3K signalling pathway, thus potential resistance to cetuximab. This analysis evaluates the impact of TP53 mutation in the EXPERT-C trial. Methods: FFPE tissue from biopsy (n=102) and resection specimens (n=99) were analysed for TP53 mutations (exons 5-8) using a multiplex PCR method followed by direct sequencing. If discordant results were encountered on paired biopsy and resection samples, analyses were repeated. Results: 53/102 (52%) biopsy and 24/99 (24%) resection samples harboured TP53 mutation, most commonly missense in exons 5 and 7. The vast majority had single TP53 mutations, only 4/53 biopsy and 1/24 resection samples had 2 mutations. 21/55 (38%) paired samples demonstrated discordant TP53 mutation status. In both all-treated and KRAS WT populations, presence of TP53 mutation had no impact on RR to neoadjuvant chemotherapy or CRT, regardless of treatment arm. A trend towards worse progression-free (PFS) (HR: 2.68; 95% CI: 0.85 - 8.43; p=0.08) and OS (HR: 4.04; 95% CI: 0.86 - 19.11; p=0.056) was observed in patients with TP53 mutation when treated with cetuximab, independent of the KRAS status. Conclusions: TP53 mutations were common in high-risk rectal cancer patients, the lower mutation rate in the resection samples was potentially due to lower tumour volume post CRT. The presence of a TP53 mutation at baseline had no impact on RR to treatment, however a trend towards worse PFS and OS was observed with the addition of cetuximab, consistent with the perceived biology.
Multicenter matched case-control study comparing laparoscopic surgery with open surgery for elderly colon and rectal cancer patients.
Authors: Kawaguchi Yasuo , Hinoi Takao , Hattori Minoru , Okajima Masazumi , Ohdan Hideki , Yamamoto Seiichiro , Hasegawa Hirotoshi , Horie Hisanaga , Murata Kohei , Yamaguchi Shigeki , Sugihara Kenichi , Yamamoto Seiichiro , Watanabe Masahiko ,   Japan Society of Laparoscopic Colorectal Surgery
Published: March 2020

e14091 Background: Laparoscopic surgery for colon cancer has gained acceptance due to advantages, although no clear equivalent evidences exist for the elderly patients. The aim of this study was to compare outcomes of open and laparoscopic colorectal surgery in patients aged 80 and above, and estimate the feasibility of laparoscopic surgery for the elderly patients. Methods: We conducted a matched case-control study using data from 41 hospitals, the member of Japan Society of Laparoscopic Colorectal Surgery. 2014 patients aged 80 and above underwent surgery for colon or rectal cancer between 2003 and 2007. Propensity score method was used to balance covariates between the surgery groups. Covariates included age, sex, BMI, ASA class, performance status, elective or emergency, previous abdominal surgery, tumor size, tumor site, T-stage, N-stage, and TNM stage. For the prediction model, calibration was assessed by the Hosmer-Lemeshow goodness-of-fit test. The primary end point was overall survival (OS). Secondary end points included disease-free survival (DFS), cancer-specific survival (CSS), and postoperative complications. Results: 1526 and 282 patients underwent surgery for colon and rectal cancer, respectively. The distribution of covariates was significantly different between the open surgery (OP) group and the laparoscopic surgery (LAP) group, in colon and rectal cancer. After propensity score matching, all covariates were balanced and no longer had significant differences, except for tumor size in colon cancer cases. There were 804 patients in 402 pairs managed with the OP or the LAP for colon cancer, and 114 patients in 57 pairs for rectal cancer. OS, DFS and CSS did not differ between the groups for either colon cancer (p = 0.916, 0.968 and 0.799 by log-rank test) or for rectal cancer (p = 0.765, 0.519, and 0.950). Overall morbidities were significantly fewer in the LAP group than in the OP group for colon cancer (24.9% vs. 36.3%, p < 0.001), and no difference for rectal cancer (47.4% vs. 40.4%, p = 0.450). Conclusions: The laparoscopic surgery was not inferior to the open procedure, and can be an acceptable alternative to open surgery for elderly patients with colon and rectal cancer.
Liver CT evaluation using a software that automatically generates report according to RECIST 1.1 criteria.
Authors: Longo Flavia , Iafrate Franco , Adua Daniela , Baldassarri Paolo , Del Bene Gabriella , Di Marco Marco , De Filippis Lucilla , Lapadula Vittoria , Gazzaniga Paola , Frati Luigi 
Published: March 2020

e14096 Background: The aim of this retrospective study is to define the usefullness of an integrated CT software that automatically generates report according to RECIST 1.1 criteria and Choi criteria, evaluating the effects of bevacizumab based chemotherapy on CRC liver metastases. Methods: 35 patients with a total of 144 CRC liver metastases underwent CT before and after treatment. Patients with peritoneal disease were excluded. Reporting time was recorded for all patients. CT images were reviewed by two radiologists in consensus, in order to correlate clinical values with CT images using a software (Median, Technologies, France) that automatically synchronizes the images and pairs lesions in repeat CT scans according to RECIST 1.1 criteria as well as lesion density variation using Choi criteria. Results: Reports showed a good correlation between CT images and laboratory values in 31/35 patients during the period of response and in 29/35 during the period of disease progression. The associated use of Choi criteria, evaluating lesion density, provided a better correlation in 33/35 patients during the period of clinical response to therapy and in 31/35 during the period of disease progression. In 6 patients with 21 lesions, lesion density difficulty matches with laboratory values due to the presence of calcifications or to lesion small size. Average reporting time ranged between 16 to 18 minutes. Serum level biomarkers correlates with history disease and circulating tumor cells number using CellSearch system, according to recent literature, always results zero. Conclusions: Using this software we provide accurate quantitative assessment of response to bevacizumab based chemotherapy in liver mCRC with a good correlation between imaging and laboratory values.
Feasibility and challenges of a biopsy-driven and biomarker discovery clinical trial in metastatic colorectal cancer to identify signatures of clinical resistance.
Authors: Diaz Zuanel ,   Quebec Clinical Research Organization in Cancer Consortium
Published: March 2020

e14108 Background: Biopsy-driven clinical trials are essential to develop personalized therapeutics, since many critical questions are best addressed in the tumor tissue being treated. In the metastatic setting, intrinsic resistance occurs even with the most advanced therapeutic agents, and even in responders, acquired resistance is inevitable. We have designed a prospective study to identify biomarkers of clinical resistance to standard first-line therapy (FOLFOX, XELOX or FOLFIRI in combination with bevacizumab in patients with metastatic CRC (NCT00984048). Methods: Eligible patients have confirmed metastatic CRC, measurable disease, and consent to three needle-core biopsies (NCBs) of a non-resectable liver metastasis before treatment and at resistance. This study is approved at several Quebec hospitals, demonstrating that Research Ethics Boards recognize the value of biopsy-driven studies without therapeutic benefit. Results: Forty patients agreed to partake in this multi-center trial and to provide NCBs. Of these, 5% were non-neoplastic, and 5% had neuroendocrine origins. Using standard operating procedures developed for this trial, we were able to both preserve morphology and obtain high-quality genomic material. We demonstrate that this material is suitable for DNA analysis (array comparative genomic, methylation profiling) and RNA analysis (gene expression profiling, splicing isoforms variants and micro RNA profiling). In parallel, we have generated resistant CRC cell lines resistant to the combination therapy to further study biomarkers of resistance. Challenges in obtaining a biopsy at time of progression include death, patient refusal, heterogeneity of tumors, metastasis at a different organ site, and time constraints for re-biopsy. No significant adverse events were reported related to the biopsy procedure. Conclusions: We conclude that obtaining serial liver NCBs are challenging, but safe and feasible in metastatic CRC patients with unresectable liver disease. This study will provide insight on the relevance of metastatic tissue in assessing signatures of clinical resistance.
Mutational status of KRAS and BRAF of an Argentinian population of colorectal tumors.
Authors: Lopez Ruitti Paula , Salanova Ruben , Nafissi Julieta , Rabossi Guillermo , Bramuglia Guillermo , Powazniak Yanina 
Published: March 2020

e14109 Background: Activating mutation of the KRAS oncogene is an established predictive biomarker for resistance to anti–epidermal growth factor receptor (anti-EGFR) therapies in advanced colorectal cancer (CRC). BRAF, another component of the EGFR-MAPK signal transduction pathway, is also subject to a common activating mutation in CRC. The aim of this report is to present the mutational status of KRAS, BRAF of an Argentinian population of CR tumors. Methods: Tumor blocks were obtained from 85 consenting patients of various public and private hospitals. We analyzed the presence of KRAS point mutations in codons 12 and 13, and the BRAF-V600E from formalin paraffin fixed sections with Polymerase Chain Reaction (PCR) amplification-sequencing. Results: From a total of 85 patients, 46% F and 54% M, with a median age of 64 years (range, 28-85), 72% (61) where found to be wild type, while the other 28% (24) showed the KRAS mutation in the following amino acids: G12V 30% (7), G12D 17% (4), G12C 17% (4), G12S 9% (2), G12A 4% (1), G13D 25% (6). We analyzed in 45 patients the mutational status of BRAF-V600E, 29 patients presented BRAF and KRAS wild type, 12 had a KRAS mutation while the BRAF was wild type, and 4 patients reveled a mutation of BRAF in the presence of a KRAS wild type. Conclusions: The type of mutation observed in this study corresponds to the findings of previous studies, where the most common KRAS mutation detected was G12V in codon 12 followed by G13D in codon 13. A preliminary report based in 146 patients from Argentine (Perazzo F, et al. 2009) revealed marked differences in KRAS mutation rates compared to our findings, showing the following percentage of mutations: G12V 62% vs. 30% , G12D 26% vs. 17% and G13R 1.7% vs. 0%, G13D 0% vs. 25%, respectively. BRAF mutational status was according to international and national reports.
Mutations in NRAS codon 61, KRAS codon 146, and BRAF V600E as prognostic factors in patients who received anti-EGFR antibody for metastatic colorectal cancer.
Authors: Takahashi Naoki , Yamada Yasuhide , Taniguchi Hirokazu , Akiyoshi Kohei , Honma Yoshitaka , Iwasa Satoru , Kato Ken , Hamaguchi Tetsuya , Shimada Yasuhiro 
Published: March 2020

e14126 Background: Previous studies showed that gene mutations (NRAS, BRAF, PIK3CA) are associated with a poor prognosis or resistance of anti-EGFR antibody in metastatic colorectal cancer (mCRC) patients with wild type (WT) of KRAS codon 12/13 (KRAS-WT). However the significance of these biomarkers has not been clarified. In addition, EGFR immunohistochemistry (IHC) and EGFR gene amplification to evaluate the efficacy of anti-EGFR antibody treatment has not been reported for mCRC. Methods: We evaluated tumor response and survival in patients who received anti-EGFR antibody by mutation analysis of KRAS, NRAS, BRAF, and PIK3CA in KRAS-WT patients with mCRC. Tumor DNA samples are obtained from patients treated in our hospital with anti-EGFR antibody between August 2008 and August 2011. Results: A total of 117 patients were enrolled in this analysis, including 100 KRAS-WT patients. Seventy-one patients (60.7%) were all WT for KRAS, NRAS, BRAF, and PIK3CA, and 46 patients (39.3%) had at least 1 mutation or had insufficient DNA samples to analyze. Mutations of KRAS codon 61 (2 patients), KRAS codon 146 (5), BRAF V600E (2), PIK3CA exon9 (8), NRAS codon 12/13 (2), and NRAS codon 61 (5) were detected. No patients had a mutation of PIK3CA exon 20. Patients with at least 1 mutation had no response. Mutations of NRAS codon 61, KRAS codon 146, and BRAF V600E were associated with a shorter progression free survival (PFS) compared with all WT patients (p=0.049, p=0.004, p=0.036, respectively). Twelve patients (12% of KRAS-WT patients) with a mutation of NRAS codon 61, KRAS codon146, and BRAF V600E had poor prognosis compared with the other KRAS-WT patients (PFS, 6.4 vs 2.0 months, p<0.001; overall survival (OS), 13.7 vs 7.9 months, p=0.012). In all WT patients, moderate to strong EGFR IHC was associated with a better response rate than negative and weak IHC (p=0.046). Conclusions: Mutations of NRAS codon 61, KRAS codon 146, and BRAF V600E could be a strong prognostic factor of anti-EGFR antibody in patients with mCRC. Combination of IHC and DISH of EGFR could identify patients with a tumor response to anti-EGFR antibody in patients that are all WT for KRAS, NRAS, BRAF, and PIK3CA.
A phase II trial of salvage treatment with gemcitabine and S-1 combination in heavily pretreated patients with metastatic colorectal cancer.
Authors: Sym Sun Jin , Hong Junshik , Jung Minkyu , Park Jinny , Cho Eun Kyung , Lee Jae Hoon , Lee Won-Suk , Baek Jeong-Heum , Shin Dong Bok 
Published: March 2020

e14137 Background: We conducted a phase II trial of gemcitabine with S-1 to evaluate the activity and toxicity of such a combination in heavily pre-treated patients (pts) with metastatic colorectal cancer (mCRC) who have progressed after treatment with 5-fluorouracil, oxaliplatin and irinotecan. Methods: Between Dec 2009 and Nov 2011, 23 pts were enrolled, with the following characteristics: 12 males and 11 females, median age 57 years (28-72). S-1 was given orally (30 mg/m2) b.i.d for 14 consecutive days and gemcitabine (1000 mg/m2) was given on days 1 and 8, every 21 days, until disease progression and for a maximum of 9 cycles. The primary endpoint was objective response rate (ORR). Results: The median number of cycles was four (range 1-9). OR was 8.7% (95% confidence interval [CI] 0-20.2) and disease control rate was 56.5% (95% CI 36.4-76.9) with two partial responses and eleven stable diseases. Median duration of disease control was 8.5 months (95% CI 3.8-13.2). Median progression-free survival was 3.2 months (95% CI 1.9-4.5) and median overall survival was 11.8 months (95% CI 4.0-19.5). Grade 3-4 toxicities were neutropenia (8%) and thrombocytopenia (4%). Conclusions: Combination chemotherapy with gemcitabine and S-1 was well tolerated and efficacious for refractory mCRC pts.
Influence of comorbidity and ECOG on efficacy and safety in irinotecan-refractory elderly patients (>65 years) with metastatic colorectal cancer (mCRC) treated with cetuximab plus irinotecan.
Authors: Jehn Christian , Böning L. , Kröning Hendrik , Possinger Kurt , Pezzutto Antonio , Lueftner Diana 
Published: March 2020

e14140 Background: In clinical practice elderly patients (pts) with comorbidities may not be treated appropriately based on perceptions about their life expectancy and ability to tolerate potential side effects of chemotherapy. We investigated the influence of comorbidity, ECOG status and age on the efficacy and safety profile of cetuximab and irinotecan in irinotecan pretreated mCRC patients aged < 65 and > 65 years. Methods: 497 irinotecan-pretreated pts with mCRC were entered in the database of this noninterventional study. Comorbid conditions were recorded and scored according to the Charlson Comorbidity Index (CCI). Descriptive statistics, χ²-or Fishers exact test and multivariate analysis were applied. Results: A total of 247 and 250 pts aged < 65 (median:59) and > 65 (median:70) years, respectively, were documented. 79% of the pts showed a reduced ECOG status of 1–2, with no difference the age groups (p=0.65). Grade III/IV toxicities occurred in 18 % of pts without any difference between age groups although older pts had more comorbidities, with a higher CCI (p=0.002). The duration of any grade of skin reaction was in pts age < 65 significant longer (42 d), than in patients aged > 65 (31 d); (p=0.04). However, there was a trend towards higher grade (≥2) skin toxicity in pts aged > 65. A total of 71% of the pts developed skin rash, which was strongly related to response (P=0.006). Age, line of therapy, ECOG, gender, CCI had no influence on response in multiple regression analysis. The objective response rates were similar for both groups: 38.1% for age < 65 vs. 36.4% for age > 65 (p=0.57). Progression-free survival (PFS) did not differ between pts 18–65 years old (6.0 months) in comparison with pts >65 years (6.1 months) (p=0.99; log-rank test). In a multivariate analysis only ECOG status had a negative impact on PFS (HR: 0,499; 95% Cl, 0.34–0.72; p=0.002), but not CCI, age or gender. Conclusions: Only ECOG had a negative influence on PFS. There were no significant differences in response rate and safety profile for patients aged < 65 and > 65 years when treated with cetuximab and irinotecan. Comorbidities had no influence on efficacy or toxicity.
Effect of the ADAPT strategy on dormant CD133+ colon cancer stem cells (CSC) and molecular complete remission measured by peripheral blood mononuclear (PBMC) CD133 mRNA.
Authors: Lin Edward H. , Xiazhen Yu , He Xi C , Wu Xifeng , Xie Yang , Deng Yanhong , Yang Guang , Tian Qiang , Li Lingheng 
Published: March 2020

e14153 Background: The median survival for patients with unresectable metastatic colorectal cancer (CRC) is ~2 years with modern chemotherapy which yields only 5-10% complete responses (CR) including metastasectomy. Recurrences after CR are very common thanks to presence of dormant CSC that are best targeted by our proposed two-step ADAPT strategy: activate from dormancy and potentiate targeting. We examine this strategy in various CRC models and reviewed the impact on stemess including CD133 mRNA, a circulating CSC marker that predict colon cancer relapse. Methods: Different CRC models (in vitro and in vivo) were interrogated similar to clinical ADAPT treatment protocol using capecitabine (or 5FU) plus celecoxib. We also conducted IRB approved retrospective review of unresectable metastatic CRC patients treated ADAPT therapy and in those who also had PBMC CD133 mRNA measured. Results: Contrary to 5FU, which eliminates proliferating CRC cells via apoptosis but also stimulates stemness, celecoxib preferentially deplete CD133+ colon cells and exert potent stemness inhibition via rapid tumor necrosis by perturbing hypoxia and energy metabolism via CA-IX. Following response to first-line chemotherapy, ADAPT strategy plus radiation improved CR or near CR rate to 49/126 (40%) in unresectable CRC patients whose median survival had reached 92.7 months (95% CI, 53.5 months - not reached). Paradoxically, none surgical CR patients (n= 16) enjoyed 100% 5-year relapse free survival compared to 42% of surgical patients (p = 0.04). The PBMC CD133 mRNA in five long-term CR patients were 0.0024, 0.29, 0.5, 0.56, 2.96 respectively, all below previously reported cutoff value of 4.79 for recurrence and far below CD133 mRNA levels (28, 375, 3997, 15662, 83240) in none CR patients. Conclusions: ADAPT plus radiation preferentially targets colon CSC via hypoxia/CA-IX and improves clinical CR rate and molecular CR as measured by PBMC CD133 mRNA. We are actively interrogating the effects of ADAPT strategies in a phase II study funded by Gateway in CRC patients and in genetic CRC animal models.