bluuebunny/crossref_metadata_2025_split huggingface dataset:
The efficacy of first-line IRIS with or without bevacizumab in patients with metastatic colorectal cancer: Analysis of two phase II studies.
Authors: Yuki Satoshi , Fukushima Hiraku , Amano Toraji , Nakamura Michio , Kudo Mineo , Sonoda Norikazu , Tateyama Miki , Kawamoto Yasuyuki , Hatanaka Kazuteru , Sogabe Susumu , Miyagishima Takuto , Akakura Nobuaki , Kato Takashi , Takagi Tomofumi , Iwanaga Ichiro , Miyashita Kencho , Onodera Manabu , Saitoh Soh , Sakata Yuh , Komatsu Yoshito 
Published: March 2020

e14604 Background: The safety and efficacy of first-line IRIS (S-1 in combination with irinotecan; Komatsu Y, et al. Oncology, 2011) and IRIS/Bev (IRIS in combination with bevacizumab (Bev); Komatsu Y, et al. Acta Oncol, 2012/Yuki S, et al. 2013 ASCO-GI) have been evaluated in patients with metastatic colorectal cancer (mCRC). This time, no randomized studies comparing these regimens have been performed. This retrospective analysis compared efficacy and safety data for the two regimens from separate phase II studies performed at Hokkaido Gastrointestinal Cancer Study Group (HGCSG). Methods: Patients with histologically confirmed unresectable metastatic or recurrent CRC and received no prior chemotherapy were enrolled. In the first trial, patients received irinotecan 100 mg/m2 on day 1,15 and oral S-1 40 mg/m2 twice daily on days 1-14 every 4 weeks (IRIS study: HGCSG0302). In the second trial, patients received the same regimen plus Bev 5 mg/kg on day 1,15 (IRIS/Bev study). Results: A total of 40 and 52 patients were enrolled the IRIS and IRIS/Bev studies, respectively. Patient characteristics were generally similar in both groups, whereas there were more cases of good performance status and less number of metastatic organ in IRIS/Bev group. The median overall survival was 39.6 months in IRIS/Bev, as compared with 23.4 months in IRIS, corresponding to a hazard ratio for death of 0.418 (p<0.001). The median progression-free survival was 17.0 months in IRIS/Bev, as compared with 8.6 months in IRIS (hazard ratio for disease progression, 0.418; p<0.001); the corresponding response rate were 63.5 percent and 52.5 percent (p=0.393).In a multivariate analysis of PFS and OS, IRIS/Bev (n=52) was significantly associated with longer PFS and OS compared with IRIS alone (n=40). Conclusions: In this retrospective comparison of two studies, the addition of Bev to IRIS appeared to improve outcome compared with IRIS alone in the first-line treatment of patients with mCRC.
Cardiac outcomes of raltitrexed in the treatment of colorectal cancer patients with 5-fluorouracil (5-FU) cardiotoxicity.
Authors: Firouzbakht Aryan , Renouf Daniel John , Chen Leo , Cheung Winson Y. 
Published: March 2020

e14607 Background: Both 5-FU and raltitrexed are thymidylate synthase inhibitors, but the latter has a toxicity profile that is distinct from 5-FU. Therefore, it is commonly used as an alternative to 5-FU in the treatment of colorectal cancer patients who have a history of cardiac problems or prior 5-FU cardiotoxicity. To date, the population-based risk of cardiac effects from raltitrexed is uncertain. Our aim was to characterize the patterns of treatment and outcomes of patients receiving raltitrexed-based chemotherapy. Methods: We conducted a retrospective study of all patients diagnosed with colorectal cancer from 1988 to 2012, evaluated at 1 of 5 regional cancer centers in British Columbia, Canada and treated with raltitrexed at any point during their disease. At the institutions in our province, raltitrexed use is limited to those in whom 5-FU is contraindicated. Using chi-squared tests and logistic regression analyses, we evaluated the associations between use of raltitrexed and various cardiovascular events, such as angina, myocardial infarction, hypertension and arrhythmias, as well as other toxicity outcomes, including nausea, vomiting and diarrhea. Results: A total of 186 patients were included: median age was 63 years (IQR 55-70), 97 (52%) were men, and 21 (11%) experienced at least one cardiovascular outcome. Only 4 (2%) patients had a documented cardiac history prior to receipt of any systemic therapy. Among the 21 cases of cardiovascular events, 10 reported angina, 1 suffered a myocardial infarction, 6 had hypertension, and 6 experienced arrhythmias. A significant number of patients also presented with other general toxicities: 25 (13%) reported fever, 11 (6%) suffered mucositis, 75 (40%) had nausea, and 51 (27%) experienced diarrhea. On regression analyses, patients with a previous history of coronary artery disease had a higher risk of cardiovascular events than those without (50 vs 11%, p=0.01). Exposure to 5-FU before raltitrexed did not increase cardiovascular outcomes (p=0.81). Conclusions: Raltitrexed is associated with a low risk of cardiovascular events, but its use should be monitored closely in those with prior coronary artery disease.
Clinical impact of histologic subtypes and somatic mutations in peritoneal carcinomatosis from colorectal cancer.
Authors: Bibeau Frederic , Gudin Amelie , Denouel Amelie , Roca Lise , Castan Florence , Lopez-Crapez Evelyne , Ho-pun-cheung Alexandre , Lamy Pierre-Jean , Saint-Aubert Bernard , Boissiere Florence , Quenet Francois 
Published: March 2020

e14621 Background: Peritoneal carcinomatosis (PC) occurs in 10 to 15% of colorectal carcinoma (CRC). Strategies combining surgical resection and hyperthermic intraperitoneal chemotherapy have improved PC outcome. The morphologic, phenotypic and molecular spectrum of CRC PC and their clinical impact are still unknown. Methods: We selected 70 CRC PC cases operated in our institute (34 men, 36 women, median age: 61, median follow-up: 3.9 years.). The following investigations were performed: pathologic review; immunohistochemistry, focused on microsatellite instability (MSI) and CRC markers; mutational status of KRAS, BRAF and TP53. Results: 51 % of PC cases were pure or mixed mucinous carcinoma. Histologic types of PC and primary CRCwere concordant in 80% of cases. Lymphovascular and perineural infiltrations were only observed in 20 and 23% of cases, probably reflecting the preferential spread of PC by surface graft. 90% of cases displayed usual CRC phenotype: CK20+/CK7-/villine+/CDX2+. 96% of PC cases were microsatellite stable (MSS) and 58, 46 and 6% showed TP53, KRAS and BRAF mutations, respectively. No significant association was observed between the histologic type and sex, location, peritoneal index or molecular profile. Mucinous PC had a better relapse free survival (RFS) than conventional lieberkuhnian PC (P=0.04). KRAS/BRAF wild type PC had a better overall survival (OS) than KRAS or BRAF mutated PC, the latter group having the worst outcome (P<0.001). Conclusions: The high rate of mucinous PC suggested a propensity for peritoneal location in primary mucinous CRC. The high rate of MSS tumors, TP53 and KRAS mutations revealed that a large part of PC could be part of the chromosomic instability molecular group. Poor RFS with lieberkuhnian PC raises the question of greater aggressiveness for this histologic type. Consistent with previous reports in metastatic CRC, poor OS was associated with KRAS and particularly BRAF mutations. These preliminary and original results may indicate a peritoneal tropism and a particular behavior for mucinous CRC and need to be prospectively confirmed to determine whether mucinous CRC and PC could benefit from particular therapeutic approaches.
Comparison of efficacy and toxicity of bevacizumab in combination with chemotherapy in the first, second, and third or higher line of treatment for metastatic colorectal carcinoma (mCRC): Data from the Czech multi-institutional registry.
Authors: Kiss Igor , Bortlicek Zbynek , Melichar Bohuslav , Poprach Alexandr , Halamkova Jana , Vyzula Rostislav , Dusek Ladislav , Buchler Tomas 
Published: March 2020

e14622 Background: Data from the Czech national registry of patients treated with targeted therapies for mCRC were analyzed retrospectively to compare treatment outcomes for bevacizumab in combination with chemotherapy in the 1st, 2nd and 3rd line of treatment. Methods: The database was launched in 2005 as a clinical registry of patients with mCRC treated with bevacizumab. Epidemiological and clinical data are entered by all Czech comprehensive cancer centers administering targeted therapy. In total, 4487 mCRC patients who received bevacizumab combined with chemotherapy in either 1st line (n=3990, 88.9%), 2nd line (n=386, 8.6%), or 3rd and higher line (n=111, 2.5%) had evaluable data and were included in the present analysis. Survival was calculated using the Kaplan-Meier method, and the differences were assessed using the log-rank test. Results: Statistically significant differences were observed in the efficacy of combination chemotherapy with bevacizumab between the treatment lines. The objective response rate (ORR) in the 1st, 2nd, and 3rd/higher line was 42.9%, 34.0% and 8.3%; (p<0.001) respectively. Similarly, in the 1st, 2nd, and 3rd/higher line median progression free survival (mPFS) was 11.3 months (95% CI 11.0-11.7 months), 9.5 months (95% CI 8.2-10.9 months) , and 7.3 months (95% CI 5.9-8.7 months; p<0.001), and median overall survival (mOS) was 28.4 months (95% CI 27.1-29.8 months), 25.9 months (95% CI 19.4-32.4 months), and 15.0 months (95% CI 10.7-19.3 months; p<0.001), respectively. The spectrum of the most common adverse events was comparable in the 1st, 2nd, or 3rd/higher line, and incidence of adverse events was similar at 11.6%, 8.8% and 8.1%, respectively. Conclusions: The efficacy of bevacizumab in combination with chemotherapy decreased when administered in later lines of treatment for mCRC while the incidence and spectrum of toxicities remains unchanged.
Differences in colon cancer incidence rates by latitude.
Authors: Shah Binay Kumar , Ghimire Krishna Bilas , Nepal Barsha 
Published: March 2020

e14627 Background: There is significant decrease in the ultraviolet B photons reaching the earth’s surface during November to February (Holick MF Am J Clin Nutr. 2004 Dec; 80(6 Suppl):1678S-88S). This results in little if any vitamin D3 production in the skin during this period. This study was conducted to evaluate difference in colon cancer age adjusted incidence rates in the northern (latitude ≥37o N) and the southern (latitude < 37oN) regions in the contiguous United States during 1973-2008. Methods: Patients, aged 20 years and older, who had been diagnosed with colong cancer during January 1973 and December 2008, were selected from the Surveillance, Epidemiology, and End Results (SEER) 13 database. Based on the counties’ centroid, northern (latitude ≥37o N) and southern (latitude < 37oN) regions were determined. We compared age adjusted incidence rates (AAIR) of colon cancer in the southern and northern regions among cohorts of patients categorized by age (≥20, 20-64, ≥65 years), gender (Men, Women) and Race (Caucasians, Blacks, Others). The AAIR was calculated per 100,000 population. We used SEER*Stat software to calculate age adjusted incidence rate, incidence ratio, confidence interval (CI, 95%) and P value. Results: There were 314,975 cases of colon cancer diagnosed among 608,245,557 US population during 1973-2008. The overall colon cancer AAIR was 57.1 per 100,000 population studied. The incidence rates were 49.1 in the south and 58.7 in the north of 37oN latitude, (95% CI 1.18-1.20, p<0.05). The AAIRs for patients in the age group 20-64 years were 17.9 and 18.8 in the southern and northern regions, (CI 95%, 1.0346-1.0697), p<0.0005 respectively. The incidence rates for patients aged ≥65 years were 194.3 and 243.9 in the southern and northern regions, (CI 95%, 1.0346-1.0697) p<0.0005. Similarly, the AAIRs were significantly higher in the northern region compared to southern region for both sexes and all ethnic groups. Conclusions: Colon cancer age-adjusted incidence rate is significantly higher in the Northern compared to the Southern region of the US. The higher incidence of colon cancer in the North may be related to lack of sunlight exposure and relative vitamin D deficiency.
Effect of diet-induced obesity on the efficacy of colon cancer treatment in mice.
Authors: Greene Michael W , Ammannagari Nischala , Gillaspie Erin , Burrington Christine M. , Horsman Melissa J , Patel Anush V. 
Published: March 2020

e14632 Background: Obesity has reached epidemic proportions globally. Colon cancer is one of the leading causes of cancer related deaths in United States and obesity is associated with one-third of incidence of colon cancer. Obesity is also associated with a worse prognosis of colon cancer. However, the mechanistic details are unknown and animal models to investigate human colon cancer in the setting of obesity are lacking. Therefore, we developed a diet-induced animal model of obesity to determine whether obesity alters the efficacy of a standard colon cancer therapeutic, 5-Fluorouracil, in mice with human colon cancer xenografts. Methods: Male Rag1 mice were placed on a High Fat Western Diet (HFWD) or a Low Fat Western Diet (LFWD) for up to 12 weeks. Body weight, biochemical parameters, and glucose and insulin tolerance were measured. To determine the efficacy of 5-Fluorouracil on human colon cancer xenograft growth, Rag1 mice were fed a LFWD or HFWD for 8 weeks and then implanted with tissue-isolated HT-29 human colon cancer tumors. After 3 weeks of tumor growth, the mice were randomly assigned to a drug (5-Flurouracil 40 mg/kg) or control (normal saline) treatment group. Tumor growth was monitored for 14 days. Results: Significant differences in body weight, and glucose and insulin tolerance were observed in the four week HFWD fed mice. Obesity, glucose intolerance, and insulin resistance were more pronounced in 8 and 12 week fed HFWD mice. Estimated HT-29 human colon cancer tumor growth was significantly greater in obese HFWD fed mice compared to lean LFWD fed mice. Treatment with 5-Fluorouracil significantly reduced HT-29 human colon cancer tumor growth in lean LFWD fed mice but was without effect in obese HFWD fed mice. Conclusions: In conclusion, our findings demonstrate that diet induced obesity impairs the efficacy of 5-Fluorouracil in an obese animal model of human colon cancer. Given that obesity is growing exponentially worldwide, more studies to understand the mechanistic links between obesity and various cancers are required.
Is oxaliplatin a good partner for EGFR monoclonal antibodies as first-line treatment in KRAS wild-type metastatic colorectal cancer? A meta-analysis.
Authors: Wen Feng , Li Qiu , Tang Ruilei , Sang Yaxiong , Li Meng , Hu Qiancheng , Du Zedong , Zhou Yi , Zhang Pengfei , He Xiaofeng 
Published: March 2020

e14645 Background: This meta-analysis was performed to determine whether the addition of monoclonal antibodies (mAbs) of epidermal growth factor receptor (EGFR) to oxaliplatin-based chemotherapy treatment improves efficacy in KRAS wild-type metastatic colorectal cancer (mCRC), and whether infusional 5-fluorouracil (5-FU) and oxaliplatin is a preferred combination for EGFR mAbs. Methods: Oxaliplatin (including treatment), EGFR mAbs, first-line treatment, KRAS wild-type, and mCRC were used as key words. The PRIME, OPUS, COIN, and NORDIC VII trials were identified by two independent authors. Time-to-event outcomes of overall survival (OS) and progression-free survival (PFS) were analyzed using HRs (Hazard Ratios) with fixed effect, and response rate (RR) using odd ratios (OR) with fixed effect. Results: A total of 1,767 patients who were KRAS wild-type were included in this meta-analysis, with 866 patients in the mAbs and chemotherapy combination group and 901 patients in the chemotherapy alone group. The addition of mAbs to oxaliplatin-based chemotherapy in patients with KRAS wild-type mCRC as first-line treatment resulted in significant improvements in PFS (HR=0.88; 95% confidence interval (CI), 0.79 to 0.99; P=0.03) and response rate (RR) (OR = 1.38; 95% CI, 1.14 to 1.66; P = 0.009) compared with chemotherapy alone, but the difference in OS was not significant (HR=0.96; 95% CI, 0.85 to 1.08; P=0.48). However, the differences neither in OS nor in PFS were not significant when mAbs were added to bolus 5-FU or capecitabine-based regimens compared with chemotherapy alone, whereas PFS improved with an infusional 5-FU and oxaliplatin combination (P=0.06; PFS, HR=0.76; 95% CI, 0.65 to 0.86; P=0.0002), and even OS was marginally significant. Conclusions: Oxaliplatin and infusional 5-FU regimen tends to be a better backbone combination with EGFR mAbs as first-line treatment in KRAS wild-type mCRC.
Treatment patterns and cost for colorectal cancer by line of therapy and metastasis status.
Authors: Seal Brian S. , Kreilick Charles , Boklage Susan H. , Shermock Kenneth M. , Asche Carl V 
Published: March 2020

e14658 Background: Patterns and cost of care are thought to vary substantially as patients with colorectal cancer (CRC) progress from first to third line therapy and in the presence of metastatic disease. Our aim was to compare patterns and cost of care in these patients. Methods: A retrospective analysis was performed using claims from the Optum Oncology Research Database. Patients 18 years and older, diagnosed with CRC and received chemotherapy or biologic therapy between Jul 1, 2004 and Dec 31, 2010, who were insured by a commercial health plan were included. Chemotherapy combinations were assessed in patients receiving first, second and third line of therapy for CRC; and for patients with/without metastatic disease. Inpatient, outpatient, chemotherapy, biologic-related, and total median annual costs were compared by the Kruskal-Wallis test. Results: 1039 patients were included. FOLFOX and fluorouracil monotherapy were the most common first-line therapies, each accounting for approximately 27% of patients who received any chemotherapy. Oxaliplatin-based regimens were the most common second-line therapy (45% of patients). Irinotecan-based regimens were the most common third line therapy (35% of patients). Biologic therapy was much more common in patients with metastases (39% vs. 5%; p<0.0001) and in patients receiving third line therapy (65% vs. 8%, p<0.0001). The total cost of care increased significantly for patients receiving first ($25,782), second ($36,951), and third ($86,944) line therapy (p<0.0001 for all pairwise comparisons). Costs were significantly greater (p<0.0001) for patients receiving third versus first line therapy for outpatient care ($39,952 vs. $15,521), inpatient care ($3,668 vs. $1,721), chemotherapy ($14,059 vs. $3,662) and biologic therapy ($28,824 vs. $4,899). Total costs were significantly greater for patients with metastases ($39,001) compared with those without ($8,989; p<0.0001). Conclusions: Treatment patterns vary significantly by line of therapy in patients with CRC. The total cost of care increased significantly as patients received additional lines of therapy and for patients with metastases. Biologics appear to be the most significant driver of these increased costs.
Beta-catenin and p53 expression in ampullary and small intestinal adenocarcinoma.
Authors: Hsiao Susan Jean , Remotti Helen Elaine 
Published: March 2020

e14659 Background: Small intestinal adenocarcinomas are rare tumors with a worse prognosis than tumors arising from the large intestine. The majority of small intestinal adenocarcinomas arise in duodenum, most commonly around the ampulla of Vater; a smaller subset arises from the jejunum and ileum. Small intestinal adenocarcinomas remain poorly characterized due to their rarity, and limited options exist for adjuvant chemotherapy. Characterization of accumulation of the p53 tumor suppressor and aberrant expression of beta-catenin, suggestive of activation of the Wnt signaling pathway, could have important clinical implications and provide therapeutic targets. Methods: Tissue microarrays of ampullary and small intestinal adenocarcinomas were created using 2 cores of formalin-fixed tissues from 57 patients who had undergone surgical resection. Primary tumors involved the ampulla of Vater in 49% of cases, peri-ampullary duodenum in 39% of cases, and jejunum/ileum in 12% of cases.Immunohistochemical stains were performed for beta-catenin and p53. Cases with accumulation of p53 were scored as positive. Normal localization of beta-catenin is membranous; nuclear (or nuclear and cytoplasmic) accumulation of beta-catenin was scored as positive. Results: Accumulation of the p53 tumor suppressor protein was observed in 67.9% of ampullary adenocarcinomas, 86.4% of peri-ampullary/duodenal adenocarcinomas, and 57.1% of jejunal/ileal adenocarcinomas. Aberrant localization of beta-catenin was observed in 10.7% of ampullary adenocarcinomas, 0% of peri-ampullary/duodenal adenocarcinomas, and 42.9% of jejunal/ileal adenocarcinomas. Conclusions: Our initial results show accumulation of p53 in a substantial proportion of cases, similar to that which has been observed in other tumors. Abnormalities in p53 is one of the most common mutations observed in tumors. This is a clinically important result, as these tumors may respond to specific therapies targeting p53. In addition, our results implicate the Wnt signaling pathway in a subset of jejunal/ileal and ampullary adenocarcinomas offering another possible avenue for targeted therapies.
Expression of transcription factor Scratch2 in colorectal cancer.
Authors: Ivanov Krasimir , Kolev Nikola , Tonev Anton , Ghenev Peter , Zgurova Nedyalka , Ivanov Georgi , Kirilova Tanya , Ignatov Valentin , Zlatarov Aleksandar , Tonchev Anton 
Published: March 2020

e14669 Background: The Scratch genes constitute an independent subgroup of the Snail superfamily of transcription factors (TFs). Vertebrates contain 2 Snail and 2 Scratch genes (Scrt1 and Scrt2). Members of the Snail/Scratch superfamilies are characterized by a having both zinc finger domains, which mediate DNA-binding and a SNAG domain that is necessary for the transcriptional repression. Under normal conditions, the Scratch genes are expressed exclusively in the nervous system, where they regulate cortical neurogenesis (Paul, Tonchev, et al. Cerebral Cortex 2012, Epub ahead of print; doi: 10.1093/cercor/bhs356). However, expression of Scrt2 under pathological conditions is poorly characterized, especially in humans. Methods: We investigated the expression of Scrt2 by immunohistochemistry in 50 primary or metastatic (hepatic metastasis) colorectal cancer biopsies acquired through routine operations at the Department of General Surgery, Medical University-Varna, Bulgaria. We also evaluated the histological type and clinical stage of the tumors. Results: We found that both the primary and the metastatic tumor strongly expressed Scrt2 protein. Interestingly, the expression was mostly in the cytoplasm, in accordance with the reported pattern in the developing cortex (Paul, Tonchev, et al. Cerebral Cortex 2012, Epub ahead of print; doi: 10.1093/cercor/bhs356). Notably, in the hepatic metastatic tumors, we found no or scarce expression in the normal hepatic parenchyma surrounding the tumor, while a strong expression in the colorectal cancer metastasis. Conclusions: Scrt2 represents a putative novel marker for colorectal cancer. Detailed correlation of the clinical parameters, such as patient survival, and the expression level of Scrt2 might yield novel prognostic value of this TF in the pathogenesis of colorectal cancer.