bluuebunny/crossref_metadata_2025_split huggingface dataset:
CHFR promoter methylation indicates poor prognosis in stage II microsatellite stable colorectal cancer.
Authors: van Engeland Manon , Cleven Arjen , Derks Sarah , Draht Muriel XG , Smits Kim M , Melotte Veerle , Weijenberg Matty P , Herman James Gordon , de Bruïne Adriaan P , Van Criekinge Wim 
Published: March 2020

e14503 Background: Data on the prognostic significance of promoter CpG island methylation in colorectal cancer (CRC) are conflicting, possibly due to associations between methylation and other factors affecting survival such as genetic alterations and use of adjuvant therapy. Here we examine the prognostic impact of promoter methylation in CRC patients treated with surgery alone in the context of microsatellite instability (MSI), BRAF- and KRAS mutations. Methods: 173 CRCs were analyzed for promoter methylation of 19 tumor suppressor- and DNA repair genes, the CpG island methylator phenotype (CIMP), MSI, the exon 15 V600E BRAF mutation and KRAS codon 12 and 13 mutations. Results: Unsupervised hierarchical clustering based on methylation status of 19 genes revealed three subgroups: cluster 1 (CL1, 57% (98/173) of CRCs), cluster 2 (CL2, 25% (43/173) of CRCs) and cluster 3 (CL3, 18% (32/173) of CRCs). CL3 had the highest methylation index (0.25, 0.49 and 0.69 respectively, p=<0.01) and was strongly associated with CIMP (p<0.01). After stratification for tumor stage, MSI and BRAF status, no statistically significant differences in survival between CL1, CL2 and CL3 nor between CIMP and non-CIMP CRCs were detected. Analyzing genes separately revealed that CHFR promoter methylation was associated with a poor prognosis in stage II, MSS, BRAF wild-type CRCs: HR=3.89 (95% CI =1.58-9.60, p=0.003) and HR=2.21 (95% CI =1.09-4.48, p=0.03) in a second population-based study (n=151). Conclusions: CHFR promoter CpG island methylation, which is associated with MSI, also occurs frequently in MSS CRCs and is a promising prognostic marker in stage II, MSS, BRAF wild-type CRCs.
Comparing KRAS mutation testing by pyrosequencing versus allele specific primary extension methods in colorectal cancer specimens.
Authors: Sampat Keeran Ravin , Patel Nirali , Deal Allison Mary , Weck Karen E , O'Neil Bert H. 
Published: March 2020

e14522 Background: KRAS mutation status is an important clinical variable for targeting treatment in metastatic colon cancer. Many community practices send out mutational analysis to laboratories which utilize allele specific primer extension (ASPE) to identify mutations in only codons 12 or 13 of the KRAS gene. Our institutional molecular pathology laboratory performs pyrosequencing (PS) of KRAS codons 12, 13, and 61 which can potentially identify more KRAS mutations. We undertook this study to determine whether there were analytical differences in the results for specific mutations between these techniques. Methods: We obtained 77 sets of paraffin slides from a local practice from patients with metastatic adenocarcinoma of the colon whose KRAS mutation status had previously been analyzed by ASPE. After macrodissection for tumor enrichment, DNA was extracted from unstained paraffin slides and analyzed for KRAS codon 12, 13, and 61 mutations using the PyroMark KRAS v2.0 test. The results of KRAS testing by PS were then compared to those by ASPE. Exact 95% confidence intervals are reported. Results: None of the patients with KRAS codon 12 or 13 mutations called by ASPE (0/77, 0% [0%-4.7%]) changed to wild-type (WT) upon retesting by PS methodology. However, six patients had a discordant result between their ASPE-based testing and PS-based testing (6/77, 7.8% [2.9%-16.2%]). Two patients had differences in the amino acid (AA) at codon 12 (2/77, 2.6% [0.3%-9.1%]). Three patients were found to have a codon 61 mutation (3/77, 3.9% [0.8%-11.0%]), including two patients who were called KRAS WT by ASPE (2/30, 7% [0.8%-22%]). Finally, one patient with a call of a codon 13 mutation by ASPE changed to WT by PS (1/77, 1.3% [0.0% - 7.0%]). Conclusions: Almost 8% of patients who had KRAS testing by PS had a discrepancy in results compared with commercial ASPE testing alone. Although ASPE appears to be very accurate in detecting KRAS mutations, it missed KRAS codon 61 mutations in about 4% of the samples tested. This may have some clinical impact as we learn more about this subgroup of patients in the future.
Association of telomere length with clinical outcomes in patients with colorectal carcinoma.
Authors: Baig Mahadi Ali , Augustine Titto A , Merla Amartej , Atzmon Gil , Budagov Temuri , Goel Sanjay , Maitra Radhashree 
Published: March 2020

e14540 Background: Telomeres (T) consist of thousands of copies of TTAGGG tandem repeats capping the ends of the chromosome. T along with enzyme telomerase provides protection against any threats to the genome that might arise as a consequence of “end replication problem”. Studies have linked short TL with premalignant and malignant stages of CRC carcinogenesis. However, the relation of TL to the clinical outcomes has not been conclusively determined. In this study we evaluated the association of TL with clinical outcomes in a cohort of 75 CRC patients. Methods: Tumor DNA was isolated from formalin fixed paraffin embedded specimens. TL was measured by using a qRT-PCR method that provided the relative T copy number, compared to reference copy number of the housekeeping gene, β-Globin, which resulted in a T/S ratio. One T/S ratio unit is equivalent to a mean TL of 4,270 base pairs (BP). Results: From 75 patients, 118 tissue samples were identified (66 primary, 52 metastases, 29 matched pairs). Age at diagnosis (>/< median) had a statistically significant difference in TL (mean BP 4700 vs. 4374; p=0.05) with shorter TL in the advanced age. Females had longer TL compared to men (mean BP 4722 vs. 3669 respectively; p=0.04). Stage at diagnosis (localized Vs Metastatic) had a statistically significant difference in TL (mean BP 4047 vs. 5704; p=0.03). Shorter TL was associated with shorter progression free survival (PFS) for patients treated with cetuximab/panitumumab (3963 vs 5295 p=0.022). Patients treated with cetuximab/panitumumab who had Shorter TL were also found to have significantly decreased Overall Survival (OS) (101.1 Months vs 153.02 Months p<0.0001). We failed to find a difference in the TL between primary and metastatic sites in the 29 patients with paired samples. There was no difference of TL seen with size of the tumor. Furthermore there was no difference in TL between various metastatic sites. Conclusions: TL is a potential biomarker predictive of clinical outcome (OS & PFS) for patients treated with cetuximab/panitumumab. Tumor TL reduces with advancing age and appears to be sex dependent. Further studies to validate TL’s predictive role in patient outcomes are underway.
Management of skin toxicity and cetuximab-based regimen compliance in first-line chemotherapy of metastatic colorectal cancer (mCRC) patients (pts): Results of observer study.
Authors: Pinto Carmine , Di Fabio Francesca , Rosati Gerardo , Lolli Ivan , Ruggeri Enzo , Ciuffreda Libero , Ferrari Daris , Tumolo Salvatore , Rosti Giovanni , Tralongo Paolo , Ferrara Raimondo , Alabiso Oscar , Chiara Silvana , Ianniello Giovanni Paolo , Di Costanzo Francesco , Frassoldati Antonio , Iacono Carmelo , Adamo Vincenzo , Mattioli Rodolfo , Valeri Michele 
Published: March 2020

e14557 Background: Cetuximab significantly improves efficacy when added to chemotherapy in mCRC pts. The ObservEr Study evaluated quality of life (QoL), skin toxicity management and treatment compliance of cetuximab-based regimens in first-line treatment of mCRC pts. Methods: ObservEr is a non-interventional, multicenter, prospective study. Primary endpoint is change in QoL during first-line treatment, with focus on the impact of dermatological toxicity. QoL (Dermatology Life Quality Index/DLQI and EORTC QLQ C30) is assessed at baseline and weekly for the first 8 weeks of treatment, then at every evaluation visit until PD or withdrawal. Secondary endpoints are efficacy, rate of liver metastasis resections, incidence of serious adverse events. Results: Between Apr 2011 and Nov 2012, 29 Italian centers enrolled 233 pts, with 226 evaluable pts. Pt characteristics: 152(67.3%) males, 74(32.7%) females; median age 65 (39-81) years; PS ECOG 0-1 95.5%; potentially resectable liver metastasis 59(27.1%); irinotecan regimens 129(57.1%), oxaliplatin regimens 60(26.5%), other regimens 37(16.4%). Median interval between request and result of KRAS test was 10 (6-15) days. Prophylactic skin treatment with vitamin K1 cream was used in 159(70.4%) pts, reactive treatment included vitamin K1 in 59(26.1%). Grade (gr) 1-2 skin toxicity was observed in 128(56.6%) pts, gr 3 in 28(12.4%); no gr 4 was detected. No significant difference in gr 3 skin toxicity was observed between males vs females (13.8 vs 9.5%; p=0.351), age <60 vs ≥60 years (18.1 vs 9.7%; p=0.077), irinotecan vs oxaliplatin regimens (12.4 vs 18.3%; p=0.278), prophylactic vs reactive treatment (15.1 vs 6.8%; p=0.339). Dose reduction, temporary and permanent discontinuation of cetuximab due to skin toxicity was required in 9(4.0%), 32(14.2%) and 7(3.1%) pts respectively; cetuximab compliance ≥70% of dose was reached in 208(92.0%) pts. Conclusions: These results suggest that appropriate skin toxicity management and prophylactic or reactive treatment with Vitamin K1 cream can improve the gr 3 skin toxicity control and the cetuximab compliance. QoL results will be shown at the 2013 ASCO Meeting. Clinical trial information: ID239.
Primary tumor resection to improve survival in patients with metastatic colorectal cancer in the post-2000 era: A California Cancer Registry analysis.
Authors: Rodriguez Fahrni Ana Milena , Gong I-Yeh , Cress Rosemary , Chen Yingjia , Semrad Thomas John , Khatri Vijay P. 
Published: March 2020

e14570 Background: Resection of primary tumors in the setting of metastatic colorectal cancer (MCRC) is controversial. Fewer primary tumor resections are being performed due to the improved tumor responses and disease control rates associated with modern systemic therapy. Recent studies suggest a survival benefit for patients with MCRC who had primary tumors resection prior to systemic therapy. This analysis evaluates the independent prognostic impact of primary tumor resection on overall survival (OS) for patients with MCRC using the California Cancer Registry (CCR). Methods: We queried the CCR for all patients with MCRC diagnosed between 2003 and 2010. Patients were categorized by whether or not they had primary tumor resection at time of diagnosis. Covariates included gender, age, race/ethnicity, socioeconomic status (SES), and rural-urban commuting area (RUCA) score of patients. Univariate comparisons were made using the Kaplan Meier method. Multivariate comparisons were performed using the Cox proportional hazards regression method. Results: 19,836 patients met the criteria for analysis of whom 11,566 (58%) had primary tumor resection. Primary tumor resection rates declined over this time period (63% in 2003 v. 52.8% in 2010, p<0.0001), varied by SES (55% v. 62%: lowest versus highest, p<0.001) and residence (63% in rural versus 58% for urban, P=0.0160). On multivariate analysis, overall survival was significantly better for patients that had primary tumor resection (HR: 0.467 [95% CI: 0.467-0.482]; p<0.0001). Survival was statistically longer in younger patients (HR: 1.385 for age 65-75, HR: 2.217 if greater than age 75), highest SES (HR: 0.869, p<0.0001), Hispanics (HR: 0.884, p<0001), and Asian/Pacific Islanders (HR:0.892, p<0.0001). Overall survival was worse for African Africans (HR:1.105, P=0.0001). Conclusions: Our study demonstrates the independent prognostic value on survival of primary tumor resection in patients with MCRC. There is significant variability of resection rates by SES and rural-urban residence. As analysis of CCR data cannot eliminate the influence of patient and provider biases, a prospective randomized trial is warranted.
A multicenter dose-finding study of irinotecan (CPT-11) based on UGT1A1 polymorphisms for metastatic colorectal cancer.
Authors: Sato Hirohiko , Shimada Mitsuo , Kurita Nobuhiro , Iwata Takashi , Yoshikawa Kozo , Miyatani Tomohiko , Kashihara Hideya , Mikami Chie , Matsumoto Noriko 
Published: March 2020

e14572 Background: Recent pharmacogenetic studies on irinotecan have revealed significant associations of UDP-glucuronosyltransferase 1A1 (UGT1A1) polymorphisms *28 and *6, the latter being specifically detected in East Asians resulting in severe toxicity such as severe diarrhea and neutropenia. It is necessary that the dose-finding trial that decided the optimal dose according to the gene polymorphism to draw out the maximum therapeutic effect while evading the side effect. Here, we present the final report of prospective trial of safety and efficacy about FOLFIRI ± bevacizumab (Bev) therapy according to each gene type of UGT1A1for Japanese patients with advanced CRC in second-line setting. Methods: Between September 2008 and March 2012, 59 patients were enrolled in this study. Grouping was defined as follows: wild group; both *28 and *6 were wild types, hetero group; *28 and either *6 was hetero type, and homo group; 28/*28 and *6/*6* or a both hetero types. In the 59 patients with advanced CRC treated with FOLFIRI ± Bev as a second line, wild and hetero groups were administered 150mg/m2 irinotecan, and homo group was 100mg/m2. The incidences of severe toxicities according to gene type of UGT1A1, the response rate and progression-free survival were investigated. Results: In the 59 patients, wild group was 28 (47%), hetero group was 26 (44.1%) and homo group was 5 (8.5%). 8 patients (29%) showed severe toxicities (grade 3 or more) in wild group, 5 patients (19%) in hetero group, 1 patient (20%) in homo group (P=0.71). Regarding the response rate, CR, PR, SD, PD was observed in 1 (4.0%), 1 (4.0%), 5 (20.0%) and 18 patients (72.0%), respectively in wild group, 0 (0.0%), 2 (8.3%), 5 (20.8%) and 17 patients (70.8%), in hetero group, 0 (0.0%), 0 (0.0%), 1 (20.0%) and 4 patients (80.0%), in homo group. The overall response rate (CR+PR) was 8.0% in wild group, 8.3% in hetero group, 0% in homo group (P=0.80). As for progression-free survival, the number of cycle to PD was 12.1 cycles (2-35 cycles) in wild group, 8.3 (2-20) in hetero group, 9.8 (6-14) in homo group (P=0.15). Conclusions: The dosages of 150mg/m2 irinotecan in hetero group, 100mg/m2 in homo group are safe and effective in FOLFIRI ± Bev therapy in the second line. Clinical trial information: UMIN000004773.
Quality of life in a multicenter phase II trial of metastasectomy for intra- and extra-hepatic metastases from colorectal adenocarcinoma.
Authors: Wei Alice Chia-chi , Serrano Aybar Pablo Emilio , Cleary Sean P. , Coburn Natalie G. , Greig Paul David , Law Calvin , Moulton Carol-anne , Gallinger Steven 
Published: March 2020

e14573 Background: The combination of intra- and extra-hepatic metastases (IHM and EHM) from colorectal cancer (CRC) has traditionally been considered a contraindication for surgery. Currently there is a growing interest in resecting IHM and EHM. The purpose of this study was to evaluate the health related quality of life (HRQoL) of patients with IHM and EHM from CRC undergoing complete metastasectomy. Methods: Participants with any number of CRC IHM and up to 3 foci of EHM, resectable with RO intent were eligible for the HRQoL component of a Phase-II multi-institutional trial. The effects of therapy on HRQoL were evaluated using: EORTC-QLQ C30, EORTC-LMC21 and FACT-HEP at baseline, prior to surgery and at 4, 8 and 12 months following complete metastasectomy. Results were compared to baseline. >10% mean score change was considered a minimally important clinical difference (MICD). Results: Twenty-five participants were enrolled with a median age: 57 (range: 32-84) years. Protocol surgery was completed in 18/25 (72%) including 11/25 (44%) staged resections. Perioperative morbidity and mortality was 11/25 (44%) and 1/25 (4%), respectively. Median disease-free survival was 6 (range: 0-17) months. 22/25, 88% participants underwent perioperative chemotherapy. EORTC-QLQ C30 Global-HRQoL remained statistically and clinically unchanged compared to baseline at 4 and 8 months but had a MCID decrease at 12 months (mean score change: 15.3) that was not statistically significant. This was associated with a significant decrease in social and role functioning and an increase in fatigue, pain and dyspnea. FACT-Hep score was statistically lower at 4 months post surgery, without reaching a MICD. There was no difference in any of the subscales analyzed in regards to sex, age or the presence of peri-operative complications. Conclusions: Aggressive metastasectomy of multi-site CRC is feasible and safe. Despite disease recurrence in the majority of patients there was no significant deterioration of Global HRQoL as a result of treatment. There was a transient effect on symptoms including fatigue, pain dyspnea and role functioning, which improved by 12 months. Clinical trial information: NCT00606398.
Lung and colon cancer costs among chemotherapy patients after an FDA policy change.
Authors: Stroupe Kevin , Tarlov Elizabeth , Weichle Thomas , Zhang Qiuying , Lee Todd , Michaelis Laura Christian , Durazo-Arvizu Ramon , Ozer Howard , Hynes Denise Marie 
Published: March 2020

e14578 Background: Emerging evidence of adverse events from erythropoietin-stimulating agents (ESAs) led FDA to add a black box warning to ESA labeling in March 2007, after which ESA use declined. We examined the impact on healthcare costs for lung and colon patients receiving chemotherapy in Department of Veterans Affairs (VA) healthcare facilities. Methods: Patients were newly diagnosed with lung or colon cancer during 2002-2008, had at least 2 chemotherapy visits, and did not have kidney disease. For each patient, we defined a chemotherapy episode as the time beginning with the first chemotherapy visit and ending with the last visit before a break of 90 days with no chemotherapy. We calculated outpatient anemia management (ESA and transfusion), cancer-related, and total healthcare costs from 30 days before to 90 days after the chemotherapy episode. We compared costs between patients with chemotherapy episodes before (PRE) and after (POST) March 2007 using multivariable regression analyses controlling for patient and facility characteristics. Costs were adjusted to 2010 dollars using the consumer price index. Results: There were 16,828 study patients: 13,630 lung and 3,198 colon. POST-period ESA use was markedly lower than PRE-period use for both groups (lung, 23% vs. 39%, P<0.01; colon, 11% vs. 23%, P<0.01). More lung cancer patients received transfusions in the POST than the PRE period, though the increase was small (27% vs. 25%, P=0.04). Consequently, adjusted POST-period anemia treatment costs were lower (lung, $526 lower, P<0.01; colon, $504 lower, P<0.01). Cancer-related and total costs were nonetheless higher in the POST period, due primarily to higher outpatient costs (adjusted cancer-related costs: lung, $4,500 higher, P<0.01; colon, $10,343 higher, P<0.01; adjusted total costs: lung, $4,706 higher, P<0.01; colon, $11,414 higher, P<0.01). Conclusions: Outpatient anemia management costs were lower during the period after the FDA policy change. There was no substitution effect of transfusion in place of ESAs. These declines in anemia management costs were not enough to offset the higher cancer-related costs, resulting in higher total healthcare costs.
Dachshund 2 protein, a novel neuroendocrine marker associated with favorable tumor characteristics and clinical outcome in colorectal cancer.
Authors: Wangefjord Sakarias , Brunnstrom Hans , Nodin Bjorn , Uhlen Mathias , Eberhard Jakob , Jirstrom Karin 
Published: March 2020

e14580 Background: The dachshund (DACH) gene encodes a nuclear protein and transcription factor that regulates metazoan development of eyes, limbs, brain, gonads and endocrine tissue. DACH2, one of two human homologues, has recently been identified as a marker of poor prognosis in epithelial ovarian cancer, but its further role in tumorigenesis and expression in normal and cancerous human tissue has not been described. Methods: In this study, immunohistochemical expression of DACH2 was evaluated in tissue microarrays with tumours from 539 cases of incident colorectal cancer in the Malmö Diet and Cancer Study. Chi Square and Spearman’s correlation tests were used to explore the associations between DACH2 expression, clinicopathological characteristics and investigative parameters. Kaplan-Meier analysis and Cox proportional hazards modelling were used to assess the relationship between DACH2 expression and cancer specific survival (CSS). Furthermore, given its distinct expression in various endocrine normal tissues and tumours in the Human Protein Atlas, we also compared DACH2 expression with a standard panel of neuroendocrine markers in 20 carcinoid tumours. Results: DACH2 expression correlated negatively with TNM-stage, differentiation grade, vascular invasion and microsatellite instability, and positively with older age, distal tumour location and expression of p27, cyclin D1, p53 Ki-67 and beta-catenin. DACH2 expression was significantly associated with an improved CSS in the whole cohort and in cases with tumour located in the colon but not rectum. These associations did however not remain significant in multivariable analysis, adjusted for established clinicopathological factors. Furthermore, DACH2 was highly expressed in all examined carcinoid tumours, with a better diagnostic performance than the majority of established markers. Conclusions: Our findings demonstrate a strong link between DACH2 expression and favourable clinicopathological characteristics and outcome in CRC. Moreover, DACH2 is abundantly expressed in neuroendocrine tumours, and its utility as a diagnostic tool for this entity warrants further study.