bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic importance of primary tumor resection and synchronous metastasis on overall survival in metastatic colorectal cancer: Data from the FIRE-3 (AIO KRK-0306) study.
Authors: von Einem Jobst C. , Stintzing Sebastian , Fischer von Weikersthal Ludwig , Decker Thomas , Kiani Alexander , Vehling-Kaiser Ursula , Al-Batran Salah-Eddin , Heintges Tobias , Lerchenmuller Christian A. , Kahl Christoph , Seipelt Gernot , Stauch Martina , Scheithauer Werner , Hielscher Joerg , Scholz Michael , Modest Dominik Paul , Jung Andreas , Kirchner Thomas , Heinemann Volker 
Published: May 2020

4070 Background: The FIRE-3 study (AIO KRK-0306) was designed as a randomized multicenter trial to compare the efficacy of FOLFIRI plus cetuximab (cet) to FOLFIRI plus bevacizumab (bev) as first-line treatment in KRAS WT mCRC patients. FOLFIRI plus cet as first-line treatment of KRAS WT mCRC patients resulted in comparable overall response rates (ORR) and progression free survival (PFS) when compared to FOLFIRI plus bev. Overall survival (OS) was significantly longer in the FOLFIRI plus cet arm. Methods: In the present analysis of the FIRE-3 trial we explored the impact of primary tumor resection on outcome in relation to anti-EGFR vs. anti-VEGF treatment. Furthermore, we investigated the prognostic value of synchronous versus metachronous metastases. Results: In patients with synchronous disease no significant difference in OS was detected when comparing resected (n=339) vs. non-resected (n=97) patients (p-value: 0.29, HR: 1.17, 95%-CI: 0.88 – 1.55). In the cetuximab arm, resection (n=167) showed no significant benefit in OS when compared to non-resection (n=52) (p-value: 0.51, HR: 1.15, 95%-CI: 0.77 – 1.71). Treated with bevacizumab, similar results were present, when comparing resection (n=172) vs. non-resection (n=45); (p-value: 0.29, HR: 1.25, 95%-CI: 0.83 – 1.9). A strong trend was seen when comparing OS in treatment arms cet. (n=219) vs. bev. (n=217)) for patients with synchronous disease; (p-value: 0.05, HR: 1,26, 95%-CI: 1.0 - 1.59). 436/592 pts suffered from synchronous, 153/592 from metachronous disease (in 3/592 pts the information was not given). Median OS in pts with synchronous disease was 24.5 months and 29.5 in pts with metachronous disease (p-value: 0.02, HR: 0.76, 95%-CI: 0.6 - 0.96). In pts treated in the cetuximab arm metachronous disease (n=77) was associated with a trend towards longer OS when compared to synchronous disease (n= 219) (p-value: 0.13, HR: 0.76, 95%-CI: 0.54 – 1.1). The same effect was present in the bevacizumab arm (p-value: 0.05, HR: 0.73, 95%-CI 0.53 – 1.0) when comparing pts with synchronous disease (n=217) vs. pts. with metachronous disease (n=76). Conclusions: In the FIRE-3 study, metachronous disease was associated with superior OS compared to synchronous disease. This finding was accentuated in the bevacizumab arm. The role of resection of the primary tumor had no impact on survival. Clinical trial information: NCT00433927 .
Colorectal cancer under the age of 50 years in U.S. Department of Veterans Affairs: Is there a role of early screening?
Authors: Khan Abdul Moiz , Ajmal Zainub , Naseer Usman , Gemoets Darren , Mehdi Syed Arzoo 
Published: May 2020

4072 Background: While the overall incidence of colorectal cancer (CRC) is decreasing, the rate has increased in population under 50, with higher stages at diagnosis and a greater proportion of African Americans (AA). Hence, there is an ongoing debate about the age of CRC screening. These trends have not been studied in the VA population. Methods: ICD-10 codes C18-C20 were used to identify the cases of colon and rectal cancer in National VA Cancer Cube Registry. 43,544 cases of colon cancer, 1,278 below and 42,254 above age 50, and 19,815 cases of rectal cancer, 862 below and 18,948 above age 50 were identified between 2003-17. Younger age group was defined as patients less than 50 years old. IRB approval was obtained. Results: Our data comprised > 97% of male patients. In younger group, in the 5 year periods, 2003-07, 2008-12 and 2013-17, colon cancer rate increased from 2.59% to 2.79% to 3.59%, while for rectal cancer it increased from 3.5% to 4.3% to 5.3% (p < .0001). Blacks comprise 31.6% cases of colon cancer and 27.15% cases of rectal cancer in under 50 group, compared to 18.5% and 15.9% of cases in above 50 group respectively (p < .0001). For under 50 group, 48.6% cases of colon and 42.2% cases of rectal cancer were diagnosed in stage III or IV compared to 35.7% and 34.05% cases in above 50 group respectively (p < .0001). For colon cancer, 51.87% of patients in the younger group have a < 5 year survival, worse compared to 45.05% in 50-60 group (p < .0001) and similar to 49.3% in 60-70 group (p = .08). For rectal cancer, 5 year survival showed no difference between these groups. Stage specific survival shows no difference for either colon or rectal cancer across < 50, 50-60 and 60-70 age groups. Conclusions: Rate of CRC is rising in < 50 age group with more advanced stage at diagnosis and higher proportion of African Americans. For colon cancer, < 50 group has a worse 5 year survival as compared to 50-60 age group likely due to increased proportion of patients in stage III or IV, as there is no difference in stage specific survival. For rectal cancer, the 5 year survival or stage specific survival shows no difference in < 50, 50-60 and 60-70 groups. These results add to our understanding of the trends of CRC and should be accounted for in the screening guidelines.
The role of primary tumor (PT) site as prognostic factor after resection of colorectal (CRC) liver metastases (LM): A mono-institutional cohort study.
Authors: Bensi Maria , Ardito Francesco , Di Stefano Brunella , Vellone Maria , Vivolo Raffaella , Mele Caterina , Ribelli Marta , Panettieri Elena , Camarda Floriana , Frascarelli Alessia , Calegari Maria Alessandra , Basso Michele , Pozzo Carmelo , Giuliante Felice , Tortora Giampaolo , Salvatore Lisa 
Published: May 2020

4081 Background: Radical resection of LM is the only chance of cure for liver-only mCRC pts. Besides the evaluation of technical resectability, several factors must be taken into account for the evaluation of recurrence risk. Among them we should consider the Fong Risk Score and its modified version, including RAS/BRAF status (Brudvik’s score). Tumor sidedness is an important prognostic factor in CRC. The impact of PT site on the outcome of LM resection is still debated. Hence, we retrospectively analysed mCRC pts, underwent to radical LM resection at our Institution, investigating the impact of PT site on DFS and OS. Methods: Liver-only mCRC pts underwent to radical LM resection were included. The association of PT site with DFS and OS was evaluated. The following variables were collected: gender; age (≥ vs < 75 years ); ECOG PS; CEA baseline level; PT site; RAS and BRAF status; mucinous histology; grading (G1-2 vs G3); RECIST response during preoperative treatment; resected PT; synchronous vs metachronous; number of LM; bilobar vs unilobar LM; LM diameter ≥ 5 cm; R0 vs R1 resection. Univariate and multivariate analyses for DFS and OS were performed. Results: A total of 463 liver-only mCRC pts underwent to radical LM resection were included. Seventy (15%) pts had a right-sided (r-s) tumor and 393 (85%) pts a left-sided (l-s) tumor. R-s CRC pts more often had RAS/BRAF mutations in comparison to l-s tumors (76% vs 37%; p < 0.0001). Median DFS and OS was 13.1 and 41.6 months, respectively, in r-s CRC vs 16.0 (p = 0.65) and 62.2 months (p = 0.033), respectively, in l-s tumors. At the multivariate analysis no significant association with survival parameters was shown for tumor sidedness. At the multivariate analysis, R0 resection was independently associated both with better DFS and OS; RAS/BRAF wt CRC and resected PT were significantly associated with improved OS. Considering all wt CRC pts (N = 237), 14 (6%) pts had r-s tumor and 223 (94%) l-s tumor. No significant association of tumor sidedness with survival was shown (DFS r = 10.0 vs l = 16.0 months, p = 0.62; OS r = 40.3 vs l = 66.2 months, p = 0.12). Conclusions: Our results showed that a significant smaller proportion of r-s CRC underwent to radical LM resection, indirectly confirming its worse prognosis. Among radically resected pts, r-s CRC was associated to a shorter OS (significant) and DFS (not significant) compared to l-s CRC, but it was not confirmed at the multivariate analysis. We can conclude that right PT site should not be considered as a contraindication for radical LM surgery, when feasible.
The effect of aspirin on colorectal cancer incidence in African Americans.
Authors: Emiloju Oluwadunni , Djibo Djeneba Audrey , Ford Jean G 
Published: May 2020

4085 Background: From 2011 to 2016, the incidence and mortality rate of colorectal cancer(CRC) were highest among African Americans(AA), compared to other US racial/ethnic groups. Long-term aspirin use is recommended as a strategy to reduce the risk of CRC. Yet, there is scant information on the chemopreventive effect of aspirin among AA. It is imperative to assess whether the reported chemo-preventive effect also occurs in AA. Our central hypothesis is that aspirin use in AA is associated with a lower incidence of CRC, irrespective of race/ethnicity. Methods: We conducted a secondary analysis, using data from AA participants in the Atherosclerosis Risk in Communities(ARIC) longitudinal study, who did not have CRC at enrollment, from 1987 to 1998. We extracted demographic, clinical and mortality data to compare the incidence of CRC among participants taking aspirin compared to those who were not taking aspirin, stratified by age, tobacco use, and body mass index. All-cause mortality and CRC mortality will also be assessed, and we will use Cox proportional hazard regression to determine the relationship between aspirin use and CRC incidence, and mortality. Results: At baseline in 1987, 15,026 participants enrolled in the ARIC study, 25% of whom were AA, median age 54(range 44-66), including 46.7% who reported using aspirin. We analyzed follow-up data from 10,960 participants in 1996-1998, 20% of whom were AA, and 56.9% of whom were taking aspirin. Non-AA participants were more likely to report using aspirin at baseline and follow-up, compared to AA, 53% vs 30% and 59% vs 50% respectively. After 10years, the total incidence of CRC in AA participants was 1% compared with 1.1% in non-AA(p = 0.7). There was no difference in CRC incidence by aspirin use among all participants, and when stratified by race(among all participants p = 0.81, amongAA p = 0.68, among non-AA p = 0.94). Conclusions: We found no difference in the incidence of CRC among AA compared to Caucasians, by aspirin use. Investigation of consistency and/or dose of aspirin use by race may provide further insights on the relationship between aspirin use and CRC incidence, comparing AA to Caucasians.
Novel methylated DNA markers in plasma detect distant recurrence of colorectal cancer.
Authors: Xie Hao , Mahoney Douglas W. , Foote Patrick H. , Burger Kelli , Doering Karen A , Taylor William R. , Cao Xiaoming , McGlinch Maria , Berger Calise K. , Hubbard Joleen Marie , Allawi Hatim T. , Lidgard Graham P. , Ahlquist David A. , Kisiel John B. 
Published: May 2020

4088 Background: Methylated DNA markers (MDMs) are broadly informative for early detection of colorectal cancer (CRC) but have not been extensively studied for post-treatment surveillance and disease monitoring. We aimed to assess the feasibility of novel CRC-associated MDMs for detection of distant recurrent CRC (rCRC) in plasma. Methods: A panel of 13 MDMs previously identified to be discriminant for primary CRC was selected. In a cross-sectional analysis of plasma samples, MDMs were assayed blindly (by target enrichment long-probe quantitative amplified signal assay) from 160 age/sex-balanced patients (60 healthy controls, 60 with resected CRC and no evidence of disease (NED), and 40 rCRC after primary tumor resection). Plasma-derived carcinoembryonic antigen (CEA) was measured on all patients. Random forest modeling was used to derive a prediction algorithm of MDMs (with and without CEA) for the endpoint of rCRC relative to healthy controls. The accuracy of the algorithm was summarized as sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) with 95% confidence intervals (CI) in the test set. Results: Median patient age was 55 (interquartile range: 49-64) years. As shown in the Table below, a single MDM with the highest AUC was significantly better than CEA ( p= 0.02). On cross validation, CEA provided no additional improvement to the performance of the panel of 13 MDMs ( p= 0.2). The cross-validated panel of MDMs detected rCRC liver metastases with 96% (79-100%) sensitivity, lung metastases with 78% (40-97%) sensitivity, and peritoneal/nodal metastases with 57% (18-90%) sensitivity. Lesions with Response Evaluation Criteria in Solid Tumors sum > 4 cm were detected with 94% (73-100%) sensitivity and ≤4 cm with 78% (52-94%) sensitivity. Conclusions: Novel MDMs in plasma detect rCRC with promising accuracy. The clinical utility of MDMs for non-invasive post-treatment surveillance and treatment monitoring in CRC warrants further evaluation in longitudinal studies with sufficient follow-up to exclude sub-clinical recurrence in those with NED. [Table: see text]
The development and validation of a novel targeted methylation sequencing technology detecting 0.003 percent tumor signal in early-stage cancer plasma.
Authors: Zhao Grace Q. , Bao Yun , Wang Heng , Wang Jianmin , Lin Shengrong 
Published: May 2020

4092 Background: Methylation analysis in cell-free DNA holds great potential for early cancer detection. In the plasma of early stage cancer patient, the tumor content is estimated to be less than 0.1%, therefore demands a highly sensitive assay. Targeted Methylation Sequencing (TMS) is the most promising approach; however, the current sensitivity and specificity are compromised by low efficiency and low recovery of target enrichment, and further hampered by background noise associated with large panels. The ideal solution would be an in-depth analysis using a focused small cancer-specific methylation biomarker panel, but is not supported by existing technologies. Methods: Here we present a new technology designed for TMS analysis in cfDNA: Point-n-Seq, featuring an enrichment of target molecules directly from cfDNA before bisulfite conversion and amplification. Particularly, this technology enables small focused panel that interrogates the methylation status of 1 to ~1000 markers. We designed a CRC panel covering 100 methylation markers in 3 steps: identify ~1000 CRC-specific markers from public databases; eliminate makers with high background signal in baseline cfDNA of healthy population; finalize the list with the most differentiating markers between patient and healthy cfDNA. Results: The capture of Point-n-Seq CRC panel is highly efficient resulting in high uniformity (94% > 0.5X) and on-target rate ( > 80%). For 20 ng cfDNA input, more than 1000 deduped informative reads were obtained for each marker on average, despite the high GC content ( > 80%). The output of informative reads was linear to the cfDNA input ranging from 1 ng to 40 ng. In titration studies, 0.6 pg (0.2X genome equivalent) methylated DNA in 20 ng cfDNA (0.003%) was reliably detected over cfDNA background. Using plasma samples from patients with CRC - early stage (I, n = 7; II, n = 7), late stage (III, n = 11; IV, n = 3), and control individuals (n = 105), the average fractions of methylated signal are 0.0034%, 0.013%, 0.09%, 0.17%, 0.29% for control, stage I, II, III, IV accordingly. With a simple cut-off using methylation fraction, Point-n Seq CRC panel achieved a sensitivity of 86% for stage I, 100% for stage (II-IV) at a specificity of 91%, with AUC = 0.96. Conclusions: Point-n-Seq TMS is the first hybridization based NGS technology enables the small focused methylation panel (e.g. 100 markers) sequencing using cfDNA, and it will greatly facilitate the development of practical and cost-effective methylation assays for clinical use.
APC and TP53 as potential biomarkers for EGFR sensitivity in colorectal cancer.
Authors: Thota Ramya , Yang Mingli , Davis Thomas , Schell Michael J. , Pledger Warren Jack , Yeatman Timothy Joseph 
Published: May 2020

4094 Background: The Consensus Molecular Subtypes (CMS) of colorectal cancer (CRC) have prognostic and predictive value in identifying patients that derive benefit from EGFR targeted therapies. The CMS2 cohort was specifically noted to predict response to cetuximab. Besides CMS classification, we recently reported a two-gene mutation signature of APC and TP53 (AP) that predicts potential response to cetuximab. In this study, we hypothesize AP mutations, in addition to CMS cohorts, predict cetuximab sensitivity. Methods: A prespecified and validated 203 gene expression signature score measuring cetuximab sensitivity (CTX S-score) was used as a surrogate for response to cetuximab sensitivity. A cohort of 458 patients with colorectal cancer was accrued between October 2006 and September 2011. The population classified into CMS cohorts, and CTX-S scores were determined across each of the cohorts based on AP mutation status. Results: Among 458 tumor samples sequenced, AP mutations were identified as significantly associated with higher CTX-S scores. Among the CMS 1-4 cohorts identified, AP mutations were noted in 13 of 77 (17%) patients in CMS1 cohort, 87 of 116 (75%) patients in CMS2 cohort, 15 of 64 (23%) patients in CMS3 cohort, 46 of 112 (41%) patients in CMS4 cohort, indicating that AP mutations are dominant in CMS2 cohort. Further CTX-S score comparisons across CMS cohorts based on AP status show that AP mutated tumors have higher CTX-S scores than non-AP mutated tumors—irrespective of the CMS cohorts (p<0.05 unpaired, two-tailed t tests). Conclusions: In our study, we noted CMS2 cohort has high predicted sensitivity to cetuximab. Across other CMS cohorts, AP mutations were associated with higher CTX-S scores compared to those with AP wild-type tumors, suggesting both CMS2 and AP mutations contribute to CTX sensitivity.
Phase II trial of adjuvant mFOLFOX6 after metastasectomy for pulmonary metastasis of colorectal cancer: WJOG5810G.
Authors: Machida Nozomu , Okumura Takehiro , Kishimoto Junji , Boku Narikazu , Nishina Tomohiro , Suyama Koichi , Ohde Yasuhisa , Shinozaki Katsunori , Baba Hideo , Tokunaga Shinya , Kawakami Hisato , Tsuda Takashi , Kotaka Masahito , Okuda Hiroyuki , Yasui Hisateru , Denda Tadamichi , Yamazaki Kentaro , Hironaka Shuichi , Muro Kei , Hyodo Ichinosuke 
Published: May 2020

4097 Background: Resection of pulmonary metastasis (PM) is widely accepted to improve the prognosis in selected patients (pts) with metastatic colorectal cancer (CRC). However, the clinical implication of adjuvant chemotherapy after metastasectomy of PM is unknown. We conducted a multi-center phase 2 trial of adjuvant chemotherapy with mFOLFOX6 after metastasectomy of PM-CRC. Methods: Main eligibility criteria were first curative metastasectomy of 4 or less PMs and no prior chemotherapy except for adjuvant chemotherapy with fluoropyrimidine monotherapy after curative resection of primary or extrathoracic CRC metastasis. The study treatment was 12 courses of mFOLFOX6 (oxaliplatin 85 mg/m2, l-leucovorin 200 mg/m2, 5-fluorouracil 400 mg/m2 bolus followed by 2400 mg/m2 continuous infusion, every 2 w). The primary endpoint was overall survival (OS). The secondary endpoints included disease-free survival (DFS), adverse events (AEs), and recurrence sites. The sample size was determined to be 93 expecting 5-year OS rate of 50% with threshold 35% (90% power, alpha error 5%). Results: Fifty-two pts from 34 institutions were enrolled between July 2011 and July 2014. Patient enrollment was closed prematurely because of slow accrual. Four patients were ineligible after enrollment and the safety and efficacy cohort comprised 52 and 48 patients, respectively. Patient backgrounds were as follows: gender (male/female) 31/21, median age (range) 63 (42-75) years, ECOG PS (0/1) 48/4, primary site (colon/rectum) 18/34, number of PM (1/2/3/4) 36/9/5/2, synchronous/metachronous PM 11/41, and unilateral/bilateral PM 40/12. With the median follow-up time of 6.0 (1.8-7.7) years, 5-year OS rate was 86% (95% CI: 72-93) and 5-year DFS rate was 59% (95% CI: 43-71). Tumors recurred in 19 patients (13 lung, 3 liver and 7 others). Total 41 pts (79%) completed 12 courses of mFOLFOX6 (reasons for discontinuation: AEs in 3, refusal due to AEs in 8). AEs ( > Grade 3) were neutropenia 50%, fatigue 8%, peripheral sensory neuropathy 8%, appetite loss 4%, diarrhea 4%, febrile neutropenia 2% and allergic reaction 2%. There was no treatment related death. Conclusions: Adjuvant mFOLFOX6 is feasible and may be effective after metastasectomy for PM-CRC, considering much better OS than we had expected. Clinical trial information: UMIN000005693 .
Is there a benefit of oxaliplatin in neoadjuvant treatment of locally advanced rectal cancer? An updated meta-analysis.
Authors: Des Guetz Gaetan , Landre Thierry , Larrouy Anne , Panis Yves , Morere Jean F. , Mathonnet Muriel , Quero Laurent 
Published: May 2020

4098 Background: Neoadjuvant fluoropyrimidine (5FU or capecitabine)-based chemoradiotherapy (CRT) has been considered the standard of care for locally advanced rectal cancer (LARC). Whether addition of oxaliplatin (OXP) will further improve clinical outcomes is still unclear. Methods: To identify clinical trials combining oxaliplatin in preoperative CRT or perioperative chemotherapy for LARC published until December 2019, we searched PubMed, the Cochrane Library. We also search for relevant ASCO conferences. Primary endpoint was Disease-Free-Survival (DFS). Data were extracted from every study to perform a meta-analysis using Review Manager (version 5.3). Results: A total of 7 Randomized Clinical Trials (ACCORD-12, CARO-AIO-04, FOWARC, JIAO, NSABP, PETACC-6 and STAR-01) with 5782 stage II or III rectal cancer patients were analysed, including 2727 patients with OXP + 5FU regimen and 3055 patients with 5FU alone regimen. Compared with 5FU-based regimen group, OXP-based regimen group improved DFS (HR = 0.90, 95% CI: 0.81−0.99, P = 0.03) and increased pathologic Complete Response (OR = 1.21, 95% CI: 1.07−1.37, P = 0.002). Patients treated with OXP-regimen had significantly less metastatic disease (OR = 0.79; 95% CI, 0.67 to 0.94; p = 0.007). Considering Adverse Events (AEs), there was more grade 3-4 diarrhoea with OXP (OR = 2.41, 95% CI: 1.74−3.32, P < 0.00001). However, there were no significant differences grade 3-4 haematologic AEs (OR = 1.16, 95% CI: 0.87−1.57, P = 0.31). Conclusions: Combining oxaliplatin with capecitabine or 5FU in preoperative chemoradiotherapy or perioperative chemotherapy seems beneficial significantly and improved DFS. It remains necessary to identify which patients benefit most from the addition of oxaliplatin.