bluuebunny/crossref_metadata_2025_split huggingface dataset:
An 18-gene blood-based IVD test for colorectal cancer early detection with high sensitivity and specificity.
Authors: Xu Ye , Xu Qinghua , Ye Xun , Wu Fei , Liu Fang , Yang Li , Cai Guoxiang , Tan Cong , Meng Xia , Cai SanJun , Du Xiang 
Published: March 2020

3551 Background: Colorectal cancer (CRC) is often curable particularly diagnosed at early stages. Different screening strategies are in place in various counties. However, the compliance rate with current CRC screening recommendations remains poor. A simple blood-based IVD test would represent an interesting alternative. We previously reported a 100-gene signature for early detection of CRC using microarray technology. Based on this result, we have developed a new blood test with real-time PCR technology. Methods: 144 CRC cases and 153 Controls were enrolled. A total of 52 genes were selected as candidate markers to be transferred from microarray to real-time PCR. The gene expression profiles from 100 CRC cases and 100 Controls were used as a training set for signature discovery. Signature identification process was conducted by Minimum Redundancy Maximum Relevance (mRMR) feature selection method and Support Vector Machine (SVM) classification algorithm under the Leave-One-Out Cross Validation (LOOCV) framework. The optimal size of signature was determined by a stepwise inclusion selection procedure which started with one gene and repeatedly added genes one by one until all genes were included. The performance of each N-gene signature by the LOOCV was estimated and used to determine the best size of signature. Results: The gene expression profiles measured by microarray and real-time PCR technology were highly comparable and resulted in a significant correlation in term of fold change ratio between CRC cases and Controls (Pearson’s Correlation Coefficient = 0.95). An 18-gene signature was identified and validated in an independent validation set with 44 CRC cases and 53 Controls. The performance of 18-gene signature in the validation set reached 88.7% accuracy (95%CI: 0.80-0.94), 88.6% sensitivity (95%CI: 0.75-0.96), and 88.7% specificity (95%CI: 0.76-0.95). Conclusions: Our new results demonstrated the feasibility of technology transfer from microarray to real-time PCR. The blood test could be offered to individuals who are unwilling or unable to undergo colonoscopy to increase the CRC screening compliance rate. Meanwhile, its high specificity could also help to avoid unnecessary colonoscopies.
Influence of BRAF mutations and RAC1b/RAC1 mRNA expression ratio on outcome in patients with metastatic colorectal cancer (mCRC) treated with first-line chemotherapy.
Authors: Alonso-Espinaco Virginia , Marmol Maribel , Alonso Vicente , Escudero Pilar , Horndler Carlos , Ortego Javier , Gallego Rosa , Garcia-Albeniz Xabier , Jares Pedro , Cuatrecasas Miriam , Lozano Juan Jose , Castells Antoni , Maurel Joan 
Published: March 2020

3553 Background: Metastatic colorectal cancer (mCRC) patients (pts), with BRAF tumor mutation (V600E) present poor overall survival (OS). RAC1b, a RAC1 spliced variant, is overexpressed in CRC, and impairs apoptosis by activation of nuclear-factor-KB. Because RAC1b and BRAF (V600E) are significantly associated in CRC (Matos et al, 2008), we evaluated if RAC1b/RAC1 mRNA expression ratio (RNA ER) was an independent prognostic factor in mCRC. Methods: We analyzed tumor samples from 186 mCRC pts, treated in first-line therapy with FOLFOX or CAPOX in three Spanish hospitals. We examined BRAF (V600E) mutational status by allelic discrimination, RAC1b/RAC1 expression ratio by mRNA RT-PCR (quantitative real time polymerase chain reaction) and mismatch repair (MMR) deficiency by microsatellite instability (MSI) analysis. We assessed whether these biomarkers were independently predictive of response rate (RR), progression free survival (PFS) or OS. Results: 88% of samples were informative for BRAF, 75% for MMR status and 85% for RAC1b/RAC1 (RNA ER). BRAF (V600E) was found in 7%, MSI-H in 5% and high >0.9-fold RAC1b/RAC1 (RNA ER) in 20% of pts. Five of 11 pts (46%) with BRAF mutation had high RAC1b/RAC1 (RNA ER) compared with 25/144 (18%) without BRAF mutation (p=0.036). All pts with BRAF mutation were MMR and none of the MSI-H pts, showed high RAC1b/RAC1 (RNA ER). Patients with low RAC1b/RAC1 (RNA ER) and BRAF WT had higher response rate (68% vs 43%; p=0.035). Response rate were not different according BRAF mutation (64% WT vs 63% mutant) (p=NS). The multivariate regression analysis identified ECOG PS (HR: 4.2 (CI 1.4-12.7) as a significant variable for PFS and LDH levels (HR: 2.26 (CI 1.3-3.8), PS (HR: 3.85 (CI 1.5-9.8) and high RAC1b/RAC1 (RNA ER) (HR: 2.6 (CI 1.1-5.9) for OS in WT BRAF pts. Conclusions: High RAC1b/RAC1 (RNA ER) constitutes a marker of poor OS and a potential marker of acquired chemo-resistance in WT BRAF mCRC pts treated with first-line oxaliplatin-based therapy.
Post-progression survival (PPS) according to treatment line, type, and time in phase III trials in advanced colorectal cancer (ACC).
Authors: Buyse Marc E. , Saad Everardo D. , Matheson Alastair 
Published: March 2020

3557 Background: Since post-progression therapy influences overall survival (OS), PPS is of interest as a determinant of OS. We quantified the relationship between several median times to event in ACC: progression-free survival (PFS), PPS and OS. We looked for factors with an impact on these times. Methods: We searched PubMed for phase III trials published between January 1998 and December 2010 in 12 leading journals. PPS is the difference between median OS and median PFS or time to tumor progression. The statistics of interest (median times [PFS, OS and PPS] and the ratio of PPS/OS) were compared using t-tests. Results: We retrieved 70 trials that yielded 71 comparisons and 156 arms (one trial was factorial) involving 38,504 patients. Trials from the period 2005-10 enrolled more patients than trials from the period 1998-2004 (medians of 246 vs 174 per arm; P=.026). PPS could be calculated for 60 trials and 135 arms (Table). Treatment type did not have an impact on any statistic. Treatment line had a significant impact on all times and on the ratio of PPS/OS, although the difference on the latter statistic was small. Treatment period had a significant impact on all times but not on the ratio of PPS/OS. Conclusions: None of the factors examined have a major impact on the ratio of PPS/OS. This suggests that in ACC, gains in PFS are translated into proportional gains in OS, one of the conditions required for PFS to be considered a surrogate for OS. [Table: see text]
Phase II study of combination therapy with S-1 and cetuximab in patients with KRAS wild-type unresectable colorectal cancer who had previously received irinotecan, oxaliplatin, and fluoropyrimidines (KSCC0901).
Authors: Kobayashi Kazuma , Emi Yasunori , Kakeji Yoshihiro , Takahashi Takao , Oki Eiji , Akagi Yoshito , Tsuji Akihito , Kodera Yasuhiro , Yoshida Kazuhiro , Baba Hideo , Shimada Mitsuo , Ogata Yutaka , Shimokawa Mototsugu , Tokunaga Shoji , Natsugoe Shoji , Maehara Yoshihiko ,   Kyushu Study Group of Clinical Cancer (KSCC)
Published: March 2020

3558 Background: Anti-epidermal growth factor receptor (anti-EGFR) antibodies alone or in combination with irinotecan (Iri) can be considered standard third-line therapy for KRAS wild-type (wKRAS) unresectable colorectal cancer (UNCRC). However, some UNCRC patients (pts) cannot tolerate Iri-containing therapy. S-1, an oral fluorouracil (FU) derivative, enhances the anti-tumor effect by inhibiting dihydropyrimidine dehydrogenase activity and reducing digestive toxicity. Combination therapy with cetuximab (C-mab) may restore 5-FU resistance in 5-FU–resistant CCs. Therefore, we examined the efficacy of S-1+C-mab therapy in wKRAS UNCRC pts, who had previously received Iri, oxaliplatin (OX), and FUs. Methods: The study design was multicenter, single-arm, open-label phase II study. The major inclusion criteria were written informed consent; histologically proven CRC and clinically proven UNCRC; presence of measurable lesions; previous therapy with Iri, OX, and 5-FU; documented progressive disease after 5-FU–based chemotherapy; wKRAS tumors; age ≥ 20 years; performance status (PS) 0–1; and adequate organ function. The treatment protocol was as follows: weekly durable intravenous (DIV) C-mab administration at 400 mg/m2 (day 1) and 250 mg/m2/week (except day 1) and oral administration of 80 mg/m2/day S-1 on days 1–28 of each 42-day cycle. The primary endpoint was progression-free survival (PFS). A sample size of 39 was planned for a threshold PFS of 3.5 months and expected value of 6.0 months, with one-sided alpha of 0.05 and beta of approximately 0.2. Results: One patient was ineligible; 38 pts (PS 0/1, 32/6; 1/2/>3 prior chemotherapy regimens, 4/23/11) were enrolled from 10/2009 to 12/2010. The median PFS (central review) was 5.5 months (90% CI: 4.4 – 5.7); median overall survival (OS), 13.1 months; and the best ORR, 36.8%. The most common grade 3–4 adverse events were neutrophils, hypokalemia, rash, and dry skin. Conclusions: This study showed that S-1+C-mab may be a promising and well-tolerated treatment choice of wKRAS UNCRC, who had previously heavily treated by Iri, OX and FUs.
Phase II study of dacarbazine for metastatic colorectal cancer with determined MGMT status.
Authors: Amatu Alessio , Sartore-Bianchi Andrea , Bencardino Katia , Moutinho Catia , Marrapese Giovanna , Belotti Alessandro , Gambaro Alessandra , Cassingena Andrea , Venturini Filippo , Giacobbe Felicia , Sporchia Andrea , Lauricella Calogero , Schiavo Roberta , Esteller Manel , Siena Salvatore 
Published: March 2020

3570 Background: O6-methylguanine-DNA-methyltransferase (MGMT) is a DNA repair protein that removes mutagenic and cytotoxic adducts from O6-guanine in DNA. Roughly 40% of colorectal cancers (CRCs) display MGMT deficiency due to promoter hypermethylation leading to silencing of the gene. Alkylating agents exert their antitumor activity by DNA methylation at the O6–guanine site, inducing base pair mismatch; therefore, activity of these compounds may be enhanced in CRCs lacking MGMT (Esteller, 2004; Pegg, 1990). Despite anecdotal reports about activity of dacarbazine in CRC (Shacham-Shmueli, 2011) no clinical trials assessed monotherapy with dacarbazine for metastatic CRC. Methods: We conducted a phase II study of dacarbazine in CRCs who had failed standard therapies (oxaliplatin, irinotecan, fluoropyrimidines and cetuximab or panitumumab if KRAS WT), PS=0-1, with adequate organ function, and measurable disease as per RECIST criteria assessed by CT scans at baseline and every 8 weeks. All patients had tumor tissue assessed for MGMT as promoter hypermethylation. Patients received dacarbazine 250 mg/m2 i.v. d1-4, q21 until PD or untolerable toxicity (with a maximum of 6 cycles in case of SD). We employed a Simon, two-stage design to determinate if the ORR of dacarbazine treatment would be ≥ 10%. Secondary endpoints were association of response/resistance with loss of expression of MGMT, PFS and disease control rate. Results: In the first stage, from June 2011 to November 2011 we enrolled 40 pts (male 68%, median age 67 y [range 29-81], PS=0 50%, KRAS mut 55%). Pts received a median of 3 cycles [range 1-11]. Toxicities included (All Grades/Grade 3-4 %): fatigue (58/5), constipation (38/0), nausea/vomiting (35/0), anemia (20/2.5), platelet count decrease (10/5). 36 pts were evaluable for objective response. Overall, 2 pts (5%) achieved PR and 5 pts (12.5%) had SD. All pts with PR had tumors with MGMT promoter hypermethylation. Conclusions: Having exceeded the boundaries of futility (at least 2 objective responses in the first stage), the trial proceeds to the second stage, enrolling 28 more patients. Analysis of MGMT promoter hypermethylation and association with sensitivity/resistance is performed at the end of the second stage.
A phase II study of high-dose cetuximab plus irinotecan in colorectal cancer patients with KRAS-wild type tumors who progressed on prior standard dose cetuximab and irinotecan.
Authors: Fora Ahmad Ali , McMahon Jeanne A , Wilding Greg , Groman Adrienne E. , Ma Wen Wee , Romano Karen S. , Fakih Marwan 
Published: March 2020

3582 Background: Prior clinical data suggest a dose-related response to cetuximab (cmab) when combined with irinotecan in patients (pts) with KRAS WT tumors who do not develop grade ≥ 2 rash with standard cmab dosing. However, the investigation of higher doses of cmab in the setting of acquired or innate resistance to standard dose cmab has not been previously investigated. We conducted a phase II clinical trial of high-dose cmab plus irinotecan in KRAS WT pts who progressed on standard-dose cmab plus irinotecan. Methods: Pts who progressed within 4 weeks from receiving a minimum of 6 weeks of standard dose cmab plus irinotecan were included in this study. Cmab was administered at 500 mg/m2/week and irinotecan was administered at the same dose/schedule on which each individual patient previously progressed. All pts received doxycyline 100 mg PO bid starting day 1 of treatment. 12-week PFS rate was the primary endpoint. The regimen was considered interesting if 7/36 patients had stable disease or response at 12 weeks. The study was closed early after meeting its primary endpoint. Results: 20 pts were treated on study: median age 65.5 yrs (44-84), 14 pts were males. 8 pts had grade ≥ 2 hypomagnesaemia (3 grade 3 and 2 grade 4), 6 pts had grade ≥ 2 skin rash (1 grade 3, 0 grade 4), and 4 pts had grade ≥ 2 diarrhea (1 grade 3, 0 grade 4). 1 pt had a confirmed PR and 12 pts had a SD (at 6 weeks). In 9 pts, SD was confirmed at 12 weeks (3 pts> 24 weeks). Median PFS and OS were 2.8 and 6.6 months, respectively. The 1-year survival was 25%. Conclusions: High-dose cmab plus irinotecan is well tolerated with an acceptable rate of diarrhea and skin toxicities but with an increased rate of grade 3-4 hypomagnesemia. The prolonged disease stabilization and single response suggest that resistance to standard dose cmab plus irinotecan can be overcome by cmab dose escalation. The identification of predictive markers of response from dose escalation will be necessary to implement this strategy selectively in KRAS WT colorectal cancer patients.
FOLFOXIRI plus bevacizumab as first-line treatment of BRAF-mutant metastatic colorectal cancer patients.
Authors: Salvatore Lisa , Loupakis Fotios , Cremolini Chiara , Schirripa Marta , Masi Gianluca , Antoniotti Carlotta , Fornaro Lorenzo , Sensi Elisa , Lupi Cristiana , Bergamo Francesca , Lonardi Sara , Zagonel Vittorina , Fontanini Gabriella , Falcone Alfredo 
Published: March 2020

3585 Background: BRAF V600E mutation plays a negative prognostic role in metastatic colorectal cancer (mCRC) patients, leading to a median PFS of 4-6 months with first-line conventional treatments. Recently, results from a retrospective exploratory analysis suggested that an up-front intensive treatment with FOLFOXIRI plus bevacizumab could improve the outcome of BRAF mutant mCRC. Methods: Fifteen consecutive BRAF mutant mCRC patients treated with first-line FOLFOXIRI plus bevacizumab were included in a validation set. The primary endpoint was 6-months progression free rate (6m-PFR). Secondary endpoints were: overall survival, response rate and the pooled analysis of all main outcome parameters in both the exploratory and validation set. Results: In the validation set, 11 out 15 patients included were progression-free at 6 months, for a 6m-PFR of 73.3%. Primary endpoint was met. At a median follow-up of 21.6 months, median progression-free survival was 9.2 months while median OS has not yet been reached. In the pooled data analysis of the validation set and the initial retrospective cohort 24 out 25 total patients were evaluable for response: partial or complete response was obtained in 17 (68%) and in 1 (4%) patient, respectively, for an overall response rate of 72%. At a median follow-up of 34.1 months, the pooled set of patients showed a median PFS of 11.8 months and a median OS of 23.8 months. Conclusions: These data suggest that FOLFOXIRI plus bevacizumab could be a reasonable option for the first-line treatment of BRAF mutant metastatic colorectal cancer patients.
Neoadjuvant capecitabine, oxliplatin, and bevacizumab (CAPOX-B) in intermediate-risk rectal cancer (RC) patients defined by magnetic resonance (MR): GEMCAD 0801 trial.
Authors: Fernandez-Martos Carlos , Estevan Rafael , Salud Antonia , Pericay Carles , Gallen Manuel , Sierra Enrique , Serra Javier , Pera Miguel , Maurel Juan , Delgado Salvadora , Safont M. José , Roig Jose Vicente , Aparicio Jorge , Feliu Jaime , Garcia Damian , Vera Ruth , Suarez Javier , Alonso Vicente , Martin-Richard Marta , Brown Gina 
Published: March 2020

3586 Background: Retrospective data suggest that RT might not be needed in all patients with stage II/III RC. Modern systemic therapy might have local efficacy similar to chemoradiation (CRT). Methods: A multicenter phase II trial was undertaken to evaluate safety and efficacy of neoadjuvant CAPOX-B in patients with T3 middle third rectal adenocarcinoma. Eligible patients (pts) had measurable disease at the baseline and candidate for R0 total mesorectal escision (TME) with intermediate-risk defined by pelvic MR a) T3 with distal border of tumor > 5 cm from the anal verge and below the sacral promontory. b) tumor ≥2 mm from the mesorectal fascia. Pts received 4 cycles of Cap 2000 mg/m2 (d1-14), Ox 130 mg/m2 (d1) and B 7.5 mg/kg (d1) every 3 weeks (last cycle without B). Pts undergo re-staging with MR. One radiologist reviewed all pre- and post-treatment MR scans independently. Pts without progression proceed to TME 4-6 weeks from the last cycle. If progression, pts were to be referred for pre-op cap/RT followed by TME. 1º Endpoint: Tumor Response (RECIST). Design: Simon 2-stage; 28 pts 1st stage and 46 pts 2nd stage. We report data on the planned analysis of pts included for 1st stage. Results: 28 eligible pts (10F/18M) were enrolled from 7/09-5/11. Tumor response, compliance and toxicity details are shown in table below. Two pN2 pts received postop Cap/RT. Conclusions: Neoadjuvant CAPOX-B is active and safe. Early parameters of efficacy are encouraging and seem similar to those observed with CRT. [Table: see text]
Neoadjuvant radiotherapy (RT) combined with capecitabine (Cape) and sorafenib (Sor) in patients with locally advanced, K-ras-mutated rectal cancer (LARC): A phase I/II trial (SAKK 41/08).
Authors: Von Moos Roger , Koeberle Dieter , Winterhalder Ralph C. , Cathomas Richard , Inauen Roman Ignaz , Zwahlen Daniel Rudolf , Roth Arnaud , Helbling Daniel , Gautschi Oliver , Baertschi Daniela , Kuehne Reto , Von Briel Thomas , Grzesiczek Anja , Samaras Panagiotis , Kollar Attila , Klingbiel Dirk , Zaugg Kathrin 
Published: March 2020

3595 Background: 40% of patients (pts) with LARC present with K-ras mutation. Sor is an inhibitor of ras/raf and of VEGFR. Furthermore Sor has radiosensitizing effects. These facts build a strong rationale to use Sor in combination with preoperative RT and Cape in pts with K-ras mutant tumors. Methods: Pts with K-ras mutated mrT3-4 and / or mrN+, M0 disease were recruited in cohorts of 7 pts per dose level (DL). Dose limiting toxicity (DLT) was defined as any G3 or higher non hematological toxicity (tox) or haematological tox during ≥ 7 days, which are possibly, probably or definitely related to trial treatment occurring during and up to 4 weeks after last administration. If ≤ 2 out of 7 pts experienced a DLT, then the next cohort was treated at a higher dose level. If > 2 out of 7 pts suffered from a DLT, this DL would be considered too toxic and a dose level below would be tested in the next cohort. The highest dose level with ≤ 2 out of 7 pts experienced a DLT would be recommended for the phase II part. In all dose levels RT was given in 25 fractions at 1.8Gy (45Gy). Results: In 8 centers in Switzerland a total of 21 pts in 3 cohorts have been treated in the phase 1 study. After observing severe skin toxicity and diarrhea (2 pt with skin toxicity G3, one patient (pt) with diarrhea G3 plus hand-foot syndrome (HFS) (G3)) an amendment was implemented to reduce the Sor dose from 400mg BID to once daily. In DL 1 after the amendment, 2 pts experienced a DLT (enteritis G3, dermatitis G3). Two pts in DL 2 suffered from a DLT (cystitis G3 plus HFS G3, cardiac ischemia G3). Further non dose-limiting G3 toxicities after the amendment were lymphopenia (G3) (1pt, DL 2) and hypocalcaemia (G3) (1 pt, DL 2). No Grade 4 toxicity was seen. DL 2 is the recommended dose for phase II. Conclusions: After reducing the Sor dose to 400mg once daily, neoadjuvant treatment with Sor in combination with full dose Cape and RT was tolerable and the toxicities manageable. [Table: see text]
Treating patients with colorectal liver metastasis: A national decision-making analysis to understand choice of therapy.
Authors: Pawlik Timothy M , Nathan Hari , Cosgrove David , Laheru Dan , Diaz Luis A. , Herman Joseph M. , Edil Barish H , Hirose Kenzo , Wolfgang Christopher Lee , Choti Michael A. , Schulick Richard D. 
Published: March 2020

3596 Background: Criteria for resectability of colon cancer liver metastases (CLM) are evolving, yet little is known about how physicians choose a therapeutic strategy for potentially resectable CLM. Methods: Physicians completed a national web-based survey that consisted of varied CLM case scenarios. Respondents choose among 3 treatment strategies: immediate liver resection(LR), preoperative chemotherapy followed by surgery(C→LR), or palliative chemotherapy (PC). Data were analyzed using multinomial logistic regression, yielding relative risk ratios (RRR). Results: Of 219 respondents, 79% practiced at academic centers and 63% were in practice ≥10 years. Median number of cases evaluated was 4/month. Surgical training varied: 51% surgical oncology (SO), 44% hepatobiliary/transplant (HB/LT), 5% no fellowship. While each factor impacted choice of CLM therapy, the relative impact differed (p<0.01). Synchronous CLM presentation increased the choice of C→LR (OR 4.27) and PC (OR 3.10) versus LR (p<0.001). For patients with more extensive intrahepatic disease (i.e., 5 tumors, both lobes) respondents strongly favored C→LR (OR 5.12) and PC (OR 9.60) versus LR (p<0.001). The presence of hilar lymph-node disease was associated with a strong aversion to LR with surgeons more likely to choose C→LR (OR 8.92) or PC (OR 49.9) (p<0.001). Interestingly, even the presence of a resectable solitary lung metastasis strongly deterred choice of LR with respondents favoring C→LR (OR 4.43) or PC (OR 6.97) (p<0.001). While other factors such as patient age, tumor size, and extent of resection impacted choice of therapy, the relative size of these effects was modest. After controlling for clinical factors, surgeons with more years in practice were more likely to choose LR (RRR 1.4). SO-trained surgeons were more likely than HB/LT-trained surgeons to choose C→LR (RRR 2.5) or PC (RRR 4.15)(p<0.001). Conclusions: This is the first study to define the relative impact of key clinical factors on choice of therapy for CLM. While clinical factors influence choice of therapy, surgical subspeciality and physician experience are also important determinants of care.