bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacodynamic effects of regorafenib in metastatic colorectal carcinoma (mCRC).
Authors: Wong Andrea Li Ann , Sinha Arvind , Gopinathan Anil , Lim Robert S.C. , Tan Chee Seng , Soh I Peng Thomas , Venkatesh Sudhakar , Titin Christina , Soong Richie Chuan Teck , Pang Brendan , Sapari Nur Sabrina , Wang Ting Ting , Zee Ying Kiat , Chuah Benjamin , Jeffers Michael , Lathia Chetan , Trnkova Zuzana , Wilhelm Scott , Goh Boon C. 
Published: March 2020

e14507 Background: Regorafenib, an oral multikinase inhibitor of VEGFR2/3, PDGFRb, KIT, FGFR, RET, RAF and TIE2, is efficacious in refractory mCRC but its mechanism of action is unclear and predictive biomarkers are lacking. Methods: We assessed tumor and circulatory biomarkers in a phase 2 study of regorafenib in refractory mCRC patients. Regorafenib was administered orally at 160mg/d for 3 out of 4 weeks. Post cycle 2 response was assessed by RECIST 1.1. Subjects were scheduled for FDG PET-CT scans (pre + D15) and paired core needle tumor biopsies for IHC analysis (pre + D21) in cycle 1. Archival tumor mutations were evaluated using Sequenom MassARRAY OncoCarta Panel V1.0 assay. Results: 35 patients were treated; 49% received > 4 prior therapies and 43% had prior bevacizumab. Median PFS was 3.45 mths (95% CI: 3.40-3.49), ORR was 3% and disease control rate [DCR] (PR + SD at 8 wks) was 57%. Early PET responses (EORTC criteria) were seen in 49%, but did not predict for DCR (p=1.0). Fatigue, hand foot skin reaction (HFSR), voice change and diarrhea occurred in > 30% of subjects. Grade 3-5 toxicities occurred in 46%, the commonest being HFSR and rash (17% each). Median relative dose intensity was 92%; 43% required > 1 dose reduction, 60% required > 1 dose interruption. KRAS (29%), BRAF (9%), EGFR (9%), NRAS (6%) KIT (3%), PIK3CA (3%), PDGFRA (3%) and CDK (3%) mutations were detected in archival tumors. None predicted for ORR or DCR; PFS was identical in KRAS mutant vs wt patients (3.45 mths, p=0.39) and similar in BRAF mutant vs wt patients (3.48 vs 3.45 mths, p=0.10). The patient with the longest PFS (12.6 mths) had a BRAF mutation. Amongst the 10 paired tumor samples available, IHC markers upregulated in >50% cases were pMEK, pERK, pJun and pJNK, whilst those downregulated/ unchanged in >50% were pKIT, pVEGFR2, CD31 [vascular endothelial cells (ECs)] and podoplanin (lymphatic ECs). The greatest change was observed in podoplanin expression, corresponding to a 60% reduction in lymphatic vessel density. Conclusions: FDG-PET responses in cycle 1 did not predict for regorafenib clinical benefit in mCRC patients. Targeting lymphatic/vascular ECs in the tumor microenvironment may be a more significant antitumor mechanism of regorafenib than MAP kinase pathway inhibition. Clinical trial information: NCT01189903.
Early prediction of therapeutic efficacy of bevacizumab (Bmab) by measuring plasma concentration of βmab-unconjugated free VEGF-α in patients with recurrent or metastatic colorectal cancer (CRC).
Authors: Cho Yukiko , Fujieda Shinji , Ozeki Mizuharu , Amagai Kenji , Kojima Hiroshi 
Published: March 2020

e14510 Background: Although Bmab plus chemotherapy is widely accepted as the standard treatment for recurrent or metastatic CRC, some patients (Pts) are eventually poor responders. We hypothesized that monitoring of Bmab-unconjugated free VEGF-A concentration (conc.) in plasma is useful for predicting the therapeutic efficacy. Methods: Plasma samples were obtained from 20 (13 males & 7 females) recurrent or metastatic CRC Pts with informed consent before Bmab administration and at 1- and 2-M of the 1st administration. VEGF-A conc. was measured by ELISA. For measuring Bmab-unconjugated free VEGF-A, Bmab-conjugated VEGF-A was immuneprecipitated by using protein A/G-Agarose. VEGF inhibitory ratio (%) was calculated by free VEGF-A / total VEGF-A. Clinical response was evaluated according to RECIST, and Pts achieving CR/PR and remaining NC more than 6 months were defined as good responders. Results: Baselineplasma conc. of VEGF-A was 78.45 ± 113.67 pg/ml (mean ± SD), which was significantly higher than that of healthy volunteers. Administration of Bmab did not result in significant decrease in the conc. of total VEGF-A (1- and 2-M: 85.26 ± 41.42 & 99.63 ± 44.87 pg/ml, respectively). In contrast, Bmab-unconjugated free VEGF-A conc. decreased significantly (30.24 ± 91.94 & 45.22 ± 51.23 pg/ml, respectively) (p<0.05), and each inhibitory ratio was 70.18 ± 25.67 and 65.12 ± 32.15%. We then set inhibitory ratio of 70% as the cut-off level, and analyzed the correlation between inhibitory ratio and therapeutic efficacy. Among 11 Pts whose inhibitory ratio reached ≥70% at both 1- and 2-M, 9 Pts (81%) were good responders. Contrary, among the remaining 9 Pts, only 3 Pts (33%) were good responders. There was no correlation between therapeutic efficacy and total or free VEGF-A conc. Conclusions: We consider that early prediction of therapeutic efficacy of Bmab is possible by monitoring the inhibitory ratio of VEGF-A, and that future prospective study for validating its usefulness was warranted.
Survival benefit associated with the number of chemotherapy/biologic treatment lines in 5,129 elderly metastatic colon cancer patients.
Authors: Hanna Nader , Zheng Zhiyuan , Woods Corinne , Onukwugha Ebere , Bikov Kaloyan A. , Seal Brian S. , Mullins C. Daniel 
Published: March 2020

e14524 Background: Metastatic colon cancer (mCC) patients often receive multiple lines of chemotherapy/biologics treatment to improve survival, yet the "real world" benefits and risks of multiple treatment lines have not been fully examined. Methods: The National Cancer Institute’s SEER-Medicare data was analyzed to determine the association between the number of treatment lines and 5-year survival in mCC patients. Patients were at least 66 years old, diagnosed with mCC in 2003-2007 and followed until death or 12/31/09. Only patients who survived at least 3 months from diagnosis were included. Cox proportional hazards regression was used along with inverse probability weighting method to adjust for the probability of receiving treatment. Results: Of 5,129 elderly Medicare mCC patients, the 5-year survival rate was 12.9% (n=664). Each incremental treatment was significantly associated with an increase in the average five-year survival by 5.4 months, 7.2 months and 2.7 months for 1st-line, 2nd-line and subsequent treatments, respectively. Significant variables associated with increased mean survival times were receipt of 1st-line, 2nd-line or subsequent treatment compared to no treatment (hazard ratio HR=0.58, 0.36 and 0.32, respectively, p<.01); resection/ablation of liver metastases (HR=0.80, p<.01) and primary site surgery (HR=0.52, p<.01). Significant variables associated with lower survival times were poorly-graded tumor (HR=1.53, p<.01), Charlson Comorbidity Index score of at least 3 compared to 0 (HR=1.15, p=.016), female (HR=1.07, p=.043) and age (in 10-year increments, HR=1.06, p=.011). Conclusions: Among elderly Medicare mCC patients who survived at least 3 months from diagnosis, receipt of 1st-line, 2nd-line and subsequent treatments was associated with incremental increases in the average survival time. However, this may reflect physician treatment patterns in healthier patients who are more likely to receive treatment. Additional factors that significantly increased survival time were primary site surgery (by 5.5 months), resection/ablation of liver metastases (by 1.9 months) and a tumor not poorly-graded (by 3.6 months).
FDG-PET/CT (PET) in the early prediction of benefit from first-line chemotherapy plus bevacizumab (bev) in metastatic colorectal cancer (mCRC).
Authors: Salvatore Lisa , Loupakis Fotios , Cremolini Chiara , Schirripa Marta , Antoniotti Carlotta , Marmorino Federica , Zoratto Federica , Bergamo Francesca , Brunetti Isa Maura , Pfanner Elisabetta , Masi Gianluca , Genovesi Dario , Filidei Elena , Giorgetti Assuero , Falcone Alfredo 
Published: March 2020

e14531 Background: The conventional assessment of response according to RECIST seems not optimal to estimate the actual benefit from antiangiogenic agents. A recent experience suggests the potential role of PET in the early prediction of benefit from first-line chemotherapy in mCRC. The objective of the present study was to evaluate the metabolic PET response to one single cycle of chemotherapy plus bev in mCRC patients (pts). Methods: PET was carried out at baseline and on day 13 in 51 unresectable mCRC pts, treated with biweekly bev-containing regimens; computed tomography (CT) scan was performed at baseline and every 2 months. PET response was defined by >15% decrease in FDG uptake in the dominant proportion of lesions, in the absence of metabolically progressive lesions. CT response was defined according to RECIST 1.0. Results: PET response rate was 73%. PET responders achieved longer PFS compared to PET non-responders (median PFS: 11.0 vs 8.3 months; HR=0.45 [95%CI 0.14-0.93] p=0.035). RECIST CT response rate was 62% and 57%, in PET responders and non-responders, respectively (p=0.76). At an exploratory analysis, among pts (N=15) reporting a RECIST-defined stable disease (SD), those with a percentage decrease in FDG uptake higher than the median value (>33%) had significantly longer PFS in comparison to those with a lower PET response (median PFS: 9.4 vs 7.4 months; HR=0.2 [95%CI 0.005-0.24] p=0.0006). Conclusions: Early PET response, assessed after one single cycle of chemotherapy plus bev, predicts PFS, while it does not correlate with traditional RECIST response. In the subgroup of pts reporting a RECIST SD, the early reduction in FDG uptake correlates with PFS. On the basis of our results, early PET response on day 13th could representan early predictor of benefit from bev plus chemotherapy in mCRC.
Disparities between young and elderly patients in the first course of treatment for stage II and III rectal cancers.
Authors: Tilahun Yaphet , Arnoletti Juan Pablo , De La Fuente Sebastian G. 
Published: March 2020

e14546 Background: The use of neoadjuvant chemoradiation for stage II and III rectal cancers is associated with higher rates of resectability, sphincter preservation and improved local control. In elderly patients, however, the feasibility and benefits of this approach are less understood. In this study, we determined disparities in the first course of therapy between young and elderly patients with rectal cancer using the National Cancer Data Base (NCDB). Methods: The NCDB was queried for cases of rectal cancer diagnosed from 2000-2009. Analyzed variables included tumor staging, age group and first course of treatment. For analytical purposes, study groups were divided in young (≤ 69 years of age) or elderly patients (≥ 70 years of age). Results: A total of 8,237 patients that received chemoradiation as the first treatment approach were identified from the NCDB during the study period. During the same time, 15,468 patients were treated with surgery first. Fifty-eight percent of patients in the neoadjuvant-first treatment group were equal or younger than 69 years of age. Subgroup analysis showed that elderly patients were treated with surgery first more frequently than with neoadjuvant chemoradiation therapy (surgery-first 72% vs. chemoradiation first 28%, p<0.04). In the contrary, no differences were noted in the first course of treatment received among younger patients (surgery-first 53% vs. chemoradiation first 47%, p=NS). Conclusions: This data shows that there is an age-bias after the age of 70 for surgery only as the first treatment approach for patients with stage II and III rectal cancers. This is probably confirmatory that patients are brought to surgery without neoadjuvant therapy because they are perceived as not being able to tolerate chemoradiation.
Neoadjuvant treatment response as a tumor necrosis grade for patients with rectal cancer.
Authors: Shim Byoungyong , Jung Ji Han , Cho Hyun Min , Kim Hyung Jin , Hong Ji Hyung , Kim Sung Whan 
Published: March 2020

e14563 Background: Neoadjuvant chemoradiotherapy for rectal cancer results in prevention of local recurrence and may achieve sphincter conserving surgery. Association between pathologic response evaluated after radical tumor resection and patient prognosis was well established. The object of this study was to assess the association between the degree of tumor necrosis after chemoradiotherapy and oncologic outcomes. Methods: In all, 225 patients with locally advanced rectal cancer (stage II and III by endorectal ultrasonography, CT and MRI) had 50.4 Gy over 5.5 weeks, plus 5-fluorouracil and leucovorin and surgery was performed at 7 to 10 weeks after completion of all therapies. Pathologic tissue necrosis after chemoradiotherapy was reviewed and scored as follows: Grade 0, no response; Grade 1, necrosis or disappearance of tumor cells less than 2/3; Grade 2, necrosis or disappearance of tumor cells more than 2/3; and Grade 3, no viable cells (ypCR). Correlation analysis was performed using Pearson’s Chi square or Fisher’s exact test, as appropriate. Recurrence-free survival and overall survival were calculated using the Kaplan-Meier method. Results: This study included cStage II (101 patients) and cStage III (124 patients) rectal cancer patients, and down stage rate was 57.3% and pCR was 16.9%. The pathologic tumor response ( pStage 0 v I v II v III) was associated with 5-year RFS (97.4 % v 81.5% v 76.6% v 50.0%; p<0.001). The tumor necrosis (Grade 0 & 1 v 2 v 3) was associated with 5-year RFS (64.4% v 76.8 v 97.4%; p=.002). Conclusions: The tumor necrosis to neoadjuvant chemoradiotherapy is a surrogate marker for recurrence and oncologic outcomes in rectal cancer patients treated with 5 flurouracil and leucovorin neo-adjuvant chemoradiotherapy.
Neoadjuvant pelvic perfusion may facilitate resection of pelvic recurrent rectal cancer.
Authors: Wanebo Harold J. , Begossi Giovanni , Belliveau James , Gustafson Eric 
Published: March 2020

e14599 Background: Pelvic recurrence of rectal cancer is a persisting therapeutic challenge in spite of wide spread use of adjuvant/neoadjuvant chemo radiation and wide resection isolated pelvic perfusion (IPP) may facilitate pelvic resection in selected high-risk patients.IPP was done in 42 patients with locally advanced previously irradiated rectal cancer, 26 as a preoperative therapy and 16 for palliation. A comparative larger non-perfused group included 63 patients with pelvic resection only for recurrent rectal cancer. Methods: Isolated pelvic perfusion (60 min) utilized pump oxygenation (Temp>41°C)with chemo agents – 5 FU 1500mg/m2, Cisplatin/Oxaliplatin 100/ 150mg/m2, Mitomycin 10-20 mg/m2, which was done in 42 patients (26 as preoperative and 16 as palliative therapy). Results: Palliative IPP in 16 advanced rectal cancer patients (pts)resulted in significant relief (1-4 months) of narcotic resistant pain (in 70%). Preoperative IPP in 26 locally advanced rectal cancer pts achieved a clinical pathologic complete response (CR) in 2 patients, and significant regression in 11 patients rendering them resectable. Seven pts had R0 pelvic resections,(6 abdominal sacral resection (ABSR) and 1 extended APR).Of 8 other patients, 3 responders refused surgery, 5 were excluded.(medical or disease related ). Median survival was 22.5 months in 15 resectable and 32 mos in 7 resected pts (2 pts were 5 year survivors). This is compared to outcome in 63 patients amenable to having pelvic resection alone: 57% had R0 resection (median OS 36 mos), 28% had R1 resection (med OS = 15 mos) and 15% had R2 resection (med OS 21 mos). Conclusions: Neoadjuvant IPP may facilitate selection of recurrent rectal cancer by identifying therapeutic responders likely to benefit from major pelvic resection and excluding non-responders most likely to benefit from non-surgical therapy. The potential to induce regression and facilitate R0 resection merits further exploration.
Phase II study of first-line combined chemotherapy bevacizumab with modified RPMI regimen for elderly or frail patients with unresectable or metastatic colorectal cancer (OGSG0802) update analysis.
Authors: Satoh Taroh , Kato Takeshi , Yoshida Motoki , Miyake Yasuhiro , Iwamoto Shigeyoshi , Nakamura Masato , Sakai Daisuke , Matsuoka Masaki , Otsuji Toshio , Furukawa Hiroshi ,   Osaka Gastrointestinal Cancer Chemotherapy Study Group (OGSG)
Published: March 2020

e14601 Background: The first-line combined chemotherapy RPMI regimen with bevacizumab (Bmab) in AVF2192g tri al were active. According to the results of efficacy and safety, a fluoropyrimidine (FU) + Bmab regimen is regarded as one of treatment options for 1st-line chemotherapy in many guidelines. We planned a phase II study of modified RPMI regimen with Bmab especially for elderly or frail Pts. Methods: Pts with confirmed unresectable/metastatic colorectal cancer without previous chemotherapy, and not suitable for intensive chemotherapy were enrolled. Pts received modified RPMI regimen (5-FU 600 mg/m2 and l-leucovorin 200 mg/m2 bolus day 1, 8, 15) and Bmab 5 mg/kg day 1, 15, q4w) until disease progression or study withdrawal. The primary endpoint was overall response rate (ORR), and the secondary endpoints were PFS, OS and safety. Results: 41 Pts were enrolled from 13 institutions. Pts characteristics were as follows; median age 76 (range 56-90); male/female, 18/23; ECOG performance status 0/1/2, 21/19/1. The ORR, the rate of best response, the disease control rate (CR+PR+SD) were 36.6%, 56.1%, 85.4%, respectively. Median follow-up period was 14.4 months(Updated results will be presented). 28 Pts (68%) had objective progression and a patient (2.4%) died without progression. The median PFS and OS were 9.0 months (95%CI, 7.5–19.6) and 24.0 months (95%CI, 20.1–NR). The incidences of grade 3 or 4 adverse events were: leukopenia (7%), neutropenia (24%), thrombocytopenia (2%), diarrhea (5%), anorexia (10%), fatigue (5%), stomatitis (7%) and hypertension (5%). Grade 3 febrile neutropenia and grade 4 pulmonary embolism was observed in one pt. Five pts (12%) discontinued the treatment due to severe or uncontrollable adverse event. Conclusions: The modified RPMI regimen with Bmab showed promising activity, and was well tolerated for elderly or frail Pts. ORR and the median PFS of this regimen were similar to historical data with FU + Bmab. This regimen may be a good option for patients with poor PS or elderly with advantages of not requiring percutaneous port placement nor compliance or oral agents. Clinical trial information: UMIN000002182.
Expression and methylation profiles associated with recurrent mutations in stage II colorectal cancer.
Authors: Pare-Brunet Laia , Sanz-Pamplona Rebeca , Lopez-Doriga Adriana , Berenguer-Llergo Antoni , Ausso Susanna , Cordero David , Closa Adria , Moreno Victor 
Published: March 2020

e14613 Background: Aberration of normal genetic and epigenetic patterns occurs at early stages of colorectal cancer (CRC) and accumulates throughout cancer progression. To characterize pre-metastatic tumors, a series of stage II, microsatellite stable, colon tumors and their paired mucosa were profiled on RNA expression and DNA methylation microarrays ( www.colonomics.org ). Our aim is to define molecular subtypes based on recurrent gene mutations, methylation and expression profiles, and explore if these molecular subtypes are associated to patients’ prognosis. Methods: We have sequenced exomes (Illumina Genome Analyzer) of a subset of 42 COLONOMICS normal-tumor paired samples (21 good and 21 bad prognosis). Variants identified in normal tissue were used to filter SNPs. DNA methylation (Infinium Human Methylation 450k) and RNA expression (Affymetrix U219) data from those samples were used in this analysis. Correlation was used to assess the association between tumor mutations and differentially expressed/methylated genes. Significant genes were subsequently used to perform tumor clustering. Results: Exome analysis revealed a mean of 150 somatic mutations per sample. From these, 12 variants were recurrently mutated (KRAS, TP53, etc) in more than 3 tumors that were used to define tumor subtypes based on gene methylation/expression patterns. We obtained 12 profiles that clearly identified the cluster of mutated samples. For some profiles, the cluster only includes those tumors with the mutation. Interestingly, some clusters included the mutated samples and additional tumors showing the same phenotype despite not having the mutation. For each mutation, the overlapping between the differently methylated/expressed genes ranged from 14 to 200 common genes. When combining data from the three platforms two main CRC molecular subtypes emerge; each of which shows molecular heterogeneity but no association with prognosis. Conclusions: Mutational status is associated with gene methylation and expression patterns in CRC patients. Although none of these clusters was associated with prognosis, different groups of tumors could be related to distinctive pathways, which may reveal useful as therapeutic targets.
Analysis of totally implantable venous access port systems (TIVAPS) related adverse events (AEs) in metastatic colorectal cancer (mCRC) patients treated with and without bevacizumab.
Authors: Tsushima Takahiro , Mori Keita , Yamazaki Kentaro , Hikosaka Tomomi , Funakoshi Taro , Tabuse Hiroyuki , Hamauchi Satoshi , Todaka Akiko , Yokota Tomoya , Machida Nozomu , Fukutomi Akira , Onozawa Yusuke , Boku Narikazu , Yasui Hirofumi 
Published: March 2020

e14623 Background: TIVAPS are widely used for cancer chemotherapy. Bevacizumab, a key drug for mCRC, associates with AEs such as thromboembolism, bleeding, and impaired wound healing. Bevacizumab may complicit in increasing incidence of TIVAPS related AEs. To assess the incidence of TIVAPS related AEs in mCRC patients who received chemotherapy with and without bevacizumab. Methods: We retrospectively reviewed the medical records of consecutive patients whose TIVAPS were placed at our institution between Apr. 2004 and Apr. 2009. Major selection criteria were histologically proven colorectal adenocarcinoma, metastatic disease, and receiving chemotherapy after TIVAPS placement. We assessed the incidence of AEs occurred from the first administration of chemotherapy via TIVAPS to TIVAPS removal, death, or the last follow-up. We compared the incidence of TIVAPS related AEs in the cases bevacizumab was administered (group A) with that in the cases without bevacizumab administration (group B). Results: TIVAPS was placed 549 times for 505 patients, and 544 TIVAPS placements for 501 patients were analyzed. Bevacizumb was administered in 174 patients (32%), and median duration of bevacizumab therapy was 9.2 months. Characteristics of the cases in the group A and B were: male (60% and 59%); primary site colon (60% and 57%); catheterized in left subclavian vein (85% and 81%); history of prior chemotherapy (53% and 60%); median time from TIVAPS placement to administration of chemotherapy (1 day and 1 day). Incidence of common AEs in the group A and B were: infection (7.5% and 6.8%); venous thromboembolism (3.4% and 1.4%); TIVAPS occlusion (2.3% and 1.9%); delay of wound healing (1.1% and 0.5%); hematoma (0.6% vs 0%). Median time to AE in the group A and B was 21 months and 9 months. There was no significant difference in the incidence of TIVAPS related AEs between group A and B. During median observation period of 40.5 months, no arterial thrombotic event or AE resulted in death occurred. Conclusions: Addition of bevacizumab did not increase TIVAPS related AEs during chemotherapy for mCRC.