bluuebunny/crossref_metadata_2025_split huggingface dataset:
The intersection of age and tumor biology with postoperative outcomes in patients after cytoreductive surgery and HIPEC.
Authors: Turgeon Michael K. , Gamboa Adriana C. , Lee Rachel M. , Zaidi Mohammad Yahya , Kimbrough Charles , Grotz Travis Edward , Fournier Keith F. , Dineen Sean Patrick , Veerapong Jula , Clarke Callisia , Mogal Harveshp , Patel Sameer H. , Lambert Laura A. , Ronnekleiv-Kelly Sean , Raoof Mustafa , Johnston Fabian McCartney , Staley Charles A. , Cloyd Jordan , Maithel Shishir K. , Winer Joshua H. 
Published: February 2020

184 Background: Patient age is often a significant factor in preoperative selection for major abdominal surgery. Its association with postoperative outcomes in patients undergoing cytoreductive surgery(CRS) and hyperthermic intraperitoneal chemotherapy(HIPEC) remains ill-defined. Methods: The US HIPEC Collaborative database(2000-2017) was reviewed for patients who underwent a CCR0/1 CRS/HIPEC. Age was categorized into < 65 or >65yrs. Primary outcomes were postoperative major complications, readmission, 30-day mortality, and non-home discharge(NHD). Analysis was stratified by disease histology: non-invasive(appendiceal LAMN/HAMN), and invasive(appendiceal/colorectal adenocarcinoma). Results: Of 1090pts identified, 22% were >65yrs(n = 240), 59% were female(n = 646), 25% had non-invasive(n = 276) and 51% had invasive(n = 555) histology. Median PCI was 13(IQR7-20). Patients >65yrs had a higher rate of major complications(37vs26%, p = 0.02), readmission(28vs22%,p = 0.05), 30-day mortality(3vs1%,p = 0.02), and NHD(12vs5%,p < 0.01) compared to those < 65yrs. On multivariable analysis accounting for extent of disease as measured by PCI, for non-invasive histology, age >65yrs was an independent predictor for NHD(OR:2.54,95%CI:1.08-5.99,p = 0.03), but not major complications. For invasive histology, even when accounting for PCI, age >65yrs was an independent predictor for both NHD(OR:2.54,95%CI:1.08-5.98,p = 0.03) and major complications(OR:2.04,95%CI:1.16-3.59,p = 0.05). Age was not associated with hospital readmission or 30-day mortality for any histology. Conclusions: Regardless of histology, patients >65yrs are nearly at three-fold increased risk for non-home discharge after CRS/HIPEC. For invasive histology, age >65yrs is also associated with increased major complication rates, but the procedure seems to be better tolerated when performed for indolent biology. These data inform preoperative counseling and risk stratification. Early planning for discharge disposition in this high-risk population can potentially translate to cost savings.
Systemic impact on tumor growth after combined immuno-thermal ablation in a murine model of colorectal cancer.
Authors: Slovak Ryan J. , Park Hong-Jai , Kamp William M. , Ludwig Johannes M. , Kang Insoo , Kim Hyun S. 
Published: February 2020

198 Background: Cryoablation exposes tumoral antigens capable of provoking an anti-cancer immune response. The addition of immunotherapy alongside cryoablation may synergistically promote a more robust systemic response. The purpose of this investigation was to study the growth of targeted and off-target tumors after combined cryoablation and dual immune checkpoint blockade (DICB). Methods: Sixty BALB/c mice were implanted with bilateral flank injections of 0.5 x 106 CT26.WT colorectal cancer cells (CRL- 2638; ATCC, Manassas, VA). Tumor volume was measured every other day via caliper (LxW2). Mice were randomly assigned to receive either sham injections (InVivoMAb IgG controls), dual anti-PD-1 and anti-CTLA-4 (DICB) (Clone J43 & Clone 9D9; BioXcell, West Lebanon, NH, USA), or DICB plus either partial or full cryoablation of a single targeted tumor. Treatment day 0 began once tumors reached a volume of ~300mm3. Injections of antibodies were given on treatment day 0, 3, and 5. Cryoablation was performed on treatment day 2. Full ablation was achieved via two 3-minute cycles at 100% power and partial ablation was defined as a single 3 minute cycle at 70% power ablation (Visual-ICE System, Galil Medical, St. Paul MN). Animals were sacrificed at 7 and 14 days after treatment. Results: There was an average of 177.15% ± 75.22 (SD) increase in tumor volume among control animals and 14.47% ± 9.69 decrease in animals treated solely with DICB. Mice that received full ablation demonstrated an average 72.39% ± 29.21 decreased volume in the target tumors and 48.94% ± 25.97 decrease in the off-target tumors. Partially ablated mice averaged 81.21% ± 16.43 decreased volume in the target tumors and 35.87% ± 16.95 decreased volume in the off-target tumors. The mean change in volume of every group was significantly less than that of the control (p < 0.05) and there was a significantly larger reduction in volume between both the full and the partial target tumors versus the DICB group (p < 0.05). Conclusions: The addition of cryoablation to DICB resulted in a significant reduction in volume of the targeted tumors. Additionally, this combination led to larger volume reductions in off-target tumors as compared to immunotherapy alone.
Gene polymorphisms of CCL3, CCL4, CCL5, and CCR5 network in metastatic colorectal cancer patients treated with regorafenib.
Authors: Suenaga Mitsukuni , Zhang Wu , Mashima Tetsuo , Schirripa Marta , Cao Shu , Okazaki Satoshi , Berger Martin D. , Miyamoto Yuji , Barzi Afsaneh , Lenz Heinz-Josef 
Published: February 2020

199 Background: We previously reported that genetic variant in the CCL5/CCR5 pathway predict efficacy of regorafenib in metastatic colorectal cancer patients (mCRC). CCL5 rs2280789 G allele and CCL5 rs3817655 T allele were associated with longer overall survival (OS) and severe skin toxicity due to low VEGF-A production via endothelial progenitor cell (EPC). CCL4 rs1634517 G allele and CCL3 rs1130371 C allele correlated with longer Progression-free survival (PFS) and OS. We investigated the biological role of CCL4 and CCL3 gene polymorphisms. Methods: We analyzed genomic DNA extracted from 79 samples of a Japanese cohort receiving regorafenib. Single nucleotide polymorphisms (SNPs) of genes in CCL5/CCR5 pathway were analyzed by PCR-based direct sequencing. Blood samples were obtained from 57 patients at baseline (BL), day 21 and progressive disease (PD), and serum CCR5, CCR5 ligands (CCL3, CCL4, CCL5) and VEGF-A levels were measured using ELISA. PFS and OS were analyzed using Kaplan-Meier curves and log-rank test. Results: Increased CCL3 levels at PD were associated with longer OS than decreased (12.6 vs 4.8 mos, P = 0.003). Patients with decreased CCL4 levels at day 21 had a trend toward longer PFS and tumor shrinkage. Positive correlation was observed between CCL3 and CCR5 throughout the treatment independent of other ligands (change at day 21: r = 0.426, P = 0.009). There was no significant correlation of CCL3 and CCL4 levels with VEGF-A levels. Patients with the G/G variant in CCL3 rs1130371 had increased CCL3, CCR5 and CCL5 levels at day 21 than any A allele. Similarly, patients with the C/C variant had increased CCL3, CCR5 and CCL5 levels at day 21 compared with those with any A allele. In contrast, both CCL5 rs2280789 G allele and CCL5 rs3817655 T allele were associated with increased CCL3 levels and decreased CCL4 levels at day 21 (P = 0.006, P = 0.043; P = 0.006, P = 0.043). Conclusions: Positive correlation of CCL3, CCR5 and CCL5 impact similarly on CCL3 and CCL4 SNPs, while different manner between CCL3 and CCL4 was found in CCL5 SNPs. This suggests an alternative mechanism of action in the network of CCR5 and the ligands except CCL5-VEGF-A signaling via EPC in mCRC patients receiving regorafenib.
Analysis of early tumor shrinkage (ETS) and depth of response (DpR) in metastatic colorectal cancer (mCRC) patients (pts) treated with second-line FOLFIRI plus panitumumab (Pani) or bevacizumab (Bev): Results from a randomized phase II WJOG6210G trial.
Authors: Izawa Naoki , Shitara Kohei , Masuishi Toshiki , Denda Tadamichi , Yamazaki Kentaro , Moriwaki Toshikazu , Okuda Hiroyuki , Kondoh Chihiro , Nishina Tomohiro , Makiyama Akitaka , Baba Hideo , Yamaguchi Hironori , Nakamura Masato , Tsuji Akihito , Esaki Taito , Miyata Yoshinori , Kotaka Masahito , Yamanaka Takeharu , Nakajima Takako Eguchi , Muro Kei 
Published: February 2020

201 Background: The WJOG 6210G trial demonstrated a similar efficacy between Pani and Bev arms at 2nd-line setting in pts with KRAS exon2 wild-type mCRC (Shitara K, et al, Cancer Sci 2016). The exploratory analyses of clinical trials evaluating 1st-line chemotherapy for mCRC have shown significant associations of ETS and DpR with prognosis; however, there is few data in 2nd-line treatment. We investigated whether ETS and DpR are associated with clinical outcomes in mCRC pts treated with 2nd-line treatment using the data of WJOG 6210G trial. Methods: ETS was defined as tumor reduction of 20% at week 8 compared to baseline in the sum of longest diameters of target lesions according to the RECIST criteria. DpR was defined as the percentage of maximum tumor shrinkage of target lesions. Fisher’s exact test and t-test were used to compare ETS and DpR between Pani and Bev arms. A Cox regression model was used to evaluate associations between ETS and progression-free survival (PFS), and overall survival (OS). The association of DpR with PFS and OS was analyzed using Spearman’s rank correlation coefficient. Results: Eighty-seven pts were evaluable for ETS and DpR (Pani, n = 41; Bev, n = 46) among 121 pts enrolled in the WJOG6210G. Pts in the Pani arm had a higher ETS rate (39.0 % vs. 8.7 %, p < 0.001) and greater DpR [median: 23.7 % (range: -49.0 to 100) vs. 0 % (range: -40.7 to 61.5), p < 0.001] than pts in the Bev arm. Pts with ETS achieved longer PFS [median: 10.5 vs. 5.4 m, HR: 0.40 (95% CI: 0.20-0.80), p = 0.009] and OS [median: 22.3 vs. 14.5 m, HR: 0.49 (95% CI: 0.23-0.98), p = 0.044] than pts without ETS in the Pani arm. Similarly, the Bev arm pts with ETS had longer PFS [median: 17.1 vs. 5.6 m, HR: 0.078 (95% CI: 0.004-0.38), p = 0.0002] and OS [median: 30.9 vs. 13.2 m, HR: 0.35 (95% CI: 0.083-0.99), p = 0.048]. There were moderately linear correlations of DpR with PFS and OS in both Pani (PFS: r = 0.75, p < 0.001; OS: r = 0.60, p < 0.001) and Bev arms (PFS: r = 0.68, p < 0.001; OS: r = 0.44, p = 0.002). Conclusions: ETS and DpR were significantly associated with PFS and OS in mCRC pts treated with 2nd-line FOLFIRI in combination with Pani or Bev. Clinical trial information: UMIN000031621.
Prediction of hepatic metastasis and relapse: Concordance analysis among noninvasive liver fibrosis scores from colorectal cancers.
Authors: Cai Sanjun , Hu Xiang , Dai Weixing , Li Yaqi , Ma Xiaoji , Peng Junjie 
Published: February 2020

202 Background: Liver fibrosis, resulted from several liver diseases, are increasing up to 25% in population globally. It remains undetermined how much of an impact liver fibrosis have on the development of hepatic metastasis and relapse in colorectal cancer (CRC). Hence the aim of this study was to clarify the role of liver fibrosis on hepatic metastasis and relapse in CRC undergoing curative therapy. Methods: We enrolled consecutive 1652 patients with radical surgery as the discovery cohort, and the validation set enrolled 432 CRC patients with hepatic metastasis treatment. To determine the degree of liver fibrosis, the NFS, FIB4 and APRI were applied. The influence of liver fibrosis on hepatic metastasis and relapse was assessed by survival analyses. Nomograms with fibrosis score incorporated was established to identify the incremental value for individualized relapse estimation, which was then assessed with respect to calibration, discrimination, and clinical usefulness. Results: The high liver fibrosis score patients had significantly worse outcomes than low score in 5-year hepatic metastasis (22.6 vs . 8.7%) in discovery cohort, and RFS (58.2 vs. 44.1%) in validation cohort. Multivariate analysis revealed liver fibrosis score as an independent prognostic factor. The distribution analysis also demonstrated higher liver fibrosis score a powerful prognostic factor for hepatic metastasis and relapse. Incorporating the liver fibrosis score into the nomogram resulted in better performance evaluated by C-index and AUC than TNM staging system and clinicopathologic nomograms. Importantly, in validation cohort, the discriminatory capacity of the fibrosis score incorporated was superior to that of the CRS score in predicting RFS, as demonstrated by the C-index and AUC. The concordance study showed well agreement among NFS, FIB4 and APRI in predicting DFS and RFS. Among these three noninvasive liver fibrosis scores, NFS score performed the best in predicting hepatic specific DFS and RFS. Conclusions: The liver fibrosis was a powerful predictor of hepatic specific DFS and RFS in CRC. Fibrosis niche may be a favorable microenvironment for metastatic formation in the liver.
Prospective study with circulating tumor cells as potential prognosis biomarker in metastatic colorectal cancer.
Authors: Souza E Silva Virgilio , Abdallah Emne Ali , Mello Celso Abdon Lopes de , Tariki Milena Shizue , Calsavara Vinicius Fernando , Chinen Ludmilla T.D. 
Published: February 2020

203 Background: Colorectal cancer (CRC) is one of the most common cancer worldwide. Around 30% present metastatic disease at diagnosis and 50%–60% of patients develop metastasis. New prognostic markers are needed and circulating tumor cells (CTCs) are a promising tool. Methods: Prospective study conducted by blood collection from 75 patients (pts) with metastatic CRC (mCRC), twice, with 2 months interval, together with image exams for therapeutic response evaluation. CTCs were detected by ISET and identified by immunocytochemistry. Results: The mean age was 57.3 years old (24-81). RAS mutations in primary tumor was found in 38% (19/50) of patients (pts) and left colon topography in 41.3% (31/75). Comparing the baseline CTC level (CTC1) with the level at first follow-up (CTC 2), pts with CTC2 – CTC1 > 5.5 per ml demonstrated poor progression-free survival (PFS) (3.2 months) when compared to CTC 2 – CTC1 ≤ 5.5 (9.1 months) (p= 0.005). The median overall survival (OS) was 24.5 months for pts with CTC 1 > 1.5 per ml and 34.2 months for those with CTC1 ≤ 1.5 per (HR=1.89, 95% CI, 1.01 to 3.52; p= 0.041). Patients with RAS mutation (P= 0.001), primary tumor in the right colon (p= 0.014) and expression of Multidrug Resistance Protein 1 in CTCs (p= 0.044) had worse OS. By multivariable analyses, CTC 1 > 1.5/mL (p= 0.025) was an independent prognostic factor. Conclusions: This prospective study confirmed that counts of CTCs at baseline (CTC1) is an important prognostic marker for monitoring mCRC and correlates with other established prognostic factors. Clinical trial information: NCT02979470.
Validation of the Glasgow Microenvironment Score in patients with colon cancer: A pathology-based prognostic tool.
Authors: Alexander Peter G , Roseweir Antonia K. , Pennel Kathryn AF , Van Wyk Hester Catharina , Powell Arfon GMT , Roxburgh Campbell SD , Horgan Paul G. , Edwards Joanne , McMillan Donald C. , Park James Hugh 
Published: February 2020

206 Background: The Glasgow Microenvironment Score (GMS), comprised of assessment of the tumour inflammatory cell infiltrate (using Klintrup-Mäkinen (KM) grade) and tumour-associated stroma (TSP), has been reported as a stage-independent prognostic score in patients with colorectal cancer. The present study aims to validate the GMS and examines its prognostic utility in the context of stage and MMR status. Methods: Patients who had undergone resection of stage I-III colon cancer were included ( n= 495). GMS was scored by combining KM and TSP as follows: high KM scores 0; low KM with low TSP scores 1; low KM and high TSP scores 2. Cancer specific (CSS) and overall survival (OS) were primary endpoints. Subgroup analysis was performed to assess the utility of GMS according to TNM, venous invasion and MMR status. Results: There were 30% of patients with GMS 0, 56% with GMS 1 and 14% with GMS 2. Five-year survival for GMS 0, 1 and 2 across the whole cohort were 89%, 74% and 66%, respectively. GMS was associated with age, mode of presentation, TNM, venous invasion and MMR status. On multivariate analysis, GMS was independently associated with CSS (HR 1.35, 95% CI: 1.02-1.79, p= 0.04) and OS (HR 1.23, 95% CI: 1.02-1.48, p= 0.03); this was independent of emergency presentation ( p< 0.01), T-stage ( p= 0.03) and N-stage ( p< 0.001) for CSS. Subgroup analysis found that GMS was able to stratify CSS regardless of node-negative or node-positive disease (both p< 0.01), venous invasion ( p< 0.05), elective presentation ( p< 0.01) and MMR-proficient tumours ( p< 0.001), although it was not able to stratify emergency presentation ( n= 154) or MMR-deficient disease ( n= 102) due to small sample size. Universally, the prognosis for GMS 0 was good, but was poor for GMS 2. The prognosis for GMS 1 varied depending on MMR and nodal status. Conclusions: This study validates the use of the GMS as an independent prognostic pathology-based tool for stratification of colon cancer. It could be readily applied to routine clinical practice and may be used to aid decision making regarding adjuvant treatments in colorectal cancer. It should be further validated in prospective randomised trials.
Assessing real-world biomarker testing rates in metastatic colon cancer.
Authors: Nakhoda Shazia , Deng Mengying , Iyer Pritish , Handorf Elizabeth A. , Jain Rishi , Meropol Neal J. , Dotan Efrat 
Published: February 2020

209 Background: Despite national guideline recommendations for universal biomarker testing (KRAS, NRAS, BRAF, and mismatch repair/microsatellite instability [MMR/MSI]) in all patients with metastatic colorectal cancer (mCRC), little is known regarding adherence to these recommendations in the community. Methods: We evaluated 20,333 patients aged >18 years with mCRC diagnosed between 1/1/2013-12/27/18 from the nationwide de-identified Flatiron Health electronic health record-derived database. Changes in rates of biomarker testing based upon chart abstraction according to date of mCRC diagnosis were assessed in patients with ≥ 6 months of follow-up using Cochran-Armitage trend tests. We also assessed whether testing differed by patient characteristics using chi-square tests. Results: Biomarker testing rates increased between 2013 and 2018 (15.3 to 65.7% for NRAS, 23.9 to 56.6% for BRAF, and 34 to 76.6% for MMR, all p < 0.0001). There was no change in rate of KRAS testing (63.8 to 68.3% p= 0.1695) over this period of time. Univariate analysis showed that patients with, worse performance status, and Medicare/Medicaid insurance were less likely to be tested (for all variables, p <0.0001). There were no meaningful differences in testing rates by tumor sidedness, race, gender, or initial stage. Conclusions: In mCRC, adoption of guideline-driven recommendations for NRAS, BRAF and MMR/MSI testing increased significantly between 2013-2018. Adoption of BRAF and NRAS testing has neared the rate of KRAS testing. Interpretation of overall testing rates must recognize potential for missing biomarker test information for care not captured within the Flatiron network. Further study is required to characterize the magnitude of and reasons for absent biomarker testing among patients with metastatic colorectal cancer.
Rate of conversion from unresectable to resectable metastatic colorectal cancer (mCRC) in real-world patients (RWP) treated with FOLFIXIRI ± bevacizumab: A population-based retrospective cohort study.
Authors: Bhatti Tayyaba , Moser Michael , Tan Jon , Zaidi Adnan , Le Duc , Chalchal Haji I. , Shaw John , Kanthan Selliah , iqbal mussawar , Luo Yigang , Haider Kamal , Asif Tehmina , Dorie-Anna Dueck , Gill Dilip , Ginther Nathan , Ahmed Shahid 
Published: February 2020

21 Background: Recent evidence from randomized trials suggests that FOLFOXIRI (5FU, oxaliplatin, and irinotecan) ± bevacizumab is associated with higher response rates with a potential for conversion of unresectable to resectable disease in mCRC. Yet limited evidence is available about efficacy and safety of this regimen in RWP with mCRC. The current study aims to evaluate conversion rate and safety of FOLFOXIRI ± bevacizumab in RWP with unresectable mCRC. Methods: Each year about 175 patients are diagnosed with mCRC in Saskatchewan. Patients who were diagnosed with unresectable mCRC between Jan 2015 to Dec 2018 and received FOLFOXIRI ±bevacizumab were assessed. Kaplan Meier survival methods and log rank test were performed. Logistic regression analysis was performed to assess factors correlate with conversion. Results: 28 eligible patients with median age of 51 yrs (IQR:39-60) and M:F of 11:16 were identified. 42% patients had a comorbid illness, and 43% had WHO performance status of 0. 39% had rectal cancer, 46% had extrahepatic disease and 46% had bilobar liver metastases. 58% patients had a positive response to therapy, 60% had grade 3/4 toxicity & 32% required hospital admission. No treatment-related mortality was noted. 54% patients underwent metastasectomy (liver 73%, peritoneum and or ovaries 20%, lung 6%). 68% had primary tumor resection, 29% received rectal radiation, 21% had ablation and 18% had second surgery for recurrence. At 4 years 50% patients are alive. Median progression free survival of patients who underwent surgery is 18 (95%CI:11.3-24.7) vs. 11 months (4-18.1) without surgery (P = 0.28). Median overall survival of patients with surgery is 33 (17.5-48.5) vs. 16 months (8.3-23.7) without surgery (P = 0.03). Positive response to treatment is correlated with conversion (odd ratio 21.7, p = 0.002). Conclusions: In the real world setting younger patients with good performance status received FOLFIRINOX ± bevacizumab. Despite high rates of toxicity, more than half of patients were able to undergo surgery. A positive response to treatment significantly correlates with metastasectomy.