bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pilot study of the safety and feasibility of immediate adjuvant chemotherapy (IAC) in nonmetastatic colonic adenocarcinoma (nmCC).
Authors: Jafari Mehraneh D. , Sujatha-Bhaskar Sarath , Brady Mathew , Mills Steven D. , Carmichael Joseph C. , Dayyani Farshid , Lee Fa Chyi , Zell Jason A. , Pigazzi Alessio 
Published: February 2020

150 Background: The optimal timing of adjuvant chemotherapy (AC) in nmCC is poorly defined. Delays in AC result in decreased survivalbut fear of postoperative complications often causes long intervals between surgery and AC initiation. Given the transient immune suppression, inflammatory changes and increase in circulating tumor cells occurring in the perioperative period, effective cytotoxic treatments should be considered at this time to limit metastatic spread. The immediate adjuvant chemotherapy concept intends to capitalize on the therapeutic benefits that can be achieved in the perioperative period (intraoperative and early postoperative). We aim to demonstrate that IAC is safe and tolerable for patients with nmCC. Methods: Patients with nmCC microsatellite stable invasive adenocarcinomas were treated with intravenous Leucovorin 20mg/m2 followed by a single dose of 5-Flurouracil 400mg/m2 at the time of minimally invasive surgical resection. High risk stage II and stage III received the first dose of standard AC at 14 days after surgery. Serial measurements of blood-based biomarkers (circulating tumor cells, cell free DNA, and neutrophil lymphocyte ratio were measured. Quality of life (QOL) was measured using EORTC QLQ-C30. Results: Of the 20 patients recruited, 40% had final pathology of stage III, 40% stage II and 20% stage I. All patients received intra-operative chemotherapy with no associated morbidity. Median length of stay was 2 days (range of 2-4). Grade 1 complications were reported in 2 (10%) of patients. No grade 2 or higher adverse events were reported. There was no mortality. Early postoperative AC was administered to 65% of patients. The median time to AC was 14 days (range 14-36). Overall quality of life and health scores were similar before surgery and at 30-day postoperatively (p < 0.05). Conclusions: A protocol based on immediate adjuvant chemotherapy starting at the time of surgical resection was found to be safe and feasible in nmCC with no adverse effects on surgical morbidity or quality of life. Further prospective studies are needed to explore the oncologic benefit of this novel systemic treatment approach.
Long-term oncologic safety of self-expandable metal stent as a bridge to surgery for malignant colorectal obstruction: Our experience.
Authors: Jang Se Hyun , Keum Bora , Kim Sanghyun , Lee Kang Won , Jeon Han Jo , Kim Sang Hoon , Choi Seong Ji , Lee Jae Min , Choi Hyuk Soon , Kim Eun Sun , Jeen Yoon Tae , Lee Hong Sik , Chun Hoon Jai , Kim Chang Duck 
Published: February 2020

153 Background: About 10-25% patients of colorectal cancer suffer from acute colonic obstruction. Traditional management of acute malignant bowel obstruction has focused on emergency resection but showed high mortality and morbidity rates. Recently, placement of a self-expanding metal stent(SEMS) was widely used and SEMS seems to be as a safe and effective “bridge to surgery” and to offer good palliation. But there is concern about long-term survival after the use of SEMS. Theoretically, tumor cell seeding can occur due to mechanical force during the stent insertion. To identify this theoretical validity, we surveyed long-term survival of malignant colonic obstruction using SEMS placement. Methods: This retrospective study included 303 patients who presented in Korea University Anam Hospital between 2006 and 2014 with obstructing CRC, and underwent surgical resection. Patients were devided into two group: the “SEMS” group included 148 patients who underwent endoscopic stent as a bridge to surgery, and the surgery group included 155 patients who underwent emergency or elective surgery without stenting. In addition, candidates for curative resection were identified (98 patients in “SEMS” group vs 101 patients in “surgery” group). The clinicopathologic characteristics, overall survival(OS), and recurrence-free survival (RFS) were compared between the two groups. Results: There was no significant difference in demographics, tumor stage between the two group. The median follow-up times were 48.5 months (IQR, 19.1-73.1 months) for the SEMS group and 39.4 months (IQR, 15.1-39.4 months) for the surgery group. There was no significant difference in 5-year OS rate between two groups (59.6% vs 56.8%; p = 0.3). The 5-year RFS rate did not significantly differ between two groups (71.0% vs. 61.3%; p = 0.221). The long-term oncologic safety did not significantly differ between two groups in either the 5-year OS rate (79.5% vs 74.5%; P= 0.6). or the 5-year RFS rate (95.8% vs 95.8%; P = 0.3). Conclusions: SEMS as bridge to surgery in obstructive CRC did not worsen the long-term oncologic outcomes compared to those of the primary surgery.
The impact of biologic agents in patients with metastatic colorectal cancer by race/ethnicity.
Authors: Tolu Seda Serra , Chergui Adel , Rao Devika , Kaumaya Meghan , Acuna-Villaorduna Ana , Kaubisch Andreas , Chuy Jennifer W. , Rajdev Lakshmi , Elrafei Tarek N. , Goel Sanjay 
Published: February 2020

156 Background: Biologic agents have shown to improve overall survival (OS) in patients with metastatic colorectal cancer (mCRC). However, minority racial/ethnic groups were underrepresented in clinical trials. A retrospective study in a racially-diverse population diagnosed between 2000 - 2011, done by our group, reported a survival benefit with biologics; but, a subgroup analysis suggested that it was restricted to Non-Hispanic whites (NHW) only. This study aims to compare OS in patients with mCRC treated with chemotherapy and biologic agents (CBT) among racial/ethnic groups. Methods: Patients diagnosed with mCRC between 2012-2018 and treated with CBT at 3 cancer centers in the Bronx, NY were identified. Clinical data was collected by retrospective review for demographics (age at metastasis, gender and race/ethnicity categorized as Non-hispanic Black (NHB), NHW or Hispanic), pathological/ treatment characteristics (tumor grade, primary location, chemotherapy regimen, biologic agent). Cases without available race/ethnicity were excluded. OS was measured as time from mCRC diagnosis to death (verified from the National Death Index) and was compared among racial/ethnic groups using Kaplan-Meier curves. Results: A total of 278 patients; of whom 84 (42.4%) were Hispanic, 70 (35.4%) NHB and 44 (22.2%) NHW were included. The median age at diagnosis was 60 years and did not differ among racial/ethnic groups (62.5 vs 55.5 vs 56 years, p=0.07). There was a female predominance in NHB and Hispanics. Bevacizumab was more frequently used in Hispanics and NHB compared to NHW (95.2% vs. 92.9% vs. 77.3%, p=0.003, respectively). There were no differences in the frequency of cetuximab and panitumumab use. Median OS did not differ by racial/ethnic groups (21 in NHW vs. 22.8 in Hispanics and 28.6 months in NHB, p=0.40). Conclusions: Minority groups attain a similar survival benefit from the addition of biologics compared to NHW. Population-based studies are required to confirm these results.
The impact of mismatch repair status to the preoperative staging of local colon cancer: Implications for clinical management.
Authors: Hansen Torben , Erbs Emilie , Trabjerg Natacha D. , Rafaelsen Soeren Rafael , Lindebjerg Jan , Jensen Lars Henrik 
Published: February 2020

16 Background: Computed tomography (CT) scan is standard in preoperative local staging of colon cancer. Tumours with a deficient mismatch repair (dMMR) system are characterised by unique clinical and pathophysiologic aspects that may impact on the accuracy of the preoperative CT staging. Methods: Data from the Danish Colorectal Cancer Group national clinical database addressing a cohort of patients operated for stage I-III colon cancer in 2010-15 was analysed. The analyses of MMR status had been conducted consecutively through means of immunohistochemistry. All CT scans were blindly assessed by a certified radiologist. Results: Data from 590 patients, operated at a specialised cancer centre were available for analyses. A dMMR phenotype was detected in 135 (22.9%) of the patients. The overall correlation of the clinical and pathological T-category was significant for both groups. There was inferior correlation between cN and pN (p > 0.05) in pMMR cancers with a higher degree of over-staging assessed by CT-scan, compared to a significant correlation between cN and pN stage in pMMR cancers (p < 0.01). Of the 91 dMMR tumours judged node-positive by the preoperative CT scan, 59 (64.8%) showed no sign of metastatic involvement at the postoperative assessment. Conclusions: The accuracy of preoperative CT lymph node staging in colon cancer seems to differ depending on MMR status and may impact the clinical management including the neoadjuvant setting.
Quantification of immune response after dual checkpoint inhibition in a microsatellite stable model of colorectal cancer.
Authors: Kamp William M. , Park Hong-Jai , Slovak Ryan J. , Ludwig Johannes M. , Kang Insoo , Kim Hyun S. 
Published: February 2020

160 Background: Checkpoint inhibitors have demonstrated significant clinical impact in colorectal cancer with deficient mismatch repair (MMR) and high microsatellite instability. However, most patients have disease with stable microsatellites and typically respond poorly to most immunotherapies. The purpose of this study was to quantify the immune responses induced by mono versus dual immune checkpoint blockade (DICB) in a MMR proficient model of colorectal cancer. Methods: A MMR proficient model of colorectal cancer was established in 30 BALB/c mice via bilateral subcutaneous flank injections of 0.5x106 CT26.WT murine colorectal cancer cells (CRL- 2638; ATCC, Manassas, VA). Mice were assigned to receive either sham antibodies (InVivoMAb IgG controls), monotherapy with anti-PD-1 antibodies (Clone J43; BioXcell, West Lebanon, NH, USA), or DICB with anti-PD-1 and anti-CTLA-1 antibodies (Clone 9D9; BioXcell). Tumor growth was monitored over time and mice were sacrificed at either 7 or 14 days post-treatment. Single cell suspensions of harvested tumors and spleens were analyzed using FACS. The number of CD8+ and CD4+ T cells as well as the expression of co-inhibitory surface molecules PD-1, LAG3, and TIM3 was quantified in each sample. Results: DICB was associated with a reduction in tumor volume as compared to either mono PD-1 inhibition or control (p < 0.05). Neither monotherapy nor DICB significantly affected tumor infiltration by lymphocytes. Tumor infiltrating CD8+ T cells in the DICB treatment group demonstrated less expression of PD-1 and LAG3 compared to the control and monotherapy groups (PD-1: 1723±90.5 [Mean fluorescence intensity ± SEM] vs 2489±119.9 & 2404±117.9; p < 0.05) (LAG3: 453.8±21.58 vs 664.1±53.21 & 719.7±14.25; p < 0.05). The DICB group also showed increased expression of TIM3 (11,779±1271 vs 2832±380.9 & 4081±426.6; p < 0.05). Conclusions: These results suggest dual therapy with anti-CTLA and anti-PD-1 antibodies inhibits the growth of stable microsatellite colorectal cancer by suppressing key immunosuppressive checkpoints. Upregulation of TIM3 represents a potential escape mechanism that could be a target for future combination immunotherapies.
A single-arm, phase II study of intrahepatic chemotherapy in patients with unresectable colorectal liver metastases.
Authors: Besel Kate Elenna , Ko Yoo-Joung , Karanicolas Paul Jack , Kim Christina Yiyoung 
Published: February 2020

162 Background: In Canada, the standard of care for patients with unresectable colorectal liver metastases (uCRLM) is systemic chemotherapy and/or best supportive care. Intrahepatic chemotherapy using floxuridine (FUDR), in addition to systemic chemotherapy, is available in the United States but its adoption outside major centers has been limited. Methods: A single-center, prospective study of intrahepatic chemotherapy for the treatment of patients with uCRLM was initiated at Sunnybrook Health Sciences Centre in 2014. Patients underwent implantation of a hepatic infusion pump with resection of their primary tumor (if in place). Patients were treated with FUDR in addition to systemic chemotherapy (FOLFIRI or FOLFOX). Study objectives include the rate of conversion to complete resection, time to progression (TTP), disease-free survival (DFS), time to progression in liver, overall survival (OS), andresponse rate (RR). Results: From 2014 to present, 46 patients have been enrolled. Median age at the time of HAIP placement was 51 years (30-72 years). Males accounted for 61% (28/46). All patients received at least one cycle of systemic chemotherapy prior to surgery. 44 patients received a minimum of one cycle of FUDR, with the median number of cycles of FUDR received being 7.5 (0-28 cycles). Only one patient was unable to receive any FUDR after surgery. Response rate was 80% (n = 37/46). Three patients are too early for assessment. Eight (17.4%) patients have undergone liver resection. Median number of cycles of FUDR prior to resection was 7 (4-13 cycles). TTP, DFS, time to progression in liver, OS, and safety will be presented. Conclusions: The addition of intrahepatic chemotherapy to best systemic therapy may provide an increase in the rate of conversion to complete hepatic resection in patients with uCRLM. Clinical trial information: ON1233.
Lateral lymph node dissection after neoadjuvant (chemo)radiotherapy may improve oncological outcomes in Western patients with low rectal cancer.
Authors: Kroon Hidde Maarten , Malakorn Songphol , Dudi-Venkata Nagendra N , Bedrikovetski Sergei , Liu Jianliang , Bednarski Brian K. , Ogura Atsushi , Van De Velde Cornelis J. H. , Rutten Harm , Beets Geerard , Thomas Michelle , Kusters Miranda , Chang George J. , Sammour Tarik 
Published: February 2020

163 Background: In the West, rectal cancer patients with pre-treatment abnormal lateral lymph nodes (LLN) are commonly treated with neoadjuvant (chemo)radiotherapy (n(C)RT) followed by total mesorectal excision (TME). Few centers perform lateral lymph node dissection (LLND) in addition to this, with the aim of improving oncological outcomes. To date, no comparative data are available in Western patients. Methods: An international multi-center cohort study was conducted comparing six centers from the Netherlands and Australia treating patients with abnormal LLN (≥5mm short-axis) with n(C)RT and TME (LLND- group) versus similarly staged patients from a dedicated cancer center in the USA who underwent a LLND in addition to n(C)RT and TME (LLND+ group). Results: Data were available on 169 patients. LLND+ patients (n = 44) consisted of significantly younger and more female patients with higher ASA-scores and ypN-stages compared to LLND- patients (n = 115). LLND+ patients also had a larger median LLN short-axis and were more likely to receive adjuvant chemotherapy (100 vs. 30%; p < 0.0001). Between groups, the lateral local recurrence rate (LLRR) was 0% for LLND+ vs. 7% for LLND- (p = 0.09) and the local recurrence rate (LRR) was 3% for LLND+ vs. 11% for LLND- (p = 0.13). No significant differences were observed in disease-free survival (DFS, p = 0.94) or overall survival (OS, p = 0.42). Sub-analysis of patients who underwent adjuvant chemotherapy (LLND- patients: n = 35) demonstrated clinically relevant though non-statistically significant trends towards a lower LLRR (0% for LLND+ vs. 6% for LLND-; p = 0.07), LRR (3% for LLND+ vs. 14% for LLND-; p = 0.06), DFS (p = 0.19) and OS (p = 0.17) in favour of the LLND+ group. Conclusions: Lateral lymph node dissection in addition to neoadjuvant (chemo)radiotherapy may improve oncological outcomes in Western patients with low rectal cancer and abnormal lateral lymph nodes.
Expression of antibody-drug conjugates (ADC) biomarkers in colorectal cancer.
Authors: Thyparambil Sheeno P. , Liao Wei-Li , An Eunkyung , Tian Yuan , Heaton Robert , Sylvester Karl G. , Ling Xuefeng B. 
Published: February 2020

17 Background: Multiple ADCs are in clinical trials for CRC and the optimal strategy for selecting patients who may benefit from the treatment is evolving. Due to the unique mechanism of ADCs, patient selection should involve screening not only for the presence of the antibody target, but also for markers of resistance or response to the payload. We have built a multiplexed ADC biomarker panel in FFPE tumor tissue that simultaneously quantifies the protein levels of the antibody targets and also the payload markers. Methods: FFPE tumor tissues from 363 CRC patients were microdissected and solubilized for mass spectrometry-based targeted proteomic analysis in our CLIA certified laboratory. We quantified protein levels of EGFR, HER2, HER3, Axl, Mesothelin, FRalpha, Trop2 (antibody targets), tubulin-beta3 and TOPO1 (payload resistance and response markers, respectively) simultaneously. The multiplexed assay also quantified additional 22 clinically relevant proteins. Results: Expression of EGFR(83%), HER2(52%), HER3(21.5%), Axl(3.7%), Mesothelin(26.5%), FRalpha(3.7%), and Trop2(59.8%) may indicate likely response to ADCs. Expression of TUBB3(+) and TOPO1 (>1350amol/µg) in antibody target-positive subset may suggest resistance or response to payloads, such as taxanes and irinotecan, respectively (Table). Previously we identified that HER2 expression >750amol/µg correlated with HER2 positivity. Accordingly, 1.4% (5/355) of CRC patients were HER2 positive, of which 40% (2/5) had TOPO1 expression >1350amol/µg (75th percentile) suggesting that these 2 patients may receive benefit from a HER2/TOPO1 ADC. (+) indicates expression ≥LOQ; (-) indicates expression <LOQ. Conclusions: In patients with CRC, quantitative proteomics identified both antibody targets and markers of resistance or response to the payloads for multiple approved and investigational ADC therapies. [Table: see text]
Detection of microbial DNA in the blood of colorectal cancer patients for the diagnosis of microbial translocation.
Authors: Sougklakos Ioannis , Messaritakis Ippokratis , Vogiatzoglou Konstantinos , Tsantaki Konstantina , Dretaki Agapi , Koulouridi Asimina , Sfakianaki Maria , Koulouris Andreas Vasileios , Tzardi Maria , Mavroudis Dimitrios , Boukovinas Ioannis 
Published: February 2020

171 Background: Dysbiosis has been associated with diseases and is of a major public health importance. Can lead to the passage of viable bacteria, their products or their fragments from the intestinal lumen through the mesenteric lymph nodes and other sites, known as bacterial translocation. The aim of the study was to determine whether microbial translocation occurs in stage II/III-IV colorectal cancer (CRC) patients and evaluate the usefulness of blood PCR for diagnosis of such translocation. Also to correlate the presence of Toll-Like Receptor and Vitamin D Receptor polymorphisms with the detection of microbial DNA fragments in the blood of CRC patients. Methods: Peripheral blood was obtained from 397 CRC patients (adjuvant n = 202 and metastatic n = 195) and 32 healthy individuals. DNA from all subjects was analyzed using PCR for amplification of genomic DNA encoding 16S rRNA, β-galactosidase gene of E. coli, Glutamine synthase gene of B. fragilis and 5.8S rRNA found in C. albicans. Results: Significantly higher rates of 16S rRNA, β-galactosidase, Glutamine synthase and 5.8S rRNA detection was observed in the pool of CRC patients than the controls ( p< 0.001). All microbial DNA fragments detected were also significantly associated with the metastatic disease ( p< 0.001) leading to shorter survival rates ( p< 0.001). Moreover, individuals with the homozygous mutant alleles of either TLR or VDR gene polymorphisms had significantly higher detection rates of microbial DNA fragments. Conclusions: The detection of microbial DNA fragments in patients with CRC highlights the role of these microbes in cancer development, progression and therefore in patients’ survival.
Circulating IL-8 levels as candidate marker of antiangiogenic therapy for metastatic colorectal cancer.
Authors: Suenaga Mitsukuni , Mashima Tetsuo , Kawata Naomi , Wakatsuki Takeru , Seimiya Hiroyuki , Yamaguchi Kensei 
Published: February 2020

172 Background: Liver metastasis (LM) confers poor prognosis in metastatic colorectal cancer (mCRC). It has not been well understood whether tumor microenvironment (TM) varies throughout cancer treatment in the presence of LM. We therefore investigated the difference of TM between first-line (FL) and savage-line (SL) anti-angiogenic therapies and tested whether specific angiogenic cytokines could predict clinical outcome in mCRC patients. Methods: A combined cohort consisting of two cohorts (N = 125) was included in this study: 71 patients received first-line treatment with bevacizumab (FL cohort: median age, 60; median follow-up, 28.9 mos) and 54 patients received salvage-line regorafenib (SL cohort: median age, 65; median follow-up, 17.2 mos). Blood samples were obtained from all patients at baseline (BL) and during the treatment, and serum levels of nine angiogenic cytokines were measured using ELISA. Progression-free survival and overall survival (OS) were analyzed using Kaplan-Meier curves, log-rank test, and Cox proportional hazard regression. Results: In univariate analysis for the combined cohort, right-sided CRC, primary unresected, KRAS wild-type, LM, metastatic site ≥2 and SL were associated with shorter OS, and LM and SL remained in multivariable analysis. Ang-2 and IL-8 levels at BL were significantly associated with LM and their cut-off values were 2190.3 pg/ml (COAng2) and 15.1 pg/ml (COIL8), respectively, and no significant interaction was shown between cytokines and cohorts. Patients with Ang-2 levels ≥COAng2 had shorter OS than those with Ang-2 levels < COAng2 (HR2.57, 95%CI: 1.47–4.51, P = 0.001), while IL-8 levels ≥COIL8 was associated with shorter OS than < COIL8 (HR4.31, 95%CI: 2.11–8.79, P < 0.001). IL-8 levels ≥COIL8 remained as significant in multivariable analysis (HR 3.24, 95%CI: 1.47–7.16, P = 0.004). In change analysis, there was no significant correlation of variation of IL-8 and Ang-2 levels with clinical outcome after the first treatment cycle in both cohorts. Conclusions: Circulating IL-8 and Ang-2 levels reflect the TM in the presence of LM, of which IL-8 may serve as solid prognostic marker of anti-angiogenic therapy regardless of the timing of treatment for mCRC.