bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunological nomograms predicting prognosis and guiding adjuvant chemotherapy in stage II colorectal cancer.
Authors: Peng Junjie , Li Yaqi , Feng Yang 
Published: January 2019

499 Background: The type, abundance, and location of tumor-infiltrating lymphocytes (TILs) have been associated with prognosis in colorectal cancer. The objective of this study was to assess the prognostic role of TILs and develop a nomogram for accurate prognostication of stage II colorectal cancer. Methods: Immunohistochemistry was conducted to assess the densities of intraepithelial and stromal CD3+, CD8+, CD45RO+ and FOXP3+ TILs, and to estimate PD-L1 expression in tumor cells for 168 patients with stage II colorectal cancer. The prognostic roles of these features were evaluated using COX regression model, and nomograms were established to stratify patients into low and high-risk groups and compare the benefit from adjuvant chemotherapy. Results: In univariate analysis, patients with high intraepithelial or stromal CD3+, CD8+, CD45RO+ and FOXP3+ TILs were associated significantly with better relapse-free survival (RFS) and overall survival (OS), except for stromal CD45RO+ TILs, whereas PD-L1 expression wasn't associated with RFS or OS. In multivariate analysis, patients with high intraepithelial CD3+ and stromal FOXP3+ TILs were associated with better RFS (p < 0.001 and p = 0.032, respectively), while only stromal FOXP3+ TILs was an independent prognostic factor for OS (p = 0.031). The nomograms were well calibrated and showed a c-index of 0.751 and 0.757 for RFS and OS, respectively. After stratifying into low and high-risk groups, the high-risk group exhibited a better OS from adjuvant chemotherapy (3-year OS of 81.9% v 34.3%, p = 0.006). Conclusions: These results may help improve the prognostication of stage II colorectal cancer and identify a high-risk subset of patients who appeared to benefit from adjuvant chemotherapy.
Safety and efficacy of durvalumab following trimodality therapy for locally advanced esophageal and GEJ adenocarcinoma: Early efficacy results from Big Ten Cancer Research Consortium study.
Authors: Mamdani Hirva , Schneider Bryan J. , Abushahin Laith I. , Birdas Thomas J , Kesler Kenneth , Lee Ahran , Burney Heather , Perkins Susan , Jalal Shadia Ibrahim 
Published: January 2019

5 Background: The standard of care for locally advanced esophageal adenocarcinoma(LA-EAC) is concurrent chemoradiation (CRT) followed by esophagectomy. Approximately 30% of patients (pts) achieve complete pathologic response (pCR) with this approach. The risk of relapse in the remaining 70% of pts is high, with 1-yr relapse free survival (RFS) of 50%. No adjuvant therapies have been shown to improve survival. Immune checkpoint inhibitors have activity in metastatic PD-L1 positive EAC. Preclinical studies have shown upregulation of PD-1 pathway with radiation +/- chemotherapy. Methods: We conducted a phase II study evaluating safety and efficacy of durvalumab (durva), a monoclonal antibody against PD-L1, in pts with LA-EAC and GE junction (GEJ) adenocarcinoma who do not achieve pCR after neoadjuvant CRT and R0 resection. Pts received durva 1500mg IV every 4 weeks for up to 1 yr after surgery. Primary objective was 1-yr RFS. Secondary objectives were incidence and severity of treatment related adverse events (AEs). Results: Twenty-four pts were enrolled from Apr 2016 to Jan 2018 (median age: 60yrs (range, 43-74)). Fourteen pts had GEJ adenocarcinoma and 10 had distal EAC. Eighteen received carboplatin/paclitaxel and six received cisplatin/5-FU concurrently with 50-50.4Gy radiation. Nineteen pts (79%) had positive lymph nodes at the time of surgery after neoadjuvant CRT, including three (12.5%) with N3, nine (37.5%) with N2, and seven (29%) with N1 disease. Among N0 pts, two had T3N0, one had T2N0, and two had T1N0 disease. At median follow-up of 11.7 mo (range 1.7-23.9 mo), seven pts (29%) have relapsed (five alive, two died); 17(67%) are disease free (six on treatment, seven completed treatment, three off-treatment); 1-yr and projected 26 mo RFS are 78.6% and 62.9%, respectively. Five pts (20.8%) developed grade 3 AEs: diarrhea (n = 1), hepatitis (n = 1), encephalopathy (n = 1), hyperglycemia (n = 1), hypoglycemia (n = 1). Most common grade 1 and 2 AEs were fatigue (33.3%), nausea (25.0%), and cough (20.8%). Conclusions: Adjuvant durva in pts with residual disease following trimodality therapy for EAC and GEJ adenocarcinoma is safe and feasible with 1-yr RFS of 78.6% compared to historical rate of 50%. Clinical trial information: NCT02639065.
MSI-H testing via hybrid capture based NGS sequencing of liquid biopsy samples.
Authors: Gowen Kyle , Clark Travis A , Gregg Jeffrey P. , Greene Mandy Z. , Murphy Annie , White Jared , Chung Jon , Kennedy Mark , Elvin Julia Andrea , Ross Jeffrey S. , Miller Vincent A. , Hughes Jason D. , Lipson Doron , Dennis Lucas 
Published: January 2019

504 Background: Microsatellite instability (MSI) testing has become critically important in clinical cancer care of patients with cancer given the recent pan-tumor FDA approval of pembrolizumab for use in patients with MSI-High (MSI-H) tumors. We previously demonstrated the robustness of a novel proprietary algorithm for determination of MSI status via NGS from solid tumor biopsy specimens (J Clin Oncol 34, 2016 (suppl; abstr 1523)). Traditional MSI tests such as PCR or IHC are impractical for pan-tumor adoption, as MSI-H prevalence outside of gastrointestinal and endometrial cancers is usually < 1%. NGS-based ctDNA profiling provides an opportunity for both MSI and actionable alteration testing in patients in whom tissue-based biopsy is not available. Methods: Genomic DNA (gDNA) from five previously characterized MSI-H cell lines: (DLD1, 22Rv1, LNCap, RL952, CL188), and one MSS cell line (SCC9) was enzymatically-fragmented to simulate ctDNA and titrated to various dilution levels with DNA from a healthy hapmap subject (NA12878). Samples were screened with a 70-gene panel, FoundationOne Liquid, that includes 180 mononucleotide repeat sequences (8-26bp long in the human reference genome). Length variability in the 180 repeat loci was utilized to generate an overall MSI score via principal components analysis. The NGS based MSI algorithm was applied to all the samples. Results: Assessment of these six cell lines, targeting five dilution levels confirmed by SNP mixing ratios, show that our NGS based MSI test for liquid biopsies has 96% sensitivity at > 2% tumor fraction with 100% PPV. The regression intercept of the MSI-H dilution samples with the pre-established MSI-H calling threshold shows our method has a LOD of 1.03% tumor fraction. MSI-H prevalence data from liquid biopsies of gastrointestinal tumors obtained during clinical care will also be presented. Conclusions: These data demonstrate the feasibility of using NGS-based liquid biopsy assays for MSI testing. This ctDNA-based approach will allow for increased access to checkpoint inhibitors in a pan-tumor setting, which would be especially relevant for cancers where routine MSI testing is impractical or when tissue is not available.
Review of updated colorectal cancer disease management data in the Colombian National Administrative Cancer Registry.
Authors: Hsu Robert , Ramirez Paula , Acuña Lizbeth , Lopes Gilberto 
Published: January 2019

508 Background: The Office of High Cost of the Colombian Health Ministry created the National Administrative Cancer Registry (NACR) in 2015 to obtain nationwide cancer data to find areas for improvement in cancer delivery. From initial data, a collaboration of healthcare experts identified 15 disease management indicators in colorectal (CRC) cancer in Colombia. In this study, we look at 2017 NACR data to investigate significant findings. Methods: We obtained NACR data compiled from the Department of Health Ministry from January 2, 2016-January 1, 2017 consisting of 32 departments and 1122 municipalities. The 2017 NACR data for CRC includes 11 of 15 updated disease management indicators - time to diagnosis, proportion of patients with colorectal cancer in situ, proportion of new cases identified in early stages, proportion of patients with TNM staging, proportion of patients with TNM staging before treatment, time before treatment, time between neoadjuvant therapy and surgery, time between surgery and adjuvant therapy, proportion of stage I and II patients receiving curative surgery, proportion of patients with nutritional support, mortality rate, and incidence. Results: The incidence of CRC was 5.2 cases per 100,000 people and the mortality was 3.6 cases per 100,000 people. The time to diagnosis was on average 50.7 days. 3.6% of CRC cases were in situ. 35.6% of cases were identified in early stages, and 51.3% of cases had TNM staging with 45.1% staged prior to treatment. The time to initial treatment was 63.7 days. The time between neoadjuvant therapy and surgery was 116.1 days and the time between surgery and adjuvant therapy was 75.5 days. 24.2% of stage I and II patients received curative surgery. 9.8% patients received nutritional support. Conclusions: The updated NACR data show significant wait times for treatment and exaggerated wait times for patients needing neoadjuvant or adjuvant therapies. The findings show significant work is needed in providing supportive services. There needs to be further investigation into follow-up after initial treatment. Further directions should include more data collection of adjuvant and neoadjuvant wait times and outcomes data of specific treatment modalities.
Prospective clinical study using expressed sequencing variants on stool-derived eukaryotic RNA transcripts (seRNA) for colorectal cancer screening.
Authors: Barnell Erica Kay , Kang Yiming , Campbell Katie Marie , Barnell Andrew Ross , Kruse Kimberly Ray , Wurtzler Elizabeth Marie 
Published: January 2019

516 Background: Colorectal cancer (CRC) is the second leading cause of cancer related deaths in the United States. The high mortality rate is largely attributable to the high frequency of late-stage diagnoses, caused by low patient compliance with screening guidelines. A reliable and noninvasive screening alternative is needed for the 40 million noncompliant patients. The development of a novel nucleic acid extraction method to isolate stool-derived eukaryotic RNA (seRNA) permits reliable and noninvasive evaluation of biomarkers derived from the gastrointestinal (GI) epithelium. This method enables sequencing-based tools for the detection of patients with CRC and adenomas. Methods: Stool samples were obtained from 96 individuals prior to undergoing a screening colonoscopy. Fecal immunochemical tests (FITs) were obtained for each sample. RNA isolates underwent custom library preparation, next-generation sequencing, and somatic variant identification. An seRNA assay assessed the probability of CRC risk using results from the FIT, mutational burden of transcripts implicated in precancerous change (APC), and mutational burden of transcripts associated with malignant transformation (KRAS / TP53). Results: When compared to results from a colonoscopy and subsequent biopsy, the seRNA risk assessment attained a 100% sensitivity for CRC, a 71.4% sensitivity for advanced adenomas, and an 88.5% specificity for no neoplastic findings. Conclusions: A single-center, IRB-approved, prospective and blinded clinical study is being conducted in 450 patients to further develop this seRNA assay. Supplemental data will include expression from 408 seRNA transcripts. Preliminary analysis described herein indicates this assay could be the most sensitive noninvasive screening test for the detection of CRC and adenomas. [Table: see text]
High-serum blood sugar level significantly enhances oxaliplatin resistance in stage III colorectal cancer patients.
Authors: Wang Jaw-Yuan 
Published: January 2019

532 Background: FOLFOX4 chemotherapy is one of the most widely used adjuvant therapies in patients with stage III colon cancer after surgical resection. However, chemotherapy resistance is associated with a poor prognosis. The prognostic impact of high blood sugar levels on oxaliplatin resistance in CRC patients is an unexplored topic. Methods: A total of 157 patients with stage III CRC were classified according to their serum blood sugar level (≥ 126 or < 126 mg/dL). Clinicopathological features and clinical outcomes (oxaliplatin resistance) of the two groups were analyzed. Results: Through multivariate analysis, both disease-free and overall survival of CRC patients was found to be significantly associated with serum blood glucose levels (both P < 0.05) but not DM history. In vitro cell proliferation assay was performed through D-(+)-glucose administration. After metformin administration, enhanced proliferation of CRC cells with D-(+)-glucose administration could be reversed and oxaliplatin sensitivity considerably increased ( P < 0.05). Furthermore, phosphorylation of two glycolysis-related target proteins, SMAD3 and MYC, notably increased with high glucose concentration. Conclusions: In summary, hyperglycemia could affect clinical outcomes in CRC patients receiving adjuvant chemotherapy, with the underlying oxaliplatin resistance mechanism possibly associated with increasing phosphorylation of SMAD3 and MYC and upregulation of G9A expression.
Anal adenocarcinoma: Treatment outcomes and trends in a rare disease entity.
Authors: White Richard , Hasan Shaakir , Raj Moses , Monga Dulabh K. , Finley Gene Grant , Kirichenko Alexander V. , McCormick James , Wegner Rodney E 
Published: January 2019

538 Background: Primary Adenocarcinoma of the rectum is a rare disease with a poor prognosis and thus tends to have a more aggressive treatment algorithm, typically involving a surgical approach. Prior to 2001, a few retrospective studies outlined improved outcomes with the incorporation of surgery with chemoradiation. However, since the publication of these studies, advancement in radiotherapy modalities and imaging have left the question of improved outcomes while reserving surgery for salvage. We conducted this NCDB-driven, retrospective study to analyze treatment trends and outcomes in the current time from 2004-2015 with respect to chemoradiation and surgery. Methods: We queried the NCDB for with AJCC stage 1-3 anal adenocarcinoma diagnosed between 2004-2015. Propensity score-matched multivariable cox regression analysis determined the association of incorporation of surgery into the definitive management of anal adenocarcinoma on survival. Results: Of the 1729 patients eligible patients in this study, 1028 were treated with surgery as up front management and 701 had definitive chemoradiation. Median overall survival for all patients was 55 months with a 5 year survival rate of 55%. Patients treated without surgery had worse overall survival, median survival of 45 months compared to 87 months (p < .0001) with 5 year survivals of 42% and 55% in favor of incorporation of surgery. Analysis across patients treated with surgery alone, surgery followed by adjuvant chemoradiation, neoadjuvant chemoradiation followed by surgery, and chemoradiation alone had median survival rates of 78, 83, 92, and 46 months, respectively (p < 0.0001). Propensity score adjusted multivariable analysis identified older age, grade 3, high comorbidity score, and lack of surgery as predictive of worse outcome. Conclusions: The results of the NCDB analysis indicate improved overall survival with the incorporation of surgery into the initial management of anal adenocarcinoma when compared to chemoradiation alone, despite the omission of surgery in up to 50% of the cases logged. Our results corroborate earlier studies published prior for surgery to be included in the definitive management of anal adenocarcinoma.
The prognostic role of PD-L1 expression according to MSI status in stage III colon cancer after curative resection.
Authors: Cho Sang-Hee , Hwang Jun Eul , Bae Woo Kyun , Chung Ik-Joo 
Published: January 2019

555 Background: Tumors expressing PD-L1 can render immune inactivated via triggering of PD-1 receptor on T cells with various pathways. Based on these mechanism, the blockade PD-1/PD-L1 pathway based been used as a therapeutic target for metastatic CRC. In the present study, we evaluated the prognostic role of PD-L1 expression associated with microsatellite status in surgically resected stage III colon cancer patients. Methods: PD-L1 expression was performed by immunohistochemistry from 182 stage III colon cancer patients after curative resection. Using the immunohistochemical stain, percentages of PD-L1 positive tumor cells and staining intensity were evaluated and categorized as ‘strong’ and ‘weak’ positive group. Clinical and histopathologic parameters including of MSI status and survival outcomes were analyzed with IDO expression which stands for the suppressive immune environment. Results: Strong PD-L1 expression was observed in 29% of all patients. PNI and lymphocyte response response were more frequently shown in strong PD-L1 patients. Among these patients, MSI was shown in 23 patients (12%). Although there was no significant difference between MSI and PD-L1 status, strong PD-L1 tended to better OS in MSS colon cancer (P = 0.056). In contrast, strong PD-L1 expression significantly correlated with significantly worse prognosis in disease free survival (P = 0.001) and overall survival (P < 0.001) than weak PD-L1 expression inMSI patients regardless of adjuvant chemotherapy. In MSI patients, the strong IDO expression was tended to be more frequently shown in strong PD-L1 expression patients (36.4%) than weak PD-L1 expression patients (14.3%). Conclusions: The expression of PD-L1 is differently affected on the survival according to the status of microsatellite. There is no significant relationship between the expression of PD-L1 and prognosis in MSS stage III colon cancer patients. However, in MSI colon cancer which has been well known as a highly immunogenic property, strong PD-L1 expression is significantly associated with poor prognosis on survival outcomes reflecting of immunosuppressive microenvironment in curative resected stage III colon cancer patient.
PD-1/PD-L1 immune check points blockade to attenuate growth of metastatic colon cancer in the CBP/β-catenin inhibited liver.
Authors: Kimura Kiminori , Osawa Yosuke , Nishikawa Koji , Kimura Masamichi , Kawakami Yutaka 
Published: January 2019

556 Background: Immune check points blockade with specific antibodies can accelerate anti-tumor immunity, resulting in a clinical response in patients with various types of cancer. Thus, a wide variety of treatment combinations based on PD-L1/ PD-1 pathway blockage are under development to enhance the therapeutic effect. Here, the effects of the combination treatment of PRI-724, a selective inhibitor of the CBP/β-catenin, with anti-PD-L1 antibody were examined in a mouse model of the liver metastasis of colon cancer. Methods: Mice were inoculated with SL4 colon cancer cells into the spleen to produce metastatic liver tumors. The animals were intraperitoneally injected with or without PRI-724 and/or anti-PD-L1 antibody (10F.9G2) 3 times a week. A part of mice treated with PRI-724 and anti-PD-L1 antibody was administrated with anti-mouse CD4 or CD8 antibody 3 times a week. First, to evaluate anti-tumor effect in those mice, we analyzed liver histology and survival rates after treatment. Next, to examine immune response in the liver, intrahepatic lymphocytes were analyzed by FACS for CD8 memory phenotype, Treg cells, macrophages, and dendritic cells, and the cytokine production from these cells (TNFa, IFNg etc.). Furthermore, inflammatory cytokines and chemokines mRNAs levels and PCR array concerned to Wnt signaling in the liver and serum cytokines levels were also analyzed. Results: The combination of the treatments resulted in regression of tumor growth, whereas monotherapy of each treatment did not show any anti-tumor activity. PRI-724 increased T lymphocytes recruitment, including CD8+ T cells, in the tumor, which may have been induced by inflammatory chemokines and a change of the macrophage property to the cytotoxic phenotype in the liver. Anti-PD-L1 antibody induced CD69+-activated T lymphocytes in the PRI-724-treated livers of mice inoculated with SL4. Administration of anti-CD8 antibody canceled the anti-tumor effects of the combination treatments of PRI-724 and anti-PD-L1 antibody. Conclusions: Targeting CBP/β-catenin combined with PD-1/PD-L1 immune check points blockade shows potential as a new therapeutic strategy for treating the liver metastasis of colon cancer.
Analysis of UGT1A’s polymorphisms and RAS: RAF mutations based on phase II study of biweekly XELIRI plus bevacizumab as a second-line therapy in patients with metastatic colorectal cancer.
Authors: Tanioka Hiroaki , Suzuki Nobuaki , Hazama Shoichi , Nagasaka Takeshi , Iwamoto Yasuo , Negoro Yuji , Nakagami Yuki , Tsunedomi Ryouichi , Nagano Hiroaki , Okajima Masazumi 
Published: January 2019

565 Background: We have previously reported biweekly XELIRI + bevacizumab 10 mg/kg as second-line chemotherapy in metastatic colorectal cancer (mCRC). In this study, we investigated relationships between efficacy/toxicity and biomarkers (polymorphisms of UGT1A’s, somatic mutations of RAS, BRAF and PIK3CA). Methods: Patients with mCRC who had received prior chemotherapy including oxaliplatin based regimen were eligible for this study. Treatment protocol administrated capecitabine 1,000 mg/m2 twice daily from the evening of day 1 to the morning of day 8, intravenous irinotecan 150mg/m2 on day 1, and bevacizumab 10 mg/kg on day 1 every 2 weeks. Results: Between January 2013 and July 2015, 51 patients were enrolled in this study. The patients’ characteristics were as follows (N=51): median age, 66 years (range 41–82); male/female, 29/22; the median PFS was 5.47 months (95% CI, 4.23–7.40 months), the median OS was 13.5months (95%CI, 11.57– 20.23months), and the median TTF was 4.5 months (95%CI, 3.97–6.93 months). The response rate was 16% (95%CI, 7.2–29.1), and the disease control rate was 76% (95%CI, 61.8-86.9). Grade 3 or higher adverse events were mainly febrile neutropenia in two patients and hypertension in 14 patients (28.6%). The patients with UGT1A7 (387G<T) genotype had a trend to suffer from diarrhea ( p=0.089 by Fisher’s exact test). The summary of somatic mutations of cancer was RAS (wild/mutant = 21/23), BRAF (wild/mutant = 39/5), PIK3CA (wild/mutant = 42/0), and MSI (MSS/MSI-H = 42/2). There was no statistical association between efficacy and somatic mutations. The sample size might influenced such the results. Conclusions: In mCRC patients, biweekly XELIRI + bevacizumab 10 mg/kg is effective and feasible as second-line chemotherapy. We found several biomarkers that predict toxicities in this study. Further study is required for predicting the efficacy based on biomarkers using somatic mutations of cancer and germline polymorphisms. Clinical trial information: UMIN000009280.