bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II Study of FOLFOX versus POF (paclitaxel plus FOLFOX) versus IP PAC (intraperitoneal paclitaxel) plus FOLFOX as a first-line treatment in advanced gastric cancer (AGC): A feasibility analysis.
Authors: Lin Rongbo , Zhao Shen , Li Hui , Liu Jie , Fan Nanfeng 
Published: March 2017

56 Background: Double regimens are commonly accepted for AGC in East Asia. However, triple regimens are recommended in west countries. POF regimen (a modified DCF reported in 2007, 2008, 2009, 2010 ASCO) appeared to be of good efficacy and was well tolerated in patients with AGC. Intraperitoneal paclitaxel showed high local concentration in abdominal cavity and low systemic toxicity. The aims of this study were to find out if the triplet POF was more effective with manageable side effects and IP PAC in combination with FOLFOX had higher local control rate and manageable systemic toxicity than doublet FOLFOX in AGC. Methods: The patients with AGC were randomized to three group. The FOLFOX regimen consisted of oxaliplatin 85 mg/m2, levoleucovorin 200 mg/m2, and 5-FU 400 mg/m2 bolus on day 1, then 5-FU 2400 mg/m2 continuous infusion over 46 hours. The POF regimen consisted of a 3-hour infusion of paclitaxel 135 mg/m2, followed by FOLFOX omitted 5-FU bolus. The IP PAC plus FOLFOX regimen consisted of paclitaxel 80 mg/m2 intraperitoneally plus FOLFOX. Every 14 days repeated for all three regimens. Up to 9 cycles of treatment were administered, followed by S-1 until disease progression Results: From 4th November 2015 to 10thJune 2016, 21 patients with ECOG PS 0-1 were assigned for the study. Grade ¾ toxicities, in the FOLFOX group (n = 7), neutropenia and nausea was one respectively; in the POF group (n = 9); neutropenia were two, stomatitis, nausea, vomiting, and fatigue was one respectively; in the IP PAC plus FOLFOX group (n = 5), neutropenia and fatigue was one respectively. No treatment-related death occurred. Median progression free survival and overall survival were 68 days and 194 days in FOLFOX group, 128 days and 282 days in POF group, 89 days and 178 days in IP PAC plus FOLFOX group. Conclusions: This pilot analysis showed three regimens including IP PAC plus FOLFOX had good safety profits. The POF group seemed to have better PFS and OS than the other two groups. This ongoing phase II study is feasible. Clinical trial information: NCT02845908.
Community that pays together stays together: Sharing of resources for colorectal cancer screening and treatment of the underserved population.
Authors: Dowd Katie E , Mishra Aparajita , Marsh Michelle , Cox Dawn , Aydin Nail , Yang Derek , Misra Subhasis 
Published: March 2017

561 Background: Bridging disparities to increase colorectal cancer (CRC) screening and treatment can be expensive and time consuming. This insurmountable cost often limits care; however, for every $1 spent on cancer screening $22.37 is saved on treatment costs and economic benefits. By finding cancer through free screening initiatives for the public, a new problem arises of how to fund further treatment. Methods: Project goals are to increase screening rates and knowledge about CRC and screening in our medically underserved region. The project provides screening at no cost, but these unfunded patients do not have coverage to treat their cancer diagnosis. By establishing partnerships with home health organizations, hospital CEOs, federally qualified health centers, locally elected officials, department of public health employees, and healthcare professionals our project has navigated patients through screening and treatment free of charge by encouraging community sharing of resources. Community relationships have been nurtured by utilizing quarterly program meetings, educational outreach for providers with CME credit, and cancer symposiums. This outreach provides an open forum to ask for feedback and coordinate care for the community with a primary focus on population healthcare management. Results: In addition to the many precancerous lesions removed, two cases were identified that needed further cancer treatment. The first patient did not qualify for county indigent clinic care. One private hospital waived the facility fees and we waived the surgeon fees, and the local cancer center agreed to cover adjuvant chemotherapy costs. Another patient was navigated to a local indigent care clinic, with CT scans paid by another nonprofit organization. This patient received surgery at no cost from the surgeon or hospital. These illustrations reflect community involvement in sharing cost for the uninsured. Conclusions: Utilizing cost and resource sharing through patient navigation can lessen the financial burden of caring for uninsured patients. By focusing on community relationships, our project is overcoming limitations to provide comprehensive care for patients.
Predictors of circulating tumor-derived methylated BCAT1 and IKZF1 DNA in colorectal cancer patients.
Authors: Symonds Erin L , Pedersen Susanne Kartin , Murray David , Baker Rohan , Young Graeme P 
Published: March 2017

567 Background: Blood tests detecting circulating tumor-derived DNA (ctDNA) are being developed for colorectal cancer (CRC) screening and monitoring. However, the underlying tumor biology resulting in circulating DNA is not well understood. This study aimed to elucidate tumor features associated with methylated BCAT1 and IKZF1 DNA in blood as well as patient demographics that predict biomarker appearance. Methods: 129 people with invasive CRC had blood collected prior to surgery. Patient sociodemographic factors were recorded. Extracted circulating cell-free DNA was assayed for methylated BCAT1 and IKZF1. Patient factors and tumor features including location, size, depth of invasion (T stage), degree of differentiation, vascularity, lymphatic and perineurial invasion, lymph node involvement and presence of metastasis were compared with blood test results using multivariate logistic regression analysis. Results: The distribution of CRC stages I to IV were 34, 43, 41 and 11, respectively and 72 (56%) were blood positive for methylated BCAT1/IKZF1. Positivity was associated with distally located tumors and a higher T stage (Table). Gender, age, BMI, race, smoking and medications were not associated with blood positivity rates, but increased alcohol intake ( > 7 drinks/week, n = 31) was associated (OR 5.7, 95% CI 1.1-28.7, p = 0.036). Conclusions: The strongest predictor for appearance of ctDNA was invasion depth of the tumor. Demographic features did not influence the positivity rate of the BCAT1/ IKZF1 CRC blood test, strengthening the validity of this blood test for CRC screening and monitoring in the general population. [Table: see text]
Vascular emboli as a prognostic factor in patients with stage III colorectal cancer undergoing radical surgery.
Authors: Pei Haiping , Pei Qian , Zhu Hong , Tan Fengbo 
Published: March 2017

570 Background: The significance of vascular emboli (VE) in stage III colorectal cancer (CRC), the mechanism of their formation and their therapy strategy remain obscure demanding enhanced research. Methods: Data from 323 consecutive patients (192 non-VE, 131 VE) receiving radical surgery and adjuvant chemotherapy in our institution between Jan. 2009 and Nov. 2014 were retrospectively collected. The follow-up deadline was Feb. 2016. Potential prognostic risk factors were tested using univariate and multivariate survival analyses. mRNAs differentially expressed between VE and non-VE stage III CRC were analyzed using Agilent Gene Expression oligo-microarrays (Version 6.5). Patient-derived xenograft (PDX) nude mouse models were constructed to evaluate the efficacy of adjuvant chemotherapy plus targeted drugs (cetuximab or bevacizumab) on VE and non-VE stage III CRC. Results: VE was significantly associated with gross tumor morphology (p = 0.001), histologic type (p < 0.001), lymph node status (p < 0.001), sub-class of stage III (p =0.001), and serum CA199 level (p = 0.022). VE and lymph node status were independent risk factors for overall survival (OS) (p < 0.001, p = 0.008) and disease-free survival (DFS) (p < 0.001, p = 0.007). The median OS and DFS in VE stage III CRC patients were 38 months and 24 months, respectively. Compared with pericarcinous tissue, 809 genes (396 up-, 413 down-regulated) were differently expressed in no-VE tissue, and 1513 genes (898 up-, 615 down-regulated) in VE tissue. The top ten up-regulated protein-coding genes in VE stage III CRC were ITGBL1 (p<0.001), PROCR (p<0.001), CENPW (p<0.001), ZNF485 (p<0.001), VEGFA (p<0.001), DSG3 (p<0.001), CYP24A1 (p=0.001), COL10A1 (p=0.001), HIST3H2A (p=0.001)and PSAT1 (p=0.002). Conclusions: VE appears to be an independent risk factor for the prognosis of stage III CRC patients treated with radical surgery and adjuvant chemotherapy. Differently regulated genes seem to be involved in the formation and progress of VE. The therapy scheme should be more individualized taking into account the VE status.
Safety and tolerability profile of raltitrexed in Chinese patients with locally advanced or recurrent and metastatic colorectal cancer: A phase IV trial.
Authors: Qin Shukui , Li Jin , Liu Yunpeng , Chen Yin , Xu Nong , Xu Jianming , Bai Yuxian , Huang Jianjin , Liang Jun , Zheng Leizhen 
Published: March 2017

571 Background: The clinical benefit and safety profile associated with raltitrexed in patients with advanced colorectal cancer (CRC) were established. However, safety information of raltitrexed in Chinese patients is rare. We aimed to assess the safety of raltitrexed monotherapy in Chinese patients with advanced CRC. Methods: This single-arm, open-label, multi-center, phase IV trial was conducted in 13 hospitals across China between March 2011 and July 2014. Patients with locally advanced or recurrent and metastatic colorectal cancer (mCRC) received raltitrexed (3mg/m2) as a 15-min infusion on day 1, every 21 days. Treatment was continued until disease progression or unacceptable toxicity. The primary objective was safety and the secondary objectives were disease control rate (DCR), progression free survival (PFS) and overall survival (OS). Results: A total of 215 patients were enrolled, and the safety was assessed in 205 patients. 92 patients had 394 Adverse events (AEs) during the study. A majority (94.4%) of AEs was grade 1/2 and only 5.3% was grade 3/4. Most AEs were either resolved spontaneously or treated successfully with standard medical interventions. Severe AEs were reported by 5.8% (12/205) of patients. The most commonly reported AEs were increase of transaminases, leukopenia, nausea and vomiting. Serum transaminase elevation, an important safety concern associated with raltitrexed therapy, were transient, self-limiting and manageable. No deaths were reported during the study. The DCR in second-line and third-line therapy by raltitrexed reached 49.5% and 37.4%, respectively. The median PFS in second-line and third-line therapy was 1.43 months and 1.47 months, respectively. The median OS was 13.6 months and 8.9 months, respectively. Conclusions: Raltitrexed monotherapy is a safe, well-tolerated and convenient therapy option for Chinese patients. The treatment-associated toxicity is manageable and does not lead to discontinuation of treatment in oncology practice.
Prevalence of pathogenic mismatch repair mutations in an Irish cohort after clinical and molecular pre-selection.
Authors: Farrell Michael P. , Hearty Kian P , Gallagher David James 
Published: March 2017

574 Background: Lynch syndrome (LS) is a highly penetrant, autosomal dominant multi-system disorder characterised by an inherited predisposition to a range of cancers. LS is caused by germline mutations in one of the mismatch repair (MMR) genes ( MSH2, MLH1, MSH2 and PMS2). Tumours from patients with LS have characteristic features resulting from the underlying molecular involvement of defective MMR, that is, the presence of microsatellite instability (MSI) and the absence of MMR protein expression by immunohistochemistry (IHC) corresponding to the mutated gene. MMR mutations are identified in approximately 60% of microsatellite instability-high (MSI-H) cancer patients fulfilling clinical criteria for LS. We sought to define the prevalence of pathogenic MMR mutations among an Irish cohort following molecular pre-selection with IHC/MSI and BRAF/MLH1 hypermethylation testing Methods: The results of diagnostic MMR genetic screening conducted on individuals following genetic counselling, in the Clinical Cancer Genetics Departments of the Mater Campus between January 2011 to September 2016, were correlated with ages at diagnoses and genetic test result. Results: This clinic-based cohort of affected individuals (n = 35) consisted of 22 females and 13 males. Median age at first cancer diagnosis was 44 years, range 23 to 86, standard deviation 12.3. Deleterious mutations were identified in 16 patients (45.7%), 6 in MLH1, 3 in MSH2, 2 in MSH6 and 5 in PMS2. Thirteen patients had a normal genetics test result (37.1%). Variants of uncertain significance (VUS) were identified in 6 patients (17.1%). With additional molecular testing and co-segregation studies in one family an MLH1 VUS was reclassified as likely pathogenic, facilitating pre-symptomatic testing for family members. This reclassification gives a revised prevalence of pathogenic mutation in this cohort of 48.5% and a VUS detection rate of 14.2%. Conclusions: We report a higher than expected VUS rate following molecular preselection of patients likely to have LS. No mutations were identified in 37% of patients supporting the presence of alternative negative regulators of the MMR pathway.
Aspirin in the prevention of colorectal cancer recurrence.
Authors: Kumari Nimisha , Mandaliya Hiren A. , Evans Tiffany , McElduff Patrick , Oldmeadow Christopher , Day Fiona Lee 
Published: March 2017

578 Background: Aspirin use reduces the incidence of colorectal adenomas, and of colorectal cancer (CRC) in patients with hereditary non-polyposis colorectal cancer. There is limited data on the effect of aspirin in the secondary prevention of CRC, currently the subject of multiple prospective randomized trials. We aimed to test the hypothesis that aspirin reduces disease recurrence in patients diagnosed with early CRC at a high volume, single institution. Methods: A retrospective analysis was conducted of all patients (pts) treated with at least one cycle of adjuvant chemotherapy for stage II or III CRC over a 5yr period (2009–13). Patients with synchronous CRC were excluded. Aspirin use at the onset of adjuvant chemotherapy was sourced from the universal electronic recording of concomitant medications. Kaplan-Meier curves and the log-rank test were used to compare crude relapse free survival (RFS) between pts who were using aspirin to those who were not. Propensity score analyses was used to balance the groups according to potentially confounding variables: tumor site (colon vs rectum), tumor stage (II vs III), and adjuvant chemotherapy (oxaliplatin-based vs no oxaliplatin). The propensity scores were estimated through a multivariable logistic regression model, and a Cox proportional hazards model used to assess the effect of aspirin use on RFS in the sample weighted according to the inverse probability of receiving aspirin. Results: A cohort of 231 pts met eligibility criteria; median age 64yr; 50% colon, 50% rectal; 19% stage II, 81% stage III; 35% received oxaliplatin; 13% (n=31) were using aspirin and 26% of pts (n=61) developed CRC recurrence in median follow-up of 2.9yr. Unadjusted RFS was not significantly different for those using aspirin (log rank p value 0.88). There was good overlap in propensity scores for the two groups. The hazard ratio for RFS with aspirin use from the weighted Cox regression model was 1.2 (95% CI 0.62-2.29), indicating no statistically significant effect of aspirin on CRC relapse. Conclusions: In this single institution series, we did not find evidence that aspirin use at onset of chemotherapy had an effect on CRC relapse free survival. These results do not exclude an aspirin effect that is modest or restricted to select CRC subgroups.
Evaluating collagen neoepitopes as pharmacodynamic biomarkers of GS-5745, an MMP9 inhibitor, in advanced gastric cancer.
Authors: Brachmann Carrie Baker , Zhang Yafeng , Zavodovskaya Marianna , Hu Jing , Maltzman Julia D. , Smith Victoria , Xiao Yuanyuan , Patterson Scott D 
Published: March 2017

58 Background: Cancer is characterized by continuous remodeling of the extracellular matrix (ECM) through a process of degradation and replacement of ECM components, such as collagens. Matrix-metalloproteinase 9 (MMP9) is involved in this remodeling and its inhibition is hypothesized to reduce ECM turnover. MMP9 expression is limited in healthy tissues, but high in tumor epithelia, infiltrating inflammatory cells and fibroblasts. Collagen I and III fragments (neoepitopes C1M and C3M) in blood may provide a measure of tumor MMP activity (BMC Cancer 13:554. 2013). GS-5745 is a monoclonal antibody that specifically inhibits MMP9 and has shown efficacy in combination with chemotherapy in advanced gastric cancer in an ongoing ph I study of multiple cancer types (NCT01803282). Exploratory analyses of collagen neoepitopes from patients in the gastric cancer cohort are reported here. Methods: C1M and C3M were measured by ELISA in serum samples (Nordic Bioscience). Healthy volunteer (HV) samples were age-matched. Pharmacodynamic evaluation and association with clinical outcomes were assessed by non-parametric tests; nominal p-values are reported. Results: Pharmacodynamic Evaluation (Table):Baseline (BL) levels of C1M and C3M were higher in gastric cancer patients than HVs. C1M and C3M displayed a pharmacodynamic response after 1 treatment cycle. Inhibition of C1M continued to decline with treatment. Association with Best Overall Response:There was no association of BL C1M or C3M level with best overall response. 13 of 20 responders had decreased C1M at C2D1; however, of the 3 patients with progressive disease, none had an on-treatment decrease in C1M. Conclusions: These data suggest an association between circulating C1M as a pharmacodynamic biomarker of GS-5745 in combination with chemotherapy in gastric cancer patients. Circulating neoepitope biomarkers will continue to be explored in all ongoing and future oncology GS-5745 studies. Clinical trial information: NCT01803282. [Table: see text]
Blood-based genomic profiling of circulating cell-free tumor DNA (ctDNA) in 1397 patients (pts) with colorectal cancer (CRC).
Authors: Strickler John H. , Banks Kimberly C. , Nagy Rebecca J , Lanman Richard B. , Talasaz AmirAli , Corcoran Ryan Bruce , Kopetz Scott 
Published: March 2017

584 Background: ctDNA is shed into the bloodstream by tumor cells throughout the body, offering a non-invasive means of genomic testing, and a way to detect heterogeneous, subclonal genomic alterations present in distinct tumor lesions within an individual pt. However, a broad comparison of mutation prevalence in CRC ctDNA versus CRC tumor tissue has not yet been performed. Methods: ctDNA from 1397 CRC pts was analyzed using a CLIA-certified digital sequencing assay (Guardant360, Guardant Health) capable of detecting single nucleotide variants (SNV) in up to 70 genes, as well as selected insertions/deletions, amplifications, and fusions. Subclonal mutations were defined as mutations with mutant allele fractions (MAF) ≤ 50% of the greatest somatic MAF in the sample. Frequencies of mutations detected were compared to two large tissue-based sequencing databases (TCGA and NHS/HPS). Results: 1500/1772 (85%) tests had at least one genomic alteration (1397 unique pts). The most common SNV mutations included TP53 (62%), APC (47%), KRAS (39%), PIK3CA (17%), EGFR (11%), SMAD4 (11%), and BRAF (11%); these frequencies were comparable to rates in TCGA and NHS/HPS. In contrast, EGFR extracellular domain (ECD) mutations (42 pts) and JAK2 V617F mutations (16 pts) detected in ctDNA were not seen in tissue sequencing, reflecting acquired resistance to EGFR antibodies and clonal hematopoiesis of indeterminate clinical potential, respectively. 88% of pts with ECD mutations had at least one additional non-ECD resistance alteration detected in ctDNA (range 1-9, median 2.6), including KRAS, NRAS, BRAF, MAP2K1, MET and ERBB2. EGFR mutations were most likely to be detected as subclonal (86%), while mutations most likely to be clonal included KRAS (71%), TP53 (65%), BRAF (65%), and APC(63%). In 84 pts with serial monitoring, 87% had either gain (61%) or loss (63%) of clones over time. Conclusions: Blood-based genomic profiling can effectively detect common genomic alterations in CRC at comparable frequencies as observed in tissue and provide novel insights into tumor clonality and clonal dynamics. Clinical trials to target EGFR ECD mutations may be limited by the multiplicity of resistance mechanisms in each pt.
RAS heterogeneity as a prognostic marker in metastatic colorectal cancer.
Authors: Loree Jonathan M. , Lam Michael , Morris Jeffrey , Overman Michael J. , Raghav Kanwal Pratap Singh , Eng Cathy , Dasari A. , Kee Bryan K. , Fogelman David R. , Wolff Robert A. , Jiang Zhiqin , Davis Jennifer S , Shaw Kenna Rael , Broaddus Russell , Routbort Mark , Luthra Rajyalakshmi , Maru Dipen M. , Menter David , Meric-Bernstam Funda , Kopetz Scott 
Published: March 2017

586 Background: The impact of intratumor heterogeneity on prognosis in metastatic colorectal cancer (mCRC) is unclear, however relative variant allele frequency (rVAF) of key mutations within a tumor may impact outcomes. Therefore, we sought to determine whether rVAF of RAS ( KRAS & NRAS) mutant (mt) clones impacts overall survival (OS) in mCRC patients (pts). Methods: Using a next generation sequencing panel of 201 cancer related genes, we tested 200 mCRC tumors / matched normals. Mutations, indels, and copy number variant (CNV) information were obtained. An rVAF of RAS clones was determined by dividing RAS mt VAF by the VAF of the mutated gene with the highest allele frequency. This truncal gene served as a marker of the total malignant population in a specimen. Pts were stratified at an rVAF of 50%. OS was compared with Kaplan-Meier curves, the log-rank test, and Cox regression. We assessed the impact of CNV on our findings by correcting the rVAF for CNVs in RASand truncal mutations. Results: Of 200 pts, 15% had RAS mt rVAF < 50%, 40.5% had rVAF ≥ 50%, and 44.5% were RAS wild type (WT). Age, gender, MSI status, histology, and stage at diagnosis were similar between groups. More RAS WT pts had BRAF mutations (19.1% vs 1.2% and 3.3%, P< 0.0001), left sided (78.7% vs 56.8% and 60%, P= 0.02), or poorly differentiated tumors (27.3% vs 8.6% and 13.3%, P= 0.003) compared to pts with rVAF ≥ 50% or rVAF < 50%, respectively. Mean coverage was 807x for RAS and 602x for truncal mutations. OS was better in pts with an rVAF < 50% compared to pts with rVAF ≥ 50% regardless of whether rVAF was corrected for CNV (HR 0.6; 95% CI 0.39-0.93, P =0.029) or not (HR 0.48; 95% CI 0.31-0.82, P= 0.010). mOS for pts with WT, rVAF < 50% and rVAF ≥ 50% tumors were 65.8, 55.7, and 38.6 months ( P= 0.0025). In multivariate models controlling for stage at diagnosis and BRAF mutation, pts with rVAF < 50% (HR 1.75; 95% CI 1.03-2.97, P = 0.04) and rVAF ≥ 50% (HR 2.46; 95% CI 1.66-3.65, P< 0.0001) had worse OS compared to WT pts. When rVAF was used as a continuous variable, every 1% increase in rVAF RAS mt resulted in a 1% increased hazard of death ( P <0.0001). Conclusions: Our findings suggest that clonal proportion of a tumor with a RAS mutation may impact OS and suggest the prognostic impact of RAS mutations is not an “all or none” phenomenon.