bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhancement of the efficacy of radiofrequency ablation by neoadjuvant oncolytic virus therapy via antitumor immunity and the booster effect of immune checkpoint inhibitors.
Authors: Yamada Tomoharu , Inou Yasushi , Iwai Miwako , Tateishi Ryosuke , Koike Kazuhiko , Todo Tomoki 
Published: January 2019

253 Background: A third generation oncolytic herpes simplex virus type 1, G47Δ, destroys tumor cells selectively and induces antitumor immune responses. Radiofrequency ablation (RFA) is a standard local therapy for hepatocellular carcinoma (HCC). Here, we examined the efficacy of G47Δ used in combination with RFA and evaluated the antitumor immune responses. Methods: In A/J mice harboring bilateral poorly immunogenic Neuro2a subcutaneous tumors, tumors on one side were treated with intratumoral injections with G47Δ (2×106 pfu) on days 0, 2 and 4 followed by RFA treatment on day 6, which results in complete regression of the treated tumors. We further treated with an immune checkpoint inhibitor (ICI) in combination. Tumor infiltrating lymphocytes in contralateral tumors were analyzed with flow cytometric analysis. To examine the contribution of CD8+ T cells, CD8+ T cells were depleted by treatment with anti-CD8 monoclonal antibody. To mimic a remote recurrence, unilateral subcutaneous tumors were treated with G47Δ and RFA, and Neuro2a cells were implanted on the same day of RFA. In a separate experiment without rechallenge, antitumor immunity was evaluated using ELISpot assay on day 20. Results: The G47Δ+RFA treatment caused smaller volumes of contralateral tumors and increased infiltration of CD8+/CD45+ T cells within the tumor, compared with RFA or G47Δ monotherapy. Without CD8+ T cells, the antitumor effect on the contralateral tumors was completely abolished. When mice were rechallenged, those cured by G47Δ+RFA rejected the Neuro2a more frequently than those cured by RFA alone. ELISpot assay revealed that the number of Neuro2a reactive splenocytes was significantly greater in the G47Δ+RFA group than the RFA group. The G47Δ+RFA+anti-PD-L1 treatment caused smaller volumes of contralateral tumors compared with G47Δ+RFA treatment, whereas anti-PD-L1 alone showed no effect. Conclusions: Intratumoral administration of G47Δ prior to RFA would enhance systemic antitumor immunity that is further enhanced by ICI.
An open-label phase Ib/2 trial of TRC105 plus sorafenib in patients with advanced/metastatic hepatocellular carcinoma (HCC) (NCT01806064).
Authors: Raghav Kanwal Pratap Singh , Lee Richard T. , Paluri Ravi Kumar , Mody Kabir , Simpson Brian , Adams Bonne J. , Theuer Charles P. , Kaseb Ahmed Omar 
Published: January 2019

268 Background: TRC105, an endoglin antibody, potentiates the activity of sorafenib (S) in preclinical HCC models, and TRC105 + S demonstrated a 33% partial response rate (5/15 pts) by RECIST, at RP2D doses of TRC105 in HCC pts ( Clin Can Res 2017). Adverse events characteristic of each drug were not increased in frequency or severity when the two drugs were administered concurrently. Methods: P1: Compare wkly TRC105 dosing vs four wkly doses followed by every other wkly dosing + S 800 mg daily. P2: Four objective responses are required in 21 pts to reject the null hypothesis that the true response rate probability is < 5% with an alpha level of 0.1 and 80% power. Key inclusion criteria: disease not amendable to surgical or local therapies, ECOG ≤ 1; Child-Pugh A or B (7 points) classification. Results: Thirteen pts were enrolled in phase 1b at TRC105 10 mg/kg wkly for four doses and 15 mg/kg every other week thereafter + S. Mean serum levels of TRC105 exceeded the target conc. following 4 wkly doses of TRC105 at 10 mg/kg (mean = 34 µg/ml, range BLOQ-80). Mean trough conc. decreased following every other week dosing (mean = 13 µg/ml, range BLOQ-31), resulting in infusion reactions or a continued requirement for premedication. Therefore, wkly dosing of TRC105 at 10 mg/kg is the recommended Phase 2 dose. ADA were detected in 10 of 14 pts and correlated with lower than expected PK conc. Common TRC105 related AEs included ≤ G2 epistaxis, ≤ G2 fatigue and ≤ G2 headache. Common S related AEs included ≤ G3 fatigue, ≤ G3 hand foot syndrome and ≤G2 epistaxis. A total of 3 out of 14 evaluable patients (21%) enrolled in phase 1 and 2 achieved durable PR, 2 of these ongoing at week 45 and 17. Conclusions: TRC105 dosed at 10 mg/kg wkly was required to achieve target conc. due to higher clearance in HCC pts, which may have been influenced by a higher rate of ADA compared to studies of TRC105 in other tumor types. The combination of TRC105 + S demonstrated encouraging signs of activity, including durable PR in 2/9 evaluable pts in Phase 1b and 1/5 pts thus far in Phase 2. An additional 16 pts will be enrolled at the RP2D to assess the primary endpoint of ORR by RECIST. Clinical trial information: NCT01806064.
KRAS and TP53 status as a predictor of survival in patients with resected pancreatic ductal adenocarcinoma.
Authors: McIntyre Caitlin A , Lawrence Sharon Anita , Wong Winston , Chou Joanne F. , Capanu Marinela , Berger Michael F. , Allen Peter , O'Reilly Eileen Mary 
Published: January 2019

276 Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. KRAS, TP53, CDKN2A and SMAD4 are established driver genes in PDAC. We aimed to determine if the mutational status of these 4 driver genes, and other frequently altered genes, are predictive of clinical outcomes in patients who undergo resection. Methods: Patients who underwent resection of PDAC and consented to targeted sequencing of their primary tumor using MSK-IMPACT, were included. Genomic alterations were determined based on MSK-IMPACT sequencing results of formalin-fixed, paraffin-embedded tumor. A prospectively maintained database and electronic medical record were queried for clinical and pathologic variables. Gene mutation status was compared with overall survival (OS) and recurrence free survival (RFS) using the log-rank test, and with pathologic variables using Wilcoxon rank-sum and Fishers exact tests. Results: Targeted genomic sequencing was performed on N = 285 primary tumors resected between 2004-2017. N = 55 (19%) patients received neoadjuvant therapy prior to sequencing and N = 220 (77%) received adjuvant therapy. Median OS was 39 months with a median follow up of 22 months. Frequency of genomic alterations and their association with OS and RFS are shown in Table 1. Alterations in both KRAS and TP53 were associated with worse OS, but not RFS, as compared to wildtype. Mutant KRAS was also associated with larger tumor size (median, 3.0 vs 2.2cm, p = 0.009). Conclusions: Alterations in KRAS and TP53 were associated with worse OS in patients with resected PDAC. Further analysis will include the association of driver gene variants, as well as other gene alterations, with clinical and pathologic outcomes. [Table: see text]
Comprehensive genomic profiling in metastatic pancreatic adenocarcinoma, correlation with early death versus prolonged survival.
Authors: Kamgar Mandana , Dyson Gregory , Shields Anthony Frank , Tesfaye Anteneh A. , Philip Philip Agop , Al Hallak Mohammed Najeeb 
Published: January 2019

282 Background: PDAC has a very poor prognosis and around 50% of the patients die within two months of their diagnosis and around 10% live beyond one year. In this study we sought to find biomarkers differentiating patients with early death from those with more prolonged survival. Methods: Tumors from our patients with PDAC were examined using NexGen sequencing (evaluating somatic mutations in 592 genes), immunohistochemistry, and in-situ hybridization (Caris Life Sciences). Tumor mutational burden, microsatellite instability, copy number variation, and gene fusion assessment were done in a subset of samples. Extremes in clinical outcome were defined as death in < 4 months and > 12 months from metastasis diagnosis. Fischer’s exact tests were used to associate the categorical clinical data and genomic factors with the extremes of clinical outcome. A t-test was used to associate the continuous clinical factors with the extreme outcomes. Hierarchical clustering using the Ward amalgamation and binary distance metric was used to define cluster based upon the genomic factors. Results: From October 2014 to August 2018, we evaluated 115 patients. 15 patients with PDAC died < 4 months and 39 died > 12 month from the time of metastasis diagnosis. Compared to the patients with prolonged survival, patients with an early death were significantly older (Average 67.5 vs. 60.5 years old, P = 0.03) and had significantly higher neutrophil counts (average 9.6 vs. 5.1, P = 0.001) and monocyte counts (average 1 vs. 0.6, P = 0.01). No genomic alteration differentiated the groups with extreme outcomes. None of the clusters defined upon the genomic factors differentiated the two outcome groups. Using classification model to predict early death vs prolonged survival, no factor evaluated by the genomic profiling was discriminatory between the groups. Conclusions: We did not find a pattern of genomic alteration difference in PDAC patients between the short-term versus the long-term survivals using Next Generation Sequencing. The short-term survivals were older and had higher neutrophil and monocyte counts at the time of metastatic disease diagnosis.
Defining DNA damage repair deficiency and replication stress in pancreatic cancer.
Authors: Dreyer Stephan , Paulus-Hock Viola , Upstill-Goddard Rosie , Lampraki Eirini , Jamieson Nigel , Cooke Susie , Bailey Peter , Biankin Andrew , Chang David Kuang-Fu 
Published: January 2019

285 Background: Integrated multi-omic analyses revealed 24% of pancreatic cancer (PC) harbor defects in DNA damage response (DDR) and a subgroup demonstrate upregulation in replication stress pathways. DDR defective tumors preferentially respond to DNA damaging agents, and clinical responses to cell cycle inhibitors are seen in undefined subgroups, representing novel therapeutic strategies for PC. The aim of this study is to define and refine therapeutic segments for agents targeting DDR and replication stress in PC. Methods: We performed whole genome and RNA sequencing (RNAseq) on 48 patient-derived cell lines (PDCL) generated and characterized as part of the International Cancer Genome Initiative (ICGC). This identified increased replication stress in a sub-group of tumours, correlating with previously defined molecular subtypes of PC, irrespective of DDR status. Cytotoxic viability assays were performed using agents targeting the DDR pathway and cell cycle checkpoints, including Cisplatin, and inhibitors of PARP, ATR, WEE1, CHK1, CDK4/6 and PLK4. Subcutaneous patient derived xenografts (PDX) were generated to test therapeutic regimens in vivo. Results: DDR defective models, as defined by signatures of homologous recombination deficiency (HRD) were highly sensitive to Cisplatin and PARP inhibitors. Replication stress predicted differential responses to cell cycle inhibitors of WEE1, CHK1, CDK4/6 and PLK4. A novel mRNA signature of ATR inhibitor sensitivity was generated and correlated with response. Response to cell cycle checkpoint inhibitors were independent of DDR status, but strongly associated with replication stress. Conclusions: This proof of concept data demonstrates DDR deficiency and increased Replication Stress to be attractive targets in PC. Therapeutic vulnerabilities extend beyond platinum chemotherapy and can be targeted with novel small molecule inhibitors, with independent biomarkers predicting response to agents targeting either DDR or cell cycle checkpoints. This has led to the design and development of several personalized medicine trials via the Precision Panc platform targeting DDR and Replication stress, and will allow clinical testing of signatures of HRD and replication stress.
Impact of obesity upon the survival of cholangiocarcinoma patients.
Authors: Surapaneni Phani Keerthi , Li Zhuo , Vemireddy Lalitha Padmanabha , Kasi Pashtoon Murtaza , Starr Jason Scott , Ritter Ashton , McMillan Jessica , Wylie Natasha , Mody Kabir 
Published: January 2019

288 Background: Obesity is a risk factor for developing cholangiocarcinoma (CCA). However, the effect of obesity on survival of CCA is unclear. The primary aim of this study was to analyze the impact of obesity upon overall survival of CCA patients. Secondary aims were to analyze impact of obesity upon other disease characteristics such as tumor site, stage, age, sex, BMI and Ca 19-9. Methods: A total of 411 unique pts diagnosed with CCA at Mayo Clinic Florida between 2000 and 2018 were retrieved from our collective SDMS database. Variables evaluated included:demographics, Body Mass Index (BMI), AJCC stage, tumor location and Ca 19-9.A total of 185 pts had all data available pertaining to these variables. We further restricted the analysis to pts with intrahepatic CCA classified BMI as per CDC criteria normal (18.5-25kg/m2), overweight (25-29.9kg/m2) and obese (≥30 kg/m2), thus leaving a total of 152 pts. Continuous and categorical variables were compared across BMI groups using Chi-squared or Fisher’s exact test. Overall survival rates after diagnosis at 1, 2 and 3 years were estimated using Kaplan-Meier method. Results: Among 152 pts included in the study, 28% were normal weight, 40% were overweight and 32% were obese. The overall survival rate at 1, 2 and 3 years for normal weight pts with all stages combined was 54.1%, 35%, and 30.7%, respectively. The overall survival rate at 1, 2 and 3 years for overweight pts with all stages combined was 59.7 %, 32.6%, and 25.4%, respectively. The overall survival rate at 1, 2 and 3 years for obese pts with all stages combined was 63.9%, 37.6%, and 26.7%, respectively(p = 0.8766). Multivariate analysis demonstrated is no significant difference in overall survival for obese pts compared to normal or overweight pts.(Table to be shown) However it showed, gender and Ca19-9 were statistically significant predictors of overall survival, with males and pts with Ca19-9≥100 doing worse (HR1.65 (CI = 1.05, 2.61, p = 0.031) and HR 2.31 (CI = 1.49, 3.59, p = < 0.01), respectively). Conclusions: BMI did not make a significant impact on the overall survival, though there may be a trend toward worse OS for ptswith higher BMI. A larger, stage focused evaluation is warranted for further exploration of this trend.
Landscape of circulating tumor DNA and tissue-based profiling in advanced cholangiocarcinoma.
Authors: Mody Kabir , Kasi Pashtoon Murtaza , Surapaneni Phani Keerthi , Bekaii-Saab Tanios S. , Ramanathan Ramesh K. , Ahn Daniel H. , Mahipal Amit , Starr Jason Scott , Ritter Ashton , McMillan Jessica , Wylie Natasha , Roberts Ali , Nagy Rebecca J , Borad Mitesh J. 
Published: January 2019

291 Background: Cholangiocarcinoma (CCA) has limited treatment options. Genomic analyses have led to development of targeted therapies now in clinical trials, and may enable discovery of new treatment options. However, biopsy often yields limited tissue, thus hampering tissue-based profiling opportunities. Comparative data regarding circulating tumor DNA (ctDNA) analysis and tissue based profiling in CCA are limited. Methods: We performed ctDNA NGS analysis along with tissue based profiling in pts with advanced CCA (January 2015- February 2018). ctDNA analysis was performed using Guardant 360 (Guardant Health, CA) which detects single nucleotide variants, amplifications, fusions, and specific insertion/deletion mutations in up to 73 different genes and the majority of tissue based profiling using Foundation One. The mutant allele fraction (MAF) for detected alterations was calculated relative to wild type in ctDNA. Therapeutic relevance was defined as alterations within OncoKB levels 1-3B and R1. The study was conducted in accordance with Mayo Clinic IRB requirements. Results: Among 124 pts and 139 total samples, ctDNA NGS revealed at least one genomic alteration (excluding variants of uncertain significance and synonymous mutations) in 89% of pts. Median number of alterations per pt was 3 [range, 1-15], with a median MAF of 0.42% (range, 0.1% - 94.2%). The total number of unique alterations was 321. The most commonly altered genes: TP53 (31%), KRAS (11%), FGFR2 (7%), APC and PIK3CA (each 5%) and ARID1A (3%). Amplifications were noted in 14 genes: BRAF, CCND1, CCND2, CCNE1, CDK4, CDK6, EGFR, ERBB2, FGFR1, FGFR2, MET, MYC, PDGFRA, and PIK3CA. Tissue-based profiling was available in 57 (46%) pts, with a median of 63 days between liquid and tissue biopsy. IDH1, FGFR2, TP53 and KRAS were most common gene mutations found in pts who had both liquid and tissue biopsy done. (Comparative results to be shown). Conclusions: ctDNA plasma profiling of pts with advanced CCA is a feasible alternative method to gather comprehensive genomic data. Further larger cohort studies comparing landscape of alterations seen on ctDNA versus tissue-based assays are needed.
Symptom burden at the end of life for neuroendocrine tumors: A population-based analysis of patient-reported outcomes.
Authors: Hallet Julie I. , Davis Laura , Mahar Alyson L. , Law Calvin , Bubis Lev , Isenberg-Grzeda Elie , Singh Simron , Myrehaug Sten , Zhao Haoyu , Beyfuss Kaitlyn , Moody Lesley , Coburn Natalie G. 
Published: January 2019

297 Background: How to best support neuroendocrine tumor (NET) patients remains unclear. While the peri-diagnostic period has been investigated, there is no data regarding symptoms at the end of life, when suboptimal symptom control may be particularly burdensome. This study examined symptom trajectories and factors associated with high symptom burden in NET at the end of life. Methods: We conducted a population-based retrospective cohort study of NET diagnosed from 2004-2015, who died between 2007-2016. Prospectively collected patient-reported Edmonton Symptom Assessment System scores were linked to provincial administrative datasets. Moderate-to-severe symptom scores in the 6 months prior to death were presented by 2-week intervals. Multivariable Poisson regression identified factors associated with moderate-to-severe symptoms scores. Results: Among 677 decedents, 2,579 symptom assessments prior to death were analyzed. Overall, moderate-to-severe scores were most commonly reported for tiredness (86%), wellbeing (81%), lack of appetite (75%), and drowsiness (68%) at any time. This proportion changed over time, progressively increasing closer to death: 56.8% to 83.9% tiredness, 50.5% to 73.1% wellbeing, 40.9% to 80.6% lack of appetite, and 41.5% to 68.8% drowsiness. The increase was steeper in the 8 weeks before death for lack of appetite, drowsiness, and shortness of breath. On multivariate analyses, the risk of moderate-to-severe symptoms was significantly higher in the last 2 months prior to death and with shorter survival from diagnosis (< 6 months). Women reported a higher burden of anxiety, nausea, and pain than men. There was no association between symptom burden and age or primary tumor site. Conclusions: NET patients suffer a high symptom burden at the end of life, not previously described. The proportion of moderate-to-severe symptoms increases steeply as death nears, highlighting an opportunity for improved management. Combined with identified factors associated with moderate-to-severe symptom, this information is important to improve patient-centred and personalized supportive care for NET at the end of life.
Efficacy and safety of trifluridine/tipiracil (FTD/TPI) in patients (pts) with metastatic gastric cancer (mGC) with or without prior gastrectomy: Results from a phase III study (TAGS).
Authors: Ilson David H. , Prokharau Aliaksandr , Arkenau Hendrik-Tobias , Ghidini Michele , Fujitani Kazumasa , Van Cutsem Eric , Thuss-Patience Peter C. , Beretta Giordano D. , Mansoor Wasat , Zhavrid Edvard , Alsina Maria , George Ben , Catenacci Daniel V.T. , Winkler Robert E. , Makris Lukas , Doi Toshihiko , Shitara Kohei 
Published: January 2019

3 Background: The phase 3 study TAGS demonstrated that the novel oral therapy FTD/TPI (TAS-102) represents an effective treatment option with a manageable safety profile for pts with heavily pretreated mGC. In an earlier single-arm Japanese phase 2 trial in mGC, no differences were found in the pharmacokinetics of either FTD or TPI in pts with or without prior gastrectomy. We evaluated the efficacy and safety of FTD/TPI in pts with or without prior gastrectomy within the TAGS study. Methods: In this global phase 3 study of adult pts with mGC who had received ≥ 2 prior regimens of chemotherapy, pts were randomized 2:1 to receive FTD/TPI (35 mg/m2 BID on days 1–5 and 8–12 of each 28-day cycle) or placebo, plus best supportive care. We performed a preplanned analysis of efficacy and safety endpoints in pt subgroups with or without prior gastrectomy. Results: Of 507 randomized pts, 221 (44%) had a prior gastrectomy (FTD/TPI, 147/337; placebo, 74/170). Baseline pt characteristics were balanced across pt subgroups. FTD/TPI prolonged survival versus placebo regardless of gastrectomy (table). The frequency of neutropenia/leukopenia appeared to be higher among FTD/TPI-treated pts with vs without gastrectomy, but this did not result in more treatment discontinuations (table). Conclusions: In the TAGS study, subgroup analysis demonstrated that FTD/TPI is an effective treatment option with a manageable safety profile for pts with heavily pretreated mGC, regardless of prior gastrectomy. Clinical trial information: NCT02500043. [Table: see text]
Feasibility of SM-88 in PC after multiple prior lines and ECOG < 2.
Authors: Noel Marcus Smith , Wang-Gillam Andrea , Ocean Allyson J. , Del Priore Giuseppe , Picozzi Vincent J. 
Published: January 2019

310 Background: Advanced PC patients with ≥ 3Ls of chemo or ECOG PS 2 are generally excluded from clinical trials. SM88 demonstrated no drug related AEs > grade 2 in an interim prostate phase 2 (JCO 2018 36:6S P 175). We sought to determine the feasibility of a trial in this vulnerable population using SM88. Methods: Prospective randomized phase 2 of SM-88 (tyrosine derivative, CYP3a4 inducer, mTOR and oxidative stress catalyst) in patients with locally PD or mPC, ECOG PS < 2 and ≥ 2 weeks from prior therapy. Results: Mean age = 64.9 (range 45.6-84.1); 45.5% female, 93.1% white, 6.9% other; median prior lines = 3 (range 1-6); 12% had prior RT and 17% surgery. Median ECOG PS was 1 with 36.6% 0, 63.3% 1 and 0% ECOG PS 2. From April 2018 to this abstract deadline, 72 patients at 24 sites have consented; 36 patients initiated therapy, 19 failed screening and 17 remained in screening. Time from opening trial to first patient consented = 5.1 wks; median time last regimen to consent = 6.7 wks; from consent to drug administration (C1D1) = 1.7 wks. Subjects traveled up to 2600 miles to enroll at a site with an open slot. Median number of subjects/site = 3 (1-15). Median time on trial is 52 days (1-22 wks). There were 15 unrelated SAEs among 36 randomized subjects; three subjects died after consenting but before receiving study drug (table). Grade 4 and 5 SAEs∗ were more common before receiving drug or unrelated to drug (26/94) than at least possibly drug related (0/17) (Fisher p < 0.05). Efficacy using RECIST, PERCIST and BICR along with CTCs, 19.9, NLR, PROs and other outcomes are being collected with high compliance. Conclusions: This prospective SM88 trial suggests that heavily pretreated PC patients with criteria that includes less than ideal ECOG can participate and gain access to novel therapies. This trial plans to enroll 99 additional subjects in under a year. Although ECOG 2 was allowed none have been consented to date and may reflect investigator bias on enrollment or PS assessment. Investigators can meet the needs of this patient population by considering them for inclusion in future drug development trials. Clinical trial information: NCT03512756. [Table: see text]