bluuebunny/crossref_metadata_2025_split huggingface dataset:
Measuring liver radioembolization dose with positron emission tomography.
Authors: Avkshtol Vladimir , Veltchev Iavor , Yu Jian Qin , Doss Mohan , Cohen Gary S , Panaro Joseph N , Denlinger Crystal S. , Anaokar Jordan , Handorf Elizabeth A. , Anderson Adam , Williams Graeme , Fourkal Eugene , Meyer Joshua E. 
Published: January 2019

290 Background: There is no established way to measure radiation dose deposition during liver radioembolization to help quantify the shortcomings of prescription calculations, which do not consider size, shape, and location of tumors. We aimed to establish a standardized method of radioembolization dose measurement though a novel technique using Positron Emission Tomography and Computed Tomography (PET-CT). Methods: Patients who were recommended for liver radioembolization treatment were enrolled in a prospective single-arm registry study. Index lesions were contoured on the patients’ CT simulation scans. Immediate post-treatment PET/CTs were used to measure the deposited radiation dose by capturing the positron emission from the Yttrium-90’s daughter nuclei. The CT simulation scans were fused to the post-treatment PET/CT scans using rigid registration around the index lesions. The primary dosimetric outcomes were mean dose and dose to 70% of the tumor volume (D70). The optimal mean dose and D70 were > 100 Gy and > 70 Gy, respectively. Results: From November 2014 to November 2015, fifteen consecutive patients with either hepatocellular carcinoma (n = 4) or liver metastases (n = 11) were enrolled in the study. A total of 43 index lesions were contoured with a mean and median size of 18.2 cc and 5.4 cc, respectively. The average mean dose to the index lesions was 99.9 Gy (mean dose range: 2 – 298 Gy; Table). The mean and median D70 were 66.9 Gy and 71 Gy, respectively (range: 1.4 – 211 Gy; standard deviation [SD]: 40.3 Gy). The mean and median D90s were 43 Gy and 41 Gy, respectively. A total of 20 (46.5%) lesions received optimal mean dose and 23 (53.5%) lesions received optimal D70 dose. Conclusions: We established a successful standardized procedure utilizing PET/CT scans to measure the radiation dose delivered during liver radioembolization. The range of the doses received by the tumors underlines the need to collect dosimetric data for future treatment optimization. Dosimetric parameters. Clinical trial information: NCT02088775. [Table: see text]
Inhibition of diacylglycerol kinase alpha to augment antitumor effector T cells in tumor-bearing host.
Authors: Okada Naoki , Sugiyama Ko , Kitamura Hidemitsu , Taketomi Akinobu 
Published: January 2019

293 Background: Diacylglycerol kinases (DGKs), lipid kinases transforming diacylglycerol to phosphatidic acid, play important roles in intracellular signal transduction. Diacylglycerol kinase alpha (DGKa), an isozyme of DGKs, is well-known to promote proliferation of cancer cells by suppression of the apoptosis. Additionally, a previous report demonstrated that activation of DGKa induced anergy state of T lymphocytes in vivo. In this study, we investigated whether inhibition of DGKa not only suppress the tumorigenesis of cancer cells but also activate anti-tumor immunity. Methods: We first investigated the effect of DGKa inhibitor on in vitro proliferation of murine hepatoma cell lines (Hepa1-6) by cell proliferation assay. Cytokine and Granzyme B productions by CD8+ T cells from OT-1 mice after the OVA antigen stimulation were evaluated by ELISA and flowcytometry, respectively. Next, we established a tumor-bearing mice model by injection of mCherry-transfected Hepa1-6 cells into spleen. Tumorigenesis and tumor-infiltrating T cells in the liver were evaluated by in vivo imaging system, HE staining, and immunohistochemistry. CD8+ T cells were collected from the liver and stimulated with PMA and Ca2+ ionophore and the IFN-g production levels were evaluated by flowcytometry. Results: Proliferation of Hepa1-6 cells were suppressed in the presence of DGKa inhibitor in vitro. IL-2 production levels of OT-1 CD8 T cells in control group was augmented by the addition of DGKa inhibitor (246 vs 579 pg/ml, p < 0.05). Granzyme B-positive cells in OT-1 CD8+ T cells were increased by the treatment with DGKa inhibitor compared to the control group (4.4 vs 8.9 %, P < 0.05) after the antigen stimulation. In vivo administration of DGKa inhibitor significantly suppressed the tumor size (fluorescence (AU) 2.0x1010 vs 6.3x109, area (μm2) 1.5x107 vs 0.9x107, p < 0.05) in the liver of tumor bearing mice. Then, the number of tumor-infiltrating T cells (582 vs 1506, 5 HPF, p < 0.05) and the IFN-g-producing cells (9.2 vs 16.0 %) in CD8+ T cells were elevated by the DGKa treatment. Conclusions: Inhibition of DGKa not only suppressed the proliferation of hepatoma but also activated anti-tumor effector T cells in vivo.
Characterization of the tumor mutation burden in hepatobiliary tumors.
Authors: Thota Ramya , Christensen Bryce , Fulde Gail , Lewis Mark Andrew , Haslem Derrick S. , Rhodes Terence Duane , Nadauld Lincoln , Barker Tyler 
Published: January 2019

295 Background: Hepatobiliary tumors are aggressive tumors with emerging evidence for increasing sensitivity to immune checkpoint inhibitors (ICI). Tumor mutation burden (TMB) was found to be a quantitative biomarker associated with production of neoantigens within the tumor and predict the sensitivity to immune therapy. Herein, we explore the TMB as a potential biomarker of response to immune therapy in hepatobiliary tumors. Methods: We retrospectively assessed all patients with hepatobiliary malignancies who have undergone next generation sequencing (NGS) between January 2013 and September 2018. We then analyzed the tumor mutation burden of these tumors and also identified frequency of patients with no clinically actionable mutations. Results: Of the 65 total patients with hepatobiliary tumors, 49 patients (75%) had at least one clinically actionable mutation while 16 patients (25%) had no clinically actionable mutations. Among 65 patients, 44 patients had hepatocellular carcinoma, 15 patients had cholangiocarcinoma and 6 patients had gallbladder carcinoma. The TMB data is available for 15 patients. The mean TMB reported was 2.7 (1.16 – 4.25), which suggests low mutation burden in general in all our HB tumors. Among the patients with available TMB, the underlying risk factor was noted as hepatitis C in 3, NASH in 1, others in 6, unknown in 5 patients. Conclusions: Our data suggests the TMB in hepatobiliary tumors is low in general irrespective of their underlying risk factors. Future larger studies are needed to evaluate TMB as a potential biomarker in hepatobiliary tumors to help select patients that will benefit from immune therapy.
Novel prognostic biomarkers and their association with survival in pancreatic cancers.
Authors: Kasi Anup , Bajwa Suhaib , Williamson Stephen K. , Sun Weijing , Baranda Joaquina Celebre , Zambrano Obdulia Covarrubias , Kalubowilage Madumali , Bossmann Stefan H 
Published: January 2019

296 Background: Early detection of pancreatic cancer would allow for improved survival outcomes. Methods: We retrospectively evaluated serum protease levels and the survival of 15 pancreatic cancer patient samples (6 localized and 9 metastatic) at the KU Cancer Center. Available serum protease assays measured matrix metalloproteinases (MMPs), urokinase plasminogen activator (uPA), arginase, neutrophil elastase (NE), cathepsin B (CTSB) and cathepsin E (CTSE). The assays utilize fluorescent nanoparticle-based nanobiosensors which increase fluorescence upon posttranslational modification or enzymatic cleavage of targeted compounds and were read by a Spectral scan plate reader. Survival analysis was performed using Kaplan-Meier methods. Results: Baseline characteristics for all 15 patients are in (Table). Median OS was 18.8m in patients with high CTSB expression (mean >51968.9) vs 9.7m in low CTSB expression (p=0.04). Similarly, median OS was 20.4m in high CTSE expression (>123264.8) vs 10m in low CTSE expression (p=0.05). Whereas, median OS was 16.3m in low NE expression (mean <30293.5) vs 9.6m in high NE expression (p=0.06). MMPs, uPA, and Arginase were not associated with survival. Conclusions: Higher CTSB expression is associated with statistically significant improvement in survival. CTSB is a lysosomal protease involved in processing antigens and overexpression could aid in immunologic cancer suppression. CTSB is also involved in the development of desmoplasia which is hypothesized to be a physical barrier to metastasis. CTSE and NE expression did not meet statistically significant association with survival, likely due to sample size. Hence, we identify CTSB as a potential prognostic biomarker in pancreatic cancer. However, these findings need to be validated in a larger study. [Table: see text]
Review of updated gastric cancer disease management data in the Colombian National Administrative Cancer Registry.
Authors: Hsu Robert , Ramirez Paula , Acuña Lizbeth , Lopes Gilberto 
Published: January 2019

30 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 16 disease management indicators in gastric cancer (GC) 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 1,122 municipalities. The 2017 NACR data for GC includes 13 of the 16 updated disease management indicators—time to diagnosis, percentage of patients with gastric cancer in situ, proportion of new cases identified in early stages, proportion of patients with TNM staging, time before treatment, time between neoadjuvant therapy and surgery, time between surgery and adjuvant therapy, proportion of stage 0-III patients receiving surgery with curative intent, proportion with nutrition support, proportion of surgical patients with nutrition support, mortality rate, and incidence. Results: The incidence of GC was 3.6 cases per 100,000 people and mortality was 3.6 cases per 100,000 people. The time to diagnosis was on average 43.7 days. 6.9% of stageable GC cases were in situ. 25.6% of cases were identified in early stages, and 50.7% of cases had TNM staging. The time to initial treatment was 60.3 days. The time between neoadjuvant therapy and surgery was 109.6 days and the time between surgery and adjuvant therapy was 75.5 days. 25.9% of stage 0-III patients received surgery with curative intent. 16.3% of GC patients received nutritional support along with 15.2% of surgical GC patients. Conclusions: Updated NACR data show long wait times for patients needing neoadjuvant or adjuvant therapies suggesting improvement in follow-up management. The low percentage of patients with nutritional support shows the need for supportive services. There should be strategies for earlier diagnosis given the low percentage of patients identified at early stages. Further directions include 2 and 5 year survival data and data on interdisciplinary care.
Line of therapy (LOT) definition impacts second-line (2L) survival duration in a metastatic pancreatic cancer (mPCa) electronic health record database.
Authors: Fish Susan Meredith , Flick E. Dawn , Swern Arlene S. , Jiang Ruiyun , Jirau-Lucca Gilbert , Ondovik Michael S. , Huang Jian Hua , Louis Chrystal Ursula 
Published: January 2019

300 Background: Establishing an accurate LOT definition in real-world data (RWD) oncology studies is critical for measuring the effects of treatments on outcomes, which informs decisions made by clinicians, regulators, and payers. However, measuring LOT in RWD analyses is challenging and varies across disease states. LOT is generally defined by treatment (tx) start and stop dates. When available, the date of disease progression (PD) can be used to enhance the LOT definition. We explored the analytical impact of varying LOT definitions on 2L survival outcomes. Methods: A retrospective analysis of patients (pts) with mPC treated in US community practices was conducted using the Flatiron Health EHR–derived database. Two algorithms were applied to define LOT: tx change or ≥ 60-day gap in tx (LOTtx) and tx change after first PD (LOTpd). The impact on 1L and 2L sample sizes as well as 2L overall survival (OS) and progression-free survival (PFS) were assessed. Results: 251 pts with an mPC diagnosis between 01 March and 31 October 2015, who initiated chemotherapy ≤ 60 days after mPC diagnosis, were analyzed. Applying the LOTtx definition, 121 pts received 1L tx only and 130 received a 2L tx. Using the LOTpd definition, 145 pts received 1L tx only and 105 received a 2L tx (12 pts were excluded due to unclear time of PD relative to tx). Applying these definitions to time-to-event analyses (from start of 2L therapy) revealed longer 2L OS with LOTtx vs LOTpd (n = 130 vs 105; median 2L OS [95% CI], 5.4 [4.1-7.4] versus 4.5 [3.7-7.3] mo) but similar 2L PFS (n = 122 vs 105; median 2L PFS [95% CI], 2.8 [2.3-3.5] versus 2.8 [2.3-3.6] mo). Conclusions: In this analysis, inclusion of PD in the LOT definition impacted 1L and 2L sample sizes and 2L survival results. In aggressive diseases like mPC, a 1-mo difference in OS estimates is clinically meaningful and may influence treatment decisions. The choice of LOT definition should be based on the research question at hand, available data, and the effort to decrease misclassification bias. Additional LOT definitions, with associated strengths and limitations, will also be presented.
Impact of renal function on the efficacy and safety of S-1 with concurrent radiotherapy for locally advanced pancreatic cancer.
Authors: Kobayashi Satoshi , Ueno Makoto , Ogawa Gakuto , Fukutomi Akira , Ikeda Masafumi , Okusaka Takuji , Sato Tosiya , Ito Yoshinori , Kadota Tomohiro , Ioka Tatsuya , Sugimori Kazuya , Sata Naohiro , Nakamori Shoji , Shimizu Kyoko , Mizuno Nobumasa , Ishii Hiroshi , Furuse Junji 
Published: January 2019

301 Background: S-1 is an oral agent consisting of a mixture of tegafur which is a prodrug of 5-fluorouracil (5-FU), 5-chloro-2,4-dihydroxypyrimidine (DHP) and potassium oxonate. Serum concentration of 5-FU increases in case of renal dysfunction due to decrease of DHP excretion into urine. The aim of this study was to evaluate the influence of renal function to the efficacy and safety of S-1 with concurrent radiotherapy (RT) for locally advanced pancreatic cancer (LAPC). Methods: This study was an integrated exploratory analysis of JCOG1106 and LAPC- S1RT, in which pts with LAPC received RT (50.4Gy/28 fr over 5.5 weeks) and concurrent S-1 (40 mg/m2/dose, bid. on the day of irradiation). Eligibility criteria for this study were pts who received both irradiation and S-1 at least once without induction chemotherapy, and who had creatinine clearance (CCr) ≥ 50 ml/min at the time of registration. We assigned pts into high (≥ 80 ml/min) and low (< 80 ml/min) CCr groups. The primary endpoint was the incidence of ≥ Grade 3 adverse reactions (ARs). Secondary endpoints were the incidence of ≥ Grade 2 gastrointestinal ARs (GI-ARs) defined as anorexia, nausea, vomiting, diarrhea and mucositis oral, relative dose intensity of S-1, CA19-9 response, progression-free survival, and overall survival. Results: Fifty and 59 pts were included in this study from JCOG1106 and LAPC-S1RT, respectively. Median age was 65 years old (range: 31–80), and 57 pts were male. Median CCr was 80.4 ml/min. High CCr group included 57 pts and the median was 97.5 ml/min (range 80.0–194.6), and low CCr group included 52 pts and the median was 64.4 ml/min (range 50.0–78.3). Low CCr group tended to have more ≥ Grade 3 ARs and ≥ Grade 2 GI-ARs compared to high CCr group (30.8% vs. 15.8% and 51.9% vs. 36.8%). However, no evident tendencies were observed in other secondary endpoints. Multivariable analysis showed risk ratio of low CCr group for ≥ G3 ARs was 1.493 [95% CI: 0.710–3.145], although risk ratio of females was 2.486 [95% CI: 1.043–5.924]. Conclusions: Our study indicated that renal dysfunction may increase adverse reactions in the treatment of S-1 with concurrent RT for LAPC, and we should pay attention to renal function and consider for dose reduction.
Clinical impact of preoperative biliary drainage on postoperataive complications in pancreaticoduodenectomy.
Authors: Okabe Hirohisa 
Published: January 2019

302 Background: Biliary drainage is sometimes necessary for patients undergoing pancreaticoduodenectomy (PD) because of tumor invasion to the biliary tract. The current study aims to explore the clinical impact of preoperative biliary drainage (PBD) on postoperative complication in PD. Methods: One hundred sixty-six patients who underwent PD from 2012–2017 were enrolled in this study. Clinical impact of PBD on clinical course was examined. Results: There were 66 patients (40%) undergoing PBD. Patients with PBD showed significantly higher infection rate of bile juice collected at surgery (p < 0.0001) and contamination rate of ascites collected from intraperitoneal drain on postoperative day 3 (POD3) (p < 0.0001) than patients without PBD. Severe postoperative complication (Clavien Dindo ≥ IIIB)was associated with contaminated ascites on POD3 (p = 0.031), but not with PBD. Among patients with PBD, fifty-two patients (79%) received preoperative ERBD. Infection of bile juice at surgery was not associated with the procedure of PBD (ERBD, ENBD or PTCD), but correlated with the duration of drainage. Receiver operating characteristic analysis revealed that patients with PBD for more than 28 days occurs contamination of bile juice at surgery. Among patients with both the contaminated bile juice at operation and the contaminated ascites on POD3 (n = 24), both were consistent in 19 patients (79%). Although Enterococcus faecalis was the most species seen in their bile juice, patients with the contamination of other species of Enterobacter (36%) and Streptococcus (2%) showed higher severe postoperative complication rate than others (p = 0.049). Conclusions: PBD was not directly associated with severe postoperative complication, but the duration of drainage for > 28 days was correlated with contamination of the bile juice. Contaminated ascites on POD3 caused by infectious bile juice at surgery was an only factor associated with severe postoperative complications and therefore needs careful management of the drain removal and selection of antibiotics after surgery.
Real-world outcomes among patients (pts) treated with gemcitabine (GEM)-based therapy post-FOLFIRINOX (FFOX) failure in advanced pancreatic cancer (APC).
Authors: Tsang Erica S , Spratlin Jennifer L. , Cheung Winson Y. , Kim Christina , Kong Shiying , Xu Yuan , Gill Sharlene 
Published: January 2019

303 Background: Limited evidence exists for the selection of chemotherapy in APC after first-line (1stL) FFOX. Gemcitabine/nab-paclitaxel (GEMNAB) is publicly funded for second-line (2ndL) use in the provinces of Alberta (AB) and Manitoba (MB), but is not covered in British Columbia (BC). We compared population-based outcomes by region to examine the utility of 2ndL GEMNAB versus GEM alone. Methods: We identified pts treated with 1stL FFOX between 2013-2015 across BC, AB, and MB. Baseline characteristics and treatment regimens were compared between AB/MB and BC. Survival outcomes were assessed by the Kaplan-Meier, and compared with log-rank test. Results: 370 pts treated with 1stL FFOX were identified (145 AB/MB, 225 BC), with a median age of 61y, 42% female, and 68% with metastatic disease (similar in both groups). Receipt of 2ndL therapy was 49% AB/MB vs 44% BC ( p = 0.35), and time from diagnosis to 2ndL therapy measured 7.6 mos AB/MB versus 9.4 mos BC ( p = 0.1). The distribution of 2ndL gemcitabine use was: 72% GEMNAB, 23% GEM in AB/MB versus 27% GEMNAB, 66% GEM in BC ( p < 0.001). Median overall survival (OS) from diagnosis was similar: 12.4 mos in AB/MB versus 10.9 mos in BC ( p = 0.75). On Cox regression analysis, region was not significant. A secondary survival analysis by 2ndL regimen demonstrated a median OS of 18.0 mos with GEMNAB versus 14.3 mos GEM ( p < 0.01). Conclusions: In our population-based comparison of APC pts treated with 1stL FFOX, survival outcomes were comparable regardless of publicly funded access to 2ndL GEMNAB versus GEM. OS by regimen favored 2ndL GEMNAB, but patient selection may be largely responsible for this difference. Randomized trials are needed to demonstrate the benefit of GEMNAB post-FFOX in APC.
A multicenter, open-label, phase I study of nivolumab alone or in combination with gemcitabine plus cisplatin in patients with unresectable or recurrent biliary tract cancer.
Authors: Ikeda Masafumi , Ueno Makoto , Morizane Chigusa , Kobayashi Satoshi , Ohno Izumi , Kondo Shunsuke , Okano Naohiro , Kimura Keisuke , Asada Suguru , Namba Yoshinobu , Okusaka Takuji , Furuse Junji 
Published: January 2019

306 Background: This phase 1 study evaluated the safety and efficacy of the immune checkpoint inhibitor nivolumab (monotherapy or combined with chemotherapy) in Japanese patients with biliary tract cancer (BTC). Methods: In the monotherapy cohort (N = 30), patients with unresectable/recurrent BTC refractory or intolerant to gemcitabine-based treatment regimens received nivolumab monotherapy (240 mg, 2-week intervals). In the combined therapy cohort (N = 30), chemonaïve patients with unresectable/recurrent BTC received nivolumab (240 mg, 2-week intervals) plus cisplatin-gemcitabine chemotherapy. The primary objective was tolerability and safety. Secondary efficacy endpoints included overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) (central assessment). Results: The most frequently reported nivolumab-related adverse events were decreased appetite (5/30, 17%), malaise (4/30, 13%), and pruritus (4/30, 13%) in the monotherapy cohort, and malaise (8/30, 27%) and decreased appetite (7/30, 23%) in the combined therapy cohort. Median duration of follow-up for efficacy (Table) was 5.1 months (mo; monotherapy cohort) and 8.2 mo (combined therapy cohort). In the monotherapy cohort, median OS and median PFS were longer in patients with programmed death-ligand 1 (PD-L1) ≥ 1% (including the patient who responded) than in those with PD-L1 < 1% (Table). In the combined therapy cohort, the ORR was higher, but median OS and median PFS were lower, in patients with PD-L1 ≥ 1% than in those with PD-L1 < 1% (Table). Conclusions: Nivolumab was well tolerated, with a manageable safety profile and signs of clinical activity, in this phase 1 study in patients with unresectable/recurrent BTC. PD-L1 expression status may predict clinical activity of nivolumab in advanced BTC. Clinical trial information: JapicCTI-153098. [Table: see text]