bluuebunny/crossref_metadata_2025 huggingface dataset:
The prognostic role of soluble transforming growth factor-β (sTGFb) and soluble programmed death-ligand 1 (sPDL1) in biliary tract cancer patients treated with binimetinib and capecitabine.
Authors: Kim Jin Won , Lee Kyung-Hun , Kim Ji-Won , Suh Koung Jin , Nam Ah-Rong , Bang Ju-Hee , Bang Yung-Jue , Oh Do-Youn
Published: January 2019

257

Background: Transforming growth factor (TGF) -β signaling is important for tumor growth and metastasis in biliary tract cancer (BTC). TGF-β attenuates tumor response to programmed death-ligand 1 (PD-L1) blockade. This study aimed to evaluate a correlation between soluble TGF-β (s TGF-β) and soluble PD-L1 (sPD-L1) and its prognostic role in BTC. Methods: Study population consisted of 34 patients enrolled in phase Ib clinical trial of binimetinib (MEK inhibitor) with capecitabine in gemcitabine-pretreated BTC (ClinicalTrials.gov: NCT02773459). Blood samples at screening, after first cycle, after second cycle, and at disease progression were prospectively collected. Plasma sTGF-β and sPD-L1 values were measured by using an enzyme-linked immunosorbent assay. Results: In total 34 patients, 25 (73.5%) and 9 patients (26.5%) were second-line and third-line setting, respectively. Median progression-free survival (PFS) and overall survival (OS) were 4.1 and 7.8 months. The mean baseline sTGF-β and sPD-L1 were 18.7 ng/ml and 3.1 ng/ml. There was a positive correlation between sTGF-β and sPD-L1 value (pearson correlation = 0.596, p < 0.001). Mean baseline value was likely to be higher in best response of progressive disease, followed by stable disease and partial response. Similarly, higher baseline sTGF-β showed significantly shorter PFS (3.4 vs 5.1 months (m), p = 0.047) and OS (5.4 vs 9.7 m, p = 0.042). Higher baseline sPD-L1 also had a trend for poor PFS and OS (PFS: 3.0 vs 4.3 m, p = 0.220; OS: 6.4 vs 9.7 m, p = 0.140). Regarding changes from baseline to after first cycle, sTGF-β change of > 3.6 ng/ml demonstrated significantly shorter OS (5.9 vs 10.8 m, p = 0.020), although PFS did not differ according to sTGF-β change (p = 0.210). In contrast, OS did not differ according to sPD-L1 change (p = 0.190). sPD-L1 change > -1.7 ng/ml even had longer PFS (5.1 vs 2.2 m, p = 0.005). Conclusions: In BTC patients with binimetinib and capecitabine, there is a positive correlation between sTGF-β and sPD-L1 value and higher baseline sTGF-β and sPD-L1 indicate a worse prognosis. The early change of sTGF-β and sPD-L1 during treatment could predict the survival.
Gastrin vaccine and immune checkpoint antibody therapy for pancreatic cancer.
Authors: Smith Jill P , Osborne Nicholas , Sundseth Rebecca , Burks Julian , Cao Hong , Liu Xunxian H , Kroemer Alexander H , Sutton Lynda Youngpeter , Cato Allen
Published: January 2019

259

Background: Pancreatic cancer is poorly responsive to therapy due to fibrosis in the tumor microenvironment and nonspecificity of treatments. The peptide gastrin stimulates growth of pancreatic cancer in an autocrine fashion. Polyclonal Antibody Stimulator (PAS) is a gastrin vaccine that in clinical trials prolongs survival of patients who develop neutralizing gastrin antibodies. We hypothesized that PAS also elicits a memory and T-cell response that would improve effectiveness of immune checkpoint antibodies. Methods: C57BL/6 mice were injected sc with syngeneic mT3 murine pancreatic cancer cells. After 1 week (tumors evident), groups were treated with PBS (control); PAS (100 μg or 250 μg); PD-1 antibody (150 μg); or combined therapy with PAS100/PD-1. PAS was given ip at weeks 0, 1 and 3. Anti-PD-1 was given on days 0, 4, 8, 15 and 21. On day 31 spleens were collected for T-cell surface analysis and cytokine activation by flow cytometry. Tumors were stained for fibrosis and with immunohistochemical stains for CD8+ and FoxP3+ tumor infiltrating lymphocytes (TILs). Results: PAS resulted in T-cell activation; however, the portion of terminally differentiated effector memory double negative T-cells (CD4- CD8-) in CD3+cells from mice treated with the combination PAS100/PD-1 was two-fold higher than those portions from mice treated with PBS, PD-1 or PAS100. Lymphocytes from PAS-treated mice elicited cytokine release (Interferon-γ, granzyme, perforin, and TNF-α) upon re-stimulation with gastrin in vitro, whereas PAS100/PD-1-treated mice show the highest endogenous cytokines levels. PAS250 monotherapy decreased tumor growth. Neither PAS100 nor anti-PD-1 monotherapy decreased tumor size, but combination PAS100/PD-1 antibody tumors were smaller, had less fibrosis, fewer T-regulatory lymphocytes, and increased CD8+ TILs. Conclusions: In addition to eliciting a B-cell response, PAS activates T-lymphocytes rendering tumors susceptible to immune checkpoint antibody treatment. Smaller tumors with combined therapy may be due to the anti-fibrotic effect of PAS on the tumor microenvironment and changes in CD8+ TILs. This study supports that PAS is an important immunotherapy that elicits both B- and T-cell anti-cancer responses.
T-cell–inflamed gene expression profile (GEP) and PD-L1 expression in patients (pts) with esophageal cancer (EC).
Authors: Steiniche Torben , Rha Sun Young , Chung Hyun Cheol , Georgsen Jeanette Bæhr , Ladekarl Morten , Nordsmark Marianne , Jespersen Marie Louise , Kim Hyo Song , Kim Hyunki , Fein Carly , Wu Ting , Savage Mary J. , Marton Matthew John , Kang S. Peter , Peter Senaka A. , Kelsen David Paul , Ku Geoffrey Yuyat
Published: January 2019

26

Background: GEP and PD-L1 expression have been associated with anti–PD-1/PD-L1 therapy. In this retrospective observational study we explored the prognostic value of GEP and PD-L1 expression in pts with EC receiving standard-of-care therapy (SOC). Methods: Tumor tissue samples collected from 2005 to 2017 were procured from Yonsei Cancer Center (South Korea), Memorial Sloan Kettering Cancer Center (USA) and Aarhus University Hospital (Denmark). GEP score was derived from an 18-gene signature using extracted tumor RNA analyzed by NanoString nCounter; GEP high/intermediate (GEP-H/I) and low were defined by a cutoff of –1.540, consistent with pembrolizumab clinical trials. PD-L1 expression was assessed by PD-L1 IHC 22C3 pharmDx assay (Agilent); positive was defined as combined positive score (CPS) ≥ 10, where CPS is the the number of PD-L1–positive cells (tumor cells, lymphocytes and macrophages) divided by the total number of viable tumor cells, multiplied by 100. Associations of GEP score and PD-L1 expression with clinicopathologic variables were analyzed by chi-square test and multiple logistic regression models. Overall survival (OS) from diagnosis date to death date/last follow-up was analyzed using Cox proportional hazards models adjusting for age, sex, stage, region and ECOG performance status (PS). Results: 294 samples with both PD-L1 and GEP data were analyzed. Median age was 65 y (range 33-88); 85% were from men, 58% were stage IV, 63% were esophageal adenocarcinoma (EAC) and 37% were esophageal squamous cell carcinoma (ESCC). Overall 36% of tumors were GEP-H/I: 46% in EAC vs 18% in ESCC. GEP was not associated with OS overall (adjusted hazard ratio [aHR] –0.90; 95% CI 0.68-1.18) or in pts with EAC (aHR 0.93; 95% CI 0.68-1.27) or ESCC (aHR 0.76; 95% CI 0.40-1.44). 21% of tumors were PD-L1-CPS ≥ 10: 18% in EAC and 26% in ESCC. PD-L1 expression was associated with ECOG PS (adjusted odds ratio 0.520; 95% CI 0.309-0.875; P = 0.014) but was not associated with OS overall (aHR 0.89; 95% CI 0.64-1.24) or in pts with EAC (aHR 0.97; 95% CI 0.63-1.49) or ESCC (aHR 1.31; 95% CI 0.73-2.34). Conclusions: Our results suggest that T-cell–inflamed GEP and PD-L1 expression may not be prognostic in pts with EC who received SOC.
Burden of carcinoid heart disease in patients initiating treatment for carcinoid syndrome.
Authors: Joish Vijay N , Perez-Olle Raul , Lapuerta Pablo , Dharba Sam , Zacks Jerome
Published: January 2019

262

Background: Carcinoid heart disease (CaHD) develops as a complication of uncontrolled carcinoid syndrome (CS) due to overproduction of serotonin. Delayed diagnosis or control of CS may result in a greater prevalence of cardiac involvement. The objective of this study was to determine the burden of CaHD in patients initiating somatostatin analogs (SSA) for CS. Methods: This retrospective study investigated claims for commercially insured adults receiving SSA for CS between 2010 and 2016. Claims were evaluated for markers of CaHD such as tricuspid or pulmonary valve-related disease. Eligible patients had ≥ 1 medical claim for CS, had initiated SSA treatment, were continuously enrolled in their health plan for 30 days prior to SSA initiation and for ≥ 1 year, had no sign of acromegaly, and did not participate in a clinical trial during the study period. Patients were followed as long as they were observed in the dataset. Descriptive statistics examined demographic and treatment characteristics and costs for patients with (cases) and without (controls) a marker for CaHD during the study period. Results: A total of 654 patients with CS met the study criteria, of which 38% (n = 248) already had ≥ 1 marker for CaHD prior to initiating SSA treatment. At least 1 CaHD marker was identified in 46% (n = 185) of patients (cases) during the follow-up period. Except for age, all demographic characteristics were similar between cases and controls (n = 221). Cases were significantly older than controls (mean 67 vs. 64 years, p = 0.004). Average follow-up was 26 months (SD 22.0) for cases and 35 months (SD 24.8) for controls. Average time to observation of first CaHD marker for cases was 16 months (SD 16.7) after SSA initiation; most (84%) had ≥ 2 CaHD markers. Markers of right heart involvement were present in 20% of cases, and aortic or mitral valve involvement in 15% and 24%, respectively. Annual per patient expenditures were significantly higher for cases versus controls (mean [SD]: $51,825 [$70,423] vs $29,068 [$56,454], respectively). Conclusions: This study revealed that CaHD is common among patients with CS both before and after initiating SSA treatment. Early diagnosis and control of CS is necessary to reduce the burden of CaHD.
Randomized phase II trial of the carboxylesterase (CES)-converted novel drug EDO-S7.1 in patients (pts) with advanced biliary tract cancers (BTC).
Authors: Pape Ulrich-Frank , Kasper Stefan , Meiler Johannes , Sinn Marianne , Vogel Arndt , Mueller Lothar , Burkhard Oswald , Caca Karel , Heeg Steffen , Laval Victor Rodriguez , Kühl Anya A , Arsenic Ruza , Jansen Holger , Utku Nalan
Published: January 2019

264

Background: The novel drug EDO-S7.1 (CAP7.1) is converted to active etoposide by CES allowing administration of higher doses, reducing resistance, and permitting treatment of advanced tumors. Methods: The primary objective was to compare disease control rate (DCR) in 22 pts with unresectable BTC randomized 1:1 to 3-week cycles of EDO-S7.1 (200 or 150mg/m2; iv) given on days (d) 1–5, or best supportive care (BSC) until progression (assessed every 4 weeks). Secondary objectives were progression-free survival (PFS), time to treatment failure (TTF), overall survival (OS) and safety. BSC pts could crossover to EDO-S7.1 upon progression. Results: DCR favored EDO-S7.1 (55.6% [CI 21.2, 86.3] vs BSC (20.0% [2.5, 55.6]; treatment difference –12.80, 72.39). More EDO-S7.1 treated pts achieved sustainable stable disease (SD) or partial response (PR) vs BSC. Progressive disease occurred in 40% EDO-S7.1 vs 70% BSC pts. Three pts (30%) who progressed on BSC achieved SD following crossover to EDO-S7.1, and one pt (10%) PR (total: 40.0% [12.2, 73.8]) vs two pts with SD following BSC (20.0% [2.5, 55.6]; treatment difference –0.17, 0.57; p=0.0786). Median PFS was 103d with EDO-S7.1 vs 39d with BSC (p=0.006), and median TTF 92d vs 39d, respectively (p=0.006). Median OS was 227d with EDO-S7.1 vs 162d with BSC (p=0.088), and estimated 1-year OS 44% vs 11.3%, respectively. EDO-S7.1 had significant efficacy in pts with metastatic disease (p=0.029) or without prior surgery (p=0.032). Seven pts were eligible for exploratory analysis of tumor CES via immunohistochemistry. 4/7 pts had CES+ tumors and longer median PFS (195d [163, 233]) and OS (302d [214, 838]) vs pts with CES– tumors (46d [46, 83] and 83d [43, 319], respectively). The most common drug-related adverse events (G3–4) (%) were leukopenia 65 (26.1), neutropenia 78.3 (56.5), thrombocytopenia 56.5 (17.4), anemia 52.2 (17.4), alopecia 34.4 (0), fatigue 26.1 (0), and abdominal pain 30.4 (0). Conclusions: EDO-S7.1 demonstrated efficacy in pts with advanced BTC and may provide a new biomarker-guided therapeutic option with stratification by intra-tumor CES assessment. These findings will be explored in a larger patient cohort. Clinical trial information: NCT02094560.
Deleterious alterations in DNA-damage repair (daDDR) genes as a predictive biomarker for platinum-based chemotherapy in metastatic pancreatic ductal adenocarcinoma (mPDAC).
Authors: Palacio Sofia , Stowe McMurry Hannah , Ali Robert , Donenberg Talia , Silva-Smith Rachel , Wideroff Gina , Sussman Daniel A. , Rocha Lima Caio Max Sao Pedro , Hosein Peter Joel
Published: January 2019

266

Background: Germline genetic testing and somatic genomic profiling using commercial multigene panels are now routine in mPDAC. A subset of these patients have deleterious alterations in genes involved with DDR. Herein we investigate the role of daDDR as a predictive biomarker for response to first-line platinum-based chemotherapy. Methods: Utilizing the IRB-approved pancreas cancer and genetics clinic databases at the University of Miami, we identified all patients with mPDAC who had germline and/or somatic mutation testing. We performed a retrospective chart review to extract demographic and clinical characteristics including treatments received, response and survival. Results: Between 2012 and 2018, 116 patients with mPDAC underwent germline (using Invitae, Ambry Counsyl or Myriad) and/or somatic testing (using FoundationOne CDx). Among these, 40 received first-line therapy with FOLFIRINOX (95%) or gemcitabine/cisplatin (5%). The median age was 59 years and 15 (38%) were female. The majority (70%) were Hispanic and 63% had de-novo mPDAC (treatment-naïve). Germline testing revealed daDDR in 5 patients and somatic NGS found an additional 4 patients with daDDR (total of 9 (23%), including 5 with BRCA2, one each with BRCA1, RAD51C, ATM and MUTYH). The median progression-free survival (PFS) was significantly longer in patients with daDDR than without (17.3 vs 7.8 months, log-rank p = 0.01). The median overall survival (OS) was not statistically different between the two groups. Three patients with daDDR had complete or near-complete radiological and tumor marker responses to FOLFIRINOX and were treated with olaparib (a PARP inhibitor) as maintenance and remain progression-free after 7, 12.4 and 13.6 months respectively. Conclusions: daDDR appears to define a subset of patients with mPDAC who may be more sensitive to platinum agents. There are currently no biomarkers for selection of first-line therapy in patients with mPDAC and we demonstrate that this composite biomarker which is easily done via commercially available assays may be able to inform treatment selection.
Mutational landscape by targeted next-generation sequencing in EBV-associated lymphoepithelioma-like cholangiocarcinoma.
Authors: Chiang Nai-Jung , Chen Ming-Huang , Chen Li-Tzong , Yanshen Shan
Published: January 2019

269

Background: Lymphoepithelioma-like cholangiocarcinoma (LELCC) is a rare variant of intrahepatic cholangiocarcinoma, which is highly associated with EBV infection and abundant lymphoplasmacytic cell infiltration. However, there’s limited data of genetic background in LELCC. Therefore, we want to explore the mutation profiles of LELCC, as well as copy number variations. Methods: Five patients’ tumor tissues diagnosed as LELCC, with positive EBER expression were retrospectively collected and microscopically dissected. Of them, two patients’ peripheral blood mononuclear cell served as background of germline mutations. Targeted next-generation sequencing was performed using the ACTOnco Comprehensive Cancer Panel (Ion AmpliSeq Comprehensive Cancer Panel, Life Technologies) to target all coding exons of 409 cancer-related genes for analysis of tumor tissue and blood. PDL1 immunohistochemistry staining with 22C3 antibody pharmDx was applied. Results: All EBV-associated LELCC showed positive expression of PDL1 staining, with combined positive score from 5% to 30%. Both somatic and germline mutations can be detected in LELCC tissue because diffuse infiltration of lymphocytes over tumor. After adjusting for background germline mutation frequency from peripheral blood, only mutations with allele frequency less than or around 10% were considered as somatic mutations. Overall, 10 nonsynonymous somatic mutations were detected in 4 (80%) patients with a range of 1-5 mutations per sample. Mutations were identified including BARD1, EPHA5, MUC16, TNFAIP3, CD19, PTEN, TET1, RECQL4, CD79B, and KDM5A. Copy number changes were rare in this special population. Interesting, one patient who failed to gemcitabine plus cisplatin got partial response after anti-PD1 inhibitor treatment. Conclusions: LELCC is highly correlated with PDL1 expression in tumor and immune cells. It’s necessary to have both tumor tissue and peripheral blood for next-generation sequencing to identify truly somatic mutations in LELCC.
Prognosis of gastric dysplasia after complete resection with endoscopic procedures.
Authors: Park Junseok , Lee Joon Seong , Kim Jin-Oh , Jeon Seong Ran , Kim Hyun Gun , Lee Tae Hee , Cho Jun-Hyung
Published: January 2019

27

Background: Gastric adenomas are considered premalignant, and some can be interpreted as cancer according to different pathologic guidelines. The dysplastic lesions share histologic characteristics including mucin phenotype that are related prognosis. The prognosis of the lesions has been studied but tends to be researched separately. Moreover, the proposed prognostic factors are mostly derived from the study of surgical specimens, and most of them did not consider the anatomical changes after surgery. Previously researched prognostic factors of gastric dysplasia were evaluated on the recurrence after complete resection with endoscopic procedure. Methods: From 2005 to 2016, 1678 gastric dysplasia were endoscopically removed in Soonchunhyang university hospital, Seoul. They were followed up with endoscopy under a standardized protocol. For the 716 lesions were histologically evaluated including mucin phenotype with immunohistochemical stain of MUC5AC, MUC6, MUC2, and CD10. Recurrence of dysplastic lesions were analyzed for the 688 lesions with at least 1 year’s follow-up. Results: Five-hundred and forty-three malignant lesions including in situ lesions were completely resected with endoscopic procedures. Endoscopic submucosal dissection was performed on 603 lesions and other lesions were removed with endoscopic mucosal resection. Submucosal invasion was on 83 lesions of carcinoma. The mucin phenotype of lesions was immunohistochemically evaluated. During median 40 months of follow-up, there was 89 cases of recurrence (12.9%). Kaplan-Meier analysis of the recurrence-free survival were estimated and the elderly over 65 years of age showed statistical significance (p = 0.039). Conclusions: Completely resected early stage of gastric dysplasia showed relatively low recurrence rate. Previously proposed histologic features did not affect prognosis. However, the age of patient showed statistical significance on recurrence-free survival. Regular surveillance on elderly patients is important to improve the clinical outcome of gastric dysplasia.
A pilot study of galunisertib (LY2157299 monohydrate) plus stereotactic body radiotherapy (SBRT) in advanced hepatocellular carcinoma (HCC).
Authors: Reiss Kim Anna , Ben-Josef Edgar , Damjanov Nevena , Hoteit Maarouf , Karasic Thomas Benjamin , Carpenter Erica , DiCicco Lisa , Garcia-Marcano Luis Anna , Mick Rosemarie , Vonderheide Robert H
Published: January 2019

270

Background: TGF-β, the strongest known immunosuppressive cytokine, modulates the hepatic immune response to various antigens and to ionizing radiation. When activated, TGF-β blocks the effector T-cell response to cellular destruction and the release of tumor-specific antigens. Preclinical data demonstrate that neutralizing TGF-β during radiation effectively generates a CD8+ T-cell response to multiple endogenous tumor antigens, thereby generating an in-situ vaccine against a tumor. We hypothesized that the combination of TGF-β receptor inhibition plus SBRT would produce a potent and clinically effective antitumor immune response against HCC. Methods: Patients received galunisertib (LY2157299 monohydrate) on days 1-14 of each 28 day cycle. SBRT was delivered in a single fraction of 18 Gy between days 15-28 of C1. Pre-treatment and on-treatment biopsies were obtained, as well as serial blood collections for CTCs, ctDNA and PBMCs. Results: 15 patients with advanced HCC and Child’s Pugh A cirrhosis were treated. 9/15 (60%) had a prior history of infectious hepatitis, three of whom had active viremia at time of enrollment. 6/15 (40%) had received prior systemic therapy for HCC and 12/15 (80%) had received prior liver directed therapy. The most common treatment-related toxicities were: fatigue (53%), nausea (47%), increased alkaline phosphatase (33%), abdominal pain (33%), vomiting (20%), decreased white blood cell count (20%). All drug-related toxicities were grade 1 or 2, with the exception of one patient who had grade 3 achalasia, thought possibly to be related to study drug. Median PFS was 3.68mo. There were two confirmed partial responses (PRs) and six additional patients had stable disease (SD) for at least four months, resulting in a disease control rate (DCR) of 53%. Both PRs included shrinkage of lesions that had not been radiated. Translational studies are currently underway. Conclusions: The combination of galunisertib with SBRT in patients with advanced HCC is a well-tolerated regimen. In this small pilot study, we observe a DCR of 53% including two PRs. These results warrant further study of this therapeutic combination in advanced HCC. Clinical trial information: NCT02906397.
The feasibility of hepatectomy for the super-elderly patients with HCC.
Authors: Ohta Shogo , Iwahashi Shuichi , Morine Yuji , Imura Satoru , Ikemoto Tetsuya , Saito Yu , Yamada Shinichiro , Shimada Mitsuo
Published: January 2019

274

Background: We previously reported the feasibility of hepatectomy for HCC patients who were above 80 years old (Yamada S, Shimada M, et al. Hepatology Res. 2012). However, there was the manuscript that it was important to assess the preoperative co-morbidity on hepatectomy in elderly patients. The aim of this study is to investigate the feasibility of hepatectomy in super-elderly patients over 85 years old focused on the postoperative complications. Methods: Two hundred twenty-nine patients with HCC who underwent primary hepatectomy from April 2004 to October 2016 were enrolled in this study. Patients were divided into three groups; above 85 years old (super-elderly, n=6), between 75 and 85 years old (elderly, n=54) and below 75 years old (non-elderly, n=169). All of patients in this study did not underwent neither preoperative treatment nor additional splenectomy. Clinicopathological data and outcomes after hepatectomy were compared between three groups. Results: There were no significant differences between the super-elderly group and other two groups in the patients’ backgrounds and tumor factors. Regarding as the rate of total postoperative complications, there was no difference between three groups However, in super-elderly group, the mortality was higher compared with other two groups (super-elderly 16.7%, elderly 0%, non-elderly 1.2%: p<0.01 One-way ANOVA, Turkey’s test). There was the one patient of liver failure in the super-elderly group, and he died due to the liver and respiratory failure. In long-term outcomes, there was no significant difference between the super-elderly group and other two groups. Conclusions: The long-term outcome of super-elderly patients was similar to that of non super-elderly, however, the careful attention to the liver failure might be paid on super-elderly hepatectomy patients. Therefore, hepatectomy might be justified for selected super-elderly patients.
Frequency and feasibility of detecting FGFR mRNA expression in archival samples of patients with cholangiocarcinoma (CCA).
Authors: Chougule Abhijit , Lennerz Jochen K , Zhu Andrew X. , Bardeesy Nabeel , Ting David Tsai , Deshpande Vikram , Goyal Lipika
Published: January 2019

281

Background: Fibroblast growth factor receptor (FGFR) inhibitors show promising activity in patients with intrahepatic CCA harboring FGFR2 fusions, but these alterations have a modest frequency of 15-20%. FGFR mRNA expression has shown preliminary potential as a predictive biomarker for FGFR inhibition in advanced urothelial cancer and is currently being used for patient selection in clinical trials. To assess if we can increase the number of patients with CCA eligible for FGFR inhibitor trials, we evaluated the frequency and feasibility of detecting FGFR mRNA overexpression in archival CCA tissue. Methods: Patients with intrahepatic and extrahepatic CCA who received treatment at the MGH between 1/2004 and 12/2013 were included. Tissue microarrays of archival specimens were stained using the FGFR1-3 pooled, FGFR1, and FGFR2 RNA in situ hybridization probes (RNAscope 2.5 assay). Clinicopathologic data were obtained from the medical record. CCA cell lines were assessed for sensitivity to the FGFR selective inhibitor BGJ398 and also for FGFR expression by qPCR. Results: 90/111 (81%) TMA specimens were evaluable: median age 62.6 years, female 63%, median tumor size 5.1cm, intrahepatic/extrahepatic 71%/29%%. Among the 90 samples, 14% samples stained negative for the pooled FGFR1-3 probe, and 23%, 32%, and 30% stained 1+, 2+, and 3+ positive, respectively. Of note, majority of the samples stained 3+ for FGFR2. Examination of 11 ICC cell lines lacking FGFR gene abnormalities revealed that the single line with marked overexpression of FGFR1 exhibited hypersensitivity to BGJ398. Conclusions: Selection of patients with CCA for treatment with FGFR inhibitors based on mRNA expression levels is feasible on archival tissue with the FGFR RNA ISH probes, and this technique may identify a subpopulation of patients without FGFR genetic abnormalities who may benefit from FGFR inhibitors. [Table: see text]
Sequential gemcitabine (G), oxaliplatin (O), and irinotecan (I) based weekly metronomic chemotherapy (MC) regimens for the treatment of metastatic pancreatic cancer (mPC): A community cancer clinic experience.
Authors: Chue Ben M. , La Course Bryce D.
Published: January 2019

284

Background: mPC has a poor prognosis with a median overall survival (mOS) ranging from 8.5 to 11.1 months (mo) with standard treatment, outlining the need for new innovative treatments. MC regimens utilize lower doses of chemotherapy that are administered more frequently which can maintain dose intensity while reducing toxicity. MC with paclitaxel (P) or nab-paclitaxel (N) may have effects on the tumor microenvironment. Methods: A retrospective analysis of treatment regimens and survival of patients (pts) with biopsy proven mPC who received treatment between August 2004 and August 2018 was performed. Results: 30 pts with biopsy proven mPC were identified. 14 pts received prior chemotherapy. mOS of this cohort was 18.9 mo after diagnosis and 14.2 mo after beginning MC. 70% of pts (21/30) survived longer than 12 mo, 37% (11/30) greater than 24 mo, and 27% (8/30) greater than 30 mo. All MC regimens were given on a weekly basis and included: P 60 mg/m² and G 600 mg/m² (PaG); P 60 mg/m², O 50 mg/m², folinic acid (L) 20 mg/m², and 5-fluorouracil (F) 425 mg/m² (POLF); P 60 mg/m², I 100 mg/m², and cisplatin (C) 20 mg/m² (PIC) or P 60 mg/m², I 100 mg/m², L 20 mg/m², and F 425 mg/m² (PILF). 21 pts received N instead of P at some point during their treatment. PaG, POLF, and PIC or PILF were purposely switched before disease progression after a median length of 13, 11 and 13 weeks respectively. 16 pts received PaG as their first regimen. 12 of these 16 pts then received POLF as their second regimen, and 7 of these 12 pts subsequently received PIC or PILF as their third regimen. These 7 pts had a mOS of 21.7 mo after diagnosis and 19.1 mo after beginning MC. 10 pts were successfully able to receive PaG, POLF, or PIC/PILF more than once. Conclusions: Weekly MC regimens such as PaG, POLF, and PIC/PILF that are given sequentially are an effective treatment for mPC. Switching regimens may prevent the development of chemotherapy resistance, allowing for chemotherapy regimens to be used again in the future. There are limitations of retrospective studies so further investigation of this treatment strategy should be done with a large randomized clinical trial.
Landscape of circulating tumor DNA profiling of advanced pancreatic cancer (PDAC).
Authors: Mody Kabir , Kasi Pashtoon Murtaza , Surapaneni Phani Keerthi , Borad Mitesh J. , Ahn Daniel H. , Mahipal Amit , Starr Jason Scott , Ritter Ashton , McMillan Jessica , Wylie Natasha , Roberts Ali , Nagy Rebecca J , Bekaii-Saab Tanios S.
Published: January 2019

289

Background: PDAC has limited treatment options. Genomic analyses have led to development of targeted therapies now in several clinical trials, and may enable the discovery of new treatment options. However, biopsy often yields limited tissue, thus hampering tissue-based profiling opportunities. Data regarding circulating tumor DNA (ctDNA) profiling in PDAC during real time clinical practice is limited. Methods: We performed ctDNA NGS analysis in pts with advanced PDAC (December 2014–August 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. The mutant allele fraction (MAF) for detected alterations was calculated relative to wild type in ctDNA. Therapeutic relevance (TR) was defined as possible treatments within OncoKB levels 1-3B and R1. The study was conducted in accordance with Mayo Clinic Institutional Review Board requirements. Results: Among 171 pts and 206 total samples, ctDNA NGS revealed at least one genomic alteration in 150 pts (88%). Median number of alterations per patient was 3 [range, 1-15]. The total number of unique alterations was 450 with the most commonly altered genes being: TP53 (181 alterations, 40%), followed by KRAS (118 alterations, 26%), CDKN2A (23 alterations, 5%), SMAD4 (15 alterations, 3%), EGFR (11 alterations, 2.4%), PIK3CA (9 alterations, 2%), GNAS (8 alterations, 1.5%). Amplifications were noted in 16 genes, including BRAF, CCND2, CCNE1, CDK4, CDK6, EGFR, ERBB2, FGFR1, FGFR2, KIT, KRAS, MET, MYC, PDGFRA, PIK3CA and RAF1. Therapeutically relevant alterations were seen in 95 pts of the 150 pts (63%). Tissue based profiling (Results to be shown) was done in 56 (33%) pts of total 171 pts with a median of 130 days between ctDNA and tissue biopsy. KRAS and TP53 were the most common gene mutations found in patients with both liquid and tissue biopsy results. Conclusions: ctDNA plasma profiling of pts with advanced PDAC is a feasible alternative method to gather comprehensive genomic data.
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.