bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of tumor growth inhibition activity of a novel multi-TRK inhibitor ABP-1119 on pancreatic tumor xenograft model.
Authors: Zhan Zheng-Yun James , Pan Wanlong , Yan Hua 
Published: May 2020

e16741 Background: Owing to its high mortality and lack of effective treatments, there is therefore an urgent unmet need to develop novel and more effective treatments for pancreatic cancer (PC). ABP-1119 is a novel and potent multi-TRK Inhibitor for several PC-related prime tyrosine kinases (TRKs), such as EGFR, HER2, ALK, and BTK. Pre-clinical studies with ABP-1119, especially study to evaluate its tumor growth inhibition activity on pancreatic tumor xenograft model, are planned. Methods: (1) Mobility-Shift Assay used to Analyze the multi-TRK (such as EGFR, HER2, ALK, and BTK) Inhibition activity of new anti-tumor compounds, (2) CTG Assay used to analyze the inhibition activity of Mia-Paca-2 Cell Line, (3) Anti-tumor inhibition study of ABP-1119 with the pancreatic cancer nude mice, (4) Safety studies of ABP-1119 for Ames, hERG, and maximum tolerated dose (MTD). Results: It was determined that its multi-TRK inhibition activity (IC50) of ABP-1119 was 0.9nM to EGFR, 4.8nM to HER2, 0.9nM to ALK, and 2.1nM to BTK, respectively. Its inhibition activity for Cell Line Mia-Paca-2 was 0.06 µM. In anti-tumor inhibition study with the Mia-Paca-2 tumor nude mice for 14 days, the anti-tumor inhibition rate of ABP-1119 (50 mg/kg, QD) was over 82% (vs Erlotinib as a positive control, 50mg/kg, QD, inhibition rate: 48%), and no any death and other serious side effects were observed during the nude mice tests. Moreover, for other safety issues, its Ames is negative and hERG is > 30 µM, and no test-article related death or adverse events occurred in MTD studies with ABP-1119 (100mg/kg, QD) for 14 days. ABP-1119 also had very good metabolic stability in Human (T1/2 = 2.5hr). Conclusions: Based on our completed preclinical study results, ABP-1119 is a novel and potent multi-TRK Inhibitor, showing excellent enzymatic activity, prominent in-vitro anti-cancer activity, and good tumor growth inhibition activity with tolerable toxicity in pancreatic tumor xenograft in nude mice model. It is warranted to continue further investigation in pancreatic cancer.
Exceptional sustained responses to ipilimumab/nivolumab (ipi/nivo) in patients (pts) with advanced pancreaticobiliary cancers and germline DNA damage repair (DDR) mutations.
Authors: Terrero Gretel , Datta Jashodeep , Pollack Terri , Naveda Alissette , Abushahin Laith I. , Sussman Daniel A. , Pimentel Agustin , Lockhart Albert Craig , Hosein Peter Joel 
Published: May 2020

e16757 Background: Immune checkpoint inhibitors (ICIs) have not shown meaningful clinical activity in unselected pts with pancreaticobiliary cancer. DDR-deficient tumors have increased genomic instability, including increased tumor mutation burden (TMB), more tumor-infiltrating immune cells, and enrichment of a T cell-inflamed signature. We hypothesized that pts with DDR deficiency may be sensitive to ICIs. Methods: Utilizing the IRB-approved database at the University of Miami, we identified pts with advanced pancreaticobiliary cancer with germline DDR mutations who were treated with dual ICI. Results: Eleven pts were identified (3 BRCA1, 4 BRCA2, 1 RAD51C, 1 RAD51D, 1 ATM, and 1 PALB2). There were two complete responses (CR), one partial response (PR), three stable disease (SD), two progressive disease (PD), and three pending evaluation. Evaluable responses are sustained for 22 months (m), 19m, and 7m, respectively. All pts had microsatellite stable tumors and none had high TMB. Among pts with responses, TMB was 4, 8, and 8 mut/Mb, respectively. One pt with a CR had gBRCA1 with pancreatic adenocarcinoma (PDAC) s/p distal pancreatectomy/splenectomy, adjuvant gemcitabine (gem)/capecitabine, biopsy-proven recurrence in lung and retroperitoneum 12m later, initiated ipi/nivo, and achieved a CR ongoing for 22m on nivo maintenance. Second pt with a CR had gBRCA1 and unresectable cholangiocarcinoma (CC), with disease progression after gem/cisplatin (cis), therapy switched to ipi/nivo. After 4 doses, an incidental cerebellar lesion was found which was biopsy-proven CC, therefore taken off treatment. Pt has been in CR for 19m without further therapy. The pt with a PR had RAD51C and metastatic PDAC s/p FOLFIRINOX for 6m, followed by olaparib for 12m. At progression, disease rapidly progressed through 5-fluorouracil/nanoliposomal irinotecan, gem/nab-paclitaxel/cis, and FOLFIRINOX. Pt was initiated on ipi/nivo with immediate improvement in pain and tumor markers; PR ongoing for 7m with continued clinical and tumor marker improvement on nivo maintenance. Additional correlative studies (RNA sequencing, Hyperion Imaging, mutation allele fraction analysis) among responders vs. nonresponders will be reported at the meeting. Conclusions: In this series, 6 out of 8 evaluable pts with advanced pancreaticobiliary cancers had disease control with ipi/nivo. This series suggests that tumors with germline DDR mutations may be responsive to ICIs. Further evaluation is warranted.
A prognostic and predictive nomogram for patients with resected pancreatic cancer and the effect of adjuvant chemotherapy in different risk groups: Data from two large cohorts in Taiwan.
Authors: Wu Hsu , Guo Jhe-Cyuan , Yang Shih-Hung , Chen Jen-Shi , Yeh Ta-Sen 
Published: May 2020

e16762 Background: Wide survival difference of pancreatic cancer in the same TNM stage had been demonstrated. Predictive nomogram for resected pancreatic cancer had been published before, but the impact of adjuvant chemotherapy was not incorporated, and the data of Asian people were lacking. We also evaluated the effect of adjuvant chemotherapy in different risk groups according to our nomogram. Methods: Pancreatic cancer patients who underwent curative surgery between 2000/1 and 2013/12 were collected from the Cancer Registry of NTUH as the training cohort. Another cohort from CGMH was studied as the validation cohort. Analyses were performed by IBM SPSS version 21.0. Age, gender, primary tumor location, tumor differentiation, LVI, PNI, T, N, AJCC 7th stage, section margin, and adjuvant chemotherapy were used for univariate and multivariate analysis. Nomogram was built and validated by software R 3.6.1. C-index was used to demonstrate the performance and discrimination ability of nomogram. Results: There were 319 and 245 patients in NTUH and CGMH cohorts. The R0 resection rates were 80.6 and 71.8%, and 24.5 and 63.7% of patients received adjuvant chemotherapy. Median OS were 16.9 and 15.7 months in NTUH and CGMH. AJCC 7th Stage, tumor differentiation, section margin, tumor location, LVI and receiving adjuvant chemotherapy were incorporated in the nomogram. C-index in NTUH cohort was 0.66 (95% CI: 0.62-0.70), which was higher then C-index of AJCC 7th Stage, 0.58 (95% CI: 0.54-0.61). The C-index in the CGMH was 0.65 (95% CI: 0.60-0.69). We grouped the two cohorts into low, medium, and high risk groups according to the nomogram score. In NTUH, there were 50, 208, and 48 patients in the low, medium, and high risk groups. In CGHM, there were 37, 156, and 45 patients in those groups. The Kaplan-Meier curves of OS separated nicely according to different risk groups (log rank p < 0.001). If excluding adjuvant chemotherapy in nomogram, C-index in NTUH was 0.63 (95% CI: 0.59-0.67) and 0.62 (95% CI: 0.58-0.66) in CGMH by the new nomogram. The relative survival hazard ratios of receiving adjuvant chemotherapy were 0.532, 0.626, and 0.358 in high, medium and low risk groups of NTUH and were 0.624, 0.798, and 0.788 in CGMH. Conclusions: The new nomogram with more clinical factors than TNM stage has better prognostic prediction. We add the impact of adjuvant chemotherapy into our predictive model. Adjuvant chemotherapy is important in resected pancreatic cancer, even in low risk population.
Superior therapy response predictions for patients with pancreatic cancer (PDAC) using Cellworks Singula: MyCare-009-05.
Authors: Moffat Gordon Taylor , Watson Drew , Kapoor Shweta , Ghosh Roy Kunal Ghosh , Parashar Rajan , Alam Aftab , Alam Aktar , Tyagi Anuj , Singh Divya , Kumari Pallavi , Choudhary Nikita Ray , Gupta Neha , Elangovan Preethi , Mandal Rema , P S Vijayashree , Nair Prashant , Husain Zakir , Sahu Diwyanshu , Mundkur Nirjhar , O'Reilly Eileen Mary 
Published: May 2020

e16766 Background: Current therapy for PDAC is modestly effective. Therapy selection guidelines are typically limited to single aberrations and ignore relevant patient-specific omics. These alterations create patient-specific resistance pathways that cancer cells use to resist one-mutation one-drug Physician Choice therapies. Singula™ utilizes the novel Cellworks Omics Biology Model (CBM), which predicts patient-specific biomarker and phenotype response of a personalized diseased cell to drug agents, radiation and cell signaling. We test the hypothesis that Singula is a more accurate predictor of patient-specific therapy response to targeted agents compared to Physician Choice. Methods: The performance of the Singula Classifier of patient therapy response was evaluated in an independent retrospective cohort of N = 52 Stage I - IV PDAC patients aged 35-85, whose omics data were included in TCGA and ICGC. The accuracy of Singula was compared to the accuracy of prescribed therapies and clinical outcomes. Comparisons in the accuracy were enabled using McNemar’s test to account for the correlation between Singula and physician recommendations. Logistic regression was used to model complete response (CR) as a function of age, prescribed therapies, and Singula against non-response (NR). Likelihood ratio tests were performed to assess if Singula provides predictive information beyond prescribed therapy and age alone. Similar analyses were performed for progression-free survival (PFS) and overall survival (OS) using proportional hazards regression. Results: Singula is a superior predictor of CR compared to Physician Choice (McNemar’s χ2 = 26.0, p-value < 0.0001), with an overall accuracy of 94.2% (84.1%, 98.8%) compared to 40.4% (27.0%, 54.9%) for Physician Choice. In regressions, Singula (p = 0.0023) remained a significant predictor of CR, but prescribed therapy (p = 0.3885) and age (p = 0.1148) were nonsignificant. Singula was also the only significant predictor of PFS (p = 0.0002) and OS (p = 0.0096). For all 28 true negatives, alternative therapy selections with predicted response were generated. Conclusions: Singula is a superior predictor of PDAC response to therapy compared to Physician Choice. The Singula report can validate therapy selection decision, potentially increasing median PFS and OS and provides alternative therapy selections for non-responders. Prospective validation is needed. [Table: see text]
Therapeutic effect and safety of individualized chemotherapy combined with sequential immunotherapy based on BRCA1 mRNA expression level in the treatment of unresectable pancreatic cancer.
Authors: Du Juan , Zhu Linxi , Sha Huizi , Zou Zhengyun , Yu Lixia , Shen Jie , Kong Weiwei , Zhao Lianjun , Qiu Yudong , Liu Baorui 
Published: May 2020

e16773 Background: Pancreatic cancer is a kind of digestive tumor with low incidence but high degree of malignancy. It is characterized by difficult in early detection and invasive metastasis. Together with high recurrence and metastasis rate after resection, the prognosis of pancreatic cancer is extremely poor. To explore the role of BRCA1 mRNA expression in the chemotherapy of unresectable pancreatic cancer and the synergistic effect of chemotherapy and immunotherapy, our center has carried out a clinical trial which focuses on individualized chemotherapy combined with sequential immunotherapy according to BRCA1 mRNA expression in the first-line treatment of unresectable pancreatic cancer. Methods: The expression of BRCA1 mRNA in tumor tissues of patients with pancreatic cancer was detected. According to the expression level, gemcitabine combined with nab-paclitaxel-based or gemcitabine combined with oxaliplatin-based biweekly chemotherapy combined with sequential GM-CSF and IL-2 immunotherapy was applied. Patients’ conditions and the efficacy and safety were assessed every 4 cycles. Results: A total of 25 patients were enrolled in the study. All of them were observed for toxic side effects and 24 of them were evaluated for efficacy. The median overall survival and median progression-free survival were 11.9 months and 6.3 months. The disease control rate was 91.7%, of which 37.5% (9/24) patients achieved partial remission (PR), 54.2% (13/24) patients achieved stable disease (SD) and 8.3% (2/24) patients were assessed as progressive disease(PD). Of the 15 patients with medium or high expression in BRCA1 mRNA, 7 achieved PR and 8 achieved SD. Of the 9 patients with low BRCA1 mRNA expression, 2 achieved PR, 5 achieved SD and 2 had PD. The proportion of eosinophils in the blood of some patients with good therapeutic effects was significantly higher than that before treatment. Hematological and non-hematological toxicity during the treatment were mostly grade 1~2. The two most common grade 3~4 adverse events were fever and thrombocytopenia. Conclusions: Our results suggest that individualized selection of chemotherapy combined with sequential immunotherapy according to BRCA1 mRNA expression level in the treatment of unresectable pancreatic cancer have curative effect and controllable adverse reactions. The improvement of treatment efficiency may be related to the activation of non-specific immune response.
A PK/PD mathematical model to forecast severe toxicities in pancreatic cancer patients treated with FOLFIRINOX regimen.
Authors: Deyme Laure , Gilabert Marine , Mineur Laurent , Toullec Clemence , Gasmi Mohamed , Ciccolini Joseph , Barbolosi Dominique , Gattacceca Florence 
Published: May 2020

e16774 Background: FOLFIRINOX regimen is the most efficient treatment in pancreatic adenocarcinoma. However, this triple-therapy causes significant and dose-limiting toxic effects leading to empirical dose-reduction, postponement of the forthcoming courses and sometimes treatment discontinuation. Dose-limiting toxicities with FOLFIRINOX are mostly oxaliplatin-induced peripheral neuropathy (OIPN) and irinotecan-induced diarrhoea (IID). The first aim of our study was to establish dose-concentration-toxicity relationships for these two main ordinal toxicities. Second, we aimed to perform in silico simulations to define the optimal FOLFIRINOX administration protocol (i.e., dosing, scheduling, sequencing) for a maximal benefit to risk ratio. Methods: We performed a retrospective pharmacometric analysis from clinical data collected in three French institutes. Patients had all confirmed diagnosis of PDAC treated with FOLFIRINOX as first line regimen. Demographic characteristics, toxicity data and dosage modifications were collected. Two mathematical models connecting dose – concentration – toxicity (PKPD Tox model) were developed using Monolix2019 to describe both OIPN and IID. Results: Data from 75 patients (36 females/39 males) treated with FOLFIRINOX regimen between 2015-2018 and representing 566 courses were collected. Median age was 65.4 years (range 29-78). The performance status at the start of treatment was 0-1 for 70% of patients. The most frequent location of the tumor was pancreatic head (50%). 91% of patients were subject to empirical dose reduction during their treatment. Oxaliplatin doses were decreased in 258 courses and stopped in 66 courses. Irinotecan doses were decreased in 257 courses and stopped in 33 courses. Overall, 130 IID and 198 OIPN events were observed. From these data, two different PKPD Tox models were developed. The individual concentrations of SN38 (active metabolite of irinotecan) and oxaliplatin were simulated with population PK models, either home-built or taken from the literature. Concentrations were translated into adequate exposure via an interface model developed by our group. Exposure was finally related to a pharmacodynamic model to predict probabilities assigned to each grade of IID or OIPN. Conclusions: These PKPD Tox models help to predict dose-limiting toxicities upon FOLFIRINOX and are useful to select the administration protocol of FOLFIRINOX minimizing the occurrence probabilities of treatment-related neuropathy and diarrhoea, while maintaining efficacy.
Results of venous resections in cancer of the pancreatic head.
Authors: Kit Oleg I. , Katelnitskaya Oksana V. , Maslov Andrey A. , Maksimov Aleksey Yu. , Kolesnikov Evgeniy N. , Gevorkyan Yuriy A. , Trifanov Vladimir S. , Kozhushko Mikhail A , Snezhko Aleksandr V. , Petrov Dmitry S. , Fomenko Yuriy A. 
Published: May 2020

e16785 Background: Studies have shown that pancreaticoduodenal resection (PDR) with resection and reconstruction of the venous segment does not interfere with surgical treatment for ductal pancreatic adenocarcinoma with suspected venous invasion. Venous resection improves survival compared to palliative interventions. However, the advantages and disadvantages of marginal resection, segmental resection with direct anastomosis, and venous segment prosthetics are not reflected. Methods: The study included 52 patients (23 women, 29 men) undergoing PDR with venous resection and reconstruction for cancer of the pancreatic head in 2015-2019. The average tumor size was 3.8 cm. Results: Superior mesenteric vein reconstruction (PTFE grafts) was performed in 17 patients (32.7%), sleeve resection with direct anastomosis - 24 (46.2%), marginal resection - 11 (21.1%). Venous reconstruction was planned in 78.8% of patients before the surgery. In the early postoperative period, thrombosis of the reconstructed zone was developed in two patients (3.8%), bleeding from the pancreatic bed - in one case (1.9%). Postoperative mortality was 5.8% (3 patients). After the final pathological examination, macroscopically incomplete resection was diagnosed only in the group with marginal resection and amounted to 3.8%. Microscopically incomplete resection was diagnosed in 9.6% of the studied preparations (in marginal resection of the vein wall - 3.8%, with direct anastomosis - 1.9%, SMV prosthetics - 3.8%). Most often, R1 resection was detected in the retroperitoneal resection margin (80%). The lowest 1-year survival was observed in the group with marginal resection (36.4%). No significant differences in survival rates were found in patients with direct venous anastomosis (62.5%) and venous prosthetics (64.7%) (RR 1.69; 95% CI 0.69-4.12, p > 0.05). Microscopically complete resection R0 improved the survival (RR 2.7; 95% CI 1.45-5.04, p < 0.05). Planning the venous resection was an additional risk factor affecting the completeness of resection (RR 4.6; CI 95% 1.5-14.5, p > 0.05). Conclusions: Expanding the surgery volume in PDR due to venous resection and reconstruction shows acceptable rates of postoperative morbidity and mortality. Planning the venous resection enhances the results of radical surgery.
Implementing a novel method to estimate the "Burden of Therapy" (BOTh) for patients with metastatic pancreatic cancer treated with gemcitabine plus afatinib vs. gemcitabine in the AIO ACCEPT trial.
Authors: Haas Michael , Abdul-Ahad Ayad , Snijder Robert , Waldschmidt Dirk Thomas , Stahl Michael , Reinacher-Schick Anke C. , Freiberg-Richter Jens , Kaiser Florian , Kanzler Stephan , Frickhofen Norbert , Seufferlein Thomas , Dechow Tobias Nicolaas , Mahlberg Rolf , Malfertheiner Peter , Illerhaus Gerald , Kubicka Stefan , Held Swantje , Boeck Stefan Hubert , von Bergwelt-Baildon Michael , Heinemann Volker 
Published: May 2020

e16786 Background: The phase II ACCEPT trial included 119 patients (pts) with histologically proven pancreatic cancer without any previous systemic treatment for metastatic disease. Pts were randomized in a 2:1 ratio to receive either afatinib 40mg orally once daily + gemcitabine (1000mg/m2 iv weekly for three weeks followed by one week of rest, repeated every four weeks) or gemcitabine alone. The addition of afatinib did not lead to improved efficacy (7.3 vs. 7.4 months, HR 1.06, p = 0.80; data previously shown). The traditional analysis of adverse events was not able to reveal the actual patient´s burden in each of the treatment arms. Methods: BOTh is a highly sensitive, novel methodology utilizing patient-level data to derive a quantitative estimate for the “Burden of Therapy/Toxicity” (BOTh) that all or individual pts experience on each day of a clinical study*. The daily burden estimate is based on number and severity of adverse events (AEs) that occur contemporaneously and consecutively, in a combination of incidence and severity resulting in a major advantage over current methods. A chart displays the total burden experienced by pts on each day throughout the study and statistical analyses are performed with the area under curve. Results: The BOTh analysis revealed that the daily burden of toxicity for pts in the gemcitabine-alone arm was 6.8 compared to 11.5 in the combination treatment arm (p = 0.0005). However, the day to day variation in burden was higher in the gemcitabine-alone arm. The higher burden in the combination arm was already visible at a very early stage of the trial when most pts were still on treatment. Conclusions: Whereas the traditional analysis of AEs only gave a static interpretation, BOTh revealed a more dynamic view on burden of toxicity on pts taking single vs combination medication in a 200 day time frame. BOTh can facilitate better informed treatment selection. *Abdulahad A. et.al, Contemporary Clinical Trials Communications 4 (2016) 186-191. Funding: The ACCEPT trial was funded by an unrestricted financial grant by Boehringer Ingelheim. Clinical trial information: NCT01728818 .