bluuebunny/crossref_metadata_2025_split huggingface dataset:
PD-L1 expression as a prognostic marker in patients with advanced biliary tract cancer.
Authors: Kim Hyera , Hong Jung Yong , Lee Jeeyun , Park Se Hoon , Park Joon Oh , Park Young Suk , Lim Ho Yeong , Kang Won Ki , Kim Seung Tae 
Published: May 2020

e16679 Background: Biliary tract cancer (BTC) is associated with poor prognosis because of its aggressive and heterogeneous nature. Programmed death ligand 1 (PD-L1) has been considered as a novel biomarker for prognosis and response of immune checkpoint inhibitors in various tumors. However, there are limited data reporting on the role of PD-L1 in advanced BTC patients. Methods: We analyzed 186 patients with advanced BTC who received palliative gemcitabine and platinum between May 2010 and December 2019. All patients were evaluated for PD-L1 expression by combined positive score (CPS) positivity. Results: In all 186 patients, the median age was 62 years (range 38-82), and the primary tumor location was intrahepatic cholangiocarcinoma (IH-CCC) in 72 patients (38.7%), extrahepatic (EH)-CCC in 90 (48.4%), and gallbladder (GB) cancer in 24 (12.9%). There were 158 (84.9%) patients with recurrent disease and 28 (15.1%) with metastatic disease. Among the 186 patients, 53 (28.5%) had PD-L1 CPS positivity, and 133 were CPS negative. The median overall survival (OS) of patients with PD-L1 CPS positivity or negativity was 12.1 and 15.4 months, respectively. The median progression-free survival (PFS) in patients with PD-L1 positivity or negativity was 5.7 and 7.1 months, respectively. The OS and PFS were not statistically different between groups. In sub-group analysis, EH-CCC patients with PD-L1 negativity had more favorable OS (17.2 vs. 11.6 months, p= 0.002) and PFS (7.8 vs. 5.4 months, p= 0.005) than those that were PD-L1 negative. However, this finding was not reproduced in patients with IH-CCC or GB cancer. Univariate analysis of the association between PD-L1 expression and OS in patients with advanced BTC indicated that PD-L1 CPS positivity has a prognostic role in sub-populations older than 60 years (HR 1.743, CI 1.001-3.034, p = 0.050), those with EH-CCC (HR 2.449, CI 1.355-4.426, p = 0.003), and those with liver metastasis (HR 2.511, CI 1.362-4.626, p = 0.003). Conclusions: This study demonstrated that PD-L1 expression might be a novel prognostic biomarker in patients with EH-CCC but not for patients with IH-CCC or GB cancer.
Sequential treatment with sorafenib (SOR) followed by regorafenib (REG) in patients (pts) with unresectable hepatocellular carcinoma (HCC): Interim analysis of the observational REFINE study.
Authors: Merle Philippe , Lim Ho Yeong , Finn Richard S. , Ikeda Masafumi , Kudo Masatoshi , Frenette Catherine T , Masi Gianluca , Kim Yoon Jun , Gerolami René , Kurosaki Masayuki , Numata Kazushi , Klümpen Heinz-Josef , Zebger-Gong Hong , Fiala-Buskies Sabine , Ozgurdal Kirhan , Qin Shukui ,   on behalf of the REFINE Investigators
Published: May 2020

e16680 Background: REG is approved for the treatment of pts with HCC who previously received SOR, based on results of the phase 3 RESORCE trial. The REFINE study was designed to evaluate the safety and effectiveness of REG in pts with HCC in real-world practice. Methods: This prospective, observational study aims to recruit 1000 pts with unresectable HCC for whom a decision to treat with REG was made by the treating physician prior to enrollment according to the local health authority approved label. The primary endpoint is the incidence of treatment-emergent adverse events (TEAEs) and dose modifications due to TEAEs (NCI-CTCAE v4.03). Secondary endpoints include overall survival (OS) and progression-free survival (investigator assessed). This interim analysis includes the first 500 pts on study for ≥4 months. Results: Of 500 pts enrolled and observed for ≥4 months, 498 received REG and were evaluable (data cut-off: November 11, 2019). Pts were Child-Pugh A 67%, B 11%, C 1%, and missing/not evaluable 21%. Most pts (98%; n = 490) had received prior systemic therapy; 97% (n = 482) had received prior SOR. REG was second line treatment in 81% of pts (n = 403), third line or higher in 17% (n = 87), and first line in 2% (n = 8). Of the 403 pts who received REG second line, 398 (99%) received prior SOR. Among the 482 pts who received SOR in any prior line, the median duration of prior SOR was 4.8 months (interquartile range 2.5–9.6), 45% (n = 216) had a last daily SOR dose of 800 mg, and 8% (n = 40) had a TEAE leading to SOR discontinuation (SOR-intolerant). OS by treatment line is shown in the Table. Among all treated pts, the most frequent TEAEs (any grade) were hand–foot skin reaction (HFSR; 30%), diarrhea (21%), fatigue (16%), and decreased appetite (14%). In SOR-intolerant pts (n = 40), the most frequent TEAEs (any grade) were diarrhea (25%), HFSR (20%), abdominal pain (15%), and decreased appetite (13%). Conclusions: In this interim analysis of REFINE, most pts received REG second line after SOR versus other lines of therapy. Median OS in this subgroup was longer than OS in RESORCE, but the proportion of censored pts was high. The most common TEAEs were similar to those in RESORCE in both the overall cohort and in SOR-intolerant pts. Clinical trial information: NCT03289273 . [Table: see text]
The natural history of fibroblast growth factor receptor (FGFR)-altered cholangiocarcinoma (CCA).
Authors: Goyal Lipika , Lamarca Angela , Strickler John H. , Cecchini Michael , Ahn Daniel H. , Baiev Islam , Boileve Alice , Tazdait Melodie , Hannan Lindsay Marie , Jia Jingquan , Marble Hetal Desai , Barzi Afsaneh , Sahai Vaibhav , Lennerz Jochen K , Kelley Robin Kate , Bekaii-Saab Tanios S. , Javle Milind M. , Uboha Nataliya Volodymyrivna , Harris William P. , Hollebecque Antoine 
Published: May 2020

e16686 Background: Genetic alterations in the FGFR pathway are emerging as promising therapeutic targets in CCA. The clinical and molecular features of patients (pts) with CCA harboring FGFR genetic alterations are reported here. Methods: A retrospective chart review was performed in pts with CCA who were found to have an FGFR alteration on tumor molecular profiling as part of routine care between 9/2007 and 12/2019. Data on demographics, risk factors, pathology, molecular characteristics, systemic therapies, radiographical response, time on treatment, and overall survival (OS) were collected in a multi-center collaborative effort across seven academic centers. Results: Among 135 pts with FGFR-altered CCA, the median age at diagnosis was 57 years old (range = 25-92 years), and 80 (59.3%) pts were female, 129 (95.6%) had intrahepatic CCA, and 6 (5.6%) had chronic HBV. At presentation, 28.2% of pts had resectable disease, including 65.0% with Stage I-II, 22.5% with Stage III, and 5.0% with Stage IV. At the time of initial diagnosis, CA19-9 was < 35U/mL in 42.6% of pts. Bone metastases were observed in 41 (30.6%) pts with advanced disease. FGFR2 fusions were the most common FGFR alteration (68.2%), followed by FGFR2 mutations (21.5%), FGFR3 mutations (3.7%), FGFR2 rearrangements (1.5%), FGFR1 amplification (1.5%), and FGFR2 amplification (1.5%). The most common FGFR2 fusion partners were BICC1 (28.3%), SORBS1 (4.4%), POC1B (3.3%), and TACC2 (3.3%). The median lines of palliative systemic therapies received was 3 (range = 0-8), and 40/135 (29.6%) pts received a liver-directed therapy. For the 55 (59.8%) pts with FGFR2 fusions who received gemcitabine/cisplatin as first-line palliative systemic therapy, the median time on treatment was 6.2 months (95% CI: 4.1-9.3). The median OS from time of initial diagnosis was 36.1 months (95% CI: 28.3-51.6) in the FGFR2 fusion positive cohort. Among the 92 pts with FGFR2 fusions, 70 (76.1%) pts received an FGFR inhibitor on a clinical trial; 12 (17.1%) were subsequently treated with a second FGFR inhibitor, and 58.3% stayed on the second FGFR inhibitor for ≥4 months. Pts with a BICC1 fusion partner (n = 16) had an overall response rate of 42.9% on FGFR-selective inhibitors compared to 30.8% in non-BICC1 fusion partners (n = 54). Conclusions: Pts with CCA harboring FGFR alterations were found to have a high rate of normal CA19-9, high rate of bone metastases, and short median time on treatment on first-line palliative gemcitabine/cisplatin. Additional comparative studies are necessary to evaluate these findings.
Diagnostic criteria of pancreatic pathology.
Authors: Neskubina Irina V. , Frantsiyants Elena M. , Kaplieva Irina V. , Surikova Ekaterina I. , Bandovkina Valeria A. , Trepitaki Lidia K. , Nemashkalova Ludmila A. , Aleynov Viacheslav A. , Trifanov Vladimir S. , Mezentsev Stanislav S. , Chernyak Maksim N. , Kit Oleg I. , Snezhko Aleksandr V. , Petrov Dmitry S. , Fomenko Yuriy A. 
Published: May 2020

e16696 Background: Vascular endothelial growth factors (VEGF) and their receptors provide malignant tumors with new blood and lymphatic vessels. However, it is unknown whether their level in the blood can help to determine the tumor nature or to distinguish malignant pathology from chronic organ inflammation. The purpose of the study was to reveal the dynamics of VEGF in the blood of patients with chronic pancreatitis and pancreatic cancer. Methods: The study included male patients with chronic pancreatitis (n = 9), pancreatic adenocarcinoma T1-3N0-1M0 (n = 10) and pancreatic neuroendocrine tumors T1-3N0-1M0 (n = 12) before treatment. Healthy males (n = 21) were controls. Blood levels of VEGF-A, VEGF-C, VEGF-R1 and VEGF-R3 were determined by ELISA using standard test systems (Cusabio, China). Results: VEGF-A in the blood of patients with pancreatic cancer increased: in adenocarcinoma by 2.6 times, in neuroendocrine tumors by 1.7 times (p < 0.05), while chronic pancreatitis was characterized with reduced VEGF-A in the blood – 2.2 times lower than in healthy people. Serum concentration of VEGF-C increased only in patients with adenocarcinoma – 1.3 times higher than the norm (p < 0.05). The amount of VEGF-R1 and VEGF-R3 receptors increased in the blood of patients with chronic pancreatitis (by 2.2 and 1.6 times respectively, p < 0.05) and pancreatic neuroendocrine tumors (2.2 and 1.3 times, p < 0.05). Conclusions: The rise of VEGF-A in the blood is a sign of malignant pancreatic pathology; its combination with the accumulation of VEGF-C in the blood is a diagnostic criterion for pancreatic adenocarcinoma, and a combination with an increase in VEGF-R1 and VEGF-R3 is a diagnostic criterion for pancreatic neuroendocrine tumors. In contrast, chronic pancreatitis is characterized by reduced VEGF-A together with the increase in both types of receptors in the blood.
Germline and somatic DNA damage repair gene mutations potentially predict the efficacy of relevant treatment in Chinese patients with pancreatic ductal adenocarcinoma.
Authors: Shui Lin , Peng Yang , Li Shuangshuang , Tian Jiangfang , Cao Dan 
Published: May 2020

e16732 Background: PDAC is a fatal disease with molecular heterogeneity, inducing differences in biological behaviour and therapeutic strategy. We conducted a study to reveal the mutation landscape of Chinese PDAC patients, and investigate the predictive role of germline and somatic DNA damage repair (DDR) status in precise treatment. Methods: 195 PDAC patients were enrolled from multiple medical centers of China between Jan 2016 to Nov 2019. Baseline clinical or genetic characteristics, and survival status were collected. NGS were performed on paraffin-embedded resected tissues or peripheral blood using a panel of 417 genes, including 50 DDR-related genes. Survival analysis was conducted using Kaplan-Meier, and Cox proportional hazard regression model. Results: The main driver genes were KRAS, TP53, CDKN2A, and SMAD4. Patients with KRAS mutation showed worse OS than those without (p = 0.048). DDR deficiency were identified in 15.38% of overall patients, mainly occurred in BRCA2 (4.62%), ATM (4.10%), RAD50 (1.54%) and MLH1 genes (1.03%). No significant improvement of OS existed between patients with or without DDR mutations (p = 0.88). Treatment with olaparib (adjusted HR, 0.2550; P = 0.0720) or platinum-based chemotherapy (adjusted HR, 0.1308; P = 0.0185) respectively decreased hazard of death in patients with DDR mutation. Besides BRCA gene, ATM mutant patients treated with olaparib harbored prolonged median OS than those without olaparib treatment (22.25 vs 15.2 month). Despite a little higher PD-L1 expression rate were seen in DDR mutant patients (29.17% vs 20.51%), no statistical correlation between tumor mutation burden level and DDR mutation was identified. And in patients treated with PD-1 blockade, 2 patients of DDR wild-type group both had SD, whereas of the remaining 5 patients with DDR deficiency, 1 was evaluated as PR, 3 as SD, and 1 as PD (ORR, 0 wt vs 20% mut). Conclusions: In this multi-center retrospective study, we deciphered the intra-tumoral genetic heterogeneity in Chinese PDAC population, which differs from western patients cohort to some extent. We found the potential role of germline and somatic DDR mutation status in predicting the response to olaparib and platinum-based chemotherapy, especially with BRCA or ATM mutation. However, DDR alteration was limited in prediction of hypermutational status and sensitivity to PD-1 blockade. Our study may provide a valuable evidence for clinical application of DDR mutation as a potential biomarker for precise treatment.
Metabolism-based GP-2250 in combination with gemcitabine as a novel approach to pancreatic cancer: A mouse xenograft study.
Authors: Braumann Chris , Buchholz Marie , Majchrzak - Stiller Britta , Hahn Stephan , Uhl Waldemar , Kasi Anup , Mueller Dr. Thomas 
Published: May 2020

e16750 Background: GP-2250, a novel oxathiazine derivative, displayed apoptotic cytotoxicity against various tumor cell lines but not normal cells. It was therefore tested whether its antineoplastic potential - alone or in combination – could be leveraged specifically against pancreatic cancer. Methods: GP-2250 is a cancer metabolism-based therapeutic. It depleted metabolic energy through inhibition of the enzyme GAPDH (glyceraldehyde-3-phosphate dehydrogenase) which is rate limiting for aerobic glycolysis. ATP was decreased in a time- and dose-dependent manner in pancreatic tumor cell lines and ROS was increased. Mitochondrial dysfunction was triggered by an increased expression of Bax and decreased expression of Bcl2, leading to apoptosis. Cytotoxicity of GP-2250 was ROS-dependent. It was blocked by N-acetylcysteine. Results: GP-2250 substantially increased the sensitivity of pancreatic tumor cells to various chemotherapeutics in particular to gemcitabine (Gem). At doses which were inactive or barely active per se, the combination of GP-2250 and Gem caused striking cytotoxicity in patient-derived primary tumor cells in vitro, pointing to a strong synergy between the two agents. This finding was substantiated in vivo by patient-derived xenograft (PDX) studies in nude mice. While GP-2250 and Gem, given as monotherapy (500 mg/kg and 50 mg/kg respectively, 2x/week), showed only a limited antineoplastic response, the combination treatment resulted in a significantly higher anti-tumor activity as shown in further PDX. Tumor regression was found in 5 out of 9 PDX based on RECIST criteria. Stable disease was reached in 3 of the remaining grafts. In 1 xenograft, which was unresponsive to Gem, the combination treatment nevertheless achieved a reduction in tumor growth which significantly exceeded that of GP-2250 monotherapy. Conclusions: GP-2250 is a novel cancer metabolism-based therapeutic. GP-2250, in combination with Gem, strongly reduces tumor growth in patient-derived xenografts exceeding by far the response to monotherapy. GP-2250 is being evaluated in a Phase I clinical trial in patients diagnosed with advanced pancreatic cancer (Clinical Trial NCT03854110).
Osteoclast-like giant cell tumors of the pancreas: Clinical characteristics, genetic testing, and treatment modalities.
Authors: Ueberroth Benjamin Edward , Liu Alex John , Graham Rondell P. , Sonbol Mohamad Bassam , Halfdanarson Thorvardur Ragnar 
Published: May 2020

e16752 Background: Undifferentiated osteoclast-like giant cell carcinoma of the pancreas is an aggressive malignancy only described by a few case reports in the literature. In this study, we sought to better characterize this entity by examining patients seen at Mayo Clinic. Methods: This study identified patients with osteoclast-like giant cell carcinoma of the pancreas using Mayo Clinic databases (MN, AZ, FL) from the year 2000 to present. Patient demographics, genetic data, and treatment modalities were reviewed. Kaplan-Meier analysis was used to evaluate median overall survival (mOS) for the cohort as well as mOS and mPFS for treatment subgroups. Results: 15 patients were identified (9 female, 6 male). Median age at diagnosis was 59 years and mOS for all patients was 11.0 mos (95% CI 6.2-15.7 mos). 3 patients (20%) had metastatic disease at diagnosis with the liver being the most common site (n = 3). Metastatic disease was associated with significantly shorter OS (3.5 vs. 14.1 mos, p = 0.005; HR 7.98 [95% CI 1.43-44.4]) compared to locoregional disease (LRD). 4 patients underwent genetic testing. The most common mutation was CDKN2A (n = 3), followed by TP53 (n = 2) and KRAS (n = 2). 13/15 patients had detailed follow-up information. 6/7 patients undergoing chemotherapy received a gemcitabine-based regimen as first line: with capecitabine (n = 2), with nab-paclitaxel (n = 2), or as monotherapy (n = 2). 1 patient received FOLFIRINOX. In patients with LRD and adequate follow-up (n = 11), 8/11 underwent surgical resection and had longer OS compared to those without resection (17.0 vs. 8.4 mos, p = 0.09). No surgical patients received neoadjuvant chemotherapy. 5/8 received adjuvant chemotherapy, 2 did not undergo chemotherapy, and 1 was lost to follow-up after surgery. PFS from time of surgery was 15.3mos (95% CI 5.0-25.6mos). 6 patients (40%) were alive at time of analysis; all 6 underwent surgical resection. Conclusions: Osteoclast-like giant cell carcinoma of the pancreas is a rare malignancy with a poor prognosis, even when diagnosed at an early stage. OS for patients of all stages in this study was less than 1 year suggesting prognosis may be even worse than that of pancreatic adenocarcinoma. The optimal therapy remains unknown but most patients received similar chemotherapy as in adenocarcinoma. Patients with LRD amenable to surgical resection experienced a PFS over 1 year from surgery, possibly associated with OS benefit, however overall prognosis is poor. Further study is warranted on a larger scale to better understand disease course and treatment options.
The pattern of mucin 5AC (MUC5AC) expression using immunohistochemistry and its prognostic significance in patients with pancreatic ductal adenocarcinoma.
Authors: Manne Ashish , Mneimneh Wadad , Elkadi Osama , Escobar Daisy E , Coley James , Guzman Gabriel Bolanos , Fnu Sameeta Moh'd , Alkharabsheh Omar , Khushman Moh'd M. 
Published: May 2020

e16756 Background: Mucin-5AC (MUC5AC) is a secreted form of mucin. Its expression correlates with poor outcome in uterine, ampullary adenocarcinoma and cholangiocarcinoma. Its prognostic significance in pancreatic ductal adenocarcinoma (PDAC) is not well established. Here, we explored the pattern of MUC5AC expression using immunohistochemistry (IHC) and its prognostic significance in patients with PDAC. Methods: This is a retrospective study conducted at the University of South Alabama/Mitchell Cancer Institute. Between 2015-2019, 218 patients with PDAC were identified. Among this cohort, only 45 patients had tissue available for MUC5AC IHC staining. Two pathologists in- dependently scored the expression of MUC5AC. Staining percentage was estimated in 10% increments. Unpaired t test and log-rank Wilcoxon tests were used for statistical analysis. Results: In our cohort, the median age was 65 years (42-85). Males represented 55%. Caucasians, African Americans and other ethnicities (e.g. Asians) represented 71%, 25% and 4% respectively. Twenty patients (44%) had metastatic stage IV disease and 25 patients (56%) had non-metastatic disease. Positive cytoplasmic and apical MUC5AC expression by IHC was seen in 82% and 80% of patients respectively. The median apical MUC5AC expression was higher in metastatic patients compared to non-metastatic patients (67.5 % vs 30%, p = 0.0187 ) while there was no difference in the median cytoplasmic MUC5AC expression between metastatic and non-metastatic patients (13.7 % vs 12.5%, p = 0.3328). In non-metastatic patients, compared to patients with positive apical MUC5AC expression, no expression (0%) was associated with worse overall survival (OS) (43 vs 13 m, p = 0.0322). In metastatic PDAC, there was no difference in OS between patients with positive or no apical MUC5AC expression (18 vs 21 m, p = 0.781). Compared to patients with positive cytoplasmic MUC5AC expression, patients with no cytoplasmic MUC5AC expression (0%) had no difference in OS in both non-metastatic (40 vs 32 m, p = 0.986) and metastatic (36 vs 12.5 m, p = 0.487) patients. Conclusions: MUC5AC expression assessment using IHC is feasible in patients with PDAC. In our cohort, apical, but not cytoplasmic, MUC5AC expression was different between metastatic and non-metatstaic patients and showed prognostic significance in non-metastatic patients. To our knowledge, this is the first study to show prognostic significance of MUC5AC expression in patients with PDAC using IHC.