bluuebunny/crossref_metadata_2025_split huggingface dataset:
Computational extraction and analysis of de-identified medical records to characterize hyperammonemia in patients with fibrolamellar carcinoma (FLC).
Authors: Zack Travis , Maisel Samantha , O'Neill Allison Frances , La Quaglia Michael P. , Herman Michael , Knox Jennifer J. , Yaqubie Amin , Venook Alan P. , Mayer Robert J. , Gordan John Dozier , Abou-Alfa Ghassan K. 
Published: June 2021

e16169 Background: Rare cancers including FLC make up 25% of adult tumors, but are difficult to study due to low incidence and incomplete case identification. FLC occurs in adolescents and young adults without liver dysfunction. Hyperammonemia has been frequently reported in FLC patients, but is poorly understood. Methods: Data from three clinical trials allowed us to establish the incidence of hyperammonemia (serum ammonia value > 75 µmol/L) in FLC. In these studies, FLC patients received everolimus, estrogen deprivation therapy (EDT) with leuprolide + letrozole or everolimus + EDT (Oncologist. 2020 25(11):925-e1603), ENMD-2076 (Oncologist. 2020 25(12):e1837-e1845), or neratinib (J Clin Oncol 39, 2021 (suppl 3; abstr 310); ammonia was tested prospectively in the latter two studies. To assess impacts of cancer therapy or liver dysfunction, we studied hyperammonemia in FLC and non-FLC patients at UCSF in parallel. Using Natural Language Processing (NLP) of pathology reports and oncology notes from > 2300 liver cancer patients from the last 12 years of UCSF records, we identified a cohort of patients with FLC, contrasting their laboratory data to all UCSF patients with ammonia testing for the last 10 years. We used leiden clustering and umap dimensionality reduction to contrast FLC and other patients to assess the clinical context of hyperammonemia. Results: Data from the 3 trials showed hyperammonemia in 10 of 32 (31.3%) FLC patients during study participation, independent of the therapy received. These patients exhibited hyperammonemia with varying levels, and at different points in their treatment. NLP identified 37 patients with FLC ( < 0.1% of liver cancer patients), with 33% showing hyperammonemia. Across all UCSF patients, we found 24,000 independent visits where ammonia was tested, with > 2400 demonstrating hyperammonemia. Using leidan clustering on all encounters with ammonia > 75 µmol/L, we found distinct subsets of hyperammonemia corresponding to known metabolic and physiologic processes (e.g., fulminant liver failure, tumor lysis syndrome, etc). FLC patients clustered separately from hepatocellular carcinoma patients with hyperammonemic encephalopathy due to cirrhosis. Conclusions: NLP of large EMRs is a valuable tool to study FLC, a rare cancer. Herein, we have defined hyperammonemia as a frequent event in FLC, not directly linked to hepatic dysfunction or individual therapies. Further investigation may determine whether hyperammonemia is related to FLC tumor biology.
Immune related biomarkers in biliary tract cancers (BTC).
Authors: Sandhu Zoya , Sanchez-Garcia Jorge , Barker Tyler , Raghunath Sharanya , Shortt Katherine , Hwang Su-Ho , Fulde Gail , Zendejas-Ruiz Ivan R , Haslem Derrick S. , Yeatman Timothy Joseph , Thota Ramya 
Published: June 2021

e16191 Background: Biliary tract cancers are aggressive tumors with limited treatment options. Several ongoing clinical trials are currently exploring role of immune therapy in advanced BTC. Programmed death-ligand 1 (PD-L1), tumor mutational burden (TMB), and microsatellite instability (MSI) are commonly used immune related-biomarkers. Herein, we analyzed the TMB, MSI and PD-L1 expression in advanced BTC. Methods: We retrospectively evaluated the association of TMB, MSI and PD-L1 expression with survival and related treatment outcomes. Results: The immune mediated biomarkers were reported in a total of 62 BTC patients (pts). The mean age of the pts is 73 (range 32-83) years, with predominant females (59%) and Caucasians (82%). The most common histology noted was intrahepatic cholangiocarcinoma (67%) followed by extrahepatic cholangiocarcinoma (18%) and gallbladder carcinoma (15%). Approximately, 40% received 2 or more lines of therapy while 20% of patients didn’t receive any treatment and over. The treatment regimen included gemcitabine-based regimen (35%), 5FU based regimen (18%), immune therapy (15%) and targeted therapy (6%). The TMB was low in 52 pts (83%), intermediate 7 pts (11%) and high in 2 pts (3%). MSI is stable in 55 pts (89%) and PD-L1 expression is negative in 29 pts (47%) and positive in 23 pts (37%). Conclusions: Our data suggests the BTC’s have in general low TMB, are microsatellite stable and have low PD-L1 expression. The potential prognostic and predictive value of these immune related- biomarkers need to be validated in larger studies.
Study of microsatellite instability in neuroendocrine tumors of pancreas and colon.
Authors: Trifanov Vladimir S. , Timoshkina Natalya N. , Gvaldin Dmitry Yu. , Mesheryakova Milana Yu. , Kolesnikov Evgeniy N. , Gaziev Umar M. , Sanamyants Sergey V. , Mezentsev Stanislav S. , Duritskiy Maksim N. , Gabrichidze Petr N. , Kit Oleg I. 
Published: June 2021

e16196 Background: Microsatellite instability (MSI), as an acquired feature of malignant tumors, is a predictive and prognostic marker. The less aggressive nature of MSI-positive tumors has been associated with high immunogenicity. In the present study, MSI was assessed in NET samples of different localizations. Methods: The sample included 50 patients with a diagnosis of pancreatic NET (G1-G3) and NET of colon (G2-G3). MSI was analyzed by fragment analysis of five microsatellite loci (Bat25, Bat26, NR21, NR24, NR27). The level of MLH1 methylation was detected by pyrosequencing. Results: MSI was noted in 25.8% cases of the NET of colon and in 13.3% cases of the NET of the pancreas. In the case of pancreatic NET, only MSI low level was identified (instability at 1/5 loci), while in the case of NET of colon, most cases were classified as MSI high level. The incidence of MSI of pancreatic NET was consistent with literature data for small intestinal NET (14%), unlike MSI NET and BRAF V600 mutated adenocarcinomas of colon, MSI-positive pancreatic NET were not associated with hypermethylation of the MLH1 promoter. MSI was more often detected in women over 60 years old, at stages of the tumor process without distant metastases (p = 0.49). The sample size did not allow us to determine significant differences in the studied clinical and pathological groups of NETs, however, we note that in all cases of an unfavorable course of the disease (progression, death), was noted MSS status of tumors. Conclusions: Thus, MSI-positive NET of colon resembles MSI-positive adenocarcinomas of colon in frequency and pathogenetic mechanisms, while in terms of the identified frequency of MSI in pancreatic NET resembles the NET of the small intestine.
Surufatinib in combination with toripalimab in patients with advanced neuroendocrine carcinoma: Results from a multicenter, open-label, single-arm, phase II trial.
Authors: Shen Lin , Yu Xianjun , Lu Ming , Zhang Xing , Cheng Ying , Zhang Yanqiao , Li Zhiping , Xu Jianming , Weng Desheng , Wu Chunjiao , Ma Yue , Cheng Ke , WANG Wenquan , Gao Heli , Li Yi , Zhou Jinghong , Shi Haiyan , Tan Panfeng , Su Weiguo 
Published: June 2021

e16199 Background: Patients with advanced neuroendocrine carcinoma (NEC) have a poor prognosis and limited treatment option after first-line treatment. Surufatinib, a multi-kinase inhibitor of VEGFR 1-3, FGFR 1 and CSF-1R, has been approved in patients with advanced or metastatic extra-pancreatic neuroendocrine tumors in China. Toripalimab is a monoclonal humanized IgG4 PD-1 antibody. Surufatinib modulates tumor immune microenvironment and has shown promising antitumor activity in combination with toripalimab in solid tumors, including neuroendocrine tumor and neuroendocrine carcinoma. Herein, we reported the efficacy and safety of surufatinib in combination with toripalimab in a cohort of advanced NEC patients. Methods: The multicenter, open-label, single-arm phase II clinical trial enrolled advanced NEC patients refractory to first-line chemotherapy, and received surufatinib 250 mg once a day orally plus toripalimab 240 mg intravenously on day 1 of a 21-day cycle. The primary end point is objective response rate (ORR) per RECIST 1.1. Results: Twenty-one patients enrolled and received combination therapy. At data cut-off (December 31, 2020), the average treatment cycles were 5.1±3.69 for surufatinib and 5.0±3.68 for toripalimab. Among 20 tumor evaluable patients, 4 patients achieved confirmed PR and 10 patients achieved stable disease. The ORR and disease control rate (DCR) are 20 % (95%CI: 5.7%-43.7%) and 70% (95%CI: 45.7%-88.1%) respectively. The median PFS is 3.94 months (95%CI: 1.31- unknown). OS is not mature till data cut-off. Adverse events (AEs) reported as related to treatment (TRAE) occurred in 100% of patients, of which Grade≥3 TRAEs occurred in 33.3% of patients. The reported Grade≥3 TRAEs were hypertension in 2 (9.5%) patients, and upper abdominal pain, oral mucositis, neutrophil count decreased, leukocyte count decreased, dermatitis, anemia and backache in 1 (4.8%) patient each. Immune related Grade ≥3 AEs, Gamma-glutamyl transpeptidase increased and dermatitis, occurred in 2 (9.5%) patients, respectively. TRAE caused surufatinib or toripalimab interruption occurred in 6 (28.6%) and 4 (19%) patients respectively. There were neither serious AEs nor AEs inducing treatment discontinuations or deaths. Conclusions: As there is no standard second-line treatment, this combination of surufatinib and toripalimab might offer a new promising choice to treat NEC as second-line treatment due to good efficacy and manageable treatment related toxicities. Clinical trial information: NCT04169672.
Neutrophil extracellular traps (NETs) and thrombosis (Thr) in pancreaticobiliary cancer (PBC).
Authors: Fountzilas Christos , Yu Han , Khan Anm Nazmul , Giridharan Thejaswini , Khorana Alok A. , Iyer Renuka V. , Segal Brahm H. 
Published: June 2021

e16230 Background: NETs are linked to tissue damage, Thr and cancer progression. Detection of NETs in pancreatic cancer (PC) tissue and NET products in plasma, such as citrullinated Histone 3 (cit-H3) and myeloperoxidase (MPO), can predict survival. A robust biomarker to identify PC patients that may benefit from prophylactic antithrombotic interventions is still lacking. We hypothesized that NET products can predict PC patients at risk of poor outcomes. Methods: Frozen plasma collected on diagnosis from a cohort of 117 patients with HPBC (69% with PC) with known tissue factor (TF) levels was analyzed for MPO and cit-H3 by ELISA. Plasma MPO is a marker of neutrophil degranulation while cit-H3 is a more specific marker of NETosis. Univariate association of clinical variables, TF, cit-H3, MPO with overall survival (OS) was performed. For multivariable analysis, Cox proportional hazards regression model and backward stepwise selection based on the Bayesian information criterion (BIC) were used. Results: We observed a strong correlation between MPO and cit-H3. MPO also correlated with TF. Only TF showed a trend with association with the risk of Thr (p=0.053). Results of the multivariable model for OS are presented in the table (all patients and stratified by Thr status). High absolute neutrophil count (ANC) predicted worse OS only in patients without Thr. Increased cit-H3 was associated with worse OS. Higher MPO predicted worse OS in stage IV patients, which is in contrast to their relationship in stage I-III patients, where increased MPO was associated with improved OS. This interaction effect is stronger in patients with thrombosis. Conclusions: Plasma cit-H3, a systemic marker of NETosis, was associated with worse OS in PBC. Significant MPO by stage interaction implies a differential association of MPO with the OS among patients in different cancer stages. The activation status of neutrophils, including degranulation and NETosis, may be an important predictive biomarker for OS in patients with HPBC with interactions with both stage and Thr. Prospective studies to confirm and extend our findings are ongoing.[Table: see text]
Molecular subtypes of pancreatic adenocarcinoma stratified based on copy number variation profile.
Authors: Zhan Qian , Wen Chenlei , Yi Zhao , Zhang Henghui , Shen Baiyong 
Published: June 2021

e16232 Background: Pancreatic adenocarcinoma (PAAD) is one of the most lethal carcinomas all over the world, with an estimate of 60,430 new cases and 48,220 deaths in United States according to the cancer statistics of 2021. It is important and urgent to identify molecular subtypes for stratifying PAAD into different groups with respective genomic footprint, appropriate treatment and prognosis status. Methods: We profiled a comprehensive landscape of genomic alterations for 608 PAAD patients in a Chinese cohort, including somatic mutations, pathogenic germline variants and copy number variations (CNVs). 233 out of 608 PAAD had disease-free survival (DFS) information with at least 6-month follow-up. Focusing on this subset of PAAD, we explored prognostic values for several kinds of genomic alterations and finally identified four molecular subtypes based on CNV profile. Results: For point mutations in highly mutated genes ( KRAS, TP53, CDKN2A and SMAD4) or homologous recombination repair (HRR) genes ( ATM, ATR, BARD1, BLM, BRCA1/2, BRIP1, CDK12, CHEK1/2, NBN, PALB2, RAD50/ 51B/ 51C/ 51D/54L and MRE11A), we found no associations between them and prognosis of PAAD patients. Instead, PAAD could be stratified into four molecular subtypes based on CNV profile through unsupervised clustering and CNV score defined by principle component analysis (PCA). According to amplification and deletion pattern of genes in DNA repair and receptor tyrosine kinase related signaling pathways, we named these four subtypes as repair-deficient, proliferation-active, repair-proficient and repair-enhanced ones. Among them, repair-deficient PAAD had the best prognosis with median DFS of 410 days, repair-proficient and proliferation-active one had median DFS of 239 and 197 days, respectively, while repair-enhanced one had the worst prognosis with DFS of 48 days. Genomic footprint analysis showed that both of repair-deficient and proliferation-active subtypes of PAAD possessed higher copy number instability (CNI), while both of repair-proficient and repair-enhanced subtypes possessed higher tumor mutational burden (TMB), implying that the former two subtypes suited for DNA damage therapies (such as platinum-based chemotherapy and PARPi) and the latter two subtypes suited for immunotherapy. Conclusions: We identified four molecular subtypes for PAAD based on CNV profile and found their respective genomic footprint, suited treatment and prognosis status, pacing key steps to precision medicine in PAAD field.
Clinical outcomes in pancreatic ductal adenocarcinoma (PDAC) patients with underlying autoimmune disease (AID).
Authors: Ahmed Gulrayz , Annunzio Kaitlin , Szabo Aniko , Eastwood Daniel , Thapa Bicky , Taylor Bradley W , Tsai Susan , Christians Kathleen K. , Clarke Callisia , Evans Douglas B. , Hall William Adrian , Erickson Beth , Kamgar Mandana , George Ben 
Published: June 2021

e16233 Background: Chronic inflammation from AID and the resultant immunosuppression from treatment increases the risk of various malignancies. Risk of PDAC is increased in patients (pts) with AID, however, there is paucity of cancer specific outcome data in these pts. We retrospectively reviewed the outcomes of pts with PDAC and AIDs to include Crohn’s disease (CD), ulcerative colitis (UC) and rheumatoid arthritis (RA). Methods: All pts aged 18 or older, diagnosed with PDAC in the setting of CD, UC and RA between January 2010 and December 2019 were included. Patients were identified using our institutional Clinical Research Data Warehouse (CRDW) and chart review. Clinical data was obtained by querying a cohort discovery tool (i2b2) from the CRDW with IRB approval. Pts with incomplete documentation were excluded. Descriptive statistics were used to report demographics. Overall survival (OS) was calculated from the time of diagnosis of PDAC to the date of death or last follow-up. Deaths from any cause were included in the survival analysis. OS and relapse free survival (RFS) were estimated using Kaplan-Meier methods. Results: We identified 51 pts who met inclusion criteria; 26 (51%) had RA, 15 (29.4%) had UC and 10 (19.6%) had CD. Median age at diagnosis of PDAC was 55.2 years, 49% were male (Table 1). Median duration from diagnosis of AID to PDAC for pts with CD, RA and UC was 173, 107 and 105 months, respectively. Metastatic disease at diagnosis was present in 19 (37.3%) of the 51 pts and 32 (62.7%) had localized disease (LD). Among the 17 pts with LD who underwent surgery, 6 (35.3%) experienced relapse with a median RFS of 14 months. The median OS of pts with LD who underwent surgery was 44 months compared to 8.25 months for those who did not. Among the 19 pts with metastatic disease at diagnosis, 0, 1, 2 & 3 lines of chemotherapy was received by 4 (21.1%), 8 (78.9%), 3 (36.8%) and 2 (21.1%) of pts, respectively. Median OS of patients with metastatic disease at diagnosis was 8.9 months. Conclusions: The inflammatory milieu and immunosuppression associated with AID treatment may be responsible for the early onset of PDAC in these pts. Although our sample size is small, pts with AID and PDAC who complete all planned curative intent therapy appear to have excellent outcomes, emphasizing the importance of early diagnosis and perhaps routine screening in pts with AID. Receipt of chemotherapy and OS of pts with metastatic PDAC in the setting of AID does not appear to be significantly compromised despite their exclusion from several clinical trials. Demographics.[Table: see text]
Evaluating survival in patients with pancreatic adenocarcinoma and lung metastasis.
Authors: Cham Jason , Ebrahimi Aren , Hermel David Jacob , Spierling Bagsic Samantha R. , Sigal Darren 
Published: June 2021

e16237 Background: Pancreatic adenocarcinoma most commonly metastasizes to the liver and peritoneum, yet can occasionally metastasize to the lungs in an isolated fashion. Anecdotal evidence suggests that patients who have isolated metastatic disease to the lungs have improved outcomes. We sought to investigate whether pancreatic cancer lung metastasis is associated with improved survival. Methods: We conducted a retrospective review of patients within the Scripps Health system with pathologically confirmed pancreatic adenocarcinoma from 2017 to 2020. Primary sites of metastatic disease were identified with imaging, and when available, confirmed by pathology. A subgroup of 101 patients from a total cohort of 598 patients was further refined to only include patients with lung and/or liver primary metastases (N=68). Analyses were conducted on subgroups defined by metastatic sites of disease in the liver only, lung only and combined liver+lung. Primary and secondary outcome analyses compared isolated lung versus liver/liver+lung. Overall survival (OS) was defined from the date of diagnosis to date of death or most recent follow up, and recurrence free survival (RFS) from the time of diagnosis to date of recurrence. Each survival outcome was analyzed using Cox Proportional Hazards tests. Additionally, proportions of each subgroup (lung v. liver/liver+lung) that had recurrence or were deceased were reported and compared by Fisher’s exact tests. Results: No significant differences were observed in OS (HR 1.91, CI 0.66 – 3.73; p= 0.311) or RFS (HR 0.98, CI 0.42 – 2.30; p= 0.968) between patients with primary lung metastases versus those with either liver or liver+lung metastases (reported as hazard ratios of liver/liver+lung relative to lung only). Although there was no overall statistically significant difference, the kaplan-meier curve for OS appears to show improved survival for patients with primary lung metastasis initially but then ultimately shows worse survival compared to liver only metastasis at later time points. Please see Table.Conclusions: We found no difference in survival outcomes among pancreatic cancer patients with only lung metastasis at diagnosis compared to patients with hepatic metastasis. However, we do observe that patients with lung metastases seem to have improved survival initially. This study was conducted on a small set of the total number of patients with pancreatic adenocarcinoma within the Scripps Health system. Further analysis is ongoing to confirm the trend we observe in this study.[Table: see text]
Cost-effectiveness analysis of platinum-based chemotherapy treatment options for germline BRCA-mutated locally advanced/borderline resectable pancreatic cancer.
Authors: Ingram Myles , Pumpalova Yoanna S , Park Jiheum , Lim Francesca , Manji Gulam Abbas , Kong Chung Yin , Hur Chin 
Published: June 2021

e16246 Background: Patients with germline BRCA1/2 mutations (gBRCAm) have an increased risk for pancreatic ductal adenocarcinoma (PDAC). The NCCN 2020 guidelines recommend platinum-based chemotherapy (FOLFIRINOX or gemcitabine plus cisplatin) in patients with gBRCAm diagnosed with borderline resectable or locally advanced (BR/LA) PDAC; for patients without progression on chemotherapy, maintenance therapy with a PAPR inhibitor (PARPi) can be considered. FOLFIRINOX and gemcitabine plus cisplatin (GemCis), with or without maintenance PARPi, have not been directly compared in this patient population. The purpose of our study was to compare treatment outcomes, toxicity, costs, and quality-of-life of the two recommended platinum-based regimens, with or without maintenance PARPi (olaparib or veliparib), in patients with gBRCAm and BR/LA PDAC. Methods: We developed a decision-analytic mathematical model comparing the total cost and health outcomes of FOLFIRINOX, FOLFIRINOX + olaparib (FOLFIRNOX-O), GemCis, and GemCis + veliparib (GCV) over twelve years. The inputs for the model were estimated using clinical trial data and published literature. Natural history was used as a comparator. The primary endpoint was incremental cost-effectiveness ratios (ICERs) with a willingness-to-pay (WTP) threshold of $100,000 per quality-adjusted-life-year (QALY). Secondary endpoints included overall survival (OS), progression-free survival (PFS), life-years (LYs) and total cost of care (USD). Results: Both FOLFIRINOX strategies were dominated by the GemCis strategies and thus eliminated from the efficiency frontier. GCV was the strategy that yielded the most life-years (2.05 LYs) but the ICER of $629,697.46 for this regimen far exceeded the WTP threshold. Therefore, GemCis was the cost-effective strategy, totaling incremental QALYs of 1.31 at a cost of $61,228.40 per QALY when compared to natural history. A one-way sensitivity analysis found that the GCV becomes the cost-effective strategy when the cost of maintenance PARPi is lowered to 4% of the base case. Conclusions: Our model found that GemCis is the cost-effective option for patients with gBRCAm and BR/LA PDAC. Neither of the strategies with maintenance PARPi were cost-effective. Additional clinical trial data with adequate follow-up are needed to confirm our findings.[Table: see text]