bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of losartan and vitamin D on outcomes in metastatic pancreatic adenocarcinoma.
Authors: Adika Adam , Ioffe Dina , Connors Meghan , Duboy Emily C. , Sorice Kristen A. , Hasler Jill , Lynch Shannon M. , Cukierman Edna , Reddy Sanjay S. , Astsaturov Igor A. , Dotan Efrat 
Published: January 2023

723 Background: Active modification of surrounding stroma is a critical mechanism of tumor cell growth in pancreatic ductal adenocarcinoma (PDAC). There is some early translational evidence that losartan (L) and vitamin D (D) may affect the tumor microenvironment and supportive stroma in PDAC to help restore a physically and biologically tumor-suppressive stroma. These effects of potentially stroma-modifying drugs have not been established in the clinical management of metastatic PDAC (mPDAC), where there have been limited advances in treatment and prognosis remains poor. Methods: This is a single center, retrospective analysis of patients with mPDAC treated at Fox Chase Cancer Center from 2010 to 2019. All data including L and D use were extracted from the medical record. Patient characteristics were compared across subgroups using Chi-square tests, Fisher’s exact tests, and Wilcoxon rank sum tests. The primary outcome was overall survival (OS) from the time of metastatic diagnosis. Kaplan-Meier curves and log-rank tests were used to compare unadjusted OS across subgroups. Cox proportional hazards models were used to characterize OS adjusted for age at metastatic diagnosis, sex, initial stage at diagnosis, performance status, Charlson Comorbidity Index (CCI), hypertension, and renal disease. Results: 518 patients were included; a majority were male (54.1%), White (82.4%), and diagnosed with de novo mPDAC (54.6%). About half of patients had hypertension (53.5%) and few had renal dysfunction (5.6%). 153 (29.5%) patients were taking D and 41 (8%) patients were taking L. Women were more likely to take D than men (p < 0.001) and White patients were more likely to take L than other races/ethnicities (p = 0.006). Median OS since metastatic diagnosis for patients taking L was 11.4 months compared to 9.6 months for patients not taking L (p = 0.07). Median OS for patients taking D was 11.3 months compared to 8.7 months for those not taking D (p = 0.10). A Cox proportional hazards model adjusting for confounders, however, showed that both L (HR 0.66, p = 0.02) and D (HR 0.81, p = 0.04) were significantly associated with improved OS from time of metastatic diagnosis. Conclusions: This large retrospective study demonstrates potential clinical and survival benefit of L and D in conjunction with mPDAC treatment. L and D are safe, well tolerated, and widely used in general medical practice. These results support further investigation of the stroma-modifying potential of L and D, as well as conducting prospective trials with these agents to further validate these findings.
Irreversible electroporation as treatment option within a multidisciplinary approach for locally advanced pancreatic cancer.
Authors: Ricker Ansley Beth , Iannitti David A 
Published: January 2023

727 Background: The treatment plan for patients diagnosed with locally advanced pancreatic cancer (LAPC) is developed by a multidisciplinary team by which systemic chemotherapy is employed followed by surgical resection. Strategies that provide local control in LAPC patients who demonstrate stability/regression without metastasis have gained increasing attention. Irreversible electroporation (IRE) is a non-thermal ablative approach that employs short, high-voltage electrical pulses to create permanent nano-defects in the tumor cell membrane resulting in lethal disruption of tumor cell homeostasis while preserving the integrity of the underlying vascular architecture. This study sought to review IRE outcomes at a high-volume, single institution hepato-pancreato-biliary surgical center. Methods: After obtaining institutional review board approval, data for patients treated with IRE was retrieved from the electronic medical record from 2013-2022. IRE in situ is defined as non-thermal ablation to a tumor without resection. Margin enhancement IRE is defined as non-thermal ablation to residual tumor that could not be resected in its entirety within the adventitial plane. IRE assisted resection is defined as non-thermal ablation to a tumor encasing surrounding structures to allow for complete resection. Results: A total of 101 IREs have been performed at our institution from 2013-2022. Demographics for our cohort include 48 (47.5%) female patients, an average age of 63 years (range 43 – 84), and an average BMI of 26.4 kg/m2 (range 17 – 47). Of these IRE operations, 27 (26.7%) were in-situ, 35 (34.7%) were margin enhancement, and 50 (49.5%) were assisted resections. 2.0% and 11.9% died within 30 and 90 days of the operation, respectively. Median disease-free survival for our patient cohort was 15 months (range 0 to 74). 1-year, 3-year, 5-year, and overall survival for the three cohorts are shown. Conclusions: Using IRE in patients presenting with LAPC provides additional treatment options to the standard treatment pathway. Further classifying IRE use to in situ, margin enhancement, and assisted resection and incorporating these procedures into a multidisciplinary treatment approach has the potential to improve survival rates for appropriately selected LAPC patients. [Table: see text]
Pressure-Enabled Drug Delivery (PEDD) of a class C TLR9 agonist in combination with checkpoint inhibitor therapy in a murine pancreatic cancer model.
Authors: Capacio Benedict , Shankara Narayanan Jayanth , Vicente Diego , Liu Yujia , LaPorte Jason , Cox Bryan , Jaroch David , Katz Steven , White Rebekah Ruth 
Published: January 2023

729 Background: Systemic immunotherapy has had limited clinical benefit in pancreatic ductal adenocarcinoma (PDAC). This is thought to be due to its desmoplastic immunosuppressive tumor microenvironment in addition to high intratumoral pressures that limit drug delivery. Recent pre-clinical cancer models and early-phase clinical trials have demonstrated the efficacy of toll-like receptor 9 agonists (TLR9a), including the synthetic CpG oligonucleotide SD101, to stimulate innate and adaptive immune cells and eliminate suppressive myeloid cells. We hypothesized that Pressure Enabled Drug Delivery (PEDD) via Pancreatic Retrograde Venous Infusion (PRVI) of a TLR9a would improve responsiveness to systemic anti-programmed death receptor-1 (PD-1) checkpoint inhibitor therapy in a murine orthotopic PDAC model. Methods: Murine PDAC (KPC4580P) tumors were implanted into the pancreatic tails of C57BL/6J mice and treated 8 days after implantation. Mice were assigned to PRVI saline (pSAL, n=9), systemic anti-PD1 100 mcg/mouse on Day 0, 2 and 4 (sAPD1, n = 6), 30mcg PRVI TLR9a (pTLR9a, n=9), 30mcg systemic TLR9a (sTLR9a, n=7) on Day 0, and combination 30mcg PRVI TLR9a on Day 0 and systemic anti-PD1 100 mcg/mouse on Day 0, 2 and 4 (COMBO, n =9). Fluorescently-labeled TLR9a (radiant efficiency [RE]) was measured on day 1. Blood and tumors were collected at necropsy 12 days after infusion. Results: All mice survived to necropsy. Site of tumor fluorescence measurements revealed higher intensity fluorescence in pTLR9a compared to sTLR9a (7.5x10^5 vs. 2.4x10^5 RE, p= 0.048). Significantly lower MDSCs in the COMBO vs. pSAL are shown. Tumor weights were significantly lower in the COMBO group compared to pSAL (400 vs. 964 mg, p=0.003), and were also lower, although not significantly, than in the pTLR9a (400 vs. 518mg, p=0.50), and sAPD1 (400 vs. 645 mg, p = 0.70) groups. Conclusions: PEDD of TLR9a by PRVI with systemic anti-PD-1 demonstrated improved PDAC tumor control. These results support study of this combination therapy in PDAC patients and expansion of ongoing PEDD clinical trials. [Table: see text]
Prognostic indicators of KRAS G12X mutations in pancreatic cancer.
Authors: Ardalan Bach , Ciner Aaron , Baca Yasmine , Darabi Sourat , Kasi Anup , Lou Emil , Azqueta Jose Ignacio , Xiu Joanne , Nabhan Chadi , Shields Anthony Frank , Pishvaian Michael J. , Korn Wolfgang Michael , Goel Sanjay 
Published: January 2023

735 Background: We have studied the role of KRAS mutations in relation to the prognosis in patients with advanced pancreatic ductal adenocarcinoma (PDAC). KRAS is a well-described oncogenic driver in PDAC, with mutations identified in over 90% of cases, typically involving codon 12. The three predominant missense variants include G12D, G12V and G12R. PDAC has the highest rate of G12R mutations compared to other malignancies, comprising 15-20% of KRAS-mutated tumors. This study presents a new finding in the progression of advanced PDAC utilizing a large clinical and genomic database to further characterize the clinical features of pathogenic KRAS variants in PDAC with a focus on G12R. Methods: PDAC samples were tested using whole transcriptome sequencing (WTS; Illumina NovaSeq) and NextGen DNA sequencing (NextSeq, 592 Genes and NovaSEQ, WES) at Caris Life Sciences (Phoenix, AZ). Transcriptomic signatures including MPAS (MAPK activation score), T-cell inflamed score and tumor micro environment (TME) characterization were calculated on WTS data. Significance was determined by X2 and Fisher-Exact and p adjusted for multiple comparisons (q) was < 0.05 (Benjamini-Hochberg). Real-world overall survival (rwOS) was obtained from insurance claims data and calculated from tissue collection to last contact; time-on-treatment (TOT) was calculated from start to finish of specific treatments; comparison was done by Kaplan-Meier test. Results: A total of 5,555 patients with PDAC harboring either KRAS G12D (n = 2,671), G12V (n = 1,871) G12R (n = 904) or G12C (n = 109) variants were identified. The patients with KRAS G12R mutant tumors had significantly longer median real-world overall survival (mRWOS) compared to G12D (452 vs 358 days, HR 0.82, CI 0.74 – 0.9, p < 0.0001). This difference persisted regardless of treatment with FOLFIRINOX or gemcitabine plus nab-paclitaxel. There was no difference in outcomesbetween patients with KRAS G12R, G12V or G12C. PD-L1 expression was significantly lower in G12R than in G12C or G12D (13% vs 27% vs 19%,) while the prevalence of TMB-H and dMMR was comparable across isoforms. Conclusions: Patients with KRAS G12R variants has improved rwOS compared to G12D irrespective of the chemotherapy regimen administered. Immune profiling suggested that the immune contexture in G12R-driven tumors are distinct from G12D as reflected by reduced PDL1 staining, decreased levels of multiple checkpoint receptors. We aim to further explore the molecular basis for these differences with a focus on PI3K and MAPK pathways. Based on this data, survivorship studies in patients with advanced PDAC should consider reporting KRAS mutational status.
Analysis of plasma circulating tumor DNA in borderline resectable pancreatic ductal adenocarcinoma treated with neoadjuvant modified FOLFIRINOX: Clinical relevance of DNA damage repair gene alterations.
Authors: Lim Dong-Hoon , Hyung Jaewon , Lee Sang Soo , Jeong Jae Ho , Ryoo Baek-Yeol , Kim Kyu-Pyo , Yoo Changhoon 
Published: January 2023

737 Background: There is no reliable biomarker to guide treatment for patient with borderline resectable pancreatic ductal adenocarcinoma (PDAC) treated with neoadjuvant modified (m)FOLFIRINOX. We investigated the role of plasma circulating tumor DNA (ctDNA) sequencing to discover potential biomarkers for patients treated with neoadjuvant mFOLFIRINOX in our phase 2 clinical trial (ClinicalTrials.gov identifier: NCT02749136). Methods: Among 44 patients enrolled in the trial, patients with plasma ctDNA analysis performed at baseline or post-operative period were included in the analysis. Plasma cell-free DNA isolation and sequencing of ctDNA were performed using the Guardant 360 assay. Association of clinical outcomes with germline or somatic mutations of DNA damage repair (DDR) genes was analyzed. Somatic alterations other than DDR genes were also analyzed to find potential biomarkers of neoadjuvant mFOLFIRINOX. Progression free-survival (PFS) was defined as time from the initiation of mFOLFIRINOX to disease progression or any cause of death. Overall survival (OS) was defined as the time from the initiation of mFOLFIRINOX to any cause of death. Results: Among 44 patients, 28 patients had ctDNA sequencing data qualified for the analysis and were included in this study (15 patients with baseline data only, 3 patients with post-operative data only, and 10 patients with both baseline and post-operative data). Median age was 59 (range, 41-73) years and 15 patients (53.6%) were male. Among 25 patients with baseline plasma ctDNA data, 11 patients (44%) had somatic or germline alteration of DDR genes detected at baseline including ATM, BRCA1, BRCA2 and MLH1, and showed significantly better PFS than those without such DDR gene alterations (median 26.6 vs. 13.5 months, log-rank p = 0.004). Although there was a trend for better OS in patients with DDR gene alterations, this was not statistically significant (log-rank p = 0.29). The most observed baseline somatic alteration was TP53 (n = 7, 28%), followed by KRAS (n = 6, 24%). Patients with somatic KRAS mutation at baseline had significantly worse OS (median 8.5 months vs. not applicable, log-rank p = 0.003) than those without. Among 13 patients with post-operative plasma ctDNA data, 8 patients (61.5%) had detectable somatic alterations. Conclusions: Detection of germline or somatic mutations of DDR genes from plasma ctDNA at baseline was associated with better survival outcomes of patients with borderline resectable PDAC treated with neoadjuvant mFOLFIRINOX. Detection of DDR gene alterations from plasma ctDNA may have a potential role as biomarker for prognosis in patients with borderline resectable PDAC treated with mFOLFIRINOX.
Relationship between inflammatory indexes and Khorana score (KS) with prognosis and survival in pancreatic ductal adenocarcinoma (PDAC).
Authors: Martín Lozano Rocío , Jiménez Rodríguez Roberto , Gonzalez Caraballo Irene , Lobato Delgado Bárbara , Gómez María Palma , Muñoz Marc Ariant Cañete , de Lucas Mónica Benavente , López Jiménez Carlos , Tirado Anula Victoria , Morón García Blanca , de Toro Carmena María , Bringas Beranek Marianela , Soto Alsar Javier , Torres Pérez-Solero Gabriela , Calvo Aitana , Ortega Laura , Soria Jose Manuel , Garcia-Alfonso Pilar , Martin Miguel , Muñoz Martín Andrés J. 
Published: January 2023

740 Background: Several inflammatory scores such as the Systemic Inflammation Response Index (SIRI), the Inflammation Index Score (IIS), and the Neutrophil Lymphocyte Ratio (NLR) have been reported to have prognostic value in PDAC with different results. We hypothesize that the KS, designed to predict the risk of cancer-associated thrombosis, may also be a surrogate marker for inflammation to be included as a relevant prognostic index for PDAC. Methods: Baseline characteristics and individual SIRI, IIS, NLR and KS indexes from 197 PDAC patients diagnosed in our center between 2019 and 2021 have been retrospectively recorded. PFS and OS (Log-rank test) have been used to compare the different scores of each index in the whole population as well as in the metastatic setting. Kruskal-Wallis test and Mann-Whitney test were also done to determine if the SIRI varies significantly between KRS values. Results: Of the 197 patients analyzed, 41 were resectable (20.8%), 54 locally advanced (27.4%) and 102 metastatic (51.8%). Patients with intermediate risk according to KS (2 points, n = 131, 66.5%) had a significantly higher median PFS (8.4 vs. 4.8 months, p = 0.03) and significantly higher OS (12.9 vs. 7.7 months, p = 0.002) than those with high-risk (> 3 points, n = 66, 33.5%). The median OS for patients with low (< 3,000) and high (> 3,000) SIRI was 13.1 and 9.3 months respectively (p = 0.05). No significant differences were observed in PFS. In the metastatic setting, a low SIRI was significantly associated with higher OS (10.6 vs. 5.8, p = 0.016). No significant differences were observed in patients with low vs. high IIS and NLR. The Kruskal-Wallis test indicates that SIRI values vary between at least two KS values (p < 0.001). The Mann-Whitney test found significant differences between the SIRI values from S 2 and 3 (p = 0.002) as well as 2 and 4 (p = 0.04). SIRI values were higher in patients with KRS > 3 vs. 2. Conclusions: This retrospective analysis showed that patients with lower KS live longer and progress later than those with higher KS. Lower SIRI is associated with better survival in metastatic patients, being on the verge of statistical significance in the whole cohort. There is a strong correlation between SIRI and KS. In this cohort of unselected PDAC patients, KS is a prognostic factor for OS and PFS that correlates with subclinical inflammation and demonstrates to be a better predictor than other inflammatory indexes that deserves further analysis.
Development of artificial intelligence–derived histological biomarkers for first-line treatment selection in metastatic pancreatic ductal adenocarcinoma (mPDAC).
Authors: Krishna Viswesh , Tiu Ekin , Krishna Vrishab , Vrabac Damir , Shah Kunal , Abuzeid Waleed , Smith Katelyn , Davelaar John , Nuesca Christopher , Larson Brent K , Fountzilas Christos , Rajpurkar Pranav , Hendifar Andrew Eugene , Collisson Eric Andrew , Joshi Anirudh , Singhi Aatur D. 
Published: January 2023

743 Background: The prognosis of metastatic pancreatic ductal adenocarcinoma (mPDAC) remains poor with a median survival time of 10-12 months. First-line treatment is largely influenced by performance status with fit patients more often receiving FOLFIRINOX (FFX) than Gemcitabine+Nab-Paclitaxel (GNP). Although the two regimens have improved outcomes over gemcitabine monotherapy, no biomarkers routinely used in clinical practice can predict which regimen is optimal to facilitate a precision medicine approach. We developed two signatures (V-FFX and V-GNP) associated with treatment outcomes for the respective first-line regimens using a retrospective cohort of mPDAC cases. Methods: We conducted a retrospective study of mPDAC patients treated at two institutions (UPMC and Cedars Sinai) from 2014 to 2021. Digitized histological H&E sections corresponding to 145 metastatic PDAC patients treated with either first-line FFX or GNP were included. Independent randomized training and test datasets were constructed for FFX-treated (train: 41, test: 25) and GNP-treated (train: 49, test: 30) patients. To construct the histological assay, a deep-learning algorithm then segmented nuclei to extract quantitative histological features. Features associated with disease-specific survival (DSS) for FFX and GNP were identified utilizing univariate Cox proportional hazards (CPH) models for the respective training sets and V-FFX and V-GNP signatures were constructed. DSS stratification of the V-FFX and V-GNP signatures were examined using Kaplan-Meier analysis and the log-rank test and DSS percentages at 12 months were calculated on the respective test sets. Results: The V-FFX and V-GNP signatures were found to be significantly associated with treatment outcomes stratified in the respective test sets (log-rank test, V-FFX: p=0.046, V-GNP: p=0.004). 29 of 55 patients tested positive for only one of either V-FFX and V-GNP signatures. Kaplan-Meier analysis demonstrated robust separation with hazard ratios for the V-FFX and V-GNP signatures of 3.01 (95% CI: 0.96, 9.45) and 4.81 (95% CI: 1.74, 13.3). DSS at 12 months for patients in V-FFX +ve vs -ve groups were 88% (8/9) vs 50% (7/14). DSS at 12 months for patients in V-GNP +ve vs -ve groups were 66% (8/12) vs 15% (2/13). Conclusions: AI derived V-FFX and V-GNP morphological signatures were strongly associated with treatment outcomes for first-line FFX and GNP and can potentially aid in the selection of first-line treatment for mPDAC patients.
Impact of KRAS mutation variants on clinicopathological features and outcomes in patients with metastatic pancreatic adenocarcinoma.
Authors: Patel Chirag , Sha Wei , Salem Mohamed E. , Musselwhite Laura W. , Hwang Jimmy J. , Kadakia Kunal C. 
Published: January 2023

749 Background: Most pancreatic ductal adenocarcinoma (PDAC) exhibit KRAS mutations. A subset of PDACs harbor KRAS wild-type (WT) and appear to carry better prognosis. Given the recent development of KRAS G12C inhibitors, it is imperative to better understand KRAS variants in contemporary cohorts. Herein, we characterized the prevalence of the different KRAS variants and its impact on clinicopathological features and outcomes. Methods: A retrospective review of patients with metastatic PDAC and a known KRAS mutation status who underwent next-generation sequencing (NGS) from liver biopsy was performed. Descriptive statistics analyzed the differences in clinicodemographic features by presence and type or absence of KRAS variants. Kaplan-Meier method was used to assess overall survival (OS). Cox regression was used to study the relationship between KRAS variants and OS when confounding factors were adjusted. Results: 50 pts with PDAC diagnosed at a single community-based institution between 2011-2018 were evaluated. Median age at diagnosis was 68 years (24-80 range), 68% were male, and 76% presented with metastases. Most (86%) tumors harbored KRAS mutations. The most frequent variants were G12V (44%), G12D (37%), G12R (9%), Q61R (5%), G12C (2%), Q61H (2%). Sex (p=0.03) and tumor differentiation (p=0.04) varied according to mutation status and KRAS variant subtype. However, no significant difference was observed in age, race, smoking status, location of primary, and performance status (PS) in KRAS variants. Overall, median OS in months was 8.9 (95% CI 6.7-14.3) for KRAS mutated patients and 11.2 (95% CI 2.1-33.5) for patients with WT. Among patients with KRAS mutations, median OS in months by variant was as following: G12V 9.6 (95%CI 6.6-17.2), G12D 8.4 (95%CI 3.9-15.4), G12R 8.2 (95%CI 1-20.8), and Q61R 11.8 (95%CI 1.3-22.3). However, these differences did not reach statistical significance (p=0.72). In multivariable analyses, female sex (HR 0.16, 95% CI 0.03-0.81, p=0.03) and no receipt of chemotherapy (38.5 95% CI 2.1-698.50, p=0.01) were significant predictors of death. KRAS mutation variant type was not an independent predictor of death. Conclusions: No significant difference was observed in metastatic PDAC with KRAS mutations compared to WT. However, numerical difference in OS were observed among the various KRAS mutation type. Hence, larger studies are needed to better define the effect of KRAS type on outcomes.