bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neoadjuvant gemcitabine, docetaxel, and capecitabine results in comparable surgical outcomes to modified FOLFIRINOX in patients with pancreatic ductal adenocarcinoma who also receive radiation: A single institution experience.
Authors: Wong Winston , Jamison Jacob K.R. , May Michael S. , Michel Alissa , Lee Tristan , Manrique David , Raufi Alexander , Pan Samuel M , Safyan Rachael A , Horowitz David Paul , Schrope Beth , Kluger Michael , Kachnic Lisa A. , Hu Jianhua , Bates Susan Elaine , Chabot John A. , Manji Gulam Abbas 
Published: January 2022

565 Background: Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis with a minority of patients (pts) eligible for curative resection. Currently, systemic treatment options for down-staging pts with borderline resectable or locally advanced PDAC is extrapolated from the metastatic setting and modified FOLFIRINOX (FFX) +/- radiation (RT) is the most widely used regimen. Herein, we report the outcomes of combination gemcitabine, docetaxel, and capecitabine (GTX) +RT as compared to FFX +RT in the neoadjuvant (NA) setting via a single institution retrospective cohort review. Methods: We retrospectively reviewed the outcomes of pts with PDAC who underwent surgical resection at Columbia University Irving Medical Center (CUIMC) between 2011-2020. We evaluated demographics, treatment, clinical, surgical, and pathological outcomes. Statistical analysis includes Kaplan-Meier analysis and paired t-tests. Results: We reviewed 717 pts who underwent surgical resection at CUIMC of which 227 pts were confirmed to have received NA chemotherapy. Of those 227 patients, 133 pts also received RT. In total, 39 pts received GTX+RT and 42 pts received FFX+RT. Median age at diagnosis of pts who received NA GTX+RT or FFX+RT was 65 and 63 years, respectively. All pts were AJCC stage III at diagnosis and ECOG 0 or 1. There was a significantly greater percentage of pts who achieved R0 resection after GTX+RT as compared to FFX+RT, 35 (89.7%) vs 29 (69.0%), respectively (p=0.022). Significantly more pts achieved N0 lymph node status after GTX+RT as compared to FFX+RT, 29 (74.4%) vs 22 (52.4%), respectively (p=0.041). No statistically significant difference was detected in recurrence-free survival (RFS) or median overall survival (mOS) in pts who received GTX+RT and achieved R0 resection as compared to FFX+RT. See Table for summary. Conclusions: GTX appears to be a viable and active NA regimen in Stage III PDAC. In our small cohort study, more patients who received GTX+RT achieved R0 resection and N0 status as compared to FFX+RT. No difference in survival was detected but this may be due to inadequate power or choice of subsequent therapies. Larger prospective studies evaluating GTX+RT as an alternative treatment in the NA setting are warranted.[Table: see text]
“Super massive” intrahepatic cholangiocarcinoma: Potential role of radiation therapy.
Authors: Abi Jaoude Joseph , De Brian , Nieves Jiménez Humberto R , Upadhyay Rituraj , Taniguchi Cullen M. , Koay Eugene Jon , Ludmir Ethan B. 
Published: January 2022

567 Background: Intrahepatic cholangiocarcinoma (ICC) is a cancer of the bile ducts within the liver. Most patients have unresectable disease and die of tumor-related liver failure (TRLF); prior data suggest that radiation therapy (RT) may play an important role in decreasing TRLF and improving survival. However, for patients with exceptionally large liver tumors, the role of RT is uncertain. Here, we present our experience using hypofractionated RT for so-called “super-massive” ICC (gross tumor volume > 800cc). Methods: We retrospectively collected data from ICC patients treated at the University of Texas MD Anderson Cancer Center. We included inoperable patients (both M0 and M1) who were treated with RT, identified those with a gross tumor volume of 800cc or more (median: 1,300cc IQR: 900-1,900). We analyzed overall survival (OS), local and distant recurrence, tumor-related liver failure (TRLF), and treatment toxicity. Results: A total of 12 patients were included. The median age was 60 (IQR: 55-67). The average maximal tumor diameter was 14.1cm (IQR: 12.6-15.8). All but 1 patient received pre-RT systemic therapy. Eight patients (67%) were treated with IMRT, and 4 patients (33%) with proton RT. RT was delivered to a median of 67.5Gy (IQR: 60-73.1) over 15 fractions. At a median follow up of 17.4 months, 5 patients were still alive (2-year OS: 41.7%). Median OS, local recurrence, and distant metastasis from RT were 20.0, 20, and 11.3 months, respectively. Two patients (16.7%) died from TRLF. No grade 2 or higher toxicities were noted. No radiation-induced liver toxicity was present. Conclusions: Hypofractionated RT was safe and showed promising clinical outcomes for patients with “super massive” inoperable ICC, compared to historical data. Future studies are still needed to better assess the role of RT in this patient population.
Prognostic factors associated with survival in patients with pancreatic cancer treated on early phase immune-checkpoint inhibitor clinical trials.
Authors: Surana Rishi , Rogers Jane E. , Nogueras-Gonzalez Graciela M. , Hong David S. , Yap Timothy A. , Rodon Ahnert Jordi , Naing Aung , Wolff Robert A. , Smaglo Brandon George , Meric-Bernstam Funda , Subbiah Vivek , Pant Shubham 
Published: January 2022

577 Background: Immune-checkpoint inhibitors (ICI) have altered the treatment landscape of various solid tumors, but clinical outcomes in patients with pancreatic ductal adenocarcinoma (PDAC) continue to remain dismal. Data are needed to determine prognostic factors of survival to ICI-therapies in pancreatic cancer to better inform future recruitment in immunotherapy-based early clinical trials. Methods: This is a single center, retrospective analysis of patients with PDAC treated with ICI-based therapy as part of phase I trials at MD Anderson Cancer Center. Patients enrolled in a phase I study and treated between 2014 to 2021 were included in the analysis. Descriptive analysis included patient characteristics, progression free survival (PFS) and overall survival (OS). Cox proportional hazards were used to assess associations between patient or tumor characteristics and survival endpoints. Results: One hundred and twenty-two patients were included in this study and received a median of two prior lines of therapy (IQR 1-3). The most commonly utilized ICI were PD-L1 inhibitors (56%) and PD-1 inhibitors (34%). Most patients (96%) received ICI in combination with another investigational agent and 9% of patients received ICI in combination with chemotherapy. The median duration of treatment was 1.38 months (IQR 0.69-2.56). The median PFS was 1.81 months (95% CI 1.78-2.04) and the median OS was 4.83 months (95% CI 4.08-5.92). Univariate analysis showed improved PFS in patients with an albumin of ≥3.5 (1.94 vs 1.32 months, HR 0.29, 95% CI 0.14-0.60, p = 0.001) and Hgb ≥10.5 (1.87 vs 1.81 months, HR 0.63, 95% CI 0.4-0.98, p = 0.039); a longer OS was demonstrated in patients who had lung only metastases (7.92 vs. 4.18 months, HR 0.4, 95% CI 0.21-0.76, p = 0.006), albumin ≥3.5 (5.52 vs. 1.68 months, HR 0.4, 95% CI 0.2-0.8, p = 0.010), and a Hgb ≥10.5 (5.29 vs 4.11 months, HR 0.59, 95% CI 0.38-0.93, p = 0.022). Patients with an ANC/ALC ratio of ≥5 had a shorter OS compared to patients with an ANC/ALC ratio of < 5 (3.98 vs 6.54 months, HR 1.78, 95% CI 1.17-2.69, p = 0.007). Multivariate analysis showed that an albumin ≥3.5 predicted improved PFS (HR 0.41, 95% CI 0.19-0.90, p = 0.026) and an ANC/ALC ratio of ≥5 predicted shorter OS (HR 2.59, 95% CI 1.59-4.19, p < 0.001). Conclusions: Results of this large, single center retrospective study demonstrate that most patients with PDAC treated with ICI based therapies as a part of early phase clinical trials experience disease progression shortly after initiation of therapy and have a limited overall survival. Pretreatment albumin ≥3.5 predicted improved PFS and ANC/ALC ratio ≥5 predicted shorter OS.
Phase 2 study of 9-ING-41, a small molecule selective glycogen synthase kinase-3 beta (GSK-3β) inhibitor, with gemcitabine/nab-paclitaxel (GnP) in first-line advanced pancreatic ductal adenocarcinoma (PDAC).
Authors: Mahalingam Devalingam , Carneiro Benedito A. , Safran Howard , Powell Steven Francis , Coveler Andrew L. , Davis Elizabeth J. , Cervantes Andres , Sahai Vaibhav , Steeghs Neeltje , Huerta Marisol , Berlin Jordan , Mulcahy Mary Frances , Giles Francis J. , Cavalcante Ludimila , Saeed Anwaar 
Published: January 2022

578 Background: GSK-3β overexpression is associated with worse prognosis and chemotherapy resistance in PDAC. GSK-3β inhibition reverses chemotherapy-resistance by inhibiting chemotherapy-induced, ATR-mediated, DNA damage response. 9-ING-41 has significant anti-tumor activity through apoptosis induction, anti-fibrotic activity and NK/T-cell effector stimulation. We hypothesized that 9-ING-41 in combination with GnP chemotherapy would lead to anti-tumor activity, with improved tumor responses in patients with advanced PDAC in the first line setting. Methods: Primary endpoint is disease control rate (DCR). DCR = confirmed complete response (CR), partial response (PR), or stable disease (SD) ≥ 16 weeks (wks). Secondary endpoints are safety and ORR (overall response rates). Eligibility: Advanced PDAC, ECOG PS 0-2, no prior therapy in the metastatic setting and no systemic therapy in prior 6 months. Pts received 9-ING-41 15mg/kg IV twice-weekly with G 1,000 mg/m2 and nP 125 mg/m2 on days 1,8,15 of a 28-day cycle. Simon 2-Stage Design for DCR of 65% and null hypothesis of 50% (historical control), 80% power and 2 sided-significance level of.05. Up to 23 fully evaluable pts planned for stage 1 and if ≥ 12 evaluable patients achieve a DCR 37 additional pts will be enrolled on a second stage or a randomized study commenced. Results: As of Sept 27, 2021, 42 pts enrolled. Median age: 67. 24 females, 18 males. 38 pts with metastatic and 4 with locally advanced disease. Prior adjuvant therapy: 4 pts each FOLFIRINOX and gemcitabine-based. No 9-ING-41-attributable SAEs to date. 9-ING-41 attributed AEs: visual disturbance: 24 (75%) G1/2, 1 (3%) G3; infusion reactions 9 (28%) G1/2. Chemotherapy-related AEs: anemia 13 (40%) G1/2, 1 (3%) G3; neutropenia 2 (6%) G1/2, 13 (40%) G3/4; thrombocytopenia 9 (28%) G1/2, 2 (6%) G3/4; diarrhea 8 (25%) G1/2, 4 (13%) G3; fatigue 9 (28%) G1/2, 3 (9%) G3; nausea/vomiting 24 (75%) G1/2, 1 (3%) G3; constipation 9 (28%) G1/2; febrile neutropenia 5 (16%) G3/4. In 21 pts currently evaluable for response, DCR was 62% and ORR 43%. There were 2 confirmed CRs, 6 confirmed and 1 unconfirmed PRs, 4 SD and 8 disease progressions were observed. Amongst responder’s median duration of response has not yet been reached. Conclusions: 9-ING-41 plus GnP demonstrated encouraging clinical activity but chemotherapy-related AEs were significant. Based on efficacy data to date, including confirmed CRs, we have commenced a randomized phase 2 study, evaluating 9-ING-41 plus GnP vs Gn P alone. Enrollment to the randomized study is now open (NCT03678883). Clinical trial information: NCT03678883.
Prognosis and correlation with Ca19.9 of circulating tumor cells (CTCs) in locally advanced and metastatic pancreatic cancer.
Authors: Muñoz Martín Andrés J. , Ortega Morán Laura , Gutiérrez Alonso Natalia , Megias Diego , Lopez-Alfonso Ana , del Monte Millán Maria , Bernat Rebeca , Martín Lozano Rocío , Jiménez Rodríguez Roberto , Gonzalez Caraballo Irene , Villarejo López Lucía , Massarrah Tatiana , Torres Pérez-Solero Gabriela , Calvo Ferrándiz Aitana , Blanco-Codesido Montserrat , Garcia-Alfonso Pilar , Martin Miguel 
Published: January 2022

586 Background: In recent years CTCs have been extensively studied in different neoplasms. However, in PC CTCs are still emerging as a potential prognostic tool and the significance in different stages of the disease and the correlation with tumor markers are poorly understood. Methods: We conducted an observational, prospective, cohort study in two Spanish centers. Isolation was carried out with Isoflux technology (Fluxion Biosciences, Inc. San Francisco, CA, USA), that is combining cell separation by immunomagnetic particles (positive selection) with a microfluidic system. Before isolation, it was performed a first cell enrichment step using the density gradient cell separation technique (Ficoll). Four different markers were used, including two mesenchymal markers, EpCAM and EGFR (EMT Enrichment Kit:EpCAM/EGFR/Mesenchymal). The count of CTCs was done in a confocal microscope using the iMSRC (intelligent Matrix Screen Remote Control). A high throughput system was performed over the entire area, using a 20x objective, increasing to a 60x objective. Primary endpoint was the prognostic significance of CTCs, correlating the number of CTCs at diagnosis with overall survival. Secondary endpoints: Correlation between number of CTCs with Ca19.9/CEA values, and the difference in the median value of CTCs in metastatic compared to locally advanced disease. CTCs were analyzed at day 0 (CTC-0), just before first chemotherapy cycle was administered. Results: Thirty-four patients were analyzed. Clinical characteristics: Table 1. Median follow up 12.0 months. Median value of CTC-0 was 347 (range 104 - 3273) for metastatic and 436 (81 - 1082) for locally advanced patients (p = 0.942). Correlation coefficient for Ca 19.9 0.006 (p = 0.97); CEA correlation coefficient 0.191 (p = 0.303). For a cutoff of 500 CTCs, we found an AUC of 0.8 for mortality. Kaplan-Meier analysis showed an estimated median overall survival for patients with ≥500 CTCs of 8.6 months (95% confident interval [95% CI] 5.3 – 12) vs not reached for patients with < 500 CTCs (p = 0.007). HR for mortality 3.3 (95% CI 1.3 – 8.4; p = 0.011) for patients with ≥ 500 CTCs. Conclusions: Our data suggest 500 CTCs might be a potential cutoff for prognostic assessment. The absence of differences of CTC-0 between metastatic and locally advanced patients supports the idea of a systemic disease irrespective of the presence of metastases at diagnosis. CTC-0 seems not to correlate with tumor markers at diagnosis.[Table: see text]
Efficacy of MDX-124, a novel anti-annexin-A1 antibody, in preclinical models of pancreatic cancer.
Authors: Dempsey Fiona C. , Al-Ali Hussein , Crichton Scott J. , Fabian Charlene , Roberts Emily , Pepper Chris , Schmid Michael C. , Parris Christopher N. 
Published: January 2022

590 Background: Pancreatic cancer is a highly fatal disease with poor survival and response to both chemotherapy and immunotherapy. Novel approaches to treat this disease are urgently required. Annexin-A1 (ANXA1) is secreted in response to several physiological stimuli where it activates formyl peptide receptors (FPR1/2) triggering multiple oncogenic processes. High ANXA1 expression in pancreatic cancer patients is associated with poor overall survival, and influences cancer progression, drug sensitivity, migration and invasion. MDX-124 is a novel humanized antibody targeting ANXA1 and we have previously presented data demonstrating its significant antiproliferative activity. Here we present further data showing the efficacy of MDX-124 in several preclinical models of pancreatic cancer. Methods: In-vitro models utilized MIA PaCa-2, PANC-1 or BxPC-3 human pancreatic cancer cell lines. Cell cycle progression was evaluated by measuring changes in DNA content via flow cytometry. Pancreatic cancer cell viability following incubation with MDX-124 (0-10 µM) and 5FU (IC50) was assessed via MTT assay. A transwell migration assay was used to evaluate the effect of MDX-124 (0-50 µM) on pancreatic cancer cell migration. In-vivo efficacy was evaluated using an orthotopic mouse model of metastatic pancreatic cancer (FC1242luc/zsGreen; KPC-derived cell line) with bioluminescent imaging used to quantify the incidence and burden of lung metastases. Results: When compared to untreated MIA PaCa-2 pancreatic cancer cells, MDX-124 treatment decreased the proportion of cells in S-phase by 29% and G2 phase by 9.1%, with a concomitant increase in G1 of 38.1%. This occurred in a dose-dependent manner and is consistent with an MDX-124 mediated increase in cell cycle arrest. MDX-124 significantly reduced the viability of MIA PaCa-2 and PANC-1 cell lines versus an IgG control in a dose-dependent manner. Additionally in these two cell lines, combination of MDX-124 with 5FU (IC50) had a significant synergistic impact reducing cancer cell viability by 99.8% and 91.2% respectively. Furthermore, MDX-124 significantly reduced the migratory ability of MIA PaCa-2 and BxPC-3 pancreatic cancer cells. In the orthotopic model of metastatic pancreatic cancer, the murine analog of MDX-124 (MDX-001), markedly reduced both the incidence and size of lung metastases. Conclusions: MDX-124 demonstrated significant anti-tumor efficacy in several preclinical models of pancreatic cancer as a single agent, with increased potency observed when used in combination with 5FU. Medannex will initiate a First-In-Human study in Q4 2021 to evaluate MDX-124 in solid malignancies, including pancreatic cancer.
Secretory leukocyte proteinase inhibitor: A key player in the dialogue between the tumor and its microenvironment in pancreatic cancer patients.
Authors: Chuluyan Eduardo , Ambrosi Nella , Fraunhoffer Nicolas , Caro Fiorella , Remolins Carla , Reiteri Macarena , Guerrieri Diego , Soubeyran Philippe , Gayet Odile , Roques Julie , Nelson Dusetti J. , Incardona Claudio A. , Iovanna Juan 
Published: January 2022

592 Background: Secretory leukocyte proteinase inhibitor (SLPI) is a non-glycosylated pleiotropic protein with anti-protease, microbicidal, healing, anti-inflammatory and immunomodulatory activity. Previous studies have shown that SLPI is associated with pancreatic tumor progression by promoting cancer cell survival and proliferation. However, SLPI can also act on the tumor microenvironment to affect the local immune response. In the present work we evaluate the role of SLPI in patients with pancreatic cancer and its activity as a tumor escape factor from the immune response. Methods: Serum levels of SLPI was measured in pancreatic cancer patients by sandwich ELISA. RNA-seq was performed on 76 patient-derived xenografts (PDX) and we computed independent component analysis focusing the study on the component that best correlated with SLPI gene. Secretome analysis was performed on 38 different cell lines cells culture derived from PDX. Human monocytes were isolated and differentiated into immature dendritic cells in the presence or absence of SLPI or in the presence of a pancreatic tumor cell line that did or did not express SLPI. Results: The frequency distribution of serum SLPI values showed patients with low and high SLPI value (cut-off value 61.5 ng/ml). Most patients with high serum SLPI concentration had unresectable tumors. There was an indirect association between serum SLPI levels and the time of disease recurrence. The transcriptome analysis showed that expression of SLPI is associated with immune and cancer functional clusters. The analysis of the secretome showed that SLPI was present in all cell lines from PDX. The heat map of the secretome exhibited that SLPI was directly associated with factors described in tumor microenvironment and related with tumor immune evasion mechanisms, such as CSF1, SECTM1, LGALS3, IL1RN, CD59, CD55, CD46, Fas, PVR, PVRL2. Remarkably, the closest group associated with SLPI was CSF1. The latter contributes to the depressed function of antigen-presenting cells, as a result of skewed differentiation of monocytes towards macrophage-like cells rather than dendritic cells. Furthermore, in vitro experiments demonstrated that SLPI or SLPI-producing pancreatic tumor cell lines impaired the differentiation of human monocytes towards dendritic cells and their immunostimulatory capacity. Conclusions: These results suggest that SLPI may contribute to the immunosuppressive microenvironment of pancreatic cancer by acting as a tumor immune evasion factor. Clinically, this SLPI activity could be reflected in the association of the serum SLPI value with disease recurrence or progression.
Comparative molecular profiling of pancreatic ductal adenocarcinoma (PDAC) of the head (H) versus body/tail (B/T) and the tumor immune microenvironment (TIME).
Authors: Abdelrahim Maen , Kasi Anup , Baca Yasmine , Xiu Joanne , Walker Phillip , Korn Wolfgang Michael , Lou Emil , Shields Anthony Frank , Weinberg Benjamin Adam 
Published: January 2022

598 Background: PDAC of the H and B/T differ in embryonic origin, cell composition, blood supply, lymphatic and venous drainage, and innervation. H tumors tend cause symptoms earlier and to present at earlier stages compared to B/T cancers. The impact of PDAC tumor location on patient presentation and survival has been shown in large national data-based analyses, although with conflicting results. We aimed to compare the molecular and tumor immune microenvironment (TIME) profiles of PDAC of the H vs. B/T. Methods: A total of 3499 PDAC samples were analyzed via next-generation sequencing (NGS) of RNA (whole transcriptome, NovaSeq), DNA (NextSeq, 592 genes or NovaSeq, whole exome sequencing) and immunohistochemistry (IHC, Caris Life Sciences, Phoenix, AZ). RNA deconvolution was performed using QuantiSeq (Finotello 2019, Genome Medicine) to quantify the immune cell infiltration. Pathway gene enrichment analyses were done using Gene Set Enrichment Analysis (GSEA, Subramaniam 2015, PNAS). Significance was determined as p values adjusted for multiple correction (q) of < 0.05. Results: Anatomic subsites of PDAC tumors were grouped by primary tumor sites into H (N = 2058) or B/T (N = 1384). There were significantly more metastatic tumors profiled from H vs. B/T (57% vs. 44%, p < 0.001). KRAS mutations (93.8% vs. 90.2%), genomic loss of heterozygosity (12.7% vs. 9.1%), and several copy number alterations ( FGF3, FGF4, FGF19, CCND1, ZNF703, FLT4, MUTYH, TNFRS14) trended higher in B/T when compared to H (p < 0.05 but q > 0.05). GNAS mutations (2.2% vs. 0.7%) trended higher in H vs. B/T (p < 0.05). No significant difference in immuno-oncology (IO) markers (TMB, PD-L1, MSI-H) were observed, but expression analysis of IO-related genes showed significantly higher expression of CTLA4 and PDCD1 in H (q < 0.05, fold change 1.2 and 1.3) and IDO1 and PDCD1LG2 expression trended higher in B/T (p < 0.05, fold change 0.95). When comparing median cell abundance values as part of TIME analysis, H had increased immune infiltration of B cells (0.045 vs. 0.043), M2 macrophages (0.035 vs. 0.032), neutrophils (0.056 vs. 0.052), NK cells (0.027 vs. 0.026), CD8+ T cells (% > 0: 48.2% vs. 43.2%), while B/T had increased infiltration of M1 macrophages (0.035 vs. 0.032) (all q < 0.05). GSEA showed enrichment of CTLA4 (normalized enrichment score (NES) 1.6, false discovery rate (FDR) 0.19) and primary immunodeficiency pathway enrichment (NES 1.7, FDR 0.11) in H. Conclusions: To our knowledge, this is one of the largest cohort of PDAC tumors subjected to broad molecular profiling. Differences in IO-related gene expression and TIME cell distribution suggest that response to IO therapies may differ in PDAC arising from H vs B/T. Subtle differences in the genomic profliles of H vs. B/T tumors were also observed.