Primary Pancreatic Cancer Research Articles

Abstract 3955: Functional evaluation of pancreatic cancer prognostic marker, LXN, utilizing multiomics analysis based on patient-derived cancer model

Abstract Background: Pancreatic cancer is the most dreadful malignant tumor and expected becoming the second cause of death in 2030. Despites of vigorous studies, there were no definitive prognostic biomoleculars marker for pancreatic cancer. Herein, we already established primary pancreatic cancer cell lines from the real patients of pancreatic cancer, using conditionally reprogrammed cell culture (CRC). We tried to find novel prognostic biomarkers with multi-omics analysis of our primary pancreatic cancer cell lines. Methods: In this study, we selected pancreatic cancer prognostic markers using established CRCs and FFPE samples and validated the molecular mechanism of LXN. As the first step, we performed both transcriptome and proteome analysis using RNA sequencing and liquid chromatography-tandem mass spectrometry (LC/MS-MS) with 6 primary pancreatic cancer cell lines established by CRC. After analysis, we mined several candidate markers of prognosis including latexin (LXN) and sialic acid acetylesterease (SIAE). And we validated these markers clinicopathologically using immunohistochemical (IHC) staining of 136 tissues from a different set of pancreatic cancer patients. And we confirmed the knock-down effect of LXN using siLXN in pancreatic cancer cells. Results: We selected 2 highly prognostic markers with LXN and SIAE after transcriptome and proteome analysis. In these genes, high LXN expression group showed longer median overall survival (OS) than low expression group, respectively (14.8 vs. 10.4 months, P-value=0.28), respectively. For the evaluation of IHC, we established 3D organoid model using CRCs and confirmed the correlation between mRNA expression and protein expression with western blotting and IHC. The expression of Akt/mTOR was decreased after siLXN treatment compared to control groups. In order to validation as a prognostic marker, we stained formalin-fixed, paraffin-embedded (FFPE) slide from 136 pancreatic cancer patients. After IHC analysis, LXN high group (H-score > 12) showed significantly longer OS than low LXN group (52 vs. 28 months, P-value = 0.043). Conclusion: In this study, we found LXN as a prognostic marker with inhibition of proliferation utilizing patient-derived cancer model and FFPE samples. Citation Format: Chan Hee Park, Hee Seung Lee, Jin Su Kim, Yoo Keung Tae, Jin Young Lee, Seungmin Bang. Functional evaluation of pancreatic cancer prognostic marker, LXN, utilizing multiomics analysis based on patient-derived cancer model. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3955.

Abstract 816: Biological evaluation of novel stearoyl gemcitabine nanoparticles in primary pancreatic cancer cells and PDX mice tumor models

Abstract Purpose: This study aimed to improve the systemic stability and enhance the anticancer activity of gemcitabine (Gem) by modifying Gem with stearic acid to form 4-N-stearoylGem (4NSG). The 4NSG compound was formulated into solid lipid nanoparticles and tested against patient-derived pancreatic cancer (PCa) cell lines and patient-derived xenograft (PDX) mice bearing subcutaneous tumors. Methods: Gem was modified by linking the 4-amino group of Gem and stearoyl acyl derivative to form 4-(N)-stearoyl-gemcitabine (4NSG). 4NSG was characterized using high-performance liquid chromatography (HPLC), nuclear magnetic resonance (NMR), and elemental analysis. 4NSG was developed into solid lipid nanoparticles (4NSG-SLN) and characterized using a particle size analyzer. Patient-derived primary PCa cells (PPCL-46 and PPCL-68) were treated with GemHCl and 4NSG-SLN. Cytotoxicity, cell migration, and cell-cycle studies were performed to determine the effectiveness of 4NSG-SLN against primary PCa cell lines. We performed antitumor efficacy testing using GemHCl and 4NSG-SLN in PDX mice bearing subcutaneous pancreatic tumors. Results: Analysis of the H-NMR spectra displayed an amide bond at 10.88 ppm, confirming the conjugated bond between the 4-amino group of Gem and stearic acid. The purity of 4NSG was 99.8%. The hydrodynamic diameter (particle size) of 4NSG-SLN was 82±2.3nm, while the blank nanoparticle (SLN) was found to be 35 ± 4.3 nm. The half-maximal inhibitory concentration of 4NSG-SLN-treated PPCL-46 (IC50 =12 ± 2.1µM) and PPCL-68 cultures (IC50 =22 ± 2.6µM) showed higher cytotoxic activity compared with GemHCl-treated PPCL-46 and PPCL-68 cultures respectively (IC50 = 56 ± 2.4 µM, IC50 = 57 ± 1.5 µM, p-value: p<0.001). Our migration study showed 4NSG-SLN treated PPCL-46 cells at 5μΜ concentrations significantly reduced cell mobility towards the wound area with (28 ± 3.5) number of cells migrated compared to GemHCl treatment which showed (120 ± 3.8). The cell-cycle analysis showed that 4NSG-SLN treated PPCL-46 cells at 5μΜ concentration had a higher G1 population (78.25%) than GemHCl (72.75%). 4NSG-SLN may have triggered apoptosis in PPCL-46 cells (2.45%) at 20μΜ in the S and G2/M phases compared to GemHCl treatments which showed a higher cell population of (9.54%).4NSG-SLN treated PDX mice exhibited a two-fold decrease in tumor growth compared to GemHCl-treated PDX mice bearing tumors. Conclusion: This study reveals that 4NSG-SLNs may potentially prolong Gem's systemic circulation, increase its bioavailability, and, most importantly, enhance the therapeutic efficacy of Gem in the treatment of PCa. Citation Format: Esther K. Frimpong, Andriana Inkoom, Nkafu B. Ndemazie, Raviteja Bulusu, Joy C. Okoro, Bo Han, Jose Trevino, Edward Agyare. Biological evaluation of novel stearoyl gemcitabine nanoparticles in primary pancreatic cancer cells and PDX mice tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 816.

Abstract 5603: Functional studies on viable circulating tumor cells (v-CTCs) and frequent expression of PD-L1 on v-CTCs in pancreatic cancer

Abstract Introduction: The analysis of CTCs as liquid biopsies provides the possibility to avoid invasive tissue biopsies, with obvious implications in cancer diagnostics and treatments. We tested new methods for v-CTCs detection in patients (pts) with pancreatic cancer (PC), and investigated the clinical potential of v-CTCs in prognosis. We analyzed the PD-L1(L1) expression in primary PC tumors, metastatic lymph nodes (LN) and v-CTCs. Pts and Methods: 7.5 ml of venous blood was collected from 39 PC pts, either upfront surgery (U group) or pre-treatment, consisted of Gem:800mg/m2; and S-1:80mg/m2 given concurrently with IMRT to 60Gy ((NACRT:N group). To detect v-CTCs, we employed a telomerase-specific replication-selective adenovirus expressing GFP. For U group, samples were obtained before/after resection. For N group, samples were obtained before/after NACRT and after resection. To distinguish between leucocyte and cells with either epithelial or mesenchymal origin, cells were stained by anti-CD45, anti-Cytokeratin and anti-Vimentin Abs. GFP-positive and CD45-negative cells were counted as v-CTCs. To assess L1 expression in PC tissues (PC tumors and LN) and on v-CTCs, L1 IHC kit (22C3, for tissues) and anti-human L1 mAb(MIH1, for CTCs) were employed. Results: U group: 24 pts aged 53~85 years (male/female=12/12) were enrolled. 24 pts underwent curative resection. No v-CTCs were detected in 6 pts at both before and after resection, and 5 of 6 pts survived without recurrence. V-CTCs were identified in 18 of 24 pts, and 13 of 18 pts developed liver metastasis. Marked decrease of CTC counts were seen after resection in 10 of 18 pts, but 9 pts developed recurrences. N group: 15 PC pts aged 44~77 years (male/female=4/11) were enrolled. 15 pts underwent curative resection. No v-CTCs at 3 sampling points were detected in 5 pts, and 5 pts survived without recurrences. V-CTCs was identified in 10 of 15 pts, and 4 out of 10 pts developed disease recurrence. Marked increase in CTC counts was observed after NACRT in 5 of 6 CTC-positive pts before NACRT, and 3 of 5 pts developed liver metastasis and died. NACRT may induce tumor cell dissemination into the blood circulation for CTC-positive pts. PD-L1 expression: L1 expression were assessed for 21 pts (U group:18, N group: 3). For PC tumors, L1 molecules were expressed in 12 pts and expression level of these pts were all low (57%, ≥50% [high]=0 pts, 1-49% [low]=12 pts {10%=6, 20%=4, 40%=2}, <1% [negative]=9 pts). For metastatic LNs, metastatic LNs were observed in 14 pts and L1-positive expression in these LNs were detected in only 4 pts (28%, all low expression). On the contrary, the majority of detected v-CTCs clearly expressed L1 molecule (92 CTCs out of 103 detected CTCs were L1-positive=89 %). Conclusions: Viable CTC detection appears as a good prognostic marker. Immunotherapy with anti-PD-1/PD-L1 Abs may target v-CTCs, resulted in improvement of poor prognosis. Citation Format: Masahiro Tanemura, Masaki Kashiwazaki, Kenichi Matsumoto, Kenta Furukawa, Manabu Mikamori, Tadafumi Asaoka, Daisaku Yamada, Shogo Kobayashi, Hidetoshi Eguchi. Functional studies on viable circulating tumor cells (v-CTCs) and frequent expression of PD-L1 on v-CTCs in pancreatic cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5603.

Small Nuclear RNA 64 (snoRNA64): A novel Tumor Biomarker for Pancreatic Cancer

The pancreatic ductal adenocarcinoma (PDAC), which represents over 90% of pancreatic cancer cases, has the highest proliferative and metastatic rate in comparison to other pancreatic cancer compartments. This study is designed to determine whether small nucleolar RNA, H/ACA box 64 (snoRNA64) is associated with pancreatic cancer initiation and progression. Gene expression data from the Gene Expression Omnibus (GEO) repository have shown that snoRNA64 expression is reduced in primary and metastatic pancreatic cancer as compared to normal tissues based on statistical analysis of the in Silico analysis. Using qPCR techniques, pancreatic cancer cell lines include PK-1, PK-8, PK-4, and Mia PaCa-2 with different levels of snoRNA64, including PK-1, PK-8, PK-4, and Mia PaCa-2. The level of expression is correlated with the cell line epithelial or mesenchymal characteristics. Cell lines displaying epithelial characteristics such as PK-1, PK-8 show high levels of snoRNA64 meanwhile, cell lines displaying mesenchymal characteristics such as PK-4, Mia PaCa-2 show low levels of snoRNA64. The level of expression is correlated with the cell line epithelial or mesenchymal characteristics. After knocking down the PK-8 with high snoRNA64 expression, the epithelial markers E. cadherin (E-cad) and Cytokeratin-8 (CK-8) are decreased, while mesenchymal markers Vimentin (Vim), Cytokeratin-19 (CK-19), Metalloprotease -2 (MMP-2), and Metalloprotease-3 (MMP-3) are activated. Those changes suggest that PK-8 responding to the snoRNA64 knock down protocol and increase in mesenchymal function. Together, snoRNA64 expression may participate in epithelial to mesenchymal transition (EMT) and mesenchymal to epithelial transition (MET), in which during metastasis these processes are crucial. In addition, snoRNA64 may be considered as a potential diagnostic biomarker for both early and invasive stages of PDAC. And due to its gradual expression decreases, it may be considered a barrier in tumor progression.

Identification of matrix-remodeling associated 5 as a possible molecular oncotarget of pancreatic cancer

Pancreatic cancer has an extremely poor prognosis. Here we examined expression, potential functions and underlying mechanisms of MXRA5 (matrix remodeling associated 5) in pancreatic cancer. Bioinformatics studies revealed that MXRA5 transcripts are significantly elevated in pancreatic cancer tissues, correlating with the poor overall survival, high T-stage, N1 and pathologic stage of the patients. MXRA5 mRNA and protein expression is significantly elevated in microarray pancreatic cancer tissues and different pancreatic cancer cells. In primary and immortalized (BxPC-3 and PANC-1 lines) pancreatic cancer cells, shRNA-induced MXRA5 silencing or CRISPR/Cas9-mediated MXRA5 knockout suppressed cell survival, proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT), while provoking cell apoptosis. Conversely, forced overexpression of MXRA5 further promoted pancreatic cancer cell progression and EMT. Bioinformatics studies and the protein chip analyses revealed that differentially expressed genes (DEGs) and differentially expressed proteins (DEPs) in MXRA5-overexpressed primary pancreatic cancer cells were enriched in the PI3K-Akt-mTOR cascade. Indeed, Akt-mTOR activation in primary human pancreatic cancer cells was inhibited by MXRA5 shRNA or knockout, but was augmented following MXRA5 overexpression. In vivo, the growth of MXRA5 KO PANC-1 xenografts was largely inhibited in nude mice. Moreover, intratumoral injection of adeno-associated virus-packed MXRA5 shRNA potently inhibited primary pancreatic cancer cell growth in nude mice. Akt-mTOR activation was also largely inhibited in the MXRA5-depleted pancreatic cancer xenografts. Contrarily MXRA5 overexpression promoted primary pancreatic cancer cell growth in nude mice. Together, overexpressed MXRA5 is important for pancreatic cancer cell growth possibly through promoting EMT and Akt-mTOR activation. MXRA5 could be a potential therapeutic oncotarget for pancreatic cancer.

Primary Human Pancreatic Cancer Cells Cultivation in Microfluidic Hydrogel Microcapsules for Drug Evaluation.

Chemotherapy is an essential postoperative treatment for pancreatic cancer, while due to the lack of effective drug evaluation platforms, the therapeutic outcomes are hampered by tumor heterogeneity among individuals. Here, a novel microfluidic encapsulated and integrated primary pancreatic cancer cells platform is proposed for biomimetic tumor 3D cultivation and clinical drug evaluation. These primary cells are encapsulated into hydrogel microcapsules of carboxymethyl cellulose cores and alginate shells based on a microfluidicelectrospraytechnique. Benefiting from the good monodispersity, stability, and precise dimensional controllability of the technology, the encapsulated cells can proliferate rapidly and spontaneously form 3D tumor spheroids with highly uniform size and good cell viability. By integrating these encapsulated tumor spheroids into a microfluidic chip with concentration gradient channels and culture chambers, dynamic and high-throughput drug evaluation of different chemotherapy regimens could be realized. It is demonstrated that different patient-derived tumor spheroids show different drug sensitivity on-chip, which is significantly consistent with the clinical follow-up study after the operation. The results demonstrate that the microfluidic encapsulated and integrated tumor spheroids platform has great application potential in clinical drug evaluation.

Pancreatic cancer with ovarian metastasis: cases report and literature review

Background: Pancreatic cancer with ovarian metastases is rare and easily misdiagnosed. Patients with ovarian metastases are first diagnosed with ovarian cancer and may miss the opportunity to receive surgical operation. We report 7 rare cases of ovarian metastases secondary to pancreatic adenocarcinoma and review the literature to analyze clinical characteristics, diagnostic methods, and potential therapeutic strategies for the rare malignancy. Cases Summary: We retrospectively analyzed the clinical data of 7 female patients with ovarian metastases of primary pancreatic cancer who were admitted to our hospital from January 01, 1985, to April 1, 2020. These 7 patients were diagnosed with ovarian metastasis at an average age of 52.28 (38–69) years. The reason for the patient’s visit was generally a mass in the lower abdomen and/or abdominal pain. Six of them had significantly higher serum Carbohydrate antigen19-9 (CA19-9) levels, 6 patients had pancreatic tumors located in the body or tail, and 1 patient had one in the head of the pancreas. All patients underwent excision of ovarian tumors and resection or biopsy of pancreatic tumors. Five patients had pancreatic ductal adenocarcinoma (PDAC), and 2 had pancreatic cystadenocarcinoma (PCC), all of which were revealed by the pathological results. Ovarian tumors were assessed by pathology and were consistent with pancreatic metastasis. Currently, all 7 patients have died (follow-up to January 2, 2021). The median survival time for all patients was 13.7 months (2.9–27 months). Conclusions: For this rare tumor, elevated serum CA19-9 may indicate that the primary lesion is in the pancreas. Enhanced pancreatic Computed Tomography (CT) can facilitate diagnostic localization. In addition, if the pancreatic tumor cannot be removed, the ovarian tumor should still be resected to reduce the tumor load and improve the quality of life.

Correction to: BTLA+CD200+ B cells dictate the divergent immune landscape and immunotherapeutic resistance in metastatic vs. primary pancreatic cancer

Correction to: BTLA+CD200+ B cells dictate the divergent immune landscape and immunotherapeutic resistance in metastatic vs. primary pancreatic cancer

Primary sclerosing cholangitis and pancreatic cancer: A retrospective cohort study of United States veterans.

This retrospective study used International Classification of Diseases, Tenth Revision (ICD-10) codes to identify patients with PSC, IBD, and pancreatic cancer from the Veterans Affairs (VA) Corporate Data Warehouse. The prevalence of pancreatic cancer in patients with PSC only, IBD only, PSC with IBD, and neither PSC nor IBD were compared. Logistic regression was used to control for age, gender, chronic pancreatitis, diabetes mellitus, and tobacco and alcohol use. A total of 946 patients with PSC were identified from a population of over 9 million veterans. 486 (51.4%) of these had concurrent IBD. Additionally 112,653 patients with IBD without PSC were identified. When adjusted for confounding factors, patients with PSC had a significantly higher prevalence of pancreatic cancer compared to the general population and those with IBD without PSC (2.4% vs. 0.2% and 0.5%, respectively). Veterans with PSC, particularly those without concomitant IBD, have a high prevalence of pancreatic cancer compared to the general veteran population. Our findings support the need for multicenter prospective studies investigating the benefits of screening for pancreatic cancer in patients with PSC.

Abstract B034: CXCR4 targeting endogenous human peptides eliminate migrating cancer stem cells by disrupting tumor-stroma crosstalk in pancreatic ductal adenocarcinomas

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer characterized by late diagnosis, lack of early symptoms and extensive metastasis. One of the foremost reasons for such startling statistics is the presence of a subpopulation of highly plastic stem-like cells within the tumor called cancer stem cells (CSCs). We have previously identified a distinct subset of these CSCs within the invasive front of patient tumors. This subset, called migrating cancer stem cells (miCSCs), is characterized by CD133+CXCR4+ expression and determines the metastatic phenotype of pancreatic cancer. Therefore, targeting CXCR4 may represent a potential therapeutic approach to lower metastatic burden in PDAC. Here, we examined the effect of endogenous human peptides EPI-X4 and other derivatives thereof as CXCR4 antagonist on (i) patient-derived primary pancreatic cancer cells and (ii) tumor-stroma crosstalk by using a dual culture system with pancreatic stellate cells. We established these peptides as novel therapeutic strategy for combating the metastatic activity of pancreatic cancer using combinatorial therapeutic approaches and testing different in vivo delivery system such as peptide fatty-acid (FA) conjugates and silica nanoparticles (Si-NP). Our results show that EPI-X4 as well as its derivatives (e.g., JM#21) strongly inhibited migratory capacity of primary pancreatic cancer cells towards the CXCR4 ligand CXCL12 in vitro. Thereby, JM#21 was identified as the most potent EPI-X4 derivate. Mechanistical analysis by western blot, gene expression and immunofluorescence revealed that JM#21 increased Cadherin-1 expression by suppression of Snail1 via inactivation of SHH pathway. Moreover, JM#21 decreased CXCL12-induced phosphorylation of AKT and IKBa as well as NANOG expression, which further suppressed self-renewal capacity and EMT in the tumor cells. Strikingly, JM#21 sensitized selected cell lines towards gemcitabine and paclitaxel. Furthermore, FA conjugated and Si-NP encapsulated JM#21 restricted miCSCs maintenance which was predominantly regulated via stellate cell secreted CXCL12. In serum conditions, both FA conjugated, and Si-NP encapsulated JM#21 was found to be stable and active, proving as a valuable delivery system for in vivo studies. In conclusion, our study reveals that targeting CXCR4/CXCL12 signaling axis using human endogenous EPI-X4 derivates particularly JM#21 inhibits tumor-stroma crosstalk which is paramount for the propagation and maintenance of miCSC. Particularly, we demonstrate, in both mechanistic and preclinical set up, that these peptides abrogate the metastatic capacity of patient-derived pancreatic cancer cells by selective targeted elimination of miCSCs. Moreover, tumor cells show increased susceptibility towards conventional treatment strategies enforcing EPI-X4 derivate as a novel combinatory therapy to treat metastatic pancreatic cancer. Citation Format: Kanishka Tiwary, Mirja Harms, Bastian Beitzinger, Roman Schmid, Syeda Inaas, Karolin Walter, Alexander Kleger, Mika Lindén, Thomas Seufferlein, Jan Münch, Patrick Christian Hermann. CXCR4 targeting endogenous human peptides eliminate migrating cancer stem cells by disrupting tumor-stroma crosstalk in pancreatic ductal adenocarcinomas [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B034.

Risk factors, prognostic predictors, and nomograms for pancreatic cancer patients with initially diagnosed synchronous liver metastasis.

Liver metastasis (LM) remains a major cause of cancer-related death in patients with pancreatic cancer (PC) and is associated with a poor prognosis. Therefore, identifying the risk and prognostic factors in PC patients with LM (PCLM) is essential as it may aid in providing timely medical interventions to improve the prognosis of these patients. However, there are limited data on risk and prognostic factors in PCLM patients. To investigate the risk and prognostic factors of PCLM and develop corresponding diagnostic and prognostic nomograms. Patients with primary PC diagnosed between 2010 and 2015 were reviewed from the Surveillance, Epidemiology, and Results Database. Risk factors were identified using multivariate logistic regression analysis to develop the diagnostic mode. The least absolute shrinkage and selection operator Cox regression model was used to determine the prognostic factors needed to develop the prognostic model. The performance of the two nomogram models was evaluated using receiver operating characteristic (ROC) curves, calibration plots, decision curve analysis (DCA), and risk subgroup classification. The Kaplan-Meier method with a log-rank test was used for survival analysis. We enrolled 33459 patients with PC in this study. Of them, 11458 (34.2%) patients had LM at initial diagnosis. Age at diagnosis, primary site, lymph node metastasis, pathological type, tumor size, and pathological grade were identified as independent risk factors for LM in patients with PC. Age > 70 years, adenocarcinoma, poor or anaplastic differentiation, lung metastases, no surgery, and no chemotherapy were the independently associated risk factors for poor prognosis in patients with PCLM. The C- index of diagnostic and prognostic nomograms were 0.731 and 0.753, respectively. The two nomograms could accurately predict the occurrence and prognosis of patients with PCLM based on the observed analysis results of ROC curves, calibration plots, and DCA curves. The prognostic nomogram could stratify patients into prognostic groups and perform well in internal validation. Our study identified the risk and prognostic factors in patients with PCLM and developed corresponding diagnostic and prognostic nomograms to help clinicians in subsequent clinical evaluation and intervention. External validation is required to confirm these results.

Neoadjuvant Treatment versus Upfront Surgery for Primary Resectable Pancreatic Cancer: An Update Meta-analysis of Comparative Studies

Neoadjuvant Treatment versus Upfront Surgery for Primary Resectable Pancreatic Cancer: An Update Meta-analysis of Comparative Studies

The influence of frailty on perioperative outcomes in patients undergoing surgical resection of liver metastases: a nationwide readmissions database study.

Liver metastases arise frequently from primary colorectal, pancreatic, and breast cancers. Research has highlighted the patient's frailty status as an important predictor of outcomes, but the literature evaluating the role of frailty in patients with secondary metastatic disease of the liver remains limited. Using predictive analytics, we evaluated the role of frailty in patients who underwent hepatectomy for liver metastases. We used the Nationwide Readmissions Database from 2016-2017 to identify patients who underwent resection of a secondary malignant neoplasm of the liver. Patient frailty was evaluated using the Johns Hopkins Adjusted Clinical Groups (JHACG) frailty-defining diagnosis indicator. Propensity score matching was performed and Mann-Whitney U testing was used to analyze complication rates. Receiver operating characteristic (ROC) curves were created following creation of logistic regression models for predicting discharge disposition. Frail patients reported significantly higher rates of nonroutine discharges, longer inpatient stays, greater costs, higher rates of acute infection, posthemorrhagic anemia, urinary tract infection (UTI), deep vein thrombosis (DVT), wound dehiscence and readmission, and greater mortality (P<0.05). Predictive models for patient discharge disposition, DVT and UTI demonstrated that the use of frailty status and age improved the area under the ROC curves significantly compared to models using age alone. Frailty was found to be significantly correlated with higher rates of medical complications during inpatient stay following hepatectomy in patients with liver metastasis. The inclusion of patient frailty status in predictive models improved their predictive capacity compared to those using age alone.

Construction of a pancreatic cancer nerve invasion system using brain and pancreatic cancer organoids

Pancreatic cancer (PC) is a fatal malignancy in the human abdominal cavity that prefers to invade the surrounding nerve/nerve plexus and even the spine, causing devastating and unbearable pain. The limitation of available in vitro models restricts revealing the molecular mechanism of pain and screening pain-relieving strategies to improve the quality of life of end-stage PC patients. Here, we report a PC nerve invasion model that merged human brain organoids (hBrO) with mouse PC organoids (mPCO). After merging hBrOs with mPCOs, we monitored the structural crosstalk, growth patterns, and mutual interaction dynamics of hBrO with mPCOs for 7 days. After 7 days, we also analyzed the pathophysiological statuses, including proliferation, apoptosis and inflammation. The results showed that mPCOs tend to approximate and intrude into the hBrOs, merge entirely into the hBrOs, and induce the retraction/shrinking of neuronal projections that protrude from the margin of the hBrOs. The approximating of mPCOs to hBrOs accelerated the proliferation of neuronal progenitor cells, intensified the apoptosis of neurons in the hBrOs, and increased the expression of inflammatory molecules in hBrOs, including NLRP3, IL-8, and IL-1β. Our system pathophysiologically replicated the nerve invasions in mouse GEMM (genetically engineered mouse model) primary and human PCs and might have the potential to be applied to reveal the molecular mechanism of nerve invasion and screen therapeutic strategies in PCs.

THE MEDIAN SURVIVAL TIME OF PANCREATIC CANCER PATIENTS IN MALAYSIA

Pancreatic cancer is an intractable disease, and its mortality rates are approximately identical to its incidence ones. Getting its early diagnosis is quite challenging and subsequently, it contributes to one of the reasons for poor survival figures. The retrospective record review of radiologically or histo-pathologically confirmed primary pancreatic cancer cases registered at State hospitals in Penang, Kedah, Kelantan and Terengganu from 1st January 2011 to 31st December 2018 were performed. The cumulative survival probabilities were estimated using the Kaplan-Meier method while the log-rank test was applied to determine the differences in overall survival among groups. The overall median survival time was 9.37 (95% CI:8.53, 10.21) months since the diagnosis. The median survival times were significantly shorter in those aged &gt;60 years, in Chinese subjects, those with smoking or alcohol consumption history, patients with some comorbidities, those presented with some signs and symptoms at the time of diagnosis. Moreover, the median survival time was found to be different based on the type of the pancreatic malignancy and staging of the disease. It was also found that the survival time was significantly longer in those who underwent surgery, those who received radiotherapy or chemotherapy whereas it was significantly shorter in those who took best supportive treatment. The disparities of overall survival time were observed depending on their socio-demographic data and clinical features at the time of diagnosis. The results of this study may serve as a solid foundation to develop robust and meaningful prediction modelling for the prognosis of pancreatic cancer.

Prostate-Specific Membrane Antigen Targeted Pet/CT Imaging in Patients with Colon, Gastric and Pancreatic Cancer.

Current imaging modalities frequently misjudge disease stage in colorectal, gastric and pancreatic cancer. As treatment decisions are dependent on disease stage, incorrect staging has serious consequences. Previous preclinical research and case reports indicate that prostate-specific membrane antigen (PSMA)-targeted PET/CT imaging might provide a solution to some of these challenges. This prospective clinical study aims to assess the feasibility of [18F]DCFPyL PET/CT imaging to target and visualize primary colon, gastric and pancreatic cancer. In this prospective clinical trial, patients with colon, gastric and pancreatic cancer were included and underwent both [18F]DCFPyL and [18F]FDG PET/CT scans prior to surgical resection or (for gastric cancer) neoadjuvant therapy. Semiquantitative analysis of immunohistochemical PSMA staining was performed on the surgical resection specimens, and the results were correlated to imaging parameters. The results of this study demonstrate detection of the primary tumor by [18F]DCFPyL PET/CT in 7 out of 10 patients with colon, gastric and pancreatic cancer, with a mean tumor-to-blood pool ratio (TBR) of 3.3 and mean SUVmax of 3.6. However, due to the high surrounding uptake, visual distinction of these tumors was difficult, and the SUVmax and TBR on [18F]FDG PET/CT were significantly higher than on [18F]DCFPyL PET/CT. In addition, no correlation between PSMA expression in the resection specimen and SUVmax on [18F]DCFPyL PET/CT was found. In conclusion, the detection of several gastrointestinal cancers using [18F]DCFPyL PET/CT is feasible. However, low tumor expression and high uptake physiologically in organs/background hamper the clear distinction of the tumor. As a result, [18F]FDG PET/CT was superior in detecting colon, gastric and pancreatic cancers.

Different effects of NK cells and NK-derived soluble factors on cell lines derived from primary or metastatic pancreatic cancers

Natural killer (NK) cells are cytotoxic lymphoid cells that play a key role in defenses against tumors. However, their function may be severely impaired in patients with pancreatic adenocarcinoma (PA). Indeed, PA cells release soluble factors, thereby generating an immunosuppressive environment that dysregulates NK-cell cytolytic function and favors tumor immune evasion. Here, we analyzed the interactions between NK and PA cells using the PANC-1 and CAPAN-1 cell lines derived from a ductal PA and metastatic lesion, respectively. Metastatic and nonmetastatic cell lines were both able to impair NK cytolytic activity. An analysis of the effect of NK cells and NK-cell-derived exosomes revealed substantial differences between the two cell lines. Thus, NK cells displayed higher cytotoxicity against nonmetastatic PA cells than metastatic PA cells in both 2D cultures and in a 3D extracellular matrix cell system. In addition, NK-derived exosomes could penetrate only PANC-1 spheroids and induce cell killing. Remarkably, when PANC-1 cells were exposed to NK-derived soluble factors, they displayed substantial changes in the expression of genes involved in epithelial-to-mesenchymal transition (EMT) and acquired resistance to NK-mediated cytolysis. These results, together with their correlation with poor clinical outcomes in PA patients, suggest that the induction of resistance to cytolysis upon exposure to NK-derived soluble factors could reflect the occurrence of EMT in tumor cells. Our data indicate that a deeper investigation of the interaction between NK cells and tumor cells may be crucial for immunotherapy, possibly improving the outcome of PA treatment by targeting critical steps of NK-tumor cell crosstalk.

Pre-existing psychological disorders, diabetes, and pancreatic cancer: A population-based study of 38,952 Finns

BackgroundIt remains unclear how pre-existing depression, anxiety, and diabetes of different durations are associated with the risk of pancreatic cancer, its clinical characteristics, treatment modalities, and subsequent survival. MethodsFrom a register-based random sample of Finns residing in Finland at the end of the period 1987–2007, 6492 patients diagnosed with primary pancreatic cancer in 2000–2014, and 32 460 controls matched for birth cohort and sex, were identified. Pre-existing depression, anxiety, and diabetes were ascertained from the records of prescribed medication purchases. Information on pancreatic cancer outcomes was obtained from the Finnish cancer register. Data were analyzed using logistic and Cox regressions. ResultsThe risk of developing pancreatic cancer was found to be associated with long-term anxiety (treatment started 36 + months before the cancer diagnosis) (odds ratio (OR): 1.13, 95% confidence interval (95%CI): 1.04–1.22) and long-term diabetes (OR 1.72, 95%CI 1.55–1.90), as well as with new-onset (treatment started 0–24 months before the cancer diagnosis) depression (OR 1.59, 95%CI 1.34–1.88), anxiety (OR 1.76, 95%CI 1.50–2.07), and diabetes (OR 3.92, 95%CI 3.44–4.48). However, the effects of these new-onset conditions were driven by cases that began treatment within 3 months before the cancer diagnosis (concomitant period). Patients with long-term depression, anxiety and diabetes and those with new-onset anxiety had a higher risk of not receiving standard treatments. Lower survival was found for pancreatic cancer patients with new-onset depression (hazards ratio (HR) 1.38, 95%CI 1.16–1.64). Survival was not associated with pre-existing anxiety or diabetes. ConclusionsThe associations between pancreatic cancer risk and pre-existing depression and anxiety were mostly driven by concomitant effects. Individuals with diabetes, regardless of duration, should be closely monitored for pancreatic cancer. Pancreatic cancer patients with new-onset depression should be targeted to improve their survival.

Abstract A004: Repetitive elements and viral mimicry co-evolve in pancreatic cancer

Abstract Overexpression of repetitive DNA is an emerging hallmark of human cancers and several repeats, such as SINE elements and satellite, transcribe immunostimulatory RNA that mimic features associated with viral infection. However, the extent to which specific repeat families affect tumor evolution and the immune microenvironment in a pro-or anti-tumorigenic manner remains poorly understood. We present an integrated, evolutionary multi-omic analysis pf repeat evolution in multiregion-sampled human metastatic and primary pancreatic cancers for the first time. We found that LINE-1 (L1) somatic insertion location coincides with tumor evolution. Moreover, we found L1 activity is negatively correlated with immunogenic SINE element expression. Two orthogonal metrics were used in quantifying immunogenicity of SINE elements: IFN signature and capability of forming dsRNA, where both methods revealed that evolutionary young SINE elements have stronger correlation with IFN signatures and are more likely to form dsRNAs. Moreover, the anti-correlation between L1 activity and SINE expression is validated through both immunohistological analysis of human samples and pancreatic cancer cell lines. In the end, we proposed that the model of hypoactive L1 is beneficial for tumors by suppression of immunogenic SINE elements through either their direct reverse transcription or accelerating their degradation. Our analysis therefore sheds light on the evolutionary role of dark matter repeats in a tumor’s adaptation to immunogenic vulnerabilities. Citation Format: Siyu Sun. Repetitive elements and viral mimicry co-evolve in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A004.

GJB3 promotes pancreatic cancer liver metastasis by enhancing the polarization and survival of neutrophil.

Connexins are membrane expressed proteins, which could assemble into hexamers to transfer metabolites and secondary messengers. However, its roles in pancreatic cancer metastasis remains unknown. In this study, by comparing the gene expression patterns in primary pancreatic cancer patients primary and liver metastasis specimens, we found that Gap Junction Protein Beta 3 (GJB3) significantly increased in Pancreatic ductal adenocarcinoma (PDAC) liver metastasis. Animal experiments verified that GJB3 depletion suppressed the hepatic metastasis of PDAC cancer cells. Further, GJB3 over expression increased the neutrophil infiltration. Mechanistic study revealed that GJB3 form channels between PDAC tumor cells and accumulated neutrophil, which transfer cyclic adenosine monophosphate (cAMP) from cancer to neutrophil cells, which supports the survival and polarization. Taken together, our data suggesting that GJB3 could act as a potential therapeutic target of PDAC liver metastasis.