Comparison of gemcitabine delivery and tumor response in a pressurized pancreatic retrograde venous infusion versus systemic infusion in an orthotopic murine model.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 737-737
Author(s):  
Diego Vicente ◽  
Jayanth Shankara Narayanan ◽  
Partha Ray ◽  
Louis F. Chai ◽  
Suna Erdem ◽  
...  
Keyword(s):  
Immune Cell ◽  
Liver Tumors ◽  
Regional Chemotherapy ◽  
Tumor Burden ◽  
Ductal Adenocarcinoma ◽  
Saline Control ◽  
Systemic Delivery ◽  
Murine Cell Line ◽  
Venous Infusion ◽  
And Control

737 Background: Pancreatic ductal adenocarcinoma (PDAC) is associated with limited response to systemic therapy (ST). Elevated tumor interstitial fluid pressures (IFP) inhibit penetration of ST. Regional Pressure Enabled Drug Delivery has recently demonstrated improved response for liver tumors in a clinical trial. However, this delivery method has not been evaluated in PDAC. We compared gemcitabine (Gem) by systemic delivery vs. a novel pressurized Pancreatic Retrograde Venous Infusion (PRVI) method in an orthotopic PDAC mouse model. Methods: PDAC murine cell line (KPC4580P) tumors were transplanted onto the pancreatic tail of C57BL/6J mice. Groups of 15 mice were randomly assigned to PRVI Gem, PRVI saline (Control), or intraperitoneal Gem (Systemic) groups. Five mice from the PRVI and Systemic groups were randomly selected after one hour post infusion to evaluate Gem tumor concentrations by liquid chromatography - tandem mass spectrometry (ng/mg), and the remainder of mice were euthanized after 7 days to evaluate treatment response. Results: Tumor concentrations of Gem were significantly higher following PRVI compared to Systemic (128 vs. 19, p < 0.01) at one hour after treatment. Seven days after treatment, PRVI Gem mice demonstrated lower mean tumor volume (mm3) than Systemic Gem and Control mice (274 vs. 857 vs. 629, p < 0.01), respectively. Histologic evaluation of tumors demonstrated decreased cellularity in the PRVI Gem mice compared to Systemic and Control mice (35 vs. 78 vs. 71%, p = 0.01), respectively. No differences were seen in Ki67% or immune cell infiltrate between groups. Conclusions: PRVI delivery resulted in increased PDAC Gem concentrations and improved treatment responses with decreased tumor burden and cellularity. These findings suggest that pressurized regional chemotherapy infusion overcomes the elevated PDAC IFP and justifies additional translational pre-clinical studies with other chemotherapeutics (including immunomodulating antibodies) with different physicochemical properties.

scholarly journals Oxaliplatin-Induced Peripheral Neuropathy Can Be Minimized By Pressurized Regional Intravascular Delivery In An Orthotopic Murine Pancreatic Cancer Model.

2022 ◽  
Author(s):  
Jayanth Surya Narayanan Shankara Narayanan ◽  
Katie Frizzi ◽  
Suna Erdem ◽  
Partha Ray ◽  
David Jaroch ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Peripheral Neuropathy ◽  
Tumor Burden ◽  
Cytotoxic Agents ◽  
Ductal Adenocarcinoma ◽  
Tumor Control ◽  
Cancer Model ◽  
Functional Assays ◽  
Venous Infusion ◽  
Regional Delivery

Abstract Purpose: There is a great need to reduce the toxicity of chemotherapy used in the management of pancreatic ductal adenocarcinoma (PDAC). Here we explore if regional pressurized delivery of oxaliplatin can minimize peripheral neuropathy in mice.Methods: We used an orthotopic PDAC mouse model and delivered a single dose of oxaliplatin through the portal vein using a pressure-enabled system (pancreatic retrograde venous infusion, PRVI). We analyzed the effects of PRVI on tumor burden and peripheral neuropathy using histopathological and functional assays.Results: Tumor weights in mice treated with 2 mg/Kg oxaliplatin using PRVI were significantly lower than in mice treated with the same dose systemically. This resulted in reduced peripheral neuropathy signatures in PRVI mice compared to the 20 mg/Kg systemic dose required to achieve similar tumor control.Conclusion: Regional delivery of highly cytotoxic agents using PRVI can reduce the therapeutic dose of these drugs, thereby lowering toxic side effects.

The effect of TGF-β on PD-L1 expression on PDAC TAMs.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 764-764
Author(s):  
Katarzyna Trebska-McGowan ◽  
Liza Makowski ◽  
Marcus A. Alvarez ◽  
Rita Kansal ◽  
S. Mazher Husain ◽  
...  
Keyword(s):  
Liver Metastases ◽  
Cell Line ◽  
Pancreatic Cancer Cell Line ◽  
Cancer Cell Line ◽  
Tumor Burden ◽  
Genetically Engineered ◽  
Ductal Adenocarcinoma ◽  
Saline Control ◽  
Genetically Engineered Mouse Model ◽  
Kpc Mice

764 Background: Pancreatic Ductal Adenocarcinoma (PDAC) has less than a 10% five year survival and will become the second leading cause of US cancer mortality in the next decade. Immunotherapy, such as checkpoint inhibition against anti-Programmed death-ligand 1 (PD-L1) has not been successful in the treatment of PDAC patients. Both tumor associated macrophages (TAMs) and the TGF-β protein are ubiquitous in PDAC tumors. We hypothesize that TGF-β increases the overall number of TAMs and degree of PD-L1 expression of TAMs in PDAC. Methods: Our lab has a mouse pancreatic cancer cell line derived from a genetically engineered mouse model (KPC mice that spontaneously form PDAC tumors that are similar to human PDAC). We orthotopically implanted this cell line into the pancreas of immunocompetent C57BL/6 (B6) mice. In groups of 5 each, mice were treated with saline (control) or TGF-β. We investigated tumor burden, the number of TAMs (CD45+, CD11b+F4/80hi, Ly6C−, Ly6G−/lo) in the tumors with flow cytometry and the percentage of TAMs expressing PD-L1 in the pancreas and metastatic lesions in the liver. Results: As a percent of leukocytes in the tumor, PDAC liver metastases had more TAMs compared to tumors in the pancreas (33 ± 5% vs 10 ± 4%, P = 0.001). Compared to controls, TGF-β treatment significantly increased the percent of PD-L1 expressing TAMs (32 ± 6 % vs 12 ± 5%, P = 0.013, see Figure) in the pancreas but no effect was evident on TAM density. In liver metastases, treatment with TGF-β decreased the overall TAM density (P = 0.039) but did not affect the number of PD-L1 positive TAMs. Conclusions: TGF-β plays pivotal role in the progression of PDAC and demonstrates context dependent activity. Our results suggest that an immunosuppressive effect mediated by PD-L1 expression on TAMs may be initiated by TGF-β. Future investigations will focus on understanding the role of the PDAC – TAM interaction to develop effective immune therapies for PDAC patients.

scholarly journals Immune-Related Circulating miR-125b-5p and miR-99a-5p Reveal a High Recurrence Risk Group of Pancreatic Cancer Patients after Tumor Resection

2019 ◽  
Vol 9 (22) ◽  
pp. 4784
Author(s):  
Vietsch ◽  
Peran ◽  
Suker ◽  
van den Bosch ◽  
Sijde ◽  
...  
Keyword(s):  
Cancer Progression ◽  
B Lymphocyte ◽  
Immune Cell ◽  
Tumor Resection ◽  
Progression Free Survival ◽  
Tumor Stroma ◽  
Recurrence Risk ◽  
High Serum ◽  
Ductal Adenocarcinoma ◽  
Before And After

Clinical follow-up aided by changes in the expression of circulating microRNAs (miRs) may improve prognostication of pancreatic ductal adenocarcinoma (PDAC) patients. Changes in 179 circulating miRs due to cancer progression in the transgenic KrasG12D/+; Trp53R172H/+; P48-Cre (KPC) animal model of PDAC were analyzed for serum miRs that are altered in metastatic disease. In addition, expression levels of 250 miRs were profiled before and after pancreaticoduodenectomy in the serum of two patients with resectable PDAC with different progression free survival (PFS) and analyzed for changes indicative of PDAC recurrence after resection. Three miRs that were upregulated ≥3-fold in progressive PDAC in both mice and patients were selected for validation in 26 additional PDAC patients before and after resection. We found that high serum miR-125b-5p and miR-99a-5p levels after resection are significantly associated with shorter PFS (HR 1.34 and HR 1.73 respectively). In situ hybridization for miR detection in the paired resected human PDAC tissues showed that miR-125b-5p and miR-99a-5p are highly expressed in inflammatory cells in the tumor stroma, located in clusters of CD79A expressing cells of the B-lymphocyte lineage. In conclusion, we found that circulating miR-125b-5p and miR-99a-5p are potential immune-cell related prognostic biomarkers in PDAC patients after surgery.

scholarly journals Stromal hyaluronan accumulation is associated with low immune response and poor prognosis in pancreatic cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kyösti Tahkola ◽  
Maarit Ahtiainen ◽  
Jukka-Pekka Mecklin ◽  
Ilmo Kellokumpu ◽  
Johanna Laukkarinen ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Cell ◽  
Geographical Area ◽  
Prognostic Significance ◽  
Staining Intensity ◽  
Ductal Adenocarcinoma ◽  
Poor Survival ◽  
Negative Prognostic Factor ◽  
High Level ◽  
Immune Cell Score

AbstractHyaluronan (HA) accumulation has been associated with poor survival in various cancers, but the mechanisms for this phenomenon are still unclear. The aim of this study was to investigate the prognostic significance of stromal HA accumulation and its association with host immune response in pancreatic ductal adenocarcinoma (PDAC). The study material consisted of 101 radically treated patients for PDAC from a single geographical area. HA staining was evaluated using a HA-specific probe, and the patterns of CD3, CD8, CD73 and PD-L1 expression were evaluated using immunohistochemistry. HA staining intensity of tumour stromal areas was assessed digitally using QuPath. CD3- and CD8-based immune cell score (ICS) was determined. High-level stromal HA expression was significantly associated with poor disease-specific survival (p = 0.037) and overall survival (p = 0.013) In multivariate analysis, high-level stromal HA expression was an independent negative prognostic factor together with histopathological grade, TNM stage, CD73 positivity in tumour cells and low ICS. Moreover, high-level stromal HA expression was associated with low ICS (p = 0.017). In conclusion, stromal HA accumulation is associated with poor survival and low immune response in PDAC.

scholarly journals Immune Cell Modulation of the Extracellular Matrix Contributes to the Pathogenesis of Pancreatic Cancer

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 901
Author(s):  
Ramiz S. Ahmad ◽  
Timothy D. Eubank ◽  
Slawomir Lukomski ◽  
Brian A. Boone
Keyword(s):  
Pancreatic Cancer ◽  
Extracellular Matrix ◽  
Immune Cells ◽  
Immune Cell ◽  
Treatment Strategies ◽  
Stellate Cells ◽  
Pancreatic Stellate Cells ◽  
Ductal Adenocarcinoma ◽  
Cellular Mechanisms ◽  
Novel Treatment Strategies

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a five-year survival rate of only 9%. PDAC is characterized by a dense, fibrotic stroma composed of extracellular matrix (ECM) proteins. This desmoplastic stroma is a hallmark of PDAC, representing a significant physical barrier that is immunosuppressive and obstructs penetration of cytotoxic chemotherapy agents into the tumor microenvironment (TME). Additionally, dense ECM promotes hypoxia, making tumor cells refractive to radiation therapy and alters their metabolism, thereby supporting proliferation and survival. In this review, we outline the significant contribution of fibrosis to the pathogenesis of pancreatic cancer, with a focus on the cross talk between immune cells and pancreatic stellate cells that contribute to ECM deposition. We emphasize the cellular mechanisms by which neutrophils and macrophages, specifically, modulate the ECM in favor of PDAC-progression. Furthermore, we investigate how activated stellate cells and ECM influence immune cells and promote immunosuppression in PDAC. Finally, we summarize therapeutic strategies that target the stroma and hinder immune cell promotion of fibrogenesis, which have unfortunately led to mixed results. An enhanced understanding of the complex interactions between the pancreatic tumor ECM and immune cells may uncover novel treatment strategies that are desperately needed for this devastating disease.

The impact of maternal protein restriction during perinatal life on the response to a septic insult in adult rats

2020 ◽  
pp. 1-8
Author(s):  
Reza Khazaee ◽  
Anastasiya Vinokurtseva ◽  
Lynda A. McCaig ◽  
Cory Yamashita ◽  
Daniel B. Hardy ◽  
...  
Keyword(s):  
Control Diet ◽  
Protein Restriction ◽  
Saline Control ◽  
Female Adult ◽  
Adult Rats ◽  
Male And Female ◽  
Maternal Protein Restriction ◽  
And Control ◽  
The Impact ◽  
Septic Insult

Abstract Although abundant evidence exists that adverse events during pregnancy lead to chronic conditions, there is limited information on the impact of acute insults such as sepsis. This study tested the hypothesis that impaired fetal development leads to altered organ responses to a septic insult in both male and female adult offspring. Fetal growth restricted (FGR) rats were generated using a maternal protein-restricted diet. Male and female FGR and control diet rats were housed until 150–160 d of age when they were exposed either a saline (control) or a fecal slurry intraperitoneal (Sepsis) injection. After 6 h, livers and lungs were analyzed for inflammation and, additionally, the amounts and function of pulmonary surfactant were measured. The results showed increases in the steady-state mRNA levels of inflammatory cytokines in the liver in response to the septic insult in both males and females; these responses were not different between FGR and control diet groups. In the lungs, cytokines were not detectable in any of the experimental groups. A significant decrease in the relative amount of surfactant was observed in male FGR offspring, but this was not observed in control males or in female animals. Overall, it is concluded that FGR induced by maternal protein restriction does not impact liver and lung inflammatory response to sepsis in either male or female adult rats. An altered septic response in male FGR offspring with respect to surfactant may imply a contribution to lung dysfunction.

scholarly journals Suppression of tumor-associated neutrophils by lorlatinib attenuates pancreatic cancer growth and improves treatment with immune checkpoint blockade

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Sebastian R. Nielsen ◽  
Jan E. Strøbech ◽  
Edward R. Horton ◽  
Rene Jackstadt ◽  
Anu Laitala ◽  
...  
Keyword(s):  
Cd8 T Cells ◽  
Immune Cell ◽  
Immune Checkpoint Blockade ◽  
Ductal Adenocarcinoma ◽  
Cancer Growth ◽  
Cancer Therapies ◽  
Cell Type ◽  
Clinical Prognosis ◽  
Tumor Associated Neutrophils ◽  
Poor Clinical Prognosis

AbstractPancreatic ductal adenocarcinoma (PDAC) patients have a 5-year survival rate of only 8% largely due to late diagnosis and insufficient therapeutic options. Neutrophils are among the most abundant immune cell type within the PDAC tumor microenvironment (TME), and are associated with a poor clinical prognosis. However, despite recent advances in understanding neutrophil biology in cancer, therapies targeting tumor-associated neutrophils are lacking. Here, we demonstrate, using pre-clinical mouse models of PDAC, that lorlatinib attenuates PDAC progression by suppressing neutrophil development and mobilization, and by modulating tumor-promoting neutrophil functions within the TME. When combined, lorlatinib also improves the response to anti-PD-1 blockade resulting in more activated CD8 + T cells in PDAC tumors. In summary, this study identifies an effect of lorlatinib in modulating tumor-associated neutrophils, and demonstrates the potential of lorlatinib to treat PDAC.

Cardiovascular parameters in a mixed-sex swine study of severe decompression sickness treated with the emulsified perfluorocarbon Oxycyte

2015 ◽  
Vol 118 (1) ◽  
pp. 71-79 ◽  
Author(s):  
R. T. Mahon ◽  
W. A. Cronin ◽  
M. Bodo ◽  
S. Tirumala ◽  
D. P. Regis ◽  
...  
Keyword(s):  
Cardiac Output ◽  
Decompression Sickness ◽  
Mortality Rates ◽  
Rapid Onset ◽  
Systemic Arterial Pressure ◽  
Saline Control ◽  
Physiological Effects ◽  
Control Groups ◽  
And Control ◽  
Observation Period

Intravenous perfluorocarbons (PFC) have reduced the effects of decompression sickness (DCS) and improved mortality rates in animal models. However, concerns for the physiological effects of DCS combined with PFC therapy have not been examined in a balanced mixed-sex population. Thirty-two (16 male, 16 female) instrumented and sedated juvenile Yorkshire swine were exposed to 200 feet of seawater (fsw) for 31 min of hyperbaric air. Pulmonary artery pressure (PAP), cardiac output (CO), and systemic arterial pressure (SAP) were monitored before (control) and after exposure. Animals were randomized to treatment with Oxycyte (5 ml/kg; Oxygen Biotherapeutics, Inc., Morrisville, NC) vs. saline (control) with 100% oxygen administered upon DCS onset; animals were observed for 90 min. Parameters recorded and analyzed included PAP, CO, and SAP. In all animals PAP began to rise prior to cutis marmorata (CM) onset, the first sign of clinical DCS, generally peaking after CM onset. Female swine, compared with castrated males, had a more rapid onset of CM (7.30 vs. 11.46 min postsurfacing) and earlier onset to maximal PAP (6.41 vs. 9.69 min post-CM onset). Oxycyte therapy was associated with a sustained PAP elevation above controls in both sexes (33.41 vs. 25.78 mmHg). Significant pattern differences in PAP, CO, and SAP were noted between sexes and between therapeutic groups. There were no statistically significant differences in survival or paralysis between the PFC and control groups during the 48-h observation period. In conclusion, Oxycyte therapy for DCS is associated with a prolonged PAP increase in swine. These species and sex differences warrant further exploration.

Prenatal cadmium exposure does not induce greater incidence or earlier onset of autoimmunity in the offspring

2021 ◽  
Author(s):  
Jamie L. McCall ◽  
Harry C. Blair ◽  
Kathryn Blethen ◽  
Casey Hall ◽  
Meenal Elliott ◽  
...  
Keyword(s):  
Immune Cell ◽  
Autoimmune Diabetes ◽  
Biological Significance ◽  
Nod Mice ◽  
Female Offspring ◽  
Micro Computed Tomography ◽  
Similar Time ◽  
Adult Mice ◽  
And Control ◽  
Cd Exposure

We previously demonstrated that exposure of adult mice to environmental levels of cadmium (Cd) alters the immune cell development and function with increases in anti-streptococcal antibody levels, as well as decreases in splenic natural regulatory T cells (nTreg) in the adult female offspring. Based on these data, we hypothesized that prenatal Cd exposure could predispose an individual to developing autoimmunity as adults. To test this hypothesis, the effects of prenatal Cd on the development of autoimmune diabetes and arthritis were investigated. Non-obese diabetic (NOD) mice were exposed to Cd in a manner identical to our previous studies, and the onset of diabetes was assessed in the offspring. Our results showed a similar time-to-onset and severity of disease to historical data, and there were no statistical differences between Cd-exposed and control offspring. Numerous other immune parameters were measured and none of these parameters showed biologically relevant differences between Cd-exposed and control animals. To test whether prenatal Cd-exposure affected development of autoimmune arthritis, we used SKG mice. While the levels of arthritis were similar between Cd-exposed and control offspring of both sexes, the pathology of arthritis determined by micro-computed tomography (microCT) between Cd-exposed and control animals, showed some statistically different values, especially in the female offspring. However, the differences were small and thus, the biological significance of these changes is open to speculation. Overall, based on the results from two autoimmune models, we conclude that prenatal exposure to Cd did not lead to a measurable propensity to develop autoimmune disease later in life.

scholarly journals MicroRNAs in Autoimmunity and Hematological Malignancies

2018 ◽  
Vol 19 (10) ◽  
pp. 3139 ◽  
Author(s):  
Mirco Marco ◽  
Alice Ramassone ◽  
Sara Pagotto ◽  
Eleni Anastasiadou ◽  
Angelo Veronese ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Hematological Malignancies ◽  
Immune Cell ◽  
Immunological Tolerance ◽  
Considerable Effort ◽  
Control Networks ◽  
Immune Cell Subsets ◽  
Bidirectional Relationship ◽  
Relevant Role ◽  
And Control

Autoimmunity and hematological malignancies are often concomitant in patients. A causal bidirectional relationship exists between them. Loss of immunological tolerance with inappropriate activation of the immune system, likely due to environmental and genetic factors, can represent a breeding ground for the appearance of cancer cells and, on the other hand, blood cancers are characterized by imbalanced immune cell subsets that could support the development of the autoimmune clone. Considerable effort has been made for understanding the proteins that have a relevant role in both processes; however, literature advances demonstrate that microRNAs (miRNAs) surface as the epigenetic regulators of those proteins and control networks linked to both autoimmunity and hematological malignancies. Here we review the most up-to-date findings regarding the miRNA-based molecular mechanisms that underpin autoimmunity and hematological malignancies.

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