The impact of the California state lockdown during the COVID-19 pandemic on management of patients with pancreatic ductal adenocarcinoma.

BACKGROUND AND OBJECTIVES: The SARS-COVID-19 pandemic significantly limited healthcare access. We sought to evaluate whether California's lockdown in March 2020 affected staging and time to treatment of pancreatic ductal adenocarcinoma (PDAC). We hypothesized that patients diagnosed after the lockdown would have longer time to treatment and higher stage at presentation. METHODS: We retrospectively identified and categorized 1294 patients presenting to five University of California healthcare systems with a new diagnosis of PDAC into "pre-lockdown" and "post-lockdown" groups based on timing of pathologic diagnosis. RESULTS: In the 12 months pre-lockdown, 835 patients were diagnosed with PDAC, and 459 patients in the 6 months post-lockdown. Demographics, staging, and treatment type were similar between eras. There was a decreased male:female ratio post- versus pre-lockdown (0.97 vs. 1.25; p = 0.03). Time from symptom onset to first treatment was significantly increased among females post-lockdown (p = 0.001). However, overall time from diagnosis to first treatment was shorter in the post-lockdown era (median 23 vs. 26 days, p < 0.001). CONCLUSIONS: The COVID-19 lockdown did not significantly delay initial presentation, diagnosis, or treatment of newly diagnosed PDAC patients. Time from diagnosis to first treatment was shorter post-lockdown. Reduced healthcare utilization for minor complaints and increased telehealth utilization may have contributed.

Local ablative therapies and the effect on antitumor immune responses in pancreatic cancer - A review.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease, projected to rank as the second most prevalent cause of cancer-related mortality by 2030. Despite significant progress in advances in surgical techniques and chemotherapy protocols, the overall survival (OS) remains to be less than 10 % for all stages combined. In recent years, local ablative techniques have been introduced and utilized as additional therapeutic approaches for locally advanced pancreatic cancer (LAPC), with promising results with respect to local tumor control and OS. In addition to successful cytoreduction, there is emerging evidence that local ablation induces antitumor immune activity that could prevent or even treat distant metastatic tumors. The enhancement of antitumor immune responses could potentially make ablative therapy a therapeutic option for the treatment of metastatic PDAC. In this review, we summarize current ablative techniques used in the management of LAPC and their impact on systemic immune responses.

Work-Life Integration for Academic Surgeons.

This Viewpoint discusses the time surgeons spend juggling work and life responsibilities by presenting a brief survey of academic surgeons who tracked their time use for 1 week.

Pressure-Enabled Drug Delivery (PEDD) of a class C TLR9 agonist in combination with checkpoint inhibitor therapy in a murine pancreatic cancer model.

BACKGROUND: Systemic immunotherapy has had limited clinical benefit in pancreatic ductal adenocarcinoma. This is thought to be due to its desmoplastic immunosuppressive tumor microenvironment in addition to high intratumoral pressures that limit drug delivery. Recent preclinical cancer models and early-phase clinical trials have demonstrated the potential of toll-like receptor 9 agonists, including the synthetic CpG oligonucleotide SD-101, to stimulate a wide range of immune cells and eliminate suppressive myeloid cells. We hypothesized that Pressure-Enabled Drug Delivery via Pancreatic Retrograde Venous Infusion of toll-like receptor 9 agonist would improve responsiveness to systemic anti-programmed death receptor-1 checkpoint inhibitor therapy in a murine orthotopic pancreatic ductal adenocarcinoma model. METHODS: Murine pancreatic ductal adenocarcinoma (KPC4580P) tumors were implanted into the pancreatic tails of C57BL/6J mice and treated 8 days after implantation. Mice were assigned to one of the following treatment groups: Pancreatic Retrograde Venous Infusion delivery of saline, Pancreatic Retrograde Venous Infusion delivery of toll-like receptor 9 agonist, systemic anti-programmed death receptor-1, systemic toll-like receptor 9 agonist, or the combination of Pancreatic Retrograde Venous Infusion delivery of toll-like receptor 9 agonist and systemic anti-programmed death receptor-1 (Combo). Fluorescently labeled toll-like receptor 9 agonist (radiant efficiency) was used to measure uptake of the drug on day 1. Changes in tumor burden were evaluated by necropsy at 2 different time points, 7 and 10 days after toll-like receptor 9 agonist treatment. Blood and tumors were collected at necropsy 10 days after toll-like receptor 9 agonist treatment for flow cytometric analysis of tumor-infiltrating leukocytes and plasma cytokines. RESULTS: All mice analyzed survived to necropsy. Site of tumor fluorescence measurements revealed 3-fold higher intensity fluorescence in Pancreatic Retrograde Venous Infusion delivery of toll-like receptor 9 agonist compared to systemic toll-like receptor 9 agonist mice. Tumor weights were significantly lower in the Combo group compared to Pancreatic Retrograde Venous Infusion delivery of saline. Flow cytometry of the Combo group demonstrated significantly increased overall T-cell number, specifically CD4+ T-cells, and a trend toward increased CD8+ T-cells. Cytokine analysis showed significantly decreased IL-6 and CXCL1. CONCLUSION: Pressure-Enabled Drug Delivery of toll-like receptor 9 agonist by Pancreatic Retrograde Venous Infusion with systemic anti-programmed death receptor-1 demonstrated improved pancreatic ductal adenocarcinoma tumor control in a murine pancreatic ductal adenocarcinoma model. These results support study of this combination therapy in pancreatic ductal adenocarcinoma patients and expansion of ongoing Pressure-Enabled Drug Delivery clinical trials.

Minitraps: A simple, compact, low-cost, and reusable method for collecting soil nematodes.

Soil organisms are a crucial part of the terrestrial biosphere and are essential for ecosystem functioning. A major part of soil and sediment ecosystems are nematodes worms, which can be used as a bioindicator of soil status. These worms represent one of the most numerous animal phyla on earth, filling all trophic levels in the soil food web. Overall nematode abundance is related to net ecosystem productivity, and regional variations in abundance provides insight into local patterns of soil fertility and functioning. Methods for extracting nematodes from soils have been established, but these can be cumbersome, or require specialist equipment or consumables, meaning they are not always suitable for the field or remote areas. We have built on previous methods to develop a simple, more compact, and zero-waste method of extracting nematodes, using basic equipment. We demonstrate this in a small collection of soils from deforested, native forest, and reforested sites. On a larger scale, this method can be used to reflect overall ecosystem function, indicating current soil status, and future success and proliferation of reforested sites.

Treatment of pancreatic cancer with irreversible electroporation and intratumoral CD40 antibody stimulates systemic immune responses that inhibit liver metastasis in an orthotopic model.

BACKGROUND: Pancreatic cancer (PC) has a poor prognosis, and most patients present with either locally advanced or distant metastatic disease. Irreversible electroporation (IRE) is a non-thermal method of ablation used clinically in locally advanced PC, but most patients eventually develop distant recurrence. We have previously shown that IRE alone is capable of generating protective, neoantigen-specific immunity. Here, we aim to generate meaningful therapeutic immune effects by combining IRE with local (intratumoral) delivery of a CD40 agonistic antibody (CD40Ab). METHODS: KPC46 organoids were generated from a tumor-bearing male KrasLSL-G12D-p53LSL-R172H-Pdx-1-Cre (KPC) mouse. Orthotopic tumors were established in the pancreatic tail of B6/129 F1J mice via laparotomy. Mice were randomized to treatment with either sham laparotomy, IRE alone, CD40Ab alone, or IRE followed immediately by CD40Ab injection. Metastatic disease and immune infiltration in the liver were analyzed 14 days postprocedure using flow cytometry and multiplex immunofluorescence imaging with spatial analysis. Candidate neoantigens were identified by mutanome profiling of tumor tissue for ex vivo functional analyses. RESULTS: The combination of IRE+CD40 Ab improved median survival to greater than 35 days, significantly longer than IRE (21 days) or CD40Ab (24 days) alone (p<0.01). CD40Ab decreased metastatic disease burden, with less disease in the combination group than in the sham group or IRE alone. Immunohistochemistry of liver metastases revealed a more than twofold higher infiltration of CD8+T cells in the IRE+CD40 Ab group than in any other group (p<0.01). Multiplex immunofluorescence imaging revealed a 4-6 fold increase in the density of CD80+CD11c+ activated dendritic cells (p<0.05), which were spatially distributed throughout the tumor unlike the sham group, where they were restricted to the periphery. In contrast, CD4+FoxP3+ T-regulatory cells (p<0.05) and Ly6G+myeloid derived cells (p<0.01) were reduced and restricted to the tumor periphery in the IRE+CD40 Ab group. T-cells from the IRE+CD40 Ab group recognized significantly more peptides representing candidate neoantigens than did T-cells from the IRE or untreated control groups. CONCLUSIONS: IRE can induce local tumor regression and neoantigen-specific immune responses. Addition of CD40Ab to IRE improved dendritic cell activation and neoantigen recognition, while generating a strong systemic antitumor T-cell response that inhibited metastatic disease progression.

Tumor FAK orchestrates immunosuppression in ovarian cancer via the CD155/TIGIT axis.

High-grade serous ovarian cancer (HGSOC) is a lethal malignancy characterized by an immunosuppressive tumor microenvironment containing few tumor infiltrating lymphocytes (TILs) and an insensitivity to checkpoint inhibitor immunotherapies. Gains in the PTK2 gene encoding focal adhesion kinase (FAK) at Chr8 q24.3 occur in ∼70% of HGSOC tumors, and elevated FAK messenger RNA (mRNA) levels are associated with poor patient survival. Herein, we show that active FAK, phosphorylated at tyrosine-576 within catalytic domain, is significantly increased in late-stage HGSOC tumors. Active FAK costained with CD155, a checkpoint receptor ligand for TIGIT (T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains), in HGSOC tumors and a selective association between FAK and TIGIT checkpoint ligands were supported by patient transcriptomic database analysis. HGSOC tumors with high FAK expression were associated with low CD3 mRNA levels. Accordingly, late-stage tumors showed elevated active FAK staining and significantly lower levels of CD3+ TILs. Using the KMF (Kras, Myc, FAK) syngeneic ovarian tumor model containing spontaneous PTK2 (FAK) gene gains, the effects of tumor intrinsic genetic or oral small molecule FAK inhibitior (FAKi; VS-4718) were evaluated in vivo. Blocking FAK activity decreased tumor burden, suppressed ascites KMF-associated CD155 levels, and increased peritoneal TILs. The combination of FAKi with blocking TIGIT antibody (1B4) maintained elevated TIL levels and reduced TIGIT+ T regulatory cell levels, prolonged host survival, increased CXCL13 levels, and led to the formation of omental tertiary lymphoid structures. Collectively, our studies support FAK and TIGIT targeting as a rationale immunotherapy combination for HGSOC.

Oxaliplatin-induced peripheral neuropathy can be minimized by pressurized regional intravascular delivery in an orthotopic murine pancreatic cancer model.

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.

Effects of Symmetry and Apparent Distance in a Parasagittal-Mirror Variant of the Rubber Hand Illusion Paradigm.

When I see my face in a mirror, its apparent position (behind the glass) is not one that my own face could be in. I accept the face I see as my own because I have an implicit understanding of how mirrors work. The situation is different if I look at the reflection of my right hand in a parasagittal mirror (parallel to body midline) when my left hand is hidden behind the mirror. It is as if I were looking through a window at my own left hand. The experience of body ownership has been investigated using rubber hand illusion (RHI) paradigms, and several studies have demonstrated ownership of a rubber hand viewed in a frontal mirror. Our "proof of concept" study was the first to combine use of a parasagittal mirror and synchronous stroking of both a prosthetic hand (viewed in the mirror) and the participant's hand, with a manipulation of distance between the hands. The strength of the RHI elicited by our parasagittal-mirror paradigm depended not on physical distance between the hands (30, 45, or 60 cm) but on apparent distance between the prosthetic hand (viewed in the mirror) and the participant's hand. This apparent distance was reduced to zero when the prosthetic hand and participant's hand were arranged symmetrically (e.g., 30 cm in front of and behind the mirror). Thus, the parasagittal-mirror paradigm may provide a distinctive way to assess whether competition for ownership depends on spatial separation between the prosthetic hand and the participant's hand.

Reflecting on culturally responsive goal achievement with indigenous clients using the Australian Therapy Outcome Measure for Indigenous Clients (ATOMIC).

INTRODUCTION: Appropriate evaluation of health services for First Australians demands culturally responsive goal setting tools that can be used by inter-professional teams. The Australian Therapy Outcome Measure for Indigenous Clients (ATOMIC) is a purpose-designed tool for measuring therapy outcomes for First Australians. The aim of this study was to establish the clinical utility of the ATOMIC by investigating its alignment with the practice perspectives of an inter-professional First Australian health service. METHODS: Using action research cycles, 12 occupational therapists and 8 speech pathologists applied two successive versions of the ATOMIC in practice. Focus group feedback after use of the first version (ATOMICv1) prompted adaptations to the tool (ATOMICv2). Therapists participated in four focus groups, two after using ATOMICv1 and two after using ATOMICv2. Focus group transcripts were analysed inductively using a qualitative description approach. RESULTS: Challenges in setting SMART goals early in therapy and defining specific measurement increments in ATOMICv1 led to therapists favouring skill-based goals that were easier to measure rather than broader daily life goals, thereby impacting on occupation- and client-centred practice. ATOMICv2 allowed goal setting at any point in therapy, evaluated goals using visual analogue scales, and gathered evidence for rating goal achievement throughout the therapy process. Therapists found the ATOMICv2 to be a culturally responsive tool that aligned with practice perspectives by foregrounding relationship building, facilitating clinical reasoning, documenting daily life changes, and providing integrated inter-professional care. CONCLUSION: The ATOMIC demonstrated good clinical utility in an inter-professional service for First Australian children. It aligned with a culturally responsive practice perspective and captured goal achievement in daily life contexts. Further research is needed to gain client perspectives across the lifespan and to investigate its application by other health professions.

Autistic traits and loneliness in autism are associated with increased tendencies to anthropomorphise.

Anthropomorphism-the attribution of human qualities to non-human objects-is believed to be a natural tendency which may serve several adaptive functions. One possibility is that anthropomorphism provides an egocentric heuristic by which we can understand the world. It may also be a strategy for reducing our subjective sense of loneliness. However, not all humans exhibit the same propensity to anthropomorphise. Recent findings suggest that autistic individuals may be more likely to anthropomorphise than non-autistic individuals. In Study 1, we conducted a large-scale survey of autistic traits and dispositional anthropomorphism in the general population (n = 870). We found that individuals who reported having more autistic traits had an increased dispositional tendency to anthropomorphise non-human entities. In Study 2, we more closely examined variation in anthropomorphism tendencies in a sample of autistic adults (n = 90) to better understand what might drive increased anthropomorphism in this population. We found that those with greater anthropomorphism tendencies experienced greater levels of self-reported loneliness. We propose that increased anthropomorphism might reflect reduced opportunities for social connection for autistic people and those with more autistic traits.

The Landmark Series: Locally Advanced Pancreatic Cancer and Ablative Therapy Options.

Locally advanced pancreatic cancer (LAPC) is a challenging disease to treat. There is consensus that systemic chemotherapy should be the first line of therapy for most patients. However, there is no consensus on how to manage those patients who do not have sufficient response to become candidates for resection but also do not have distant progression after weeks or months of systemic therapy. Radiation therapy is the most commonly used and best-studied local ablative therapy. One recent randomized controlled trial (LAP-07) failed to demonstrate an overall survival benefit for conventional chemoradiation therapy after induction chemotherapy versus chemotherapy alone. This study had several limitations, and ongoing studies are re-evaluating the role of chemoradiation after more effective chemotherapy regimens as well as more advanced radiation techniques. In parallel, there has been increasing interest in other thermal and non-thermal methods of ablation. In particular, irreversible electroporation has gained traction for treatment of LAPC, with at least one ongoing randomized controlled trial designed to address its role compared with systemic chemotherapy alone. Multiple preclinical and clinical studies are investigating combinations of local ablation and immunotherapy with the goal of generating immune responses that will meaningfully improve outcomes.

Optimizing Patient Selection for Irreversible Electroporation of Locally Advanced Pancreatic Cancer: Analyses of Survival.

BACKGROUND: Irreversible electroporation (IRE) has emerged as a viable consolidative therapy after induction chemotherapy, in which this combination has improved overall survival of locally advanced pancreatic cancer (LAPC). Optimal timing and patient selection for irreversible electroporation remains a clinically unmet need. The aim of this study was to investigate preoperative factors that may assist in predicting progression-free and overall survival following IRE. METHODS: A multi-institutional, prospectively maintained database was reviewed for patients with LAPC treated with induction chemotherapy followed by open-technique irreversible electroporation from 7/2015-5/2019. RECIST 1.1 criteria were used to assess tumor response and radiological progression. Overall survival (OS) and progression-free survival (PFS) were recorded. Survival analyses were performed using Kaplan Meier and Cox multivariable regression analyses. RESULTS: 187 LAPC patients (median age 62 years range, 21 - 91, 65% men, 35% women) were treated with IRE. Median PFS was 21.7 months and median OS from diagnosis was 25.5 months. On multivariable analysis, age ≤ 61 (HR 0.41, 95%CI 0.21-0.78, p<0.008) and no prior radiation (HR 0.49, 95%CI 0.26-0.94, p=0.03) were positive predictors of OS after IRE. Age ≤ 61(HR 0.53, 95%CI, 0.28-.99, p=0.046) and FOLFIRINOX followed by gemcitabine/abraxane induction chemotherapy (HR 0.37,95%CI 0.15-0.89, p=0.027) predicted prolonged PFS after IRE. Abnormal CA19-9 values at the time of surgery negatively impacted both OS (HR 2.46, 95%CI 1.28-4.72, p<0.007) and PFS (HR 2.192, 95%CI 1.143-4.201, p=0.018) following IRE. CONCLUSIONS: Age, CA 19-9 response, avoidance of pre-IRE radiation, and FOLFIRINOX plus gemcitabine/abraxane induction chemotherapy are prominent factors to consider when referring or selecting LAPC patients to undergo IRE.

Role of lymphadenectomy in resectable pancreatic cancer.

BACKGROUND: Pancreatic cancer (PC) remains one of the most devastating malignant diseases, predicted to become the second leading cause of cancer-related death by 2030. Despite advances in surgical techniques and in systemic therapy, the 5-year relative survival remains a grim 9% for all stages combined. The extent of lymphadenectomy has been discussed intensively for decades, given that even in early stages of PC, lymph node (LN) metastasis can be detected in approximately 80%. PURPOSE: The primary objective of this review was to provide an overview of the current literature evaluating the role of lymphadenectomy in resected PC. For this, we evaluated randomized controlled studies (RCTs) assessing the impact of extent of lymphadenectomy on OS and studies evaluating the prognostic impact of anatomical site of LN metastasis and the impact of the number of resected LNs on OS. CONCLUSIONS: Lymphadenectomy plays an essential part in the multimodal treatment algorithm of PC and is an additional therapeutic tool to increase the chance for surgical radicality and to ensure correct staging for optimal oncological therapy. Based on the literature from the last decades, standard lymphadenectomy with resection of at least ≥ 15 LNs is associated with an acceptable postoperative complication risk and should be recommended to obtain local radicality and accurate staging of the disease. Although radical surgery including appropriate lymphadenectomy of regional LNs remains the only chance for long-term tumor control, future studies specifically assessing the impact of neoadjuvant therapy on extraregional LNs are warranted.

Real gains: development of a tool to measure outcomes for urban First Australian children accessing culturally responsive interprofessional therapy.

Healthcare services are accountable to their clients, communities, governments and funding sources to clearly demonstrate the effectiveness of interventions. A First Australian children's therapy service delivering culturally responsive, interprofessional collaborative practice aimed to evaluate their service. However, this process was constrained by available outcome measures which lacked the flexibility necessary for meaningful use within the dynamic and relational nature of their service delivery. This paper outlines an action research process in three cycles which was used to develop the Australian Therapies Outcome Measure for Indigenous Clients (ATOMIC) with the aim of evaluating therapy outcomes for urban First Australian children engaged in culturally responsive interprofessional therapy. Interrater reliability values of 0.995 and 0.982 were established for ATOMIC pre- and post-therapy measures, respectively, during a pilot phase involving 16 participants. Participants in the main study were 80 First Australian children aged two to 16 years who attended between two and nine interprofessional therapy sessions with occupational therapists and speech pathologists. Pre- and post-therapy ATOMIC scores confirmed progress on pre-determined functional goals across a range of skill domains. Outcomes of this study demonstrated that real gains are being made in urban First Australian children's lives following interprofessional collaborative service provision.

Emerging zoonotic diseases originating in mammals: a systematic review of effects of anthropogenic land-use change.

Zoonotic pathogens and parasites that are transmitted from vertebrates to humans are a major public health risk with high associated global economic costs. The spread of these pathogens and risk of transmission accelerate with recent anthropogenic land-use changes (LUC) such as deforestation, urbanisation, and agricultural intensification, factors that are expected to increase in the future due to human population expansion and increasing demand for resources.We systematically review the literature on anthropogenic LUC and zoonotic diseases, highlighting the most prominent mammalian reservoirs and pathogens, and identifying avenues for future research.The majority of studies were global reviews that did not focus on specific taxa. South America and Asia were the most-studied regions, while the most-studied LUC was urbanisation. Livestock were studied more within the context of agricultural intensification, carnivores with urbanisation and helminths, bats with deforestation and viruses, and primates with habitat fragmentation and protozoa.Research into specific animal reservoirs has improved our understanding of how the spread of zoonotic diseases is affected by LUC. The behaviour of hosts can be altered when their habitats are changed, impacting the pathogens they carry and the probability of disease spreading to humans. Understanding this has enabled the identification of factors that alter the risk of emergence (such as virulence, pathogen diversity, and ease of transmission). Yet, many pathogens and impacts of LUC other than urbanisation have been understudied.Predicting how zoonotic diseases emerge and spread in response to anthropogenic LUC requires more empirical and data synthesis studies that link host ecology and responses with pathogen ecology and disease spread. The link between anthropogenic impacts on the natural environment and the recent COVID-19 pandemic highlights the urgent need to understand how anthropogenic LUC affects the risk of spillover to humans and spread of zoonotic diseases originating in mammals.

Pressure-enabled delivery of gemcitabine in an orthotopic pancreatic cancer mouse model.

BACKGROUND: We describe the use of pancreatic retrograde venous infusion in an orthotopic murine model of pancreatic ductal adenocarcinoma and hypothesize that pancreatic retrograde venous infusion delivery of gemcitabine will increase concentrations of gemcitabine in the tumor and the subsequent tumor response to treatment. METHODS: Murine pancreatic ductal adenocarcinoma (KPC4580P) was transplanted onto the pancreatic tail of C57BL/6J mice. Groups (n = 15) of mice were assigned to sham laparotomy and 100 mg/kg intraperitoneal infusion of gemcitabine (systemic gemcitabine), pancreatic venous isolation with pancreatic retrograde venous infusion of 100 mg/kg gemcitabine, or pancreatic retrograde venous infusion with saline infusion. Tumor pressures were recorded during pancreatic retrograde venous infusion. Mice were killed at 1 hour or 7 days after infusion. RESULTS: Baseline tumor pressures were 45 ± 8 mm Hg, and pancreatic retrograde venous infusion increased tumor pressures by 29 ± 6 mm Hg (P < .01). Pancreatic retrograde venous infusion gemcitabine mice had greater tumor gemcitabine concentrations compared with systemic gemcitabine (127 vs 19 ng/mg; P < .01) and lesser tumor volumes compared with both systemic gem and pancreatic retrograde venous infusion with saline (274 vs 857 vs 629 mm3; P < .01). CONCLUSION: Pancreatic retrograde venous infusion increased tumor pressures greater than baseline, improved gemcitabine delivery, and increased the treatment response. These findings suggest that pressurized, regional delivery overcomes the increased pressure barrier in pancreatic ductal adenocarcinoma. Additional preclinical studies with cytotoxic and immunotherapeutic agents and clinical trials using pressure-enabled drug delivery with pancreatic retrograde venous infusion devices are underway.