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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%. 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. 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.

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.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.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 mmPancreatic 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.

Gastrointestinal stromal tumor (GIST), the most common sarcoma, is characterized by KIT protein overexpression, and tumors are frequently driven by oncogenic KIT mutations. Targeted inhibition of KIT revolutionized GIST therapy and ushered in the era of precision medicine for the treatment of solid malignancies. Here, we present the first use of a KIT-specific DNA aptamer for targeted labeling of GIST. We found that an anti-KIT DNA aptamer bound cells in a KIT-dependent manner and was highly specific for GIST cell labeling in vitro. Functionally, the KIT aptamer bound extracellular KIT in a manner similar to KIT mAb staining, and was trafficked intracellularly in vitro. The KIT aptamer bound dissociated primary human GIST cells in a mutation agnostic manner such that tumors with KIT and PDGFRA mutations were labeled. In addition, the KIT aptamer specifically labeled intact human GIST tissue ex vivo, as well as peritoneal xenografts in mice with high sensitivity. These results represent the first use of an aptamer-based method for targeted detection of GIST in vitro and in vivo.

This report presents a case of necrotizing pancreatitis resulting in a large hepatic subcapsular hematoma that led to development of hepatic ischemia and early stages of liver failure. Following surgical decompression, liver function dramatically improved, but large areas of peripheral hepatic infarction had developed. This case demonstrates the risks of a rapidly expanding hepatic subcapsular hematoma, emphasizes the importance of recognizing and aggressively treating active bleeding, and cautions against administering anticoagulation and tissue-plasminogen activator in this clinical scenario. Keywords: Hepatic hematoma, Hepatic infarct, Necrotizing pancreatitis

Objective The revolutionary results of immunotherapy have not yet translated to pancreatic cancer (PC). Irreversible electroporation (IRE) is a non-thermal ablative therapy that can generate tumor-specific immune responses, yet not sufficient to eradicate distant metastatic disease. Post-translational protein modification (PTM) by small ubiquitin-like modifier (SUMO) is involved in carcinogenesis and PD-L1 mediated immunosuppression. TAK-981 is a novel inhibitor of SUMOylation that has demonstrated induction anti-tumor immune responses in preclinical models. Our hypothesis is that TAK-981 will augment the effects of IRE in an immunocompetent orthotopic mouse model of PC. Methods The PC cell line (KPC4580P) was derived from an autochthonous tumor arising in a genetically engineered mouse model (KPC). The tumors were implanted orthotopically into the pancreas via laparotomy. Once tumors reached 5-7 mm in diameter, mice were randomized to one of four treatment groups: IRE alone, TAK-981 alone, IRE + TAK-981, or no treatment. IRE versus sham laparotomy (150 x 90 microsec pulses at 1500 V/cm) was performed once through second laparotomy. TAK-981 (7.5mg/kg) versus vehicle was delivered via subcutaneous injection twice weekly x four doses, starting on the day of IRE. Tumors were harvested on day 14 for flow cytometric analysis. Results Ultrasound was performed on days 8, 14 and 20 after initiation of treatment. Tumor growth in the IRE + TAK-981 group was significantly inhibited compared to sham-treated tumors (Fig. 1, *p=0.0002), and this effect persisted to day 20, even after treatment with TAK-981 was stopped on day 11 (p Conclusion Our results suggest that the combination of IRE with TAK-981 is associated with better local tumor control and a significant increase of CD8+ T-cells and IFN-gamma+ CD8+ T-cells. We expect that this combination might contribute systemic immune responses that would prevent or even eradicate distant metastasis. Given that immunosuppression mediated by PD-L1 is regulated by ubiquitination and is seen in 50% of PC tumors, targeting PTM with TAK-981 might also render PC responsive to immunotherapy with checkpoint inhibitors.

Pancreatic ductal adenocarcinoma (PDAC) typically has nonspecific symptoms and is often found too late to treat. Because diagnosis of PDAC involves complex, invasive, and expensive procedures, screening populations at increased risk will depend on developing rapid, sensitive, specific, and cost-effective tests. Exosomes, which are nanoscale vesicles shed into blood from tumors, have come into focus as valuable entities for noninvasive liquid biopsy diagnostics. However, rapid capture and analysis of exosomes with their protein and other biomarkers have proven difficult. Here, we present a simple method integrating capture and analysis of exosomes and other extracellular vesicles directly from whole blood, plasma, or serum onto an AC electrokinetic microarray chip. In this process, no pretreatment or dilution of sample is required, nor is it necessary to use capture antibodies or other affinity techniques. Subsequent on-chip immunofluorescence analysis permits specific identification and quantification of target biomarkers within as little as 30 min total time. In this initial validation study, the biomarkers glypican-1 and CD63 were found to reflect the presence of PDAC and thus were used to develop a bivariate model for detecting PDAC. Twenty PDAC patient samples could be distinguished from 11 healthy subjects with 99% sensitivity and 82% specificity. In a smaller group of colon cancer patient samples, elevated glypican-1 was observed for metastatic but not for nonmetastatic disease. The speed and simplicity of ACE exosome capture and on-chip biomarker detection, combined with the ability to use whole blood, will enable seamless "sample-to-answer" liquid biopsy screening and improve early stage cancer diagnostics.

Despite the identification of more active systemic therapy combinations for pancreatic cancer, cures remain elusive and feasible only in patients with localized, operable disease. When examining outcome data from phase III adjuvant trials conducted during the past decade, the survival for patients with localized disease has improved, likely owing to a combination of factors including more active adjuvant therapy and improved surgical and perioperative care. Perhaps the greatest recent change in the care of patients with localized pancreatic cancer has been the extension of surgery to tumors previously thought to be inoperable because of involvement of major blood vessels. These so-called "borderline resectable pancreatic cancers" have now been objectively defined, and their management is being studied in randomized trials. This has been made feasible by the availability of more active systemic therapy combinations that are increasingly being used in the neoadjuvant setting. Given the increasing activity of systemic regimens, the challenges in delivering such therapy in the postoperative setting, and the numerous novel agents in late stages of clinical development, it is reasonable to hypothesize that the neoadjuvant setting may eventually become the standard of care for patients with resectable disease.

Activation of the RNA-sensing pattern recognition receptor (PRR) in cancer cells leads to cell death and cytokine expression. This cancer cell death releases tumor antigens and damage-associated molecular patterns (DAMPs) that induce anti-tumor immunity. However, these cytokines and DAMPs also cause adverse inflammatory and thrombotic complications that can limit the overall therapeutic benefits of PRR-targeting anti-cancer therapies. To overcome this problem, we generated and evaluated two novel and distinct ssRNA molecules (immunogenic cell-killing RNA [ICR]2 and ICR4). ICR2 and ICR4 differentially stimulated cell death and PRR signaling pathways and induced different patterns of cytokine expression in cancer and innate immune cells. Interestingly, DAMPs released from ICR2- and ICR4-treated cancer cells had distinct patterns of stimulation of innate immune receptors and coagulation. Finally, ICR2 and ICR4 inhibited in vivo tumor growth as effectively as poly(I:C). ICR2 and ICR4 are potential therapeutic agents that differentially induce cell death, immune stimulation, and coagulation when introduced into tumors.

Irreversible electroporation (IRE) is a nonthermal ablation technique that is used clinically in selected patients with locally advanced pancreatic cancer, but most patients develop recurrent distant metastatic disease. We hypothesize that IRE can induce an in situ vaccination effect by releasing tumor neoantigens in an inflammatory context. Using an immunocompetent mouse model, we demonstrated that IRE alone produced complete regression of subcutaneous tumors in approximately 20% to 30% of mice. IRE was not effective in immunodeficient mice. Mice with complete response to IRE demonstrated prophylactic immunity and remained tumor free when rechallenged with secondary tumors on the contralateral flank. CD8+ T cells from IRE-responsive mice were reactive against peptides representing model-inherent alloantigens and conferred protection against tumor challenge when adoptively transferred into immunocompromised, tumor-naïve mice. Combining IRE with intratumoral Toll-like receptor-7 (TLR7) agonist (1V270) and systemic anti-programmed death-1 receptor (PD)-1 checkpoint blockade resulted in improved treatment responses. This combination also resulted in elimination of untreated concomitant distant tumors (abscopal effects), an effect not seen with IRE alone. These results suggest that the systemic antitumor immune response triggered by IRE can be enhanced by stimulating the innate immune system with a TLR7 agonist and the adaptive immune system with anti–PD-1 checkpoint blockade simultaneously. Combinatorial approaches such as this may help overcome the immunosuppressive pancreatic cancer microenvironment.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer in part due to inherent resistance to chemotherapy, including the first-line drug gemcitabine. Although low expression of the nucleoside transporters hENT1 and hCNT3 that mediate cellular uptake of gemcitabine has been linked to gemcitabine resistance, the mechanisms regulating their expression in the PDAC tumor microenvironment are largely unknown. Here, we report that the matricellular protein cysteine-rich angiogenic inducer 61 (CYR61) negatively regulates the nucleoside transporters hENT1 and hCNT3. CRISPR/Cas9-mediated knockout of CYR61 increased expression of hENT1 and hCNT3, increased cellular uptake of gemcitabine and sensitized PDAC cells to gemcitabine-induced apoptosis. In PDAC patient samples, expression of hENT1 and hCNT3 negatively correlates with expression of CYR61 . We demonstrate that stromal pancreatic stellate cells (PSCs) are a source of CYR61 within the PDAC tumor microenvironment. Transforming growth factor-β (TGF-β) induces the expression of CYR61 in PSCs through canonical TGF-β-ALK5-Smad2/3 signaling. Activation of TGF-β signaling or expression of CYR61 in PSCs promotes resistance to gemcitabine in PDAC cells in an in vitro co-culture assay. Our results identify CYR61 as a TGF-β-induced stromal-derived factor that regulates gemcitabine sensitivity in PDAC and suggest that targeting CYR61 may improve chemotherapy response in PDAC patients.

Introduction: Pancreatic Cancer (PC) has a highly immunosuppressive microenvironment with a low mutational burden and has so far been resistant to immunotherapy. Irreversible electroporation (IRE) is a non-thermal method of inducing tumor cell death, without damage to adjacent blood vessels, that is being used clinically for selected patients with locally advanced PC. Despite local control rates greater than 90%, most IRE patients develop distant recurrence, emphasizing the need for better methods to treat micrometastatic disease. Using an immunocompetent mouse model of PC, we have previously shown that IRE induces complete regression in 25-33% of subcutaneous tumors, and complete responders are protected from a tumor rechallenge. However, IRE alone did not produce significant therapeutic immunity (abscopal effects) against concomitant distant tumors. We hypothesized that combination of IRE with innate immune stimulators would also enhance the adaptive immune response. Methods: We used a cell line generated from a genetically engineered (KPC) mouse establish bilateral flank tumors. The “primary” tumor was treated with IRE alone or in combination with local delivery of a toll-like receptor 7 (TLR7) agonist (1V270) and CD40 agonistic antibody (CD40Ab). 15 parameter procartaplex (Thermo) was used for cytokine analysis and RNA-Seq was performed using an Illumina MiSeq 1000 platform with total RNA from excised tumor all on day 7 post procedure. Results: We observed complete regression in 8/10 tumors treated with the combination (Combo) of IRE, 1V270 and CD40Ab compared to 3/10 in IRE alone. However, the combo was much more effective than IRE alone at inducing regression of the untreated secondary flank tumor, including complete regression of 7/10 untreated tumors. CD40Ab alone had minimal effect on local or secondary tumor growth. Analysis of systemic cytokines using multiplex analysis showed 112 fold increase in IFNy levels in plasma with the Combo compared to untreated mice (P Conclusion: These data suggest that local delivery of CD40Ab and TLR7 agonists augment the systemic immune effects of IRE and have the potential to improve the overall survival of patients undergoing IRE for locally advanced PC by reducing distant recurrence. Citation Format: Jayanth Surya Narayanan Shankara Narayanan, Diego Vicente, Partha Ray, Thomas Whisenant, Rebekah White. Combining irreversible electroporation with TLR7 and CD40 agonists confers systemic anti-tumor immunity in a murine pancreatic cancer model [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2221.

High-grade serous ovarian cancer (HGSOC) is the leading cause of death from gynecologic malignancies. Many patients initially respond well to surgery followed by chemotherapy, yet ~80% of patients recur with disease that is frequently recalcitrant to chemotherapy. Across a number of chemoresistant cancers, immunotherapies have shown great promise. Correlative studies in patients with HGSOC support a role for immune system in patient outcome. Yet the HGSOC tumor microenvironment (TME) is highly immunosuppressive, which constitutes a major barrier to immunotherapy success. Understanding the molecular signals in HGSOC that promote resistance to chemo- or immunotherapies is required for identification of actionable targets within HGSOC; yet, there are limited models that recapitulate the TME in ovarian cancer. We have generated a new syngeneic C57Bl6 mouse model of ovarian cancer that exhibits genomic copy number gains in KRAS, MYC, and (PTK2) FAK genes (termed KMF) and aggressive malignant phenotypes commonly observed in HGSOC. The KMF TME, like HGSOC, is populated by immunosuppressive myeloid-derived suppressor cells (MDSC) and T-regulatory (Treg) cells but lacks CD8+ T cell infiltration. We find that tumor-associated FAK expression and kinase activity are essential for KMF tumor growth. Mechanistically, by knockout and cell reconstitution approaches, FAK promotes expression of a select group of proteins mediating chemo- and immune-resistance. Inhibiting FAK modulates checkpoint inhibitor protein expression, limits MDSC and Treg recruitment, and enhances CD4 and CD8 T cell infiltration. Pharmacologic FAK inhibition reduced CD112/CD155 expression on KMF cells and, together with anti-TIGIT immunotherapy, significantly increased mouse survival from 28 to 60+ days. The chemoresistant KMF model recapitulates key aspects of the aggressive HGSOC TME including the generation of an immunosuppressive milieu, and may be used as a preclinical model to identify new therapeutic targets for HGSOC. Citation Format: Duygu Ozmadenci, Jayanth S. Shankara Narayanan, Jacob R. Andrew, Allison M. Barrie, Shulin Jiang, Esra Bilir, Thomas Bertotto, Rebekah R. White, Vijay K. Kuchroo, Jonathan A. Pachter, Dwayne G. Stupack, David D. Schlaepfer. Modeling the ovarian cancer immune response and tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr A26.

Gastrointestinal dysmotility represents a severe constellation of symptoms resulting from malfunction of the stomach, small intestine, or large intestine. By definition excluding organic origins of obstruction, the etiologies of the condition range from diabetes to Parkinson’s to more exotic myopathies, although idiopathy remains the most commonly cited cause. Patient presentation typically includes epigastric pain, nausea, vomiting, early satiety, and poor oral intake; constipation characterizes lower GI dysmotility. Severity of the symptoms can range from mildly aggravating to requiring a feeding jejunostomy or even total parental nutrition for survival. CT scan, EGD, and barium swallow are helpful to rule out organic causes, but nuclear medicine emptying studies are required to make diagnosis. Treatment options remain poor. Symptomatic relief with various anti-nausea medications can alleviate minor cases. Metoclopromide remains the only FDA-approved medication for gastroparesis but comes with well-described, severe side effects. Other, more exotic interventions like intrapyloric botulinum injections and implanted gastric pacemakers lack convincing evidence of efficacy. More dramatic, surgical cures like pyloroplasty, jejunostomy feeding tubes, and even small bowel transplant are indicated in particularly severe cases.

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.

Background The optimal treatment and management of locally advanced pancreatic cancer (LAPC) remains unclear and controversial. This study aimed to report the initial outcomes of the AHPBA Registry and evaluate the reproducibility of existing evidence that the addition of Irreversible Electroporation (IRE), a nonthermal ablative treatment, confers survival benefits beyond standard therapeutic options for patients with LAPC. Methods From December 2015 to October 2017, patients with LAPC were treated with open-technique IRE following the AHPBA Registry Protocols. Patient demographics, long-term outcomes, and adverse events were recorded. Survival analyses were performed using Kaplan-Meier (KM) curves for overall survival (OS), progression free survival (PFS) and time to progression (TTP). Results A total of 152 patients underwent successful IRE. Morbidity and mortality were 18% and 2% respectively, with 19 (13%) patients experiencing severe adverse events. Nine (6%) patients presented with local recurrence. Median TTP, PFS, and OS from diagnosis were 27.3 months, 22.8 months, and 30.7 months respectively. Conclusion The combination of IRE with established multiagent therapy is safe and demonstrates encouraging survival among patients with LAPC. IRE is associated with a low rate of serious adverse events and has been optimized for more widespread adoption through the standardized protocols available through the AHPBA registry.

Pancreatic cancer (PC), a disease which kills approximately 40,000 patients each year in the US, has successfully evaded several therapeutic approaches including the promising immunotherapeutic strategies. Irreversible electroporation (IRE) is a non-thermal ablation technique that induces tumor cell death without destruction of adjacent collagenous structures, thus enabling the procedure to be performed in tumors very close to blood vessels. Unlike thermal ablation techniques, IRE results in gradual apoptotic cell death, along with immediate ablation induced necrosis, and is currently in clinical use for selected patients with locally advanced PC. An ablative, non-target specific procedure like IRE can induce a myriad of responses in the tumor microenvironment. A few studies have addressed the effects of IRE on tumor growth in other tumor types, but none have focused on PC. We have developed a syngeneic mouse model of PC in which subcutaneous (SQ) and orthotopic tumors can be successfully treated with IRE in a highly controlled setting, facilitating various longitudinal studies post procedure. This animal model serves as a robust system to study the effects of IRE and ways to improve the clinical efficacy of IRE.

Nucleic acid binding polymers (NABPs) have been extensively used as vehicles for DNA and RNA delivery. More recently, we discovered that a subset of these NABPs can also serve as anti-inflammatoryagents by capturing pro-inflammatory extracellular nucleic acids and associated protein complexes that promote activation of toll-like receptors (TLRs) in diseases such as lupuserythematosus. Nucleic-acid-mediated TLR signaling also facilitates tumor progression and metastasis in several cancers, including pancreatic cancer (PC). In addition, extracellular DNA and RNA circulate on or within lipid microvesicles, such as microparticles or exosomes, which also promote metastasis by inducing pro-tumorigenic signaling in cancer cells and pre-conditioning secondary sites for metastatic establishment. Here, we explore the use of an NABP, the 3rd generation polyamidoamine dendrimer (PAMAM-G3), as an anti-metastatic agent. We show that PAMAM-G3 not only inhibits nucleic-acid-mediated activation of TLRs and invasion of PC tumor cells invitro, but can also directly bind extracellular microvesicles to neutralize their pro-invasive effects as well. Moreover, we demonstrate that PAMAM-G3 dramatically reduces liver metastases in a syngeneic murine model of PC. Our findings identify a promising therapeutic application of NABPs for combating metastatic disease in PC and potentially other malignancies.

In this retrospective review, we evaluate a standardized care plan (SCP) for patients undergoing pancreaticoduodenectomy, which included selective placement of feeding jejunostomy tubes (FJTs) and a perioperative fast-track recovery pathway (FTRP).A review of 242 patients undergoing pancreaticoduodenectomy was completed. Patients treated pre- and post-SCP implementation were compared. Univariate comparison followed by multivariable linear regression were performed to identify predictors of hospital length of stay (HLOS).SCP patients (n = 100) were slightly older but otherwise similar to pre-SCP patients (n = 142). FJT placement occurred less frequently in SCP patients (38 versus 94%, P 0.001). All SCP patients were initiated on the FTRP. Among SCP patients, an oral diet was introduced earlier (5 versus 8.5 d, P 0.001) and HLOS was shorter (11 versus 13 d, P = 0.015). Readmission rates were similar. Following adjustment with linear regression, we confirmed SCP status as a predictor of HLOS. To assess SCP components, HLOS was evaluated separately based on FTRP status and FJT placement. Although both were highly associated with HLOS, neither was independently predictive in multivariable analysis.Implementation of an SCP resulted in shorter HLOS without an increase in readmissions. Future studies are necessary to identify specific components of SCPs that most influence outcomes.

Introduction The drive to improve outcomes and the inevitability of mandated public reporting necessitate uniform documentation and accurate databases. The reporting of wound classification in patients undergoing hepato-pancreatico-biliary (HPB) surgery and the impact of inconsistencies on quality metrics were investigated. Methods The 2005–2011 National Surgical Quality Improvement Program (NSQIP) participant use file was interrogated to identify patients undergoing HPB resections. The effect of wound classification on post-operative surgical site infection (SSI) rates was determined through logistic regression. The impact of variations in wound classification reporting on perceived outcomes was modelled by simulating observed-to-expected (O/E) ratios for SSI. Results In total, 27 376 patients were identified with significant heterogeneity in wound classification. In spite of clear guidelines prompting at least ‘clean-contaminated’ designation for HPB resections, 8% of all cases were coded as ‘clean’. Contaminated [adjusted odds ratio (AOR): 1.39, P = 0.001] and dirty (AOR: 1.42, P = 0.02] cases were associated with higher odds of SSI, whereas clean-contaminated were not ( P = 0.99). O/E ratios were highly sensitive to modest changes in wound classification. Conclusions Perceived performance is affected by heterogeneous reporting of wound classification. As institutions work to improve outcomes and prepare for public reporting, it is imperative that all adhere to consistent reporting practices to provide accurate and reproducible outcomes.

Background Previous studies have indicated that clinical pathways may shorten hospital length of stay (HLOS) among patients undergoing distal pancreatectomy (DP). Here, we evaluate an institutional standardized care pathway (SCP) for patients undergoing DP. Materials and methods A retrospective review of patients undergoing DP from November 2006 to November 2012 was completed. Patients treated before and after implementation of the SCP were compared. Multivariable linear regression was then performed to identify independent predictors of HLOS. Results There were no differences in patient characteristics between SCP ( n = 50) and pre-SCP patients ( n = 100). Laparoscopic technique (62% versus 13%, P versus 38%, P = 0.117), and concomitant major organ resection (24% versus 13%, P = 0.106) were more common among SCP patients. Overall, important complication rates were similar (24% versus 26%, P = 0.842). SCP patients resumed a normal diet earlier (4 versus 5 d, P = 0.025) and had shorter HLOS (6 versus 7 d, P = 0.026). There was no increase in 30-d resurgery or readmission. In univariate comparison, SCP, cancer diagnoses, intraductal papillary mucinous neoplasm diagnoses, neoadjuvant therapy, operative technique, major organ resection, and feeding tube placement were associated with HLOS; however, after multivariable adjustment, only laparoscopic technique (−33%, P = 0.001), concomitant major organ resection (+38%, P P Conclusions Implementation of a clinical pathway did not improve HLOS at our institution. The increasing use of laparoscopy likely accounts for shorter HLOS in the SCP cohort. In the future, it will be important to identify clinical scenarios most likely to benefit from implementation of a clinical pathway.

Groove pancreatitis is a rare form of chronic pancreatitis that affects the groove anatomical area between the head of the pancreas, duodenum, and common bile duct. We provide a summary of the clinical findings of 4 groove pancreatitis cases diagnosed at a tertiary academic medical center over a 5-year period. A detailed review of the current literature surrounding this clinical entity is also provided. Although rare, groove pancreatitis should be considered in the differential diagnosis of patients presenting with pancreatic head mass lesions, as appropriate diagnosis can help avoid unnecessary surgical procedures.

Despite the rising incidence of hepatocellular carcinoma (HCC), challenges and controversy persist in optimizing treatment. As recent randomized trials suggest that ablation can have oncologic equivalence compared with resection for early HCC, the relative morbidity of the 2 approaches is a central issue in treatment decisions. Although excellent contemporary perioperative outcomes have been reported by a few hepatobiliary units, it is not clear that they can be replicated in broader practice. Our objective was to help inform this treatment dilemma by defining perioperative outcomes in a broader set of patients as represented in NSQIP-participating institutions.Mortality and morbidity data were extracted from the 2005-2010 NSQIP Participant Use Data Files based on Current Procedural Terminology (hepatectomy and ablation) and ICD-9 (HCC). Perioperative outcomes were reviewed, and factors associated with morbidity and mortality were identified with multivariable logistic regression.Eight hundred and thirty-seven (52%) underwent minor hepatectomy, 444 (28%) underwent major hepatectomy, and 323 (20%) underwent surgical ablation. Mortality rates were 3.4% for minor hepatectomy, 3.7% for ablation, and 8.3% for major hepatectomy (p0.01). Major complication rates were 21.3% for minor hepatectomy, 9.3% for ablation, and 35.1% for major hepatectomy (p0.01). When controlling for confounders, ablation was associated with decreased mortality (adjusted odds ratio = 0.20; 95% CI, 0.04-0.97; p = 0.046) and major complications (adjusted odds ratio = 0.34; 95% CI, 0.22-0.52; p0.001).Exceedingly high complication rates after major hepatectomy for HCC exist in the broader NSQIP treatment environment. These data strongly support the use of parenchymal-sparing minor resections or ablation over major hepatectomy for early HCC when feasible.

OBJECTIVES: Patients with pancreatic adenocarcinoma often present with distant metastatic disease. We aimed to assess whether improvements in survival of clinical trials translated to a population-based level. METHODS: The US Surveillance, Epidemiology, and End Results registry was queried. Adult patients with distant metastatic adenocarcinoma of the pancreas were included from 1988 to 2008. Overall survival was analyzed using Kaplan-Meier curves as well as multivariable-adjusted Cox proportional hazards models. RESULTS: In total, 32,452 patients were included. Mean age was 67.6 (SD: 11.7) years, and 15,341 (47.3%) were female. Median overall survival was 3 months (95% confidence interval [CI], 3-3 months), which increased from 2 (CI, 2-2) months in 1988 to 3 (CI, 3-4) months in 2008. After adjustment for multiple covariates, the hazard ratio (HR) decreased by 0.977 per year (CI, 0.975-0.980). In multivariable-adjusted survival analyses, tumor location in the pancreatic body/tail (HR, 1.10), male sex (HR, 1.09), increasing age (HR, 1.016), African American ethnicity (HR, 1.16), nonmarried civil status (HR, 1.18), and absence of radiotherapy (HR, 1.41) were associated with worse survival (P < 0.001 for all predictors). CONCLUSIONS: The improvement in overall survival over the past 2 decades among patients with metastatic pancreatic adenocarcinoma is modest and disappointing. More effective therapeutic strategies for advanced disease are desperately needed.

The objective of this study was to compare survival between all patients with radiographically resectable adenocarcinoma of the proximal pancreas who underwent preoperative chemoradiation therapy (PRE-OP CRT) or surgical exploration first (SURGERY) with “intention to resect.” Pancreatic cancer patients who undergo resection after PREOP CRT live longer than patients who undergo resection without PREOP CRT, a difference that may be attributable to patient selection. We retrospectively identified 236 patients with pancreatic head adenocarcinoma seen between 1999 and 2007 with sufficient data to be confirmed medically and radiographically resectable. The outcomes of 144 patients who underwent PREOP CRT were compared to those of 92 patients who proceeded straight to SURGERY. The groups were similar in age and gender. Tumors were slightly larger in the PREOP CRT group (mean 2.5 cm vs. 2.1 cm, P

Objectives: To compare outcomes and the use of multimodality therapy in young and elderly people with pancreatic cancer undergoing surgical resection. Design: Retrospective, single-institution study. Setting: National Cancer Institute/National Comprehensive Cancer Network cancer center. Participants: Two hundred three individuals who underwent pancreaticoduodenectomy for pancreatic adenocarcinoma at Duke University Medical Center comprised the study population. Participants were divided into three groups based on age (

Ampullary carcinoma is a rare malignancy. Despite radical resection, survival rates remain low with high rates of local failure. We performed a single-institution outcomes analysis to define the role of concurrent chemoradiotherapy (CRT) in addition to surgery. A retrospective analysis was performed of all patients undergoing potentially curative pancreaticoduodenectomy for adenocarcinoma of the ampulla of Vater at Duke University Hospitals between 1976 and 2009. Time-to-event analysis was performed comparing all patients who underwent surgery alone to the cohort of patients receiving CRT in addition to surgery. Local control (LC), disease-free survival (DFS), overall survival (OS), and metastases-free survival (MFS) were estimated using the Kaplan–Meier method. A total of 137 patients with ampullary carcinoma underwent Whipple procedure. Of these, 61 patients undergoing resection received adjuvant (n = 43) or neoadjuvant (n = 18) CRT. Patients receiving chemoradiotherapy were more likely to have poorly differentiated tumors (P = .03). Of 18 patients receiving neoadjuvant therapy, 67% were downstaged on final pathology with 28% achieving pathologic complete response (pCR). With a median follow-up of 8.8 years, 3-year local control was improved in patients receiving CRT (88% vs 55%, P = .001) with trend toward 3-year DFS (66% vs 48%, P = .09) and OS (62% vs 46%, P = .074) benefit in patients receiving CRT. Long-term survival rates are low and local failure rates high following radical resection alone. Given patterns of relapse with surgery alone and local control benefit in patients receiving CRT, the use of chemoradiotherapy in selected patients should be considered.

Introduction: Cancer immunotherapy has made waves of progress in recent years with the advent of checkpoint inhibitor therapies against several cancers. However, pancreatic cancer (PC), a disease which kills approximately 40,000 patients each year in the US, has successfully evaded immunotherapy approaches. PC hosts a notoriously immunosuppressive microenvironment comprised of an abundance of immunosuppressive tumor associated macrophages, myeloid derived suppressor cells (MDSCs) and regulatory T-cells with a scarcity of effector CD8+ T-cells. Irreversible electroporation (IRE) is a non-thermal ablation technique that induces tumor cell death without destruction of adjacent collagenous structures. Unlike thermal ablation techniques, IRE results in a gradual apoptotic cell death and is currently in clinical use for selected patients with locally advanced PC. We hypothesize that the abundant release of antigens by IRE can induce an “in situ vaccination” effect that can elicit adaptive T-cell-mediated anti-tumor immune responses. Methods: We have developed a robust syngeneic immunocompetent mouse model of PC using a cell line established from a tumor arising in a LSL-KrasG12D/+; LSL-Trp53R172H/+; PDX1Cre/+; LSL-ROSA26 Luc/+ mouse (KPC). We have utilized the ECM 830 square wave pulse generator to deliver IRE (100 μsec pulses of electricity at 1500 V/cm using a two-needle array probe) to subcutaneous tumors measuring 5-7 mm in diameter. The effects of IRE on primary tumor growth and secondary tumor challenge were observed. Flow cytometry-based immunoprofiling studies of tumors at one week post-IRE were performed in triplicate and presented as mean difference between IRE and no treatment (standard error). *P Results: Vaccination studies with irradiated KPC cells confirmed that they were immunogenic in C57BL/6 mice. In preliminary studies, we identified the minimal IRE dose to induce tumor regression to be 150 pulses, with complete regression in 3 of 9 tumors (33%). Survival was prolonged in the IRE groups, particularly in mice with complete regression. This outcome was confirmed to be immune-mediated, as IRE of tumor-bearing immunodeficient Rag-1-/- mice, which lack functional T and B cell components, results in progressive outgrowth with similar kinetics as untreated mice. When immunocompetent mice with tumor regression were re-challenged two weeks later with 105 cells injected into the contralateral flank, we observed no growth in the secondary tumors, confirming adaptive immune activation post-IRE. Tumor immunoprofiling revealed a 43±2%* decrease in the number of tumor-infiltrating MDSCs (CD11b+/CD11c+/Gr-1hi) post-IRE, with a similar decrease in the respective tumor draining inguinal lymph nodes. An increase in total tumor infiltrating lymphocytes (TILs) was also observed, including an 18±2%* increase in CD8+ TILs and a concomitant large increase (2.5 fold*) in PD-1+/CD8+ double positive T-cells. Conclusion: These results suggest that IRE is capable of triggering an antitumor immune response that contributes to the local effects of IRE and inhibits growth of secondary tumor re-challenge. IRE affects the composition of immune cells in the tumor microenvironment, including a large increase in PD-1+/CD8+ TILs. These effects may be augmented by combining IRE with checkpoint blockade, which is a focus of our ongoing studies. Citation Format: Jayanth Shankara Narayanan, Tomoko Hayashi, Aaron M. Miller, Stephen P. Schoenberger, Rebekah R. White. Irreversible electroporation (IRE) acts as an “in situ vaccine” and induces antitumor immune responses in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B78.

Background and Hypothesis: Pancreatic cancer (PC) has the poorest prognosis of all major cancers, with a 5-year survival of less than 5%. Cell-free DNA (cfDNA) has been well validated as a biomarker that correlates with tumor burden. More recently, a role for cfDNA in tumor progression has also been identified. The latter occurs through activation of Toll-like receptors (TLRs) in both tumor cells and the host environment, which can upregulate prometastatic signaling pathways. In addition, tumor-derived extracellular vesicles (EVs) such as microparticles and exosomes have also been implicated in promoting metastasis by activating proinvasive pathways in tumor cells and preconditioning secondary sites for metastatic establishment. Our laboratory has previously shown that cationic polymers can neutralize cfDNA and abrogate inflammation in disease models of autoimmunity and infection. We investigated the ability of the cationic polymer, PAMAM-G3, to bind and inhibit cfDNA and EVs and thereby inhibit tumor invasion in vitro and metastasis in vivo. Methods and Results: Transwell-Matrigel invasion assays were performed using multiple PC cell lines. Cells were plated in the upper chamber with no serum +/- cfDNA, EVs, or PAMAM-G3. The bottom chamber was plated with complete media as a chemo-attractant. Cells treated with cfDNA, EVs, or PAMAM-G3 were also analyzed for activation of pro-inflammatory pathways (NFkB, MAPK, etc.). The in vivo model was performed in C57B6 mice that were injected with bioluminescent murine PC cells into their spleens and followed for liver metastases with bioluminescent imaging. Experimental mice were treated biweekly with intraperitoneal PAMAM-G3 (20 mg/kg) or saline starting 48 hours after pancreatic tumor cell implantation. PAMAM-G3 significantly inhibited in vitro invasion of pancreatic cancer cell lines in response to cancer patient serum-derived cfDNA and extracellular vesicles. Moreover, PAMAM-G3 (20 mg/kg) treatment led to a significant reduction in liver metastasis without affecting primary tumor growth in vivo. Serum derived from saline-treated mice induced higher levels of invasion than serum from polymer-treated mice and exogenous polymer blocked this effect (**** = p Discussion: Cationic polymers such as PAMAM-G3 may represent a novel class of therapeutics to combat pancreatic cancer metastasis. These polymers can bind and neutralize cfDNA and tumor-derived EVs, thereby blocking activation of pro-inflammatory pathways within tumor cells, and reducing tumor invasion and metastasis. Cationic polymers will be tested in other preclinical models of cancer and in dosing studies for potential progression to clinical translation. Citation Format: Ibtehaj A. Naqvi, Ruwan Gunaratne, Jessica McDade, Douglas Rouse, Jen Jen Yeh, David Pisetsky, Jaewoo Lee, Rebekah White, Bruce Sullenger. Cationic polymer inhibits pancreatic cancer invasion and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4189.

Aptamers are single-stranded DNA or RNA oligonucleotides that assume specific 3D structures and bind to target molecules with high affinity. The unique specificity of aptamers has made them attractive agents for targeted cancer therapy. Aptamers have been developed against a variety of cancer targets, including extracellular ligands and cell surface proteins. In addition, aptamers have been incorporated into novel constructs involving siRNAs, chemotherapeutic agents, cell toxins and nanoparticles, in which they function as delivery agents for therapeutic cargo. In this article, we review recent developments in the use of aptamers for targeted cancer therapy, particularly focusing on novel applications of aptamers targeting the cell surface.

The purposes of this study were to retrospectively investigate the effectiveness and safety of CT-guided percutaneous drainage in the treatment of patients with acute appendicitis complicated by perforation and to identify CT findings and procedure-related factors predictive of clinical and procedure outcome.From March 2005 through December 2008, 41 consecutively registered patients (24 men, 17 women; age range, 18-75 years) underwent CT-guided percutaneous drainage for the management of acute appendicitis complicated by perforation and abscess. Three board-certified radiologists independently reviewed preprocedure CT images. Patients were assigned to one of three risk categories on the basis of the CT findings. Success and failure of percutaneous drainage were defined on a per-patient (i.e., clinical outcome) and per-procedure (i.e., technical outcome) basis. Immediate, periprocedure, and delayed complications were recorded. The association between candidate predictive variables, including demographic characteristics, preprocedure CT findings, and procedure-related factors and clinical or technical outcome was assessed with logistic regression models.Fifty-two CT-guided procedures were performed on 41 patients. Percutaneous drainage had clinical and technical success rates of 90% (37 of 41 patients, 47 of 52 procedures) with no procedure-related complications. In seven patients (19%) clinical success required repeated drainage procedures. A large, poorly defined periappendiceal abscess and an extraluminal appendicolith on preprocedure CT images were independent predictors of clinical failure of percutaneous drainage.CT-guided percutaneous drainage is both effective and safe in the treatment of patients with acute appendicitis complicated by perforation and abscess. The clinical and technical success rates are high.

The optimal timing of chemotherapy relative to resection of synchronous colorectal liver metastases (SCRLM) is not known. The objective of this retrospective multi-institutional study was to assess the influence of chemotherapy administered before and after hepatic resection on long-term outcomes among patients with initially resectable SCRLM treated from 1995 to 2005. Clinicopathologic data, treatments, and long-term outcomes from patients with initially resectable SCRLM who underwent partial hepatectomy at three hepatobiliary centers were reviewed. Four hundred ninety-nine consecutive patients underwent resection; 297 (59.5%) and 264 (52.9%) were treated with chemotherapy before and after resection. Chemotherapy strategies included pre-hepatectomy alone (n = 148, 24.7%), post-hepatectomy alone (n = 115, 23.0%), perioperative (n = 149, 29.0%), and no chemotherapy (n = 87, 17.4%). Male gender (p = 0.0029, HR = 1.41 [1.12-1.77]), node-positive primary tumor (p = 0.0046, HR = 1.40 [1.11-1.77]), four or more SCRLM (p = 0.0005, HR = 1.65 [1.24-2.18]), and post-hepatectomy chemotherapy treatment for 6 months or longer (p = 0.039, HR = 0.75 [0.57-0.99]) were associated with recurrence-free survival after discovery of SCRLM. Carcinoembryonic antigen >200 ng/ml (p = 0.0003, HR = 2.33 [1.48-3.69]), extrahepatic metastatic disease (p = 0.0025, HR = 2.34 [1.35-4.05]), four or more SCRLM (p = 0.033, HR = 1.43 [1.03-2.00]), and post-hepatectomy chemotherapy treatment for 2 months or longer (p < 0.0001, HR = 0.59 [0.45-0.76]) were associated with overall survival. Pre-hepatectomy chemotherapy was not associated with recurrence-free or overall survival. Patients treated with perioperative chemotherapy had similar outcomes as patients treated with post-hepatectomy chemotherapy only. We conclude that chemotherapy administered after but not before resection of SCRLM was associated with improved recurrence-free and overall survival. However, prospective randomized trials are needed to determine the optimal timing of chemotherapy.

Background and Objectives Few studies have addressed the optimal duration of chemotherapy, particularly prior to liver resection for colorectal liver metastases (CLM). The purpose of this retrospective analysis was to evaluate time to maximal response in patients receiving systemic ± hepatic arterial infusion (HAI) chemotherapy alone for the treatment of CLM. Methods We reviewed 35 patients with CLM on clinical trials of HAI floxuridine/dexamethasone plus systemic oxaliplatin with 5-fluorouracil/leucovorin or irinotecan (PUMP + SYSTEMIC). We retrospectively identified 35 patients with CLM who received first-line systemic 5FU/leucovorin/oxaliplatin (FOLFOX) ± bevacizumab (SYSTEMIC) during the same time period. Measurable disease was evaluated on CT scans performed at 2-month intervals. The sum of the products of bi-dimensional tumor measurements for representative lesions was compared both to baseline imaging and between consecutive time points. Results In responders to therapy, mean cumulative tumor reduction increased from 61% at 2 months to 73% at 4 months in the PUMP + SYSTEMIC group (P

The ability to selectively target disease-related tissues with molecules is critical to the design of effective therapeutic and diagnostic reagents. Recognizing the differences between the in vivo environment and in vitro conditions, we employed an in vivo selection strategy to identify RNA aptamers (targeting motifs) that could localize to tumor in situ. One of the selected molecules is an aptamer that binds to the protein DHX9, an RNA helicase that is known to be upregulated in colorectal cancer. Upon systemic administration, the aptamer preferentially localized to the nucleus of cancer cells in vivo and thus has the potential to be used for targeted delivery.

Background The risk of local recurrence in the pancreatic remnant after resection of noninvasive intraductal papillary mucinous neoplasm (IPMN) is not well defined. Study Design We performed a retrospective review of a prospectively maintained pancreatic resection database that identified 78 patients who underwent resection for noninvasive IPMN between 1983 and 2006. Local recurrence was determined radiographically and confirmed either pathologically or clinically. Results At a median followup of 40 months, 6 patients (7.7%) have recurred locally, with a median interval of 22 months (range 8 to 62 months) from the time of resection. Three patients did not undergo additional operative treatment and died of disease progression. Three patients underwent additional resection and are alive without evidence of disease. The estimated 5-year local recurrence-free survival for all patients with noninvasive IPMN is 87%. One of 50 patients (2%) with margins negative for IPMN recurred versus 4 of 23 patients (17%) with margins positive for IPMN (p=0.02). Conclusions Patients who have undergone resection for noninvasive IPMN require indefinite surveillance because local recurrences may be identified several years from the initial operation and be resected while still noninvasive. Although the risk of local recurrence appears to increase in the setting of positive margins, the majority of patients with positive margins have not developed local recurrence. Negative margins should be the goal of the operation when achievable with partial pancreatectomy, but the risk of local recurrence is not high enough to mandate total pancreatectomy for microscopic positive margins.

The purpose of this study was to compare rates and patterns of disease progression following percutaneous, image-guided radiofrequency ablation (RFA) and nonanatomic wedge resection for solitary colorectal liver metastases. We identified 30 patients who underwent nonanatomic wedge resection for solitary liver metastases and 22 patients who underwent percutaneous RFA because of prior major hepatectomy (50%), major medical comorbidities (41%), or relative unresectability (9%). Serial imaging studies were retrospectively reviewed for evidence of local tumor progression. Patients in the RFA group were more likely to have undergone prior liver resection, to have a disease-free interval greater than 1 year, and to have had an abnormal carcinoembryonic antigen (CEA) level before treatment. Two-year local tumor progression-free survival (PFS) was 88% in the Wedge group and 41% in the RFA group. Two patients in the RFA group underwent re-ablation, and two patients underwent resection to improve the 2-year local tumor disease-free survival to 55%. Approximately 30% of patients in each group presented with distant metastasis as a component of their first recurrence. Median overall survival from the time of resection was 80 months in the Wedge group vs 31 months in the RFA group. However, overall survival from the time of treatment of the colorectal primary was not significantly different between the two groups. Local tumor progression is common after percutaneous RFA. Surgical resection remains the gold standard treatment for patients who are candidates for resection. For patients who are poor candidates for resection, RFA may help to manage local disease, but close follow-up and retreatment are necessary to achieve optimal results.

Surgical resection is the most effective treatment modality for liver metastases from colorectal cancer. However, most patients with liver metastases are not candidates for resection due to extensive intrahepatic disease. Approximately one-half of the patients who are able to undergo resection will eventually recur within the remnant liver. Hepatic arterial infusion (HAI) chemotherapy takes advantage of the arterial blood supply of colorectal liver metastases to increase tumor exposure to chemotherapy while minimizing systemic toxicity. HAI chemotherapy has been utilized in patients with unresectable disease in the neoadjuvant setting in an effort to convert them to resectability as well as in patients with resectable disease in the adjuvant setting in an effort to prevent recurrence. This article reviews the roles of HAI chemotherapy in an aggressive approach toward colorectal liver metastases.

The majority of patients with pancreatic cancer present with disease that is unresectable due to local invasion. This article reviews the evidence (or lack thereof) that chemoradiation therapy (CRT) helps these patients in four areas: survival, tumor downstaging, palliation of obstructive symptoms, and pain control. We believe that CRT allows a small percentage of patients with locally advanced disease to undergo potentially curative resection while providing effective palliative treatment.

The advantages of neoadjuvant (preoperative) chemoradiation therapy for pancreatic cancer include the assurance that all resected patients receive multimodality therapy; the opportunity for patients with occult metastatic disease to manifest themselves; and the potential to improve resectability. Since 1994, Duke University Medical Center has treated over 180 patients with localized pancreatic cancer using neoadjuvant 5-fluorouracil (5FU)-based chemoradiation therapy (CRT). Approximately 20% of patients demonstrate distant disease progression during CRT and avoid the morbidity of laparotomy. Almost 20% of locally advanced tumors on initial-staging CT can be resected following CRT. Patients who have successfully undergone resection have experienced favorable survival with an estimated 5-year survival rate of 36%. This article reviews the authors' experience and the lessons learned from it.

Studies have suggested an increased risk of peritoneal seeding in patients with pancreatic cancer diagnosed by percutaneous FNA. EUS-FNA is an alternate method of diagnosis. The aim of this study was to compare the frequency of peritoneal carcinomatosis as a treatment failure pattern in patients with pancreatic cancer diagnosed by EUS-FNA vs. percutaneous FNA.Retrospective review of patients with non-metastatic pancreatic cancer identified 46 patients in whom the diagnosis was made by EUS-FNA and 43 with the diagnosis established by percutaneous FNA. All had neoadjuvant chemoradiation. Patients underwent restaging CT after completion of therapy, followed by attempted surgical resection if there was no evidence of disease progression.There were no significant differences in tumor characteristics between the two study groups. In the EUS-FNA group, one patient had developed peritoneal carcinomatosis compared with 7 in the percutaneous FNA group (2.2% vs. 16.3%; p0.025). No patient with a potentially resectable tumor in the EUS-FNA group had developed peritoneal carcinomatosis.Peritoneal carcinomatosis may occur more frequently in patients who undergo percutaneous FNA compared with those who have EUS-FNA for the diagnosis of pancreatic cancer. A concern for peritoneal seeding of pancreatic cancer via percutaneous FNA is warranted. EUS-guided FNA is recommended as the method of choice for diagnosis in patients with potentially resectable pancreatic cancer.

Pancreatic cancer has the poorest prognosis of all major cancers with a 5-year survival of less than 5%. Cell-free DNA (cfDNA) has been well-validated as a biomarker that correlates with tumor burden. More recently, a role for cfDNA in facilitating tumor progression has also been identified. The latter occurs through activation of nucleic acid sensing receptors such as toll-like receptors (TLRs) in both tumor cells and the host environment, which can upregulate pro-metastatic signaling pathways. In addition, tumor-derived extracellular vesicles such as microparticles and exosomes have also been implicated in promoting metastasis by activating pro-invasive pathways in tumor cells and pre-conditioning secondary sites for metastatic establishment. Our laboratory has previously shown that cationic polymers can scavenge negatively charged nucleic acids like cfDNA and abrogate aberrant inflammation in disease models of autoimmunity and infection. Herein, we investigated the ability of the cationic polymer, PAMAM-G3, to bind and inhibit cfDNA as well as anionic tumor-derived extracellular vesicles using in vitro models of pancreatic cancer cell line invasion. We also evaluated the effect of PAMAM-G3 treatment in a bioluminescent syngeneic murine model of pancreatic cancer metastasis. PAMAM-G3 significantly inhibited in vitro invasion of pancreatic cancer cell lines in response to both cfDNA and tumor-derived extracellular vesicles. Moreover, biweekly intraperitoneal treatment with PAMAM-G3 (20 mg/kg) starting 48 hours after pancreatic tumor cell implantation led to a significant reduction in liver metastasis without affecting primary tumor growth. Thus, cationic polymers such as PAMAM-G3 may represent a novel class of therapeutics to combat pancreatic cancer metastasis. Citation Format: Ibtehaj A. Naqvi, Ruwan Gunaratne, Jessica McDade, Douglas Rouse, Jen Jen Yeh, David Pisetsky, Jaewoo Lee, Rebekah White, Bruce Sullenger. Cationic polymer inhibits pancreatic cancer invasion in vitro and metastasis in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4903. doi:10.1158/1538-7445.AM2017-4903

The purpose of this study was to define the learning curves for laparoscopic pancreaticoduodenectomy (LPD) with and without laparoscopic reconstruction, using paired surgical teams consisting of advanced laparoscopic-trained surgeons and advanced oncologic-trained surgeons. All patients undergoing PD without vein resection at a single institution were retrospectively analyzed. LPD was introduced by initially focusing on laparoscopic resection followed by open reconstruction (hybrid) for 18 months prior to attempting a totally LPD (TLPD) approach. Cases were compared with Chi square, Fisher’s exact test, and Kruskal–Wallis analysis of variance (ANOVA). Between March 2010 and June 2013, 140 PDs were completed at our institution, of which 56 (40 %) were attempted laparoscopically. In 31/56 procedures we planned to perform only the resection laparoscopically (hybrid), of which 7 (23 %) required premature conversion before completion of resection. Following the first 23 of these hybrid cases, a total of 25 TLPDs have been performed, of which there were no conversions to open. For all LPD, a significant reduction in operative times was identified following the first 10 patients (median 478.5 vs. 430.5 min; p = 0.01), approaching open PD levels. After approximately 50 cases, operative times and estimated blood loss were consistently lower than those for open PD. In our experience of building an LPD program, the initial ten cases represent the biggest hurdle with respect to operative times. For an experienced teaching center using a staged and team-based approach, LPD appears to offer meaningful reductions in operative time and blood loss within the first 50 cases.

The use of neoadjuvant (preoperative) chemoradiotherapy (CRT) for pancreatic cancer has been advocated for its potential ability to optimize patient selection for surgical resection and to downstage locally advanced tumors. This article reports our experience with neoadjuvant CRT for localized pancreatic cancer.Since 1995, 111 patients with radiographically localized, pathologically confirmed pancreatic adenocarcinoma have received neoadjuvant external beam radiation therapy (EBRT; median, 4500 cGy) with 5-flourouracil-based chemotherapy. Tumors were defined as potentially resectable (PR, n = 53) in the absence of arterial involvement and venous occlusion and locally advanced (LA, n = 58) with arterial involvement or venous occlusion by CT.Five patients (4.5%) were not restaged due to death (n = 3) or intolerance of therapy (n = 2). Twenty-one patients (19%) manifested distant metastatic disease on restaging CT. Twenty-eight patients with initially PR tumors (53%) and 11 patients with initially LA tumors (19%) were resected after CRT. Histologic examination revealed significant fibrosis in all resected specimens and two complete responses. Surgical margins were negative in 72%, and lymph nodes were negative in 70% of resected patients. Median survival in resected patients has not been reached at a median follow-up of 16 months.Neoadjuvant CRT provided an opportunity for patients with occult metastatic disease to avoid the morbidity of resection and resulted in tumor downstaging in a minority of patients with LA tumors. Survival after neoadjuvant CRT and resection appears to be at least comparable to survival after resection and adjuvant (postoperative) CRT.

Species cross-reactivity facilitates the preclinical evaluation of potentially therapeutic molecules in animal models. Here we describe an in vitro selection strategy in which RNA ligands (aptamers) that bind both human and porcine thrombin were selected by "toggling" the protein target between human and porcine thrombin during alternating rounds of selection. The "toggle" selection process yielded a family of aptamers, all of which bound both human and porcine thrombin with high affinity. Toggle-25, a characteristic member, inhibited two of thrombin's most important functions: plasma clot formation and platelet activation. If appropriate targets are available, the toggle strategy is a simple measure that promotes cross-reactivity and may be generalizable to related proteins of the same species as well as to other combinatorial library screening strategies. This strategy should facilitate the isolation of ligands with needed properties for gene therapy and other therapeutic and diagnostic applications.

Regional lymph node metastasis is a powerful predictor of decreased overall survival from malignant melanoma. However, the therapeutic value of elective node dissections and the role of adjuvant therapy for node-positive disease have been highly controversial. Sentinel lymph node biopsy has reshaped the debate by allowing for staging of the regional lymph nodes with less morbidity and greater accuracy. This review summarizes the current consensus on the management of node-positive melanoma in the era of sentinel lymph node biopsy.