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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.

BackgroundIrreversible 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.MethodsA 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.Results187 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

Cell-SELEX is performed to select for cell binding aptamers. We employed an additional selection pressure by using RNAse to remove surface-binding aptamers and select for cell-internalizing aptamers. A common RNA sequence was identified from independent cell-SELEX procedures against two different pancreatic cancer cell lines, indicating a strong selection pressure towards this sequence from the large pool of other available sequences present in the aptamer library. The aptamer is not specific for the pancreatic cancer cell lines, and a similar sequence motif is present in previously published internalizing aptamers. The identified sequence forms a structural motif that binds to a surface protein, which either is highly abundant or has strong affinity for the selected aptamer sequence. Deselecting (removing) this sequence during cell-SELEX may increase the probability of identifying aptamers against cell type-specific targets on the cell surface.

Aptamers are a class of therapeutic oligonucleotides that form specific three-dimensional structures that are dictated by their sequences. They are typically generated by an iterative screening process of complex nucleic acid libraries employing a process termed Systemic Evolution of Ligands by Exponential Enrichment (SELEX). SELEX has traditionally been performed using purified proteins, and cell surface receptors may be challenging to purify in their properly folded and modified conformations. Therefore, relatively few aptamers have been generated that bind cell surface receptors. However, improvements in recombinant fusion protein technology have increased the availability of receptor extracellular domains as purified protein targets, and the development of cell-based selection techniques has allowed selection against surface proteins in their native configuration on the cell surface. With cell-based selection, a specific protein target is not always chosen, but selection is performed against a target cell type with the goal of letting the aptamer choose the target. Several studies have demonstrated that aptamers that bind cell surface receptors may have functions other than just blocking receptor-ligand interactions. All cell surface proteins cycle intracellularly to some extent, and many surface receptors are actively internalized in response to ligand binding. Therefore, aptamers that bind cell surface receptors have been exploited for the delivery of a variety of cargoes into cells. This review focuses on recent progress and current challenges in the field of aptamer-mediated delivery.

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.

Introduction: The Australian Therapy Outcome Measure for Indigenous Clients (ATOMIC) is a goal-setting tool designed to measure therapy outcomes with First Australians. It was originally developed and validated for use with First Australian children as a culturally responsive alternative to traditional western outcome measures. This research explored the applicability, responsiveness and clinical utility of the ATOMIC when used with First Australian adults attending an urban health service., Methods: Separate parallel studies investigated responsiveness and clinical utility. The first employed quantitative methods to investigate change over time via pre- and post-intervention data. The second employed a qualitative phenomenological approach to determine the clinical utility of the tool. Semi-structured interviews and focus groups were used, respectively, to understand the experience of using the ATOMIC from a client and clinician perspective. Client perspectives on the purpose of the tool and its alignment with their views on health care and therapists' perspective on the ease of use and applicability of the tool to the health service setting were explored. These data were analysed using reflexive thematic analysis., Consumer and Community Consultation: The methodological approach followed National Health and Medical Research Council (NHMRC, 2018) guidelines in considering cultural continuity, reciprocity and equity. This project was initiated and guided by Aboriginal and Torres Strait Islander leaders (the advisory group) as a prioritised need for a robust way of reporting outcomes to complement existing statistical and narrative data within a large community-controlled health service. The advisory group provided high level governance from project conception to conclusion and were involved in yarn-backs about research findings., Results: Responsiveness: Wilcoxon test showed a statistically significant increase (P = 0.00) in ATOMIC scores pre- (mean = 1.8) and post- (mean = 8) intervention. Effect size (Cohen d) was deemed significant calculated at 2.1., Clinical Utility: Findings included: First Australian clients are adept at self-managing their conditions; the ATOMIC is a clinically useful outcome measure, which reflects this; ATOMIC is an acceptable tool to First Australian clients and clinicians and supports culturally responsive goal setting and occupational therapy practice., Plain Language Summary: The Australian Therapy Outcome Measure for Indigenous Clients (ATOMIC) was created to measure how well therapy works for First Australian children. This research investigates whether it also works with adult First Australians. Two studies were undertaken: a quantitative study to see whether ATOMIC scores changed before and after therapy and a qualitative study, which asked people what they thought about using the ATOMIC. ATOMIC scores went up after therapy, indicating it is sensitive to change, and both clients and therapists liked using the ATOMIC and found it useful. It matched well with how First Australian adults see health care and helped set goals for therapy. The results of the study show that the ATOMIC is helpful for both clients and therapists in understanding how well therapy works and helps to set goals that make sense culturally. This study looked at one health service in one regional area, so more research is needed to establish whether it works elsewhere. Overall, the results indicate the ATOMIC is a promising step towards better therapy for Indigenous Australians., (© 2024 The Author(s). Australian Occupational Therapy Journal published by John Wiley & Sons Australia, Ltd on behalf of Occupational Therapy Australia.)

Purpose: Mucinous neoplasms of the gastrointestinal tract are characterized by a propensity for metastasis to the peritoneum, resulting in peritoneal mucinous carcinomatosis (PMC). A subset of these tumors, most often originating in the appendix, harbor mutations in the GNAS oncogene. While the natural history of GNAS -mutant PMC varies, patient outcomes are generally poor, as is response to cytotoxic chemotherapy. The purpose of this study was to evaluate the clinical efficacy of single-agent palbociclib, a cyclin-dependent kinase (CDK)4/6 inhibitor, in patients with GNAS -mutant PMC., Patients and Methods: We enrolled 16 patients with PMC in a single-arm personalized cancer therapy trial. For all patients, tumor tissue and/or circulating tumor DNA genomic profiling using next-generation sequencing and, when possible, PD-L1 expression, tumor mutational burden, and microsatellite instability status was assessed. Twelve of 16 patients had previous disease progression on at least one previous line of chemotherapy. The primary tumor was appendix in 13 patients, unknown in two patients, and pancreas in one patient. Eleven cases were classified as low grade, and five as high grade., Results: In 13 of 16 patients, we observed a decrease in carcinoembryonic antigen (CEA), and in six patients, the CEA declined by >50%. As measured by clinical and modified peritoneal RECIST criteria, 50% of evaluable patients had stable disease after 12 months of palbociclib. At a median follow-up of 17.6 months, median survival has not been reached. Clinical response to CDK4/6 inhibition was mirrored in tumors with GNAS mutation and mucinous histology using an ex vivo preclinical platform., Conclusion: CDK4/6 inhibition with palbociclib had clinical activity in PMC characterized by mutations in GNAS that was superior to that previously reported with cytotoxic chemotherapy. CDK4/6 inhibition is a novel therapeutic strategy worthy of further evaluation in this subgroup of gastrointestinal neoplasms.

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., (© 2022. The Author(s).)

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., (© 2021 Occupational Therapy Australia.)

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.

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.

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.

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.

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., (Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Neuroendocrine tumors comprise a broad family of tumors, the most common of which are carcinoid and pancreatic neuroendocrine tumors. The NCCN Neuroendocrine Tumors Guidelines discuss the diagnosis and management of both sporadic and hereditary neuroendocrine tumors. Most of the recommendations pertain to well-differentiated, low- to intermediate-grade tumors. This updated version of the NCCN Guidelines includes a new section on pathology for diagnosis and reporting and revised recommendations for the surgical management of neuroendocrine tumors of the pancreas.

Background: 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., Methods: 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., Results: 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., Conclusions: 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.

Background: The routine use of staging laparoscopy in patients with radiographically resectable pancreatic and peripancreatic neoplasms remains controversial., Study Design: We reviewed a prospective database that identified 1,045 patients who underwent staging laparoscopy for radiographically resectable pancreatic or peripancreatic tumors between 1995 and 2005. Radiographic resectability was determined by review of radiographic reports, surgeons' notes, and cross-sectional imaging studies. Factors were assessed for their association with the laparoscopic identification of radiographically occult unresectable disease. Recursive partitioning was used to build a decision tree, with laparoscopic identification of unresectable disease as the outcomes, including only patients since 1999 (modern imaging) and factors available preoperatively., Results: Unresectable disease was identified laparoscopically in 145 of the 1,045 radiographically resectable patients (14%). Factors associated with radiographically occult unresectable disease included the time period of the study, whether imaging was performed at our institution (internal versus external imaging), primary site, histology, weight loss, and jaundice. Primary site (pancreatic versus nonpancreatic) was identified as the strongest predictor of yield. In patients with nonpancreatic tumors, the yield of laparoscopy was 4%. In patients with pancreatic tumors, the yield of laparoscopy was 14% overall, but was 8.4% in patients with internal imaging versus 17% in patients with external imaging (p < 0.01). This higher-risk subgroup was partitioned by the presence of weight loss, then by primary site within the pancreas., Conclusions: During the time period of this study, the yield of staging laparoscopy decreased and exceeded 10% only for patients with pancreatic adenocarcinoma. When high-quality cross-sectional imaging reveals no evidence of unresectable disease, routine staging laparoscopy may not be warranted for pancreatic or peripancreatic tumors other than presumed pancreatic adenocarcinoma.

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.

Background: 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., Methods: 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., Results: 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%; p<0.025). No patient with a potentially resectable tumor in the EUS-FNA group had developed peritoneal carcinomatosis., Conclusions: 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.