Clinical Significance and Resource Burden of Double Duct Sign in Non-jaundiced Patients.

Aim The study aims to determine the incidence of malignancy at presentation and subsequent risk of malignancy (at 12 months follow-up) in a cohort of patients with double duct sign (DDS) on cross-sectional imaging but no visible stigmata of jaundice. The study also correlates malignancy with liver enzyme dysfunction and estimates the resource burden incurred during the investigation of these patients. Methods A search for the key term "double duct sign" was undertaken in the radiological database of a tertiary hepatopancreatobiliary (HPB) centre between March 2017 and March 2022. Radiological reports, clinic letters, blood results, and multidisciplinary team meeting (MDT) outcomes were reviewed during this period and at one year. The national tariff payment system was reviewed to identify tariffs for different investigations required for the cohort and to calculate the total cost incurred. Results Ninety-seven patients with DDS were identified. Sixty-four patients (66%) had a normal bilirubin (0-21 µmol/L) at presentation and were included in the analysis. Seven patients (10.9%) were diagnosed with malignant peri-ampullary tumours, and 21 (32.8%) were diagnosed with benign diseases. In 34 patients (53%) with DDS, the underlying cause remained uncharacterised. Most patients had mild abnormalities of liver enzymes, but two patients (4.3%) were diagnosed with malignant peri-ampullary tumours despite having normal serological values. Patients who had a benign diagnosis and/or who had cancer excluded without a definitive diagnosis did not go on to develop a malignancy at 12 months follow-up. However, in those patients where the underlying aetiology could not be characterised, extended surveillance was required with a total of 80 MDT discussions and multiple surveillance scans (103 CT and 65 MRI scans). Twenty-six patients underwent endoscopic ultrasound (EUS) with three patients requiring more than one EUS examination (29 investigations in total). The cost of these investigations was £38,926.89. Conclusion This study confirms that DDS even in patients without clinical jaundice or with normal liver enzymes requires careful investigation to exclude malignancy despite the resource burden this entails. This supports previously reported results in the literature, and despite the increased use of cross-sectional imaging, DDS remains a clinically significant finding. Large cohort risk stratification studies would be useful to determine clinical urgency and allow the appropriate allocation of resources.

A Systematic Review of the Barriers to the Implementation of Artificial Intelligence in Healthcare.

Artificial intelligence (AI) is expected to improve healthcare outcomes by facilitating early diagnosis, reducing the medical administrative burden, aiding drug development, personalising medical and oncological management, monitoring healthcare parameters on an individual basis, and allowing clinicians to spend more time with their patients. In the post-pandemic world where there is a drive for efficient delivery of healthcare and manage long waiting times for patients to access care, AI has an important role in supporting clinicians and healthcare systems to streamline the care pathways and provide timely and high-quality care for the patients. Despite AI technologies being used in healthcare for some decades, and all the theoretical potential of AI, the uptake in healthcare has been uneven and slower than anticipated and there remain a number of barriers, both overt and covert, which have limited its incorporation. This literature review highlighted barriers in six key areas: ethical, technological, liability and regulatory, workforce, social, and patient safety barriers. Defining and understanding the barriers preventing the acceptance and implementation of AI in the setting of healthcare will enable clinical staff and healthcare leaders to overcome the identified hurdles and incorporate AI technologies for the benefit of patients and clinical staff.

Assessment of long-term graft function following total pancreatectomy and autologous islet transplantation: the Leicester experience.

Background: Total pancreatectomy and islet autotransplantation (TPIAT) is a recognised treatment for chronic pancreatitis (CP) with the potential to mitigate or prevent pancreatogenic diabetes. We present our 10-year follow-up of TPIAT patients. Methods: The University Hospitals of Leicester performed 60 TPIAT procedures from September 1994 to May 2011. Seventeen patients completed their 10-year assessment and were grouped using the modified Auto-Igls criteria; good response, n=5 (insulin-independent for first 5 years post-TPIAT); partial response, n=6 (insulin requirements <20 iU/day post-TPIAT) and poor response, n=6 (insulin requirements ≥20 iU/day post-TPIAT). C-peptide, haemoglobin A1c (HbA1c) and oral glucose tolerance test (OGTT) were undertaken preoperatively (baseline), then at 3, 6 months and then yearly for 10 years. Data was analysed using analysis of variance (ANOVA). Results: Median C-peptide levels were significantly higher, 120 minutes following OGTT, in the "good response" compared to "partial" and "poor" groups (two-way ANOVA test, P<0.0001). All groups demonstrated preservation of C-peptide release. HbA1c levels were significantly lower in the "good response" compared to "partial" and "poor" groups (two-way ANOVA test, P<0.0003 and P<0.0001). Median fasting glucose levels at 30 and 120 min following OGTT, were significantly lower in the "good response" compared to "partial" and "poor" groups (two-way ANOVA test, P<0.0001 and P<0.0001). Conclusions: TPIAT preserves long-term islet graft functions in 10-year follow up. Even in patients in the poor response group, there is evidence of C-peptide release (>0.5 ng/mL) after OGTT stimulation potentially preventing long-term diabetes-related complications.

Development of a Novel Ex Vivo Porcine Hepatic Segmental Perfusion Proof-of-Concept Model Towards More Ethical Translational Research.

Introduction Ex vivo machine perfusion describes the technique where organs are continuously perfused and oxygenated extracorporeally (at physiological conditions) to maintain the organs' viability. To our knowledge, there are currently no reported studies describing ex vivo perfusion of a single hepatic segment. Here, we describe the development of a porcine ex vivo hepatic segmental perfusion model to demonstrate proof of concept and support further research into the ex vivo perfusion of the human liver using discarded tissue.  Methods Whole livers were retrieved from abattoir-derived pigs and connected to a normothermic extracorporeal perfusion circuit. Constant segmental perfusion via the common or segmental hepatic artery and portal vein with heparinised autologous blood was established. The viability of the perfused organ was assessed by monitoring perfusion pressures, flow rates and histology samples. Results Following perfusion and optimisation of the model for three hepatic segments, the third perfusion demonstrated viable hepatocytes centrally after 4 h of segmental perfusion. Conclusion Ex vivo hepatic segmental perfusion is technically challenging but its success in a porcine model and the principles learned should facilitate the development of an analogous human model using discarded tissue following formal liver resections. The model would use a healthy liver segment following a major formal resection such as a hemi-hepatectomy and ex vivo perfusion performed via a segmental hepatic artery and portal vein. If successful this model would represent a significant development and enable ethical translation research to assess the response of human livers to a variety of stressors, including toxicity and infection.

A Narrative Review of the Applications of Ex-vivo Human Liver Perfusion.

Ex-vivo perfusion describes the extra-corporeal delivery of fluid to an organ or tissue. Although it has been widely studied in the context of organ preservation and transplantation, it has also proven to be an invaluable tool in the development of novel models for translational pre-clinical research. Here, we review the literature reporting ex-vivo human liver perfusion experiments to further understand current perfusion techniques and protocols together with their applications. A computerised search was made of Ovid, MEDLINE, and Embase using the search words "ex-vivo liver or hepatic perfusion". All relevant studies in English describing experiments using ex-vivo perfusion of human livers between 2016 and 2021, inclusive, were included. Of 21 reviewed studies, 19 used ex-vivo human liver perfusion in the context of allogeneic liver transplantation. The quality and size of the studies varied considerably. Human liver perfusion was almost exclusively limited to whole organs and "split" livers, although one study did describe the successful perfusion of tissue sections following a partial hepatectomy. This review of recent literature involving ex-vivo human liver perfusion demonstrates that the technique is not limited to whole liver perfusion. Split-liver perfusion is extremely valuable allowing one lobe to act as a control and increasing the number available for research. This review also highlights the present lack of any reports of segmental liver perfusion. The discarded donor liver is a scarce resource, and the successful use of segmental perfusion has the potential to expand the available experimental models to facilitate pre-clinical experimentation.

Induction Implications: Shaping the Competence and Confidence of Junior Doctors Within Complex Medical Specialties.

Introduction The newly qualified junior doctors in the United Kingdom face challenges due to their limited experience and unfamiliarity with their rotations. We aim to share the experience of establishing a hepato-pancreato-biliary (HPB) surgery-specific induction program at the University Hospitals of Leicester NHS Trust and assess its impact on doctors' knowledge and experience. Methods A booklet was distributed to new junior doctors, and a two-hour structured teaching session was also conducted, with pre- and post-session assessments using multiple-choice questions and a feedback survey. The survey measured understanding of HPB anatomy, interventions, and satisfaction with the teaching methodology. Results The pre-session questionnaire included 22 participants, while the post-session had 20 participants. Regarding HPB anatomy understanding, in the pre-session, six (28.6%) and 11 (52.4%) participants reported levels 2 and 3, respectively, while levels 4 and 5 were reported by three (13.3%) and one (4.8%) participants. In the post-session, levels 4 and 5 were reported by six (30%) and 13 (65%), with only one (5%) reporting level 3 and none at levels 1 or 2. Similar trends were observed in understanding HPB investigation. In the pre-session, levels 2 and 3 were reported by eight (36.4%) and 11 (50%), while levels 4 and 5 were reported by two (9.1%) and one (4%). In the post-session, eight (40%) and 11 (55%) reported levels 4 and 5, with only one (5%) at level 3 and none at levels 1 or 2. For HPB management methods before teaching, levels 2 and 3 were equally reported by eight (36.4%), level 4 by four (22.7%), and none at level 5. After teaching, nine (45%) and 10 (50%) reported levels 4 and 5, with only one (5%) at level 3 and none at levels 1 or 2. Factual knowledge showed a 38% increase, rising from 49% pre-session to 87% post-session. In post-session feedback, 12 (60%) strongly agreed that the session helped augment their medical practice, and six (30%) agreed, with two (10%) neutral. Feedback on the teaching session's organization was positive, with 13 (65%) strongly agreeing that it was structured coherently, and six (30%) agreeing, with only one (5%) neutral regarding the clarity of the structure and delivery method. Conclusion Specialty-specific induction programs are crucial for providing support and ensuring the development of competent doctors. Efforts should be made to create supportive working environments for junior doctors to alleviate stress and improve their well-being.

Impact of COVID-19, gender, race, specialty and seniority on mental health during surgical training: an international study.

BACKGROUND: Superior patient outcomes rely on surgical training being optimized. Accordingly, we conducted an international, prospective, cross-sectional study determining relative impacts of COVID-19, gender, race, specialty and seniority on mental health of surgical trainees. METHOD: Trainees across Australia, New Zealand and UK enrolled in surgical training accredited by the Royal Australasian College of Surgeons or Royal College of Surgeons were included. Outcomes included the short version of the Perceived Stress Scale, Oxford Happiness Questionnaire short scale, Patient Health Questionnaire-2 and the effect on individual stress levels of training experiences affected by COVID-19. Predictors included trainee characteristics and local COVID-19 prevalence. Multivariable linear regression analyses were conducted to assess association between outcomes and predictors. RESULTS: Two hundred and five surgical trainees were included. Increased stress was associated with number of COVID-19 patients treated (P = 0.0127), female gender (P = 0.0293), minority race (P = 0.0012), less seniority (P = 0.001), and greater COVID-19 prevalence (P = 0.0122). Lower happiness was associated with training country (P = 0.0026), minority race (P = 0.0258) and more seniority (P < 0.0001). Greater depression was associated with more seniority (P < 0.0001). Greater COVID-19 prevalence was associated with greater reported loss of training opportunities (P = 0.0038), poor working conditions (P = 0.0079), personal protective equipment availability (P = 0.0008), relocation to areas of little experience (P < 0.0001), difficulties with career progression (P = 0.0172), loss of supervision (P = 0.0211), difficulties with pay (P = 0.0034), and difficulties with leave (P = 0.0002). CONCLUSION: This is the first study to specifically describe the relative impacts of COVID-19 community prevalence, gender, race, surgical specialty and level of seniority on stress, happiness and depression of surgical trainees on an international scale.

Does powered stapler improve the mechanical integrity of gastrojejunal anastomosis compared to the current techniques? Experimental study in ex vivo porcine models.

BACKGROUND: Numerous techniques have been described for fashioning gastrojejunostomy (GJ) in a Roux-en-Y gastric bypass. These include hand-sewn anastomosis (HSA) and mechanical anastomosis; the latter includes circular stapled anastomosis (CSA) or manual linear stapled anastomosis (mLSA). More recently, this list also includes powered linear stapled anastomosis (pLSA). The aim of this study was to analyse if addition of power to stapling would improve the integrity of GJ anastomosis in ex vivo porcine models. SUBJECTS AND METHODS: The present study included five groups - mLSA1, mLSA2, HSA, CSA, and pLSA. Sequential infusions of methylene blue-coloured saline were performed into the GJ models. Pressure readings were recorded till the point of leak denoting burst pressure (BP). Total volume (TV) and site of leak were recorded. Compliance was calculated from the equation ΔTV/ΔBP. RESULTS: Differences in pouch and intestinal thickness were not statistically significant between the models. BPs were higher in the mechanical anastomosis groups, i.e., pLSA 21 ± 9.85 mmHg, CSA 20.33 ± 5.78 mmHg, mLSA1 18 ± 4.69 mmHg and mLSA2 11 ± 2.94 mmHg, when compared to HSA 9.67 ± 3.79 mm Hg, which was found to be statistically significant (Kruskal-Wallis test, P = 0.03). Overall, the highest BP was recorded for powered stapling followed by circular, and then, linear stapling; however, this difference was not statistically significant (P = 0.86). There was no statistically significant difference among groups with regard to compliance (Kruskal-Wallis test, P = 0.082). CONCLUSION: Despite the limited number of samples, mechanical anastomosis showed a statistically higher BP when compared to HSA, suggesting better anastomotic integrity. The pLSA group showed promising results with the highest BP recorded among all groups; however, this did not reach statistical significance.

Analyzing Macrophage Infection at the Organ Level.

Classical in vivo infection models are oftentimes associated with speculation due to the many physiological factors that are unseen or not accounted for when analyzing experimental outputs, especially when solely utilizing the classic approach of tissue-derived colony-forming unit (CFU) enumeration. To better understand the steps and natural progression of bacterial infection, the pathophysiology of individual organs with which the bacteria interact in their natural course of infection must be considered. In this case, it is not only important to isolate organs as much as possible from additional physiological processes, but to also consider the dynamics of the bacteria at the cellular level within these organs of interest. Here, we describe in detail two models, ex vivo porcine liver and spleen coperfusion and a murine infection model, and the numerous associated experimental outputs produced by these models that can be taken and used together to investigate the pathogen-host interactions within tissues in depth.

Interaction of Klebsiella pneumoniae with tissue macrophages in a mouse infection model and ex-vivo pig organ perfusions: an exploratory investigation.

BACKGROUND: Hypervirulent Klebsiella pneumoniae (hvKp) strains of capsule type K1 and K2 cause invasive infections associated with hepatic abscesses, which can be difficult to treat and are frequently associated with relapsing infections. Other K pneumoniae strains (non-hvKp), including lineages that have acquired carbapenem resistance, do not manifest this pathology. In this work we aimed to test the hypothesis that within-macrophage replication is a key mechanism underpinning abscess formation in hvKp infections. METHODS: In this exploratory investigation, to study the pathophysiology of abscess formation, mice were intravenously infected with 106 colony forming units (CFU) of either hvKp isolates (six strains) or non-hvKp isolates (seven strains). Intracellular bacterial replication and neutrophil influx in liver and spleen was quantified by fluorescence microscopy of sliced cryopreserved organs of mice collected 30 min, 6 h, and 24 h after infection with the aim to provide data of bacterial association to Kupffer cells in the liver and to the different tissue macrophages in the spleen. Microbiological and microscopy analysis of an ex-vivo model of pig liver and spleen infection were used to confirm within-macrophage replication. Pig organs were perfused with heparinised, autologous pig's blood and injected with 6·5 × 107 CFU of hvKp K2 sequence type 25 strain GMR151. Blood and tissue biopsies collected before infection and 30 min, 1 h, 2 h, 3 h, 4 h, and 5 h after infection were used to measure bacterial counts and to identify the subcellular localisation of bacteria by immunohistochemistry analysis. FINDINGS: We show that hvKp resisted phagocyte-mediated clearance and replicated in mouse liver macrophages to form clusters 6 h after infection, with a mean of 7·0 bacteria per Kupffer cell (SD 6·2); however, non-hvKp were efficiently cleared (mean 1·5 bacteria per cell [SD 1·1]). HvKp infection promoted neutrophil recruitment to sites of infection, which in the liver resulted in histopathological signs of abscess formation as early as 24 h post-infection. Experiments in pig organs which share a high functional and anatomical resemblance to human organs, provided strong evidence for the propensity of hvKp to replicate within the hepatic macrophages. INTERPRETATION: These findings show subversion of innate immune processes in the liver by K pneumoniae and resistance to Kupffer cell mediated clearance as an explanation for the propensity of hvKp strains to cause hepatic abscesses. FUNDING: University of Oxford and a Royal Society Wolfson grant funded biosafety facility.

Mass spectrometric detection of KRAS protein mutations using molecular imprinting.

Cancer is a disease of cellular evolution where single base changes in the genetic code can have significant impact on the translation of proteins and their activity. Thus, in cancer research there is significant interest in methods that can determine mutations and identify the significant binding sites (epitopes) of antibodies to proteins in order to develop novel therapies. Nano molecularly imprinted polymers (nanoMIPs) provide an alternative to antibodies as reagents capable of specifically capturing target molecules depending on their structure. In this study, we used nanoMIPs to capture KRAS, a critical oncogene, to identify mutations which when present are indicative of oncological progress. Herein, coupling nanoMIPs (capture) and liquid chromatography-mass spectrometry (detection), LC-MS has allowed us to investigate mutational assignment and epitope discovery. Specifically, we have shown epitope discovery by generating nanoMIPs to a recombinant KRAS protein and identifying three regions of the protein which have been previously assigned as epitopes using much more time-consuming protocols. The mutation status of the released tryptic peptide was identified by LC-MS following capture of the conserved region of KRAS using nanoMIPS, which were tryptically digested, thus releasing the sequence of a non-conserved (mutated) region. This approach was tested in cell lines where we showed the effective genotyping of a KRAS cell line and in the plasma of cancer patients, thus demonstrating its ability to diagnose precisely the mutational status of a patient. This work provides a clear line-of-sight for the use of nanoMIPs to its translation from research into diagnostic and clinical utility.

Outcomes of peri-operative glucocorticosteroid use in major pancreatic resections: a systematic review.

BACKGROUND: There is increasing evidence that peri-operative glucocorticosteroid can ameliorate the systemic response following major surgery. Preliminary evidence suggests peri-operative usage of glucocorticosteroid may decrease post-operative complications. These positive associations have been observed in a range of different operations including intra-abdominal, thoracic, cardiac, and orthopaedic surgery. This review aims to investigate the impact of peri-operative glucocorticosteroid in major pancreatic resections. METHODS: A systematic review based on a search in Medline and Embase databases was performed. PRISMA guidelines for systematic reviews were followed. RESULTS: A total of five studies were analysed; three randomised controlled trials and two retrospective cohort studies. The total patient population was 1042. The glucocorticosteroids used were intravenous hydrocortisone or dexamethasone. Three studies reported significantly lower morbidity in the peri-operative glucocorticosteroid group. The number needed to treat to prevent one major complication with hydrocortisone is four patients. Two studies demonstrated that dexamethasone was associated with a statistically significantly improved median overall survival in pancreatic cancer. CONCLUSION: This is the first systematic review conducted to investigate the significance of peri-operative glucocorticosteroid in patients undergoing pancreatic resection. This review shows a correlation of positive outcomes with the administration of glucocorticosteroid in the peri-operative setting following a major pancreatic resection.. More randomised clinical trials are required to confirm if this is a true effect, as it would have significant implications.

Splenic macrophages as the source of bacteraemia during pneumococcal pneumonia.

BACKGROUND: Severe community-acquired pneumococcal pneumonia is commonly associated with bacteraemia. Although it is assumed that the bacteraemia solely derives from pneumococci entering the blood from the lungs it is unknown if other organs are important in the pathogenesis of bacteraemia. Using three models, we tested the relevance of the spleen in pneumonia-associated bacteraemia. METHODS: We used human spleens perfused ex vivo to explore permissiveness to bacterial replication, a non-human primate model to check for splenic involvement during pneumonia and a mouse pneumonia-bacteraemia model to demonstrate that splenic involvement correlates with invasive disease. FINDINGS: Here we present evidence that the spleen is the reservoir of bacteraemia during pneumonia. We found that in the human spleen infected with pneumococci, clusters with increasing number of bacteria were detectable within macrophages. These clusters also were detected in non-human primates. When intranasally infected mice were treated with a non-therapeutic dose of azithromycin, which had no effect on pneumonia but concentrated inside splenic macrophages, bacteria were absent from the spleen and blood and importantly mice had no signs of disease. INTERPRETATION: We conclude that the bacterial load in the spleen, and not lung, correlates with the occurrence of bacteraemia. This supports the hypothesis that the spleen, and not the lungs, is the major source of bacteria during systemic infection associated with pneumococcal pneumonia; a finding that provides a mechanistic basis for using combination therapies including macrolides in the treatment of severe community-acquired pneumococcal pneumonia. FUNDING: Oxford University, Wolfson Foundation, MRC, NIH, NIHR, and MRC and BBSRC studentships supported the work.

Dissecting spatial heterogeneity and the immune-evasion mechanism of CTCs by single-cell RNA-seq in hepatocellular carcinoma.

Little is known about the transcriptomic plasticity and adaptive mechanisms of circulating tumor cells (CTCs) during hematogeneous dissemination. Here we interrogate the transcriptome of 113 single CTCs from 4 different vascular sites, including hepatic vein (HV), peripheral artery (PA), peripheral vein (PV) and portal vein (PoV) using single-cell full-length RNA sequencing in hepatocellular carcinoma (HCC) patients. We reveal that the transcriptional dynamics of CTCs were associated with stress response, cell cycle and immune-evasion signaling during hematogeneous transportation. Besides, we identify chemokine CCL5 as an important mediator for CTC immune evasion. Mechanistically, overexpression of CCL5 in CTCs is transcriptionally regulated by p38-MAX signaling, which recruites regulatory T cells (Tregs) to facilitate immune escape and metastatic seeding of CTCs. Collectively, our results reveal a previously unappreciated spatial heterogeneity and an immune-escape mechanism of CTC, which may aid in designing new anti-metastasis therapeutic strategies in HCC.

A comparison of the inflammatory response following autologous compared with allogenic islet cell transplantation.

BACKGROUND: The initial response to islet transplantation and the subsequent acute inflammation is responsible for significant attrition of islets following both autologous and allogenic procedures. This multicentre study compares this inflammatory response using cytokine profiles and complement activation. METHODS: Inflammatory cytokine and complement pathway activity were examined in two cohorts of patients undergoing total pancreatectomy followed either by autologous (n=11) or allogenic (n=6) islet transplantation. Two patients who underwent total pancreatectomy alone (n=2) served as controls. RESULTS: The peak of cytokine production occurred immediately following induction of anaesthesia and during surgery. There was found to be a greater elevation of the following cytokines: TNF-alpha (P<0.01), MCP-1 (P=0.0013), MIP-1α (P=0.001), MIP-1ß (P=0.00020), IP-10 (P=0.001), IL-8 (P=0.004), IL-1α (P=0.001), IL-1ra (0.0018), IL-10 (P=0.001), GM-CSF (P=0.001), G-CSF (P=0.0198), and Eotaxin (P=0.01) in the allogenic group compared to autografts and controls. Complement activation and consumption was observed in all three pathways, and there were no significant differences in between the groups although following allogenic transplantation ∆IL-10 and ∆VEGF levels were significantly elevated those patients who became insulin-independent compared with those who were insulin-dependent. CONCLUSIONS: The cytokine profiles following islet transplantation suggests a significantly greater acute inflammatory response following allogenic islet transplantation compared with auto-transplantation although a significant, non-specific inflammatory response occurs following both forms of islet transplantation.

Significance of indeterminate pulmonary nodules in resectable pancreatic adenocarcinoma-a review.

BACKGROUND: The clinical significance of indeterminate pulmonary nodules (IPN) in patients with resectable pancreatic adenocarcinoma (PDAC) is unknown. The rate of detection on IPN has risen due to enhanced staging investigations to determine resectability. IPNs detected on preoperative imaging represent a clinical dilemma and complicate decision-making. Currently, there are no recommendations on the management of IPN. This review provides a comprehensive overview of the current knowledge on the natural history of IPN detected among patients with resectable PDAC. METHODS: A systematic review based on a search in Medline and Embase databases was performed. All clinical studies evaluating the significance of IPN in patients with resectable PDAC were included. PRISMA guidelines were followed. RESULTS: Five studies met the inclusion criteria. The total patient population was 761. The prevalence of IPN reported ranged from 18 to 71%. The median follow-up duration was 17 months. The median overall survival was 19 months. Patients with pre-operative IPN which subsequently progressed to clinically recognizable pulmonary metastases, ranged from 1.5 to 16%. Four studies found that there was no significant difference in median overall survival in patients with or without IPNs. CONCLUSION: This is a first review on the significance of IPN in patients with resectable PDAC. The preoperative presence of IPN does not demonstrate an association with overall survival after surgery. The identification of IPN is a significant finding however it should not preclude patients with resectable PDAC from undergoing curative resection.

Proteomic Characterization of Circulating Molecular Perturbations Associated With Pancreatic Adenocarcinoma Following Intravenous ω-3 Fatty Acid and Gemcitabine Administration: A Pilot Study.

BACKGROUND: Administration of intravenous ω-3 fatty acid (ω-3FA) in advanced pancreatic adenocarcinoma patients receiving gemcitabine chemotherapy shows disease stabilization and improved progression-free survival. Using high-definition plasma proteomics, the underlying biological mechanisms responsible for these clinical effects are investigated. METHODS AND RESULTS: A pilot study involving plasma that was collected at baseline from 13 patients with histologically confirmed, unresectable pancreatic adenocarcinoma (baseline group) after 1-month treatment with intravenous gemcitabine and ω-3FA (treatment group) and intravenous gemcitabine only (control group) and was prepared for proteomic analysis. A 2-arm study comparing baseline vs treatment and treatment vs control was performed. Proteins were isolated from plasma with extensive immunodepletion, then digested and labeled with isobaric tandem mass tag peptide tags. Samples were then combined, fractionated, and injected into a QExactive-Orbitrap Mass-Spectrometer and analyzed on Proteome Discoverer and Scaffold with ensuing bioinformatics analysis. Selective reaction monitoring analysis was performed for verification. In total, 3476 proteins were identified. Anti-inflammatory markers (C-reactive protein, haptoglobin, and serum amyloid-A1) were reduced in the treatment group. Enrichment analysis showed angiogenesis downregulation, complement immune systems upregulation, and epigenetic modifications on histones. Pathway analysis identified direct action via the Pi3K-AKT pathway. Serum amyloid-A1 significantly reduced (P < .001) as a potential biomarker of efficacy for ω-3FA. CONCLUSIONS: This pilot study demonstrates administration of ω-3FA has potential anti-inflammatory, antiangiogenic, and proapoptotic effects via direct interaction with cancer-signaling pathways in patients with advanced pancreatic adenocarcinoma. Further studies in a larger sample size is required to validate the clinical correlation found in this preliminary study.