Benign Pancreatic Disease Research Articles

Pancreaticoduodenectomy for benign and pre-malignant pancreatic and ampullary disease: is robotic surgery the better approach?

Presenter: Benedetto Mungo MD | University of Pittsburgh Medical Center Background: The robotic platform is increasingly being utilized in pancreatic surgery, yet its overall merits and putative advantages – compared to the classic laparotomy approach – remain to be adjudicated. The majority of available comparative analysis focuses primarily on pancreatic adenocarcinoma where surgical outcomes are influenced and conditioned by the complex underlying pathology and the need for peri-operative systemic therapy. We hypothesize that the benefits of minimally invasive pancreatic surgery are maximized in pancreatic benign and premalignant disease, in the setting of friable pancreatic tissue and small pancreatic duct. Methods: Retrospective analysis of a single institution prospectively maintained pancreatic database of all consecutive patients who underwent pancreaticoduodenectomy (PD) for benign or premalignant conditions between 2010 to 2020. Peri-operative outcomes and long-term complications (> 90 days post-PD) were compared between robotic pancreaticoduodenectomy (RPD) and open pancreaticoduodenectomy (OPD). Continuous variables were reported as means and standard deviation or medians and interquartile ranges and compared using two-sided t-test, while categorical variables were reported as frequencies and percentages and compared using Pearson chi-squared (p<0.05). Results: Two hundred and four (n=204) patients met our inclusion criteria, of which 68 were OPD and 136 RPD. Selected histologies included but were not limited to adenoma with dysplasia (any grade), intraepithelial neoplasia, intraductal oncocytic papillary neoplasm, intraductal papillary mucinous neoplasm, pseudopapillary neoplasm, serous cystadenoma and neuroendocrine tumor with no invasive or metastatic features. Findings are summarized in Table 1. There were no significant differences in baseline characteristics between the two groups, exception made for a higher rate of coronary artery disease (24.2% vs. 11%, p=0.015) in the OPD group. Patients in the RPD group were more likely to undergo a classic Whipple procedure (84.6% vs. 55.9%, p<0.001) had shorter operative time (387.80±114.11 vs. 453.79±159.18 minutes, p<0.001) and lesser lymph node yield (21 vs. 20, p=0.011) when compared to those in the open group. Notable post-operative merits of the RPD included a significantly shorter length of stay (LOS) (7 vs. 10 days, p=0.004), fewer grade B pancreatic fistulas (8.8% vs. 32.3%, p=0.001) and lower 90-day mortality (0.7% vs. 5.9%, p=0.025) as compared to OPD. Finally, rates of long-term complications were comparable between the two groups, exception made for a higher chance of needing surgery for small bowel obstruction in the open group (3.1% vs. 0%, p=0.039). Conclusion: The results of our analysis suggest that robotic pancreaticoduodenectomy has lower 90-day mortality, shorter LOS and lower rates of selected complications when compared to open pancreaticoduodenectomy. While randomized data are needed to strengthen our conclusions, our results make a compelling argument for the prioritization of the robotic platform in the surgical treatment of benign and premalignant pancreatic diseases, in the appropriate patient population.

Cytokeratin-positive cells in the bone marrow from patients with pancreatic, periampullary malignancy and benign pancreatic disease show no prognostic information

BackgroundPancreatic and periampullary carcinoma are aggressive tumours where preoperative assessment is challenging. Disseminated tumour cells (DTC) in the bone marrow (BM) are associated with impaired prognosis in a variety of epithelial cancers. In a cohort of patients with presumed resectable pancreatic and periampullary carcinoma, we evaluated the frequency and the potential prognostic impact of the preoperative presence of DTC, defined as cytokeratin-positive cells detected by immunocytochemistry (ICC).MethodsPreoperative BM samples from 242 patients selected for surgical resection of presumed resectable pancreatic and periampullary carcinoma from 09/2009 to 12/2014, were analysed for presence of CK-positive cells by ICC. The median observation time was 21.5 months. Overall survival (OS) and disease-free survival (DFS) were calculated by Kaplan-Meier and Cox regression analysis.ResultsSuccessful resections of malignant tumours were performed in 179 of the cases, 30 patients resected had benign pancreatic disease based on postoperative histology, and 33 were deemed inoperable intraoperatively due to advanced disease. Overall survival for patients with resected carcinoma was 21.1 months (95% CI: 18.0–24.1), for those with benign disease OS was 101 months (95% CI: 69.4–132) and for those with advanced disease OS was 8.8 months (95% CI: 4.3–13.3). The proportion of patients with detected CK-positive cells was 6/168 (3.6%) in resected malignant cases, 2/31 (6.5%) in advanced disease and 4/29 (13.8%) in benign disease. The presence of CK-positive cells was not correlated to OS or DFS, neither in the entire cohort nor in the subgroup negative for circulating tumour cells (CTC).ConclusionsThe results indicate that CK-positive cells may be present in both patients with malignant and benign diseases of the pancreas. Detection of CK-positive cells was not associated with differences in prognosis for the entire cohort or any of the subgroups analysed.Trial registrationclinicaltrials.gov (NCT01919151).

Abstract PR-010: Blinded and meta-analysis validation of an improved serological test for PDAC using the combination of CA19-9 and the sTRA glycan

Abstract Improvements in the clinical outcomes of pancreatic cancer patients may be achieved if physicians could identify the disease earlier. Recent studies demonstrated the promise of a biomarker panel is a simple combination between CA19-9 and another marker called sTRA, so named because it detects the sialylated version of the glycan bound by the TRA-1-60 (tumor-related antigen) antibody. The sTRA glycan is structurally related to the CA19-9 antigen and is produced by a different subtype of cancer cells than make CA19-9. We hypothesized that, among patients with PDAC, different patients have plasma elevations in CA19-9 than have plasma elevations in sTRA, and that as a result, a panel comprising the two markers detects more cancers at high specificity (low false-positive rate) than either marker alone. To test this hypothesis, we analyzed the relationships and biomarker performance of CA19-9 and sTRA across seven different datasets, encompassing 729 patient samples collected from four different clinical centers. We tested whether unique elevation occurred for each marker in each dataset, and whether the combination of markers performed better than then individual markers for distinguishing PDAC from healthy subjects and from benign pancreatic disease. We observed complementary elevations of sTRA or CA19-9 in the PDAC patients in each dataset. A two-marker panel composed of CA19-9 and sTRA and a three-marker panel composed of CA19-9 and two versions of the sTRA immunoassay gave statistically significant improvements over CA19-9 across the datasets for distinguishing PDAC from non-PDAC samples (healthy, chronic pancreatitis, pancreatic cyst, and biliary stricture/stones). At 95% specificity, sensitivity was improved from 36-55% across datasets for CA19-9 to 61-67% across datasets for the three-marker panel. The lead panel further showed 95% specificity and 61% sensitivity using blinded calls on another validation set (N = 340). This analysis serves as broad support for an improved serological test for PDAC using the combination of CA19-9 and sTRA. In light of this level of validation, the lead panel could be considered the most promising panel from the currently available information. If further validated using clinical assays, it may be good enough for surveillance among patients with increased risk for PDAC, in combination with follow-up modalities to establish diagnosis. Citation Format: Ying Liu, Ben Staal, Daniel Barnett, Zonglin He, Chongfeng Gao, Mark Hurd, Pamela Bartlett, Aatur Singhi, J. Bradley Morrow, Gregory Cote, Anirban Maitra, Ying Huang, Randall Brand, Brian Haab. Blinded and meta-analysis validation of an improved serological test for PDAC using the combination of CA19-9 and the sTRA glycan [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PR-010.

Characterization of Oral Microbiome and Exploration of Potential Biomarkers in Patients with Pancreatic Cancer.

Pancreatic cancer (PC) is highly malignant and lacks an effective therapeutic schedule, hence that early diagnosis is of great importance to achieve a good prognosis. Oral bacteria have been proved to be associated with pancreatic cancer, but the specific mechanism has not been comprehensively illustrated. In our study, thirty-seven saliva samples in total were collected with ten from PC patients, seventeen from benign pancreatic disease (BPD) patients, and ten from healthy controls (HC). The oral bacterial community of HC, PC, and BPD groups was profiled by 16S rDNA high-throughput sequencing and bioinformatic methods. As shown by Simpson, Inverse Simpson, Shannon and Heip, oral microbiome diversity of HC, BPD and PC groups is in increasing order with the BPD and PC groups significantly higher than the HC group. Principal coordinate analysis (PCoA) suggested that grouping by PC, BPD and HC was statistically significant. The linear discriminant analysis effect size (LEfSe) identified high concentrations of Fusobacterium periodonticum and low concentrations of Neisseria mucosa as specific risk factors for PC. Furthermore, predicted functions showed changes such as RNA processing and modification as well as the pathway of NOD-like receptor signaling occurred in both PC and HC groups. Conclusively, our findings have confirmed the destruction of oral bacterial community balance among patients with PC and BPD and indicated the potential of Fusobacterium periodonticum and Neisseria mucosa as diagnostic biomarkers of PC.

Brain metabolites in cholinergic and glutamatergic pathways are altered by pancreatic cancer cachexia.

BackgroundCachexia is a major cause of morbidity in pancreatic ductal adenocarcinoma (PDAC) patients. Our purpose was to understand the impact of PDAC‐induced cachexia on brain metabolism in PDAC xenograft studies, to gain new insights into the causes of cachexia‐induced morbidity. Changes in mouse and human plasma metabolites were characterized to identify underlying causes of brain metabolic changes.MethodsWe quantified metabolites, detected with high‐resolution 1H magnetic resonance spectroscopy, in the brain and plasma of normal mice (n = 10) and mice bearing cachexia (n = 10) or non‐cachexia (n = 9) inducing PDAC xenografts as well as in human plasma obtained from normal individuals (n = 24) and from individuals with benign pancreatic disease (n = 20) and PDAC (n = 20). Statistical significance was defined as a P value ≤0.05.ResultsThe brain metabolic signature of cachexia‐inducing PDAC was characterized by a significant depletion of choline of −27% and −21% as well as increases of glutamine of 13% and 9% and formate of 21% and 14%, relative to normal controls and non‐cachectic tumour‐bearing mice, respectively. Good to moderate correlations with percent weight change were found for choline (r = 0.70), glutamine (r = −0.58), and formate (r = −0.43). Significant choline depletion of −38% and −30%, relative to normal controls and non‐cachectic tumour‐bearing mice, respectively, detected in the plasma of cachectic mice likely contributed to decreased brain choline in cachectic mice. Similarly, relative to normal controls and patients with benign disease, choline levels in human plasma samples of PDAC patients were significantly lower by −12% and −20% respectively. A comparison of plasma metabolites from PDAC patients with and without weight loss identified significant changes in glutamine metabolism.ConclusionsDisturbances in metabolites of the choline/cholinergic and glutamine/glutamate/glutamatergic neurotransmitter pathways may contribute to morbidity. Metabolic normalization may provide strategies to reduce morbidity. The human plasma metabolite changes observed may lead to the development of companion diagnostic markers to detect PDAC and PDAC‐induced cachexia.

S0039 Outcomes of Portal and Superior Mesenteric Veins Stenting for Relief of Symptomatic Venous Stenosis Due to Malignant and Benign Pancreatic Diseases

S0039 Outcomes of Portal and Superior Mesenteric Veins Stenting for Relief of Symptomatic Venous Stenosis Due to Malignant and Benign Pancreatic Diseases

Serum Exo-EphA2 as a Potential Diagnostic Biomarker for Pancreatic Cancer

Pancreatic cancer (PC) is a highly malignant tumor with poor detection sensitivity and specificity in biomarkers and diagnosis. Previous research indicated that serum Ephrin type-A receptor 2 in exosomes (Exo-EphA2) was highly expressed and might have facilitated cell migration in PC cells. However, the dynamics of clinical performance of serum Exo-EphA2 in PC patients are unknown. Thus, this study evaluated serum Exo-EphA2 as a potential diagnostic biomarker in PC. The expressions of serum Exo-EphA2 were assessed by enzyme-linked immunosorbent assay for N = 353 serum samples, including from 204 PC patients, 75 patients with benign pancreatic disease, and 74 healthy control patients. Carbohydrate antigen 19-9 (CA 19-9) and carbohydrate antigen 242 (CA 242) were measured by automated immunoassay. Serum Exo-EphA2 levels were significantly higher in PC patients than in benign pancreatic disease and healthy control patients. Receiver operating characteristic curve analysis suggested that using combined diagnoses of Exo-EphA2 with CA 19-9 and CA 242 was more effective to discriminate early stage (stage I and II) in PC than in healthy controls and benign disease patients. Novel findings suggest that serum Exo-EphA2 is a potential early diagnostic biomarker complementing CA 19-9 and CA 242 in PC.

Abstract 4603: Detection of pancreatic cancer using rapid dielectrophoresis based recovery of tumor derived extra cellular vesicles and exosomes from plasma

Abstract Tumor derived extracellular vesicles, including exosomes, carry cancer related proteins on their outer surfaces making them a valuable source of tumor biomarkers in blood. However, these vesicles are difficult to recover from plasma and this prevents them from being widely used for clinical diagnostic tests. Here we present a technique that uses high conductance dielectrophoresis to rapidly recover these vesicles from plasma allowing for immunofluorescence detection of cancer related biomarkers. We demonstrate this technique can be used to detect biomarkers that successfully distinguish patients with pancreatic cancer from those with benign pancreatic disease, such as pancreatitis, as well as healthy individuals. What makes dielectrophoresis different from other vesicle recovery techniques is that it takes advantage of the large contrast in the dielectric properties between the vesicles and the surrounding plasma. The dielectrophoretic force preferentially draws vesicles to an electrode array at the bottom of a microfluidic chip where they are held in place allowing a fluidic wash to remove the bulk plasma. The vesicles are concentrated at the electrode edge thereby increasing the signal to noise ratio of the fluorescent immunostaining signal and placing the particles in known locations allowing for automated detection and quantification of biomarker levels. This technique takes 30 min to complete, requires 30-50 µl of plasma, and can be highly automated to reduce labor effort making it a promising technology for future translation into the clinical laboratory setting and enabling the use of extracellular vesicles and exosomes for diagnostic applications. Citation Format: Augusta Modestino, Jesus Bueno Alvarez, Michael Heller, Stuart Ibsen. Detection of pancreatic cancer using rapid dielectrophoresis based recovery of tumor derived extra cellular vesicles and exosomes from plasma [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 4603.

Ligand-targeted polymerase chain reaction for the detection of folate receptor-positive circulating tumour cells as a potential diagnostic biomarker for pancreatic cancer.

ObjectivesTo detect folate receptor (FR)‐positive circulating tumour cells (FR+ CTCs) by using ligand‐targeted polymerase chain reaction (LT‐PCR) in periampullary cancer patients and to investigate the diagnostic value of FR+ CTCs in distinguishing pancreatic cancer (PC) from benign pancreatic disease.Materials and MethodsCTCs were enriched from 3 mL of peripheral blood and portal vein blood by immunomagnetic depletion of leucocytes and were then detected by LT‐PCR. The diagnostic performance of FR+ CTCs in PC was investigated by receiver‐operating characteristic curve analysis.ResultsIn total, 57 consecutive patients, including 46 patients with PC, five patients with non‐pancreatic periampullary cancer (non‐PC) and six patients with benign pancreatic diseases, were enrolled. FR+ CTC levels were significantly higher in patients with malignant diseases (PC and non‐PC) than in patients with benign pancreatic diseases (P < .01). There was no notable difference in CTC levels between patients with PC and those with non‐PC (P > .05). The combination of FR+ CTCs with carbohydrate antigen 19‐9 (CA19‐9) had better diagnostic efficiency than each of these two markers alone, with high sensitivity (97.8%) and specificity (83.3%).ConclusionsLT‐PCR is feasible and reliable for detecting FR+ CTCs in patients with periampullary cancer. FR+ CTCs, especially when used in combination with CA19‐9, have potential as a biomarker for the diagnosis of PC.

Predictive value of CA 19-9 in patients with pancreatic tumours

Background: Pancreatic carcinoma is a disease with high modality and has a high incidence of recurrence after surgical resection. The prognosis depends on early diagnosis and treatment. Numerous international studies have reported use of CA 19-9 in diagnosis of pancreatic cancer. We planned this study to validate role of CA 19-9 in our local population. The objective of this study is to correlate raised serum CA 19-9 levels in patients with pancreatic tumours to distinguish between benign and malignant pancreatic disease.&#x0D; Subjects and methods: The present study is a validation study. Thirty-five patients with diagnosis of pancreatic tumor on radiological imaging were included after their informed consent. Data collection forms were filled, blood samples were taken and serum CA 19-9 was estimated by ELISA in Biochemistry department, SIMS. Histopathology samples were collected at time of surgical resection, sent to pathology departments of respective hospitals and histopathological reports collected. All data was collected and analysed by using descriptive method. The study was conducted in Biochemistry department of PGMI and SIMS, Lahore from May 2015 till June 2016.&#x0D; Results: Out of 35 patients, nineteen (54.3%) were female and sixteen (45.7%) were male. Thirty [85.7%] patients were between third to seventh decades of their life. The mean age range around 47.28. Thirty-four patients had malignant tumor and 1 benign on histopathology. CA 19-9 was raised (&gt;37 U/ml) in 33 out of 34 patients with malignant pathology. The patient with benign pathology had CA 19-9 level &lt;37U/ml (the cut off value). Head of pancreas was the commonest site in 32 patients (65%) for tumour occurrence. Total 28 (82%) patients had adenocarcinoma as the histological type of pancreatic tumour. Cholangiocarcinoma in Periampullary region of pancreas was second in frequency, 4 patients (12%). CA 19-9 shows sensitivity of 97% and specificity of 100% to diagnose carcinoma of pancreas in patients with pancreatic tumour. CA 19-9 has 100% positive predictive value to diagnose benign tumour and 50% negative predictive value to diagnose malignant tumours.&#x0D; Conclusion: Raised levels of CA 19-9 has an important role in diagnosis of patients with pancreatic tumour to differentiate between benign and malignant pathology.

Pancreatic Adenocarcinoma with Primary Tumor Calcification and Calcified Liver Metastasis: Report of a Rare Case and Review of Literature

AbstractCalcification is a feature of benign pancreatic diseases such as chronic calcific pancreatitis (CCP) or benign pancreatic tumors such as solid and papillary epithelial neoplasm of the pancreas and serous cystadenoma. The presence of calcification in a primary malignant pancreatic tumor is uncommon except for neuroendocrine tumors of the pancreas. Calcification in adenocarcinoma of the pancreas involving the primary tumor as well as the metastasis resulting thereof is extremely rare in the absence of CCP. To our knowledge, this is the first report of a case of primary adenocarcinoma of the pancreas that presented with calcification of the primary tumor as well as the metastatic liver nodules, accompanied by hypercalcemia.

The Applicability of a Checklist for the Diagnosis and Treatment of Exocrine Pancreatic Insufficiency: Results of the Italian Exocrine Pancreatic Insufficiency Registry.

To evaluate a rapid checklist capable of identifying exocrine pancreatic insufficiency in outpatients. Prospective observational study of a multicenter cohort. One hundred and two patients were enrolled; 61.8% of the patients had medically-treated benign or malignant pancreatic disease, and 38.2% had a pancreatic resection. Visual examination of the feces was evaluated in 84 patients and it was related to steatorrhea in 51 patients (50.0%). Receiver operating characteristic curves were evaluated for each symptom or clinical sign and four of them (ie, increase in daily bowel movements, number of bowel movements, fatty stools, >10% weight loss) had a satisfactory area under the curve. At multivariate analysis, fatty stools and >10% weight loss entered into this analysis having an area under the curve of 0.916 (95% confidence interval, 0.851-0.981). At 1 month and at one year of follow-up, the pancreatic enzyme replacement therapy administered showed that pancreatic extracts were able to significantly improve the increase in daily bowel movements, the number of bowel movements, fatty and bulky stools and >10% weight loss. Both fatty stools and >10% weight loss were able to clinically evaluate steatorrhea, and their improvement was sufficient to evaluate substitution therapy.

EUS-guided needle biopsy for autoimmune pancreatitis.

Endoscopic ultrasound (EUS)-guided fine needle aspiration (FNA), though a well-established method for specimen acquisition from pancreatic neoplasm, has a limited role for non-focal benign pancreatic diseases such as autoimmune pancreatitis (AIP) due to sample inadequacy and architectural distortion. Core biopsies through EUS-trucut biopsy (EUS-TCB) or newer generation EUS-fine needle biopsy (EUS-FNB) enable better histopathologic review through greater tissue specimen size and visualization of the histologic milieu. We systematically reviewed EUS-guided sample acquisition (FNA or core biopsy) and the role ofEUS-guided needle biopsy in evaluation of AIP. EUS-guided needle biopsy provided significantly higher adequacy of specimen (96.8% vs 79.8%; p = 0.016) and higher diagnostic sensitivity (60.20% vs 42.02%; p < 0.0001) compared to EUS-FNA for AIP. More evidence is imperative in evaluating the feasibility, safety, and diagnostic utility of EUS-guided needle biopsy for AIP.

Biodegradable Pancreatic and Biliary Stents—Still Searching For Disappearing Wonder?

AbstractBiodegradable stents hold considerable promise in the treatment of benign biliary or pancreatic diseases with the major advantage being avoidance of repeated interventions for stent removal or stent exchange. They have been confirmed to have good biocompatibility and current evidence shows acceptable rates of clinical efficacy and safety. In the current news and views, we discuss an interesting study that has evaluated a new type of biodegradable biliary and pancreatic stent (the Archimedes stent) in benign biliary and pancreatic diseases.

Sa1462 FEASIBILITY, SAFETY, AND DIAGNOSTIC YIELD OF ENDOSCOPIC ULTRASOUND (EUS)-GUIDED FINE NEEDLE CORE BIOPSY FOR NON-FOCAL, BENIGN, PANCREATIC PARENCHYMAL DISEASES

Endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) is a well-established method for specimen acquisition in suspected pancreatic malignancies. However, the role of EUS-FNA for, non-focal, non-neoplastic, benign pancreatic diseases such as chronic pancreatitis and autoimmune pancreatitis is diminished by the sample inadequacy and architectural distortion. This is evaded by histologic core biopsies obtained through newer generation EUS-fine needle biopsy (EUS-FNB). This pilot study aimed to evaluate the feasibility, safety, and diagnostic yield of EUS-FNB for non-focal, benign, pancreatic parenchymal diseases. This is a retrospective analysis of a prospectively collected database of all patients who underwent EUS-FNB for suspected non-focal, benign, parenchymal pancreatic disease at a single tertiary-care referral center from 10/04/2016 to 10/16/2019. We abstracted and analyzed patient demographics, EUS findings, histopathology, clinical management, and follow-up data. A total of 12 EUS-guided FNB were performed using a 22-gauge needle (83.3% (n=10) with Acquire (Boston Scientific, Natick, MA) needle and 2 with SharkCore (Medtronic Corp., Boston, MA) needle) for suspected non-focal, benign, parenchymal pancreatic disease during the study period. Eleven patients (mean age 39.1±20 years; 54% females) were included in this study. Transgastric (87%) or transduodenal (13%) EUS-FNB was successful in all patients (technical success: 100%). The mean number of FNB passes was 1.7 (median 2, range 1-3) (Figure 1). EUS-FNB provided pancreatic tissue cores that were adequate for histopathological diagnosis in all cases. The mean length of the core biopsy specimen obtained was 12±8.1 mm. Histopathologic diagnoses included: chronic pancreatitis in 4 (36.3%) patients, autoimmune pancreatitis (AIP) in 3 (27.3%), and parenchyma with no diagnostic abnormality in the remaining 4 patients (36.3%). Based on the histopathological diagnosis of AIP, 3 patients were treated with steroid therapy with excellent clinical response. No adverse events such as bleeding, perforation, or post-biopsy pancreatitis were observed during median follow-up of 8 months (range, 1-37; mean 15.6±15.5). EUS-guided FNB using the newer generation 22-gauge biopsy needle is a feasible and safe procedure and provides adequate pancreatic tissue specimen (core biopsy) in all cases for histopathological diagnosis of non-focal, benign, pancreatic parenchymal diseases.

A Novel Serum Metabolomic Profile for the Differential Diagnosis of Distal Cholangiocarcinoma and Pancreatic Ductal Adenocarcinoma.

The diagnosis of adenocarcinomas located in the pancreas head, i.e., distal cholangiocarcinoma (dCCA) and pancreatic ductal adenocarcinoma (PDAC), constitutes a clinical challenge because they share many symptoms, are not easily distinguishable using imaging techniques and accurate biomarkers are not available. Searching for biomarkers with potential usefulness in the differential diagnosis of these tumors, we have determined serum metabolomic profiles in healthy controls and patients with dCCA, PDAC or benign pancreatic diseases (BPD). Ultra-high-performance liquid chromatography coupled to mass spectrometry (UHPLC-MS) analysis was performed in serum samples from dCCA (n = 34), PDAC (n = 38), BPD (n = 42) and control (n = 25) individuals, divided into discovery and validation cohorts. This approach permitted 484 metabolites to be determined, mainly lipids and amino acids. The analysis of the results led to the proposal of a logistic regression model able to discriminate patients with dCCA and PDAC (AUC value of 0.888) based on the combination of serum levels of nine metabolites (acylcarnitine AC(16:0), ceramide Cer(d18:1/24:0), phosphatidylcholines PC(20:0/0:0) and PC(O-16:0/20:3), lysophosphatidylcholines PC(20:0/0:0) and PC(0:0/20:0), lysophosphatidylethanolamine PE(P-18:2/0:0), and sphingomyelins SM(d18:2/22:0) and SM(d18:2/23:0)) and CA 19-9. In conclusion, we propose a novel specific panel of serum metabolites that can help in the differential diagnosis of dCCA and PDAC. Further validation of their clinical usefulness in prospective studies is required.

MON-705 Islet Auto-Transplantation Following Partial Pancreatectomy Improves Glycemic Outcomes and Reduces Length of Hospital Stay: Multi-Center, Case-Control Study

Introduction: Islet auto-transplantation (IAT) is increasingly being performed to prevent brittle diabetes following pancreatic resection in patients with benign pancreatic diseases. While patients undergoing total or completion pancreatectomy clearly benefit from IAT, the glycemic benefit of IAT in patients undergoing partial pancreatic resection is not known. We aimed to determine if IAT improved glycemic outcomes in patients undergoing partial pancreatectomy for benign pancreatic diseases. Methods: We performed a multicenter, retrospective case-control study of patients who underwent partial pancreatic resection with IAT at two tertiary care centers. Case patients were compared to controls who underwent partial pancreatic resection without IAT at one center prior to offering IAT. The primary outcome was the mean change in pre vs. post-operative HgA1c following transplant as well as the development of new post-operative diabetes. Results: 9 patients requiring partial pancreatectomy for benign disease underwent IAT and were compared to 13 historical controls without IAT. Baseline characteristics were similar between groups including age, etiology of pancreatitis, the presence of diabetes and pre-operative HgA1c (5.7 vs. 5.2, p=0.448). With a median follow-up of 22 months, those who received an IAT had a smaller increase in their pre- vs. post-operative HgA1c (0.42 vs 2.83, p=0.004) and one case patient (14.3%) vs. three control patients (23.1%) developed new post-operative diabetes (p=0.581). Patients who underwent IAT had a shorter length of stay (6 days vs 11 days, p=0.039) compared to control patients. Conclusions: Patients undergoing partial pancreatic resection for benign pancreatic disease should be considered for IAT, as long-term glycemic outcomes are improved in those undergoing transplant. The shorter length of hospital stay is likely related to less brittle glucose control after the surgery with some endogenous insulin production by auto-islet graft function.

Robotic spleen-preserving distal pancreatectomy: the Verona experience.

The minimally invasive approach in spleen-preserving distal pancreatectomy has currently been emphasized in benign and pre-malignant pancreatic diseases. The study aims to demonstrate the safety and feasibility of our technique of robotic spleen-preserving distal pancreatectomy (RSPDP) by a stepwise approach. The data of consecutive patients presented for RSPDP from 2014 to 2019 at Verona University were retrieved from a prospectively maintained database. The patients were divided into two groups based on the surgical procedure performed, such as Kimura's (KG) or Warshaw's (WG) technique, and then compared. In the study period, 32 patients underwent RSPDP. Twenty-three patients presented for the Kimura procedure (72%), while nine patients underwent the Warshaw procedure (28%). A higher body mass index was found in the KG (26±4 vs. 22±3, p = 0.037). Regarding the pathological data, the WG group differed in the tumor dimension, and the lymph nodes harvested (30±2 vs. 17±10, 9±5 vs. 3±4, p = 0.0028, and p = 0.005, respectively). Notably, no conversions and mortality were recorded. The overall morbidity was 25% ( eight patients) with no difference between the groups (p = 0.820). The mean length of stay was 8days, and was similar between the groups (p = 0.350). The present study suggests that RSPDP is a valid option for the treatment of benign or pre-malignant pancreatic diseases of the distal pancreas, with comparable morbidity with the standard treatment and no mortality. Further research is needed to standardize the technique and to assess the immunological, surgical, and financial benefits of the procedure.

Promoter DNA Hypermethylation of the Cysteine Dioxygenase 1 (CDO1) Gene in Intraductal Papillary Mucinous Neoplasm (IPMN).

Intraductal papillary mucinous neoplasm (IPMN) involves adenoma (IPMA), a precancerous lesion, cancer (IPMC) including high-grade dysplasia (HGD), and invasive carcinoma (IC). DNA markers of IPMN are required for detection of invasive disease, and cysteine dioxygenase 1 (CDO1) gene promoter hypermethylation is a potential candidate. However, it has never been investigated in the context of IPMN. A total of 107 IPMN tumor tissues, including 41 IPMC and 66 IPMA, were studied. CDO1 promoter methylation was quantified using TaqMan quantitative methylation-specific polymerase chain reaction (qMSP) in patients with IPMN and other pancreatic cystic disorders after pancreatectomy. The methylation values (TaqMeth Vs) of CDO1 increased when noncancerous pancreas tissues were compared with IPMA and HGD (p < 0.0001). Among IPMC, the TaqMeth Vs in IC were not significantly higher than in HGD. The TaqMeth Vs of the solid tumors were higher than those of the cystic tumors (p = 0.0016), which were in turn higher than the corresponding noncancerous tissues (p < 0.0001). Prognostic analysis revealed that high TaqMeth Vs (≥ 14.1) resulted in a poorer prognosis than low TaqMeth Vs (< 14.1) (p < 0.0001). In other pancreatic cystic diseases, only malignant mucinous cystic neoplasm showed DNA hypermethylation of its promoter. A pilot study in pancreatic juice confirmed methylation in all IPMN samples but not in benign pancreatic diseases (p = 0.0277). CDO1 promoter hypermethylation is extremely specific to IPMN and may accumulate with IPMN tumor progression during the adenoma-carcinoma sequence. It might be a promising candidate as a diagnostic marker of pancreatic cystic diseases.

Detection of pancreatic ductal adenocarcinoma with galectin-9 serum levels

Pancreatic ductal adenocarcinoma (PDAC) responds poorly to checkpoint blockade, such as anti-CTLA-4 and anti-PD-1. Galectin-9, a β-galactoside-binding lectin, promotes immune suppression through T-cell inhibition, and programming of tolerogenic macrophages. Of all cancers tested, PDAC showed the highest expression of LGALS9 (galectin-9) mRNA. We analyzed formalin-fixed and paraffin-embedded specimens from 83 patients with PDAC stained for galectin-9. Using flow cytometry, we determined galectin-9 expression on immune cells from tumor and matched blood samples from 12 patients with resectable PDAC. Furthermore, we analyzed galectin-9 serum levels by enzyme-linked immunosorbent assay using serum samples from 70 patients with PDAC, from 36 individuals with benign pancreatic disease, and from 28 healthy controls. Galectin-9 was highly expressed in human PDAC compared with normal pancreas and present on both tumor and immune cells. Tumor-infiltrating immune cells, especially CD3+ T cells, showed upregulation of galectin-9 compared with immune cells from matched blood. Blood γδ T cells from PDAC patients had higher galectin-9 expression than γδ T cells from healthy individuals. Galectin-9 polarized macrophages toward a protumoral M2 phenotype leading to suppressed T-cell cytokine secretion. Furthermore, serum concentration of galectin-9 was able to discriminate PDAC from benign pancreatic disease and healthy individuals, and was prognostic for stage IV patients. Galectin-9 is a new biomarker for the detection of PDAC.