Invasive Pancreatic Adenocarcinoma Research Articles

Migrated duodenal stent 8 months after placement for invasive pancreatic adenocarcinoma

Migrated duodenal stent 8 months after placement for invasive pancreatic adenocarcinoma

Distinct Indications for Adjuvant Therapy in Resected Invasive Mucinous Cystic Neoplasms of the Pancreas Compared with Pancreatic Ductal Adenocarcinoma

BackgroundSurgical and adjuvant management of mucinous cystic neoplasms (MCNs) lacks formal guidelines and data is limited to institutional studies. Factors associated with receipt of adjuvant therapy and any associated impact on survival remain to be clarified. In the absence of other data, guidelines that recommend adjuvant chemotherapy for invasive pancreatic adenocarcinoma have been extrapolated to MCN.Patients and MethodsThe National Cancer Database (2004–2019) was utilized to identify all patients that underwent pancreatic resection for invasive MCNs. Patients that received neoadjuvant therapy or did not undergo lymphadenectomy were excluded. Patient, tumor, and treatment factors associated with survival were assessed.ResultsFor 161 patients with invasive MCN, median overall survival (OS) was 133 months and 45% of patients received adjuvant therapy. Multivariable analysis demonstrated that poorly differentiated tumors [odds ratio (OR) 4.19, 95% confidence interval (CI) 1.47–11.98; p = 0.008] and positive lymph node status (OR 2.67, 95% CI 1.02–6.98; p = 0.042) were independent predictors of receiving adjuvant therapy. Lymph node positivity [hazard ratio (HR) 2.90, 95% CI 1.47–5.73; p = 0.002], positive margins (HR 5.28, 95% CI 2.28–12.27; p < 0.001), and stage III disease (HR 12.46, 95% CI 1.40–111.05; p = 0.024) were associated with worse OS. Receipt of adjuvant systemic therapy was independently associated with decreased risk of mortality in node positive patients (HR 0.23, 95% CI 0.10–0.69; p = 0.002). Survival was not associated with adjuvant therapy in patients with negative lymph nodes or margin negative status.ConclusionIn contrast to pancreatic ductal adenocarcinoma (PDAC), where adjuvant therapy improves OS for every tumor stage, surgery alone for invasive MCN is not associated with improved OS compared with surgery plus adjuvant therapy in node-negative patients. Surgery alone is likely sufficient for a subset of invasive MCN.

Discovery of novel DNA methylation biomarker panels for the diagnosis and differentiation between common adenocarcinomas and their liver metastases

Differentiation between adenocarcinomas is sometimes challenging. The promising avenue for discovering new biomarkers lies in bioinformatics using DNA methylation analysis. Utilizing a 2853-sample identification dataset and a 782-sample independent verification dataset, we have identified diagnostic DNA methylation biomarkers that are hypermethylated in cancer and differentiate between breast invasive carcinoma, cholangiocarcinoma, colorectal cancer, hepatocellular carcinoma, lung adenocarcinoma, pancreatic adenocarcinoma and stomach adenocarcinoma. The best panels for cancer type exhibit sensitivity of 77.8–95.9%, a specificity of 92.7–97.5% for tumors, a specificity of 91.5–97.7% for tumors and normal tissues and a diagnostic accuracy of 85.3–96.4%. We have shown that the results can be extended from the primary cancers to their liver metastases, as the best panels diagnose and differentiate between pancreatic adenocarcinoma liver metastases and breast invasive carcinoma liver metastases with a sensitivity and specificity of 83.3–100% and a diagnostic accuracy of 86.8–91.9%. Moreover, the panels could detect hypermethylation of selected regions in the cell-free DNA of patients with liver metastases. At the same time, these were unmethylated in the cell-free DNA of healthy donors, confirming their applicability for liquid biopsies.

Expression heterogeneity, tumor immune characteristics and the prognosis effects of OPRL1 in patients with tumors: a pan-cancer study combined with bioinformation analyses and in vitro validation

PurposeOpioids are currently the most frequently prescribed analgesics in clinical practice. However, their effect on cancer progression remains a topic of debate. Opioid receptors (ORs) are present in various types of tumor cells and their expression levels vary depending on the type of tumor. This study aims to explore and preliminarily characterize the association between four different ORs (μ, δ, κ, and nociception/orphanin FQ peptide receptor) and the prognosis of different types of tumors for comparison, with a focus on nociception/ orphanin FQ peptide receptor.MethodsThe expression levels of four ORs in normal tissues and immune cells were obtained from Human Protein Atlas (HPA) RNA-seq dataset, Monaco dataset, and Consensus dataset. Pan-cancer analysis was performed using the The Cancer Genome Atlas (TCGA) dataset, which included the expression of four ORs in different cancer types, significant copy-number alterations (sCNA), gene mutations of the four ORs, survival analysis, co-expression genes analysis, functional enrichment analyses, and correlations between ORs and immune cell infiltration levels. Based on the results of bioinformatic analysis, we selected 10 cancer cell lines for validation in vitro using specific agonists for the four ORs.ResultsOPRL1 (opioid related nociceptin receptor 1 gene) exhibited the highest abundance across different types of cancers, while OPRM1 (opioid receptor mu 1 gene) and OPRD1 (opioid receptor delta 1 gene) were barely detectable in multiple cancer types. Pan-cancer survival analysis revealed the overall worse/better prognosis of the four ORs in certain cancer types. Elevated levels of OPRM1 appear to be associated with poorer outcomes in breast invasive carcinoma and kidney renal clear cell carcinoma. Elevated OPRD1 levels are connected to worsen outcomes in kidney renal clear cell carcinoma and liver hepatocellular carcinoma, but better prognosis in bladder urothelial carcinoma. Increased OPRK1 (opioid receptor kappa 1 gene) expression is linked to a poorer prognosis in kidney renal papillary cell carcinoma. Furthermore, high OPRL1 expression relates to worse outcomes in bladder urothelial carcinoma and liver hepatocellular carcinoma, but better outcomes in breast invasive carcinoma and pancreatic adenocarcinoma. Functional enrichment analyses found that immune-related pathways were enriched in OPRK1 and OPRL1, with OPRL1 exhibiting the highest correlation with immune cell infiltration. Different effects on cell growth, migration, and invasion were observed in different cancer types upon the administration of agonists for the four ORs.ConclusionOPRL1 may play a vital role in monocytes and regulating the immune response and tumor-infiltrating macrophages. Due to its high abundance in different types of tumors, it may hold greater clinical significance for oncology patients. OPRK1 also participates in immune-related pathways. OPRL1 could potentially serve as therapeutic targets for different types of cancers.Graphical

Pan-cancer analysis reveals the characteristics and roles of tooth agenesis mutant genes.

Tooth development is regulated by numerous genes and signaling pathways. Some studies suggest that mutations in these genes may be associated with several cancer types. However, the tooth agenesis mutated genes role in the prognosis and their clinical therapeutic potentials in pan-cancer have not been elaborately explored. Moreover, the intrinsic correlation between tooth agenesis and cancers also needs to be further verified. We preliminarily analyzed expression levels and prognostic values of causative genes of tooth agenesis, and explored the correlation between the expression of tooth agenesis mutated genes and TME, Stemness score, clinical characteristic, immune subtype, and drug sensitivity in pan-cancer, which based on updated public databases and integrated some bioinformatics analysis methods. In addition, we conducted the enrichment analysis of tooth agenesis mutant genes from KOBAS database. We observed that TA mutant genes had significant gene expression differences in multiple cancer types compared with normal tissues. The expression of causative genes of TA is associated with the prognosis in several cancers from different databases. For example, AXIN2 and MSX1 were correlated to the overall survival (OS) of uterine corpus endometrial carcinoma. PAX9 and TP63 were related to OS of lung squamous cell carcinoma. And TP63 was associated with OS in breast invasive carcinoma and pancreatic adenocarcinoma. Furthermore, the expression of TA mutant genes also has a significant correlation with stromal and immune scores, and RNA stemness score and DNA stemness score in pan-cancer. Besides, we observed that all causative genes of TA were significantly correlated with immune subtypes. Moreover, KEGG pathway analysis showed that causative genes of TA were associated with the development and progression of breast cancer, basal cell carcinoma, gastric cancer, and hepatocellular carcinoma. Finally, AXIN2 expression has a significantly positive or negative correlation with drug sensitivity. Our study indicates the great potential of TA mutant genes as biomarkers for prognosis and provides valuable strategies for further investigation of TA mutant genes as potential therapeutic targets in cancers. Our study can further verify that there may be an intrinsic correlation between tooth agenesis and the occurrence of multiple cancers.

Invasive Pancreatic Adenocarcinoma with Squamous Differentiation Arising in an IOPN with Novel MDM2 Amplification

Abstract Introduction/Objective Intraductal oncocytic papillary neoplasms (IOPNs) are rare pancreatic tumors that are genetically distinct from intraductal papillary mucinous neoplasms (IPMNs). Morphologic and molecular characterization of invasive adenocarcinomas associated with IOPNs remains limited due to the rarity of this entity. Methods/Case Report We present a 68-year-old female who initially presented with abdominal pain and jaundice. MRI revealed a 2.6 cm mass in the pancreatic head with abutment of the superior mesenteric vein and dilation of the biliary and pancreatic duct. Biopsy revealed adenocarcinoma with mucinous features. The patient was started on gemcitabine and abraxane. Her treatment course was complicated by biliary and duodenal obstruction requiring common bile duct and duodenal stenting. Surgical management with pancreaticoduodenectomy was performed six months following initial diagnosis. Gross examination revealed a 2.5 cm ill-defined tumor surrounding the main pancreatic duct adjacent to the common bile duct. Microscopy revealed an IOPN arising within the pancreatic duct exhibiting a complex papillary growth pattern. There was an associated moderately to poorly differentiated invasive carcinoma with mucinous and squamous differentiation with lymph node metastasis. Molecular testing (FoundationOne®CDx) revealed ARID1A mutation and amplification of MDM2, CDK4, and ERBB3. Patient is alive and without radiologic evidence of disease recurrence at 6 months follow-up. Results (if a Case Study enter NA) NA Conclusion To our knowledge, our case is the first report of an invasive pancreatic adenocarcinoma with squamous differentiation arising in association with an IOPN. In addition, our case showed MDM2 amplification which has not been previously identified in pancreatic adenocarcinoma arising in IOPNs. Although recent literature demonstrated that less than 30% of IOPN showed invasive disease and even fewer cases with lymph node metastasis, our case showed extensive invasion with metastases to 2 lymph nodes. This may suggest that MDM2 amplification may play a role in more aggressive disease since it is implicated with poorer outcome in conventional pancreatic adenocarcinoma. Further molecular studies of IOPN may help to identify prognostic features of this entity.

CMTM6 as a potential therapy target is associated with immunological tumor microenvironment and can promote migration and invasion in pancreatic adenocarcinoma

CMTM6 has been connected to the development of several malignancies. However, it is still unknown what function CMTM6 serves in pancreatic adenocarcinoma (PAAD). We obtained RNA sequencing information of PAAD from public datasets and predicted statistical significance of CMTM6 survival in accordance with Kaplan–Meier curves. Gene set enrichment assessment (GSEA) was employed to analyze changes in pathways. Then, we systematically investigated the association involving CMTM6 and the immunological traits within the tumor microenvironment (TME) of PAAD, including immune pathways, immunomodulators, immune infiltrating cells, inflammatory activities, and immunotherapy response prediction. To demonstrate the biologically malignant properties of CMTM6 expression, the Cell Counting Kit-8, transwell experiments, colony formation, and wound healing were utilized. Upregulated CMTM6 expression was revealed within PAAD tissues, which was associated with more frequent somatic mutations and worse survival outcomes. Specifically, CMTM6 expression represented stronger immune infiltration, inflammatory activity, and better immunotherapeutic response in TME. Functional studies revealed that CMTM6 promoted the ability to proliferate, migrate, and invade. Additionally, CMTM6 and PD-L1 had a positive relationship, and CMTM6 can co-immunocoprecipitate with PD-L1 protein in pancreatic cell lines. CMTM6 overexpression shapes the inflammatory TME with a strong immune response. These findings support that CMTM6 is an immunotherapeutic target with promising effect to treat PAAD.

Somatic loss of ATM is a late event in pancreatic tumorigenesis.

Understanding the timing and spectrum of genetic alterations that contribute to the development of pancreatic cancer is essential for effective interventions and treatments. The aim of this study was to characterize somatic ATM alterations in noninvasive pancreatic precursor lesions and invasive pancreatic adenocarcinomas from patients with and without pathogenic germline ATM variants. DNA was isolated and sequenced from the invasive pancreatic ductal adenocarcinomas and precursor lesions of patients with a pathogenic germline ATM variant. Tumor and precursor lesions from these patients as well as colloid carcinoma from patients without a germline ATM variant were immunolabeled to assess ATM expression. Among patients with a pathogenic germline ATM variant, somatic ATM alterations, either mutations and/or loss of protein expression, were identified in 75.0% of invasive pancreatic adenocarcinomas but only 7.1% of pancreatic precursor lesions. Loss of ATM expression was also detected in 31.0% of colloid carcinomas from patients unselected for germline ATM status, significantly higher than in pancreatic precursor lesions [pancreatic intraepithelial neoplasms (p = 0.0013); intraductal papillary mucinous neoplasms, p = 0.0040] and pancreatic ductal adenocarcinoma (p = 0.0076) unselected for germline ATM status. These data are consistent with the second hit to ATM being a late event in pancreatic tumorigenesis. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Pan-cancer analysis of forkhead box Q1 as a potential prognostic and immunological biomarker.

Forkhead box Q1 (FOXQ1) is a member of the forkhead transcription factor family involved in the occurrence and development of different tumors. However, the specific expression patterns and functions of FOXQ1 in pan-cancer remain unclear. Therefore, we collected the expression, mutation, and clinical information data of 33 tumors from The Cancer Genome Atlas database. Via public pan-cancer transcriptome data analysis, we found that FOXQ1 is differentially expressed in various tumors at tissue and cell levels, such as liver hepatocellular carcinoma, colon adenocarcinoma, lung adenocarcinoma, lung squamous cell carcinoma, thyroid carcinoma, and kidney renal clear cell carcinoma. Kaplan–Meier and Cox analyses suggested that FOXQ1 expression was associated with poor overall survival of cutaneous melanoma and thymoma. Its expression was also associated with good disease-specific survival (DSS) in prostate adenocarcinoma but poor DSS in liver hepatocellular carcinoma. In addition, FOXQ1 expression was associated with poor disease-free survival of pancreatic adenocarcinoma. Moreover, FOXQ1 expression was closely related to the tumor mutational burden in 14 tumor types and microsatellite instability (MSI) in 8 tumor types. With an increase in stromal and immune cells, FOXQ1 expression was increased in breast invasive carcinoma, pancreatic adenocarcinoma, thyroid carcinoma, lung adenocarcinoma, and ovarian serous cystadenocarcinoma, while its expression was decreased in pancreatic adenocarcinoma, bladder urothelial carcinoma, and stomach adenocarcinoma. We also found that FOXQ1 expression was related to the infiltration of 22 immune cell types in different tumors (p < 0.05), such as resting mast cells and resting memory CD4 T cells. Last, FOXQ1 was coexpressed with 47 immune-related genes in pan-cancer (p < 0.05). In conclusion, FOXQ1 expression is closely related to prognosis, clinicopathological parameters, cancer-related pathway activity, the tumor mutational burden, MSI, the tumor microenvironment, immune cell infiltration, and immune-related genes and has the potential to be a diagnostic and prognostic biomarker as well as an immunotherapy target for tumors. Our findings provide important clues for further mechanistic research into FOXQ1.

Invasive Large Duct Type Pancreatic Adenocarcinoma: A Diagnostically Challenging Entity

Abstract Introduction/Objective Large duct type invasive pancreatic adenocarcinoma is a morphological variant of pancreatic ductal adenocarcinoma that poses a radiologic and pathologic diagnostic challenge as it closely mimics other non- invasive neoplasms, including mucinous cystic neoplasms and intraductal papillary mucinous neoplasms (IPMN). We report a case of large duct type invasive adenocarcinoma that on radiology closely mimics an IPMN. Methods/Case Report The case id that of a 73-year-old male presenting with weight loss and chronic diarrhea. Abdominal imaging revealed features suggestive of main duct IPMN with possible side branch extension into the pancreatic head. Endoscopic retrograde cholangiopancreatography showed a bile duct stricture that was stented and biopsied, revealing mucinous material with neoplastic cells. A Whipple procedure was performed, revealing a 3.3 cm, tank-pink, papillary lesion in the pancreatic head, that is partially cystic with mucinous contents, and displaying exophytic extension into the main pancreatic duct. Microscopically, the lesion consists of a high-grade IPMN involving the main pancreatic duct with side branch extension, and associated with invasive adenocarcinoma, the majority of which is of the large duct type, showing irregularly distributed large ducts with jagged edges and surrounding desmoplasia, with intra-luminal mucinous material and neutrophils. The lining cells show focal pseudo-stratification and bland cytology. Foci of conventional type invasive adenocarcinoma, clusters of invasive tumor cells, and peri-neural invasion are also identified. Post- procedure, the patient underwent chemotherapy with marked symptomatic improvement. Results (if a Case Study enter NA) NA Conclusion Large duct type invasive adenocarcinoma of the pancreas can closely mimic non-invasive pancreatic neoplasms, posing diagnostic challenges that require identification of subtle features to achieve the correct diagnosis and guide treatment.

S1666 EUS Choledochoduodenostomy: A Novel Way to Treat Recurrent Malignant Biliary Obstruction in the Setting of an Existing Biliary and Duodenal Stent

Introduction: EUS-guided choledochoduodenostomy (EUS-CD) is an effective way to manage patients with malignant biliary obstruction and an inaccessible papilla. It involves creation of a fistula between the duodenal bulb and distal common biliary duct (CBD) using a lumen-apposing metal stent (LAMS). Data shows high technical and clinical success rates, with low adverse event rates and improved morbidity and mortality. Advantages of this approach include the ability to provide drainage to altered or inaccessible anatomy, and minimal invasiveness due to internalized drainage. We present a report of a patient with cholangitis due to recurrent biliary and gastric outlet obstruction (GOO) treated successfully with duodenal stenting and EUS-CD despite indwelling hardware. Case Description/Methods: A 71-year-old male with as history of locally invasive pancreatic adenocarcinoma presented with cholangitis and intolerance to oral intake. His prior course was complicated by GOO and biliary obstruction that required biliary fully covered self-expandable metal stent (FC-SEMS) and uncovered duodenal stent placement. Despite palliative chemotherapy, he presented 6 months later with cholangitis and imaging findings concerning for CBD stent occlusion, partial GOO and new ascites. Upper endoscopy showed significant stenosis within the duodenal stent that involved the major papilla, preventing conventional ERCP. The decision was made to evaluate for EUS biliary drainage. Presence of significant ascites precluded hepaticogastrostomy or gastrojejunostomy, however, there was an area superior to the indwelling biliary stent amenable to EUS-CDS. A 10mm x10mm LAMS was placed into the common hepatic duct with drainage of purulent fluid (Figure 1). Cholangiogram confirmed correct placement and excluded a leak. An uncovered duodenal stent was deployed through the indwelling duodenal stent and placement confirmed radiographically (Figure 1). The patient was discharged 2 days later with downtrending liver chemistries and tolerating oral intake. Discussion: Patients with combined malignant biliary and duodenal obstruction can be challenging to manage. Existing hardware complicates management even further. This case highlights the versatility of EUS biliary drainage allowing patient directed therapy with EUS-CDS in the setting of an existing biliary stent as an effective means of biliary drainage when ERCP was not possible.Figure 1.: A: occluded biliary stent B: LAMS with pigtail stents C: duodenal stent D: KUB showing stents in place.

High Matrix Metalloproteinase 28 Expression is Associated with Poor Prognosis in Pancreatic Adenocarcinoma

PurposePancreatic adenocarcinoma (PAAD) is a devastating disease with high mortality and morbidity. Matrix metalloproteinase 28 (MMP28) has been associated with carcinogenesis of many human cancers. However, little is known about the potential prognostic value and underlying regulatory mechanisms of MMP28 in PAAD.MethodsThe relationship between MMP28 expression level and various clinicopathological parameters was analyzed in TCGA-PAAD cohorts. MMP28-correlated genes in the TCGA-PAAD cohort were identified and enrichment analysis according to the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes was conducted using LinkedOmics. Protein–protein interaction and transcription factors-miRNA co-regulatory networks were constructed with the use of NetworkAnalyst. Then, the distribution of immune cells related to MMP28 expression in blood was analyzed using the Human Protein Atlas, and the tumor microenvironment of PAAD was analyzed by the TIMER 2.0 database. To investigate the biological function of MMP28 in PAAD, siRNA was constructed to knock down the MMP28 gene in vitro.ResultsHigh MMP28 expression is associated with poor overall survival and disease-free survival in PAAD patients. The expression of MMP28 in PAAD is most significantly correlated with KRT19, IL1RN, and ANXA2 genes. Network analysis revealed that MIR-181 family, TAFs, and CDC6 are potential regulators of MMP28. Furthermore, naive CD4+ T cell, naive CD8+ T cell, and mucosal-associated invariant T cell enrichment in blood were correlated with MMP28 expression. Furthermore, high MMP28 expression was correlated with a decrease in B cell, naive CD4+ T cell, naive CD8+ T cell, and endothelial cell presence in the tumor microenvironment in PAAD. Finally, genetic knockdown of MMP28 could restrain the proliferation, migration, and invasion of PAAD cells.ConclusionOur findings indicate that high MMP28 expression in PAAD is associated with cancer progression, invasion, and metastasis. Hence, MMP28 might serve as an independent prognostic biomarker and a prospective therapeutic target for PAAD.

Pancreatic adenocarcinoma: A review of recent paradigms and advances in epidemiology, clinical diagnosis and management.

Pancreatic cancer is one of the dreaded malignancies for both the patient and the clinician. The five-year survival rate of pancreatic adenocarcinoma (PDA) is as low as 2% despite multimodality treatment even in the best hands. As per the Global Cancer Observatory of the International Agency for Research in Cancer estimates of pancreatic cancer, by 2040, a 61.7% increase is expected in the total number of cases globally. With the widespread availability of next-generation sequencing, the entire genome of the tumors is being sequenced regularly, providing insight into their pathogenesis. As invasive PDA arises from pancreatic intraepithelial neoplasia and mucinous neoplasm and intraductal papillary neoplasm, screening for them can be beneficial as the disease is curable with resection at an early stage. Routine preoperative biliary drainage has no role in patients suffering from PDA with obstructive jaundice. If performed, metallic stents are preferred over plastic ones. Minimally invasive procedures are preferred to open procedures as they have less morbidity. The duct-to-mucosa technique for pancreaticojejunostomy is presently widely practiced. The role of intraperitoneal drains after surgery for PDA is controversial. Neoadjuvant chemoradiotherapy has been proven to have a significant role both in locally advanced as well as in resectable PDA. Many new regimens and drugs have been added in the arsenal of chemoradiotherapy for metastatic disease. The roles of immunotherapy and gene therapy in PDA are being investigated. This review article is intended to improve the understanding of the readers with respect to the latest updates of PDA, which may help to trigger new research ideas and make better management decisions.

Undifferentiated Pancreatic Carcinoma With Osteoclast-Like Giant Cells: What Do We Know So Far?

Undifferentiated carcinoma of the pancreas is an aggressive but rare tumor for which several other terms have been used to describe its histological appearance. In addition, as osteoclast-like giant cells may accompany undifferentiated carcinoma of the pancreas, the WHO Classification distinguishes undifferentiated carcinoma with osteoclast-like giant cells (UC-OGC) from plain undifferentiated carcinoma since there are a few histopathological and clinical differences. UC-OGC was initially thought to be associated with worse prognosis compared to invasive ductal pancreatic adenocarcinoma, since it is often unresectable at diagnosis and tends to recur rapidly even if completely resected. When true UC-OGGs are carefully dissected out from other anaplastic carcinomas, it becomes, however, clear that UC-OGCs do have more indolent behavior, especially the pure UC-OGCs. This mini-review summarizes the current knowledge on UC-OGC.

Feasibility of modeling human intraductal papillary mucinous neoplasms of the pancreas using an organoid approach

Presenter: Nicholas Peters MD | Yale University School of Medicine Background: Intraductal papillary mucinous neoplasm (IPMN) is a mucin-producing, premalignant cystic lesion arising from the pancreatic ducts that can result in invasive pancreatic adenocarcinoma. The molecular origin of IPMN and etiology of malignant degeneration remains poorly understood, in part due to the lack of an in vitro model for study. Organoid-based systems have emerged as a genetically-tractable approach for tumor study. We sought to assess the feasibility of creating an organoid-based model system for the study of human IPMN. Methods: Patients undergoing surgical resection for presumed IPMN of any histological subtype or category of dysplasia were eligible for study inclusion. Within 30 minutes of resection, fresh aliquots of IPMN and grossly normal pancreatic duct were obtained. Specimens were enzymatically digested to oligo-cell clusters, embedded in solubilized basement membrane (Matrigel), and grown in permissive media promoting enrichment of the ductal epithelial fraction. Creation of spherical organoids capable of sustained growth, defined as 3 sequential culture passages, was defined as a successfully propagated culture. Microscopy, immunohistochemistry (IHC), and genotypic analysis of known highly-penetrant IPMN mutations were then performed on mature organoid cultures when possible. Results: 29 unique cyst wall or adjacent, grossly normal pancreatic ductal tissue sections from 11 patients (range, 1-6 sections/patient) were freshly harvested from surgical pancreatectomy specimens. The source tissues were then subsequently confirmed as IPMN via histologic examination by an experienced pancreatic surgical pathologist. The harvested tissue subjected to enzymatic digestion and culture ranged from 18 – 164mg. Spheroid formation and successful, sustained growth for at least three passages was attained in 11 organoid cultures (38%) as demonstrated by phase-contrast microscopy (Figure 1A). Continuous cultures were sustained in successful isolates from 22 - 385 days (median, 92 days). Genomic DNA was successfully isolated from 10 organoid cultures. Targeted sequencing was completed in 4 samples and revealed KRAS G12x/Q61x or GNAS R201x mutations in 3/3 IPMN samples, and 0/1 adjacent normal samples. To date, IHC analysis of 1 organoid demonstrated recapitulation of pathognomonic IPMN-defining protein expression consistent with the clinical tissue of origin (CDX2, MUC2, MUC5AC shown in Figure 1 B, C, and D, respectively). Conclusion: Creation of sustained human-derived IPMN organoids is feasible and the current data shows recapitulation of key driver mutations and IPMN-specific protein expression in vitro. Future improvements in organoid generation efficiency, durability and characterization will enhance the applicability of this approach.

Endoscopic ultrasound for differential diagnosis of malignant pancreatic cystic lesions: case report and review of literature

A 63-year-old female patient was admitted to the hospital for an in-depth diagnosis of accidentally found pancreatic cystic lesion. The lesion was detected by computed tomography scan and magnetic resonance imaging of the abdomen and identified as potentially malignant mucinous cystic neoplasm (MCN). Endoscopic ultrasound-guided fine-needle aspiration biopsy with the analysis of the fluid from the cyst was performed as well and it confirmed the malignancy of the cystic lesion. The patient was qualified for surgery and the final diagnosis based on histopathological examination of the surgical material confirmed MCN with the accompanying invasive pancreatic adenocarcinoma.

Molecular characterization of organoids derived from pancreatic intraductal papillary mucinous neoplasms.

Intraductal papillary mucinous neoplasms (IPMNs) are commonly identified non-invasive cyst-forming pancreatic neoplasms with the potential to progress into invasive pancreatic adenocarcinoma. There are few in vitro models with which to study the biology of IPMNs and their progression to invasive carcinoma. Therefore, we generated a living biobank of organoids from seven normal pancreatic ducts and ten IPMNs. We characterized eight IPMN organoid samples using whole genome sequencing and characterized five IPMN organoids and seven normal pancreatic duct organoids using transcriptome sequencing. We identified an average of 11,344 somatic mutations in the genomes of organoids derived from IPMNs, with one sample harboring 61,537 somatic mutations enriched for T→C transitions and T→A transversions. Recurrent coding somatic mutations were identified in 15 genes, including KRAS, GNAS, RNF43, PHF3, and RBM10. The most frequently mutated genes were KRAS, GNAS, and RNF43, with somatic mutations identified in six (75%), four (50%), and three (37.5%) IPMN organoid samples, respectively. On average, we identified 36 structural variants in IPMN derived organoids, and none had an unstable phenotype (> 200 structural variants). Transcriptome sequencing identified 28 genes differentially expressed between normal pancreatic duct organoid and IPMN organoid samples. The most significantly upregulated and downregulated genes were CLDN18 and FOXA1. Immunohistochemical analysis of FOXA1 expression in 112 IPMNs, 113 mucinous cystic neoplasms, and 145 pancreatic ductal adenocarcinomas demonstrated statistically significant loss of expression in low-grade IPMNs (p < 0.0016), mucinous cystic neoplasms (p < 0.0001), and pancreatic ductal adenocarcinoma of any histologic grade (p < 0.0001) compared to normal pancreatic ducts. These data indicate that FOXA1 loss of expression occurs early in pancreatic tumorigenesis. Our study highlights the utility of organoid culture to study the genetics and biology of normal pancreatic duct and IPMNs. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Relationship between cachexia and perineural invasion in pancreatic adenocarcinoma.

BACKGROUNDCachexia is responsible for the low quality of life in pancreatic adenocarcinoma (PDAC). The rapid disease progression and patient deterioration seems related to perineural invasion, but the relationship between cachexia and perineural invasion for the evolution of the disease has been rarely studied. As perineural invasion is difficult to be highlighted, a biomarker such as the neurotrophic factor Midkine (MK) which promotes the neuronal differentiation and the cell migration could be helpful. Also, Activin (ACV) has been described as cachexia related to PDAC. However, their role for assessing and predicting the disease course in daily practice is not known.AIMTo assess the relationship between perineural invasion and cachexia and their biomarkers, MK and ACV, respectively, and their prognostic value.METHODSThis study included prospectively enrolled patients with proven adenocarcinoma and a matched group of controls without any malignancies. Patients with other causes of malnutrition were excluded. The plasma levels of ACV and MK were analyzed using western blotting and were correlated with the clinicopathological features and survival data. These results were validated by immunohistochemical analyses of the pancreatic tumor tissue of the patients included in the study and a supplementary group of surgically resected specimens from patients with a benign disease.RESULTSThe study comprised 114 patients with PDAC, 125 controls and a supplementary group of 14 benign pancreatic tissue samples. ACV and MK were both overexpressed more frequently in the plasma of patients with PDAC than in the controls (63% vs 32% for ACV, P < 0.001; 47% vs 16% for MK, P < 0.001), with similar levels in pancreatic tissue the MK protein expression was closely related to the advanced clinical stage (P = 0.006), the presence of metastasis (P = 0.04), perineural invasion (P = 0.03) and diabetes (P = 0.002), but with no influence on survival. No correlation between clinicopathological factors and ACV expression was noted. Cachexia, present in 19% of patients, was unrelated to ACV or MK level. Higher ACV expression was associated with a shorter survival (P = 0.008).CONCLUSIONThe MK was a biomarker of perineural invasion, associated with tumor stage and diabetes, but without prognostic value as ACV. Cachexia was unrelated to perineural invasion, ACV level or survival.

1298 Pancreatic Adenocarcinoma Presenting as Acute Large Bowel Obstruction

INTRODUCTION: Acute large bowel obstruction is a rare presentation of pancreatic carcinoma with only 7 cases described in the literature. When located in the head of the pancreas, pancreatic adenocarcinoma commonly presents with abdominal pain, weight loss and jaundice. Pancreatic masses in the body and tail tend to have an insidious onset and may only present with vague abdominal pain. In the case described, a patient presenting with 2 weeks of constipation was found to have a large bowel obstruction in the setting of locally invasive pancreatic adenocarcinoma. CASE DESCRIPTION/METHODS: A 64-year-old woman with past medical history of chronic constipation presented to the emergency department with a chief complaint of constipation for 14 days. During these 14 days the patient had developed increasing abdominal distension as well as nausea, vomiting and abdominal pain. Vital signs were unremarkable except for a heart rate of 132. Physical examination was significant for an uncomfortable appearing woman with a diffusely tender and distended abdomen. Laboratory studies showed a leukocytosis of 16.2/uL. CT scan of the abdomen revealed findings suggestive of a primary colon carcinoma of the splenic flexure with upstream colonic obstruction and likely invasion of the pancreatic tail and spleen. General surgery and Gastroenterology were consulted who recommended colonoscopy for evaluation of the presumed mass at the splenic flexure, however, on the day following admission the patient's clinical status deteriorated. The patient was taken for emergent exploratory laparotomy at which time a markedly distended cecum and right colon were noted. The mass was found to involve the splenic flexure posteriorly as well as the tail of the pancreas and spleen. The patient underwent En Bloc resection of the splenic flexure, spleen and pancreatic tail. Pathology revealed moderately differentiated pancreatic ductal adenocarcinoma and the patient was started on FOLFIRINOX chemotherapy. DISCUSSION: There have been 3 cases resulting in large bowel obstruction due to local invasion and 4 cases causing obstruction in the setting of metastatic disease. In this case report, we describe an acute obstruction caused by local invasion of pancreatic tail adenocarcinoma. Usual suspects of large bowel obstruction include colorectal carcinoma, volvulus, adhesions, strictures from diverticulitis and hernias. We believe that although rare, once should consider pancreatic carcinoma as part of the differential for large bowel obstruction.

1303 More Than Meets the Eye: Pancreatic Panniculitis as Presenting Sign of Invasive Pancreatic Adenocarcinoma

INTRODUCTION: Despite its first description by Chiari in 1883, pancreatic panniculitis remains an atypical manifestation of pancreatic disease, appearing in only 0.3-2% of patients. Although the pathogenesis remains unclear, biopsy-proven subcutaneous liquefactive fat necrosis has implicated elevated lipase, amylase, and trypsin in dissemination and subcutaneous deposition/lipolysis, manifesting as edematous, erythematous superficial nodules of the lower extremities, thigh, and buttock. CASE DESCRIPTION/METHODS: A 91-year-old male presented with 2-week history of painful erythematous nodular rash of bilateral anterior lower extremities. Rash began as small singleton lesion, approximately 1 cm each in size, which grew in diameter with progressively worsening tenderness. Outpatient punch biopsy revealed lobular fat necrosis and local inflammatory infiltrate, consistent with pancreatic panniculitis. Labs were significant for amylase 1026 U/L (ULN 100), lipase of 4366 U/L (ULN 78), CA 19-9 1600 U/mL, and CEA of 9.4 ng/mL. CT-abdomen/pelvis without contrast showed a normal appearing liver, atrophic pancreas with 1.5 cm cystic structure at the pancreatic head, and a 9 mm cystic structure within the pancreatic body. EUS/ERCP for suspected choledocholithiasis with concomitant malignancy revealed 5 mm dilation of the main pancreatic duct with associated 21 mm × 17 mm mass of mixed solid and cystic consistency with multiple anechoic lesions throughout the pancreas suggestive of cysts. Fine needle biopsy revealed invasive ductal adenocarcinoma with associated high grade intraductal papillary mucinous neoplasm. He completed staging work-up and underwent Whipple Procedure with negative margins. DISCUSSION: Although a rare dermatologic manifestation of underlying pathology, pancreatic panniculitis serves as a herald of severe pancreatic pathology. Subcutaneous biopsy of suspicious lesions is invaluable in identifying the etiology and ultimately diagnosing underlying pancreatic pathology. Histologic evaluation following punch biopsy of nodules reveals liquefactive fat necrosis, surrounded by a neutrophil-rich mixed inflammatory infiltrate with pathognomonic “ghost cells”. Treatment of the underlying disease process can lead to resolution of the nodules. Our patient presented with pancreatic panniculitis as the initial manifestation of internal occult malignancy in the absence of typical symptoms. Prompt recognition and biopsy of suspicious nodules led to an expedient diagnosis of locally resectable disease.