Anaplastic Carcinoma Arising in a Mucinous Cystic Neoplasm Masquerading as Pancreatic Pseudocyst

Mucinous cystic neoplasms (MCN) of the pancreas can vary from benign to premalignant and malignant. Preoperative diagnosis is essential to offer the patient appropriate treatment. Occasionally these cases may harbor anaplastic carcinoma while clinically masquerade as a pseudocyst. Here in, we report an unusual case of a 37‐year old female presented with recurrent abdominal pain that was suspected clinically and by imaging studies to have a pseudocyst. EUS‐FNA with internal drainage of the cyst was performed. Cytological evaluation of the cyst fluid showed numerous inflammatory cells composed mainly of many neutrophils admixed with macrophages reminiscent of the usual pseudocyst content but there were scattered rare dyscohesive malignant cells which were highly pleomorphic with multinucleation. Immunostains on the cell block showed immunoreactivity of these cells including the multinucleated cells for Cam 5.2 and AE1/AE3 and focally for Ber‐Ep4, Moc ?31, and CA19‐9. The subsequent resection confirmed the presence of anaplastic (undifferentiated) carcinoma (AC) arising in a MCN of the pancreas. Diagn. Cytopathol. 2016;44:538–542. © 2016 Wiley Periodicals, Inc.     

AAVP displaying octreotide for ligand-directed therapeutic transgene delivery in neuroendocrine tumors of the pancreas

Patients with inoperable or unresectable pancreatic neuroendocrine tumors (NETs) have limited treatment options. These rare human tumors often express somatostatin receptors (SSTRs) and thus are clinically responsive to certain relatively stable somatostatin analogs, such as octreotide. Unfortunately, however, this tumor response is generally short-lived. Here we designed a hybrid adeno-associated virus and phage (AAVP) vector displaying biologically active octreotide on the viral surface for ligand-directed delivery, cell internalization, and transduction of an apoptosis-promoting tumor necrosis factor (TNF) transgene specifically to NETs. These functional attributes of AAVP-TNF particles displaying the octreotide peptide motif (termed Oct-AAVP-TNF) were confirmed in vitro, in SSTR type 2-expressing NET cells, and in vivo using cohorts of pancreatic NET-bearing Men1 tumor-suppressor gene KO mice, a transgenic model of functioning (i.e., insulin-secreting) tumors that genetically and clinically recapitulates the human disease. Finally, preclinical imaging and therapeutic experiments with pancreatic NET-bearing mice demonstrated that Oct-AAVP-TNF lowered tumor metabolism and insulin secretion, reduced tumor size, and improved mouse survival. Taken together, these proof-of-concept results establish Oct-AAVP-TNF as a strong therapeutic candidate for patients with NETs of the pancreas. More broadly, the demonstration that a known, short, biologically active motif can direct tumor targeting and receptor-mediated internalization of AAVP particles may streamline the potential utility of myriad other short peptide motifs and provide a blueprint for therapeutic applications in a variety of cancers and perhaps many nonmalignant diseases as well.A long-standing goal of targeted anticancer therapy is to deliver the drug solely to the tumor and eliminate toxicity to nonmalignant tissues. To this end, bacteriophage (phage)-based vectors are attractive, because ligand peptide motifs can be displayed on the pIII coat protein to allow viral binding to and internalization into target cells in vitro and in vivo (1), and the phage can be genetically modified to deliver gene products that kill tumor cells (2–7). In previous work, we combined phage and adeno-associated virus (AAV) to form a hybrid AAV/phage (termed AAVP) vector that enables superior ligand-directed delivery and cellular transduction of transgenes as a targeted platform (2). Indeed, combining the functional attributes of prokaryotic phage (i.e., robust nontoxic particles multipliable at low cost) with those of eukaryotic AAV (i.e., strong mammalian cell transduction) allows incorporation of the beneficial aspects of each into the new particle. The targeting capacities and engineered tropism for cells specifically expressing a receptor of interest permits gene expression with limited amounts of circulating AAVP after systemic administration, increasing efficacy with minimal toxicity.The ligand-directed AAVP-based system has enabled a theranostic approach wherein a single transgene functions as a noninvasive molecular imaging reporter and therapeutic gene in preclinical models of prostate and breast cancer (2), soft-tissue sarcomas (3), and glioblastomas (4). These previous chimeric AAVP vectors were each targeted on the specific tumor type by ligand motifs identified by phage display from combinatorial peptide libraries. To date, however, no studies have shown that short peptides with known biological activity would function as a ligand displayed in viral systems used for genetic delivery, including phage, AAV, or AAVP. The use of known, biologically active peptides eliminates the need to a priori screen, identify, and validate ligand–receptor pairs with substantial time and cost savings, and reveals a minimal risk avenue for tumor attack via known ligands or receptors overexpressed specifically in tumors.Brazeau’s landmark discovery of somatostatin two decades ago (8), along with a large body of ensuing investigations (9, 10), have identified the avidity of malignant tumors overexpressing receptors for somatostatin or its analogs (SSTRs). Generally, tumors arising from neuroendocrine tissues often express at least one SSTR family member at the cell membrane level, most often SSTR type 2 (SSTR2), and thereby provide a specific path for ligand-directed targeting and molecular imaging (11). Unfortunately, the half-life of native somatostatin in the circulation is only ∼2–3 min (12), which essentially eliminates its medical utility and has prompted the development of synthetic analogs (13). One such synthetic cyclic somatostatin analog, termed octreotide (single-letter residue sequence, FCFWKTCT), mimics native somatostatin but with a much longer half-life (∼90 min), specific SSTR2 affinity, and potent inhibition of growth hormone and glucagon activity and insulin release (14, 15).Human pancreatic NETs are relatively rare. The sole potentially curative intervention is surgical resection, but patients are often ineligible (i.e., with unresectable, metastatic, or inoperable tumors), leaving limited therapeutic options (16). However, given that these tumors frequently overexpress SSTR2, they often clinically respond to synthetic somatostatin analogs such as octreotide and lanreotide (16–19). Indeed, diagnostic imaging studies of SSTR targets are standard for so-called “octreotide-avid” tumors (20), and peptide-based receptor radionuclide therapy also has been used to clinical effect (21). Thus, we reasoned that octreotide-targeted cellular transduction would enable the expression of tumor necrosis factor (TNF) within the SSTR2-expressing tumor cells after systemic administration through the vulnerable tumor-associated blood vessels of pancreatic NETs without off-target vascular or parenchymal toxicity to normal organs.TNF is an inflammatory cytokine with variable physiological and pathological functions, including antivascular and antitumor effects. Unfortunately, TNF has limited application clinically because of predictable but severe systemic toxicity, which calls for localized administration or targeted delivery (5, 6). Here we introduce an AAVP particle displaying the octreotide peptide motif to enable ligand-directed genetic TNF delivery (termed Oct-AAVP-TNF) in the preclinical context of pancreatic NETs. Our central hypothesis, evaluated in vitro, in cellulo, and in vivo, is that the motif display of a clinically active peptide, such as octreotide, in the setting of AAVP particles can functionally emulate the specific binding attributes of the native biological ligand–receptor system.     

External Versus Internal Pancreatic Duct Drainage for the Early Efficacy After Pancreaticoduodenectomy: A Retrospectively Comparative Study

Purpose: To compare the early efficacy of external versus internal pancreatic duct drainage after pancreaticoduodenectomy (PD), providing clinical evidence for selecting the optimal approach to pancreatic duct drainage. Material and Methods: The clinical data of 395 consecutive patients undergoing PD from 2006 to 2013 were analyzed retrospectively. All the patients were divided into external and internal drainage group. Intraoperative blood loss, surgery duration, postoperative hospitalization duration, mortality rate, PF, and other complications were compared between the two groups. The perioperative relative risk factors that might induce PF were analyzed. Results: External drainage significantly reduced the incidences of post-PD PF, delayed gastric emptying, abdominal infection, bowel obstruction, overall complications, and shortened the healing time of PF (p < .05). The univariate analysis showed that the pancreatic duct drainage method, body mass index (BMI), preoperative serum bilirubin level, perioperative blood transfusion, pancreaticojejunostomy approach, pancreatic texture, pancreatic duct diameter, and primary disease differed markedly between the two groups (p < .05). A multivariate analysis revealed that BMI ≥ 25 kg/m², internal pancreatic duct drainage, pancreatic duct diameter <3 mm, soft pancreatic texture, and ampullary disease were independent risk factors for PF. Conclusions: External pancreatic duct drainage can effectively reduce the morbidity of PF and overall complications after PD.     

Myoferlin plays a key role in VEGFA secretion and impacts tumor‐associated angiogenesis in human pancreas cancer

Pancreatic ductal adenocarcinoma is one of the most deadly forms of cancers with no satisfactory treatment to date. Recent studies have identified myoferlin, a ferlin family member, in human pancreas adenocarcinoma where its expression was associated to a bad prognosis. However, the function of myoferlin in pancreas adenocarcinoma has not been reported. In other cell types, myoferlin is involved in several key plasma membrane processes such as fusion, repair, endocytosis and tyrosine kinase receptor activity. In this study, we showed that myoferlin silencing in BxPC‐3 human pancreatic cancer cells resulted in the inhibition of cell proliferation in vitro and in a significant reduction of the tumor volume in chick chorioallantoic membrane assay. In addition to be smaller, the tumors formed by the myoferlin‐silenced cells showed a marked absence of functional blood vessels. We further demonstrated that this effect was due, at least in part, to an inhibition of VEGFA secretion by BxPC‐3 myoferlin‐silenced cells. Using immunofluorescence and electron microscopy, we linked the decreased VEGFA secretion to an impairment of VEGFA exocytosis. The clinical relevance of our results was further strengthened by a significant correlation between myoferlin expression in a series of human pancreatic malignant lesions and their angiogenic status evaluated by the determination of the blood vessel density.