Pancreatic Ascites Research Articles

A Tumor-targeting Adenovirus with High Gene-transduction Efficiency for Primary Pancreatic Cancer and Ascites Cells

Optimizing targeting strategies for vectors in order to enhance antitumor activity and secure patient safety is important for cancer gene therapy. We previously identified two pancreatic cancer-targeting ligands (PFWSGAV: PFW and SYENFSA: SYE) by screening an adenovirus library in vivo and in vitro, respectively. To examine clinical usefulness, we assessed gene-transduction efficiency using surgically-resected pancreatic cancer specimens and ascites cells. For surgical specimens, vectors displaying PFW and SYE improved transduction efficiency by 4.4- and 4.3-fold, respectively. The SYE-displaying vector was >2-fold more efficient for all seven cases, whereas the PFW-displaying vector increased efficiency in two out of four cases. For ascites samples, both vectors increased gene-transduction efficiency of epithelial cell adhesion molecule (EpCAM)-positive ascites cells by >2-fold in two out of five cases. Both vectors enhanced adenovirus infectivity of pancreatic cancer cells and have potential for gene therapy of pancreatic cancer; therefore they should be further evaluated in clinical studies.

Pancreatic cancer ascites xenograft-an expeditious model mirroring advanced therapeutic resistant disease.

Pancreatic ductal adenocarcinoma has limited treatment options. There is an urgent need for developing appropriate pre-clinical models recapitulating metastatic disease, the most common clinical scenario at presentation. Ascites accumulation occurs in up to 20–30% of patients with pancreatic cancer; this milieu represents a highly cellular research resource of metastatic peritoneal spread. In this study, we utilized pancreatic ascites/pleural effusion cancer cells to establish patient derived xenografts.Ascites/pleural effusion-patient derived xenografts were established from twelve independent cases. Xenografts were serially passed in nude mice and tissue bio-specimen banking has been established. Histopathology of emergent tumors demonstrates poorly to moderately differentiated, glandular and mucin producing tumors, mirroring morphology of primary pancreatic cancer tumors. Whole genome sequencing of six patient derived xenografts samples demonstrates common mutations and structural variations similar to those reported in primary pancreatic cancer. Xenograft tumors were dissociated to single-cells and in-vitro drug sensitivity screen assays demonstrated chemo-resistance, correlating with patient clinical scenarios, thus serving as a platform for clinically relevant translational research.Therefore, establishment of this novel ascites/pleural effusion patient derived xenograft model, with extensive histopathology and genomic characterization, opens an opportunity for the study of advanced aggressive pancreatic cancer. Characterization of metastatic disease and mechanisms of resistance to therapeutics may lead to the development of novel drug combinations.

Efficacy of Pancreatic Endotherapy In Pancreatic Ascites And Pleural Effusion.

Pancreatic ascites and effusion is a challenging complication to manage, hence our aim was to evaluate the efficacy of pancreatic endotherapy in pancreatic ascites and pleural effusion. Endotherapy included endoscopic retrograde cholangiopancreatography (ERCP) with a pancreatogram and pancreatic stent placement across the leak in patients with pancreatic ascites/effusion. A total of 53 patients were included after successful cannulation. The male:female ratio was 7.8:1. The pancreatogram revealed a leak from the pancreatic duct in 20/53 (37.73%) patients. The most common leak site was the pancreatic body in 10/53 (18.9%) patients followed by the tail in 6/53 (11.32%) patients and the genu in 4/53 (7.5%) patients. In 29/53 (54.7%) patients, stent was placed beyond the leak site. Sphincterotomy was done in 7/53 (13.2%) patients, and in five patients with an obscure leak site, stent was placed empirically. A total of 39/53 (73.6%) patients benefited in terms of achieving the complete resolution of ascites and pleural effusion. The factors which were significant for the success of pancreatic endotherapy in the multivariate analysis were the site of the pancreatic ductal leak (p value = 0.008) and the ability of the stent to cross the leak site (p value = 0.004). To sum up, bridging the pancreatic ductal leak by stent offers a high rate of success. Pancreatic endotherapy is less invasive and highly effective in managing pancreatic ascites/pleural effusion.

Surgical management of pancreatic ascites

Background: Pancreatic ascites is a challenging problem faced by clinicians. The management requires a multidisciplinary approach. Timely surgical intervention is the key especially in patients with chronic pancreatitis and pancreatic ascites where conservative and endoscopic treatments were not successful.Methods: The data was retrieved from a prospectively maintained database for a period of 4 years. A total of 14 patients were included. They were initially optimized with ascitic fluid drainage, nutritional supplementation either enteral or parenteral. Endoscopic retrograde cholangio pancreatography (ERCP) was done in patients with failed conservative treatment after 2 weeks. Endoscopic pancreatic stenting was attempted in proximal ductal disruptions. Nonresponders were taken up for surgery. The type of surgery was based on the site of leak and associated pancreatic pathology like pseudocyst.Results: Initially three patients were responded to conservative management. ERCP was done in 9/14 patients. ERCP demonstrated leak of contrast into peritoneal cavity in 3 (3/9), leaking pancreatic pseudocyst in 3 (3/9) and non-visualisation of distal duct in 2 (2/9). ERCP and stenting of pancreatic duct was attempted in three patients and was successful in resolution of symptoms in one. Nine out of fourteen needed surgical intervention. Surgery was based on site of leak and presence of pseudocyst.Conclusions: Majority of the patients in our study were ethanolics and a change in life style early in the course can prevent this morbid disease. Nasojejunal tube feeding with blendarized home feeds will improve the nutritional status. CECT abdomen and ERCP will give a road map in deciding the type of intervention. For proximal ductal disruption endoscopic stenting should be tried before going for a major surgical intervention. Surgery provides definitive cure.

Impact of endoscopic ultrasound-guided fine needle aspiration from peritoneal lesions for avoiding diagnostic laparoscopy (ipad study): The first prospective study (preliminary results)

Background:In patients with undiagnosed peritoneal lesions, diagnostic laparoscopy is often required for tissue diagnosis. Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is another possible approach but has never been prospectively evaluated.Objectives:To study the efficacy of EUS-FNA for avoiding diagnostic laparoscopy in patients with peritoneal lesions.Methods:From December 2015 to October 2016, 18 consecutive patients with peritoneal lesions were enrolled. Diagnostic laparoscopy was planned if pathological result of EUS-FNA was negative.Results:Computed tomographic findings were soft tissue nodules/mass deposit in the peritoneum (n = 13; 72.2%), ascites (n = 12; 66.7%), omental cake appearance (n = 6; 33.3%), and stranding of mesentery (n = 3; 16.7%). Two benign cases were pancreatic ascites confirmed by laparoscopy and peritoneal tuberculosis confirmed by successful treatment. EUS-FNA showed positive results of malignancy in 14/18 patients (77.8%) and 28/54 passes (51.8%). Of 28 passes with positive results, 22/28 (78.6%) and 6/28 (21.4%) were obtained from hypoechoic and hyperechoic lesions, respectively. No adverse events were observed. Of four patients with negative results of EUS-FNA, two patients underwent diagnostic laparoscopy showing multiple omental and peritoneal nodules from metastatic stomach cancer (n = 1) and pancreatic ascites (n = 1) and another two patients refused laparoscopy; one had advanced staged pancreatic cancer with poor performance status and another was clinically diagnosed as peritoneal tuberculosis with successful treatment. The sensitivity and specificity of EUS-FNA were 87.5% and 100%, respectively. Diagnostic laparoscopy can be avoided in 14/18 (77.8%) patients.Conclusions:In this prospective study, EUS-FNA has a high sensitivity rate for diagnosing causes of peritoneal lesions and can avoid diagnostic laparoscopy in majority of patients.

Eosinophilic pancreatitis confirmed by cyst wall biopsy of walled-off necrosis through nagi stent

An 18-year-old male presented 3 months after acute severe pancreatitis with ascites and large pancreatic fluid collection (PFC). He had no history of alcohol, drug abuse, or allergies. Blood count showed peripheral eosinophilia (44%) with high absolute eosinophilic count (1800 cells/mm3). Percutaneous drainage (PCD) was done for significant pancreatic ascites. Ascitic fluid analysis showed low-gradient ascites with eosinophilic predominance (800 cells/mm3 with 80% eosinophils) and raised fluid amylase levels (1331 U/L). Due to persistent pain and PFC, he underwent EUS-guided cystogastric drainage of walled-off necrosis (WON) with Nagi stent. WON fluid analysis had high amylase levels (49,500 U/l) with normal eosinophil count. He continued to have high volume drainage in PCD. Later, he required endoscopic necrosectomy for infected necrosis during which a cyst wall biopsy was also taken. Histology confirmed eosinophilic pancreatitis. After resolution of infected WON, he was treated with oral prednisolone (40 mg/day) with rapid recovery.

手術により救命しえた全身状態不良に陥った難治性膵性腹水の3例

手術により救命しえた全身状態不良に陥った難治性膵性腹水の3例

Spectrum of acute pancreatitis in a patient- progression of complications

Background Acute pancreatitis is defined as an acute condition presenting with abdominal pain, and is usually associated with raised pancreatic enzyme levels in the blood or urine, as a result of pancreatic inflammation. Acute pancreatitis may recur, severe episodes, however, may involve a progression to sterile and infected peripancreatic fluid collections, pancreatic necrosis and pancreatic abscess, pancreatic pseudocyst, pancreatic ascites and pancreaticopleural fistulas. These can be divided into acute or delayed, depending on whether such a collection is of less than or more than 4 weeks' duration. Pancreatic Abscess is a circumscribed intra-abdominal collection of pus, usually in proximity to pancreas. Pancreatic abscess is often a late complication of acute necrotizing pancreatitis, occurring more than 4 weeks after the initial attack. The reported mortality rate due to pancreatic abscesses after acute pancreatitis has been 30 to 50%, a statistic that has remained unchanged for decades.

Duplication duodénale révélée par une pancréatite aiguë

Duodenal duplications are rare congenital malformations whose revealing signs are highly variable and nonspecific. We report the case of a female infant who presented with neonatal acute pancreatitis complicated by recurrent ascites, profound hypoalbuminemia responsible for pleural and pericardial effusions, revealing a duodenal duplication cyst. The unusual and original clinical presentation as well as the difficulty detecting the duplication radiologically delayed the diagnosis. A prolonged medical treatment with octreotide, albumin infusions, and exclusive parenteral nutrition led to an almost total disappearance of the ascites before surgery. The outcome was favorable after surgical removal of the duplication with 1year of follow-up. The diagnosis of duodenal duplication can be difficult and it may be necessary to repeat the ultrasound examinations. Surgical resection is delicate, especially when there is an abundant pancreatic ascites. Therefore, an adequate prolonged medical treatment to reduce this ascites is recommended before the surgery.

Translational aspects of chronic pancreatitis

Intrapancreatic activation of proteases is believed to play a major role in the pathogenesis of acute necrotizing pancreatitis. Several authors have questioned, however, the central role of trypsin in autodigestion of the pancreas. To clarify the direct effects of pancreatic enzymes and other related factors on acinar cells, we used the model of isolated pancreatic acini. Acini were prepared from male Wistar rats by collagenase digestion. Protein synthesis was measured by incubation of acini with [35S]methionine. Acini were resuspended thereafter in fresh buffer and further incubated for 30–90 min under various conditions [e.g., with pancreatic homogenates, ascites (from rats with pancreatitis induced by sodium taurocholate), pure pancreatic enzymes, and other factors]. The percentage of release of newly synthesized proteins into the culture medium was regarded as a biochemical parameter of cellular integrity. A morphologic score of cellular integrity was obtained via light microscopic evaluation of acini at the end of the various incubations by measuring the degree of cell lysis, loss of cell granules, ballooning, formation of vacuoles, and karyopyknosis. When normal [35S]methionine-labeled pancreatic acini were incubated with various factors, the percentage of release of labeled proteins into the medium was as follows: incubation with HEPES/Ringer's buffer, 1.8%; hemorrhagic pancreatic ascites, 3.8%; pancreatic homogenates, 2.0%; lipase, 1.8%; phospholipase A2, 3.0%; phospholipase A2 + lecithin, 3.2%; trypsin, 2.5%; 5% olive oil, 1.8%; ascites + olive oil, 78.3%; ascites + homogenized epididymal fat, 79.9%; lipase + olive oil, 32.0%; pancreatic homogenates + olive oil, 28.0%; diolein, 2.65%; and oleic acid, 62.9%. The cellular release of radiolabeled proteins showed an inverse correlation with cellular integrity as shown by light microscopy. We postulate that interstitial release of degradation products from triglycerides by lipase causes cellular disruption. Whereas phospholipase A2 and proteases do not seem to be very harmful in the early phases of cellular damage, lipase may play a major role in acute necrotizing pancreatitis.

A case of chronic pancreatitis with difficult control of persistent pancreatic ascites

A case of chronic pancreatitis with difficult control of persistent pancreatic ascites

Internal pancreatic fistulas (pancreatic ascites, effusion) – an algorithmic approach and comparison of treatment options: experience from a tertiary care center

Internal pancreatic fistulas (pancreatic ascites, effusion) – an algorithmic approach and comparison of treatment options: experience from a tertiary care center

Internal pancreatic fistulas (pancreatic ascites, pleural effusion) – experience from a tertiary care center

Internal pancreatic fistulas (pancreatic ascites, pleural effusion) – experience from a tertiary care center

Primary early surgical management of pancreatic ascites(Pa) in chronic pancreatitis – a single centre experience

Primary early surgical management of pancreatic ascites(Pa) in chronic pancreatitis – a single centre experience

Laparoscopic “Step-up” approach for treatment of pancreatic ascites

Laparoscopic “Step-up” approach for treatment of pancreatic ascites

Unexplained ascites.

Unexplained ascites.

Hemosuccus pancreaticus due to a tumor hemorrhage treated with a self-expandable metallic stent in a patient with unresectable pancreatic carcinoma

A 79-year-old man was referred to our hospital with severe nemia. Laboratory data showed a hemoglobin level of 6.9 mg/dL. pper GI endoscopy showed hemorrhage from the papilla of Vater Fig. 1A). Computed tomography (CT) revealed a solid tumor in the ancreatic head, dilatation of the main pancreatic duct, liver metasasis and ascites (Fig. 1B). The celiac trunk, superior mesenteric rtery, and common hepatic artery were constricted by tumor invaion. Neither a pseudoaneurysm nor pseudocyst was apparent, and hus we diagnosed hemosuccus pancreaticus due to tumor hemrrhage. On endoscopic retrograde cholangiopancreatography, the ancreatic duct of the head was constricted. A plastic stent was laced to press upon the tumor to stop the hemorrhage, but this ailed.

Contrast-enhanced computed tomography – an effective tool in identifying pancreatic duct disruption in acute pancreatitis: A case series

Pancreatic duct disruption may follow acute pancreatitis, chronic pancreatitis, pancreatic surgery, and trauma. Diagnosis in these patients is usually made by endoscopic retrograde cholangiopancreaticogram or secretin-stimulated magnetic resonance cholangiopancreaticogram. We report five cases where pancreatic duct disruption was diagnosed by contrast-enhanced computed tomography (CECT). Five patients with acute pancreatitis were studied; three were secondary to alcohol and two were posttraumatic. Three patients developed pancreatic ascites, one developed pancreatico-pleural effusion, and the other had pancreatic pseudocyst. CECT of the abdomen revealed pancreatic ductal injury in all the patients. In one patient with pancreatic ascites, multiple peripancreatic collections and dilated and disrupted pancreatic duct communicating with the peritoneal cavity were noted. The patient of traumatic pancreatitis had a fracture of the head of the pancreas, with peripancreatic collection communicating with the main pancreatic duct (MPD). In the other traumatic pancreatitis, there was a pseudocyst near the head of pancreas communicating with the MPD. CECT can provide a comprehensive assessment in acute pancreatitis including duct integrity, type and location of pancreatic ductal injury and can be an effective noninvasive alternative imaging modality in diagnosing pancreatic duct disruption.

Gastroduodenal Artery Pseudoaneurysm Causing Hemosuccus Pancreaticus

Patient is a 66 year old male with an extensive past medical history including chronic pancreatitis secondary to alcohol abuse and chronic portal vein/SMV thrombus with CT scan for abdominal pain in October 2014 revealing for a pancreatic mass. Subsequent MRI revealed a pseudoaneurysm in the pancreatic head, and patient underwent gastroduodenal artery embolization by IR. In January 2015, patient was readmitted with severe epigastric abdominal pain. He was noted to have elevated amylase and lipase with hemoglobin of 5. Abdominal exam on admission revealed a distended abdomen with positive fluid wave. No peritoneal signs were present. Repeat CT scan revealed new large volume ascites with evidence of hemoperitoneum. Given the history of previous GDA aneurysm, IR angiography was pursued which revealed no evidence of extravasation from previous pseudoaneurysm. Peritoneal catheter was placed for symptomatic relief revealing dark serosanguinous fluid with fluid analysis revealing >100,000 RBCs, 535 WBC (33% PMN) suggestive of hemoperitoneum with no bacterial peritonitis. Repeat fluid analysis revealed amylase >99,000 suggestive of pancreatic ascites, which raised concern for possible pancreatic duct disruption. ERCP was subsequently performed, and pancreatogram revealed an ansa deformity of the ventral pancreatic duct with a very narrow ductal connection between the ventral and dorsal duct, consistent with incomplete pancreatic divisum. Only the proximal dorsal duct could be visualized revealing a filling defect, however, upstream duct could not be filled likely due to partial divisum and ductal obstruction. At that point, we elected for EUS guided access to better evaluate the dorsal pancreatic duct for leak. EUS revealed a fluid collection adjacent to the pancreatic head representing residual GDA pseudoaneursym with pancreatic duct dilation to 4mm starting at the neck. A 25 gauge needle was used to access the dorsal duct, and 20 cc of maroon colored fluid consistent with old blood was aspirated until clear fluid was noted. Pancreatogram of the dorsal duct revealed beaded appearance of the dorsal pancreatic duct with dilated side branches, likely due to partial pancreatic duct obstruction by clot from partial communication with GDA pseudoaneurysm. Stent placement to facilitate pancreatic drainage and prevent further obstruction from hemosuccus pancreaticus was not technically possible in setting of incomplete divisum. During the course of admission, patient was also diagnosed with a DVT, and an IVC filter was placed. Anticoagulation was deferred given concern for recurrent hemoperitoneum and pancreatic duct obstruction.This is the first reported case of a GDA aneurysm with pancreatic ductal communication resulting in hemosuccus pancreaticus, and this should be considered in the differential for gastrointestinal bleeding in these patients.Figure 1Figure 2

Abstract 293: Therapeutic effects of the bromodomain inhibitors JQ1 and I-BET 762 on pancreatic cancer

Abstract Pancreatic cancer is expected to be the second most deadly cancer by 2030 with very few effective therapeutic options to improve patient survival. Bromodomain inhibitors (JQ1 and I-BET 762) are a new generation of chemotherapeutic drugs that target BET proteins, impairing their ability to bind to acetyl modified lysines and therefore interfering with transcriptional initiation and elongation. BET proteins regulate several genes responsible for cell cycle, apoptosis and inflammation. I-BET 762 is currently in clinical trials for cancer and has the advantage of oral administration. Kras is one of the most common mutated genes in pancreatic cancer (90%); however its protein is a difficult drug target. p-Erk, responsible for several pathways regulating cell survival, is a downstream effector of Kras that has been shown to be essential for the progression and maintenance of pancreatic cancer. LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre (KPC) and LSL-KrasG12D/+;Pdx-1-Cre (KC) mouse models are commonly used to study pancreatic cancer. KPC mice develop the full spectrum of pancreatic cancer by an average age of 20 weeks. The KC mouse model is commonly used to study pancreatic cancer progression after stimulation with a pancreatic inflammatory agent, such as cerulein. JQ1 and I-BET 762 reduce the protein levels of p-ERK 1/2 in cells lines derived from a pancreatic tumor or ascites of KPC animals. JQ1 and I-BET 762 are also effective at inhibiting cell growth in human pancreatic cells harboring Kras mutations. When KC mice are injected with LPS to induce inflammation and pancreatitis, p-ERK 1/2 protein levels are significantly increased. This model is being used to test the effects of JQ1 and I-BET 762 after a single LPS injection, in KC mice. Pancreatic cancer is driven by several cytokines and chemokines, including CCL2 and IL-6, which recruit and regulate the inflammatory cells (macrophages, T cells and MDSC (Myeloid derived suppressor cells) cells) in the tumor. Levels of IL-6 and CCL2 in cell lines developed from KPC mice are reduced when treated with JQ1 and I-BET 762. KC mice stimulated with LPS also have higher levels of CCL2 and IL-6 than mice stimulated with saline. In conclusion this study showed that the bromodomain inhibitors JQ1 and I-BET 762 had positive effects in suppressing targets of inflammation in pancreatic cancer. We thank James Bradner for the generous gift of JQ1. Citation Format: Ana S. Leal, Charlotte R. Williams, Michael B. Sporn, Karen T. Liby. Therapeutic effects of the bromodomain inhibitors JQ1 and I-BET 762 on pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 293. doi:10.1158/1538-7445.AM2015-293