Catastrophic antiphospholipid syndrome (CAPS)-induced ischemic pancreatic ducts injury mimicking intraductal papillary mucinous neoplasm (IPMN).

OBJECTIVES: Catastrophic antiphospholipid syndrome (CAPS) is a life-threatening disease characterized by multiple small-vessel occlusions of rapid onset. Ischemic pancreatic duct lesions secondary to CAPS have never been reported. METHODS: We describe 4 patients who presented lesions suspected to be intraductal papillary mucinous neoplasm (IPMN) of the pancreas following a CAPS. RESULTS: All patients had a history of CAPS months or years before the IPMN diagnosis. They had abdominal pain or abnormal liver test results and had undergone radiography. In a 36-year-old man, endoscopic ultrasonography and magnetic resonance cholangiopancreatography demonstrated parietal thickening, stenoses and dilatations of the main pancreatic duct, which suggested IPMN. A pancreatic resection was performed because of presumed risk of malignancy. Histology revealed pancreatitis and thrombosis of small pancreatic vessels but no IPMN. The 3 other cases had lesions consistent with IPMN disclosed on MRI. From the first case experience, regular radiography surveillance was decided for the 3 other patients. After more than 4 years of follow-up, lesions remained unchanged. CONCLUSION: Physicians must be aware that these lesions may be encountered in CAPS and may closely mimic IPMN, with subsequent risk of performing unnecessary pancreatectomy.

Locally advanced pancreatic duct adenocarcinoma: pancreatectomy with planned arterial resection based on axial arterial encasement.

Pancreatectomy with arterial resection for locally advanced pancreatic duct adenocarcinoma (PDA) is associated with high morbidity and is thus considered as a contraindication. The aim of our study was to report our experience of pancreatectomy with planned arterial resection for locally advanced PDA based on specific selection criteria. MATERIAL AND METHODS: All patients receiving pancreatectomy for PDA between October 2008 and July 2014 were reviewed. The patients were classified into group 1, pancreatectomy without vascular resection (66 patients); group 2, pancreatectomy with isolated venous resection (31 patients), and group 3, pancreatectomy with arterial resection for locally advanced PDA (14 patients). The primary selection criteria for arterial resection was the possibility of achieving a complete resection based on the extent of axial encasement, the absence of tumor invasion at the origin of celiac trunk (CT) and superior mesenteric artery (SMA), and a free distal arterial segment allowing reconstruction. Patient outcomes and survival were analyzed. RESULTS: Six SMA, two CT, four common hepatic artery, and two replaced right hepatic artery resections were undertaken. The preferred arterial reconstruction was splenic artery transposition. Group 3 had a higher preoperative weight loss, a longer operative time, and a higher incidence of intraoperative blood transfusion. Ninety-day mortality occurred in three patients in groups 1 and 2. There were no statistically significant differences in the incidence, grade, and type of complications in the three groups. Postoperative pancreatic fistula and postpancreatectomy hemorrhage were also comparable. In group 3, none had arterial wall invasion and nine patients had recurrence (seven metastatic and two loco-regional). Survival and disease-free survival were comparable between groups. CONCLUSION: Planned arterial resection for PDA can be performed safely with a good outcome in highly selected patients. Key elements for defining the resectability is based on the extent of the axial arterial encasement with two criteria: the origin of the CT and SMA are free from tumor invasion and the possibility of distal reconstruction.

Imaging and Endoscopic Approaches to Pancreatic Cancer.

Imaging and endoscopy both play important and complementary roles in the initial diagnosis, staging, monitoring, and symptomatic management of pancreatic cancer. This article provides an overview of the uses of each of the diagnostic modalities, common imaging findings, alternative considerations, and areas of ongoing work in diagnostic imaging. This article also provides details of the uses of endoscopy for diagnosis, staging, and intervention throughout the course of a patient's care. These modalities each play important roles in the complex multidisciplinary care of patients with pancreatic cancer.

Key contribution of CPEB4-mediated translational control to cancer progression.

Malignant transformation, invasion and angiogenesis rely on the coordinated reprogramming of gene expression in the cells from which the tumor originated. Although deregulated gene expression has been extensively studied at genomic and epigenetic scales, the contribution of the regulation of mRNA-specific translation to this reprogramming is not well understood. Here we show that cytoplasmic polyadenylation element binding protein 4 (CPEB4), an RNA binding protein that mediates meiotic mRNA cytoplasmic polyadenylation and translation, is overexpressed in pancreatic ductal adenocarcinomas and glioblastomas, where it supports tumor growth, vascularization and invasion. We also show that, in pancreatic tumors, the pro-oncogenic functions of CPEB4 originate in the translational activation of mRNAs that are silenced in normal tissue, including the mRNA of tissue plasminogen activator, a key contributor to pancreatic ductal adenocarcinoma malignancy. Taken together, our results document a key role for post-transcriptional gene regulation in tumor development and describe a detailed mechanism for gene expression reprogramming underlying malignant tumor progression.

Interstitial cells of Cajal: pacemaker cells of the pancreatic duct?

OBJECTIVES: Ramon y Cajal discovered interstitial cells in the pancreas associated with intrinsic nerves. It was our aim to provide evidence for or against the hypothesis that the pancreatic duct harbors interstitial cells of Cajal (ICCs) that may function as pacemakers for duct motility. METHODS: We used immunohistochemistry using c-Kit as the ICC marker and protein gene product 9.5 for nerves. Electron microscopy further characterized the cells and their interrelationships. RESULTS: c-Kit-positive cells were associated with smooth muscle cells and nerve fibers of the duct wall and were rich in mitochondria, rough endoplasmic reticulum, and intermediate filaments; they possessed occasional caveolae and had a discontinuous basal lamina. They were connected by small gap junctions to each other and to smooth muscle cells. c-Kit-positive cells around large blood vessels were similar. c-Kit-positive cells within acini were similar in structure but were not associated with smooth muscle cells. CONCLUSIONS: The c-Kit-positive cells around the main duct were identified as ICCs and have the morphological criteria to likely function as pacemaker cells for the previously observed spontaneous rhythmic pancreatic duct contractions. Interstitial cells of Cajal around the large blood vessels likely affect vessel wall rhythmicity.

Nonclosure technique with saline-coupled bipolar electrocautery in management of the cut surface after distal pancreatectomy.

BACKGROUND/PURPOSE: Management of the pancreatic remnant after distal pancreatectomy is still debated, the most serious complication is development of a pancreatic fistula. We developed a nonclosure technique with saline-coupled bipolar electrocautery for preventing fistula formation after distal pancreatectomy as an alternative to traditional stump closure methods. METHODS: The distinguishing feature of this technique is nonclosure of the stump, relying instead upon dependable ligation of the main pancreatic duct and sealing of the cut surface by shrinkage accomplished by low-temperature coagulation using saline-coupled bipolar electrocautery. A recent addition has been intraoperative stenting of the remnant pancreatic duct. RESULTS: To date we have used the nonclosure technique in 40 cases, among which 5 (12.5%) developed fistulas: 4 in the nonstenting subgroup (14.8%) and 1 in the stenting subgroup (7.7%). According to a recent classification, 4 fistulas were considered grade A; 1, grade B; and 0, grade C. The grade B patient did not undergo stenting. CONCLUSION: Our preliminary experience should prompt more widespread evaluation of the nonclosure technique.

Multiple-detector computed tomographic angiography of pancreatic neoplasm for presurgical planning: comparison of low- and high-concentration nonionic contrast media.

OBJECTIVE: To evaluate the degree of contrast enhancement, image quality, and accuracy of predicting resectability of pancreatic neoplasm with 16-row multiple-detector computed tomography (MDCT) angiography using low- and high-concentration (300 and 370 mg of iodine per milliliter, respectively) contrast media (CMs). MATERIALS AND METHODS: Forty patients who had undergone pancreatic CT angiography (CTA) on 16-MDCT scanner and had surgery were included. Contrast medium of 2 iodine concentrations (group A, 300 mg/mL, n = 20; group B, 370 mg/mL, n = 20) from the same vendor (Isovue; Bracco Diagnostics), with iodine dose of 550 to 600 mg/kg of body weight, was injected at a rate of 5 mL/s. Dual-phase 16-row MDCT was performed using 1.25- and 5-mm collimation for the arterial and portal phases, respectively. For the quantitative analysis, Hounsfield units values in the aorta, superior mesenteric artery, portal vein, and pancreas during arterial and venous phases were measured. Two readers subjectively rated the overall image enhancement, 3-dimensional image quality, and lesion and pancreatic duct conspicuity. Accuracy of lesion resectability was also established for each patient. The data were compared using Student t test for statistical analysis. RESULTS: The quantitative analysis for the degree of enhancement (Hounsfield unit) of the aorta, superior mesenteric artery, and pancreas during the arterial phase demonstrated similar values in groups A (low-concentration CM) and B (high-concentration CM), with no statistically significant difference with each other (P > 0.05). During the portal venous phase, we found superior enhancements in the superior mesenteric and portal veins in group A (P < 0.05). The qualitative assessments of the overall image enhancement and 3-dimensional image quality on a 5-point scale were 4.3 and 4.65, respectively (P < 0.05), in group A and 4.6 and 4.75, respectively, in group B, whereas on a 3-point scale, the pancreatic duct display and lesion conspicuity were 2.75 and 2.85, respectively, in group A and 2.9 and 2.9, respectively, in group B. The accuracy for lesion resectability was 95% (19/20) in group A and 100% (20/20) in group B (P > 0.05). CONCLUSION: Both CMs demonstrated comparable performance for 16-row MDCT of the pancreas for presurgical planning. However, high-concentration CM (370 mg of iodine per milliliter) provides higher overall enhancement and superior-quality 3-dimensional images with a shorter injection duration.

Morphometric microvascular characteristics in the prognosis of pancreatic and ampullary carcinoma.

OBJECTIVES: To evaluate multiple morphometric microvascular characteristics in addition to microvascular density (MVD) in pancreatic ductal and ampullary adenocarcinomas and provide a better approach in examining the relationship among angiogenesis, several clinicopathologic parameters, and prognosis. METHODS: Histological sections from 32 pancreatic ductal and 17 ampullary adenocarcinomas, immunostained with CD34, were evaluated by image analysis for the quantification of MVD, total vascular area, and microvascular branching, as well as several morphometric parameters related to the vessel size and shape factor. RESULTS: In pancreatic ductal carcinoma, higher levels of MVD, total vascular area, branching, and shape factor were related to N1 tumors. Moreover, MVD, shape factor, and minor axis length were identified as independent prognostic factors of survival. In the ampullary carcinoma group, higher shape factor values were observed in well-differentiated tumors. CONCLUSIONS: In pancreatic ductal carcinoma patients, the assessment of MVD and several morphometric microvascular characteristics provides significant prognostic information. The biologic behavior of the ampullary carcinomas does not seem to be dependent on any of the above mentioned factors of angiogenesis.

Influence of nitric oxide-donating nonsteroidal anti-inflammatory drugs on the evolution of acute pancreatitis.

Microcirculatory disturbances and leukocyte activation are main events in the pathogenesis of acute pancreatitis (AP) that is characterized by inflammatory up-regulation. Nitric oxide-donating nonsteroidal anti-inflammatory drugs (NO-NSAIDs) regulate vascular function and mitigate inflammation. To investigate the influence of NO-NSAIDs on AP. AP was induced by the biliopancreatic duct outlet exclusion-closed duodenal loops model. Treatment with NO-flurbiprofen, NO-ibuprofen, NO-aspirin, or their parental drugs was done (i) 1 h before, (ii) 1 h after, (iii) 1 h before and 4 h after, or (iv) 4 h after surgery. The degree of severity was evaluated using biochemical and histopathological analyses. NO-NSAIDs given before and during the first hour of the noxia decreased blood levels of amylase, lipase, C-reactive protein, IL-6, IL-10, heat shock protein 72, prostaglandin E2 inactive metabolite, and 8-isoprostane, as well as pancreatic and lung myeloperoxidase and cyclooxygenase. Acinar and fat necrosis, hemorrhage, and leukocyte infiltrate were also reduced. The best protection was achieved when treatment was performed 1 h before and 4 h after triggering AP. NO-flurbiprofen was the most effective drug. AP severity was significantly ameliorated by NO-NSAIDs being the administration time essential to achieve optimal pancreatic protection that may result to be useful in the prevention of postendoscopic severe AP.

Focal changes of chronic pancreatitis and duct-arteriovenous relationships: avoiding a diagnostic pitfall.

A prior study of pancreatic duct-arteriovenous relationships suggested that finding ducts near muscularized blood vessels without intervening pancreatic acini indicated adenocarcinoma was present. Because focal changes of chronic pancreatitis are often seen at autopsy, it seemed reasonable to use the autopsy to test the hypothesis that this finding might be nonspecific. An unselected, consecutive series of 81 adult decedent pancreases without known pancreas cancer was evaluated for the presence of ducts near muscularized blood vessels, for fibrosis and/or atrophy, for chronic inflammation, and for duct reduplication and/or proliferation. Autolysis precluded assessment of 26% of the cases. Of evaluable cases, 37% displayed ducts near muscularized blood vessels without intervening pancreatic acini, 23% chronic inflammation, 62% fibrosis and/or atrophy, and 55% duct reduplication and/or proliferation. The finding of ducts near muscularized blood vessels was closely associated with fibrosis and/or atrophy (odds ratio = 28.87, chi = 14.59, P = 0.0001), with duct reduplication and/or proliferation (odds ratio = 19.23, chi = 15.88, P = 0.0001), but not with chronic inflammation (odds ratio = 1.41, chi = 0.05, P > 0.30). Because changes of chronic pancreatitis are associated with ducts near muscularized blood vessels and because chronic pancreatitis can mimic pancreas cancer, care should be exercised when using the finding of ducts near muscularized blood vessels without intervening pancreatic acini as a criterion for the diagnosis of pancreas cancer.

The pancreatic duct and its arteriovenous relationship: an underutilized aid in the diagnosis and distinction of pancreatic adenocarcinoma from pancreatic intraepithelial neoplasia. A study of 126 pancreatectomy specimens.

Pancreatic intraepithelial neoplasia (PanIN) may be difficult to differentiate from isolated glands of pancreatic adenocarcinoma. We studied the normal relationship between the pancreatic ducts and the pancreatic muscular blood vessels in 126 pancreata, 64 of which were removed for pancreatic adenocarcinoma and 62 for other diagnoses. We also examined the effects that atrophy and PanIN have on this relationship. In normal pancreatic parenchyma and in mild to moderate atrophy, blood vessels are guideposts of the interlobular space. The pancreatic acinar parenchyma ensheathes the pancreatic ductal system and separates it from the muscular pancreatic vasculature. Since these blood vessels do not accompany the pancreatic ducts, the presence of a well-differentiated duct-like structure, which may resemble PanIN, located adjacent to a pancreatic blood vessel should be a clue to the infiltrative and hence malignant nature of that gland. Ducts showing PanIN appear to resist atrophy. Since lobular outlines and vascular landmarks are ultimately lost in severe atrophy, they cannot be relied on to aid in the distinction between PanIN and invasive carcinoma. However, it is unusual to see PanIN1 in such severe atrophy (2%), and although the normal vascular landmarks are no longer there to aid in the interpretation, the presence of well-differentiated duct-like structures resembling PanIN1 in this background should be viewed with suspicion for well-differentiated adenocarcinoma.

[Anatomical and surgical considerations concerning the segmentation of the pancreas]. / Consideratii asupra segmentatiei anatomo-chirurgicale a pancreasului.

Pancreatic vascularization, especially the right segment (the head of the pancreas) has great surgical importance, due to its anatomical variety. From this practical point of view, establishing the type of the patient's pancreatic vascular pattern is highly recommended not just diagnosis purposes, but especially for its indispensable role in surgical decision. Selecting the appropriate technique, based on the imagistic evidences must consider the anatomical studies, which propose a systematic vision of the cephalic area vascularization, detecting two major types of arterial distribution. The first type is especially anastomotic; meanwhile the second one is terminal, these two varieties leading to a different surgical technique, best adapted for avoiding hemorrhages or ischemic necroses. Between the classic two segments of the pancreas (cephalic and caudal parts) there is a less vascularized area, which includes just an intersegmentary artery and the pancreatic duct, surgically sectioned during the separation operation of the two pancreatic segments. Vascular variety of the pancreas may be related to both embryological development of the pancreatic tissue, and that of the abdominal aortic branches.

Blood supply to the duodenal papilla and the communicating artery between the anterior and posterior pancreaticoduodenal arterial arcades.

The communicating artery (ComA) between the anterior and posterior pancreaticoduodenal arterial arcades is little understood, although it has been described several times during the past 100 years. In 44 of 51 cadaveric specimens in the present study, the typical ComA was observed to pass between the major and accessory pancreatic ducts. In addition, a second ComA was sometimes found crossing inferior to the major pancreatic duct. The typical ComAs often (36 of the 44) issued papillary branch(es). Although direct papillary branches of the posterior arcade were often observed to either coexist with (9 specimens) or exist independently (4 specimens), the ComA-derived branch seemed to be critical for papillary blood supply, because of its shorter length, greater thickness, and higher frequency. Moreover, the typical ComA could be a good landmark during limited pancreatic resection, such as duodenum-preserving subtotal resection of the pancreatic head or pancreatic segment resection, because the artery is likely to be an indicator of the borders between the celiac and superior mesenteric arterial territories, as well as those between the ventral and dorsal segments of the pancreas.

Pancreatoscopy for the next generation: development of the peroral electronic pancreatoscope system.

BACKGROUND: To improve visualization of the pancreatic duct with a pancreatoscope, we have developed the smallest known electronic endoscope, that is, the peroral electronic pancreatoscope. METHODS: This instrument (2.1 mm, external diameter) was developed with a 50k-pixel interline charge coupled device. A peroral fiberoptic pancreatoscope was used as control, connected to a video converter. The visibility of both systems was studied with a test chart. The model pancreatic duct, the oral mucosa, and the pancreatic ducts of a healthy control subject and patients with chronic pancreatitis were examined with both systems. RESULTS: The smallest visible interval (with a 5 mm distance between the object and the distal end of the endoscope) was 0.07 mm with the peroral electronic pancreatoscope and 0.2 mm with the peroral fiberoptic pancreatoscope. The electronic instrument produced better images of the model pancreatic duct than the fiberoptic endoscope. A clear image of the small vessels of the oral mucosa was obtained with the electronic but not with the fiberoptic instrument. The fine vessel network of the pancreatic duct was visualized only with the electronic instrument; pancreatic duct stones and rough-surfaced pancreatic duct were shown more precisely with the electronic endoscope. CONCLUSIONS: The peroral electronic pancreatoscope provides images of the fine detail of the pancreatic duct and will contribute to the diagnosis of pancreatic diseases.

Morphology of the pancreatic duct system in mammals.

The morphology of pancreatic excretory duct segments was reviewed in mammals. The fine structure of the epithelial lining was described in intercalated ducts, intra- and extralobular ducts, and in major pancreatic ducts. Morphological characteristics of the various cell types comprising to the duct epithelium were detailed. Principal cells in the epithelial linings of interlobular and major pancreatic ducts ("Wirsungiocytes") were discussed with respect to their appearance as either clear or dark variety. In addition, the capacity of both these cell types in elaborating mucoid glycoprotein, secretions was considered and intra- and extraepithelial mucoid glands of major pancreatic ducts (ductular glands, accessory glands) was described. Finally, the wall composition of the various excretory duct segments was described. The presence of smooth muscle cells, myofibroblasts, and a peculiar periductal vascular plexus in major interlobular ducts and in main pancreatic ducts was emphasized.

Angioarchitecture of the atrophic pancreas.

The pancreas has a complex vasculature which comprises both exocrine and endocrine structures. Copper deficiency induces highly selective acinar cell degeneration and progressive noninflammatory lipomatosis in pancreas while Langerhans islets, ducts, and nerves remain unaffected. Pancreatic vasculature was examined in rats that had dietary copper deficiency to characterize changes in the angioarchitecture of the gland. This model was used to assess the degree to which the vasculature of non-acinar components of the gland are potentially altered under conditions of exocrine atrophy. Ultrastructure of pancreas was examined by histology, enzyme histochemistry and immunohistochemistry, corrosion casting and scanning electron microscopy, in situ vascular staining, microsphere injection, biochemical analysis, and morphometry in copper-deficient rats. Results show that no acute angiopathic changes indicative of vascular disorganization accompany atrophy. Only a reduction in the complexity of the capillary beds, which normally vascularize the dense acinar parenchyma, was found. Microsphere quantitation also showed that blood flow to the lipomatous gland remains intact. Furthermore, analysis of the angioarchitecture of the atrophied pancreas supports a largely autonomous blood supply to islets and ducts. These observations support the hypothesis that while the vasculature of the atrophied gland is modified in vascular regions severely targeted by acinar necrosis, the overall structural features of the angioarchitecture are preserved. The atrophied gland thus provides an experimental model to study the vascular routes supplying islet and ductal blood flow within the complex pancreatic circulation.

Pathological changes in pancreatic ducts from patients with chronic pancreatitis.

CONCLUSION: Chronic pancreatitis and restricted pancreatic outflow are accompanied by pathological changes in the ducts, including inflammation and alterations in the microvasculature. These changes and loss of epithelium provide a likely explanation for increased release of serum proteins, immunoglobulins, and lactoferrin into the juice, and the possibility of luminal contents entering the extracellular space and bloodstream. BACKGROUND: Enlargement of pancreatic ducts is a well-known phenomenon accompanying chronic pancreatitis and conditions restricting outflow of pancreatic juice. However, the relationship between ductal pathology and concomitant changes in the pancreatic juice is incompletely understood. METHODS: Segments of pancreatic ducts removed at surgery from patients with chronic pancreatitis and conditions restricting outflow were studied by light and electron microscopy to assess the pathological changes. RESULTS: Pathological changes in ducts from patients with chronic pancreatitis include chronic inflammation in the wall, enlarged and numerous capillaries packed with erythrocytes and leukocytes close to the lumen, and loss of epithelium and sometimes basement membrane. Plasma cells provide a source for increased immunoglobulins. Ducts from patients with diseases restricting outflow show significant pathology.

Ductal vasculature in the atrophic pancreas: evidence for autonomous ductal angioarchitecture.

Although it is known that ducts remain intact in the atrophied pancreata of rats rendered dietarily copper-deficient, no information is available that characterizes the ductal angioarchitecture of the experimentally altered gland. Furthermore, since the vascular relationship between pancreatic ducts and the parenchyma of the normal gland has not been well defined, this atrophy model was used to examine blood flow to ducts in the atrophied gland where acinar tissue undergoes selective necrosis. Scanning electron microscopy (SEM) of pancreatic corrosion casts produced from Mercox-injected rats was used. SEM was compared with light microscopic study of stain-injected cleared pancreata and correlated with histological and ultrastructural studies. The results indicate that duct cells and ductal vasculature remain unaffected by surrounding acinar cell necrosis and glandular lipomatous atrophy. Furthermore, the results support a largely autonomous blood supply for the ductal system by arterial blood that flows directly from major extralobular arteries of the pancreas or their interlobular branches. In the same manner, venous blood draining the ductal system returns to major extralobular veins or by way of their interlobular branches. No evidence could be established for manifest acinoductal or ductoacinar portal systems. There were, however, places in the route of both ductal and acinar vessels where the vessels were found to anastomose. These places were found near the source of major arteries or veins that supply and drain confluent acinar and ductal tissues. It is concluded that, while some acinoductal or ductoacinar exchange may take place, the role of these putative portal systems would appear less significant than the direct route of blood to and from pancreatic ducts.

Hemoductal pancreatitis.

A case of gastrointestinal hemorrhage from a splenic artery pseudoaneurysm secondary to chronic pancreatitis with bleeding into the pancreatic duct is reported. This rare phenomenon known as hemoductal pancreatitis represents a diagnostic dilemma since bleeding is intermittent and the source of hemorrhage may not be appreciated at either angiography or surgery.