Pancreatic stellate cells – Multi-functional cells in the pancreas

There is accumulating evidence that activated pancreatic stellate cells (PSCs) play a pivotal role in pancreatic fibrosis in chronic pancreatitis and pancreatic cancer. In addition, we have seen great progress in our understanding of the cell biology of PSCs and the interactions between PSCs and other cell types in the pancreas. In response to pancreatic injury or inflammation, quiescent PSCs are activated to myofibroblast-like cells. Recent studies have shown that the activation of intracellular signaling pathways such as mitogen-activated protein kinases plays a role in the activation of PSCs. microRNAs might also play a role, because the microRNA expression profiles are dramatically altered in the process of activation. In addition to producing extracellular matrix components such as type I collagen, PSCs have a wide variety of cell functions related to local immunity, inflammation, angiogenesis, and exocrine and endocrine functions in the pancreas. From this point of view, the interactions between PSCs and other cell types such as pancreatic exocrine cells, endocrine cells, and cancer cells have attracted increasing attention of researchers. PSCs might regulate exocrine functions in the pancreas through the cholecystokinin-induced release of acetylcholine. PSCs induce apoptosis and decrease insulin expression in β-cells, suggesting a novel mechanism of diabetes in diseased pancreas. PSCs promote the progression of pancreatic cancer by multiple mechanisms. Recent studies have shown that PSCs induce epithelial–mesenchymal transition and enhance the stem-cell like features of pancreatic cancer cells. In conclusion, PSCs should now be recognized as not only profibrogenic cells but as multi-functional cells in the pancreas.     

Liver and pancreas: ‘Castor and Pollux’ regarding the relationship between hepatic steatosis and pancreas exocrine insufficiency

BackgroundPancreatic exocrine insufficiency (PEI) is found in 30–50% of diabetes mellitus (DM). Insulin resistance is triggering factor in both DM and nonalcoholic fatty liver disease (NAFLD). Therefore, we aimed to investigate frequency of PEI in NAFLD, and relationship of fecal pancreatic elastase (PE) levels with liver histology and pancreatic fat.MethodsNinety-seven biopsy proven NAFLD patients and 50 controls were enrolled. Pancreas exocrine functions were measured by PE. Magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF) was used to quantify fat.ResultsNAFLD patients had significantly lower PE levels than controls (297 [204–517] vs. 500 [298–678] μg/g, p < 0.01). PEI (PE < 200 μg/g) ratio of NAFLD patients (22.7%, n = 22) was higher than PEI ratio of controls (6%, n = 3) (p = 0.011). Among diabetic (n = 35) NAFLD patients, 9 (25.7%) exhibited PEI, compared to 13 (21%) of non-diabetics. There was no significant difference in patients with and without DM in terms of PEI (p = 0.592). Among NASH (n = 68) patients 16 (23.5%) exhibited PEI, compared to (20.7%) of non-NASH (p = 0.76). Multiple analysis revealed NAFLD as a predictor of PEI independent of age, sex and DM (OR = 4.892, p = 0,021). Mean pancreas MRI-PDFF was significantly higher in diabetics (13.7% ± 3.6% vs. 8.7% ± 5.1%, p = 0.001). There was no significant pancreas MRI-PDFF difference between NASH and non-NASH (P = 0.95). Mean pancreas MRI-PDFF was significantly higher in patients with PEI (13.7% ± 3.4% vs. 8.9% ± 5.2%, P < 0.01).ConclusionThis is the first study demonstrating the high frequency of PEI in NAFLD independent of DM. Moreover, increasing pancreatic steatosis appears to be associated with higher frequency of PEI in NAFLD.     

Pancreatic nociception – Revisiting the physiology and pathophysiology

BackgroundPain management of many pancreatic diseases remains a major clinical concern. This problem reflects our poor understanding of pain signaling from the pancreas.ObjectivesThis review provides an overview of our current knowledge, with emphasis on current pain management strategies and recent experimental findings.MethodsA systematic search of the scientific literature was carried out using EMBASE, PubMed/MEDLINE, and the Cochrane Central Register of Controlled Trials for the years 1965–2011 to obtain access to all publications, especially randomized controlled trials, systematic reviews, and meta-analyses exploring pain and its management in disease states such as acute pancreatitis (AP), chronic pancreatitis (CP) and pancreatic cancer (PC).ResultsOver the last decade, numerous molecular mediators such as nerve growth factor and the transient receptor potential (TRP) cation channel family have been implicated in afferent nerve signaling. More recent animal studies have indicated the location of the receptive fields for the afferent nerves in the pancreas and shown that these are activated by agents including cholecystokinin octapeptide, 5-hydroxytryptamine and bradykinin. Studies with PC specimens have shown that neuro-immune interactions occur and numerous agents including TRP cation channel V1, artemin and fractalkine have been implicated. Experimental studies in the clinical setting have demonstrated impairment of inhibitory pain modulation from supraspinal structures and implicated neuropathic pain mechanisms.ConclusionsOur knowledge in this area remains incomplete. Characterization of the mediators and receptors/ion channels on the sensory nerve terminals are required in order to facilitate the development of new pharmaceutical treatments for AP and CP.     

Diagnosis and treatment of solid-pseudopapillary tumor of the pancreas

BACKGROUND: Solid-pseudopapillary tumor (SPT) of the pancreas is a rare exocrine pancreatic tumor. Despite the increasing recognition of the tumor in recent years, its pathogenesis and apparent therapeutic algorithm remain unclear. This study was designed to define the clinical, imaging, and pathologic features and to improve the diagnosis and treatment of this rare disease. METHOD: The clinical, imaging, and pathologic findings of 9 SPT patients managed in our hospital between 2001 and 2005 were retrospectively analyzed, and related literatures were reviewed. RESULTS: In the 9 patients aged from 14 to 68 years, 8 were female and 1 male. The mean age of these patients at diagnosis was 30 years. Initially, 8 patients complained of vague abdominal pain and one patient had pancreatic mass detected incidentally by abdominal CT. The levels of blood and urine amylase and tumor markers were all within the normal range. B-US, CT and MRI demonstrated that tumors were well encapsulated and contained some degree of internal hemorrhage or cystic degeneration. The mean transverse diameter of these tumors was 5.4 cm (range, 2-10.5 cm). The tumors were located at the head (2 patients), body (2), body and tail junction (4), and tail (1) of the pancreas. Surgical procedures included pancreaticoduodenectomy, distal pancreatectomy, distal pancreatectomy with splenectomy, and enucleation. Histological examination showed solidified cystic areas and papillary protrusions. Two malignant tumors demonstrated retroperitoneal metastases and vascular invasion. Follow-up for 2.5 years on average showed that one patient died of tumor recurrence at 10 months and the rest were alive. CONCLUSIONS: SPT exhibits unique clinical and pathologic features and is readily diagnosed by its characteristic imaging and histological appearance. Surgical resection of the primary tumor and metastases is the treatment of choice.     

Pancreatic regenerating protein (regⅠ) and regⅠreceptor mRNA are upregulated in rat pancreas after induction of acute pancreatitis

AIM: Pancreatic regenerating protein (regⅠ) stimulates pancreatic regeneration after pancreatectomy and is mitogenic to ductal andβ-cells. This suggests that regⅠand its receptor may play a role in recovery after pancreatic injury. We hypothesized that regⅠand its receptor are induced in acute pancreatitis. METHODS: Acute pancreatitis was induced in male Wistar rats by retrograde injection of 3% sodium taurocholate into the pancreatic duct. Pancreata and serum were collected 12, 24, and 36 hours after injection and from normal controls (4 rats/group). RegⅠreceptor mRNA, serum regⅠprotein, and tissue regⅠprotein levels were determined by Northern analysis, enzyme-linked immunosorbent assay (ELISA), and Western analysis, respectively. Immunohistochemistry was used to localize changes in regⅠand its receptor. RESULTS: Serum amylase levels and histology confirmed necrotizing pancreatitis in taurocholate treated rats. There was no statistically significant change in serum regⅠconcentrations from controls. However, Western blot demonstrated increased tissue levels of regⅠat 24 and 36 h. This increase was localized primarily to the acinar cells and the ductal cells by immunohistochemistry. Northern blot demonstrated a significant increase in regⅠreceptor mRNA expression with pancreatitis. Immunohistochemistry localized this increase to the ductal cells, islets, and acinar cells. CONCLUSION: Acute pancreatitis results in increased tissue regⅠprotein levels localized to the acinar and ductal cells, and a parallel threefold induction of regⅠreceptor in the ductal cells, islets, and acinar cells. These changes suggest that induction of reg I and its receptor may be important for recovery from acute pancreatitis.     

Intraductal papillary mucinous neoplasm of the pancreas – epidemiology,risk factors,diagnosis, and management

Intraductal papillary mucinous neoplasm (IPMN) is one of the most common cystic neoplasms of the pancreas. It is a heterogeneous disease and can be divided into ductal types and morphological subtypes. The incidence of IPMN is increasing, likely due to the widespread use of cross-sectional imaging and a growing elderly population. IPMN poses an increasing demand on the health care system. Current guidelines provide indications for surgery and recommendations for surveillance, but management of IPMN is still challenging in routine clinical practice. In this article, we review current knowledge about IPMN and provide future directions for improving diagnosis and management.     

Morphological heterogeneity in ductal adenocarcinoma of the pancreas – Does it matter?

Morphological heterogeneity is a common finding in pancreatic ductal adenocarcinoma. Inter- and intra-tumour heterogeneity relates not only to the microscopic appearances of the tumour cell population, but pertains also to other essential aspects of the cancer, including the grade of differentiation, growth pattern and desmoplastic stroma. While the existence of considerable morphological variation is well known among pathologists, it is usually not fully appreciated by the wider community. Morphological heterogeneity in pancreatic cancer is only partially represented in the WHO classification, and current pathology guidelines do not recommend reporting on morphological variation other than the conventional variants of ductal adenocarcinoma. Although tumour heterogeneity is increasingly recognized as a major determinant of therapeutic response, morphological heterogeneity has been left unconsidered as a possible proxy for underlying aberrations – genomic or otherwise – that determine the effect of treatment. Various aspects of morphological heterogeneity in pancreatic ductal adenocarcinoma are illustrated in this article and discussed along with the possible implications for patient management and research.     

Improved early diagnosis of cystadenocarcinoma of the pancreas

IntroductionT here are great differences between the therapy for cystadenocarcinomas and benign pancreatic lesions. Early diagnosis is propitious to selecting the appropriate therapy, and may directly influence the prognosis.[1-4] Differential diagnosis between cystadenocarcinoma and benign pancreatic lesion is difficult, because they lack typical clinical symptoms in early stage. In the commonly used examinations, the specificity of B-ultrasonography (B-US) and CT is very poor; they are di…     

Solid-pseudopapillary tumor of the pancreas： Clinical experience and literature review

AIM: To evaluate the clinical presentations of solid-pseudopapillary tumor of the pancreas (SPT) and examine the diagnosis, treatment, low grade malignant potential of this rare disease. METHODS: We retrospectively reviewed a series of seven patients with SPT managed in our hospital between July 1990 and October 2003. Six females and one male with mean age of 31 years (range 13 to 50 years) were diagnosed with SPT at our institution. RESULTS: Clinical presentation included a palpable abdominal mass in two patients and vague abdominal discomfort in another two. Two patients were asymptomatic; their tumors were found incidentally on abdominal sonographic examination for other reasons. The final patient was admitted with hemoperitoneum secondary to tumor rupture. The mean diameter of the tumors in the seven patients was 10.5 cm (range 5 to 20 cm). The lesions were located in the body and tail in five cases and in the head of the pancreas in two. Surgical procedures included distal pancreatectomy (3), distal pancreatectomy with splenectomy (2), pancreaticoduodenectomy (1) and a pylorus-preserving Whipple procedure (1). There were gross adhesions or histological evidence of infiltration to the adjacent pancreas and/or splenic capsule in four cases. None of the patients received adjuvant therapy. The mean follow up was 7 years (range 0.5 to 14 years). One patient developed multiple liver metastases after 14 years of follow up. CONCLUSION: SPT is a rare tumor that behaves less aggressively than other pancreatic tumor. However, in cases with local invasion, long-term follow up is advisable.     

Does neoplastic gastrin expression remodel the embryonal pattern of the protein? A study in human pancreas

BACKGROUND/AIMS: To determine the immunoreactivity of gastrin during the development of the human fetal pancreas and ductal pancreatic adenocarcinoma, given that, gastrin positive cells were demonstrated either into its embryonic anlage or into pancreatic cancer. METHODOLOGY: Tissue sections from 15 pancreatic fetal specimens, and an equal number of ductal adenocarcinoma specimens, were assessed using immunohistochemical methods for gastrin. RESULTS: The density of positive cells in the primitive exocrine ductal walls and outgrowing buds was significantly higher than the relevant density in the neoplastic pancreatic tissue of mixed (ductal endocrine) and pure ductal type (p1=0.017, p2<0.0001, p3<0.0001 and p4=0.019, respectively). The above values were estimated from 20-22 weeks of gestation. There was no significant difference in the density of positive cells in the islet cell epithelium from 25-30 weeks, and the neoplastic tissue of mixed (p5=0.24) and pure ductal type (p6=0.55). CONCLUSIONS: The immunostaining for gastrin identifies a subgroup of pancreatic ductal adenocarcinomas with a neuroendocrine component (initially considered as pure ductal tumors), and mixed ductal-endocrine tumors. This pattern of expression in neoplasms recapitulates the normal pattern during the embryonal development of the organ, and may be important for the development of new therapeutic approaches with eventual clinical utility.     

Intraductal papillary mucinous neoplasms of the pancreas – a cost-effectiveness analysis of management strategies for the branch-duct subtype

Background

Branch-duct intraductal papillary mucinous neoplasm (BD-IPMN) presents a clinical conundrum. Rigorous long-term surveillance or surgical resection is recommended. The economic consequences of the management have not been fully investigated.

Solid-pseudopapillary tumor of the pancreas:CT and MRI features of 3 cases

BACKGROUND: Solid-pseudopapillary tumor of the pancreas is a rather rare but low-grade malignant tumor with good prognosis after surgical excision. METHODS: In 3 patients with solid-pseudopapillary tumor of the pancreas which were proved pathologically, the imaging features ( CT in all and MRI in one patient) of the tumor were analyzed. RESULTS: In the 3 female patients under 35-year-old who presented no jaundice, CT revealed that huge solid-cystic masses of the pancreatic head with calcification in one and slight dilation of the pancreatic duct in another, but without dilation of the bile duct system in all. MRI demonstrated mixed signal intensity on T1WI and T2WI of the mass in one patient. CT and MRI revealed obvious enhancement of the cystic wall and solid part of the masses. CONCLUSIONS: CT and MRI findings of solid-pseudopapillary tumor of the pancreas are characteristic, and the diagnosis can be made preoperatively with the combination of clinical features.     

Huge primitive neuroectodermal tumor of the pancreas： Report of a case and review of the literature

INTRODUCTION Primitive neuroectodermal tumors (PNETs) are small round cell tumors arising from soft tissue belonging to the Ewing’s sarcoma family. These neoplasms all exhibit a neural phenotype, express the MIC2-protein (CD99) and display the same chrom…     

Pancreatic pseudocysts – when and how to treat?

Pancreatic pseudocysts are a well-known complication of acute or chronic pancreatitis, with a higher incidence in the latter. Currently several classification systems are in use that are based on the origin of the pseudocyst, their relation to pancreatic duct anatomy and a possible pseudocyst-duct communication. Diagnosis is accomplished most often by CT scanning, by endoscopic retrograde cholangiopancreaticography (ERCP) or by ultrasound, and rapid progress in the improvement of diagnostic tools has enabled detection with high sensitivity and specificity. There are different therapeutic strategies: endoscopic transpapillary or transmural drainage, percutaneous catheter drainage, or open surgery. The feasibility of endoscopic drainage is highly dependent on the anatomy and topography of the pseudocyst, but provides high success and low complication rates. Percutaneous drainage is used for infected pseudocysts. However, its usefulness in chronic pancreatitis-associated pseudocysts is questionable. Internal drainage and pseudocyst resection are frequently used as surgical approaches with a good overall outcome, but a somewhat higher morbidity and mortality compared with endoscopic intervention. We therefore conclude that pseudocyst treatment in chronic pancreatitis can be effectively achieved by both endoscopic and surgical means.     

Are islet cells the gatekeepers of the pancreas?

The pancreas is one of the body's most complex tissues composed of a mixture of endocrine and exocrine cell components. Although, islets comprise 1–2% of the pancreatic volume, there is some evidence that they control the function and the integrity of the pancreas and play the role of a gatekeeper. This review intends to highlight the importance of islet cells, not only for glucose metabolism, but also for their significant role in drug metabolism and diseases, especially in pancreatic cancer.     

Aggressive behaviour of solid-pseudopapillary tumor of the pancreas in adults：A case report and review of the literature

Solid-pseudopapillary tumor （SPT） is a rare neoplasm of the pancreas that usually occurs in young females. It is generally considered a low-grade malignant tumor that can remain asymptomatic for several years. The occurrence of infiltrating varieties of SPT is around 10%-15%. Between 1986 and 2006, 282 cystic tumors of the pancreas were observed. Among them a SPT was diagnosed in 8 patients （2.8%） with only one infiltrating variety. This was diagnosed in a 49-year-old female 13 years after the sonographic evidence of a small pancreatic cystic lesion interpreted as a pseudocyst. The tumor invaded a long segment of the portal- mesenteric vein confluence, and was removed with a total pancreatectomy, resection of the portal vein and reconstruction with the internal jugular vein. Histological examination confirmed the R-0 resection of the primary SPT, although a vascular invasion was demonstrated. The postoperative course was uneventful, but 32 mo after surgery the patient experienced diffuse liver metastases. Chemotherapy with different drugs was started. The patient is alive and symptom-free, with stable disease, 75 mo after surgery. Twenty-five patients with invasion of the portal vein and/or of mesenteric vessels were retrieved from the literature, 16 recent patients with tumor relapse after potentially curative resection were also retrieved. The best treatment remains a radical resection whenever possible, even in locally advanced or metastatic disease. The role of chemotherapy, and/or radiotherapy, is still to be defined.