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Genes expressed in the developing endocrine pancreas and their importance for stem cell and diabetes research.

The genes that regulate endocrine pancreas development, maintain adult endocrine cells, and stimulate progenitor/stem cells during regeneration remain largely unstudied. There is ample evidence that many of the genes involved in endocrine pancreas development also function in the homeostasis of the adult islet. In light of the potential benefits to diabetic research, it is surprising that there is little information about the genes expressed throughout the ontogeny of the endocrine pancreas. In the past few years, efforts have been made to establish the Endocrine Pancreas Consortium database (EPConDB), in which many of the genes expressed in the developing endocrine pancreas are in a database with a corresponding publicly available clone bank. In addition, advances in microarray technology now allow for a quantitative expression analysis of thousands of genes simultaneously, which makes it possible to generate a quantitative catalog of the genes expressed at each step of endocrine differentiation, from embryonic endoderm to mature beta cells. In this review, I will discuss how genes discovered by virtue of their role in endocrine pancreas development may function in the maintenance of pancreatic stem cells and the regeneration of islets. I will further summarize the recent advances in genomics-based studies of the developing endocrine pancreas and will discuss how they might impact on the discovery of diagnostics and research into stem cell-based approaches for the treatment of diabetes.

Animals↗

Ventral pancreatic resection for adenoma and low-grade malignancies of the head of the pancreas.

The head of the pancreas can be anatomically divided into two sections, one drained by the duct of the Santorini system, and the other drained by the ventral pancreatic duct. This study was undertaken to determine whether independent resection of the ventral pancreas drained by the ventral pancreatic duct could be performed safely and effectively, by employing the following method in four patients. First, the duodenum and pancreas were sufficiently separated preserving the mesoduodenum and the posterior pancreaticoduodenal artery. Next, the main pancreatic duct was divided at the papillary portion, and sectioned at its junction with the duct of Santorini, ensuring preservation of the intrapancreatic bile duct. After the ventral pancreas had been detached from the glistening intrapancreatic bile duct, the ventral pancreas was connected with the dorsal pancreas by only the pancreatic parenchyma. The ventral pancreatic resection was completed following the incision of this border. A pancreatic fistula developed in one patient postoperatively, but this healed within 30 days. The hospital stay after surgery ranged from 35 to 58 days, and a good quality of life was maintained in all four patients. Thus, we conclude that ventral pancreatic resection can be safely performed and is especially valuable for treating the increasingly frequent adenomas and borderline malignancies in the main pancreatic duct system of the head of the pancreas.

Adenoma↗

Experimental studies on cadaver pancreas preserved by perfusion.

pancreatic transplantation is the most effective therapy of advanced diabetes mellitus. However, the problem is whether the cadaver pancreas can be used as a donor, because the living pancreas cannot be used as a donor from an anatomical standpoint. In case of the cadaver pancreas another problem is coming up that the pancreas proceeds to rapid autolysis. So, brain death is recommended as the most available condition for this transplantation. In this study we investigated the viability of the cadaver pancreas from decapitated rats preserved by the cold perfusion method. The results obtained were as follows: 1) The perfusing time affected the ratio of degenerative islets/normal islets. A large number of degenerative islets appeared with long perfusion time. 2) The cold (4 degrees C) perfusion method could preserve cadaver pancreas for 5 hours. 3) Insulin-secretion of cadaver pancreatic islets preserved for 5 hours under cold perfusion was 60% or more of that of normal pancreatic islets. 4) Three hundred islets from cadaver pancreas preserved for 5 hours under cold perfusion were transplanted into the portal vein of streptozotocin-induced diabetic rats. Four of these 11 rats recovered from diabetic state and maintained the non-diabetic state for 20 weeks after transplantation.

Animals↗

Comparison of local resection of the head of the pancreas combined with longitudinal pancreaticojejunostomy (frey procedure) and duodenum-preserving resection of the pancreatic head (beger procedure).

The etiology of pain in chronic pancreatitis may be ductal hypertension, increased parenchymal pressure, or neural damage. It is difficult to assess the severity of pain in this patient population, a problem made more challenging by the frequency of narcotic dependency. Therapeutic interventions developed to relieve the pain of chronic pancreatitis include denervation of the pancreas, decompression of the main duct of the pancreas, resection of part or all of the diseased pancreas, and reduction of pancreatic secretion. Operative intervention for patients with chronic pain is indicated when severe pain, complications of pain, or potential malignancy are present. The operations that consistently provide long-lasting pain relief all have in common resection of all or a portion of the head of the pancreas. Adverse effects on exocrine and endocrine function, nutrition, and quality of life are related to the amount of pancreas resected. The ideal procedure should be easy to perform, have a low morbidity and mortality rate, provide long-lasting pain relief, and not augment endocrine and exocrine insufficiency. No single operation fulfills this ideal. The local resection of the head of the pancreas combined with longitudinal pancreaticojejunostomy (LR-LPJ) proposed by Frey and the duodenum-preserving resection of the head of the pancreas (DPHR) proposed by Beger are discussed. The conceptualization, development, and technique of LR-LPJ are discussed, and comparisons of patient outcomes are made with the outcomes of other procedures for chronic pancreatitis.

Chronic Disease↗

Extracellular matrix distribution and islet morphology in the early postnatal pancreas: anomalies in the non-obese diabetic mouse.

Previously, we reported elevated numbers of macrophages in the pancreas of NOD mice, a spontaneous animal model for T1D, during the early postnatal period. Extracellular matrix plays an important role in the tissue trafficking and retention of macrophages as well as in postnatal pancreas development. Therefore, we have examined the expression and distribution of laminin and fibronectin, two major extracellular matrix proteins and their corresponding integrin receptors, in the pre-weaning pancreases of NOD mice and control mouse strains. In addition, we have characterized the pancreas morphology during this period, since the morphology of the pre-weaning pancreas before the onset of lymphocytic peri-insulitis, when the pancreas is still subject to developmental changes, has been poorly documented. We show that laminin labeling is mainly associated with exocrine tissue, whereas fibronectin labeling was mostly localized at the islet-ductal pole, islet periphery and in intralobular septa. Moreover, the protein expression level of fibronectin was increased in NOD pancreases at the early stage of postnatal development, as compared to pancreases of C57BL/6 and BALB/c mouse strains. Interestingly, pancreatic macrophages were essentially found at sites of intense fibronectin labeling. The increased fibronectin content in NOD neonatal pancreas coincided with altered islet morphology, histologically reflected by enlarged and irregular shaped islets and increased percentages of total endocrine area as compared to that of control strains. In conclusion, increased levels of the extracellular matrix protein fibronectin were found in the early postnatal NOD pancreas, and this is associated with an enhanced accumulation of macrophages and altered islet morphology.

Animals↗

Intraductal papillary-mucinous tumor of the pancreas head with complete absence of the ventral pancreatic duct of Wirsung.

A case of intraductal papillary mucinous tumor of the pancreas with complete absence of the ventral pancreatic duct of Wirsung is presented. A 74-year-old Japanese man was admitted to our hospital because of elevated serum amylase concentration. Abdominal computed tomography (CT) scanning revealed diffuse dilatation of the main pancreatic duct and a diffuse and uncircumscribed area with heterogeneous density in the pancreas head. Endoscopic retrograde cholangiopancreatography revealed that the main pancreatic duct was connected with an accessory papilla and was diffusely dilated, without any irregularity of the duct wall being observed in the entire length of the duct. The common bile duct was detected only by cannulation through Vater's papilla, and no pancreatic duct or its communicating branch was found. Some branches, directed to the dorsal portion of the pancreas head, were found arising from the accessory pancreatic duct. Intraductal ultrasound examination performed through the accessory papilla and the common bile duct revealed a small tumor with a heterogeneous echo level in the pancreas head. From these findings, intraductal papillary-mucinous tumor (IPMT) occurring in the pancreas head was diagnosed, and pylorus-preserving pancreaticoduodenectomy was performed. The resected specimen revealed IPMT in the pancreas head. A roentgenographic study of the resected specimen revealed a defect caused by the tumor located in the pancreatic duct connected with the accessory papilla and showed that there was complete absence of the pancreatic duct connected with Vater's papilla. Surgical resection enabled us to completely analyze the duct system of pancreas divisum. Although it is not known whether there is a relationship between the pathogenesis of IPMT and embryological anomaly of the pancreatic duct system, this case may provide an insight into the pathogenesis of IPMT.

Adenocarcinoma, Mucinous↗

Invasive carcinoma of the pancreas derived from intraductal papillary adenocarcinoma without mucin hypersecretion but with changes in the pancreatic duct on pancreatography.

We present a case of invasive carcinoma of the pancreas derived from intraductal papillary adenocarcinoma without mucin hypersecretion in a 65-year-old man with a 45-year history of alcohol abuse and a 2-year follow-up of chronic pancreatitis. Two years previously, in May 1998, he was admitted for investigation of abdominal pain. Computed tomography (CT) showed diffuse dilation of the main pancreatic duct with atrophy of the pancreatic parenchyma. Endoscopic retrograde pancreatography (ERP) showed a diffusely dilated main pancreatic duct with irregular side branches in the head of the pancreas. Chronic alcoholic pancreatitis was diagnosed on the basis of the pancreatography findings. The patient was readmitted for investigation of progressive weight loss in August 2000. Serum CA19-9 levels were markedly elevated (750 U/ml) and CT showed enlargement of the head and body of the pancreas. ERP showed irregularity of the main pancreatic duct in the head of the pancreas, and the distal main pancreatic duct (which was dilated on initial ERP examination) was interrupted in the body of the pancreas. Suspected pancreatic carcinoma was diagnosed, and pylorus-preserving pancreatoduodenectomy was performed. Frozen section examination of the cut end of the pancreas revealed ductal carcinoma, and total pancreatoduodenectomy with portal vein resection was performed. Histologically, the resected tumor was diagnosed as an invasive carcinoma derived from intraductal papillary adenocarcinoma without mucin hypersecretion. We recommend observing changes in the pancreatic duct on pancreatography to diagnose invasive carcinoma of the pancreas derived from intraductal papillary adenocarcinoma in a resectable state.

Adenocarcinoma, Papillary↗

Focal pancreatic hemorrhage mimicking pancreas carcinoma with lymph node metastasis.

A 67-year-old man was referred to our department because of a mass in the pancreas tail. Pancreatic tail cancer with lymph node metastasis was diagnosed, based on various radiological findings. Computed tomography (CT) revealed a slightly enhanced tumor mass around the celiac plexus, and endoscopic retrograde pancreatography (ERP) showed complete obstruction of the main pancreatic duct at the tail, although magnetic resonance imaging (MRI) demonstrated no elevation of the mean pixel value of the tumor after gadolinium (Gd) injection, and tumor markers of pancreas cancer were within normal limits. At surgery, the mass around the celiac plexus was found to be blood coagulation, and the pancreas tail tumor was found to be a focal hematoma in the pancreas. Pathologically, the hematoma was not encapsulated, and it was diagnosed as hemorrhage in the pancreas parenchyma. Both hemorrhagic lesions were suspected to have developed respectively. It is difficult to distinguish pancreas hemorrhage from carcinoma in the pancreas with chronic pancreatitis, especially when the hemorrhage is small in size and there are other extrapancreatic hemorrhagic lesions. For such diagnosis, the superiority of MRI with Gd injection is indicated.

Aged↗

Pancreas divisum: is it a normal anatomic variant?

One thousand five hundred twenty-nine pancreatograms were obtained between 1973 and 1985. Complete pancreas divisum was demonstrated in 41 patients, for an incidence of 2.7 percent, and incomplete pancreas divisum in 14 cases, for an incidence of 0.9 percent. No increased incidence of pancreas divisum was found in any of four groups: an incidental group, a group with alcoholic pancreatitis, a group with unexplained upper abdominal pain, and an idiopathic pancreatitis group. The majority of patients (80 percent) were found to have pancreas divisum as an incidental finding or in association with alcoholic pancreatitis. Of 82 patients with idiopathic pancreatitis, only 2 had pancreas divisum. The three patients with pancreas divisum who had sphincteroplasty of the minor papilla were not helped by the procedure. We conclude that pancreas divisum is a normal anatomic variant and is very seldom a cause of pancreatic pain.

Abdomen↗

Early indicators of exocrine pancreas carcinogenesis produced by non-genotoxic agents.

In the past 40 years the incidence of pancreatic cancer in many Western countries had increased. Since no single factor responsible for the development of pancreatic cancer has been identified, it is believed that non-genotoxic factors may play an important role in the pathogenesis of this highly fatal form of cancer. Focal abnormalities of acinar cells, referred to as atypical acinar cell foci or nodules, occur spontaneously in rats and some other species. Their incidence increases with age from zero at birth to about 75% in 2-year-old rats. These spontaneous lesions have a phenotype that cannot be distinguished from the putative, atypical preneoplastic, acinar cell foci induced in rat pancreas by the carcinogen azaserine. Unsaturated fat (corn oil) has been found to increase the incidence of atypical acinar cell nodules and adenomas in the pancreas of non-carcinogen-treated rats without influencing the weight of the pancreas. Furthermore, unsaturated fat has a specific promoting effect on the growth potential of atypical acinar cell foci and nodules induced in rat pancreas by azaserine, resulting in an increase in the number and size of these lesions. Rats fed raw soya flour or trypsin inhibitors develop an enlarged pancreas as a result of hypertrophy and hyperplasia. They also develop acidophilic atypical acinar cell foci and nodules, adenomas and adenocarcinomas after being fed full-fat raw soya flour for 2 years. It may be concluded from the observations in rat pancreas that non-genotoxic compounds or conditions that enhance pancreatic growth may be classified as non-genotoxic pancreatic tumour promoters. The observations with corn oil, however, indicate that there may be non-genotoxic compounds that specifically enhance growth of spontaneous initiated atypical acinar cell foci without causing hyperplasia of the pancreas. The possible mechanisms whereby unsaturated fat and trypsin inhibitors exert their effects on exocrine pancreatic carcinogenesis are discussed.

Animals↗

A comprehensive characterization of lymphoepithelial cyst associated with the pancreas.

BACKGROUND: Lymphoepithelial cyst of the pancreas is a rare but distinctive cystic lesion lined by a mature, keratinizing squamous epithelium and surrounded by lymphoid tissue. METHODS: To gain more insights into this entity, we describe 5 examples of lymphoepithelial cyst of the pancreas (2 of which were briefly described before) and compare them with similar cases in the literature for a total of 19 cases. RESULTS: The male:female ratio was 16:3; patients' ages ranged from 32 to 73 years (mean and median 51). The lymphoepithelial cyst was incidentally found at autopsy in 4 patients (21%) or during evaluation for unrelated diseases in another 4 patients (21%). In the remaining 11 patients, the cyst was associated with abdominal pain in 9 (47% of all patients), nausea/vomiting in 3 (16%), diarrhea in 1 (5%), and nonspecific systemic symptoms in 6 (32%) (some patients had more than 1 associated symptom). Computed axial tomography scan, with or without ultrasonographic study, was done in 16 cases and uniformly displayed a single, well-circumscribed, cystic mass protruding beyond the surface of the pancreas; the rest of the pancreas was normal. Intraoperatively, the cyst was readily apparent once the lesser sac was entered and the surface of the pancreas exposed; the cyst was located at the head (3 cases), neck (1 case), body (6 cases), and tail (9 cases). Surgery was done for all 15 clinical cases and included local excision of the cyst with a thin rim of attached, underlying pancreas (6 cases), or distal pancreatectomy with (4 cases) or without (3 cases) splenectomy. Follow-up information, available in 7 cases, showed that all symptoms disappeared and the patients were alive and well up to 6 years after surgery. CONCLUSIONS: This rare cyst of the pancreas has a uniform and characteristic clinicopathologic profile, enabling easy and accurate diagnosis. Although the histogenesis of lymphoepithelial cysts is not known, they are benign and can be cured by local excision.

Adult↗

Intraductal papillary mucinous tumors of the pancreas: the preoperative value of cytologic and histopathologic diagnosis.

BACKGROUND: The preoperative diagnosis of intraductal papillary mucinous tumors of the pancreas must be as certain as possible because removal of a large portion of the pancreas or even total pancreatectomy may be necessary. The value of cytologic and histopathologic analysis of specimens obtained by preoperative endoscopic investigations is unknown. The aim of this study was to assess the value of such analyses of specimens obtained by EUS-guided FNA and/or biopsy, or transpapillary biopsy specimens obtained during endoscopic retrograde pancreatography for the diagnosis of intraductal papillary mucinous tumors of the pancreas and for the detection of malignancy. METHODS: Between 1992 and 2001, 42 patients (22 men, 20 women; median age 64 years) underwent surgical resection for intraductal papillary mucinous tumors of the pancreas and had preoperative pancreatic tissue sampling. In the case of isolated dilatation of pancreatic ducts, pancreatic juice was obtained by EUS-guided FNA for cytologic analysis. In the presence of a solid lesion or main pancreatic duct stenosis, biopsy specimens were obtained by EUS-guided FNA biopsy or endoscopic retrograde pancreatography, which permitted histopathologic assessment. The accuracy of cytology and histopathology was evaluated for the following: (1) positive diagnosis of intraductal papillary mucinous tumors of the pancreas and (2) assessment of malignancy, by comparison with histopathologic examination of surgical resection specimens. RESULTS: Cytologic analysis was performed in 19 patients; it was positive in 4 (21%) and noninformative in 15 (79%). Histopathologic analysis was performed in 23 patients; it was positive in 21 (91%) and negative in 2 (9%). Histopathologic analysis yielded a positive result in 83% of patients who did not have extrusion of mucus from a patulous papilla. The sensitivity, specificity, and positive and negative predictive values of histopathologic analysis for the diagnosis of malignancy were, respectively, 44%, 100%, 100%, and 33%. When histopathologic analysis was positive, the tumor grade was similar to that determined by final histopathologic examination in 38% of patients, whereas the grade was underestimated in 62%. No complication occurred as a result of tissue sampling. CONCLUSIONS: The sensitivity of histopathologic analysis of EUS-guided FNA biopsy specimens or transpapillary biopsy specimens is 91% for the positive diagnosis of intraductal papillary mucinous tumors of the pancreas with a solid component, which is of particular interest as extrusion mucus from the papilla was absent in most patients. Histopathologic analysis of biopsy specimens of malignant intraductal papillary mucinous tumors of the pancreas often underestimates tumor grade. The result for cytologic analysis of juice obtained from dilated pancreatic ducts is disappointing.

Aged↗

Pancreas-sparing duodenectomy: indications, surgical technique, and results.

BACKGROUND: Pancreatoduodenectomy, originally performed for malignancy of the pancreas and duodenum, is also commonly used for potentially malignant lesions. Because a normal pancreas should be spared, we investigated the concept of duodenectomy alone with the pancreas intact for diseases such as familial adenomatous polyposis syndrome. METHODS: Five patients underwent pancreas-sparing duodenectomy for nonmalignant lesions performed by means of meticulous detachment of the duodenum from the pancreas, transecting the bile and pancreatic ducts outside the duodenum. Reconstruction was accomplished by advancing the jejunum to anastomose end-to-end with the juxtapyloric duodenal cuff, implanting the bile and pancreatic ducts in a location corresponding to the native papilla. The hospital course, complications, and long-term follow-up status of all patients are reviewed in detail. RESULTS: No deaths occurred in this series. Delayed gastric emptying was seen in one patient and transient pancreatic fistula in another. Long-term endoscopic follow-up showed no stenosis of the ductal anastomoses. Endoscopic surveillance, including endoscopic retrograde cholangiopancreatography, was not hampered by this technique of reconstruction. CONCLUSIONS: Pancreas-sparing duodenectomy is a practical operation for nonmalignant duodenal lesions where the pancreas is not involved by the disease process.

Adenomatous Polyposis Coli↗

The endocrine pancreas in virgin and pregnant offspring of diabetic pregnant rats.

Diabetes of the mother during pregnancy induces structural and functional adaptations in the fetal endocrine pancreas. We have previously shown in our experimental rat model, that the impact of this abnormal intra-uterine milieu leads, in the adult offspring, to a disturbance of the glucose homeostasis and to the development of gestational diabetes. The aim of the present work is to investigate wether these functional differences can be explained by structural differences at the level of the endocrine pancreas. Therefore the size and the structure of the endocrine pancreas, as well as the contribution of the insulin-, glucagon-, somatostatin- and PP-cells, were investigated morphometrically in the adult youngsters of mildly and of severely diabetic mothers, since both display a disturbed glucose tolerance but with divergent characteristics. Also the adaptation of their endocrine pancreas to pregnancy was measured and compared to that of a control pregnancy. In the offspring of mildly diabetic mothers, the size of the endocrine pancreas and the distribution of the islets of Langerhans are normal. Also the doubling of the endocrine mass during pregnancy is similar to controls. The high proportion of A-cells, especially in relation to a normal B-cell mass and the low amount of PP-cells, might play a role in the impairment of the insulin response in these animals and in the development of gestational diabetes. In the offspring of severely diabetic mothers a clear hypertrophy of the endocrine pancreas is noted, which is mainly due to the presence of numerous small islets and which does not increase further during pregnancy. In these animals, the size of the endocrine pancreas and of the B-cell mass have reached 'pregnant' values without pregnancy, which coincides with an exaggerated insulin output and peripheral insulin resistance, as during normal pregnancy. No further increase in islet mass is seen during pregnancy, which is associated with gestational diabetes.

Animals↗

Progression of atypical ductal hyperplasia/carcinoma in situ of the pancreas to invasive adenocarcinoma.

Although atypical ductal hyperplasia and carcinoma in situ of the pancreas have been well-documented, the natural history and rate of progression of these lesions are unknown. We report two patients, 68 and 52 years of age, who underwent Whipple's procedures for chronic pancreatitis. Histologic sections of the pancreas from both patients showed numerous foci of atypical ductal hyperplasia/carcinoma in situ that extended to the surgical margins of resection. Twenty-nine years after the Whipple's procedure, the first patient had a fine needle aspiration biopsy of a mass in the residual pancreas. The fine needle aspirate and cell block showed a conventional infiltrating ductal carcinoma of the pancreas. Nine years after the Whipple's procedure, the second patient underwent a distal pancreatectomy for a mass involving the body and tail of the pancreas that histologically proved to be a conventional infiltrating ductal carcinoma. These two cases suggest that progression of atypical ductal hyperplasia/carcinoma in situ of the pancreas to invasive carcinoma may take many years. This information about the natural history of these lesions may provide impetus for early detection and improved therapy and survival. Specimens of chronic pancreatitis obtained by Whipple's procedure provide surgical pathologists with the opportunity to search and become familiar with atypical ductal lesions of the pancreas not associated with invasive carcinoma.

Adenocarcinoma↗

False pancreas divisum. Acquired pancreatic duct obstruction simulating the congenital anomaly.

Eight patients with recurrent acute pancreatitis were found by ERCP to have foreshortening of the duct of Wirsung simulating the radiographic appearance of the congenital anomaly pancreas divisum. In contrast to 44 patients with true pancreas divisum, who were predominantly young (mean 32 years), nonalcoholic (42/44), and female (34/44), patients with false pancreas divisum were older (mean 48 years), male (7/8), and alcoholic (5/8). False pancreas divisum is most often an acquired obstructing lesion resulting from irremediable injury to the pancreatic duct during acute pancreatitis, often associated with pseudocyst formation and subsequent healing by scar at the site of duct injury. Appreciation of the radiographic differences between pancreatograms in true and false pancreas divisum and the different findings at operation allow for proper selection of therapy. Whereas accessory papilla sphincteroplasty appears to be effective for recurrent pancreatitis associated with true pancreas divisum, false pancreas divisum requires distal pancreatectomy or pancreaticojejunostomy to overcome the irreversible obstruction of the main pancreatic duct.

Acute Disease↗

Possible oncogenesis of mucinous cystic tumors of the pancreas lacking ovarian-like stroma.

BACKGROUND/AIMS: Clinicopathological features and postoperative results from mucinous cystic tumors of the pancreas (MCTs) were reviewed. MCTs with ovarian-like stroma (MCTs-OLS+; n = 6) and those lacking ovarian-like stroma (MCTs-OLS-; n = 4) were compared to elucidate the oncogenesis of MCT without OLS. PATIENTS AND METHODS: Ten patients with MCT were studied. RESULTS: The 6 MCTs-OLS+ cases occurred in females and were located in the body and tail of the pancreas. The mean tumor size was 6.5 cm (range 2-11 cm). The majority (5/6) of MCTs-OLS+ were multilocular and exhibited tiny loculi on the cyst wall and septum characteristic of MCTs-OLS+. Pathological classifications were adenoma in 4 patients and noninvasive adenocarcinoma in 2 patients. All 6 patients were alive without tumor recurrence 6-124 months after tumor resection. Of the 4 MCTs-OLS- cases, 2 were males and 2 females; MCTs- OLS- were located in the tail of the pancreas. The mean tumor size was 6.9 cm (range 4-8.4 cm). Invasive cancer in the pancreatic parenchyma or extrapancreatic tissue was recognized in all 4 patients, and the pathological classification of epithelia of the cyst wall were adenocarcinomas. These findings were also compatible with common invasive ductal carcinomas of the pancreas with secondary retention cyst on pseudocyst. All patients died of the disease (15, 27, 31 and 80 months after resection, respectively). Whether or not OLS is specific for MCTs of the pancreas should be clarified in future studies. CONCLUSION: The results of our study led to three hypotheses regarding the oncogenesis of MCTs-OLS-: (1) MCTs in which OLS disappears during the development of invasive carcinoma; (2) advanced cancer derived from intraductal papillary mucinous tumor of the pancreas, and (3) invasive ductal carcinoma of the pancreas with secondary cyst.

Adenoma↗

Trefoil factors are expressed in human and rat endocrine pancreas: differential regulation by growth hormone.

Trefoil factors (TFFs) 1, 2, and 3 are expressed in mucosal epithelia. TFFs are particular abundant in the intestine in which they play a crucial role in maintenance and restitution of the epithelium. Because pancreas developmentally arises from the primitive foregut, we explored the expression of TFFs in the pancreas in man and rat. Immunocytochemical staining of adult human pancreas showed abundant TFF3 immunoreactivity in pancreatic islets and some duct cells, whereas weak TFF1 and no TFF2 staining were detected. In the islets TFF3 localized to most insulin and some glucagon and pancreatic polypeptide-producing cells. TFF3 immunoreactivity was colocalized with insulin and glucagon in distinct cell clusters in human fetal pancreas at wk 14 and in the newborn rat pancreas. In isolated human and rat islets, TFF3 and TFF1 mRNA was identified by RT-PCR, and TFF3 protein was detected in human pancreas and islets by ELISA. Exposure of neonatal rat islets or insulinoma cells to GH, a known beta-cell growth factor, resulted in markedly increased TFF3 but decreased TFF1 mRNA levels. The effect of GH on TFF3 expression was confirmed by Western blot. Culture of neonatal rat islets in the presence of TFF3 resulted in attachment and migration of the islet cells, but no effects on proliferation, insulin secretion or cytokine-induced apoptosis were seen. These data demonstrate expression of TFFs in the endocrine pancreas, but their possible functions remain unknown.

Adult↗