Serous cystic neoplasm of the pancreas: a multinational study of 2622 patients under the auspices of the International Association of Pancreatology and European Pancreatic Club (European Study Group on Cystic Tumors of the Pancreas).

OBJECTIVES: Serous cystic neoplasm (SCN) is a cystic neoplasm of the pancreas whose natural history is poorly known. The purpose of the study was to attempt to describe the natural history of SCN, including the specific mortality. DESIGN: Retrospective multinational study including SCN diagnosed between 1990 and 2014. RESULTS: 2622 patients were included. Seventy-four per cent were women, and median age at diagnosis was 58 years (16-99). Patients presented with non-specific abdominal pain (27%), pancreaticobiliary symptoms (9%), diabetes mellitus (5%), other symptoms (4%) and/or were asymptomatic (61%). Fifty-two per cent of patients were operated on during the first year after diagnosis (median size: 40 mm (2-200)), 9% had resection beyond 1 year of follow-up (3 years (1-20), size at diagnosis: 25 mm (4-140)) and 39% had no surgery (3.6 years (1-23), 25.5 mm (1-200)). Surgical indications were (not exclusive) uncertain diagnosis (60%), symptoms (23%), size increase (12%), large size (6%) and adjacent organ compression (5%). In patients followed beyond 1 year (n=1271), size increased in 37% (growth rate: 4 mm/year), was stable in 57% and decreased in 6%. Three serous cystadenocarcinomas were recorded. Postoperative mortality was 0.6% (n=10), and SCN's related mortality was 0.1% (n=1). CONCLUSIONS: After a 3-year follow-up, clinical relevant symptoms occurred in a very small proportion of patients and size slowly increased in less than half. Surgical treatment should be proposed only for diagnosis remaining uncertain after complete workup, significant and related symptoms or exceptionally when exists concern with malignancy. This study supports an initial conservative management in the majority of patients with SCN. TRIAL REGISTRATION NUMBER: IRB 00006477.

Vacuum channeling radiation by relativistic electrons in a transverse field of a laser-based Bessel beam.

Relativistic electrons counterpropagating through the center of a radially polarized J_{1} optical Bessel beam in vacuum will emit radiation in a manner analogous to the channeling radiation that occurs when charged particles traverse through a crystal lattice. However, since this interaction occurs in vacuum, problems with scattering of the electrons by the lattice atoms are eliminated. Contrary to inverse Compton scattering, the emitted frequency is also determined by the amplitude of the laser field, rather than only by its frequency. Adjusting the value of the laser field permits the tuning of the emitted frequency over orders of magnitude, from terahertz to soft X rays. High flux intensities are predicted (~100 MW/cm^{2}). Extended interaction lengths are feasible due to the diffraction-free properties of the Bessel beam and its radial field, which confines the electron trajectory within the center of the Bessel beam.

Measurements of DIII-D poloidal field by fiber-optic pulsed polarimetry.

A new technique for measuring the spatial and temporal structure of the poloidal field is presented, whereby the magnetic field causes the polarization of light traveling through an optical fiber to rotate via the Faraday effect by an amount proportional to the strength of the field oriented along the fiber. In fiber optic pulsed polarimetry, changes in the polarization of the backscatter light from the fiber are detected, thereby permitting measurement of the field as a function of position along the fiber. In this proof-of-principle experiment, specially prepared single-mode fibers with weak fiber Bragg gratings were installed in the poloidal direction on the outside of the thermal blanket on DIII-D. Light at 532 nm from a mode-locked Nd:YAG laser was injected into the optical fibers. The laser repetition rate was 895 kHz with a pulse length of <10 ps, resulting in ∼1 µs temporal resolution. A photodetector system measured the Stokes polarization components necessary to determine the amount of polarization rotation. For this experiment, bandwidth limitations of the detectors resulted in a spatial resolution of ≈2 cm. The measured temporal and spatial distributions of the poloidal field are consistent with inductive probe measurements and Elastodynamic Finite Integration Technique reconstructions of the spatial distribution. This demonstrates the ability of this technique to provide real-time detection of the temporal and spatial variations of the poloidal field. Besides revealing more detailed information about the plasma, this new diagnostic capability can also help in detecting instabilities in real time, thereby enabling enhanced machine protection.

Suppressive effect of basic fibroblast growth factor on transendothelial emigration of CD4(+) T-lymphocyte.

The effect of basic fibroblast growth factor (b-FGF), one of the commonest angiogenic factors in various cancer types, on lymphocyte adhesion and transmigration across the endothelial cell monolayer was investigated using human umbilical vein-derived endothelial cells (HUVEC) and type I collagen gel. Forty-eight h exposure of HUVEC with 2 ng/ml b-FGF significantly decreased the basal adhesion of lymphocytes to endothelial cells. The decrease ratio is further enhanced by the addition of shear stress in this assay system. When HUVEC was stimulated for the last 24 h with optimal conditions of recombinant interleukin 1 beta, the percentages of transmigration as well as adhesion were also decreased significantly by the presence of b-FGF. The expression of intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 was down-regulated by b-FGF exposure in both resting and activated conditions by recombinant interleukin 1 beta, supposedly the main reason for this phenomenon. The migrating cells across b-FGF-stimulated HUVEC contained a markedly lower percentage of CD4(+) T-cells than those across non-treated HUVEC, although the 4B4(+)/2H4(+) ratio in CD4(+) T-cell populations did not differ significantly. These facts suggest that the presence of b-FGF in the angiogenic area suppresses lymphocyte emigration, especially that of CD4(+) T-cells, and thus causes insufficient helper function in local immune response. This effect of b-FGF was possibly one of the critical mechanisms by which cancer cells escape from the host immune reactions in the angiogenic stage of tumor development.

Distinct methylation patterns of two APC gene promoters in normal and cancerous gastric epithelia.

The adenomatous polyposis coli (APC) tumor suppressor gene is mutationally inactivated in both familial and sporadic forms of colorectal cancers. In addition, hypermethylation of CpG islands in the upstream portion of APC, a potential alternative mechanism of tumor suppressor gene inactivation, has been described in colorectal cancer. Because a subset of both gastric and colorectal cancers display the CpG island methylator phenotype, we hypothesized that epigenetic inactivation of APC was likely to occur in at least some gastric cancers. APC exhibits two forms of transcripts from exons 1A and 1B in the stomach. Therefore, we investigated CpG island methylation in the sequences upstream of exons 1A and 1B, i.e., promoters 1A and 1B, respectively. We evaluated DNAs from 10 gastric cancer cell lines, 40 primary gastric cancers, and 40 matching non-cancerous gastric mucosae. Methylated alleles of promoter 1A were present in 10 (100%) of 10 gastric cancer cell lines, 33 (82.5%) of 40 primary gastric cancers, and 39 (97.5%) of 40 noncancerous gastric mucosae. In contrast, promoter 1B was unmethylated in all of these same samples. APC transcripts from exon 1A were not expressed in nine of the 10 methylated gastric cancer cell lines, whereas APC transcripts were expressed from exon 1B. Thus, expression from a given promoter correlated well with its methylation status. We conclude that in contrast to the colon, methylation of promoter 1A is a normal event in the stomach; moreover, promoter 1B is protected from methylation in the stomach and thus probably does not participate in this form of epigenetic APC inactivation.

Molecular cloning of MINK, a novel member of mammalian GCK family kinases, which is up-regulated during postnatal mouse cerebral development.

A new germinal center kinase (GCK) family kinase, Misshapen/NIKs-related kinase (MINK), has been cloned and its expression has been characterized in several tissues and various developmental stages of the mouse brain. MINK encodes a 1300 amino acid polypeptide, consisting of an N-terminal kinase domain, a proline-rich intermediate region, and a C-terminal GCK homology region. The expression of MINK is up-regulated during the postnatal development of the mouse brain. MINK activates the cJun N-terminal kinase and the p38 pathways.

Spleen-preserving distal pancreatectomy with conservation of the splenic artery and vein.

BACKGROUND: The significance of preserving the spleen has recently been shown. However, there are few reports of spleen-preserving distal pancreatectomy for lesions of the body and tail of the pancreas, and this procedure is not generally performed. The aim of this study was to clarify the technique and indications for spleen-preserving distal pancreatectomy with conservation of the splenic artery and vein for benign lesions of the distal pancreas. METHODS: Four patients (two each with an endocrine tumor and a cystic lesion) underwent the procedure. We also performed the spleen-preserving Puestow's procedure with removal of the tail of the pancreas in a 22-year-old male patient with familial chronic pancreatitis. An important technique is to remove the splenic vein from the pancreas from the body of the pancreas toward the spleen and to remove the splenic artery from the pancreas in the other direction. The splenic vein is identified behind the pancreas and within the thin connective tissue membrane, which is cut longitudinally above the splenic vein. It is important to remove the splenic vein from the pancreas from the body of the pancreas toward the spleen, because it is very difficult to remove it in the other direction. There are many branches from the splenic vein on both sides; these branches should be carefully ligated and cut. The pancreas is removed from the splenic artery from the spleen toward the head of the pancreas. This procedure is much easier than removal of the pancreas from the vein. RESULTS: The postoperative course was uneventful in four of the five patients. A pancreatic fistula remained in one patient for several weeks. The mean and standard deviation of the operative blood loss, the duration of the operation, and the postoperative hospital stay in the four uneventful cases, excluding the one in which Puestow's procedure was performed, were 600 +/- 479 ml, 290 +/- 48 minutes, and 40 +/- 21 days, respectively. No severe complications occurred in any of the five patients. CONCLUSIONS: Spleen-preserving distal pancreatectomy with conservation of the splenic artery and vein is easy and safe and should be performed for benign lesions of the distal pancreas.

Problems in the diagnosis and treatment of a so-called mucin-producing tumor of the pancreas.

Reports of a so-called "mucin-producing tumor of the pancreas" are increasing worldwide. Although the clinicopathologic features and therapeutic strategies of this tumor have been enthusiastically investigated, there are still many unanswered questions regarding this ailment. In this study, problems in the diagnosis and treatment of mucin-producing tumor were analyzed, based on the 259 reported cases of this tumor. The overall 5-year survival rate for resected cases is 83%, which is much higher than that for ordinary duct cell carcinoma (17.3%). However, the 5-year survival rate for carcinoma cases with infiltration into other organs is 28%, which is much lower than those for carcinoma cases without infiltration (86%) and carcinoma cases with infiltration that remained within the pancreatic parenchyma (74%). These results demonstrate that patients with this tumor have a poor prognosis if the tumor infiltrates other organs. In addition, when the spread of the tumor is >6 cm, the prognosis is significantly worse than when the tumor has a spread of <6 cm. The significance of using the presence of K-ras mutation in the pancreatic juice for diagnosis of this tumor and problems of duodenum-preserving pancreatic head resection are discussed.

Role of phospholipase A2 in pancreatic acinar cell damage and possibilities of inhibition: studies with isolated rat pancreatic acini.

Phospholipase A2 (PLA2) has been postulated to play an important role in the pathogenesis of acute pancreatitis. To study the mechanism through which PLA2 may cause cellular damage, we used an in vitro model of isolated rat pancreatic acini prepared by collagenase digestion. Newly synthesized proteins were labeled by [35S]methionine. Cellular destruction was measured by the degree of release of radiolabeled proteins. Incubation of pancreatic acini with PLA2 alone caused only minor damage when very high concentrations of this enzyme were used. However, when acini were incubated with PLA2 in combination with its substrate, lecithin, cells were destroyed in a time- and concentration-dependent manner. Incubating cells with pancreatic homogenates and lecithin caused damage only when there had been prior activation of homogenates with either trypsin or enterokinase. The damage could be simulated by incubating acini with pure lysolecithin. Alcohol and cerulein did not further increase the destruction caused by PLA2 and lecithin. When acini were incubated with supernatants from another set of acini to which oleic acid had been added, a similar degree of damage resulted as compared with acini incubated with oleic acid alone. However, adding PLA2 to supernatants from acini preincubated with fatty acids significantly increased the degree of cellular necrosis. The destruction by PLA2 and lecithin was inhibited by albumin but could not be inhibited by gabexate mesilate, nafamostat mesilate, or cytidine diphosphocholine. We conclude that PLA2 could play a role in pancreatic acinar cell damage, especially in the spread of cellular necrosis within the organ, provided that its substrate, lecithin, is present.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of 5-fluorouracil on secretion and synthesis of pancreatic digestive enzymes: studies in isolated pancreatic acini and perfused pancreas derived from normal rats and from rats with acute necrotizing pancreatitis.

5-Fluorouracil (5-FU) has been claimed to have beneficial effects in human pancreatitis because of its ability to inhibit protein synthesis and secretion. However, the effect of 5-FU has not been studied in the pancreas of animals in more detail and the data in human pancreatitis are mostly derived from uncontrolled studies. Thus, we studied potential short-term effects of 5-FU on protein synthesis and secretion in isolated pancreatic acini from normal rats and from rats with sodium taurocholate-induced pancreatitis. Furthermore, we used the isolated perfused pancreas, damaged by taurocholate, to study whether arterial perfusion with 5-FU has any beneficial effects. When pancreatic acini were incubated with various concentrations of 5-FU, CCK-8-stimulated amylase secretion was not altered. Furthermore, 5-FU had no short-term effects on protein synthesis. Protein synthesis and secretion was already markedly depressed in isolated pancreatic acini derived from rats with sodium taurocholate-induced pancreatitis. 5-FU did not further decrease protein synthesis or secretion. Retrograde injection of sodium taurocholate in the main pancreatic duct of the isolated perfused pancreas resulted in a steep increase of amylase and lipase in the portal effluate. Arterial perfusion with 5-FU had no influence on enzyme release into the portal blood. We may conclude that our data, derived from experimental pancreatitis in rats, do not encourage investigation of the effect of 5-FU, an anticancer drug with possibly toxic side effects, in human pancreatitis.

Immunohistochemical study of the distribution of pancreastatin in endocrine tumors of the pancreas and in normal pancreatic tissue: analysis of autopsy cases.

Using sixteen cases (sixteen lesions) of endocrine tumor of the pancreas, found in 1,300 consecutive autopsy cases (661 men and 639 women; mean age, 79.0 years), we examined distribution patterns of pancreastatin (PST) in these endocrine tumors and in normal tissues around them, using immunohistochemical staining. In addition, the distribution patterns of PST was compared with those of insulin (INS), glucagon (GLU), somatostatin (SOM), and pancreatic polypeptide (PP), in these tissues. Normal islets of Langerhans were stained completely and evenly for PST. Two endocrine tumors did not stain for PST at all, six were partially stained, and eight were stained as densely as normal islets, or even more densely. Acinar cells were only partially stained for PST in 11 cases and showed scattered staining in three cases. Epithelial cells of ducts or ductuli were partially stained for PST in 10 cases and showed scattered staining in three cases. Distribution patterns of PST coincided with that of INS in 56% (9/16) of cases, GLU in 81% (13/16), SOM in 31% (5/16), and PP in 31% (5/16). In the eight tumors that were stained at least as densely for PST as normal islets, the staining pattern did not coincide with that of INS in any case (0%), coincided with that of GLU in all 8 cases (100%), and coincided with those of SOM and PP in one case each (13%). Therefore, the distribution of GLU-producing cells (A cells) coincided most closely with that of PST. It is concluded that most PST is secreted from A cells in human pancreas.

Incidence and pathogenesis of villous tumors of the gallbladder, and their relation to cancer.

The aim of this study was to investigate the incidence and pathogenesis of villous tumors of the gallbladder, and their relation to cancer. Five hundred and thirty-three cases of cholecystectomy and 1300 randomly selected autopsy cases, mainly elderly individuals, were investigated. Gallbladders were fixed in 10% formalin after operation or at autopsy, followed by macroscopic study. In cases of villous tumors, the entire gallbladder was cut into 5-mm-thick serial sections, embedded in paraffin, cut to 4-microns, stained with hematoxylin and eosin (H&E), and histologically studied. To investigate cancer-associated antigens, i.e., carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9, deparaffinized sections were examined by the peroxidase-antiperoxidase (PAP) immunohistochemical technique with anti-CEA and anti-CA 19-9 antibodies. Villous tumor was found in two resected cases (0.38%) and in one autopsy case (0.08%). Histologically, one of the villous tumors consisted mainly of a proliferation of lining epithelia; the other two consisted mainly of a proliferation of glands. In all three cases, the patients had had accompanying chronic or acute inflammation and two were accompanied by cholecystolithiasis, which made us aware of the importance of inflammation or trauma from stones in the pathogenesis of such neoplasms. Although no apparent cancerous epithelium was observed in any of these tumors by studying H&E specimens, moderate structural and cellular atypism was found in one of them. The atypical epithelium in this case was positively stained for CEA and CA 19-9. It was concluded that villous tumor should be considered to be a premalignant lesion.

A small glucagonoma of the pancreas with evident ductular and tubular structures.

A 54-year-old woman was admitted to our department for assessment of a tumor of the pancreas found incidentally on abdominal ultrasonography. Examination revealed a hypovascular 1-cm sized tumor in the body of the pancreas. Surgical examination revealed that the tumor was solitary and located in the pancreas body, with no invasion to the adjacent organs iof lymph node involvement. Distal pancreatectomy, preserving the spleen, was performed. Histologically, the tumor was a glucagonoma with evident ductular and tubular structures, suggesting that its site of origin was ductal epithelia.

Exocrine function of caerulein-induced acute pancreatitis in anesthetized rats.

Exocrine function was studied in anesthetized rats that had received two specific doses of caerulein (maximal stimulation and supramaximal stimulation). Male Wistar rats (body weight, 200-250 g) were divided into three groups: the control group (4-h saline infusion), the maximal stimulation group (0.25 microgram/kg per h caerulein for 4 h), and the caerulein pancreatitis group (10 micrograms/kg per h for 4h). Histologically, interstitial edema and cytoplasmic vacuolization were observed only in the caerulein pancreatitis group, with no abnormal findings in the other groups. The volume of pancreatic juice was significantly increased in both the maximal stimulation group and the caerulein pancreatitis group. The protein output and the amylase output in the 1st h of caerulein infusion were also significantly increased, to 459% and 338% in the maximal stimulation group, and to 925% and 1430% respectively, in the caerulein pancreatitis compared to the baseline values. We also found that the pancreatic juice of the caerulein pancreatitis group contained precipitated protein, and high trypsin activity, and protein degradation was confirmed by electrophoresis. These findings were not observed in the other groups. These results strongly suggest that hypersecretion and the appearance of trypsin activity in pancreatic juice plays an important role in the induction of histological changes in this pancreatitis model in anesthetized rats.

Mucin-producing adenoma associated with pancreas divisum and hepatic hilar carcinoma: an autopsy case.

We present the autopsy case of an 82-year-old Japanese woman with a mucin-producing adenoma accompanied by pancreas divisum and a hepatic hilar carcinoma. She had suffered from a cholangiocellular carcinoma at the hepatic hilus for 2 months, which was treated with radiation and chemotherapy. She did not complain of any abdominal pain. Obstructive jaundice deteriorated despite percutaneous transhepatic bile duct drainage, and she died of hepatic insufficiency. At autopsy, a hepatic tumor was confirmed to have caused severe obstructive jaundice. Histological examinations showed moderately to poorly differentiated cholangiocellular adenocarcinoma with squamous metaplasia, probably due to radiation. A yellowish mucinous tumor was found in the head of the pancreas near the minor papilla. It consisted of multiple rice-sized cystic lesions with thin septa. Although it had no capsule, its margin was clear. Neither a wide opening of the major or minor papilla nor mucous drainage was observed. Gross examinations revealed unfused pancreatic ducts. The slightly dilatated dorsal duct and a branch of the mildly dilatated ventral duct showed tumor involvement. Histological examinations showed mild atypia of the epithelia, and this pancreatic tumor was diagnosed as branch duct-type mucin-producing adenoma with postradiation dysplasia. The combination of a mucin-producing tumor and pancreas divisum is rare, and this is only the third reported case.

Pancreatic carcinoma accompanied by pseudocyst: report of two cases.

Two cases of pancreatic cancer accompanied by pseudocyst are reported. Case 1 was a 60-year-old man who was admitted to our hospital complaining of left lower abdominal discomfort. A cystic lesion, about 3 cm in diameter, was found in the pancreatic tail by ultrasonography (US) and computed tomography (CT). No signs of chronic pancreatitis were found. At operation, an elastic, hard, white tumor, about 1 cm in diameter, was felt adjacent to the cystic lesion on the duodenal side. Histologically, this tumor was a duct cell carcinoma with an adjacent pseudocyst upstream of the pancreas. Case 2 was a 57-year-old man who complained of back pain and loss of body weight. US and CT examination revealed a cystic lesion, 11 x 7 cm in size, in the tail of the pancreas. Histological examination of the resected specimen revealed both a duct cell carcinoma, 3 cm in size, in the body of the pancreas and a pseudocyst, 9 cm in size. Pseudocysts accompanying carcinoma are thought to develop from obstruction of the pancreatic duct by the carcinoma, followed by intraductal high pressure and disruption of ductules upstream of the pancreas. Thus, we should pay careful attention to pseudocyst of the pancreas, especially when signs of diffuse chronic inflammation cannot be found, to help identify duct cell carcinoma in the early stage. Further detailed examinations of the cyst fluid or pancreatic juice, such as cytology, tumor marker determinations, or establishment of K-ras codon 12 mutation, are needed.

Acute acalculous cholecystitis with a decrease in CD4/CD8 ratio.

Acute acalculous cholecystitis (AAC) usually occurs in the elderly and in those with severe pre-existing pathological conditions. However, there have recently been reports of AAC in relatively young immunosuppressed patients, such as those with acquired immunodeficiency syndrome (AIDS). We report here a 27-year-old woman with AAC who received an emergent cholecystectomy. Although anti-human immunodeficiency virus antibody (anti-HIV) was not detected, a decrease in the CD4/CD8 ratio in sera was found. This rare case of AAC in a patient with decreased CD4/CD8 ratio who showed no other related diseases suggests that surgeons should keep in mind the possible presence of immunosuppression in this condition.

Measuring the anterior capsule opening after cataract surgery to assess capsule shrinkage.

PURPOSE: To measure anterior capsule opening (ACO) size after acrylic intraocular lens (IOL) implantation and study the natural course of ACO reduction. SETTING: Kimura Eye and Internal Medicine Hospital, Hiroshima, Japan. METHODS: This study comprised 32 patients (38 eyes) having continuous curvilinear capsulorhexis, phacoemulsification, acrylic IOL implantation, and a self-sealing incision performed by 1 surgeon. A retroillumination photograph of the ACO was obtained with the Anterior Eye Segment Analysis System and converted to a computer image. The images were used to measure ACO size postoperatively and calculate the reduction ratio. Follow-up was 6 months. RESULTS: The postoperative reduction ratio in ACO size was 2.14% at 1 week, 3.83% at 1 month, 4.29% at 3 months, and 5.03% at 6 months. In a few cases, the reduction was progressively severe throughout the follow-up. CONCLUSIONS: The anterior capsule opening shrank rapidly during the first month after acrylic IOL implantation, followed by a slower progressive reduction in the subsequent 6 months. When severe, progressive shrinkage occurs, an anterior neodymium:YAG laser capsulotomy should be performed within 2 months postoperatively.

Comparison of shape recovery ratios of single-piece poly(methyl methacrylate) intraocular lens haptics.

We studied shape recovery ratios of several single- and three-piece intraocular lens (IOL) haptics after conducting compression tests for various lengths of time. Results of the comparison of poly(methyl methacrylate) (PMMA) IOL haptics configured of a single piece and of three pieces showed a superior shape recovery ratio for single-piece haptics. Comparisons of the shape recovery ratios among single-piece PMMA haptics and conventional three-piece haptics made of polyvinylidene fluoride (PVDF), PMMA, and polypropylene (PP) revealed that the shape recovery ratio of single-piece PMMA haptics was higher than the ratios of the conventional three-piece PMMA and PP haptics. The ratios of two of three of the single-piece PMMA haptics, however, were lower than the ratios of three-piece PVDF haptics. The form and manufacturing procedures of haptics likely have a significant impact on the shape recovery ratio of haptics, even those made of the same material. Since decentration after IOL surgery could be caused by the condition of the patient's lenticular capsule and Zinn's zonule, it is difficult to conclude that the shape recovery ratio is the only factor in IOL stability. Nevertheless, this study indicates that IOL haptics that cause less decentration and have better mechanical properties should be developed.