Carcinoma arising in the pancreas 17 years after primary excision of a choledochal cysts: report of a case.

We report herein the case of a 42-year-old woman in whom a pancreatic carcinoma was found 17 years after excision of a choledochal cyst with Roux-en-Y hepaticojejunostomy. Although the incidence of biliary carcinoma associated with choledochal cyst is high, reports of cancer developing in the remaining intrapancreatic biliary tract or pancreas in patients who have previously undergone primary excision of a choledochal cyst are extremely rare. Long-term follow-up is recommended even for patients who have undergone excisional surgery for a choledochal cyst, in consideration of the possibility that cancer associated with the intrapancreatic biliary tract or pancreas may develop.

Electron microscopic observation of established chondrocytes derived from human intervertebral disc hernia (KTN-1) and role of macrophages in spontaneous regression of degenerated tissues.

BACKGROUND CONTEXT: Biological and pathological cell processes during the degeneration of intervertebral discs are as yet poorly understood. PURPOSE: An electron microscope was used to observe disc hernia degeneration at the cellular level as expressed in extruded tissue from a human intervertebral disc and in cultured chondrocytes. The mechanism of spontaneous regression was analyzed in order to investigate the effects of homologous macrophages, and the results of this analysis may be developed into a clinical therapy. STUDY DESIGN/SETTING: Extruded tissue specimens excised during surgery on human intervertebral disc hernia and cultured chondrocytes isolated from the excised tissue were observed by means of electron microscopy. Extracellular matrix metalloproteinase-3 (MMP-3) and its antagonist, tissue inhibitor of metalloproteinases-1 (TIMP-1), were observed by means of immune electron microscopy. Macrophages confirmed by CD68 immunostaining were added to the chondrocyte culture and observed by means of electron microscopy. PATIENT SAMPLE: All control subjects and patients gave written consent to the study. OUTCOME MEASURES: KTN-1 was directly observed without culture, and nuclei degeneration, the development of chromatin granules, changes in the osmotic pressure of the nuclear membrane and rough-surfaced endoplasmic reticulum, and the development of fat droplets were observed. METHODS: Tissues excised during surgery were divided, a part of the tissues were fixed in various fixatives for electron microscopy and immune electron microscopy analysis, and the other part was treated with collagenase. In addition, chondrocytes were isolated and cultured. Human peripheral blood mononuclear cells were separated using the Ficoll method. After culturing the cells, macrophages were collected, added to the chondrocyte culture, and observed under an electron microscope. CD68 positivity of the macrophages was confirmed by CD68 immunostaining. RESULTS: Freshly isolated chondrocytes in the hernia's extruded region differed markedly from cultured chondrocytes. By means of immunoelectron microscopy, MMP-3 and TIMP-1 were localized at the endoplasmic reticulum of the cultured chondrocytes. Infiltration of macrophages among the chondrocytes was observed in the mixed culture. CONCLUSIONS: The tissue extruded from the intervertebral disc showed obvious signs of degeneration, such as changes in osmotic pressure. Macrophages were observed to be the mechanism of spontaneous regression.

Carcinoma of the ampulla of Vater associated with other organ malignancies.

Because of its location with respect to the biliary system, carcinoma of the ampulla of Vater is considered to manifest earlier in its course of development than carcinoma of the pancreas. The most common physical finding is jaundice, which occurs in 93-100% of cases [1,2]. This retrospective study describes the results of the treatment and prognosis for double primary cancers in which cancer of the ampulla of Vater was associated with malignancies in other organs in 5 patients who were diagnosed and treated at Kurume University Hospital. The patients included 5 men with an average age of 72.8 years. There were 3 synchronous double and 2 metachronous double cancer patients. Regarding prognoses of these patients, 1 patient with associated lung cancer died because of postoperative complications after pneumonectomy, 1 patient died due to carcinomatosa peritonei developing from the ampulla Vater carcinoma, and 1 patient died because of metastatic liver tumors from the ampullary carcinoma. In multiple cancers including ampulla Vater carcinoma, gastrointestinal cancers such as gastric or colon cancer occur frequently. Therefore, a careful gastrointestinal examination should be done preoperatively. We report our experience with 5 cases of ampullary carcinoma associated with malignancies in other organs and review the literature.

Insulinoma occurring in association with fatty replacement of unknown etiology in the pancreas: report of a case.

A 66-year-old woman with a 10-year-history of diabetes mellitus was admitted to our hospital for investigation of several recent attacks of hypoglycemia. Her fasting blood glucose level was very low, at 30-40 mg/dl, and abdominal ultrasonography and computed tomography revealed a tumor in the pancreatic tail with fatty changes. Endoscopic retrograde cholangiopancreatography revealed absence of the main pancreatic duct from the body to tail of the pancreas. Abdominal angiography showed a hypervascular tumor stain in the pancreas, and percutaneous transhepatic portal vein sampling demonstrated a step-up of immunoreactive insulin levels in the splenic vein. Based on these clinical findings, we made a preoperative diagnosis of an insulinoma accompanied by fatty changes in the pancreatic body and tail. During laparotomy for the insulinoma, fat tissue was identified in the anatomic location of the pancreatic body and tail, and resected. Pathological examination of the resected specimen revealed a number of Langerhans islets in the adipose tissue, and an islet cell tumor with fatty replacement of the pancreatic tissue around the tumor. The insulinoma was found not to have caused obstruction of the main pancreatic duct. We present herein a rare case of an insulinoma that developed in the pancreas, and was associated with fatty replacement of unknown etiology.

Mechanism of delayed gastric emptying in naturally occurring CCK-A receptor gene knockout (OLETF) rats.

We recently found a specific strain of rats (OLETF rats) in which CCK-A receptor gene expression is lacking because of a genetic abnormality. As delayed gastric emptying has been reported in this strain, we examined its mechanism. A liquid gastric load containing phenol red was administered using an orogastric tube into the stomach in OLETF and control (LETO) rats. The stomach was removed 0, 15, 30 and 45 min after meal ingestion and the content of phenol red was measured to estimate the rate of gastric emptying. Pretreatment of reserpine enhanced gastric emptying in both strains. A tenfold dose of reserpine was required in OLETF rats to induce a similar effect to LETO rats. The plasma noradrenalin level was significantly higher in OLETF than LETO rats. When the smooth muscle of the stomach was isolated and contraction in vitro was examined, the smooth muscle functions were not deteriorated in OLETF rats. The thickness of muscle determined by hematoxylin-eosin staining was not different between strains. It is suggested that the delayed gastric emptying in OLETF rats may be due to increased sympathetic nerve function.

Large acinar cell carcinoma of the pancreas in a patient with elevated serum AFP level.

A pancreatic carcinoma, associated with elevated serum alpha-fetoprotein level, was resected from a 67-year-old man. The tumor was strongly suggested to be an acinar cell carcinoma of the pancreas, based on the histological findings of the resected specimen. The tumor measured 12 x 10 x 9 cm, and the cut surface was soft, whitish-yellow, focally necrotic, and hemorrhagic. Under a light microscope, the tumor cells were not arranged in a tubular and trabecular pattern, but rather, showed a tendency toward an acinar structure. Immunohistochemically, alpha 1-antitrypsin- and alpha 1-antichymotrypsin-positive reactions were diffusely positive in most of the tumor cells, while staining for chromogranin, neuron-specific enolase, Grimelius, glucagon, insulin, and alpha-fetoprotein was negative in the tumor cells. We report a large acinar cell carcinoma (associated with elevated serum alpha-fetoprotein level), which had been misdiagnosed as hepatocellular carcinoma preoperatively.

Resectable carcinoma of the pancreatic head developing 7 years and 4 months after distal pancreatectomy for carcinoma of the pancreatic tail.

A 67-year-old woman was referred with an abnormal finding on an abdominal echogram but presented with no symptoms; a pancreatic tail tumor was detected by ultrasonography. Biochemical examinations showed slight elevation of serum carcinoembryonic antigen level. The lesion was resected by tail and body pancreatectomy and her postoperative course was uneventful. Seven years and 4 months after the initial operation, however, her serum level of carbohydrate antigen 19-9 was found to be elevated, and a recurrence of pancreatic cancer was suspected. Examinations revealed a mass in the head of the remnant pancreas. The lesion was radically resected by total remnant pancreatectomy. Histological examinations showed that the initial tumor was a well differentiated tubular adenocarcinoma, while the second tumor was characterized as a moderately differentiated tubular adenocarcinoma. The surgical margins of the distal pancreatectomy specimen were free of atypical cells. Therefore, the position of the second lesion diminished the likelihood that it had developed by intrapancreatic metastasis. This suggests that the second carcinoma in the head of the pancreas may have been a second primary lesion.

Synchronous or metachronous double cancers of the pancreas and other organs: report on 12 cases.

Pancreatic carcinoma carries a poor prognosis, especially invasive ductal carcinoma of the pancreas. This retrospective study describes the results of the treatment and prognosis for double cancers in which cancer of the pancreas was associated with malignancies in other organs in 12 patients who were diagnosed and treated at Kurume University Hospital. The patients included 4 women and 8 men, with an average age of 67 years. Of the 12 tumors, 7 were metachronous pancreatic cancers which occurred after resections of other organ malignancies. Five patients had synchronous double cancers, one of whom was diagnosed to have gastric cancer on admission. Two other patients of this group were diagnosed to have lung cancer, while the remaining 2 patients suffered from colon cancer. By the time pancreatic cancer was diagnosed, gastrectomies had been performed in 7 patients for either gastric cancer or ulcers. In addition, one patient underwent a hysterectomy for uterine carcinoma and another received a low anterior resection for rectal carcinoma. Four of 5 patients in the synchronous group had nonresectable tumors and a palliative bypass operation was performed in 2 of these patients. Six patients who had metachronous double cancers died because of pancreatic cancer recurrence or metastases. We conclude that the prognosis of double cancers, where cancer of the pancreas is associated with other organ malignancies, primarily depends on the prognosis of the pancreatic carcinoma, and the present study suggests the necessity of long-term follow-up examinations for gastrectomy patients in order to make an early diagnosis of pancreatic cancer.

A case of synchronous double cancers of the pancreas and stomach.

Pancreatic cancer carries a poor prognosis, especially invasive ductal carcinoma of the pancreas. We present here the case of a 76-year-old man who developed synchronous double cancers of the stomach and pancreas. He was referred to our hospital in December, 1997, with a provisional diagnosis of carcinoma of the stomach. Laboratory data on admission showed normal levels except for the serum carcinoembryonic antigen level. Abdominal ultrasonography revealed a low echoic mass anterior to the pancreas, suggestive of a nodal metastasis. Intraoperative histological findings from the pancreatic nodule confirmed a primary pancreatic cancer. The diagnosis of double cancers of the stomach and pancreas was made, and subtotal gastrectomy and distal pancreatectomy with lymph nodes dissection were carried out. The histologic sections from the stomach showed a moderately differentiated tubular adenocarcinoma, whereas those from the pancreas showed a well to moderately differentiated tubular adenocarcinoma. Double carcinomas in this association are relatively rare.

Induction of acute pancreatitis by cerulein in human IL-6 gene transgenic mice.

Whether acute pancreatitis induced by cerulein was aggravated in human interleukin 6 (IL-6) transgenic mice and whether a specific anti-IL-6 receptor antibody improved pancreatitis were investigated. To induce acute pancreatitis, cerulein (50 microg/kg, seven injections) with or without 1 mg/kg lipopolysaccharides (LPS) was injected intraperitoneally every hour. In some mice, a monoclonal anti-IL-6 receptor antibody was administered before the first cerulein injection. The animals were killed 1 hour after the last injection. The pancreatic wet weight induced by cerulein alone was significantly higher in IL-6 transgenic mice compared with wild-type mice, but pretreatment with a specific anti-IL-6 receptor antibody did not reduce interstitial edema. When cerulein was administered with LPS, the pancreatic wet weight increased much more than when pancreatitis was induced by cerulein alone in both genotypes, and pretreatment with the anti-IL-6 receptor antibody decreased the pancreatic edema only in human-IL-6 transgenic mice. These results suggest that anticytokine antibodies may be effective in improving acute pancreatitis.

Kinetics of apoptotic cells in experimental autoimmune uveoretinitis.

PURPOSE: To investigate the role of apoptosis in immunopathogenic mechanisms of experimental autoimmune uveoretinitis (EAU), the kinetics of apoptotic cells and expression of Fas and Fas ligand (FasL) in the eye with EAU were studied. METHODS: Male inbred Lewis rats were immunized with S-antigen (40 microg/rat), and eyes were examined to detect apoptotic cells on days 1, 4, 8, and 10 post-immunization and days 0, 2, 4, 6, and 8 after the onset of EAU. The clinical and pathologic scores were used for estimating EAU. Apoptotic cells were analyzed by TdT-mediated dUTP nick-end labeling, electron microscopic and immunohistologic examinations, and agarose gel electrophoresis. The anti-rat Fas and anti-rat FasL antibodies were used to examine the expression of Fas and FasL. RESULTS: Apoptotic cells were detected in the infiltrating cells in the aqueous humor, the vitreous body, the iris-ciliary body, and the retina. Apoptotic cells were observed as early as the day of EAU onset and reached a peak on day 2 after the disease onset. Fas and FasL were expressed on the infiltrating cells in the aqueous humor and the vitreous. FasL was expressed on resident cells of the ciliary body. The kinetics of the expression of FasL corresponded with the kinetics of apoptotic cells. CONCLUSIONS: Fas-FasL-mediated apoptosis is considered to occur in the eye with EAU and plays a role in the immunopathogenic mechanisms to eliminate ocular infiltrating cells, thereby down-regulating the inflammatory processes.

Regulation of pancreatic secretion by vagal nerve during short-term duct occlusion in conscious rats.

The basal exocrine secretion of the pancreas is maintained at a constant level in conscious rats. We examined the changes in basal secretion with respect to the effect of various time periods of pancreatic duct occlusion (PDL). Male Wistar rats were prepared with cannulae that separately drained bile and pancreatic juice as well as with a duodenal cannula. Rats were placed in restraint cages, and experiments were conducted without anesthesia 4 days after the operation. Cholecystokinin (CCK) release was artificially prevented by the continuous infusion of bile with trypsin into the duodenal lumen throughout the experimental period to avoid the modification of pancreatic response by CCK. After 2-h basal collection, a pancreatic secretion was interrupted for 0.5-4 h, and then the collection of pancreatic juice was initiated again for an additional 2-4.5 h. The pancreatic secretion after the reopening of the 0.5-to 3-h PDL was comparable to basal secretion levels. However, protein secretion was significantly inhibited after the removal of 4-h PDL. Both vagotomy and capsaicin treatment abolished this inhibition, and the protein secretion after 1-h PDL in vagotomized rats increased 1.5-fold high compared with the basal value. These observations indicate that protein secretion was ceased during PDL via vagal nerve, and this may be a self-protective mechanism.

Disruption of cholecystokinin (CCK)-B receptor gene did not modify bile or pancreatic secretion or pancreatic growth: a study in CCK-B receptor gene knockout mice.

Pancreatic exocrine function and bile secretion were examined in cholecystokinin (CCK)-B receptor gene-targeted mice and compared among different genotypes [i.e., CCK-B receptor gene: (+/+), wild-type; (+/-), heterozygous; and (-/-), homozygous deficient]. The histology and protein concentrations in the pancreas also were examined. Amylase release from the dispersed acini was examined in vitro by using the various doses of CCK-8, carbachol, and secretin. In vivo, the bile and pancreatic juice were collected, and the concentrations of amylase and bile acid were measured in anesthetized mice. The responses to CCK (100 pmol/kg) or acetyl-beta-methylcholine (500 nmol/kg) were examined. In vitro studies showed that the maximal effective concentrations of CCK-8 (10(-l0) M), carbachol (10(-5) M), and secretin (5 x 10(-7) M) were comparable for all genotypes. Fluid, amylase, and bile acid outputs in vivo also were comparable for all genotypes. Pancreatic wet weight and protein concentrations were not significantly different, and no abnormal findings were observed on histologic examination in any genotype. These results indicated that the CCK-B receptor has no role in pancreatic growth, exocrine secretion, or bile secretion in adult mice.

A resected case of pancreatic metastasis from primary renal cell carcinoma.

A 71-year-old man, who had received a right nephrectomy for a primary renal cell carcinoma 8 years earlier, and had two years later received a distal gastrectomy for duodenal ulcer, was admitted. In the subsequent clinical course, a solitary low echographical tumor was found in the pancreas. Abdominal computed tomography revealed a tumor of low density area, and celiac angiography revealed a hypervascular tumor stain of the pancreas. From the above findings, a diagnosis of pancreatic tumor was made, and a distal pancreatectomy was performed. Examination of the resected tissues confirmed the presence of a solitary tumor in the pancreatic tail. Histologically, the tumor corresponded to the initial renal cell carcinoma and pancreatic metastasis of renal cell carcinoma was diagnosed. We report a resected case of such a metastasis and review the literature.

Immunohistochemical analysis of Bcl-2, Bax, and Bak expression in thyroid glands from patients with subacute thyroiditis.

Bcl-2 family proteins are important regulators of apoptosis. To clarify a role of apoptosis and the expression of Bcl-2 family proteins in the pathogenesis of subacute thyroiditis (SAT), we evaluated the expression of Bcl-2, Bax, and Bak by immunohistochemistry and apoptosis by in situ end labeling of fragmented DNA in thyroid tissues from 11 patients with SAT. Apoptotic nuclei were found in granulomas, especially in macrophages/histiocytes and lymphocytes, and in the regenerating follicular cells, but were rarely found in the area of fibrosis. The mean (+/-SD) percentage of apoptotic follicular cells was significantly greater in SAT than that in controls (1.4 +/- 0.8% vs. 0.4 +/- 0.6%). Bcl-2, Bak, and Bax were strongly expressed in the granulomas and regenerating thyroid follicular cells from patients with SAT. Bcl-2 and Bak, but not Bax, were expressed in follicular cells from normal controls. The percentage of apoptotic cells and the expression of Bax in follicular cells did not correlate with age or serum levels of thyroid hormones, C-reactive protein, or thyroglobulin. These data suggest that apoptosis may be involved in the development of SAT and that Bax expression in regenerating thyrocytes may be important for the recovery of SAT.

Molecular and histological evaluation of pancreata from patients with a mitochondrial gene mutation associated with impaired insulin secretion.

A mutation in mitochondrial DNA, which was originally identified in patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), can be associated with a subtype of diabetes mellitus. To determine the molecular and histological basis of impaired insulin secretion in the subjects with this mutation, we studied autopsy pancreata specimens from eight subjects diagnosed as having MELAS. The 3243 bp mutation was identified in seven out of eight pancreata examined. Immunohistochemical studies demonstrated a reduction in total islet mass, and in the numbers of both B and A cells. No evidence of insulitis or apoptosis was found. These data suggested that the 3243 bp mutation may cause the reduction of islet cells, mainly through mechanisms other than autoimmune destruction.

Nesidioblastosis with hyperinsulinemic hypoglycemia in adults: report of two cases.

We report herein the cases of two women, aged 34 years and 39 years, respectively, found to have hyperinsulinemic hypoglycemia after presenting with a history of episodes of temporary loss of consciousness, nausea, and fainting. Under the suspected diagnosis of insulinoma, localization procedures were carried out, but no tumor was found. In both patients, a definite gradient in insulin concentration was found in the pancreas by percutaneous transhepatic or intraoperative portal venous sampling, and a misdiagnosis of insulinoma of the pancreatic body was made. During exploratory laparotomy no tumor was palpable in the pancreas, and intraoperative ultrasonography showed no low echoic mass in the pancreas. A distal pancreatectomy was performed in both patients, and histopathological examination of the resected specimens revealed graded slight hyperplasia of the islet cells.

Atropine-resistant secretion of a putative luminal CCK-releasing peptide in conscious rats.

The changes in levels of the newly discovered luminal CCK-releasing factor (LCRF) in the small intestinal lumen before and after bile-pancreatic juice diversion in conscious rats were examined by a specific RIA. Moreover, we also examined whether LCRF secretion was under cholinergic control. Anti-LCRF antiserum was raised in rabbits, and a sensitive RIA was established. The localization of LCRF was examined by immunohistochemistry. The luminal content of LCRF was significantly increased by bile-pancreatic juice diversion, during which luminal trypsin activity was eliminated. The increase in luminal LCRF content was not inhibited by intravenous infusion of atropine. The changes in plasma levels of CCK and pancreatic secretion were similar to those in luminal LCRF contents. LCRF immunostaining was observed in villus tip enterocytes of the small intestine and was most prominent in the duodenal portion. These results support our original hypothesis that LCRF may be released spontaneously into the small intestinal lumen from the villus tip enterocytes and its intraluminal degradation by proteases regulates CCK release. Furthermore, LCRF release was not subject to cholinergic regulation.

Gene expression of erythropoietin in renal cell carcinoma.

A 57-year-old man with renal cell carcinoma and erythrocytosis showed a high serum level of erythropoietin (EPO). High EPO signal was observed on Northern blot analysis and RT-PCR in the total RNA extracted from the renal tumor. Immunohistochemical staining also demonstrated tumor tissue with high immunostaining of EPO. Nucleotide sequences of EPO cDNA in the tumor were normal. To date, only one report has discussed the nucleotide sequences of a tumor's EPO gene; it showed mutant EPO cDNA in hepatocellular carcinoma tissue. This is the first demonstration of normal EPO cDNA in renal cell carcinoma.