Immunoglobulin A secretion into pancreatic juice as a novel marker of local immune defense and exocrine pancreatic function.

The importance of secretory immunoglobulin A (IgA) of local immune defense in the gastrointestinal tract has gained increasing acceptance. Bacterial contamination is a major factor related to mortality in acute pancreatitis. However, very little is known about IgA in pancreatic juice. Pure pancreatic juice was collected from 40 patients undergoing pancreatoduodenectomy. The patients were divided into three groups according to the degree of preoperative pancreatic duct obstruction, as follows: normal, narrowed, and obstructed. IgA concentration, amylase activity, and daily volume of pancreatic juice were measured. Daily IgA secretion into pancreatic juice was constant during the early period after the operation. The concentration of IgA in the control group was 5 +/- 0.8 microg/ml, and IgA daily secretion was 1.2 +/- 0.2 mg/day. Pancreatic duct obstruction resulted in a marked decrease in both amylase and pancreatic juice secretion. The concentration of IgA, however, was markedly increased in the narrowed group (11.1 +/- 2.4 microg/ml) and the obstructed group (32.5 +/- 5.4 microg/ml). The concentration of amylase increased with the increase in pancreatic juice. Conversely, the concentration of IgA increased with the decrease in volume of pancreatic juice. Similarly, the increased in IgA concentrations positively correlated with the decrease in amylase activity. In conclusion, the mechanisms that modulate IgA secretion in the human pancreas are essentially different from those that modulate digestive enzyme and fluid secretion. IgA in pancreatic juice may play an important role in pathological conditions such as pancreatic duct obstruction. As such, the measurement of IgA in pancreatic juice may potentially be used as a new marker of local immune defense and exocrine pancreatic function.

Membrane fluidity correlates with liver cancer cell proliferation and infiltration potential.

We developed a method to measure membrane fluidity of living cancer cells in two- and three-dimensional cultures, and found that there was a close relationship between the membrane fluidity of cancer cells and their proliferative and infiltrative ability. Membrane fluidity is thus a promising indicator of the probability of cancer recurrence.

Expression of thioredoxin and glutaredoxin, redox-regulating proteins, in pancreatic cancer.

Pancreatic cancer (pancreatic ductal carcinoma) is one of the most malignant solid tumors with poor prognosis. There is accumulating evidence that cellular reduction/oxidation (redox) status is deeply involved in the growth promotion and drug resistance of cancer cells. We therefore investigated the expression of redox-regulating proteins, such as thioredoxin (TRX) and glutaredoxin (GRX) in surgically resected pancreatic tissues and cis-diamminedichloroplatinum (CDDP)-resistant cells. Plasma levels of TRX were also measured in subjects with pancreatic diseases. Pancreatic ductal carcinoma tissues were immunohistochemically more positive for TRX (24/32 cases) and GRX (29/32 cases) than pancreatic cystadenocarcinoma or normal pancreas tissues. Plasma levels of TRX (mean +/- SD) measured by ELISA were significantly higher in patients with pancreatic ductal carcinoma (54.8 +/- 37.6 ng/ml, n = 60) than in healthy controls (24.4 +/- 12.9 ng/ml, n = 81). CDDP-resistant subclones of HeLa cells, HeLa-CP5 cells, had higher expression of TRX (1.5 fold) and GRX (1.6 fold) compared with parental HeLa cells by immunoblotting. These results indicate the possible association of TRX and GRX with malignant potential of pancreatic ductal carcinoma.

Differential expression of human spasmolytic polypeptide (trefoil factor family-2) in pancreatic carcinomas, ampullary carcinomas, and mucin-producing tumors of the pancreas.

Human spasmolytic polypeptide (hSP) is a member of the trefoil peptide group, thought to be involved in mucin production and cell growth. It has been reported that hSP protein is expressed in digestive cancers but not in normal pancreas. The expression of hSP in pancreatic neoplasms has not been investigated in detail. The immunohistochemical expression of hSP protein was investigated in pancreatic carcinomas, ampullary carcinomas, mucin-producing tumors, serous cystadenomas and islet cell tumors of the pancreas. hSP was expressed in 23% of pancreatic duct cell carcinomas, and hSP protein was more frequently detected in cases of early-stage or histologically low-grade duct cell carcinomas than in cases of late-stage or histologically high-grade carcinomas. Patients with hSP protein expression showed a better prognosis than did those with negative hSP expression. hSP expression was detected in 92% of mucin-producing tumors, but was not detected in serous cystadenoma or islet cell tumors. Immunohistochemical hSP expression is related to differentiation and a better prognosis in pancreatic duct cell carcinomas. Furthermore, hSP protein is related to the pathogenesis and clinical characteristics of mucin-producing tumors of the pancreas.

Perioperative quantitative analysis of cytokeratin 20 mRNA in peripheral venous blood of patients with colorectal adenocarcinoma.

Hematogenous dissemination is a significant short-coming of colorectal carcinoma treatment. To screen patients with high risk for such blood-borne metastasis, we previously developed a highly sensitive system for the detection of cytokeratin 20 (CK-20) mRNA in blood. For a more practical application, we improved this system by making it quantitative and capable of analyzing peripheral venous blood for the detection of perioperative changes in CK-20 mRNA. CK-20 mRNA was not always detected in the preoperative blood, even in patients in an advanced stage, but it was identified without fail in intra- and post-operative blood. In addition, more copies of CK-20 mRNA were observed in the intra-operative blood than in pre- and post-operative blood. This study suggests that analysis of perioperative changes may provide important information for the precise evaluation of hematogenous dissemination and of the effect of surgical maneuvers on recurrence.

Tumor staging of pancreatic adenocarcinoma using early- and late-phase helical CT.

OBJECTIVE: We compared early-phase CT with late-phase CT in the evaluation of pancreatic adenocarcinoma. MATERIALS AND METHODS: Both early- and late-phase CT images of 25 pancreatic adenocarcinomas were compared with surgical-pathologic findings. We evaluated tumor detectability, tumor size, and local tumor invasion. RESULTS: Tumor detectability was 96% on early-phase CT imaging and 64% on late-phase CT imaging (p < .01). Sensitivity for anterior serosal invasion, retroperitoneal invasion, and arterial invasion on early-phase CT exceeded sensitivity on late-phase CT (p < .05). However, specificity for all factors on early-phase CT was less than or equal to specificity on late-phase CT. The grade of local tumor invasion on early-phase CT achieved better agreement with the surgical-pathologic results than did late-phase CT, especially for tumor size and retroperitoneal invasion. CONCLUSION: Early-phase CT was better than late-phase CT in revealing tumors, tumor size, and retroperitoneal invasion.

Characterization of six cell lines established from human pancreatic adenocarcinomas.

BACKGROUND: Six human pancreatic carcinoma cell lines, designated as KMP-1 to KMP-6, were established and maintained in vitro for > 3 years. All were derived from pancreatic ductal adenocarcinomas. The six cell lines originated from either primary pancreatic tumors, metastatic liver tumors, or metastases to lymph nodes. METHODS: Each cell line was characterized by its morphology, doubling time, colony forming efficiency (CFE) on plastic dishes, tumorigenicity in nude mice, chromosomal analysis, and the amount of tumor markers secreted into the culture medium. Furthermore, mutations in the K-ras, p53, and p16/INK4a genes were analyzed. RESULTS: All cell lines grew as an adhering monolayer and were cultured in medium supplemented with 2% fetal bovine serum. The doubling time ranged from 16-70 hours, and the CFE ranged from 0.1-11%. Subcutaneous transplantation of these carcinoma cells into nude mice resulted in the formation of tumors. Chromosomal analysis showed that the modal numbers ranged from 43-124, and each karyotype was unique. Each cell line secreted detectable amounts of squamous cell carcinoma antigen, carcinoembryonic antigen, carbohydrate antigen 19-9, Dupan-II, and cytokeratin 19 fragment, respectively. Genetic alterations of the K-ras, p53, and p16 genes were detected in six, three, and five, respectively, of the six cell lines. CONCLUSIONS: The authors believe that these newly established pancreatic carcinoma cell lines will contribute to wide ranging studies regarding pancreatic carcinoma progression.

Detection of extrapancreatic nerve plexus invasion of pancreatic adenocarcinoma. Cytokeratin 19 staining and K-ras mutation.

BACKGROUND: Neural invasion is known to be one of the aggressive characteristics of pancreatic adenocarcinoma. However, there have been no systematic studies on intraoperative examination of neural invasion of pancreatic carcinomas after wide dissection of the retroperitoneum, particularly at the surgical margin. METHODS: We performed intraoperative immunostaining on the frozen sections of several excised plexus specimens, using peroxidase-labeled anti-cytokeratin 19 antibody in 17 cases of resectable pancreatic carcinoma. Postoperatively, we also tried to detect occult micrometastasis by direct sequencing of the K-ras gene in the same samples. RESULTS: Intraoperative staining for cytokeratin 19 was positive in 4 of 17 (23.5%) cases. Patients with margin-positive neural invasion had significantly worse prognosis than patients who were margin negative (P < 0.05). One patient had micrometastasis in the nerve plexus, revealed by K-ras mutation, whereas neither cytokeratin 19 staining nor postoperative pathological investigation detected involvement of the analyzed portion. In the four patients margin-positive for cytokeratin 19 staining, the diagnosis of neural invasion by cytokeratin 19 staining was in agreement with the K-ras gene analysis. CONCLUSION: Intraoperative staining for cytokeratin 19 is useful for detecting pancreatic cancer involvement of the neural plexus margin. The results can be also utilized as a prognostic indicator during the follow-up period.

FDG uptake, GLUT-1 glucose transporter and cellularity in human pancreatic tumors.

UNLABELLED: We previously reported that grading of GLUT-1 glucose transporter expression was related closely to FDG accumulation in FDG PET in human cancers. But in this strong GLUT-1 expression group, there was an enormous range of standardized uptake values (SUVs) within them. METHODS: To evaluate other factors determining the FDG PET uptake, FDG PET was performed in 36 preoperative patients (mean age 62.0 yr) suspected of having pancreatic tumors, including 33 malignant and 3 benign neoplastic tumors. FDG uptake at 50 min after injection of 185 MBq 18F-FDG with > 5 hr fasting condition was semiquantitatively analyzed as SUVs. The GLUT-1 expression was studied by immunohistochemistry of paraffin sections from these tumors after the operation using the antiGLUT-1 antibody. The number of tumor cells within a 5- x 5-mm square was counted manually using x200 magnification photographs and was graded immunohistochemically as strong, weak or negative. RESULTS: In all 36 cases there were 3 cases of GLUT-1 negative, 8 of GLUT-1 weak positive and 25 of GLUT-1 strong positive. In all cases, the total number of tumor cells had no significant value for SUVs. Among 33 GLUT-1 positive cases, the number of GLUT-1 positive tumor cells correlated significantly with SUVs (p < 0.01). Only in 25 strong grade cases, the number of GLUT-1 strong positive tumor cells had a more significant value for SUVs (p < 0.005). Computational multivariate analysis using multiple regression for SUVs was performed evaluating the five variables as follows: tumor size, GLUT-1 immunohistochemical grading, number of total tumor cells, number of total GLUT-1 positive tumor cells and number of GLUT-1 strong positive cells. This analysis revealed that only the variable, the number of GLUT-1 strong positive cells, had a significant regression coefficient for SUVs (standard regression coefficient = 0.855, p < 0.0001). CONCLUSION: These data indicate that GLUT-1 expression plays an essential role in higher FDG accumulation in pancreatic tumor FDG PET, and the cellularity has a significant influence on SUVs only in the condition of GLUT-1 strong positive expression.

Intracellular Ca2+ response of pancreatic acini in cerulein-induced acute pancreatitis in rats.

BACKGROUND/AIMS: To approach the mechanism of impaired signal transduction in cerulein-induced pancreatitis, in vitro acinar cell responses including the intracellular Ca2+ dynamics were evaluated. METHODOLOGY: Rats were infused with 10 micrograms/kg/h of cerulein for 4 hours, and the pancreas was dispersed. A binding study for 125I-CCK, intracellular Ca2+ measurement, and an amylase secretion analysis were performed in dispersed pancreatic acini. RESULTS: The binding study for 125I-CCK revealed that the CCK-binding capacity (Bmax) was decreased, although the binding affinities (Kd high and Kd low) were not altered. An in vitro amylase secretion analysis evoked higher basal secretion but little response. In the control acini, the in vitro application of a physiological dose of CCK (10 pM) evoked intracellular Ca2+ oscillations, and a higher dose of CCK (100 pM, 1 nM) evoked a large transient rise in the intracellular Ca2+ concentration. In cerulein-treated acini, 10 pM CCK evoked no intracellular Ca2+ release, and 100 pM CCK evoked only oscillated Ca2+ concentrations. A higher dose (1 nM) of CCK evoked a transient rise, but the peak Ca2+ level was significantly lower than that in the control (p < 0.05). CONCLUSIONS: These data suggest that both CCK receptors and intracellular Ca2+ mobilizations are similarly desensitized. The attenuation of amylase secretion is partly due to impaired signal transduction, including impaired intracellular Ca2+ release.

Expression of membrane-type matrix metalloproteinase-1 in human pancreatic adenocarcinomas.

The expression of a new type of matrix metalloproteinase, membrane-type matrix metalloproteinase-1 (MT-MMP-1), was examined in 24 cases of primary pancreatic adenocarcinomas and 9 cases of secondary liver tumors derived from pancreatic adenocarcinomas, using a non-radioactive in situ hybridization and immunohistochemical methods. Out of 24 cases of primary pancreatic adenocarcinomas, 18 showed positive expression of MT-MMP-1 transcripts in cancer cells and 20 of 24 showed positive expression in the tumor stromal cells. The immunoreactivity of the gene products for MT-MMP-1 was demonstrated to be almost the same, as shown by in situ hybridization in these 24 cases. In particular, both the staining intensity for MT-MMP-1 transcripts and the immunoreactivity of the gene products in the tumor stromal cells of mucinous cystadenocarcinomas were significantly weaker than those of common-type ductal adenocarcinomas among the 24 cases. All of the 9 cases of secondary liver tumors derived from pancreatic adenocarcinomas showed positive expression for MT-MMP- transcripts but less immunoreactivity for the gene products. These results suggest that MT-MMP-1 is transcribed and translated in both cancer cells and the tumor stromal cells in human pancreatic adenocarcinomas. Furthermore, considering that common-type ductal adenocarcinoma of the pancreas usually shows a strong desmoplastic reaction, while mucinous cystadenocarcinoma typically does not, MT-MMP-1 expressed in the tumor stromal cells of common-type adenocarcinomas may be involved in processes leading to the desmoplastic reaction.

An immunohistochemical study of bcl-2 and p53 protein expression in pancreatic carcinomas.

BACKGROUND: Only a few articles have examined the relationship between bcl-2 expression and clinical findings or bcl-2 expression and p53 expression in pancreatic carcinomas. METHODS: We investigated bcl-2 protein and p53 protein expression by means of immunohistochemical methods. RESULTS: The immunostaining for bcl-2 was positive in 16 (20%) of 81 cases of pancreatic carcinoma. There were no significant correlations between bcl-2 expression and the age, gender, region of sampling, or clinical stage of the patients. Bcl-2 protein was detected more frequently in histologically high-grade pancreatic carcinomas (grade III, 31%; grade II, 14%; grade I, 0%); however, there was no significant difference in prognosis between patients with and without bcl-2 protein expression. Immunostaining for the p53 protein was positive in 45 (56%) of 81 cases of pancreatic carcinoma. There was no significant correlation between bcl-2 protein expression and p53 protein expression. CONCLUSION: Bcl-2 was often detected in histologically high-grade pancreatic carcinomas, although there was no significant correlation between bcl-2 expression and the prognosis.

Cytokeratin 20 mRNA in peripheral venous blood of colorectal carcinoma patients.

A highly sensitive system was previously developed by us to detect the presence of colorectal carcinoma cells in blood in the form of cytokeratin 20 (CK20) mRNA. In the present study, we used an improved version of this system to analyse the peripheral blood of 28 patients with colorectal carcinoma, five patients with non-cancerous intestinal diseases and six normal controls for the presence or absence of CK20 mRNA and to investigate the relationship between the mRNA results and prognosis. All eight patients with recurrence were positive for CK20 mRNA, as were four patients in the Dukes' C stage with either distant metastasis or dissemination. Five of the nine patients in the Dukes' C stage with neither distant metastasis nor dissemination were positive, and three of these developed recurrence within 11 months after the analysis. Only one of the seven patients in the Dukes' A or B stage was positive, and none showed recurrence during the 1-19 months of observation. None of the five patients without carcinomas or of the six normal controls was positive. Although the follow-up period is limited and the recurrences were all local at present, these results suggest that the presence of CK20 mRNA in circulation may be a useful indicator for the screening of advanced colorectal carcinoma patients with a high risk of recurrence.

Overexpression of the rhoC gene correlates with progression of ductal adenocarcinoma of the pancreas.

It has been reported that the rho genes, which consist of a ras-related small GTPase protein family, regulate cytoskeletal structures and have the potential to transform cultured cells. To investigate the biological relevance of the rho genes in pancreatic carcinogenesis, we examined expressions of the rhoA, B and C genes by polymerase chain reaction after reverse transcription (RT-PCR) in 33 cases of ductal adenocarcinoma of the pancreas. In addition, mutations of the K-ras, rhoA, B and C genes were studied in the same series of tumour tissues to correlate with rho gene expressions. The expression levels of the rhoC gene were significantly higher in tumours than in non-malignant portions (P < 0.001). Metastatic lesions overexpressed the rhoC gene compared with primary tumours (P < 0.05). Carcinoma tissues with perineural invasion and lymph node metastasis exhibited significantly higher expressions of the rhoC gene than tumours without these manifestations (P < 0.001 and P < 0.05 respectively). Overexpression of the rhoC gene significantly correlated with poorer prognosis of patients with pancreatic adenocarcinoma (P < 0.05). In contrast, the expression levels of the rhoA and B genes showed no significant relationship with clinicopathological findings. Mutation was not found either in the rhoA, B or C gene sequences examined. K-ras gene mutation, detected in 27 out of 33 (81.8%) cases, did not affect the expression levels in any of the rho genes. These suggest that elevated expression of the rhoC gene may be involved in the progression of pancreatic carcinoma independent of K-ras gene activation.

Gastrinoma with multiple liver metastases: effectiveness of dacarbazine (DTIC) therapy.

Gastrinoma when associated with liver metastasis results in markedly reduced survival. However, a standard chemotherapeutic protocol for patients with unresectable tumors has not been established. We treated two patients with gastrinoma with multiple liver metastases with intravenous administration of 5-dimethyltriazenoimidazole-4-carboxamide (DTIC; dacarbazine) at a dose of 200 mg/body for 5 consecutive days. The first patient showed a marked decrease in serum gastrin levels, from 338 000 pg/ml to 22 900 pg/ml (normal range, >220pg/ml), as well as a decrease in the size and number of peripancreatic and liver tumors, after four courses of DTIC. An additional nine courses of the treatment were given, and the peripancreatic tumor was resected. The patient has been in good overall condition for more than 3(1/2) years. The second patient was treated with a total of ten courses of DTIC. Serum gastrin levels did not increase and the hepatic tumor did not change in size for more than 4 years. DTIC was effective in controlling the clinical and biochemical manifestations of gastrinoma associated with liver metastasis without serious side effects. As the toxity of DTIC is minimal, (e.g., nausea and vomiting) DTIC therapy should be considered useful for islet cell carcinomas with multiple metastases.

Expression of glucose transporters in human pancreatic tumors compared with increased FDG accumulation in PET study.

UNLABELLED: Although overexpression of GLUT-1 glucose transporter has already been reported in human cancers, the mechanism of glucose entry into pancreatic cancers remains unknown. To evaluate the relationship between GLUT glucose transporters and FDG uptake, FDG-PET was performed in 34 preoperative patients (mean age, 60.9 yr) with suspected pancreatic tumors, including 28 malignant and 6 benign tumors. METHODS: FDG uptake at 50 min after injection of 185 MBq of [18F]FDG with >5 hr of fasting was semiquantitatively analyzed as standardized uptake values (SUVs). The GLUT expression was studied by immunohistochemistry of paraffin sections from these tumors after operation using anti-GLUT-1, -2, -3, -4 and -5 antibodies to obtain immunohistochemical grading ("strong," "weak" and "negative") by three experienced physicians. RESULTS: Of 26 malignant tumors proved by histological examination, 23 (88%) tumors were positive for the expression of GLUT-1 glucose transporter, and 17 (61%) showed strong expression. On the other hand, 13 (46%), 0 (0%), 9 (36%) and 13 (46%) malignant tumors were positive for the expression of GLUT-2, -3, -4 and -5 glucose transporters, respectively. Three of six benign tumors showed strong GLUT-1 expression. Concerning GLUT-2, -3, -4 and -5, only one benign tumor showed positive GLUT-5 expression. Thus, GLUT-1 showed relatively high sensitivity but low specificity (50%) for detecting malignant tumors, whereas GLUT-2, -3, -4 and -5 had lower sensitivities but higher specificities. Correlations between SUVs and grading of GLUT immunoreactivity were significant in GLUT-1 (strong, 4.49 +/- 2.95; weak, 3.42 +/- 1.21; negative, 2.52 +/- 0.84) (p < 0.05) but not in the remaining four GLUT transporters. CONCLUSION: These data indicate that GLUT-1 has a significant role in the malignant glucose metabolism and may contribute to the increased uptake of FDG in PET imaging in patients with pancreatic tumor.

External and intraoperative radiotherapy for resectable and unresectable pancreatic cancer: analysis of survival rates and complications.

PURPOSE: Clinical results of intraoperative radiotherapy (IORT) and/or external beam radiotherapy (EBRT) for both resectable and unresectable pancreatic cancer were analyzed. METHODS AND MATERIALS: Between 1980 and 1995, 332 patients with pancreatic cancer were treated with surgery and/or radiation therapy (RT). Of the 332 patients, 157 patients were treated with surgical resection of pancreatic tumor, and the remaining 175 patients had unresectable pancreatic tumors. Among the 157 patients with resected pancreatic cancer, 62 patients were not treated with RT, while 40 patients were treated with EBRT alone (mean RT dose; 46.3 Gy) and 55 patients with IORT (25.2 Gy) +/- EBRT (44.0 Gy). On the other hand, among the 175 patients with unresectable pancreatic cancer, 58 patients were not treated with RT, 46 patients were treated with EBRT alone (39.2 Gy), and the remaining 71 patients with IORT (29.3 Gy) +/- EBRT (41.2 Gy). RESULTS: For 87 patients with curative resection, the median survival times (MSTs) of the no-RT, the EBRT, and the IORT +/- EBRT groups were 10.4, 13.0, and 15.5 months, respectively, without significant difference. For 70 patients with noncurative resection, the MSTs of the no-RT, the EBRT, and the IORT +/- EBRT groups were 5.3, 8.7, and 6.5 months, respectively. When the EBRT and the IORT +/- EBRT groups were combined, the survival rate was significantly higher than that of the no RT group for noncuratively resected pancreatic cancers (log rank test; p = 0.028). The 2-year survival probability of the IORT +/- EBRT group (16%) was higher than that of the EBRT group (0%). For unresectable pancreatic cancer, the MSTs of 52 patients without distant metastases were 6.7 months for palliative surgery alone, 7.6 months for EBRT alone, and 8.2 months for IORT +/- EBRT. The survival curve of the IORT +/- EBRT group was significantly better than that of the no-RT group (p < 0.05), and the difference between the IORT +/- EBRT and the EBRT alone groups was marginally significant (p = 0.056). In addition, the 2-year survival probability for the IORT +/- EBRT group was 14%, while no 2-year survival was observed in the no RT or the EBRT groups. Multivariate analysis using the Cox proportional hazards model revealed that tumor size, stage (Stages 1, 2 vs. Stages 3, 4), and curability of resection were significant variables for resectable pancreatic cancer, while distant metastases and performance of IORT were significant variables for unresectable pancreatic cancer. The dose of EBRT was a marginally significant factor for both resectable and unresectable tumors (both p = 0.06). In terms of complications, ulcers of gastrointestinal tract were noted in 14% of the 126 patients treated with IORT. CONCLUSION: Although prolongation of the MST by IORT was not remarkable, long survivals (>2 years) were obtained by IORT +/- EBRT for noncuratively resected and unresectable pancreatic cancer. IORT combined with EBRT is indicated for noncurative resected or unresectable pancreatic cancer without distant metastases.

Immunohistochemical expression of nm23 gene product, nucleotide diphosphate kinase, in pancreatic neoplasms.

CONCLUSION: Our findings suggest that contrary to the proposed role for the nm23 protein as a tumor metastasis suppressor, in pancreatic tumors, the nm23 protein does not play an important role as a suppressor against tumor metastasis. BACKGROUND: The nm23 gene product, nucleotide diphosphate kinase, is believed to suppress tumor metastasis. Although a number of studies on many kinds of tumors have examined the relationship between nm23 expression and metastatic potential, the antimetastatic activity of nm23 remains controversial. The expression of the nm23 protein has not been examined in pancreatic tumors, except for a few reports on pancreatic duct cell carcinomas. METHODS: We have investigated nm23 expression in pancreatic duct cell carcinomas, islet cell tumors, and ampullary carcinomas by immunohistochemical methods. RESULTS: In 73 cases of pancreatic duct cell carcinomas, the nm23 expression was increased when compared with the adjacent normal pancreatic ducts; diffuse immunostaining was detected in 21 (29%) cases, focally positive immunostaining in 47 (64%) cases, and negative immunostaining in 5 cases (7%). All five negative samples were obtained from distant metastatic regions. However, there was no significant difference in the nm23 expression between primary tumors and regional lymph node metastases. Furthermore, there was no significant correlation between nm23 expression and the prognosis of the 55 resected cases. In the 15 cases of ampullary carcinomas, all 15 tumors were positive for nm23 protein (6 diffuse and 9 focal), and the staining intensity was stronger than in normal pancreatic ducts. There was no significant difference in the nm23 expression in the primary regions between patients with and without lymph node metastasis (2 diffuse and 5 focal out of 7 patients with lymph node metastasis, and 4 diffuse and 4 focal out of 8 patients without lymph node metastasis). All 12 islet cell tumors showed strong and diffuse staining for the nm23 protein.

Cytokeratin 19 fragment in serum and tissues of patients with pancreatic diseases.

CONCLUSION: The present study has shown that increased serum levels of cytokeratin 19 fragment reflect increases in the size of the pancreatic carcinomas, although the sensitivity for detecting small pancreatic carcinomas was low. BACKGROUND: Cytokeratin is a member of the intermediate family of filaments in epithelial cells. The cytokeratin 19 fragment is an acidic cytokeratin, which is found in various epithelial tissues. Recently, the serum fragment of cytokeratin 19 has been measured and found to be a good marker for squamous cell carcinoma. Cytokeratin 19 is known to be expressed in normal pancreatic tissues and pancreatic carcinomas. However, serum cytokeratin 19 levels in pancreatic diseases have not been precisely detailed. METHODS: In this study, we evaluated serum cytokeratin 19 levels and the immunohistochemical expression of cytokeratin 19 in various pancreatic diseases. RESULTS: Serum cytokeratin 19 levels were high (> 2 ng/mL) in 51 of 99 (52%) cases of pancreatic duct cell carcinoma, but were low in all 24 cases of chronic pancreatitis and in 7 cases of islet cell tumors. The sensitivity of the cytokeratin 19 assay increased with increased size of the pancreatic carcinomas, but was not influenced by the presence of obstructive jaundice. Immunohistochemical studies using a monoclonal anticytokeratin 19 antibody showed that staining for cytokeratin was positive in all 38 of the pancreatic carcinomas examined and in 2 of 6 islet tumors.