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Objectives: The aim of this study was to evaluate the effects of single-nucleotide polymorphisms (SNPs) on advanced pancreatic cancer risk and overall survival (OS) in a candidate-gene approach., Methods: Overall, 5438 SNPs in 219 candidate genes encoding several drug-metabolizing enzymes or transporters were analyzed. In the screening study, 3 SNPs were found associated with OS (P ≤ 0.0005). We validated these SNPs as part of the randomized phase 3 study (GEST study). The associations between OS and SNPs were investigated using log-rank test and Cox proportional hazards model., Results: From the GEST study, the SNP rs4149086 in the 3' UTR of the solute carrier organic anion transporter family member 1B1 (SLCO1B1) gene showed significant interaction with treatment (P = 0.02). In the gemcitabine group, the SNP was associated with short OS (hazard ratio [HR], 3.75; 95% confidence interval [CI], 1.30-10.8; P = 0.008) even after multiple-comparisons adjustment. In contrast, the SNP was not associated with OS in S-1 (HR, 0.77; 95% CI, 0.33-1.81; P = 0.55) or gemcitabine plus S-1 groups (HR, 1.18; 95% CI, 0.46-3.00; P = 0.72)., Conclusions: Patients with advanced pancreatic cancer with the rs4149086 AG or GG genotype may obtain good clinical results when treated with S-1-containing regimens.

Background/objectives: We evaluated the usefulness of positron emission tomography (PET)/contrast-enhanced computed tomography (CE-CT) in discriminating between malignant and benign intraductal papillary mucinous neoplasms (IPMNs)., Methods: PET/CE-CT imaging was conducted on 29 IPMN lesions, which subsequently underwent surgery. Preoperative findings on PET/CE-CT imaging were compared with the histological findings of the resected specimens to determine the diagnostic accuracy of PET/CE-CT imaging for evaluation of the differential diagnosis between benign and malignant IPMNs., Results: The final diagnoses of the 29 IPMN lesions were 9 benign and 20 malignant. Overall, 18 of the 20 malignant cases were positive for FDG uptake, while 7 of 9 benign cases were negative. The sensitivity, specificity, and diagnostic accuracy for benign/malignant differentiation using FDG uptake as a marker were 90.0%, 77.8%, and 86.2%, respectively. When guideline-based high-risk findings were used as markers, sensitivity, specificity, and diagnostic accuracy for mural nodules were 50.0%, 66.7%, and 55.2%, while they were 40.0%, 56%, and 48.3% for main duct dilatation, respectively., Conclusions: FDG uptake on PET is a useful new marker for malignancy in benign/malignant differentiation. Because PET/CE-CT imaging is a noninvasive imaging modality that can evaluate FDG uptake in addition to the conventional high-risk findings, we believe it should be the first-line method for determining therapeutic approaches to IPMN., (Copyright © 2017 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Peritoneal dissemination is a frequent occurrence in pancreatic cancer, which is associated with a poor prognosis. MET is associated with the progression of pancreatic cancer; therefore, we evaluated the effect of a MET inhibitor, crizotinib, on peritoneal dissemination of pancreatic cancer. Crizotinib inhibited the growth of 8 pancreatic cancer cell lines with the IC50 ranging from 1.4 to 4.3 µM. Invasion of the pancreatic cancer cell line Suit-2, was suppressed in vitro at a concentration of 1.0 µM, which is sufficient for the inhibition of MET phosphorylation. This effect on cell invasion was also recapitulated by the reduction of MET expression in Suit-2 with siRNA. Crizotinib also inhibited RhoA activation in addition to MET phosphorylation. We further evaluated the effect of crizotinib on peritoneal dissemination of pancreatic cancer in vivo. Crizotinib reduced tumor burden and ascites accumulation due to development of peritoneal dissemination after inoculation of Suit-2. Taken together, crizotinib may be a potent drug for treating peritoneal dissemination of pancreatic cancer by inhibiting cancer cell proliferation and invasion, at least in part through the suppression of HGF/MET signaling and RhoA activation.

Background: The purpose of the present study was to explore novel biomarkers that can predict the clinical outcome of patients before treatment or during vaccination. These would be useful for the selection of appropriate patients who would be expected to exhibit better treatment outcomes from vaccination, and for facilitating the development of cancer vaccine treatments., Methods: From a single-arm, non-randomized, human leukocyte antigen (HLA)-A-status-blind phase II trial of a vaccine treatment using three HLA-A*2402-restricted peptides for advanced pancreatic cancer (PC), we obtained peripheral blood samples from 36 patients of an HLA-A*2402-matched group and 27 patients of an HLA-A*2402-unmatched group., Results: Multivariate analysis (HR = 2.546; 95% CI = 1.138 to 5.765; p = 0.0231) and log-rank test (p = 0.0036) showed that a high expression level of programmed death-1 (PD-1) on CD4+ T cells was a negative predictive biomarker of overall survival in the HLA-A*2402-matched group . Moreover, a high expression level of PD-1 on CD4+ T cells was a negative predictor for the induction of cytotoxic T lymphocytes (p = 0.0007). After treatment, we found that the upregulation of PD-1 and T cell immunoglobulin mucin-3 (Tim-3) expression on CD4+ and CD8+ T cells was significantly associated with a poor clinical outcome in the HLA-A*2402-matched group (p = 0.0330, 0.0282, 0.0046, and 0.0068, respectively). In contrast, there was no significant difference for these factors in the HLA-A*2402-unmatched group., Conclusions: Our results indicate that the upregulation of PD-1 and Tim-3 expression on CD4+ and CD8+ T cells may restrict T cell responses in advanced PC patients; therefore, combination immunotherapy with blockade of PD-1 and Tim-3 to restore T cell responses may be a potential therapeutic approach for advanced PC patients., Trial Registration: Clinical-Trail-Registration: UMIN000008082 .

Background: We aimed to compare the efficacy and safety of irinotecan/S-1 (IRIS) therapy with S-1 monotherapy in patients with gemcitabine-refractory pancreatic cancer., Methods: Patients were treated with oral S-1 (80-120 mg for 14 days every 4 weeks) plus intravenous irinotecan (100 mg m -2 on days 1 and 15 every 4 weeks; IRIS group) or oral S-1 group (80-120 mg daily for 28 days every 6 weeks). The primary endpoint was progression-free survival (PFS)., Results: Of 137 patients enrolled, 127 were eligible for efficacy. The median PFS in the IRIS group and S-1 monotherapy group were 3.5 and 1.9 months, respectively (hazard ratio (HR)=0.77; 95% confidence interval (CI), 0.53-1.11; P=0.18), while the median overall survival (OS) were 6.8 and 5.8 months, respectively (HR=0.75; 95% CI, 0.51-1.09; P=0.13). Response rate was significantly higher in the IRIS group than in the S-1 monotherapy group (18.3% vs 6.0%, P=0.03). Grade 3 or higher neutropenia and anorexia occurred more frequently in the IRIS group., Conclusions: There was a trend for better PFS and OS in the IRIS group that could be a treatment arm in the clinical trials for gemcitabine-refractory pancreatic cancer.

We previously conducted a phase I clinical trial combining the HLA-A*2402-restricted KIF20A-derived peptide vaccine with gemcitabine for advanced pancreatic cancer (PC) and confirmed its safety and immunogenicity in cancer patients. In this study, we conducted a multicenter, single-armed, phase II trial using two antiangiogenic cancer vaccines targeting VEGFR1 and VEGFR2 in addition to the KIF20A peptide. We attempted to evaluate the clinical benefit of the cancer vaccination in combination with gemcitabine. Chemotherapy naïve PC patients were enrolled to evaluate primarily the 1-year survival rate, and secondarily overall survival (OS), progression free survival (PFS), response rate (RR), disease control rate (DCR) and the peptide-specific immune responses. All enrolled patients received therapy without the HLA-A information, and the HLA genotypes were used for classification of the patients. Between June 2012 and May 2013, a total of 68 patients were enrolled. No severe systemic adverse effects of Grade 3 or higher related to these three peptides were observed. The 1-year survival rates between the HLA-A*2402-matched and -unmatched groups were not significantly different. In the HLA-A*2402 matched group, patients showing peptide-specific CTL induction for KIF20A or VEGFR1 showed a better prognosis compared to those without such induction (P = 0.023, P = 0.009, respectively). In the HLA-A*2402-matched group, the patients who showed a strong injection site reaction had a better survival rate (P = 0.017) compared to those with a weak or no injection site reaction. This phase II study demonstrated that this therapeutic peptide cocktail might be effective in patients who demonstrate peptide-specific immune reactions although predictive biomarkers are needed for patient selection in its further clinical application., (© 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: We evaluated the efficacy and toxicity of adding oral leucovorin (LV) to S-1 when compared with S-1 monotherapy in patients with gemcitabine-refractory pancreatic cancer (PC)., Patients and Methods: Gemcitabine-refractory PC patients were randomly assigned in a 1:1 ratio to receive S-1 at 40, 50, or 60 mg according to body surface area plus LV 25 mg, both given orally twice daily for 1 week, repeated every 2 weeks (SL group), or S-1 monotherapy at the same dose as the SL group for 4 weeks, repeated every 6 weeks (S-1 group). The primary end point was progression-free survival (PFS)., Results: Among 142 patients enrolled, 140 were eligible for efficacy assessment (SL: n = 69 and S-1: n = 71). PFS was significantly longer in the SL group than in the S-1 group [median PFS, 3.8 versus 2.7 months; hazard ratio (HR), 0.56; 95% confidence interval (CI), 0.37-0.85; P = 0.003]). The disease control rate was significantly higher in the SL group than in the S-1 group (91% versus 72%; P = 0.004). Overall survival (OS) was similar in both groups (median OS, 6.3 versus 6.1 months; HR, 0.82; 95% CI, 0.54-1.22; P = 0.463). After adjusting for patient background factors in a multivariate analysis, OS tended to be better in the SL group (HR, 0.71; 95% CI, 0.47-1.07; P = 0.099). Both treatments were well tolerated, although gastrointestinal toxicities were slightly more severe in the SL group., Conclusion: The addition of LV to S-1 significantly improved PFS in patients with gemcitabine-refractory advanced PC, and a phase III trial has been initiated in a similar setting., Clinical Trials Number: Japan Pharmaceutical Information Center: JapicCTI-111554., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Objectives: Fluorodeoxyglucose (FDG)-positron emission tomography/contrast-enhanced computed tomography (PET/CE-CT) involving whole-body scanning first by non-CE-CT and FDG-PET followed by CE-CT has been used for detailed examination of pancreatic lesions. We evaluated PET/CE-CT images with regard to differential diagnosis, staging, treatment response, and postoperative recurrence in pancreatic cancer., Methods: Positron emission tomography/CE-CT was conducted in 108 patients with pancreatic cancer and in 41 patients with other pancreatic tumor diseases., Results: The maximum standardized uptake value (SUV(max)) overlapped in benign and malignant cases, suggesting that differential diagnosis of pancreatic tumors based on the SUV(max) is difficult. In the evaluation of staging in 31 resectable pancreatic cancer by PET/CE-CT, the diagnostic accuracy rate was more than 80% for most factors concerning local invasion and 94% for distant metastasis but only 42% for lymph node metastasis. Significant positive correlations were found between the SUV(max) and tumor size/markers, suggesting that SUV(max) may be a useful indicator for the treatment response. Regarding the diagnosis of the postoperative recurrence, PET/CE-CT correctly detected local recurrence in all the 11 cases of recurrence, whereas abdominal CE-CT detected only 7 of 11 cases, suggesting that PET/CE-CT is superior in this context., Conclusions: Positron emission tomography/CE-CT is useful for the clinical management of pancreatic cancer.

Pancreatic cancer is characterized by intraperitoneal dissemination and often by large volumes of ascites. Aminobisphosphonates exhibit potent antitumor effects and are currently being tested against human solid tumors. Several aminobisphosphonates inhibit cancer cell migration by preventing the activation of Rho through inhibition of the mevalonate pathway. We evaluated the ability of an aminobisphosphonate, incadronate, to inhibit the growth of disseminated pancreatic cancer in vivo. We established an in vivo pancreatic cancer model with i.p. carcinomatosis in nude mice. Incadronate administration started from the day of tumor inoculation, and reduced tumor burden and ascites accumulation. Further, we evaluated the effect of incadronate on the inhibition of pancreatic cancer cell proliferation, migration and invasion in vitro. Incadronate induced growth inhibition and apoptotic death of pancreatic cancer cells. It also inhibited migration presumably by preventing the activation of Rho by lysophosphatidic acid. Thus, the in vivo antitumor effect may result from the inhibition of cancer cell proliferation and migration. The potent effects of incadronate in reducing tumor burden and ascites suggest that it will be of value in regimens for the treatment of pancreatic cancer.

Pancreatic cancer shows the worst prognosis among the solid tumors, and survival for patients with high-grade liver metastasis is estimated at around a few months. We reported the effects of combination therapy with gemcitabine and S-1 (GS therapy) on pancreatic cancer patients with high-grade hepatic metastasis. Patients with severe metastatic pancreatic cancer received chemotherapy comprising S-1 (30mg/m² p.o. b.i.d., days 1-14) and gemcitabine (1000mg/m² on days 1 and 8), repeated every 3 weeks. Fourteen patients (7 men, 7 women) received treatment at a mean age of 56.5 years (range, 39-76 years), achieving complete response in 1 patient, partial response in 5 patients, and stable disease in 3 patients and progressive disease in 5 patients. The response rate was thus 43%. Median progression-free survival was 186 days (95% confidence interval, 40-247 days). Median overall survival was 261 days (95% confidence interval, 162-358 days). GS therapy appears to be well-tolerated and effective in patients with high-grade hepatic metastasis.

Erlotinib combined with gemcitabine has not been evaluated in Japanese patients with unresectable pancreatic cancer. This two-step phase II study assessed the safety and pharmacokinetics of erlotinib 100 mg/day (oral) plus gemcitabine 1000 mg/m(2) (i.v. days 1, 8, 15) in a 28-day cycle in the first step, and efficacy and safety in the second step. The primary end-point was safety. One hundred and seven patients were enrolled (first step, n = 6; second step, n = 101). The most common adverse event was RASH (compiled using the preferred terms rash, acne, exfoliative rash, dermatitis acneiform, erythema, eczema, dermatitis and pustular rash) in 93.4% of patients. One treatment-related death occurred. While interstitial lung disease-like events were reported in nine patients (8.5%; grade 1/2/3, 3.8/2.8/1.9%), all patients recovered or improved. The median overall survival, the 1-year survival rate and median progression-free survival were 9.23 months, 33.0% and 3.48 months, respectively. The overall response and disease control rates were 20.3% and 50.0%, respectively. In Japanese patients with unresectable pancreatic cancer, erlotinib plus gemcitabine had acceptable toxicity and efficacy that was not inferior to that seen in Western patients., (© 2010 Japanese Cancer Association.)

The primitive neuroectodermal tumor (PNET) of the pancreas, a member of Ewing's sarcoma family of tumors, is extremely rare. We treated a 37-year-old Japanese man who had a solitary pancreatic tumor 40 mm in diameter and multiple hepatic tumors with surgical resection. The PNET was positive for CD99 on immunohistochemical staining. Fluorescence in situ hybridization (FISH) was also performed, which revealed a Ewing sarcoma breakpoint region 1 (EWSR1) 22q12 rearrangement. According to the Japan-Ewing protocol, chemotherapy with Ifomide (ifosfamide), etoposide, vincristine, and cyclophosphamide was given after surgery. To the best of our knowledge, to date 13 PNET cases have been reported with a mean age for all patients of 19.3 years old. Surgical resection was performed in most cases and some patients received postoperative chemotherapy. The clinicopathologic characteristics and management of this extremely rare disease are also discussed.

A 17-year-old man was admitted to hospital because of epigastric pain. Various imaging studies showed a solid tumor (4cm in diameter) in the tail of the pancreas, multiple hypovascular tumors in liver. Serum levels of DUPAN2, SPAN1 and NSE were elevated slightly. Biopsy of hepatic tumor demonstrated that tumor cells had eosinophilic cytoplasm generally and unevenly distributed polymorphic nucleus. These data suggested that this tumor is poorly differentiated pancreatic carcinoma originated from the epithelium. Therefore, we administered 5-fluorouracil and cisplatin, combined with gemcitabine. The clinical status improved temporarily by the treatment, however, worsened rapidly. He died 81days after the treatment. Final diagnosis of autopsy was pancreatic ductal adenocarcinoma. Pancreatic ductal adenocarcinoma in the young patients is rare, and we reported this case in addition to consideration on literature.

Prognosis of pancreatic cancer is one of the worst among various cancers, however, incidence of bone metastasis has been increased even in pancreatic cancer in recent years. Therefore, we examined clinical features of pancreatic cancer presenting bone metastases who were treated in our cancer center, and propose how to manage these patients. We experienced 13 patients (7.3%) with pancreatic cancer with bone metastases during 2000-2003. Among these patients, pancreatic cancer was located at pancreatic body to tail in 10 cases, while it was located at pancreatic head in 3 cases. Liver metastasis was noted in 7 of 13 cases with bone metastases. Radiographical imagings of bone lesions revealed osteolytic bone destruction, and serum levels of bone resorption marker, 1CTP, were elevated in these patients. Stimulation of osteoclastic bone resorption is a critical step for bone metastasis, thus, serum levels of cytokines (PTHrP, IL-6, VEGF), which exert a promotive effect on bone resorption, were measured. Serum levels of IL-6 and VEGF were elevated in most of these patients, while elevation of serum PTHrP levels was found in 3 of 13 patients with bone metastases. Survival periods of pancreatic cancer patients with bone metastases was not long, however, treatment for bone metastases is important in terms of quality of life (QOL). An earlier diagnosis is essential to prevent deterioration in the QOL of pancreatic cancer patients presenting bone metastases. Periodical measurement of serum 1CTP in addition to bone scintigraphy is helpful for the earlier diagnosis for bone metastases.

Background: Pancreatic carcinoma is often associated with diabetes mellitus. The interrelationship between them is very interesting and important for clinical examination and treatment., Methods: We examined diabetes mellitus in our patients with pancreatic carcinoma, especially those with invasive ductal pancreatic carcinoma, who were admitted to the National Kyushu Cancer Center between 1972 and 1998, in relation to secondary (pancreatic) diabetes, obstructive pancreatitis, angiopathies, treatment, and prognosis., Results: Diabetes mellitus was found at a high frequency (53.1%) in patients with invasive ductal pancreatic carcinoma and was mostly thought to be secondary diabetes (45.9%), caused, in part, by obstructive pancreatitis following pancreatic tumor recognized on the first admission. Control of blood glucose with insulin was sometimes difficult, but was indispensable for the treatment of pancreatic carcinoma. Diabetic angiopathies are usually not seen in patients with pancreatic diabetes caused by pancreatic carcinoma, because the survival period of patients with pancreatic carcinoma has been limited. Furthermore, in spite of the absence of angiopathies, the survival period was significantly lower in pancreatic carcinoma patients with diabetes than in those without diabetes., Conclusion: Diabetes in patients with invasive ductal pancreatic carcinoma is usually secondary diabetes, occurring in part as a consequence of obstructive pancreatitis shown at the beginning of the clinical course. The duration of diabetes is too short for marked diabetic angiopathies to develop, and the survival period in patients with invasive ductal pancreatic carcinoma with diabees is also short compared with that of those patients without diabetes.

MTA1 has been identified as a metastasis-promoting gene, and its gene expression is correlated with serosal invasion and lymph node metastasis in the gastrointestinal and esophageal cancers. We examined MTA1 mRNA expression levels in 13 cell lines and 23 tumor tissues of pancreatic cancer by quantitative reverse transcription polymerase chain reaction. MTA1 mRNA expression was found in all the cell lines, however its levels were not correlated with the metastatic pontential of each cell line representing hematogenous distant metastasis. In the pancreatic cancer tissues, the overexpression of MTA1 mRNA (tumor/normal ratio >/=1) was observed in 12 out of 23. Pancreatic cancer tissues overexpressing MTA1 mRNA (T/N ratio >/=1) tended to have higher incidence of lymph node metastasis. These results together with previous findings in the gastrointestinal and esophageal cancers suggest that MTA1 might be involved in the progression, particularly in lymph node metastasis of pancreatic cancer.

The incidence of invasive ductal carcinoma of the pancreas was 3.1% (6 cases) in 196 patients with definite chronic pancreatitis. Five patients (3 men and 2 women) had calcific pancreatitis and 1 patient (man) had non-calcific pancreatitis. Large pancreatic stones were recognized in 2 women. Most of the patients complained of continuous intractable abdominal pain and/or back pain together with weight loss and appetite loss. Serum CA19-9 levels and exacerbation of glucose intolerance were retrospectively noted to have been elevated in 1 patient. However, it was difficult to obtain a definitive diagnosis by imaging examinations earlier, due to the presence of chronic pancreatitis. Median survival of the 6 patients was 6.5 months from admission.

Various genetic changes are involved in progression of various cancers. We examined alterations (deletion, sequence abnormalities, methylation) of the CDKN2A gene in cell lines and tumor tissues of pancreatic cancers. Some alterations of this gene were found in all the 12 cell lines examined. In the primary lesions of pancreatic cancers, homozygous or hemizygous deletion were found in 8 of 24 ductal carcinoma and 4 of 9 other types of carcinomas. It appears that there is an association between the alteration of this gene and tumor size, regional lymph node metastasis and hematogenous distant metastasis in the ductal carcinoma, but not in the other types of carcinomas. All the 5 liver metastatic lesions of the ductal carcinoma examined revealed homozygous or hemizygous deletion and 3 bp deletion. These results suggest that inactivation of the CDKN2A gene occurs more frequently in cell lines than in pancreatic cancer tissues. Such genetic events on the CDKN2A gene may play an important role possibly at a later step in the progression of pancreatic ductal carcinoma.

Hypercalcemia represents one of the important paraneoplastic syndromes affecting morbidity and mortality of cancer patients. We and others have demonstrated that vitamin D analogs with little calcemic activities suppress the transcription of the parathyroid hormone-related peptide (PTHrP) gene, a major humor responsible for cancer hypercalcemia, and thereby prevent the development of hypercalcemic syndrome. The present study was undertaken: to compare the therapeutic efficacy of a vitamin D analog, 22-oxa-1,25-dihydroxyvitamin D3 (OCT), and a bisphosphonate (disodium 3-amino-1-hydroxypropylidene-1,1-bisphosphonate pentahydrate [AHPrBP]), an inhibitor of osteoclastic bone resorption, on cancer-induced hypercalcemia; and to see if the effect could be enhanced by combination treatment, using a nude mouse model implanted with a human pancreas carcinoma (FA-6). After a single intravenous administration, OCT (5 microg/kg of body weight [BW]) was as effective as AHPrBP (10 mg/kg of BW) in lowering blood ionized calcium levels in tumor-bearing nude mice, and their combination further enhanced the therapeutic effect. Although AHPrBP lost its efficacy after repeated injections, OCT was still effective after the third administration. The therapeutic effect of OCT in cancer hypercalcemia was observed in four other human tumors, including another pancreas carcinoma (PAN-7), two squamous cell carcinomas of the lung (KCC-C1 and LC-6), and a squamous carcinoma of the pharynx (PHA-1), all of which elaborated PTHrP into the circulation. Treatment with OCT resulted in a decrease in circulating PTHrP levels by approximately 50% in two representative models. However, the mechanism underlying the antihypercalcemic effect of OCT seemed complex, involving inhibition of PTHrP production, suppression of excessive bone resorption, and an antitumor activity. OCT also markedly inhibited the body weight loss with tumor growth, while AHPrBP, which exhibited a similar antihypercalcemic effect, was less effective than OCT in preventing cachexia. The anticachectic activity of their combination did not exceed that of OCT alone, suggesting a hypercalcemia-dependent as well as an independent mechanism of cancer cachexia. It is concluded that OCT may be useful, either as a single agent or in combination with bisphosphonates, for the treatment of cancer-associated hypercalcemia and cachexia.

Background & Aims: Point mutations of the Ki-ras gene at codon 12 have been frequently identified in pure pancreatic juice of patients with pancreatic cancer in studies examining pancreatic cancer tissues. The aim of this study was to examine mutations of the Ki-ras codon 12 in the duodenal juice collected from patients with various pancreatic disorders., Methods: The duodenal juice was collected through a Dreiling tube installed in the duodenum during a secretin test. Analysis of the Ki-ras mutations was performed using the enriched polymerase chain reaction--single-strand conformation polymorphism technique., Results: Point mutations were detected in 12 of 19 patients with pancreatic cancer; of the 12 patients, 10 had ductal tubular adenocarcinoma and 2 intraductal papillary adenocarcinoma. Mutational patterns included GAT (n = 4), GTT (n = 3), CGT (n = 1), and double mutations of GTT and GAT (n = 3) and GAT and CGT (n = 1). In 41 patients with benign pancreatic disorders, a point mutation was detected in only 1 patient with chronic pancreatitis., Conclusions: Analysis of the Ki-ras codon 12 mutations in the duodenal juice is useful in the diagnosis of pancreatic cancer.

The collagen content in human pancreatic cancer tissue, tissue of tumor-associated chronic pancreatitis (TACP), and normal pancreatic tissue was determined in 14 patients with pancreatic cancer by measuring the amount of 4-hydroxyproline. Four patients with alcoholic chronic pancreatitis (AlCP) were also analyzed. The mean collagen content in both pancreatic cancer tissue and TACP tissue was approximately threefold higher than in normal pancreatic tissue. Cyanogen bromide peptides of type I, III, and V collagens from invasive ductal carcinomatous tissue of the pancreas and from TACP tissue of eight patients were analyzed sequentially using high-performance liquid chromatography with ion-exchange and gel-permeation columns. No difference in the proportion of type I, III, and V collagens was detected between pancreatic cancer tissue and TACP tissue. The mean collagen content in AlCP tissue was significantly lower than that in TACP tissue, but no difference in the proportion of type I, III, and V collagens was detected between these two tissues. These results indicate a similar quantity and distribution pattern of fibrillar collagen in human pancreatic cancer and TACP.

Plasma pancreastatin (PST) and GAWK, peptides processed from chromogranin A and B, were elevated in patients with various neuroendocrine tumors. In the present study, we measured plasma PST- and GAWK-like immunoreactivity (LI) concentrations in 12 patients with pancreatic islet cell tumors and evaluated them as a marker for these tumors. We also performed the gel filtration of the plasma from a gastrinoma patient and investigated the processing of PST and GAWK in plasma. Elevation of plasma PST-LI was found in 4 of 12 patients (33%) and elevation of plasma GAWK-LI was found in 6 of 12 patients (50%). A significant correlation was not found between plasma PST- and GAWK-LI concentrations of the patients. In the gel permeation chromatography of the plasma from a gastrinoma patient, PST-LI composed of a single peak but GAWK-LI composed of several components with wide range molecular weights.

Plasma 7B2 was measured in 13 patients with pancreatic islet cell tumors, 11 with pancreatic adenocarcinoma and 31 normal subjects as a control. The mean (+/- SD) concentrations of plasma 7B2 in the normal subjects and the patients with pancreatic islet cell tumors were 67 +/- 10 and 1041 +/- 1786 pmol/l, respectively, and the value in the patients with pancreatic islet cell tumors was significantly higher than that in the normal subjects (p less than 0.01). Elevation of plasma 7B2 over the normal range, defined as less than the mean + 3SD value of those in the normal subjects, was found in 10 of 13 patients with pancreatic islet cell tumors including 4 with nonfunctioning tumor. Plasma 7B2 dropped into the normal range postoperatively in 3 patients with nonfunctioning tumor. Plasma 7B2 concentrations in the patients with pancreatic adenocarcinoma remained in the normal range. These results raise a possibility that 7B2 is a useful marker for pancreatic islet cell tumors, in particular nonfunctioning tumor.

Production and secretion of somatostatin (SRIF) were studied using a carcinoembryonic antigen (CEA)-producing cell line (QGP-1) established from a human pancreatic islet cell carcinoma. High concentrations of SRIF (274 +/- 51 ng/mg of protein, mean +/- SD, n = 5) and CEA (3083 +/- 347 ng/mg of protein, mean +/- SD, n = 5) were present in QGP-1 cells, and the basal secretion rates of SRIF and CEA by the cells (n = 5) were 46.4 +/- 4.8 and 1690 +/- 78 pg/10(5) cells/h, respectively. Immunohistochemical studies revealed the presence of SRIF in xenografts of QGP-1 cells and colocalization of SRIF and CEA. Secretion of SRIF by QGP-1 cells was stimulated in the presence of high K+ (50 mmol) and theophylline (10 mmol), but arginine (10 mmol) and glucose (300 mg/dl) had no effect on the SRIF secretion. The QGP-1 cell line may be useful for studying the regulation mechanism of SRIF secretion.

A patient with a somatostatin (SRIH)-secreting islet cell tumor, whose only symptoms were dyspepsia and anemia, is described. The diagnosis of somatostatinoma was based on high plasma SRIH concentrations and immunocytochemical findings. The pancreatic exocrine response to secretin was decreased, whereas the insulin and/or glucagon responses to glucose and arginine were normal. Although the basal plasma GH concentration was normal, the plasma GH response to GHRH was subnormal. Gel permeation chromatography studies indicated that SRIH-14 was the predominant form of SRIH in plasma as well as in tumor tissue.

Plasma pancreastatin (PST)-like immunoreactivity in normal subjects and patients with various diseases was estimated by a RIA, using antiserum raised against a synthetic C-terminal peptide of human PST deduced from the sequence of human chromogranin-A. The mean level +/- SEM was 13.2 +/- 0.6 pmol/L in normal subjects, but was significantly higher in patients with chronic renal failure (526.7 +/- 48.5). An immunoreactive form corresponding to a human PST-like sequence [human chromogranin-A-(250-301)] and a larger form were detected by gel filtration of plasma from these patients, suggesting accumulation of the larger molecular form in these patients. A significant increase in PST-like immunoreactivity was also found in patients with liver cirrhosis (20.8 +/- 3.0 pmol/L), but not in patients with noninsulin-dependent diabetes mellitus, chronic pancreatitis, or pancreatic cancer. Elevated levels were found in 16 of the 21 patients with small cell lung carcinoma examined. High levels were also found in 3 of 11 patients with islet cell tumor.