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Endoscopic biliary drainage is the recommended 1st-line treatment for malignant biliary obstruction. Although a high incidence of febrile neutropenia has been reported in patients treated with FOLFIRINOX and a biliary stent, it remains unknown whether the biliary stent contributes to patient survival. Thus, we aimed to elucidate the effects of biliary stents on the survival of patients with advanced pancreatic cancer treated with modified FOLFIRINOX (mFFX). We retrospectively reviewed medical charts of patients with advanced pancreatic cancer treated with mFFX between January 2014 and April 2020. We compared the overall survival (OS) of patients with and without biliary stent during mFFX treatment and examined the independent effect on mortality using propensity score matching. Overall, we included 89 patients (stent group, n = 24; non-stent group, n = 65). The proportion of patients with pancreatic head cancer was significantly higher in the stent group than in the non-stent group (P < .01). Stratification analysis in patients with pancreatic head cancer revealed that OS was significantly shorter in the stent group than in the non-stent group (P = .03). After propensity score matching, 19 pairs of patients in each group were analyzed. The stent group revealed a significantly shorter survival than the non-stent group (median OS, 10.3 vs 24.9 months; P < .01). The incidences of febrile neutropenia (P = .01) and biliary tract-related events that required biliary stenting or stent replacement (P < .01) were significantly higher in the stent group than in the non-stent group. Stent insertion was an independent risk factor for overall mortality. Biliary stents may reduce survival in patients with advanced pancreatic cancer. The rate of febrile neutropenia was higher in the stent group than in the non-stent group. There is a need to assess the patient's condition with discretion and develop a treatment strategy with short prognosis in mind after stent insertion., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

A 71-year-old man presented to our hospital with abdominal pain. He was diagnosed with acute pancreatitis and pancreatic cancer. Peritoneal washing cytology(CY)was positive, and laparotomy findings revealed severe inflammatory changes of pancreatitis, suggesting a high likelihood of the need for combined resection of other organs. Therefore, following the exploratory laparotomy, mFOLFIRINOX was initiated as chemotherapy. After 24 courses of mFOLFIRINOX, he developed drug-induced pneumonia. Therefore, chemotherapy was interrupted, and a steroid was started. Radiotherapy was administered during steroid tapering. There was no evidence of local progression or distant metastasis. A radical resection that included pancreaticoduodenectomy and right hemicolectomy was performed 23 months after the exploratory laparotomy. CY was negative and R0 resection was achieved. However, 5 months after the operation, he developed liver abscesses and cholangitis and was suspected to have liver metastasis. He underwent PTAD and PTCD, but died due to liver failure 8 months postoperatively. The early recurrence of this case might have been caused by the lack of postoperative chemotherapy due to his frailty. Surgical indications should be carefully judged if there is a high risk of recurrence after NAC and a high possibility that ACT cannot be performed after radical surgery.

Background: Postoperative infection after pancreatectomy in patients with pancreatic cancer often leads to poor prognosis. The aim of this study was to determine the prognostic effect of postoperative infection in patients with pancreatic cancer., Methods: A multicenter cohort study was performed using a common database of patients with pancreatic cancer who underwent curative pancreatic resections between April 2013 and March 2015 at 15 high-volume centers in Japan. The rate of postoperative infection was determined, and patient demographic characteristics, clinicopathologic factors, and prognostic factors for overall survival were analyzed., Results: Of the 462 eligible patients who underwent curative pancreatectomy, postoperative infection occurred in 141 patients (31%), including 114 surgical site infections (25%), 50 remote infections (11%), and 23 combined infections (5%). Risk factors for postoperative infection included high body mass index, nondiabetes, and longer operation time. In the survival analysis, patients with postoperative infection had significantly worse overall survival than patients without postoperative infection. The median survival times were 21.9 and 33.0 months (P = .023), respectively, for patients with and without postoperative infection. According to the multivariate analysis for overall survival, lack of adjuvant therapy (P = .002), but not postoperative infection (P = .829), predicted poor prognosis. The multivariate analysis revealed that postoperative infection (P < .001) was an independent risk factor for lack of adjuvant therapy., Conclusion: Postoperative infection in patients with pancreatic cancer may indirectly worsen the prognosis by preventing timely adjuvant therapy., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background and Aims: This large multicenter randomized controlled trial compared the diagnostic yields of 22-gauge standard and 22-gauge Franseen needles for EUS-guided tissue acquisition (EUS-TA) of solid pancreatic lesions., Methods: Consecutive patients with solid pancreatic lesions were prospectively randomized to EUS-TA using standard or Franseen needles. Samples obtained with the first needle pass and with second and subsequent passes were evaluated separately. The primary endpoint was the rate of accuracy for diagnosis of malignancy. Other endpoints were technical success rate, sample cellularity, adverse events, diagnostic accuracy in patient subgroups, and the diagnostic accuracy and numbers of second and subsequent needle passes., Results: Of 523 patients undergoing EUS-TA, 260 were randomized to using standard 22-gauge needles and 263 to 22-gauge Franseen needles. The technical success rate in each group was 99.6%, with similar adverse event rates in the standard (1.5%) and Franseen (.8%) needle groups. First-pass EUS-TA using the Franseen needle resulted in significantly greater diagnostic accuracy (84.0% vs 71.2%, P < .001) and sensitivity (82.4% vs 66.7%, P < .001) than first-pass EUS-TA using a standard needle and also resulted in superior diagnostic accuracy in patients requiring immunostaining. Second and subsequent EUS-TA using Franseen needles showed significantly greater accuracy (94.7% vs 90.0%, P = .049) and sensitivity (94.0% vs 88.6%, P = .047) and required fewer needle passes (1.81 vs 2.03, P = .008) than using standard needles., Conclusions: EUS-TA with the Franseen needle is superior to EUS-TA with a standard needle with respect to diagnostic accuracy per pass, particularly in patients who require immunostaining, and number of passes when using macroscopic on-site evaluation. (Clinical trial registration numbers: UMIN000030634 and jRCTs052180062.)., (Copyright © 2022 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Background: Endoscopic ultrasonography (EUS) is proven to be a more specific and sensitive method for detecting pancreatic lesions. However, usefulness of EUS after pancreatectomy has not been reported. This study aimed to evaluate the observational capability of EUS for the remnant pancreas (RP) after pancreatectomy., Patient and Methods: This single-center, retrospective study enrolled 395 patients who underwent pancreatectomy at Onomichi General Hospital between December 2002 and March 2016, 45 patients who underwent EUS for RP were included for analysis. We evaluated the usefulness of EUS for RP using logistic regression analysis., Results: Complete observation of the RP was done in 42 patients (93%). In the initial surgical procedure, 21 patients underwent pancreaticoduodenectomy (PD), and 24 patients underwent distal pancreatectomy (DP). PD and DP were observed in 85% (18/21) and 100% (24/24) cases, respectively. A comparison of the detection capability of EUS and contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) showed that EUS was significantly superior to contrast-enhanced CT or MRI (p < 0.01). Eight of the 45 patients showed recurrence lesions in the RP. The median recurrence period was 33 months. Predictive factors for recurrence in the univariate and multivariate analyses were significantly different in space occupying lesion with EUS findings (p < 0.01) and elevated CA19-9(p < 0.01)., Conclusions: EUS was able to observe the RP in almost all cases. In addition, the detection capability of EUS was significantly superior to those of CT or MRI. We recommend that all patients with RP should undergo EUS, and a longer follow-up must be performed., Competing Interests: The authors have declared that no competing interests exist.

Endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNAB) is safe and useful for the diagnosis of pancreatic cancer. However, sometimes a diagnosis cannot be established by EUS-FNAB. The efficacy of serial pancreatic juice aspiration cytological examination (SPACE) for pancreatic cancer was reported. SPACE may be useful in cases in which diagnosis by EUS-FNAB is difficult; however, this has not been reported previously. We herein report two cases of pancreatic cancer diagnosed by SPACE when diagnosis by EUS-FNAB was difficult. Case 1 was a 77-year-old female. She was suspected of pancreatic cancer because of new-onset diabetes. We performed EUS-FNAB to the lesion in the pancreatic body; however, diagnosis failed. We performed SPACE and diagnosed pancreatic cancer finally. Case 2 was 72 years old female. She was suspected of having pancreatic cancer because of the dilatation of the pancreatic duct. We performed EUS-FNAB twice to the lesion in the pancreatic head, however, diagnosis failed. Therefore, we performed SPACE and got final diagnosis as pancreatic cancer. From our experience, we suggest that SPACE is a useful diagnostic method for patients with pancreatic cancer that are difficult to diagnose.

A previously healthy 52-year-old man was referred to our hospital for further evaluation of main pancreatic duct dilatation. The preoperative work-up was consistent with intraductal papillary mucinous carcinoma (IPMC) derived from a mixed type intraductal papillary mucinous neoplasm (IPMN), because multilocular cysts with enhancing thickened pancreatic head walls and dilated pancreatic ducts lined with dysplastic mucinous epithelium, with papillary proliferation from the pancreatic body to the tail, were observed; in addition, the pancreatic juice cytology was class V, which is suggestive of adenocarcinoma. Total pancreatectomy was performed because a definite mass was not found before surgical resection and the tumors could have spread to the tail. The pathological diagnosis was mixed adenoneuroendocrine carcinoma of the pancreatic head. IPMN with high- or low-grade dysplasia was not observed anywhere in the pancreatic duct. The pancreatic ductal adenocarcinoma consisted of large caliber malignant glands with intraluminal flat or papillary structures; therefore, we were unable to recognize a definite pancreatic mass before surgical resection, and suspected an IPMC derived from a mixed type IPMN.

An 81-year-old woman, who had undergone left radical nephrectomy for renal cell carcinoma 17 years previously, was found to have a mass approximately 5cm in diameter in the body of the pancreas and an early gastric cancer. The patient was suspected of having pancreatic metastasis from renal cell carcinoma and an early gastric cancer and underwent distal pancreatectomy, splenectomy, and distal gastrectomy. Histologic examination showed that the pancreatic tumor was a clear cell renal cell carcinoma that had metastasized to the body of the pancreas and that the gastric cancer was a well-differentiated adenocarcinoma that had invaded the mucosa. Twenty months after the operation, the patient was well, without any evidence of recurrence. Renal cell carcinoma metastatic to the pancreas with gastric cancer rarely occurs, and surgical resection might have improved the quality of life in this patient. Careful long-term follow-up is necessary for patients who have undergone surgery for renal cell carcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy that frequently metastasizes and that overexpresses transforming growth factor-beta s (TGF-beta s). To determine whether TGF-beta s can act to enhance the metastatic potential of PDAC, PANC-1 human pancreatic cancer cells were transfected with an expression construct encoding a soluble type II TGF-beta receptor (sT beta RII) that blocks cellular responsiveness to TGF-beta 1. When injected s.c. in athymic mice, PANC-1 clones expressing sT beta RII exhibited decreased tumor growth in comparison with sham-transfected cells and attenuated expression of plasminogen activator inhibitor 1 (PAI-1), a gene associated with tumor growth. When tested in an orthotopic mouse model, these clones formed small intrapancreatic tumors that exhibited a suppressed metastatic capacity and decreased expression of plasminogen activator inhibitor 1 and the metastasis-associated urokinase plasminogen activator. These results indicate that TGF-beta s act in vivo to enhance the expression of genes that promote the growth and metastasis of pancreatic cancer cells and suggest that sT beta RII may ultimately have a therapeutic benefit in PDAC.

Unlabelled: Human pancreatic ductal adenocarcinomas overexpress transforming growth factor-betas (TGF-betas). This overexpression has been correlated with decreased patient survival. TGF-betas bind to a type II TGF-beta receptor (TbetaRII) dimer, which heterotetramerizes with a type I TGF-beta receptor (TbetaRI) dimer, thereby activating downstream signaling., Purpose and Experimental Design: To determine whether blocking TGF-beta actions would suppress pancreatic cancer cell growth in vivo, we expressed a soluble TbetaRII, encoding amino acids 1-159 of the extracellular domain in COLO-357 human pancreatic cancer cells. This cell line expresses all of the three mammalian TGF-beta isoforms and is growth inhibited by TGF-beta in vitro., Results: COLO-357 clones expressing soluble TbetaRII were no longer growth inhibited by exogenous TGF-beta1 and exhibited a marked decrease in their invasive capacity in vitro. When injected s.c. into athymic mice, these clones exhibited attenuated growth rates and angiogenesis and decreased levels of plasminogen activator inhibitor-1 mRNA as compared with tumors formed by sham-transfected cells., Conclusions: These results indicate that endogenous TGF-betas can confer a growth advantage in vivo to a pancreatic cancer cell line that is growth inhibited in vitro and suggest that a soluble receptor approach can be used to block these tumorigenic effects of TGF-betas.

Transforming growth factor-beta (TGF-beta) signaling is dependent on the heterodimerization of the type II TGF-beta receptor (TbetaRII) with the type I TGF-beta receptor (TbetaRI). Activated TbetaRI then mediates TGF-beta signals by inducing the phosphorylation of Smad2 and/or Smad3, which separately hetetorodimerize with Smad4 and translocate to the nucleus. Phosphorylation of Smad2/Smad3 by activated TbetaRI is inhibited by two newly discovered members of the Smad family, Smad6 and Smad7. We now report that Smad7 mRNA levels are increased in human pancreatic cancer by comparison with the normal pancreas, and that by in situ hybridization, Smad7 is over-expressed in the cancer cells within the tumor mass. Stable transfection of COLO-357 human pancreatic cancer cells with a full-length Smad7 construct leads to complete loss of the growth inhibitory response to TGF-beta1, without altering TGF-beta1-mediated induction of PAI-I. Furthermore, Smad7 transfected COLO-357 cells display enhanced anchorage-independent growth and accelerated growth in nude mice. These findings point to a previously unrecognized mechanism for selective suppression of TGF-beta-mediated growth inhibition in cancer cells that allows for continued activation of the PAI-I promoter by TGF-beta1, which may act to enhance the tumorigenicity of certain cancer cells.

Id proteins antagonize basic helix-loop-helix proteins, inhibit differentiation, and enhance cell proliferation. In this study we compared the expression of Id-1, Id-2, and Id-3 in the normal pancreas, in pancreatic cancer, and in chronic pancreatitis (CP). Northern blot analysis demonstrated that all three Id mRNA species were expressed at high levels in pancreatic cancer samples by comparison with normal or CP samples. Pancreatic cancer cell lines frequently coexpressed all three Ids, exhibiting a good correlation between Id mRNA and protein levels, as determined by immunoblotting with highly specific anti-Id antibodies. Immunohistochemistry using these antibodies demonstrated the presence of faint Id-1 and Id-2 immunostaining in pancreatic ductal cells in the normal pancreas, whereas Id-3 immunoreactivity ranged from weak to strong. In the cancer tissues, many of the cancer cells exhibited abundant Id-1, Id-2, and Id-3 immunoreactivity. Scoring on the basis of percentage of positive cells and intensity of immunostaining indicated that Id-1 and Id-2 were increased significantly in the cancer cells by comparison with the respective controls. Mild to moderate Id immunoreactivity was also seen in the ductal cells in the CP-like areas adjacent to these cells and in the ductal cells of small and interlobular ducts in CP. In contrast, in dysplastic and atypical papillary ducts in CP, Id-1 and Id-2 immunoreactivity was as significantly elevated as in the cancer cells. These findings suggest that increased Id expression may be associated with enhanced proliferative potential of pancreatic cancer cells and of proliferating or dysplastic ductal cells in CP.

Macrophage Proinflammatory Human Chemokine-3alpha (Mip-3alpha/LARC/Exodus) belongs to a large family of chemotactic cytokines, which participate in directing inflammatory cell migration and in modulating angiogenesis. Mip-3alpha signals through a recently identified G-protein linked 7-transmembrane receptor, CCR6. In this study, we have characterized the expression of Mip-3alpha and CCR6 in 12 normal and 16 cancerous human pancreatic tissues and in 4 cultured pancreatic cancer cell lines, and assessed the effects of Mip-3alpha on growth and invasion of these cell lines. Pancreatic cancer tissues markedly overexpressed Mip-3alpha in comparison with normal pancreatic samples. By in situ hybridization Mip-3alpha and CCR6 mRNA moieties were present in cancer cells within the tumors. In addition, Mip-3alpha was abundant in the macrophages infiltrating the tumor mass. Mip-3alpha and its receptor CCR6 were expressed in all 4 tested pancreatic cancer cell lines. Mip-3alpha stimulated the growth of one cell line, enhanced the migration of another cell line, and was without effect in the other 2 cell lines. Together, our findings suggest that Mip-3alpha has the potential to act via autocrine and paracrine mechanisms to contribute to the pathobiology of human pancreatic cancer.

Background & Aims: Bone morphogenetic proteins (BMPs) belong to the transforming growth factor beta superfamily of signaling molecules. We characterized the expression of BMP-2 and its receptors in human pancreatic tissues and pancreatic cancer cell lines and examined the effects of BMP-2 on mitogenesis., Methods: Expression of BMP-2 and its receptors was determined by Northern blot analysis using specific complementary DNA probes. Distribution of BMP-2 in pancreatic cancers was examined by immunohistochemistry and in situ hybridization. Effects of BMP-2 on mitogenesis were assessed by monitoring cell proliferation and activation of mitogen-activated protein kinase (MAPK)., Results: Compared with the normal pancreas, pancreatic cancers showed a 12.5-fold (P < 0.01), 2-fold (P < 0.01), and 8-fold (P < 0.01) increase of BMP-2, BMP receptor (R)-IA, and BMPR-II messenger RNA levels, respectively. By immunohistochemistry and in situ hybridization, BMP-2 was expressed in the cancer cells within the tumor mass. There was a significant correlation between the presence of BMP-2 immunostaining in the tumors and shorter postoperative survival. Pancreatic cancer cell lines expressed variable levels of messenger RNA encoding BMP-2 and its receptors. BMP-2 stimulated the growth of two pancreatic cancer cell lines (ASPC-1 and CAPAN-1). This mitogenic effect was associated with MAPK activation and blocked by the MAPK inhibitor PD98059 in CAPAN-1 but not in ASPC-1 cells. In both cell lines, expression of wild-type Smad4 abolished the BMP-2-mediated growth stimulation. BMP-2 inhibited the growth of COLO-357 cells, an effect that was blocked by expressing a dominant negative Smad4. BMP-2 had no effect in three cell lines that underexpressed either the BMP receptors or Smad1., Conclusions: These findings indicate that BMP-2 has the capacity to act as a mitogen when Smad4 is mutated and suggest that it might play a role in the pathobiology of human pancreatic cancer.

Transforming growth factor (TGF)-beta signaling is initiated by heterodimerization of TGF-beta receptor type I (TbetaRI) and type II (TbetaRII). Subsequently, the signal is transduced via Smad proteins, which upon phosphorylation and heterodimerization translocate to the nucleus and regulate gene transcription. Smad6 functions as an intracellular antagonist of TGF-beta signaling. In the present study we demonstrate that Smad6 is overexpressed in vivo in human pancreatic cancer cells. We also show that stable transfection of a full-length Smad6 construct into COLO-357 pancreatic cancer cells abrogates TGF-beta1 induced growth inhibition, and leads to enhanced anchorage-independent growth. Thus, enhanced expression of the TGF-beta signaling inhibitor Smad6 in pancreatic cancer may present a novel mechanism of TGF-beta resistance, which might have the potential to enhance the transformed phenotype of human cancer cells., (Copyright 1999 Academic Press.)

Insulin receptor substrate-2 (IRS-2) is a multisite docking protein implicated in mitogenic signaling after activation of the insulin and insulin-like growth factor (IGF)-I receptors. In the present study, we characterized IRS-2 expression and function in human pancreatic cancer. IRS-2 mRNA and protein were expressed in ASPC-1 and COLO-357 human pancreatic cancer cell lines. Insulin, IGF-I, and IGF-II enhanced the growth of both cell lines, stimulated tyrosine phosphorylation of IRS-2, and increased IRS-2-associated phosphatidylinositol (PI) 3-kinase activity. The mitogenic effects of insulin, IGF-I, and IGF-II were markedly attenuated by the PI 3-kinase inhibitor LY 294002. Northern blot analysis of total RNA extracted from normal and cancerous tissues revealed that IRS-2 mRNA levels were increased in the cancer tissues (P = 0.032). In the normal pancreas, IRS-2 immunoreactivity was present at low levels in some ductal and acinar cells and at moderate levels in a heterogeneous pattern in all of the endocrine islets. In the pancreatic cancers, IRS-2 was abundant in the ductal-like cancer cells. These findings indicate that IRS-2 is overexpressed in human pancreatic cancer and suggest that it may contribute to enhanced mitogenic signaling via the PI 3-kinase pathway, thereby leading to excessive growth stimulation in this malignancy.

A case of Ki-1-positive anaplastic large cell lymphoma of the pancreas is presented. The patient complained of abdominal pain and was jaundiced. Examination of a biopsy specimen obtained by duodenal endoscopy revealed malignant lymphoma, and surgery confirmed a large mass located in the region from the intra-pancreatic tissue around the lower common bile duct to the peri-pancreatic lymph nodes. Histologically, this tumor was composed mainly of large and giant neoplastic cells. Immunohistochemically, these cells were diffusely positive for Ki-1 and CD45RO antigens, indicating the features of Ki-1 anaplastic large cell lymphoma with a T-cell phenotype among non-Hodgkin's lymphoma. The histologic types of the majority of malignant lymphomas of the pancreas reported previously were considered to be diffuse-type non-Hodgkin lymphoma (probably with predominance of the B-cell phenotype), except for a single Japanese lymphoma case with a T-cell phenotype. This is therefore the first known case of Ki-1 anaplastic large cell lymphoma of the pancreas.

The effects of dietary administration of catechol (CC), paramethylcatechol (PMC) and di(2-ethylhexyl)phthalate (DEHP) were compared with that of butylated hydroxyanisole (BHA) in Syrian hamsters initiated with N-nitrosobis(2-hydroxypropyl)amine (BHP). Development of pancreatic atypical hyperplasias and adenocarcinomas in terms of combined multiplicity was significantly reduced by CC and DEHP. A similar slight but non-significant tendency was observed for BHA, while PMC was without effect. No statistically significant reduction of liver or gall bladder lesions was observed. The results thus suggest that both antioxidant and peroxisome proliferator categories of agents can inhibit pancreatic carcinogenesis in hamsters.

To assess the temporal changes of the pancreatic duct following the administration of N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) in two dogs, serial pancreatography was performed. They received intraductal administration of a total of 595 and 500 mg ENNG in each one, over the periods of 12 and 13.5 months, respectively. In one dog, sequential changes of the main duct were observed, a small round filling defect developed a circumferential defect and became a severe stenosis associated with proximal dilatation of the duct. While no gross tumors were macroscopically detected at autopsy, continuous lesions with features of hyperplasia, atypical hyperplasia, and cancerous change of duct epithelial cells were microscopically seen. In the other one, a small round filling defect was detected by pancreatography, which was histopathologically hyperplasia of pancreatic duct, rather than cancerous cells. The present dog model for induction of pancreatic duct carcinomas appears useful for elucidating clinico-pathological changes occurring during cancer development.

The modifying effects of the phenolic antioxidant catechol (CC) and its analogs hydroquinone (HQ) and resorcinol (RN) on pancreatic carcinogenesis were evaluated in 146 female Syrian golden hamsters. Groups of animals received either saline or 70 mg/kg body wt N-nitrosobis(2-oxopropyl)amine (BOP) s.c. injections, twice with a 2 week interval, followed by basal diet or diet containing 1.5% of CC, HQ or RN, and 0.75% CC from week 4. All hamsters were killed at week 20 and histopathologically examined for development of pancreatic, liver and gall bladder lesions. The total numbers of pancreatic lesions comprising carcinomas, atypical ductal hyperplasias and ductal hyperplasias per hamster were significantly decreased in animals receiving BOP followed by CC, HQ and RN when compared to those in hamsters given BOP followed by basal diet. Incidence values for atypical ductal hyperplasias were also significantly decreased by the RN or 0.75% CC treatments. The results thus suggest that pancreatic carcinogenesis initiated by BOP in Syrian hamsters can be inhibited by treatments with phenolic antioxidants such as CC, HQ and RN for a relatively short experimental period.

The potential initiating activity of diethylnitrosamine (DEN) was studied in a rapid production model for pancreatic carcinogenesis in hamsters developed in our laboratory incorporating the principle of selection based on resistance of cytotoxicity, originally demonstrated for liver carcinogenesis in rats. Female Syrian golden hamsters were given DEN at a dose of 100 mg/kg body weight or N-nitrosobis-(2-oxopropyl)amine (BOP) at a dose of 70 mg/kg body weight as initiators followed by 3 cycles of augmentation pressure (choline-deficient diet combined with DL-ethionine, L-methionine upon return to basal diet and then administration of 20 mg/kg body weight BOP), and killed 10 weeks after the beginning of the experiment. DEN followed by the augmentation pressure induced a 65% incidence of total pancreatic lesions including 15% carcinomas, while BOP followed by the augmentation pressure induced 100% incidence of total pancreatic lesions and 84.2% for carcinomas. These yields were significantly greater than those observed for augmentation pressure alone. The results thus indicate that DEN possesses weak initiating activity for pancreatic carcinogenesis under the present experimental conditions.

Pancreatic tumorigenesis of azaserine by a single intraperitoneal (i.p.) injection after partial pancreatectomy in male Wistar rats was studied. Pancreatic lesions developed in all rats 52 weeks after the administration of azaserine at doses of 50 mg (Group 1) or 100 mg/kg body wt (Group 2). Histologically, there were hyperplastic nodules in 4 of 12 rats and 4 of 7 rats, in Groups 1 and 2, respectively, adenomas 100% in both groups, and adenocarcinomas 2 of 7 rats of Group 2. It appears that pancreatic regeneration induced by partial pancreatectomy enhances the azaserine tumorigenesis.

PCAA, a glycoprotein antigen identified and purified from ascited fluid of a pancreatic cancer patient and sharing the identical immunogenicity with Gelder's POA (Shimano, 1981) and PaA, a novel pancreas tissue antigen (Loor, 1981) purified from saline extract of human pancreas were studied. (1) Chemical composition: The purified PCAA from ascites fluid of a pancreatic cancer patient has a molecular weight of 10,000,000. The same antigenic substance as PCAA was also isolated and purified from normal colonic mucosa. Amino acid compositions of these antigens were similar. PCAA appeared to be a N-glycosidic glycoprotein. Antisera against these antigens were immunologically identical to Gelder's anti-POA in gel diffusion. The purified PaA has a molecular weight of 44,000, a sedimentation coefficient of 3.4S and an isoelectric point of 4.9. (2) Tissue localization: In pancreatic cancer tissues, PCAA and PaA were detected at apical cytoplasm of cancer cells, though positive cells were in different proportions and with different distribution each other. PCAA-positive cells were well differentiated while PaA-positive cells were less differentiated in histology. (3) Serum levels: A sensitive and reproducible sandwich-type enzyme immunosorbent assay has been developed for quantitation of PCAA and PaA. Using 18.6 micrograms/ml (mean + 2 S.D. of normal controls) as an upper limit, 43 of 76 pancreatic cancer (56%) and 34 of 167 other diseases (20%) had an elevated PCAA level. Using 21.5 ng/ml as an upper limit, 50 of 76 pancreatic cancer (66%) and 13 of 167 other diseases (8%) had an elevated PaA level. The sensitivity of simultaneous assay of PCAA and PaA for the detection of pancreatic cancer increased to be 90% (69/76) while false positive was 24% (40/167). The results indicate that combination assay of PCAA and PaA may be useful in immunodiagnosis of pancreatic cancer.

PCAA, a glycoprotein antigen fractionated from the ascites fluid of a patient with pancreatic cancer and sharing an identical immunogenicity with Gelder's POA, and PaA, a novel pancreatic tissue antigen, were studied immunohistologically. Serial paraffin sections were prepared from surgical specimens of 11 cases of pancreatic cancer, 15 of gastric cancer, 12 of colonic cancer, and 2 of gallbladder cancer; these were then subjected to immunofluorescence and immunoperoxidase stainings. In noncancerous tissues, PCAA was detected unexpectedly at goblet cells of the whole intestine, but was completely absent in pancreatic tissues, while PaA was not demonstrated in intestinal tissues, but was positive at acinar cells of the pancreas. In pancreatic cancer tissues, PCAA and PaA were detected at apical cytoplasm of cancer cells, although positive cells were in different proportions and had different distributions. PCAA-positive cells were mucin-producing (positive in PAS-alcian blue staining) and were well differentiated histologically, while PaA-positive cells were less differentiated and poor in mucin production. Among 11 cases of pancreatic cancer, both PCAA- and PaA-positive cells were demonstrated in 3 cases, PCAA-positive cells alone were found in 3 cases, and PaA-positive cells alone were seen in 4 cases. In 27 gastrointestinal cancer tissues, PCAA was detected in 7 cases of mucin-producing cancer, and PaA was demonstrated in 2 cases of poorly differentiated adenocarcinoma.

Cytokeratin 20 belongs to the epithelial subgroup of the intermediate filament family. Because of its restricted range of expression in humans, it has become an important tool for detecting and identifying metastatic cancer cells by immunohistochemistry and by PCR analysis. Despite its widespread diagnostic use in colorectal cancer and occasional use in pancreatic cancer, little is known about the expression of CK 20 in these tumors in vivo. Therefore, in the present study we characterized CK 20 expression in pancreatic and colorectal cancer by comparison with its expression in the normal pancreas and colon. Tissue samples from 24 patients with pancreatic cancer and from 41 patients with colorectal cancer were examined for CK 20 expression by Northern blot analysis, immunohistochemistry, and in situ hybridization. CK 20 expression was observed in the cancer cells of both cancer types. A subgroup of the pancreatic cancers exhibited a 3.2-fold increase in CK 20 mRNA by comparison with respective normal controls. In contrast, colon cancers underexpressed CK 20 mRNA by comparison with the respective controls. In the normal tissues, CK 20 immunoreactivity was relatively faint and sparse in the pancreatic ductal cells but intense and abundant in the apical portions of the colonic mucosa. CK 20 immunoreactivity was also evident in the ductal cells from the chronic pancreatitis-like lesions adjacent to the cancer cells. Furthermore, distant metastases from pancreas carcinomas exhibited strong CK 20 immunoreactivity. It is concluded that CK 20 is overexpressed in pancreatic cancer and that it can serve as an excellent marker for metastatic pancreatic cancer.