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The role of computed tomography (CT) in the initial diagnosis of pancreatic cancer (PC) is well-known. CT reports made by radiologists are important as not all patients with PC are examined by specialists; however, some cases are not identified based on CT reports. Diagnosis via imaging of PC is sometimes difficult, and the diagnostic rate of PC and other pancreatic diseases can vary across radiologists. This study aimed to examine the diagnostic rate of PC in initial CT reports and the details of cases with diagnostic difficulties. This single-centered, retrospective study collected clinical data of 198 patients with histologically diagnosed PC between January 2018 and April 2022. Out of these contrast-enhanced CT was performed in 192 cases. PC was not reported as the main diagnosis in 18 patients (9.4%; 11 men and 7 women). Among these 18 cases, intrapancreatic mass lesions were detected in 3 (1.6%), indirect findings such as bile/pancreatic duct stenosis or dilation were detected in 5 (2.6%), and no PC-related findings were found in 10 (5.2%). The specialists suspected PC in 15 of these 18 cases based on initial CT reports. 17 cases were confirmed by endoscopic ultrasound-fine needle aspiration and one by biopsy after upper gastrointestinal endoscopy. To improve accuracy of its diagnosis, it is important that specialists provide feedback to diagnostic radiologists regarding the findings they did not report. Endoscopic ultrasound-fine needle aspiration should be performed by specialists when there is clinical information which indicates pancreatic disease of any kind., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Pancreatic ductal adenocarcinoma is speculated to become the second leading cause of cancer-related mortality by 2030, a high mortality rate considering the number of cases. Surgery and chemotherapy are the main treatment options, but they are burdensome for patients. A clear histological diagnosis is needed to determine a treatment plan, and endoscopic ultrasound (EUS)-guided tissue acquisition (TA) is a suitable technique that does not worsen the cancer-specific prognosis even for lesions at risk of needle tract seeding. With the development of personalized medicine and precision treatment, there has been an increasing demand to increase cell counts and collect specimens while preserving tissue structure, leading to the development of the fine-needle biopsy (FNB) needle. EUS-FNB is rapidly replacing EUS-guided fine-needle aspiration (FNA) as the procedure of choice for EUS-TA of pancreatic cancer. However, EUS-FNA is sometimes necessary where the FNB needle cannot penetrate small hard lesions, so it is important clinicians are familiar with both. Given these recent dev-elopments, we present an up-to-date review of the role of EUS-TA in pancreatic cancer. Particularly, technical aspects, such as needle caliber, negative pressure, and puncture methods, for obtaining an adequate specimen in EUS-TA are discussed., Competing Interests: Conflict-of-interest statement: The authors declare that they have no conflicts of interest., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

We herein describe an 82-year-old patient who presented with proteinuria and systemic edema. He was diagnosed with minimal change disease (MCD) and was found to have stage III pancreatic cancer. He could not undergo surgical resection due to invasion to the celiac artery and he was thus treated with chemotherapy. After a month of chemotherapy, his proteinuria improved to a normal level. After two months of chemotherapy, computed tomography indicated a partial response to the therapy. MCD can occur as paraneoplastic syndrome in patients with malignant disease, and chemotherapy can be effective for MCD associated with paraneoplastic syndrome.

Background: Cell-free DNA (cfDNA) shed from tumors into the circulation offers a tool for cancer detection. Here, we evaluated the feasibility of cfDNA measurement and utility of digital PCR (dPCR)-based assays, which reduce subsampling error, for diagnosing pancreatic ductal adenocarcinoma (PDA) and surveillance of intraductal papillary mucinous neoplasm (IPMN)., Methods: We collected plasma from seven institutions for cfDNA measurements. Hot-spot mutations in KRAS and GNAS in the cfDNA from patients with PDA (n = 96), undergoing surveillance for IPMN (n = 112), and normal controls (n = 76) were evaluated using pre-amplification dPCR., Results: Upon Qubit measurement and copy number assessment of hemoglobin-subunit (HBB) and mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 1 (MT-ND1) in plasma cfDNA, HBB offered the best resolution between patients with PDA relative to healthy subjects [area under the curve (AUC) 0.862], whereas MT-ND1 revealed significant differences between IPMN and controls (AUC 0.851). DPCR utilizing pre-amplification cfDNA afforded accurate tumor-derived mutant KRAS detection in plasma in resectable PDA (AUC 0.861-0.876) and improved post-resection recurrence prediction [hazard ratio (HR) 3.179, 95% confidence interval (CI) 1.025-9.859] over that for the marker CA19-9 (HR 1.464; 95% CI 0.674-3.181). Capturing KRAS and GNAS could also provide genetic evidence in patients with IPMN-associated PDA and undergoing pancreatic surveillance., Conclusions: Plasma cfDNA quantification by distinct measurements is useful to predict tumor burden. Through appropriate methods, dPCR-mediated mutation detection in patients with localized PDA and IPMN likely to progress to invasive carcinoma is feasible and complements conventional biomarkers.

Introduction: Surgical management is not a standard treatment option for metastatic recurrence of pancreatic adenocarcinoma. However, the surgical management of a solitary metastasis is useful in selected cases., Patient Concerns: A 42-year-old woman was referred to our hospital on account of epigastric pain associated with a mass in the pancreatic body. The patient had a family history of branch duct-type intraductal papillary mucinous neoplasm of the pancreas., Diagnosis: The patient was diagnosed with pancreatic ductal adenocarcinoma (PDA) complicated with pancreatitis due to pancreatic duct involvement., Interventions: The patient underwent distal pancreatectomy, and pathological examination revealed a tubular adenocarcinoma. Solitary liver and lung metastatic tumors were found 6 and 43 months after the initial presentation, respectively, and sequential metastasectomies were performed., Outcomes: The patient survived until 8 years after her initial presentation. The genetic profiles of the resected specimens, primary PDA, and recurrent tumors in the liver and lung possessed identical KRAS mutations at codon 12, whereas there were no mutations in the main tumor suppressor genes, such as TP53, CDKN2A, and SMAD4. Multiplex polymerase chain reaction-based microsatellite instability assay demonstrated microsatellite stability., Conclusion: In our case, the patient with pancreatic adenocarcinoma survived for over 8 years following the resection of the primary tumor and resections of metachronous metastatic tumors. The outcome of PDA may be associated with the genetic profile that regulates its biological behavior. Operative management of solitary metastatic tumors may be a therapeutic options for selected patients with pancreatic cancer.

Pancreatic granular cell tumors (GCTs) are rare and making an imaging diagnosis of pancreatic GCT is difficult because it has no definite characteristics on contrast-enhanced computed tomography (CE-CT) or magnetic resonance imaging (MRI) owing to varying findings. We report about a 32-year-old woman who presented with an incidental finding of a pancreatic tumor with a past history of excision of a right forearm GCT nodule 12 years ago. CE-CT revealed a 23-mm-sized homogeneous low enhancement tumor in the arterial phase in the pancreatic body. Abdominal MRI revealed a lobulated hypointense mass in T1WI and high signal in DWI. Endoscopic ultrasonography (EUS) revealed that the tumor was oval, hypoechoic with posterior echo enhancement, and had a well-defined border. Although EUS-guided fine needle aspiration revealed benign granular cells of the pancreas, she underwent laparoscopic surgery because the metastatic tumor from the past lesion was not excluded. The pathological finding was benign GCT of the pancreas and it was considered as an original lesion. In the previous reports, most of the resected cases were considered to be pancreatic cancer or neuroendocrine tumor preoperatively. Compared to CE-CT and MRI, EUS imaging and EUS-FNA are more reliable diagnosis tools for pancreatic GCT. Although malignant GCT accounts for approximately 1-2% of all cases, surgical resection or strict follow-up should be considered because it is difficult to predict its biological behavior.

Objectives: to determine the diagnostic yield of endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) for suspected pancreatic malignancy. As well as to identify factors that affect the incidence of false-negative cases and evaluate the value of repeated EUS-FNA in patients with inconclusive results., Methods: we retrospectively evaluated the data of patients who underwent EUS-FNA due to a suspected pancreatic malignancy in our hospital from January 2015 to December 2016., Results: a total of 194 EUS-FNA procedures performed and 175 cases were analyzed. The overall sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy were 83.4% (151/181), 100% (13/13), 100% (151/151), 30.2% (13/43), and 84.5% (164/194), respectively. The combination of cytological and histological examination significantly increased the diagnostic performance compared to either method alone. The diagnostic sensitivity in metastatic tumors was significantly lower than that for adenocarcinoma. EUS-FNA performed using standard needles combined with the "slow-pull" technique had a lower sensitivity than other methods. According to the multivariate analysis, neither the combination of needle type and suction technique nor final diagnosis were independent factors that affected the diagnostic sensitivity. The sensitivity of repeated EUS-FNA was 50.0% (8/16). Definitive results after a repeated puncture were more likely for pancreatic body and tail masses, heterogeneous lesions and poorly demarcated lesions. However, the difference was not significant., Conclusions: EUS-FNA was accurate for the evaluation of a suspected pancreatic malignancy. Metastatic tumors and the use of a standard needle in combination with the slow-pull technique may increase the incidence of false-negative results. Repeated EUS-FNA has limited value but should be considered for selected cases where the suspicion of malignancy persists.

Genetic alterations responsible for the initiation of cancer may serve as immediate biomarkers for early diagnosis. Plasma levels of cell-free DNA (cfDNA) in patients with cancer are higher than those in healthy individuals; however, the major technical challenge for the widespread implementation of cfDNA genotyping as a diagnostic tool is the insufficient sensitivity and specificity of detecting early-stage tumors that shed low amounts of cfDNA. To establish a protocol for ultrasensitive droplet digital polymerase chain reaction (ddPCR) for quantification of low-frequency alleles within a limited cfDNA pool, two-step multiplex ddPCR targeting eight clinically relevant mutant KRAS variants was examined. Plasma samples from patients with colorectal (n = 10) and pancreatic cancer (n = 9) were evaluated, and cfDNA from healthy volunteers (n = 50) was utilized to calculate reference intervals. Limited cfDNA yields in patients with resectable colorectal and pancreatic cancers did not meet the requirement for efficient capture and quantification of rate mutant alleles by ddPCR. Eight preamplification cycles followed by a second-run ddPCR were sufficient to obtain approximately 5000-10 000 amplified copies per ng of cfDNA, resolving the subsampling issue. Furthermore, the signal-to-noise ratio for rare mutant alleles against the extensive background presented by the wild-type allele was significantly enhanced. The cutoff limit of reference intervals for mutant KRAS was determined to be ~ 0.09% based on samples from healthy individuals. The modification introduced in the ddPCR protocol facilitated the quantification of low-copy alleles carrying driver mutations, such as oncogenic KRAS, in localized and early-stage cancers using small blood volumes, thus offering a minimally invasive modality for timely diagnosis., (© 2017 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Background: Pancreatic involvement of angiosarcoma is extremely rare., Methods: We herein report a rare case of angiosarcoma associated with chronic lymphedema (Stewart-Treves syndrome) with pancreatic metastasis that was diagnosed using endoscopic ultrasound (EUS)/fine needle aspiration (FNA)., Results: A 43-year-old woman with a history of radical hysterectomy with bilateral inguinal lymphadenectomy and chemoradiotherapy for cervical cancer 15 years prior noticed the presence of erythematous indurative plaques on her right femoral region, where chronic lymphedema had developed. Contrast-enhanced computed tomography (CT) revealed not only multiple nodules in the subcutaneous tissue of the right femoral region but also a 25 mm × 20 mm solid mass in the region of the pancreatic tail. A histological analysis of the specimens obtained using EUS/FNA revealed angiosarcoma that was immunohistochemically positive for platelet/endothelial cell adhesion molecule-1 but negative for cytokeratin. The patient was diagnosed as Stewart-Treves syndrome that had metastasized to the pancreas. Chemotherapy was performed, but the patient died 14 months after her diagnosis., Conclusion: Unfortunately, this patient was not followed up, even though she had chronic lymphedema of the right femoral region due to the repeated occurrence of phlegmon. To improve the survival rate of this fatal secondary malignant complication of radical lymphadenectomy, an early diagnosis with consecutive and long-term clinical follow-up and close monitoring for Stewart-Treves syndrome is therefore important.

The hedgehog pathway is known to promote proliferation of pancreatic ductal adenocarcinoma (PDA) and has been shown to restrain tumor progression. To understand how hedgehog causes these effects, we sought to carefully examine protein expression of hedgehog signaling components during different tumor stages. Genetically engineered mice, Pdx1-Cre;LSL-KrasG12D and Pdx1-Cre;LSL-KrasG12D;p53lox/+, were utilized to model distinct phases of tumorigenesis, pancreatic intraepithelial neoplasm (PanIN) and PDA. Human pancreatic specimens of intraductal papillary mucinous neoplasm (IPMN) and PDA were also employed. PanIN and IPMN lesions highly express Sonic Hedgehog, at a level that is slightly higher than that observed in PDA. GLI2 protein is also expressed in both PanIN/IPMN and PDA. Although there was no difference in the nuclear staining, the cytoplasmic GLI2 level in PDA was modest in comparison to that in PanIN/IPMN. Hedgehog interacting protein was strongly expressed in the precursors, whereas the level in PDA was significantly attenuated. There were no differences in expression of Patched1 at early and late stages. Finally, a strong correlation between Sonic Hedgehog and GLI2 staining was found in both human and murine pancreatic tumors. The results indicate that the GLI2 protein level could serve as a feasible marker of ligand-dependent hedgehog activation in pancreatic neoplasms.

Purpose: To determine the relationship between the fractional interstitial volume (Fis), as calculated at dynamic contrast material-enhanced (DCE) computed tomography (CT), and tumor-associated stroma and to analyze its spatial relationship with tumor hypoxia in several xenograft tumor models., Materials and Methods: All animal experiments were approved by the animal research committee. Mice with three different xenograft tumors (U251, CFPAC-1, and BxPC-3; n = 6, n = 8, and n = 6, respectively) underwent DCE CT then hypoxia imaging with fluorine 18 ((18)F) fluoromisonidazole (FMISO) positron emission tomography (PET) within 24 hours. Immunohistochemical analysis was performed in harvested tumors to detect hypoxia markers and to quantify microvascular and stromal density. Two DCE CT parameters (amount of interstitial space associated with the amount of stroma [Fis] and flow velocity [Fv]) were identified and quantitatively validated by using immunohistochemistry. FMISO uptake within the tumor was also assessed in relation to DCE CT parameters. Imaging and immunohistochemical parameters were assessed by using the Kruskal-Wallis test, Wilcoxon rank-sum test with Bonferroni correction, and Pearson correlation coefficient., Results: Almost no α-smooth muscle actin-positive cells were found in the U251 xenograft, while abundant stroma was found in the entire BxPC-3 xenograft and in the periphery of the CFPAC-1 xenograft. Quantitative analysis showed a significant correlation (R = 0.83, P < .0001) between Fis and stromal density. FMISO uptake had a negative correlation with Fis (R = -0.58, P < .0001) and Fv (R = -0.53, P < .0001)., Conclusion: DCE CT can be used to quantify parameters associated with tumor-associated stroma. Tumor hypoxia was Complementarily localized in tumor-associated stroma in these models.

Background & Aims: Endoscopic sphincterotomy (ES) is performed routinely before self-expandable metallic stents (SEMS) are placed in malignant distal biliary strictures to prevent postprocedural pancreatitis. However, it is not clear whether ES actually prevents pancreatitis or affects other adverse events (AEs). We conducted a noninferiority trial to examine the necessity of ES before SEMS placement., Methods: Two hundred patients with distal biliary strictures caused by unresectable pancreatic cancer were assigned randomly to groups that received ES or did not receive ES (non-ES) before SEMS placement, at 25 hospitals in Hokkaido, Japan, from August 2010 through November 2012. The primary outcome was early AEs (≤30 d) specifically related to the presence or absence of ES (pancreatitis, bleeding, or perforation). Secondary outcomes measured included the effect of ES omission on time to SEMS dysfunction and patient survival times., Results: The proportions of patients with early AEs were 9.2% in the non-ES group and 10.4% in the ES group (a difference of 1.2%, noninferior). The median times to SEMS dysfunction was longer than 594 days in the non-ES group and 541 days in the ES group (P = .88). The median overall survival times were 202 in the ES group vs 255 days in the non-ES group; P = .20)., Conclusions: ES before SEMS does not affect the incidence of AEs, SEMS patency, or patient survival times. Our data provide no evidence for a benefit of ES to patients undergoing SEMS placement for a biliary stricture caused by pancreatic cancer. UMIN clinical trials registry number: 000004044., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background/purpose: Although pancreatic cancer produces upstream obstructive pancreatitis, acute pancreatitis is a less common manifestation of pancreatic cancer. This study aimed to clarify the subgroup of pancreatic cancer patients who present with an episode of acute pancreatitis (Group I) in comparison with a matched group of pancreatic cancer patients without pancreatitis (Group II) and another group of acute pancreatitis patients without pancreatic cancer (Group III)., Methods: This was a retrospective comparative study of 18 patients in Group I, 300 patients in Group II and 141 patients in Group III., Results: The mean age of Group I was 63.7 years and the male to female ration was 1:0.3. Serum CA 19-9 levels were elevated in 80 %. The main pancreatic duct was incompletely obstructed in 7 patients. There were no significant differences in location of tumor, clinical stage, resection rate and survival months between Group I and II. Acute pancreatitis secondary to pancreatic cancer was more likely to be mild (94 vs. 72 %,p < 0.05) and relapsed (39 vs. 16 %,p < 0.05) compared with Group III., Conclusions: Anatomic evaluation of the pancreas should be performed in patients with acute pancreatitis with no obvious etiology, even if the pancreatitis is mild, to search for underlying malignancy., (© 2013 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Background/aims: Coexistence of autoimmune pancreatitis (AIP) and pancreatic cancer, elevation of serum IgG4 levels in pancreatic cancer patients, and infiltration of IgG4-positive plasma cells in peritumorous pancreatitis have been described in a few reports. This study examined the relationship between intraductal papillary mucinous neoplasm (IPMN) of the pancreas and peritumorous IgG4-positive lymphoplasmacytic infiltrates., Methods: Serum IgG4 levels were measured in 54 patients with IPMN (median 70 years, 26 males and 28 females; 13 main duct type and 41 branch duct type). Histological findings focusing on dense lymphoplasmacytic infiltration, storiform fibrosis, and obliterative phlebitis were reviewed, and immunostaining with IgG4 and IgG was performed in 23 surgically resected IPMN cases (18 main duct type and 5 branch duct type). The presence of IgG4-positive plasma cells >10/hpf and an IgG4-positive/IgG-positive plasma cell ratio >40% were considered significant., Results: Serum IgG4 levels were elevated in 2 (4%) IPMN patients. Significant infiltration of IgG4-positive plasma cells was detected in 4 IPMN cases (17%). The IgG4-positive/IgG-positive plasma cell ratio was >40% in all 4 cases. In one case with a markedly elevated serum IgG4 level (624 mg/dL), typical lymphoplasmacytic sclerosing pancreatitis (AIP type 1) lesions surrounded the whole IPMN. In the 3 other cases, infiltration of IgG4-positive plasma cells with fibrosis was focally detected mainly in the periductal area around the IPMN., Conclusions: In a few patients with IPMNs, IgG4-positive plasma cell infiltration can occur in the peritumorous area. The association of an IPMN with AIP type 1-like changes seems to be exceptional and coincidental., (Copyright © 2013 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Objective: The aim of this study was to define the relevance of mural nodules (MNs) as a "direct" indicator of malignancy of intraductal papillary mucinous neoplasm (IPMN) of the pancreas., Methods: Thirty-nine surgically resected IPMNs excluding obviously invasive carcinomas were examined. The distribution of the most severely dysplastic lesions was mapped on specimens. Immunohistochemical analysis for MUC1 and MUC2 was performed on sections containing the histologically predominant lesions and the most severely dysplastic areas., Results: The presence of MNs correlated well with the histological grade of IPMN (P < 0.01); however, the most severely dysplastic lesions were associated with a flat/nonelevated area rather than MNs (78.9%). In the MUC1-positive subgroup, minimally invasive carcinoma was colocalized to MNs, whereas most severely dysplastic foci including minimally invasive carcinoma with components of mucinous and tubular adenocarcinoma were observed in the areas apart from MNs in the MUC2-positive and MUC1/2-negative subgroups, respectively., Conclusions: Although our data support the concept that MNs represent areas of higher-grade dysplasia within IPMN, development of invasive lesions from MNs may be limited to cases that are MUC1-positive. Careful attention should be paid to the emergence of invasive IPMN from flat foci in MUC2-positive and MUC1/2-negative cases.

Blood vessels deliver oxygen and nutrients to tissues, and vascular networks are spatially organized to meet the metabolic needs for maintaining homeostasis. In contrast, the vasculature of tumors is immature and leaky, resulting in insufficient delivery of nutrients and oxygen. Vasculogenic processes occur normally in adult tissues to repair "injured" blood vessels, leading us to hypothesize that bone marrow mononuclear cells (BMMNC) may be able to restore appropriate vessel function in the tumor vasculature. Culturing BMMNCs in endothelial growth medium resulted in the early outgrowth of spindle-shaped attached cells expressing CD11b/Flt1/Tie2/c-Kit/CXCR4 with proangiogenic activity. Intravenous administration of these cultured vascular proangiogenic cells (VPC) into nude mice bearing pancreatic cancer xenografts and Pdx1-Cre;LSL-Kras(G12D);p53(lox/+) genetically engineered mice that develop pancreatic ductal adenocarcinoma significantly reduced areas of hypoxia without enhancing tumor growth. The resulting vasculature structurally mimicked normal vessels with intensive pericyte coverage. Increases in vascularized areas within VPC-injected xenografts were visualized with an ultrasound diagnostic system during injection of a microbubble-based contrast agent (Sonazoid), indicating a functional "normalization" of the tumor vasculature. In addition, gene expression profiles in the VPC-transplanted xenografts revealed a marked reduction in major factors involved in drug resistance and "stemness" of cancer cells. Together, our findings identify a novel alternate approach to regulate abnormal tumor vessels, offering the potential to improve the delivery and efficacy of anticancer drugs to hypoxic tumors.

A 63-year-old man was admitted with left pleural effusion, and an amylase level of 30994IU/l. A diagnosis of pancreaticopleural fistula was made, based on the findings of magnetic resonance cholangiopancreatography and endoscopic retrograde pancreatography (ERP). After the placement of an endoscopic naso-pancreatic drainage tube, the pleural effusion markedly reduced. When ERP was performed for internal drainage, the main pancreatic duct and stricture were biopsied and showed pancreatic ductal adenocarcinoma histologically. CT revealed a mass in the head of the pancreas. He underwent pylorus-preserving pancreaticoduodenectomy. To the best of our knowledge this is the first case of pancreatic carcinoma presenting as pancreaticopleural fistula with pancreatic pleural effusion. Clinicians should pay attention to the possible presence of cancer and pancreaticopleural fistula in patients with pancreatic pleural effusion.

Background: The hedgehog (Hh) pathway has been implicated in the pathogenesis of cancer including pancreatic ductal adenocarcinoma (PDAC). Recent studies have suggested that the oncogenic function of Hh in PDAC involves signaling in the stromal cells rather than cell autonomous effects on the tumor cells. However, the origin and nature of the stromal cell type(s) that are responsive to Hh signaling remained unknown. Since Hh signaling plays a crucial role during embryonic and postnatal vasculogenesis, we speculated that Hh ligand may act on tumor vasculature specifically focusing on bone marrow (BM)-derived cells., Methodology/principal Findings: Cyclopamine was utilized to inhibit the Hh pathway in human PDAC cell lines and their xenografts. BM transplants, co-culture systems of tumor cells and BM-derived pro-angiogenic cells (BMPCs) were employed to assess the role of tumor-derived Hh in regulating the BM compartment and the contribution of BM-derived cells to angiogenesis in PDAC. Cyclopamine administration attenuated Hh signaling in the stroma rather than in the cancer cells as reflected by decreased expression of full length Gli2 protein and Gli1 mRNA specifically in the compartment. Cyclopamine inhibited the growth of PDAC xenografts in association with regression of the tumor vasculature and reduced homing of BM-derived cells to the tumor. Host-derived Ang-1 and IGF-1 mRNA levels were downregulated by cyclopamine in the tumor xenografts. In vitro co-culture and matrigel plug assays demonstrated that PDAC cell-derived Shh induced Ang-1 and IGF-1 production in BMPCs, resulting in their enhanced migration and capillary morphogenesis activity., Conclusions/significance: We identified the BMPCs as alternative stromal targets of Hh-ligand in PDAC suggesting that the tumor vasculature is an attractive therapeutic target of Hh blockade. Our data is consistent with the emerging concept that BM-derived cells make important contributions to epithelial tumorigenesis.

Objective: Although branch duct intraductal papillary mucinous neoplasms (BD-IPMNs) are slow-growing tumors with a favorable prognosis, the synchronous occurrence of pancreatic ductal adenocarcinomas (PDAs) in patients with BD-IPMNs has been reported. This study was aimed to elucidate the development of PDAs in long-term follow-up patients with BD-IPMNs., Methods: We investigated 89 BD-IPMN patients who had no mural nodules and followed them up conservatively at least 2 years (median follow-up, 64 months; range, 25-158 months). All subjects underwent examinations by imaging modalities including endoscopic retrograde pancreatography. We calculated the standardized incidence ratio (SIR) from the vital statistics compiled by the Ministry of Health, Labor, and Welfare of Japan., Results: Among the 89 patients, 4 cases of PDAs distant from BD-IPMN were observed in 552 patient-years of follow-up (7.2 per 1000 patient-years). The expected number was 0.25, and the SIR of PDAs was 15.8 (95% confidence interval [CI], 4.3-40.4; P = 0.00014). Subgroup analyses showed that the incidence of PDAs was significantly increased in patients 70 years or older (SIR 16.7; 95% CI, 3.4-48.7; P = 0.0008) and in women (SIR 22.5; 95% CI, 2.7-81.1; P = 0.0037)., Conclusions: Patients with BD-IPMNs are at a high risk for PDAs. During the follow-up, careful examination is required to detect the development of PDAs in patients with BD-IPMNs.

Background/aims: Although branch duct intraductal papillary mucinous neoplasms of the pancreas (BD-IPMN) are being diagnosed with increasing frequency, the incidence of concomitant pancreatic carcinoma (PC) is not well known. We investigated the incidence and clinical features of synchronous and metachronous PC in patients with BD-IPMN., Methods: We studied 168 BD-IPMN patients diagnosed by various imaging modalities, including endoscopic retrograde pancreatography, between 1990 and 2008. We reviewed the medical records and clinical features in both patients developing and not developing PC. The diagnosis of PC was histologically verified in all patients., Results: PC was observed in 9 (5.4%) of 168 patients. Five were synchronously detected at the time of BD-IPMN diagnosis, whereas four were metachronously identified during the follow-up period. All PCs occurred in regions separate from the BD-IPMN lesion. All PCs represented histologically invasive ductal adenocarcinomas, whereas the BD-IPMN lesion was diagnosed as adenoma. Patients developing PC were significantly older than patients not developing PC (p = 0.017). The diameters of the BD-IPMN lesions and main pancreatic ducts were significantly smaller in patients developing PC than patients not developing PC (p = 0.013 and p < 0.001, respectively)., Conclusions: It was not infrequent for PC to occur in the pancreas with BD-IPMN. Particular attention should therefore be paid to the development of PC, even in low-risk BD-IPMN, as well as to changes in BD-IPMN., (Copyright 2010 S. Karger AG, Basel.)

The present retrospective study aimed to evaluate the anti-tumor activity and toxicity of combination chemotherapy with gemcitabine (GEM) and oral S-1 or UFT in patients with advanced or metastatic pancreatic cancer. Ninety-four patients received chemotherapy. Among them, sixty-three were treated with GEM alone, twenty-two with UFT and GEM (UFT/GEM), and nine with S-1 and GEM(S-1/GEM). The median survival time was 8.7 months with GEM, 7.3 months with UFT/GEM, and 23.3 months with S-1/GEM. The overall response rate was 11.1%, 10.0%, and 22.2%, respectively. The 1-year survival rate was 29.5%, 36.4%, and 85.7%, respectively. Although the treatment-related adverse effects were not infrequent in patients treated with S-1/GEM, they were moderate in intensity. The combination chemotherapy with S-1/GEM was well tolerated and yielded a high response rate in patients with pancreatic cancer.

The present study reports the growth rate in two cases of main duct pancreatic intraductal papillary-mucinous neoplasms (MD-IPMNs) demonstrating significant changes over several years' observation. The first patient was a 74-year-old woman with an incidental finding of diffuse dilatation of the main pancreatic duct (MPD). Endoscopic retrograde pancreatography (ERP) identified a 5 mm filling defect. Three years later computed tomography (CT) revealed a 20 mm mass occupying the MPD. The second patient was a 67-year-old woman who presented with back pain. Abdominal CT revealed a 5 mm mass in the dilated MPD. Five years later, CT and ERP showed a 20 mm mass occupying the markedly dilated MPD. Both patients subsequently underwent pancreatectomy. Histologically, the tumors showed an intraductal papillary growth occupying the dilated MPD and comprised of mucin-containing columnar epithelial cells. The tumor volume doubling time of these MD-IPMNs was 141 and 304 days in patient 1 and 2, respectively, with a mean of 222.5 days. The present reports demonstrate the ability of benign MD-IPMNs to grow at a significant rate, supporting the current consensus guidelines that MD-IPMNs require surgical resection.

A 52-year-old man with a history of distal gastrectomy for gastric cancer was admitted to our hospital because of jaundice. CT scan revealed double tumors in the pancreatic head and body concomitant with multicystic lesions of the pancreas. Total pancreatectomy with splenectomy and remnant gastrectomy was performed. Final histological diagnosis was double invasive ductal carcinomas of the pancreas head and tail with multifocal branch duct intraductal papillary mucinous adenomas of the pancreas. The present case suggests that entire pancreas might have malignant potential in patients with intraductal papillary mucinous neoplasms.

To identify predictive molecular markers for gemcitabine resistance, we investigated changes in the expression of four genes associated with gemcitabine transport and metabolism during the development of acquired gemcitabine resistance of pancreatic cancer cell lines. The expression levels of human equilibrative nucleoside transporter-1 (hENT1), deoxycytidine kinase (dCK), RRM1, and RRM2 mRNA were analysed by real-time light cycler-PCR in various subclones during the development of acquired resistance to gemcitabine. Real-time light cycler-PCR demonstrated that the expression levels of either RRM1 or RRM2 progressively increased during the development of gemcitabine resistance. Expression of dCK was slightly increased in cells resistant to lower concentrations of gemcitabine, but was decreased below the undetectable level in higher concentration-resistant subclones. Expression of hENT1 was increased in the development of gemcitabine resistance. As acquired resistance to gemcitabine seems to correlate with the balance of these four factors, we calculated the ratio of hENT1 x dCK/RRM1 x RRM2 gene expression in gemcitabine-resistant subclones. The ratio of gene expression decreased progressively with development of acquired resistance in gemcitabine-resistant subclones. Furthermore, the expression ratio significantly correlated with gemcitabine sensitivity in eight pancreatic cancer cell lines, whereas no single gene expression level correlated with the sensitivity. These results suggest that the sensitivity of pancreatic cancer cells to gemcitabine is determined by the ratio of four factors involved in gemcitabine transport and metabolism. The ratio of the four gene expression levels correlates with acquired gemcitabine-resistance in pancreatic cancer cells, and may be useful as a predictive marker for the efficacy of gemcitabine therapy in pancreatic cancer patients.

Background: Gemcitabine is widely accepted as the first-line agent for advanced pancreatic cancer. The antitumor cell activity of gemcitabine is higher when administered after 5-fluorouracil (5-FU) rather than before 5-FU in an in vitro study. The present study was conducted to define the maximum tolerated dose and dose-limiting toxicity associated with an oral fluoropyrimidine prodrug that combines uracil and tegafur (UFT), given prior to weekly intravenous gemcitabine in patients with advanced pancreatic cancer., Methods: Over a 21-day cycle, gemcitabine was given intravenously over 30 min on days 8 and 15, while UFT was given orally from days 1 to 14. The dose of UFT used was 400 mg per day, given as two doses. The dose of gemcitabine was escalated in a stepwise fashion from 800 (level 1, n = 3) to 900 mg/m2 (level 2, n = 6) and then to 1,000 mg/m2 (level 3, n = 3), such that totally 12 patients received the combination chemotherapy., Results: During the first cycle, grade 3 leukopenia was observed in 2 patients at dose level 1. Only 1 patient treated at dose level 2 experienced dose-limiting toxicity (grade 3 elevated transaminase), including additional patients treated at this dose level. No grade 3/4 toxicities occurred in patients treated at dose level 3. A significant response was observed in 1 out of 12 patients (8.3%). Seven patients (58.3%) had stable disease, while 4 patients (33.3%) showed disease progression., Conclusions: The combination chemotherapy of oral UFT and gemcitabine was convenient, well tolerated and may benefit patients with advanced pancreatic cancer. Doses recommended for further study of this schedule are gemcitabine 1,000 mg/m2 and UFT 400 mg/day., (Copyright 2006 S. Karger AG, Basel.)

Background: Gemcitabine is a pyrimidine nucleoside analog that is clinically active against pancreatic cancer. We have recently demonstrated that p38 MAPK is specifically activated by gemcitabine and that pharmacological blockade of p38 MAPK signaling prevented gemcitabine-induced apoptosis in human pancreatic cancer cells. In this study, we further investigated the implication of p38 MAPK in the cytotoxic action of gemcitabine., Materials and Methods: Cells expressing a dominant-negative mutant of p38 MAPK were generated. Clonogenic assays were used to assess the long-term effect on cancer cell viability in the human pancreatic cancer cells, PK1 and PCI43. The p38 MAPK activation level was assessed using an antibody specific to the phosphorylated form., Results: Gemcitabine increased the activation level of p38 MAPK in a dose-dependent manner and induced apoptosis in the two tested human pancreatic cancer cell lines. The selective p38 MAPK inhibitors, SB203580 and SB202190, reduced gemcitabine-induced activation of p38 MAPK, prevented the gemcitabine-induced apoptosis and increased long-term clonogenic survival. Overexpression of a dominant-negative p38 mutant in cells resulted in the reduction of gemcitabine-induced p38 MAPK activation and apoptosis, and increases in clonogenic survival., Conclusion: These results strongly suggest that the activation of p38 MAPK signaling is necessary for gemcitabine-induced cell death in human pancreatic cancer cells. Based upon these results, we suggest that molecules of p38 MAPK signaling pathways should be listed as novel targets for gemcitabine-based therapy.

Purpose: To evaluate the necessity of morphological images (MI) in reading somatostatin receptor scintigraphy (SRS) in patients with suspected neuroendocrine gastroenteropancreatic (GEP) tumors., Material and Methods: A Japanese multicenter clinical trial of SRS was conducted in 40 patients with suspected GEP tumors. Three experienced radiologists interpreted the images in three separate sessions in a blinded manner (1: SRS images alone, 2: MI alone, 3: SRS and MI analyzed simultaneously), and the reading results of each session were compared. In addition, the diagnostic abilities of SRS, MI and SRS alone and simultaneous SRS and MI readings were compared for patients where final diagnosis was obtained., Results: SRS detected more suspected lesions (positive or inconclusive uptake) than morphological images did (51 vs 27 lesions), but included many physiological uptakes detected as positive or inconclusive uptakes. Combined reading of SRS and morphological images helped to correctly recognize these physiological uptakes, and also helped in determining the anatomical localization of the abnormal uptakes. Combined reading of SRS and morphological images gave the highest diagnostic impact., Conclusion: The sensitivity of SRS with regard to GEP is high. However the specificity is very low. Morphologic imaging is necessary for the exclusion of physiological uptake and correct anatomic location of an abnormal tracer uptake. The combined reading of SRS and morphologic imaging studies gives the highest diagnostic impact.

In this study, we investigated the involvement of Akt and members of the mitogen-activated protein kinase (MAPK) superfamily, including ERK, JNK, and p38 MAPK, in gemcitabine-induced cytotoxicity in human pancreatic cancer cells. We found that gemcitabine induces apoptosis in PK-1 and PCI-43 human pancreatic cancer cell lines. Gemcitabine specifically activated p38 MAPK in a dose- and time-dependent manner. A selective p38 MAPK inhibitor, SB203580, significantly inhibited gemcitabine-induced apoptosis in both cell lines, suggesting that phosphorylation of p38 MAPK may play a key role in gemcitabine-induced apoptosis in pancreatic cancer cells. A selective JNK inhibitor, SP600125, failed to inhibit gemcitabine-induced apoptosis in both cell lines. MKK3/6, an upstream activator of p38 MAPK, was phosphorylated by gemcitabine, indicating that the MKK3/6-p38 MAPK signaling pathway is indeed involved in gemcitabine-induced apoptosis. Furthermore, gemcitabine-induced cleavage of the caspase substrate poly(ADP-ribose) polymerase was inhibited by pretreatment with SB203580, suggesting that activation of p38 MAPK by gemcitabine induces apoptosis through caspase signaling. These results together suggest that gemcitabine-induced apoptosis in human pancreatic cancer cells is mediated by the MKK3/6-p38 MAPK-caspase signaling pathway. Further, these results lead us to suggest that p38 MAPK should be investigated as a novel molecular target for human pancreatic cancer therapies.

We describe a sporadic case with familial adenomatous polyposis, multiple endocrine neoplasia type 1 (MEN1)-related tumors (an endocrine cell tumor of the pancreas and bilateral parathyroid tumors), and a papillary thyroid carcinoma. To clarify how mutations of the adenomatous polyposis coli ( APC ) gene and the MEN1 gene, responsible for familial adenomatous polyposis and MEN1, respectively, might have contributed to tumorigenesis in this case, we studied germline mutations in both genes and loss of heterozygosity at their genetic loci in multiple lesions. In addition, we performed immunohistochemistry for beta-catenin, associated with the function of the APC gene. A germline mutation was found in the APC gene but not in the MEN1 gene. Normal allelic loss at the APC gene locus was observed in bilateral parathyroid tumors. Immunohistochemical staining of beta-catenin demonstrated accumulation in the cytoplasm in addition to membrane staining in all analyzed tumors and a strong nuclear reaction in the endocrine cell tumor of the pancreas. The presence of normal allelic deletions of the APC gene in bilateral parathyroid tumors and nuclear staining of beta-catenin in the pancreatic tumor in addition to the germline mutations suggests that functional loss of the APC gene played an important role not only in familial adenomatous polyposis but also in the MEN1-related tumors in this case.