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Abstracts of Papers Submitted to the International Symposium on Pancreas Cancer 2012, Cosponsored by the Japan Pancreas Society, October 4–6, 2012, Kyoto, Japan

doi: 10.1097/MPA.0b013e31826a15f2
Abstracts
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Proposal of Splenectomy-Omitting Radical Pancreatectomy in Well-Selected Left-Sided Pancreatic Cancer-A Pilot Study

C. M. Kang,1,2,3 H. K. Hwang,1,2,3 S. H. Choi,1,2,3 W. J. Lee1,21Division of Hepatobiliary and Pancreas, Department of Surgery, Yonsei University College of Medicine, 2Pancreaticobiliary Cancer Clinic, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea; and 3Young Yonsei Pancreatic Tumor Study Group.

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Backgrounds and Objectives

Splenectomy has been performed not only for margin-negative resection but also for effective clearance of the splenic hilar lymph nodes when performing distal pancreatectomy for pancreatic body and tail cancer. However, incidence of splenic hilar lymph node metastasis is not fully understood.

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Methods

From April 2010 to June 2011, we prospectively analyzed medical records of consecutive 12 patients who underwent radical antergrade modular pancreatosplenectomy (RAMPS) for ductal adenocarcinoma of the pancreas. In each surgical specimens, potential remnant soft tissue around the splenic hilum, which would have been left following extended Warshaw’s procedure, was dissected, and subsequently sent to pathologic examination as splenic hilar lymph node to confirm lymph node metastasis.

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Results

All patients had ductal adenocarcinoma in the distal pancreas. The median tumor size was 2 cm (range, 0.8–4 cm) and the median number of retrieved lymph nodes was 17 (range, 5–29). Six patients were reported to have lymph node metastasis. Median 4 (range, 1–6) splenic hilar lymph nodes were evaluated; however, no lymph node metastasis was noted in splenic hilum.

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Conclusions

Under the present circumstance that spleen-preserving distal pancreatectomy with segmental resection of both splenic vessels is practiced in clinical setting, the role of routine splenectomy for potential clearing splenic hilar lymph node metastasis in treating left-sided pancreatic cancer needs to be re-evaluated because actual incidence of splenic hilar lymph node metastasis is apparently very low.

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Laparoscopic Minimum Resection of Pancreas in Solid Pseudopapillary Tumor of Pancreatic Head

J. H. Im, C. M. Kang, W. J. Lee Division of Biliopancreas, Department of Surgery, Yonsei University College of Medicine; Pancreaticobiliary Cancer Clinic, Institute of Gastroenterology, Yonsei University Health System, Seoul, Korea.

Solid pseudopapillary tumor of the pancreas (SPT) is predominantly found in young female patients. Successful surgical extirpation is certain for long-term survival because most cases follow benign course after compete tumor resection. Therefore, surgeons always consider quality of life in treating benign and low grade malignant pancreatic tumors, and minimally invasive and function-preserving pancreatectomy would be ideal surgical option for them. Here, we present a 24-year-old female patient who underwent laparoscopic minimum resection of pancreas for SPT arising in pancreatic head portion. Patients cold go home 7 days after surgery without complications.

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Pioglitazone and Alogliptin Promotes the In Vivo Regeneration of Transplanted MIP-luc Islets in Immunosuppressed Recipients

Z. Fu,1 H. Yin,1 A. Chong,2 H. Wang31Department of Surgery, Transplant Section, Shanghai Changzheng Hospital, Shanghai, China; 2Department of Surgery, Transplantation Section, University of Chicago, Chicago, United States; 3Cellular Therapy Center, University of South Carolina, Carolina, United States.

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Background

Only a minority of islet transplant recipients remains insulin independent at 5 years post-transplantation under the Edmonton protocol. The loss of beta-cell function could reflect incomplete control of auto- and allo-immunity as well as beta-cell toxicity due to the immunosuppressive drugs and metabolic stress on the beta-cells. Better immunosuppressive and regeneration-promoting strategies are therefore required to improve long-term outcomes.

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Methods

A total of 50-60 islets from C57BL/6 mice expressing the insulin promoter-luciferase (MIP-luc) transgene were transplanted under the kidney capsule of streptozotocin-induced diabetic albino C57BL/6 mice. These mice were then divided into 3 groups: Control islet transplant, transplant + Rapamycin+Tacrolimus (IS group) and transplant + IS + Pioglitazone+Alogliptin (IS+Pio/Alog). Blood glucose were controlled with insulin tablets and functional beta-cell mass was quantified using the Xenogen IVIS System, every 2 weeks for 12 weeks. Body weight and random blood glucose were also monitored.

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Results

We observed that, following transplantation, there was a gradual increase in bioluminescent signal over the 12-week period in the control group (Fig 1). In contrast, the bioluminescent signal was dramatically reduced by 42 % on day 28 and 49% by day 90 in the IS group (P<0.05). In the IS + Pio/Alog group bioluminescent signal also reduced by 42% by day 28, but dramatically increased by 165% from day 28–90.

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Conclusions/Significance

These data clearly indicate IS, together with transplantation trauma and sub-optimal transplanted beta-cell mass, was acutely toxic, and that the combination of Pio+Alog was able to restore the transplanted beta-cell function/mass even in the presence of continued IS. Future studies will use this syngeneic model, as well as allogeneic islets, to define the optimum combination of immunosuppressants that controls destructive immunity while sparing beta-cells, and also agents that enhance of beta-cell regeneration in the presence of immunosuppression.

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Role of ERCP in Cytological Confirmation for Possibly Resectable Pancreatic Ductal Adenocancinoma (PDAC) in the Era of EUS-FNA

T. Ohtsuka,1 N. Ideno,1 T. Aso,1 Y. Nagayoshi,1 H. Kono,1 K. Tamura,1 J. Ueda,1 S. Takahata,1 S. Aishima,2 T. Ito,3 A. Asou,3 K. Mizumoto,1 S. Shimizu,1 M. Tanaka11Departments of Surgery and Oncology; 2Anatomic Pathology; 3Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

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Background

EUS-FNA has recently taken the place of ERCP for the assessment of various pancreatic diseases; however, in case of possibly resectable PDAC, there might be a risk of seeding of cancer cells and dissemination during EUS-FNA. Thus, we have been attempting to get a preoperative cytological confirmation of PDAC by ERCP first, then followed by EUS-FNA only in unsuccessful cases. The aim of this study was to assess the validity of our diagnostic strategy.

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Methods

Medical records of consecutive 98 patients diagnosed as having possibly resectable PDAC from 2010 to 2011 were retrospectively reviewed, and abilities to detect cancer cells (class IV or V) of ERCP and EUS-FNA were evaluated.

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Results

ERCP were performed in 90 patients, 55 of whom (63%) showed positive cancer cells. On the other hand, 23 patients underwent EUS-FNA, and 22 (96%) demonstrated positive results. Post-ERCP pancreatitis developed in 8 patients (9%), all of which were mild, while there was no adverse event after EUS-FNA. A total of 81 patients (83%) had preoperative confirmation of the cancer cells, and the confirmation rate was higher in pancreas head lesions (91%, 64/70) than in body to tail (61%, 17/28, p<0.01). Ninety-six patients (98%) had final diagnosis of cancer after operation (93 PDACs, 2 bile duct cancers, and one neuroendocrine carcinoma), while the other 2 without preoperative cytological confirmation had PanIN-II and autoimmune pancreatitis.

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Conclusion

Our strategy using “ERCP first” to get cytological confirmation for possibly resectable PDAC seems to be adequate with the high confirmation rate and low morbidity. Further investigation is necessary to clarify whether EUS-FNA might really affect postoperative outcomes.

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New Strategy of Distal Pancreatectomy With En-Bloc Celiac Axis Resection in Patients With Pancreatic Body/Tail Carcinoma

K. Okada, M. Kawai, H. Yamaue, M. Tani, S. Hirono, M. Miyazawa, A. Shimizu, Y. Kitahata Second Department of Surgery, Wakayama Medical University, Wakayama, Japan.

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Background

The indications for DP-CAR in potentially resectable pancreatic carcinoma have not yet been fully defined.

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Methods

The medical records of 52 consecutive patients who underwent distal pancreatectomy with D2 node dissection, including 36 standard distal pancreatectomies (standard DP) and 16 DP-CAR, for pancreatic carcinoma were reviewed retrospectively.

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Results

Microscopically positive margins were identified at the dissection sites around the cut-margins of the splenic arteries, and were more frequently detected in the patients with tumors situated ≤10mm from the root of the splenic artery after standard DP (13.9%), whereas they were identified in the periarterial nerve plexuses and retropancreatic tissue around the celiac artery in patients who underwent DP-CAR (62.5%). The overall 1- and 2-year survival rates after standard DP / DP-CAR were 80.5/81.3% and 51.8/52.5%, and the median survival time was 32/25 months, respectively, with no significant differences noted between the groups. There were no significant differences in the mortality rates and the incidence of each complication between the two groups except for delayed gastric emptying.

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Conclusions

DP-CAR was a feasible and safe procedure, similar to standard DP, and the survival following DP-CAR was the same as that after standard DP. To improve the R0 resection rate, the indications for DP-CAR can be extended for some patients with potentially resectable pancreatic carcinoma near the root of the splenic artery, and for borderline resectable pancreatic carcinoma, neoadjuvant multimodal therapy should be given.

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Proton Therapy for Pancreatic Cancer - Toxicity Data and Early Outcomes

R.C. Nichols,1 T. George,2 R. Zaiden,3 G. Kim,4 Z. Awad,5 H. Asbun,6 J. Stauffer,6 W. Mendenhall,1 N.P. Mendenhall,1 B.S. Hoppe11Department of Radiation Oncology, University of Florida Proton Therapy Institute, Jacksonville, United States; 2Department of Medical Oncology, University of Florida College of Medicine, Gainesville, United States; 3Department of Medical Oncology, University of Florida College of Medicine, Jacksonville, United States, 4Department of Medical Oncology, Mayo Clinic, Jacksonville, United States, 5Department of Surgery, University of Florida College of Medicine, Jacksonville, United States, and 6Department of Surgery, Mayo Clinic, Jacksonville, United States.

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Purpose

To review treatment toxicity and disease control status for patients with pancreatic and ampullary cancer treated with proton therapy at our institution.

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Methods and Materials

From March 2009 through April 2012, 22 patients were treated with proton therapy and concomitant capecitabine (1000mg PO twice daily) for resected (N=5); marginally resectable (N=5); and unresectable/inoperable (N=12) biopsy-proven pancreatic and ampullary adenocarcinoma. Two patients with unresectable disease were excluded from the analysis for reasons unrelated to treatment. Proton doses ranged from 50.40 cobalt gray equivalent (CGE) to 59.40 CGE.

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Results

Median follow-up for surviving patients was 9 months. No patient demonstrated any grade 3 toxicity during treatment or during the follow-up period. Grade 2 gastrointestinal toxicities occurred in 3 patients, consisting of vomiting (N=3); and diarrhea (N=2). Median weight loss during treatment was 2.8 lbs. (1.75% of body weight). Chemotherapy was well tolerated with a median 99% of the prescribed doses delivered. Percentage weight loss was reduced (p=0.0390) and grade 2 gastrointestinal toxicity was eliminated (p=0.0009) in patients treated with plans that avoided anterior and left lateral fields which were associated with reduced small bowel and gastric exposure.

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Conclusion

Proton therapy may allow for significant sparing of the small bowel and stomach and is associated with a low rate of gastrointestinal toxicity. Although long-term follow-up will be needed to assess efficacy, we believe that the favorable toxicity profile associated with proton therapy may allow for radiotherapy dose escalation, chemotherapy intensification, and possibly increased acceptance.

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The Application of New DNA Methylation Analysis, Designated Methylation Specific Electrophoresis (MSE) for Pancreatic Juice Analysis

S. Yokoyama,1 S. Kitamoto,1 T. Hara,2 Y. Arisaka,3 K. Takaori,4 T. Yamamoto,5 T. Niihara,6 H. Nishimata,6 S. Tanaka,7 M. Higashi,1 S. Yonezawa11Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan; 2Division of GI Endscopy, Chiba Cancer Center, Chiba, Japan; 3Department of Gastroenterology, Kobe University Graduate School of Medicine, Kobe, Japan; 4Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto; 5Department of Internal Medicine, National Sanatorium Hoshizuka-Keiaien, Kagoshima, Japan; 6Division of Digestive Tract Internal Medicine, Nanpuh Hospital, Kagoshima, Japan; and 7Division of Pathology, Nanpuh Hospital, Kagoshima, Japan.

Methylation of CpG sites in genomic DNA plays an important role in gene regulation and especially in gene silencing. We have reported mechanisms of epigenetic regulation for expression of mucins, which are markers of malignancy potential and early detection of human neoplasms. Thus, detection of methylation status is important for early diagnosis of cancer.

Here, we report a modified version of the bisulfite denaturing gradient gel electrophoresis) using a nested PCR approach. We designated this method as methylation specific electrophoresis (MSE). The MSE method greatly decreases the amount of input DNA. The lower detection limit for distinguishing different methylation status is <0.1% and the detectable minimum amount of DNA is 20 pg. We also show that MSE can be used for analysis of challenging samples, from which only a small amount of DNA can be extracted. Interestingly, in the pancreatic juice analysis, MSE revealed a degree of methylation that differed significantly between subtypes of intraductal papillary mucinous neoplasm (IPMN): intestinal-type IPMN and gastric-type IPMN. A further study is needed to clarify the biological significance of this observation, but this result may provide an approach for early diagnosis of pancreatic neoplasms.

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The Retropancreatic Fusion Fascia Plays as a Barrier Against the Infiltration of the Pancreatic Carcinomas

H. Kitagawa,1 H. Tajima,1 H. Nakagawa,1 I. Makino,1 Y. Hayashi,1 H. Takamura,1 H. Takamura,1 H. Terakawa,1 I. Ninomiya,1 S. Fushida,1 I. Ohnishi,2 M. Kayahara,2 H. Ikeda,2 T. Ohta11Department of Gastroenterologic Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa Japan; 2Department of Pathology, Kanazawa Medical Center. Kanazawa, Japan.

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Introduction

We often experience that the pancreatic carcinoma infiltrate toward posterior beyond the parenchyma, however the involvement of the IVC or the adrenal grand is rare. The pancreas is fixed at the posterior side and the fusion fascia exists between the pancreatic parenchyma and the retroperitoneal organ. The retropancreatic dissection plane and the concomitant resection of retroperitoneal organ are controversial. We investigated the infiltration of pancreatic carcinoma toward the posterior of the pancreas.

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Methods

We studied 140 pancreatic carcinomas which were resected in our institute from 1997 to 2011. Ninety-four cases were performed PD and 46 cases were performed DP. Resected specimens were cut consecutively into 5mm slices. Specimens after PD were cut perpendicularly to the body axis, and the specimens after DP were cut perpendicularly to the apsis of specimens. The retropancreatic infiltration was divided three grades; Grade 0: carcinoma confined within the parenchyma, Grade 1: carcinoma infiltrate beyond the parenchyma but respect the fusion fascia (include abut to the fusion fascia), Grade 2: carcinoma infiltrate retroperitoneal tissues beyond the fusion fascia.

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Results

The retropancreatic infiltration was assessed by the grades. Grade 0 was verified in 22%, 28%, 24% of PD, DP, total patients, respectively. Grade 1 was verified in 76%, 68%, 73% of PD, DP, total patients, respectively. Grade 2 was verified in 2%, 4%, 3% of PD, DP, total patients, respectively.

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Conclusions

We divided the degree of retropancreatic infiltration in 3 grades. The carcinomas infiltrate beyond the parenchyma at the posterior site are revealed over 70% in our series. On the contrary, the Grade 2 was very rare (3%). The carcinoma infiltration confined to the upper side of the fusion fascia in almost cases, even if the pancreatic carcinoma abut to the IVC or adrenal grand by MDCT or MRI. The fusion fascia plays a role of a barrier against the infiltration of the pancreatic carcinomas.

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Risk Factors of Familial Pancreatic Cancer in Japan: Current Smoking and Recent Onset of Diabetes

H. Matsubayashi,1 K. Uesaka,2 K. Yamazaki,3 Y. Miyagi,4 N. Kakushima,1 M. Tanaka,1 K. Hotta,1 Y. Yamaguchi,1 T. Takao,1 H. Ono11Department of Endoscopy, Shizuoka Cancer Center, Shizuoka, Japan; 2Department of Hepato-pancreatic-biliary Surgery, Shizuoka Cancer Center, Shizuoka, Japan; 3Department of GI Oncology, Shizuoka Cancer Center, Shizuoka, Japan; 4Center for Cancer Screening, Shizuoka Cancer Center, Shizuoka, Japan.

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Aims

In the western countries, about 7∼10% of patients of pancreatic cancer (PC) have a familial predisposition to their disease. The aim of this study was to determine the familial susceptibility to PC in Japan.

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Methods

577 cases with PC and 577 age- and gender-matched controls without a cancer history were analyzed for cancer history in their first degree relative(s) (FDRs) and demographic factors.

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Results

Patients with PC were more likely to have a FDR with PC (6.9%) than controls (2.9%) (odds ratio [OR]: 2.5, P=0.02). Three cases (0.5%) but no control had a family history of PC in multiple FDRs. Smoking (OR: 1.3, P=0.04), especially current smoking (OR: 1.5, P=0.005), and diabetes mellitus (DM)(OR: 1.7, P=0.001) were also associated with PC. The odds of having PC increased up to eight-fold if cases were positive for these three risk factors. Cases with Familial PC (FPC) were more likely to be current smokers (40%) and to have DM (32.5%) than sporadic cases (30.1% and 20.1%, OR: 1.6 and 1.9).

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Conclusions

The incidence of FPC in Japan was similar to that in the western countries. A family history of PC is more common in cases than in controls, as is a personal history of diabetes and smoking. It is prudent to inform kindred of FPC patients of the risk of smoking and to follow carefully if affected family members develop diabetes.

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Immunohistochemical Study of Intraductal Papillary Mucinous Neoplasms Using Cytological Specimens of Pancreatic Juice

K. Inayama,1 T. Wakasa,1 Y. Okabe,2 F. Mastuda,2 J. Nakajima,2 A. Arimoto,3 A. Nakajima,3 K. Wakasa,4 M. Ohsawa,4 T. Honda,1 Y. Osaki,2 M. Shintaku11Department of Pathology, Osaka Red Cross Hospital, Osaka, Japan; 2Department of Internal Medicine, Osaka Red Cross Hospital, Osaka, Japan, 3Department of Diagnostic Pathology, Osaka City University, Osaka, Japan.

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Objectives

Intraductal papillary mucinous neoplasms (IPMN) show noninvasive expansive growth and a favorable outcome. IPMN were classified into adenoma (IPMA), borderline malignancy (IPMN borderline malignancy), and carcinoma in situ (IPMC). As some IPMN, diagnoses changed to invasive ductal carcinoma (IDC), it is very important to evaluate the malignant potential of IPMN to decide on the clinical management. In this study, we investigated the cytological features and mucin profile of IPMN of pancreatic juice based of the ERCP procedure and EUS-FNA.

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Materials and Methods

Between October 2008 and December 2011, 10 patients who were referred to our hospital for a diagnosis of IPMN were included in this study.

The pancreatic juice was collected by ERCP, and mixed with 10 ml of Hanks solution (Nichirei, Tokyo, Japan) at 4°C immediately.

The cells were smeared onto 2 glass slides and fixed in 95% ethanol. The specimens were stained with Papanicolaou method, and cytological diagnoses were made.

After the diagnosis, the same cytological specimens underwent immunohistochemical staining (IHC) for MUC 1, 2, 5AC, and 6 using the cell transfer method (Malinol, Muto chemical, Japan).

The final diagnosis was made based on surgical specimens.

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Results

Four cases were IDC, 3 cases were IPMC, 1 was IPMN borderline malignancy, and 2 were IPMA. Compared with the IPMA and IPMN borderline, the IPMN borderline showed smaller cell clusters, increased chromatin, and more irregular nuclei. Compared with IPMN borderline and IPMC, IPMC showed severe nuclear atypia and more prominent nucleoli.

The cytological diagnosis showed 5 cases as IPMA, but the final diagnosis revealed that 1 case was IPMA, 3 cases were IPMC, and 1 case was invasive ductal carcinoma (IDC). Compared with the results of Papanicolaou staining and IHC, in the 3 cases of IPMC, the diagnosis using IHC agreed with the final diagnosis. In 1 case of IPMA, the diagnosis using IHC was overdiagnosis. In the case of IDC, both diagnoses were underestimates, but the result using IHC was closer to the final diagnosis.

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Conclusion

Using only Papanicolaou staining, we can differentiate the IDC from IPMN. Besides using the IHC of mucins, we can divide IPMC and IPMA.

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Evaluation of Adjuvant Chemotherapy in Patients with Advanced Pancreatic Cancer

M. Tanaka, I. Matsumoto, M. Sinzeki, S. Asari, T. Goto, H. Mukubou, S. Shirakawa, H. Yamashita, A. Takebe, M. Takahashi, T. Okazaki, M. Kido, T. Fukumoto, T. Aziki, Y. Ku Department of Hepato-biliary-pancreatic Surgery, Kobe University, Kobe, Japan.

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Background

Adjuvant chemotherapy (AC) is a current standard treatment for pancreatic cancer (PC). However, the subjects of reported randomized controlled trial were only included relatively good performance status with R0 or R1 resections postoperatively. The purpose of this study is to assess efficacy and problem of AC with intention-to-treat based analysis.

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Patients and Methods

Between January 2001 and December 2011, 178 patients with PC underwent surgical resection with curative intent in our institution. Among these, JPS p-Stage III (n=63) and p-Stage IVa (n=58) patients were retrospectively analyzed.

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Results

In Stage III patients, 15 patients did not receive AC (MST: 20.8m) and 43 received AC (MST 42.0m). Among 43 patients, 27 completed and 16 discontinued AC. The causes of discontinued AC were adverse events in 13, early recurrence in 1 and unknown with insufficient documentation of treatment data in 2 patients, respectively. Completed group showed significantly better survival than discontinued group (MST: 71.5m vs 20.8m). In a multivariate analysis, PD procedure, operative time, serum albumin level at the time of starting AC were associated with discontinued AC. In Stage IV patients, 11 did not receive AC (MST: 20.0m) and 43 received AC (MST 22.1m). Among 43 patients, 21 completed AC and 22 discontinued AC. The causes of discontinued AC were adverse events in 9 and early recurrence in 13 patients, respectively. Significant poor survival in patients with early recurrence was shown compared to that without early recurrence (MST: 12.5m vs 27.6m). In a multivariate analysis, histological grading (tub2 or por) was associated with early recurrence.

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Conclusion

The ratio of completed standard therapy was low. Survival benefit with AC was shown in Stage, but not Stage IVa patients. Shorten the operative time and improve nutrition status might be increase the introduction of AC. Predictor of early recurrence in Stage IVa patients was warranted.

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Nestin-Regulating Stem Cell-Related Molecule Network in Pancreatic Cancer

Y. Matsuda,1 H. Yoshimura,1 M. Korc,2 T. Ishiwata21Departments of Pathology and Integrative Oncological Pathology, Nippon Medical School; 2Departments of Medicine, and Biochemistry and Molecular Biology, Indiana University School of Medicine and the Melvin and Bren Simon Cancer Center.

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Introduction

Nestin, a class VI intermediate filament, is expressed in pancreatic exocrine progenitor cells. Previously, we reported that 30% of pancreatic ductal adenocarcinoma (PDAC) cases expressed nestin, and its expression was correlated with tumor invasion. Knockdown of nestin using short hairpin RNA (shRNA) in human PDAC cell lines inhibited cell migration and invasion in vitro and liver metastasis in vivo. In this study, we analyzed the relationship between nestin and stemness, and nestin-regulating molecules in PDAC.

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Methods

The expressions of various types of stem cell marker and nestin were analyzed using immunocytochemistry and real-time PCR in PDAC cell lines and pancreatic cancer tissues. To assess cancer stem cells, a sphere formation assay was performed as follows: cells were grown on an ultra-low attachment surface plate supplemented with EGF and FGF2. Nestin-regulating molecules were clarified by DNA microarray and microRNA array analyses.

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Results

The expression level of nestin was high in sphere-forming PDAC cells, and its expression levels correlated with the sphere-forming ability. In DNA microarray analysis using nestin shRNA-transfected clones and nestin-expression vector transfected-clones, at a 2-fold cut-off, only TCF4 showed a compatible change coincident with nestin expression. Furthermore, nestin-shRNA-transfected cells showed increased expression levels of miR-20a, miR-34a, and miR-421, thereby, targeting molecules for these microRNAs were decreased.

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Conclusion

Nestin expression is closely correlated with cancer stem-like cells in PDAC, and nestin regulates migration, invasion, and metastasis by altering the intracellular signaling network concerning stem cell functions.

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Three Cases of Pancreatic Cancer Associated With Autoimmune Pancreatitis

H. Miyoshi, K. Sumimoto, Y. Fukui, T. Ikeura, T. Fukui, K. Uchida, M. Matsushita, M. Takaoka, K. Okazaki Department of Gastroenterology and Hepatology, Kansai Medikal University, Osaka, Japan.

While several reports have speculated on the prognosis of AIP, the relationship between autoimmune pancreatitis (AIP) and pancreatic cancer (PaC) remain unclear. From 2006 to 2012, we experienced three cases of PaC associated with AIP. All cases (An 80-year-old man and 45, 64-year-old women) had been diagnosed with AIP for which steroid therapy had induced remission. Extrapancreatic lesion, such as screlosing cholangitis, thyroiditis and sialoadenitis, were observed in all cases, and a case had associated diabetes mellitus. All cases developed PaC after several years of steroid therapy and imaging studies in these cases showed localized enlargements in the pancreas and irregular narrowing in pancreatic main ducts around the tumors. The diagnosis was confirmed by endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNA) for diagnosis before surgery, which revealed adenocarcinoma. 2 cases diagnosed with pancreatic head cancer underwent pancreatoduodenectomy, and histological examination of the resected tissue revealed diffuse interacinar and intraacinar fibrosis with infiltration of IgG4-positive plasma cells around the tumors. Another case was unresectable pancreatic body cancer due to peritoneal metastasis confirmed by cytological examination of the peritoneal lavage.

Increased cell turnover in chronic inflammation and fibrosis is believed to induce mutations that can increase the risk of cancer in these patients. It is, therefore, possible that AIP may also predispose to PaC. We must carefully monitor AIP patients for the simultaneous presence of PaC, even when a diagnosis of AIP is confirmed.

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Detection of Small Concomitant Carcinomas Distinct From Intraductal Papillary Mucinous Neoplasms Under the Surveillance of the Whole Pancreas Using EUS

K. Kamata,1 M. Kitano,1 M. Kudo,1 H. Sakamoto,1 K. Kadosaka,1 T. Miyata,1 H. Imai,1 T. Komaki,1 K. Maekawa,2 T. Chikugo,3 M. Kumano,4 T. Hyodo,4 T. Murakami,4 Y. Takeyama51Department of Gastroenterology and Hepatology, Kinki University Hospital, Osaka, Japan; 2Section of Abdominal Ultrasound, Kinki University Hospital, Osaka, Japan; 3Department of Pathology, Kinki University Hospital, Osaka, Japan; 4Department of Radiology, Kinki University Hospital, Osaka, Japan; 5Department of Surgery, Kinki University Hospital, Osaka, Japan.

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Objective

During the follow-up of intraductal papillary mucinous neoplasms (IPMNs), concomitant pancreatic ductal adenocarcinomas (PDAC) sometimes arise.

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Methods

Between April, 2001, and March, 2009, 167 consecutive patients with IPMNs underwent EUS, 42 of whom underwent surgery. Of the remaining 125 patients, 102 who had unresected branch duct IPMNs without mural nodules were followed-up by EUS twice a year. When patients underwent EUS, the whole pancreas was observed to check for the presence of concomitant PDACs. The ability of EUS to depict concomitant PDACs was compared to that of ultrasonography (US), multi-detector-row computed tomography (MDCT) and magnetic resonance imaging (MRI).

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Results

Eleven PDACs that were distinct from IPMNs were incidentally detected at the first examinations. For the unresected IPMNs, the median follow-up duration was 42 months (range, 12–122). Seven (7%) PDACs distinct from IPMNs occurred in the 102 patients who were followed up. IPMN-derived carcinomas were not observed during follow-up. The IPMNs with a concomitant PDAC were all branch duct IPMNs. Although EUS depicted all PDACs, US, MDCT and MRI could only depict 39% (7/18), 56% (10/18) and 50% (9/18) of all PDACs, respectively. US, MDCT and MRI could depict 64% (7/11), 64% (7/11) and 55% (6/11) of the PDACs detected by the initial EUS examinations, while only 0% (0/7), 43% (3/7) and 43% (3/7) of the PDACs detected during the follow-up period, respectively.

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Conclusion

EUS of the whole pancreas plays an important role in the management of IPMNs as it allows the early detection of small concomitant invasive carcinomas.

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A Novel Technique of Anastomosis With Using a Short Term Degradable Stent for Pancreatico-jejunostomy and Development of the Endoscopic Stenting

K. Kasuya,1 T. Itoi,2 Y. Abe,3 Y. Nagakawa,1 M. Shimazu,3 A. Tsuchida11Surgery, Tokyo Medical University, Tokyo, Japan; 2Internal Medicine, Tokyo Medical University, Tokyo, Japan; 3Surgery, Hachioji Medical Center, Tokyo Medical University, Tokyo, Japan.

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Background

A novel technique of anastomosis with a short term degradable stent for pancreatico-jejunostomy has been developed to avoid problems caused by long term placement of the stent and to obviate the need for removed. We evaluated its shape-retentive capability under conditions of exposure to digestive fluid and its clinical usability.

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Methods

The stent was braided manually using Monocryl© and PDS-II© of 2-0 wire and heat-treated at 80 degrees Celsius for 3 hours, under a vacuum. We measured it maximum resistance to compression strength and elastic modules of the stent under exposure to artificial gastric or intestinal fluids. We evaluated the usability of the stent with 3 mm in diameter and 35 mm in length in 7 patients under pancreatico-jejunostomy and in 6 patients under hepatico-jejunostomy. As the next trial, endoscopic experimental study in 4 pig models at a tertiary referral center animal laboratory. Stent was mounted on a custom-made introducer just before the insertion. After obtaining pancreatography, the stent was placed in the pancreatic duct across the papilla. Immediate necropsy was performed for gross inspection in all cases.

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Results

The compression strength of the stent was preserved for about 3 weeks after which it collapsed. The elastic features were retained under exposure to gastric fluid, but it lost under an intestinal juice exposure. Using this stent, “suturing of tissue with the stent on” was possible as a novel technique of anastomosis for pancreatico- or hepatico-jejunostomy and induced little complications. Endoscopic pancreatic stents were successfully inserted and easily deployed across the papilla in the pancreatic duct in all the animals. At immediate necropsy for gross inspection, both stents were placed across the papilla and stent patency was achieved in all cases.

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Conclusion

The stent was suitable for digestive tract anastomosis as the degradable stent for short term placement. In the experimental study, endoscopic stenting of this novel stent seems feasible and safe.

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Imageable Orthotopic Nude Mouse Models of Patient Pancreatic Cancer Specimens for Identifying Improved Individualized Therapy

R.M. Hoffman,1,2 A. Suetsugu,1,2,3 M. Katz,4 J. Fleming,4 M. Truty,4 R. Thomas,4 S. Saji,3 H. M.,3 M. Bouvet21AntiCancer Inc., San Diego, CA, United States; 2Department of Surgery, University of California San Diego, San Diego, CA, United States; 3Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu, Japan; Department of Surgical Oncology; 4MD Anderson Cancer Center, Houston, TX, United States.

In order to help develop individualized, and therefore more effective treatment, for pancreatic cancer, we have previously developed a multicolor, imageable, orthotopic mouse model for individual human pancreatic-cancer patients by passaging the patient tumors through nude mice expressing green fluorescent protein (GFP), red fluorescent protein (RFP) or cyan fluorescent protein (CFP). The patient tumors acquired brightly fluorescent stroma from the transgenic host mice, which was stably associated with the tumors through multiple passages. In the present study, pancreatic cancer patient tumor specimens were initially established in NOD/SCID mice. The tumors were then passaged orthotopically into transgenic nude mice ubiquitously-expressing GFP and subsequently to nude mice ubiquitously-expressing RFP. The pancreatic cancer patient tumors, with very bright GFP and RFP stroma, were then orthotopically passaged to non-colored nude mice. The brightly fluorescent patient tumors could be non-invasively imaged longitudinally as they progressed in the non-colored nude mice. This non-invasively imageable tumor-graft model will be valuable for screening for effective treatment options for individual pancreatic cancer patients, as well as for discovery of improved agents for this treatment-resistant disease.

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Risk of Pancreatic Cancer in Relation to ABO Blood Group, Hepatitis B and Hepatitis C Virus Infection in Korea: A Case-Control Study

S.M. Woo,1 J. Joo,2 W. J. Lee,1 M. Lee,1 B.A. Kim,1 S.J. Park,1 S.S. Han,1 T.H. Kim,1 Y. H. Koh,1 E.K. Hong11Center for Liver Cancer, Biometric Research Branch; 2National Cancer Center, Goyang, Republic of Korea.

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Background

Several studies have reported that ABO blood group, hepatitis B virus (HBV) and hepatitis C virus (HCV) infection contribute to the development of pancreatic cancer. The main aim of the current study was to evaluate the association between these factors and pancreatic cancer development in the Korean population.

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Patients and Methods

We retrospectively recruited 753 patients with pancreatic cancer and 3,012 healthy controls, matched 4 to1 with cancer patients for age and sex, between 2001 and 2011, at the National Cancer Center, Korea. A multivariable logistic regression analysis was employed to estimate adjusted odds ratios (AORs).

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Results

The AOR for pancreatic cancer in subjects with non-O blood types (A, AB, and B), compared to blood type O, was 1.29 (95% CI, 1.05–1.58; p = 0.01). Seropositivity for hepatitis B virus surface antigen (HBsAg) was not significantly related to pancreatic cancer, either in univariable (Odds ratio 1.03; 95% CI, 0.69-1.53; p = 0.91) or multivariable analysis (AOR, 1.02; 95% CI, 0.67-1.56; p = 0.93). The AOR for pancreatic cancer in subjects displaying seropositivity for anti-HCV was 2.30 (95% CI, 1.30–4.08; p < 0.01).

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Conclusions

Our results suggest that the ABO blood group and seropositivity for anti-HCV, but not HBV infection, may be associated with pancreatic cancer risk in Korea, where HBV is endemic.

Key Words: ABO blood group, hepatitis B virus, hepatitis C virus, pancreatic cancer, Korea

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Indication of Resection for Branch Duct Type IPMN

S. Hirono, M. Tani, M. Kawai, K. Okada, M. Miyazawa, A. Shimizu, Y. Kitahata, H. Yamaue Second Department of Surgery, Wakayama Medical University, Wakayama, Japan.

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Introduction

Main duct type intraductal papillary mucinous neoplasm (IPMN) has been recommended for resection, because of high malignant potential. However, the indications for resection of the branch duct type IPMN have been controversial. Therefore, in this study, we identified predictors of malignancy to determine indications for surgery for the patients with branch duct type IPMN.

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Methods

We retrospectively analyzed the clinicopathological factors of 148 patients who underwent resection for branch duct type IPMN at Wakayama Medical University Hospital from 1999 to 2011, to identify predictors of the malignant behavior of this neoplasm. The cutoff values of tumor size, main pancreatic duct (MPD) size, mural nodule size, and carcinoembryonic antigen (CEA) level in the pancreatic juice obtained during preoperative endoscopic retrograde pancreatography (ERP) were analyzed using receiver-operator characteristic curves.

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Results

We found 6 significant predictors for malignancy in the branch duct type IPMN in a univariate analysis; jaundice, MPD size >5 mm, mural nodule size >5 mm, serum CA19-9 level, positive cytology in the pancreatic juice, and CEA level in the pancreatic juice >30 ng/ml. In a multivariate analysis, a mural nodule size >5 mm and a CEA level in the pancreatic juice >30 ng/ml were independent factors associated with malignancy. When the combination of a mural nodule size >5 mm and a CEA level in the pancreatic juice >30 ng/ml is used, the positive predictive value was 100%, and the negative predictive value was 96.6%.

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Conclusion

We identified two useful predictive factors for malignancy in branch duct type IPMN; a mural nodule size >5 mm and a CEA level in the pancreatic juice obtained by preoperative ERP >30 ng/ml.

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Feasibility of Gemcitabine-Concurrent Proton Radiotherapy for Locally Advanced Pancreatic Cancer Abutting on Gastrointestinal Tract

T. Iwasaki,1,2 K. Terashima,1 O. Fuji,1 N. Hashimoto,1 M. Araya,1 M. Mima,1 Y. Niwa,1 Y. Demizu,1 I. Matsumoto,1 Y. Ku,2 N. Fuwa11Department of Radiology, Hyogo Ion Beam Medical Center; 2Department of Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medicine.

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Background

We have treated locally advanced pancreatic cancer (LAPC) with gemcitabine (GEM)-concurrent proton radiotherapy (GPT) (proton beam: 67.5Gy equivalent [GyE] in 25 fractions, GEM:800mg/m2/week for 3 weeks). Although rare, severe late gastro-intestinal (GI) toxicities were seen. Those should be put on the review in terms of dose-fraction especially in the LAPC abutting on GI tract.

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Purpose

We conducted the study to assess the feasibility of low dose GPT for LAPC abutting on GI tract.

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Patients and methods

Of all 20 patients who participated in the study, every patient had a tumor abutting on GI tract (1 with postoperative local recurrence and the other 19 with LAPC). All patients received low dose GPT (proton:50GyE/25fr, GEM:800mg/m2/week for 3 weeks). To assess acute and late toxicities, all patients were followed up including gastro-intestinal fiberscope.

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Result

The median follow-up period was 9.9 months. GI toxicities were observed in 16 patients at acute phase and in 10 at late phase. None of these toxicities were grade 3 and greater except for one case. This patient died of duodenal hemorrhage 6.5 months after irradiation completion. In this case, metallic stent was placed for biliary drainage before the low dose GPT. We currently made the metallic stent to be contraindicated for use in the GPT. Twelve patients could not receive the scheduled GEM administration because of acute hematologic toxicities.

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Conclusion

Except for one case with metallic stent, the toxicities were acceptable and the low dose GPT for LAPC abutting on GI tract is feasible. To improve the local tumor control, we aim to dose up of proton beam.

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Impact of Novel Biomarkers for Pancreatic Cancer by Using Metabolomic Analysis

J. Umeda,1 T. Itoi,1 M. Sugimoto,2 T. Soga,3 M. Sunamura,4 F. Moriyasu11Gastroenterology and Hepatology, Tokyo Medical University, Tokyo, Japan; 2Medical Innovation Center, Kyoto University, Kyoto, Japan; 3Environmental Information, Keio University, Tokyo, Japan; 4Digestive Tract Surgery and Transplantation Surgery, Tokyo Medical Center, Tokyo, Japan.

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Objective

Pancreatic enzymes and tumor markers, such as CEA, CA19-9, DUPAN-2 and SPAN-1, have been commonly used for diagnosis of pancreatic cancer. However, it is known that there are still many false negative cases, even though these tumor markers increase in advanced cancers.

Metabolomics, a new omics, provides a comprehensive profiling of small molecules (metabolites) that enables us to analyse cellular functions and to diagnosis a wide range of diseases. The purpose of this study is to evaluate the potential ability to diagnose pancreatic cancer with serum and saliva metabolomics.

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Methods

Blood and saliva samples were obtained from 45 patients with pancreatic cancer, 12 with chronic pancreatitis and 10 healthy adult volunteers. Capillary electrophoresis-time-of-flight mass spectrometry (CE-TOFMS) was employed for comprehensive analysis of charged metabolites mostly observed in the primary metabolic pathways. Blood tumor markers (CEA, CA19-9, SPAN-1 and DUPAN-2) were also analyzed from the identical patients. And we analyzed samples of 6 patients underwent operation for pancreatic cancer, to assess the changes before and after operation.

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Result

CE-TOFMS-based analysis detected 288 metabolites in the saliva and 150 metabolites in the blood. There are metabolites in saliva, which have statistically significant differences between the patients with pancreatic cancer and healthy adult volunteers. Principle component analysis clearly separated pancreatic cancer patients from the healthy volunteers in both serum and saliva samples.

Logistic regression of the combination of multiple metabolites successfully identified patients with pancreatic cancer from chronic pancreatitis and healthy controls with accuracy of AUC 0.87 in saliva and 0.89 in serum.

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Conclusion

We identified pancreatic cancer-specific metabolite profiles using CE-TOFMS and multivariate analysis demonstrated their diagnostic potential of pancreatic cancer. Although extensive research are needed, our data suggested high potential for pancreatic cancer diagnosis with saliva and serum metabolomics.

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Covered Self-Expandable Metal Stent Deployment Provides Patients with Borderline Resectable Pancreatic Head Cancer With Safe Neoadjuvant Chemotherapy

K. Kubota,1 T. Sato,1 S. Watanabe,1 K. Hosono,1 I. Endo,2 A. Nakajima11Department of Gastroenteroloy, Yokohama City University Hospital; 2Department of Surgery, Yokohama City University Hospital, Yokohama, Japan.

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Background

Borderline resectable pancreatic head cancer (BRPHC) is often associated with stent trouble and being expected margin-negative resection (R0). Recently, patients with BRPHC try to treat with neoadjuvant chemotherapy (NAC) using metallic stent, however, the efficacy and influence to the BRPHC undergone covered self-expanding metal stent (CSEMS) has not evaluated yet.

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Aims

To evaluate the efficacy and complication of CSEMS during the NAC and surgical period.

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Methods

We reviewed the outcomes of consecutive patient with BRPHC, transpapillary cytology and/or biopsy using EUS-FNA-proven pancreatic adenocarcinoma and resulting biliary obstruction, then, divide chronologically them into three groups, Group A; Plastic stent deployment was done from April 2006 and July 2008. Group B; Plastic stent deployment plus NAC from August 2009 and October 2010. Group C; CSEMS deployment (covered wall stent 10mm/6cm, Boston Scientific) plus NAC from November 2010 and January 2013. Patients were categorized as borderline resectable based on NCCN guideline established in 2011. Data on demographics, stent patency, complications, re-intervention rate, the rate of R0 and complications after resection (bleeding, leakage and cholangitis) were studied. Safe R0 surgery is defined as Ro surgery without re-intervention of ERCP during the NAC period and no post operative complication.

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Results

There were 43 BRPHC (Group A, B and C was 13, 13 and 17, respectively). Median time from stent placement to surgery was 96 days for all patients (Group A, B and C were 38, 101 and 136 days, respectively). Double stent for biliary and duodenum were placed in three patients with group C. Stent patency were followed; Group A, B and C were 25, 56 and 117 days respectively (p<0.05). No severe complication was noted in all patients. R0 surgery was obtained in Group A, B and C was 69% (9/13), 100% (13/13) and 94% (16/17), respectively. CSEMS did not interfere with pancreaticoduodenectomy in any patients. Finally, Safe R0 surgery obtained in Group B and C were 31% (4/13) and 82% (14/17), respectively (p<0.05).

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Conclusions

CSEMS should be considered to relieve biliary with/without duodenum obstruction in patients with BRPHC receiving NAC in view of their superior biliary patency rate, fewer re-interventions rate for recurrent biliary obstruction and high attainability rate of safe R0 surgery compared to that with plastic stent deployment.

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A New Surgical Technique for Pancreatic Head-body Cancer With Splenic Artery Invasion: Proximal Subtotal Pancreatectomy With Splenic Artery (PD-SAR)

M. Kishiwada, S. Isaji, S. Mizuno, A. Tanemura, Y. Azumi, N. Kuriyama, I. Osawa, M. Usui, H. Sakurai, M. Tabata Department of Hepato-biliary-pancreatic and Transplant surgery, Mie University, Tsu, Japan.

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Introduction/Background

Pancreatic adenocarcinoma arising from the head-body region often invades the origin of splenic artery and thus we cannot be able to avoid total pancreatectomy (TP). Although TP can be safely performed, it results in an extreme form of pancreatogenic diabetes: iatrogenic hypoglycemia affects patient’s QOL and prognosis. For such tumors, we developed a new surgical technique of proximal subtotal pancreatectomy with splenic artery and vein resection (PD-SAR) usually after preoperative chemoradiotherapy in consideration of the balance between operative radicality and postoperative QOL. Blood flow to the pancreas tail can be obtained by the left gastroepiploic artery and posterior epiploic artery even if we have to resect the left gastric artery combined with total gastrectomy and splenectomy (Mizuno & Isaji, Surgery Today, 2011) .

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Method

From February 2005 to Jun 2012, we performed proximal pancreatectomy in 56 patients with pancreatic adenocarcinoma: PD-SAR in 13 patients (T3:4,T4:9) and pancreaticoduodenectomy (PD) in 43 patients (T3: 30, T4: 13). Most patients were treated by preoperative chemoradiotherapy (45 Gy radiation in 25 fractions with 800 mg/m2 gemcitabine weekly intravenously for 5 weeks including one-week break) or preoperative chemotherapy ( S-1; tegafur, gimeracil, oteracil potassium : 60 mg/m2 p.o. b.i.d. from day 1 to 21 and gemcitabine :600 mg/m2 on Day8 and 21 ). PD-SAR group received chemoradiotherapy in 10 and chemotherapy in 2. PD group received chemoradiotherapy in all 43. We compared the two groups with respect to prognosis and postoperative pancreatic function. Prognosis was evaluated by 1- and 3-year survival rate and median survival times (MST). Pancreatic function was measured preoperatively , and at 1, 3 , 6 and 12 months postoperatively: glucose control (FBS, HBA1c, insulin therapy), lipid metabolism (cholesterol), nutrition (weight, alb), frequency of bowel movement and amount of pancreatic enzyme supplementation.

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Result

Overall 1- and 3-year survival rates and MST in PD-SAR vs. PD groups were 67.5%, 45% and 23.5 months vs. 64.7%, 40.6% and 24.9 months, respectively (p=0.69). With regard to pancreatic function, glucose tolerance in PSP-SAVR group was significantly impaired, but there were no obvious hypoglycemic attacks and deterioration of QOL. PD-SAR group needed large amounts of pancreatic enzymes, but there were no significant differences in lipid metabolism, nutrition and frequency of bowel movement.

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Conclusion

PD-SAR with preoperative chemoradiotherapy or chemotherapy seems to be promising surgical strategy for pancreatic head-body adenocarcinoma with invasion of the origin of splenic artery, in regard to the balance between operative radicality and postoperative QOL.

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Surgical Outcome and Gastrointestinal Function After Non-Stented Hepaticojejunostomy in Pancreaticoduodenectomy

H. Imai, S. Osada, Y. Sasaki, T. Takahashi, K. Yamaguchi, K. Yoshida Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan.

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Introduction

In patients with obstructive jaundice, internal biliary drainage is better than external biliary drainage for improving nutritional status and the mucosal immune system. Although external biliary drainage was widely used after pancreaticoduodenectomy (PD), no-stent hepaticojejunostomy (HJ) was introduced from 2009 in our institute. The aim of this study was to compare postoperative gastrointestinal function and complications of PD with and without an external drainage stent for HJ.

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Patients and methods

Between June 2005 and September 2011, 66 patients who underwent PD, including 40 patients with externally-stented HJ (ES group) and 26 patients with non-stented HJ (NS group), were included in this study, and operative time, blood loss, postoperative bowel movements, oral intake, and complications were investigated.

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Results

The type of pancreatic duct stent, number of intraperitoneal drains, and the rate of patients with tube jejunostomy for enteral nutrition were different between the groups, because several operative procedures were modified around the same time. Although times to removal of nasogastric tube and tolerance of water or solid food were comparable between the two groups, time to first defecation was significantly shorter in NS group patients than in ES group patients (3.2 ± 1.6 versus 4.6 ± 1.7 days; p = 0.002). There were no differences in the incidence and severity of postoperative pancreatic fistulas, biliary leakage, and delayed gastric emptying, whereas the incidence of postoperative cholangitis was significantly higher in ES group patients (25.0%) than in NS group patients (3.8%; p = 0.024).

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Conclusion

External biliary drainage may have a negative impact on biliary complications after PD, especially on the incidence of postoperative cholangitis; therefore, further investigations and prospective trials are necessary.

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Surgical Resection After Chemoradiation Utilizing Intensity Modulated Radiation: A Case of Locally Advanced Pancreatic Cancer

M. Habu,1 K. Takaori,1 Nakamura,2 S. Itasaka,2 M. Kawaguchi,1 Y. Kawaguchi,1 M. Hiraoka,2 S. Uemoto11Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan; 2Department of Radiation Oncology and Image-applied Therapy, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

A 62-year-old male was referred to our hospital with elevated tumor maker levels. CT scan revealed a pancreatic tumor within the pancreatic head and suggested the plexus invasion at the origin of gastroduodenal artery from common hepatic artery. There was no other finding of distant metastases. We conducted a gemicitabine-based chemoradiation therapy, utilizing intensity modulated radiao therapy (IMRT). The local lesion well controlled by the chemoradiation, and the levels of tumor markers were decreased remarkably to almost normal values. Staging laparoscopy was carried out 2 months after the completion of chemoradiation therapy and no evidence of peritoneal dissemination or liver metastasis was found. Subsequently, a pancreaticoduodenectomy was performed. Pathohistological examination of the resected specimen showed scattered carcinoma cells in the center of markedly fibrous tissue, suggesting Grade-2 effects of preoperative chemoradiation. Postoperative course was uneventful. Postoperative adjuvant chemotherapy with gemcitabine was administered. In conclusion, gemcitabine-based chemoradiation utilizing IMRT may be a promising preoperative therapy for locally advanced pancreatic carcinoma.

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Sub-emergent Pancreaticoduodenectomy After IVR for Carcinoma of the Head of the Pancreas Invaded Duodenum

H. Urakami,1 J. Hagiwara,1 A. Matsunaga,1 Y. Kawaguchi,1 J. Tokuyama,1 K. Osumi,1 S. Seki,1 A. Shimada,1 A. Matsui,1 T. Oishi,1 Y. Ishobe,1 Y. Isobe,2 S. Matsumoto11Department of Surgery, NHO Tokyo Medical Center, Tokyo, Japan; 2Department of Radiology, NHO Tokyo Medical Center, Tokyo, Japan.

We experienced a case of carcinoma of the head of the pancreas undergoing IVR for duodenal bleeding followed by pancreaticoduodenectomy. The patient was 70-year-old male and visited ER at our hospital due to vomiting and nausea. The blood examination showed liver dysfunction and slight anemia, and CT demonstrated a tumor lesion of head of the pancreas and hematoma in the stomach. Conservative therapy was chosen, however, hematemesis observed and Upper GI endoscopy showed blood clots at the duodenum but no active bleeding observed at this time. Hemorrhagic shock observed and emergent IVR was done showing extravasation at the duodenum from peripheral branch of the GDA. Titanium coils were embolized and active bleeding was completely controlled. We underwent semi-emergent pancreaticoduodenectomy since one coil was prolapsed during IVR and we recognized the risk of further prolapse during the evaluation period for the tumor. The tumor directly invaded portal vein and very close to the root of GDA, and curative resection was done. The blood loss was 1690 ml and operation time was 695 minutes. No severe complication observed and he discharged from our hospital 20 days after surgery. The pathological finding showed invasive ductal carcinoma directly invaded portal vein, bile duct and the duodenum mucosa where ulcer lesion existed, and severe neural invasion and moderate vesicular and lymphatic invasion observed. The TNM stage was IIB and adjuvant chemotherapy consisted of GEM inducted. In conclusion, IVR was successfully done and exactly useful procedure to prevent the “real” emergent surgery following IVR.

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CD271+ Pancreatic Stellate Cells are Correlated With Prognosis of Patients With Pancreatic Cancer and Regulated by Interaction With Cancer Cells

K. Fujiwara,1 K. Ohuchida,1 K. Mizumoto,1 K. Shindo,1,2 D. Eguchi,1 S. Kozono,1 N. Ikenaga,1 T. Ohtsuka,1 S. Takahata,1 S. Aishima,2 M. Tanaka11Department of Surgery and Oncology, 2Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

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Purpose

Pancreatic cancer is characterized by excessive desmoplasia. Pancreatic stellate cells (PSCs) play a crucial role in the aggressive behavior of pancreatic cancer. Although functional heterogeneity of PSCs has been identified, the role of PSCs remains unclear. CD271 is focused upon because it is one of the markers of human mesenchymal stem cells. We characterized CD271+ PSCs in human pancreatic cancer.

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Methods

Immunohistochemical staining of CD271 was performed for 31 normal pancreatic tissues and 105 pancreatic ductal adenocarcinomas (PDACs). We performed quantitative RT-PCR (qRT-PCR), and assessed CD271 expression in PSCs isolated from pancreatic tissues and the changes in CD271 expression in PSCs co-cultured with cancer cells.

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Results

In the immunohistochemical analyses, the CD271-positive rates in pancreatic stroma of normal pancreatic tissues and PDACs were 2/31 (6.5%) and 29/105 (27.6%), respectively (p=0.0069). In PDACs, CD271+ stromal cells were frequently observed on the edge of the tumors. Stromal CD271 expression was associated with a good prognosis (p=0.0040). The qRT-PCR analyses revealed that CD271 mRNA expression was increased in PSCs after co-culture. However, the level of CD271 mRNA expression subsequently decreased after the transient increase.

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Conclusions

CD271 is expressed in PSCs on the edge of pancreatic cancers, but not in the center of the tumors, and decreases after co-culture with pancreatic cancer cells. These findings suggest that CD271+ PSCs appear at the early stage of interaction with pancreatic carcinogenesis and that CD271 expression is significantly correlated with a better prognosis of patients with PDAC.

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P38 MAPK/Thioredoxin-Interacting Protein Axis: A Novel Mechanism for Glucose-induced Increase of Reactive Oxygen Species in Human Pancreatic Cancer

W. Li, Q. Ma, Q. Sun Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College, Xi’an Jiaotong University, Xi’an, China.

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Objective

Needless to mention the life quality, the curative operation rate is significantly lower in the pancreatic cancer patients with hyperglycemia compared with one in pancreatic cancer patients with euglycemia. Our previous study has demonstrated that hyperglycemia increases the production of reactive oxygen species (ROS) in pancreatic cancer cells. Herein, we aim to discuss the inner mechanism of this increase.

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Methods

Immunohistochemistry was used to test the expression of Thioredoxin (TRX), Thioredoxin-interacting protein (TXNIP) and phospho-p38 in 59 specimens of pancreatic cancer with or without hyperglycemia. The mRNA and protein level of both TRX and TXNIP were also measured by RT-PCR and Western blotting in the pancreatic cancer tissues. The human pancreatic cancer cell lines BxPC-3 and Panc-1 were grown either in 5.5 or 25 mM glucose. We determined the intracellular ROS using DCFH-DA and inspected the protein expression (TRX, TXNIP, phospho-p38 and p38).

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Results

The expression level of TXNIP and phospho-p38 were higher in the hyperglycemia patient group than that in the euglycemia patient group. However, there was little difference on TRX expression in the two groups. When both BxPC-3 and Panc-1 cells were exposed to high glucose, the phospho-p38 MAPK was activated and levels of ROS and TXNIP were increased, meanwhile, the thioredoxin activity was reduced. N-acetyl-cysteine and p38 MAPK inhibitor SB203580 were shown to impair these effects induced by high glucose.

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Conclusion

p38 MAPK/TXNIP axis is involved in diabetes-mediated oxidative stress in pancreatic cancer.

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Infectivity Selective Oncolytic Adenovirus for Pancreatic Cancer by Redesigning the AB-loop via Adenovirus Library Screening

Y. Miura, J. Davydova, M. Yamamoto Department of Surgery, University of Minnesota, Minneapolis, MN.

Although adenovirus (Ad) has frequently been used as a backbone of oncolytic viral agents, lack of selectivity to pancreatic cancer cell at the stage of infection has greatly hampered in vivo efficacy. We have developed a new class of oncolytic virus system, Infectivity-Selective Oncolytic Adenovirus via direct screening of a high diversity Ad-formatted targeting ligand library. In this study, we identified novel oncolytic Ad retargeted mesothelin (MSLN), which is over-expressed in pancreatic cancer but not in normal tissue. Ad with random 7 amino acid sequence in the AB-loop of the fiber-knob was screened with MSLN-expressing 293 cells, and the library sequence converged to one dominant clone. The binding was corresponded to the level of MSLN-expression. The anti-MSLN siRNA/antibody blocked the binding to MSLN-expressing cells. These data indicates that mesothelin is a receptor moiety for isolated targeting ligand. The in vivo antitumor effect was compared in Panc-1 (MSLN+) and MiaPaCa-2 (MSLN-) subcutaneous xenografts. The injection of the MSLN-retargeted oncolytic Ad showed significant antitumor effect against Panc-1 tumors, and about half of the tumor disappeared. Contrarily, the same virus did not show antitumor effect in MiaPaCa-2. Viral DNA quantitation showed the selective viral replication in Panc-1. Upon systemic administration in the nude mice with Panc-1 subcutaneous xenografts, the biodistribution of this virus to the liver was significantly lower than that of wild-type Ad5, and the copy number of this retargeted virus was significantly (<1000 fold) higher in the tumor . In this study, we successfully identified MSLN targeting Ad vector, and this clone exhibited significant infectivity to MSLN+ pancreatic cancer cells in vitro and in vivo. This new genetically modified Ad transductionally retargeted to pancreatic cancer may embody a next generation targeting for this devastating disease in clinical settings.

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The Preoperative Biliary Drainage Dose Not Affect on Surgical Site Infection after Pancreatoduodenectomy

A. Chikamoto, D. Hashimoto, Y. Ikuta, T. Beppu, H. Baba Department of Gastroenterological Surgery, Kumamoto University, Kumamoto, Japan.

The correlation between incidences of surgical site infection (SSI) following pancreatoduodenectomy (PD) and the type of preoperative biliary drainage was analyzed. From July 2009 to March 2012, 51 PDs were performed for various malignancies including 25 pancreatic cancers, 12 bile duct cancers, 7 cancers of papilla Vater, and 1 gallbladder cancer in Kumamoto University Hospital. In all cases, intraoperative bile specimens were collected prospectively. Correlations between results of bile culture and surgical site infection were analyzed. Fifty-one PD cases were categorized into 4 groups; cases without preoperative biliary drainage (N, n=26), percutaneous transhepatic biliary drainage group (PTBD, n=5), endoscopic retrograde biliary drainage group (ERBD, n=8), and 12 endoscopic nasobiliary drainage group (n=12). Positive bacterial cultures were observed in 11% of N, 100% of PTBD and ERBD, and 67% of ENBD.

Enterococcus species were detected by bacterial culture most frequently. Nineteen of 51 had superficial surgical site infection, but there were no significant differences of the incidences among the 4 groups. Twelve had surgical site infections in the abdominal cavities. There were also no significant differences of the incidences among the 4 groups. Although 8 of the 12 deep SSI cases had bacterial contaminations in the intraoperative bile specimens, the kinds of bacteria of bile specimen and those of SSI were similar in only 3 cases. Eight of the 12 had leakages of pancreatico-gastrostomy or hepetico-jejunostomy. The incidences of these leakages and SSI in the abdominal cavity was correlated (p<0.0001). In conclusion, preoperative biliary drainage prior to pancreatoduodenectomy had a correlation with biliary bacterial contamination, but not with any type of SSI.

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How Should We Treat Glucose Intolerance as a Risk Factor for Pancreatic Cancer?

E. Sato,1 Y. Tando,1 M. Yanagimachi,1 H. Tanaka,1 Y. Matsugashi,1 A. Matsumto,1 A. Kakizaki,1 S. Chikazawa,1 A. Kon,1 T. Nakamura21Department of Endocrinology and Metabolism, Hirosaki University School of Medicine; 2Department of Health science, Hirosaki University School of Medicine, Hirosaki, Japan.

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Background

The number of patients diagnosed with diabetes mellitus (DM) is increasing year by year, and approximately one out of five adults may have diabetes in Japan. DM is well known to be a risk factor for pancreatic cancer. If we could clearly identify more high risk individuals among this population, it could lead to early detection and treatment of pancreatic cancer. AIM: To identify biomarkers of pancreatic cancer in diabetic patients.

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Methods

We examined the clinical features of 39 pancreatic cancer patients with DM. Results: Thirty-three patients were diagnosed with DM before the diagnosis of pancreatic cancer, and 6 patients were diagnosed at the same time. The number of them had smoked and had family history of cancer, and the frequencies of each were approximately 50–60 % and 70–80 %. Patients with DM preceding pancreatic cancer had a mean increase of 2.0 % in HbA1C levels, and experienced about 6 kg weight loss 1 year before they were diagnosed with pancreatic cancer. Seven patients were diagnosed with pancreatic cancer because their blood glucose controls turned worse. Among them, 2 patients were screened immediately and diagnosed with pancreatic cancer in stage II and III, and they have survived for 53 and 89 months after diagnosis of pancreatic cancer.

None of patients within 2-year history or newly diagnosed with DM had family history of DM, so they were supposed to be pancreatic diabetes.

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Conclusions

Diabetic patients with an aggravation of DM and body weight loss, or newly onset diabetic patients without family history of DM are suspected to have pancreatic cancer and should be screened accordingly.

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Novel Diagnostic Value of Circulating miR-18a in Plasma of Patients with Pancreatic Cancer

R. Morimura, S. Komatsu, D. Ichikawa, H. Takeshita, M. Tsujiura, Y. Murayama, A. Shiozaki, Y. Kuryu, H. Ikoma, M. Nakanishi, H. Fujiwara, K. Okamoto, T. Ochiai, Y. Kokuba, E. Ootsuji Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan.

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Abstract

Background

Several recent studies have demonstrated that microRNAs (miRNAs) are detectable in plasma/serum. We hypothesized that miR-18a in plasma is a potential biomarker in patients with pancreatic cancer.

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Methods

MiR-18a is located in the miR-17-92 cluster and reported to be highly expressed in pancreatic cancer tissues. This study was divided into three parts. Confirmation of higher miR-18a levels in primary pancreatic cancer tissue and cell lines than normal pancreatic tissues and human fibroblasts. Evaluation of the plasma miR-18a assay using quantitative RT-PCR by comparing results from 36 patients with pancreatic cancer and 30 healthy volunteers Evaluation of the assay for monitoring tumor dynamics assay in patients with pancreatic cancer.

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Results

The expression of miR-18a was significantly higher in pancreatic cancer tissues (p=0.012) and pancreatic cancer cell lines (p=0.015) than normal tissues and fibroblasts. The plasma concentrations of miR-18a were significantly higher in pancreatic cancer patients than controls (p<0.0001). The value of the area under the receiver-operating characteristic curve (AUC) was 0.9369. The plasma levels of miR-18a were significantly lower in postoperative samples than preoperative samples (p=0.0077).

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Conclusion

Circulating miR-18a might provide new complementary tumor marker for pancreatic cancer.

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Phase 1 & 2 Trials of Combination Therapy with Gemcitabine/Candesartan in Advanced Pancreatic Cancer

Y. Nakai,1 H. Isayama,1 H. Ijichi,1 T. Sasaki,1 Y. Ito,2 S. Matsubara,3 H. Yagioka,4 R. Nagano, K. Kawakubo,1 H. Kogure,1 N. Yamamoto,1 N. Sasahira, K. Hirano,1 M. Tada,1 K. Koike11Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo; 2Department of Gastroenterology, Japanese Red Cross Medical Center; 3Department of Gastroenterology, Tokyo Metropolitan Police Hospital; 4Department of Gastroenterology, JR Tokyo General Hospital; 5Department of Gastroenterology, Kanto Central Hospital, Tokyo, Japan.

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Background

Inhibition of renin-angiotensin (RA) system is one of attractive treatment targets for pancreatic cancer (PaC). Our retrospective analysis showed association of inhibition of RA system with better prognosis in advanced PaC. Here we reported phase 1 & 2 trials of gemcitabine & candesartan (GECA) in PaC.

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Patients

In phase1 trial in normotensive pts, candesartan was administered orally at escalating dose (4/8/16/32mg) qd daily & gemcitabine was administered 1000mg/m2 30min i.v. day 1/8/15, every 4 weeks. DLT was defined as grade4 hematological toxicities, grade2 hypotension, abnormal creatinine or potassium & grade3/4 other non-hematological toxicities. In phase2 trial, candesartan was administered 16mg in normotensive pts and 8mg in pts with hypertension, followed by increase up to 16mg. Eligible criteria were advanced PaC without any prior treatment, PS 0-2 & normal renal function.

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Results

In phase1 trial, 14 pts (locally advanced/metastatic 7/7) were enrolled. 1/6 pts at 16 mg demonstrated DLT of grade 4 neutropenia & 2/2 pts at 32mg demonstrated DLT of grade2 hypotension. Response rate (RR) & disease control rate (DCR) was 0% & 79%. PFS & OS were 7.6 & 22.9 months. In phase2 trial, 35 pts (locally advanced/metastatic 9/26) were enrolled. Major severe adverse events were neutropenia 24% & thrombocytopenia 18%. Grade2 hypotension was seen in 3 pts. RR & DCR were 11% & 63%. Median PFS & OS were 4.3 & 7.7 months.

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Conclusion

GECA in advanced PaC appeared safe & promising.

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Fucosylated Haptoglobin is a Novel Type of Biomarker for Pancreatic Cancer

Y. Sasaki, Y. Nonaka, H. Asazawa, N. Terao, S. Takamatsu, S. Shinzaki, Y. Kamada, E. Miyoshi Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Osaka, Japan.

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Background and Aim

Changes in oligosaccharide structures have been reported in some types of malignant transformations and could be used for tumor markers in certain types of cancer. We previously reported that fucosylated haptoglobin (Fuc-Hpt) was increased in sera of patients with pancreatic cancer (PC) and developed a Fuc-Hpt detection kit as a sandwich enzyme-linked immune sorbent assay (ELISA) using Aleuria aurantia lectin (AAL) and the Fab portion of anti-haptoglobin antibody. In the present study, we investigated the availability of Fuc-Hpt for a diagnosis of PC.

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Results

Three hundred cases of PC and 315 cases of normal volunteers were enrolled in this study. Serum levels of Fuc-Hpt were significantly increased in patients with PC. In terms of the clinical stage, significant increase was observed at stage IV of PC than at other stages. However, a few cases of PC at stage I/II also showed high Fuc-Hpt levels. Since the prognosis of PC is quite poor, the relationship between overall / relapse-free survival and Fuc-Hpt levels was investigated in 77 cases of colorectal cancer. As a result of this analysis, we found that distant metastasis is an independent factor for increased Fuc-Hpt levels and the combination of Fuc-Hpt and CEA is a better serologic marker to predict prognosis after operation. Similar investigation for PC is underway.

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Discussion

Most of Hpt is produced in the liver. Our previous study demonstrated that total Hpt levels are not correlated with Fuc-Hpt levels. This discrepancy might be caused that Fuc-Hpt is produced in limited lesion of the liver/liver metastasis, lymphnode metastasis, and the original pancreatic cancer itself. It is thought that Fuc-Hpt production was also affected with interleukin-6 (IL-6) and loss of cellular polarity. The present study suggests the utility of Fuc-Hpt as a marker for early (liver) metastasis.

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Clinical Validation of the Guidelines for Management of Pancreatic Branch-duct Intraductal Papillary Mucinous Neoplasms

Y. Hashimoto, Y. Murakami, K. Uemura, T. Sudo, N. Kondo, H. Sasaki, K. Okada, T. Sueda Department of Surgery, Applied Life Sciences Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.

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Background

Based on consensus guidelines, surgical resection of branch duct intraductal papillary mucinous neoplasm (BD-IPMN) is indicated in patients with symptoms of cyst size ≥30mm, intramural nodules, or positive cytology. To evaluate the validity of the guideline in the management of BD-IPMN and assess characteristics at presentation of resected BD-IPMN <30mm with or without a solid component.

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Methods

A retrospective review of clinicopathological data in patients who underwent a pancreatectomy for IPMN (n=120) from a single institution’s prospectively maintained database (2000–2011). IPMNs were classified as main-duct predominant (MD; main duct size ≥5mm) or branch-duct predominant (BD; <5mm) based on preoperative imaging.

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Methods

Of 120 patients, 70 (58%) were MD-IPMNs and 50 (42%) were BD-IPMNs. Of 50 BP-IPMNs, the average age at presentation was 66 years and 70% were males. Thirty-seven (74%) were located in the head/uncinate and 13 (26%) in the body/tail. The average cyst size was 30mm (range, 10–80mm) and 26 (52%) BD-IPMNs had solid components on radiology. Pathology revealed the following: 48% (n=24) low-grade dysplasia, 24% (n=12) moderate-grade dysplasia and 26% (n=13) high-grade dysplasia (carcinoma in situ; CIS), and only 2% (n=1) BD-IPMN with associated invasive cancer; therefore malignant BD-IPMN was present in 14 (28%).

All neoplasms with malignancy were larger than 30mm in size and/or had intramural nodules and/or caused symptoms. In the subgroup of BD-IPMN with cyst size < 30mm (n=26), malignancy was present 27% (n=7; 6 CISs and 1 invasive). In BD-IPMNs < 30mm without a solid component (n=12), three (25%) were diagnosed as CIS BD-IPMN, but not invasive cancer.

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Conclusions

This large cohort of resected BD-IPMNs shows that cancer is present in 28% of cases and validates the recent guidelines that indicate absence of invasive cancer in tumors < 30mm, without symptoms or intramural nodules. However, given the high proportion of CIS in small lesions without a solid component, prospective clinical trials are needed to determine whether smaller lesions should be resected before they progress to invasive cancer or if other characteristics can be identified to stratify this group further.

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Repeated Pancreatectomy for Locally Recurrent of Pancreatic Ductal Adenocarcinoma Following Primary Pancreatic Resection

D. Hashimoto,1 A. Chikamoto,1 M. Ohmuraya,2 M. Hirota,3 H. Baba11Department of Gastroenterological Surgery; 2Institute of Resource Development and Analysis, Kumamoto University Graduate School of Medical Sciences; 3Department of Surgery, Kumamoto Regional Medical Center, Kumamoto, Japan.

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Background

There have been some reports of a remnant pancreatic carcinoma after pancreatectomy for invasive ductal carcinoma of the pancreas. However, the clinical features and the efficacy of repeated pancreatectomies for remnant pancreatic carcinoma are obscure, because of the limited number of cases.

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Objective

To make clear the efficacy of repeated pancreatectomy for recurrent of pancreatic ductal adenocarcinoma

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Methods

Following primary pancreatic resection for pancreatic adenocarcinoma, 7 patients developed recurrent pancreatic cancer between April 2005 and April 2012. The clinical course and operative findings were reviewed retrospectively.

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Results

Five patients underwent repeated pancreatectomy for recurrent pancreatic tumor (resected group), while 2 patients were not operated and underwent chemotherapy because of multiple liver metastasis with the recurrent pancreatic tumor (unresected group). Recurrent on the edge of the pancreas were suspected in both patients of unresected group. Median time between the initial resection and the recurrence was 36 months in resected group and 21 months in unresected group. In resected group, while only one patient died 34 months after the1st operation, 4 patients have survived until now with 66 months as median observation period. Median survival of unresected group after the 1st operation was 32.5 months.

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Conclusion

Our results suggested that repeated pancreatectomy for the recurrent tumor in the pancreatic remnant can prolong survival of pancreatic cancer patients. Further studies are required to address the question whether a subgroup of patients might actually benefit from this procedure.

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Immunohistochemical Investigation Toward Qualitative Diagnosis in Pancreas Tumor

K. Abe,1 Y. Uchida,1 A. Koido,1 M. Yasuda,1 Y. Komura,1 M. Shibata,2 H. Saito,2 T. Iijima,3 J. Imura 1Clinical Laboratory Pathology Department; 2Department of Diagnostic Pathology, Ibaraki Prefectural Central Hospital and Cancer Center, Kasama, Japan; 3Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.

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Introduction

According to advances in diagnostic radiology, there are increasing opportunities to detect the small pancreatic lesions. On the other hand, a precise qualitative to diagnosis including the spread of EUS-FNA is expected in the pathological diagnosis. However, it may be difficult to diagnosis because a specimen is small, it is a problem to delay the treatment and to give an excessive aggressiveness to a patient. Therefore we report the immunohistochemical examination about the apoptotic factor concerned for the purpose of investigating the newly biomarkers of the pancreatic malignant lesions. Materials and methodsMaterials are the formalin fixed and paraffin embedding materials to obtain from the patients of 51 pancreatic lesions to be diagnosed pathologically. The immunohistochemical examination was carried out using S-100P, S-100A11, S-100A2, P53, Survivin, an antibody for X-linked inhibitor of apoptosis protein (XIAP).

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Results

The S-100P and S-100A11 are highly expressed in the initial stage of tumorigenesis, and the expression of S100A2 and XIAP were observed in cancer. The expression pattern of P53 and Survivin showed similar tendency and increased the expression intensity according to the cancerization. As a result of multiple regression analysis, S-100P and S-100A11 (p<0.01) were effective factors to divide in the differential diagnosis of neoplasia and non-neoplasia, XIAP (p<0.01) and S-100A2 (p=0.03) were in cancer and non-cancer, XIAP was in IPMC and PDA.

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Conclusions

It was suggested that S-100P, S-100A11 became the marker to diagnose in tumorgenesis, XIAP and S100A2 were in malignant transformation and XIAP was in PDA. The immunohistochemical examination using the apoptotic factor concerned was useful for the differential diagnosis of the pancreatic lesions. These examinations should be applicable in the cytodiagnostic specimens, and it was suggested the possibility for the early diagnosis and the patient stratification in future.

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A Novel Immunotherapy for Pancreatic Cancer Stem Cells by Tumor Lysate Vaccine, Expressing α-gal Epitopes

M. Tanemura,1 T. Tanida,2 E. Miyoshi,3 H. Nagano,2 H. Eguchi,2 K. Furukawa,2 Y. Nonaka,3 K. Kawamoto,2 H. Wada,2 S. Kobayashi,2 K. Taniyama,1 W. Kamiike,1 M. Mori,2 Y. Doki21Department of Surgery and Institute for Clinical Research, National Hospital Organization Kure Medical Center, 2Chugoku Cancer Center, Kure, Japan; Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan; 3Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Osaka, Japan.

Pancreatic cancer (PC) cells, expressing the markers CD44, CD24, and epithelial-specific antigen (ESA) were identified as PC stem cells (CSCs). Treatments targeting the CSCs may be more effective in resulting in PC cure. Human natural Ab, anti-Gal is an IgG known to be present in large amounts in normal subjects and cancer patients, comprising ∼1% of serum circulating IgG. Anti-Gal specifically interacts with α-gal epitopes (Galα1, 3Galβ1, 4GlcNAc-R), synthesized by α1, 3 galactosyltransferase (α1,3GT) on cell surface glycolipids and glycoproteins. We hypothesized that biosynthesis of α-gal epitopes on the carbohydrate of CSC markers, including CD44, CD24 could effectively induce Ab production against CSCs and immune-mediate eradication of PC CSCs. A human PC cell line, PANC1 was employed and transfected with α1,3GT gene (α-gal PANC1). To generate tumor lysate, 2 X 106 of either parental or α-gal PANC1 were injected S.C. into NOD/SCID mice, and the grown tumors were enucleated and homogenized. High anti-Gal α1,3GT KO mice, which displayed anti-Gal titers similar to those found in humans, were generated by immunization of pig tissue. These mice were vaccinated intraperitoneally (ip) by 100 mg of either parental (parental group) or α-gal PANC1 tumor lysate (α-gal group). In FACS analysis, a marked Ab production against both CSCs and differentiated cancer cells were observed in α-gal group. To demonstrate in vivo tumor destruction, splenocytes from vaccinated KO mice were prepared, then these cells were transferred ip (30X106 cells/ip X 3 times) into NOD/SCID mice. Transferred mice were challenged with S.C. injection with either 1 X 107 of live PANC1 or 5 X 106 of CD44+CD24+ PANC1. PANC1 tumors in mice transferred from parental group reached the size of 150 mm2 at 45 days after injection. For tumors in mice transferred from α-gal group, regrowth of tumor was completely prevented. Survival of α-gal transferred mice was significantly prolonged [α-gal vs. parental: 82.5±21.9 vs. 48.0±6.7 days, p<0.0001]. CSC tumors in mice transferred from parental group reached the size of 100 mm2 at 49 days after injection. For CSC tumors in mice from α-gal group, no tumor formation was observed. Survival was significantly prolonged [α-gal vs. parental: 85.0±20.8 vs. 49.3±14.3 days, p=0.0002]. We conclude that immunotherapy with tumor lysate vaccine, expressing α-gal epitopes effectively targets both differentiated and PC CSCs and may provide PC cure by destruction of micro-metastasis and minimal residual cancer.

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Regulation of Claudin-4 via Protein Kinase C Signal Pathway in Normal Human Pancreatic Duct Epithelial Cells and Cancer Cells

H. Yamaguchi,1 T. Kojima,2 D. Kyuno,1 T. Ito,1 M. Imamura,1 Y. Kimura,1 N. Sawada,2 K. Hirata11Department of Surgery, Sapporo Medical University, Sapporo, Japan; 2 Department of Pathology, Sapporo Medical University, Sapporo, Japan.

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Introduction

Claudin (CL)-4 is an important component of epithelial tight junctions and also a high-affinity receptor for Clostridium perfringens enterotoxin (CPE). Recently, it is revealed that in pancreatic intraepithelial neoplasia and pancreatic cancer, CL-4 is frequently overexpressed and a promising target for novel diagnostic and therapeutic strategies using CPE. However, the regulation of CL-4 in pancreatic cancer remains unknown. We previously reported that protein kinase C (PKC) signal pathway regulated the expression of CL-4 in normal human pancreatic duct epithelial (HPDE) cells.

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Objective

We investigated the role of the PKC signal pathway in the regulation of CL-4 and the effects of CPE treatment, using normal HPDE cells and cancer cells.

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Method

We used human telomerase reverse transcriptase (hTERT)-transfected HPDE cells (hTERT-HPDE cells) as normal HPDE cells and pancreatic cancer cell lines. Fetal bovine serum (FBS) and 12-O-tetradecanoylphorbol 13-acetate (TPA) were used to activate PKC.

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Result

In normal HPDE cells, CL-4 was highly-expressed at the apical tight junction area by PKC activation, but cytotoxic effects of CPE were not observed. In pancreatic cancer cells, CL-4 was expressed at both apical and basolateral cell membranes and acute dose-dependent cytotoxic effects of CPE were observed. In TPA-treated pancreatic cancer cells, epithelial to mesenchymal transition-like changes were observed and CL-4 disappeared at cell membranes, attenuating cytotoxic effects of CPE. PKC inhibitors prevented the mislocation of CL-4 by TPA and restored the cytotoxic effects of CPE.

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Conclusion

The PKC signal pathway is an important factor to develop novel diagnostic and therapeutic methods targeting claudin-4 for pancreatic cancer.

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Real-time Visualization of Pancreatic Leak in Resection for Pancreatic Cancer Using a Novel Fluorescent Probe Activated by Chymotrypsin

S. Yamashita,1 T. Ishizawa,1 S. Tamura,1 J. Kaneko,1 Y. Sakamoto,1 T. Aoki,1 Y. Sugawara,1 K. Hasegawa,1 M. Sakabe,2 Y. Urano,2 N. Kokudo11Hepato-Biliary-Pancreatic Surgery Division, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; 2Laboratory of Chemical Biology and Molucular Imaging, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

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Background and Aims

Although pancreatic resection has been the only potentially curative treatment for pancreatic cancer, postoperative pancreatic fistula remains life-threatening postoperative complication. The aim of this study was to develop novel fluorescent probe enabling real-time identification of pancreatic leak (PL).

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Methods

In the 18 consecutive patients who underwent resection for pancreatic neoplasms, trypsin-added glutamyl-phenylalanine hydroxymethyl rhodamine green (gPhe-HMRG-Try), which was activated in the presence of chymotrypsinogen, was sprayed onto a paper transcribing the pancreatic stump and its ability to visualize PL from the stump and to predict postoperative pancreatic fistula (PF) were evaluated. In addition, gPhe-HMRG-Try was directly sprayed on the proximal pancreatic stump in a swine model and fluorescent images were obtained.

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Results

Fluorescence imaging using Phe-HMRG-Try visualized PL from the main pancreatic duct and/or its branches on a paper transcribing the pancreatic stump within a minute in 11 of the 18 patients. Postoperatively, PF developed in 5 out of the 11 patients (45%) with visualization of PL by Phe-HMRG-Try, while none of the remaining 7 patients without identification of PL encountered PF (0%, P = 0.036). In a swine model, fluorescent imaging enabled identification of PL from the pancreatic stump following the division of the pancreas with an electrocautery or a stapler device.

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Conclusions

gPhe-HMRG-Try probe has the potential to allow visualization of PL to be arrested during pancreatic resection and prediction of postoperative PF, enhancing the safety of surgical treatments for pancreatic cancer.

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Prognostic Analysis after Pancreaticoduodenectomies for Patients With Pancreas Head Cancer; Eleven-Year Experience at a Single Institution

S. Nara, K. Shimada, M. Esaki, Y. Kishi, T. Kosuge Hepatobiliary and Pancreatic Surgery Division, National Cancer Center Hospital, Tokyo, Japan.

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Background

Pancreatic cancer remains the most lethal cancer among a variety of gastrointestinal neoplasms, and the multidisciplinary treatment is employed to achieve a long time survival. To define rational criteria for up-front surgery, the investigation of postoperative prognostic factors is essential.

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Patients and Method

Prognostic factors were retrospectively investigated in 297 patients who underwent pancreaticoduodenectomy (PD) for a pancreatic head adenocarcinoma (excluding invasive IPMN) between 2000 and 2010 at our institution. All the patients underwent standardized preoperative (multi-detector) CT, PD with or without combined vascular and/or SMA plexus resection and clinical-path based postoperative care.

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Results

There were 2 postoperative deaths (1%). Postoperative complication of Clavien-Dindo grade IIIa or more were noted in 31 patients (10%). Ninety two patients (31%) underwent adjuvant chemotherapy, while 2 patients underwent pre-operative chemotherapy. In univariate analysis, CA19-9 &gt;100U/ml, size &gt;3cm, portal vein resection (+), operation time &gt;8hrs, blood loss &gt;1000ml, blood transfusion (+), ly&ge;2 (according to the classification of Japan Pancreas Society), v&ge;2, ne&ge;2, DU (+), RP (+), PV (+), PL (+), lymph node (LN) metastasis (+), para-aorta LN metastasis (+), lavage cytology (+), R1, adjuvant chemotherapy (-) and borderline resectable were significant poor prognostic factors of overall survival. In multivariate analysis, CA19-9 &gt;100 U/ml, size &gt;3cm, blood transfusion (+), ly&ge;2, para-aorta LN metastasis (+), lavage cytology (+), adjuvant chemotherapy (-) were significant poor prognostic factors.

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Conclusion

Patients with CA19-9 &gt;100U/ml and tumor size &gt;3cm showed decreased survival after up-front surgery, and may be good candidates for neo-adjuvant chemo (radio) therapy.

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Impact of Human Equilibrative Nucleoside Transporter 1 Expression on Long Term Survival of Pancreatic Cancer Patients Treated with Gemcitabine Based Adjuvant Chemotherapy After Surgical Resection

N. Kondo, Y. Murakami, K. Uemura, T. Sudo, Y. Hashimoto, N. Nakagawa, T. Sueda Institute of Biomedical and Health Sciences Applied Life Sciences Surgery, Hiroshima University, Hiroshima, Japan.

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Background and Aims

Expression of intratumoral human equilibrative nucleoside transporter 1 (hENT1) has been reported to be associated with chemosensitivity to gemcitabine based chemotherapy. However, long term result of predictive power of hENT1 is still unclear. The aim of this study is to investigate impact of intratumoral hENT1 expression on long term survival of patients treated with gemcitabine based adjuvant chemotherapy after surgical resection for pancreatic cancer.

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Methods

Intratumoral hENT1 expression was investigated by immunohistochemistry for 105 pancreatic adenocarcinoma patients who received gemcitabine based adjuvant chemotherapy after surgical resection. Association between clinicopathological factors including hENT1 expression and survival was evaluated by univariate and multivariate analyses.

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Results

All 105 patients were observed for at least 24 months. The median follow-up time after surgery was 54 months (range 24 – 140 months) for all patients. High hENT1 expression was observed in 73 (68%) patients. Five-year disease-free survival (DFS) and overall survival (OS) rates for all 105 patients were 32% and 37%, respectively. Univariate analysis revealed that patients with high hENT1 expression experienced significantly longer DFS (P = 0.005) and OS (P = 0.002) than those with low hENT1 expression. Multivariate analysis revealed thathENT1 expression was independently associated with DFS (P = 0.005) and OS (P = 0.009).

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Conclusion

Intratumoral hENT1 expression can predict long term survival of pancreatic cancer patients treated with gemcitabine based adjuvant chemotherapy, and enables the stratification of these patients based on their likelihood of survival.

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Predictive Factor for the Safety Drain Management After Pancreatoduodenectomy

H. Kosaka, N. Kuroda, K. Suzumura, A. Yada, H. Sueoka, Y. Uda, S. Hai, Y. Kondo, S. Tanaka, I. Nakamura, Y. Asano, T. Okada, T. Hirano, Y. Iimuro, J. Fujimoto Department of Surgery, Hyogo College of Medicine, Hyogo, Japan.

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Introduction

The post operative pancreatic fistula (POPF) is one of fatal complication after Pancreatoduodenectomy (PD). Some reports proved that early removal of drain makes less clinical relevant POPF (ISGPF grade B/C). However, there are potentially risks of hidden intra-abdominal abscess after drain removal. In this study, we will define the predictive factor of clinical relevant POPF and will establish the criteria for the safety drain management.

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Method

Between June 2009 and June 2012, the postoperative factors in 89 consecutive patients underwent PD and duct to mucosa pancreatojejunostomy were retrospectively investigated. To define the clinical relevant POPF risk factors, postoperative factors are analyzed by logistic regression analysis and then the cut off value was fixed by ROC curve.

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Result

The rate of clinical POPF was 28.4%. The mortality rate was 0%. The univariate analysis revealed that eight postoperative factors on postoperative day 4 (POD4) significantly differed between clinical relevant POPF and others (WBC, Segmented cell, CRP, Amylaze in Serum, Amylaze in drainage fluid, Quantity of pancreatic juice, drainage fluid characteristics and body temperature, P<0.05). The logistic regression analysis proved WBC on POD4 was the independent postoperative risk factor of clinical relevant POPF (P=0.011<0.05). Cut off value of WBC on POD4 was 73.65 (×102/μl, AUC 0.813, Sensitivity 88.5, Specificity 68.3 ). The negative predictive value for clinical relevant POPF was 93.5%.

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Conclusion

We defined WBC on POD4 is the only predictive factor for clinical relevant POPF. We should pay attention to WBC on POD4 for the safety drain management after PD.

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The Specific Genes Related to the Invasion Process in Pancreatic Cancer, as Demonstrated by Genome-wide Expression Profiling – the Role of MUC16 and Mesothelin

A. Shimizu, S. Hirono, M. Tani, M. Kawai, K. Okada, M. Miyazawa, Y. Kitahata, H. Yamaue Second Department of Surgery, School of Medicine, Wakayama Medical University, Wakayama, Japan.

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Aims

The invasion process is the most crucial step for PDAC. However, genes associated with invasion of PDAC remain unclear. We used genome-wide expression profiling in an attempt to identify the specific genes that are differentially expressed between infiltrating cancer cells and pancreatic intraepithelial neoplasms (PanIN)-3 cells in patients with pancreatic ductal adenocarcinoma (PDAC).

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Methods

We performed expression profiling using Human Genome U133 Plus 2.0 GeneChips. Microarray data of 5 pairs of RNA samples with infiltrating components were compared to PanIN-3 cells, which were harvested from the same PDAC patients. Among the genes identified by expression profiling, immunohistochemical, coimmunoprecipitation, and invasion analyses of MUC16 and mesothelin were performed to confirm the biologic significance of these molecules for patients with PDAC.

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Results

A total of 109 genes were differentially expressed between infiltrating components and PanIN-3. These included 87 genes that were up-regulated and 22 genes that were down-regulated in the infiltrating cancer. Immunohistochemical analysis revealed that MUC16 and mesothelin were expressed only in infiltrating cancer cells and not in PanIN-3 cells or normal pancreatic epithelial cells. Immunoprecipitation assay indicated that MUC16 and mesothelin can bind in PDAC. The down-regulation of MUC16 by short hairpin RNA and the blockage of MUC16 binding to mesothelin by antibody inhibited both invasion and migration of pancreatic cancer cell lines. MUC16 high/mesothelin high expression in PDAC was an independent factor predicting shorter survival.

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Conclusion

We identified two specific genes, MUC16 and mesothelin, that are associated with the invasion process in patients with PDAC.

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Protein Kinase C-alpha Regulates Claudin-1 via Snail-dependent and -independent Pathways in Pancreatic Cancer

D. Kyuno,1,2 T. Kojima,2 H. Yamaguchi,1 T. Ito,1 M. Imamura,1 Y. Kimura,1 A. Takasawa,2 M. Murata,2 M. Murata,2 K. Hirata11Department of Surgery, 2Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.

Protein kinase C (PKC) is overexpressed in cancer, including pancreatic cancer, compared with normal tissue. In pancreatic cancer, PKC-alpha is higher than normal tissue and is thought to be one of the biomarkers for the diagnosis of cancers. Although tight junction molecule claudin-1 which plays a crucial role on epithelial cell polarity is downregulated via Snail gene during epithelial-mesenchymal transition (EMT), the effects of PKC-alpha on claudin-1 and Snail remain unclear. In the present study, we confirmed activation of PKC-alpha of pancreatic cancer tissues and cell lines, and investigated the mechanisms of regulation of claudin-1 via a PKC-alpha signal pathway in pancreatic cancer cells and normal human pancreatic duct epithelial cells (HPDE). By immunostaining, overexpression of PKC-alpha was observed in poor-differentiated human pancreatic cancer tissues and a pancreatic cancer cell line PANC-1. Treatment with a PKC-alpha inhibitor Gö6976 decreased Snail and increased claudin-1 at mRNA level in PANC-1, whereas in HPDE, upregulation of not only claudin-1 but also claudin-4, -7 and occludin was observed without the change of Snail. The effects of the PKC-alpha inhibitor in PANC-1 in part ware regulated via an ERK signaling pathway. The PKC-alpha inhibitor also prevented upregulation of Snail and downregulation of claudin-1 in PANC-1 but not HPDE during EMT induced by treatment with TGF-beta and hypoxia. These findings suggest that PKC-alpha regulates claudin-1 via Snail during EMT of human pancreatic cancers, and PKC-alpha inhibitors may present potential therapeutic agents against human pancreatic cancer cells.

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Characteristics of Patients With Pancreatic Ductal Adenocarcinoma Developed After Treatment of Pancreatolithiasis

S. Yamamoto, K. Inui, J. Yoshino, H. Miyoshi, T. Kobayashi, H. Matsura Department of Internal Medicine, Fujita Health University Second Teaching Hospital, Nagoya, Japan.

We treated 112 patients with pancreatolithiasis between 1992 and 2011 by extracorporeal shock-wave lithotripsy (ESWL) and endoscopic procedures in our hospital. In 6 of 112 (5.4%) patients, pancreatic ductal carcinoma (PDAC) was developed, and we examined the 6 patients about the characteristics, clinical courses, diagnosis and prognoses. The mean follow-up duration was 78 months (1 to 179). Male: female ratio was 1:1, and the mean age was 64 years. Etiology was alcohol-related in 3 patients, and idiopathic in 3. Three patients had a single stone. Distribution of stone was pancreatic head in 5, body in 3, tail in 2 (there is duplication). The mean diameter of the stones was 17mm, ranged from 11 to 23mm. Three patients had ductal strictures in the head of the pancreas. Two patients had the whole pancreatic atrophy. Fragmentation of stones was achieved in all patients, and the complete stone-clearance after ESWL alone or ESWL in combination with interventional endoscopy was 5 patients. The mean time diagnosed as PDAC was 74 months (1 to 167) after diagnosing and treatment of chronic pancreatitis. The site of PDAC was pancreatic head in 3, body in 4, tail in 1 (there is duplication). The cancer staging at diagnosis were stage IB in 1, stage IIA in 1, stage III in 2, and stage IV in 2. Two patients of stage IB/IIA were resected, and they had pancreatic atrophy. Other 4 patients who could not be resected were without pancreatic atrophy. Chronic pancreatitis with PDAC had diffuse calculus and more than 10mm in diameter. Because pancreatolithiasis is a high risk factor of PDAC and it is difficult to diagnose within early stage, it is necessary to perform a close follow-up examination after treatment of pancreatolithiasis.

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Amphiregulin and Epiregulin Expression in Pancreatic Cancer

O. Inatomi,1 R. Osaki,1 H. Imaeda,1 Y. Fujiyama,1 A. Andoh21 Division of Gastroenterology, Shiga University of Medical Science; 2Division of Mucosal Immunology, Graduate School of Medicine, Shiga University of Medical Science, Shiga, Japan.

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Backgrounds

Amphiregulin and epiregulin belong to the epidermal growth factor family and mediate the biological functions of epithelial and mesenchymal cells through epidermal growth factor receptors in various organs such as the intestine. In this study, we investigated amphiregulin and epiregulin expression in human pancreatic cancer and pancreatic myofibloblasts.

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Methods

Amphiregulin and epiregulin mRNAs expression in cultured myofibroblasts and cancer cell lines (Panc-1 and MIAPaca-2) were evaluated by real time PCR. Surgically-obtained specimens were stained using standard immuno- histochemical procedures.

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Results

Amphiregulin and Epiregulin mRNAs were not detected in unstimulated myofibloblasts. Among the various kind of cytokines and growth factors, Interleukin (IL)-1β strongly induced amphiregulin and epiregulin mRNA expression. In addition, amphiregulin and epiregulin induced their own mRNA expressions by their stimulations in Panc-1 cells. Amphiregulin and epiregulin were not expressed in the normal pancreas tissue, but were clearly detectable in neoplastic lesions. In particular, amphiregulin was mainly expressed in myofibroblasts and epiregulin was expressed in the adenocarcinoma cells.

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Conclusion

We demonstrated that amphiregulin and epiregulin were expressed in human pancreatic cancer. Furthermore, myofibroblasts are local secretion site for amphiregulin and epiregulin. Amphiregulin and epiregulin may play an important role in the mechanism of pancreatic cancer growth through epithelial-mescenchymal interaction.

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Quantitative Perfusion Analysis of Contrast-Enhanced Harmonic Endoscopic Ultrasonography in Solid Lesions of the Pancreas

M. Fukasawa, S. Takano, M. Kadokura, H. Shindo, E. Takahashi, T. Sato, N. Enomoto First Department of Internal Medicine, University of Yamanashi, Yamanashi, Japan.

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Background and aims

Distinguishing pancreatic adenocarcinoma from other pancreatic masses remains challenging with current imaging techniques. This study aimed to evaluate the value of software-aided quantitative analysis of contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) for diagnosis of pancreatic solid lesions.

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Methods

A total of 119 patients presenting with solid pancreatic lesions were prospectively enrolled. All patients had conventional B mode and CH-EUS with a second-generation contrast agent. Time-intensity curves (TIC) were obtained for all exams in 2 regions of interest (ROI) within the lesion and within the normal pancreatic tissue. Images were processed using DAS-RS1 software; the following parameters were obtained: baseline intensity, maximum intensity, intensity at 1 minute, and time-to-peak. Absolute values and the ratio of the lesion to the normal tissue were evaluated.

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Result

Histology analysis revealed 68 pancreatic ductal adenocarcinomas (PDACs), 22 autoimmune pancreatitis (AIP), 14 chronic pancreatitis (CP), and 15 pancreatic neuroendocrine tumors (PNETs). The peak ratio of the lesion to the normal tissue was significantly lower in PDACs and higher in PNETs compared to AIP and CP. Among PDACs 62 out of 68 (91%) had low peak ratio. AIP and MFP were mostly iso peak ratio (20/22 in AIP and 12/14 in CP). Among PNET 8 out of 15 (53%) had hyper peak ratio and 7 had iso peak ratio. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), and accuracy of the low peak ratio for diagnosing PDAC were 91%, 94%, 95%, 89%, and 92%. Absolute values of intensity and time-dependent parameters were not significantly different among pancreatic disease.

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Conclusions

In cases of PDAC, AIP, MFP, and PNET exhibit different perfusion pattern at capillary level that can be visualized using the small microbubbles of ultrasound contrast agents. Contrast quantification software supplements a subjective visual assessment with objective criteria to facilitate the differential diagnosis of pancreatic solid lesions.

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Initial Experience of Laparoscopic Distal Pancreatectomy in Our Institution

Y. Toyama,1 S. Yoshida,1 R. Saito,1 Y. Tanabe,1 N. Okui,2 H. Kitamura,2 S. Yanagisawa,1 K. Yanaga21Department of Surgery, Jikei University Kashiwa Hospital; 2Department of Surgery, Jikei University School of Medicine, Kashiwa, Japan.

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Purpose

Laparoscopic distal pancreatectomy is gradually gaining acceptance even in Japan, however, its ultimate benefit is still confirmed. This study aimed to report our initial experience with laparoscopic distal pancreatectomy.

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Methods

A retrospective review of a prospectively collected database including 12 patients during the period 2010-2012 was conducted. The mean age was 55.4 ± 18.0 years (range, 22-78 years), and the female-to-male ratio was even, 6:6. The preoperative diagnoses included benign and malignant conditions. Complete or hand-assisted laparoscopic distal pancreatectomies were performed. The pancreas was divided with a stapler in most of the patients (83%), and drains were placed in 10 patients (67%).

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Results

Two patients underwent hand-assisted laparoscopic surgery because of splenomegary, and one operation was converted an open procedure due to hemorrhagic and thick pancreas with severe inflammation. The operating time was 197.5 ± 50.0 min (range, 130-300 min). The tumor size was 5.4 ± 1.0 cm (range, 3.2-7.0 cm), and the estimated blood loss was 212.5 ± 575.1 ml (range, 10-2,030 ml). The time to resumption of diet was 4.5 ± 1.6 days (range, 3-8 days), and the length of hospital stay was 10.4 ± 3.8 days (range, 8-20 days). There were no mortalities. The overall postoperative morbidity rate was 8.3% (1 patient), which consisted of pancreatic minor leakage. The tumor margins were negative in all patients. At a median follow-up period of 9.0 months (range, 1-30 months), all of the relevant 8 patients had no evidence of disease recurrence.

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Conclusions

Laparoscopic distal pancreatectomy to pancreatic disease is safe and technically feasible. Further continuous studies with longer follow-up periods are required to establish the role of laparoscopic surgery in the management of pancreatic disease.

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Utility of Rapid On-Site Cytology in Endoscopic Ultrasonography-Guided Fine Needle Aspiration for Pancreatic Cancer

A. Furuhata,1 H. Shirahase,1 S. Minamiguchi,2 H. Haga,2 A. Nakaizumi31Department of Laboratory Medicine, Kyoto University Hospital, Kyoto, Japan; 2Department of Diagnostic Pathology, Kyoto University School of Medicine, Kyoto, Japan; 3Human Health Science, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

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Background

Endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA) is a safe and effective method for obtaining samples for cytological diagnosis. Pancreatic cancer is extremely serious and often aggressive, so early detection and diagnosis is important. Therefore, we actively perform EUS-FNA for cytopathological diagnosis of pancreatic cancer.

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Materials and methods

EUS-FNA for pancreatic cancer was performed in 129 patients from January 2007 to May 2012 at Kyoto University Hospital. To eliminate both quantitatively and qualitatively inadequate samples, we performed EUS-FNA with rapid on-site cytology. Two squash preparations of the collected cells from biopsy were retrieved. One was stained on-site with Giemsa for rapid cytology to evaluate the quantity and quality of the collected cells. If necessary, second or third trials were carried out to obtain an adequate quantity of malignant cells for final cytology diagnosis. The other was wet-fixed and used for Papanicolaou staining.

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Results

In this study, 125 of 129 cases (97%) were diagnosed as positive, but 4 cases (3%) were false-negative by cytology. The number of centesis for sampling was once in 68 cases, twice in 31 cases and more than twice in 30 cases. The sensitivity of EUS-FNA cytology was 97%, and its specificity was 100%.

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Conclusion

Results of our examination suggest that the combination of EUS-FNA and rapid on-site cytology is a highly specific and sensitive test for detection of pancreatic cancer, and may contribute to reduce excessive centesis.

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EUS-Guided FNAB for Diagnosis of Pancreatic Cancer (PC)

F. Matsuda,1 Y. Okabe,1 J. Nakajima,1 Y. Osaki,1 K. Inayama,2 T. Wakasa,2 M. Shintaku21Department of Gastroenterology and Hepatology; 2Department of Pathology, Osaka Red Cross Hospital, Osaka, Japan.

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Objective

To determine the diagnostic accuracy of EUS-FNAB for pancreatic cancer.

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Method

Between March 2007 and March 2012, we performed EUS-FNAB for 81 pancreatic lesions, consisting of 62 pancreatic cancers, 3 malignant lymphoma, 13 benign masses, and 3 other lesions. Under endosonographic guidance, pancreatic lesion was punctured with mainly 22-gauge needle, sometimes 25-gauge needle. For the purpose of protection against deterioration of the specimen, it was pushed out directly into culture solution (Hanks’ solution). The collecting materials were examined histologically and cytologically, dividing into 5 groups as inadequate, benign, atypical, suspicious or malignant. Definitive diagnosis was based on histological exploration of surgical specimen or clinical follow-up over 6 months.

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Results

The specimen collection rate (SPR), sensitivity, specificity and accuracy of Histology/Cytology showed 96%/96%, 80%/88%, 100%/100% and 80%/87% respectively. However, using both methods together, SPR, sensitivity, specificity and accuracy of EUS-FNAB were 97%, 89%, 100% and 88% respectively. The overall complication rate was 2% (2 cases), but both cases soon improved.

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Conclusion

EUS-FNAB is a highly accurate diagnostic tool for solid neoplasms of the pancreas. Furthermore, the diagnostic accuracy increases using histological and cytological methods simultaneously.

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A Resection Case Report of Mixed Acinar-ductal Carcinoma Which was Recurrence of Remnant Pancreas

T. Shonaka,1 M. Inagaki,1 H. Akabane,1 N. Yanagida,1 H. Shomura,1 T. Orimo,1 T. Aiyama,1 T. Tsuji,1 N. Yanagawa,2 K. Oikawa,3 T. Mitsuhashi,4 S. Nakano11Division of Surgery, 2Department of Gastroenterology, Hokkaido P.W.F.A.C Asahikawa-Kosei General Hospital, Asahikawa, JAPAN; 3Department of Surgical Pathology, Asahikawa Medical College Hospital, Asahikawa, Japan; 4Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan.

The patient was 71-year-old female. 18 months ago, she had epigastric discomfort and examined computed tomography (CT) and endoscopic retrograde cholangiopancreatography (ERCP). CT showed cystic lesion with some solid component in the tail of pancreas and ERCP showed dilated main pancreatic duct of the pancreatic body and tail. Positron emission tomography computed tomography (PET-CT) showed staining in the tail of pancreas. Pancreas tail resection and splenectomy, with duodemun, jejunum, and transverse colon partial resection was performed. In the pathological diagnosis, acinar-like component and papillary growth component was shown, and each component was over 30%. Immunostaining, α-1 antitrypsin, CEA and MUC1 was positive. So, mixed acinar-ductal carcinoma was diagnosed.

Follow-up CT showed low density area of the pancreas head and PET-CT showed staining in the same position. Pylorus-preserving pancreatoduodenectomy (PPPD) with pancreaticogastrostomy was performed. Mixed acinar-ductal carcinoma was diagnosed in the pathological diagnosis.

Mixed acinar-ductal carcinoma has been classified acinar cell neoplasms in the World Health Organization (WHO) classification of tumors of the pancreas. It was very rare and unclear with respect to disease. We experienced a mixed acinar-ductal carcinoma of recurrence at remnant pancreas. It was extremely rare. We represented a case of mixed acinar-ductal carcinoma which was recurrenced of remnant pancreas and resected it.

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The Evaluation of SOX9 Expression in Pancreatic Ductal Adenocarcinoma and Intraductal Papillary Mucinous Neoplasm

T. Tanaka,1 T. Kuroki,1 T. Adachi,1 M. Hirabaru,1 A. Soyama,1 A. Kitasato,1 M. Takatsuki,1 T. Hayashi,2 S. Eguchi11Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; 2Department of Pathology, Nagasaki University Hospital, Nagasaki, Japan.

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Objectives

Sex-determining region Y (SRY) box 9 (SOX9) is an important transcription factor required for development and has been implicated in several types of cancer. However, SOX9 has never been linked to pancreatic ductal adenocarcinoma (PDAC) and intraductal papillary mucinous neoplasm (IPMN) of the pancreas. The aim of this study is to investigate the relation between SOX9 and PDAC, as well as SOX9 and IPMN.

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Methods

Surgical specimens were obtained from 55 patients with PDAC and 68 patients with IPMN and were investigated using SOX9 immunohistochemical analysis.

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Results

The rate of SOX9 positive cells to total pancreatic duct epithelial cells in a normal pancreas was 82.7%. On the other hand, the SOX9 positive rate in PDAC was 0.8%. There was a significant difference between the normal pancreas and PDAC (p=0.0002). In IPMN, the SOX9-positive rate gradually decreased according to tumor progression, with the following rates observed: intraductal papillary mucinous adenoma (66.3%); intraductal papillary mucinous carcinoma (46.3%); minimally invasive intraductal papillary mucinous carcinoma (30.5%); and invasive carcinoma originating in intraductal papillary mucinous carcinoma (2.3%). There were significant differences between each group (p<0.05).

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Conclusion

Our data suggested that SOX9 might contribute to carcinogenesis in PDAC and IPMN.

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Multicenter Study of Pancreatic Juice Cytology Scoring System for Differential Diagnosis in Pancreatic Neoplasm

Y. Uchida,1 K. Abe,1 M. Shibata,1 Y. Komura,1 M. Yasuda,1 A. Koido,1 S. Koyamatsu,3 N. Yonekawa,3 H. Saito,1 T. Iijima,1 J. Imura21Department of Pathology, Ibaraki Prefectural Central Hospital and Cancer Center, Kasama, Japan; 2Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan; 3Department of Pathology, Mito Saiseikai General Hospital, Mito, Japan.

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Introduction

We perform multicenter study for diagnostic precision improvement of the pancreatic juice cytology and examined the scoring system for the differential diagnoses in pancreatic neoplasm.

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Materials and method

The pancreatic juice cytology specimens were obtained from the patients pathologically diagnosed with IPMA (6 cases), IPMC (5 cases) and invasive ductal carcinoma:IDC (4 cases). Using the virtual slide microscopy, twenty-eight cytotechnologists of many institutes participated in this examination. Several multivariate analyses were carried out to sort the diagnostic clue of cell findings to be important. Furthermore, ROC analysis was performed whether it was diagnostic using the selected factors.

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Results

As a result of multivariate analysis, the important findings to distinguish adenocarcinoma from adenoma were the mucinous background, the intracytoplasmic mucin, the cellular stratification, the peripheral irregularity of cell cluster, the irregular nuclear arrangement, the irregular nuclear appearance and the abnormal chromatin distribution. By the ROC analysis, the degree of precision for the differential diagnosis showed the 96 % of sensitivity and the 90% of specificity between the IPMAs and the IPMCs, and showed the 86% of specificity and the 96% of sensitivity between the IPMAs and the IPMCs+IDCs.

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Conclusion

By using pancreatic juice cytology in this scoring system, the possibility to determine with high accuracy IPMA and IPMC was suggested. This diagnostic system might be expected as an examination to contribute to the patient stratification.

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Psammoma Bodies in Typical Pancreatic Cancer

K. Kawamoto,1,2 T. Ueki,2 J. Ohara,1 T. Matui,2 A. Iwashita31Department of Gastroenterology, Tanushimaru Central Hospital, Kurume, Japan; 2Department of Gastroenterology, Fukuoka University Chikushi Hospita, Chikushino, Japan; 3Department of Pathology, University Chikushi Hospita, Chikushino, Japan.

An extremely rare case of psammoma bodies associated with typical pancreatic cancer is reported. A 59-year-old man with polydipsia, polyuria, and poorly controlled glycemia was found to have a 33×22 mm hypoechoic mass in the pancreatic head on abdominal ultrasound, and he was referred to our department. His fasting glucose (157 mg/dl), HbA1c (9.0%), and CA19-9 (215 U/ml) levels were high. Abdominal computed tomography showed a low-density area in the pancreatic head that was gradually stained, with venous phase enhancement similar to surrounding tissue. On endoscopic retrograde cholangiopancreatography, there was stenosis of the main duct in the pancreatic head, with main duct tortuosity and dilatation of the caudal portion of the main and accessory pancreatic ducts. Further, duct branches between the stenosed and dilated regions were poorly depicted. On endoscopic ultrasound, a 25-mm-diameter, hypoechoic tumor was seen in the pancreatic head containing an acoustic shadow with a strong, clear echo. Pancreatoduodenectomy was performed suspecting typical pancreatic cancer after percutaneous tumor biopsy. Grossly, a 25x20 mm, whitish tumorous lesion was seen in the pancreatic head. Pathologically, atypical epithelial cells with irregularly sized nuclei were seen in the main pancreatic duct, with clusters of atypical ducts with psammoma bodies within the tumor. The tumor was stage III (T3, N1, M0) with group 17b lymph node metastasis. Psammoma bodies are concentric, laminated, basophilic microcalcifications, 30-100 μm in diameter, often seen in tumor ducts in thyroid, breast, and ovarian cancers; they have also been reported in stomach, colorectal, and gallbladder cancers, but there has been only one published case associated with pancreatic cancer. The patient was still alive without reccurrence 24 months after surgery.

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Changes in the Expression Pattern of Tight Junction Factors During the Progression of Pancreatic Cancer

J. Imura,1 K. Abe,2 Y. Uchida,2 T. Nakajima,1 S. Miwa,1 S. Hayashi,1 K. Nomoto,1 K. Tsuneyama11Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan; 2Department of Pathology, Ibaraki Prefectural Central Hospital and Cancer Center, Kasama, Japan.

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Introduction

Zonula Occludin (ZO), occludin and claudins, members of family of junction proteins, regulate the integrity and function of tight junctions. We reported that these factors expressed in pancreatic cancer and might be related with tumor progression. In this report, we examined about the changes in cellular localization of these factors during tumor progression.

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Material and Methods

Established pancreatic cancer cell lines were cultured with conventional monolayer condition or three dimensional culture method. Human tissues were obtained from the operatively resected specimens. The culture cells and sections from tissues were immunohistochemically examined. The mRNA levels of these factor expressions were analyzed by real time PCR method.

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Results

The ZO-1, occludin were expressed between the cell-cell adhered cell membrane. Claudin-1 was diffusely distributed in the cytoplasm. The patterns of expression were different by not only each cell but also the culture condition. The mRNA level of each factor was elevated in three dimensional culture condition.

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Conclusions

The tight junction related factors may play important role in the progression of pancreatic neoplasia.

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Pancreatic Juice Cytology for Improvement of Diagnostic Accuracy

C. Hayakawa,1 A. Furuhata,2 K. Kimijiri,3 Y. Fukuda,3 S. Baba,3 J. Koike11Department of Pathology, St. Marianna University School of Medicine, Kawasaki Municipal Tama Hospital, Kanagawa, Japan; 2Division of Biomedical Imaging Research, Juntendo University Graduate School of Medicine, Tokyo, Japan; 3Endscopy Center, St. Marianna University School of Medicine, Kawasaki Municipal Tama Hospital, Kanagawa, Japan.

Pathological diagnosis is required for the differentiation of benign and malignant pancreatic lesions. However, collecting samples by pathological examination is often difficult, and cytological examination plays an important role. In our hospital, cytology samples from pancreatic lesions are obtained by endoscopic retrograde pancreatic juice aspiration, or brush cytology in which samples are obtained by brushing the pancreatic duct and washing the tip of the brush. These modalities are not always used concomitantly. In this study, we evaluated the results of 41 pancreatic cytology samples (benign 7, malignant 34) obtained under ERP between 2006 and 2011, of pancreatic juice aspiration (32) alone vs. brush cytology (22) alone vs. combination of pancreatic juice aspiration and brush cytology to determine (13) which modality provides improved diagnostic abilities. Also, the results of pancreatic juice aspiration were compared by the number of examination sessions, including five cases in which examinations were repeated.

The diagnostic accuracy rate of pancreatic cytology samples (41 patients), pancreatic juice aspiration (32), brush cytology (22) and combination of both modalities (13) was 34%, 28%, 36% and 38% respectively, with a high rate for the combination of both modalities. The diagnostic accuracy rate of pancreatic juice aspiration, in which examinations were repeated, increased from 19% to 25% and up to 28% with the time of examination.

The diagnostic accuracy rate was higher for brush cytology than pancreatic juice aspiration, and the rate increased when brush cytology was combined with pancreatic juice aspiration, suggesting the usefulness of combining both modalities in improving the accuracy of cytological diagnosis. When pancreatic juice aspiration is only available, it may be important to repeat examinations, because the diagnostic accuracy rate of pancreatic juice aspiration increased with the time of examination.

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Pancreatic VIPoma: Recurrence 15 Years After Surgical Treatment

Y. Hamada, Y. Nakayama Department of Pathology, School of Medicine, Fukuoka University, Fukuoka, Japan.

Although the biological behavior of VIPomas is rather indolent, the individual disease course is unpredictable. We herein describe a case of pancreatic VIPoma with hepatic metastases 15 years after surgery.

A 52-year-old male patient presented to our hospital with watery diarrhea and general fatigue. A pancreatic mass was detected by abdominal ultrasonography (US) and computed tomography (CT). The profuse diarrhea was treated with a somatostatin analogue, and the patient underwent distal pancreatectomy with en bloc splenectomy. The tumor measured 43 x 40 x 35 mm. On macroscopic examination, the tumor was solid and surrounded by a thin capsule, and its cut surface was light yellow. Neither necrosis nor hemorrhage was observed. Microscopically, the tumor was composed of a proliferation of uniform polygonal cells with round nuclei and scant cytoplasm with a medullary arrangement and gland-like structures. The tumor cells had argyrophilic granules as detected by Grimelius stain. Immunohistochemistry showed that the tumor cells were focally positive for vasoactive intestinal peptide. Mitotic figures were ≤2/high power field. The surgical margin was negative for tumor cells. The patient’s watery diarrhea disappeared after surgery. However, 15 years after surgery, the watery diarrhea recurred and the patient returned to our hospital. Abdominal US and CT revealed multiple small mass lesions in the liver. Needle biopsy was performed because of suspected recurrence of VIPoma. Pathological examination showed features identical to those of the previous pancreatic VIPoma by hematoxylin and eosin, histochemical, and immunohistochemical stains.

Neuroendocrine neoplasms generally grow slowly, and it is difficult to predict the prognosis based on histopathological findings. Therefore, long-term follow-up is recommended. However, the ideal postoperative follow-up period remains to be defined.

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Invasion of the Splenic Artery is an Important Prognostic Factor After Distal Pancreatectomy for Pancreatic Adenocarcinoma of the Body and Tail

K. Ishido, Y. Toyoki, D. Kudo, N. Kimura, T. Wakiya, T. Matsumura, S. Sakuraba, S. Yonaiayama, T. Yokoyma, S. Narumi, K. Hakamada Department of Gastroenterology, Hirosaki University Graduate School of Medicine.

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Background

Survival after curative resection for pancreatic ductal adenocarcinoma (PDA) of the body and tail remains poor. In PDA of the head, infiltration to the superior mesenteric artery or vein is reported to be associated with poor prognosis, even if curative resection is performed. However, in PDA of the body and tail, the correlation between prognosis and infiltration to the splenic artery and vein has been poorly investigated. Therefore, we evaluated prognostic factors in PDA of the body and tail after curative resection,

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Methods

Between 1992 and 2012 in our institution, 66 patients who underwent distal pancreatectomy (DP) for PDA of the body and tail were analyzed. Clinicopathological prognostic factors for survival were evaluated. Univariate and multivariable analyses were performed.

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Results

The 1-, 3-, and 5-year survival rate were 60.9%, 31.7%, and 20.1%, respectively. Invasion of the splenic artery (SA) was observed in 24 patients (36.4%). Patients with SA invasion had a significantly poor prognosis compared with those without SA invasion (median survival: 10.9 vs 38.7 months, p=0.001). On the other hand, splenic vein (SV) invasion did not affect prognosis. On multivariable analysis, lymph node metastases and SA invasion were independent predictors of survival.

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Conclusion

SA invasion and lymph node metastasis were crucial prognostic factors in PDA of the body and tail, whereas SV invasion was not associated with poor prognosis.

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Inhibitory Effects of Fibroblast Growth Factor Receptor 2 in Pancreatic Cancer

T. Ishiwata,1 H. Yoshimura,1, M. Korc,2, Y. Matsuda11Departments of Pathology and Integrative Oncological Pathology, Nippon Medical School, Tokyo, Japan; 2Departments of Medicine, and Biochemistry and Molecular Biology, Indiana University School of Medicine and the Melvin and Bren Simon Cancer Center, Indianapolis, United States.

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Introduction

The alternative splicing of the C-terminal half of the third Ig-like domain of FGFR-2 generates IIIb and IIIc isoforms. FGFR-2 IIIb expression correlates with VEGF-A and MMP-9 expression, as well as venous invasion of pancreatic ductal adenocarcinoma (PDAC). By contrast, FGFR-2 IIIc expression correlates with the decreased duration of the development of liver metastasis after surgery, and increased growth rates and invasion of the cancer (Ishiwata et al. Am J Pathol 2012). These findings suggest that FGFR-2 isoforms play crucial roles in aggressiveness of PDAC. In the present study, we inhibited the expression of both FGFR-2 isoforms using an RNA silencing strategy to clarify the therapeutic effectiveness of FGFR-2 knockdown in PDAC.

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Methods

FGFR-2 gene amplification was examined using FISH and copy number assays. FGFR-2 short hairpin (sh) RNA targeting the both IIIb and IIIc isoforms was stably transfected PANC-1 cells (Sh cells). Sham vectors were transfected into PANC-1 cells as negative controls (Sc cells). The growth rates in in vitro and in vivo, cell migration and invasion abilities and VEGF-A expression levels of Sh and Sc cells were examined.

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Results

Half of the PDAC cell lines had FGFR-2 gene amplification. The growth rates of Sh cells were lower than those of Sc cells in vitro and in the subcutaneous tissue of nude mice. The migration and invasion were decreased in Sh cells, and the cells expressed lower levels of VEGF-A compared to Sc cells.

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Conclusion

These findings indicate that FGFR-2 exerts important roles in pancreatic cancer cell growth and angiogenesis, and the inhibition of FGFR-2 may be a therapeutic target in PDAC.

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Immunological Effect of Neoadjuvant Chemoradiotherapy on Tumor Microenvironment of Pancreatic Cancer

Y. Homma, K. Taniguchi, R. Matsuyama, T. Murakami, K. Nakagawa, R. Mori, K. Nojiri, T. Kumamoto, M. Ueda, K. Takeda, Y. Ichikawa, K. Tanaka, I. Endo Department of Gastroenterological Surgery, Yokohama City University, Yokohama, Japan.

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Background

Immunosuppressive state is one of the important feature of pancreatic cancer and may relates to its aggressive malignant behaviors. However, little is known about the immune response in the tumor microenvironment after neoadjuvant chemoradiotherapy (NACRT).

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Aim

To explore the impact of NACRT on the tumor microenvironment, we compared tumor infiltrating lymphocytes (TILs) between NACRT and non-NACRT patients in the resected pancreatic cancer specimens.

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Methods

Fifty-two pancreatic cancer patients were enrolled in this study. 22 patients underwent NACRT followed surgical resection (NACRT group) and 30 patients underwent straightforward surgical resection (SF group). NACRT consisted of 2 courses of Gemcitabine (GEM) + S1 regimens following radiation therapy (30Gy). GEM + S1 regimens consisted of intravenous 1,000mg / m2 GEM on day 8 and 15, combined with 60 mg/m2 oral S-1 on days 1-14. Histomorphological response of NACRT was defined based on Evans criteria. TILs were counted by immunohistochemical stainings of CD4-, CD8-, Foxp3, CD68- and CD163. TILs were evaluated microscopically in high power field (×200) by manual counts. We also examined MIB-1 index of the tumor by Ki-67 immunohistochemical staining. This study was approved by our institutional review board.

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Results

Histological effect of NACRT were as follows; Grade 1 in two patients, Grade 2a in 8 patients, Grade 2b in 11 patients, and Grade 3 in one patients. In term of MIB-1 index, there were no difference between NACRT and SF group (29±28%, 37±24%, respectively, p=0.480). The number of CD4- and CD8- positive T cells in tumor were significantly higher in the NACRT patients (p=0.040, 0.003, respectively). Moreover, infiltration of Foxp3-positive T cells and CD163 positive cells (M2 macrophages marker) had lower tendencies in NACRT patients (p=0.060, 0.070, respectively). There were no correlation between Histological effect and the infiltration of CD4-andCD8- positive T cells.

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Conclusion

Neoadjuvant chemoradiotherapy using GEM plus S-1 in pancreatic cancer has an immunomudulatory effect due to induction of CD4- and CD8- T lymphocytes in the tumor microenvironment.

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Single Port Laparoscopic Distal Pancreatectomy

H.J. Han, S.O. Suh, W.B. Kim, T.J. Song, S. B. Choi, S. Y. Choi, S.Y. Yoon, P. Park Department of Surgery/Division of HBP and Transplant Surgery, Korea University, Seoul, South Korea.

Single-port laparoscopic surgery has become popular and widened indications to more various types of minimal invasive surgical field. This report will present our initial experience with distal pancreatectomy technique through a small transumbilical incision using the single-port approach for a cystic tumor of pancreatic tail. The surgery was done using single-port instruments and conventional laparoscopic instruments. The total operative time for this surgery is 230 minutes, and it was completed with a drain via single incision. Patient was discharged from the hospital on the fifth day postoperatively without any event.

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Expression of Fatty Acid Synthase (FAS) in Pancreatic Ductal Carcinoma, its Clinicopathological Significance

H. Maekawa,1, K. Sato,1, H. Orita,1, M. Sakurada,1, T. Ito,1, M. Ikota,1, K. Sugimoto,1, M. Saita,1, R. Wada21Department of Surgery, Juntendo University Shizuoka Hospital, Izu-no-kuni, Japan; 2Department of Pathology, Juntendo University Shizuoka Hospital, Izu-no-kuni, Japan.

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Introduction

Fatty acid synthase (FAS) expression is normally regulated and minimized in normal tissues. But in some cancer tissues such as breast, prostate and esophagus cancers, it has been known that FAS was highly expressed and played important roles for tumor growth activities. We previously reported that FAS was highly expressed in pancreatic ductal carcinoma. The aim of this study is to search FAS expresssion is correlated with other tumor growth marker such as p53 and Ki-67 expressions. And FAS expression had relations to pathological findings and prognosis.

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Material/ Method

We studied 50 patients surgically treated for pancreatic ductal carcinoma between January 2002 and January 2012. We investigated the expressions of FAS, p53 and Ki-67 on tissue sections cut from the carcinoma specimens formalin-fixed and paraffin-embedded with immunohistochemical stainings. Positive expression of FAS was considered when more than 30% of carcinoma cells were stained. Positive expressions of p53 and Ki-67 were considered when more than 30% of carcinoma cells were stained as same manner. We compared the positivities for FAS staining with that for p53 or Ki-67 microscopically. Next, we compared FAS stainings with other pathological findinds and postoperative prognosis using statistical analysis.

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Result

All 50 cases were adenocarcinomas. FAS were positive in 30 patients. FAS expression and Ki-67 expression correlated to each other. But FAS expression had no relation to p53 expression using immunohistological staining. FAS expression had relation to node metastases and tumor differentiation pathologically. And the cases of positive FAS expression had poor prognoses.

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Conclusion

High FAS expression may suggest highly proliferation of carcinoma cells and may mean poor prognosis. FAS may be a reliable marker of tumor aggressiveness.

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Usefulness of Pancreatic Juice Cytology for Early Detection of Pancreatic Cancer

N. Kawada,1 H. Uehara,1 R. Takada,1 T. Yamai,1 N. Fukutake,1 K. Katayama,1 Y. Tomita21Department of Gastroenterology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan; 2Department of Pathology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.

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Background/Aim

Because pancreatic ductal carcinoma is rarely detected within early stage, its characteristics have not been well documented. This study aimed to elucidate useful method for detecting pancreatic cancer within early stage.

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Methods

Patients who underwent surgery between April 1995 and March 2012 for pancreatic cancer which were histologically diagnosed as either Stage 0 or Stage I were included. Patients who underwent neo-adjuvant therapy prior to surgery were excluded. i) How these Stage 0 and Stage I cancer were successfully detected was reviewed. ii) Diagnostic accuracy of pancreatic juice cytology was evaluated. iii) Length of ductal cancerization was measured.

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Results

There were 15 patients (9 patients with Stage 0 and 6 with Stage I). i) Four patients had risk factors of pancreatic cancer, and had been followed up periodically. Five patients had symptom related to the pancreas. Among 10 patients without symptom, pancreatic cancer was detected during the regular follow-up in 4 patients, and it was detected accidentally in the remaining 6. Detectabilities of stricutred and/or dilated main pancreatic duct in CT, US, EUS, ERP and MRP were 87% (13/15), 100% (12/12), 92% (11/12), 93% (14/15), 92% (11/12), respectively. ii) Pancreatic juice cytology was performed for all cases, and 93% (14/15) of them were correctly diagnosed as adenocarcinoma. iii) Length of ductal cancerization ranged from 5 mm to 60 mm (median 20 mm).

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Conclusion

Pancreatic juice cytology is shown to be useful for diagnosing pancreatic cancer within early stage. It is recommended for patients with the strictured and/or dilated main pancreatic duct that can be detected by imaging study with high accuracy. Some early pancreatic cancers appear to spread intraductally rather than invading into stroma.

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The Efficacy of Preoperative Neo-adjuvant Chemoradiotherapy for the Patients With Pancreatic Cancer

M. Tani, M. Kawai, S. Hirono, K. Okada, M. Miyazawa, A. Shimizu, Y. Kitahata, H. Yamaue Second Department of Surgery, Wakayama Medical University, School of Medicine, Wakayama, Japan.

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Background

R0 resection is predicted the favorable factor for the resectable pancreatic cancer patients. However, the pancreatic cancer patients with arterial involvement are possible to have margin positive, and a neo-adjuvant therapy is thought to be necessary for the improvement of their survival.

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Method

After staging laparoscopy to neglect peritoneal dissemination and small distant metastasis, the neo-adjuvant chemoradiotherapy (NACRT) was performed; alternate-day administrations of S-1 was performed during 6 weeks and radiotherapy was delivered at the dose of 50 Gy in 25 fractions of 2 Gy per fractions per day, 5 days/week, over 5 weeks. It was determined clinical target volume at the hot spot which showed the high frequency of R1/2 resection.

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Results

Twenty-four patients were entered in this study. Although only one patient shows neutropenia (grade 3), NACRT was demonstrated no severe adverse effect. Of all, 21 patients (87.5%) were performed pancreatectomy (TP 1, PrPD 10, DP-CAR 10). Sixteen patients (76%) had lymph node metastasis. Fourteen patients (67%) had pathological degeneration more than grade 2 classified by Evans (grade 2a; n=10, grade 2b; n=3, grade 3; n=1). R0 resection was performed in 17 of 21 patients (81%).

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Conclusion

NACRT is possible to improve the survival of advanced pancreatic cancer patients due to induction of R0 resection.

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Erlotinib Prolongs Survival in Pancreatic Cancer by Blocking Gemcitabine-Induced MAPK Signaling

K. Miyabayashi,1 H. Ijichi,1 D. Mohri,1 M. Tada,2 Y. Asaoka,1 K. Tateishi,1 S. Mizuno,1 T. Sasaki,1 H. Kogure,1 N. Yamamoto,1 Y. Nakai,1 K. Hirano,1 H. Isayama,1 M. Tada,1 K. Koike11Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; 1Department of Clinical Oncology and Medicine, Chiba University, Chiba, Japan.

Pancreatic ductal adenocarcinoma (PDAC) is the most deadly cancer worldwide. Among many regimens against PDAC, an EGFR inhibitor erlotinib in combination with gemcitabine (GEM) is the only molecular target drug superior to GEM alone. However, the mechanism of EGFR inhibitor against KRAS-mutant PDAC remains largely unknown. In this study, we evaluated the efficacy and mechanism of erlotinib using a murine PDAC model with TGF-beta receptor II knockout plus Kras activation, which recapitulates histological features of human PDAC.

We treated the PDAC mice and PDAC cells with GEM and erlotinib, and investigated the mode of action of these drugs, including intracellular signaling and phospho-tyrosine kinase receptor assays, quantification of EGFR ligands and heterodimer formation of EGFR and ErbB2.

GEM + erlotinib inhibited PDAC progression and significantly prolonged the survival of the PDAC mice compared to GEM alone. Interestingly, GEM induced MAPK signaling, which was dramatically inhibited by erlotinib even in the Kras-mutant PDAC. The suggested mechanisms were that GEM induced EGFR ligand expression and also ErbB2 activation by increasing heterodimer formation with EGFR and maintaining high ErbB2 protein level in PDAC cells. Erlotinib inhibited the ErbB2 activation by inhibiting heterodimer formation with EGFR and decreasing ErbB2 protein level in PDAC cells.

This study provides clinical insights into potent therapeutic strategies for this difficult cancer.

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Nafamostat Mesilate, an Inhibitor of Nuclear Factor-kappa B, Limits Oncogenic Properties of Pancreas Carcinoma Cells

Y. Takezaki,1 T. Okabayashi,2 M. Munekage,1 K. Ichikawa,1 K. Hanazaki11Department of Surgery, Kochi University School of Medicine, Kochi, Japan; 2Department of Surgery, Kochi Health Sciences Center, Kochi, Japan.

Accumulating evidence demonstrated that pancreas cancers overexpressing nuclear factor-kappa B (NF-κB) show a significant resistance to chemo-radiation therapy, causally resulting in a poor prognosis. Consistently, several reports revealed that inhibition of activated NF-κB can suppress cell growth and enhance cellular sensitivity to conventional anti-cancer drugs. Recently, clinical studies of nafamostat mesilate (Futhan®), a protease inhibitor that suppresses an activated form of NF-κB, have demonstrated appreciable responses in individuals with a certain type of relapsed and refractory malignancies. Here we show that nafamostat mesilate alone could inhibit cell proliferation in three different types of pancreas carcinoma cells (Miapaca2, BxPC3, and SUIT2), and a combination with imatinib mesylate (Gleevec®) synergistically suppressed cell growth in these cells. In addition, this combinational therapy could lead to exhibit enhanced sensitivity to apoptosis, and thus efficiently inhibited the tumorigenic potential in vivo, via modulation of unique sets of apoptosis-associated genes. Compared with conventional anti-cancer drugs showing concentration-dependent cytotoxic activity, our data provide strong evidence that nafamostat mesilate in combination with imatinib mesylate efficiently abrogate cell survival and oncogenic properties of pancreas carcinoma cells. We believe that our proposed strategy shows the potential feasibility to complement conventional therapy in patients with pancreatic cancer.

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Association Between Nonalcoholic Fatty Liver Disease and Exocrine Pancreatic Insufficiency After Pancreatoduodenectomy

N. Nakagawa, Y. Murakami, K. Uemura, T. Sudo, Y. Hashimoto, N. Kondo, T. Sueda Department of Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.

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Background

In recent years, nonalcoholic fatty liver disease (NAFLD) after pancreatoduodenectomy (PD) has been controversial, but the precise mechanism of postoperative NAFLD has remained unclear. The purpose of this study was to determine risk factors for NAFLD after PD.

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Methods

In 91 patients who underwent PD, abdominal unenhanced computed tomography (CT) were utilized to assess the fatty liver and a 13C-labeled mixed triglyceride breath test was performed to assess exocrine pancreatic function. The CT attenuation in the liver was used for quantification of fatty liver. Percent 13CO2 cumulative dose at seven hours < 5% was considered diagnostic of exocrine pancreatic insufficiency (EPI).

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Results

The twenty-one of 91 patients (23.1%) were diagnosed with NAFLD. Univariate analysis identified significant associations between one perioperative factor, a pancreatic carcinoma (P = .048), and two postoperative factors, EPI (P = .001) and a postoperative thin pancreatic parenchyma in CT (P = .019). Multivariate analysis determined that EPI was only independent factor (P = .003). Conclusions: EPI is the only independent risk factor of NAFLD after PD, and that 13C-labeled mixed triglyceride breath test is useful for evaluating the EPI and for predicting NAFLD after PD.

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Comparative Study of hENT1 Expression in Pancreatic Cancer; EUS-FNB Samples Before Gemcitabine-Based Chemoradiatherapy Versus Resected Specimens After Chemoradiotherapy

R. Yamada,1 S. Isaji,2 Y. Murata21Department of Gastroenterology and Hepatology; 2Department of the Hepatobiliary Pancreatic and Transplant Surgery, Mie University graduate School of Medicine, Tsu, Mie, Japan.

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Background

Previous studies reported that intratumoral Human equilibrative nucleoside transporter 1 (hENT1) expression was associated with an increased survival for patients receiving gemcitabine after pancreatic cancer (PC) surgery. This study aimed to evaluate if hENT1 is available to predict the prognosis using endoscopic ultrasonography-guided fine- needle biopsy (EUS-FNB) samples before the initiation of gem-CRT.

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Methods

From February 2005 to July 2010, 93 PC patients who were proved histologically or cytologically had been enrolled for our gem-CRT protocol (UICC-T3: 57, T4: 36). Of 55 patients described above, 23 (41.8%) were histologically diagnosed as pancreatic adenocarcinoma by EUS-FNB, the other patients were cytologically diagnosed by endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) cytology or pancreatic juice cytology. The intratumoral hENT1 expression was analyzed immunohistochemically in the EUS- FNB samples, and scoring for hENT1 was on the basis of relative intensities of the caner cells with reference to the normally present hENT1 staining of lymphocytes.

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Results

Among the 23 tumors diagnosed by EUS-FNB, the hENT1 expression was positive in 16 patients (69.6%), and negative in 7 (30.4%). The hENT1 expression in EUS-FNB samples was identical in 87% (20/23) with that of resected specimens after gem-CRT (T3: 14/16; 87,5%, T4: 6/7; 85.7%). 16 patients with positive hENT1 expression in EUS-FNB samples had significantly longer overall and recurrence free survival rates than 7 with negative hENT1 expression (2-yr OS and RFS rates: 67.5, 29.2 vs. 35.7, 0%).

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Conclusions

Our data provides the evidence that intratumoral hENT1 expressions in EUS-FNB samples are available to predict treatment outcome before the initiation of preoperative gem-CRT.

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Differential Diagnosis in Blood Flow of Splenic Vein between Autoimmune Pancreatitis and Pancreas Cancer

J. Sakagami, K. Kataoka, H. Yasuda, Y. Sogame, E. Yamashita, N. Iwai, Y. Itoh, Y. Naito, T.Yoshikawa Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan.

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Background

Obliterative phlebitis of the pancreatic and peri-pancreatic veins has been frequently seen in the autoimmune pancreatitis (AIP). Peri-pancreatic vascular complications have been reported to occur in about one-quarter of the AIP patients. Despite advances in imaging technique, it is sometimes difficult to distinguish AIP from pancreas cancer (PC). We have reported reduced blood flow of splenic vein (SV) at active phase of AIP.

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Aims

Recent advance in ultrasonographic technology has made it capable to detect flow signals in the various splanchnic vessels and calculating the concomitant velocities using fast-Fourier transformation. We aimed to compare the hemodynamic change of AIP with that of PC.

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Methods

Twenty patients with AIP were enrolled in this study (AIP group). Eighty healthy individuals were randomly selected as controls with age and gender matched (NC group). The maximum velocity (Vmax), cross sectional area (CSA), flow volume (FV), and congestion index (CI) of SV were measured. We examined the same parameters in 109 patients with PC at the time of diagnosis (PC group).

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Results

CSAs of both AIP and PC were significantly smaller than that of NC. Significant decreases in Vmax and FV were observed during the active phase of AIP. Unlike in the case of AIP, Vmax of PC was significantly greater than that of NC.

In AIP, the hemodynamic decline of SV was significantly restored by the treatment with corticosteroids, but FV of PC gradually dropped over time.

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Conclusions

The decline in hemodynamic parameter of splenic vein might be a sign of active AIP. The changes are restored to normal after steroid therapy. The slender splenic vein with low velocity might be one of the imaging feature of AIP. The feature mimics that of PC, but the velocity of splenic vein of PC was greater than that of control subjects.

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A Social Program for Diagnosis of The Stage 0 Pancreatic Cancer in a Rural Doctor’s Association

K. Hanada,1 T. Iiboshi,1 N. Hirano K. Yamao,1 T. Fukuda,2 S. Yonehara,3 H. Katayama41Gastroenterology, Onomichi General Hospital, Onomichi, Japan; 2Surgery, Onomichi General Hospital, Onomichi, Japan; 3Pathology, Onomichi General Hospital. Onomichi, Japan; 4Pathology, Onomichi General Hospital, Onomichi, Japan.

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Introduction

Despite advances in imaging techniques, pancreatic carcinoma (PC) remains the fifth leading cause of cancer related mortality in Japan. Detection of PC at an early stage with curative surgery is the approach with the potential to significantly improve long-term patient outcome.

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Aim

To establish a social program for diagnosis of the small pancreatic cancer in a rural doctor’s association.

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Methods

In 2007, Onomichi Medical Association (OMA) tried to start a social program for diagnosis of the small pancreatic cancer. Specialized doctors for pancreatic cancer (SDPC) in medical centers enlightened practicing doctors about risk factors of PC, abnormal findings of ultrasonography (US), or elevated serum pancreatic enzymes.

Simultaneously, if practicing doctors experienced the patient with these previous problems, they aggressively consulted SDPC each other. SDPC firstly performed computed tomography (CT), magnetic resonance pancreatocholangiography (MRCP), and endoscopic ultrasonography (EUS). If these imaging examinations demonstrated the irregular stenosis in the main pancreatic duct (PD), or the dilatation in the branch of PD, SDPC performed endoscopic retrograde pancreatography (ERP). In the patients with irregular stenosis diagnosed by ERP, SDPC preformed the repeated cytology using pancreatic juice collected by endoscopic naso-pancreatic drainage (ENPD).

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Results

From January 2007 to September 2011, a total of 1616 cases were consulted with SDPC in Onomichi General Hospital. Out of these patients, CT was performed on 1420 cases, MRI was performed on 1181 cases, and EUS was performed on 952 cases. Among these cases, ERCP was performed on 470 cases with the irregular stenosis in the main PD, or the dilatation in the branch of PD. ENPD and the repeated cytology using pancreatic juice were performed in 40 cases. Finally, 18 cases were proved as adenocarcinoma. After surgical operations, 10 cases out of 18 were diagnosed as the stage 0 PC histopathologically.

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Conclusions

To detect of early stage of PC, the relationship between SDPC in medical centers and practicing doctors is very important. ENPD and repeated cytology using pancreatic juice also play important roles in diagnosis of the early stage of PC.

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Surgical Resection for Pancreatic Ductal Adenocarcinoma is Acceptable in the Elderly, Even in Patients Over 80 Years of Age

C. Kitami, Y. Kawachi, A. Nishimura, S. Makino, M. Kawahara, K. Nikuni Department of Surgery, Nagaoka Chuo General Hospital, Nagaoka City, Niigata, Japan.

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Background

The elderly population has been steadily increasing in several decades. Indications for cancer treatment in elderly patients have expanded, because surgical techniques and medical management have improved remarkably. The purpose of the present study was to evaluate the safety of surgery in elderly patients 80 years of age and older and to show the influence of advanced age on the morbidity and mortality associated with this operation.

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Patients and methods

Subjects were 118 patients who underwent surgical resection for pancreatic ductal adenocarcinoma during the time period from January 2001 to Decemberl 2011. The main outcomes were postoperative complications, mortality, and the length of hospital stay among the elderly patients, and they were analyzed in three groups: elderly patients over 80 years old (n=10), septuagenarians (n=48), and those under 70 years of age (n=60).

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Results

One hundred-two patients underwent pancreaticoduldenectomy, 15 patients underwent distal pancreatectomy, and one underwent total pancreatectomy. The prevalence of cardiovascular disease preoperatively was higher in patients over 70 years (p=0.02). Blood loss and surgical time were not significantly different among three groups. There were no statistical differences in mortality rate, morbidity rate, and mean length of hospital stay among three groups. Long-term survival was also no statistically significant difference using the log-rank test.

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Conclusion

We believe that surgical resection for pancreatic ductal adenocarcinoma can be feasible for elderly patients who had a good performance status.

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β2-AR-HIF-1α: A Novel Regulatory Axis for Stress- Induced Pancreatic Tumor Growth and Angiogenesis

J. Ma, Q. Ma, T. Shan Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College, Xi’an Jiaotong University, Xi’an, China.

Recent studies using mouse model of ovarian carcinoma have shown that chronic stress may influence tumor growth and angiogenesis by modulating the expression of matrix metalloproteinases (MMP) and vascular endothelial growth factor (VEGF) through the β-adrenergic receptor (β-AR)–cyclic AMP (cAMP)–protein kinase A (PKA) pathway. Our previous in vitro experiment data described that HIF-1α as regulatory hinge mediated β-AR signaling pathway. The purpose of this study was to test the hypothesis that chronic stress in a negative social and psychological state plays a critical role in pancreatic cancer development and progression. In this study, we created a new stress model system to determine the effects of chronic stress on pancreatic cancer progression. Here we show that chronic stress not only results in mice gaining depression behavior due to an elevated level of epinephrine, but also induces cancer progression. We further demonstrate that the pancreatic cancer development and progression induced by chronic stress was blocked by a β2-AR inhibitor ICI118 551 or a HIF-1α inhibitor 2-Methoxyestradiol and that the chronic stress up-regulates the expression of MMP-2, MMP-9, and VEGF via a HIF-1α-dependent β-AR signaling pathway. Our data suggest that β2-AR-HIF-1α axis regulates stress-induced pancreatic tumor growth and angiogenesis. This study may have a therapeutic or preventive potential for the patients with pancreatic cancer who are especially subject to psychosocial stress.

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An Autopsy Case of Pseudomyxoma Peritonei Presenting After A Distal Pancreatectomy for A Main Duct-Type Intraductal Papillary Mucinous Neoplasm

N. Iwai,1 J. Sakagami,2 H. Yasuda,2 M. Iwai,2 R. Takada,1 K. Kataoka,1 T. Yoshikawa21Department of Gastroenterology, Otsu Municipal Hospital; 2Department of Gastroenterology and Hepatology, Kyoto Prefectual University of Medicine.

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Introduction

Pseudomyxoma peritonei (PMP) is an extremely rare complication after the pancreatic surgery for intraductal papillary mucinous neoplasm (IPMN). We report an autopsy case of an 83-year-old Japanese male with postsurgical state of IPMN.

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Case report

The patient had been under treatment for chronic pancreatitis since 1980 at an outside institution. During the follow-up period, dilation of the main pancreatic duct was pointed out in 2003, he was transferred to our hospital thereafter. He underwent extensive distal pancreatectomy under the diagnosis of main duct-type IPMN. Since the resected specimen partly had invasive adenocarcinoma, he had received adjuvant gemcitabine with 1000 mg psm, but mucinous retention had developed intraperitoneal cavity one year later. Thereafter, he responded the combination therapy with gemcitabine and S-1 as a second line chemotherapy. However, intraperitoneal mucinous collection has again increased rapidly in 2009. We selected biweekly paclitaxel with 80mg psm as a third line chemotherapy, and he tolerated well with this therapy. Pancreatic dysfunction has been gradually exacerbated and he died of malnutrition and septicemia on December 2010. At the autopsy, remnant pancreas showed marked atrophy and no apparent regional recurrence was noted. The abdominal cavity was filled with mucinous and gelatinous fluid over 5600 ml. In addition, the mucoceles coated with connective tissue extended into the intestinal lumen as well as the abdominal wall.

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Conclusion

PMP is caused by dissemination of mucinous carcinoma mostly arising from appendix or ovary. Only 7 cases have been reported in English literature in which PMP arising from IPMN.We must keep it in mind that PMP is one of the complications after surgery for IPMN.

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Secondary Hematologic Malignancy Occurred in Long-Term Survived Pancreatic Cancer Patients Might be Associated With Chemotherapy

H. Shimamura, K. Takeda Department of Surgery, Sendai Medical Center, Sendai, Japan.

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Background

Treatment outcome of invasive ductal carcinoma of pancreas (IDC) is dramatically improving by performing adequate surgical operation in combination with adequate use of chemotherapeutic drugs, such as gemcitabine (Gem) and/or S-1, which was proved to be beneficial. In spite of increasing number of long-term survivor of IDC, we recently experienced two pts with hematologic malignancy occurred after long-term survival of IDC.

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Case 1

56y-old-male. He was diagnosed as IDC of pancreatic head and underwent pancreaticoduodenectomy (PD) in our institute. According to UICC, this case was classified as pT3pN0cM0, StageIIA (cell differentiation; G1). He was administered Gem for a couple of cycles, followed by intake of S-1 for more than one year. On periodical check, 52 months after surgery, blood counts of WBC and platelets began to increase without any symptoms. We eventually referred him to a hematologist, who diagnosed him as chronic myelogenous leukemia (CML). Then, administration of imatinib has led him to complete remission of CML. He has become one of our 5y survivors of IDC, with taking imatinib.

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Case 2

71y-old-male. He was diagnosed as IDC of pancreatic head and underwent PD. According to UICC, this case was also classified as pT3pN0cM0, StageIIA and G1. He was also administered Gem and S-1. During follow up and about 57M after PD, we realized his pancytopenia. The hematologist diagnosed him as myelodysplastic syndromes (MDS). Although he survived more than 5y after PD, he chose conservative therapy and was deceased of MDS.

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Discussion

Both points above underwent chemotherapy using both Gem and S-1 several years before onset of CML/MDS. Association of these drugs with hematologic malignancies cannot be ruled out. When IDC pts, who underwent surgery plus chemotherapy, are expected to be a long survivor, hematologic malignancy should also be considered during follow up.

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The Role of Gemcitabine/S-1 in the Neoadjuvant Setting for Locally Advanced Pancreatic Cancer

S. Kinoshita, M. Sho, A. Takahiro, T. Nomi, I. Yamato, D. Hokuto, S. Yasuda, Y. Nakajima Department of Surgery, Nara Medical University, Kashihara, Japan.

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Introduction

Systemic Gemciabine/S-1 combined therapy is effective for unresectable, locally advanced pancreatic cancer. Locally advanced pancreatic cancer (LAPC), Gemcitabine/S-1 combined therapy (GS therapy).

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Patients/ Methods

81 cases of unresectable pancreas cancer were treated over the period of Oct. 2007, to May 2012. The median survival time (MST) was 12.3 months, and the 1 year survival rate was 51%. MST according to unresectability status was 8.3, 13.3, 11.2 months for liver metastasis (36 cases), locally advanced (34 cases), and other distant metastasis (11 cases), respectively. 27 cases (79%) of LAPCs were treated with GS therapy. Of the 16 cases (47%) treated primarily by GS, 4 (11.8%) showed partial response. In 3 cases out of these 4, GS was followed by radiation therapy with concurred systemic gemcitabine, and surgical resection was preformed. 11 cases.

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Improved Effect of Chemoradiotherapy in Combination With Adenovirus-Mediated Interferon Therapy

J. Han,1 Y. Miura R. Shanley,1 X. Luo,2 K. Aoki,3 S. M. Vickers,1 M. Yamamoto,1 J. Davydova11Department of Surgery, 2Division of Biostatistics, University of Minnesota, Minneapolis, MN; 3National Cancer Center Research Institute, Tokyo, Japan.

An interferon-α (IFN) emerged as a powerful tool in recent clinical studies against pancreatic ductal adenocarcinoma (PDAc). Although, IFN therapy sensitized chemoradiotherapy and greatly improved survival, excess toxicity remains as a main obstacle. To overcome, we employed the application of oncolytic adenovirus as a vector to locally produce IFN at therapeutic concentration. We hypothesize that replication competent adenovirus expressing IFN (AdIFN) in combination with either chemotherapies (5FU) or radiotherapy would significantly enhance anti-cancer effect of existing IFN-based regimens while reducing toxicity. The significance of our design strategy was exemplified through analysis of the cytocidal effect in human and hamster PDAc cell lines. The in vitro assays revealed that combination of AdIFN with either 5FU or radiation killed cancer cells better than either of the single treatments. Furthermore, we established pancreatic tumors in immunocompetent hamsters and performed in vivo experiments to test the therapeutic effect of combination therapies. We discovered that combination of AdIFN with either 5FU or radiation resulted in remarkable tumor shrinkage and was superior to radiation and 5FU alone or both of these combined. Successively, the triple therapy (AdIFN+Rad+5FU) outperformed all treatment groups. The evaluation of the survival rate showed statistically significant improvement in groups treated with dual (AdIFN+Rad) and triple therapies. These results reinforce the impact of adenovirus-induced IFN expression to sensitize anti-tumor effect of chemotherapy and radiation. Enhancing the therapeutic effect while greatly reducing the side-effects, adenovirus-mediated IFN therapy may improve the prognosis of pancreatic cancer patients.

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Antegrade En Bloc Pancreaticoduodenectomy With Plexus Hanging Maneuver for Borderline Resectable Pancreatic Ductal Adenocarcinoma - Total Mesopancreatic Excision

S. Mizuno, S. Isaji, M. Kishiwada, A. Tanemura, Y. Azumi, N. Kuriyama, I. Ohsawa, M. Usui, H. Sakurai, M. Tabata Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University School of Medicine, Mie, Japan.

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Background

The mesopancreas, which is a perineural lymphatic layer between the pancreas parenchyma and the superior mesenteric artery (SMA), is focused on because of the primary site for positive resection margins of the pancreas head adenocarcinoma. Although antegrade en bloc pancreaticoduodenectomy including mesopancreas is appropriate for invasive pancreatic head ductal adenocarcinoma (PDAC), this technique is not easy to perform because the end-point of deep vertical resections cannot be controlled.

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Methods

A tape for guidance was passed in a space behind the pancreatic parenchyma and above the SMA, followed by sagital resection of the pancreas parenchyma with the splenic vein and dissection of the exposed anterior plexus above SMA. Another tape was passed behind the lateral plexus between the pancreas head and the roots of the celiac and SMA. Mesopancreas was dissected close to the SMA resulting in completion of total mesopancreatic excision.

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Results

This technique was applied in 11 patients with borderline resectable (BR) PDAC based on NCCN guideline 2010. Nine patients received chemoradiotherapy before surgery. All cases were needed to undergo reconstruction of the portal vein because of tumor involvement. Two patients needed to remove right colon because of tumor invasion to the mesocolon including marginal arteries and veins and one patient underwent gastrectomy and splenectomy because of tumor invasion to the left gastric artery and splenic artery. The mean duration of surgery and blood loss was 570 min and 1026 ml, respectively. Postoperateive complication occurred in 8 patients: grade I and II in 6 patients and grade IIIb in two patients according to the Clavian’s classification, w ithout any pancreatic fistula. Median hospital stay was 36 days (25-51). Pathological findings of the resected specimen revealed that an R0 resection was achieved in 7 patients, 3 had a margin less than 1 mm (R01) and only one case had a positive margin (R1). All patients alive but two patients were diagnosed as liver metastasis of PDAC 7 and 13 months after surgery, respectively. The mean survival time was 14.8 months from initial treatment and 10.8 months after surgery.

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Conclusions

Plexus hanging maneuver is an innovative, appropriate and simple technique to obtain complete resection of mesopancreas, which secures a negative surgical margin.

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Novel Theranostic for Imaging and Treatment of Pancreatic Cancer

J. Han,1 M. Trujillo,2 M. Oneal,2 S. McDonough,2 S. Vickers,1 J. Morris,2 J. Davydova11Department of Surgery, University of Minnesota, Minneapolis, MN; 2Division of Endocrinology, Mayo Clinic, Rochester, MN.

The natural expression of sodium-iodide symporter (NIS) in the thyroid has been successfully exploited as a way to achieve non-invasive imaging and radiotherapy of thyroid cancer for more than 50 years. In this research, we hypothesized that diagnosis and treatment of pancreatic cancer would benefit greatly from the development of oncolytic adenovirus expressing NIS selectively in pancreatic cancer cells. NIS will induce uptake of radionuclide and facilitate: i) high-sensitivity detection of pancreatic cancer, and ii) radiotherapy with 131I. Clinical application of this approach may bring the following advances: i) Simultaneous delivery of diagnostic and therapeutic agents may greatly improve management of pancreatic cancer; ii) SPECT/CT imaging of selective NIS expression may give more sensitivity and specificity than other imaging modalities; iii) The combination of enhanced oncolytic virus efficacy with the bystander effect of 131I therapy may offer a new approach for treatment of inoperable pancreatic cancer patients.

We cloned and generated a novel Conditionally-Replicative Adenovirus (CRAd) overexpressing NIS. This vector exhibited selective and greatly improved oncolytic potency in S2O13, S2VP10, AsPC1 and MiaPaca2 pancreatic cancer cells. Radioiodine uptake was shown to be time- and dose-dependent and was significantly greater than that with a replication-deficient control counterpart. The therapeutic and imaging abilities of novel CRAd were further evaluated in a subcutaneous prostate cancer model in mice. A single intravenous injection of CRAd efficiently suppressed tumor growth and resulted in sufficient noninvasive SPECT/CT tumor imaging. Importantly, survival rate was greatly improved when it was combined with 131I. This indicates the feasibility of our system to treat and visualize cancer upon systemic CRAd delivery and efficacy of combination therapy with 131I.

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The Softer the Pancreas, the More the Leakage?

M. Hatano,1 J. Watanabe,1 T. Takebayashi,1 E. Ito,1 H. Inoue,1 Y. Yonenaga,1 A. Takai,1 T. Tohyama,1 F. Kushihata,1 M. Koizumi,1 T. Kumagi,2 Y. Takada11Department of HBP Surgery and Transplantation, Ehime University, Toon, Japan; 2Department of Internal Medicine, Ehime University, Toon, Japan.

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Background

It has been reported that soft pancreas leads to pancreatic leak after pancreatectomy. Pancreatic hardness/consistency has been judged subjectively by surgeons. Ultrasound elastografphy (UE) has been used and shown to be useful to assess consistency of liver cirrhosis, etc. We applied UE to assess the relationship between pancreatic consistency and postoperative pancreatic leak.

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Patients and methods

Twenty six pancreatectomy cases (19 Whipple, 7 distal pancreatectomies) from July 2010 to Marh 2012 were studied. Pancreatic consistency was measured three times at the cutting edge (above portal vein) by UE. The relationship of pancreatic leak (defined by ISGPF definition) and pancreatic consistency (mean UE value) were studied along with other risk factors, such as patient’s age, sex, BMI, operation time, blood loss, main pancreatic duct diameter, exocrine function (PFD test) and endocrine function (IRI, C-Peptide, Hb A1c).

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Results

Of those 26 patients, 9 were pancreatic cancer, 6 were intraductal papillary mucinous neoplasm, 7 were bile duct cancer, 2 were duodenal papilla Vater cancer, 1 was chronic pancreatitis and one was serous cystic tumor. Postoperative pancreatic fistula was found in 13 cases (50%). Low UE values (softer pancreas), IRI value and C-peptide were determined to be risk factors for pancreatic leak by uni-variate analysis.

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Conclusion

Softer pancreas (low value in intraoperative ultrasound elastography) is one of risk factors leading to pancreatic leak after pancreatectomy along with IRI value and C-peptide.

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The Ultimate Radical Surgical Procedure for Locally Advanced Pancreatic Body Cancer-Distal Pancreatectomy with en bloc Celiac Axis Resection-DP-CAR

E. Tanaka, S. Hirano, T. Nakamura, T. Tsuchikawa, J. Matsumoto, K. Kato, Y. Ebihara, Y. Kurashima, T. Shichinohe Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

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Introduction

We have already reported the feasibility, safety, and excellent long-term results of distal pancreatectomy with en-bloc celiac axis resection (DP-CAR) for locally advanced pancreatic body cancer. The perioperative complication rate in patients with DP-CAR was reported to be high, and international standard for the surgical technique of DP-CAR has yet to be established.

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Method

DP-CAR was carefully performed in 53 patients in Hokkaido University Hospital from 1998 to Dec. 2009. Postoperative adjuvant chemotherapy has been performed since 2006. Arterial blood flow alteration and collateral flow development toward the liver and stomach was obtained following preoperative routine transcatheter arterial embolization of the common hepatic artery. The right-sided approach to the superior mesenteric artery and celiac artery, and the preservation of the inferior pancreatoduodenal artery during the dissection of the plexus around the pancreatic head, are the key techniques in DP-CAR for radical resection of the plexuses of Celiac Axis and Superior mesenteric artery, retroperitoneal tissue eradication and safety of this procedure.

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Results

The operative morbidity and mortality were 62 and 6%, respectively. R0 resection could be done in 49 (92%) patients. Median operation time and intraoperative blood loss were 444 min (272–1037) and 1030 ml (350–15970), respectively. Ischemic gastropathy was complicated in 5 (12%) patients, but liver abscess was found in only one patient and no liver failure was encountered. Overall 5-year survival rate was 35%, and disease free survival rate was 21%. Postoperative adjuvant chemotherapy was performed in 22 patients, and 5-year survival rate was 65%.

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Conclusion

DP-CAR should be an ultimate surgical procedure for curative resection in locally advanced pancreatic body cancer. Standard surgical technique for DP-CAR should be established. Postoperative adjuvant chemotherapy in DP-CAR patients should be feasible. More convincing evidence for adjuvant chemotherapy in advanced pancreatic body cancer patients is needed to be established.

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Twice Resections for Liver Metastasis of Ductal Pancreatic Cancer - Report of a Case

T. Ohkubo, T. Takayama, T. Higaki, M. Moriguchi, H. Nakayama, O. Aramaki, S. Yamazaki Department of Digestive Surgery, Nihon University School of Medicine, Tokyo, Japan.

A 53 year old woman was performed curative pancreatoduodenectomy for the ductal pancreatic cancer of the pancreatic head. A tumor size was 2.5 x 1.8 x 1.5 cm. The pathological diagnosis was invasive ductal carcinoma, tubular adenocarcinoma, well differentiated type of pancreas; INFr, Ph, ch(+), du(+), s(-), rp(-), ly1, v0, ne3, mpd(+), pcm(-), bcm(-), dpm(-), n(-)0/85, stage III. After 2 years one month from primary surgery, she had liver metastasis in S7. It was single tumor and there was not any recurrence site using FDG-positron emission CT. Therefore, we performed liver resection. After liver resection, she was received adjuvant chemotherapy. We used Gemcitabine Hydrochloride 1200mg/body. After 5 years 4 months from primary surgery, she had new liver metastasis in S7 again. It was also single tumor, there was not any recurrence site. We performed liver resection again. After 7 years 3 months from primary surgery, she felt appetite loss and admitted our hospital. She had multiple recurrences, and then died in the hospital. It occurred after 2 years 0 month from secondly liver resection. However, she could receive liver resection twice, as result survived more than 5years from primary surgery.

It is very rare that liver resections were done twice for metastasis of the ductal pancreatic cancer.

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Weekly Intravenous and Intraperitoneal Paclitaxel Combined With S-1 for Gemcitabine-Refractory Pancreatic Cancer With Malignant Ascites: An Interim Analysis

N. Takahara,1 H. Isayama,1 Y. Nakai,1 T. Sasaki,1 H. Ishigami,2 H. Yamashita,3 H. Yamaguchi,3 S. Mizuno,1 H. Kogure,1 N. Yamamoto,1 K. Hirano,1 M. Tada,1 J. Kitayama,3 T. Watanabe,3 K. Koike11Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; 2Department of Outpatient Chemotherapy, University of Tokyo, Tokyo, Japan; 3Department of Surgical Oncology, University of Tokyo, Tokyo, Japan.

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Purpose

The prognosis of pancreatic cancer patients with peritoneal metastasis remain dismal. We developed a new regimen of intravenous and intraperitoneal paclitaxel combined with S-1, which was previously reported to be effective in gastric cancer with peritoneal metastasis. Here, we reported an interim analysis of a phase II trial of this regimen for gemcitabine-refractory pancreatic cancer with malignant ascites.

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Methods

Paclitaxel was administered intravenous at 50 mg/m2 and intraperitoneal at 20 mg/m2 on days 1 and 8 every 3 weeks, and S-1 was administered at 80 mg/m2/day for 14 days, followed by 7 days rest. An interim analysis of the first 10 out of a total of 30 cases was planned to assess feasibility of this regimen.

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Results

Between April 2011 to February 2012, 10 patients were enrolled. Of the 7 completed the first two cycles. Malignant ascites was completely disappeared in 2 and partially decreased in 3. A partial response was achieved in 2 and a disease control rate was 50%. The median time to progression and overall survival were 3.2 and 5.9 months, respectively. Major grade 3/4 adverse events were neutropenia (50%) and catheter-related infection (10%).

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Conclusions

This novel combination chemotherapy was feasible and showed promising results in pancreatic cancer patients with malignant ascites.

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Sonic Hedgehog is the Most Sensitive and Specific Parameter in Pancreatic Ductal Adenocarcinoma, Compared to MUC1, p16, p53, and Smad4

S. Izumi, I. Suzuka, Y. Onoda, R. Ohasi, T. Yamakawa, T. Oka Department of Digestive Surgery, Kagawa Prefectural Central Hospital, Takamatsu, Japan.

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Background

One of the notable histological features of pancreatic ductal adenocarcinoma (PDA) is the presence of abundant fibrosis and hypercellular stoma in the tumor area, which is called desmoplastic reaction (DR). Recently, it has been reported that Sonic hedgehog (Shh) pathway is associated with the presence of desmoplastic reaction. The purpose of this study is to clarify the expression and significance of SHH in the PDA.

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Material/Method

The 32 PDA leasions that were resected in our hospital were evaluated by immunohistochemistry (IHC) for Shh. Moreover, 18 PanIN lesions (low-grade and high-grade PanINs are 10 and 8.) around the tumor and 12 metastatic lesions in the lymph nodes were also evaluated by IHC. Moreover, to compare the expression of Shh with other molecular abnormalities in association with tumor progression, the IHC for MUC1, p16, p53, and Smad4 was performed in 23 PDA lesions.

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Results

The mean tumor size is 2.4 (0.8–4.0) cm and pathological stage I/II/III/IV is 4/3/8/14. Histologically, desmoplastic reaction was recognized with various degrees in all cases. The rate of positive Shh expression in 32 PDA lesions, 12 metastatic lesions in the lymph nodes, and 18 PanINs was 100% (32), 92% (11), and 17% (3). On the other hand, the rate of abnormal-immunolabeling for MUC1, p53, p16, and Smad4 in 23PDA lesions was 91% (21), 83% (19), 96% (24), and 43% (10). Moreover, the rate of diffuse positive-immunolabeling is significantly higher in Shh (94%) than MUC1 (70%)

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Conclusion

Shh, MUC1, and p16 are sensitive parameters to the PDA lesions. However, although abnormal immunolabeling for MUC1 and p16 are often expressed in PanIN lesions, Shh showed low-expression rate in them. In summary, SHH may be the most sensitive and specific parameter in the PDA.

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Acinar Cell Carcinoma of the Pancreas With Intraductal Papillary Growth and Synchronous Liver Metastasis: Report of a Case

H. Ishikawa, H. Kinoshita, G. Nakayama, K. Takahashi, M. Akashi, Y. Kawashima, R. Kawahara, T. Hisaka, M. Yasunaga, H. Horiuchi, K. Okuda, K. Shirouzu Department of Surgery, Kurume University, Kurume, Japan.

Acinar cell carcinoma (ACC) of the pancreas is a rare malignancy, accounting for 1-2% of pancreatic exocrine malignancies. Little is reported on strategy of the treatment of ACC of the pancreas with synchronous liver metastasis. A 63-year-old man was referred hospital for the investigation of a solid tumor in the body and tail of the pancreas, which had been pointed out 3years before. Abdominal CT scan demonstrated a solid tumor, 14cm in diameter, with a distinct border in the body and tail of the pancreas. Endoscopic retrograde cholangiopancreatography showed a filing defect in the main pancreatic duct. Brush cytology was negative for malignant cells. Endosonographic fine needle aspiration biopsy confirmed an ACC. At laparotomy a synchronous liver metastasis, 1mm in diameter, was found. Total pancreatectomy with enucleation of the liver metastasis was performed. The pathological diagnosis by immunohistochemical staining was ACC of the pancreas with intraductal tumor growth to the main pancreatic duct and synchronous liver metastasis. Postoperative course of the patient has been good, and he was free of disease for 28 months with gemcitabine (GEM) and S-1 adjuvant chemotherapy. Although the prognosis of patients with unresectable ACC of the pancreas is unfavorable, it is suggested that the aggressive surgery and the GEM/S-1combination chemotherapy is effective for these patients.

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Distal Pancreatectomy Wth En Bloc Celiac Axis Resection (DP-CAR) for Locally Unresectable Pancreatic Body Cancer

T. Nakamura, E. Tanaka, K. Kato, J. Matsumoto, T. Asano, Y. Nakanishi, Y. Kurashima, Y. Ebihara, T. Tsuchikawa, T. Shichinohe, S. Hirano Department of Digestive Surgery II, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

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Background

To evaluate the prognostic impact of surgical intervention for initially-unresectable pancreatic body ductal adenocarcinomas with long-term favorable responses to chemotherapy.

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Method

Six patients with initially-unresectable pancreatic body cancer who underwent radical surgery after a favorable response to chemotherapy for six months or longer in principle were enrolled in this study. We retrospectively reviewed the charts of these 6 patients and performed a survival analysis.

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Results

Initially, the included patients were unable to undergo resection secondary to locally-advanced disease in 6 patients The length of preoperative therapy was eight to 44 months (median 22). The operative procedure included resection of celiac axis initially involved by tumor. The postoperative mortality and morbidity rates were 0% for patients with locally-advanced disease. R0 resection was achieved in five patients (83%) and pathological CR was seen in one patient. Median survival from initial therapy was 44 month (range 22 to 63 month).

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Conclusion

Surgical intervention should be considered for patients with initially-unresectable pancreatic body cancers who demonstrate long-term favorable responses to chemotherapy. Large cohort prospective studies will be necessary to demonstrate the efficacy of this strategy.

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Role of Neoadjuvant Chemo(radiation) Therapy for Patients With Locally Advanced Pancreatic Cancer

K. Taniguchi, R. Matsuyama, R. Mori, K. Takeda, T. Kumamoto, K. Nojiri, M. Ueda, H. Akiyama, K. Tanaka, I. Endo Gastroenterological Surgery, Yokohama City University, Yokohama, Japan.

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Objectives

Neoadjuvant chemo(radiation) therapy (NAC(RT)) has been used to improve survival in pancreatic cancer. The aim of this study is to clarify usefulness of NAC(RT) for locally advanced pancreatic cancer.

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Patients and Methods

Between 2001 and 2011, 118 patients with locally advanced pancreatic cancer who were suspected to have portal vein invasion or extrapancreatic perineural invasion at the initial presentation were enrolled. 63 patients received NAC(RT) and the other 55 patients underwent surgical resection without neoadjuvant therapy (Straight group). Surgical outcome, pathological findings and long term survival were compared. Results: Of the 63 patients who received neoadjuvant therapy, 16 patients were turned out to be unresectable after chemotherapy because of distant metastasis and further 4 patients (6%) deemed unresectable due to peritoneal dissemination or liver metastasis at laparotomy. It was significantly fewer than in Straight group (14/55; 25%, P=0.026). Thus, 43 patients underwent surgical resection after NAC(RT) (NAC(RT)-S group) and 41 patients underwent resection without NAC(RT) (Straight-S group). Histological examination of resected specimen revealed that rates of portal vein invasion (9% vs 49%; P<0.001) and lymph node metastasis (60% vs 85%; P=0.014) in NAC(RT)-S group were significantly lower than in Straight-S group, respectively. The rate of R0 resection was significantly higher in NAC(RT)-S group than in Straight-S group (91% vs 51%; P<0.001). NAC(RT)-S group showed significantly better overall survival compared with Straight-S group (median survival, 45 vs 15 months; P=0.01).

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Conclusions

NAC(RT) may improve the rate of resection with clear margins and decrease the rate of metastatic lymph nodes in selected patients, resulting in improved long-term survival of locally advanced pancreatic cancer.

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Pancreatic Adenosquamous Carcinoma Presenting as Gastric Bleeding With Elevation of Serum SCC Level: A Case Report

Y. Miyata, Y. Seyama, M. Nishida, A. Yonenaga, M. Matsuda, N. Umekita Hepato-biliary-pancreatic Surgery Division, Department of Surgery, Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan.

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Background

Adenosquamous carcinoma is a rare pathological type in the pancreas cancer. Additionally, a report of pancretic adenosquamous carcinoma presenting as gastrointestinal bleeding was limited. There are no characteristic findings of pancreatic adenosquamous carcinoma, and then it is usually diagnosed pathologically after resection as a pancreatic ductal carcinoma. Herein we report a case of adenosquamous carcinoma of the pancreas presenting as gastric bleeding with elevation of serum SCC level.

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Case

A 77 year-old man was presented with severe anemia, and underwent gastroendoscopy. There was submucosal mass with ulcer bleeding located in the upper gastric body, and biopsy revealed that it was adenosquamous carcinoma. Computed tomography showed that there was a poorly enhanced mass, 10cm in diameter, in the pancreas body to tail, and the tumor was infiltrating the stomach and spleen. Serum CA19-9 (76.8U/ml) and SCC (56.8ng/ml) was elevated. Preoperative diagnosis was pancreatic adenosquamous carcinoma with invasion of other organs and liver metastasis (Stage4b). We performed operation because gastric bleeding was not controlled endoscopically and blood transfusion was frequently needed.

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Result

Total gastorectomy and distal pancreatectomy was carried out. Postoperative course was uneventful, and the patient discharged on the 17 postoperative days. Pathological diagnosis was pancreatic adenosquamous carcinoma with central necrosis. Most part of the tumor was adenosquamous carcinoma with a small part of ductal carcinoma. Serum SCC level was returned to normal range after resection.

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Conclusion

Gastric bleeding can be an initial symptom of pancreatic adenosquamous carcinoma. Serum SCC level is useful to diagnose pancreatic adenosquamous carcinoma preoperatively.

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Oral S-1 With Concurrent Radiotherapy for Locally Advanced Pancreatic Cancer

H. Shinchi, S. Takao, K. Maemura, Y. Mataki, H. Kurahara, S. Natsugoe Department of HBP Surgery, Kagoshima University, Kagoshima, Japan.

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Introduction

S-1 is a new oral fluoropyrimidine anticancer agent shown to be effective for pancreatic cancer. In a previous phase I trial, we evaluated the safety of S-1 combined with radiotherapy to determine the MTD and DLT in patients with unresectable pancreatic cancer. This phase II study was conducted to further evaluate the efficacy and toxicity of radiotherapy combined with S-1.

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Methods

Eligible patients had locally advanced and unresectable pancreatic cancer without distant metastases, an ECOG performance status of 0-1, adequate organ and marrow functions, and no prior anticancer therapy. Patients initially received 4 weeks of chemoradiotherapy. S-1 was given orally at a dose of 80 mg/m2/day twice daily on days 1 to 21. Radiotherapy was delivered in fractions of 1.25 Gy twice daily, 5 days per week for 4 weeks (total dose: 50 Gy in 40 fractions). One month after the completion of chemoradiotherapy, S-1 was administered for 14 days followed by a 14-day rest period. This cycle was repeated as maintenance therapy until disease progression or unacceptable toxicity.

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Results

Fifty patients were enrolled in this phase II study. Forty-three patients (86%) completed the scheduled course of chemoradiotherapy. There was no treatment-related death or grade 4 toxicity. The major toxic effects were leukopenia and nausea. The objective tumor responses by RECIST criteria included 15 PR (30%), 23 SD (46%) and 12 PD (24%). Median PFS and median OS were 6.7 months and 14.3 months, respectively. Survival rates at 1 and 2 years were 62% and 27%, respectively.

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Conclusion

Combination therapy with S-1 and radiation in patients with locally advanced and unresectable pancreatic cancer is considered a promising, well-tolerated regimen that can be recommended as an effective treatment for locally advanced pancreatic cancer.

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Successful EUS-Guided Pancreatic Duct Stent Placement With a Rendezvous Technique for an Anastomotic Stricture After Pancreatogastrostomy: A Case Report

E. Yamashita, H. Yasuda, J. Sakagami, Y. Naito, T. Yoshikawa Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan.

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Background

Pancreaticogastrostomy (PG) and pancreaticojejunostomy (PJ) have been the most commonly used methods for pancreaticoenteric reconstruction after pancreaticoduodenectomy (PD). Anastomotic stricture sometimes occurs as a long-term complication of PG, which may cause obstructive pancreatitis. Endoscopic ultrasonography(EUS)-guided drainage of obstructed pancreatic ducts has been reported as an effective procedure, when anastomotic stricture interrupts guide wire insertion.

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Patient and method

We report a 38-years-old Japanese male who had undergone PD with PG in a steering wheel injury 10 years ago. Four years after the surgery, he began to suffer from frequent acute pancreatitis and he was referred to our hospital. MRCP showed the dilation of pancreatic duct due to anastomotic stricture. Despite conservative treatment, he occasionally complained of abdominal pain with pancreatic enzyme elevation. Hence endoscopic pancreatic duct stent placement was applied to prevent acute pancreatitis. A first attempt on stent placement was failed because of difficulty in passing the tight stricture. Secondly, we used EUS-guided rendezvous technique. Under EUS guidance, 19G needle was inserted into the pancreatic duct, and 0.025 inch guide wire was passed through the needle directed to the anastomotic stricture. Guide wire was advanced anterograde across the anastomotic orifice into the stomach. After the anastomotic site was dilated using a balloon dilator over the guide wire, pancreatic stent was then placed across the anastomosis.

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Results

His symptom was alleviated steadily and was discharged uneventfully. Imaging studies also showed the reduction of the dilated pancreatic duct.

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Conclusion

EUS-guided pancreatic duct stent placement with rendezvous technique appears to be an effective method for the treatment of anastomotic stricture after PG.

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Prognostic Relevance of LN-Ratio, Number of LN Metastasis, Number of Resected Nodes, and N-Category After Resection of Pancreatic Cancer

Y. Yamamoto, H. Ikoma, R. Morimura, H. Konishi, Y. Murayama, S. Komatsu, A. Shiozaki, Y. Kuriu, T. Kubota, M. Nakanishi, D. Ichikawa, H. Fujiwara, K. Okamoto, T. Ochiai, E. Otsuji Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan.

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Background

The aim of this study is to evaluate predictors of survival in patients who underwent resection for pancreatic cancer (PC), focusing specifically on the prognostic value of lymph node ratio (LNR), number of LN metastasis, number of resected nodes, and N-category according to the Japanese pancreatic society (JPS) classification.

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Patients and methods

Sixty-seven patients underwent macroscopic curative resection for PC between January 2001 and December 2009. Of these, 11 of PC derived from IPMN were excluded, and total of 56 patients was analyzed. Pancreaticoduodenectomy was performed in 37 patients, distal pancreatectomy in 16, and total pancreatectomy in 3, respectively. Nineteen factors, including the number of LN metastasis, the number of dissected LN, N category according to JPS classification, and LNR, were analyzed using univariate and multivariate analyses.

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Results

The overall 5-year survival rate was 26.9%. Based on the minimum p value approach, the optimal cutoff value was 0.2 for LNR and two nodes for the number of LN metastasis. Positive surgical margin (p = 0.027) and LN ratio > 0.2 (p = 0.025) were identified as an independent prognostic factors. With regard to the subgroup analysis among the 33 patients with regional LN metastasis, there was significant difference in survival between patients with LNR >= 0.2 and LNR < 0.2 (MST 14 vs. 26 mo., p = 0.048), however, the differences in survival between N1 and N2 in JPS classification are not statistically significant (MST 25 vs. 21 mo., p = 0.85).

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Conclusion

Our results suggested that the LNR might be more useful than other parameters as a predictor for survival after resection for PC.

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Effectiveness of Duodenal Stenting for Duodenal Obstruction in Patients With Unresectable Pancreatic Cancer

Y. Niina, H. Igarashi, L. Lee, M. Hijioka, K. Ueda, T. Takaoka, M. Uchida, T. Nakamura, T. Oono, R. Takayanagi, T. Ito Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan.

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Background

Malignant gastric outlet obstruction(GOO) is commonly seen in patients with pancreatic cancer(PC), of whom approximately 10 to 20% experience obstructive symptoms in the course of the disease. Treatment of GOO is indicated because a poor clinical condition caused by vomiting and malnutrition quickly develops in these patients. Traditionally, GOO has been treated with surgically performed gastrojejunostomy(GJJ), while duodenal stent has been suggested to be a less-invasive treatment with faster relief of symptoms compared with GJJ.

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Aim

The aim of this study was to examine the effectiveness of duodenal stent for GOO in patients with unresectable PC.

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Patients and methods

From April 2009 and June 2012, the medical records of 18 patients with unresectable PC who underwent endoscopic duodenal stent placement in our hospital were analyzed retrospectively. Duodenal stenting was performed endoscopically with uncovered Ultraflex or Wallflex Duodenal Stent (Boston Scientific).

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Results

Mean age of the 18 patients (male:female = 14:4) was 66.2(49–86). Oral feeding was possible at a mean 1.84 days after duodenal stenting. GOO Scoring System score of the patients was improved significantly. The median time of duodenal stent patency was 113(32–293) days. In most cases, patients did not suffer from GOO symptoms after stent placement until their death. As complications of duodenal stent, there were two cases of cholangitis, two cases of temporary occlusion. In two cases, we had to perform endoscopic reintervention due to kink of stent. In one case, stent was occluded by the tumor, GJJ was performed 107 days after first stent placement.

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Conclusion

Duodenal stenting for duodenal obstruction seem to be relatively safe and effective with faster relief of symptoms in patients with advanced PC.

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A Case of Small Mass-Forming Pancreatitis Mimicking Pancreatic Neuroendocrine Tumor

H. Matsuura, K. Inui, J. Yoshino, H. Miyoshi, T. Kobayashi, S. Yamamoto Department of Gastroenterology, Second Teaching Hospital, Fujita Health University, Aichi, Japan.

A 63-year-old man was admitted to our hospital with complaints of epigastralgia and anoexia in November 2011. Laboratory data on admission including tumor marker, cancer antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA), were within normal range. Serum levels of insulin, gastrin, and somatostatin were also within normal range. Ultrasonography revealed a hypoechoic mass, 10mm in diameter, with clear boundaries in the head of the pancreas. Endoscopic ultrasonography revealed hyperechoic lesions in the hypoechoic mass. Dynamic multiple-detector-raw computed tomography (MD-CT) showed a non-enhanced mass with strongly enhanced margin in the head of the pancreas. Contrast-enhanced ultrasonography also revealed a hypoechoic mass with an enhanced margin. Magnetic resonance cholangiopancretogram (MRCP) revealed a high-intensity mass in T1-weighted images, and a low-intensity mass in T2-weighted images. MRCP did not show the dilation of the main pancreatic duct. Endoscopic retrograde pancreatogram revealed an abrupt obstruction of the Santorini’s duct in the head of the pancreas. Under diagnosis of neuroendocrine tumor of the pancreas, he was performed pancreatoduodenectomy in December 2011. Pathologic examinations of the resected specimens revealed mass-forming chronic pancreatitis. It was unusual that the images suggested neuroendocrine tumor of the pancreas in case of small mass-forming pancreatitis, and the mass-lesion obstructed perpendicularly the pancreatic duct.

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Changes in the Characteristics and Long-term Outcomes of Pancreatic Cancer in the Gemcitabine Era

T. Kumagi, T. Kuroda, T. Yokota, H. Seike, M. Nishiyama, Y. Imai, H. Tatsukawa, N. Inada, N. Shibata, S. Imamine, S. Okada, M. Koizumi, H. Yamanishi, N. Azemoto, M. Onji, Ehime Pancreato-Cholangiology (EPOCH) Study Group, Japan.

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Background

Although the outcomes of pancreatic cancer (PC) have been improved by gemcitabine, the changes in its characteristics and long-term outcomes in the gemcitabine era remain unclear. Therefore, we analyzed the clinical characteristics of PC patients within the gemcitabine era.

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Methods

A retrospective chart review was performed at 10 centers for 1,248 consecutive patients who were once considered diagnosis of PC. Data were collected for demographics, diagnosis date, clinical stage, treatment, and outcome; 1,082 patients met the inclusion criteria and were further analyzed.

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Results

The clinical stage distribution was as follows: I, 2.2%; II, 3.4%; III, 13%; IVa, 27%; and IVb, 55%. Chemotherapy alone was administered to 42% of the patients; 17% underwent resection. The 1-, 3-, and 5-year survival rates were 39%, 13%, and 6.9%, respectively. The median survival time was 257 days but differed considerably among treatments and clinical stages. The demographics, distribution of clinical stage, and cause of death did not differ between groups A (2001–2005, n = 406) and B (2006–2010, n = 676). However, group B included more patients who underwent chemotherapy (P < 0.0001) and fewer treated with best supportive care (P = 0.0004), mirroring improvements in this group’s long-term outcomes (P = 0.0063).

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Conclusions

Gemcitabine-based chemotherapy has improved long-term outcomes in PC even within the gemcitabine era, suggesting the importance of offering chemotherapy to patients previously considered for best supportive care. Most patients are still diagnosed at an advanced stage, making clinical strategy development for diagnosing PC at earlier stages essential.

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The Feature of Pancreatic Fistula After Distal Pancreatectomy According to the Manner of Cutting

R. Mori, R. Matsuyama, K. Taniguchi, T. Kumamoto, K. Nojiri, M. Ueda, K. Takeda, K. Tanaka, I. Endo Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

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Aim

To clarify the feature of pancreatic fistula (PF) after distal pancreatectomy according to the manner of cutting.

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Material and methods

We retrospectively reviewed the medical records of 61 consecutive patients who underwent distal pancreatectomy for the disease of pancreatic body and tail from May 2006. According to the manner of cutting pancreas, those patients were divided into two groups (L and S groups). In L group, staplers were used for cutting and closure of pancreatic stump and in S group a scalpel was used for cutting and hand-sewn closure or stop the bleeding were done. The incidences of PF according to ISGPF classification, the concentration of amylase in drain discharge, the duration of drainage were compared in these two groups.

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Results

In 61 patients, 31 patients were enrolled in L and 30 were S group. Incidence of PF did not differ between L (51.6%), and S (73.3%) group. Also, Grade B&C PF rate also did not differ between L (10 cases, 32.3%) and S (8 cases, 26.7%). However, PF in Grade A were significantly reduced in L group (19.4% vs S; 46.7%, p=0.022). The amylase concentration of drain discharge in postoperative day 1 in L group were significantly lower than those in S (p=0.002). Duration of drainage in L group were significantly shorter than those in S (15.1 days vs 19.4 days, p=0.023). In the patients with Grade B&C PF in L group, five patients (50%) have a prolonged drainage period without removal of the drainage tubes. The other five patients had late onset PF after removal of drainage tubes more than 14 days after operation. In S group, only one patient had late onset PF among 8 patients with Grade B&C PF.

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Conclusion

There is no significant difference of incidence of PF between L and S. However, late onset PF should be noted in L group.

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Predictors of Early Recurrence After Resection of Pancreatic Ductal Adenocarcinoma

T. Anazawa, T. Tsuchiya, A. Kenjo, T. Kimura, J. Haga, T. Sato, N. Sato, M. Gotoh Department of Regenerative Surgery, Fukushima Medical University, Fukushima, Japan.

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Objective

Surgical resection offers only a chance of cure for pancreatic ductal adenocarcinoma (PDA), however, early recurrence frequently occurs even after radical resection. We aimed to assess predictors for early recurrence in order to establish therapeutic approach for PDA.

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Methods

Between January 2003 and December 2011, 60 patients who underwent pancreatectomy for PDA were divided into two groups: 25 patients developed recurrence within 1 year after surgery (Group 1) and the others remained recurrence free (Group 2). Clinicopathologic factors and survivals were retrospectively analyzed between the two groups using univariate and multivariate methods.

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Results

Median survival time and 5-year survival were significantly lower in Group 1 (1.1 years, 0%) compared to Group 2 (4.0 years, 37.9%; P<0.0001). On univariate analysis, undifferentiated (moderately and poorly) adenocarcinoma, lymphatic invasion, portal vein invasion, retropancreatic tissue invasion, lymph node metastasis and larger tumor size were significantly associated with early recurrence. On the other hand, patient’s age, tumor markers, operative time, intraoperative bleeding, intraoperative radiotherapy, and adjuvant chemotherapy were not the case. Logistic regression analysis revealed that undifferentiated adenocarcinoma (HR=72.2; 95%CI 4.1–1277.4), retropancreatic tissue invasion (HR=47.3; 95%CI 3.1–717.6), portal system invasion (HR=20.8; 95%CI 1.4–311.3), and lymph node metastasis (HR=2.8; 95%CI 1.3–6.2), were the predictors directly related to early recurrence.

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Conclusion

Undifferentiated histology, invasion of retropancreatic tissue and portal vein and lymph node metastasis should be considered “high risk of recurrence” for PDA. Surgical resection and novel approach including chemotherapy, radiotherapy, and immunotherapy might be necessary to improve patient survival.

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Novel Multimodal Treatment for Resectable Pancreatic Cancer

M. Sho,1 T. Tanaka,2 T. Akahori,1 S. Kinoshita,1 T. Yamada,1 T. Nomi,1 I. Yamato,1 D. Hokuto,1 C. Kawaguchi,1 S. Yasuda,1 M. Nagai,1 H. Nishiofuku,2 K. Kichikawa,2 Y. Nakajima11Department of Surgery, 2Department of Radiology, Nara Medical University, Nara, Japan; 2Department of Radiology, Nara Medical University, Nara, Japan.

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Background

Despite considerable improvements of diagnostic and therapeutic options, pancreatic cancer remains most fatal disease. Although only surgery offers a hope of complete cure, a number of patients often develop recurrence even after curative-intent surgery. Therefore, further studies are clearly required to improve postoperative prognosis.

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Methods

To improve patient prognosis, we are trying to establish pre- and postoperative strategy. As neoadjuvant chemoradiotherapy (NACRT), we treated pancreatic cancer patients with full-dose gemcitabine (GEM: 1 g/m2) with concurrent radiation (50 or 54 Gy). As postoperative adjuvant chemotherapy, patients received weekly high-dose 5-FU through the hepatic artery using a port-catheter system (WHF: 1g/m2/5hours) plus concurrent systemic GEM (1g/m2).

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Results

Sixty-four patients received NACRT. The toxicity was acceptable and this regimen was well feasible as an outpatient treatment. Sixty-two patients (97%) completed NACRT. The rate of pancreatic fistula was lower and the hospital stay was shorter compared to patients who did not receive NACRT as control group. The rate of lymph node metastasis and stage was lower in the NACRT group. Furthermore, R0 resection could be achieved in 92% of patients treated with NACRT. Forty patients completed postoperative adjuvant chemotherapy of WHF/GEM. In those patients, the 1-, 2-, 3-year overall survival rates were 100, 69.1, and 59.1%, respectively.

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Conclusion

Our novel multimodal treatment holds a great promise for the patients with resectable pancreatic cancer.

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The Outcomes Following Pancreatoduodenectomy With Pancreaticogastric Anastomosis

H. Ikoma, Y. Yamamoto, R. Morimura, H. Konishi, Y. Murayama, S. Komatsu, A. Shiozaki, Y. Kuriu, M. Nakanishi, D. Ichikawa, H. Fujiwara, K. Okamoto, T. Ochiai, Y. Kokuba, E. Otsuji Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan.

The outcomes following pancreatoduodenectomy with pancreaticogastric anastomosis.

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Introduction

To determine short-term outcomes following pancreatoduodenectomy with pancreaticogastric anastomosis in our institute.

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Methods

From April 2008 through to March 2012, 53 patients were submitted for PD reconstructed by pancreaticogastrostomy. The study consisted of 34men and 19 women, with a median age of 65.6 years old. The main indications for PD were cholangiocarcinoma in 20 patients, pancreatic ductal carcinoma in 16 patients, IPMN in 8 patients, pancreatic neuroendocrine tumor in 4 patients. Reconstruction by pancreatogastrostomy was performed, the stump of pancreas was invaginated into the posterior wall of the stomach by using a pancreatic stent.

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Results

The median of duration of operation was 521 minute (range292∼839), and the amount of blood loss 653ml (range55∼10991). The overall in-hospital morbidity and mortality rate was 48% and 0%, respectively. Pancreatic fistula at the grade B/C in ISGPF occurred in four (9.43%) patients and three patients at the grade B was treated conservatively with good outcome. One patient at the grade C reoperated to drainage abdominal abscesses due to pancreatic fistula with good outcome, too. No patients developed postoperative new or worsening endocrine or exocrine insufficiency.

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Conclusion

Pancreatoduodenectomy with pancreaticogastric anastomosis in our method offers a safe alternative to the pancreaticojejunostomy and may be technically simpler.

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Dendritic Cells Adenovirally-Transduced With Full-Length Mesothelin cDNA Elicit Mesothelin-Specific Cytotoxicity Against Pancreatic Cancer Cell Lines In Vitro

M. Miyazawa, M. Iwahashi, T. Ojima, M. Katsuda, M. Nakamura, N. Mikihito, H. Yamaue Second Department of Surgery, Wakayama Medical University, Wakayama, Japan.

Mesothelin (MSLN) is an attractive candidate as a molecular target for pancreatic cancer immunotherapy. The purpose of this study was to demonstrate that cytotoxic T lymphocytes (CTLs) generated from peripheral blood mononuclear cells (PBMCs) by stimulation with genetically-modified dendritic cells (DCs) expressing MSLN could produce specific anti-tumor immunity against pancreatic cancer cells endogenously expressing MSLN. MSLN-specific CTLs were generated from PBMCs of healthy donors by in vitro stimulation with DCs adenovirally-transduced with the full-length MSLN gene (DC-AxCAMSLN). The cytotoxic activity was tested using a 4-hour 51Cr-release assay. The pancreatic cancer cell lines (PK1, CfPAC1, AsPC1), a lymphoblastoid cell lines (LCL) transduced with the MSLN gene, and LCL pulsed with MSLN-epitope peptides were used as target cells. MSLN-specific CTLs induced by in vitro stimulation with DC-AxCAMSLN killed pancreatic cancer cell lines expressing MSLN in an HLA-restricted fashion. These CTLs also showed cytotoxic activity against autologous LCL pulsed with multiple MSLN-derived epitope peptides. In addition, CD8+ T cells, as well as CD4+ T cells, sorted from these CTLs showed significant production of interferon-γ when stimulated with DC-AxCAMSLN. The in vitro stimulation of PBMCs with DCs transduced with the full-length MSLN gene elicited a potent MSLN-specific cytotoxic activity against pancreatic cancer cell lines endogenously expressing MSLN by recognizing multiple MSLN epitopes and activating both CD8+ T cells and CD4+ helper T cells. These results therefore suggest the potential of developing future clinical applications of the vaccines using genetically modified DCs expressing MSLN.

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Clinical Features of Synchronous and Metachronous PDAC in Patients With Branch Duct IPMN

S. Tanno Department of Gastroenterology, Kotoni Royal Hospital, Sapporo, Japan.

Branch duct intraductal papillary mucinous neoplasm of the pancreas (BD-IPMN) has been increasingly recognized and is now being diagnosed with increasing frequency as a result of recent improvements in imaging techniques and increased clinician awareness. Recent follow-up studies of patients with BD-IPMN suggest that the vast majority of BD-IPMN without mural nodules remain unchanged over time.

On the other hand, pancreatic ductal adenocarcinoma (PDAC) is sometimes found distant from the original BD-IPMN. There have also been reports of PDAC developing in the remnant pancreas several years after resection of a BD-IPMN. Furthermore, small BD-IPMN may be incidentally detected in pancreases resected from PDAC patients.

Recent our findings suggest that patients with BD-IPMN are at high risk for PDAC development. PDAC was observed in 9 (5.4%) of 168 patients with BD-IPMN. Five were synchronously detected at the time of BD-IPMN diagnosis, and four were metachronously identified during the follow-up period. All PDAC occurred in regions distant from the BD-IPMN lesion and represented histologically invasive ductal adenocarcinomas. The BD-IPMN lesion was diagnosed as adenoma. Since PDAC can potentially develop even in patients with low-risk BD-IPMN, careful follow-up with periodic surveillance of the entire pancreas is crucial for all BD-IPMN patients. We recommend that follow-up intervals should not be lengthened, even if no changes are observed for ≥2 years. Clinicians should pay close attention to the development of PDAC in patients with BD-IPMN, as well as to changes in BD-IPMN lesions.

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Preoperative Histological Subtype Classification of Intraductal Papillary Mucinous Neoplasms (IPMN) by Pancreatic Juice Cytology With MUC Stain

T. Hara,1 T. Yamaguchi,2 D. Ikebe,3 K. Sudo,2 K. Nakamura,2 K. Seza,5 H. Yamamoto41Department of Endoscopy; 2Department of Gastroenterology; 3Department of Surgical Pathology; 4Depattment of Gastroenterological Surgery, Chiba Cancer Center, Chiba, Japan.

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Background

IPMN are classified into four subtypes based on their histomorphology and mucin phenotype, and varied degrees of malignant nature and prognosis among these subtypes have been shown.

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Objective

To prospectively evaluate the diagnostic value and clinical usefulness of preoperative histological subtyping of IPMN by pancreatic juice cytology with MUC stain.

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Methods

The subjects were 36 patients with surgically confirmed IPMN, who underwent PJC preoperatively by endoscopic retrograde cholangiopancreatography.

Histological subtyping of cytological samples with or without MUC stain was compared with that of resected specimens.

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Results

Histologically, low grade dysplasia was found in 4 patients, intermediate in 10, high grade in 11, and invasive carcinoma in 11. Gastric, intestinal, pancreatobiliary and oncocytic subtypes corresponded to 16, 14, 5 and 1 patient, respectively. The rate of high grade dysplasia(HGD)and /or invasive IPMN was 25% for gastric subtype, 85.7% for intestinal subtype, and 100% for both pancreatobiliary and oncocytic subtypes, showing a significant correlation between histological subtype and rate of HGD and /or invasive IPMN (p&lt;0.01 for gastric vs non-gastric).

Histological subtype was successfully diagnosed by PJC in 42% (15/36) without MUC stain and the rate was significantly improved to 89% (32/36) with MUC stain (p&lt;0.01). The sensitivity, specificity and overall accuracy of PJC with MUC stain were 86%, 100% and 94% for intestinal subtype, respectively.

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Conclusions

Preoperative pancreatic juice cytology with MUC stain proved to be highly reliable for identifying the histological subtype of IPMN and may provide useful information for deciding surgical indication.

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Definitive Radiotherapy for Patients With Isolated Local Recurrence of Primarily Resected Pancreatic cancer

A. Nakamura,1 K. Shibuya,1 K. Takaori,2 Y. Kawaguchi,2 M. Yoshimura,1 Y. Matsuo,1 S. Itasaka,1 Y. Katagiri,1 T. Mizowaki,1 and M. Hiraoka11Department of Radiation Oncology and Image-applied Therapy, Graduate School of Medicine, Kyoto University, Kyoto, Japan; 2Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

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Background

Only surgical resection can provide a chance of long-term survival for patients with pancreatic cancer, but loco-regional recurrence remains a major challenge. Curative re-operation is seldom attainable but has been suggested to have a survival benefit. We hypothesized that radiotherapy (RT) could offer a good control for the unresectable local recurrence and improve survival. This work aims to evaluate the efficacy and tolerability of definitive RT for patients with isolated locally-recurrent pancreatic cancer.

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Methods

A total of 27 patients, who developed local recurrence of primarily resected pancreatic cancer and received RT between 2000 and 2011, were retrospectively analyzed. The isolated local recurrence was diagnosed with the radiological images and tumor marker relapse. The overall survival (OS) and local control rate (LC) were calculated from the start day of RT and estimated by Kaplan-Meier method. The treatment-related toxicity was assessed.

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Results

The median total dose of RT was 50.4 Gy (range, 39.6–60 Gy). Concurrent chemotherapy consisted of gemcitabine (63%), S-1 (19%), and 5-fluorouracil (4%). At a median follow-up time of 14.8 months, the 1-year and median OS were 76% and 18.2 months, respectively. The 1-year LC was 65%. Grade ≥3 hematological toxicity was seen in 63%. Grade ≥ 3 of acute gastrointestinal toxicity was not observed. At a late phase, Grade 3 ileus observed in one, and Grade 3 gastric bleeding ulcer was seen in one patient.

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Conclusions

Definitive RT resulted in encouraging local control and overall survival for patients with isolated locally-recurrent pancreatic cancer. This treatment strategy should be further evaluated prospectively.

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A Challenge to the Specific Detection of Target Tumors Using Clinical MRI - Selective Tumor Detection by mAb-conjugated Superparamagnetic Iron Oxide

T Koyama,1 M Shimura,1 Y Minemoto,1 S Nohara,2 S Shibata,3 Y Iida,4 S Iwashita,5 M Hasegawa,2 T Kurabayashi,6 H Hamada,7 K Kono,8 E Honda,9 I Aoki,3 Y Ishizaka1 1Department of Intractable Diseases, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan; 2Nagoya Research Laboratory, Meito Sangyo Co. Ltd., Aichi, Japan; 3Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan; 4Inorganic Analysis Laboratories, Toray Research Center Inc., Shiga, Japan; 5R&D Division, Katayama Chemical Industries Co. Ltd, Osaka, Japan; 6Oral and Maxillofacial Radiology, Tokyo Medical and Dental University, Tokyo, Japan; 7Department of Molecular Medicine, Sapporo Medical University, Sapporo, Japan; 8Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, Osaka, Japan; 9Oral and Maxillofacial Radiology, The University of Tokushima Graduate School, Tokushima, Japan.

Recent advances in nanotechnology have resulted in the development of various nanosize devices applicable to cancer diagnosis and therapy. These nanodevices, when combined with specific tumor ligands, are potentially powerful tools for safe cancer therapy. Active targeting by monoclonal antibodies (mAbs) combined with MRI contrast agents, nanosize superparamagnetic iron oxide (SPIO) is a promising technology for MRI diagnosis. However, the clinical applicability of this technology has not been investigated using appropriate controls. In this study, we measured mAb-conjugated dextran-coated SPIO nanoparticles (CMDM) in vivo using clinical 1.5-Tesla MRI. We chose mAbs, which recognize native form of phosphatidic acid phosphatase 2a (PAP2a) that is highly expressed in pancreatic cancer cells. We compared PAP2a-positive and negative tumors derived from the same genetic background in each mouse and evaluated the tumor-targeting specificity of the mAb-CMDM conjugates. The system provided significant tumor-targeting specificity of the target tumor using clinical 1.5-Tesla MRI. Our observations provide clues for reliable active targeting using mAb-conjugated SPIO in clinical applications.

© 2012 Lippincott Williams & Wilkins, Inc.