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A 52-year-old man was initially diagnosed with an unresectable acinar cell carcinoma of the pancreas with liver metastasis and involvement of the superior mesenteric artery. After 5 courses of systemic chemotherapy(gemcitabine and S-1), the size of the pancreatic tumor had decreased from 31mm to 19mm and the liver metastasis had disappeared. We initiated chemoradiotherapy( CRT: S-1+56 Gy)for further local treatment. After CRT the size of the pancreatic tumor decreased to 13mm and his serum CA 19-9 level decreased from 677.2 U/mL to 38.1 U/mL. After 2months of S-1 administration, we performed subtotal stomach-preserving pancreaticoduodenectomy with D2 lymph node dissection. Histopathological examination revealed that most of the pancreatic cancer was replaced by fibrosis and only a few atypical epithelial cells existed. No cancer cells were found at the surgical margin. The patient remains alive without any signs of recurrence 59 months after the systemic chemotherapy and 51 months after the surgical resection.

It is important to minimize surgical invasiveness in the therapy of patients with hepatocellular carcinoma (HCC), and consequently laparoscopic hepatic resection is widely performed. However, most anatomical resections, except left lateral sectionectomy, remain difficult technically, and laparoscopy-assisted procedures have been introduced as an alternative approach because of the safety and curative success of the operation. We reported previously pure laparoscopic subsegmentectomy of the liver using puncture of the portal branch under percutaneous ultrasound (US) with artificial ascites. Herein, we describe pure anatomical laparoscopic segmentectomy using the puncture method with indocyanine green (ICG) injection under laparoscopic US.Pure laparoscopic segmentectomy was planned for 2 patients with HCC of the liver. Identification of the segment was performed by ICG injection for optical imaging using near-infrared fluorescence under laparoscopic US guidance.The procedures were completed successfully, and the postoperative courses were uneventful.Pure laparoscopic segmentectomy for HCC with a conventional puncture technique by ICG injection under laparoscopic US is considered to be a useful procedure featuring both low invasiveness and curative success.

During pancreaticoduodenectomy (PD), early ligation of critical vessels such as the inferior pancreaticoduodenal artery (IPDA) has been reported to reduce blood loss. Color Doppler flow imaging has become the useful diagnostic methods for the delineation of the anatomy. In this study, we assessed the utility of the intraoperative Doppler ultrasonography (Dop-US) guided vessel detection and tracking technique (Dop-Navi) for identifying critical arteries in order to reduce operative bleeding. Ninety patients who received PD for periampullary or pancreatic disease were enrolled. After 14 patients were excluded because of combined resection of portal vein or other organs, the remaining were assigned to 1 of 2 groups: patients for whom Dop-Navi was used (n = 37) and those for whom Dop-Navi was not used (n = 39; controls). We compared the ability of Dop-Navi to identify critical vessels to that of preoperative multi-detector computed tomography (MD-CT), using MD-CT data, as well as compared the perioperative status and postoperative outcome between the 2 patient groups. Intraoperative Dop-US was significantly superior to MD-CT in terms of identifying number of vessels and the ability to discriminate the IPDA from the superior mesenteric artery (SMA) based on blood flow velocity. The Dop-Navi patients had shorter operation times (531 min versus 577 min; no significance) and smaller bleeding volumes (1120 mL versus 1590 mL; P < 0.01) than the control patients without increasing postoperative complications. Intraoperative Dop-Navi method allows surgeons to clearly identify the IPDA during PD and to avoid injuries to major arteries.

Introduction Therapeutic strategies for pancreatic trauma vary greatly depending on its severity. Surgical intervention is recommended in cases of severe pancreatic injuries for which standard therapy is not advised. We present a two-step treatment method for severe pancreatic injury using an endoscopic ultrasound (EUS)-guided transgastric internal stent. Clinical case A 50 year-old male with blunt abdominal trauma sustained in a traffic accident was transported with vital signs indicating shock and CT findings of complete transection of the proximal pancreas and a huge haematoma. A life-saving primary emergency damage control operation was performed. A secondary EUS-guided transgastric internal stent was placed into the pancreatic fluid collection on post-operative day 8 (POD 8). The pancreatic juice secreted from the transected pancreatic tail eventually flowed along the internal stent and emptied completely into the stomach. The patient did not display prognostic symptoms at discharge. Discussion EUS-guided transgastric internal stenting is currently considered the first line of therapy for pancreatic pseudocysts. It is recommended that pseudocyst drainage occur at least four weeks or more after its formation. In this severe case of blunt pancreatic trauma, the primary damage control operation saved the patient's life. Following primary surgery, a secondary early operation involved insertion of an EUS-guided transgastric internal stent into the collection of pancreatic juice secreted from the transected pancreatic tail, which allowed complete recovery without surgical extraction or reconstruction of the pancreatic tail. Conclusion In cases of severe pancreatic trauma, practitioners should consider the value of early EUS-guided transgastric internal stenting.

Sugar chains play a significant role in various biological processes through sugar chain-protein and sugar chain-sugar chain interactions. To date, various tools for analyzing sugar chains biofunctions have been developed. Fluorescent nanoparticles (FNPs) functionalized with carbohydrate, such as quantum dots (QDs), are an attractive imaging tool for analyzing carbohydrate biofunctions in vitro and in vivo. Most FNPs, however, consist of highly toxic elements such as cadmium, tellurium, selenium, and so on, causing problems in long-term bioimaging because of their cytotoxicity. In this study, we developed cadmium-free sugar-chain-immobilized fluorescent nanoparticles (SFNPs) using ZnS-AgInS2 (ZAIS) solid solution nanoparticles (NPs) of low or negligible toxicity as core components, and investigated their bioavailability and cytotoxicity. SFNPs were prepared by mixing our originally developed sugar-chain-ligand conjugates with ZAIS/ZnS core/shell NPs. In binding experiments with lectin, the obtained ZAIS/ZnS SFNPs interacted with an appropriate lectin to give specific aggregates, and their binding interaction was visually and/or spectroscopically detected. In addition, these SFNPs were successfully utilized for cytometry analysis and cellular imaging in which the cell was found to possess different sugar-binding properties. The results of the cytotoxicity assay indicated that SFNPs containing ZAIS/ZnS have much lower toxicity than those containing cadmium. These data strongly suggest that our designed SFNPs can be widely utilized in various biosensing applications involved in carbohydrates.

Background Little is known about the effects of neoadjuvant therapy on outcomes in patients with pancreatic cancer. This study evaluated the effects of neoadjuvant therapy on resectability and perioperative outcomes. Methods A total of 992 patients were enrolled, with 971 deemed eligible. Of these, 582 had resectable tumors and 389 had borderline resectable tumors, and 388 patients received neoadjuvant therapy. Demographic characteristics and peri- and postoperative parameters were assessed by a questionnaire survey. Results The R0 rate was significantly higher in patients with resectable tumors who received neoadjuvant therapy than in those who underwent surgery first, but no significant difference was noted in patients with borderline resectable tumors. Operation time was significantly longer and blood loss was significantly greater in patients who received neoadjuvant therapy than in those who underwent surgery first, but there were no significant differences in specific complications and mortality rates. The node positivity rate was significantly lower in the neoadjuvant than in the surgery-first group, indicating that the former had significantly lower stage tumors. Conclusions Neoadjuvant therapy may not increase the mortality and morbidity rate and may be able to increase the chance for curative resection against resectable tumor.

Background Hypoxia is an important condition to promote angiogenesis that is essential to tumor progression, including pancreatic ductal adenocarcinoma (PDAC). We evaluated whether the immunohistochemistry for hypoxia inducible factor-1α (HIF-1α) was correlated with hepatic metastases in PDAC. Methods We examined the expression of HIF-1α, vascular endothelial growth factor-A (VEGF-A), thymidine phosphorylase (TP) and basic fibroblast growth factor (bFGF) in a total of 100 paraffin-embedded PDAC primary tumors using immunohistochemical staining, and assessed their clinicopathologicalcorrelations.Wedeterminedmicrovessel count (MVC) and apoptotic index (AI), and assessed their correlations with hepatic metastases. Student’s t-test, the Mann‐Whitney U-test, and Spearman correlation coefficients were used to validate the model, and regression analysis was used to test the model. Results Hypoxia inducible factor-1α expression induced the expression of multiple angiogenic factors, leading to a higher MVC and a lower AI. HIF-1α expression (P = 0.0087) and angiogenic factors (P = 0.0079) were significantly associated with not only the microvessel status (P = 0.022) but also the high incidence of hepatic metastasis (P = 0.02), resulting in the worse survival of PDAC patients (P < 0.05). Conclusions Hypoxia inducible factor-1α plays a pivotal role in hepatic metastasis through its association with the expression of angiogenic factors in PDAC patients. These results may contribute future therapeutic strategies to prevent pancreatic cancer metastasis.

A multicenter survey was conducted to explore the role of adjuvant surgery for initially unresectable pancreatic cancer with a long-term favorable response to non-surgical cancer treatments. Clinical data including overall survival were retrospectively compared between 58 initially unresectable pancreatic cancer patients who underwent adjuvant surgery with a favorable response to non-surgical cancer treatments over 6 months after the initial treatment and 101 patients who did not undergo adjuvant surgery because of either unchanged unresectability, a poor performance status, and/or the patients’ or surgeons’ wishes. Overall mortality and morbidity were 1.7 and 47 % in the adjuvant surgery group. The survival curve in the adjuvant surgery group was significantly better than in the control group (p

It is important to minimize surgical invasiveness in the therapy of patients with hepatocellular carcinoma (HCC) and, consequently, laparoscopic hepatic resection is widely performed. However, most anatomic resections, except left lateral sectionectomy, are still difficult technically and, as an alternative approach, laparoscopy-assisted procedures also have been introduced because of the safety and curative success of the operation. Herein, we describe pure laparoscopic subsegmentectomy of the liver using puncture of the portal branch under percutaneous ultrasound (US) with artificial ascites.Pure laparoscopic subsegmentectomy of segment 6 (S6) was planned for a patient with HCC of S6 of the liver. The identification of the segment was performed by dye injection under percutaneous US guidance with artificial ascites.The procedure was completed successfully in a minimally invasive manner with an operative time of 260 minutes and with intraoperative blood loss of 10 mL. The difference between the size of the resected specimen and that estimated by 3-dimensional computed tomography was very small. The postoperative course was uneventful and the patient was discharged 10 days after surgery.Pure laparoscopic subsegmentectomy for HCC with a conventional puncture technique under percutaneous US with artificial ascites is considered to be a useful procedure featuring both low invasiveness and curative success.

The clinical and biological characteristics of metachronous esophageal squamous cell cancer (ESCC) after gastrectomy for gastric cancer have yet to be sufficiently elucidated. The aim of the present study was to examine carcinogenesis in such patients. Subjects comprised 11 patients with metachronous carcinoma in whom ESCC occurred after gastric cancer (metachronous ESCC), 9 patients with simultaneously occurring gastric cancer and ESCC (simultaneous ESCC) and 52 patients with ESCC alone. We investigated the clinicopathological findings and biological properties using p53, p21 and cyclin D1 expression. The positive rate for the intraepithelial spread of tumor was higher for metachronous ESCC than for simultaneous ESCC (p

OBJECTIVE Tumor-associated macrophages (TAMs) are reportedly involved in lymphangiogenesis in primary tumors, playing a crucial role in lymphatic metastasis. Furthermore, nodal lymphangiogenesis precedes and promotes regional lymph node (RLN) metastasis. We investigated the relationship of M2-polarized TAM infiltration of the RLNs, nodal lymphangiogenesis, and occult nodal involvement in pN0 pancreatic cancer. METHODS Hematoxylin-eosin-stained primary tumor and regional LN specimens from 40 patients diagnosed with pN0 pancreatic cancer according to the pathological TNM classification were assessed. To evaluate lymphangiogenesis, lymphatic vessel density was measured by using D2-40 antibody. CD163 and cytokeratin AE1/AE3 antibodies were used to detect M2-polarized TAMs and isolated tumor cells in the RLNs, respectively. RESULTS The nodal lymphatic vessel density had a strong association with the M2-polarized TAM density in the RLNs (P < 0.0001). Most of these TAMs expressed vascular endothelial growth factor C. Furthermore, in the RLNs, the M2-polarized TAM density was significantly associated with the incidence of isolated tumor cells (P = 0.0477). CONCLUSIONS M2-polarized TAM infiltration of RLNs is significantly associated with nodal lymphangiogenesis and occult nodal involvement in pN0 pancreatic cancer. Node-infiltrating M2-polarized TAMs may facilitate nodal lymphangiogenesis via the production of vascular endothelial growth factor C and thus promote RLN metastasis.

Background: Surgical radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) is associated with superior oncological outcome in comparison with percutaneous RFA. The present study aimed to retrospectively evaluate the relative perioperative safety and postoperative outcome of the laparoscopic or thoracoscopic approach versus the open approach to RFA for small HCC., Methods: A retrospective analysis was performed in 55 consecutive patients who underwent open (n = 32) or laparoscopic/thoracoscopic (LTS) RFA (n = 23) for primary unresectable HCC between January 2005 and December 2010. Baseline characteristics, survival/recurrence rates, and complications after treatment were compared between the two groups., Results: There was a trend showing that LTS RFA was performed for tumors located in the anterior segment (e.g., segments III, V, VIII). The LTS RFA group had a significantly lower intraoperative blood loss, shorter operative time, and shorter postoperative hospital stay, compared with the open RFA group. No major postoperative complications occurred in patients who underwent LTS RFA. No significant differences in overall survival, recurrence-free survival and local recurrence rates were observed between the two groups., Conclusions: In consideration of operative invasiveness and postoperative recovery, LTS RFA is superior to the open approach in patients with small HCC. Moreover, the surgical outcome did not differ between the two approaches. Laparoscopic/thorascopic RFA can be considered to be a useful procedure for ablation therapy.

Background/aim Maternal embryonic leucine zipper kinase (MELK) is categorized as a member of AMP-activated protein kinase families. Various MELK-associated cellular and biological processes affect multiple stages of tumorigenesis. The aim of the present study was to clarify the relationship between MELK expression and hepatocellular carcinoma (HCC) clinicopathological features. Materials and methods In thirty conserved frozen primary HCC and non-HCC samples MELK mRNA expression was examined by quantitative real-time polymerase chain reaction (PCR). Results HCC tissues exhibited significantly higher expression levels compared to non-cancerous tissues. MELK expression had a statistically parallel correlation between tumor diameter and protein induced by vitamin K absence or antagonist II (PIVKA-II). The overall survival (OS) and recurrence-free survival (RFS) of the low MELK mRNA expression group was significantly longer than that of the high MELK mRNA expression group. Conclusion MELK expression in HCC is extremely intense compared to its expression reported in other types of cancer. MELK could be a promising effective tumor marker of HCC and further consideration is needed.

Objectives The aim of the present study was to investigate the effectiveness of serum carbohydrate antigen (CA) 19.9 and duke pancreatic monoclonal antigen type 2 (DUPAN-2) levels in the prediction of early hematogenous metastases and as indicators of neoadjuvant therapy in patients with pancreatic ductal adenocarcinoma (PDAC). Methods Of the 293 enrolled PDAC patients, 61 had hematogenous metastases at the initial evaluation. One hundred and twenty patients without metastases underwent surgical resection. Of the 120 patients who underwent surgical resection, 45 underwent preoperative treatment and 29 developed early hematogenous metastases within 1 year after the surgery. In patients who underwent preoperative therapy, serum CA 19.9 and DUPAN-2 levels were measured within 2 weeks before the preoperative therapy and the subsequent surgery. Results The elevated serum CA 19.9 and DUPAN-2 levels were significantly associated with hematogenous metastasis at initial evaluation and early hematogenous metastasis after surgery. The rate of early hematogenous metastasis and overall survival (OS) in patients with high CA 19.9 and/or high DUPAN-2 (CA 19.9 > 200 U/mL and/or DUPAN-2 >300 U/mL) were 46.3% and 18 months, respectively, whereas the metastatic rate and OS in patients with low CA 19.9 and DUPAN-2 were 12.7% and 37.5 months, respectively. Furthermore, in patients with high CA 19.9 and/or high DUPAN-2, preoperative therapy significantly reduced the rate of early hematogenous metastasis and prolonged the OS. Conclusions Serum CA 19.9 and DUPAN-2 levels are useful predictors of early hematogenous metastasis and indicators for effectiveness of neoadjuvant therapy in PDAC patients.

Pancreatic neuroendocrine tumors (PNETs) are a rare type of malignancy with a prognosis that is relatively good, compared with that of pancreatic adenocarcinoma. However, a number of patients with PNETs have distant metastasis and a less favorable prognosis. Epithelial-mesenchymal transition (EMT) is essential for tumor progression and metastasis. Snail and E-cadherin serve key roles in the process of EMT in numerous tumor types, including gastric and pancreatic adenocarcinoma. However, the role of EMT in PNETs remains unclear. The aim of the present study was to investigate the significance of Snail and E-cadherin expression in PNETs. Tissue samples were obtained from 40 resected PNETs. The expression of Snail and E-cadherin was evaluated in the primary tumors using immunohistochemical staining. The association between protein expression and patient clinicopathological features was then analyzed. High and low Snail expression levels were observed in 11 (27.5%) and 29 (72.5%) patients, respectively. Preserved and reduced E-cadherin expression was observed in 19 (47.5%) and 21 (52.5%) patients, respectively. Patients with low Snail expression and preserved E-cadherin expression had a significantly lower risk of vascular invasion, lymphatic invasion, lymph node metastasis and liver metastasis and a lower WHO classification, as compared with the group that included patients with high Snail and reduced E-cadherin, high Snail and preserved E-cadherin, and low Snail and reduced E-cadherin expression. In addition, the patients with low Snail expression levels and preserved E-cadherin expression had more a favorable prognosis compared with the other group. The present study indicates that EMT serves an important role in tumor progression in PNETs. Immunohistochemical evaluation of Snail and E-cadherin is useful for predicting the risk of vessel invasion and metastasis in PNETs.

Background and Objecties Phenotypic plasticity of cancer cells via epithelial–mesenchymal transition (EMT) and mesenchymal–epithelial transition (MET) is essential for tumor progression and metastasis. Methods Tissue samples were obtained from 76 pancreatic head cancers. We assessed the expression of E-cadherin, vimentin, ZEB-1, and ZEB-2 by immunohistochemical and immunofluorescence staining. Next, 147 metastatic lymph nodes from 45 pancreatic cancers with low expression of E-cadherin were obtained and divided into two categories according to the maximum diameter of the metastases: 2 mm or more and less than 2 mm. Results High expressions of ZEB-1 and ZEB-2 in the primary tumors were significantly associated with repression of E-cadherin (P = 0.0007), and poorer prognosis (P = 0.0322). Forty-three (29.3%) of the 147 metastatic tumors from pancreatic cancers with low expression of E-cadherin showed high E-cadherin expression. Cancer cells in the larger metastases showed high expression of E-cadherin (P = 0.0061) and low expression of ZEB-1 (P = 0.0170) and ZEB-2 (P = 0.0036) compared with those in the smaller metastases. Conclusions In primary pancreatic tumors and metastatic lymph nodes, high and low expression of ZEB-1 and ZEB-2 was associated with mesenchymal and epithelial phenotype of cancer cells, respectively. J. Surg. Oncol. 2012; 105:655–661. © 2011 Wiley Periodicals, Inc.

Purpose As laparoscopy can detect imaging-occult metastatic lesions, it has been validated as a means of improving the assessment of tumor staging. Although controversy exists as to whether the procedure should be used routinely or selectively in pancreatic cancer patients, patients considered for treatment protocols for locally unresectable pancreatic cancer should be staged laparoscopically before initiation of therapy. We evaluate the feasibility and safety of advanced staging laparoscopy including peritoneal lavage cytology, laparoscopic ultrasound sonography (LUS), and LUS-guided biopsy through a single incision for locally advanced pancreatic cancer. Methods Staging laparoscopy was performed in 44 patients with pancreatic cancer for deciding on treatment strategy. Our procedures included extensive peritoneal lavage of abdominal cavity for cytology, LUS for small metastasis detection, and tissue sample excision including LUS-guided biopsy. Eleven consecutive patients were treated with a single-incision staging laparoscopy approach (SI-SL group). The clinical parameters were compared between the SI-SL group and the multi-incision staging laparoscopy group (multi-incision group). Results The mean operating time was longer and bleeding volume was less in the SI-SL group, although the differences were without statistical significance. The conversion rates to laparotomy were 9% in the SI-SL group and 30% in the multi-incision group. There were no severe postoperative complications. LUS-guided biopsy revealed malignancy for 3 patients in the SI-SL group. Conclusions Advanced SI-SL is a feasible and safe alternative to the multi-incision approach for pancreatic cancer.

Pancreatic fistula still remains a persistent problem after pancreaticoduodenectomy. We have devised a pancreas-transfixing suture method of pancreaticogastrostomy with duct-to-mucosa anastomosis. This technique is simple and reduces the risk of pancreatic leakage by decreasing the risk of suture injury of the pancreas and by embedding the transected stump into the wall of the stomach. This novel technique of pancreaticogastrostomy is an effective reconstructive procedure following pancreaticoduodenectomy, especially for patients with a soft and fragile pancreas. Electronic supplementary material The online version of this article (doi:10.1007/s00534-011-0469-3) contains supplementary material, which is available to authorized users.

Background Significance and timing of drain removal after pancreatic surgery remain unclear. The aim of this study was to identify optimal indicators to predict severe intra-abdominal complications and determine the appropriate timing of prophylactic drain removal after pancreatoduodenectomy. Materials and methods This study included 151 consecutive patients who underwent pancreatoduodenectomy. We investigated associations between postoperative intra-abdominal complications, drain amylase levels, and duration of postoperative inflammatory response. Results Patients who developed severe intra-abdominal complications showed re-elevation of drain amylase levels after postoperative d 3 and prolonged postoperative inflammatory response, which were most pronounced in patients with severe pancreatic fistula and intra-abdominal abscess, respectively. In contrast, patients with a steady decline in drain amylase levels and short-term postoperative inflammatory response did not develop severe complications, and safe drain removal was possible even when the drain amylase value was more than three times the upper limit of normal serum amylase. Conclusion A combination of trends in the drain amylase level and duration of the inflammatory response in the postoperative period may be optimal indicators for early detection of severe intra-abdominal complications and appropriate timing of drain removal.

Background Bone morphogenetic proteins (BMPs) are secreted signaling molecules belonging to the transforming growth factor-β (TGF-β) superfamily of growth factors. Recent studies have shown that the influence of the expression of BMP7 was altered in several tumors. The purpose of the current study was to examine the expression of BMP7 in esophageal squamous cell carcinoma and to clarify the clinical impact of BMP7 expression in esophageal squamous cell carcinoma (ESCC). Methods A total of 180 patients with ESCC who underwent surgical resection from 1991 to 2004 were eligible for this study. The expression of BMP7 in esophageal tumor tissues was examined immunohistochemically. Results BMP7 expression was found in the cytoplasm of cancer cells. BMP7 positivity was observed in 61.7% of tumors. The BMP7-positive group had deeper progression, more advanced stages, and greater venous invasion than those without BMP7 expression (p

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 maximum tolerated dose and dose-limiting toxicity in patients with unresectable pancreatic cancer. The recommended dose of S-1 for phase II trials of chemoradiotherapy was determined as 80 mg/m(2)/day given on days 1-21 of a 28-day cycle. This phase II study was conducted to further evaluate the efficacy and toxicity of radiotherapy combined with S-1 (UMIN000004794).Eligible patients had locally advanced and unresectable pancreatic cancer without distant metastases, an Eastern Cooperative Oncology Group 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/m(2)/day twice daily on days 1-21. 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.Fifty patients were enrolled in this phase II study. Median follow-up was 14.6 months (range 5.4-58.9 months). 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 response according to the Response Evaluation Criteria in Solid Tumours criteria was partial response in 15 patients (30%) (95% confidence interval (CI), 18-45%), stable disease in 23 (46%), and progressive disease in 12 (24%). Median progression-free survival and median overall survival were 6.7 months (95% CI, 4.7-11.2 months) and 14.3 months (95% CI, 10.8-20.8 months), respectively. Survival rates at 1 and 2 years were 62 and 27%, respectively.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.

Background The roles of infiltrating macrophages within the tumor microenvironment are complex because of their functional variety. The aim of this study is to examine the role and prognostic significance of tumor-associated macrophages (TAMs) that have an M2 polarized function in pancreatic cancer. Materials and Methods Formalin-fixed, paraffin-embedded blocks were obtained from 76 patients with pancreatic head cancer. All patients underwent macroscopic curative resection. We assessed the number of infiltrating macrophages within the tumor invasive front by not only CD68 but also by CD163 and CD204, which are specific receptors on M2-polarized macrophages. Furthermore, to evaluate lymphangiogenesis, we measured the density of lymphatic vessels in the tumor invasive front by using D2-40. Results High incidence of lymph node metastasis was shown in cases with a high number of CD163- or CD204-positive macrophages. Significantly increased lymphatic vessel density (LVD) was shown in cases with lymph node metastasis compared with cases without lymph node metastasis (P = 0.0094). Significantly increased LVD (P = 0.0175) and a poor prognosis (P = 0.0171) were shown in cases with a high number of macrophages that express CD163 or CD204, however, there was no significant difference according to the number of CD68-positive macrophages. Conclusions M2-polarized TAMs in the invasive front of pancreatic cancer are associated with a poor prognosis due to accelerated lymphatic metastasis, and inhibition of the functional interaction between M2-polarized TAMs and tumor cells may improve the prognosis.

It is important to predict the development of clinically relevant pancreatic fistula (grade B/C) in the early period after pancreaticoduodenectomy (PD). This study has been carried out as a project study of the Japanese Society of Hepato-Biliary-Pancreatic Surgery (JSHPBS) to evaluate the predictive factors associated with clinically relevant pancreatic fistula (grade B/C).The data of 1,239 patients from 11 medical institutions who had undergone PD between July 2005 and June 2009 were retrospectively analyzed to review patient characteristics and perioperative and postoperative parameters.A drain amylase level4,000 IU/L on postoperative day (POD) 1 was proposed as the cut-off level to predict clinical relevant pancreatic fistula by the receiver operating characteristic (ROC) curve. The sensitivity, specificity, and accuracy of this cut-off level were 62.2, 89.0, and 84.8%, respectively. A multivariate logistic regression analysis revealed that male [odds ratio (OR) 1.7, P = 0.039], intraoperative bleeding1,000 ml (OR 2.5, P = 0.001), soft pancreas (OR 2.7, P = 0.001), and drain amylase level on POD 14,000 IU/L (OR 8.6, P 0.001) were the significant predictive factors for clinical pancreatic fistula.The four predictive risk factors identified here can provide useful information useful for tailoring postoperative management of clinically relevant pancreatic fistula (grade B/C).

Recent studies have shown that intraoperative blood loss and blood transfusions promote postoperative recurrence of hepatocellular carcinoma (HCC). Hyperbaric oxygen therapy (HBOT) is a specific method of oxygen administration, which is independent of fluid therapy or blood transfusion. The aim of the present study was to assess the usefulness of acute HBOT after liver resection for patients with HCC in order to minimize the requirement for perioperative blood transfusions. Forty-one consecutive patients who showed Hb level < 9.0 mg/dl at the end of hepatic resection were randomly assigned to a control group (n = 21) or an HBOT group (n = 20). HBOT at 2.0 atm. with inhalation of 100% oxygen for a duration of 60 min was performed at 3, 24, and/or 48 h after the end of the hepatectomy. Regarding postoperative hepatic hemodynamics, liver function tests, and outcome data, prospective comparisons were completed in both groups. The two groups of patients were similar with respect to results from preoperative assessments. In six patients from the HBOT group, who experienced intraoperative major bleeding or showed fatal hepatic hypoxia (ShvO2 < 50%), the levels of ShvO2 and serum lactate were significantly improved after HBOT. When compared to the control group, the HBOT group showed better changes of ShvO2, serum lactate, and bilirubin levels for the first 3 postoperative days following surgery. Additionally, the HBOT group did not experience any fatal complications and had a lower incidence of postoperative hyperbilirubinemia than the control group. We also observed that postoperative NK cell activity and cancer-free survival in the HBOT group tended to be better than in the control group, although the differences did not reach significance. These results suggest that acute HBOT after hepatectomy, aimed at reducing perioperative erythrocyte transfusions, may be employed for overcoming deficiencies in systemic and hepatic oxygen supply and thus diminishing postoperative complications. As an added benefit, such therapy may affect postoperative immunological responses and long-term survival after liver resection in HCC patients. Further analyses of the use of HBOT is warranted to confirm surgical outcome data and to assess the economic impact on healthcare costs.

Background and Objectives The aim of this study was to investigate the significance of lymphangiogenesis in primary pancreatic tumors and in draining lymph nodes during lymphatic metastasis of pancreatic head cancers. Methods Specimens were obtained from 70 patients. To evaluate lymphangiogenesis, we measured lymphatic vessel density (LVD) using D2-40 antibody in the primary tumors and in the draining lymph nodes. AE1/AE3 antibody was used to detect tiny, histologically negative metastases in lymph nodes. Results Patients with high LVD of primary tumors had significantly higher incidence of node metastasis (P = 0.0006) and lower postoperative survival rate (P = 0.0066) than those with low LVD. Intranodal LVDs increased with increasing size of the intranodal metastases. The LVDs of non-metastatic nodes in patients with node metastasis were also significantly higher than those of non-metastatic nodes in patients without node metastasis (P

Background: Several tumor-suppressor genes, such as 53-kDa protein (p53), are inactivated in some pancreatic cancers. The lack of a functional p53 has been proposed to be a component of resistance to chemotherapy, resulting in the inhibition of apoptosis. Therefore, reintroduction of wild-type p53 is a commonly used gene therapy strategy for the treatment of various types of cancer, including pancreatic cancer. Objective: The aim of this study was to examine the ability of the histone deacetylase inhibitor, sodium butyrate (NaB), to modulate the expression of p53. Methods: Five human pancreatic carcinoma cell lines (SW-1990, BxPC-3, PANC-1, MIA PaCa-2, JHP-1) were utilized. Two of the cell lines (SW-1990 and JHP-1) lacked p53 expression, as determined by Western blot analysis, and were investigated further. Expression of p53 was determined by densitometry of all bands present in the Western blot. Drug sensitivity was measured with a tetrazolium-based assay by exposing the cells to graded concentrations of NaB and/or anticancer drugs (cisplatin, fluorouracil, SN-38, and paclitaxel). Apoptosis was observed using gel electrophoresis. Results: In the SW-1990 and JHP-1 cell lines, use of 1 mM NaB was found to induce histone acetylation and p53 expression compared with those not treated with NaB (P = 0.01 and P = 0.018, respectively). Sensitivity to cisplatin (P = 0.021), fluorouracil (P = 0.046), and SN-38 (P = 0.039) was significantly enhanced by NaB treatment compared with nontreatment. However, sensitivity to paclitaxel was not significantly different between untreated and NaB-treated cells. A higher frequency of apoptosis was observed in NaB-treated cells compared with that of control cells. Conclusion: This in vitro study found that NaB induced p53 expression in 2 pancreatic cancer cell lines (SW-1990 and JHP-1). Moreover, NaB acted on a biochemical modulator for antieuplastic therapy. Future research is necessary to assess the value of these findings.

Surgery remains difficult for hepatocellular carcinoma (HCC) originating in the caudate lobe. Our objective was to evaluate the safety and problems associated with caudate lobectomy combined with other types of hepatectomy. We performed caudate resection for HCC in 12 patients. Clinical and operative characteristics and survival were analyzed. Tumors were located in the Spiegel lobe in three patients, the caudate process in six, and the paracaval portion in three. The procedure performed most was isolated partial caudate lobe resection (six patients). Three patients underwent partial caudate lobe resection combined with other hepatectomy, and the remainder underwent total caudate lobe resection combined with other hepatectomy. Tumors of the patients who underwent combined total caudate lobe resection were mainly in the paracaval portion. The median operating time for the six patients who underwent combined resection was 400 min, and their median intraoperative blood loss was 1,683 ml. There were no postoperative complications in patients who underwent combined total caudate lobe resection, except one case of total resection combined with central bisegmentectomy. In that case, the remaining right posterior sector was twisted after liver extraction, causing blockage of the outflow of the right hepatic vein. The overall and recurrence-free survival rates did not differ between the isolated and combined resection groups. For removal of HCC located in the caudate lobe, especially the paracaval portion, partial or total caudate lobe resection with other types of hepatectomy contributes to safe, curative surgery if the liver functional reserve and complications associated with surgery are well understood.

Background: Recent studies have suggested that CD44 and/or CD133 expressing pancreatic cancer cells have potential abilities of self-renewal, tumorigenesis and tumor metastasis. The aim of this study was to investigate whether CD44 and CD133 expressions in primary tumor cells correlate to the survival and clinicopathological findings of pancre- atic cancer patients. Methods: Pancreatic head carcinoma specimens from 80 patients who underwent surgical resection were immunohisto- chemically assessed for CD44 and CD133 expressions. Results: Of the 80 specimens, 34 (42.5 %) and 48 (60%) specimens were immunohistochemically positive for CD44 and CD133 expression, respectively. CD44 was expressed on the cell surface and CD133 expression was observed in the cy- toplasm of the positive cells, which were located at the peripheral adenocarcinoma glandular structures. There was no sig- nificant difference in the 5-year survival rate of patients based on CD44 expression, but the 5-year survival rate of CD133-positive patients was significantly lower than that of CD133-negative patients (P = 0.0002). Multivariate analysis revealed that CD44-positive and CD133-negative expression was a favorable prognostic indicator (P = 0.0424). Conclusions: CD44 and CD133 expressions are association with survival and malignant behavior in pancreatic cancer pa- tients.

粘液産生胆管腫瘍の生物学的特徴に関してはまだ不明な点が多い．今回，我々は粘液産生胆管癌に対して，計5回の治療を施行し，約11年間の長期経過を観察している症例に関して，文献的考察を加えて報告する．症例は67歳の男性で，最初にB4胆管を主座とする粘液産生胆管腫瘍を指摘され，肝内側区切除術＋左尾状葉切除術を施行した．病理組織学的検査では深達度mの粘液産生胆管癌であった．半年後に右尾状葉枝根部の腫瘍に対してYAGレーザー焼灼を施行し，さらにその半年後に総肝管の腫瘍に対して，総肝管切開腫瘍摘出術を施行した．2年4か月後に右肝管の腫瘍を指摘され，肝外胆管切除術＋胆管空腸吻合術を施行し，その2か月後に肝後区域枝の腫瘍に対してYAGレーザー焼灼施行した．最終治療から7年後の現在まで再発を認めておらず，厳重な経過観察と根気強い外科的治療の繰り返しで長期生存を得ることが可能であることが示唆された．

症例は74歳，男性．平成17年8月より全身の皮疹が出現し，近医にて加療されていたが軽快再燃を繰り返すため，原因検索目的に平成19年6月当院皮膚科紹介受診．皮疹は多形紅斑と診断．原因として感染症・薬剤アレルギー等は否定された．更なる精査目的行った腹部CT検査で，脾臓に腫瘍性病変を指摘されたため，当科紹介となった．Gaシンチグラフィー，PETにて同部位に集積を認めた．また，血液生化学検査において，可溶性IL-2レセプター抗体・チミジンキナーゼのいずれも陽性．これらの所見より，脾原発悪性リンパ腫と診断し，同年9月腹腔鏡下脾臓摘出術施行．術後1日目より皮疹の軽快を認め，術後3日目には掻痒感が消失，その後多形紅斑は消失した．脾臓の病理診断はdiffuse large B cell lymphomaであった．術後は補助化学療法を施行し現在術後10カ月無再発生存中である．本症例では多形紅斑と脾原発悪性リンパ腫との因果関係が示唆され，脾摘が多形紅斑の治療に極めて有効であった．

動門脈瘻を伴う肝内動脈瘤の1例を経験したので報告する．症例は57歳の女性で，C型肝炎ウイルスによる肝硬変に発生した肝細胞癌の精査中に肝動脈瘤を診断された．血管造影検査にて左胃動脈より起始する副左肝動脈に径約3 cmの動脈瘤を認め，動門脈瘻を伴っていた．塞栓術による治療を検討したが，側副血行路と動門脈瘻があり，塞栓術単独での根治は困難と考えられたため，肝外側区域切除術を行った．病理組織学的には真性動脈瘤であった．本症は比較的まれな疾患で，破裂例の死亡率は高いが，近年では未破裂の肝動脈瘤が診断されることが増加している．根治には動脈瘤への完全な血流遮断が必要であるが，肝内動脈瘤では側副血行路の存在が問題となるため，慎重な検討が必要である．

症例は41歳の男性で，1995年4月に下部胆管癌に対して幽門輪温存膵頭十二指腸切除術を施行した．切除標本の病理組織学的診断は中分化型腺癌，ly1，v1，pn1，pPanc1，pDu2，pN1，pHM0，pEM0のstage IIIであった．術後8か月の腹部CTにて肝S6に径1.6 cm大の転移を認め，Methotrexate（以下，MTX）と5-fluorouracil（以下，5-FU）による全身化学療法を5クール施行した．径3.8 cmへ肝転移巣の増大を認めたため，1996年4月肝部分切除を施行した．術後MTXと5-FU，Cisplatin（以下，CDDP）による予防肝動注化学療法を1年間施行した．さらに，2002年2月まで全身化学療法を行った．肝転移再発切除後12年経過した現在無再発生存中である．肉眼的に完全切除の可能性のある症例に対しては，積極的に切除し，術後肝動注療法などの集学治療を行うことが長期生存につながる可能性が示唆された．

症例は54歳，女性．腹部CTで偶然発見された膵体部の内分泌腫瘍の診断で当科紹介．入院後精査にて，転移性肝腫瘍を伴っていたが，膵体部の腫瘍より尾側の膵に実質組織や主膵管を認めず，膵体尾部欠損合併膵内分泌腫瘍の診断．治療方針として，膵腫瘍は切除を行い，転移性肝腫瘍は肝動注療法を中心とした化学療法を行う方針とした．手術所見では，膵体部に腫瘍を認め，それより尾側は分厚い脂肪組織に置換し，膵実質・主膵管を認めなかった．膵中央切除術を行い，膵の消化管再建は行わなかった．組織学的には，高分化型神経内分泌癌であり，膵腫瘍の尾側は，ほぼ脂肪置換しており，ラ島を散在性に認めたが，膵外分泌細胞は認めなかった．術後の膵内分泌機能は良好で，耐糖能異常を認めなかった．膵体尾部脂肪置換を合併した膵内分泌腫瘍に対して膵中央切除術を行い，尾側膵の消化管への再建を行わなかった極めて稀な症例を経験したので報告する．

Lymphatic dissemination is one of the most important metastatic routes for pancreatic cancer. According to previous reports, the presence of histologically positive nodal metastases is an important prognostic factor in patients with pancreatic cancer. However, outcome of patients, even those without nodal metastases, who underwent a histologically curative operation for pancreatic cancer is significantly worse than expected, indicating that the presence of immunohistochemically positive nodal micrometastases is an unfavorable prognostic factor in these patients.

Although CD133 has been shown to be a marker for cancer stem cells in various tumours, its expression in pancreatic cancer has not yet been clinically reported. In this study, we investigated the relationship between CD133 expression and clinicopathological factors in pancreatic cancer. Pancreatic head carcinoma specimens from 80 patients who underwent surgical resection were immunohistochemically assessed for CD133, vascular endothelial growth factor (VEGF)-C, CXCR4, CD34, Ki-67, and cytokeratin (CK) expressions. Sixty percentage (48/80) of specimens were CD133-positive, with less than 15% cells per specimen expressing the marker. CD133-positive cells were found at the peripheral site of adenocarcinoma glandular structures and were negative for CK. There was a significant correlation between CD133 expression and clinicopathological factors, including histological type, lymphatic invasion, and lymph node metastasis (P=0.0215, 0.0023, and 0.0024, respectively). Vascular endothelial growth factor-C expression was also significantly correlated with CD133 expression (P=0.0002). Consequently, the 5-year survival rate of CD133-positive patients was significantly lower than that of CD133-negative patients (P=0.0002) and multivariate analysis revealed that CD133 expression was an independent prognostic factor (P=0.0103). These results suggest that CD133 expression in pancreatic cancer was significantly associated with lymphatic metastasis, VEGF-C expression, and prognosis.

Midkine (MK) is a heparin-binding growth factor and a product of a retinoic acid-responsive gene. Midkine is overexpressed in many carcinomas and thought to play an important role in carcinogenesis. However, no studies have been focussed on the role of MK in pancreatic carcinoma. This study sought to evaluate the clinical significance of MK expression in pancreatic head carcinoma, including the relationship between immunohistochemical expression and clinicopathologic factors such as prognosis. Immunohistochemical expression of MK and CD34 was evaluated in pancreatic head carcinoma specimens from 75 patients who underwent surgical resection. Midkine was expressed in 53.3% of patients. Midkine expression was significantly correlated with venous invasion, microvessel density, and liver metastasis (P=0.0063, 0.0025, and 0.0153, respectively). The 5-year survival rate was significantly lower for patients positive for MK vs patients negative for MK (P=0.0073). Multivariate analysis revealed that MK expression was an independent prognostic factor (P=0.0033). This is the first report of an association between MK expression and pancreatic head carcinoma. Midkine may play an important role in the progression of pancreatic head carcinoma, and evaluation of MK expression is useful for predicting malignant properties of pancreatic head carcinoma.