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Chemotherapy for pancreatic cancer has diversified following the addition of more treatment regimens; however, in spite of this, pancreatic cancer remains a fatal disease. Preoperative (neoadjuvant) chemotherapy (NAC) or neoadjuvant chemoradiation therapy (NACRT) has been developed and implemented. For patients with borderline resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC), a number of clinical trials have been conducted; NACRT was demonstrated to improve resectability, R0 resection rate, overall survival rate, disease-free survival rate and even an LAPC and BRPC survival advantage over NAC. However, from the knowledge obtained from resected specimens following preoperative treatment, residual pancreatic cancer tissues following NAC are rich in chemoresistant cancer stem-like cells and epithelial-mesenchymal transition (EMT) markers. Conversely, metformin, angiotensin receptor blocker, statins and low-dose paclitaxel are well-known as drugs that inhibit EMT, which is associated with cancer stem cell-like characteristics. Although clinical effectiveness is unlikely to be achieved using one of these as an anticancer agent, it is reasonable to use these drugs for patients with comorbidities in the treatment of pancreatic cancer. Furthermore, gemcitabine (GEM) affects antitumor immunity by stimulating the expression of major histocompatibility complex class I-related chain A on the surface of cancer cells to enhance the cytotoxicity of natural killer cells. Considering EMT and antitumor immunity, there is a possibility that GEM and nanoparticle albumin-bound paclitaxel therapy is the most suitable regimen for treating pancreatic cancer. However, even as preoperative treatment progresses, R0 resection is the most important factor for the long-term survival of pancreatic cancer patients. © 2017, Spandidos Publications. All rights reserved., Embargo Period 6 months

Taxanes, paclitaxel and docetaxel (DTX) are anticancer agents that exhibit cytotoxicity by inhibiting microtubule polymerization. They enhance the radiosensitivity of various cancers by blocking the cell cycle in the most radiosensitive G2/M phase. Recently, taxanes have been reported to have different mechanisms of action depending on dose intensity. However, the mechanism of the radio-enhancing effect of DTX in relation to the drug dose intensity is not clearly understood. In the present study, we experimentally investigated the radio-enhancing effects of various concentrations of DTX against esophageal squamous cell cancer (ESCC); KES cells were used for in vitro confirmation of the effective administration schedule for DTX in chemoradiotherapy involving ESCC. DTX enhanced radiation cell killing in a concentration-dependent manner in KES cells. High cytotoxic concentrations (>10 nM) of DTX strongly enhanced radiosensitivity. Low concentrations (

We investigated the effect of gemcitabine (GEM), a key drug for pancreatic cancer treatment, on the expression of cell surface MICA/B in pancreatic cancer cells and resulting cytotoxicity of γδ T cells. We assessed the effect of GEM on the upregulation of cell surface MICA/B expression by flow cytometry, utilizing six pancreatic cancer cell lines. MICA and CD16 expressions from resected pancreatic cancer patient specimens, which received neoadjuvant chemotherapy (NAC) with GEM, were analyzed by immunohistochemistry. GEM could increase MICA/B expression on cell surface in pancreatic cancer cell lines (in 2 of 6 cell lines). This effect was most effectively at concentration not affecting cell growth of GEM (0.001 μM), because MICA/B negative population was appeared at concentration at cytostatic and cytotoxic effect to cell growth (0.1 and 10 μM). The cytotoxic activity of γδ T cells against PANC-1 was detected and functions through interactions between NKG2D and MICA/B. However, the enhancement of NKG2D-dependent cytotoxicity with increased MICA/B expression, by GEM treatment, was not observed. In addition, soluble MIC molecules were released from pancreatic cancer cell lines in culture supernatant with GEM treatment. Immunohistochemical staining demonstrated that MICA expression in tumor cells and CD16 positive cells surrounding tumors were significantly higher in the NAC group compared to that of the control group. There was a significant correlation between NAC and MICA expression, as well as NAC and CD16 positive cell expression. The present results indicate that low-dose GEM-induced MICA/B expression enhances innate immune function rather than cytotoxicity in pancreatic cancer. In addition, our result suggests that the inhibition of cleavage and release of MIC molecules from the tumor surface could potentially improve NKG2D-dependent cytotoxicity.

Breast cancer encompasses a heterogeneous group of diseases at the molecular level. It is known that chemo-sensitivity of breast cancer depends on its molecular subtype. We investigated the growth inhibitory effect of valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, and the mechanism of this inhibition on four breast cancer cell lines with different molecular subtypes. The growth inhibitory effect of VPA in the four different breast cancer cell lines was investigated. The alteration of levels of p21 WAF1, cleaved caspase-3, acetylated Heat shock protein (Hsp) 90, acetylated Hsp70, and acetylated α-tubulin by VPA was examined in VPA-sensitive, human epidermal receptor 2 (HER2)-overexpressing SKBR3 cells. The cell growth inhibition of breast cancer cell lines was dependent on the dose and exposure time of VPA. The cell growth of HER2-overexpressing SKBR3 cell line was inhibited by VPA to a much greater degree than other cell lines studied. In SKBR3 cell line, VPA upregulated expression of p21 WAF1 and cleaved caspase-3 in the early phase. VPA markedly increased Hsp70 acetylation in a time-dependent manner but did not increase Hsp90 acetylation. Our data demonstrated that VPA inhibited cell proliferation and induced cell cycle arrest and apoptosis of HER2-overexpressing breast cancer cells. This anti-proliferation effect might be the direct function of VPA as an HDAC inhibitor. We propose an alternative mechanism whereby acetylation of Hsp70 disrupts the function of Hsp90 and leads to downregulation of its client proteins, including HER2 that might be the indirect function of VPA, in the sense that non-histone proteins are acetylated.

The use of hepatectomy for the treatment of metastatic liver tumors (MLTs) arising from squamous cell carcinomas (SCCs) has not been well investigated. The use of hepatectomy for MLTs from SCCs, especially in advanced cases, needs further investigation. Three patients with SCC-derived MLTs underwent hepatectomy. On clinicopathologic examination, the primary lesions were found to be oral cancer, lung cancer, and oropharyngeal cancer, with synchronous metastasis in 2 patients and metachronous metastasis in 1 patient. One case also involved adrenal metastasis, and another involved direct invasion of the diaphragm and lung. In all cases, surgery was performed to eliminate any residual tumor tissue. After the hepatectomy, 1 patient died (22 months postoperatively) of an unrelated disease, 1 remains alive (30 months postoperatively) with a recurrent tumor, and 1 remains alive (60 months postoperatively) without recurrence. For the patients with solitary MLT derived from SCC, hepatectomy gives a chance for a cure. Thus, aggressive hepatectomy is an important modality in the multidisciplinary approach for controlling SCC-derived MLTs.

Patient: Male, 60 Final Diagnosis: Sepsis Symptoms: Fever • shock Medication: Sivelestat sodium hydrate Clinical Procedure: PMX-DHP • CHDF Specialty: Infectious Diseases Objective: Unusual clinical course Background: In a patient with severe sepsis, we sometimes observe immediate decrease of the counts of white blood cells (WBCs) and neutrophils, which is known as an indicator for poor prognosis. We observed marked decrease of white blood cells and neutrophils on blood examination and interesting findings on dynamic CT. Here, we present the case of a patient with severe postoperative sepsis occurring after major abdominal surgery and we discuss the mechanism of such clinical presentations. Case Report: A 60-year-old man received pancreatoduodenectomy with colectomy for pancreatic cancer. He developed a high fever on postoperative day 3. We observed marked decrease of WBCs and neutrophils on blood examination. We also observed slight swelling of the liver, inhomogeneous enhancement of liver parenchyma in arterial phase, and periportal low density in the Glisson capsule in portal phase, without any findings indicating infectious complications on dynamic CT. WBCs and neutrophils increased above normal range in just 6 hours. Blood culture examination performed while the patient had a high fever was positive for Aeromonas hydrophila. After receiving intensive care, he promptly recovered from severe sepsis. The CT findings disappeared on second dynamic CT examination performed 3 days after the first examination. Conclusions: We treated a patient with severe sepsis after major abdominal surgery who presented very rapid change of the counts of WBCs and neutrophils and interesting CT findings in the liver. We rescued him from a critical situation by prompt and intensive treatment. Research is needed to accumulate and analyze data from more patients who present a similar clinical course to better understand their pathophysiological conditions.

Background and Objective: Platelets, the smallest anucleate hematopoietic cells, are increasingly recognized as the key regulator of tumor progression and metastasis in breast cancer. They contribute significantly to hematogenous metastasis, which increases tumor invasiveness, by protecting tumor cells from shear stress or immune surveillance and facilitating their extravasation to distant sites. Additionally, recent studies have demonstrated direct signaling between platelets and tumor cells during epithelial–mesenchymal transition (EMT) in the blood stream. However, the existence of platelets in primary breast cancer and its relationship with clinicopathological factors and pathological response to chemotherapy remain poorly understood. This study aimed to investigate (1) the presence of platelet infiltration in tumor tissue, (2) relationships between platelets and clinicopathological features, and (3) the association of platelets with pathological complete response (pCR) to neoadjuvant chemotherapy and EMT markers in primary breast cancer. Methods: We retrospectively analyzed the pre-chemotherapeutic biopsy specimens from 100 breast cancer patients who underwent surgical resection after anthracycline/taxane-based neoadjuvant chemotherapy at Kanazawa University Hospital. Platelet subsets (glycoprotein Ib [CD42b]) and the expression of EMT markers (E-cadherin, vimentin, and β-catenin) were evaluated by immunohistochemistry and correlated with pCR after neoadjuvant chemotherapy. Platelet-predominant breast cancer (PPBC) was defined as the presence of ≥10% of anucleate cells positively stained for CD42b in direct contact with tumor cells. pCR was defined as the absence of residual invasive tumor cells in breast and lymph nodes (ypT0/is, ypN0). Results: PPBC was observed in 48 patients (48%). The prevalence of PPBC was significantly higher in human epidermal growth factor receptor 2 (HER2)-negative patients (HER2 [+] vs. HER2 [-]; 65% vs. 90%, p = 0.008). There was no significant association between CD42b expression and stage, nuclear grade, histology, and estrogen receptor status. PPBC patients had a significantly decreased pCR rate (6/48, 12.5%) compared to non-PPBC patients (33/51, 64.7%; p < 0.001). Tumor cells surrounded by platelets exhibited EMT-like morphological changes, EMT marker expression, nuclear-staining of β-catenin, loss of E-cadherin expression, and expression of vimentin. Conclusions: Our results suggested the presence of tumor-associated platelets in breast cancer as a new predictor of response to neoadjuvant chemotherapy. Platelets might facilitate EMT at the primary site by potentiating tumor cell adhesion. Platelet-tumor interaction might be a new therapeutic strategy for breast cancer. If our finding is validated in further investigations, it might serve as the basis for novel therapeutic approaches of combining conventional chemotherapy with antiplatelet therapy. Our data also identified new predictive parameters to stratify patients with an increased chance of response to anthracycline/taxane-based neoadjuvant chemotherapy. Citation Format: Satoko Ishikawa, Masafumi Inokuchi, Hironori Hayashi, Katsunobu Oyama, Hisatoshi Nakagawara, Tomoharu Miyashita, Hidehiro Tajima, Hiroyuki Takamura, Itasu Ninomiya, Hirohisa Kitagawa, Sachio Fushida, Takashi Fujimura, Tetsuo Ohta. Platelet predominant breast cancer is a new predictor for pathological complete response to neoadjuvant chemotherapy [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-34.

金沢大学医薬保健研究域医学系, A 33-year-old female was diagnosed with a solid pseudopapillary tumor (SPT) of the pancreas and multiple liver metastases at the Department of Gastroenterological Surgery, Ishikawa Prefectural Central Hospital (Kanazawa, Japan). Distal pancreatectomy and postoperative systemic chemotherapy with gemcitabine (GEM) and S-1, an oral fluoropyrimidine derivative, was administered, however, liver metastases became enlarged and local recurrence occurred. Therefore, the patient was referred to the Department of Gastroenterologic Surgery at the Graduate School of Medicine (Kanazawa, Japan) for hepatic arterial infusion (HAI) chemotherapy. Oral S-1 (80 mg/m2) was administered as well as HAI chemotherapy with GEM (1,000 mg/standard liver volume). Following 18 cycles, tumor sizes were reduced and 18-fluorodeoxyglucose positron emission tomography (18FDG-PET) examination revealed obvious reduction of tumor FDG uptake. Transarterial tumor embolization (TAE) was performed for the previously unresectable right subphrenic liver tumor, and the other tumors were surgically resected. The resected tumors were diagnosed as liver metastases and a local recurrence of SPT in the postoperative pathological examination, which revealed that the resected tumors were composed of sheets of bland cells, which were positive for CD10, CD56, vimentin, neuron-specific enolase and α-antitrypsin. The postoperative course was uneventful, and the patient is currently under observation at an outpatient clinic; postoperative adjuvant chemotherapy with oral S-1 has continued, and additional TAE is planned. In the future, if the middle segment of the liver becomes enlarged, surgery for the residual right lobe tumor may be possible. This case demonstrates one method of SPT treatment: Preoperative HAI chemotherapy with GEM, plus oral S-1 and TAE. If complete resection can be achieved, the majority of patients with SPT have a favorable prognosis. In patients with unresectable metastases from SPT, it is crucial to conduct systematic multimodal treatment to maximize treatment success. © 2015, Spandidos Publications. All Rights Reserved., Embargo Period 6 months

Sinusoidal obstruction syndrome (SOS), previously known as veno-occlusive disease, is relatively rare subsequent to liver transplantation (LT). SOS refractory to medical therapy, however, can result in centrilobular fibrosis, portal hypertension and liver failure. Although sinusoidal endothelial cell damage around central venules (zone 3) occurs early in the development of SOS, the detailed mechanism of SOS development and its association with thrombocytopenia are not yet completely understood. The present report describes a patient who experienced SOS with unexplained thrombocytopenia following living donor LT. The progression of SOS resulted in graft dysfunction and the patient succumbed. The presence of platelets in the liver allograft was assayed immunohistochemically using antibody to the platelet marker cluster of differentiation 42b (platelet glycoprotein Ib). Platelet aggregates were found attached to hepatocytes along the sinusoid and within the cytoplasm of hepatocytes, particularly in zone 3. By contrast, no staining was observed in zone 1. These findings suggested that extravasated platelet aggregation in the space of Disse and the phagocytosis of platelets by hepatocytes were initiated by sinusoidal endothelial cell damage due to the toxicity of the immunosuppressant tacrolimus or a corticosteroid pulse, and that platelet activation and degranulation may be at least partially involved in the mechanism responsible for SOS.

Lymph node metastasis from gallbladder cancer is often found in the pericholedochal area; however, these regional lymph nodes are not typically accompanied by arteries. We hypothesized that the artery accompanying pericholedochal lymph nodes was either the regressed embryonic right hepatic artery (eRHA) or an aberrant right hepatic artery (aRHA) remaining without regression. This study aimed to determine the artery supplying pericholedochal lymph nodes. We obtained serial tissue sections of resected specimens from 10 patients who underwent pancreaticoduodenectomy with combined resection of the superior mesenteric artery and vein and investigated the association between the distribution of enlarged lymph nodes and the course of blood vessels in each section. In 2 cases with aRHA, enlarged lymph nodes were distributed in the posterosuperior area, pancreaticoduodenal region and retroportal area along this artery. By contrast, no blood vessels accompanied enlarged lymph nodes in 8 patients exhibiting a normal hepatic artery branching pattern, although these nodes exhibited a distribution pattern similar to that of patients with the aRHA. Thus, the artery supplying pericholedochal lymph nodes appears to be either the regressed eRHA or an aRHA persisting without regression.

Animal models are important for the development of novel therapies for esophageal cancer. Histone deacetylase 1 (HDAC1)/metastasis-associated gene (MTA1) complexes inhibit p53 acetylation and thus, inhibit p53-induced apoptosis. The aim of the present study was to evaluate HDAC1 and MTA1 expression in esophageal carcinogenesis in rats. The rats underwent a total gastrectomy followed by esophagojejunostomy to induce chronic duodenal content reflux esophagitis. The rats were sacrificed sequentially at 20, 30, 40 and 50 weeks post-surgery and the esophagi were examined. Immunohistochemical analysis was conducted to assess the expression and localization of HDAC1 and MTA1. At 20 weeks post-surgery, squamous proliferative hyperplasia and Barrett’s metaplasia (BM) were observed. While, adenocarcinoma-associated BM and squamous cell carcinoma were observed at 30–50 weeks post-surgery. The nuclear expression of HDAC1 and MTA1 was observed in all of the stages of squamous carcinogenesis and adenocarcinogenesis, although not in the normal esophageal epithelium. The expression of HDAC1 and MTA1 may be involved in duodenoesophageal reflux-induced neoplastic transformation of the esophageal mucosa into cancer cells with squamous and adeno differentiation.

Intraperitoneal (i.p.) chemotherapy with paclitaxel (PTX) has been shown to be a promising treatment strategy for peritoneal metastasis. The present study focused on the comparative evaluation of the therapeutic efficacy of nanoparticle albumin-bound PTX (Nab-PTX) and i.p. administration of the conventional solvent-based PTX (Sb-PTX). We also investigated the difference in antitumor activity depending on the route of administration in the Nab-PTX treatment. Nab-PTX was administered i.p. or intravenously (i.v.) and Sb-PTX was administered i.p. at equitoxic and equal doses to nude mice bearing gastric cancer OCUM-2MD3 cell subcutaneous and peritoneal xenografts. Therapeutic efficacy of Sb-PTX and Nab-PTX was evaluated as inhibition of tumor growth using a peritoneal metastatic model with subcutaneous xenografts. The survival rate was also investigated using mouse peritoneal models. For assessment of subcutaneous tumors, the change in tumor volume was measured, and for assessment of peritoneal tumors, the weight of ascitic fluid and the total peritoneal tumor burden were measured for each individual mouse. At equitoxic doses, treatment with Nab-PTX resulted in a greater reduction in the size of subcutaneous tumors and the weight of ascites and peritoneal burden as compared with i.p. Sb-PTX (p

We presented a very rare case of hemangiomatosis of the spleen and intrapancreatic accessory spleen in the tail of the pancreas. A previously healthy 45-year-old woman felt left back pain and received CT scan. Multiple splenic masses and a pancreatic mass in the tail were detected. Both the lesions presented gradual and weak enhancement and pooling of the contrast medium until very late phase on dynamic MRI. Since the lesions in the spleen and the pancreas presented the same characteristics on dynamic CT/MRI, ultrasonography, and positron emission tomography using fluorine-18-fluorodeoxyglucose, we suspected these lesions as hemangiomatosis of the spleen and intrapancreatic accessory spleen. We performed distal pancreatectomy with splenectomy, and pathological diagnosis was hemangiomatosis of the spleen and intrapancreatic accessory spleen. We should consider the possibility of splenic tumors arising from the spleen and intrapancreatic accessory spleen when we find similar lesions in the spleen and the tail of the pancreas. Gradual and weak enhancement and pooling of the contrast medium until very late phase may be important findings for diagnosing splenic hemangiomatosis.

Determination of the human epidermal growth factor receptor 2 (HER2) status of gastric cancer patients is indispensable in clinical practice. However, the clinical value of serum HER2-extracellular domain (ECD) in gastric cancer has not yet been defined.The serum level of HER2-ECD was measured using the chemiluminescence immunoassay method, and its relationship with tissue HER2 status and clinicopathologic features was examined. Transition of serum HER2-ECD level was examined in patients during chemotherapy to clarify the correlation between changes in the level of HER2-ECD in serum and response to chemotherapy.A total of 150 gastric cancer patients were enrolled in this study; changes in HER2-ECD level were examined in 36 of these patients during chemotherapy. Serum levels of HER2-ECD ranged from 4.8 to 180.0 ng/ml (median 9.2 ng/ml) and were positive (cutoff value 15.2 ng/ml) in ten patients (6.7 %). There was a significant correlation between serum HER2-ECD level and tissue HER2 status (P 0.001); however, no correlation with TNM stage was found. Change in serum HER2-ECD level during chemotherapy was significantly correlated with response to chemotherapy in patients with HER2-positive tumor tissue.Serum HER2-ECD is a potential biomarker of gastric cancer and could be used as a diagnostic marker with regard to tissue HER2 status, and also as a monitoring marker in relation to response to chemotherapy.

金沢大学医薬保健研究域医学系, We herein report a case of anaplastic carcinoma of the pancreas with remarkable intraductal tumor growth into the main pancreatic duct. A 76-year-old male was referred to our hospital for treatment of a pancreatic tumor. Preoperative examinations revealed a poorly defined tumor in the main pancreatic duct in the body of the pancreas, accompanied with severe dilatation of the main pancreatic duct, which was diagnosed as an intraductal papillary-mucinous neoplasm. We performed distal pancreatectomy and splenectomy. The pathological examination revealed that the tumor consisted of a mixture of anaplastic carcinoma (giant cell type) and adenocarcinoma in the pancreas. There was a papillary projecting tumor composed of anaplastic carcinoma in the dilated main pancreatic duct. The patient is now receiving chemotherapy because liver metastasis was detected 12 mo after surgery. In this case, we could observe a remarkable intraductal tumor growth into the main pancreatic duct. We also discuss the pathogenesis and characteristics of this rare tumor with specific tumor growth. © 2014 Baishideng Publishing Group Co., Limited. All rights reserved.

Blood purification therapy is indispensable for liver transplant recipients. The case of a living donor liver transplant recipient who represented graft insufficiency and was supported by novel blood purification “plasma diafiltration” immediately after operation is presented. A 60-year-old woman was referred for living donor liver transplant because of liver cirrhosis due to hepatitis C. Elective living donor liver transplant was performed, but the graft was small for size. Thus, the signs of graft insufficiency appeared immediately after the operation, and plasma diafiltration was used as a bridge to graft regeneration. After plasma diafiltration was started, the recipient recovered promptly, and withdrawal was performed 35 hours after induction without any complications. Plasma diafiltration is a useful and safe liver support for liver transplant recipients, including immediately after liver transplantation.

Epidermal-mesenchymal transition (EMT) confers an advantage to cancer cells by improving their invasive capacity and metastatic potential. This phenomenon by which epidermal cells change into mesenchymal cells and therefore acquire a higher ability to automaticity, is considered a key process in cancer development. Transforming growth factor-β (TGF-β) is a significant factor for accelerating EMT through the activation of proteins, including members of the Smad pathway. Furthermore, previous studies have shown that low-dose paclitaxel (PTX) inhibits EMT in certain cell lines, including those of cancer cells. The present study determined whether low-dose PTX was able to inhibit EMT in a human cholangiocarcinoma CCKS-1 cell line that had been treated with TGF-β1. First, the cytotoxic concentration of PTX for the CCKS-1 cells was identified to be ~5 nM by MTT assay and dead cell staining. Therefore, the concentrations of PTX were set as 1 nM, 2.5 nM and 5 nM for the subsequent experiments. In the morphological investigation, the CCKS-1 cells changed into a spindle morphology and became separated by the administration of TGF-β1. However, low-dose PTX inhibited these changes and the morphology resembled the control cells in a dose-dependent manner. Similarly, immunofluorescence and immunoblotting investigations revealed that the CCKS-1 cells expressed mesenchymal markers following the administration of TGF-β1. However, low-dose PTX inhibited the expression of the mesenchymal markers and the CCKS-1 cells expressed the epithelial marker, E-cadherin. In particular, a concentration-dependent effect was observed in the immunoblotting experiments. These results show that PTX may be able to inhibit EMT in cancer cells, depending on the dose concentration.

Hepatic metastasis is a common cause of treatment failure following resection of pancreatic cancer. In this study, we report our results of hepatic arterial infusion (HAI) chemotherapy with gemcitabine (GEM) plus 5-fluorouracil (5-FU) or oral S-1 treatment for postoperative liver metastases from pancreatic cancer. Seven patients with postoperative liver metastases from pancreatic cancer received HAI with GEM plus 5-FU or oral S-1 between October, 2008 and September, 2010 at Kanazawa University Hospital (Kanazawa, Japan). Three out of the 7 cases exhibited a partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) and stable disease (SD) was achieved in 3 out of the 7 cases (response rate, 85.7%). A decrease in serum tumor marker CA 19-9 levels was observed after 10 HAI treatment cycles in 5 out of the 7 cases. The median time to treatment failure was 8 months (range, 0–17 months). Adverse events included grade 3 leukocytopenia in 1 case and anemia in all 7 cases, although 5 out of the 7 patients were anemic prior to HAI therapy. Grade 2 thrombocytopenia was also observed in 2 cases. Non-hematological events, such as nausea, diarrhea, liver injury or neuropathy and life-threatening toxicities were not reported; however, 6 patients (85.7%) developed catheter-related complications and the HAI catheter and subcutaneous implantable port system had to be removed. These findings demonstrated that HAI may deliver high doses of chemotherapeutic agents directly into the tumor vessels, producing increased regional levels with greater efficacy and a lower incidence/severity of systemic side effects. In conclusion, HAI chemotherapy is a safe and effective treatment for liver metastases from pancreatic cancer.

Necrotizing pancreatitis is a serious condition that is associated with high morbidity and mortality. Although vasospasm is reportedly involved in necrotizing pancreatitis, the underlying mechanism is not completely clear. In addition, the local renin‑angiotensin system has been hypothesized to be involved in the progression of pancreatitis and trypsin has been shown to generate angiotensin II under weakly acidic conditions. However, to the best of our knowledge, no studies have reported elevated angiotensin II levels in tissue with pancreatitis. In the present study, the concentration of pancreatic angiotensin II in rats with experimentally induced acute pancreatitis was measured. Acute pancreatitis was induced by retrograde injection of 6% sodium taurocholate into the biliopancreatic duct. Control rats were sacrificed without injection into the biliopancreatic duct. The concentration of tissue angiotensin II was measured using the florisil method. Angiotensin II concentration in tissues with acute pancreatitis measured at 3, 6, 12 and 24 h following taurocholate injection were significantly higher than that of normal pancreatic tissue. In addition, the concentration of angiotensin II increased in a time‑dependent manner. The results demonstrated that the angiotensin II generating system is involved in the transition from edematous to necrotizing pancreatitis in experimental animals. We hypothesize that locally formed angiotensin II affects the microenvironment in pancreatitis.

Residual mucosa in the gastric stump after pylorus-preserving gastrectomy (PPG) is considered a risk factor for the development of gastric stump carcinoma (GSC). Duodenogastric reflux (DGR) and Helicobacter pylori (H. pylori) infection are suspected to contribute to the development of GSC. The aim of this study was to investigate the prevalence of H. pylori in the residual stomach after PPG for gastric cancer and to assess factors associated with the presence of H. pylori. We investigated 72 patients who had undergone PPG at least 1 year prior to the study and were confirmed to be positive for H. pylori infection on presurgical endoscopic biopsy. The extent of DGR, the prevalence of H. pylori infection based on H. pylori stool antigen (HpSA) tests and the severity of gastritis were analyzed in these post-PPG patients. None of the patients had DGR, as shown by (99m)Tc-PMT. Of the 72 post-PPG patients, 33 (46%) were positive for HpSA. The prevalence of H. pylori infection was significantly lower after surgery than before surgery. The endoscopic severity of remnant gastritis, as well as histological inflammation and activity, were higher in H. pylori-positive patients than in H. pylori-negative patients. In conclusion, some patients who undergo PPG and are negative for DGR experience spontaneous clearance of H. pylori infection.

SummaryIssues related to small-for-size grafts in living donor liver transplantation (LDLT) are highly important. The neutrophil lymphocyte ratio (NLR) has been reported to be an inexpensive index of systemic inflammation for various diseases. We retrospectively evaluated the relationship between NLR and clinical course of 61 adult LDLT recipients in our institute until post-operative day 14. Patients were classified into two groups based on the graft volume divided by standard liver volume, as over 35% of graft volume divided by standard liver volume (GV/SLV) (Group L; n = 55) and under 35% of GV/SLV (Group S; n = 6). No differences were seen in background of the patients between the two groups. Also, absolute neutrophil, lymphocyte and platelet counts in both the groups showed no significant differences. In contrast, the NLR between the groups differed significantly from post-operative day 3 to 10, being higher in the Group S. In addition, the incidence of prolonged hyperbilirubinemia and small for size graft syndrome differed significantly between the two groups. Therefore, the elevation of post-operative NLR in the smaller graft group reflect suggestive pathophysiology of endothelial injuries that related to small for size graft syndrome in LDLT.

Cancer stem cells (CSCs) have self-renewal and pluripotency capabilities and contribute to cancer progression and chemoresistance. It has been proposed that the treatment resistance and heterogeneity of CSCs are deeply involved in the prognosis of patients with esophageal squamous cell carcinoma (ESCC). The objective of this study was to identify the influence of the expression status of the CSC markers CD44 and CD133 on chemotherapeutic efficacy and prognosis in ESCC patients who underwent radical esophagectomy after neoadjuvant chemotherapy (NAC). Endoscopically biopsied specimens taken before NAC and surgically resected specimens after NAC were immunohistochemically assessed for CD44 and CD133 expression for 47 ESCC patients who underwent NAC followed by radical esophagectomy. The correlation between CD44 and CD133 expression status and clinicopathological findings and the prognosis of ESCC patients after NAC followed by esophagectomy were analyzed. The percentages of CD44-positive cells and CD133-positive cells in specimens were increased after NAC. CD44 and CD133 expression status before NAC did not correlate with the degree of tumor progression and had no impact on the chemotherapeutic effect. However, strong expression of CD44 or CD133 and a high proportion of CD133-expressing cells before NAC were significantly associated with poorer esophageal cancer-specific survival. Patients with strong expression of CD44 or CD133 and those with a high ratio of CD133-positive tumor cells showed significantly poor prognosis regardless of the effect of chemotherapy. Multivariate analysis showed that simultaneous strong expression of CD44 and CD133 before NAC, a high rate of CD133-positive tumor cells before NAC, and primary tumor remission assessed by preoperative endoscopy were significant independent prognostic factors for ESCC. Our data indicate that CD44 and CD133 expression status prior to treatment dictates the malignant potential of ESCC and may be a novel predictor of recurrence and prognosis of ESCC patients after treatment.

Gastro-duodenal content reflux from gastro-esophageal reflux disease (GERD) induces the inflammation-metaplasia-dysplasia-adenocarcinoma sequence. Proton pump inhibitors (PPIs) are potent blockers of gastric acid secretion, which are widely used for treating GERD and peptic ulcer-associated acid-secreting diseases. The effect of PPI therapy on esophageal carcinogenesis remains unclear. While some studies suggest PPIs result in a significant reduction in the risk of developing dysplasia and adenocarcinoma in patients with Barrett's esophagus, others suggest that PPIs have no effect. Recent studies have revealed that PPIs can exert anti-inflammatory effects such as anti-oxidant properties and immunomodulatory effects through their interactions with neutrophils, monocytes, endothelial and epithelial cells. In addition, PPIs have the ability to prevent adhesion molecule binding in malignant cells and suppress metastasis. This article reviews the role of PPIs in esophageal carcinogenesis and their use as antitumor agents.

Cytokeratin 18 (CK18) fragments are released into circulation during epithelial cell death. M30 (reflects caspase-cleaved CK18 fragment) and M65 (reflects total CK18 fragment) enzyme-linked immunosorbent assay (ELISA) detect circulating CK18 fragments released during caspase-dependent or total cell death, respectively; thus, CK18 has the potential of being a biomarker for epithelial cancers. In the present study, we investigated the serum levels of M30 and M65 in patients with gastric cancer, determined correlation of these levels with clinical features, and evaluated the usefulness of these enzymes as diagnostic and prognostic markers. We enrolled 54 gastric cancer patients and 12 healthy volunteers in this study. We measured the serum levels of M30 and M65 by quantitative ELISA. The levels of M30 and M65 in gastric cancer patients were significantly higher than those in healthy volunteers (P = 0.001, P < 0.001). The enzyme levels were elevated with the progress of gastric cancer. The sensitivity and specificity of M30 as a diagnostic marker were 67.5 and 90.9 %, respectively, and those of M65 were 70.1 and 90.9 %, respectively. The serum levels of M30 and M65 in patient with early gastric cancer were elevated in 38.1 and 66.7 %, respectively. Further, increased serum level of M65 is an independent indicator of poor prognosis (P = 0.036). The serum levels of M30 and M65 may be useful biomarkers for gastric cancer as diagnostic markers that can reflect the extent of cancer. Moreover, M65 levels can be used as a prognostic indicator. © 2012 Springer-Verlag.

金沢大学医薬保健研究域医学系, Several recent studies have reported that selectins are produced during ischemia-reperfusion injury, and that selectin ligands play an important role in cell binding to the endothelium and in liver metastasis. Portal clamping during pancreaticoduodenectomy with vessel resection for pancreatic head cancer causes hepatic ischemia-reperfusion injury, which might promote liver metastasis. We investigated the liver colonization of pancreatic cancer cells under hepatic ischemia-reperfusion and examined the involvement of E-selectin and its ligands. A human pancreatic cancer cell line (Capan-1) was injected into the spleen of mice after hepatic ischemia-reperfusion (I/R group). In addition, to investigate the effect of an anti-E-selectin antibody on liver colonization in the IR group, mice received an intraperitoneal injection of the anti-E-selectin antibody following hepatic ischemia-reperfusion and tumor inoculation (IR+Ab group). Four weeks later, mice were sacrificed and the number of tumor nodules on the liver was compared to mice without hepatic ischemia-reperfusion (control group). The incidence of liver metastasis in the I/R group was significantly higher (16 of 20, 80%) than that in the control group (6 of 20, 30%) (P, Embargo Period 6 months

金沢大学医薬保健研究域医学系, We previously reported that hepatic stellate cells (HSCs) activated by angiotensin II (AngII) facilitate stromal fibrosis and tumor progression in intrahepatic cholangiocarcinoma (ICC). AngII has been known as a growth factor which can promote epithelial-to-mesenchymal transition (EMT) in renal epithelial cells, alveolar epithelial cells and peritoneal mesothelial cells. However, in the past, the relationship between AngII and stromal cell-derived factor-1 (SDF-1) in the microenvironment around cancer and the role of AngII on EMT of cancer cells has not been reported in detail. SDF-1 and its specific receptor, CXCR4, are now receiving attention as a mechanism of cell progression and metastasis. In this study, we examined whether activated HSCs promote tumor fibrogenesis, tumor progression and distant metastasis by mediating EMT via the AngII/AngII type 1 receptor (AT-1) and the SDF-1/CXCR4 axis. Two human ICC cell lines and a human HSC line, LI-90, express CXCR4. Significantly higher concentration of SDF-1αwas released into the supernatant of LI-90 cells to which AngII had been added. SDF-1α increased the proliferative activity of HSCs and enhanced the activation of HSCs as a growth factor. Furthermore, addition of SDF-1α and AngII enhanced the increase of the migratory capability and vimentin expression, reduced E-cadherin expression, and translocated the expression of β-catenin into the nucleus and cytoplasm in ICC cells. Co-culture with HSCs also enhanced the migratory capability of ICC cells. These findings suggest that SDF-1α, released from activated HSCs and AngII, play important roles in cancer progression, tumor fibrogenesis, and migration in autocrine and paracrine fashion by mediating EMT. Our mechanistic findings may provide pivotal insights into the molecular mechanism of the AngII and SDF-1α-initiated signaling pathway that regulates fibrogenesis in cancerous stroma, tumor progression and metastasis of tumor cells expressing AT-1 and CXCR4., Embargo Period 6 months

OBJECTIVES The most serious, life-threatening complication after living-donor liver transplant is a hepatic arterial thrombosis. Although possible therapies for acute hepatic arterial thrombosis include revascularization to salvage the graft, or retransplant, these may be difficult to perform owing to technical aspects and donor shortages. Previously, we reported the usefulness of partial portal arterialization in such cases. MATERIALS AND METHODS Four cases of partial portal arterialization for hepatic arterial occlusion after living-donor liver transplant were reviewed. The surgical procedure of partial portal arterializations involves making an arteriovenous shunt via a side-to-side anastomosis, using mesenteric vessels approximately 2 mm in diameter. RESULTS After partial portal arterialization, hepatic arterial flow was not detected, but graft injury owing to hypoxia gradually improved in all cases. In 1 case, occlusion of the arteriovenous shunt itself and the collateral artery to the graft were identified by angiography 45 days after partial portal arterialization. In another case, massive ascites, pleural effusion, and variceal changes of the mesenteric veins owing to portal hypertension were identified, and surgical closure of the shunt was performed 152 days after partial portal arterialization. In the other 2 cases, there were no definite problems related to partial portal arterialization, but the patients died owing to other complications. CONCLUSIONS When hepatic arterial thrombosis occurs after living-donor liver transplant, revascularization should be performed first. However, this sometimes may be difficult, as when the arterial dissection reaches into the graft. Partial portal arterialization is an easy and effective surgical procedure. Therefore, partial portal arterialization appears to be a useful option to gain time until collateral arterial vessels develop or retransplant, even if revascularization cannot be performed.

Summary Background/Objective Recently, endoscopic and radiological procedures for various symptoms related to cirrhosis have improved. Thus, the role of Hassab's operation (gastroesophageal decongestion and splenectomy) has changed for cirrhotic patients. Methods Hassab's operation was performed on patients who had gastroesophageal varices that were difficult to control with balloon occluded retrograde transvenous obliteration or an endoscopic procedure, or had hypersplenism. Thirteen consecutive patients underwent this operation, and the outcomes of all patients were reviewed retrospectively. Results There was no operative morbidity or rebleeding varices. In the preoperative endoscopic injection sclerotherapy treated group ( n =6), only one patient (16.7%) developed recurrent varices. Mean platelet counts were significantly higher 6 months after surgery (201±65×10 3 /mm 3 ) than preoperatively (64±54×10 3 /mm 3 ). In patients with hepatocellular carcinoma, percutaneous therapies, such as radio frequency ablation, were safely performed with adequate therapeutic effect. Interferon therapy was given to patients with hepatitis C virus (HCV)-related cirrhosis without interruption. Conclusion Hassab's operation is a satisfactory approach to controlling varices, especially when combined with preoperative endoscopic treatment. Platelet counts were significantly higher after surgery. This therapy was important for cirrhotic patients contraindicated for liver transplantation in that they could continue their therapy for hepatocellular carcinoma (HCC) and HCV as needed.

Results of surgery alone for pancreatic cancer are disappointing. We retrospectively evaluated the efficacy and tolerability of neoadjuvant chemotherapy (NAC) with gemcitabine and oral S-1 in patients with potentially resectable pancreatic cancer. A total of 34 patients with pancreatic ductal adenocarcinoma, radiologically diagnosed preoperatively as having potentially resectable tumors, underwent pancreatic resection with lymphadenectomy at Kanazawa University Hospital. NAC was administered to 13 patients (NAC group). The remaining 21 patients were surgically treated without preoperative chemotherapy (control group). Surgical results were compared between these two groups, with follow-up for at least 24 months. No statistically significant differences were found in the clinicopathological background data (tumor location, age, gender, lymph node metastases, tumor stage and tumor size) between the NAC and control groups. Following preoperative chemotherapy, no patients were judged to be unable to undergo laparotomy, i.e., neither distant metastasis nor tumor progression was observed. Radiologically, all 13 NAC group patients had stable disease, whereas, histopathologically, all tumor specimens showed evidence of tumor cells. The treatment effect was judged by Evans grading to be grade IIa in 11 patients and grade IIb in 2 patients. Toxicity was evaluated in 11 patients. Grade III side effects were regarded as hematological toxicity, i.e., leucopenia (7.7%) and thrombocytopenia (15.4%). Moreover, the incidence of perioperative complications did not differ significantly between the NAC and control groups. The one- and three-year overall survival rates of the NAC group with pancreatic head cancer were 88.9 and 55.6%, respectively, superior to 88.9 and 29.6% in the control group (p=0.055). Therefore, NAC with gemcitabine and S-1 is well tolerated and potentially effective against pancreatic head cancer. A phase I study of NAC with gemcitabine and S-1 is under way in patients with resectable pancreatic cancer.

金沢大学医薬保健研究域医学系, Histone acetylation and deacetylation have been thought to be related to gene expression, and there are many reports indicating that histone deacetylase inhibitors (HDACis) exert antifibrogenic effects in several organs. In injured livers, hepatic stellate cells (HSCs) are activated in response to profibrogenic mediators and produce large amounts of extracellular matrix. In particular, transforming growth factor-β1 (TGF-β1) is considered as a key factor in accelerating hepatic fibrosis because it is released from activated HSCs and further stimulates them. The present study aimed to clarify whether sodium valproate (VPA) has suppressive effects on cultured human HSCs (LI90). We showed that treatment with VPA had no significantly suppressive effect on cell proliferation at a concentration of 1 mM, which corresponded approximately to the serum concentration obtained by the administration of a clinical dose. However, VPA prevented the morphological changes characteristic for activation and inhibited the expression of collagen type 1 α1 (COL1A1) and TGF-β1 in activated LI90 cells at the mRNA and protein levels. Our results support the hypothesis that VPA exerts antifibrogenic activity with little cytotoxicity at 1 mM, and HDACis are expected to be used in clinical practice for the treatment of fibrotic diseases., Embargo Period 6 months

Background The prognosis of gastric cancer with para-aortic lymph node (PAN) metastasis is poor. We applied triple combination chemotherapy with docetaxel, cisplatin, and S-1 (DCS therapy) as pre-operative chemotherapy and investigated the outcome of the combination of this therapy and gastrectomy with para-aortic lymph node dissection (PAND). Methods We retrospectively identified 44 patients with pathologically positive PAN who underwent curative surgery at Kanazawa University Hospital between 1990 and 2008. Among the 44 patients, 16 received pre-operative DCS therapy and subsequent surgical resection after two courses of the therapy. Results Pre-operative DCS therapy showed high clinical response ratio (68.8%) and disease control ratio (100%). The pathological response ratio of resected specimen was 87.5%. At 2 years after surgery, the overall survival ratio was 93.8% and relapse-free survival was 75.0%. Pre-operative DCS therapy was only independent prognostic factor in multivariate analysis. Grade 3/4 toxicity was observed only in 25.0% of patients who underwent DCS therapy. Surgical complication was observed in 31.3% of patients, and this ratio was equal to that of patients who did not receive DCS therapy. Conclusion Multimodal therapy comprising combined pre-operative DCS therapy and gastrectomy with PAND was extremely effective and feasible for advanced gastric cancer with PAN metastasis. J. Surg. Oncol. 2012; 105:535–541. © 2011 Wiley Periodicals, Inc.

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).

SUMMARY Attainment of proficiency in video-assisted thoracoscopic radical esophagectomy (VATS) for thoracic esophageal cancer requires much experience. We have mastered this procedure safely under the direction of an experienced surgeon. After adoption of the procedure, the educated surgeon directed induction of this surgical procedure at another institution. We evaluated the efficacy of instruction during the induction period by comparing the results at the two institutions in which VATS had been newly induced. We defined the induction period as the time from the beginning of VATS to the time when the last instruction was carried out. From January 2003 to December 2007, 53 patients were candidates for VATS at Kanazawa University (institution 1). Of these, 46 patients underwent curative VATS by a single operator. We divided this period into three parts: the induction period of VATS, post-induction period, and proficient period when the educated surgeon of institution 1 directed the procedure at Maebashi Red Cross Hospital (institution 2). At institution 1, 12 VATS were scheduled, and nine procedures (75%) (group A) including eight instructions were completed during the induction period (from January 2003 to August 2004). Thereafter, VATS was performed without instruction. In the post-induction period, nine VATS were scheduled, and eight procedures (88.8%) (group B) were completed from September 2004 to August 2005. Subsequently, 32 VATS were scheduled, and 29 procedures (90.6%) (group C) were completed during the proficient period (from September 2005 to December 2007). The surgeon at Maebashi Red Cross Hospital (institution 2) started to perform VATS under the direction of the surgeon who had been educated at institution 1 from September 2005. VATS was completed in 13 (76.4%) (group D) of 17 cases by a single surgeon including seven instructions during the induction period at institution 2 from September 2005 to December 2007. No lethal complication occurred during the induction period at both institutions. We compared the results of VATS among four groups from the two institutions. There were no differences in the background and clinicopathological features among the four groups. The number of dissected lymph nodes and amount of thoracic blood loss were similar in the four groups (35 [22–52] vs 41 [26–53] vs 32 [17–69] vs 29 [17–42] nodes, P = 0.139, and 170 [90–380] vs 275 [130–550] vs 220 [10–660] vs 210 [75–543] g, P = 0.373, respectively). There was no difference in the duration of the thoracic procedure during the induction period at the two institutions. However, the duration of the procedure was significantly shorter in the proficient period of institution 1 (group C: 266 [195–555] minutes) than in the induction period of both institutions (group A: 350 [280–448] minutes [P = 0.005] and group D: 345 [270–420] mL [P = 0.002]). There were no surgery-related deaths in any of the groups. The incidence of postoperative complications did not differ among the four groups. Thoracoscopic radical esophagectomy can be mastered quickly and safely with a flat learning curve under the direction of an experienced surgeon. The educated surgeon can instruct surgeons at another institution on how to perform thoracoscopic esophagectomy. The operation time of thoracoscopic surgery is shortened by experience.

Serous microcystic adenomas are rare and account for 1–2% of all exocrine pancreatic tumors and 25% of all pancreatic cystic neoplasms. Recently, with advances in imaging techniques, these adenomas have been identified at an increasing frequency. A 63-year-old woman visited her doctor in 1999 due to a gastric deformity detected by upper gastrointestinal endoscopy. An abdominal computed tomography scan revealed a cystic lesion measuring 6.0 cm in diameter, resulting in a diagnosis of serous microcystic adenoma of the pancreatic head. During follow-up, the tumor increased steadily in size, measuring 6.0 cm in diameter in 1999 and 13.0 cm in 2008, while remaining asymptomatic throughout this period of time. The risk of malignant transformation appears to be low even over the long-term. However, some cases of malignant transformation to serous cystadenocarcinoma have recently been reported. In this case, assessment of the relationship between the tumor and adjacent vascular structures, such as massive drainage vein development on the surface or tumor flow into the portal and superior mesenteric veins and the celiac and superior mesenteric arteries, was critical for determining tumor resectability. The risk of massive intra-operative hemorrhage was felt to be considerable, given the extent of the veins on the surface of the tumor, as well as the size and location of the primary pancreatic mass. Therefore, preoperative embolization of the tumor-feeding arteries arising from the celiac axis (gastroduodenal, splenic and dorsal pancreatic arteries) was performed. Tumor resection with pancreaticoduodenectomy was performed without a blood transfusion, with an estimated blood loss of 570 ml. The final pathology confirmed the diagnosis of serous microcystic adenoma. The patient is currently alive and disease-free. Preoperative partial embolization of the tumor feeding arteries and intra-operative resection of the right gastric and inferior pancreatoduodenal arteries, allowed the tumor blood supply to be arrested without preoperative tumor necrosis. Subsequently, intraoperative blood loss was reduced. Preoperative partial embolization of the feeding arteries is useful for the resection of hypervascular large tumors of the pancreas.

金沢大学医薬保健研究域医学系, In primary malignant liver tumors, trypsinogen-immunoreactivity was present in 70% of intrahepatic cholangiocarcinoma (ICC) specimens, but absent in hepato-cellular carcinoma (HCC) specimens. We suggest the secretion of trypsinogen to be a key difference in biological behavior between ICC and HCC cells. The purpose of this study was to investigate the secretion of tumor-derived trypsin and the expression of its specific receptor, protease-activated receptor-2 (PAR-2), in ICC using cell lines and surgical specimens. The expression of trypsinogen-1 mRNA was observed in three of four ICC cell lines, but none of three HCC cell lines. Western blot analysis detected trypsinogen-1 in serum-free conditioned medium from one of the ICC cell lines positive for the mRNA. Gelatin zymography revealed a gelatinolytic activity for trypsin, the activated form of trypsinogen, in the same conditioned medium. PAR-2 mRNA and protein were observed in ICC cell lines. The proliferative activity of ICC cells was increased by concentrations of trypsin as low as 10 nM, and peaked at 100 nM. The effect of trypsin was suppressed by a serine protease inhibitor, gabexate mesilate. PAR-2 expression was detected in 64% of ICC surgical specimens immunohistochemically. In addition, stroma fibroblasts expressed PAR-2 in 52% of ICC specimens. These results suggest that trypsinogen-1 contributes to the growth of ICC cells and also tumor-associated fibroblasts., Embargo Period 6 months

症例は30歳の男性で，体重120 kg，BMI 41の高度肥満であった．重症急性膵炎と診断され当院に紹介された．CTでは両側胸水，膵実質の不明瞭化，後腎傍腔に及ぶ滲出液が認められた（Grade IV）．また，SIRS，急性循環不全の状態であった．入院後4病日，炎症反応の持続とCTにて膵頭部の血流障害が認められ，感染性膵壊死と判断し，necrosectomyを行った．腸管・組織浮腫のため，閉腹によるabdominal compartment syndromeが危ぐされたため，術後zipper techniqueとして衣類圧縮用袋を腹壁に固定し，腹腔内洗浄を伴うplanned necrosectomyを継続し，残存膵壊死組織の除去を行った．退院1年目の現在，患者は職場復帰している．衣類圧縮用袋を用いたzipper techniqueは高度肥満を有する感染性膵壊死の術後に有用な処置と考えられ若干の文献を加え報告する．

Here, we present a case of post-operative liver metastases from pancreatic head cancer in a patient with leukocytopenia, who was safely treated by hepatic arterial infusion (HAI) chemotherapy consisting of gemcitabine and 5-FU. The patient was a 61-year-old woman who underwent pancreaticoduodenectomy for pancreatic head cancer, but was found to be an unsuitable candidate for adjuvant systemic chemotherapy due to the presence of leukocytopenia. Five months after surgery, a follow-up CT revealed two liver metastases. Intravenous systemic chemotherapy was also contraindicated due to the leukocytopenia. In the apparent absence of recurrence, excepting the liver metastases, we decided to administer HAI chemotherapy, which had already been administered following the curative surgery. HAI chemotherapy has been shown to be associated with a lower incidence of systemic side effects. Gemcitabine at a dose of 400 mg was administered via a bedside pump and infused over 30 min. After gemcitabine infusion, 250 mg of 5-FU was infused continuously over 24 h from days 1 to 5. This comprised 1 cycle of therapy. The treatment cycles were continued biweekly. After 10 cycles without severe side effects, it was found that though the size of the metastatic tumors was not reduced, tumor vascularity was. However, after the 13th treatment cycle, local recurrence and lymph node metastases were detected. By this time, the patient had recovered from the leukocytopenia, and could thus be administered systemic chemotherapy. In conclusion, HAI chemotherapy is useful and safe for the treatment of malignancies confined to the liver, even in cases where the patient is in a reduced physical condition.

Sivelestat sodium hydrate (Ono Pharmaceutical Co., Osaka, Japan) is a selective inhibitor of neutrophil elastase (NE) and is effective in reducing acute lung injury associated with systemic inflammatory response syndrome (SIRS). We conducted a prospective randomized controlled study to investigate the efficacy of perioperative administration of sivelestat sodium hydrate to prevent postoperative acute lung injury in patients undergoing thoracoscopic esophagectomy and radical lymphadenectomy. Twenty-two patients with thoracic esophageal cancer underwent video-assisted thoracoscopic esophagectomy with extended lymph node dissection in our institution between April 2007 and November 2008. Using a double-blinded method, these patients were randomly assigned to one of two groups preoperatively. The active treatment group received sivelestat sodium hydrate intravenously for 72 hours starting at the beginning of surgery (sivelestat-treated group; n= 11), while the other group received saline (control group; n= 11). All patients were given methylprednisolone immediately before surgery. Postoperative clinical course was compared between the two groups. Two patients (one in each group) were discontinued from the study during the postoperative period because of surgery-related complications. Of the remaining 20 patients, 2 patients who developed pneumonia within a week after surgery were excluded from some laboratory analyses, so data from 18 patients (9 patients in each group) were analyzed based on the arterial oxygen pressure/fraction of inspired oxygen ratio, white blood cell count, serum C-reactive protein level, plasma cytokine levels, plasma NE level, and markers of alveolar type II epithelial cells. In the current study, the incidence of postoperative morbidity did not differ between the two groups. The median duration of SIRS in the sivelestat-treated group was significantly shorter than that in the control group: 17 (range 9-36) hours versus 49 (15-60) hours, respectively (P= 0.009). Concerning the parameters used for the diagnosis of SIRS, the median heart rates on postoperative day (POD) 2 were significantly lower in the sivelestat-treated group than in the control group (P= 0.007). The median arterial oxygen pressure/fraction of inspired oxygen ratio of the sivelestat-treated group were significantly higher than those of the control group on POD 1 and POD 7 (POD 1: 372.0 [range 284.0-475.0] vs 322.5 [243.5-380.0], respectively, P= 0.040; POD 7: 377.2 [339.5-430.0] vs 357.6 [240.0-392.8], P= 0.031). Postoperative white blood cell counts, serum C-reactive protein levels, plasma interleukin-1beta, tumor necrosis factor-alpha levels, and plasma NE levels did not differ significantly between the two groups at any point during the postoperative course, nor did serum Krebs von den Lungen 6, surfactant protein-A, or surfactant protein-D levels, which were used as markers of alveolar type II epithelial cells to evaluate the severity of lung injury. Plasma interleukin-8 levels were significantly lower in the sivelestat-treated group than in the control group on POD 3 (P= 0.040). In conclusion, perioperative administration of sivelestat sodium hydrate (starting at the beginning of surgery) mitigated postoperative hypoxia, partially suppressed postoperative hypercytokinemia, shortened the duration of SIRS, and stabilized postoperative circulatory status after thoracoscopic esophagectomy.

The objective of this study was to evaluate prognostic predictors for patients with gallbladder cancer (GBC) in a Japanese nationwide data base.GBC is the most common cancer of the biliary tract in Japan. Differences in the survival rates between Japan and other countries have been noted.The authors analyzed 4424 patients with GBC in Japan between 1988 and 1997. Staging was determined in accordance with American Joint Committee on Cancer stage.Survival is related closely to the surgical stage. Five-year survival rates for stage I, II, III, IVA, and IVB (5th edition) were 83%, 70%, 45%, 23%, and 9%, respectively. These differences were significant (P0.0001). The survival rate for patients aged60 years was significantly better (P0.05). The survival rate for patients aged69 years was significantly worse (P0.01). The cholecystectomy plus combined resection of bile duct and/or liver bed resection had an effect on prolonging the survival in stage II or III disease, but extended resection did not. The patients with anomalous pancreaticobiliary ductal junction had a survival advantage over those with cholelithiasis by univariate analysis. However, multivariate analyses indicated that only age, sex, stage, operative procedures were independent prognostic factors. Stage was the strongest covariate; patients diagnosed with stage II, III, IVA, or IVB disease were 2.2, 4.2, 8.1, and 13.6 times, respectively, were more likely to die.Staging is the strongest prognostic factor for GBC, but patient outcomes were also affected by age, sex, and operative procedures. The data do not support any advantage for extended resection. Neither gallstones nor anomalous pancreaticobiliary ductal junction influenced the GBC patient outcome.

Although extrapancreatic nerve plexus (PLX) invasion is an important prognostic factor in pancreatic carcinoma, the spreading patterns of carcinoma via PLX have not been carefully explored because of the complex anatomical structures around the pancreas.Fifty-eight patients underwent pancreaticoduodenectomy for carcinoma of the head of the pancreas. The patterns of PLX invasion were evaluated by careful pathological examination. The relationship between tumor location considering the embryological structure of the pancreas and the site of PLX invasion was investigated with an immunohistochemical study using pancreatic polypeptide.Forty-six patients (79%) had PLX invasion. The typical patterns of PLX invasion were detected by pathological examination. Patients with carcinoma in ventral pancreas frequently had pancreatic head plexus 1, pancreatic head plexus 2, and superior mesenteric arterial plexus invasion. Patients with carcinoma in dorsal pancreas had invasion into common hepatic artery plexus and plexus within the hepatoduodenal ligament. A significant correlation between tumor location and the site of PLX invasion was observed.Extrapancreatic nerve plexus invasion by carcinoma of the head of the pancreas could be divided into 2 patterns based on an embryological structure of the pancreas and the location of the tumor. These results about PLX invasion may provide important information to determine surgical strategy for carcinoma of the head of the pancreas.

金沢大学医学部附属病院肝胆膵・移植外科, Background/Purpose: Management of the pancreatic remnant after distal pancreatectomy is still debated, the most serious complication is development of a pancreatic fistula. We developed a nonclosure technique with saline-coupled bipolar electrocautery for preventing fistula formation after distal pancreatectomy as an alternative to traditional stump closure methods. Methods: The distinguishing feature of this technique is nonclosure of the stump, relying instead upon dependable ligation of the main pancreatic duct and sealing of the cut surface by shrinkage accomplished by low-temperature coagulation using saline-coupled bipolar electrocautery. A recent addition has been intraoperative stenting of the remnant pancreatic duct. Results: To date we have used the nonclosure technique in 40 cases, among which 5 (12.5%) developed fistulas: 4 in the nonstenting subgroup (14.8%) and 1 in the stenting subgroup (7.7%). According to a recent classification, 4 fistulas were considered grade A; 1, grade B; and 0, grade C. The grade B patient did not undergo stenting. Conclusion: Our preliminary experience should prompt more widespread evaluation of the nonclosure technique. © Springer Japan 2008.