Serum regulates cortisol bioactivity by corticosteroid-binding globulin-dependent and independent mechanisms, as revealed by combined bioassay and physicochemical assay approaches.

CONTEXT: Corticosteroid-binding globulin (CBG) is the principal carrier of natural glucocorticoids in the circulation, and we hypothesized that it modulates glucocorticoid bioactivity (GBA). Alterations in CBG, the presence of noncortisol, naturally occurring glucocorticoids and the use of potent, synthetic glucocorticoids, all make it difficult to assess adrenal activity in-vivo; these problems can be addressed by a glucocorticoid bioassay. DESIGN AND SUBJECTS: A bioassay was developed for serum GBA and a physicochemical ultrafiltration-liquid chromatography-tandem mass spectrometry assay for free serum cortisol (FreeF). We studied individuals homozygous and heterozygous for a nonfunctioning CBG variant (CBG G237V) and healthy controls. RESULTS: FreeF concentrations were similar in healthy controls, and those with absent functional CBG, but surprisingly we found low GBA in CBG null individuals. This may suggest that CBG delivers cortisol to target cells. However, further experiments revealed that dilution of serum in the bioassay caused release of cortisol from CBG, resulting in elevated GBA measurements in all but the CBG G237V homozygotes. Furthermore, we identified a specific and potent inhibitory effect of high concentration serum on glucocorticoid sensitivity of the recipient cells used in the bioassay. Analysis of inflammatory synovial fluid, a filtrate of serum with lower CBG concentration, revealed elevated free cortisol compared to noninflammatory synovial fluid, a change not attributable to interconversion between cortisol and cortisone. CONCLUSIONS: Our findings reveal that dilution of CBG enhances cortisol release, and so bioactivity, and also that serum potently induces glucocorticoid resistance in target cells.

Prospective randomized controlled study on the effects of perioperative administration of a neutrophil elastase inhibitor to patients undergoing video-assisted thoracoscopic surgery for thoracic esophageal cancer.

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.

Learning of thoracoscopic radical esophagectomy: how can the learning curve be made short and flat?

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.

Glucocorticoid receptor overexpression exerts an antisurvival effect on human small cell lung cancer cells.

Small cell lung cancer (SCLC) is an aggressive tumour with an abysmal prognosis. These cancers are characteristically resistant to glucocorticoid (Gc) action, owing to impaired expression of the glucocorticoid receptor (GR). We identified reduced GR expression in human SCLC cell lines, compared to a non-SCLC cell line. The SCLC cells also showed no Gc inhibition of proliferation, in contrast to non-SCLC cells. Retroviral overexpression of GR resulted in significantly increased cell death, which was partially blocked by the GR antagonist, RU486. Indeed, in cells sorted for GR expression, there was rapid, near complete loss of live cells by 72 h, in contrast to control cells that proliferated as expected. Flow cytometry using Annexin V revealed that cell death was by apoptosis. In addition, confocal analysis of fixed cells showed that cells overexpressing GR displayed a significant increase in fragmenting apoptotic nuclei. Microarray studies showed that transgenic GR expression upregulated the proapoptotic genes, BAD and BAX. We have, therefore, identified a profound apoptotic effect of GR in SCLC cells, which may explain the low levels of endogenous GR in SCLC cells. Understanding how GR overexpression leads to apoptotic cell death in SCLC cells may uncover new therapeutic strategies.

Multiple organ failure caused by end-stage liver disease successfully treated with living donor liver transplantation using perioperative percutaneous cardiopulmonary support: a case report.

A 54-year-old female diagnosed with primary biliary cirrhosis (PBC) 10 years earlier was referred for a living donor liver transplant (LDLT). During her workup, she developed pulmonary edema and respiratory failure due to aspiration pneumonia, which required artificial ventilation. The PaO2/FiO2 (P/F) ratio at that time was 60. Although continuous hemodiafiltration (CHDF) and plasma exchange (PE) were initiated, improvement in the P/F ratio was limited to 133. As transplantation was the only approach to save this patient, we performed LDLT using a right lobe graft aided by percutaneous cardiopulmonary support (PCPS). The graft weight was 650 g and the graft weight/recipient weight ratio was 1.6%. During LDLT, the patient's cardiopulmonary function was stable with PCPS, and the surgical procedure was completed without complications. Following the surgery, she continued to have high-end inspiratory pressure and progressed to the chronic phase of adult respiratory distress syndrome (ARDS). We treated her with low-dose steroid therapy and she improved gradually. The patient was weaned off mechanical ventilation and was discharged approximately 25 weeks after LDLT. In the condition of cardiac or respiratory failure, cadaveric liver transplantation using plasmapheresis is contraindicated because of the associated high mortality rate. Our case suggests that if infections are controlled, a patient with multiple organ failure (MOF) due to end-stage liver disease might be successfully treated with LDLT aided by plasmapheresis and PCPS.

Proliferative activity of carcinoma of the papilla of vater - an immunohistochemical study demonstrating proliferating cell nuclear antigen (pcna).

The expression of proliferative cell nuclear antigen (PCNA) in carcinomas of the papilla of Vater were studied. The PCNA LI of the specimens ranged from 13.0 to 72.8% (mean +/- standard deviation=43.1 +/- 16.4%). The tumors with lymph node involvement had a higher PCNA LI than those without lymph node involvement. The PCNA LI of tumors extending to duodenum or pancreas was significantly higher than that of tumors restricted to the muscle of the sphincter of Oddi. These results indicate that PCNA LI is one of the important factors indicating spread of tumor, i.e., lymph node involvement and depth of invasion.

Surgical-management of carcinoma of the middle and distal bile-duct.

Forty patients underwent surgical resection for cancer of the middle and distal bile duct. Nineteen patients underwent a curative resection with 3- and 5-year survival rates of 63% and 48%, respectively. None of the patients who underwent a palliative resection survived two years. The factor most strongly associated with recurrence was the presence of tumor in the surgical margin. Recurrence was frequent in patients with disease in the middle portion of the bile duct who underwent extrahepatic biliary resection with choledochojejunostomy, while lower bile duct cancer was associated with peri-aortic or retroperitoneal recurrence. Pancreatoduodenectomy, with combined resection of the portal vein in middle bile duct cancer, regional lymphadenectomy, including peri-aortic lymph nodes and nerve plexus is required for curative resection of middle and distal biliary carcinoma beyond the early noninvasive stage.

Human pancreatic cancer cells disable function of Fas receptors at several levels in Fas signal transduction pathway.

The aims of this study were to evaluate the functional expression of Fas receptors (Fas) in human pancreatic cancer cell lines; Capan-1, AsPC-1, BxPC-3, PANC-1, and MIA PaCa-2 and to search for the mechanisms of receptor-mediated inhibition of Fas signaling in these cells. Despite the expression of Fas receptors at considerable levels, exposure of these cells to agonistic Fas antibodies (500 ng/ml) induced only minimal apoptosis in 4 cell lines. The mechanisms allowing resistance to Fas-mediated apoptosis are complex. Using RT-PCR, we identified molecules which might counteract the apoptogenic signal at several levels of Fas signal transduction pathway. The most striking findings were the overexpression of Fas decoy receptors (DcR3), Fas associated phosphatase-1 (FAP-1), and FLICE-inhibitory protein (c-FLIP) in the resistant cell lines as well as in pancreatic cancer surgical specimens. In conclusion, pancreatic cancer cells express three molecules that can abrogate Fas function at different levels of Fas signaling cascade, resulting in resistance to Fas-mediated apoptosis, and this may promote the progression of this malignancy.

Human pancreatic cancer cells express non-functional Fas receptors and counterattack lymphocytes by expressing Fas ligand; a potential mechanism for immune escape.

The aim of this study was to investigate the expression and functional status of Fas ligand (FasL) and its receptor (Fas) in human pancreatic cancers. Using RT-PCR and Western blotting, Fas and FasL were expressed in seven surgically resected pancreatic cancer specimens and five cell lines; Capan-1, AsPC-1, BxPC-3, PANC-1, and MIA PaCa-2. In the resected specimens, pancreatic cancer cells induced apoptosis in the surrounding lymphoid cells. In coculture experiments of pancreatic cancer and Jurkat T cells, 50% of Jurkat T cells underwent apoptosis after 2 days, however, almost all pancreatic cancer cells remained viable. In addition, by testing Fas function using anti-Fas antibody (CH11), all cell lines were resistant to Fas-mediated apoptosis except Capan-1 cells which showed sensitivity similar to that of Jurkat T cells. These results suggest that pancreatic cancer cells evade immune surveillance by expression of FasL and non-functioning Fas that allow them to activated T-cells. These tumor escape mechanisms may contribute to the rapid fatal course of pancreatic cancer.

PPARgamma ligand (thiazolidinedione) induces growth arrest and differentiation markers of human pancreatic cancer cells.

The aim of this study was to examine whether a specific PPARgamma ligand can inhibit the growth of human pancreatic cancer cells through induction of terminal differentiation. PPARgamma was expressed in five human pancreatic cancer cell lines: Capan-1, AsPC-1, BxPC-3, PANC-1, and MIA PaCa-2. Treatment of these cells with a specific PPARgamma ligand, thiazolidinedione (TZD), resulted in inhibition of both cellular and clonogenic growth, and G1 cell cycle arrest. Finally, thiazolidinedione treatment resulted in induction of p21WAF-1 and increased expression of differentiation markers. These results suggest that thiazolidinedione treatment inhibits growth and induces cellular differentiation in pancreatic cancer cells and thereby reduces their development in favor of differentiated and stable cell phenotype.

Differential expression of vacuolar-type H+-ATPase between normal human pancreatic islet B-cells and insulinoma cells.

Recent studies have shown that bafilomycin A(1)-sensitive vacuolar type H+-ATPase (V-ATPase) is responsible for the acidification of intracellular compartments in eukaryotic cells. B-cells of pancreatic islets also are known to include acidifying secretory vesicles which are the major cellular site of proinsulin to insulin conversion. This study was designed to examine immunohistochemically the level of V-ATPase protein expression in normal pancreas (five cases) and benign insulinoma (six cases), using mouse monoclonal antibody raised against the 116 kDa subunit of human V-ATPase. Light microscopic immunohistochemistry revealed that moderate to marked V-ATPase expression was observed in normal islet B-cells, while insulinoma cells in each case expressed V-ATPase faintly or not at all. By immunoelectron microscopy, the majority of secretory vesicles in insulinoma cells did not express V-ATPase protein at their endomembranes, although mild to marked V-ATPase expression was noted at the endomembrane of secretory vesicles in normal islet B-cells. Thus, differential expression of V-ATPase protein at the endomembrane of secretory vesicles was observed between normal islet B-cells and insulinoma cells. These findings suggest that the reduced activity of V-ATPase per insulin secretory vesicle in insulinoma cells have a profound effect on the efficiency of proteolytic cleavage of proinsulin.

Inhibitory effect of a serine protease inhibitor, FOY-305 on the invasion and metastasis of human pancreatic cancers.

We examined the inhibitory effect of a serine protease inhibitor, FOY-305, on the invasion and metastasis of human pancreatic cancers. The in vitro matrigel invasion assay showed that the invasiveness of Capan-1 human pancreatic cancer cells was inhibited by FOY-305 treatment in a dose-dependent manner at concentrations greater than 100 nM. Intrasplenic injection of Capan-1 cells in nude mice resulted in frequent metastases to liver, however, its incidence was significantly decreased by FOY-305 treatment. These findings suggest that a serine protease inhibitor, FOY-305 can inhibit tumor invasion and metastasis by blocking the serine protease-mediated activation cascade.

Activated lansoprazole inhibits cancer cell adhesion to extracellular matrix components.

Integrins play an important role in tumor dissemination. The purpose of this study was to examine whether a SH-reactive reagent inhibits the adhesion of the human pancreatic cancer cell line AsPC-1 to extracellular matrix components. Activated lansoprazole (AG-2000) was used as the SH-reactive reagent because this compound is known to react with SH groups but does not permeate the cell membrane. The effect of AG-2000 on the adhesion of AsPC-1 cells to matrix was examined, using both an in vitro adhesion assay and an in vivo nude mouse xenograft model of peritoneal implantation. In the in vitro adhesion assay, a 60-min exposure of AsPC-1 cells to AG-2000 resulted in a dose-dependent inhibition of AsPC-1 cell adhesion to laminin, fibronectin and type IV collagen, although AG-2000 did not affect the viability of AsPC-1 cells by MTT assay. In the in vivo assessment of AsPC-1 cell implantation, the AsPC-1 cells were initially preincubated with AG-2000 for 60 min to ensure adequate exposure of the AsPC-1 cells to AG-2000 before intraperitoneal injection. AG-2000 significantly inhibited the peritoneal implantation of the AsPC-1 cells in nude mice. These findings suggest that a short exposure of cancer cells to AG-2000 can inhibit cancer cell adhesion to extracellular matrix components.

Surgical strategy for carcinoma of the papilla of Vater on the basis of lymphatic spread and mode of recurrence.

BACKGROUND: Nodal status is one of the most important prognostic factors for carcinoma of the papilla of Vater. The pattern of lymphatic spread and mode of recurrence were analyzed by determining the frequency of nodal involvement and antemortem and postmortem examination of patients with recurrent disease. METHODS: From 1974 to 1994, 36 patients with carcinoma of papilla of Vater underwent pancreatectomy at the Kanazawa University Hospital. A precise evaluation of the nodal involvement was determined by means of careful pathologic review of the extended lymphadenectomy specimen. The mode of recurrence was determined by use of autopsy and radiographic examinations. RESULTS: Fifteen (42%) of 36 patients had nodal involvement. The lymph nodes with the highest metastatic rates were the inferior pancreaticoduodenal lymph nodes (number 13b) and the superior mesenteric lymph nodes (number 14) (13b, 31%; 14, 17%). There were no metastases in the perigastric lymph nodes. A significant relationship existed between the gross appearance of the primary tumor and nodal involvement (protruding, 22%; mixed type, 42%; ulcerative, 100%). The 5-year survival rates were 74% in the absence of nodal metastasis versus 31% with nodal metastasis. The 5-year survival rates for patients with protruding, mixed type, and ulcerative tumors were 75%, 49%, and 17%, respectively. Survival and recurrence were significantly correlated to gross appearance and nodal involvement. Retroperitoneal recurrence and liver metastasis were main modes of recurrence. CONCLUSIONS: Lymph node 13b is important in lymphatic metastasis to the superior mesenteric lymph nodes for carcinoma of papilla of Vater. Nodal dissection around the superior mesenteric artery is needed to improve the prognosis of carcinoma of papilla of Vater except in the nonexposed protruding tumor. Pylorus-preserving pancreatoduodenectomy may be indicated in patients with carcinoma of the papilla of Vater.

Surgical strategy for carcinoma of the pancreas head area based on clinicopathologic analysis of nodal involvement and plexus invasion.

BACKGROUND: The pattern of tumor spread, vis-à-vis nodal involvement and invasion of the extrapancreatic plexus (Plx), has not been thoroughly described for carcinoma of the pancreatic head area. METHODS: From 1973 to 1991, 110 patients (49 with carcinoma of the pancreatic head [Ph], 29 with distal bile duct cancer [Bi], and 32 with carcinoma of the papilla of Vater [Pv]) underwent pancreatectomy at Kanazawa University Hospital. Nodal involvement and Plx invasion were precisely evaluated by histopathologic examination. RESULTS: Thirty-seven (76%) of the 49 patients with Ph, 20 (69%) of the 29 with Bi, and 14 (44%) of the 32 with Pv had nodal involvement. The lymph nodes most commonly involved for Ph were the posterior pancreaticoduodenal lymph nodes (numbers 13a [superior] and 13b [inferior]), the superior mesenteric lymph nodes (number 14), the paraaortic lymph nodes (number 16), and the anterior pancreaticoduodenal lymph nodes (number 17) (13a, 51%; 13b, 47%; 14, 36.7%; 16, 18.4%; 17a, 33%; 17b, 22%). In patients with Bi, lymph nodes around the hepatoduodenal ligament (number 12) and lymph nodes numbers 13a and 14 were most commonly involved (12, 27.6%; 13a, 51.7%; 14, 34.5%). In patients with Pv, lymph node numbers 13b and 14 were most frequently involved (13b, 34.4%; 14, 15.6%). No significant correlation was noted between the tumor size and nodal involvement in these three lesions. Nodal involvement was an important prognostic factor for carcinoma of the pancreatic head area. Plx invasion in these three carcinomas was observed in 61% of patients with Ph, 29% of patients with Bi, and 3% of patients with Pv. CONCLUSIONS: Nodal involvement and Plx invasion differed significantly among carcinomas of the pancreatic head area. We believe that nodal dissection of at least group number 14 is needed for Ph, Bi, and Pv cancers. In addition, dissection of lymph nodes of number 16 and the Plx around the superior mesenteric artery and celiac axis are needed in Ph cancer. Plx dissection of the first portion of plexus pancreaticus capitalis is needed in Bi cancer.

Histopathologic prognostic factors for ductal carcinoma of the head of the pancreas.

To establish useful prognostic factors for carcinoma of the head of the pancreas a retrospective analysis of histopathologic factors was performed for 44 patients treated with resection. Overall survival rates after 1, 2, 3 and 5 years were 63.6%, 34.5%, 26.9% and 23.9%, respectively. Eight patients lived for 5 years. The significant factors affecting survival were nodal involvement (n), retroperitoneal invasion (rp), and the degree of cancer cell invasion to the exposed cut surface (ew). Tumor size (t), serosal invasion (s) and histologic type did not influence survival by univariate analysis. According to the Cox multiregression analysis, nodal involvement is the only useful prognostic factor. Lymph node metastasis is the most important prognostic factor. To improve the prognosis of pancreatic cancer it is necessary to perform extended lymph node dissection.

Expression of pancreatic trypsinogen in human extrapancreatic gastrointestinal carcinomas.

Pancreatic trypsinogen expression in 149 surgically resected extrapancreatic gastrointestinal neoplasms was evaluated immunohistochemically. Immunohistochemistry was performed using a monoclonal antibody against human pancreatic trypsinogen. Pancreatic trypsinogen expression was detected in 28 of 55 gastric carcinomas (50.9%), 22 of 44 colorectal cancers (50%), 12 of 20 gallbladder cancers (60%), nine of 10 extrahepatic bile duct cancers (90%), and none of 20 hepatocellular carcinomas. The intensity of immunoreactivity in the tumor area varied from specimen to specimen, and from area to area within the same specimen. In most cases, however, immunoreactivity was more pronounced at the infiltrative margin of the tumor. Additionally, the highly differentiated carcinoma cells tended to display a focal, fine granular immunoreactive pattern, usually present in the supranuclear cytoplasm, while the poorly differentiated carcinoma cells displayed a fine granular pattern, usually present over the entire cytoplasm. These findings suggest that some extrapancreatic gastrointestinal neoplasms express pancreatic trypsinogen immunoreactive peptides, raising the possibility that secreted pancreatic trypsinogen plays a role in carcinoma invasion and metastasis, as has been shown for other classes of proteases.

Trypsinogen expression in colorectal cancers.

The purpose of this study was to evaluate the trypsinogen expression in human colorectal cancers. We observed the trypsinogen-1 mRNA expression in five of ten human colorectal cancer cell lines by reverse transcriptase-polymerase chain reaction (RT-PCR), and gelatinolytic activity in conditioned medium of cancer cells at acidic pH by gelatin zymography. Furthermore, trypsinogen protein expression was observed in 68 out of 154 (44.2%) surgical specimens of colorectal cancer immunohistochemically. However, there was no statistically significant relationship between the trypsinogen expression and the clinicopathological findings. These findings suggest that trypsinogen might be involved in cancer invasion and metastasis throughout the cancer progression.

Cationic trypsinogen produced by human pancreatic ductal cancer has the characteristics of spontaneous activation and gelatinolytic activity in the presence of proton.

We examined whether human pancreatic ductal cancer cells express and secrete pancreatic cationic trypsinogen in vitro which can be spontaneously converted into active trypsin at acidic pH (pH 4.5-5. 5), in contrast to anionic trypsinogen. Cationic trypsinogen expression at the mRNA level was observed in differentiated Capan-1 and BxPC-3 cell lines. However, expression was not detected in either poorly-differentiated Panc-1 or undifferentiated MIAPaCa-2 cell line. The gelatinolytic activity of the activated form of trypsinogen in each conditioned medium in the presence of enterokinase (1.0 microg/ml) (a band with a molecular weight of approximately 23 kDa) corresponded well to the level of cationic trypsinogen mRNA. The spontaneous activation of trypsinogen also was observed by gelatin zymography of the acid-loaded conditioned medium (pH 5.5). These findings suggest that trypsinogen produced by human pancreatic ductal cancer has the characteristics of spontaneous activation and gelatinolytic activity in the presence of proton.

Total resection of the head of the pancreas preserving the duodenum, bile duct, and papilla with end-to-end anastomosis of the pancreatic duct.

Many surgeons have recently attempted operative procedures for limited resection of the head of the pancreas. This site-specific approach has emerged as a result of precise diagnostic radiologic studies that have become available. The author performed a new operative procedure in 2 patients with mucin-producing pancreatic cysts that included total resection of the head of the pancreas with careful regard to its vasculature. The procedure provided a way of resecting the head of the pancreas while preserving the duodenum, bile duct, and papilla. The pancreatic duct was cut 5 mm before the point of confluence with the bile duct, and an end-to-end anastomosis was performed on the pancreatic duct. Both patients were discharged within 1 to 1.5 months after surgery, without complication. The operative procedure requires no processing of the jejunum, only a simple anastomosis of the pancreatic duct.