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Recently, apoptosis has been implicated as one of the end points of cells exposed to chemotherapeutic agents. The p53 and Bcl-2 family of proteins are involved in chemotherapy-induced apoptosis, but in a cell type-dependent manner. We sought to determine the roles played by the p53 and Bcl-2 family of proteins in 5-fluorouracil (5-FU)-induced apoptosis of human colon cancer cell lines. We first studied the p53 genetic and functional status, and then 5-FU, at inhibitory concentration of 50% (IC50) doses, was used to induce apoptosis, which was confirmed by morphological analysis and enzyme-linked immunosorbent assay (ELISA). Bcl-2, Bcl-X(L), Bax, Bad, Bak and p53 protein expression was analysed by Western blotting. Using five human colon cancer cell lines, we found that equitoxic (IC50) doses of 5-FU induced apoptosis in both wild-type p53 and mutant p53 cells. Analysis of the steady-state levels of Bcl-2 family proteins showed high expression of Bcl-X(L) in all of the cell lines except Colo320. Bcl-2 was expressed in two of them. Bax presented with the lowest basal expression and Bad showed homogeneous expression. On the other hand, Bak expression varied more than fivefold among these cells. In cells containing wild-type p53 (e.g. LoVo), 5-FU-induced apoptosis was accompanied by increased expression of Bax and Bak without consistent modulation of other bcl-2 family proteins. In contrast in cells containing mutant p53 (e.g. DLD1), Bak expression was remarkably increased. There was a significant correlation between chemosensitivity and Bcl-X(L) to Bax ratio, rather than Bcl-2 to Bax. In conclusion, these results suggest that some members of the Bcl-2 family of proteins, in human colon cancer cell lines, are modulated by 5-FU and that the ratio of Bcl-X(L) to Bax may be related to chemosensitivity to 5-FU. Images Figure 1 Figure 2 Figure 3

Mutation of the adenomatous polyposis coli (APC) gene is frequently found in colorectal tumors from both familial adenomatous polyposis (FAP) and non-FAP patients. Analysis of APC mutation is time-consuming and costly due to the large size of the APC gene. As the majority of APC mutations result in the truncation of gene products, the detection of truncated APC proteins may be used as a screening method for APC mutations. The aim of this study is to establish a practical method of detecting truncated APC proteins for the screening of APC mutations. APC proteins in human colorectal cancer cell lines were analyzed by western blotting. Truncated APC proteins were expressed in all of the colorectal cancer cell lines studied. Two species of truncated APC proteins were expressed in two cell lines. Western blotting is a rapid, reliable screening method for APC mutations and provides information on both alleles.

Objectives: To examine the effects of the anti-angiogenic drug AGM1470 on smooth muscle cell (SMC) migration activity stimulated by endothelial cell (EC)-derived mitogen. Materials and Methods: Study 1; EC's were cultured under pulsatile flow using MCDB151 medium. From the supernatant of these EC dishes we devised two types of conditioned medium; anti-PDGF(+) containing 10 g/ml anti-PDGF antibody, and anti-PDGF(−) containing no antibody. SMC's were cultured using both media. Study 2; EC's were cultured under the same conditions using both types of medium; MCDB151 medium containing 10 ng/ml AGM1470, and MCDB151 medium alone. After the AGM1470 concentration had been adjusted to 10 ng/ml, SMC's were cultured using each medium; AGM-exposed EC and AGM-non-exposed EC. SMC colony spreading distances were measured as an index of mitogenic activity for 4 days. Results: Study 1; the anti-PDGF(−) group showed an apparently greater spreading distance than the anti-PDGF(+) group. Study 2; the AGM-non-exposed EC group showed a significantly greater spreading distance than the AGM-exposed EC group. However, MTT assay revealed no differences in proliferation between the two groups. Conclusion: AGM1470 suppresses the EC production of this PDGF-like mitogen as well as SMC migration activity.

BACKGROUND: Although the pathogenesis of Crohn's disease remains unclear, an elemental diet has been shown to be clinically effective. Glutamine is an energy source for many cell types including colonocytes. PURPOSE: This study was designed to assess the potential clinical effects on colitis of changing the dietary quantity of glutamine. METHODS: Colitis was induced by intrarectal administration of 30 mg of trinitrobenzenesulfonic acid with 50 percent ethanol vehicle in Sprague-Dawley rats. Rats were randomly allocated into three dietary groups: Group 1, a commercial elemental diet-based diet without glutamine; Group 2, a commercial elemental diet (glutamine: 12 percent of amino acid content); Group 3, elemental diet with 24 percent glutamine. Diets were started one week before colitis induction and continued until sacrifice. Rats were killed at one, three, and five weeks after colitis induction, and colons were excised. Damage evaluation was based on the percent-age of rats with ulcer, macroscopic damage score, average ulcer area, and microscopic damage score. RESULTS: Group 2 rats weighed more than Group 1 rats at three weeks because of their higher dietary intake. At one week after colitis induction, all groups had comparable damage. At three weeks, the macroscopic damage score was higher in Group 3 than in Groups 1 and 2. At five weeks, rats in Group 3 had significantly more severe damage than those in Groups 1 and 2 in terms of all four indexes. CONCLUSION: We conclude that excess glutamine has a deleterious effect on ulcers in trinitrobenzenesulfonic acid-induced colitis.

In this report we review our results with the double stapling technique (DST) in 162 patients with colorectal diseases in an attempt to identify some of the potential pitfalls of this new technique. Among these 162 patients, there were 125 patients with colorectal cancer, 25 with chronic ulcerative colitis (UC), 9 with familial adenomatous polyposis (FAP), 2 with adult Hirschsprung's disease, and 1 with sigmoid colon fistula. A total of 46 anastomoses (28 for rectal cancer, 13 for UC, 3 for FAP, and 2 for adult Hirschsprung's disease) were performed at or near the dentate line. Of these, 10 had protective diverting colostomy or ileostomy. The results showed that 6 patients with rectal cancer had anastomotic leakage (3.7%); however, 4 of the 6 patients had also received preoperative irradiation. All the leaks healed after the patients had undergone diverting colostomy, but 7 patients with rectal cancer suffered from neurogenic bladder postoperatively (4.3%). Wound infection occurred in 4 patients (2.5%), anastomotic bleeding in 3 (1.9%), and anal pain in 1 (0.6%), respectively. One patient with rectal cancer and multiple liver metastases died of disseminated intravascular coagulation (DIC). These results thus suggest that the double stapling technique provides a safe anastomosis at or near the dentate line not only for rectal cancer but also for UC, FAP, and adult Hirschsprung's disease.

We assessed the usefulness of revision for hemodialysis arteriovenous fistulae.From 1985 to 1994, 287 arteriovenous fistulae were created at our facility. "Primary" patency was defined as the duration of fistula patency without revision, and "secondary" patency was defined as the duration of fistula patency after successful revision in the forearm not requiring prosthesis.The secondary patency rate was significantly better than the primary patency rate (89% versus 41% at 5 years, P0.01). The secondary patency rate in diabetic patients did not differ from that in nondiabetics, although there was a significant difference in the primary patency rate between these two patient groups (diabetics 30% versus nondiabetics; 45% at 5 years, P0.01).Revision is a reliable procedure for salvaging a failed fistula, which yields an acceptable patency rate regardless of the patient's risk factors for arteriosclerosis.

Background The recurrence rate of early gastric cancer is low and so second malignancies developing after treatment of this cancer have potential prognostic significance. Methods Some 633 patients with early gastric cancer were studied. The median observation time was 123 months. To examine the characteristics of patients with early gastric cancer and subsequent malignancy, two groups of patients, those with and those without non-gastric malignancy, were compared using univariate analysis with respect to various clinicopathological factors. To determine which parameters were independently significant, computer-based multivariate discriminant function analysis was applied. To estimate the prognostic significance of non-gastric malignancy, death rates from these diseases in patients treated for early gastric cancer were compared with the mortality rates attributable to the same diseases in the general population of Japan. Results The frequency of other malignancies, 9.6 per cent (61 of 633), was significantly higher than the gastric cancer recurrence rate of 2·4 per cent (15 of 633). After treatment for early gastric cancer patients with subsequent non-gastric malignancy had a significantly poorer outcome than those free from other cancers. Lung cancers were the major neoplasms occurring after the trcatmcnt of early gastric cancer. Univariate and multivariate analysis revealed male sex to be an independent risk factor for the subsequent development of non-gastric malignancy. Comparison of mortality rates revealed that men with early gastric cancer have a higher risk of death from non-gastric malignancy than the general male population. Conclusion These results suggest that systemic surveillance is particularly important for male patients after the treatment of early gastric cancer.

Nitric oxide (NO) is a regulator of leukocyte adhesion in the microcirculation. This study was designed to examine the effects of a NO synthase inhibitor on neutrophil adhesion in the peritoneum, lung, liver, and kidney in a rat peritonitis model using a fluorescence microscopic method. Sprague-Dawley rats were given normal saline (control) or N omega-nitro-L-arginine methyl ester (L-NAME) at dosages of 10 mg/kg (N10) or 100 mg/kg (N100) (n = 66) intraperitoneally. One hour after pretreatment fluorescein-labeled neutrophils were infused without bacterial challenge (0 hr). Other rats received an injection of 10(7) Escherichia coli into the peritoneal cavity 1 hr after pretreatment. Labeled neutrophils were infused 1 and 5 hr after bacterial challenge. Just 2 min after neutrophil injection, blood samples were obtained and the animals were killed. Five peritoneal samples (omentum, mesentery, parietal peritoneum, colon, and ileum), both lungs, the liver, and the right kidney were harvested for counting of labeled neutrophils under epifluorescent microscopy. Combined plasma nitrite/nitrate levels were determined. In another set of rats (n = 36), an arterial catheter was inserted after L-NAME treatment and bacterial challenge. At 0, 1, 5, and 12 hr after challenge, blood pressure, heart rate, and arterial blood gas data were measured. One hour after E. coli challenge, the number of neutrophils in the peritoneum was significantly lower in both L-NAME-treated groups than in the control group. In contrast, the number of labeled neutrophils in the lungs was significantly higher in the N100 group than in the control group. Neutrophil accumulation in the lungs and peritoneum at 0 and 5 hr and in the liver and kidney at 0, 1, and 5 hr did not differ among groups, nor did combined plasma nitrite/nitrate levels. L-NAME treatment had no influence on either hemodynamic or blood gas data. In conclusion, administration of L-NAME increases neutrophil adhesion in the lung, while decreasing that in the peritoneum. NO plays an important role in neutrophil adhesion at the inflammatory site, as well as in remote organs, during peritonitis. NO inhibition may be detrimental, due to neutrophil sequestration, in this peritonitis model.

The impact of lymph node metastasis on the survival of early gastric cancer (EGC) cases remains controversial. A retrospective study of 621 patients with EGC undergoing gastrectomy with lymphadenectomy during the period 1966-1993 was performed to evaluate the influence of node involvement on long-term outcomes. Lymph node metastasis was observed in 63 cases (10.1%). Two groups, EGC with and without node involvement, were compared with respect to long-term results and various clinicopathologic factors. The median observation period was 123 months. EGC cases without metastatic nodes had significantly better outcomes than those with node involvement in terms of overall survival as well as survival excluding deaths due to diseases unrelated to the primary EGC. Survival rates for EGC patients with node involvement did not, however, differ significantly according to the number of metastatic nodes. Three factors-submucosal invasion, large tumor size, and recurrence-were significantly related to lymph node metastasis. Age, sex, family history of malignancy, histologic type, and multiple occurrence of gastric cancer were unrelated to the prevalence of node involvement. The frequency of recurrence in EGC cases without node involvement was low (1.8%, 10 of 558). Recurrence was not, however, exceptional in those with metastatic nodes (9.5%, 6 of 63). EGC patients with lymph node metastasis, even with only a single positive node, constitute a high risk group for EGC recurrence.

There are few detailed reports on the heterogeneity of the nuclear DNA ploidy pattern in carcinoma of the gallbladder. We studied twelve autopsied cases who died of extended gallbladder carcinoma. Multiple samples were taken from the primary site (Pri), from direct invasion of the liver (Hinf), from hematogenous metastasis to the liver (H), from lymphatic metastasis (LN) and from peritoneal dissemination (P). The DNA ploidy pattern was investigated by image cytometry. Heterogeneity of the DNA ploidy pattern in Pri, Hinf, H, LN and P was found in 7/11, 2/10, 5/10, 2/6 and 3/6 cases, respectively. Aneuploidy was more frequently found in Hinf than at the Pri. The DNA index of Hinf was significantly higher than that of Pri. Several stemlines, with different quantities of DNA, were found in Pri. Most of these stemlines were also observed in other sites. These facts may suggest that polyclonal cancer cells rather than one cancer cell or monoclonal cancer cells of a Pri metastasize or infiltrate, and that various polyclonal cancer cells proliferate to different degrees under different circumstances.

253番ないし216番リンパ節転移陽性のS状結腸癌と直腸癌の,臨床病理学的特徴と旁大動脈リンパ節郭清の意義を明らかにする目的で,大腸癌研究会に所属する全国107施設にアンケート調査を行った.労大動脈リンパ節郭清は全体の4分の3の施設で行われていた.ほとんどの場合下腹神経は切除されていた.253番ないし216番リンパ節転移症例は,壁深達度が深く,低分化腺癌・粘液癌・印環細胞癌の頻度が高く,腹膜播種,肝転移,遠隔転移を伴うことが多く,治癒切除の困難な症例であった.旁大動脈リンパ節郭清による予後の改善は,S状結腸癌216番転移陽性例にのみ認められると考えられた.これらの症例における旁大動脈リンパ節郭清の意義を明らかにするには,今後prospective randomized trialが必要であると考えられた.

To study the altered mechanisms of cell cycle regulation in colorectal cancer, the expressions of cyclins, cyclin-dependent kinases (CDKs), CDK inhibitors, p53 and retinoblastoma (Rb) protein were analyzed by western blotting in a series of human colorectal cancer cell lines. The colorectal cancer cell lines exhibited various expression patterns of cell cycle regulators, which may reflect differences in the biological characteristics of cancer cells and in the genetic backgrounds of carcinogenesis. A correlation was found between p53 gene alteration and p21 expression, suggesting that p53 gene mutation usually suppresses p21 expression, though p21 expression could be induced via both a p53-dependent and a p53-independent pathway in colorectal cancer. None of the cell lines studied expressed p16 protein, suggesting that inactivation of p16 may be a common alteration in colorectal cancer. Moreover, all the D-type cyclins, especially D2 and D3, were expressed at a high level in most of the cell lines. Loss of p16 expression and increased expression of D-type cyclins promote CDK-mediated Rb phosphorylation. All of the colorectal cancer cell lines studied herein expressed Rb protein, but the growth-suppressive properties of Rb may be inactivated by the loss of p16 expression and increased expressions of D-type cyclins. In view of the pivotal role of Rb in cell cycle regulation, loss of p16 expression and overexpression of D-type cyclins may be critical alterations in colorectal cancer.

Previous human studies have investigated the influences of nutritional routes on the serum kinetics of cytokines following intravenous administration of lipopolysaccharide. However, it is unclear whether preoperative nutritional routes influence responses of systemic cytokines in patients after surgery. This study was designed to investigate whether preoperative total parental nutrition (TPN) influences systemic interleukin-6 (IL-6) and interleukin-8 (IL-8) responses in patients following surgery for colorectal cancer. Patients with colorectal cancer received TPN (TPN group, n = 6) or an oral diet (oral group, n = 6) for more than 7 d before the operation. Patients in the TPN group received standard TPN. Patients in the oral group received an ordinary hospital diet. Blood samples were collected before the operation, on postoperative day 1 (POD1), POD3, and POD7. Levels of IL-6, IL-8, and C-reactive protein (CRP) in plasma were determined. The characteristics of patients in the TPN and oral groups were comparable. Mean carbohydrate intake was greater (28 versus 19 kCal/kg), and lipid intake was smaller (0 versus 7 kCal/kg) in the TPN group than in the oral group. Plasma CRP levels did not differ between the two groups. Plasma IL-6 and IL-8 levels were marginally higher before the operation and were significantly higher on POD1 in the TPN group than in the oral group. The IL-6 levels showed a positive regression relation with the amounts of blood loss only in the TPN group (P < 0.05, r = 0.881). The slope of the regression line was steeper in the TPN group than in the total enteral nutrition (TEN) group (P < 0.01). In conclusion, routes of nutritional supply have an impact on the production of systemic cytokines after insult. The postoperative systemic IL-6 and IL-8 responses in patients who received standard TPN preoperatively were greater than in patients who received an oral diet. Preoperative nutrition via the enteral route may provide better regulation of cytokine responses after surgery than parenteral nutrition.

B16-F10 is a B16 mouse melanoma subline that preferentially metastasizes to the lung following intravenous injection. Previously we isolated TI-241 (LRF-1 homologue related to Jun-Fos) gene that was expressed higher in the high metastatic clone B16-F10 than the low metastatic clone F1. Transfection of TI-241 into F1 converted it into a high-metastatic cell. We studied the effect of antisense oligonucleotide designed to reduce the expression of TI-241 in B16-F10 cells, and observed an unexpected increase in the TI-241 level. The increase in the expression was maximal at 30 h, then it decreased during further culture with or without TI-241 antisense oligonucleotide. This increased TI-241 expression by antisense oligonucleotide was also observed in B16-F1cells whereas sense oligonucleotide did not affect the expression. B16-F10 cells cultured with TI-241 antisense oligonucleotide showed enhanced experimental metastatic potential to the mouse lungs compared with untreated B16-F10 and B16-F10 cultured with TI-241 sense oligonucleotide. © Rapid Science 1998

The significance of lateral pelvic lymph node (LPLN) metastasis in advanced low rectal cancer treated with preoperative chemoradiotherapy (CRT) remains unclear. The objective of this study was to evaluate the outcomes of selective LPLN dissection (LPLD) based on the pretreatment imaging in patients with advanced low rectal cancer treated with preoperative CRT. We reviewed 127 consecutive patients with clinical stage II–III low rectal cancer below the peritoneal reflection who underwent preoperative CRT and curative resection. LPLD was performed in patients with suspected LPLN metastasis based on MDCT or MRI before CRT (LPLD group, N = 38), and only total mesorectal excision (TME) was performed in patients without suspected LPLN metastasis (TME group, N = 89). Clinical characteristics and the oncological outcome were compared between groups. The median tumor-to-anal verge distance was 40 mm in both groups. The median maximum long-axis LPLN diameter before CRT was 0 mm in the TME group and 10.5 mm in the LPLD group. Pathological LPLN metastasis was confirmed in 25 patients (66 %) in the LPLD group. Local recurrence at LPLN developed in 3 patients (3.4 %) in the TME group and in none (0 %) of the LPLD group. Multivariate analysis showed that only ypN was an independent prognostic factor for relapse-free survival (RFS), but LPLN metastasis was not associated with poor RFS. The incidence of LPLN metastasis is high even after preoperative CRT, and LPLD might improve local control and survival of patients with LPLN metastasis in advanced low rectal cancer treated with preoperative CRT.

Pancreatic exocrine hypofunction is markedly deteriorated during acute exacerbation in a rat model with chronic pancreatitis.Little is known about pancreatic exocrine function during acute exacerbation in patients with chronic pancreatitis. We investigated changes in pancreatic exocrine function after inducing acute pancreatitis in an animal model of spontaneous chronic pancreatitis.WBN/Kob rats with chronic pancreatitis sequentially underwent pancreatic exocrine function test 1-6 d after surgical preparation with external pancreatic fistula. We induced acute pancreatitis in another WBN/Kob rats by i.v. administration of cerulein at a rate of 10 micrograms/kg/h for 4 h 4 d after surgical preparation. Pancreatic exocrine function test was undertaken in a conscious state 1 d before and after cerulein administration.In WBN/Kob rats not given cerulein, pancreatic exocrine function remained almost constant at 3-6 d after surgery. Marked hyperamylasemia developed immediately after cerulein administration. After its administration, the pancreas microscopically showed prominent interstitial edema and intracellular vacuolization of acinar cells in addition to the finding of pre-existing chronic pancreatitis. Basal and cholecystokinin-stimulated flow rate, bicarbonate output, and protein output, which were substantially impaired 1 d before cerulein administration, were further reduced 1 d after its administration.

A 53-year-old man with a 22-year history of ulcerative colitis(UC) (pancolitis), had an ulcerating rectal tumor. Resection of the rectum and sigmoid colon was performed. Pathology showed an expansive ulcerating adenocarcinoma tumor (type 2) invading the adventitia against a background of UC in a resolving phase. Dysplasia was also found in granular and flat mucosa adjacent to the invading carcinoma. Immunostaining for p53 showed diffuse positivity in both the carcinoma and dysplasia, and also in the mucosa with indefinite dysplasia or no dysplasia neighboring the dysplasia and carcinoma. Mapping of neoplasms and the area with p53 protein overexpression showed that the grade of dysplasia increased as the lesion approached the invasive carcinoma and that the mucosa with dysplasia was surrounded by mucosa without dysplasia or indefinite for dysplasia, but with p53 protein overexpression. In some areas without dysplasia showing p53 overexpression, there was significant morphometric enlargement of the area and diameter of the nucleus p53 Immunostaining is a good marker for assessing the genetic alterations that precede histological abnormalities and for diagnosing carcinoma in UC. Objective findings such as p53-protein overexpression and morphometric values should be used to evaluate cytological abnormalities in UC, as well as in common colorectal cancer.

BACKGROUND To evaluate the immunologic activity of regional lymph nodes, the phenotype of lymphocytes and the functional expression of cell adhesion molecules (CAMs) on lymph node lymphocytes (LNL−: uninvolved, LNL+: involved) were investigated in patients with gastrointestinal carcinoma. METHODS The lymphocyte subpopulation and the expression of CD11a, CD44, and CD29 on CD4+ and CD8+ cells in peripheral blood lymphocytes (PBL), LNL−, and LNL+ derived from 37 patients with gastrointestinal carcinoma were studied. In addition, the adherence of CD8+ cells to ICAM-1 which reflects the adhesive function of CD11a, was examined, and changes in this adherence were studied by experimental coculture with cancer cells (DLD-1). RESULTS Although there were no differences in the overall proportion of T cells between the groups, CD8+ cells and CD16+ cells were considerably diminished in LNL+. The expression of CD11a and CD29 on CD4+ and CD8+ cells was significantly lower in LNL than in PBL, whereas the expression of CD44 showed no significant differences. The expression levels of these CAMs were almost the same in LNL− and LNL+. Only CD11a expression on CD8+ cells in LNL+ was significantly lower than that in LNL− (P < 0.005). The adherence of CD8+ cells in LNL+ to ICAM-1 was lower than that in PBL and LNL−, and was extremely enhanced by experimental coculture with cancer cells (DLD-1). CONCLUSIONS These data indicate that the functional expression of CD11a (LFA-1) on CD8+ T cells is suppressed in cancer-involved regional lymph nodes in patients with gastrointestinal carcinoma. Cancer 1996;78:1677-85.

PURPOSE: Laparoscopic colectomy has increasingly been advocated as an option for treatment of colonic disease. The purpose of this study was to compare effects of laparoscopicassisted sigmoid colectomy (LAS) and conventional open colectomy (OPEN) on postoperative cytokine and stress hormone responses. METHODS: Fourteen patients with sigmoid colon cancer, apparently free of preoperative complications, were analyzed. Patients in both groups underwent sigmoid colectomy with lymphadenectomy. LAS was performed by the gasless abdominal wall-lifting method. A 5 cm incision was placed at the beginning of the operation. Blood samples were taken preoperatively and postoperatively for measurement of interleukin-6, glucagon and C-reactive protein. Urinary catecholamine excretions were also determined postoperatively. RESULTS: The two groups of patients were similar with respect to age (61±7 for LASvs.64±9 for OPEN) and sex. Intraoperative blood loss did not differ significantly between groups (112±97 ml for LASvs.366±380 ml for OPEN). Operative times for LAS tended to be longer than those for OPEN (231±67vs.169±45 minutes;P=0.08). Similar time courses of postoperative interleukin-6, C-reactive protein, and stress hormone responses were observed in both groups. No significant differences were observed in the magnitude of changes except that the serum interleukin-6 level on day of surgery (postoperative day 0) was significantly higher in LAS patients than in those receiving OPEN. In addition, interleukin-6 levels showed a significant positive correlation with operative duration (r=0.582;P

We previously developed a new bioreactor of the bioartificial liver composed of non-woven fabric. We have also experimented with hepatocyte spheroids, with the aim of improving the efficiency of this NWF bioreactor. In this study, we compared the efficiencies of NWF bioreactors employing hepatocyte spheroids versus single hepatocytes. Hepatocytes were isolated from a whole pig liver by Seglen's method. 1.0 × 1010 single hepatocytes were immobilized in the NWF bioreactor. Another 1.0 × 1010 hepatocytes were allowed to form spheroids by 24 hr suspension culture in a 4-L culture vessel, before being immobilized in the bioreactor. Hepatocyte spheroids were found to be functionally superior, on a per-cell basis, to single hepatocytes in the NWF bioreactor. However, the NWF bioreactor employing hepatocyte spheroids exhibited lower efficiency than that employing single hepatocytes, because the total number of the hepatocytes had decreased during the 24 hr suspension culture.

A total of 594 flat colorectal polyps, removed at endoscopy, were histologically classified into non-neoplastic (n = 49) and neoplastic (n = 545) polyps. Non-neoplastic polyps were subdivided into metaplastic (n = 45) and hyperplastic (n = 4), whereas neoplastic polyps were subdivided into adenomas (n = 481), intramucosal carcinomas (n = 28) and invasive adenocarcinomas (n = 36). Several adenoma phenotypes were discerned: tubular (n = 375), serrated (n = 59), villous (n = 39), mixed (n = 7) and fenestrated (n = 1). Intramucosal carcinomas were subdivided into tubular (n = 26) and serrated (n = 2), and invasive adenocarcinomas into tubular (n = 32), serrated (n = 3) and fenestrated (n = 1). The microscopic characteristics of each histologic phenotype described in this communication are defined and illustrated.

The effect of oral administration of protease inhibitor (camostat) on pancreatic morphology and exocrine function (conscious rat model) was investigated using WBN/Kob rats with spontaneous chronic pancreatitis. In nontreated WBN/Kob rats (2-12 months of age), pancreatic fibrosis and parenchymal destruction compatible with human chronic pancreatitis appeared at 3 months and advanced with each month. Pancreatic secretion was markedly impaired at all ages. In WBN/Kob rats fed diets containing camostat (from 2-3 or 4-5 months of age), the pancreas was hypertrophic and did not show any histological appearances compatible with chronic pancreatitis, and moreover, exocrine function was thoroughly restored with increased plasma cholecystokinin concentrations. Oral administration of protease inhibitor has both preventive and therapeutic effects on pancreatic lesions and dysfunction in an animal model of chronic pancreatitis, probably via endogenous cholecystokinin release.

When taurocholate was injected into the common bile duct, high ductal pressure due to ligation of the pancreatic duct did not produce more damage in the pancreas of both old rats and young adult rats, and levels of pancreatic enzymes in portal venous effluent were lower in old rats than in younger rats The effects of ligation of the pancreatic, duct and aging on acute pancreatitis caused by taurocholate are still unclear. Young adult and old male Wistar rats were used. Six hours after ligation of the common bile duct in both the duodenum and liver hilus, rats were killed and the pancreata were perfused. Taurocholate or normal saline was injected retrogradely into the common bile duct. The levels of amylase and lipase in the portal venous effluent were determined as markers of damage to the pancreas. The pancreas was also histologically examined after the perfusion experiments using an Image Analysis System. (1) A nonsignificant elevation of pancreatic enzymes was found in portal venous effluent by the retrograde injection of saline into the common bile duct. Injection of taurocholate caused a marked elevation of enzymes in the effluent for the first 30 min after injection, which then gradually decreased. (2) Basal levels of pancreatic enzymes were significantly higher in the ligation group than in the nonligation group. Injection of saline into the common bile duct had no apparent effect on enzymes in the effluent. In contrast, taurocholate injection into the common bile duct produced a marked increase in enzymes in the portal venous effluent. However, no significant difference was found between the ligation group and the nonligation group. (3) Similar findings were obtained when old rats were used. (4) Although basal levels of enzymes were almost the same in nonligated old and young adult rats, taurocholate injection into the pancreatic duct in old rats resulted in a significant depression of enzymes compared to that in young adult rats. In the ligation group, pancreatic enzymes in the portal venous effluent following taurocholate injection tended to be lower in old rats than in young adult rats. The results were histologically supported in that various degrees of fibrosis were found in the pancreata of old rats.

Objective: To examine the effects of three nitric oxide synthase inhibitors on survival in a murine sepsis model.Design: Prospective randomized experimental trials.Setting: Laboratory.Subjects: Female Balb/c mice.Interventions:Escherichia coli (108 colony-formingunits/body) were injected into the peritoneal cavities of Balb/c mice. NG-nitro-L-arginine-methyl-ester, NG-monomethyl-L-arginine, or N-iminoethyl-L-ornithine was given at various concentrations, intraperitoneally, one hour before bacterial challenge.Measurements: One hundred and fifteen animals were observed for survival.Results: These inhibitors provided the mice no protection from the bacterial challenge. Notably, pretreatment with NG-nitro-L-arginine-methyl-ester (100 mg/kg i.p.) actually reduced survival time afterE. coli challenge.Conclusions: Inhibition of nitric oxide production improved neither the survival time nor rate in this murine sepsis model.

BACKGROUND Because flat adenoma shows a higher malignancy rate compared with other types of polyps, it is considered to play an important role in the carcinogenesis of colorectal carcinoma. In the present study, we examined flat adenomas in hereditary nonpolyposis colorectal carcinoma (HNPCC) patients. METHODS Nine HNPCC patients who presented with flat adenomas were examined. All patients underwent either surgery or endoscopic polypectomy for colorectal carcinoma and/or adenoma. In all patients, annual colonoscopy had been performed once a year throughout the follow-up period after the initial treatment. When colorectal polyps were detected during follow-up colonoscopy, all lesions were endoscopically excised. Clinicopathologic features and microsatellite instability of both malignant lesions and adenomas were examined. RESULTS Thirteen malignant lesions were detected: seven advanced carcinomas and six early carcinomas. Among 4 early carcinomas with submucosal invasion, 3 lesions (75%) were categorized as superficial type, with a configuration similar to flat adenoma. The frequency of flat adenoma was strikingly high in HNPCC patients in the present study. Among 73 polyps detected, 37 (50.7%) were flat adenomas. Both malignant lesions and flat adenomas had proximal predominance, 61.5% and 59.5%, respectively. Eleven of 15 lesions (73.3%) showed replication error. CONCLUSIONS These results suggest the importance of flat adenoma as a precursor of colorectal carcinoma in some groups of HNPCC patients. Further study is essential to elucidate the natural history of flat adenomas in HNPCC patients. Cancer 1996; 77:627-34.

OBJECTIVE: The authors' aim was to investigate whether antecedent nutritional routes influence immune responses after surgical insult. SUMMARY BACKGROUND DATA: Total parenteral nutrition (TPN) may influence host responses to infection. To the best of the authors' knowledge, however, no study has focused on the mechanisms underlying the influence of nutritional route on local, systemic, and remote organ (lung) responses after surgical insult. METHODS: Sixty-eight rats were divided into TPN and total enteral nutrition (TEN) groups. The two groups received identical nutrients for 7 days and were then challenged intraperitoneally with 3 x 10(8) Escherichia coli. In the first experiment, the rats were observed for survival. In the second experiment, the rats were killed before (0 hours) challenge or 2 or 6 hours after challenge. Peritoneal exudative cells (PEC) and bronchoalveolar cells (BALC) were harvested and cultured in vitro. Colony-forming units of bacteria in the peritoneal lavage fluid (PLF) were determined. Tumor necrosis factor (TNF), interleukin-1 alpha (IL-1 alpha), interferon-gamma (IFN-gamma) levels in serum, PLF, bronchoalveolar lavage fluid (BALF), and cell culture supernatants were measured. RESULTS: The 48-hour survival rate was higher in TEN than in TPN rats. Local immunity was depressed in the TPN group. Bacterial colony counts in PLF were significantly higher in the TPN group than in the TEN group after challenge. The number of PECs was significantly lower, and at 2 hours, local cytokine (TNF and IL-1 alpha) responses were diminished in the TPN group compared with the TEN group at 2 hours. The number of PECs showed a significant positive correlation with levels of local cytokines in the TEN group but not in the TPN group. Elevation of local IFN-gamma was significant from 0 to 6 hours in the TEN group but not in the TPN group. In vitro production of TNF by PEC was impaired in the TPN rats before challenge. Remote organ (lung) responses were suppressed in the TPN group. The number of BALCs and the TNF levels in BALF declined significantly between 0 and 2 hours in the TEN group but not in the TPN group. Interferon-gamma levels in BALF were higher in the TEN group than in the TPN group at 2 hours. Systemic cytokine responses were disturbed in the TPN group. Production of systemic TNF was greater, but the IFN-gamma response was diminished in the TPN group compared with the TEN group after intraperitoneal bacterial challenge. CONCLUSION: Local, systemic, and remote organ (lung) immune responses to intraperitoneal bacterial challenge are suppressed in TPN-treated animals, leading to poor survival after challenge. Enteral nutrition before surgical insult may enhance host immune responses after the insult as compared to parenteral nutrition.

Exocrine function was studied in anesthetized rats that had received two specific doses of caerulein (maximal stimulation and supramaximal stimulation). Male Wistar rats (body weight, 200-250 g) were divided into three groups: the control group (4-h saline infusion), the maximal stimulation group (0.25 microgram/kg per h caerulein for 4 h), and the caerulein pancreatitis group (10 micrograms/kg per h for 4h). Histologically, interstitial edema and cytoplasmic vacuolization were observed only in the caerulein pancreatitis group, with no abnormal findings in the other groups. The volume of pancreatic juice was significantly increased in both the maximal stimulation group and the caerulein pancreatitis group. The protein output and the amylase output in the 1st h of caerulein infusion were also significantly increased, to 459% and 338% in the maximal stimulation group, and to 925% and 1430% respectively, in the caerulein pancreatitis compared to the baseline values. We also found that the pancreatic juice of the caerulein pancreatitis group contained precipitated protein, and high trypsin activity, and protein degradation was confirmed by electrophoresis. These findings were not observed in the other groups. These results strongly suggest that hypersecretion and the appearance of trypsin activity in pancreatic juice plays an important role in the induction of histological changes in this pancreatitis model in anesthetized rats.

症例は84歳男性. 1985年ごろより労作時の胸痛あり, ECG上, 下壁側壁の陳旧性心筋梗塞が疑われ, 心臓カテーテル検査で冠状動脈3枝病変 (LAD: distal で95%狭窄, LCX: proximal で75%狭窄, RCA: #2で100%閉塞) が発見された. また1990年2月より左側腹部痛があり同年7月CT, 血管造影にて最大径5.3cm大のAAAを指摘された. 当時, 高齢 (80歳) ということからPTCAやCABGの適応ではないとされ, AAAについてもそのまま follow されていた. 1993年10月CT上AAAの急速な増大傾向 (最大径7cm) を認めたので, 手術適応と判断され入院した. 同年12月CABG2枝 (LAD, RCA) を先行させ, 1994年2月AAAに対して瘤切除, 人工血管置換術を施行, 第17病日に独歩退院し, 現在社会復帰している. 本症例の治療経験から, 重症冠病変を伴ったAAAでは, 瘤破裂の危険が高い増合は, 高齢であっても, 患者にとって有益であると判断した例では積極的に冠状動脈再建を行ったほうがよいと考えられた.

There have been few reports on (1) the nature and pathogenesis of small cystic lesions of the pancreas, (2) their incidence, age distribution, and location, and (3) their significance as potential precursors of intraductal papillary tumors, mucinous cystic tumors, and duct cell carcinomas. Materials: Epithelial growth of small cystic lesions in 300 consecutive autopsy cases and in seven cases of small duct cell carcinoma from among 2300 elderly autopsy cases, was evaluated by histopathological analysis. One hundred eighty-six cystic lesions were found in 73 of 300 autopsy cases (24.3%). The incidence of cystic lesions increased with age. Cystic lesions were equally distributed throughout the pancreas. Epithelial atypia was histologically classified into five groups: normal epithelium; papillary hyperplasia without atypia; atypical hyperplasia; carcinomain situ; and invasive carcinoma. The incidence of each group was 47.5, 32.8, 16.4, 3.4, and 0%, respectively. Epithelia of atypical hyperplasia or carcinomain situ were more prevalent in small cystic lesions (less than 4 mm in diameter) than in larger lesions (chi-square test,p

Microsatellite instability characterizes a sub-set of sporadic colorectal cancers (CRCs) as well as CRCs from patients with hereditary non-polyposis colorectal cancer (HNPCC). In order to clarify when the cells acquire a replication-error phenotype (RER) during colorectal-tumor progression, we examined the incidence of RER in 80 primary tumors and 36 liver metastases at 8 microsatellite loci; I mono-, 5 di-, I tetra- and I penta-nucleotide. RER were detected in 20.1% (17/80) of primary tumors, including 5 tumors showing RER at 2 or more loci (RER2), while the incidence of RER in liver metastases (22.2%, 8/36) was almost the same as that in primary tumors, and there was only one RER2 case in metastases. There were 3 cases in which both primary tumors and liver metastases had the same type of RER at the same locus, and there were 2 cases that showed RER in primary tumors but not in liver metastases. In contrast, there was no case in which RER was detected in a metastasis but not in the corresponding primary tumor. The RER phenotype did not show correlation with any clinicopatho-logical parameters of cancer-cell aggressiveness, such as clinical staging, histological grade and survival. These results indicate that a sub-set of CRCs acquire the RER phenotype in the relatively early stages of colorectal carcinogenesis, and that the RER phenotype is not associated with aggressiveness of CRCs. © 1995 Wiley-Liss, Inc.

Background. There has been considerable controversy with regard to surgical strategies for the treatment of superficial esophageal carcinoma, which is characterized by tumor confined within the epithelium (EP), muscularis mucosae (MM), or submucosa (SM). The relationships among macroscopic shape, depth of invasion, and lymph node involvement in superficial tumors were investigated to devise therapeutic strategies for patients with such disease. Methods. Thirty-three patients with superficial primary esophageal cancer underwent esophagectomy with regional lymph node dissection (3 EP, 6 MM, and 24 SM). Tumors were divided into two types according to macroscopic characteristics: (1) tumors with elevated components and (2) flat or depressed tumors without an elevated component. Results. Tumors with an elevated component (n = 19) showed invasion of the deep layer, and a high incidence of lymph node metastasis. Conversely, tumors without an elevated component (n = 14) showed varied depths of invasion, and, with one exception, had no lymph node involvement. Conclusions. The existence of an elevated component in superficial esophageal cancer is an important macroscopic feature suggesting submucosal invasion and a high probability of lymph node involvement. More intensive treatment should be adopted for such tumors, whereas localized resection may be feasible for tumors without an elevated component. Cancer 1995;75:1061–4.

Background. To clarify genetic changes in coiorectal tumorigenesis, K-ras codon 12 point mutations were examined in 101 ordinary coiorectal carcinomas and 6 that complicated ulcerative colitis (UC) with special attention to growth patterns. Methods. The depths of invasion of ordinary carcinoma were submucosa (SMCa) in 39 cases, muscularis propria (PMCa) in 33, and far-advanced in 29. Growth patterns of SMCa and PMCa were classified into three types: polypoid-growth type without central depression (Type 1), polypoid-growth type with central depression (Type 2), and nonpolypoid-growth type. DNA samples were extracted from formalin fixed paraffin embedded sections, and K-ras codon 12 mutations were examined by two-step polymerase chain reaction-restriction fragment length polymorphism. Results. K-ras mutation frequency was higher in Type 1 SMCa than in nonpolypoid SMCa, 56% (9/16) versus 6% (1/17), respectively, and in PMCa, 78% (7/9) versus 23% (3/13), respectively. In 6 UC carcinomas, a K-ras mutation was detected in only one polypoid carcinoma and none were detected in five nonpolypoid carcinomas. Conclusions. These results and the authors' previous study suggest that nonpolypoid carcinomas may be derived from flat adenomas, whose K-ras mutation incidence also was low, and this pathway is different from a genetic model based on the ordinary adenoma-carcinoma sequence through polypoid adenomas. Cancer 1995;75:953-7.

We describe a case in which segmental resection of the third portion of the duodenum was performed for a gastrointestinal stromal tumor (GIST). A 31-year-old woman was found to have a 3.5 cm hypovascular tumor at the posterior inferior aspect of the pancreatic head. Preoperative duodenal biopsy revealed that the tumor was positive for c-kit and vimentin, and was diagnosed as a duodenal GIST. Segmental resection of the third portion of the duodenum with papilloplasty and duodenojejunostomy was carried out and there were no postoperative complications. Pancreatoduodenectomy is not always necessary in the treatment of a duodenal GIST. This duodenectomy procedure can serve as a less extensive resection for a duodenal GIST located in the third portion of the duodenum.

A treatment strategy for tumors with only venous invasion and characteristics of small rectal carcinoids with metastasis have not been clearly documented. The present study aims to determine the risk factors for lymph node metastasis and to elucidate characteristics of small tumors with metastasis.We investigated a total of 229 patients with rectal carcinoids. The relationship between each clinicopathological variable and the presence of lymph node metastasis was evaluated.Tumor size (larger than 10 mm), presence of central depression, depth of tumor invasion, lymphatic invasion, and venous invasion were significantly associated with the incidence of lymph node metastasis (P0.001). Multivariate analysis revealed that tumor size (odds ratio: 63.3, P0.001) and venous invasion (odds ratio: 40.9, P0.001) were independently predictive of lymph node metastasis. In 204 patients with small (no larger than 10 mm) tumors, 10 patients had lymph node metastasis. All 10 tumors had low proliferation values indicated by mitosis and Ki-67 index. Multivariate analysis for the 204 patients revealed that only venous invasion was independently associated with metastasis (odds ratio: 40.1, P0.001). Five-year disease free survival rates of the total patients with metastasis and without metastasis were 81.1% and 95.5%, respectively (P0.001, log-rank test).Venous invasion as well as tumor size and lymphatic invasion indicates high malignant potential to metastasize to lymph node and would provide useful information in considering the addition of radical surgery. Postoperative pathological examinations of specimens obtained by local resection are very important to avoid underestimation.

Objective To evaluate whether lateral pelvic lymph nodes (LNs) in low rectal cancer are metastatic disease or part of regional LNs that are amenable to curative resection. Background It is highly controversial whether lateral pelvic LNs should be considered as regional or distant disease, although the American Joint Committee on Cancer (AJCC) defines internal iliac LNs as regional LNs of rectal cancer. Methods Data of patients with stage I to III low rectal cancer who underwent curative resection from 1978 to 1998 were extracted from the multi-institutional registry of large bowel cancer in Japan. Patients with only mesorectal LN metastasis were classified as the mesorectal-LN group. Patients with lateral pelvic LN metastasis localized to or extending beyond the internal iliac area were classified as the internal lateral pelvic lymph nodes (LPLN) group and external-LPLN group, respectively. Overall survival (OS) and cancer-specific survival (CSS) were compared between the groups. Results Lateral pelvic LN dissection was performed in 5789 (50%) of 11,567 patients. Overall, 3905 (34%), 411 (3.6%), and 244 (2.1%) patients were classified as the mesorectal-LN, internal-LPLN, and external-LPLN groups, respectively. When the mesorectal LN group was subdivided as defined by the AJCC, both 5-year OS and CSS were not significantly different between the N2a and internal-LPLN groups (OS: 45% vs 45%, P = 0.9585; CSS: 51% vs 49%, P = 0.5742), and the N2b and external-LPLN groups (OS: 32% vs 29%, P = 0.3342; CSS: 37% vs 34%, P = 0.4347). OS and CSS were significantly better in the external-LPLN group than in stage IV patients who underwent curative resection (OS: 29% vs 24%, P = 0.0240; CSS: 34% vs 27%, P = 0.0117). Conclusions Lateral pelvic LNs can be considered as regional LNs in low rectal cancer, although metastasis extending beyond the internal iliac area is associated with poorer survival.

Purpose To examine whether chromosomal instability (CIN) phenotype, determined by the severity of CIN, can predict survival for stages II and III colorectal cancer (CRC). Patients and Methods We determined microsatellite instability (MSI) and loss of heterozygosity (LOH) status in 1,103 patients (training [n = 845] and validation [n = 258] sets with stages II and III CRC). The LOH ratio was defined as the frequency of LOH in chromosomes 2p, 5q, 17p, and 18q. According to the LOH ratio, non–MSI high tumors were classified as CIN high (LOH ratio ≥ 33%) or CIN low (LOH ratio < 33%). CIN-high tumors were subclassified as CIN high (mild type; LOH ratio < 75%) or CIN high (severe type; LOH ratio ≥ 75%). We used microarrays to identify a gene signature that could classify the CIN phenotype and evaluated its ability to predict prognosis. Results CIN high showed the worst survival (P < .001), whereas there was no significant difference between CIN low and MSI high. CIN high (severe type) showed poorer survival than CIN high (mild type; P < .001). Multivariate analysis revealed that CIN phenotype was an independent risk factor for disease-free and overall survival, respectively, in both the training (P < .001 and P = .0155) and validation sets (P < .001 and P = .0076). Microarray analysis also revealed that survival was significantly poorer in those with the CIN-high than in the CIN-low gene signature (P = .0203). In a validation of 290 independent CRCs (GSE14333), the CIN-high gene signature showed significantly poorer survival than the CIN-low signature (P = .0047). Conclusion The CIN phenotype is a predictive marker for survival and may be used to select high-risk patients with stages II and III CRC.

To determine the factors which influence perioperative coagulative and fibrinolytic function, we studied 41 patients who underwent surgical repair of unruptured abdominal aortic aneurysm (AAA) and 30 patients who underwent arterial reconstruction for arteriosclerosis obliterans (ASO). In patients with AAA, the levels of fibrin/fibrinogen degradation products (FDP) (11.4 +/- 20.1 micrograms/ml), thrombin-antithrombin III complex (TAT) (22.0 +/- 21.8 micrograms/l), plasmin-alpha 2 plasmin inhibitor complex (PIC) (2.6 +/- 2.9 micrograms/ml) and d-dimer of cross-linked fibrin degradation products (D-D) (8.4 +/- 10.8 micrograms/ml) were elevated, particularly when the AAAs had a large mural thrombus surface area or were accompanied by aneurysm of the iliac or femoral artery. In arterial aneurysms, blood coagulability and secondary fibrinolytic activity were believed to be enhanced. In patients with ASO, the level of TAT (17.2 +/- 24.8 micrograms/l) was so elevated that they were considered to show chronic hypercoagulability. Among the ASO patients with aorto-iliac lesions, those with concomitant graft occlusion or anastomotic aneurysm had significantly elevated levels of TAT. Proximal arterial occlusion or accompanying aneurysm in the ASO patients was associated with increased levels of PIC and D-D. Postoperative fluctuations in conventional hematological variables did not differ significantly among the surgical procedures. Conventional markers showed a transient decrease due to consumption during surgery, and a subsequent recovery or an actual increase within several days after surgery.(ABSTRACT TRUNCATED AT 250 WORDS)

The mechanisms of lysis of endothelial cells derived from human umbilical vein (HUVEC) by autologous lymphokine-activated killer (LAK) cells, generated from cord blood lymphocytes of the same donor, were investigated. Freshly isolated HUVEC as well as HUVEC cultured for several passages were efficiently lysed by autologous LAK cells, and their susceptibility to the LAK cells was almost the some as that of allogenic HUVEC. Complement-depletion experiments revealed that the lysis was mainly dependent on CD16+ natural killer (NK) LAK cells. pretreatment of HUVEC with recombinant interferon gamma (rIFN gamma) for 24 h made them resistant to lysis by autologous LAK cells, while pretreatment with either rIL-1 beta. rTNF alpha, or acidic or basic fibroblast growth factor did not alter the lytic sensitivity of HUVEC. The resistance of rIFN gamma-treated HUVEC was specific to lysis by CD16+ NK LAK cells, and their lysis by CD3+ T-LAK cells was not significantly altered. Moreover, in comparison with control HUVEC or rIL-1 beta-treated HUVEC, rIFN gamma-treated HUVEC had a significantly less potent inhibitory effect on the lysis of untreated HUVEC, when used as an unlabeled target. This suggests that rIFN gamma treatment may down-regulate the recognition of some molecules on HUVEC by rIL-2-activated NK cells. These data suggest that damage of the endothelium during LAK therapy is mainly dependent on LAK cells with a NK phenotype that can specifically recognize a certain molecule on autologous endothelial cells.

The intracellular distribution and action of a new synthetic protease inhibitor, E3123, were studied in cerulein-induced acute pancreatitis in rats. Acute pancreatitis was induced by a 4-h iv infusion of a supramaximal dose of cerulein, and was treated by prophylactic (pretreatment) or therapeutic (posttreatment) continuous administration of E3123. Pancreatic edema and hyperamylasemia were ameriolated only by prophylactic treatment. A subcellular fractionation study showed that the activities of cathepsin-B and trypsin in the zymogen granule-enriched fraction of the cerulein-pancreatitis group were remarkably increased. Both prophylactic and therapeutic treatment significantly prevented the elevation of these enzyme activities. These effects were accompanied by amelioration of pancreatic histopathological features, including intracellular vacuolization and fat necrosis. A microscopic autoradiographic study using 3H-labeled E3123 showed diffuse intracellular distribution of E3123, and the radioactivity of 3H-E3123 in the posttreatment group was three times greater than that in the pretreatment group. This study provides the first experimental evidence that, even when administered therapeutically, exogenous protease inhibitors are transported into pancreatic acinar cells, thereby reducing the severity of early intracellular alterations in cerulein-induced acute pancreatitis.

In order to clarify genetic changes in flat adenomas, K-ras codon 12 point mutations were examined in 56 flat adenomas, 81 polypoid adenomas and 42 cancers of colon and rectum. The mutation frequency in flat adenomas was 23% (13/56), significantly lower than that in polypoid adenomas (67%: 54/81) and cancers (76%: 32/42). Even mildly dysplastic adenomas or small (less than 5 mm) adenomas showed higher mutation incidence in polypoid type (62%, 57%) than in flat type (23%, 19%). Among flat adenomas, flat elevated lesions exhibited relatively higher mutation frequency than completely flat or depressed ones. As for cancers, 14 tumors (33%) contained mutations only in a minor tumor cell population, indicating that these mutations occur at a late stage of tumorigenesis. These results suggest that the adenoma-carcinoma sequence through flat adenomas may be different from that through polypoid adenomas, and genetic changes may be heterogeneous in colorectal carcinogenesis.

The aim of this study was to investigate the differences between the clinicopathological findings in two histologic types of carcinoma of the papilla of Vater. We histologically classified carcinoma of the papilla into two types: 1) an intestinal type that resembles tubular adenocarcinoma of the stomach or colon, and 2) a pancreaticobiliary type that is characterized by papillary projections with scant fibrous cores. We examined 53 cases of resected carcinoma of the papilla. The intestinal-type carcinomas were similar to the intestinal mucosa in that they had lysozyme-containing, Paneth or argyrophil cells, as demonstrated by the immunohistochemically positive stainings for the anti-lysozyme antibody. Although both the sizes of the two types of carcinomas and the age distributions of cases with the two types of carcinoma were almost the same, the prognosis of the cases with the intestinal type was much better than that of the cases with the pancreaticobiliary type. Histological lymph node metastasis was found significantly more often in the pancreaticobiliary type. This result was supported by the fact that small carcinomas of the intestinal type showed little or no invasion into the surrounding interstitium, as opposed to the pancreaticobiliary type, which had a strong infiltrative tendency. The pathogenesis of carcinoma of the papilla of Vater should be further evaluated, taking into consideration the existence of these two histologic types.

X線写真上識別可能な3種類のX線不透過マーカーをおのおの5日前,3日前,1日前に経口投与して腹部単純撮影を1回行う方法で,消化管に器質的な異常のない慢性機能性便秘症例19例の大腸通過時間を検査した.19例中12例は大腸通過時間に異常な延長のないnormal transit,残る7例は通過時間の延長のあるslow transitと判定された.slow transitの7例については,3日間経過したマーカーの分布の重心位置が脾彎曲部より遠位にある3例をrectosigmoid delay,これが脾彎曲より近位にある4例をwhole colo ndelayとした.re-ctosigmoiddelayは直腸肛門部での便排泄障害によると考えられ,whole colon delayは大腸運動機能の低下によると考えられる.3種類のマーカーを用いる大腸通過時間検査は,少ないX線被曝と短い拘束時間で,慢性便秘症例の病態の鑑別とそれに基づいた治療法の選択を可能にする有用な検査法である.

This study was made to evaluate the significance of fecal occult blood test (RPHA method) in screening surgical patients for the presence of colorectal neoplasms. The subjects were inpatients scheduled for operation for extracolonic diseases. From January 1990 to December 1991, 817 patients were admitted to our department and 599 had extracolonic diseases. Of the 599 patients, 434 (72%) had preoperative immunological fecal occult blood test of RPHA method. Twenty-eight (6.5%) patients showed positive, and among them, three had colorectal cancer and two, colonic polyp. The incidence of 0.50% of colorectal cancer in 599 patients with extracolonic diseases is higher than that reported for colorectal cancer screening in general population. We conclude that as the risk of colorectal disease is considerably high among inpatients with other diseases, the fecal occult blood test screening should be performed routinely in these patients.

正常大腸粘膜固有層の神経線維の分布,大腸癌およびtransitional mucosa(TM)間質における神経組織の異常について,VIPを中心に免疫組織化学的手法を用いて検討した.対象は31例の大腸癌および非癌部の移行部粘膜と背景粘膜で,粘液組織染色(HID-AB染色),免疫組織染色(VIPおよびS-100蛋白陽性神経線維)を施行し,TM,非癌大腸粘膜の腺窩長,固有層のVIP,S-100蛋白陽性神経線維の長さを自動画像解析装置により定量的に測定した,その結果,正常大腸粘膜ではVIPおよびS-100蛋白陽性神経線維は肛門側に向うにつれて減少しており,右側大腸と左側大腸を比較すると右側では有意に陽性神経線維が多かった.またTMではVIP陽性神経線維(2505vs9175μm/mm2)およびS-100蛋白陽性神経線維(4364vs12179μm/mm2)が共に対照より有意に減少していた,TMでは神経組織の異常があり,形態学的,粘液学的異常に影響を及ぼしている可能性が示唆された.

A 67-year-old female presented with intermittent right upper quadrant pain. A gallstone was visualized on ultrasonography and CT. First, extracorporeal shock wave lithotripsy (ESWL) was attempted 4 times but abdominal discomfort prevented completion of the treatment. Laparoscopic cholecystecomy was then performed. The gallbladder was almost normal laparoscopically. Cannulation of the cystic duct for an intraoperative cholangiogram was unsuccessful and a drip intravenous cholangiogram (DIC) was performed. The cystic duct could not, however, be clearly visualized. The duct was divided after clipping. No biliary leakage was detectable at the end of the surgery. On the first postoperative day (POD), substantial biliary leakage from the abdominal drain occurred. Endoscopic retrograde cholangiography (ERC) was performed immediately and the contrast material was seen to be leaking from the remnant cystic duct. A naso-biliary drainage (ENBD) tube was then placed, producing a marked reduction in biliary leakage from the abdominal drain. The abdominal drain was removed on the 4th POD. A cholangiogram obtained on the 7th POD confirmed the cessation of leakage from the cystic duct, and the ENBD tube was extracted on the 14th POD. The patient was discharged from the hospital. We present herein the clinical course of a case in which biliary leakage, following laparoscopic cholecystectomy, was successfully managed with ENBD rather than surgery.

Objective: The number of lymph nodes retrieved is recognized to be a prognostic factor of Stage II colorectal cancer. However, the prognostic significance of the number of lymph nodes retrieved in Stage III colorectal cancer remains controversial. Methods: The relationship between the number of lymph nodes retrieved and clinical and pathological factors, and significance of the number of lymph nodes retrieved for prognosis of Stage II and III colorectal cancer were investigated. A total of 16 865 patients with T3/T4 colorectal cancer who had R0 resection were analysed. Results: The arithmetic mean of the number of lymph nodes retrieved of all cases was 20.0. The number of lymph nodes retrieved were varied according to several clinical and pathological variables with significant difference, and the greater difference was observed in scope of nodal dissection. Survival of Stages II and III was significantly associated with the number of lymph nodes retrieved. Five-year overall survival of the patients with � 9 of the number of lymph nodes retrieved and those with .27 differed by 6.4% for Stage II colon cancer, 8.8% for Stage III colon cancer, 12.5% for Stage II rectal cancer and 10.6% for Stage III rectal cancer. With one increase in the number of lymph nodes retrieved, the mortality risk was decreased by 2.1% for Stage II and by 0.8% for Stage III, respectively. The cut-off point of the number of lymph nodes retrieved was not obtained. Conclusions: The number of lymph nodes retrieved was shown to be an important prognostic variable not only in Stage II but also in Stage III colorectal cancer, and it was most prominently determined by the scope of nodal dissection. A cut-off value for the number of lymph nodes retrieved was not found, and it is necessary to carry out appropriate nodal dissection and examine as many lymph nodes as possible.