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.

Molecular and genetic analysis of multiple changes in the levels of production of virulence factors in a subcultured variant of Streptococcus mutans.

We previously isolated a variant strain, Xc100L, which shows decreased production of a surface protein antigen with a molecular mass of 190 kDa (PAc), after repeated subculturing of Streptococcus mutans strain Xc [Koga, T. et al. (1989) J.Gen. Microbiol. 135, 3199-3202]. In the present study, the levels of expression of the gtfB, gtfC, gtfD and ftf genes coding for polysaccharide-synthesizing enzymes in strain Xc100L were compared with those in strain Xc. Western blot analysis revealed multiple differences in the levels of production of these enzymes between these two strains. The amounts of the gtfB and gtfC gene products responsible for water-insoluble glucan synthesis in strain Xc100L were lower than those in strain Xc, whereas the amounts of the gtfD and ftf gene products responsible for water soluble glucan synthesis and fructan synthesis, respectively, in strain Xc100L were higher than those in strain Xc. Northern blot analysis revealed that the amounts of the four enzymes and PAc produced by strain Xc100L reflected the relative amounts of mRNAs from the genes. The chloramphenicol acetyltransferase gene was fused with each of these five genes, and the transcriptional activity of each gene in strain Xc100L was quantitatively compared with that in strain Xc. The chloramphenicol acetyltransferase assay also indicated that the phenotypic differences between strain Xc and strain Xc100L were due to differences in the transcriptional activities of the virulence genes. No differences in the nucleotide sequences of the promoter regions of the gtfB, gtfC, gtfD, ftf and pac genes were found between strain Xc and strain Xc100L. It is possible that a factor(s) affecting the levels of transcription of the multiple virulence genes exists in S. mutans.

Esophageal stricture secondary to candidiasis without underlying disease.

Candidiasis of the esophagus progressing to stricture formation in a 74-year-old male is reported. Esophageal candidiasis develops in the presence of various predisposing conditions such as long-standing administration of antibiotics or corticosteroids, and malignancy. The first endoscopic examination of this patient revealed unusual multiple black plaques in the esophagus. Despite intensive exploration, no predisposing factors were found. The stricture was progressive, despite the administration of adequate antifungal therapy, and its presence necessitated several attempts at dilatation. Case reports of esophageal candidiasis without underlying disease are very rare.

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.

Neural invasion and nodal involvement in distal bile duct cancer.

Nodal status and neural plexus invasion are important prognostic factors in pancreaticobiliary cancer. The relationship between neural invasion and nodal involvement is evaluated, and its significance for therapy discussed. During the last 20 years, 29 patients with distal bile duct cancer underwent pancreaticoduodenectomy at our institute. An accurate evaluation of the relationship between nodal involvement and plexus invasion was done by histological examination. Twenty of the 29 patients had nodal involvement (68.9%) including 11 patients (37.9%) with nodal involvement of the third group of lymph node (n3). None of these 11 patients had tumors confined to the bile duct wall (panc0 disease). Eight patients (27.6%) had plexus invasion. None of these patients had panc0 disease. The most frequent site of extrapancreatic plexus invasion was the first portion of the plexus pancreaticus capitalis. Nodal dissection around the superior mesenteric artery, and plexus dissection in the hepatoduodenal ligament, around the hepatic artery, and at the first portion of plexus pancreaticus capitalis is necessary in the treatment of distal bile duct cancer, except in patients with no evidence of pancreatic invasion.

[Inhibitory effect of FOY-305 on liver metastasis of the pancreatic cancer].

The potential for hepatic metastasis in nude mice was studied by the intrasplenic implantation method with five human pancreatic cancer cell lines, Capan-1, BxPC-3, AsPC-1, Panc-1, and MIAPaCa-2, especially in relation to serine protease expression, including urokinase-type plasminogen activator and pancreatic trypsinogen 1 (cationic form). The inhibitory effect of a serine protease inhibitor agent, FOY-305, on hepatic metastasis was also a assessed. As a result, the potential for hepatic metastasis was well correlated with expression of pancreatic trypsinogen 1 in these cell lines, and the incidence of metastasis was significantly decreased by FOY-305. These findings suggest that pharmacologic inhibition of serine protease activity may be a new strategy for the therapy of pancreatic cancer metastasis.

Prognostic value of nucleolar organizer regions in endoscopically biopsied tissues of colorectal cancers.

We studied the proliferative activity in endoscopically biopsied tumors by means of argyrophil-protein nucleolar organizer region (AgNOR) scores. AgNOR scores of 109 colorectal cancers ranged from 2.48 to 6.72 (mean: 3.27 +/- 0.52). The 109 tumors were divided into two groups by the median value of AgNOR counts. There was no significant correlation between the AgNOR scores and the histologic type, invasion of bowel wall, lymph node metastases or peritoneal metastases. There was a significant association between the AgNOR scores and lymphatic invasion or liver metastases. Patients with higher AgNOR score tumors had significantly poorer prognoses than those with lower AgNOR score tumors. In Dukes' stage C, especially, the survival rate for patients with higher AgNOR score tumors was significantly lower than for those with lower AgNOR score tumors. Recurrence was found in 8.7% of the tumors with lower AgNOR scores and 19.4% of the tumors with higher scores. Aneuploid tumors had higher AgNOR scores than tumors with the diploid pattern. The results suggest that the AgNOR scores may possibly be a useful prognostic marker of colorectal cancer.

Identification of a fourth gene involved in dTDP-rhamnose synthesis in Streptococcus mutans.

We had isolated three genes (rmlA, rmlB, and rmlC) involved in dTDP-rhamnose synthesis in Streptococcus mutans and found that three genes were insufficient for dTDP-rhamnose synthesis (Y. Tsukioka, Y. Yamashita, T. Oho, Y. Nakano, and T. Koga, J. Bacteriol. 179:1126-1134, 1997). The rmlD gene of S. mutans, encoding the enzyme which catalyzes the last step of dTDP-rhamnose synthesis, has been cloned and sequenced. The cell extract of Escherichia coli expressing the rmlD gene of S. mutans exhibited enzymatic activity corresponding to its counterpart in Shigella flexneri, a gram-negative bacterium. Rhamnose was not detected in the cell wall preparation purified from the mutant in which the cloned gene was insertionally inactivated. Rabbit antiserum against S. mutans serotype c-specific antigen did not react with autoclaved extracts from the mutant. The rmlD gene product of S. mutans compensated for the incompleteness of dTDP-rhamnose synthesis by the three previously isolated genes. These results indicate that the rmlD gene product is indispensable for the dTDP-rhamnose pathway and subsequently for the synthesis of serotype-specific antigen in S. mutans. Furthermore, conservation of the rmlD gene in Streptococcus species was demonstrated by Southern blot analysis.

Proliferative activity of bile duct epithelium after bacterial infection in dogs.

To clarify the relationship between proliferative activity in bile duct epithelia and bacterial infection in the dog, we induced obstructive cholestasis with a bacterial infection in two lobes of the liver. The bile duct branch draining the left lateral lobes of the liver was cannulated in all mongrel dogs. The dogs were divided into three groups and treated as follows: in group 1 the cannula was clamped after the injection of 10(7) Escherichia coli (aerobic bacteria) and 10(7) Bacteroides fragilis (anaerobic bacteria) cells; in group 2 the cannula was clamped after the injection of 10(7) E. coli cells; and in group 3 the cannula was clamped without the injection of any bacteria. Three months and 9 months later dogs from each group were killed, and their livers were examined. In the group 1 dogs papillary hyperplasia and severe dysplasia were noted in association with chronic cholangitis at 3 months and 9 months, respectively, after operation. In the group 2 dogs periductal fibrosis was severe, but epithelial papillary hyperplasia was less pronounced than in the group 1 dogs at each period. In the group 3 dogs no periductal fibrosis or epithelial papillary hyperplasia was seen at either 3 or 9 months postoperatively. These findings suggest that papillary hyperplasia and/or severe dysplasia of the bile duct epithelium may be caused by aerobic and anaerobic bacterial infection of the biliary tract in combination with bile stasis.

Complete response achieved following administration of S-1 in a patient with adrenal gland metastasis of 5-FU-resistant gastric cancer: a case report.

A 62-year -old male patient who had undergone total extirpation of type 3 cancer of the greater curvature of the upper stomach body at another hospital received postoperative chemotherapy with 5-FU and methotrexate. The patient was subsequently treated with oral 5-FU. About 1 year later, a 4 cm tumor of the left adrenal gland was revealed by abdominal CT and diagnosed as gastric cancer metastasizing to the adrenal gland. The patient was referred to our hospital for close examination and treatment and admitted. After his informed consent had been obtained, the patient received one course (4-week administration and 2-week withdrawal) of S-1 at 50 mg/body x 2/day. Abdominal computed tomography performed after the end of the one course revealed that the tumor had become undetectable. This condition was still maintained at the end of two courses and judged to be complete response (CR) (in accordance with the WHO Efficacy Judgment Criteria). CR has continued to be maintained to the present time, even after seven courses. There has been no previous report of S-1 showing remarkable effectiveness in a patient with 5-FU-resistant gastric cancer metastasizing to the adrenal gland. We consider that the efficacy of S-1 for treatment of 5-FU-resistant gastric cancer should be verified.

Oral delivery of synthetic eel calcitonin, elcatonin, in rats.

This study was designed to develop an oral dosage form of elcatonin (EC), a hypocalcemic peptide. The EC absorption was estimated by the reduction in plasma calcium concentrations. When EC was orally coadministered with nitroso-N-acetyl-D,L-penicillamine (SNAP, 4.0 mg) and 0.02% Carbopol solution or with taurocholate (20 mM) and 0.02% Carbopol solution, the lowering effect was increased compared with that after EC alone, but the F values (0.32 and 0.30%) were extremely small. The oral administration of the mucoadhesive emulsion, which was prepared by coating the W/O/W emulsion with 0.1% Carbopol, enhanced the calcium lowering effect, with the F value of 0.43%. The strong mucoadhesion of the mucoadhesive emulsion to the gastrointestinal mucosa was observed. A capsule containing EC (500 microg), taurocholate (6 mg) and lyophilized Carbopol (3.5 mg) administered orally gave a sustained but comparatively small calcium lowering effect. In the in vitro enzymatic hydrolysis experiment, EC was more rapidly hydrolyzed in the intestinal fluid than in the mucosal extract. The combination of 20 mM taurocholate with 0.02% Carbopol showed the greatest inhibitory effect in both fluid and extract. These data indicated that EC was effectively absorbed through the intestinal wall, but the peptide was dominantly degraded by proteolytic enzymes in the GI tract. These results will offer a potential approach to the oral delivery of EC.

Biological function of the dTDP-rhamnose synthesis pathway in Streptococcus mutans.

We have cloned a new gene locus that comprises three genes concerned with the biosynthesis of the serotype c-specific polysaccharide antigen in Streptococcus mutans. The genes encode proteins exhibiting significant homology to the rfbA, rfbB, and rfbD gene products that are involved in the anabolism of dTDP-L-rhamnose from D-glucose-1-phosphate. This anabolism pathway pertains to biosynthesis of the O antigen of lipopolysaccharide in gram-negative bacteria. The cell extract of Escherichia coli expressing each of the cloned genes of S. mutans exhibited enzymatic activity corresponding to the homologous counterpart of the rfb gene products. Rhamnose was not detected in the cell wall preparation purified from the mutant in which each of the three cloned genes was insertionally inactivated. Rabbit antiserum against S. mutans serotype c-specific antigen did not react with the autoclaved extracts from these mutants. These results indicate that the gene products identified in the present study are involved in the dTDP-L-rhamnose synthesis pathway and that the pathway relates to the biosynthesis of the serotype-specific polysaccharide antigen of S. mutans. Southern hybridization analysis revealed that genes homologous to the cloned genes involved in the dTDP-L-rhamnose synthesis pathway were widely distributed in a variety of streptococci. This is the first report of the biological function of the dTDP-rhamnose pathway in streptococci.

Genes involved in cell wall localization and side chain formation of rhamnose-glucose polysaccharide in Streptococcus mutans.

We identified in Streptococcus mutans six new genes (rgpA through rgpF), whose disruption results in a loss of serotype-specific antigenicity, specified by the glucose side chains of rhamnose-glucose polysaccharide from the cell wall. Rhamnose and glucose content of the cell wall decreased drastically in all these disruption mutants, except that in the rgpE mutant only the glucose content decreased. RgpC and RgpD are homologous to ATP-binding cassette transporter components and may be involved in polysaccharide export, whereas RgpE may be a transferase of side chain glucose.

Expression of apolipoprotein A-1 mRNA in normal intrahepatic biliary tree.

Our previous study demonstrated that apolipoprotein A-1 (apo A-1) immunoreactive peptides were located diffusely in the cytoplasm, not only of human normal hepatocytes, but also of intrahepatic bile ducts and peribiliary glands. It is important to determine whether the presence of these immunoreactive peptides in intrahepatic biliary tree is caused by pinocytosis from the bile, or by intracellular protein synthesis. Thus, we investigated whether apo A-1 is synthesized by cells that line the biliary tree. Normal human liver samples obtained at surgery were used; and the expression and distribution of apo A-1 mRNA in normal human liver tissues were examined, using in situ hybridization histochemistry with a 35S-labeled oligonucleotide probe specific for apo A-1. On the autoradiogram, many silver grains were found to be distributed uniformly in hepatocytes. In addition, an appreciable apo A-1 mRNA signal was also observed in both the surface epithelial lining of the bile ducts and the epithelial cells of the peribiliary glands. In conclusion, these findings suggest that the apo A-1 found in bile is secreted both by hepatocytes and by intrahepatic bile duct cells and peribiliary glands.

Results of extensive surgery for pancreatic carcinoma.

BACKGROUND: Since 1973, 210 patients with pancreatic carcinoma have undergone surgery in our clinic, including 144 with carcinoma of the head of the pancreas. Of these 144 patients, macroscopic curative resections were performed on 53 (36.8%). Five patients (9.4%) died within 30 postoperative days, and an additional 3 (5.7%) died within 60 days. The overall median survival was 13 months. Eight of the patients who underwent macroscopic curative resection survived 5 years, giving a 5-year survival rate of 27.4% using the Kaplan-Meier method. The 5-year survival rate was 39.7% after a microscopically curative resection and 0% after a microscopically noncurative resection. METHODS: Outcome was compared based on the extent of pancreatic cancer by constructing survival curves according to the general rules published by the Japan Pancreas Society. RESULTS: There was no statistically significant difference in survival based on tumor size or stage. However, there was a significant difference in the survival of patients with the absence (so) or presence (se) of invasion to the anterior capsule of the pancreas, the absence (rpo) or presence (rpe) of invasion of the retroperitoneal tissue, the absence (ew0) or presence (ew2) of invasion at the surgical margin of resection, and the extent (n0 to n2) of lymph node metastasis. CONCLUSIONS: The results of this study suggest that extended radical pancreatectomy may be indicated for patients with pancreatic carcinoma because standard dissection may fail when the tumor has spread to the retroperitoneum or extrapancreatic nerve plexus.

Intraperitoneal hyperthermic treatment for peritoneal dissemination of colorectal cancers.

Continuous hyperthermic peritoneal perfusion (CHPP) combined with administration of anticancer drugs was performed in eight colorectal cancer patients with peritoneal dissemination. An overall response rate of 50 percent was achieved in the eight patients. Two of three complete responders are long, recurrence-free survivors for 15 and 30 months. The two-year survival has been achieved in 18.8 percent of the patients receiving CHPP, and this rate is significantly higher than the rates in P2 and P3 patients who did not receive CHPP. The complications of CHPP with administration of anticancer drugs were mild bone marrow suppression in two (25 percent) of the eight patients and also a mild grade of renal dysfunction in one (12.5 percent), though not lethal. The results suggest that the combination of CHPP with the administration of anticancer drugs is a safe and effective therapy for peritoneal dissemination of colorectal cancers.

Expression of argyrophilic nucleolar organizer regions in ductal adenocarcinoma of the pancreas and its relationship to prognosis.

The aim of the present study was to investigate the relationship between Ag-NOR count levels and survival in 33 patients undergoing resection for ductal adenocarcinoma of the pancreas at Kanazawa University Hospital from 1985 to 1991. To determine the biologic behavior of invasive ductal adenocarcinoma of the pancreas, 33 tumors were classified into two groups according to the median value of Ag-NOR counts: Group 1, Ag-NOR count > or = 3.25 (higher Ag-NOR count group); Group 2, Ag-NOR count < 3.25 (lower Ag-NOR count group). As a result, we found that tumors with a higher Ag-NOR count were more likely to have liver or peritoneal metastasis than those with a lower Ag-NOR count, although the differences were not statistically significant. Tumors with lower Ag-NOR count levels were associated with favorable prognoses 2 and 3 yr after surgery, whereas those with higher Ag-NOR count levels were related to poor prognosis. Our results indicate that a Ag-NOR count level is a reliable prognostic parameter in resected pancreatic ductal adenocarcinoma.

A new nonoperative method of percutaneous transgastric fistulo-drainage for an intractable external pancreatic fistula--a case report.

The external pancreatic fistula is a well-known complication of pancreatectomy and is conventionally classified as either a partial fistula or a total fistula. A partial fistula usually closes spontaneously and operative intervention is rarely needed, whereas, a total fistula on the other hand, very often does not close and may therefore require surgical intervention. We report herein, a case of an intractable total pancreatic fistula following pancreatoduodenectomy which was successfully repaired by a new non-operative method of percutaneous transgastric fistulo-drainage (PTFD). This technique, performed under the control of a two-way X-ray television system, is safe and considered useful for the treatment of an intractable total pancreatic fistula. In the future, this may be the method of choice for the management of such refractory total pancreatic fistulae.