Evaluation of the fat plane of the pancreatic groove using multidetector CT.

AIM: To assess the pancreatic groove fat plane in the normal population and compare this with the fat plane in patients with groove pancreatitis or carcinoma using multidetector computed tomography (CT). MATERIAL AND METHODS: The pancreatic groove fat plane was evaluated retrospectively in 460 normal subjects (normal group), and in 25 patients with groove pancreatitis or carcinoma (pathology group) using 5 mm- and 1 mm-thick slices of unenhanced axial multidetector CT images. Two investigators independently assessed the degree of pancreatic groove fat plane visualisation using a four-point scale (grade 1: visualisation of 0-25%, grade 2: 26-50%, grade 3: 51-75%, grade 4: 76-100%). Pancreatic parenchymal condition, age, sex, body mass index, diabetes mellitus, and dyslipidaemia were also evaluated. RESULTS: The interobserver agreement for the visualisation grades was almost perfect (k-value = 0.95). In the normal group, grade 4 visualisation of the pancreatic groove fat plane was more common in those aged >80 years (78.6%) compared with younger age groups. Pancreatic atrophy and fatty infiltration significantly improved fat plane visualisation. In the pathology group, grade 4 visualisation of the pancreatic groove fat plane was not seen in either groove carcinoma or pancreatitis. A cut-off point of ≤50% visualisation of the pancreatic groove fat plane showed 95% sensitivity and 82% specificity for detecting possible abnormalities in older patients (>60 years). The clinical factors investigated were not significantly related to pancreatic groove fat plane visualisation. CONCLUSION: Pancreatic groove fat plane visualisation could be a good predictor for detecting groove abnormalities.

A randomized phase II study of S-1 plus oral leucovorin versus S-1 monotherapy in patients with gemcitabine-refractory advanced pancreatic cancer.

BACKGROUND: We evaluated the efficacy and toxicity of adding oral leucovorin (LV) to S-1 when compared with S-1 monotherapy in patients with gemcitabine-refractory pancreatic cancer (PC). PATIENTS AND METHODS: Gemcitabine-refractory PC patients were randomly assigned in a 1:1 ratio to receive S-1 at 40, 50, or 60 mg according to body surface area plus LV 25 mg, both given orally twice daily for 1 week, repeated every 2 weeks (SL group), or S-1 monotherapy at the same dose as the SL group for 4 weeks, repeated every 6 weeks (S-1 group). The primary end point was progression-free survival (PFS). RESULTS: Among 142 patients enrolled, 140 were eligible for efficacy assessment (SL: n = 69 and S-1: n = 71). PFS was significantly longer in the SL group than in the S-1 group [median PFS, 3.8 versus 2.7 months; hazard ratio (HR), 0.56; 95% confidence interval (CI), 0.37-0.85; P = 0.003]). The disease control rate was significantly higher in the SL group than in the S-1 group (91% versus 72%; P = 0.004). Overall survival (OS) was similar in both groups (median OS, 6.3 versus 6.1 months; HR, 0.82; 95% CI, 0.54-1.22; P = 0.463). After adjusting for patient background factors in a multivariate analysis, OS tended to be better in the SL group (HR, 0.71; 95% CI, 0.47-1.07; P = 0.099). Both treatments were well tolerated, although gastrointestinal toxicities were slightly more severe in the SL group. CONCLUSION: The addition of LV to S-1 significantly improved PFS in patients with gemcitabine-refractory advanced PC, and a phase III trial has been initiated in a similar setting. CLINICAL TRIALS NUMBER: Japan Pharmaceutical Information Center: JapicCTI-111554.

Carcinoid tumors of the pancreas: dynamic CT and MRI features with pathological correlation.

BACKGROUND: Carcinoid tumor of the pancreas is rare, and there are few reports that described its CT or magnetic resonance imaging (MRI) findings. We describe the characteristic CT and MRI findings in four cases of carcinoid tumor of the pancreas. METHODS: Radiologic and pathologic features were analyzed in four patients. All patients underwent triple-phase dynamic CT and MRI. RESULTS: The tumor size in the four cases ranged 15-20 mm and intratumoral calcification was detected in one case. On triple-phase dynamic CT, the peak enhancement of the tumors was seen at the arterial dominant phase in three cases; the remaining one was at the portal venous phase with prolonged contrast-enhancement effect. The tumors showed low to high signal intensity on T2-weighted images. Dilatation of the main pancreatic ducts (MPDs) distal to the tumors was seen in three cases, in which tumor invasion into the MPDs was pathologically confirmed. Furthermore, the tumors having mild to severe fibrosis pathologically invaded into the peripancreatic lymphatics or nerves. CONCLUSION: It would be characteristic of carcinoid tumor of the pancreas to be well enhanced at the arterial dominant phase on dynamic CT, and to highly invade into the MPDs and the peripancreatic lymphatics or nerves.

Adenomatoid tumour of the liver.

An unusual primary adenomatoid tumour arising in the normal liver is described. Hepatectomy was performed, and the patient is alive and free of disease 1 year postsurgery. Grossly, the tumour showed a haemorrhagic cut surface with numerous microcystic structures. Histological examination revealed cystic or angiomatoid spaces of various sizes lined by cuboidal, low-columnar, or flattened epithelioid cells with vacuolated cytoplasm and round to oval nuclei. The epithelioid cells were entirely supported by proliferated capillaries and arteries together with collagenous stroma. Immunohistochemical studies showed that the epithelioid cells were strongly positive for a broad spectrum of cytokeratins (AE1/AE3, CAM5.2, epithelial membrane antigen and cytokeratin 7) and mesothelial markers (calretinin, Wilms' tumour 1 and D2-40). These cells were negative for Hep par-1, carcinoembryonic antigen, neural cell adhesion molecule, CD34, CD31 and HMB45. Atypically, abundant capillaries were observed; however, the cystic proliferation of epithelioid cells with vacuoles and immunohistochemical profile of the epithelioid element were consistent with hepatic adenomatoid tumour.

Enhancement of nitric oxide and superoxide generations by alpha-tocopheryl succinate and its apoptotic and anticancer effects.

Tocopheryl succinate (TS), a succinyl ester of alpha-tocopherol (alpha-T), has been reported to have various biological activities. In this communication, we review the current findings about TS including our recent studies of its effects on nitric oxide (NO) and superoxide (O2-) generations implicated in cancer and atherosclerosis. First, we investigated the effect of TS on NO production in vascular smooth muscle cells (VSMC) under atherosclerosis-like conditions using lipopolysaccharide (LPS) and interferon-gamma (IFN). TS enhanced LPS/IFN-dependent NO production, but alpha-T itself did not. The enhancement by TS of NO production was inhibited by alpha-T but not by antioxidants such as ascorbic acid and 2[3]-t-butyl-4-hydroxyanisole (BHA). TS enhanced the amount of protein kinase Calpha (PKCalpha) in VSMC, and PKC inhibitors inhibited TS-enhanced NO production, suggesting that the enhancing effect of TS on NO production is caused by up-regulation of PKC. Second, we found that TS induced apoptosis in VSMC associated with increase in O2- generation via NADPH-dependent oxidase. We further observed that a mouse breast cancer cell line C127I was more susceptible for TS-induced apoptosis than a mouse breast normal cell line NmuMG, and that superoxide dismutase, alpha-T, and BHA inhibited TS-caused morphological cell damage in C127I. From these results, O2- itself and/or other reactive oxygen species are assumed to associate with TS-induced cell toxicity, and antioxidative defense systems are supposed to be lowered in cancer cells. Finally, we found that intravenous injection of TS vesicles completely inhibited the growth of melanoma cells B16-F1 inoculated on the back of hairless mice and enhanced their survival time.

Gastrectomized patients are in a state of chronic protein malnutrition analyses of 23 amino acids.

BACKGROUND/AIMS: Malnutrition is one of the major postoperative complications of radical subtotal or total gastrectomy for gastric cancer. This study was conducted to clarify the nutritional consequences of radical gastrectomy with respect to protein metabolism. METHODOLOGY: To evaluate the nutritional status and the abnormalities in protein metabolism in such cases, serum concentrations of 23 amino acids were measured by high performance liquid chromatography in 40 patients who had undergone either subtotal (n = 20) or total (n = 20) gastrectomy more than 6 months prior to this analysis. RESULTS: Serum concentrations of total amino acids and nonessential amino acids were the same between gastrectomized patients and healthy controls (n = 50). However, concentrations of essential amino acids, essential amino acid/nonessential amino acid and branched-chain amino acid/total amino acid ratios were significantly lower in patient groups than in normal controls. Each essential amino acid was decreased and concentrations of glutamate and citrulline were increased in both patient groups compared with controls. The major differences between patients with subtotal and total gastrectomies included an increased ornithine and a decreased arginine concentration in patients with subtotal gastrectomy. CONCLUSIONS: These changes suggest that malabsorption of protein from the intestinal tract causes persistent proteolysis in the skeletal muscle for long periods of time after surgery in these patients and that changes in ornithine and citrulline levels may reflect more severe alterations in those with total gastrectomy.

A comparative study of the ability of ferric nitrilotriacetate [correction of nitriloacetate] and other iron chelators to assist membrane lipid peroxidation by superoxide radicals.

This study examined some of the variables determining the efficiency of lipid peroxidation in egg yolk phosphatidylcholine liposomes and in microsomes exposed to enzymatically-generated superoxide radicals. The initiation of peroxidation required the presence of preformed lipid peroxides and a chelated metal catalyst. Comparison of the relative effectiveness of four iron chelating agents showed that the chelate must bind to the membrane by coulombic attraction between the charged membrane and a chelate carrying an opposite net charge. Of the chelates tested, only the carcinogenic ferric nitrilotriacetate [corrected] (Fe(3+)-NTA) was an effective catalyst of oxidation of all membranes, whether carrying a net charge, or not. We postulate that the unique catalytic capacity of the ferric nitrilotriacetate [corrected] (Fe(3+)-NTA) can be explained by its existence in two forms at neutral pH, each binding to oppositely charged membranes and initiating their peroxidation. This gives the complex the unique ability to bind to any membrane, which may be a factor in its carcinogenicity.

Expression of facilitative glucose transporter 1 mRNA in colon cancer was not regulated by k-ras.

The expression of facilitative glucose transporter isoforms in colon adenocarcinoma and the possible role of k-ras in inducing GLUT (glucose transporter) mRNA were studied. RT-PCR demonstrated GLUT2 and GLUT3 expression in 100% of the ten normal colon mucosa samples but detected no GLUT1 mRNA. By contrast, GLUT1 mRNA was detected in all 20 (100%) colon cancer samples examined. GLUT4 mRNA was not detected in either normal mucosa or colon cancer tissues. Semiquantitative PCR demonstrated equal amounts of GLUT2 and GLUT3 mRNA in both normal mucosa and colon cancer samples. A point mutation in codon 12 of k-ras was detected in only six of the 20 (30%) colon cancer samples. Thus, a major difference between normal colon epithelia and colon cancer was the acquisition of GLUT1 expression, which was unlikely to have been induced by a point mutation in codon 12 of k-ras.

Expression of facilitative glucose transporters in gastric tumors.

BACKGROUND/AIMS: Although cancer cells are known to have an increased rate of glucose metabolism, the complete mechanism for increased glucose uptake in tumor cells is unknown. METHODOLOGY: The presence of mRNA for 5 facilitative glucose transporter (GLUT) isoforms was evaluated by reverse transcription-polymerase chain reaction (RT-PCR) in paired samples of normal gastric mucosa and gastric tumor from 20 individuals. Expression of GLUT proteins was immunohistochemically determined in 70 resected gastric cancer specimens. RESULTS: By using RT-PCR, GLUT2 mRNA was detected in 80% of normal gastric mucosal samples, while GLUT4 mRNA was seen in only 40%, GLUT1 mRNA was not detected in normal gastric mucosa. In gastric carcinoma samples, GLUT1 mRNA was detected in 19 out of 20 cases (95%) and GLUT2, GLUT3, and GLUT4 mRNAs in all samples. By immunohistochemistry, GLUT1 protein was detected in 19% of the tumors. A majority of tumors (61%) expressed 1 or more transporter protein. The presence of GLUT1 protein in a tumor was positively correlated with the tumor's invasion into the gastric wall, lymphatics or blood vessels and with lymph node metastases. The post-operative survival of patients with tumor expressing GLUT1 protein was significantly worse than those with tumor without GLUT1 protein. CONCLUSIONS: Gastric cancer cells may acquire the ability to produce GLUT1 mRNA by malignant transformation. Increased expression of the high-affinity glucose transporters, GLUT1 and/or GLUT4, in tumor cells may drain glucose preferentially to the tumor at the expense of the tumor-bearing host.

High incidence of synchronous cancer of the oral cavity and the upper gastrointestinal tract.

A high incidence of synchronous esophageal or gastric carcinoma in preoperative patients with carcinoma of the oral cavity was reported. Esophageal carcinoma was found in seven out of 56 patients (12.5%) and gastric cancer in five patients (8.9%) by videoendoscopy aided with lugol staining in the esophagus and indigocarmine solution in the stomach, although all patients were completely asymptomatic for these lesions. All patients were male, regular drinkers and heavy smokers. The depth of invasion of such tumors was limited to either mucosa or submucosa. Those esophageal and gastric lesions beside the primary oral cancers were positive for p53 protein by immunohistochemistry. Careful preoperative evaluation of not only the esophagus but also the stomach should be a routine procedure in patients with carcinoma of the oral cavity.

Expression of nitric oxide synthase in gastric cancer.

The expression of endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) in samples of normal gastric mucosa and gastric cancer were examined by reverse transcriptase-polymerase chain reaction (RT-PCR) and semi-quantitative Western blot. In normal gastric mucosa, eNOS protein was found in all samples examined (mean, 70.2 +/- 60.1), relative to a standard protein. In gastric cancer specimens, eNOS protein was also detected in all samples, but the quantity (86.5 +/- 76.6) was not different from that found in samples of normal mucosa. The quantity of eNOS in gastric cancer tissues was negatively correlated with serosal invasion. iNbS mRNA, detected in nine of 18 cases, was slightly related to massive lymph node metastasis (n1-3 vs. n4). Neither tumor necrosis factor alpha (TNF-alpha) mRNA nor interleukin-6 (IL-6) mRNA was related to the expression of iNOS mRNA. These results suggest that iNOS not eNOS plays a role in gastric cancer tumor extension, but iNOS mRNA appears not to be induced by either TNF-alpha or IL-6.

Helicobacter pylori of the remnant stomach and its eradication.

BACKGROUND/AIMS: Many authors have reported that Helicobacter pylori (H. pylori) is one of the major causes of gastritis and peptic ulcer. This study was conducted to evaluate the incidence of H. pylori infection and the curative effects of amoxicillin and omeprazole on H. pylori in the remnant stomach. METHODOLOGY: Biopsy specimens were obtained from 70 patients who underwent gastrectomy for gastric cancer. H. pylori was subsequently diagnosed by CLO test and culture of H. pylori. Gastritis was assessed by the scoring of four characteristic pathological parameters. Patients with positive H. pylori were eligible for the eradication study. Amoxicillin, 750 mg per day for 2 weeks, and omeprazole, 20 mg per day for 8 weeks, were administered to them. Endoscopic reexamination was performed 12 weeks after the initiation of treatment. RESULTS: The overall positive rate of H. pylori was 37.1%; 39.6% in Billroth I reconstruction, 0% in Billroth II reconstruction, and 55.6% in pylorus preserving gastrectomy, respectively. The positive H. pylori rate of Billroth II reconstruction was significantly low. However, there was no association of positive rate of H. pylori with time. There was no significant difference of gastritis scores between H. pylori infected patients and non-infected patients. The eradication rate was 70.0%. CONCLUSIONS: H. pylori was present in 37.1% of patients who underwent gastrectomy. Gastritis was not significantly severe in H. pylori infected patients. The treatment with amoxicillin and omeprazole was effective for these patients.

A case of primary adenosquamous/squamous cell carcinoma of gallbladder directly invaded duodenum.

A rare case of primary gallbladder carcinoma is reported. A 67 year-old woman was admitted to our hospital for treatment of suspected duodenal carcinoma. A series of radiographic examinations demonstrated a giant tumor involving the duodenum, gallbladder, pancreatic head, and transverse colon. These extensions made it difficult to identify the primary origin of the carcinoma. Pancreatoduodenectomy, cholecystectomy, and resection of the transverse colon were performed. Macroscopically, ulcerative lesions were seen in both the gallbladder and the duodenum. Microscopic examination revealed adenosquamous cell carcinoma of the gallbladder, invasive of the adjacent organs, including circumferential invasion of the second portion of the duodenum. The patient tolerated the operation well and was discharged 28 days post-operatively, but died of liver metastasis 4 months after surgery. Local invasion of the surrounding tissues is characteristic of adenosquamous/squamous cell carcinoma of the gallbladder. Although surgery for cure is deemed possible, the rapid growth rate of this type of tumor may cast doubt on the value of extensive radical surgery.

Positive and negative controls by protein kinases of sodium-dependent Ca2+ efflux from cultured bovine adrenal chromaffin cells stimulated by lysophosphatidic acid.

We previously found that lysophosphatidic acid (LPA), a bioactive phospholipid, induced Na+-dependent Ca2+ efflux from cultured bovine adrenal chromaffin cells, possibly by activating a Na+/Ca2+ exchanger. The present study on the structure-activity relationship of its action revealed that 1-acyl type LPAs were stronger stimulants than the corresponding 1-O-alkyl type LPAs having a long alkyl moiety with the same chain length. Lysophosphatidylglycerol, suramin and N-palmitoyl-tyrosine phosphoric acid have all been reported to inhibit the action of LPA in some animal cells and platelets, but only lysophosphatidylglycerol was found to inhibit selectively LPA-induced Ca2+ efflux from chromaffin cells. LPA-induced Ca2+ extrusion was suggested to be involved in both acceleration of return of intracellular Ca2+ in Fura 2-loaded bovine chromaffin cells after addition of carbachol, and inhibition of carbachol-induced catecholamine release when the cells were co-incubated with LPA. The Ca2+ efflux from chromaffin cells stimulated by LPA was augmented by their pretreatment with staurosporine or calphostin C, inhibitors of protein kinase C, but reduced by their preincubation with phorbol 12-myristate 13-acetate. Furthermore, the response to LPA was potentiated by sodium vanadate, a protein tyrosine phosphatase inhibitor, but inhibited by genistein, an inhibitor of protein tyrosine kinase. These results suggest that protein kinase C and protein tyrosine kinase are involved negatively and positively, respectively, in the signal transduction triggered by LPA, leading to activation of the Na+/Ca2+ exchanger.

Insulin resistance in cancer patients is associated with enhanced tumor necrosis factor-alpha expression in skeletal muscle.

The roles of tumor necrosis factor (TNF)-alpha and the facilitative glucose transporter (GLUT) 4 on the induction of insulin resistance in peripheral tissues of cancer patients was examined by quantitative competitive PCR on biopsies of abdominal rectal muscle from patients with gastrointestinal cancer. The degree of insulin resistance in these patients was measured by the euglycemic hyperinsulinemic glucose clamp using a high physiologic insulin concentration (100 microU/ml). Quantitative competitive PCR was carried out using DNA competitors constructed by deleting 20-30 bp between the two primer annealing sites. Decreased glucose uptake (M value) in peripheral tissues was accompanied by a significantly increased TNF-alpha mRNA in skeletal muscle (r=0.867, p=0.0025). GLUT4 mRNA, however, was positively correlated with M values (r=0.739, p=0.015). The amounts of mRNAs for TNF-alpha and GLUT4 in skeletal muscle were not correlated. Serum TNF-alpha concentrations remained below the limit of detection. These findings suggest that the insulin resistance in peripheral tissues of cancer patients is in part due to the induction TNF-alpha mRNA and the down regulation of GLUT4 mRNA in peripheral tissues.

Flow cytometric analysis of nuclear DNA heterogeneity in gastric cancer.

Flow cytometric analysis of nuclear DNA ploidy was performed to evaluate the clinical significance of DNA-ploidy heterogeneity and DNA-index heterogeneity between the superficial layer and the deep layer of the tumor obtained from 88 advanced gastric cancer patients. DNA-ploidy heterogeneity was observed in 28 patients (31.8%) and characterized mainly by diploidy in the superficial layer and aneuploidy in the deep layer. More than 10% difference in the DNA index among aneuploidy (DNA-index heterogeneity) was observed in 10 (26.3%) of 38 patients with aneuploidy. There was no tendency for the DNA index to increase with deep infiltration. DNA-ploidy and DNA-index heterogeneities were not correlated with the various clinicopathological characteristics. Patients with aneuploidy had significantly poorer prognosis than did those with diploidy. The survival rate for patients with DNA heterogeneity was not significantly different from that for patients without DNA heterogeneity. These results suggest that the DNA-ploidy pattern may be an important prognostic factor, but that DNA heterogeneity may not have an impact on the survival in advanced gastric cancer.

[A case of postbulbar duodenal ulcer due to adjuvant chemotherapy after gastrectomy for gastric cancer].

We encountered a rare case of postbulbar ulcer caused by adjuvant chemotherapy after gastrectomy. A 64 year-old woman, who received chemotherapy with CDDP-5-FU after gastrectomy, developed severe hematemesis. Endoscopic examination revealed a gigantic ulcer at the anal site of Vater's papilla. The ulcer was healed with PPI and soft diet.

Vincristine resistant HL-60 cells show cross-resistance to hypoxanthine-xanthine oxidase.

This is the first observation that active an oxygen-producing system showed cross-resistance to vincristine (VCR) resistant cells or other anticancer agent-resistant cells. The extent of cross-resistance against oxygen radicals and anticancer agents in wild type and VCR resistant human promyelocytic leukemia cell line, HL-60 and HL-60/VCR, is compared. Superoxide was generated by reaction with hypoxanthine(HX)-xanthine oxidase(XO). HL-60/VCR was 81-fold resistant to VCR, 11.8-fold resistant to adriamycin, and 8.5-fold resistant to the XO concentration required for 50% growth inhibition compared with HL-60. Because oxygen radicals injure the cell membrane, the results indicate an increased resistance to membrane damage by oxygen radicals in drug resistant cells.

Alterations in DNA proliferation in gastric stump mucosa with special reference to topography.

BACKGROUND: Gastric stump carcinoma occurs more frequently at the anastomotic site than at other areas of the gastric remnant. This study was conducted to determine whether alterations in cell dynamics could be detected in the normal-looking gastric remnant mucosa and to ascertain any difference in cell dynamics between the anastomotic site and other area. METHODS: Sixty-three patients who underwent curative subtotal gastrectomy for gastric adenocarcinoma were examined 8 to 130 months after operation. Mucosa at the anastomotic site and at the greater curvature were endoscopically biopsied. Cell dynamic changes were examined by flow cytometry, bromodeoxyuridine in vitro labeling, and oncogene (K-ras and c-myc) amplification and translocation by Southern blot analyses. RESULTS: Inflammatory changes were observed in more than 60% of the cases both at the anastomotic site and at the greater curvature both macroscopically and microscopically. Blood flow, measured by laser Doppler flowmeter, was significantly decreased at the anastomotic site compared with the greater curvature (25.0 +/- 8.1 and 32.2 +/- 9.4 mg/min/100 mg tissue, respectively; p < 0.05). Analysis of DNA histograms obtained by flow cytometry revealed a small peak at the right shoulder of 2N peak in 33% of the specimens obtained from the anastomosis site and in 15% of those from the greater curvature (p < 0.05). The number of cells at S phase measured by bromodeoxyuridine in vitro labeling was also significantly greater at the anastomotic site than at the greater curvature. None of the five patients with aneuploid DNA histograms at the anastomotic site had detectable amplification or translocation of K-ras or c-myc gene in mucosal tissue. CONCLUSIONS: More marked changes in the mucosal cell dynamics observed at the anastomotic site may partially explain the higher incidence of gastric stump carcinoma at the anastomotic site.