[Combination chemotherapy of doxifluridine plus mitomycin C for colorectal lung metastasis--phase II study].

PURPOSE: We conducted a multi-center study to investigate the usefulness of a combination drug therapy with doxifluridine (5'-DFUR) and mitomycin C (MMC) in colorectal cancer patients with lung metastasis. PATIENT AND METHODS: Subjects were advanced/recurrent colorectal cancer patients with lung metastasis, who underwent concomitant drug administration with 533 mg/m2/day of 5'-DFUR orally and 4 mg/m2/day of MMC every 2 weeks intravenously. RESULTS: Of 84 patients registered, 54 patients who were evaluable for tumor response showed results such as: complete response, one; partial response, 4; no change, 30; and progressive disease, 19, corresponding to a response rate of 9.3%. The median survival period of 54 patients was long at 473 days. The median administration days of 5'-DFUR was 201.5 days and the median number of MMC administrations was 14, indicating a long administration period of the combined therapy. The incidence of adverse drug reactions (ADRs) was 37.2% which included thrombocytopenia, 16.7%, and leukocytopenia, 11.5%; only a few ADRs were grade 3 or over. CONCLUSIONS: While combined therapy with 5'-DFUR and MMC resulted in a low response rate, the regimen suggested a survival effect in the patients.

Identification of N(omega)-carboxymethylarginine, a new advanced glycation endproduct in serum proteins of diabetic patients: possibility of a new marker of aging and diabetes.

A new advanced glycation end product (AGE), N(omega)-carboxymethyl-arginine (CMA), was found in acid-soluble skin collagen of a newborn bovine prepared by in vitro glycation with 1 M glucose incubation at 37 degrees C for about 30 days [ 1 ]. CMA production was increased with incubation time in parallel, and after 30 days incubation the yield was 100 times higher than that of pentosidine [ 1 ]. This result suggested the importance of CMA as a major AGE in collagen. We have detected and measured the CMA level in human serum proteins by electrospray ionization/liquid chromatography/mass spectrometry (ESI/LC/MS), using CMA standard concentration curve. In this report, we first show the existence of CMA in vivo, and its serum level is significantly elevated in diabetic serum proteins, compared to age-matched control serum proteins. These results provide strong evidence that CMA is a new diagnostic marker of glycation in diabetes.

Thymidine phosphorylase expression and effect of doxifluridine: a phase II study.

Doxifluridine (5'-DFUR), an active intermediate metabolite of capecitabine, is converted to 5-fluorouracil by thymidine phosphorylase (TP). We used immunohistochemical staining to investigate the relation between TP expression and 5'-DFUR effects in 40 patients with advanced/recurrent lung metastases from colorectal cancer. Cox regression analysis suggested that TP-positive cancer cells (risk ratio 3.72), were independent factors in survival whereas factors in progression-free survival were TP-positive cancer cells (2.93), and TP-positive stromal cells (0.24). It is suggested that TP expression in cancer cells and in stromal cells are opposite prognostic factors in patients treated with 5'-DFUR.

Mass spectrometry proves under-O-glycosylation of glomerular IgA1 in IgA nephropathy.

BACKGROUND: The IgA1 molecule, which is predominantly deposited in glomeruli in IgA nephropathy (IgAN), is a unique serum glycoprotein because it has O-glycan side chains in its hinge region. Our study was conducted to investigate the O-glycan structure in the glomerular IgA1 in IgAN. METHODS: The IgA1 was separated from 290 renal biopsy specimens of 278 IgAN patients and from four serum IgA1 samples (IgAN, 2; control, 2). The variety of O-glycan glycoform was determined by estimating the precise molecular weights of the IgA1 hinge glycopeptides using matrix-assisted laser desorption ionization time of flight mass spectrometry. RESULTS: The peak distribution of IgA1 hinge glycopeptides clearly shifted to lesser molecular weights in both glomerular and serum IgA1 in IgAN compared with the serum IgA1 of controls. In the five major peaks of IgA1 hinge glycopeptides in each sample, the numbers of carbohydrates composing O-glycans (GalNAc, Gal, and NANA) in the deposited and serum IgA1 in IgAN patients were significantly fewer than those in the serum IgA1 in the control groups. CONCLUSION: The O-glycan side chains in the hinge of the glomerular IgA1 were highly underglycosylated in IgAN. These results indicate that the decreased sialylation and galactosylation of the IgA1 hinge glycopeptides play a crucial role in its glomerular deposition in IgAN.

Analysis of the microheterogeneity of the IgA1 hinge glycopeptide having multiple O-linked oligosaccharides by capillary electrophoresis.

It was found that the self-aggregation of IgA1 was closely connected with the glycoform of a mucin-type sugar chain on its hinge portion. In this report, normal human serum IgA1 was separated into two subfractions by a jacalin column. The elution condition, 25 mM galactose, used here was similar to that reported for the glycoprotein with a single mucin-type sugar chain per molecule. The IgA1 eluted under this condition was substantially the monomeric form. In contrast, the remaining IgA1 eluted from the column with 0. 8 M galactose was substantially the aggregated form. An analytical method for the microheterogeneity of the IgA1 hinge glycopeptide (HGP33) was developed to determine the difference between these IgA1 fractions by capillary electrophoresis (CE). Native HGP33 from both IgA1 fractions was separated into peaks 1-11, depending on their glycoforms. Because the sialic acid-rich component migrated slowly on CE, the 25 mM fraction was abundant in the sialic acid-rich components (peaks 7-11), but the 0.8 M fraction was abundant in the sialic acid-poor components (peaks 1-4). Comparison of the number of sugar chains per hinge peptide indicated that the 25 mM fraction was relatively well glycosylated. Thus, application of CE analysis to the HGP33 indicated that the monomeric IgA1 was composed of a relatively complete molecule with respect to the glycoform rather than the aggregated IgA1.

Recent results in the surgical treatment of gastric cancer according to the Japanese and TNM classification.

BACKGROUND: Recent outcomes based on surgical long-term follow-up of patients with gastric cancer using current staging systems have not been fully evaluated. MATERIALS AND METHODS: A total of 1357 patients with primary gastric carcinoma (911 males and 446 females, ranging in age from 20 to 87 years; average 59.1 years) who had undergone gastric resection between 1986 and 1996 were examined with respect to their clinicopathological features, surgical procedures and patient survival according to Japanese and UICC-TNM classifications. RESULTS: The 5-year survival rate was 95.3% for stage Ia, 85.5% for stage Ib, 73.8% for stage II, 45.7% for stage IIIa, 20.9% for stage IIIb, 17.3% for stage IVa and 5.8% for stage IVb (8.8% for IVa and IVb) on the Japanese classification. By way of contrast, the 5-year survival rate was 95.6% for stage Ia, 85.0% for stage Ib, 72.1% for stage II, 49.3% for stage IIIa, 30.2% for stage IIIb and 12.0% for stage IV on the TNM classification. CONCLUSION: Although minor problems are associated with both the Japanese and TNM classification systems, both appear to be clinically significant and appropriate independent predictors of prognosis. The findings of the present study provide important information for comparing results among different institutes and for introducing new clinical trials for gastric cancer at the beginning of the new century.

An in-vitro model of scirrhous carcinoma of the stomach using stomach fibroblasts derived from gastric cancer patients.

BACKGROUND/AIMS: The mechanisms of the particular stromal changes that occur upon cancer invasion by scirrhous carcinoma of the stomach, in particular, the relationships among cancer cells, stomach fibroblasts and collagen, a major constituent of the stroma of the invasive tumor, have yet to be clarified. METHODOLOGY: Three different human fibroblast cell lines (TIG-101, MF-2, MKF-1) and a cancer cell line derived from scirrhous carcinoma of the stomach (KATO III) were cultured three-dimensionally in collagen gels to investigate collagen gel contraction by these cells as a model of scirrhous carcinoma of the stomach. RESULTS: The gels contracted and gradually decreased in size in all of the fibroblast (TIG-101, MF-2 and MKF-1) cultures, but not in the KATO III culture, and the extent of gel contraction was not uniform among the fibroblast cell lines. The extent of gel contraction when fibroblasts derived from stomach (MF-2, MKF-1) were co-cultured with KATO III cells in collagen gel was almost similar to that of fibroblasts alone. Moreover, microscopic examination following Masson's trichrome staining revealed condensation and remodeling of collagen fibrils only around the fibroblast cells. CONCLUSIONS: The extent of collagen gel contraction by fibroblasts may depend on their in vivo origin. This property appears to be characteristic of fibroblasts, but not of malignant epithelial cells, under this culture system. Furthermore, the results of the present study demonstrate that stomach fibroblasts may play an important role in the stromal changes associated with scirrhous gastric cancer.

[Combined laparoscopic-endoscopic procedure in stomach carcinoma]. / Kombiniertes laparoskopisch-endoskopisches Vorgehen beim Magencarcinom.

The purpose of this review is to outline the laparoscopic-endoscopic procedures that we perform for early gastric cancer. These procedures were applied to 29 patients. Preoperative work-up included gastric endoscopy, barium X-ray examination, endoscopic ultrasonography, and histological examination, and surgery was performed in patients diagnosed as having mucosal gastric cancer for which endoscopic mucosal resection (EMR) was difficult. Laparoscopic wedge resection of the stomach using the lesion-lifting method, by which a wedge resection is made while pulling up the full-thickness gastric wall, was carried out in the 16 patients with lesions of the anterior wall, lesser curvature, and greater curvature of the stomach. On pathological examination of resected specimens, the surgical margin and lymphatic or venous invasion were negative in all these patients. The histological depth of the lesions was m (mucosal cancer) in 15 patients and sm1 (slight cancer infiltration into the submucosal layer) in one. This one patient later underwent gastrectomy but no lymph node metastases were found. Oral nutrition was resumed for a mean (+/- SD) of 2.9 +/- 0.8 days after operation, and the duration of hospitalization after operation was 12.3 +/- 3.4 days. The 13 patients with lesions of the posterior wall of the stomach and near the cardia or the pylorus received laparoscopic intragastric mucosal resection. Laparotomy was required in 1 of these patients due to intraoperative hemorrhage. The surgical margins were negative in all 12 patients in whom laparoscopic intragastric mucosal resection was successful. Lymphatic or venous invasion was positive in 2, both of whom had sm1 cancer lesions of both of these patients were located in the cardiac region, total gastrectomy was avoided, and careful observation is continued. Oral nutrition was resumed 4.0 +/- 1.6 days after operation, and the duration of hospitalization after operation was 12.0 +/- 3.5 days. In addition, no postoperative complication was noted after either procedure, and all patients have been recurrence free for a follow-up period of 460 months. Selected properly, these laparoscopic endoscopic procedures are considered to be curative and minimally invasive treatments for early gastric cancer.

Feasibility of a novel weekday-on/weekend-off oral UFT schedule as postoperative adjuvant chemotherapy for colorectal cancer. UFT Compliance Study Group, Kanagawa, Japan.

PURPOSE: When oral anticancer agents are used for adjuvant chemotherapy of colorectal cancer, compliance and feasibility become issues because of the long treatment time. Appropriate studies of these issues are lacking. We investigated compliance and feasibility during a weekday-on/weekend-off schedule of oral UFT (uracil-tegafur) over a period of 1 year administered as adjuvant chemotherapy to patients with colorectal cancer. PATIENTS AND METHODS: A UFT dose of 600 mg/day was prescribed according to a weekday-on/weekend-off schedule to 87 patients after potentially curative resection. Compliance was investigated in three ways: physician interview, patient self-report, and chemical analysis of urine. The results were compared with the dose prescribed. Feasibility was evaluated on the basis of two indices: relative performance (RP), which was the ratio of the actual total dose taken to the total dose planned, and individual dose intensity (IDI), which was the ratio of the actual dose taken to the dose planned during a given period. RESULTS: The compliance assessed by physician interview and by patient self-report conformed well with the prescribed dose, the rate of agreement among the three compliance measures being more than 94%. Chemical analysis of urine in 38 of the patients revealed that they were actually taking the drug. The RP was 0.72, and the IDI was 0.8. CONCLUSION: From these results, the feasibility of the weekday-on/weekend-off schedule was judged to be good. It is suggested that the feasibility would be even better if the dose of UFT was set according to body surface area.

[Problems concerning the prices of surgical operations in Japan. Union of Social Medical Insurance Committee Members of Surgical Societies in Japan].

The Union of Social Medical Insurance Committee Members of Surgical Societies in Japan was established in 1967. The union has tried to develop scientific methods to assess the price of surgical operations in Japan and proposed a tentative plan for the assessment of the price of operations. The price of an operation includes personnel expenses and other costs such as the prime costs to repay loans for land and buildings, and taxes. Personnel expenses are calculated by the grade of technical difficulties, the number of doctors and nurses and the duration of the operation. A more precise method to judge the difficulties of the operation seems to be necessary. To examine the recent increase in expenses for surgical materials, the cooperation of main hospitals authorized by surgical societies will be necessary. The prices of surgical operations presented by the Ministry of Health and Welfare of Japan correlated well with the prices proposed by the Union.

Three-dimensional reconstruction of colorectal tumors from serial tissue sections by computer graphics: a preliminary study.

BACKGROUND/AIMS: We present herein the three-dimensional reconstruction of colorectal tumors, with particular reference to growth pattern into each layer of the colorectal wall, and measurement of tumor volume and surface area. METHODOLOGY: Conventional tissue section images of colorectal tumors were analyzed using a computer graphics analysis program. The two-dimensional extent of invasion by each tumor into each layer of intestinal wall were determined from the images of each section. Based on data from multiple sections, tumor and surrounding normal tissue layers were reconstructed three-dimensionally, and volume and surface area of the tumors were determined. RESULTS: Using this technique, three-dimensional morphology of tumor and tumor progression into colorectal wall could be determined. Volume and surface area of the colon tumor were 4871 mm3 and 1741 mm2, respectively. Volume and surface area of the rectal tumor were 1090 mm3 and 877 mm2, respectively. CONCLUSIONS: This technique may provide a new approach for pathological analysis of colorectal carcinoma.

Surgical outcome of curative resection in patients with Borrmann type IV gastric carcinoma with particular reference to the extent of lymph node metastasis.

BACKGROUND/AIMS: The prognosis after curative resection for Borrmann type IV carcinoma, according to the extent of lymph node metastasis, is poorly understood. METHODOLOGY: The surgical outcome of curative resection was examined in 78 patients with T2-T3 Borrmann type IV gastric carcinomas, with particular reference to the extent of lymph node metastasis. RESULTS: The 5-year survival rate was 35.7% for the n0 patients, 27.8% for the n1 patients, 18.2% for the n2 patients and 0% for the n3 or n4 patients. The survival curve for the n3 or n4 patients differed significantly from those of the n0 (P < 0.0001), n1 (P = 0.0009) and n2 (P = 0.0203) patients. However, no other statistically significant differences between the curves were found. CONCLUSIONS: The results of the present study indicate that patients with Borrmann type IV carcinoma of the stomach may indeed be cured by curative surgery, and that the surgical outcome of this disease does not depend on the extent of lymph node metastasis under curative resection if lymph node metastasis is restricted to the n2 lymph nodes.

Benign esophageal schwannoma: report of a case.

We report herein the case of an otherwise asymptomatic 62-year-old woman who was found to have an incidental esophageal lesion during endoscopic follow-up of an unrelated disorder. An esophageal submucosal tumor was diagnosed, and the patient was subsequently monitored on a regular yearly basis. As the diameter of the tumor doubled over a 4-year period, the possibility of a malignant lesion could not be excluded, and she was admitted to our hospital for further investigations. Esophagography, endoscopy, endoscopic ultrasonography, and computed tomography confirmed a submucosal tumor, 35 mm in length, in the thoracic midesophagus. A leiomyoma or leiomyosarcoma was suspected based on the known incidence of such tumors, and tumor enucleation was performed. Gross inspection revealed a solid tumor arising from the wall of the esophagus. Histopathologic examination showed intertwined bundles of spindle cells with spiral-like proliferation, and immunohistochemical studies were positive for S-100 protein, whereby a diagnosis of esophageal schwannoma was established. The patient experienced no postoperative complications, and her clinical course to date has been satisfactory. To date, 2 years 8 months after surgery, she has shown no sign of tumor recurrence and remains in good health.

Tumor volume: a novel prognostic factor in patients who undergo curative resection for gastric cancer.

BACKGROUND AND AIMS: The present study evaluates the significance of tumor volume as a prognostic factor in gastric cancer. PATIENTS/METHODS: Tumor volume was measured from serial tissue sections of 101 patients who had undergone curative resection for solitary carcinoma of the stomach using a computer graphics analysis program. These patients were analyzed with respect to survival based on univariate and multivariate analyses of clinicopathological factors, including tumor volume, to determine an independent prognostic factor. RESULTS: Significant differences in survival were found with respect to depth of tumor invasion (P=0.001), status of lymph-node metastasis (P=0.018), tumor diameter (P=0.005), and tumor volume (P<0.0001) based on univariate analysis. However, multivariate analysis indicated only tumor volume as a valid factor in determining prognosis among the nine variables and was significantly associated with the prognosis (P=0.0005; relative risk 18.23; 95% confidence interval 3.52-94.37). CONCLUSION: The present findings indicate that tumor volume is an important prognostic factor in patients who undergo curative resection for gastric cancer and may be an alternative to conventional factors, thus providing a novel independent prognostic factor in gastric cancer.

Is extended lymphadenectomy valuable in palliatively gastrectomized patients with gastric cancer and simultaneous peritoneal metastasis?

BACKGROUND/AIMS: The optimal extent of lymphadenectomy in patients with gastric cancer and simultaneous peritoneal metastasis upon non-curative resection remains unclear. The aim of the present study was to evaluate the efficacy of extended lymphadenectomy in palliatively gastrectomized patients with gastric cancer and simultaneous peritoneal metastasis. METHODOLOGY: The significance and limit of extended lymphadenectomy according to the extent of peritoneal metastasis was analyzed retrospectively in 110 patients with gastric cancer and simultaneous peritoneal metastasis who had undergone palliative gastrectomy. RESULTS: Of the 47 patients with P1 metastasis, the median survival period of the 23 patients who underwent extended lymphadenectomy and the 24 patients who underwent limited lymphadenectomy was 21.7 months and 17.2 months, respectively. Of the 63 patients with P2 or P3 metastasis, the median survival period of the 16 patients who underwent extended lymphadenectomy and the 47 patients who underwent limited lymphadenectomy was 10.4 months and 12.8 months, respectively. No significant differences in survival time based on extent of lymphadenectomy were observed either in the patients with P2 or P3 metastasis (P = 0.262) or in those with P1 metastasis (P = 0.277). CONCLUSIONS: The results of the present study demonstrate that extended lymphadenectomy in gastric cancer yields no positive impact on survival upon non-curative resection either in patients with gastric cancer and simultaneous metastases to the adjacent peritoneum (P1) or to the distant peritoneum (P2 or P3).

Direct evidence for decreased sialylation and galactosylation of human serum IgA1 Fc O-glycosylated hinge peptides in IgA nephropathy by mass spectrometry.

Human serum immunoglobulin IgA1 is produced in bone marrow and interacts with specific cellular receptors that mediate biological events. In this study, we have analyzed the detailed glycoform structure of the human serum IgA1 Fc O-glycosylated hinge region by electrospray ionization liquid mass spectrometry. The IgA1 fragments containing the hinge glycopeptide were separated from 4 IgA nephropathy patient (IgAN) pooled sera, 10 non-IgAN pooled sera with other primary glomerulonephritides, and 5 healthy control subject pooled sera by trypsin treatment and Jacalin affinity chromatography. The molecular weights of IgA1 hinge glycopeptide were estimated using mass spectrometry, and 13 sialo and 8 asialo glycopeptide groups were identified. The results obtained clearly showed a decrease of GalNAc, Gal, and sialic acid in IgAN compared with non-IgAN and normal controls, and those strongly suggested the possibility that the decreased galactosylation and sialylation of the IgA1 hinge result in its glomerular deposition in IgAN.

Preoperative evaluation to predict technical difficulties of laparoscopic cholecystectomy on the basis of histological inflammation findings on resected gallbladder.

BACKGROUND: No papers have heretofore documented histological studies of cases involving the inflammation of resected gallbladder or examined surgical difficulties on the basis of pathological findings. METHODS: On the basis of the histological inflammation findings on the resected gallbladders of 437 patients who underwent laparoscopic cholecystectomy (LC), the factors affecting the technical difficulty of the operation were examined through preoperative clinical findings (13 items), diagnostic imaging (22 items), and blood test findings (6 items), using multivariate analysis. RESULTS: In accordance with the four-stage classification of inflammation findings for the resected gallbladder, the inflammation findings on the resected gallbladder indicated a higher correlation with the time required for gallbladder dissection (30.2 +/- 16.3 minutes) than with the operation time (77.6 +/- 32.7 minutes). Thus, the technical difficulty of the operation was judged according to the time required for gallbladder dissection. For the preoperative findings on 418 patients who underwent successful LC, the most influential factors on the time required for gallbladder dissection were the presence of abnormal findings on computed tomography, the degree of fever, obesity index, nonvisualized gallbladder cholangiography, and cystic duct length. According to the multiple regression equation of these five factors, the gallbladder dissection for the 19 patients who underwent conversion to open cholecystectomy (OC) due to extreme inflammation was calculated to require 61.9 +/- 12.3 minutes, and the patients who showed a gallbladder dissection time longer than 49.6 minutes were judged to have high technical difficulty predicted from the preoperative evaluation. In the preoperative evaluation, sensitivity was 79.6%, specificity was 97.6%, accuracy was 95.0%, positive predictive value was 85.0%, and negative predictive value was 96.6%. Next, each finding was scored on the basis of a multiple regression equation of five factors, and the technical difficulty of the operation was quantified using these scores. The score of the patients who underwent conversion to OC was 8.0 +/- 2.0, and the patients who showed a score higher than 6 were judged to have high technical difficulty. Almost the same results as in the aforementioned preoperative evaluation were obtained using these scores. CONCLUSION: The judgment using the scores was satisfactory in terms of the simplicity of evaluating the technical difficulties associated with each patient and the ease of obtaining information for each factor. The quantification of technical difficulty using the scores is useful for preoperative prediction of which patients will have difficulties in gallbladder dissection and the conversion to OC in LC. Our results suggest that the consideration of technical difficulties is important for conducting safe operations with avoiding intraoperative complications.

Measuring the tumor volume of gastric carcinoma by computer image analysis: clinical significance.

The tumor diameter of gastric carcinoma, measured by gross or histologic examination, is a rough indicator of actual tumor size. Therefore we investigated the utility of three-dimensional reconstruction of tumors in gastric carcinoma. Altogether 105 primary gastric carcinoma lesions, consisting of 16 advanced and 89 early carcinomas, were analyzed. A total of 942 lesion tissue sections, comprising 2 to 37 sections per lesion (mean 9 sections), were examined histologically. Surface rendering using a computer graphics analysis program was then performed from serial sections to create a three-dimensional reconstruction of tumor morphology from which to measure tumor volume. For the 105 lesions the tumor diameter ranged between 4 and 106 mm (average +/- SE: 32.4 +/- 2.0 mm), and tumor volume ranged between 4 and 5853 mm3 (average +/- SE: 773.0 +/- 104.6 mm3). A significant correlation was found between tumor diameter and the log of the tumor volume (r = 0.733, p < 0.0001). Although the logs of tumor volume for advanced carcinomas were all > 2.5, in 11 of these 16 patients (66%) the tumor diameter was < 4 cm, and in one patient < 2 cm. In addition, tumor diameter did not differ significantly between the 16 advanced and the 89 early gastric carcinomas (p = 0.114), whereas the log of the tumor volume did (p < 0.0001). In conclusion, conventional measurements of tumor diameter as a rough indicator of tumor size can predict the actual tumor size of a gastric carcinoma. Three-dimensional reconstruction using computer graphics provides a better estimation of true tumor size and extent of progression than tumor diameter.

Marginal ulcer on the jejunum after proximal gastrectomy by jejunal interposition.

Marginal ulcer after proximal gastrectomy has never been previously reported, despite that this procedure preserves the fundic gland area of the stomach, which secretes gastric acid. In this report, we describe a patient who developed a marginal ulcer on the oral side of the gastrojejunal anastomosis after proximal gastrectomy by jejunal interposition. This case serves as a reminder that gastric acid secretion of the remnant stomach must be carefully monitored after proximal gastrectomy in gastric cancer surgery.